Toggle navigation Topics by Science.gov Home About STEM Opportunities Sign In Sample records for targeting bone metastases « 1 2 3 4 5 » 1. Bone-Targeted Agents for the Management of Breast Cancer Patients with Bone Metastases PubMed Central Simos, Demetrios; Addison, Christina L.; Kuchuk, Iryna; Hutton, Brian; Mazzarello, Sasha; Clemons, Mark 2013-01-01 Despite advances in adjuvant therapy for breast cancer, bone remains the most common site of recurrence. The goal of therapy for these patients is palliative and focused on maximizing the duration and quality of their life, while concurrently minimizing any disease or treatment-related complications. Bone metastases predispose patients to reduced survival, pain, impaired quality of life and the development of skeletal-related events. With an increased understanding of the pathophysiology of bone metastasis, effective treatments for their management have evolved and are now in widespread clinical use. This article will discuss the pathogenesis of bone metastases and review the key clinical evidence for the efficacy and safety of currently available systemic bone-targeted therapies in breast cancer patients with an emphasis on bisphosphonates and the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitors. We will also discuss novel strategies and therapies currently in development. PMID:26237063 2. The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases PubMed Central Boucharaba, Ahmed; Serre, Claire-Marie; Guglielmi, Julien; Bordet, Jean-Claude; Clézardin, Philippe; Peyruchaud, Olivier 2006-01-01 Platelet-derived lysophosphatidic acid (LPA) supports the progression of breast and ovarian cancer metastasis to bone. The mechanisms through which LPA promotes bone metastasis formation are, however, unknown. Here we report that silencing of the type 1 LPA receptor (LPA1) in cancer cells blocks the production of tumor-derived cytokines that are potent activators of osteoclast-mediated bone destruction and significantly reduces the progression of osteolytic bone metastases. Moreover, functional blockade of LPA action on its cognate receptor LPA1 using a pharmacological antagonist mimics the effects of silencing LPA1 in tumor cells in vitro and substantially reduces bone metastasis progression in animals. Overall, these results suggest that inhibition of platelet-derived LPA action on LPA1 expressed by tumor cells may be a promising therapeutic target for patients with bone metastases. PMID:16769891 3. Targeting mast cells in gastric cancer with special reference to bone metastases PubMed Central Leporini, Christian; Ammendola, Michele; Marech, Ilaria; Sammarco, Giuseppe; Sacco, Rosario; Gadaleta, Cosmo Damiano; Oakley, Caroline; Russo, Emilio; De Sarro, Giovambattista; Ranieri, Girolamo 2015-01-01 Bone metastases from gastric cancer (GC) are considered a relatively uncommon finding; however, they are related to poorer prognosis. Both primary GC and its metastatic progression rely on angiogenesis. Several lines of evidence from GC patients strongly support the involvement of mast cells (MCs) positive to tryptase (MCPT) in primary gastric tumor angiogenesis. Recently, we analyzed infiltrating MCs and neovascularization in bone tissue metastases from primary GC patients, and observed a significant correlation between infiltrating MCPT and angiogenesis. Such a finding suggested the involvement of peritumoral MCPT by infiltrating surrounding tumor cells, and in bone metastasis angiogenesis from primary GC. Thus, an MCPT-stimulated angiogenic process could support the development of metastases in bone tissue. From this perspective, we aim to review the hypothetical involvement of tumor-infiltrating, peritumoral MCPT in angiogenesis-mediated GC cell growth in the bone microenvironment and in tumor-induced osteoclastic bone resorption. We also focus on the potential use of MCPT targeting agents, such as MCs tryptase inhibitors (gabexate mesylate, nafamostat mesylate) or c-KitR tyrosine kinase inhibitors (imatinib, masitinib), as possible new anti-angiogenic and anti-resorptive strategies for the treatment of GC patients affected by bone metastases. PMID:26457010 4. MicroRNAs in Lung Cancer and Lung Cancer Bone Metastases: Biomarkers for Early Diagnosis and Targets for Treatment. PubMed Zhao, Qian; Li, Ping; Ma, Junrong; Yu, Xijie 2015-01-01 Lung cancer is the leading cause of malignancy-related mortality worldwide. Metastases, which account for 90% of lung cancer deaths, frequently target the skeleton, leading to rapid deterioration in quality of life and premature death. The molecular mechanism underlying this progression, especially the development of bone metastases, is largely unknown. MicroRNAs (miRNAs) are small, endogenous, noncoding RNAs that function as negatively posttranscriptional gene regulators. Changes in miRNAs, which may exhibit either oncogenic or tumor suppressive activity, are common in lung cancer. Over-expressed miRNAs may contribute to oncogenesis by down-regulating tumor suppressors, whereas the loss of selected miRNAs may negatively regulate oncogenes or factors related to tumorigenesis and progression. MiRNAs may activate or repress metastases. Specific miRNA expression profiles may correlate with the response in treatment. We summarize recent findings and patents in the pathological roles of miRNAs in the progression and bone metastases in lung cancer, and discuss the diagnostic and therapeutic options in the clinical management of lung cancer. 5. Skeletal complications in cancer patients with bone metastases PubMed Central Tsuzuki, Shunsuke; Park, Sun Hee; Eber, Matthew R.; Peters, Christopher M.; Shiozawa, Yusuke 2017-01-01 Due to significant improvements in current therapies, the life expectancy of cancer patients with bone metastases has dramatically improved. Unfortunately, these patients often experience skeletal complications that significantly impair their quality of life. The major skeletal complications associated with bone metastases include: cancer-induced bone pain, hypercalcemia, pathological bone fractures, metastatic epidural spinal cord compression, and cancer cachexia. Once cancer cells invade the bone, they perturb the normal physiology of the marrow microenvironment, resulting in bone destruction, which is believed to be a direct cause of skeletal complications. However, full understanding of the mechanisms responsible for these complications remains unknown. In this review, we will discuss the complications associated with bone metastases along with matched conventional therapeutic strategies. A better understanding of this topic is crucial, since targeting skeletal complications can improve both morbidity and mortality of patients suffering from bone metastases. PMID:27488133 6. Molecular mechanisms of breast cancer metastases to bone. PubMed Guise, Theresa A; Kozlow, Wende M; Heras-Herzig, Ailleen; Padalecki, Susan S; Yin, Juan Juan; Chirgwin, John M 2005-02-01 Bone metastases lead to hypercalcemia, bone pain, fractures, and nerve compression. They cause increased morbidity and mortality in patients with advanced breast cancer. Animal models reproduce many of the features seen in patients with breast cancer and permit identification of tumor- and bone-derived factors important in skeletal metastasis. These factors provide novel targets for therapeutic interventions. Specific tumor-bone molecular interactions mediated by these factors drive a vicious cycle that perpetuates skeletal metastases. In breast cancer, osteolytic metastases are most common, but mixed and osteoblastic metastases occur in a significant number of patients. Parathyroid hormone-related protein is a common osteolytic factor, and vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1 (ET-1), but there are a variety of other potential osteoblastic factors. Stimulation of osteoblasts can paradoxically increase osteoclast function, as bone-synthesizing osteoblasts are the main regulators of bone-destroying osteoclasts. Coexpression of osteolytic and osteoblastic factors can thus produce mixed metastases or increased osteolysis. Cancer treatments, especially sex steroid deprivation therapies, stimulate bone loss. Bone resorption results in the release of bone growth factors, which may unintentionally increase the formation of bone metastases by activating the vicious cycle. Clinically approved bisphosphonates prevent bone resorption and reduce the release of bone growth factors. Parathyroid hormonerelated protein-neutralizing antibody, inhibitors of the receptor activator of nuclear factor-kB ligand pathway, and ET-1 receptor antagonists are in clinical trials. These agents act on bone cells rather than tumor cells. Recent experiments identify new potential targets for prevention of bone metastases. 7. Targeting G-Protein Signaling for the Therapeutics of Prostate Tumor Bone Metastases and the Associated Chronic Bone Pain DTIC Science & Technology 2013-07-01 results in increased activity/expression of key pain-sensing receptor channels, such as TRPV1 , such that the channels are constitutively activated...Keywords: Prostate Cancer Bone Metastasis, Bone Cancer Pain, Heterotrimeric G protein betagamma subunits, G protein coupled receptors (GPCRs), TRPV1 ...cell growth, migration and invasion in vitro, as well as mediating GPCR-regulated TRPV1 channel function in cultured mouse sensory neurons (Aim 1 8. Targeting G-Protein Signaling for the Therapeutics of Prostate Tumor Bone Metastases and the Associated Chronic Bone Pain DTIC Science & Technology 2014-07-01 effectively block tumor growth in bones and relieve the associated bone cancer pain. This proposal aims to define the key role of the Gï¢ï§ subunits of...signaling plays a key role in mediating proliferation of several prostate cancer cell lines, including LNCaP, PC3, DU145 and 22Rv1. Moreover, we show...imperative to develop novel therapeutic approaches for the treatment of advance prostate cancer. This proposal aims to define the key role of the Gβγ 9. Spontaneous bone metastases in a preclinical orthotopic model of invasive lobular carcinoma; the effect of pharmacological targeting TGFβ receptor I kinase. PubMed Buijs, Jeroen T; Matula, Kasia M; Cheung, Henry; Kruithof-de Julio, Marianna; van der Mark, Maaike H; Snoeks, Thomas J; Cohen, Ron; Corver, Willem E; Mohammad, Khalid S; Jonkers, Jos; Guise, Theresa A; van der Pluijm, Gabri 2015-04-01 Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the most frequently occurring histological subtypes of breast cancer, accounting for 80-90% and 10-15% of the total cases, respectively. At the time of diagnosis and surgical resection of the primary tumour, most patients do not have clinical signs of metastases, but bone micrometastases may already be present. Our aim was to develop a novel preclinical ILC model of spontaneous bone micrometastasis. We used murine invasive lobular breast carcinoma cells (KEP) that were generated by targeted deletion of E-cadherin and p53 in a conditional K14cre;Cdh1((F/F));Trp53((F/F)) mouse model of de novo mammary tumour formation. After surgical resection of the growing orthotopically implanted KEP cells, distant metastases were formed. In contrast to other orthotopic breast cancer models, KEP cells readily formed skeletal metastases with minimal lung involvement. Continuous treatment with SD-208 (60 mg/kg per day), an orally available TGFβ receptor I kinase inhibitor, increased the tumour growth at the primary site and increased the number of distant metastases. Furthermore, when SD-208 treatment was started after surgical resection of the orthotopic tumour, increased bone colonisation was also observed (versus vehicle). Both our in vitro and in vivo data show that SD-208 treatment reduced TGFβ signalling, inhibited apoptosis, and increased proliferation. In conclusion, we have demonstrated that orthotopic implantation of murine ILC cells represent a new breast cancer model of minimal residual disease in vivo, which comprises key steps of the metastatic cascade. The cancer cells are sensitive to the anti-tumour effects of TGFβ. Our in vivo model is ideally suited for functional studies and evaluation of new pharmacological intervention strategies that may target one or more steps along the metastatic cascade of events. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on 10. Pharmacologically Inactive Bisphosphonates as an Alternative Strategy for Targeting Osteoclasts: In Vivo Assessment of 5-Fluorodeoxyuridine-Alendronate in a Preclinical Model of Breast Cancer Bone Metastases. PubMed Schem, Christian; Tower, Robert J; Kneissl, Philipp; Rambow, Anna-Christina; Campbell, Graeme M; Desel, Christine; Damm, Timo; Heilmann, Thorsten; Fuchs, Sabine; Zuhayra, Maaz; Trauzold, Anna; Glüer, Claus C; Schott, Sarah; Tiwari, Sanjay 2017-03-01 Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolite-bisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p < 0.001). This finding is supported by time-lapse micro-computed tomography analyses, which revealed bone formation volume to be on average 1.6-fold higher with 5-FdU-ale treatment compared with alendronate (p < 0.001). We conclude that 5-FdU-ale, which is a poor prenylation inhibitor but maintains potent antiresorptive activity, does not reduce bone formation and has cytostatic antitumor efficacy. These results document that conjugation of an antimetabolite with 11. Design of polyaspartic acid peptide-poly (ethylene glycol)-poly (ε-caprolactone) nanoparticles as a carrier of hydrophobic drugs targeting cancer metastasized to bone. PubMed Liu, Jinsong; Zeng, Youyun; Shi, Shuai; Xu, Lihua; Zhang, Hualin; Pathak, Janak L; Pan, Yihuai 2017-01-01 Treatment of cancer metastasized to bone is still a challenge due to hydrophobicity, instability, and lack of target specificity of anticancer drugs. Poly (ethylene glycol)-poly (εcaprolactone) polymer (PEG-PCL) is an effective, biodegradable, and biocompatible hydrophobic drug carrier, but lacks bone specificity. Polyaspartic acid with eight peptide sequences, that is, (Asp) 8 , has a strong affinity to bone surface. The aim of this study was to synthesize (Asp) 8 -PEG-PCL nanoparticles as a bone-specific carrier of hydrophobic drugs to treat cancer metastasized to bone. 1 H nuclear magnetic resonance, Fourier transform infrared spectroscopy, and transmission electron microscopy data showed that (Asp) 8 PEG-PCL nanoparticles (size 100 nm) were synthesized successfully. (Asp) 8 -PEG-PCL nanoparticles did not promote erythrocyte aggregation. Fluorescence microscopy showed clear uptake of Nile red-loaded (Asp) 8 -PEG-PCL nanoparticles by cancer cells. (Asp) 8 -PEG-PCL nanoparticles did not show cytotoxic effect on MG63 and human umbilical vein endothelial cells at the concentration of 10-800 μg/mL. (Asp) 8 -PEG-PCL nanoparticles bound with hydroxyapatite 2-fold more than PEG-PCL. Intravenously injected (Asp) 8 PEG-PCL nanoparticles accumulated 2.7-fold more on mice tibial bone, in comparison to PEG-PCL. Curcumin is a hydrophobic anticancer drug with bone anabolic properties. Curcumin was loaded in the (Asp) 8 -PEG-PCL. (Asp) 8 -PEG-PCL showed 11.07% loading capacity and 95.91% encapsulation efficiency of curcumin. The curcumin-loaded (Asp) 8 -PEG-PCL nanoparticles gave sustained release of curcumin in high dose for >8 days. The curcumin-loaded (Asp) 8 -PEG-PCL nanoparticles showed strong antitumorigenic effect on MG63, MCF7, and HeLa cancer cells. In conclusion, (Asp) 8 -PEG-PCL nanoparticles were biocompatible, permeable in cells, a potent carrier, and an efficient releaser of hydrophobic anticancer drug and were bone specific. The curcumin-loaded (Asp) 8 -PEG 12. Microwave Ablation for Palliation of Bone Metastases. PubMed Kinczewski, Leigh 2016-06-01 Bone metastases are the most common source of pain for patients with cancer. For pain that is refractory to conventional measures, microwave ablation (MWA) is an emerging alternative therapy. Studies show that MWA is effective in reducing pain and analgesic requirements while improving function. This article describes studies of MWA that include patients with bone metastases to a variety of locations from a range of primary malignancies. Although studies are limited, MWA has proven to be well tolerated with impressive efficacy. 
. 13. [Surgical treatment of spinal bone metastases]. PubMed Saqui, Abderrazzak El; Aggouri, Mohamed; Benzagmout, Mohamed; Chakour, Khalid; Chaoui, Mohamed El Faiz 2017-01-01 Surgery for metastatic tumor is usually a palliative surgery, especially for spinal metastases, due to their anatomical localization. Surgical procedure should be accurately established to have simple outcomes and to start adjuvant treatment as soon as clinically possible. Therapeutic strategy should proceed after multidisciplinary consultation meeting (RCP). The main risk of spinal bone metastases is neurological, hence this surgery should be most commonly preventive. Its main objective is to improve patient's quality of life. 14. Bone metastases, general and clinical issues. PubMed Greco, C; Forte, L; Erba, P; Mariani, G 2011-08-01 The skeleton is the most common organ for metastasis from solid tumours. Bone metastases pose significant diagnostic and clinical challenges and represent an important cause of cancer-related morbidity. Without appropriate bone-directed therapy, many patients will be at high risk for potentially debilitating skeletal-related events (SREs), such as pain, bone fractures, neurologic deficits and hypercalcemia, severely impacting on the patient's quality of life. Because of their high incidence, bone metastases impose significant demands on health care resources. The optimal management of skeletal metastases depends on the underlying biology of the disease, the extent of bone involvement, the presence and severity of symptoms, the availability of effective systemic therapies and life expectancy of the patient. This article discusses clinical issues concerning diagnosis and available treatment approaches based on the presentation of skeletal involvement. Emphasis is placed on the role of external beam-radiotherapy as a local mode of treatment for palliation of bone pain, decompression of epidural compression and as potential ablative approach through high-dose image-guided irradiation (IGRT) in patients presenting with oligometastatic disease. 15. TARGETING POLYMER THERAPEUTICS TO BONE PubMed Central Low, Stewart; KopeÄek, JindÅ™ich 2012-01-01 An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides an unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drugcarrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems. PMID:22316530 16. AR Expression in Breast Cancer CTCs Associates with Bone Metastases. PubMed Aceto, Nicola; Bardia, Aditya; Wittner, Ben S; Donaldson, Maria C; O'Keefe, Ryan; Engstrom, Amanda; Bersani, Francesca; Zheng, Yu; Comaills, Valentine; Niederhoffer, Kira; Zhu, Huili; Mackenzie, Olivia; Shioda, Toshi; Sgroi, Dennis; Kapur, Ravi; Ting, David T; Moy, Beverly; Ramaswamy, Sridhar; Toner, Mehmet; Haber, Daniel A; Maheswaran, Shyamala 2018-02-16 Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing was performed of circulating tumor cells (CTC) isolated from blood samples of women with metastatic estrogen receptor (ER) + breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it contributes to acquired resistance to endocrine therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER + breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients. Implications: This study highlights a role for the AR in breast cancer bone metastasis, and suggests that therapeutic targeting of the AR may benefit patients with metastatic breast cancer. Mol Cancer Res; 1-8. ©2018 AACR. ©2018 American Association for Cancer Research. 17. The Surgical Treatment of Pelvic Bone Metastases PubMed Central Müller, Daniel A.; Capanna, Rodolfo 2015-01-01 Pelvic bone metastases are a growing concern in the field of orthopedic surgery. Patients with pelvic metastasis are individually different with different needs of treatment in order to attain the best possible quality of life despite the advanced stage of disease. A holistic collaboration among the oncologist, radiation therapist, and orthopedic surgeon is mandatory. Special attention has to be directed to osteolytic lesions in the periacetabular region as they can provoke pathological fractures and subsequent functional impairment. Different reconstruction techniques for the pelvis are available; the choice depends on the patient's prognosis, size of the bone defect, and response of the tumor to adjuvant treatment. If all the conservative treatments are exhausted and the patient is not eligible for surgery, one of the various percutaneous ablation procedures can be considered. We propose a pelvic analogue to the treatment algorithm in long bone metastasis and a scoring system in pelvic metastasis. This algorithm aims to simplify the teamwork and to avoid under- or overtreatment of pelvic bone metastases. PMID:25810925 18. The surgical treatment of pelvic bone metastases. PubMed Müller, Daniel A; Capanna, Rodolfo 2015-01-01 Pelvic bone metastases are a growing concern in the field of orthopedic surgery. Patients with pelvic metastasis are individually different with different needs of treatment in order to attain the best possible quality of life despite the advanced stage of disease. A holistic collaboration among the oncologist, radiation therapist, and orthopedic surgeon is mandatory. Special attention has to be directed to osteolytic lesions in the periacetabular region as they can provoke pathological fractures and subsequent functional impairment. Different reconstruction techniques for the pelvis are available; the choice depends on the patient's prognosis, size of the bone defect, and response of the tumor to adjuvant treatment. If all the conservative treatments are exhausted and the patient is not eligible for surgery, one of the various percutaneous ablation procedures can be considered. We propose a pelvic analogue to the treatment algorithm in long bone metastasis and a scoring system in pelvic metastasis. This algorithm aims to simplify the teamwork and to avoid under- or overtreatment of pelvic bone metastases. 19. Bone metastases and skeletal-related events from neuroendocrine tumors PubMed Central Van Loon, Katherine; Zhang, Li; Keiser, Jennifer; Carrasco, Cendy; Glass, Katherine; Ramirez, Maria-Teresa; Bobiak, Sarah; Nakakura, Eric K; Venook, Alan P; Shah, Manisha H; Bergsland, Emily K 2015-01-01 Neuroendocrine tumors (NETs) metastasize to bone; however, a multi-institution evaluation of the natural history and complications of bone metastases across multiple NET subtypes has not, to our knowledge, previously been conducted. At two tertiary academic centers, we identified patients with bone metastases from databases of patients with a diagnosis of NET between 2004 and 2008. Detection of bone metastases, occurrence of skeletal-related events (SREs), and interventions were analyzed using summary statistics and categorical methods. Time-to-event data were assessed using Kaplan–Meier estimates and log-rank tests. Between 2004 and 2008, 82 out of 691 NET patients (12%) were reported to have bone metastases. Of the 82 patients with bone metastases, 55% were men and their median age was 49. Bone metastases occurred in 25% of pheochromocytomas and paragangliomas, 20% of high-grade neuroendocrine carcinomas, 9% of carcinoid tumors, and 8% of pancreatic NETs. At time of detection of bone metastases, 60% reported symptoms, including pain; 10% developed cord compression, 9% suffered a pathological fracture, and 4% developed hypercalcemia. Occurrence of SREs did not differ significantly with regard to tumor histology. Of patients with bone metastases, 67 (82%) received at least one form of bone-directed treatment, 50% received radiation, 45% received a bisphosphonate, 18% underwent surgery, 11% received 131I-MIBG, 5% received denosumab, and 46% were treated with more than one treatment modality. Bone metastases occur in a substantial number of patients diagnosed with NETs. Patients are often symptomatic and many develop SREs. Given the recent therapeutic advances and increasing life expectancy of patients with NETs, development of guidelines for surveillance and clinical care of bone metastases from NETs is needed. PMID:25430999 20. SU-E-T-588: Optimization of Imaging Following 223Ra Administration in Targeted Alpha-Emitting Radionuclide Therapy of Bone Metastases SciTech Connect Benabdallah, N; Bernardini, M; Desbree, A 2015-06-15 Purpose: With a growing demand of alpha-emitting radiopharmaceuticals, especially Xofigo ({sup 223}RaCl{sub 2}) which is used in the treatment of metastatic bone disease, the optimization of dosimetry becomes necessary. Indeed, in Europe, as stated on the council directive 2013/59/euratom, exposures of target volumes for radiotherapeutic purposes shall be individually planned taking into account that doses to non-target volumes and tissues shall be as low as reasonably achievable. To that aim, the possibility of imaging {sup 223}Ra was first investigated. Methods: The experiments were conducted at the Hopital Europeen Georges Pompidou with an Infinia Hawkeye 4 gamma camera, equipped with amore » medium-energy collimator. Imaging parameters, such as sensibility, spatial resolution and energy spectrum, were determined using several physical phantoms with a source of 6 MBq of {sup 223}Ra. Bone metastases were modeled with a NEMA Body Phantom to investigate image degradation based on the concentration of {sup 223}Ra. Results: The acquired energy spectrum allowed to visualize several photon peaks: at 85, 154 and 270 keV. Camera sensitivity measured from the phantom study was 102.3 cps/MBq for the 85 keV ± 20 %, 89.9 cps/MBq for the 154 ± 20 % window and 65.4 cps/MBq for the 270 ± 10 % window. The spatial resolution (full-width at half-maximum) was respectively 1.7, 1.9 and 1.8 cm for the three energy windows. SPECT/CT images of NEMA Body Phantom without and with attenuation have permitted to determine the best reconstruction parameters. Conclusion: This study has demonstrated that it is possible to obtain clinically relevant information from images of {sup 223}Ra. All these results will be valuable to analyze biodistribution imaging of the radiopharmaceutical in the patient body and go further in the reconstruction of patient images in order to personalize the dosimetry.« less « 1 2 3 4
5 » « 1 2 3 4 5 » 21. Do Androgen Receptor Splice Variants Facilitate Growth of Bone Metastases DTIC Science & Technology 2016-11-01 AWARD NUMBER: W81XWH-15-1-0223 TITLE: Do Androgen Receptor Splice Variants Facilitate Growth of Bone Metastases? PRINCIPAL INVESTIGATOR...therapy is expression of constitutively active AR splice variants, which lack the carboxyl terminal hormone binding domain. The best characterized...signaling has been implicated in growth of bone metastases. We hypothesize that AR-V7 mediated induction of Notch signaling to promotes growth of bone 22. Variations in target volume definition and dose to normal tissue using anatomic versus biological imaging (18 F-FDG-PET) in the treatment of bone metastases: results from a 3-arm randomized phase II trial. PubMed Berwouts, Dieter; De Wolf, Katrien; De Neve, Wilfried; Olteanu, Luiza Am; Lambert, Bieke; Speleers, Bruno; Goethals, Ingeborg; Madani, Indira; Ost, Piet 2017-02-01 To report the impact on target volume delineation and dose to normal tissue using anatomic versus biological imaging (18 F-FDG-PET) for bone metastases. Patients with uncomplicated painful bone metastases were randomized (1:1:1) and blinded to receive either 8 Gy in a single fraction with conventionally planned radiotherapy (ConvRT-8 Gy) or 8 Gy in a single fraction with dose-painting-by-numbers (DPBN) dose range between 6 and 10 Gy) (DPBN-8 Gy) or 16 Gy in a single fraction with DPBN (dose range between 14 and 18 Gy) (DPBN-16 Gy). The primary endpoint was overall pain response at 1 month. Volumes of the gross tumour volume (GTV) - both biological (GTVPET ) and anatomical (GTVCT ) -, planning target volume (PTV), dose to the normal tissue and maximum standardized-uptake values (SUVMAX ) were analysed (secondary endpoint). Sixty-three percent of the GTVCT volume did not show 18 F-FDG-uptake. On average, 20% of the GTVPET volume was outside GTVCT . The volume of normal tissue receiving 4 Gy, 6 Gy and 8 Gy was at least 3×, 6× and 13× smaller in DPBN-8 Gy compared to ConvRT-8 Gy and DPBN-16 Gy (P < 0.05). Positron emitting tomography-information potentially changes the target volume for bone metastases. DPBN between 6 and 10 Gy significantly decreases dose to the normal tissue compared to conventional radiotherapy. © 2016 The Royal Australian and New Zealand College of Radiologists. 23. Prevention and Treatment of Bone Metastases in Breast Cancer PubMed Central Carla, Ripamonti; Fabio, Trippa; Gloria, Barone; Ernesto, Maranzano 2013-01-01 In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as well as the reduction of the risk of complications (e.g., bone fractures, spinal cord compression). Bisphosphonates, as potent inhibitors of osteoclastic-mediated bone resorption are a well-established, standard-of-care treatment option to reduce the frequency, severity and time of onset of the skeletal related events in breast cancer patients with bone metastases. Moreover bisphosphonates prevent cancer treatment-induced bone loss. Recent data shows the anti-tumor activity of bisphosphonates, in particular, in postmenopausal women and in older premenopausal women with hormone-sensitive disease treated with ovarian suppression. Pain is the most frequent symptom reported in patients with bone metastases, and its prevention and treatment must be considered at any stage of the disease. The prevention and treatment of bone metastases in breast cancer must consider an integrated multidisciplinary approach. PMID:26237068 24. Therapeutic Strategies for Bone Metastases and Their Clinical Sequelae in Prostate Cancer PubMed Central Autio, Karen A.; Scher, Howard I. 2013-01-01 Opinion statement Skeletal metastases threaten quality of life, functionality, and longevity in patients with metastatic castration-resistant prostate cancer (mCRPC). Therapeutic strategies for bone metastases in prostate cancer can palliate pain, delay/prevent skeletal complications, and prolong survival. Pharmacologic agents representing several drug classes have demonstrated the ability to achieve these treatment goals in men with mCRPC. Skeletal-related events such as fracture and the need for radiation can be delayed using drugs that target the osteoclast/osteoblast pathway. Cancer-related bone pain can be palliated using beta-emitting bone-seeking radiopharmaceuticals such as samarium-153 EDTMP and strontium-89. Also, prospective randomized studies have demonstrated that cytotoxic chemotherapy can palliate bone pain. For the first time, bone-directed therapy has been shown to prolong survival using the novel alpha-emitting radiopharmaceutical radium-223. Given these multifold clinical benefits, treatments targeting bone metabolism, tumor-bone stromal interactions, and bone metastases themselves are now central elements of routine clinical care. Decisions about which agents, alone or in combination, will best serve the patient’s and clinician’s clinical goals is contingent on the treatment history to date, present disease manifestations, and symptomatology. Clinical trials exploring novel agents such as those targeting c-Met and Src are under way, using endpoints that directly address how patients feel, function, and survive. PMID:22528368 25. Inhibition Of Prostate Cancer Skeletal Metastases By Targeting Cathepsin K DTIC Science & Technology 2010-02-01 New treatments are urgently needed for patients known to have bone metastases and those who are at high risk for having bone metastases in PCa...take rate, as opposed to a 20-30% take rate using the vascular approach ( cardiac -injection). But we are aware that direct injection has the...disadvantage of not modeling the entire metastatic cascade. Therefore, in PC3 cells, we have used cardiac -injection model. We will continue to collect the 26. Inhibition of Prostate Cancer Skeletal Metastases by Targeting Cathepsin K DTIC Science & Technology 2009-05-01 bone metastases and those who are at high risk for having bone metastases in PCa patients. Cathepsin K (CatK) is a cystine protease enzyme that can...advantage of nearly a 100% take rate, as opposed to a 20-30% take rate using the vascular approach ( cardiac -injection). But we are aware that direct...injection has the disadvantage of not modeling the entire metastatic cascade. Therefore, we will use cardiac - injection model that we have gained great 27. Prostatic Acid Phosphatase Alters the RANKL/OPG System and Induces Osteoblastic Prostate Cancer Bone Metastases PubMed Central Kirschenbaum, Alexander; Izadmehr, Sudeh; Yao, Shen; O'Connor-Chapman, Kieley L.; Huang, Alan; Gregoriades, Elias M.; Yakar, Shoshana 2016-01-01 Prostate cancer (PCa) is unique in its tendency to produce osteoblastic (OB) bone metastases. There are no existing therapies that specifically target the OB phase that affects 90% of men with bone metastatic disease. Prostatic acid phosphatase (PAP) is secreted by PCa cells in OB metastases and increases OB growth, differentiation, and bone mineralization. The purpose of this study was to investigate whether PAP effects on OB bone metastases are mediated by autocrine and/or paracrine alterations in the receptor activator of nuclear factor κ-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. To investigate whether PAP modulated these factors and altered the bone reaction, we knocked down PAP expression in VCaP cells and stably overexpressed PAP in PC3M cells, both derived from human PCa bone metastases. We show that knockdown of PAP in VCaP cells decreased OPG while increasing RANK/RANKL expression. Forced overexpression of PAP in PC3M cells had the inverse effect, increasing OPG while decreasing RANK/RANKL expression. Coculture of PCa cells with MC3T3 preosteoblasts also revealed a role for secretory PAP in OB-PCa cross talk. Reduced PAP expression in VCaP cells decreased MC3T3 proliferation and differentiation and reduced their OPG expression. PAP overexpression in PC3M cells altered the bone phenotype creating OB rather than osteolytic lesions in vivo using an intratibial model. These findings demonstrate that PAP secreted by PCa cells in OB bone metastases increases OPG and plays a critical role in the vicious cross talk between cancer and bone cells. These data suggest that inhibition of secretory PAP may be an effective strategy for PCa OB bone lesions. PMID:27783536 28. Characterization of bone quality in prostate cancer bone metastases using Raman spectroscopy NASA Astrophysics Data System (ADS) Bi, Xiaohong; Patil, Chetan; Morrissey, Colm; Roudier, Martine P.; Mahadevan-Jansen, Anita; Nyman, Jeffry 2010-02-01 Prostate cancer is the most common primary tumor in men, with a high propensity to metastasize to bone. Bone metastases in prostate cancer are associated with active pathologic bone remodeling, leading to increased mortality and morbidity. Detailed characterization of bone metastases is important in the management of prostate cancer. Raman spectroscopy was applied in this study to investigate the structure and composition of metastatic bone in prostate cancer with the ultimate goal of identifying spectral features that are related to the alterations in bone quality as the bone metastases develop. Osteoblastic-, osteolytic- and tumor-absent bone specimens from prostate cancer patients were investigated using bench-top Raman microspectroscopy. Raman derived measurements of collagen mineralization, mineral crystallinity, and carbonate substitution were calculated. The osteolytic lesions demonstrated significantly lower collagen mineralization, determined by phosphate ν1/proline, and higher carbonate substitution than normal and osteoblastic bones. Mineral crystallinity was significantly lower in both blastic and lytic specimens. In addition, a significant increase in the ratio of hydroxyproine: proline was observed in the osteoblastic specimen, indicating an increase in the content of hydroxyproline at the blastic lesions. This study demonstrate that Raman spectroscopy shows promise in determining alterations in osteoblastic and osteolytic bone metastases as well as assessing the response of metastatic bone to therapies. 29. Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance PubMed Central Zabkiewicz, Catherine; Resaul, Jeyna; Hargest, Rachel; Jiang, Wen Guo 2017-01-01 Bone morphogenetic proteins (BMPs) belong to the TGF-β super family, and are essential for the regulation of foetal development, tissue differentiation and homeostasis and a multitude of cellular functions. Naturally, this has led to the exploration of aberrance in this highly regulated system as a key factor in tumourigenesis. Originally identified for their role in osteogenesis and bone turnover, attention has been turned to the potential role of BMPs in tumour metastases to, and progression within, the bone niche. This is particularly pertinent to breast cancer, which commonly metastasises to bone, and in which studies have revealed aberrations of both BMP expression and signalling, which correlate clinically with breast cancer progression. Ultimately a BMP profile could provide new prognostic disease markers. As the evidence suggests a role for BMPs in regulating breast tumour cellular function, in particular interactions with tumour stroma and the bone metastatic microenvironment, there may be novel therapeutic potential in targeting BMP signalling in breast cancer. This review provides an update on the current knowledge of BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease-specific bone metastasis. PMID:28733469 30. Complications and survival of megaprostheses after resection of bone metastases. PubMed De Gori, M; D’Arienzo, A; Andreani, L; Beltrami, G; Campanacci, D A; De Biase, P; Frenos, F; Giannotti, S; Sacchetti, F; Totti, F; Parchi, P; Capanna, R Treatment of bone metastases is often palliative, aiming at pain control and stabilization or prevention of pathological fractures. However, a complete resection with healing purposes can be performed in selected cases. The aim of our work was to evaluate the survival of megaprostheses used for reconstruction after bone metastases. Between January 2001 and March 2015, we implanted 169 Megasystem-C® (Waldemar LINK® GmbH & Co. KG, Hamburg, Germany) after bone metastasis resection. Patients, 95 females and 74 males, were operated at an average age of 61 (12-87) years for proximal femoral resection in 135 (79.9%) cases, distal femur in 24 (14.2%), proximal tibia in 6 (3.6%), total femur in 3 (1.8%) and intercalary femur in 1 (0.6%). Mostly, breast cancer metastases (30.8%), kidney (17.8%) and lung (14.2%) were treated. At an average follow-up of 21 (1-150) months, we found a 99.4% overall limb salvage and a 96.1% overall survival rate at 1 year, 92.8% at 2 years, and 86.8% at 5 and 10 years. We found 9 (5.3%) mobilization cases of the proximal femoral implant, 3 needed surgical reduction; 2 (1.2%) cases of aseptic loosening of the prosthetic stem; 2 (1.2%) periprotetic infection cases, one requiring a 2-stage revision. Few literature studies have evaluated the survival of megaprosthetic implant in the treatment of bone metastases. Our data show how in this specific context the rate of complications is significantly lower than expected in general orthopedic orthopedic surgery. The use of modular prostheses is a valid reconstructive strategy after bone metastasis resection in selected patients. The rate of short-term complications is exceptionally low; further studies will have to confirm this in the longer term. 31. Micro-CT evaluation of bone defects: applications to osteolytic bone metastases, bone cysts, and fracture. PubMed Buie, Helen R; Bosma, Nick A; Downey, Charlene M; Jirik, Frank R; Boyd, Steven K 2013-11-01 Bone defects can occur in various forms and present challenges to performing a standard micro-CT evaluation of bone quality because most measures are suited to homogeneous structures rather than ones with spatially focal abnormalities. Such defects are commonly associated with pain and fragility. Research involving bone defects requires quantitative approaches to be developed if micro-CT is to be employed. In this study, we demonstrate that measures of inter-microarchitectural bone spacing are sensitive to the presence of focal defects in the proximal tibia of two distinctly different mouse models: a burr-hole model for fracture healing research, and a model of osteolytic bone metastases. In these models, the cortical and trabecular bone compartments were both affected by the defect and were, therefore, evaluated as a single unit to avoid splitting the defects into multiple analysis regions. The burr-hole defect increased mean spacing (Sp) by 27.6%, spacing standard deviation (SpSD) by 113%, and maximum spacing (Spmax) by 72.8%. Regression modeling revealed SpSD (β=0.974, p<0.0001) to be a significant predictor of the defect volume (R(2)=0.949) and Spmax (β=0.712, p<0.0001) and SpSD (β=0.271, p=0.022) to be significant predictors of the defect diameter (R(2)=0.954). In the mice with osteolytic bone metastases, spacing parameters followed similar patterns of change as reflected by other imaging technologies, specifically bioluminescence data which is indicative of tumor burden. These data highlight the sensitivity of spacing measurements to bone architectural abnormalities from 3D micro-CT data and provide a tool for quantitative evaluation of defects within a bone. Copyright © 2013 IPEM. Published by Elsevier Ltd. All rights reserved. 32. The Wnt inhibitor dickkopf-1: a link between breast cancer and bone metastases. PubMed Mariz, Kasoha; Ingolf, Juhasz-Böss; Daniel, Herr; Teresa, Ney Jasmin; Erich-Franz, Solomayer 2015-12-01 Breast cancer is the second leading cause of cancer death in women and metastasizes to bone in greater than 80 % of advanced-disease patients. Once breast cancer bone metastases are established, the disease is incurable and drives numerous complications that increase morbidity and diminish patients' quality of life. Many mechanisms have been implicated in bone metastases of breast cancer. The critical role of Wnt signalling pathway inhibition in initiating bone lesions has been demonstrated in a variety of bone diseases and tumours. Overexpression of dickkopf-1 (Dkk1) protein, a negative regulator of the Wnt/β-catenin pathway, has been found in breast cancer cell lines that form osteolytic metastases preferentially and in serum from breast cancer patients with osteolytic bone metastases. Further understanding of the mechanistic role of Dkk1 as a link between primary breast tumours and secondary osteolytic bone metastases may facilitate development of anti-Dkk1 antibody therapeutic tools. 33. A new protocol of surgical treatment of long bone metastases. PubMed Capanna, Rodolfo; De Biase, Pietro; Campanacci, Domenico A 2003-06-30 Background. The choice of proper treatment way is one of the most important things in surgically treated long bones metastases. The aim of this research was evaluation of the treatment way according to neoplasm's type and metastasis localisation and spreading. Material and methods. The evaluation underwent 158 patients who were divided in 4 groups. The first one consists of 13 patients with single metastasis of cancer with good prognosis. In the second group were 69 patients with bone fracture. The third group included 36 patients with such bone destruction that fracture was expected. The last fourth one had 40 patients with osteoblastic metastases or osteolitic in unloaded bones. Results and Discussion. In group I long lasting reconstructive implants are required and postoperative irradiation is recommended, in groups II and III the aggressiveness of treatment should be related to three parameters: survival expectancy, mechanical properties of the affected bone, predictive response to adjuvants. Based on the above parameters the quidelines of the protocol allow to identify the most appropriate reconstructive indication for every single case ranging from simple osteosynthesis (bad prognosis, low fracture risk, goodresponse to adjuvants) to prosthetic replacement (good prognosis, high fracture risk, bad response to adjuvants). Patients from group IV were admitted to oncology treatment ward after biopsy. 34. [Bone metastases : New aspects of pathogenesis and systemic therapy]. PubMed Rachner, T D; Jakob, F; Hofbauer, L C 2016-07-01 The occurrence of bone metastases, in particular secondary to breast and prostate cancer, represents a complex medical condition that is debilitating for affected patients. In order to provide an efficient and personalized therapy, an interdisciplinary treatment approach is mandatory; therefore, systemic pharmacological therapy represents a core element of the overall treatment concept. In terms of pathophysiology, the cancer cells cause a massive disturbance of the local bone microenvironment, which as a rule leads to activation of bone resorbing osteoclasts. In addition to bisphosphonates, which can be considered classical antiresorptive agents, the monoclonal receptor activator of nuclear factor-kappa B ligand (RANKL) antibody denosumab has been in use in clinical practice since 2011. The alpha-emitting radioisotope Alpharadin was also recently approved for the treatment of metastatic prostate cancer. This article provides a summary of the most recent knowledge on the pathogenesis of how cancer cells alter the bone microenvironment as well as a review of established and future systemic treatment options. 35. Targeting CD81 to Prevent Metastases in Breast Cancer DTIC Science & Technology 2015-10-01 cancer metastases, CD81, Circulating Tumor Cells ( CTCs ) 16. SECURITY CLASSIFICATION OF: U 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF...circulating tumor cell ( CTC ) detection technology, we will determine whether CD81 is critically involved in the generation of CTCs and if it plays a key role...in the development of breast cancer tumor metastases. We will then test the use of CD81 targeting antibodies to curb CTC generation and metastatic 36. Hypoxia and TGF-beta drive breast cancer bone metastases through parallel signaling pathways in tumor cells and the bone microenvironment. PubMed Dunn, Lauren K; Mohammad, Khalid S; Fournier, Pierrick G J; McKenna, C Ryan; Davis, Holly W; Niewolna, Maria; Peng, Xiang Hong; Chirgwin, John M; Guise, Theresa A 2009-09-03 Most patients with advanced breast cancer develop bone metastases, which cause pain, hypercalcemia, fractures, nerve compression and paralysis. Chemotherapy causes further bone loss, and bone-specific treatments are only palliative. Multiple tumor-secreted factors act on the bone microenvironment to drive a feed-forward cycle of tumor growth. Effective treatment requires inhibiting upstream regulators of groups of prometastatic factors. Two central regulators are hypoxia and transforming growth factor (TGF)- beta. We asked whether hypoxia (via HIF-1alpha) and TGF-beta signaling promote bone metastases independently or synergistically, and we tested molecular versus pharmacological inhibition strategies in an animal model. We analyzed interactions between HIF-1alpha and TGF-beta pathways in MDA-MB-231 breast cancer cells. Only vascular endothelial growth factor (VEGF) and the CXC chemokine receptor 4 (CXCR4), of 16 genes tested, were additively increased by both TGF-beta and hypoxia, with effects on the proximal promoters. We inhibited HIF-1alpha and TGF-beta pathways in tumor cells by shRNA and dominant negative receptor approaches. Inhibition of either pathway decreased bone metastasis, with no further effect of double blockade. We tested pharmacologic inhibitors of the pathways, which target both the tumor and the bone microenvironment. Unlike molecular blockade, combined drug treatment decreased bone metastases more than either alone, with effects on bone to decrease osteoclastic bone resorption and increase osteoblast activity, in addition to actions on tumor cells. Hypoxia and TGF-beta signaling in parallel drive tumor bone metastases and regulate a common set of tumor genes. In contrast, small molecule inhibitors, by acting on both tumor cells and the bone microenvironment, additively decrease tumor burden, while improving skeletal quality. Our studies suggest that inhibitors of HIF-1alpha and TGF-beta may improve treatment of bone metastases and increase 37. Dosimetric and clinical impact of 3D vs. 2D planning in palliative radiotherapy for bone metastases. PubMed Pope, Kathy; Fitzpatrick, David; Potter, Andrew; Holwell, Michael; Wang, Lisa; Lau, Michelle; Levin, Wilfred; McLean, Michael; Balaura, Laura Zurawel; Bezjak, Andrea; Wong, Rebecca K S 2013-08-01 The incorporation of three-dimensional (3D) planning for the treatment of bone metastases has been embraced in many North American practices with assumed superior tumor targeting, sparing of normal structures, and improvement in patient outcomes. The goal of our project was to evaluate the dosimetric and clinical impact of 3D vs. two-dimensional (2D) planning for patients who require simple palliative radiotherapy techniques (≤ 2 beams) for bone metastases. Patients undergoing palliative radiation therapy for bone metastases were eligible. The study oncologists first documented the intended treatment target, defined the treatment target/field using digital radiographs (2D), followed by using full 3D planning computerized tomography volumetric datasets. Treatment plans were compared dosimetrically, and patient-reported outcomes (pain, fatigue, anorexia, and nausea) were compared against a historical cohort treated with 2D plans. Eighty-five patients were enrolled in the study group. Review of the 3D datasets led to changes in the target area of interest in 44/85 (52 %) of cases, of which 21/85 (25 %) were clinically significant. 3D plans resulted in superior target coverage and normal tissue sparing. There was no significant difference in patient-reported outcomes however. 3D radiotherapy planning resulted in superior treatment plans but we were unable to demonstrate a significant benefit in clinical outcomes. Prospective study designs are needed to describe the contemporary expectation of palliative radiotherapy for bone metastases in the modern era of 3D planning. 38. The practicing orthopedic surgeon's guide to managing long bone metastases. PubMed Cheung, Felix H 2014-01-01 Long bone skeletal metastases are common in the United States, with more than 280,000 new cases every year. Most of these will be managed by the on-call orthopedic surgeon. A practical primer is offered for the evaluation and surgical management for the practicing orthopedist, including questions to ask during the history, pertinent physical examination findings, appropriate imaging requests, proper laboratory work, and biopsy options. Finally, 7 scenarios are presented to encompass most situations a practicing orthopedic surgeon will encounter, and guidelines for treatment and referral are offered. Copyright © 2014 Elsevier Inc. All rights reserved. 39. Bisphosphonates for the relief of pain secondary to bone metastases. PubMed Wong, R; Wiffen, P J 2002-01-01 Bisphosphonates form part of standard therapy for hypercalcemia and the prevention of skeletal events in some cancers. However, the role of bisphosphonates in pain relief for bony metastases remains uncertain. To determine the effectiveness of bisphosphonates for the relief of pain from bone metastases. MEDLINE (1966-1999), EMBASE (1980-1999), CancerLit (1966-1999), the Cochrane library (Issue 1, 2000) and the Oxford Pain Database were searched using the strategy devised by the Cochrane Pain, Palliative and Supportive Care Group with additional terms 'diphosphonate', 'bisphosphonate', 'multiple myeloma' and 'bone neoplasms'. (Last search: January 2000). Randomized trials of bisphosphonates compared with open, blinded, or different doses/types of bisphosphonates in cancer patients were included where pain and/or analgesic consumption were outcome measures. Studies where pain was reported only by observers were excluded. Article eligibility, quality assessment and data extraction were undertaken by both reviewers. The proportions of patients with pain relief at 4, 8 and 12 weeks were assessed. The proportion of patients with analgesic reduction, the mean pain score, mean analgesic consumption, adverse drug reactions, and quality of life data were compared as secondary outcomes. Thirty randomized controlled studies (21 blinded, four open and five active control) with a total of 3682 subjects were included. For each outcome, there were few studies with available data. For the proportion of patients with pain relief (eight studies) pooled data showed benefits for the treatment group, with an NNT at 4 weeks of 11[95% CI 6-36] and at 12 weeks of 7 [95% CI 5-12]. In terms of adverse drug reactions, the NNH was 16 [95% CI 12-27] for discontinuation of therapy. Nausea and vomiting were reported in 24 studies with a non-significant trend for greater risk in the treatment group. One study showed a small improvement in quality of life for the treatment group at 4 weeks. The 40. Managing bone metastases and reducing skeletal related events in prostate cancer. PubMed Gartrell, Benjamin A; Saad, Fred 2014-06-01 Advanced-stage prostate cancer is associated with skeletal complications related to metastatic disease and its treatment. On the one hand, metastatic disease to bone is commonly associated with skeletal-related events (SREs); on the other hand, treatment with androgen-deprivation therapy (ADT) leads to loss in bone mineral density (BMD) and increased risk of fracture. Despite osteoblastic appearance on radiography, bone metastases from prostate cancer are associated with increased osteoblast and osteoclast activity providing the rationale for treatment with osteoclast-targeted agents. The bisphosphonate zoledronic acid and the monoclonal antibody denosumab reduce the incidence of SREs in metastatic castration-resistant prostate cancer (mCRPC). A number of agents prevent loss of BMD associated with ADT, but only denosumab is approved to reduce fractures in patients with non-metastatic prostate cancer. Another recently approved agent-radium-223-improves survival and delays SREs in mCRPC. The inhibitors of androgen receptor signalling, abiraterone and enzalutamide, improve survival in mCRPC and delay SREs, although the latter is likely related to control of disease rather than a direct effect on bone. Finally, the tyrosine kinase inhibitor cabozantinib shows promising activity in bone metastases from mCRPC. This Review addresses the skeletal morbidity associated with prostate cancer and the therapeutic options that exist to treat it. « 1 2 3 4 5 » « 1 2 3 4 5 » 41. Prostatic Acid Phosphatase Plays a Causal Role in Prostate Cancer Bone Metastases DTIC Science & Technology 2013-02-01 RANKL expression in osteoblasts +/- PAP from PCa conditioned medium. RANKL stains brown. PAP decreased RANKL expression. Inhibition of PAP ...bone metastases, there are no therapies that inhibit the later, osteoblastic phase. Prostatic acid phosphatase ( PAP ) is a protein secreted by PCa...cells and is highly expressed in PCa osteoblastic bone metastases. We previously demonstrated that PAP secreted by PCa cells induces the proliferation 42. Patient-reported outcome instruments used to assess pain and functioning in studies of bisphosphonate treatment for bone metastases. PubMed Matza, Louis S; Fallowfield, Lesley J; Chung, Karen C; Currie, Brooke M; Van Brunt, Kate; Patrick, Donald L 2012-04-01 When treating metastatic bone disease, relief of bone pain is often a key outcome. Because pain cannot be quantified with objective clinical measures, patient-reported outcome (PRO) measures are required to assess patients' subjective experience. The goal of the current review was to examine measures used to assess pain, as well as the impact of pain on functional status and health-related quality of life (HRQL), in trials of bisphosphonates for the treatment of bone metastases. A literature search focused on articles published from January 1999 to April 2009. A total of 49 articles were located that used PROs to assess pain-related outcomes of bisphosphonate treatment for bone metastases. The Brief Pain Inventory was the most commonly used multi-item instrument. However, the most common approach for assessing pain was to administer a single-item scale such as a visual analog scale, numerical rating scale, or verbal rating scale. Of the 49 studies, 19 included a PRO assessing functional status or HRQL. Although pain is an important outcome of trials examining treatment for bone metastases, the current review suggests that there is little consistency in PRO measurement across studies. Furthermore, presentation of measures often
lacked clear description, information on measurement properties, citations, clarity regarding method of administration, and consistent instrument names. Recommendations are provided for instrument validation within the target population, assessment of content validity, use of PRO instruments recently developed for patients with bone metastases, clear description of instruments, and implementation of measures consistent with recommendations from instrument developers. 43. Natural History of Non-Small-Cell Lung Cancer with Bone Metastases PubMed Central Daniele, Santini; Sandro, Barni; Salvatore, Intagliata; Alfredo, Falcone; Francesco, Ferraù; Domenico, Galetta; Luca, Moscetti; Nicla, La Verde; Toni, Ibrahim; Fausto, Petrelli; Enrico, Vasile; Laura, Ginocchi; Davide, Ottaviani; Flavia, Longo; Cinzia, Ortega; Antonio, Russo; Giuseppe, Badalamenti; Elena, Collovà ; Gaetano, Lanzetta; Giovanni, Mansueto; Vincenzo, Adamo; Filippo, De Marinis; Satolli, Maria Antonietta; Flavia, Cantile; Andrea, Mancuso; Tanca, Francesca Maria; Raffaele, Addeo; Marco, Russano; Sterpi, M; Francesco, Pantano; Bruno, Vincenzi; Giuseppe, Tonini 2015-01-01 We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival. PMID:26690845 44. Natural History of Non-Small-Cell Lung Cancer with Bone Metastases. PubMed Santini, Daniele; Daniele, Santini; Barni, Sandro; Sandro, Barni; Intagliata, Salvatore; Salvatore, Intagliata; Falcone, Alfredo; Alfredo, Falcone; Ferraù, Francesco; Francesco, Ferraù; Galetta, Domenico; Domenico, Galetta; Moscetti, Luca; Luca, Moscetti; La Verde, Nicla; Nicla, La Verde; Ibrahim, Toni; Toni, Ibrahim; Petrelli, Fausto; Fausto, Petrelli; Vasile, Enrico; Enrico, Vasile; Ginocchi, Laura; Laura, Ginocchi; Ottaviani, Davide; Davide, Ottaviani; Longo, Flavia; Flavia, Longo; Ortega, Cinzia; Cinzia, Ortega; Russo, Antonio; Antonio, Russo; Badalamenti, Giuseppe; Giuseppe, Badalamenti; Collovà , Elena; Elena, Collovà ; Lanzetta, Gaetano; Gaetano, Lanzetta; Mansueto, Giovanni; Giovanni, Mansueto; Adamo, Vincenzo; Vincenzo, Adamo; De Marinis, Filippo; Filippo, De Marinis; Satolli, Maria Antonietta; Cantile, Flavia; Flavia, Cantile; Mancuso, Andrea; Andrea, Mancuso; Tanca, Francesca Maria; Addeo, Raffaele; Raffaele, Addeo; Russano, Marco; Marco, Russano; Sterpi, Michelle; Sterpi, M; Pantano, Francesco; Francesco, Pantano; Vincenzi, Bruno; Bruno, Vincenzi; Tonini, Giuseppe; Giuseppe, Tonini 2015-12-22 We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival. 45. Mutational profiling of bone metastases from lung adenocarcinoma: results of a prospective study (POUMOS-TEC) PubMed Central Confavreux, Cyrille B; Girard, Nicolas; Pialat, Jean-Baptiste; Bringuier, Pierre-Paul; Devouassoux-Shisheboran, Mojgan; Rousseau, Jean-Charles; Isaac, Sylvie; Thivolet-Bejui, Françoise; Clezardin, Philippe; Brevet, Marie 2014-01-01 Targeted therapies have improved patient survival in metastatic lung adenocarcinoma. Molecular diagnosis is a key element to identify oncogenic drivers predicting the efficacy of these agents. In stage IV patients, histopathological diagnosis is often performed on bone metastases biopsy, but routine procedure of decalcification may alter DNA quality for subsequent molecular tests. We set up a procedure to perform molecular analyses on bone metastasis and describe the results of mutational profiling. POUMOS-TEC is a prospective study conducted in stage IV lung adenocarcinomas. Bone metastasis specimens from surgery and CT-scan guided biopsies were sent fresh for immediate formalin-fixation. Decalcification was performed, only when necessary, using EDTA. Controls were processed with acid decalcification. DNA extraction was performed after laser microdissection. Mutational profiling of oncogenic drivers was conducted as recommended by the French National Cancer Institute. Diagnosis efficiency of the computed tomography (CT)-scan guided biopsy process was assessed. Among 177 collected bone metastases specimens, 49 came from lung adenocarcinomas. Specimens processed with no decalcification or EDTA (n=45) provided high-quality DNA. Molecular profiling was performed in 44/45 (98%) of cases. The results of the whole panel of oncogenic drivers (EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK) were obtained in 41/45 (91%) of cases. A mutation was observed in 50% of cases including 32% of KRAS and 14% of epidermal growth factor receptor (EGFR) mutations. CT-scan biopsy efficiency rate was 96%. We demonstrated the feasibility to routinely conduct mutational profiling on bone metastases biopsies. We observed a higher rate of EGFR mutations (+42%) in comparison with the average rate of all stage IV lung adenocarcinomas. This procedure is a new step toward the goal of personalized medicine to treat lung cancers and other osteophilic tumors. PMID:25328676 46. Mutational profiling of bone metastases from lung adenocarcinoma: results of a prospective study (POUMOS-TEC). PubMed Confavreux, Cyrille B; Girard, Nicolas; Pialat, Jean-Baptiste; Bringuier, Pierre-Paul; Devouassoux-Shisheboran, Mojgan; Rousseau, Jean-Charles; Isaac, Sylvie; Thivolet-Bejui, Françoise; Clezardin, Philippe; Brevet, Marie 2014-01-01 Targeted therapies have improved patient survival in metastatic lung adenocarcinoma. Molecular diagnosis is a key element to identify oncogenic drivers predicting the efficacy of these agents. In stage IV patients, histopathological diagnosis is often performed on bone metastases biopsy, but routine procedure of decalcification may alter DNA quality for subsequent molecular tests. We set up a procedure to perform molecular analyses on bone metastasis and describe the results of mutational profiling. POUMOS-TEC is a prospective study conducted in stage IV lung adenocarcinomas. Bone metastasis specimens from surgery and CT-scan guided biopsies were sent fresh for immediate formalin-fixation. Decalcification was performed, only when necessary, using EDTA. Controls were processed with acid decalcification. DNA extraction was performed after laser microdissection. Mutational profiling of oncogenic drivers was conducted as recommended by the French National Cancer Institute. Diagnosis efficiency of the computed tomography (CT)-scan guided biopsy process was assessed. Among 177 collected bone metastases specimens, 49 came from lung adenocarcinomas. Specimens processed with no decalcification or EDTA (n=45) provided high-quality DNA. Molecular profiling was performed in 44/45 (98%) of cases. The results of the whole panel of oncogenic drivers (EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK) were obtained in 41/45 (91%) of cases. A mutation was observed in 50% of cases including 32% of KRAS and 14% of epidermal growth factor receptor (EGFR) mutations. CT-scan biopsy efficiency rate was 96%. We demonstrated the feasibility to routinely conduct mutational profiling on bone metastases biopsies. We observed a higher rate of EGFR mutations (+42%) in comparison with the average rate of all stage IV lung adenocarcinomas. This procedure is a new step toward the goal of personalized medicine to treat lung cancers and other osteophilic tumors. 47. Cabozantinib, a New Standard of Care for Patients With Advanced Renal Cell Carcinoma and Bone Metastases? Subgroup Analysis of the METEOR Trial. PubMed Escudier, Bernard; Powles, Thomas; Motzer, Robert J; Olencki, Thomas; Arén Frontera, Osvaldo; Oudard, Stephane; Rolland, Frederic; Tomczak, Piotr; Castellano, Daniel; Appleman, Leonard J; Drabkin, Harry; Vaena, Daniel; Milwee, Steven; Youkstetter, Jillian; Lougheed, Julie C; Bracarda, Sergio; Choueiri, Toni K 2018-01-08 Purpose Cabozantinib, an inhibitor of tyrosine kinases including MET, vascular endothelial growth factor receptors, and AXL, increased progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with advanced renal cell carcinoma (RCC) after previous vascular endothelial growth factor receptor-targeted therapy in the phase III METEOR trial. Because bone metastases are associated with increased morbidity in patients with RCC, bone-related outcomes were analyzed in METEOR. Patients and Methods Six hundred fifty-eight patients were randomly assigned 1:1 to receive 60 mg cabozantinib or 10 mg everolimus. Prespecified subgroup analyses of PFS, OS, and ORR were conducted in patients grouped by baseline bone metastases status per independent radiology committee (IRC). Additional end points included bone scan response per IRC, skeletal-related events, and changes in bone biomarkers. Results For patients with bone metastases at baseline (cabozantinib [n = 77]; everolimus [n = 65]), median PFS was 7.4 months for cabozantinib versus 2.7 months for everolimus (hazard ratio, 0.33 [95% CI, 0.21 to 0.51]). Median OS was also longer with cabozantinib (20.1 months v 12.1 months; hazard ratio, 0.54 [95% CI, 0.34 to 0.84]), and ORR per IRC was higher (17% v 0%). The rate of skeletal-related events was 23% with cabozantinib and 29% with everolimus, and bone scan response per IRC was 20% versus 10%, respectively. PFS, OS, and ORR were also improved with cabozantinib in patients without bone metastases. Changes in bone biomarkers were greater with cabozantinib than with everolimus. The overall safety profiles of cabozantinib and everolimus in patients with bone metastases were consistent with those observed in patients without bone metastases. Conclusion Cabozantinib treatment was associated with improved PFS, OS, and ORR when compared with everolimus treatment in patients with advanced RCC and bone metastases and represents a good treatment 48. Mechanoresponsive stem cells to target cancer metastases through biophysical cues. PubMed Liu, Linan; Zhang, Shirley X; Liao, Wenbin; Farhoodi, Henry P; Wong, Chi W; Chen, Claire C; Ségaliny, Aude I; Chacko, Jenu V; Nguyen, Lily P; Lu, Mengrou; Polovin, George; Pone, Egest J; Downing, Timothy L; Lawson, Devon A; Digman, Michelle A; Zhao, Weian 2017-07-26 Despite decades of effort, little progress has been made to improve the treatment of cancer metastases. To leverage the central role of the mechanoenvironment in cancer metastasis, we present a mechanoresponsive cell system (MRCS) to selectively identify and treat cancer metastases by targeting the specific biophysical cues in the tumor niche in vivo. Our MRCS uses mechanosensitive promoter-driven mesenchymal stem cell (MSC)-based vectors, which selectively home to and target cancer metastases in response to specific mechanical cues to deliver therapeutics to effectively kill cancer cells, as demonstrated in a metastatic breast cancer mouse model. Our data suggest a strong correlation between collagen cross-linking and increased tissue stiffness at the metastatic sites, where our MRCS is specifically activated by the specific cancer-associated mechano-cues. MRCS has markedly reduced deleterious effects compared to MSCs constitutively expressing therapeutics. MRCS indicates that biophysical cues, specifically matrix stiffness, are appealing targets for cancer treatment due to their long persistence in the body (measured in years), making them refractory to the development of resistance to treatment. Our MRCS can serve as a platform for future diagnostics and therapies targeting aberrant tissue stiffness in conditions such as cancer and fibrotic diseases, and it should help to elucidate mechanobiology and reveal what cells "feel" in the microenvironment in vivo. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. 49. The TGFβ Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone PubMed Central Fournier, Pierrick GJ.; Juárez, Patricia; Jiang, Guanglong; Clines, Gregory A.; Niewolna, Maria; Kim, Hun Soo; Walton, Holly W.; Peng, C. Xiang Hong; Liu, Yunlong; Mohammad, Khalid S.; Wells, Clark D.; Chirgwin, John M.; Guise, Theresa A. 2015-01-01 SUMMARY Transforming growth factor-β (TGFβ) regulates the expression of genes supporting breast cancer cell in bone but little is known about prostate cancer bone metastases and TGFβ. Our study reveals that the TGFBR1 inhibitor SD208 effectively reduces prostate cancer bone metastases. TGFβ upregulates in prostate cancer cells a set of genes associated with cancer aggressiveness and bone metastases, and the most upregulated gene was PMEPA1. In patients, PMEPA1 expression decreased in metastatic prostate cancer and low Pmepa1 correlated with decreased metastasis-free survival. Only membrane-anchored isoforms of PMEPA1 interacted with R-SMADs and ubiquitin ligases, blocking TGFβ signaling independently of the proteasome. Interrupting this negative feedback loop by PMEPA1 knockdown increased prometastatic gene expression and bone metastases in a mouse prostate cancer model. PMID:25982816 50. A definition of "uncomplicated bone metastases" based on previous bone metastases radiation trials comparing single-fraction and multi-fraction radiation therapy. PubMed Cheon, Paul M; Wong, Erin; Thavarajah, Nemica; Dennis, Kristopher; Lutz, Stephen; Zeng, Liang; Chow, Edward 2015-03-01 The most recent systematic review of randomized trials in patients with bone metastases has shown equal efficacy of single fraction (SF) and multiple fraction (MF) palliative radiation therapy in pain relief. It is important to determine the patient population to which the evidence applies. This study aims to examine the eligibility criteria of the studies included in the systematic review to define characteristics of "uncomplicated" bone metastases. Inclusion and exclusion criteria of 21 studies included in the systematic review were compared. Common eligibility criteria were documented in hopes of defining the specific features of a common patient population representative of those in the studies. More than half of the studies included patients with cytological or histological evidence of malignancy. Patients with impending and/or existing pathological fracture, spinal cord compression or cauda equina compression were excluded in most studies. Most studies also excluded patients receiving retreatment to the same site. "Uncomplicated" bone metastases can be defined as: presence of painful bone metastases unassociated with impending or existing pathologic fracture or existing spinal cord or cauda equina compression. Therefore, MF and SF have equal efficacy in patients with such bone metastases. 51. Dissecting the Role of Bone Marrow Stromal Cells on Bone Metastases PubMed Central Buenrostro, Denise; Park, Serk In; Sterling, Julie A. 2014-01-01 Tumor-induced bone disease is a dynamic process that involves interactions with many cell types. Once metastatic cancer cells reach the bone, they are in contact with many different cell types that are present in the cell-rich bone marrow. These cells include the immune cells, myeloid cells, fibroblasts, osteoblasts, osteoclasts, and mesenchymal stem cells. Each of these cell populations can influence the behavior or gene expression of both the tumor cells and the bone microenvironment. Additionally, the tumor itself can alter the behavior of these bone marrow cells which further alters both the microenvironment and the tumor cells. While many groups focus on studying these interactions, much remains unknown. A better understanding of the interactions between the tumor cells and the bone microenvironment will improve our knowledge on how tumors establish in bone and may lead to improvements in diagnosing and treating bone metastases. This review details our current knowledge on the interactions between tumor cells that reside in bone and their microenvironment. PMID:25054153 52. Sex Differences and Bone Metastases of Breast, Lung, and Prostate Cancers: Do Bone Homing Cancers Favor Feminized Bone Marrow? PubMed Central Farach-Carson, Mary C.; Lin, Sue-Hwa; Nalty, Theresa; Satcher, Robert L. 2017-01-01 Sex-associated differences in bone metastasis formation from breast, lung, and prostate cancer exist in clinical studies, but have not been systematically reviewed. Differences in the bone marrow niche can be attributed to sexual dimorphism, to genetic variations that affect sex hormone levels, or to the direct effects of sex hormones, natural or exogenously delivered. This review describes the present understanding of sex-associated and sex hormone level differences in the marrow niche and in formation of bone metastasis during the transition of these three cancers from treatable disease to an often untreatable, lethal metastatic one. Our purpose is to provide insight into some underlying molecular mechanisms for hormonal influence in bone metastasis formation, and to the potential influence of sexual dimorphism, genetic differences affecting sex assignment, and sex hormone level differences on the bone niche and its favorability for metastasis formation. We reviewed publications in PubMed and EMBASE, including full length manuscripts, case reports, and clinical studies of relevance to our topic. We focused on bone metastasis formation in breast, lung, and prostate cancer because all three commonly present with bone metastases. Several clear observations emerged. For breast cancer bone metastasis formation, estrogen receptor (ER) signaling pathways indicate a role for ER beta (ERβ). Estrogen influences the bone microenvironment, creating and conditioning a favorable niche for colonization and breast cancer progression. For lung cancer, studies support the hypothesis that females have a more favorable bone microenvironment for metastasis formation. For prostate cancer, a decrease in the relative androgen to estrogen balance or a “feminization†of bone marrow favors bone metastasis formation, with a potentially important role for ERβ that may be similar to that in breast cancer. Long-term estrogen administration or androgen blockade in males may feminize the 53. [Pain therapy in multiple bone metastases in breast carcinoma with rhenium 186 HEDP]. PubMed Hauswirth, A E; Palmedo, H; Dierke-Dzierzon, C; Biersack, H J; Krebs, D 1998-01-01 Therapeutic means for patients with disseminated painful bone metastases in breast cancer are strongly limited. There is a big need of an effective and well tolerated therapy. The aim of this study was to evaluate the efficacy of rhenium-186 HEDP for pain palliation in patients with bone metastases in breast cancer. 17 patients with painful bone metastases taking analgesics received one or more injections of 1295 MB9 rhenium-186 HEDP. In 59% of the patients the therapy resulted in a significant reduction of pain. The duration of pain relief partially hold on up to nine weeks. The main side effects of therapy were a short decrease of platelets and leucocytes and an increase of pain for 1-2 days. As conclusion we found out that therapy with rhenium-186 HEDP can be used complementarily to analgesic therapy and radiation in patients with painful disseminated bone metastases in breast cancer. 54. Sclerosing epithelioid fibrosarcoma of the thigh: report of two cases with synchronous bone metastases. PubMed Righi, A; Gambarotti, M; Manfrini, M; Benini, S; Gamberi, G; Cocchi, S; Casadei, R; Picci, P; Vanel, D; Dei Tos, A P 2015-09-01 We report two cases of sclerosing epithelioid fibrosarcoma occurring in the deep soft tissue of the thigh, confirmed by molecular analysis and associated with bone metastases in the lumbar vertebrae and the iliac wing at the time of diagnosis. Synchronous bone metastases of sclerosing epithelioid fibrosarcoma are extremely difficult to diagnose because clinical and radiological features are not specific. In addition, the range of differential diagnoses is very wide, including metastatic carcinoma and osteosarcoma. At present, all but three published cases of sclerosing epithelioid fibrosarcoma with bone metastases showed bone metastases during follow-up. We confirm in our two cases that the distinct pattern of immunohistochemical staining for MUC4, associated with the absence of staining for both SATB2, a marker of osteoblastic differentiation, and pan-cytokeratin, allows differentiating between sclerosing epithelioid fibrosarcoma and metastatic carcinoma or osteosarcoma. 55. Uveal Melanoma: Identifying Immunological and Chemotherapeutic Targets to Treat Metastases. PubMed Jager, Martine J; Dogrusöz, Mehmet; Woodman, Scott E 2017-01-01 Uveal melanoma is an intraocular malignancy that, depending on its size and genetic make-up, may lead to metastases in up to 50% of cases. Currently, no therapy has been proven to improve survival. However, new therapies exploiting immune responses against metastases are being developed. The primary tumor is well characterized: tumors at high risk of developing metastases often contain macrophages and lymphocytes. However, these lymphocytes are often regulatory T cells that may suppress immune response. Currently, immune checkpoint inhibitors have shown marked efficacy in multiple cancers (eg, cutaneous melanoma) but do not yet improve survival in uveal melanoma patients. More knowledge needs to be acquired regarding the function of T cells in uveal melanoma. Other therapeutic options are related to the biochemical pathways. Targeting the RAF-MEKERK pathway with small molecule MEK inhibitors abrogates the growth of UM cells harboring GNAQ/GNA11 Q209 mutations, suggesting that these aberrant G-protein oncogenes mediate, at least in part, their effect through this hallmark proliferation pathway. Other pathways are also implicated, such as those involving c-Jun and YAP. Further studies may show how interference in the different pathways may affect survival. Copyright 2017 Asia-Pacific Academy of Ophthalmology. 56. The Breast Cancer to Bone (B2B) Metastases Research Program: a multi-disciplinary investigation of bone metastases from breast cancer. PubMed Brockton, Nigel T; Gill, Stephanie J; Laborge, Stephanie L; Paterson, Alexander H G; Cook, Linda S; Vogel, Hans J; Shemanko, Carrie S; Hanley, David A; Magliocco, Anthony M; Friedenreich, Christine M 2015-07-10 Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases. These include the impact of lifestyle factors and inflammation on risk of bone metastases, the gene expression features of the primary tumour, the potential role for metabolomics in early detection of bone metastatic disease and the signalling pathways that drive the metastatic lesions in the bone. The B2B Research Program is enrolling a prospective cohort of 600 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a five year period. At baseline, pre-treatment/surgery blood samples are collected and detailed epidemiologic data is collected by in-person interview and selfadministered questionnaires. Additional self-administered questionnaires and blood samples are completed at specified follow-up intervals (24, 48 and 72 months). Vital status is obtained prior to each follow-up through record linkages with the Alberta Cancer Registry. Recurrences are identified through medical chart abstractions. Each of the four projects applies specific methods and analyses to assess the impact of serum vitamin D and cytokine concentrations, tumour transcript and protein expression, serum metabolomic profiles and in vitro cell signalling on breast cancer bone metastases. The B2B Research Program will address key issues in breast cancer bone metastases including the association between lifestyle factors (particularly a comprehensive assessment of vitamin D status) inflammation and bone metastases, the significance or primary tumour gene expression in tissue tropism, the 57. Efficacy of Magnetic Resonance-guided Focused Ultrasound Surgery for Bone Metastases Pain Palliation NASA Astrophysics Data System (ADS) Kawasaki, Motohiro; Nanba, Hirofumi; Kato, Tomonari; Tani, Toshikazu; Ushida, Takahiro 2011-09-01 Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a novel treatment method that achieves non-invasive thermal ablation by focusing many ultrasound waves on a target tissue with real-time monitoring of the location and temperature of the target during the procedure. We investigated the palliative effect on pain and safety of MRgFUS in painful bone metastases. Six patients (mean age, 65.8 years) who met eligibility criteria for the clinical study approved by our Institutional Ethics Committee based on the cooperative protocol were treated with MRgFUS. Targeted sites included the sacrum (n = 1), ilium (n = 2), scapula (n = 2), and femur (n = 1). The mean follow-up period was 9.2 months. All procedures were performed as a single-session treatment using the treatment system that is integrated into the patient table of a magnetic resonance image (MRI) scanner. Endpoints were change in the intensity of pain due to bone metastases from before to after the treatment, as measured on a numerical rating scale, pain interference with daily activities as determined by the Brief pain inventory (BPI), change in images, and safety. Pain relief was obtained in all patients early after treatment, with a reduction in the mean pain score from 6.0±1.3 at baseline to 1.2±1.0 at the end of follow-up as well as in pain interference with daily activities. The mean time required for a single-session treatment was 83.7±37.0 min, with a mean number of sonications required of 13.3±3.7 and mean energy applied of 846.4±273.5 J. No significant growth of tumors was observed, nor were there treatment-related adverse events. These results suggest that MRgFUS has a non-invasive palliative effect on the localized pain in patients with bone metastasis. MRgFUS could become an option in treatment strategies for painful bone metastases in the future. 58. Bony expansion in skeletal metastases from carcinoma of the prostate as seen by bone scintigraphy SciTech Connect Resnik, C.S.; Garver, P.; Resnick, D. 1984-10-01 Carcinoma of the prostate often metastasizes to the skeletal system, the usual radiologic pattern being widespread patchy areas of increased density without change in the contour of the involved bones. Radionuclide correlation generally shows multiple foci of increased tracer activity. Less commonly, there is bony sclerosis with expansion of the diameter of the involved bone. Several cases of expansile skeletal metastases from carcinoma of the prostate have appeared in the literature but we know of no published descriptions of the radionuclide findings. We present three patients with carcinoma of the prostate who had skeletal metastases with evidence of bony expansion on both roentgenographic and radionuclide examination. 15 references, 8 figures. 59. Validation of International Classification of Diseases coding for bone metastases in electronic health records using technology-enabled abstraction PubMed Central Liede, Alexander; Hernandez, Rohini K; Roth, Maayan; Calkins, Geoffrey; Larrabee, Katherine; Nicacio, Leo 2015-01-01 Objective The accuracy of bone metastases diagnostic coding based on International Classification of Diseases, ninth revision (ICD-9) is unknown for most large databases used for epidemiologic research in the US. Electronic health records (EHR) are the preferred source of data, but often clinically relevant data occur only as unstructured free text. We examined the validity of bone metastases ICD-9 coding in structured EHR and administrative claims relative to the complete (structured and unstructured) patient chart obtained through technology-enabled chart abstraction. Patients and methods Female patients with breast cancer with ≥1 visit after November 2010 were identified from three community oncology practices in the US. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of bone metastases ICD-9 code 198.5. The technology-enabled abstraction displays portions of the chart to clinically trained abstractors for targeted review, thereby maximizing efficiency. We evaluated effects of misclassification of patients developing skeletal complications or treated with bone-targeting agents (BTAs), and timing of BTA. Results Among 8,796 patients with breast cancer, 524 had confirmed bone metastases using chart abstraction. Sensitivity was 0.67 (95% confidence interval [CI] =0.63–0.71) based on structured EHR, and specificity was high at 0.98 (95% CI =0.98–0.99) with corresponding PPV of 0.71 (95% CI =0.67–0.75) and NPV of 0.98 (95% CI =0.98–0.98). From claims, sensitivity was 0.78 (95% CI =0.74â €“0.81), and specificity was 0.98 (95% CI =0.98–0.98) with PPV of 0.72 (95% CI =0.68–0.76) and NPV of 0.99 (95% CI =0.98–0.99). Structured data and claims missed 17% of bone metastases (89 of 524). False negatives were associated with measurable overestimation of the proportion treated with BTA or with a skeletal complication. Median date of diagnosis was delayed in structured data (32 days) and claims (43 60. Elderly Patients With Painful Bone Metastases Should be Offered Palliative Radiotherapy SciTech Connect Campos, Sarah; Presutti, Roseanna; Zhang Liying; Salvo, Nadia; Hird, Amanda; Tsao, May; Barnes, Elizabeth A.; Danjoux, Cyril; Sahgal, Arjun; Mitera, Gunita; Sinclair, Emily; DeAngelis, Carlo; Nguyen, Janet; Napolskikh, Julie; Chow, Edward 2010-04-15 Purpose: To investigate the efficacy of palliative radiotherapy (RT) in relieving metastatic bone pain in elderly patients. Methods and Materials: The response to RT for palliation of metastatic bone pain was evaluated from a prospective database of 558 patients between 1999 and 2008. The pain scores and analgesic intake were used to calculate the response according to the International Bone Metastases Consensus Working Party palliative RT endpoints. Subgroup analyses for age and other demographic information were performed. Results: No significant difference was found in the response rate in patients aged >=65, >=70, and >=75 years compared with younger patients at 1, 2, or 3 months after RT. The response was found to be significantly related to the performance status. Conclusion: Age alone did not affect the response to palliative RT for bone metastases. Elderly patients should be referred for palliative RT for their painful bone metastases, regardless of age, because they receive equal benefit from the treatment. « 1 2 3 4 5 » « 2 3 4 5 6 » 61. [Clinical features and prognosis in 104 colorectal cancer patients with bone metastases]. PubMed Hong, Ruo-xi; Lin, Qiu-ju; Luo, Jian; Dai, Zhen; Wang, Wen-na 2013-10-01 To investigate the clinical features and prognosis of bone metastases in colorectal cancer patients. The clinical data of 104 cases of colorectal cancer with bone metastasis were collected and retrospectively analyzed. Among all the 104 patients included, 45 (43.3%) patients had multiple bone metastases, and 59 (56.7%) patients had single bone metastasis. Pelvis (46.1%) was the most common site, followed by thoracic vertebrae (41.3%), lumbar vertebrae (40.4%), sacral vertebrae (29.8%) and ribs (29.8%). One hundred and two patients (98.1%) were complicated with other organ metastases. The median time from colorectal cancer diagnosis to bone metastasis was 16 months, and the median time from bone metastasis to first skeletal-related events (SREs) was 1 month. The most common skeletal-related events (SREs) were the need for radiotherapy (44.2%), severe bone pain (15.4%) and pathologic fracture (9.6%). The median survival time of patients with bone metastases was 10.0 months, and 8.5 months for patients with SREs. ECOG score, systemic chemotherapy and bisphosphonate therapy were prognostic factors by univariate analysis (all P < 0.05). ECOG score and systemic chemotherapy were independent prognostic factors by Cox multivariate analysis. Bone metastasis in colorectal cancer patients has a poor prognosis and the use of chemotherapy and bisphosphonates may have a benefit for their survival.
62. Evaluating the Potential of Adipose Tissue-Derived MSCs as Anticancer Gene Delivery Vehicles to Bone-Metastasized Prostate Cancer DTIC Science & Technology 2010-04-01 W81XWH-09-1-0195 TITLE: Evaluating the Potential of Adipose Tissue-Derived MSCs as Anticancer Gene Delivery Vehicles to Bone-Metastasized...SUBTITLE 5a. CONTRACT NUMBER PC080811 Evaluating the Potential of Adipose Tissue-Derived MSCs as Anticancer Gene Delivery Vehicles to Bone-Metastasized...have tumor-homing potential and can be used to deliver anti-cancer genes to bone metastasized prostate cancer (PCa) cells. The ease of isolation 63. Disseminated tumor cells in the bone marrow negatively influence survival after resection of colorectal liver metastases. PubMed Hinz, Sebastian; Bockhorst, Jessica; Röder, Christian; Egberts, Jan-Hendrik; Schafmayer, Clemens; Küchler, Thomas; Becker, Thomas; Kalthoff, Holger 2012-08-01 Despite all efforts in extending the resectability rates of colorectal liver metastases, thus improving the prognosis of the patients, tumor recurrence occurs in many patients. Occult dissemination of tumor cells might reflect a minimal residual disease that is not eliminated by primary surgery. Because the prognostic effect of disseminated tumor cells (DTC) is still uncertain in this clinical setting, we analyzed these cells in the peripheral blood and bone marrow of patients undergoing hepatic resection of colorectal liver metastases. In 108 patients with colorectal liver metastases, the presence of DTC in the peripheral blood and bone marrow was detected with CK20 RT-PCR. Clinical data were prospectively collected, and multiple variables were analyzed regarding their influence on overall survival. DTC in the peripheral blood were detected in 40% of the patients. In 25% of the patients, DTC were detected in the bone marrow. The median follow-up was 34 months. Fifty-nine of 108 patients died from tumor relapse. Multivariate analysis determined detection of DTC in the bone marrow to be an independent prognostic factors for overall survival (P = 0.038). This large series of patients with hepatic resection of colorectal liver metastases demonstrated that detection of CK20-positive DTC via RT-PCR in the bone marrow compartment negatively influences overall survival. The evidence of DTC in the bone marrow might serve as an additional individual marker to select patients for adjuvant treatment after liver metastases resection. 64. Bone Sarcomas: From Biology to Targeted Therapies PubMed Central Gaspar, Nathalie; Di Giannatale, Angela; Geoerger, Birgit; Redini, Françoise; Corradini, Nadège; Enz-Werle, Natacha; Tirode, Franck; Marec-Berard, Perrine; Gentet, JeanClaude; Laurence, Valérie; Piperno-Neumann, Sophie; Oberlin, Odile; Brugieres, Laurence 2012-01-01 Primary malignant bone tumours, osteosarcomas, and Ewing sarcomas are rare diseases which occur mainly in adolescents and young adults. With the current therapies, some patients remain very difficult to treat, such as tumour with poor histological response to preoperative CT (or large initial tumour volume for Ewing sarcomas not operated), patients with multiple metastases at or those who relapsed. In order to develop new therapies against these rare tumours, we need to unveil the key driving factors and molecular abnormalities behind the malignant characteristics and to broaden our understanding of the phenomena sustaining the metastatic phenotype and treatment resistance in these tumours. In this paper, starting with the biology of these tumours, we will discuss potential therapeutic targets aimed at increasing local tumour control, limiting metastatic spread, and finally improving patient survival. PMID:23226965 65. Bone metabolism markers: Indicators of loading dose intravenous ibandronate treatment for bone metastases from breast cancer. PubMed Wang, Ruliang; Zhang, Shaohua; Jiang, Zefei; Tian, Jizheng; Wang, Tao; Song, Santai 2017-01-01 To investigate the changes in bone metabolism markers after second-line treatment with loading dose intravenous (i.v.) ibandronate in patients with bone metastases (BM) from breast cancer, 80 patients were enrolled in this study during January 2010 to April 2014. All the patients were treated with a second-line loading dose ibandronate for advanced breast cancer with BM and moderate-to-severe bone pain. Ibandronate (6 mg) was intravenously administered on three consecutive days followed by maintenance treatment every 34 weeks. Clinical data, including pain score, Karnofsky performance status (KPS) score, and changes in bone metabolism markers, were analyzed. Sixty-two patients were included in the final analysis. Compared with their pre-treatment scores, patients exhibited significantly increased KPS scores (P < .01) and a reduced dose of analgesic medication (oxycodone) (P < .01) after 3 and 6 weeks' post-treatment. The levels of serum bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase (TRACP-5b), and cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) were significantly reduced after 3 and 6 weeks' post-treatment (P < .001). Aside from a few adverse events, no liver or renal toxicity was observed. Bone metabolism markers decreased by varying degrees after treatment with a loading dose of ibandronate in patients with BM from breast cancer. It might be convenient using bone metabolism markers to potentially evaluate the efficacy of bisphosphonates treatment for bone metastasis. © 2016 John Wiley & Sons Australia, Ltd. 66. Palliative Radiotherapy for Bone Metastases: An ASTRO Evidence-Based Guideline SciTech Connect Lutz, Stephen; Berk, Lawrence; Chang, Eric; Chow, Edward; Hahn, Carol; Hoskin, Peter; Howell, David; Konski, Andre; Kachnic, Lisa; Lo, Simon; Sahgal, Arjun; Silverman, Larry; Gunten, Charles von; Mendel, Ehud; Vassil, Andrew; Bruner, Deborah Watkins; Hartsell, William 2011-03-15 Purpose: To present guidance for patients and physicians regarding the use of radiotherapy in the treatment of bone metastases according to current published evidence and complemented by expert opinion. Methods and Materials: A systematic search of the National Library of Medicine's PubMed database between 1998 and 2009 yielded 4,287 candidate original research articles potentially applicable to radiotherapy for bone metastases. A Task Force composed of all authors synthesized the published evidence and reached a consensus regarding the recommendations contained herein. Results: The Task Force concluded that external beam radiotherapy continues to be the mainstay for the treatment of pain and/or prevention of the morbidity caused by bone metastases. Various fractionation schedules can provide significant palliation of symptoms and/or prevent the morbidity of bone metastases. The evidence for the safety and efficacy of repeat treatment to previously irradiated areas of peripheral bone metastases for pain was derived from both prospective studies and retrospective data, and it can be safe and effective. The use of stereotactic body radiotherapy holds theoretical promise in the treatment of new or recurrent spine lesions, although the Task Force recommended that its use be limited to highly selected patients and preferably within a prospective trial. Surgical decompression and postoperative radiotherapy is recommended for spinal cord compression or spinal instability in highly selected patients with sufficient performance status and life expectancy. The use of bisphosphonates, radionuclides, vertebroplasty, and kyphoplasty for the treatment or prevention of cancer-related symptoms does not obviate the need for external beam radiotherapy in appropriate patients. Conclusions: Radiotherapy is a successful and time efficient method by which to palliate pain and/or prevent the morbidity of bone metastases. This Guideline reviews the available data to define its proper use 67. EANM guidelines for radionuclide therapy of bone metastases with beta-emitting radionuclides. PubMed Handkiewicz-Junak, Daria; Poeppel, Thorsten D; Bodei, Lisa; Aktolun, Cumali; Ezziddin, Samer; Giammarile, Francesco; Delgado-Bolton, Roberto C; Gabriel, Michael 2018-02-16 The skeleton is the most common metastatic site in patients with advanced cancer. Pain is a major healthcare problem in patients with bone metastases. Bone-seeking radionuclides that selectively accumulate in the bone are used to treat cancer-induced bone pain and to prolong survival in selected groups of cancer patients. The goals of these guidelines are to assist nuclear medicine practitioners in: (a) evaluating patients who might be candidates for radionuclide treatment of bone metastases using beta-emitting radionuclides such as strontium-89 ( 89 Sr), samarium-153 ( 153 Sm) lexidronam ( 153 Sm-EDTMP), and phosphorus-32 ( 32 P) sodium phosphate; (b) performing the treatments; and ©) understanding and evaluating the treatment outcome and side effects. 68. Statins may decrease skeletal-related events in breast cancer patients with bone metastases. PubMed Dincer, Murat; Bulut, Nilufer; Harputluoglu, Hakan; Altundag, Kadri 2006-01-01 Metastasis to the skeleton frequently occurs in breast carcinoma patients resulting in different skeletal-related events including pain, hypercalcemia, pathological fracture, and spinal cord or nerve root compression. Bisphosphonates are class of agents most frequently used to reduce skeletal-related events in patients with bone metastases by inhibiting osteoclast activity through inhibition of mevolanate pathway which is also important in cholesterol synthesis. Statins are cholesterol lowering agents and inhibit the same pathway. Therefore statins may also reduce skeletal-related events in breast cancer patients with bone metastases by inhibiting osteoclastic activity. 69. Effect of a High Bone Turnover State Induced by Estrogen Deficiency on the Development and Progression of Breast Cancer Metastases DTIC Science & Technology 2007-04-01 metastases, breast cancer, ovariectomy , bisphosphonates, zoledronic acid 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF...induced by ovariectomy (OVX), on the development and progression of human breast cancer metastases to bone in a mouse model (hypothesis 1...Rosen C and Guise TA. 2005 Aromatase inhibition causes lower bone density than ovariectomy in mice, an effect prevented by bisphosphonates. Journal 70. Effect of Bone Reading CT software on radiologist performance in detecting bone metastases from breast cancer. PubMed Ha, Ji Y; Jeon, Kyung N; Bae, Kyungsoo; Choi, Bong H 2017-04-01 To evaluate the effect of CT software that generates rib unfolding images and automatically numbers ribs and thoracic spines on radiologist performance in detecting thoracic bone metastases from breast cancer. A total of 126 patients with breast cancer who underwent chest CT and fludeoxyglucose (FDG)-positron emission tomography (PET)/CT and/or bone scans were retrospectively reviewed. One board-certified radiologist (R1) and one radiology resident (R2) independently assessed the original chest CT and rib unfolding images using a commercially available post-processing software (Bone Reading) application to evaluate metastasis in the ribs and thoracic spines. Results were compared with reference standard based on CT, FDG-PET/CT and/or bone scan with follow-up. Based on reference standard, 78 metastatic bone lesions in 26 patients were identified. On per-patient-based analysis, Bone Reading assessed by R1/R2 had a sensitivity of 84.6%/80.8% and a specificity of 94.0%/94.0% with an accuracy of 92.1%/91.3%. The original CT reading yielded a sensitivity of 73.1%/57.7% and a specificity of 95.0%/94.0% with an accuracy of 90.5%/86.5%. The sensitivity and accuracy of Bone Reading were significantly higher than those of CT reading, as assessed by R2 (both p = 0.031). On per-lesion-based analysis, Bone Reading assessed by R1/R2 yielded a sensitivity of 84.6%/82.1% and a specificity of 99.7%/99.6% with an accuracy of 99.4%/99.3%, while the original CT reading yielded a sensitivity of 71.8%/62.8% and a specificity of 99.6%/99.5% with an accuracy of 99.2%/98.9%. The sensitivity and accuracy with Bone Reading application were significantly higher than those with CT reading by both readers (R1, p = 0.006 and p†‰= 0.036, respectively; R2, both p < 0.001). The mean reading time needed for Bone Reading application was significantly shorter than that for original chest CT reading (p < 0.001). Bone Reading application helped readers find small and sclerotic lesions 71. Effect of a High Bone Turnover State Induced by Estrogen Deficiency on the Development and Progression of Breast Cancer Bone Metastases DTIC Science & Technology 2006-04-01 treatments on bone quality. 15. SUBJECT TERMS aromatase inhibitors, letrozole, bone metastases, breast cancer, ovariectomy , bisphosphonates, zoledronic...effects of estrogen deficiency, induced by ovariectomy (OVX), on the development and progression of human breast cancer metastases to bone in a...53. • W.M. Kozlow, K. Mohammad, R. McKenna, M. Niewolna and T.A. Guise. Aromatase inhibition results in lower bone density than ovariectomy in mice 72. Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods SciTech Connect Guerra Liberal, Francisco D. C., E-mail:
[email protected], E-mail:
[email protected]; Tavares, Adriana Alexandre S., E-mail:
[email protected], E-mail:
[email protected]; Tavares, João Manuel R. S., E-mail:
[email protected] 2014-11-01 Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bonemore » metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 ({sup 32}P), strontium-89 ({sup 89}Sr), yttrium-90 ({sup 90}Y ), tin-117 ({sup 117m}Sn), samarium-153 ({sup 153}Sm), holmium-166 ({sup 166}Ho), thulium170 ({sup 170}Tm), lutetium-177 ({sup 177}Lu), rhenium-186 ({sup 186}Re), rhenium-188 ({sup 188}Re), and radium-223 ({sup 223}Ra). Results: {sup 223}Ra alpha particles, {sup 177}Lu beta minus particles, and {sup 170}Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by {sup 89}Sr and {sup 153}Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than {sup 177}Lu beta minus particles and {sup 223}Ra alpha particles. Conclusions: {sup 223}Ra and {sup 177}Lu hold the highest potential for palliative treatment of bone metastases of 73. [Benign metastasizing leiomyoma: An unusual cause of aggressive femoral bone tumor]. PubMed Alexandre, L; Taillieu, F; Arlet, J-B; Passeron, A; Michon, A; Bats, A-S; Pouchot, J; Ranque, B 2018-03-01 Benign metastasizing leiomyoma (BML) is a rare condition characterized by histologically benign "metastatic" smooth muscle tumors, which can affect women with history of uterine surgery. We report the case of a patient with bone metastases of BML. A 78-year-old woman who had undergone uterine surgery six years before hospital admission, was diagnosed with large pulmonary and pleural metastases that necessitated surgical removal. Pathological examination allowed the diagnosis of BML with positive staining for estrogen and progesterone receptors. Three years later, a BML metastasis in the right femoral diaphysis was unexpectedly discovered and treated by osteosynthesis because of a high risk of fracture. Despite an aromatase-inhibitor treatment, new lungs lesions appeared in the next few months. BML is a potential cause of aggressive, although histologically benign, bone tumor in women with a history of uterine surgery. Copyright © 2018. Published by Elsevier SAS. 74. Biochemical markers for assessment of bone metastases in patients with breast cancer. PubMed Hou, M F; Tsai, L Y; Tsai, S M; Huang, C J; Huang, Y S; Hsieh, J S; Chan, H M; Wang, J Y; Chuang, C H; Chen, F M; Huang, T J 1999-08-01 Breast cancer commonly metastasizes to bones, producing both osteolytic and osteoblastic deposits. Different markers for quantitative determination of bone turnover have been developed to evaluate bone metastases of breast cancer. The urinary deoxypyridinoline (Dpd), a crosslink product of collagen molecules found in bone and excreted in urine during bone degradation, and bone specific alkaline phosphatase (B-ALP), an isoenzyme localized in the membrane of osteoblasts and released in circulation during bone formation, were recently described as a group of markers of bone turnover in metastatic cancer. The urinary Dpd/creatinine (Cre) ratios and the serum B-ALP activity were determined in the samples from 148 patients who suffered from breast cancer (BC patients) with or without bone metastases, and 42 healthy women. For comparison, other biochemical markers, e.g. carcinoembryonic antigen (CEA), CA15-3, tissue polypeptide antigen (TPA), tissue polypeptide specific antigen (TPSA), and total alkaline phosphatase (T-ALP) in these samples were also evaluated. The results showed that there was a significant difference in urinary Dpd/Cre ratio between the control group and the patients with breast cancer (BC group) (mean +/- S.D., 5.69 +/- 1.26 vs. 8.19 +/- 3.95 nM/mM, P < 0.05). However, there was no significant difference between their B-ALP activities in the two groups. In addition, the BC patients with bone metastases showed elevated urinary Dpd/Cre ratios and B-ALP activities and ratios of (Dpd/Cre)/B-ALP in compare with BC patients without bone metastases (P < 0.05). Meanwhile, the urinary Dpd/Cre ratios (10.50 +/- 5.04 nmol/mmol) in the advanced stage of BC patients were higher than those in an early stage (7.45 +/- 3.23 nmol/mmol) (P < 0.05), but their serum B-ALP activities increased only in stage IV (P < 0.05). The urinary Dpd/Cre ratios also increased progressively according to the degree of bone metastases (P < 0.05), but their serum B-ALP activities only 75. Tumor Response After Stereotactic Body Radiation Therapy to Nonspine Bone Metastases: An Evaluation of Response Criteria SciTech Connect McDonald, Rachel; Probyn, Linda; Poon, Ian 2015-11-15 Purpose: To evaluate the applicability of the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and University of Texas MD Anderson (MDA) Cancer Center criteria in the setting of stereotactic body radiation therapy (SBRT) to nonspine bone metastases. Methods: Patients who were treated with SBRT to nonspine bone metastases were identified by retrospective chart review. An independent musculoskeletal radiologist evaluated response to treatment using computed tomography (CT) scans. Results: Thirty-three patients were treated to 42 nonspine bone metastases. The most common primary cancer cites were renal cell carcinoma (RCC) (33.3%), lung (24.2%), and prostate (18.2%). Bone metastases were either mainlymore » lytic (57.1%), mainly sclerotic (28.6%), or mixed (14.3%). When lytic and sclerotic lesions were evaluated according to RECIST 1.1, local control (LC) was 83%, 85%, 88%, and 80% for those with CT imaging between months 1 to 3, 4 to 6, 7 to 9, and 10 to 12, respectively. When evaluated by the MDA criteria by density, LC within each time period was slightly greater. Overall LC decreased considerably when evaluated by MDA in terms of size. Conclusions: Consensus definitions of response are required as they have implications on clinical trials and disease management. Without consistent response criteria, outcomes from clinical trials cannot be compared and treatment efficacy remains undetermined.« less 76. Tumor Response After Stereotactic Body Radiation Therapy to Nonspine Bone Metastases: An Evaluation of Response Criteria SciTech Connect McDonald, Rachel; Probyn, Linda; Poon, Ian; Erler, Darby; Brotherston, Drew; Soliman, Hany; Cheung, Patrick; Chung, Hans; Chu, William; Loblaw, Andrew; Thavarajah, Nemica; Lang, Catherine; Chin, Lee; Chow, Edward; Sahgal, Arjun 2015-11-15 Purpose: To evaluate the applicability of the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and University of Texas MD Anderson (MDA) Cancer Center criteria in the setting of stereotactic body radiation therapy (SBRT) to nonspine bone metastases. Methods: Patients who were treated with SBRT to nonspine bone metastases were identified by retrospective chart review. An independent musculoskeletal radiologist evaluated response to treatment using computed tomography (CT) scans. Results: Thirty-three patients were treated to 42 nonspine bone metastases. The most common primary cancer cites were renal cell carcinoma (RCC) (33.3%), lung (24.2%), and prostate (18.2%). Bone metastases were either mainly lytic (57.1%), mainly sclerotic (28.6%), or mixed (14.3%). When lytic and sclerotic lesions were evaluated according to RECIST 1.1, local control (LC) was 83%, 85%, 88%, and 80% for those with CT imaging between months 1 to 3, 4 to 6, 7 to 9, and 10 to 12, respectively. When evaluated by the MDA criteria by density, LC within each time period was slightly greater. Overall LC decreased considerably when evaluated by MDA in terms of size. Conclusions: Consensus definitions of response are required as they have implications on clinical trials and disease management. Without consistent response criteria, outcomes from clinical trials cannot be compared and treatment efficacy remains undetermined. 77. Stromal Gene Expression and Function in Primary Breast Tumors that Metastasize to Bone Cancer DTIC Science & Technology 2006-07-01 cerevisiae) 1428725_at 4.91E-05 0.487 Mus musculus adult male medulla oblongata cDNA TASK 2: Verify expression of differentially expressed genes found...whose expression is different between the highly aggressive bone metastasizing lines (4T1.2 and 4T1.13) and the poorly metastatic lines 6 (66cl4 78. Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases SciTech Connect Chow, Edward; Hoskin, Peter; Mitera, Gunita; Zeng Liang; Lutz, Stephen; Roos, Daniel; Hahn, Carol; Linden, Yvette van der; Hartsell, William; Kumar, Eshwar 2012-04-01 Purpose: To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time. Methods and Materials: A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadian Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey. Results: Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments. Conclusion: An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis. 79. Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases SciTech Connect Chow, Edward, E-mail:
[email protected]; Hoskin, Peter; Mitera, Gunita 2012-04-01 Purpose: To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time. Methods and Materials: A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadianmore » Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey. Results: Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments. Conclusion: An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis.« less 80. Clinical and biologic behavior of bone metastases from differentiated thyroid carcinoma SciTech Connect Marcocci, C.; Pacini, F.; Elisei, R.; Schipani, E.; Ceccarelli, C.; Miccoli, P.; Arganini, M.; Pinchera, A. ) 1989-12-01 Thirty (3.8%) of 780 patients with differentiated thyroid cancer seen between 1970 and 1987 had bone metastases. The primary tumor was follicular in 26 patients and papillary in four. Mean age at diagnosis was 61 years. The manifestation of bone metastases was the presenting symptom in 18 patients (60%). Treatment included total thyroidectomy, levothyroxine sodium therapy, and radioactive iodine treatments. Twenty-seven patients had bone metastases from the initial observation, with 44 sites involved. Of the sites, 27 (61%) were shown both on iodine 131 whole-body scan (WBS) and on x-ray film, 11 (25%) only on WBS, and six (14%) only on x-ray film. Multiple involvement was observed in 11 patients. The radiologic appearance was invariably osteolytic. Serum thyroglobulin was elevated in all patients. After radioactive iodine, no WBS+/X-ray+ metastases showed a complete response, although a sclerotic border was noted in several cases, whereas six WBS+/X-ray- lesions were no longer detectable by WBS. Treatment with radioactive iodine and bone surgery resulted in a complete cure in three patients and in a reduction of tumor mass in three. Twenty-one (70%) of the patients died of thyroid cancer after a mean survival of 86 months. Of the nine patients still alive, two are free of disease, three have a good quality of life, and four have severe disability. « 2 3 4 5 6 » « 3 4 5 6 7 » 81. Cross-linked type I collagen C- and N-telopeptides in women with bone metastases from breast cancer. PubMed Ulrich, U; Rhiem, K; Schmolling, J; Flaskamp, C; Paffenholz, I; Sälzer, H; Bauknecht, T; Schlebusch, H 2001-01-01 This study documents values of biochemical markers of bone remodeling in 106 patients with breast cancer. Based on scintigraphic and radiological findings, patients were divided into 3 groups: 19 patients with bone metastases, 65 patients without bone metastases and normal bone scintigrams, and 22 patients with pathological, non-malignant findings on scintigraphy without proof of bone metastases. Urinary cross-linked type I collagen N-telopeptides (NTx) and serum cross-linked type I collagen C-telopeptides (ICTP) were assessed as markers of bone resorption. Bone alkaline phosphatase (BAP) was assessed as a marker of bone formation. All three markers were significantly higher in patients with bone metastases compared to both patients without skeletal recurrence and those with pathological, non-malignant scintigraphic findings (p < 0.01). There were no statistically significant differences between the latter two groups. The clinical sensitivity for diagnosing bone metastases was 44% for NTx, 65% for ICTP, and 26% for BAP, respectively. The clinical specificitiy for discriminating patients with bone disease from those without were 79%, 91%, and 92% for NTx, ICTP, and BAP, respectively. In conclusion, markers of bone remodeling are increased in patients with breast cancer metastatic to the skeleton. The sensitivity of the markers presented in this paper did not seem to be sufficient enough for early identification of patients with subclinical bone recurrence in a clinical practice setting. 82. Bone metastases in soft tissue sarcoma: a survey of natural history, prognostic value and treatment options PubMed Central 2013-01-01 Background We surveyed the natural history of bone metastases in patients affected by soft tissue sarcoma (STS). Methods This multicenter retrospective observational study included 135 patients. Histological subtype, characteristics of bone metastases, treatment, skeletal related events (SREs) and disease outcome were recorded. Results The most represented histological subtypes were leiomyosarcoma (27%) angiosarcoma (13%) and undifferentiated sarcoma (8%). Axial skeleton was the most common site for bone involvement (70%). In 27% of cases, bone metastases were present at the time of diagnosis. Fifty-four (40%) patients developed SREs and the median time to first SRE was 4†‰months (range 1–9). The most common SRE was the need for radiotherapy (28%) followed by pathological fracture (22%). Median survival after bone progression was 6†‰months (range 1–14). SREs were associated with decreased overall survival (OS) (P = 0.04). A subgroup analysis revealed that bisphosphonates significantly prolonged median time to first SRE (5 versus 2 months; P = 0.002) while they did not determine an improvement in OS, although a favourable trend was identified (median: 7 versus 5 months; P = 0.105). Conclusions This study illustrates the burden of bone disease from STS and supports the use of bisphosphonates in this setting. PMID:23594799 83. Cyclooxygenase-2 inhibitor suppresses tumour progression of prostate cancer bone metastases in nude mice. PubMed Garcia, Marta; Velez, Roberto; Romagosa, Cleofé; Majem, Blanca; Pedrola, Núria; Olivan, Mireia; Rigau, Marina; Guiu, Marc; Gomis, Roger R; Morote, Juan; Reventós, Jaume; Doll, Andreas 2014-05-01 To assess whether celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor with anti-cancer properties, has an inhibitory effect on tumour establishment and progression of prostate cancer (PCa) bone metastases. PC-3 stable luciferase-expressing cells were injected into male nude mice by intracardiac (i.c.) and intratibial (i.t.) injections, and the effect of celecoxib on bone metastases was then recorded using bioluminescence image analysis. In cases of chemoprevention, mice received 3 mg/kg celecoxib from 1 week before cell implantation until the end of the study, and to test the therapeutic effect, mice received celecoxib 1 week after cell implantation until the end of the study. Tumour tissue samples were histologically examined and COX-2 expression was quantified at the protein level. Celecoxib significantly decreased cell viability and the proliferation of human PCa cells in vitro in a dose-dependent manner. Bone metastases were detected after i.c. injection in nude mice. Celecoxib (15 ppm) administered before i.c. injection did not inhibit the cellular metastatic potential, as the numbers of bone metastases were similar in both groups. However, celecoxib did decrease metastatic progression in the osseous environment when cells were injected directly into the tibia (P < 0.05). At the protein level, COX-2 expression was significantly decreased in the celecoxib treatment group (P < 0.01). In a preclinical mice model, celecoxib administered orally at the standard human dose inhibits the progression of established PCa bone metastases. © 2013 The Authors. BJU International © 2013 BJU International.
84. Radiological changes on CT after stereotactic body radiation therapy to non-spine bone metastases: a descriptive series. PubMed Chiu, Nicholas; Probyn, Linda; Raman, Srinivas; McDonald, Rachel; Poon, Ian; Erler, Darby; Brotherston, Drew; Soliman, Hany; Cheung, Patrick; Chung, Hans; Chu, William; Loblaw, Andrew; Thavarajah, Nemica; Lang, Catherine; Chin, Lee; Chow, Edward; Sahgal, Arjun 2016-04-01 In recent years, stereotactic body radiation therapy (SBRT) has become increasingly used for the management of non-spine bone metastases. Few studies have examined the radiological changes in bone metastases after treatment with SBRT and there is no consensus about what constitutes radiologic response to therapy. This article describes various changes on CT after SBRT to non-spine bone metastases in eight selected cases. A retrospective review was conducted for patients treated with SBRT to non-spine bone metastases between November 2011 and April 2014 at Sunnybrook Health Sciences Centre. A musculoskeletal radiologist identified eight illustrative cases of interest and provided a description of the findings. Different radiological changes following SBRT were described, including: remineralization of lytic bone metastases, demineralization of sclerotic bone metastases, pathologic fracture, size progression and response in different lesions, as well as lung fibrosis after SBRT to a rib metastasis. We reviewed the radiological images of eight selected cases after SBRT to nonspine bone metastases and a number of characteristic findings were highlighted. We recommend future studies to correlate radiologic changes with clinical outcomes including pain relief, toxicity and long-term local control. 85. Elderly Patients With Painful Bone Metastases Should be Offered Palliative Radiotherapy SciTech Connect Campos, Sarah; Presutti, Roseanna; Zhang Liying 2010-04-15 Purpose: To investigate the efficacy of palliative radiotherapy (RT) in relieving metastatic bone pain in elderly patients. Methods and Materials: The response to RT for palliation of metastatic bone pain was evaluated from a prospective database of 558 patients between 1999 and 2008. The pain scores and analgesic intake were used to calculate the response according to the International Bone Metastases Consensus Working Party palliative RT endpoints. Subgroup analyses for age and other demographic information were performed. Results: No significant difference was found in the response rate in patients aged >=65, >=70, and >=75 years compared with younger patients atmore » 1, 2, or 3 months after RT. The response was found to be significantly related to the performance status. Conclusion: Age alone did not affect the response to palliative RT for bone metastases. Elderly patients should be referred for palliative RT for their painful bone metastases, regardless of age, because they receive equal benefit from the treatment.« less 86. Prevalence of Vitamin D Deficiency in Patients with Bone Metastases and Multiple Myeloma. PubMed Maier, Gerrit Steffen; Horas, Konstantin; Kurth, Andreas Alois; Lazovic, Djordje; Seeger, Jörn Bengt; Maus, Uwe 2015-11-01 Breast and prostate cancer are amongst the most prevalent malignancies globally and up to 40% of patients will develop metastatic disease, particularly to the skeleton. Multiple myeloma is the most common cancer to affect bone with up to 90% of patients developing bone lesions. Although several studies demonstrated that endocrine changes such as vitamin D deficiency promote secondary cancer growth in bone, relatively few have reported its prevalence. For this reason, the purpose of the present study was to evaluate the prevalence of hypovitaminosis D in patients with bone metastases and multiple myeloma. Serum 25-OH-D levels of patients with metastatic bone disease were measured on admission. Statistical analyses was performed to evaluate for possible confounders of hypo-vitaminosis D. We found a widespread and alarming rate of vitamin D deficiency in patients with metastatic bone disease and multiple myeloma. Of note, patients with bone metastases due to breast cancer, prostate cancer and multiple myeloma rarely reached sufficient serum 25-OH-D levels. It is of utmost clinical importance to assess vitamin D levels in cancer patients, especially in those with, or at high risk of developing metastatic bone disease. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved. 87. Evaluation of (111)In-pentetreotide, (131)I-MIBG and bone scintigraphy in the detection and clinical management of bone metastases in carcinoid disease. PubMed Zuetenhorst, J M; Hoefnageli, C A; Boot, H; Valdés Olmos, R A; Taal, B G 2002-08-01 Bone metastases are assumed to be rare in carcinoid disease and to be associated mainly with bronchial primaries. The aim of the present study was to evaluate the occurrence of bone metastases in patients with metastatic carcinoid tumours, and the role of various nuclear medicine modalities (bone scintigraphy, (111)In-pentetreotide and (131)I-MIBG) in its detection and clinical management. Nine (2 women, 7 men, median age 65 years) out of 86 consecutive carcinoid patients treated between 1987 and 1998 developed bone metastases (10%) with a median interval of 37 months between the diagnosis of metastatic carcinoid and bone metastases. Seven of them had non-bronchial primaries. (111)In-pentetreotide scintigraphy failed to detect the bone lesions in 50% of the cases, and (131)I-meta-iodobenzylguanidine(MIBG) scintigraphy in almost 80% of cases. Standard bone scintigraphy, however, was positive in all. Pain relief of bone metastases by means of radiation therapy was obtained in 5 of 6 patients. In another patient palliation of pain symptoms was obtained with Rhenium-186-hydroxyethylidene diphosphonate. Octreotide, Interferon of MIBG were ineffective for this purpose. It is concluded that bone metastases in carcinoid patients may be missed on (131)I-MIBG and (111)In-pentetreotide scintigraphy. Bone scintigraphy is a sensitive imaging technique. Diagnostic nuclear medicine modalities may be helpful in the clinical management of carcinoid disease. 88. Excess TGF-β mediates muscle weakness associated with bone metastases in mice PubMed Central Reiken, Steven; Xie, Wenjun; Andersson, Daniel C.; John, Sutha; Chiechi, Antonella; Wright, Laura E.; Umanskaya, Alisa; Niewolna, Maria; Trivedi, Trupti; Charkhzarrin, Sahba; Khatiwada, Pooja; Wronska, Anetta; Haynes, Ashley; Benassi, Maria Serena; Witzmann, Frank A.; Zhen, Gehua; Wang, Xiao; Cao, Xu; Roodman, G. David; Marks, Andrew R.; Guise, Theresa A. 2015-01-01 Cancer-associated muscle weakness is poorly understood and there is no effective treatment. Here, we find that seven different mouse models of human osteolytic bone metastases, representing breast, lung and prostate cancers, as well as multiple myeloma exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancerassociated muscle weakness. We found that TGF-β, released from the bone surface as a result of metastasis-induced bone destruction upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor/calcium (Ca2+) release channel (RyR1). The oxidized RyR1 channels leaked Ca2+, resulting in lower intracellular signaling required for proper muscle contraction. We found that inhibiting RyR1 leak, TGF-β signaling, TGF-β release from bone or Nox4 all improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast cancer- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, higher levels of Nox4 protein and Nox4 binding to RyR1, and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a non-malignant metabolic bone disorder associated with increased TGF-β activity. Thus, metastasis-induced TGF-β release from bone contributes to muscle weakness by decreasing Ca2+-induced muscle force production. PMID:26457758 89. Effect of Bisphosphonates, Denosumab, and Radioisotopes on Bone Pain and Quality of Life in Patients with Non-Small Cell Lung Cancer and Bone Metastases: A Systematic Review. PubMed Hendriks, Lizza E L; Hermans, Bregtje C M; van den Beuken-van Everdingen, Marieke H J; Hochstenbag, Monique M H; Dingemans, Anne-Marie C 2016-02-01 Bone metastases are common in patients with non-small cell lung cancer (NSCLC), often causing pain and a decrease in quality of life (QoL). The effect of bone-targeted agents is evaluated by reduction in skeletal-related events in which neither pain nor QoL are included. Radioisotopes can be administered for more diffuse bone pain that is not eligible for palliative radiotherapy. The evidence that bone-targeted agents relieve pain or improve QoL is not solid. We performed a systematic review of the effect of bone-targeted agents on pain and QoL in patients with NSCLC. Our systematic literature search included original articles or abstracts reporting on bisphosphonates, denosumab, or radioisotopes or combinations thereof in patients with bone metastases (≥5 patients with NSCLC), with pain, QoL, or both serving as the primary or secondary end point. Of the twenty-five eligible studies, 13 examined bisphosphonates (one also examined denosumab) and 12 dealt with radioisotopes. None of the randomized studies on bisphosphonates or denosumab evaluated pain and QoL as the primary end point. In the single-arm studies of bisphosphonates a decrease in pain or analgesic consumption was found for 38% to 77% of patients. QoL was included in five of 13 studies, but improvement was found in only two. No high-level evidence that bisphosphonates or denosumab reduce pain or improve QoL was found. Although the data are limited, radioisotopes seem to reduce pain with a rapid onset of action and duration of response of 1 to 3 months. The evidence that bisphosphonates or denosumab reduce or prevent pain in patients with NSCLC and bone metastases or that they have an influence on QoL is very weak. Radioisotopes can be used to reduce diffuse pain, although there is no high-level evidence supporting such use. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. 90. Redirecting immune cells against bone metastases: Immunotherapy of prostate cancer metastases using genetically programmed immune effector cells. PubMed Eshhar, Zelig; Waks, Tova; Pinthus, Jehonathan 2005-06-01 Extract: Metastasis of the bone is common in two of the major gender-specific malignancies -- breast and prostate cancers. Although both primary breast and prostate cancer are manageable by "classical" therapies such as surgery, irradiation, and chemotherapy, when metastases (secondary cancers) disseminate to the bones these diseases are, by and large, incurable. Metastasis to the bone is implicated in around 70% of prostate and breast cancer deaths. The idea of harnessing the immune system to fight disseminated cancer has proven to be effective in experimental animal models against transplanted tumors. Here, both arms of the immune system, namely, the humoral one characterized by anti-tumor antibodies and the cellular one composed of a type of white blood cell, specifically the cytotoxic T-lymphocytes (CTLs), were found to cause tumor rejection either following immunization of the experimental mice before the tumor inoculations (active-vaccination) or after adoptive transfer of cancer-specific antibodies or CTLs into tumor-bearing mice (passivevaccination). Encouraged by these results, scientists and clinicians have joined forces in extensive efforts to apply both active and passive vaccination for the immunotherapy of cancer patients. These attempts have flourished over the last fifteen years following the discovery of the first human tumor antigens in melanoma patients. 91. Bone marrow-targeted liposomal carriers PubMed Central Sou, Keitaro; Goins, Beth; Oyajobi, Babatunde O.; Travi, Bruno L.; Phillips, William T. 2011-01-01 Introduction Bone marrow targeted drug delivery systems appear to offer a promising strategy for advancing diagnostic, protective, and/or therapeutic medicine for the hematopoietic system. Liposome technology can provide a drug delivery system with high bone marrow targeting that is mediated by specific phagocytosis in bone marrow. Area covered This review focuses on a bone marrow specific liposome formulation labeled with technetium-99m (99mTc). Interspecies differences in bone marrow distribution of the bone marrow targeted formulation are emphasized. This review provides a liposome technology to target bone marrow. In addition, the selection of proper species for the investigation of bone marrow targeting is suggested. Expert opinion It can be speculated that the bone marrow macrophages have a role in the delivery of lipids to the bone marrow as a source of energy and for membrane biosynthesis or in the delivery of fat soluble vitamins for hematopoiesis. This homeostatic system offers a potent pathway to deliver drugs selectively into bone marrow tissues from blood. High selectivity of the present BMT-liposome formulation for bone marrow suggests the presence of an active and specific mechanism, but specific factors affecting the uptake of the bone marrow MPS are still unknown. Further investigation of this mechanism will increase our understanding of factors required for effective transport of agents to the bone marrow, and may provide an efficient system for bone marrow delivery for therapeutic purposes. PMID:21275831 92. Does colon cancer ever metastasize to bone first? a temporal analysis of colorectal cancer progression PubMed Central 2009-01-01 Background It is well recognized that colorectal cancer does not frequently metastasize to bone. The aim of this retrospective study was to establish whether colorectal cancer ever bypasses other organs and metastasizes directly to bone and whether the presence of lung lesions is superior to liver as a better predictor of the likelihood and timing of bone metastasis. Methods We performed a retrospective analysis on patients with a clinical diagnosis of colon cancer referred for staging using whole-body 18F-FDG PET and CT or PET/CT. We combined PET and CT reports from 252 individuals with information concerning patient history, other imaging modalities, and treatments to analyze disease progression. Results No patient had isolated osseous metastasis at the time of diagnosis, and none developed isolated bone metastasis without other organ involvement during our survey period. It took significantly longer for colorectal cancer patients to develop metastasis to the lungs (23.3 months) or to bone (21.2 months) than to the liver (9.8 months). Conclusion: Metastasis only to bone without other organ involvement in colorectal cancer patients is extremely rare, perhaps more rare than we previously thought. Our findings suggest that resistant metastasis to the lungs predicts potential disease progression to bone in the colorectal cancer population better than liver metastasis does. PMID:19664211 93. From palliative therapy to prolongation of survival: (223)RaCl2 in the treatment of bone metastases. PubMed Liepe, Knut; Shinto, Ajit 2016-07-01 Patients with hormone-refractory prostate cancer often have multiple bone metastases. The resulting bone pain is associated with reduced life quality, increased cost of therapy and impairment of overall survival. Trials with bone-targeting β-emitters have mostly showed an effect on alleviation of bone pain along with prolongation in survival, documented in only a limited number of patients. A randomized phase III trial (ALSYMPCA) using the α-emitter (223)RaCl2 (Xofigo®) showed for the first time, a longer overall survival of 3.6 months in treated patients as a sign of an antitumor effect. The time to first skeletal-related events was also significantly longer in the therapy group compared with placebo. Because of the short range of α-emitter, the bone marrow toxicity of radium therapy is low, and so this radionuclide could also be a candidate for combination with chemotherapy. The elimination of (223)RaCl2 is mainly through the gastrointestinal tract and side effects are mainly in this area. The procedure is similar to treatment with other bone-seeking agents and consists of six administrations of 50 kBq/kg bodyweight Xofigo®, repeated every 4 weeks. At present Xofigo® is only approved for hormone-refractory prostate cancer. 94. Patterns of Care Among Patients Receiving Radiation Therapy for Bone Metastases at a Large Academic Institution SciTech Connect Ellsworth, Susannah G.; Alcorn, Sara R., E-mail:
[email protected]; Hales, Russell K. 2014-08-01 Purpose: This study evaluates outcomes and patterns of care among patients receiving radiation therapy (RT) for bone metastases at a high-volume academic institution. Methods and Materials: Records of all patients whose final RT course was for bone metastases from April 2007 to July 2012 were identified from electronic medical records. Chart review yielded demographic and clinical data. Rates of complicated versus uncomplicated bone metastases were not analyzed. Results: We identified 339 patients whose final RT course was for bone metastases. Of these, 52.2% were male; median age was 65 years old. The most common primary was non-small-cell lung cancer (29%). Most patientsmore » (83%) were prescribed ≤10 fractions; 8% received single-fraction RT. Most patients (52%) had a documented goals of care (GOC) discussion with their radiation oncologist; hospice referral rates were higher when patients had such discussions (66% with vs 50% without GOC discussion, P=.004). Median life expectancy after RT was 96 days. Median survival after RT was shorter based on inpatient as opposed to outpatient status at the time of consultation (35 vs 136 days, respectively, P<.001). Hospice referrals occurred for 56% of patients, with a median interval between completion of RT and hospice referral of 29 days and a median hospice stay of 22 days. Conclusions: These data document excellent adherence to American Society for Radiation Oncolology Choosing Wisely recommendation to avoid routinely using >10 fractions of palliative RT for bone metastasis. Nonetheless, single-fraction RT remains relatively uncommon. Participating in GOC discussions with a radiation oncologist is associated with higher rates of hospice referral. Inpatient status at consultation is associated with short survival.« less 95. Patterns of Care Among Patients Receiving Radiation Therapy for Bone Metastases at a Large Academic Institution SciTech Connect Ellsworth, Susannah G.; Alcorn, Sara R.; Hales, Russell K.; McNutt, Todd R.; DeWeese, Theodore L.; Smith, Thomas J. 2014-08-01 Purpose: This study evaluates outcomes and patterns of care among patients receiving radiation therapy (RT) for bone metastases at a high-volume academic institution. Methods and Materials: Records of all patients whose final RT course was for bone metastases from April 2007 to July 2012 were identified from electronic medical records. Chart review yielded demographic and clinical data. Rates of complicated versus uncomplicated bone metastases were not analyzed. Results: We identified 339 patients whose final RT course was for bone metastases. Of these, 52.2% were male; median age was 65 years old. The most common primary was non-small-cell lung cancer (29%). Most patients (83%) were prescribed ≤10 fractions; 8% received single-fraction RT. Most patients (52%) had a documented goals of care (GOC) discussion with their radiation oncologist; hospice referral rates were higher when patients had such discussions (66% with vs 50% without GOC discussion, P=.004). Median life expectancy after RT was 96 days. Median survival after RT was shorter based on inpatient as opposed to outpatient status at the time of consultation (35 vs 136 days, respectively, P<.001). Hospice referrals occurred for 56% of patients, with a median interval between completion of RT and hospice referral of 29 days and a median hospice stay of 22 days. Conclusions: These data document excellent adherence to American Society for Radiation Oncolology Choosing Wisely recommendation to avoid routinely using >10 fractions of palliative RT for bone metastasis. Nonetheless, singlefraction RT remains relatively uncommon. Participating in GOC discussions with a radiation oncologist is associated with higher rates of hospice referral. Inpatient status at consultation is associated with short survival. 96. Cost-Effectiveness of Treatments for the Management of Bone Metastases: A Systematic Literature Review. PubMed Andronis, Lazaros; Goranitis, Ilias; Bayliss, Sue; Duarte, Rui 2018-03-01 Metastatic cancers occur when cancer cells break away from the primary tumour. One of the most common sites of metastasis is the bone, with several therapeutic options currently available for managing bone metastases. In a resource-constrained environment, policy makers and practitioners need to know which options are cost effective. The aim of this systematic review was to review and appraise published economic evaluations on treatments for the management of bone metastases. We searched eight bibliographic databases (MEDLINE, MEDLINE in Process, EMBASE, CSDR, DARE, HTA, EED and CPCI) for relevant economic evaluations published from each database's inception date until March 2017. Study selection, quality assessment and data extraction were carried out according to published guidelines. Twenty-four relevant economic analyses were identified. Seventeen of these studies focused on bone metastases resulting from a particular type of cancer, i.e. prostate (n = 8), breast (n = 7), lung (n = 1) or renal (n = 1), while seven report results for various primary tumours. Across types of cancer, evidence suggests that bisphosphonates result in lower morbidity and improved quality of life, for an additional cost, which is typically below conventional cost-effectiveness thresholds. While denosumab leads to health gains compared with zoledronic acid, it also results in substantial additional costs and is unlikely to represent value for money. The limited literature on the radiopharmaceutical strontium-89 (Sr89) and external beam radiotherapy (EBR) suggest that these treatments are cost effective compared with no treatment. The reviewed evidence suggests that bisphosphonate treatments are cost-effective options for bone metastases, while denosumab is unlikely to represent value for money. Evidence on EBR and Sr89 is limited and less conclusive. 97. Skeletal-related events due to bone metastases from differentiated thyroid cancer. PubMed Farooki, Azeez; Leung, Vivien; Tala, Hernan; Tuttle, R Michael 2012-07-01 In oncology, the clinical impact of metastatic bone disease is conveyed via a composite end point termed skeletal-related events (SRE), which encompasses spinal cord compression, pathological fracture, a need for external beam radiation or surgery to bone, and hypercalcemia of malignancy. An appreciation for the high incidence of SRE in other advanced cancers involving the bone has led to the approval of potent antiresorptive agents because they delay the time to the first SRE and decrease the incidence of SRE. The risk and rate of SRE after diagnosis of bone metastasis have not been described in thyroid cancer; antiresorptive agents are not routinely used. This was a retrospective review of 245 differentiated thyroid cancer patients with bone metastases identified as part of routine clinical care at Memorial Sloan-Kettering Cancer Center between 1960 and 2011. The occurrence of SRE was recorded from the initial diagnosis of bone metastasis until final follow-up or death. Seventy-eight percent of patients (192 of 245) either presented with or developed at least one SRE after the diagnosis of metastatic bone disease. The median time from identification of bone metastasis to first SRE was 5 months (excluding the 97 patients in whom first SRE occurred at the time of the bone metastasis diagnosis). Of the patients who sustained an initial SRE, 65% (120 of 192) went on to sustain a second SRE at a median of 10.7 months after the first event. SRE were frequently multiple; 39% (74 of 192) sustained three or more discrete SRE. Thyroid cancer bone metastases identified as part of routine clinical followup frequently cause significant and recurrent morbidity. The incidence of SRE and median time to first SRE in metastatic thyroid cancer to bone are similar to those reported in other solid tumors. Prospective clinical trials to assess the efficacy of antiresorptive agents in this population are needed. 98. Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases PubMed Central Sottnik, Joseph L.; Dai, Jinlu; Zhang, Honglai; Campbell, Brittany; Keller, Evan T. 2015-01-01 Crosstalk between tumor cells and their microenvironment is critical for malignant progression. Crosstalk mediators including soluble factors and direct cell contact have been identified, but roles for the interaction of physical forces between tumor cells and the bone microenvironment have not been described. Here we report preclinical evidence that tumor-generated pressure acts to modify the bone microenvironment to promote the growth of prostate cancer bone metastases. Tumors growing in mouse tibiae increased intraosseous pressure. Application of pressure to osteocytes, the main mechanotransducing cells in bone, induced PCa growth and invasion. Mechanistic investigations revealed that this process was mediated in part by upregulation of CCL5 and matrix metalloproteinases in osteocytes. Our results defined the critical contribution of physical forces to tumor cell growth in the tumor microenvironment, and they identified osteocytes as a critical mediator in the bone metastatic niche. PMID:25855383 99. An Easy Tool to Predict Survival in Patients Receiving Radiation Therapy for Painful Bone Metastases SciTech Connect Westhoff, Paulien G.; Graeff, Alexander de; Monninkhof, Evelyn M.; Bollen, Laurens; Dijkstra, Sander P.; Steen-Banasik, Elzbieta M. van der; Vulpen, Marco van; Leer, Jan Willem H.; Marijnen, Corrie A.; Linden, Yvette M. van der 2014-11-15 Purpose: Patients with bone metastases have a widely varying survival. A reliable estimation of survival is needed for appropriate treatment strategies. Our goal was to assess the value of simple prognostic factors, namely, patient and tumor characteristics, Karnofsky performance status (KPS), and patient-reported scores of pain and quality of life, to predict survival in patients with painful bone metastases. Methods and Materials: In the Dutch Bone Metastasis Study, 1157 patients were treated with radiation therapy for painful bone metastases. At randomization, physicians determined the KPS; patients rated general health on a visual analogue scale (VAS-gh), valuation of life on a verbal rating scale (VRS-vl) and pain intensity. To assess the predictive value of the variables, we used multivariate Cox proportional hazard analyses and C-statistics for discriminative value. Of the final model, calibration was assessed. External validation was performed on a dataset of 934 patients who were treated with radiation therapy for vertebral metastases. Results: Patients had mainly breast (39%), prostate (23%), or lung cancer (25%). After a maximum of 142 weeks' follow-up, 74% of patients had died. The best predictive model included sex, primary tumor, visceral metastases, KPS, VAS-gh, and VRS-vl (C-statistic = 0.72, 95% CI = 0.70-0.74). A reduced model, with only KPS and primary tumor, showed comparable discriminative capacity (C-statistic = 0.71, 95% CI = 0.69-0.72). External validation showed a C-statistic of 0.72 (95% CI = 0.70-0.73). Calibration of the derivation and the validation dataset showed underestimation of survival. Conclusion: In predicting survival in patients with painful bone metastases, KPS combined with primary tumor was comparable to a more complex model. Considering the amount of variables in complex models and the additional burden on patients, the simple model is preferred for daily use. In addition, a risk table for survival is provided. 100. An Easy Tool to Predict Survival in Patients Receiving Radiation Therapy for Painful Bone Metastases SciTech Connect Westhoff, Paulien G., E-mail:
[email protected]; Graeff, Alexander de; Monninkhof, Evelyn M. 2014-11-15 Purpose: Patients with bone metastases have a widely varying survival. A reliable estimation of survival is needed for appropriate treatment strategies. Our goal was to assess the value of simple prognostic factors, namely, patient and tumor characteristics, Karnofsky performance status (KPS), and patient-reported scores of pain and quality of life, to predict survival in patients with painful bone metastases. Methods and Materials: In the Dutch Bone Metastasis Study, 1157 patients were treated with radiation therapy for painful bone metastases. At randomization, physicians determined the KPS; patients rated general health on a visual analogue scale (VAS-gh), valuation of life on amore » verbal rating scale (VRS-vl) and pain intensity. To assess the predictive value of the variables, we used multivariate Cox proportional hazard analyses and C-statistics for discriminative value. Of the final model, calibration was assessed. External validation was performed on a dataset of 934 patients who were treated with radiation therapy for vertebral metastases. Results: Patients had mainly breast (39%), prostate (23%), or lung cancer (25%). After a maximum of 142 weeks' follow-up, 74% of patients had died. The best predictive model included sex, primary tumor, visceral metastases, KPS, VAS-gh, and VRS-vl (C-statistic = 0.72, 95% CI = 0.70-0.74). A reduced model, with only KPS and primary tumor, showed comparable discriminative capacity (C-statistic = 0.71, 95% CI = 0.69-0.72). External validation showed a C-statistic of 0.72 (95% CI = 0.70-0.73). Calibration of the derivation and the validation dataset showed underestimation of survival. Conclusion: In predicting survival in patients with painful bone metastases, KPS combined with primary tumor was comparable to a more complex model. Considering the amount of variables in complex models and the additional burden on patients, the simple model is preferred for daily use. In addition, a risk table for survival is « 3 4 5 6 7 » « 4 5 6 7 8 » 101. Osteoprotegerin in Bone Metastases: Mathematical Solution to the Puzzle PubMed Central Ryser, Marc D.; Qu, Yiding; Komarova, Svetlana V. 2012-01-01 Bone is a common site for cancer metastasis. To create space for their growth, cancer cells stimulate bone resorbing osteoclasts. Cytokine RANKL is a key osteoclast activator, while osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic tumor burden in bone. However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth. We propose that OPG produced by cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the tumor and towards the bone tissue, resulting in faster resorption and tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL, PTHrP, osteoclasts, tumor and bone mass. We demonstrate that at lower expression rates, tumor-derived OPG enhances the chemotactic RANKL gradient and osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases osteolysis and tumor burden. Moreover, tumor expression of a soluble mediator inducing RANKL in the host tissue, such as PTHrP, is important for correct orientation of the RANKL gradient. A meta-analysis of OPG, RANKL and PTHrP expression in normal prostate, carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic prostate cancer, and positive correlation between OPG and PTHrP in metastatic prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes. PMID:23093918 102. Targeting Neuropilin-1 in Prostate Cancer Bone Metastasis DTIC Science & Technology 2011-04-01 osteoblasts, and/or respond to bone- derived growth factors, cytokines /chemokines, or extracellular matrices. To metastasize to bone, cancer cells must be... cytokines on the growth of prostate cancer cells derived from soft tissue versus bone metastases in vitro. Int J Oncol 2003;22(4):921-6. 308. Taichman...Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Approved for public release ; distribution unlimited 103. International variations in radiotherapy fractionation for bone metastases: geographic borders define practice patterns? PubMed van der Linden, Y; Roos, D; Lutz, S; Fairchild, A 2009-11-01 Although it may be argued that single fraction (SF) radiotherapy (RT) should be regarded as the standard palliative treatment for pain due to uncomplicated bone metastases, its widespread clinical use is still underexploited. In this chapter, the authors discuss a number of surveys investigating doctors and patients' preferences for palliative RT schedules, discuss the possible reasons for this phenomenon, and suggest potential strategies to increase the use of SF. 104. Targeting CD81 to Prevent Metastases in Breast Cancer DTIC Science & Technology 2015-10-01
immunocompetent host had an effect on metastasis and on circulating tumor cells ( CTCs ); 2) the presence of CD81 in the tumor had an effect on primary...tumor growth, on metastasis, and on CTCs in a syngeneic immunocompetent wild type host. 15. SUBJECT TERMS Breast cancer, CD81 knockout (CD81KO...Circulating tumor cells ( CTCs ), Primary tumor, Metastases Myeloid-derived suppressor cells (MDSCs), Regulatory T (Treg) cells, Wild type (WT) 16 105. The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases PubMed Central Moraes, Fabio Ynoe; Taunk, Neil K.; Marta, Gustavo Nader; Suh, John H. 2016-01-01 Brain metastases are the most common intracranial malignancy. Many approaches, including radiation therapy, surgery, and cytotoxic chemotherapy, have been used to treat patients with brain metastases depending on the patient’s disease burden and symptoms. However, stereotactic surgery (SRS) has revolutionized local treatment of brain metastases. Likewise, targeted therapies, including small-molecule inhibitors and monoclonal antibodies that target cancer cell metabolism or angiogenesis, have transformed managing systemic disease. Prospective data on combining these treatments for synergistic effect are limited, but early data show favorable safety and efficacy profiles. The combination of SRS and targeted therapy will further individualize treatment, potentially obviating the need for cytotoxic chemotherapy or whole-brain radiation. There is a great need to pursue research into these exciting modalities and novel combinations to further improve the treatment of patients with brain metastases. This article discusses reported and ongoing clinical trials assessing the safety and efficacy of targeted therapy during SRS. Implications for Practice: Treatment of patients with brain metastases requires a multidisciplinary approach. Stereotactic radiosurgery is increasingly used in the upfront setting to treat new brain metastasis. Targeted therapies have revolutionized systemic treatment of many malignancies and may sometimes be used as initial treatment in metastatic patients. There is sparse literature regarding safety and efficacy of combining these two treatment modalities. This article summarizes the supporting literature and highlights ongoing clinical trials in combining radiosurgery with targeted therapy. PMID:26764249 106. Effectiveness of Reirradiation for Painful Bone Metastases: A Systematic Review and Meta-Analysis SciTech Connect Huisman, Merel; Bosch, Maurice A.A.J. van den; Wijlemans, Joost W.; Vulpen, Marco van; Linden, Yvette M. van der; Verkooijen, Helena M. 2012-09-01 Purpose: Reirradiation of painful bone metastases in nonresponders or patients with recurrent pain after initial response is performed in up to 42% of patients initially treated with radiotherapy. Literature on the effect of reirradiation for pain control in those patients is scarce. In this systematic review and meta-analysis, we quantify the effectiveness of reirradiation for achieving pain control in patients with painful bone metastases. Methods and Materials: A free text search was performed to identify eligible studies using the MEDLINE, EMBASE, and the Cochrane Collaboration library electronic databases. After study selection and quality assessment, a pooled estimate was calculated for overall pain response for reirradiation of metastatic bone pain. Results: Our literature search identified 707 titles, of which 10 articles were selected for systematic review and seven entered the meta-analysis. Overall study quality was mediocre. Of the 2,694 patients initially treated for metastatic bone pain, 527 (20%) patients underwent reirradiation. Overall, a pain response after reirradiation was achieved in 58% of patients (pooled overall response rate 0.58, 95% confidence interval = 0.49-0.67). There was a substantial between-study heterogeneity (I{sup 2} = 63.3%, p = 0.01) because of clinical and methodological differences between studies. Conclusions: Reirradiation of painful bone metastases is effective in terms of pain relief for a small majority of patients; approximately 40% of patients do not benefit from reirradiation. Although the validity of results is limited, this meta-analysis provides a comprehensive overview and the most quantitative estimate of reirradiation effectiveness to date. 107. Effectiveness of Reirradiation for Painful Bone Metastases: A Systematic Review and Meta-Analysis SciTech Connect Huisman, Merel, E-mail:
[email protected]; Bosch, Maurice A.A.J. van den; Wijlemans, Joost W. 2012-09-01 Purpose: Reirradiation of painful bone metastases in nonresponders or patients with recurrent pain after initial response is performed in up to 42% of patients initially treated with radiotherapy. Literature on the effect of reirradiation for pain control in those patients is scarce. In this systematic review and meta-analysis, we quantify the effectiveness of reirradiation for achieving pain control in patients with painful bone metastases. Methods and Materials: A free text search was performed to identify eligible studies using the MEDLINE, EMBASE, and the Cochrane Collaboration library electronic databases. After study selection and quality assessment, a pooled estimate was calculated formore » overall pain response for reirradiation of metastatic bone pain. Results: Our literature search identified 707 titles, of which 10 articles were selected for systematic review and seven entered the meta-analysis. Overall study quality was mediocre. Of the 2,694 patients initially treated for metastatic bone pain, 527 (20%) patients underwent reirradiation. Overall, a pain response after reirradiation was achieved in 58% of patients (pooled overall response rate 0.58, 95% confidence interval = 0.49-0.67). There was a substantial between-study heterogeneity (I{sup 2} = 63.3%, p = 0.01) because of clinical and methodological differences between studies. Conclusions: Reirradiation of painful bone metastases is effective in terms of pain relief for a small majority of patients; approximately 40% of patients do not benefit from reirradiation. Although the validity of results is limited, this meta-analysis provides a comprehensive overview and the most quantitative estimate of reirradiation effectiveness to date.« less 108. Surgical management of bone metastases: quality of evidence and systematic review. PubMed Wood, Thomas J; Racano, Antonella; Yeung, Herman; Farrokhyar, Forough; Ghert, Michelle; Deheshi, Benjamin M 2014-12-01 Surgical management of metastatic bone disease (MBD) is typically reserved for lesions with the highest risk of fracture. However, the high risk of perioperative complications associated with surgery may outweigh the benefits of improved pain and/or function. The goal of this study was to (1) assess the quality of current evidence in this domain; (2) confirm that surgical management of metastases to the long bones and pelvis/acetabulum provides pain relief and improved function; and (3) assess perioperative morbidity and mortality rates. We conducted a systematic review of the literature for clinical studies that reported pain relief and function outcomes, as well as perioperative complications and mortality, in patients with MBD to the long bones and/or pelvis/acetabulum treated surgically. Multiple databases were searched up to January 2012. Pooled weighted proportions are reported. Forty-five studies were included in the final analysis, with 807 patients. All included studies were level IV with 'moderate' overall quality of evidence using the Methodological Index for Non-Randomized Studies scale. Pain relief following surgical management of metastases was 93, 91, and 93 % in the humerus, femur, and pelvis/acetabulum, respectively. Maintained or improved function after surgery was seen in 94, 89, and 94 % in the humerus, femur, and pelvis/acetabulum, respectively. Perioperative complications and mortality were 17 and 4 %, respectively. Despite the inherent limitations of the current evidence, a benefit for the surgical management of bone metastases to the long bones and pelvis/acetabulum is evident; however, there is still substantial risk of perioperative morbidity and mortality that should be considered. 109. Inhibition of Prostate Cancer Skeletal Metastases by Targeting Cathepsin K DTIC Science & Technology 2008-05-01 RAW 264.7 cells into the 24-wells of BD Biocate osteologic bone cell culture system that consist of sub-micro synthetic calcium phosphate thin...first collected CM from C4-2B cell culture. Then we seeded murine osteoclast precusor RAW 264.7 cells into the 24- wells of BD Biocate osteologic bone 110. Closed intramedullary nailing with percutaneous cement augmentation for long bone metastases. PubMed Kim, Y-I; Kang, H G; Kim, J H; Kim, S-K; Lin, P P; Kim, H S 2016-05-01 The purpose of the study was to investigate whether closed intramedullary (IM) nailing with percutaneous cement augmentation is better than conventional closed nailing at relieving pain and suppressing tumours in patients with metastases of the femur and humerus. A total of 43 patients (27 men, 16 women, mean age 63.7 years, standard deviation (sd) 12.2; 21 to 84) underwent closed IM nailing with cement augmentation for long bone metastases. A further 27 patients, who underwent conventional closed IM nailing, served as controls. Pain was assessed using a visual analogue scale (VAS) score pre-operatively (pre-operative VAS), one week post-operatively (immediate post-operative VAS), and at six weeks post-operatively (follow-up post-operative VAS). Progression of the tumour was evaluated in subgroups of patients using F-18-fludeoxyglucose (F-18-FDG) positron emission tomography (PET)/computed tomography (CT) and/or bone scintigraphy (BS), at a mean of 8.8 and 7.2 months post-operatively, respectively. The mean pain scores of patients who underwent closed nailing with cement augmentation were significantly lower than those of the control patients post-operatively (immediate post-operative VAS: 3.8, sd 0.9 versus 6.0, sd 0.9; follow-up post-operative VAS: 3.3, sd 2.5 versus 6.6, sd 2.2; all p < 0.001). The progression of the metastasis was suppressed in 50% (10/20) of patients who underwent closed nailing with augmentation, but in only 8% (1/13) of those in the control group. Percutaneous cement augmentation of closed IM nailing improves the relief of pain and limits the progression of the tumour in patients with metastases to the long bones. Percutaneous cement augmentation while performing closed IM nailing has some advantages for long bone metastases. Cite this article: Bone Joint J 2016;98-B:703-9. ©2016 The British Editorial Society of Bone & Joint Surgery. 111. Functional Interference Clusters in Cancer Patients With Bone Metastases: A Secondary Analysis of RTOG 9714 SciTech Connect Chow, Edward; James, Jennifer; Barsevick, Andrea; Hartsell, William; Ratcliffe, Sarah; Scarantino, Charles; Ivker, Robert; Roach, Mack; Suh, John; Petersen, Ivy; Konski, Andre; Demas, William; Bruner, Deborah 2010-04-15 Purpose: To explore the relationships (clusters) among the functional interference items in the Brief Pain Inventory (BPI) in patients with bone metastases. Methods: Patients enrolled in the Radiation Therapy Oncology Group (RTOG) 9714 bone metastases study were eligible. Patients were assessed at baseline and 4, 8, and 12 weeks after randomization for the palliative radiotherapy with the BPI, which consists of seven functional items: general activity, mood, walking ability, normal work, relations with others, sleep, and enjoyment of life. Principal component analysis with varimax rotation was used to determine the clusters between the functional items at baseline and the follow-up. Cronbach's alpha was used to determine the consistency and reliability of each cluster at baseline and follow-up. Results: There were 448 male and 461 female patients, with a median age of 67 years. There were two functional interference clusters at baseline, which accounted for 71% of the total variance. The first cluster (physical interference) included normal work and walking ability, which accounted for 58% of the total variance. The second cluster (psychosocial interference) included relations with others and sleep, which accounted for 13% of the total variance. The Cronbach's alpha statistics were 0.83 and 0.80, respectively. The functional clusters changed at week 12 in responders but persisted through week 12 in nonresponders. Conclusion: Palliative radiotherapy is effective in reducing bone pain. Functional interference component clusters exist in patients treated for bone metastases. These clusters changed over time in this study, possibly attributable to treatment. Further research is needed to examine these effects. 112. Functional Interference Clusters in Cancer Patients With Bone Metastases: A Secondary Analysis of RTOG 9714 SciTech Connect Chow, Edward, E-mail:
[email protected]; James, Jennifer; Barsevick, Andrea 2010-04-15 Purpose: To explore the relationships (clusters) among the functional interference items in the Brief Pain Inventory (BPI) in patients with bone metastases. Methods: Patients enrolled in the Radiation Therapy Oncology Group (RTOG) 9714 bone metastases study were eligible. Patients were assessed at baseline and 4, 8, and 12 weeks after randomization for the palliative radiotherapy with the BPI, which consists of seven functional items: general activity, mood, walking ability, normal work, relations with others, sleep, and enjoyment of life. Principal component analysis with varimax rotation was used to determine the clusters between the functional items at baseline and the follow-up.more » Cronbach's alpha was used to determine the consistency and reliability of each cluster at baseline and follow-up. Results: There were 448 male and 461 female patients, with a median age of 67 years. There were two functional interference clusters at baseline, which accounted for 71% of the total variance. The first cluster (physical interference) included normal work and walking ability, which accounted for 58% of the total variance. The second cluster (psychosocial interference) included relations with others and sleep, which accounted for 13% of the total variance. The Cronbach's alpha statistics were 0.83 and 0.80, respectively. The functional clusters changed at week 12 in responders but persisted through week 12 in nonresponders. Conclusion: Palliative radiotherapy is effective in reducing bone pain. Functional interference component clusters exist in patients treated for bone metastases. These clusters changed over time in this study, possibly attributable to treatment. Further research is needed to examine these effects.« less 113. Time of survival and quality of life of the patients operatively treated due to pathological fractures due to bone metastases. PubMed Dutka, Julian; Sosin, Paweł 2003-06-30 Background. 1) evaluation of the quality of life of the patients after surgical treatment of bone metastases, 2) evaluation of survival rate of the patients after surgical treatment of bone metastases, 3) presentation of the authors' clinical score system for evaluation of the treatment results of bone metastases, 4) analysis of general complications rate after surgical treatment of bone metastases. Material and methods. Retrospective evaluation of 62 patients with bone metastases treated operatively in our Ward during last 13 years was made. Mean age of patients was 63,6 years. There were 41 women (mean age; 62,8 years) and 21 men (mean age: 64,3). In 49 cases (79%) we were able to diagnose primary localization of the tumour: breast carcinoma - 22, ovary cancer - 6, lung cancer - 5, prostate cancer - 5, kidney cancer - 6, gastric cancer - 1, vaginal cancer - 1, hepatocellular cancer - 1, melanoma - 1 and plasmocytoma - 1. We could not reveal primary focus of the tumour in 13 cases (21%). Localizations of bone metastases are as follow: femur - 49 cases, humerus - 10, tibia - 3. After being accepted to operavite treatment, the patients had been cured as quickly as possible - sometimes during emergency service. In 2 cases with metastases in the tibia there were amputations made in femur regions. In remainq patients we made local excisions of metastatic tumours with internal osteosynthesis and bone cement application in 47 cases, with internal osteosynthesis only in 7 cases, with hip arthroplasty in 8 cases. Results. We have poor results in 4,8%, because of the death of 3 patients. Mean time of follow-up since surgical procedure was 6 months. In 82,3% we have very good or good results - no pain, good function and independence in daily activities. Mean survival time is 17,5 months (range: 5-36 months). Conclusions. Efficacy of the surgical procedures of pathological fracures due to bone metastases in reliving the pain, improvement of 114. Therapeutic opportunities for castration-resistant prostate cancer patients with bone metastases. PubMed Zustovich, Fable; Fabiani, Francesca 2014-08-01 Patients with castration-resistant prostate cancer are burdened not only with an unavoidable risk of mortality but also by severe mobility issues. This disease has a high tendency to induce bone metastases with concomitant general suffering, impaired mobility, and reduced self-sufficiency. The treatment of bone pain consists of opioids, nonsteroidal antiinflammatory drugs, radiopharmaceuticals, and radiotherapy. To date, abiraterone, enzalutamide, zoledronate and denosumab are the only drugs able to delay skeletal events, and docetaxel is the only chemotherapeutic agent able to prolong survival after castration progression. Recently, 5 new drugs have proven to be efficacious in prolonging survival. Sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, and radium-223 have broadened the therapeutic choices, thus changing the clinical paradigm. This review analyzes the data supporting the use of all presently available therapeutic approaches for the management of pain, skeletal events, and survival in castration-resistant prostate cancer patients with bone metastases. Data based on phase 3 trials could identify new approaches depending on patient, disease, and therapy characteristics. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved. 115. Evaluation of Prostate Cancer Bone Metastases with 18F-NaF and 18F-Fluorocholine PET/CT. PubMed Beheshti, Mohsen; Rezaee, Alireza; Geinitz, Hans; Loidl, Wolfgang; Pirich, Christian; Langsteger, Werner 2016-10-01 18F-fluorocholine is a specific promising agent for imaging tumor cell proliferation, particularly in prostate cancer, using PET/CT. It is a beneficial tool in the early detection of marrow-based metastases because it excludes distant metastases and evaluates the response to hormone therapy. In addition, 18F-fluorocholine has the potential to differentiate between degenerative and malignant osseous abnormalities because degenerative changes are not choline-avid; however, the agent may accumulate in recent traumatic bony lesions. On the other hand, 18F-NaF PET/CT can indicate increased bone turnover and is generally used in the assessment of primary and secondary osseous malignancies, the evaluation of response to treatment, and the clarification of abnormalities on other imaging modalities or clinical data. 18F-NaF PET/CT is a highly sensitive method in the evaluation of bone metastases from prostate cancer, but it has problematic specificity, mainly because of tracer accumulation in degenerative and inflammatory bone diseases. In summary, 18F-NaF PET/CT is a highly sensitive method, but 18F-fluorocholine PET/CT can detect early bone marrow metastases and provide greater specificity in the detection of bone metastases in patients with prostate cancer. However, the difference seems not to be significant. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc. 116. Monte Carlo simulation of age-dependent radiation dose from alpha- and beta-emitting radionuclides to critical trabecular bone and bone marrow targets NASA Astrophysics Data System (ADS) Dant, James T.; Richardson, Richard B.; Nie, Linda H. 2013-05-01 Alpha (α) particles and low-energy beta (β) particles present minimal risk for external exposure. While these particles can induce leukemia and bone cancer due to internal exposure, they can also be beneficial for targeted radiation therapies. In this paper, a trabecular bone model is presented to investigate the radiation dose from bone- and marrow-seeking α and β emitters to different critical compartments (targets) of trabecular bone for different age groups. Two main issues are addressed with Monte Carlo simulations. The first is the absorption fractions (AFs) from bone and marrow to critical targets within the bone for different age groups. The other issue is the application of 223Ra for the radiotherapy treatment of bone metastases. Both a static model and a simulated bone remodeling process are established for trabecular bone. The results show significantly lower AFs from radionuclide sources in the bone volume to the peripheral marrow and the haematopoietic marrow for adults than for newborns and children. The AFs from sources on the bone surface and in the bone marrow to peripheral marrow and haematopoietic marrow also varies for adults and children depending on the energy of the particles. Regarding the use of 223Ra as a radionuclide for the radiotherapy of bone metastases, the simulations show a significantly higher dose from 223Ra and its progeny in forming bone to the target compartment of bone metastases than that from two other more commonly used β-emitting radiopharmaceuticals, 153Sm and 89Sr. There is also a slightly lower dose from 223Ra in forming bone to haematopoietic marrow than that from 153Sm and 89Sr. These results indicate a higher therapy efficiency and lower marrow toxicity from 223Ra and its progeny. In conclusion, age-related changes in bone dimension and cellularity seem to significantly affect the internal dose from α and β emitters in the bone and marrow to critical targets, and 223Ra may be a more efficient 117. Radiofrequency Ablation Therapy Combined with Cementoplasty for Painful Bone Metastases: Initial Experience SciTech Connect Toyota, Naoyuki Naito, Akira; Kakizawa, Hideaki; Hieda, Masashi; Hirai, Nobuhiko; Tachikake, Toshihiro; Kimura, Tomoki; Fukuda, Hideki; Ito, Katsuhide 2005-06-15 The purpose of this study was to assess the efficacy and safety of percutaneous radiofrequency (RF) ablation therapy combined with cementoplasty under computed tomography and fluoroscopic guidance for painful bone metastases. Seventeen adult patients with 23 painful bone metastases underwent RF ablation therapy combined with cementoplasty during a 2year period. The mean tumor size was 52 x 40 x 59 mm. Initial pain relief, reduction of analgesics, duration of pain relief, recurrence rate of pain, survival rate, and complications were analyzed. The technical success rate was 100%. Initial pain relief was achieved in 100% of patients (n = 17). The mean VAS scores dropped from 63 to 24 (p < 0.001) (n = 8). Analgesic reduction was achieved in 41% (7 out of 17 patients). The mean duration of pain relief was 7.3 months (median: 6 months). Pain recurred in three patients (17.6%) from 2 weeks to 3 months. Eight patients died and 8 patients are still alive (a patient was lost to follow-up). The one-year survival rate was 40% (observation period: 1-30 months). No major complications occurred, but one patient treated with this combined therapy broke his right femur 2 days later. There was transient local pain in most cases, and a hematoma in the psoas muscle (n = 1) and a hematoma at the puncture site (n = 1) occurred as minor complications. Percutaneous RF ablation therapy combined with cementoplasty for painful bone metastases is effective and safe, in particular, for bulky tumors extending to extraosseous regions. A comparison with cementoplasty or RF ablation alone and their long-term efficacies is needed. 118. Prophylaxis of radiotherapy-induced nausea and vomiting in the palliative treatment of bone metastases. PubMed Dennis, Kristopher; Nguyen, Janet; Presutti, Roseanna; DeAngelis, Carlo; Tsao, May; Danjoux, Cyril; Barnes, Elizabeth; Sahgal, Arjun; Holden, Lori; Jon, Florencia; Wong, Shun; Chow, Edward 2012-08-01 To document the incidence and timing of radiotherapy-induced nausea and vomiting (RINV) in the treatment of bone metastases among patients receiving prophylaxis with a 5HT(3) receptor antagonist. Patients receiving single (SF) or multiple fraction (MF) palliative radiotherapy (RT) of moderate or low emetogenic risk for bone metastases were prescribed prophylactic Ondansetron. The frequency and duration of prophylaxis and the use of rescue antiemetics were left to the discretion of the treating physicians. Patients documented episodes of nausea (N) and vomiting (V) in daily diaries before and during RT, and until 10 days following RT completion. Rates of complete prophylaxis (CP) for N&V, respectively (CP = no event and no rescue medication), were calculated for the acute phase (the period from the start of RT to the first day following RT completion inclusive) and the delayed phase (the second to tenth days following RT completion inclusive). Fifty-nine patients were enrolled, and 32 were evaluable. CP rates were as follows: moderaterisk SF group (n = 16), acute phase (CP for N = 56%, CP for V = 69%) and delayed phase (CP for N = 31%, CP for V = 44%); moderate-risk MF group (n = 7), acute phase (CP for N = 71%, CP for V = 57%) and delayed phase (CP for N = 43%, CP for V = 57%); low-risk SF group (n = 8), acute phase (CP for N = 50%, CP for V = 100%) and delayed phase (CP for N = 43%, CP for V = 57%); and low-risk MF group (n = 1), acute phase (CP for N = 100%, CP for V = 100%) and delayed phase (CP for N = 100%, CP for V = 100%). Despite prophylaxis, RINV was common among patients receiving palliative radiotherapy for bone metastases, especially during the delayed phase. 119. Combination ibandronate and radiotherapy for the treatment of bone metastases: Clinical evaluation and radiologic assessment SciTech Connect Vassiliou, Vassilios; Kalogeropoulou, Christine; Christopoulos, Christos; Solomou, Ekaterini; Leotsinides, Michael; Kardamakis, Dimitrios . E-mail:
[email protected] 2007-01-01 Purpose: Ibandronate is a single-nitrogen, noncyclic bisphosphonate with proven efficacy for reducing metastatic bone pain. In this study, we assessed the palliative effects of combined ibandronate and radiotherapy. Methods and Materials: Forty-five patients with bone metastases from various solid tumors received external-beam radiotherapy, 30-40 Gy over 3-4.5, weeks combined with 10 cycles of monthly intravenous ibandronate, 6 mg. Results: After combined therapy, mean bone pain scores (graded from 0 to 10) were reduced from 6.3 at baseline to 0.8 after 3 months, with further reductions at later time points (all p < 0.001). Opioid use decreased from 84% of patients at baseline (38/45) to 24% (11/45) at 3 months, with further subsequent reductions (all p < 0.001). Mean performance status and functioning scores also significantly improved. Bone density (assessed by computed tomography scan) increased by 20% vs. baseline at 3 months, 46% at 6 months, and 73% at 10 months (all p < 0.001). Lesion improvement was also demonstrated by magnetic resonance imaging. Treatment was well tolerated with no renal toxicity. Conclusions: In this pilot study, combined radiotherapy and ibandronate provided substantial bone pain relief and increased bone density. Computed tomography-based or magnetic resonance imaging-based evaluations offer objective methods for assessing therapeutic outcomes. 120. Ga-PSMA PET/CT in the evaluation of bone metastases in prostate cancer. PubMed Sachpekidis, Christos; Bäumer, P; Kopka, K; Hadaschik, B A; Hohenfellner, M; Kopp-Schneider, A; Haberkorn, U; Dimitrakopoulou-Strauss, A 2018-01-23 The aims of this retrospective analysis were to compare 68 Ga-PSMA PET findings and low-dose CT findings (120 kV, 30 mA), and to obtain semiquantitative and quantitative 68 Ga-PSMA PET data in patients with prostate cancer (PC) bone metastases. In total, 152 PET/CT scans from 140 patients were evaluated. Of these patients, 30 had previously untreated primary PC, and 110 had biochemical relapse after treatment of primary PC. All patients underwent dynamic PET/CT scanning of the pelvis and lower abdomen as well as whole-body PET/CT with 68 Ga-PSMA-11. The PET/CT scans were analysed qualitatively (visually), semiquantitatively (SUV), and quantitatively based on a two-tissue compartment model and a noncompartmental approach leading to the extraction of the fractal dimension. Differences were considered significant for p values <0.05. In total, 168 68 Ga-PSMA-positive and 113 CT-positive skeletal lesions were detected in 37 patients (8 with primary PC, 29 with biochemical recurrence). Of these 168 lesions, 103 were both 68 Ga-PSMA PET-positive and CT-positive, 65 were only 68 Ga-PSMA-positive, and 10 were only CT-positive. The Yang test showed that there were significantly more 68 GaPSMA PET-positive lesions than CT-positive lesions. Association analysis showed that PSA plasma levels were significantly correlated with several 68 Ga-PSMA-11-associated parameters in bone metastases, including the degree of tracer uptake (SUV average and SUV max ), its transport rate from plasma to the interstitial/intracellular compartment (K 1 ), its rate of binding to the PSMA receptor and its internalization (k 3 ), its influx rate (K i ), and its distribution heterogeneity. 68 Ga-PSMA PET/CT is a useful diagnostic tool in the detection of bone metastases in PC. 68 Ga-PSMA PET visualizes more bone metastases than low-dose CT. PSA plasma levels are significantly correlated with several 68 Ga-PSMA PET parameters. « 4 5 6 7 8 » « 5 6 7 8 9 » 121. [68Ga]PSMA-HBED-CC Uptake in Osteolytic, Osteoblastic, and Bone Marrow Metastases of Prostate Cancer Patients. PubMed Janssen, Jan-Carlo; Woythal, Nadine; Meißner, Sebastian; Prasad, Vikas; Brenner, Winfried; Diederichs, Gerd; Hamm, Bernd; Makowski, Marcus R 2017-12-01 The aim of this study was to evaluate potential differences in "Glu-NH-CO-NH-Lys" radio-labeled with [ 68 Ga]gallium N,N-bis[2-hydroxy-5(carboxyethyl)benzyl]ethylenediamine-N,N-diacetic acid ([ 68 Ga]PSMA-HBED-CC) uptake in osteolytic, osteoblastic, mixed, and bone marrow metastases in prostate cancer (PC) patients. This retrospective study was approved by the local ethics committee. Patients who received [ 68 Ga]PSMA-HBED-CC positron emission tomography/computed tomography ([ 68 Ga]PSMA-PET/CT) with at least one positive bone metastasis were included in this study. Only patients who have not received systemic therapy for their PC were included. Bone metastases had to be confirmed by at least one other imaging modality or follow-up investigation. The maximum standardized uptake value (SUV max ) and mean Hounsfield units (HU mean ) of each metastasis were measured. Based on CT, each metastasis was classified as osteolytic (OL), osteoblastic (OB), bone marrow (BM), or mixed (M). One hundred fifty-four bone metastases in 30 patients were evaluated. Eighty out of 154 (51.9%) metastases were classified as OB, 21/154 (13.6%) as OL, 23/154 (14.9%) as M, and 30/154 (19.5%) as BM. The SUV max for the different types of metastases were 10.6 ± 7.07 (OB), 24.0 ± 19.3 (OL), 16.0 ± 21.0 (M), and 14.7 ± 9.9 (BM). The SUV max of OB vs. OL and OB vs. BM metastases differed significantly (p ≤ 0.025). A significant negative correlation between HU mean and SUV max (r = -0.23, p < 0.05) was measured. [ 68 Ga]PSMA-HBED-CC uptake is higher in osteolytic and bone marrow metastases compared to osteoblastic metastases. Information derived from [ 68 Ga]PSMA-PET and CT complement each other for the reliable diagnosis of the different types of bone metastases in PC patients. 122. A definition of “uncomplicated bone metastases†based on previous bone metastases radiation trials comparing single-fraction and multi-fraction radiation therapy PubMed Central Cheon, Paul M.; Wong, Erin; Thavarajah, Nemica; Dennis, Kristopher; Lutz, Stephen; Zeng, Liang; Chow, Edward 2015-01-01 The most recent systematic review of randomized trials in patients with bone metastases has shown equal efficacy of single fraction (SF) and multiple fraction (MF) palliative radiation therapy in pain relief. It is important to determine the patient population to which the evidence applies. This study aims to examine the eligibility criteria of the studies included in the systematic review to define characteristics of “uncomplicated†bone metastases. Inclusion and exclusion criteria of 21 studies included in the systematic review were compared. Common eligibility criteria were documented in hopes of defining the specific features of a common patient population representative of those in the studies. More than half of the studies included patients with cytological or histological evidence of malignancy. Patients with impending and/or existing pathological fracture, spinal cord compression or cauda equina compression were excluded in most studies. Most studies also excluded patients receiving retreatment to the same site. “Uncomplicated†bone metastases can be defined as: presence of painful bone metastases unassociated with impending or existing pathologic fracture or existing spinal cord or cauda equina compression. Therefore, MF and SF have equal efficacy in patients with such bone metastases. PMID:26579484 123. 18F-Fluorodeoxyglucose-positron Emission Tomography/Computed Tomography Imaging of Metastatic Nasopharyngeal Cancer with Emphasis on the Distribution of Bone Metastases PubMed Central Al Tamimi, Ammad Shanoon; Zaheer, Sumbul; Ng, David Chee; Osmany, Saabry 2017-01-01 Distant metastases change the prognosis of patients with nasopharyngeal carcinoma (NPC) which most commonly metastasizes to the bone. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is reported as useful in imaging NPC metastases. Our study assesses the incidence and distribution of bone metastases detected by 18F-FDG PET/CT in NPC. 717 18F-FDG PET/CT scan reports of histologically proven NPC patients imaged in Singapore General Hospital, Singapore, between 2003 and 2009 were reviewed for the total number of metastases (scanned from vertex to mid-thigh) and analyzed for distribution. Of the 709 FDG avid metastases in these reports, 357/709 (50.35%) were locoregional nodal metastasis and 352/709 (49.65%) were distant metastases of which 192/709 (27.08%) of total metastases and 54.54% of distant metastases (192/352) were in the bones. The majority of the bone lesions 125/192 (65.1%) were in the axial skeleton with 109/192 (56.77%) in the lower skeleton (thoracolumbar spine, sacrum, and pelvis). The incidence of bone metastases in our study (27.08%) was higher than that reported in other studies, for example, 15% by Liu et al. and 11% (230 patients) by Caglar et al. Bone metastases have been reported in the femurs and the feet and as such some metastases may have been outside the field of view of the scans. In our study, 27% of FDG avid NPC metastases are in the bones. PMID:28670176
124. The Difficult Task of Diagnosing Prostate Cancer Metastases on Dry Bone. PubMed Castoldi, Elisa; Cappella, Annalisa; Gibelli, Daniele; Sforza, Chiarella; Cattaneo, Cristina 2017-08-17 The interpretation of pathology on skeletal remains is mandatory for implementing the biological profile and for disease recognition. Prostate cancer is one of the most common tumors, with a high preference for the skeleton as a primary site of metastasis. Its diagnosis on bone is however still ambiguous, due to its "osteoblastic" and resorptive manifestation. This study investigates distribution and appearance of prostate cancer metastases on dry bone on six known cases (selected from the Milano Cemetery Skeletal Collection) and one healthy individual. A macroscopic inspection was performed highlighting the abnormalities observed, describing location, shape, dimension, and aspect. A great amount of proliferative and mixed lesions was noticed, but also cases of pure lytic lesions were displayed. The multiple appearances of the manifestations observed display the difficulty in correctly identifying such a pathology, but also the potential and advantages provided by investigating a study sample with known antemortem history. © 2017 American Academy of Forensic Sciences. 125. Comparison of percutaneous long bone cementoplasty with or without embedding a cement-filled catheter for painful long bone metastases with impending fracture. PubMed Liu, Xun-Wei; Jin, Peng; Liu, Kai; Chen, Hao; Li, Li; Li, Min; Tang, Hai; Sun, Gang 2017-01-01 To compare the efficacy of percutaneous long bone cementoplasty (PLBC) with and without embedding a cement-filled catheter in the medullary canal (ECFC) for painful long bone metastases with impending fracture. A retrospective study was conducted in 36 consecutive patients undergoing PLBC and ECFC combination (n = 17, group A) or PLBC alone (n = 19, group B). All patients had a high risk of impending fracture in the long bone based on Mirels' scoring system. Clinical effects were evaluated using both a pre- and a postoperative visual analogue scale (VAS) and Karnofsky performance scale (KPS). Overall pain relief rate with excellent (VAS 0-2) and good (VAS 2.5-4.5) results during followup was significantly higher in group A than in group B (88.2 % vs. 57.9 %, P<0.05). The average VAS and KPS changes in group A were significantly higher than those in group B at 1, 3 and 6 months postoperatively (P<0.05). Also, the rate of fractures of the treated long bone in group A was significantly lower than that in group B (P<0.05). Combined PLBC and ECFC is a safe and effective procedure for long bone metastases with impending fracture. • Metastases in long bones may cause pain and subsequent pathological fractures. †¢ Cementoplasty resulted in significant pain relief in patients with long bone metastases. • Combination of PLBC and ECFC may reduce the incidence of fractures. 126. Detection of bone metastases in breast cancer patients in the PET/CT era: Do we still need the bone scan? PubMed Caglar, M; Kupik, O; Karabulut, E; Høilund-Carlsen, P F 2016-01-01 To examine the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for the detection of bone metastasis in breast cancer patients and assess whether whole body bone scan (BS) with (99m)Tc-methylene diphosphonate provides any additional information. Study group comprised 150 patients, mean age 52 years (range 27-85) with breast cancer, suspected of having bone metastases. All patients had undergone both FDG-PET/CT and BS with or without single photon emission tomography/computed tomography (SPECT/CT) within a period of 6 weeks. The final diagnosis of bone metastasis was established by histopathological findings, additional imaging, or clinical follow-up longer than 10 months. Cancer antigen 15-3 (CA15-3) and carcinoembryogenic antigen (CEA) were measured in all patients. Histologically 83%, 7% and 10% had infiltrating ductal, lobular and mixed carcinoma respectively. Confirmed bone metastases were present in 86 patients (57.3%) and absent in 64 (42.7%). Mean CA15-3 and CEA values in patients with bone metastases were 74.6ng/mL and 60.4U/mL respectively, compared to 21.3ng/mL and 3.2U/mL without metastases (p<0.001). The sensitivity of FDG-PET/CT for the detection of bone metastases was 97.6% compared to 89.5% with SPECT/CT. In 57 patients, FDG-PET/CT correctly identified additional pulmonary, hepatic, nodal and other soft tissue metastases, not detected by BS. Our findings suggest that FDG-PET/CT is superior to BS with or without SPECT/CT. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved. 127. Registration of CT to pre-treatment MRI for planning of MR-HIFU ablation treatment of painful bone metastases NASA Astrophysics Data System (ADS) Noorda, Yolanda H.; Bartels, Lambertus W.; Huisman, Merel; Nijenhuis, Robbert J.; AAJ van den Bosch, Maurice; Pluim, Josien PW 2014-08-01 MR-HIFU is a new non-invasive treatment modality that can be used for palliation in patients with painful bone metastases. Since treatment strategies are mainly focused on the ablation of periosteal nerves, information on the presence and geometry of cortical bone influences the treatment strategy, both in determining the acoustic power and in avoiding safety issues related to far-field heating. Although MRI is available for imaging during treatment, CT is best used for examining the cortical bone. We present a registration method for registering CT and MR images of patients with bone metastases prior to therapy. CT and MRI data were obtained from nine patients with metastatic bone lesions at varying locations. A two-step registration approach was used, performing simultaneous rigid registration of all available MR images in the first step and an affine and deformable registration with an additional bone metric in the second step. The performance was evaluated using landmark annotation by clinical observers. An average registration error of 4.5 mm was obtained, which was comparable to the slice thickness of the data. The performance of the registration algorithm was satisfactory, even with differences in MRI acquisition parameters and for various anatomical sites. The obtained CT overlay is useful for treatment planning, as it allows an assessment of the integrity of the cortical bone. CT-MR registration is therefore recommended for HIFU treatment planning of patients with bone metastases. 128. Bone metastases in well-to-moderately differentiated neuroendocrine tumors: a single institutional review from the Ohio State University Medical Center. PubMed Kavecansky, Juraj; Wei, Lai; Caronia, Lisa; Ramirez, Maria-Teresa; Bloomston, Mark; Shah, Manisha H 2015-03-01 In this study, we look at the clinical features associated with bone metastasis in patients with well-to-moderately differentiated neuroendocrine tumors (NETs), specifically primary tumor characteristics, complications, elevated hormone levels, and survival. A retrospective study at the Ohio State University was performed on patients diagnosed with well-tomoderately differentiated NETs from 2000 to 2010 who were found to have bone metastases. A control group of patients with metastatic NETs without bone metastases was matched with regard to demographic and clinical data. Of 341 patients with well-to-moderately differentiated NETs, 40 patients were found with bone metastases within the 10-year study period. Patients with bone metastases had shorter survival (median, 52 months) compared to the control group (median, 98 months; P = 0.024). Of 26 patients with bone metastases who died, 6 (23%) patients had a cause of death related to their bone metastatic disease. There were 8 patients with spinal cord compression, and 6 with pathologic fractures. Our study suggests that patients with well-to-moderately differentiated NETs metastatic to bone have larger tumors, more frequently elevated pancreastatin, and shorter survival than patients without bone metastases, with complications of bone metastases significantly contributing to mortality and morbidity. 129. Comparison of 18 FDG PET-CT and bone scintigraphy for detection of bone metastases in breast cancer patients. A meta-analysis. PubMed Rong, Jian; Wang, Siyang; Ding, Qiue; Yun, Miao; Zheng, Zhousan; Ye, Sheng 2013-06-01 We performed a meta-analysis to compare the accuracy of (18)FDG PET-CT and bone scintigraphy for the detection of bone metastases in breast cancer patients. Studies about (18)FDG PET-CT and bone scintigraphy for the detection of bone metastases in breast cancer patients were systematically searched in the MEDLINE and EMBASE databases. We calculated sensitivities, specificities, diagnostic odds ratios, and likelihood ratios, and constructed summary receiver operating characteristic curves using bivariate regression models for (18)FDG PET-CT and bone scintigraphy, respectively. Across 7 studies (668 patients), sensitivity and specificity of PET-CT 0.93 (95% confidence interval [CI] = 0.82-0.98) and 0.99 (95% CI = 0.95-1.00), and of bone scintigraphy were 0.81 (95% CI = 0.58-0.93) and 0.96 (95%CI = 0.76-1.00), respectively. Area under curves for PET-CT and bone scintigraphy was 0.98 (95% CI = 0.98-1.00) and 0.94 (95% CI = 0.92-0.96), respectively. Compared with bone scintigraphy, (18)FDG PET-CT may higher sensitivity and accuracy for detection of bone metastases in breast cancer patients. Copyright © 2013 Elsevier Ltd. All rights reserved. 130. Serum biomarkers of bone metabolism in castration resistant prostate cancer patients with skeletal metastases USDA-ARS?s Scientific Manuscript database Background. Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value ... 131. Mechanisms of Radiation-Induced Bone Loss and Effects on Prostate Cancer Bone Metastases DTIC Science & Technology 2013-06-01 and in vivo bone imaging [months 6-10]. b. Determine apoptosis of bone cells (OT, OB & OC) by quantifying TUNEL staining [months 6-10]. Animal...Zoledronic acid will be used as positive control for inhibition of apoptosis and also inhibition of resorption [month 10]. c. Perform in vivo bone imaging ...described and presented in Task 3. Task 5: Image calvarial osteocytes in real-time after single dose exposure of 2 Gy [months 6-12] A single dose of 132. Engineering a humanized bone organ model in mice to study bone metastases. PubMed Martine, Laure C; Holzapfel, Boris M; McGovern, Jacqui A; Wagner, Ferdinand; Quent, Verena M; Hesami, Parisa; Wunner, Felix M; Vaquette, Cedryck; De-Juan-Pardo, Elena M; Brown, Toby D; Nowlan, Bianca; Wu, Dan Jing; Hutmacher, Cosmo Orlando; Moi, Davide; Oussenko, Tatiana; Piccinini, Elia; Zandstra, Peter W; Mazzieri, Roberta; Lévesque, Jean-Pierre; Dalton, Paul D; Taubenberger, Anna V; Hutmacher, Dietmar W 2017-04-01 Current in vivo models for investigating human primary bone tumors and cancer metastasis to the bone rely on the injection of human cancer cells into the mouse skeleton. This approach does not mimic species-specific mechanisms occurring in human diseases and may preclude successful clinical translation. We have developed a protocol to engineer humanized bone within immunodeficient hosts, which can be adapted to study the interactions between human cancer cells and a humanized bone microenvironment in vivo. A researcher trained in the principles of tissue engineering will be able to execute the protocol and yield study results within 4-6 months. Additive biomanufactured scaffolds seeded and cultured with human bone-forming cells are implanted ectopically in combination with osteogenic factors into mice to generate a physiological bone 'organ', which is partially humanized. The model comprises human bone cells and secreted extracellular matrix (ECM); however, other components of the engineered tissue, such as the vasculature, are of murine origin. The model can be further humanized through the engraftment of human hematopoietic stem cells (HSCs) that can lead to human hematopoiesis within the murine host. The humanized organ bone model has been well characterized and validated and allows dissection of some of the mechanisms of the bone metastatic processes in prostate and breast cancer. 133. Targeted Therapies for the Treatment of Brain Metastases in Solid Tumors. PubMed Bohn, Jan-Paul; Pall, Georg; Stockhammer, Guenther; Steurer, Michael 2016-06-01 Brain metastases are a major cause of morbidity and mortality in cancer patients. While the mainstay treatment comprises surgery and radiation therapy, the role of systemic agents remains controversial. In general, it has been presumed that poor blood-brain barrier (BBB) penetration and inherently more resistant metastatic brain disease preclude a favorable systemic treatment approach. However, a better understanding of tumor biology and the subsequent development of targeted drugs have reawakened interest in systemic therapy. Despite still limited brain distribution, a variety of targeted drugs have demonstrated activity in brain metastases in early clinical trials. Nevertheless, disease progression commonly occurs, and it remains to be elucidated whether limited CNS drug distribution or the acquisition of resistant metastatic clones must be held responsible for this prognosis. Moreover, micrometastatic brain disease beyond an intact BBB-and ultimately prevention of brain metastasis formation-may generally remain inaccessible for first-generation targeted agents with poor CNS penetration. To overcome limited brain distribution and possibly emerging acquired resistance, highly potent next-generation targeted drugs with enhanced CNS distribution have been developed. In view of this emerging but yet undefined role of targeted therapies in the treatment of brain metastases from solid tumors, this review aims to summarize the current knowledge from clinical trials and discusses clinically relevant obstacles to overcome. 134. Bone metastases: assessment of therapeutic response through radiological and nuclear medicine imaging modalities. PubMed Vassiliou, V; Andreopoulos, D; Frangos, S; Tselis, N; Giannopoulou, E; Lutz, S 2011-11-01 Radiological and nuclear medicine imaging modalities used for assessing bone metastases treatment response include plain and digitalised radiography (XR), skeletal scintigraphy (SS), dual-energy X-ray absorptiometry (DEXA), computed tomography (CT), magnetic resonance imaging (MRI), [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) and PET/CT. Here we discuss the advantages and disadvantages of these assessment modalities as evident through different clinical trials. Additionally, we present the more established response criteria of the International Union Against Cancer and the World Health Organization and compare them with newer MD Anderson criteria. Even though serial XR and SS have been used to assess the therapeutic response for decades, several months are required before changes are evident. Newer techniques, such as MRI or PET, may allow an earlier evaluation of response that may be quantified through monitoring changes in signal intensity and standard uptake value, respectively. Moreover, the application of PET/CT, which can follow both morphological and metabolic changes, has yielded interesting and promising results that give a new insight into the natural history of metastatic bone disease. However, only a few studies have investigated the application of these newer techniques and further clinical trials are needed to corroborate their promising results and establish the most suitable imaging parameters and evaluation time points. Last, but not least, there is an absolute need to adopt uniform response criteria for bone metastases through an international consensus in order to better assess treatment response in terms of accuracy and objectivity. Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. 135. Combined Microwave Ablation and Cementoplasty in Patients with Painful Bone Metastases at High Risk of Fracture SciTech Connect Pusceddu, Claudio, E-mail:
[email protected]; Sotgia, Barbara, E-mail:
[email protected]; Fele, Rosa Maria, E-mail:
[email protected] 2016-01-15 PurposeTo retrospectively evaluate the effectiveness of computed tomography-guided percutaneous microwave ablation (MWA) and cementoplasty in patients with painful bone metastases at high risk of fracture.Materials and MethodsThirty-five patients with 37 metastatic bone lesions underwent computed tomography-guided MWA combined with cementoplasty (polymethylmethacrylate injection). Vertebrae, femur, and acetabulum were the intervention sites and the primary end point was pain relief. Pain severity was estimated by visual analog scale (VAS) before treatment; 1 week post-treatment; and 1, 6, and 12 months post-treatment. Functional outcome was assessed by improved patient walking ability. Radiological evaluation was performed at baseline and 3 and 12 months post-procedure.ResultsIn all patients, painmore » reduction occurred from the first week after treatment. The mean reduction in the VAS score was 84, 90, 90 % at week 1, month 1, and month 6, respectively. Improved walking ability occurred in 100 and 98 % of cases at the 1- and 6-month functional outcome evaluations, respectively. At the 1-year evaluation, 25 patients were alive, and 10 patients (28 %) had died because of widespread disease. The mean reduction in the VAS score and improvement in surviving patients’ walking ability were 90 and 100 %, respectively. No patients showed evidence of local tumor recurrence or progression and pathological fracture in the treated sites.ConclusionOur results suggest that MWA combined with osteoplasty is safe and effective when treating painful bone metastases at high risk of fracture. The number of surviving patients at the 1-year evaluation confirms the need for an effective and long-lasting treatment.« less 136. Combined Microwave Ablation and Cementoplasty in Patients with Painful Bone Metastases at High Risk of Fracture SciTech Connect Pusceddu, Claudio; Sotgia, Barbara Fele, Rosa Maria; Ballicu, Nicola; Melis, Luca 2016-01-15 PurposeTo retrospectively evaluate the effectiveness of computed tomography-guided percutaneous microwave ablation (MWA) and cementoplasty in patients with painful bone metastases at high risk of fracture.Materials and MethodsThirty-five patients with 37 metastatic bone lesions underwent computed tomography-guided MWA combined with cementoplasty (polymethylmethacrylate injection). Vertebrae, femur, and acetabulum were the intervention sites and the primary end point was pain relief. Pain severity was estimated by visual analog scale (VAS) before treatment; 1 week post-treatment; and 1, 6, and 12 months post-treatment. Functional outcome was assessed by improved patient walking ability. Radiological evaluation was performed at baseline and 3 and 12 months post-procedure.ResultsIn all patients, pain reduction occurred from the first week after treatment. The mean reduction in the VAS score was 84, 90, 90 % at week 1, month 1, and month 6, respectively. Improved walking ability occurred in 100 and 98 % of cases at the 1- and 6-month functional outcome evaluations, respectively. At the 1-year evaluation, 25 patients were alive, and 10 patients (28 %) had died because of widespread disease. The mean reduction in the VAS score and improvement in surviving patients’ walking ability were 90 and 100 %, respectively. No patients showed evidence of local tumor recurrence or progression and pathological fracture in the treated sites.ConclusionOur results suggest that MWA combined with osteoplasty is safe and effective when treating painful bone metastases at high risk of fracture. The number of surviving patients at the 1-year evaluation confirms the need for an effective and long-lasting treatment. 137. Randomized Controlled Trial of Early Zoledronic Acid in Men With Castration-Sensitive Prostate Cancer and Bone Metastases: Results of CALGB 90202 (Alliance) PubMed Central Smith, Matthew R.; Halabi, Susan; Ryan, Charles J.; Hussain, Arif; Vogelzang, Nicholas; Stadler, Walter; Hauke, Ralph J.; Monk, J. Paul; Saylor, Philip; Bhoopalam, Nirmala; Saad, Fred; Sanford, Ben; Kelly, W. Kevin; Morris, Michael; Small, Eric J. 2014-01-01 Purpose Zoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer. Patients and Methods Men with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply. Results Early zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups. Conclusion In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs. PMID:24590644 138. Time evaluation of image-guided radiotherapy in patients with spinal bone metastases. A single-center study. PubMed Rief, H; Habermehl, D; Schubert, K; Debus, J; Combs, S E 2014-03-01 Time is an important factor during immobilization for radiotherapy (RT) of painful spinal bone metastases. The different RT techniques currently in use have differing impacts on medical staff requirements, treatment planning and radiation delivery. This prospective analysis aimed to evaluate time management during RT of patients with spine metastases, focusing particularly on the impact of image-guided RT (IGRT). Between 21 March 2013 and 17 June 2013, we prospectively documented the time associated with the core work procedures involving the patient during the first day of RT at three different linear accelerators (LINACs). The study included 30 patients; 10 in each of three groups. Groups 1 and 2 were treated with a single photon field in the posterior-anterior direction; group 3 received a three-dimensional conformal treatment plan. The median overall durations of one treatment session were 24 and 25.5 min for the conventional RT groups and 15 min for IGRT group. The longest single procedure was patient immobilization in group 1 (median 9.5 min), whereas this was image registration and matching in groups 2 and 3 (median duration 9.5 and 5 min, respectively). Duration of irradiation (beam-on time) was similar for all groups at 4 or 5 min. The shortest immobilization procedure was observed in group 3 with a median of 3 min, compared to 4 min in group 2 and 9.5 min in group 1. With this analysis, we have shown for the first time that addition of modern IGRT does not extend the overall treatment time for patients with painful bone metastases and can be applied as part of clinical routine in a palliative setting. The choice of treatment technique should be based upon the patient's performance status, as well as the size of the target volume and location of the metastasis. 139. Concurrent dendritic cell vaccine and strontium-89 radiation therapy in the management of multiple bone metastases. PubMed Liu, J; Li, J; Fan, Y; Chang, K; Yang, X; Zhu, W; Wu, X; Pang, Yan 2015-06-01 In addition to its direct cytotoxic effects, radiation therapy renders tumor cells more susceptible to T cell-mediated cytotoxicity by modulating cell surface molecules involved in antigen presentation. The purpose of the present study was to determine the benefit of combined 89Sr radiation and dendritic cell (DC) vaccine therapy in bone metastasis patients. Patients were treated with intravenous 89Sr at a dose of 40 μCi/kg of body weight on the first day after the peripheral blood mononuclear cell collection. Seven days later, patients received DCs once a week for 6 weeks. The first three vaccines were administered by intravenous infusion, and the last three vaccines were administered by 24-point intradermal injection. Clinical response was evaluated by the number of bone metastatic foci demonstrated on bone scintigraphy; cell-mediated cytotoxicity response was evaluated by delayedtype hypersensitivity (DTH) reaction. All treatment-related toxicities including vaccine-induced fever and 89Sr-associated hematological toxicity were carefully monitored. Twentysix patients with histologically diagnosed with primary cancers and multiple bone metastases demonstrated on bone scintigraphy were studied. The overall survival rate was 58.3%. The total positive DTH rate was 50%. The efficiency rate for pain relief was 60% (6/10), for quantity of life was 80%, and for clinic responses was 90%. Out of 10 cases, the Grade 1 or 2 of hematological depression in 4, erythema in 1, and fever in 7 were observed. The study has important implications for that combined 89Sr radiation, and DC vaccine therapy can benefit cancer patients with bone metastasis. 140. ‘Who’, ‘when’ and ‘how’ in re-irradiation of recurrent painful bone metastases PubMed Central Mok, Florence; Li, Kenneth; Yeung, Rebecca; Wong, Kam-Hung; Yu, Brian; Wong, Erin; Bedard, Gillian; Chow, Edward 2013-01-01 Re-irradiation of painful bony metastases is increasingly performed since patients are receiving better systemic treatments and having longer life expectancy, and may also be due to the increase use of initial single fraction radiotherapy. However, randomized control trial on the efficacy of re-irradiation is lacking. A recent meta-analysis concluded with a 58% response rate for pain relief by re-irradiation of symptomatic bone metastases. In this review, the effectiveness of re-irradiation in terms of clinical and economical aspects, and clinical questions on who, when, and how to re-irradiate would be discussed. A brief review of other treatment options and comparison with re-irradiation of bone metastases would be performed. PMID:26909270 « 5 6 7 8 9 » « 6 7 8 9 10 » 141. High levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases. PubMed Djusberg, Erik; Jernberg, Emma; Thysell, Elin; Golovleva, Irina; Lundberg, Pia; Crnalic, Sead; Widmark, Anders; Bergh, Anders; Brattsand, Maria; Wikström, Pernilla 2017-05-01 The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 142. A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer. PubMed Dafermou, A; Colamussi, P; Giganti, M; Cittanti, C; Bestagno, M; Piffanelli, A 2001-07-01 A multicentre observational study was conducted by the Italian Association of Nuclear Medicine between 1996 and 1998. Twenty-nine Nuclear Medicine Departments participated. The aims of the study were to systematically evaluate the efficacy, toxicity and repeatability of radionuclide therapy of painful bone metastases (RTBM) in a large number of patients and to assess its incidence in patients with prostate cancer. Out of 818 treatments performed with a single i.v. dose of 148 MBq of strontium-89 chloride or 1,295 MBq of rhenium186 hydroxyethylidene diphosphonate (HEDP), 610 could be evaluated (527 with 89Sr and 83 with 186Re-HEDP). Eighty-one patients received multiple (up to five) RTBM. The total number of retreatments was 100. Patients were followed up for a period of 3-24 months. Results, assessed according to pain relief and consumption of analgesic drugs, were expressed at four levels: 1, no response; 2, mild response; 3, good response; 4, excellent response. Responses were: level 1 in 19%, level 2 in 21.3%, level 3 in 33.3% and level 4 in 26.4% of cases. Retreatments showed significantly (P<0.01) worse responses (48% levels 3+4), in comparison to first RTBM. Duration of palliation was 5.0+/-3.5 months, and was longer in cases of excellent response, in first RTBM, in patients with limited metastases and when 89Sr was used. Better responses were found in cases of limited skeletal disease, under good clinical conditions, when life expectancy exceeded 3 months, and in radiologically osteoblastic or mixed bone lesions. The only statistically significant predictive factor was life expectancy (P<0.001). Flare phenomenon (14.1% of cases) did not correlate with the response. Haematological toxicity (mild to moderate in most cases) mainly affected platelets, and was observed in 25.5% of cases overall and in 38.9% of retreatments. RTBM did not seem to prolong life, though in some cases scintigraphic regression of bone metastases was observed. The two 143. Tumor-targeting Salmonella typhimurium A1-R inhibits human prostate cancer experimental bone metastasis in mouse models. PubMed Toneri, Makoto; Miwa, Shinji; Zhang, Yong; Hu, Cameron; Yano, Shuya; Matsumoto, Yasunori; Bouvet, Michael; Nakanishi, Hayao; Hoffman, Robert M; Zhao, Ming 2015-10-13 Bone metastasis is a frequent occurrence in prostate cancer patients and often is lethal. Zoledronic acid (ZOL) is often used for bone metastasis with limited efficacy. More effective models and treatment methods are required to improve the outcome of prostate cancer patients. In the present study, the effects of tumor-targeting Salmonella typhimurium A1-R were analyzed in vitro and in vivo on prostate cancer cells and experimental bone metastasis. Both ZOL and S. typhimurium A1-R inhibited the growth of PC-3 cells expressing red fluorescent protien in vitro. To investigate the efficacy of S. typhimurium A1-R on prostate cancer experimental bone metastasis, we established models of both early and advanced stage bone metastasis. The mice were treated with ZOL, S. typhimurium A1-R, and combination therapy of both ZOL and S. typhimurium A1-R. ZOL and S. typhimurium A1-R inhibited the growth of solitary bone metastases. S. typhimurium A1-R treatment significantly decreased bone metastasis and delayed the appearance of PC-3 bone metastases of multiple mouse models. Additionally, S. typhimurium A1-R treatment significantly improved the overall survival of the mice with multiple bone metastases. The results of the present study indicate that S. typhimurium A1-R is useful to prevent and inhibit prostate cancer bone metastasis and has potential for future clinical use in the adjuvant setting. 144. Bone metastases and skeletal-related events in patients with malignant pheochromocytoma and sympathetic paraganglioma. PubMed Ayala-Ramirez, Montserrat; Palmer, J Lynn; Hofmann, Marie-Claude; de la Cruz, Maxine; Moon, Bryan S; Waguespack, Steven G; Habra, Mouhammed Amir; Jimenez, Camilo 2013-04-01 Bone metastases (BM) can cause severe pain, spinal cord compression, pathological fractures, and/or hypercalcemia. These skeletal-related events (SREs) may cause immobilization, loss of independence, poor quality of life, and reduced survival. There is limited information on the clinical effects of BM and SREs in patients with malignant pheochromocytoma or sympathetic paraganglioma (PHEO/sPGL). We studied the prevalence and clinical characteristics of BM and SREs in patients with PHEO/sPGL and investigated the risk factors for SRE development. Using a large institutional database, we conducted a retrospective study of 128 patients with malignant PHEO/sPGL at The University of Texas MD Anderson
Cancer Center from 1967 through 2011. Of the patients, 91 (71%) had BM, and 57 of these (63%) developed metachronous BM at a median time of 3.4 years (range, 5 months to 23 years) after the primary tumor diagnosis. Metastatic disease was confined exclusively to the skeleton in 26 of 128 (20%) patients. Sufficient information to assess SRE occurrence was available for 67 patients, and 48 of 67 (72%) patients had at least 1 SRE. The median overall survival for the 128 patients was 12 years for patients with only BM, 7.5 years for patients with nonosseous metastases, and 5 years for patients with both BM and nonosseous metastases (log rank test P value = .005). We were unable to identify factors predictive of SRE development, but the occurrence of a first SRE was associated with the development of subsequent SREs in 48% of subjects. In responsive patients, the use of systemic therapy was associated with fewer SREs (P < .0001). BM and SREs are frequent in patients with malignant PHEO/sPGL. SREs often develop shortly after the diagnosis of BM; severe pain is the most frequent SRE. These patients should be followed long-term by a multidisciplinary team to promptly identify the need for medical or surgical intervention. 145. TU-A-12A-08: Computing Longitudinal Material Changes in Bone Metastases Using Dual Energy Computed Tomography SciTech Connect Schmidtlein, CR; Hwang, S; Veeraraghavan, H 2014-06-15 Purpose: This study demonstrates a methodology for tracking changes in metastatic bone disease using trajectories in material basis space in serial dual energy computed tomography (DECT) studies. Methods: This study includes patients with bone metastases from breast cancer that had clinical surveillance CT scans using a General Electric CT750HD in dual energy mode. A radiologist defined regions-of-interested (ROI) for bone metastasis, normal bone, and marrow across the serial DECT scans. Our approach employs a Radon transform to forward-projection the basis images, namely, water and iodine, into sinogram space. This data is then repartitioned into fat/bone and effective density/Z image pairsmore » using assumed energy spectrums for the x-ray energies. This approach both helps remove negative material densities and avoids adding spectrum-hardening artifacts. These new basis data sets were then reconstructed via filtered back-projection to create new material basis pair images. The trajectories of these pairs were then plotted in the new basis space providing a means to both visualize and quantitatively measure changes in the material properties of the tumors. Results: ROI containing radiologist defined metastatic bone disease showed well-defined trajectories in both fat/bone and effective density/Z space. ROI that contained radiologist defined normal bone and marrow did not exhibit any discernible trajectories and were stable from scan to scan. Conclusions: The preliminary results show that changes in material composition and effective density/Z image pairs were seen primarily in metastasis and not in normal tissue. This study indicates that by using routine clinical DECT it may be possible to monitor therapy response of bone metastases because healing or worsening bone metastases change material composition of bone. Additional studies are needed to further validate these results and to test for their correlation with outcome.« less 146. TU-A-12A-08: Computing Longitudinal Material Changes in Bone Metastases Using Dual Energy Computed Tomography SciTech Connect Schmidtlein, CR; Hwang, S; Veeraraghavan, H; Fehr, D; Humm, J; Deasy, J 2014-06-15 Purpose: This study demonstrates a methodology for tracking changes in metastatic bone disease using trajectories in material basis space in serial dual energy computed tomography (DECT) studies. Methods: This study includes patients with bone metastases from breast cancer that had clinical surveillance CT scans using a General Electric CT750HD in dual energy mode. A radiologist defined regions-of-interested (ROI) for bone metastasis, normal bone, and marrow across the serial DECT scans. Our approach employs a Radon transform to forward-projection the basis images, namely, water and iodine, into sinogram space. This data is then repartitioned into fat/bone and effective density/Z image pairs using assumed energy spectrums for the x-ray energies. This approach both helps remove negative material densities and avoids adding spectrum-hardening artifacts. These new basis data sets were then reconstructed via filtered back-projection to create new material basis pair images. The trajectories of these pairs were then plotted in the new basis space providing a means to both visualize and quantitatively measure changes in the material properties of the tumors. Results: ROI containing radiologist defined metastatic bone disease showed welldefined trajectories in both fat/bone and effective density/Z space. ROI that contained radiologist defined normal bone and marrow did not exhibit any discernible trajectories and were stable from scan to scan. Conclusions: The preliminary results show that changes in material composition and effective density/Z image pairs were seen primarily in metastasis and not in normal tissue. This study indicates that by using routine clinical DECT it may be possible to monitor therapy response of bone metastases because healing or worsening bone metastases change material composition of bone. Additional studies are needed to further validate these results and to test for their correlation with outcome. 147. Different patterns of change in bone turnover markers during treatment with bone-modifying agents for breast cancer patients with bone metastases. PubMed Nishimukai, Arisa; Higuchi, Tomoko; Ozawa, Hiromi; Yanai, Ayako; Miyagawa, Yoshimasa; Murase, Keiko; Imamura, Michiko; Takatsuka, Yuichi; Miyoshi, Yasuo 2017-03-01 Bone-modifying agents are effective for treatment of breast cancer patients with bone metastases. Since their action is mediated through suppression of the osteoclast function, their efficacy can be determined by monitoring bone turnover markers. However, the clinical significance of these markers is yet to be compared. For this study, 52 breast cancer patients with bone metastases treated with zoledronic acid (n = 36) or denosumab (n = 22) were enrolled (6 patients were treated sequentially with both agents). Serum tartrateresistant acid phosphatase-5b (TRACP-5b), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP), N-terminal cross-linking telopeptides of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) were measured at pretreatment and 1, 3 and 6 months after treatment. Serum TRACP-5b (p < 0.0001), NTX (p = 0.0007) and BAP (p = 0.0032) decreased significantly after treatment. The baseline median value of TRACP-5b (457.5 mU/dL, range 173-1630 mU/dL) decreased to 137 mU/dL (91-795 mU/dL) 1 month after treatment. Reduction in serum NTX and BAP was greatest after 3 and 6 months, respectively. TRACP-5b, NTX and BAP were above normal levels at baseline in 62.5, 25 and 35.3 % of patients, respectively, and nearly 80 % of these patients attained normal levels during the treatment. Although bone-modifying agents reduced the baseline levels of TRACP-5b, NTX and BAP significantly, the reduction patterns differed. TRACP-5b appears to affect levels most quickly and sensitively, possibly due to its direct link to the number and activity of osteoclasts. These findings suggest that the efficacy of TRACP-5b is clinically significant when considering which bone-modifying agents to use for breast cancer patients with bone metastases. 148. Preclinical Evaluation of Serine/Threonine Kinase Inhibitors Against Prostate Cancer Metastases DTIC Science & Technology 2008-11-01 TGFβ signaling in prostate cancer. To summarize, it is a useful target for treatment of prostate cancer bone metastases, provided that the tumor...targets for pharmacological treatment of prostate cancer bone metastases. There is no advantage to combined treatment targeting TGFβ receptors and p38...metastases. Additional experiments with this class of inhibitor and the combined treatments proposed in Aim 3 have consequently been abandoned 149. Evaluation of prognostic scoring systems for bone metastases using single-center data. PubMed Shimada, Hirofumi; Setoguchi, Takao; Nakamura, Shunsuke; Yokouchi, Masahiro; Ishidou, Yasuhiro; Tominaga, Hiroyuki; Kawamura, Ichiro; Nagano, Satoshi; Komiya, Setsuro 2015-11-01 Recent progress in cancer treatment has improved patient survival, but has increased the number of patients with metastatic bone tumors. Data were collected from all bone metastasis patients at Kagoshima University, where almost all patients with metastatic bone tumors who reside in Kagoshima province are treated surgically. The scoring systems used in bone metastasis patients were then evaluated to identify those most suitable for our patients. Clinical data were collected from 145 patients with bone metastases. The patients were assigned prognostic scores based on four scoring systems, namely those described by the Ratasvuori, Mizumoto, Tokuhashi and Katagiri groups. Statistical examinations were performed to assess patient distribution regarding prognostic factors and the four data sets reported in the literature. The patient distributions for all prognostic factors were significantly different between the Scandinavian Sarcoma Group (SSG) and Kagoshima data. The distributions of patients for 3 of 5 and for 5 of 7 prognostic factors were statistically different between the Kagoshima data and the Katagiri and Tokuhashi data, respectively. Additionally, the distribution of patients in each scoring group was statistically different between the Kagoshima data and the Katagiri, Tokuhashi and Mizumoto data. The predictions of prognosis were significantly different between the results of each group and ours. The Tokuhashi scoring system detected the highest survival at 6 months (88.8%) in the Kagoshima data. Patients with a life expectancy of >6 months benefited from tumor excision and reconstruction. These findings suggest that the Tokuhashi scoring system is the most suitable for identifying patients who should be assessed for curative surgical intervention. SSG scoring, however, was suitable for identifying patients expected to survive for <6 months (91.3%). Prior to selecting a scoring system to predict prognosis, it is important to determine which scoring system is 150. Incidental Benign Metastasizing Leiomyoma in a Patient with Bone Sarcoma: A Case Report PubMed Central del Real-Romo, Zanndor Jacob; Montero-Cantú, Carlos; Villegas-Cabello, Oscar; DÃaz-Elizondo, José Antonio; Reyes-Salas, Danae; Palomo-Hoil, Rene; Peralta-Castillo, Guillermo; MartÃnez-Sánchez, David; Flores-Villalba, Eduardo 2014-01-01 Background. The benign metastasizing leiomyoma is an exceptionally rare entity; it presents with ectopic leiomyoma nodules with a benign pattern. Symptoms vary according to the anatomic location. The diagnosis is histopathological, usually in patients with history of hysterectomy. Case Presentation. A 36-year-old female with 2-month history of left knee pain was diagnosed with bone fibrosarcoma. A CT scan showed pulmonary nodules. The patient started neoadjuvant chemotherapy. Conservative surgery of pelvic limb was achieved. A new CT scan reported pulmonary nodules that remained in relation to the previous CT. A nodule resection by thoracotomy and TOB (transoperative biopsy) was performed. The final pathology report described benign proliferative lesions consistent with benign metastatic leiomyoma. Conclusions. Benign metastatic leiomyoma is a rare condition presenting with uterine and extrauterine nodules most commonly in the lung. The diagnosis is histopathological. The surgical procedure must be reserved for selected patients. PMID:25221682 151. Quality of Life in Relation to Pain Response to Radiation Therapy for Painful Bone Metastases SciTech Connect Westhoff, Paulien G.; Graeff, Alexander de; Monninkhof, Evelyn M.; Pomp, Jacqueline; Vulpen, Marco van; Leer, Jan Willem H.; Marijnen, Corrie A.M.; Linden, Yvette M. van der 2015-11-01 Purpose: To study quality of life (QoL) in responders and nonresponders after radiation therapy for painful bone metastases; and to identify factors predictive for a pain response. Patients and Methods: The prospectively collected data of 956 patients with breast, prostate, and lung cancer within the Dutch Bone Metastasis Study were used. These patients, irradiated for painful bone metastases, rated pain, QoL, and overall health at baseline and weekly afterward for 12 weeks. Using generalized estimating equations analysis, the course of QoL was studied, adjusted for primary tumor. To identify predictive variables, proportional hazard analyses were performed, taking into account death as a competing risk, and C-statistics were calculated for discriminative value. Results: In total, 722 patients (76%) responded to radiation therapy. During follow-up, responders had a better QoL in all domains compared with nonresponders. Patients with breast or prostate cancer had a better QoL than patients with lung cancer. In multivariate analysis, baseline predictors for a pain response were breast or prostate cancer as primary tumor, younger age, good performance status, absence of visceral metastases, and using opioids. The discriminative ability of the model was low (C-statistic: 0.56). Conclusions: Responding patients show a better QoL after radiation therapy for painful bone metastases than nonresponders. Our model did not have enough discriminative power to predict which patients are likely to respond to radiation therapy. Therefore, radiation therapy should be offered to all patients with painful bone metastases, aiming to decrease pain and improve QoL. 152. Quality of Life in Relation to Pain Response to Radiation Therapy for Painful Bone Metastases SciTech Connect Westhoff, Paulien G., E-mail:
[email protected]; Graeff, Alexander de; Monninkhof, Evelyn M. 2015-11-01 Purpose: To study quality of life (QoL) in responders and nonresponders after radiation therapy for painful bone metastases; and to identify factors predictive for a pain response. Patients and Methods: The prospectively collected data of 956 patients with breast, prostate, and lung cancer within the Dutch Bone Metastasis Study were used. These patients, irradiated for painful bone metastases, rated pain, QoL, and overall health at baseline and weekly afterward for 12 weeks. Using generalized estimating equations analysis, the course of QoL was studied, adjusted for primary tumor. To identify predictive variables, proportional hazard analyses were performed, taking into account death asmore » a competing risk, and C-statistics were calculated for discriminative value. Results: In total, 722 patients (76%) responded to radiation therapy. During follow-up, responders had a better QoL in all domains compared with nonresponders. Patients with breast or prostate cancer had a better QoL than patients with lung cancer. In multivariate analysis, baseline predictors for a pain response were breast or prostate cancer as primary tumor, younger age, good performance status, absence of visceral metastases, and using opioids. The discriminative ability of the model was low (C-statistic: 0.56). Conclusions: Responding patients show a better QoL after radiation therapy for painful bone metastases than nonresponders. Our model did not have enough discriminative power to predict which patients are likely to respond to radiation therapy. Therefore, radiation therapy should be offered to all patients with painful bone metastases, aiming to decrease pain and improve QoL.« less 153. International Patterns of Practice in Palliative Radiotherapy for Painful Bone Metastases: Evidence-Based Practice? SciTech Connect Fairchild, Alysa, E-mail:
[email protected]; Barnes, Elizabeth; Ghosh, Sunita 2009-12-01 Purpose: Multiple randomized controlled trials have demonstrated the equivalence of multifraction and single-fraction (SF) radiotherapy for the palliation of painful bone metastases (BM). However, according to previous surveys, SF schedules remain underused. The objectives of this study were to determine the current patterns of practice internationally and to investigate the factors influencing this practice. Methods and Materials: The members of three global radiation oncology professional organizations (American Society for Radiology Oncology [ASTRO], Canadian Association of Radiation Oncology [CARO], Royal Australian and New Zealand College of Radiologists) completed an Internet-based survey. The respondents described what radiotherapy dose fractionation they would recommendmore » for 5 hypothetical cases describing patients with single or multiple painful BMs from breast, lung, or prostate cancer. Radiation oncologists rated the importance of patient, tumor, institution, and treatment factors, and descriptive statistics were compiled. The chi-square test was used for categorical variables and the Student t test for continuous variables. Logistic regression analysis identified predictors of the use of SF radiotherapy. Results: A total of 962 respondents, three-quarters ASTRO members, described 101 different dose schedules in common use (range, 3 Gy/1 fraction to 60 Gy/20 fractions). The median dose overall was 30 Gy/10 fractions. SF schedules were used the least often by ASTRO members practicing in the United States and most often by CARO members. Case, membership affiliation, country of training, location of practice, and practice type were independently predictive of the use of SF. The principal factors considered when prescribing were prognosis, risk of spinal cord compression, and performance status. Conclusion: Despite abundant evidence, most radiation oncologists continue to prescribe multifraction schedules for patients who fit the eligibility criteria 154. A radiobiological model of metastatic burden reduction for molecular radiotherapy: application to patients with bone metastases NASA Astrophysics Data System (ADS) Denis-Bacelar, Ana M.; Chittenden, Sarah J.; Murray, Iain; Divoli, Antigoni; McCready, V. Ralph; Dearnaley, David P.; O'Sullivan, Joe M.; Johnson, Bernadette; Flux, Glenn D. 2017-04-01 Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone lesions and to reduce the metastatic burden was investigated in a cohort of 22 patients with bone metastases from castration-resistant prostate cancer. A metastatic burden reduction curve was generated for each patient, which predicts the reduction in metastatic burden as a function of the patient mean absorbed dose, defined as the mean of all the lesion absorbed doses in any given patient. In the patient cohort studied, the median of the patient mean absorbed dose predicted to reduce the metastatic burden by 50% was 89 Gy (interquartile range: 83-105 Gy), whilst a median of 183 Gy (interquartile range: 107-247 Gy) was found necessary to eradicate all metastases in a given patient. The absorbed dose required to eradicate all the lesions was strongly correlated with the variability of the absorbed doses delivered to multiple lesions in a given patient (r  =  0.98, P  <†‰â€‰0.0001). The metastatic burden reduction curves showed a potential large reduction in metastatic burden for a small increase in absorbed dose in 91% of patients. The results indicate the range of absorbed doses required to potentially obtain a significant survival benefit. The metastatic burden reduction method provides a simple tool that could be used in routine clinical practice for patient selection and to indicate the required administered activity to achieve a predicted patient mean absorbed dose and reduction in metastatic tumour burden. 155. TU-G-204-02: Automatic Sclerotic Bone Metastases Detection in the Pelvic Region From Dual Energy CT SciTech Connect Fehr, D; Schmidtlein, C; Hwang, S 2015-06-15 Purpose: To automatically detect sclerotic bone metastases in the pelvic region using dual energy computed tomography (DECT). Methods: We developed a two stage algorithm to automatically detect sclerotic bone metastases in the pelvis from DECT for patients with multiple bone metastatic lesions and with hip implants. The first stage consists of extracting the bone and marrow regions by using a support vector machine (SVM) classifier. We employed a novel representation of the DECT images using multi-material decomposition, which represents each voxel as a mixture of different physical materials (e.g. bone+water+fat). Following the extraction of bone and marrow, in the secondmore » stage, a bi histogram equalization method was employed to enhance the contrast to reveal the bone metastases. Next, meanshift segmentation was performed to separate the voxels by their intensity levels. Finally, shape-based filtering was performed to extract the possible locations of the metastatic lesions using multiple shape criteria. We used the following shape parameters: area, eccentricity, major and minor axis, perimeter and skeleton. Results: A radiologist with several years of experience with DECT manually labeled 64 regions consisting of metastatic lesions from 10 different patients. However, the patients had many more metastasic lesions throughout the pelvis. Our method correctly identified 46 of the marked 64 regions (72%). In addition, our method also identified several other lesions, which can then be validated by the radiologist. The missed lesions were typically very large elongated regions consisting of several islands of very small (<4mm) lesions. Conclusion: We developed an algorithm to automatically detect sclerotic lesions in the pelvic region from DECT. Preliminary assessment shows that our algorithm generated lesions agreeing with the radiologist generated candidate regions. Furthermore, our method reveals additional lesions that can be inspected by the radiologist 156. TU-G-204-02: Automatic Sclerotic Bone Metastases Detection in the Pelvic Region From Dual Energy CT SciTech Connect Fehr, D; Schmidtlein, C; Hwang, S; Deasy, J; Veeraraghavan, H 2015-06-15 Purpose: To automatically detect sclerotic bone metastases in the pelvic region using dual energy computed tomography (DECT). Methods: We developed a two stage algorithm to automatically detect sclerotic bone metastases in the pelvis from DECT for patients with multiple bone metastatic lesions and with hip implants. The first stage consists of extracting the bone and marrow regions by using a support vector machine (SVM) classifier. We employed a novel representation of the DECT images using multi-material decomposition, which represents each voxel as a mixture of different physical materials (e.g. bone+water+fat). Following the extraction of bone and marrow, in the second stage, a bi -histogram equalization method was employed to enhance the contrast to reveal the bone metastases. Next, meanshift segmentation was performed to separate the voxels by their intensity levels. Finally, shape-based filtering was performed to extract the possible locations of the metastatic lesions using multiple shape criteria. We used the following shape parameters: area, eccentricity, major and minor axis, perimeter and skeleton. Results: A radiologist with several years of experience with DECT manually labeled 64 regions consisting of metastatic lesions from 10 different patients. However, the patients had many more metastasic lesions throughout the pelvis. Our method correctly identified 46 of the marked 64 regions (72%). In addition, our method also identified several other lesions, which can then be validated by the radiologist. The missed lesions were typically very large elongated regions consisting of several islands of very small (<4mm) lesions. Conclusion: We developed an algorithm to automatically detect sclerotic lesions in the pelvic region from DECT. Preliminary assessment shows that our algorithm generated lesions agreeing with the radiologist generated candidate regions. Furthermore, our method reveals additional lesions that can be inspected by the radiologist, thereby 157. The effect of radiotherapy, and radiotherapy combined with bisphosphonates or RANK ligand inhibitors on bone quality in bone metastases. A systematic review. PubMed Groenen, Karlijn H J; Pouw, Martin H; Hannink, Gerjon; Hosman, Allard J F; van der Linden, Yvette M; Verdonschot, Nico; Tanck, Esther 2016-05-01 The role of radiotherapy in stabilizing metastatic bones is unclear. This systematic review assessed the effects of (1) radiotherapy, (2) radiotherapy combined with bisphosphonates, and (3) radiotherapy combined with RANK ligand (RANKL) inhibitors on bone quality and bone strength in bone metastases originating from solid tumors. Pubmed, EMBASE and the Cochrane Library were searched. Any type of study design and type and dose of radiotherapy, bisphosphonates and RANKL inhibitors were allowed. 39 articles were identified. Animal studies showed that radiotherapy had similar effects on bone quality and strength as receiving no treatment, whereas adding bisphosphonates to radiotherapy restored bone quality and strength. In patient studies, bone density increased after radiotherapy and radiotherapy combined with bisphosphonates. However, due to the often non-optimal study design and study quality, it was unclear whether this increase could be attributed to these treatments. There was insufficient evidence to assess the additional effect of bisphosphonates or RANKL inhibitors. Despite the clinical experience that radiotherapy is an effective treatment for bone metastases, there was no sufficient evidence for a positive effect on bone quality and fracture risk. Animal studies showed that adding bisphosphonates to radiotherapy restored bone quality and strength, whereas this was not proven in patients. There were no studies addressing the adjunct effect of RANKL inhibitors to radiotherapy. Although associated with several methodological, practical and ethical challenges, randomized controlled trials are needed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved. 158. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody DTIC Science & Technology 2014-05-01 in May 2013, the difference between nude mice (which lack T- cells , but still have a partially functional adaptive and innate immune system) and NSG...Mangada J, Greiner DL, Handgretinger R. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human...Targeting of Cerebral Breast Cancer Metastases Using a T- Cell Receptor Mimic Antibody PRINCIPAL INVESTIGATOR: Ulrich Bickel 159. Breast cancer and bone metastases: the association of axial skeleton MRI findings with skeletal-related events and survival. PubMed van der Pol, Christian B; Schweitzer, Mark E; Di Primio, Gina; Sampaio, Marcos L; Kielar, Ania; Clemons, Mark; Jaberi, Arash 2014-08-01 The purpose of this study was to determine if bone metastasis characteristics on axial skeleton MRI are associated with either skeletal-related events (SREs) or survival in breast cancer patients. A retrospective review was performed on 247 breast cancer patients with bone metastases identified on axial skeleton MRI. MRI studies were reviewed for metastases T1 signal, signal uniformity, complete vertebral metastatic marrow replacement, metastases quantity, and distribution. Odds ratio (OR) and hazard ratios (HR) were calculated, with 95 % confidence intervals (95 % CI), to determine association with either future SREs or survival. At the time of analysis, 174 (70 %) patients had developed SREs and 176 (71 %) patients were dead. Features of skeletal metastases associated with SREs included the presence of complete metastatic marrow replacement within any vertebra; OR 2.363 (95 % CI 1.240-4.504, P = 0.0090), and more widely distributed metastases; OR 1.239 (95 % CI 1.070-1.435, P = 0.0040). Features associated with shorter survival included the presence of complete metastatic marrow replacement within any vertebra; HR 1.500 (95 % CI 1.105-2.036, P = 0.0093), and more widely distributed metastases; HR 1.141 (95 % CI 1.047-1.243, P = 0.0027). Metastases T1 signal, signal uniformity, and surprisingly quantity were not associated with SREs or survival. Axial skeleton MRI was able to identify characteristics predictive of future SREs and survival. These characteristics could be used for risk stratification for future trials if prospectively validated. 160. Management of long bone metastases: recommendations from the Italian Orthopaedic Society bone metastasis study group. PubMed Capanna, Rodolfo; Piccioli, Andrea; Di Martino, Alberto; Daolio, Primo Andrea; Ippolito, Vincenzo; Maccauro, Giulio; Piana, Raimondo; Ruggieri, Pietro; Gasbarrini, Alessandro; Spinelli, Maria Silvia; Campanacci, Domenico Andrea 2014-10-01 The purpose of this article is to outline the current approach to patients affected by metastasis to the long bones and to present a clinical and surgical algorithm available for clinicians and for future research. A modern approach to patients affected by long bone metastasis in fact requires a multidisciplinary contest where oncologists, radiotherapists, surgeons and physical therapists cooperate with a shared vision, in order to provide the best possible integrated treatments available. The authors of this article constitute the Bone Metastasis Study Group of the Italian Orthopaedic Society (SIOT): a national group of orthopedic tumor surgeons who are dedicated to studying the approach, techniques and outcomes of surgery for metastatic tumours of the musculoskeletal system. « 6 7 8 9 10 » « 7 8 9 10 11 » 161. Bone marrow metastases in an otherwise operable gall bladder cancer: rare site of distant metastases detected on FDG PET/CT. PubMed Puranik, Ameya D; Purandare, Nilendu; Agrawal, Archi; Shah, Sneha; Rangarajan, Venkatesh 2014-02-01 Primary carcinoma of gall bladder is a highly aggressive malignancy, most often detected in late stage in majority of the affected patients. It commonly spreads to the adjacent liver parenchyma and, via lymphatics, to mesenteric nodes. Extra-abdominal metastatic sites are extremely rare, with lung being the commonest site. We report a rare occurrence of isolated asymptomatic bone marrow metastases from gall bladder cancer, in the absence of locoregional adenopathy, detected on whole-body F-FDG PET/CT at initial staging. 162. Incidence of bone metastases in breast cancer patients in the United Kingdom: results of a multi-database linkage study using the general practice research database. PubMed Hagberg, Katrina Wilcox; Taylor, Aliki; Hernandez, Rohini Khorana; Jick, Susan 2013-06-01 Bone is a frequent site for metastases among women with breast cancer. We conducted a study using the General Practice Research Database (GPRD), with linkage to the National Cancer Registry (NCR) and Hospital Episode Statistics (HES), to estimate the incidence of bone metastases in women with breast cancer in the United Kingdom. We identified all women in the GPRD aged 20-99 with a first-time diagnosis of breast cancer between 2000 and 2006. To address potential underreporting, we developed and validated an algorithm to serve as a proxy for bone metastases. Bone metastases were defined as (1) a bone cancer diagnosis code on the same day or following breast cancer diagnosis date, or (2) another metastasis code plus codes consistent with bone metastases diagnosis or treatment using the algorithm. We sent questionnaires to a sample of general practitioners to validate these definitions. We included 13,207 breast cancer patients (median age at diagnosis of 61 years) who contributed 70,885 person-years of follow-up. The majority of patients had stage 1 or 2 breast cancer (90.4%), and 2.6% had metastatic breast cancer at diagnosis. We identified 788 women (6.0%) with bone metastases after a median follow-up of 5.4 years. Questionnaire results validated the diagnosis of bone metastases in 88% of patients with a bone cancer code and for 70% identified with the algorithm. This is the first time the GPRD has been linked to HES and NCR to study the epidemiology of bone metastases, adding important information on the burden of bone metastasis. Copyright © 2013 Elsevier Ltd. All rights reserved. 163. Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment SciTech Connect Park, Se Young; Kim, Hyun-Jeong; Kim, Ki Rim; Lee, Sun Kyoung; Lee, Chang Ki; Park, Kwang-Kyun Chung, Won-Yoon 2014-03-01 Many breast cancer patients experience bone metastases and suffer skeletal complications. The present study provides evidence on the protective and therapeutic potential of betulinic acid on cancer-associated bone diseases. Betulinic acid is a naturally occurring triterpenoid with the beneficial activity to limit the progression and severity of cancer, diabetes, cardiovascular diseases, atherosclerosis, and obesity. We first investigated its effect on breast cancer cells, osteoblastic cells, and osteoclasts in the vicious cycle of osteolytic bone metastasis. Betulinic acid reduced cell viability and the production of parathyroid hormone-related protein (PTHrP), a major osteolytic factor, in MDA-MB-231 human metastatic breast cancer cells stimulated with or without tumor growth factor-β. Betulinic acid blocked an increase in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin ratio by downregulating RANKL protein expression in PTHrP-treated human osteoblastic cells. In addition, betulinic acid inhibited RANKL-induced osteoclastogenesis in murine bone marrow macrophages and decreased the production of resorbed area in plates with a bone biomimetic synthetic surface by suppressing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Furthermore, oral administration of betulinic acid inhibited bone loss in mice intra-tibially inoculated with breast cancer cells and in ovariectomized mice causing estrogen deprivation, as supported by the restored bone morphometric parameters and serum bone turnover markers. Taken together, these findings suggest that betulinic acid may have the potential to prevent bone loss in patients with bone metastases and cancer treatmentinduced estrogen deficiency. - Highlights: • Betulinic acid reduced PTHrP production in human metastatic breast cancer cells. • Betulinic acid blocked RANKL/OPG ratio in PTHrP-stimulated human osteoblastic cells. • Betulinic 164. Elevated serum periostin levels in patients with bone metastases from breast but not lung cancer. PubMed Sasaki, Hidefumi; Yu, Chih-Yi; Dai, Meiru; Tam, Carmen; Loda, Massimo; Auclair, Daniel; Chen, Lan Bo; Elias, Anthony 2003-02-01
Periostin is a recently identified gene that is preferentially expressed in periosteum, indicating a potential role in bone formation and maintenance of structure. We independently identified and isolated periostin from cancer tissue, using the palindromic PCR-driven cDNA Differential Display technique. For the present work, we developed a novel sandwich chemiluminescence assay to detect serum periostin level using newly developed monoclonal and polyclonal antibodies. We investigated serum periostin levels in breast cancer and small cell lung cancer patients, especially in patients with bone metastasis. The study included 58 breast cancer and 44 small cell lung cancer patients. Serum periostin levels were elevated in breast cancer patients presenting with bone metastases (92.0 +/- 28.6 ng/ml) compared to similar breast cancer patients without evidence of bone metastasis (55.0 +/- 16.6 ng/ml, p = 0.04). No correlation was found between the serum periostin level and any other prognostic factors, such as clinical stage and lymph node metastasis in breast cancer. Serum periostin levels thus appear to serve as a marker of bone metastasis from breast cancer. In contrast, serum periostin levels were similar in samples from patients with small cell lung cancer who did or did not have bone metastasis. However, increasing T-stage and N-stage of patients with small cell lung cancer were correlated with higher periostin levels (T4, 126.5 +/- 29.7 ng/ml v.s. T2, 64.9 +/- 16.1 ng/ml, p = 0.03; and T4 v.s. T1, 36.3+/- 7.5 ng/ml, p = 0.01; N3, 108.7 +/- 17.3 ng/ml v.s. N2, 49.7+/- 10.9 ng/ml, p = 0.01). Periostin has a substantial homology with the insect cell adhesion molecule, fasciclin I. Thus, expression of periostin may facilitate tumor cell adhesion to the bone surface. In fact, we found by in situ RNA hybridization, that the periostin gene was highly expressed in the stromal cells immediately surrounding the tumor, but not within the breast cancer cells themselves. 165. Anatomical distribution and sclerotic activity of bone metastases from thyroid cancer assessed with F-18 sodium fluoride positron emission tomography. PubMed Schirrmeister, H; Buck, A; Guhlmann, A; Reske, S N 2001-07-01 Currently, bone scintigraphy (BS) is considered to lack sensitivity in detecting bone metastases (BM) from thyroid cancer. We evaluated the anatomical distribution and metabolic behavior of BM as well as the accuracy of BS with and without combination of whole-body iodine scintigraphy (WBI) in detecting metastatic bone disease in thyroid carcinoma. F18 positron emission tomography (PET), x-ray, BS, and WBI were performed in 35 patients with known or suspected bone metastases from papillary (9 patients) or follicular (26 patients) thyroid carcinoma. Twenty-two metastases were previously known in 14 patients. The indication was staging in 21 patients with high risk for BM, elevated thyroglobulin (Tg)-levels or evaluation of exact extent of BM (14 patients). In addition, results of WBI (35 patients), X-ray (35 patients) F-18 PET (35 patients), MRI of the spine (13 patients), and FDG-PET (15 patients) as well as the clinical course (1.5-4 years) were correlated. BM were detected in 18 patients. Solitary, bifocal, or multiple lesions were present in 9, 2, and 7 patients, respectively. The anatomical distribution of BM (n = 43) was as follows: spine, 42%; skull, 2%; thorax, 16%; femur, 9%; pelvis, 26%; humerus and clavicle, 5%. Sensitivity of BS in interpreting patients as positive or negative for having BM was 64%-85% (specificity, 95%-81%). The combination of BS and WBI was 100% sensitive in detecting metastatic bone disease. One patient had a single BM that was positive at BS but negative on WBI. All metastases were osteolytic on x-ray and two-thirds presented a missing or very limited osteosclerotic bone reaction on F-18 PET. Our data confirm the limited sensitivity of planar BS in detecting BM from thyroid cancer. The combination of BS and WBI, however, was highly accurate. Compared to other malignancies, the distribution pattern of BM presented a lower percentage of vertebral metastases and more patients with single metastases. Those findings in combination with a 166. Association of Quality and Quantity of Bone Metastases and Computed Tomography Volumetric Bone Mineral Density With Prevalence of Vertebral Fractures in Breast Cancer Patients. PubMed Neuhaus, Victor; Abdullayev, Nuran; Hellmich, Martin; Krämer, Stefan; Maintz, David; Krug, Barbara; Borggrefe, Jan 2016-10-01 In the present study, we investigated the potential for routine staging computed tomography (CT) to assess fracture risk in breast cancer patients. A total of 184 randomized CT data sets of women with breast cancer were studied. Intellispace Density software (Philips, Amsterdam, Netherlands) was used to determine the mean volumetric bone mineral density (vBMD) of 3 nonfractured vertebral bodies (T12-L4) and predictors according to the quantitative and qualitative tumor morphology. Two radiologists detected prevalent vertebral fractures and classified them (osteoporotic vs. metastatic). For the determination of an association between bone mineral density, metastatic vertebral bone involvement, and the prevalence of vertebral fractures, a statistical analysis was conducted using multivariable logistic regression and receiver operating characteristic analyses. Of 184 women, 50 (27%) were diagnosed with prevalent vertebral metastases, of whom, 42 had vertebral fractures (23%). Of these fractures, 20 were found to be osteoporotic (11%), and 22 were associated with metastatic bone disease (12%). The vBMD T score showed the strongest association with osteoporotic fractures (odds ratio, 2.9; 95% confidence interval, 1.4-6.0; area under the curve [AUC], 0.89; P < .01). Metastatic vertebral fractures showed a strong association with the simple prevalence of metastases, regardless of tumor size (odds ratio, 9.8; 95% confidence interval, 4.3-22.3; AUC, 0.90; P < .01). Compared with the prevalence of metastases in the multivariate receiver operating characteristic statistic, the further detection of tumor size T0 and cortical bone infiltration showed a nonsignificant greater association with prevalent vertebral fractures (AUC, 0.92, P = .3; and AUC, 0.93, P = .07). vBMD measurements and the detection of metastases and their morphology from routine staging CT allow the discrimination of breast cancer with and without vertebral fractures. The simple prevalence of vertebral 167. Prognostic Factors and Skeletal-Related Events in Patients with Small Cell Lung Cancer with Bone Metastases at the Time of Diagnosis. PubMed Kang, Eun Joo; Lee, Suk Young; Kim, Hong Jun; Min, Kyung Hoon; Hur, Gyu Young; Shim, Jae Jeong; Kang, Kyung Ho; Oh, Sang Cheul; Seo, Jae Hong; Lee, Sung Yong; Kim, Jun Suk 2016-01-01 The aim of this study was to evaluate the characteristics and prognostic factors of small cell lung cancer (SCLC) with bone metastases. We also investigated the characteristics and predictive factors of skeletal-related events (SREs) in these patients. Sixty-one patients who were first diagnosed with SCLC with bone metastases at our institution were included in this retrospective analysis. The overall survival (OS) of patients with bone metastases was shorter than that of patients without bone metastases (4.13 vs. 6.17 months, p = 0.015). Poor Eastern Cooperative Oncology Group (ECOG) performance status (PS; ≥2) and higher serum alkaline phosphatase (ALP; above upper normal limit × 2) were independent poor prognostic factors (p = 0.027 for ECOG PS, p = 0.002 for ALP). More than 1 SRE occurred in 21 patients (34.4%). Cervical spine metastasis, thoracic spine metastasis, pelvic bone metastasis, more than 5 bone metastatic regions and higher serum lactate dehydrogenase were correlated with the occurrence of SREs. Thoracic spinal metastasis was a strong predictive factor for the occurrence of SREs (odds ratio = 5.475; 95% CI: 1.080-27.755). Our study demonstrates the poor prognosis of SCLC patients with bone metastases. Physicians should treat SCLC patients with bone metastases with caution. © 2016 S. Karger AG, Basel. 168. Subjective and metabolic effects of clodronate in patients with advanced breast cancer and symptomatic bone metastases. PubMed Neri, B; Gemelli, M T; Sambataro, S; Colombi, L; Benvenuti, F; Ludovici, M; Pacini, P 1992-04-01 Twenty postmenopausal women (aged between 46 and 67 years old) with skeletal metastases from breast carcinoma were treated with clodronate 450 mg i.v. daily for 5 days and thereafter with 100 mg i.m. daily for 10 days. All patients received standard hormonal therapy (tamoxifen). Symptomatic pain (evaluated according to a linear analog scale), performance status (according to Karnofsky), serum alkaline phosphatase, serum creatinine and osteocalcin were measured before and after treatment on days 5, 15, 30 and 45. Scanning by radiology were performed pre- and post-therapy. Bone pain was significantly reduced in 15 out of 20 patients. After clodronate treatment the base line value of circulating osteocalcin (3.2 +/- 1.6 ng/ml) showed a significant increase on days 30 and 45 (p less than 0.001). Radiological assessment of bone lesions showed stable disease in 18 patients and progression in two patients. No adverse side effects were observed. These data show that clodronate provided pain relief in 75% of treated patients and the increase in circulating osteocalcin levels can be considered a marker of the stabilization of skeletal metastatic lesions. 169. Temporal Subtraction of Serial CT Images with Large Deformation Diffeomorphic Metric Mapping in the Identification of Bone Metastases. PubMed Sakamoto, Ryo; Yakami, Masahiro; Fujimoto, Koji; Nakagomi, Keita; Kubo, Takeshi; Emoto, Yutaka; Akasaka, Thai; Aoyama, Gakuto; Yamamoto, Hiroyuki; Miller, Michael I; Mori, Susumu; Togashi, Kaori 2017-11-01 Purpose To determine the improvement of radiologist efficiency and performance in the detection of bone metastases at serial follow-up computed tomography (CT) by using a temporal subtraction (TS) technique based on an advanced nonrigid image registration algorithm. Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. CT image pairs (previous and current scans of the torso) in 60 patients with cancer (primary lesion location: prostate, n = 14; breast, n = 16; lung, n = 20; liver, n = 10) were included. These consisted of 30 positive cases with a total of 65 bone metastases depicted only on current images and confirmed by two radiologists who had access to additional imaging examinations and clinical courses and 30 matched negative control cases (no bone metastases). Previous CT images were semiautomatically registered to current CT images by the algorithm, and TS images were created. Seven radiologists independently interpreted CT image pairs to identify newly developed bone metastases without and with TS images with an interval of at least 30 days. Jackknife free-response receiver operating characteristics (JAFROC) analysis was conducted to assess observer performance. Reading time was recorded, and usefulness was evaluated with subjective scores of 1-5, with 5 being extremely useful and 1 being useless. Significance of these values was tested with the Wilcoxon signed-rank test. Results The subtraction images depicted various types of bone metastases (osteolytic, n = 28; osteoblastic, n = 26; mixed osteolytic and blastic, n = 11) as temporal changes. The average reading time was significantly reduced (384.3 vs 286.8 seconds; Wilcoxon signed rank test, P = .028). The average figure-of-merit value increased from 0.758 to 0.835; however, this difference was not significant (JAFROC analysis, P = .092). The subjective usefulness survey response showed a median score of 5 for use of the technique 170. Mechanisms of Radiation-Induced Bone Loss and Effect on Prostate Cancer Bone Metastases DTIC Science & Technology 2012-06-01 Develop intravital multiphoton fluorescence microscopy (IVFM) for real-time imaging of osteocytes in calvariae of transgenic mice using i) GFP to...OT, OB counting) and in vivo bone imaging (months 6-10) 8 20 week old female C57Bl/6 mice (n=30) were used in this experiment. The mice were...divided into 2 groups. One group (group A, n=15) was imaged twice by microCT during the experiment that included a baseline microCT that was given 2 days 171. Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing. PubMed Kovaleva, Valentina; Geissler, Anna-Lena; Lutz, Lisa; Fritsch, Ralph; Makowiec, Frank; Wiesemann, Sebastian; Hopt, Ulrich T; Passlick, Bernward; Werner, Martin; Lassmann, Silke 2016-10-18 Targeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases. Case-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer Panel TM , MiSeq sequencing and data analyses (Illumina). By tNGS primary tumours were RAS wildtype in 5/14 and mutated in 9/14 (8/9 KRAS exon 2; 1/9 NRAS Exon 3) of cases. RAS mutation status was maintained in case-matched metastases throughout the disease course, albeit with altered allele frequencies. Case-matched analyses further identified a maximum of three sequence variants (mainly in APC, KRAS, NRAS, TP53) shared by all tumour specimens throughout the disease course per individual case. In addition, further case-matched de novo mutations were detected in synchronous and/or metachronous liver and/or lung metastases (e.g. in APC, ATM, FBXW7, FGFR3, GNAQ, KIT, PIK3CA, PTEN, SMAD4, SMO, STK11, TP53, VHL). Moreover, several de novo mutations were more frequent in synchronous (e.g. ATM, KIT, PIK3CA, SMAD4) or metachronous (e.g. FBXW7, SMO, STK11) lung metastases. Finally, some de novo mutations occurred only in metachronous lung metastases (CDKN2A, FGFR2, GNAS, JAK3, SRC). Together, this study employs an adapted FFPE-based tNGS approach to confirm conservation of RAS mutation status in primary and metastatic tissue specimens of CRC 172. Prostate Cancer Metastases Alter Bone Mineral and Matrix Composition Independent of Effects on Bone Architecture in Mice A Quantitative Study Using microCT and Raman Spectroscopy PubMed Central Bi, Xiaohong; Sterling, Julie A.; Merkel, Alyssa R.; Perrien, Daniel S.; Nyman, Jeffry; Mahadevan-Jansen, Anita 2013-01-01 Prostate cancer is the most common primary tumor and the second leading cause of cancer-related deaths in men in the United States. Prostate cancer bone metastases are characterized by abnormal bone remodeling processes and result in a variety of skeletal morbidities. Prevention of skeletal complications is a crucial element in prostate cancer management. This study investigated prostate cancer-induced alterations in the molecular composition and morphological structure of metastasis-bearing bones in a mouse model of prostate cancer using Raman spectroscopy and micro-computed tomography (microCT). LNCaP C4-2B prostate cancer cells were injected into the right tibiae of 5-week old male SCID mice. Upon sacrifice at 8 weeks post tumor inoculation, two out of the ten tumor-bearing tibiae showed only osteoblastic lesions in the radiographs, 4 osteolytic lesions only and 4 mixed with osteoblastic and osteolytic lesions.. Carbonate substitution was significantly increased while there was a marked reduction in the level of collagen mineralization, mineral crystallinity, and carbonate:matrix ratio in the cortex of the intact tumor-bearing tibiae compared to contralateral controls. MicroCT analysis revealed a significant reduction in bone volume/total volume, trabecular number and trabecular thickness, as well as significant increase in bone surface/volume ratio in tibiae with osteolytic lesions, suggesting active bone remodeling and bone loss. None of the changes in bone compositional properties were correlated with lesion area from radiographs or the changes in bone architecture from microCT. This study indicates that LNCaP C4-2B prostate cancer metastases alter bone tissue composition independent of changes in architecture, and altered bone quality may be an important contributor to fracture risk in these patients. Raman spectroscopy may provide a new avenue of investigation into interactions between tumor and bone microenvironment. PMID:23867219 173. Fractionation of Palliative Radiation Therapy for Bone Metastases in Ontario: Do Practice Guidelines Guide Practice? SciTech Connect Ashworth, Allison; Cancer Center of Southeastern Ontario, Kingston, Ontario; Kong, Weidong 2016-01-01 Purpose: To evaluate the effect of a provincial practice guideline on the fractionation of palliative radiation therapy for bone metastases (PRT.B) in Ontario. Methods and Materials: The present retrospective study used electronic treatment records linked to Ontario's population-based cancer registry. Hierarchical multivariable regression analysis was used to evaluate temporal trends in the use of single fractions (SFs), controlling for patient-related factors associated with the use of SFs. Results: From 1984 to 2012, 43.9% of 161,835 courses of PRT.B were administered as SFs. The percentage of SF courses was greater for older patients (age <50 years, 39.8% vs age >80 years, 52.5%), thosemore » with a shorter life expectancy (survival >12 months, 36.9% vs < 1 month, 53.6%), and those who lived farther from a radiation therapy center (<10 km, 42.1% vs > 50 km, 47.3%). The percentage of SFs to spinal fields was lower than that to other skeletal sites (31.5% vs 57.1%). The percentage of SFs varied among the cancer centers (range, 26.0%-67.8%). These differences were all highly significant in the multivariable analysis (P<.0001). In 2004, Cancer Care Ontario released a practice guideline endorsing the use of SFs for uncomplicated bone metastases. The rate of use of SFs increased from 42.3% in the pre-guideline period (1999-2003) to 52.6% in the immediate post-guideline period (20042007). However, it subsequently decreased again to 44.0% (2009-2012). These temporal trends were significant after controlling for patient-related factors in the multivariable analysis (P<.0001). Large intercenter variations in the use of SFs persisted after publication of the guideline. Conclusions: The publication of an Ontario practice guideline endorsing the use of SF PRT.B was associated with only a transient increase in the use of SFs in Ontario and did little to reduce intercenter variations in fractionation.« less 174. Fractionation of Palliative Radiation Therapy for Bone Metastases in Ontario: Do Practice Guidelines Guide Practice? SciTech Connect Ashworth, Allison; Kong, Weidong; Chow, Edward; Mackillop, William J. 2016-01-01 Purpose: To evaluate the effect of a provincial practice guideline on the fractionation of palliative radiation therapy for bone metastases (PRT.B) in Ontario. Methods and Materials: The present retrospective study used electronic treatment records linked to Ontario's population-based cancer registry. Hierarchical multivariable regression analysis was used to evaluate temporal trends in the use of single fractions (SFs), controlling for patient-related factors associated with the use of SFs. Results: From 1984 to 2012, 43.9% of 161,835 courses of PRT.B were administered as SFs. The percentage of SF courses was greater for older patients (age <50 years, 39.8% vs age >80 years, 52.5%), those with a shorter life expectancy (survival >12 months, 36.9% vs < 1 month, 53.6%), and those who lived farther from a radiation therapy center (<10 km, 42.1% vs > 50 km, 47.3%). The percentage of SFs to spinal fields was lower than that to other skeletal sites (31.5% vs 57.1%). The percentage of SFs varied among the cancer centers (range, 26.0%-67.8%). These differences were all highly significant in the multivariable analysis (P<.0001). In 2004, Cancer Care Ontario released a practice guideline endorsing the use of SFs for uncomplicated bone metastases. The rate of use of SFs increased from 42.3% in the pre-guideline period (1999-2003) to 52.6% in the immediate post-guideline period (2004-2007). However, it subsequently decreased again to 44.0% (2009-2012). These temporal trends were significant after controlling for patient-related factors in the multivariable analysis (P<.0001). Large intercenter variations in the use of SFs persisted after publication of the guideline. Conclusions: The publication of an Ontario practice guideline endorsing the use of SF PRT.B was associated with only a transient increase in the use of SFs in Ontario and did little to reduce intercenter variations in fractionation. 175. A systematic review on in vitro 3D bone metastases models: A new horizon to recapitulate the native clinical scenario? PubMed Salamanna, Francesca; Contartese, Deyanira; Maglio, Melania; Fini, Milena 2016-07-12 While the skeleton is not the only organ where metastasis can occur, it is one of the preferred sites, with a significant impact in patients' quality of life. With the aim of delineating the cellular and molecular mechanisms of bone metastasis, numerous studies have been employed to identify any contributing factors that trigger cancer progression. One of the major limitations of studying cancer-bone metastasis is the multifaceted nature of the native bone environment and the lack of reliable, simple, and not expensive models that strictly mimic the biological processes occurring in vivo allowing a correct translation of results. Currently, with the growing acceptance of in vitro models as effective tools for studying cancer biology, three-dimensional (3D) models have emerged as a compromise between two-dimensional cultures of isolated cancer cells and the complexity of human cancer xenografts in immunocompromised animal hosts. This descriptive systematic literature review summarizes the current status of advanced and alternative 3D in vitro bone metastases models. We have also reviewed the strategies employed by researchers to set-up these models with special reference to recent promising developments trying to better replicate the complexity and heterogeneity of a human metastasis in situ, with an outlook at their use in medicine. All these aspects will greatly contribute to the existing knowledge on bone metastases, providing a specific link to clinical scenarios and thus making 3D in vitro bone metastasis models an attractive tool for multidisciplinary experts. 176. A systematic review on in vitro 3D bone metastases models: A new horizon to recapitulate the native clinical scenario? PubMed Central Salamanna, Francesca; Contartese, Deyanira; Maglio, Melania; Fini, Milena 2016-01-01 While the skeleton is not the only organ where metastasis can occur, it is one of the preferred sites, with a significant impact in patients' quality of life. With the aim of delineating the cellular and molecular mechanisms of bone metastasis, numerous studies have been employed to identify any contributing factors that trigger cancer progression. One of the major limitations of studying cancer-bone metastasis is the multifaceted nature of the native bone environment and the lack of reliable, simple, and not expensive models that strictly mimic the biological processes occurring in vivo allowing a correct translation of results. Currently, with the growing acceptance of in vitro models as effective tools for studying cancer biology, three-dimensional (3D) models have emerged as a compromise between two-dimensional cultures of isolated cancer cells and the complexity of human cancer xenografts in immunocompromised animal hosts. This descriptive systematic literature review summarizes the current status of advanced and alternative 3D in vitro bone metastases models. We have also reviewed the strategies employed by researchers to set-up these models with special reference to recent promising developments trying to better replicate the complexity and heterogeneity of a human metastasis in situ, with an outlook at their use in medicine. All these aspects will greatly contribute to the existing knowledge on bone metastases, providing a specific link to clinical scenarios and thus making 3D in vitro bone metastasis models an attractive tool for multidisciplinary experts. PMID:27027241 177. Repeatability of quantitative parameters of 18F-fluoride PET/CT and biochemical tumour and specific bone remodelling markers in prostate cancer bone metastases. PubMed Wassberg, Cecilia; Lubberink, Mark; Sörensen, Jens; Johansson, Silvia 2017-12-01 18F-fluoride PET/CT exhibits high sensitivity to delineate and measure the extent of bone metastatic disease in patients with prostate cancer. 18F-fluoride PET/CT could potentially replace traditional bone scintigraphy in clinical routine and trials. However, more studies are needed to assess repeatability and biological uptake variation. The aim of this study was to perform test-retest analysis of quantitative PET-derived parameters and blood/serum bone turnover markers at the same time point. Ten patients with prostate cancer and verified bone metastases were prospectively included. All underwent two serial 18F-fluoride PET/CT at 1 h post-injection. Up to five dominant index lesions and whole-body 18F-fluoride skeletal tumour burden were recorded per patient. Lesion-based PET parameters were SUVmax, SUVmean and functional tumour volume applying a VOI with 50% threshold (FTV 50% ). The total skeletal tumour burden, total lesion 18F-fluoride (TLF), was calculated using a threshold of SUV of ≥15. Blood/serum biochemical bone turnover markers obtained at the time of each PET were PSA, ALP, S-osteocalcin, S-beta-CTx, 1CTP and BAP. A total of 47 index lesions and a range of 2-122 bone metastases per patient were evaluated. Median time between 18F-fluoride PET/CT was 7 days (range 6-8 days). Repeatability coefficients were for SUVmax 26%, SUVmean 24%, FTV 50% for index lesions 23% and total skeletal tumour burden (TLF) 35%. Biochemical bone marker repeatability coefficients were for PSA 19%, ALP 23%, S-osteocalcin 18%, S-beta-CTx 22%, 1CTP 18% and BAP 23%. Quantitative 18F-fluoride uptake and simultaneous biochemical bone markers measurements are reproducible for prostate cancer metastases and show similar magnitude in test-retest variation. 178. Phase II study of concurrent capecitabine and external beam radiotherapy for pain control of bone metastases of breast cancer origin. PubMed Kundel, Yulia; Nasser, Nicola J; Purim, Ofer; Yerushalmi, Rinat; Fenig, Eyal; Pfeffer, Raphael M; Stemmer, Salomon M; Rizel, Shulamith; Symon, Zvi; Kaufman, Bella; Sulkes, Aaron; Brenner, Baruch 2013-01-01 Pain from bone metastases of breast cancer origin is treated with localized radiation. Modulating doses and schedules has shown little efficacy in improving results. Given the synergistic therapeutic effect reported for combined systemic chemotherapy with local radiation in anal, rectal, and head and neck malignancies, we sought to evaluate the tolerability and efficacy of combined capecitabine and radiation for palliation of pain due to bone metastases from breast cancer. Twenty-nine women with painful bone metastases from breast cancer were treated with external beam radiation in 10 fractions of 3 Gy, 5 fractions a week for 2 consecutive weeks. Oral capecitabine 700 mg/m(2) twice daily was administered throughout radiation therapy. Rates of complete response, defined as a score of 0 on a 10-point pain scale and no increase in analgesic consumption, were 14% at 1 week, 38% at 2 weeks, 52% at 4 weeks, 52% at 8 weeks, and 48% at 12 weeks. Corresponding rates of partial response, defined as a reduction of at least 2 points in pain score without an increase in analgesics consumption, were 31%, 38%, 28%, 34% and 38%. The overall response rate (complete and partial) at 12 weeks was 86%. Side effects were of mild intensity (grade I or II) and included nausea (38% of patients), weakness (24%), diarrhea (24%), mucositis (10%), and hand and foot syndrome (7%). External beam radiation with concurrent capecitabine is safe and tolerable for the treatment of pain from bone metastases of breast cancer origin. The overall and complete response rates in our study are unusually high compared to those reported for radiation alone. Further evaluation of this approach, in a randomized study, is warranted. ClinicalTrials.gov NCT01784393NCT01784393. 179. Efficacy of single fraction conventional radiation therapy for painful uncomplicated bone metastases: a systematic review and meta-analysis. PubMed Chow, Ronald; Hoskin, Peter; Hollenberg, Drew; Lam, Michael; Dennis, Kristopher; Lutz, Stephen; Lam, Henry; Mesci, Aruz; DeAngelis, Carlo; Chan, Stephanie; Chow, Edward 2017-04-01 Single fraction radiotherapy (SFRT) and multiple fraction radiotherapy (MFRT) are effective for painful uncomplicated bone metastases and have been shown to be of similar efficacy. The optimal conventional external beam SFRT dose for maximum pain relief remains uncertain. The aim of this systematic review was to comprehensively review and synthesize overall pain response rates by dose. A literature search was conducted in Ovid MEDLINE(R) (1946 to June 2016 week 3), Embase Classic & Embase (1947 to 2016 week 26) and Cochrane Central Register of Controlled Trials (May 2016) using keywords such as bone metastases, radiotherapy and single fraction (SF). The 635 results from the search were screened, and ultimately 27 were included for quantitative synthesis. The review indicated that 10 and 6 Gy may produce superior overall response (OR) and complete response (CR) rates compared to 8 Gy, and 6 Gy may result in better partial response (PR) than 8 Gy. However, only a few studies documented doses other than 8 Gy. In trials that directly compared 8 Gy to 4 Gy or 6 Gy, 8 Gy was deemed statistically superior. 8 Gy SFRT was the most commonly administered dose for palliation of bone metastases supporting its efficacy and safety. Future studies should explore the efficacy of 10 Gy while minimizing its side effects. 180. Prognostic value of the bone scan index using a computer-aided diagnosis system for bone scans in hormone-naive prostate cancer patients with bone metastases. PubMed Miyoshi, Yasuhide; Yoneyama, Shuko; Kawahara, Takashi; Hattori, Yusuke; Teranishi, Jun-ichi; Kondo, Keiichi; Moriyama, Masatoshi; Takebayashi, Shigeo; Yokomizo, Yumiko; Yao, Masahiro; Uemura, Hiroji; Noguchi, Kazumi 2016-02-19 The bone scan index (BSI) using a computer-aided diagnosis system for bone scans is expected to be an objective and quantitative clinical tool for evaluating bone metastatic prostate cancer. This study aimed to evaluate the pretreatment BSI as a prognostic factor in hormone-naive prostate cancer patients with bone metastases. The study included 60 patients with hormone-naive, bone metastatic prostate cancer that was initially treated with combined androgen blockade therapy. The BONENAVI system was used for calculating the BSI. We evaluated the correlation between overall survival (OS) and pretreatment clinicopathological characteristics, including patients' age, initial prostate-specific antigen (PSA) value, Gleason scores, clinical TNM stage, and the BSI. Cox proportional hazards regression models were used for statistical analysis. The median follow-up duration was 21.4 months. Clinical or PSA progression occurred in 37 (61.7%) patients and 18 (30.0%) received docetaxel. Death occurred in 16 (26.7%) patients. Of these deaths, 15 (25.0%) were due to prostate cancer. The median OS was not reached. In multivariate analysis, age and the BSI were independent prognostic factors for OS. We evaluated the discriminatory ability of our models, including or excluding BSI by quantifying the C-index. The BSI improved the C-index from 0.751 to 0.801 for OS. Median OS was not reached in patients with a BSI â ‰¤ 1.9 and median OS was 34.8 months in patients with a BSI >1.9 (p = 0.039). The pretreatment BSI and patients' age are independent prognostic factors for patients with hormone-naive, bone metastatic prostate cancer. « 7 8 9 10 11 » « 8 9 10 11 12 » 181. Efficacy of multiple fraction conventional radiation therapy for painful uncomplicated bone metastases: A systematic review. PubMed Chow, Ronald; Hoskin, Peter; Chan, Stephanie; Mesci, Aruz; Hollenberg, Drew; Lam, Henry; DeAngelis, Carlo; Chow, Edward 2017-03-01 Radiation therapy is effective for painful uncomplicated bone metastases, with multiple fraction radiation therapy (MFRT) administered frequently. The optimal dose for MFRT to yield maximum pain relief remains unclear. The aim of this systematic review was to determine pain response across MFRT doses. A literature search was conducted in Ovid MEDLINE(R) <1946 to July Week 3 2016>, Embase Classic & Embase <1947 to 2016Week 30> and Cochrane Central Register of Controlled Trials . Pain response rates and the side effects for MFRT doses were extracted. From the 3719 articles identified from the search, 17 were included for quantitative synthesis. 22.5Gy/5 had the highest overall response (OR) rate, 30Gy/15 had better complete response (CR) rate and 20Gy/2 had better partial response (PR) rate. Only 4 of the 17 included studies directly compared MFRT doses with each other - one reported marginally-better OR for 24Gy/6 over 20Gy/2; another found 20Gy/10 to be slightly more efficacious than 30Gy/15 and 22.5Gy/5 for OR. Two randomized trials compared 20Gy/5 and 30Gy/10 - one favored 20Gy/5 while the other concluded 30Gy/10 to be the better option. The overall rate of GI toxicities, nausea, and vomiting did not differ greatly between MFRT doses. No major difference exists between the schedules and toxic events studied in these trials. This is consistent with the wealth of randomized data which show no dose response for pain relief after radiotherapy for metastatic bone pain. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved. 182. SU-D-303-01: Spatial Distribution of Bone Metastases In Metastatic Castrate-Resistant Prostate Cancer SciTech Connect Perk, T; Bradshaw, T; Harmon, S; Perlman, S; Liu, G; Jeraj, R 2015-06-15 Purpose: Identification of metastatic bone lesions is critical in prostate cancer, where treatments may be more effective in patients with fewer lesions. This study aims characterize the distribution and spread of bone lesions and create a probability map of metastatic spread in bone. Methods: Fifty-five metastatic castrate-resistant prostate cancer patients received up to 3 whole-body [F-18]NaF PET/CT scans. Lesions were identified by physician on PET/CT and contoured using a threshold of SUV>15. An atlas-based segmentation method was used to create CT regions, which determined skeletal location of lesions. Patients were divided into 3 groups with low (N<40), medium (40100) numbers of lesions. A combination of articulated and deformable registrations was used to register the skeletal segments and lesions of each patient to a single skeleton. All the lesion data was then combined to make a probability map. Results: A total of 4038 metastatic lesions (mean 74, range 2–304) were identified. Skeletal regions with highest occurrence of lesions included ribs, thoracic spine, and pelvis with 21%, 19%, and 15% of the total number lesions and 8%, 18%, and 31 % of the total lesion volume, respectively. Interestingly, patients with fewer lesions were found to have a lower proportion of lesions in the ribs (9% in low vs. 27% in high number of lesions). Additionally, the probability map showed specific areas in the spine and pelvis where over 75% of patients had metastases, and other areas in the skeleton with a less than 2% of metastases. Conclusion: We identified skeletal regions with higher incidence of metastases and specific sub-regions in the skeleton that had high or low probability of occurrence of metastases. Additionally, we found that metastatic lesions in the ribs and skull occur more commonly in advanced disease. These results may have future applications in computer-aided diagnosis. Funding from the Prostate Cancer Foundation.
183. [Risk of radionecrosis after hypofractionated stereotactic radiotherapy targeting the postoperative resection cavity of brain metastases]. PubMed Keller, A; Doré, M; Antoni, D; Menoux, I; Thillays, F; Clavier, J B; Delpon, G; Jarnet, D; Bourrier, C; Lefebvre, F; Chibbaro, S; Darié, I; Proust, F; Noël, G 2017-08-01 To investigate the factors that potentially lead to brain radionecrosis after hypofractionated stereotactic radiotherapy targeting the postoperative resection cavity of brain metastases. A retrospective analysis conducted in two French centres, was performed in patients treated with trifractionated stereotactic radiotherapy (3×7.7Gy prescribed to the 70% isodose line) for resected brain metastases. Patients with previous whole-brain irradiation were excluded of the analysis. Radionecrosis was diagnosed according to a combination of criteria including clinical, serial imaging or, in some cases, histology. Univariate and multivariate analyses were performed to determine the predictive factors of radionecrosis including clinical and dosimetric variables such as volume of brain receiving a specific dose (V8Gy-V22Gy). One hundred eighty-one patients, with a total of 189 cavities were treated between March 2008 and February 2015. Thirty-five patients (18.5%) developed radionecrosis after a median follow-up of 15 months (range: 3-38 months) after hypofractionated stereotactic radiotherapy. One third of patients with radionecrosis were symptomatic. Multivariate analysis showed that infra-tentorial location was predictive of radionecrosis (hazard ratio [HR]: 2.97; 95% confidence interval [95% CI]: 1.47-6.01; P=0.0025). None V8Gy-V22Gy was associated with appearance of radionecrosis, even if V14Gy trended toward significance (P=0.059). Analysis of patients and treatment variables revealed that infratentorial location of brain metastases was predictive for radionecrosis after hypofractionated stereotactic radiotherapy for postoperative resection cavities. Copyright © 2017. Published by Elsevier SAS. 184. Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment SciTech Connect Park, Se Young; Kim, Hyun-Jeong; Kim, Ki Rim 2014-03-01 Many breast cancer patients experience bone metastases and suffer skeletal complications. The present study provides evidence on the protective and therapeutic potential of betulinic acid on cancer-associated bone diseases. Betulinic acid is a naturally occurring triterpenoid with the beneficial activity to limit the progression and severity of cancer, diabetes, cardiovascular diseases, atherosclerosis, and obesity. We first investigated its effect on breast cancer cells, osteoblastic cells, and osteoclasts in the vicious cycle of osteolytic bone metastasis. Betulinic acid reduced cell viability and the production of parathyroid hormone-related protein (PTHrP), a major osteolytic factor, in MDA-MB-231 human metastatic breast cancer cells stimulatedmore » with or without tumor growth factor-β. Betulinic acid blocked an increase in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin ratio by downregulating RANKL protein expression in PTHrP-treated human osteoblastic cells. In addition, betulinic acid inhibited RANKL-induced osteoclastogenesis in murine bone marrow macrophages and decreased the production of resorbed area in plates with a bone biomimetic synthetic surface by suppressing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Furthermore, oral administration of betulinic acid inhibited bone loss in mice intra-tibially inoculated with breast cancer cells and in ovariectomized mice causing estrogen deprivation, as supported by the restored bone morphometric parameters and serum bone turnover markers. Taken together, these findings suggest that betulinic acid may have the potential to prevent bone loss in patients with bone metastases and cancer treatmentinduced estrogen deficiency. - Highlights: • Betulinic acid reduced PTHrP production in human metastatic breast cancer cells. • Betulinic acid blocked RANKL/OPG ratio in PTHrP-stimulated human osteoblastic cells. â 185. A Simple and Effective Daily Pain Management Method for Patients Receiving Radiation Therapy for Painful Bone Metastases SciTech Connect Andrade, Regiane S.; Proctor, Julian W.; Slack, Robert; Marlowe, Ursula; Ashby, Karlotta R.; Schenken, Larry L. 2010-11-01 Purpose: The incidence of painful bone metastases increases with longer survival times. Although external beam radiation therapy (EBRT) is an effective palliative treatment, it often requires several days from the start of treatment to produce a measurable reduction in pain scores and a qualitative amelioration of patient pain levels. Meanwhile, the use of analgesics remains the best approach early on in the treatment course. We investigated the role of radiation therapists as key personnel for collecting daily pain scores to supplement assessments by physician and oncology nursing staff and manage pain more effectively during radiation treatment. Methods and Materials: Daily pain scores were obtained by the radiation therapists for 89 patients undertaking a total of 124 courses of EBRT for bone metastases and compared with pretreatment pain scores. The majority of patients (71%) were treated to 30 Gy (range, 20-37.5) in 10 fractions (range, 8-15 fractions). Results: One hundred nineteen treatment courses (96%) were completed. Pain scores declined rapidly to 37.5%, 50%, and 75% of the pretreatment levels by Days 2, 4, and 10, respectively. Pain was improved in 91% of patients with only 4% of worse pain at the end of treatment. Improved pain scores were maintained in 83% of patients at 1-month follow-up, but in 35% of them, the pain was worse than at the end of treatment. Conclusions: Collection of daily pain scores by radiation therapists was associated with an effective reduction in pain scores early on during EBRT of painful osseous metastases. 186. Palliative therapy with I-131 labeled bezylidenediphosphonic acid: In vivo kinetics and response to pain induced by bone metastases SciTech Connect Eisenhut, M.; Berberich, R.; Kimmig, B. 1985-05-01 I-131 labeled ..cap alpha..-amino-(4-hydroxybenzylidene)diphosphonic acid (BDP3) was recently suggested as a palliative acting radiopharmaceutical against pain syndromes associated with disseminated bone metastases. Such an application was supported by the in vivo kinetics of I-131-BDP3 in rats. The authors investigated the palliative effectiveness of I-131-BDP3 in 18 patients with typical pain symptoms induced by bone metastases of various primary carcinoma. The blood clearance was rapid. More than 90% disappeared from the blood pool at 4 hr after injection. The excretion of the activity occured solely through the kidneys and the median total body retention at 48 hr was 51% (range 3064%).more » The thyroid activity decreased during therapy indicating no cleavage reactions as long as I-131-BDP3 is bound to the bone tissue. The binding of I-131-BDP3 to bone is very long since the effective half life was in the order of magnitude of the physical half life. Additionally the effective half lifes in the metastatic ares (median 182 hr; range 177-205 hr) proved to be longer than in unaffected areas (145 hr; 140-165 hr). The palliative therapies were performed with doses of 6 - 48 mCi. The response amounted to 44% complete pain relief, 6% substantial pain relief, 22% minimal improvement and 28% no change. The duration of response ranged between 1 and 8 weeks.« less 187. Palliative therapy with I-131 labeled bezylidenediphosphonic acid: In vivo kinetics and response to pain induced by bone metastases SciTech Connect Eisenhut, M.; Berberich, R.; Kimmig, B.; Oberhausen, E.; Georgi, P.; Zum Winkel, K. 1985-05-01 I-131 labeled ..cap alpha..-amino-(4-hydroxybenzylidene)diphosphonic acid (BDP3) was recently suggested as a palliative acting radiopharmaceutical against pain syndromes associated with disseminated bone metastases. Such an application was supported by the in vivo kinetics of I-131-BDP3 in rats. The authors investigated the palliative effectiveness of I-131-BDP3 in 18 patients with typical pain symptoms induced by bone metastases of various primary carcinoma. The blood clearance was rapid. More than 90% disappeared from the blood pool at 4 hr after injection. The excretion of the activity occured solely through the kidneys and the median total body retention at 48 hr was 51% (range 30-64%). The thyroid activity decreased during therapy indicating no cleavage reactions as long as I-131-BDP3 is bound to the bone tissue. The binding of I-131-BDP3 to bone is very long since the effective half life was in the order of magnitude of the physical half life. Additionally the effective half lifes in the metastatic ares (median 182 hr; range 177-205 hr) proved to be longer than in unaffected areas (145 hr; 140-165 hr). The palliative therapies were performed with doses of 6 - 48 mCi. The response amounted to 44% complete pain relief, 6% substantial pain relief, 22% minimal improvement and 28% no change. The duration of response ranged between 1 and 8 weeks. 188. Targeting BMI1+Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma. PubMed Chen, Demeng; Wu, Mansi; Li, Yang; Chang, Insoon; Yuan, Quan; Ekimyan-Salvo, Mari; Deng, Peng; Yu, Bo; Yu, Yongxin; Dong, Jiaqiang; Szymanski, John M; Ramadoss, Sivakumar; Li, Jiong; Wang, Cun-Yu 2017-05-04 Squamous cell carcinoma in the head and neck (HNSCC) is a common yet poorly understood cancer, with adverse clinical outcomes due to treatment resistance, recurrence, and metastasis. Putative cancer stem cells (CSCs) have been identified in HNSCC, and BMI1 expression has been linked to these phenotypes, but optimal treatment strategies to overcome chemotherapeutic resistance and eliminate metastases have not yet been identified. Here we show through lineage tracing and genetic ablation that BMI1 + CSCs mediate invasive growth and cervical lymph node metastasis in a mouse model of HNSCC. This model and primary human HNSCC samples contain highly tumorigenic, invasive, and cisplatin-resistant BMI1 + CSCs, which exhibit increased AP-1 activity that drives invasive growth and metastasis of HNSCC. Inhibiting AP-1 or BMI1 sensitized tumors to cisplatin-based chemotherapy, and it eliminated lymph node metastases by targeting CSCs and the tumor bulk, suggesting potential regimens to overcome resistance to treatments and eradicate HNSCC metastasis. Copyright © 2017 Elsevier Inc. All rights reserved. 189. Magnetic resonance guided focused ultrasound surgery (MRgFUS) of bone metastases: From primary pain palliation to local tumor control NASA Astrophysics Data System (ADS) Napoli, A.; Leonardi, A.; Andrani, F.; Boni, F.; Anzidei, M.; Catalano, C. 2017-03-01 Purpose: To evaluate the clinical performance of MRgFUS in primary pain palliation of painful bone metastases and in local tumor control. Materials and Methods: We enrolled 26 consecutive patients (female/male 12/14; age: 64.7±7.5yrs) with painful bone metastases. Before and 3 months after MRgFUS treatment pain severity and pain interference scores were assessed according to Brief Pain Inventory-Quality of Life (BPI-QoL) criteria and patients underwent both CT and MRI. Local tumor control was evaluated according to lesion size, density and perfusion at CT, dynamic contrast enhancement at MRI (Discovery 750HD, GE; Gd-Bopta, Bracco) and metabolic activity at PET or scintigraphy. Patients were classified as responders or non-responders. Results: No treatment-related adverse events were recorded during the study. As statistically significant difference between baseline and follow-up values for both pain severity and pain interference scores was observed (p<0.05). Increased bone density was observed in 9/26 (34.6%) patients. Non-Perfused Volume values ranged between 20% and 92%. There was no difference in NPV values between responders and non-responders (46.7±24.2% [25 - 90 %] vs. 45±24.9% [20 - 93 %]; p=0.7). In 6 patients (5 prostate and 1 breast primary cancer) there was nearly absence of metabolic activity after treatment (mean SUV=1.2). Conclusion: MRgFUS can be safely and effectively used as the primary treatment for pain palliation in patients with painful bone metastases; moreover our experience demonstrated also a potential role for the MRgFUS in local tumor control. 190. Safety and feasibility of image-guided robotic radiosurgery for patients with limited bone metastases of prostate cancer. PubMed Muacevic, Alexander; Kufeld, Markus; Rist, Carsten; Wowra, Berndt; Stief, Christian; Staehler, Michael 2013-05-01 To determine the safety and feasibility after image-guided single fraction robotic stereotactic radiosurgery (SRS) in patients with bone metastases of prostate cancer. Forty patients with 64 bone metastases of prostate cancer were prospectively enrolled in a single center study and underwent 54 consecutive outpatient single session SRS procedures during a 4year period. F-18 choline PET/CT in addition to standard CT imaging was done prior to SRS in all patients. Nineteen patients were under anti-androgen therapy, 8 patients had undergone chemotherapy before SRS. Overall survival and freedom from local tumor recurrence was analyzed with the Kaplan-Meier method. Mean follow-up was 14 months (3-48 months). Seventy-five percent of patients had a single bone metastasis. The median tumor volume was 13 cc. The mean prescribed tumor dose was 20.2 Gy (16.5-22 Gy). Eight patients had died at the time point of the data analysis. The actuarial 6-months, 12-months, and 24-months local tumor control rate was 95.5% (95% CI: 83.0-98.8) as measured by MRI and PET CT imaging. The median initial PSA before SRS was 5.4 ng/dl (CI: 1.4-8.2) and dropped to 2.7 ng/dl (CI: 0.14-10) after 3 months. One case of progressive neurological deficits was documented. This first report on single session, image-guided robotic SRS documents a safe, feasible, and patient-friendly treatment option in selected patients with bone metastases of prostate cancer. Copyright © 2013 Elsevier Inc. All rights reserved. 191. Dosimetric evaluation of radionuclides for VCAM-1-targeted radionuclide therapy of early brain metastases PubMed Central Falzone, Nadia; Ackerman, Nicole L.; Rosales, Liset de la Fuente; Bernal, Mario A.; Liu, Xiaoxuan; Peeters, Sarah GJA; Soto, Manuel Sarmiento; Corroyer-Dulmont, Aurélien; Bernaudin, Myriam; Grimoin, Elisa; Touzani, Omar; Sibson, Nicola R.; Vallis, Katherine A. 2018-01-01 Brain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this study was to use a model of early brain metastasis to evaluate the efficacy of α-emitting radionuclides, 149Tb, 211At, 212Pb, 213Bi and 225Ac; β-emitting radionuclides, 90Y, 161Tb and 177Lu; and Auger electron (AE)-emitters 67Ga, 89Zr, 111In and 124I, for targeted radionuclide therapy (TRT). METHODS: Histologic sections and two photon microscopy of mouse brain parenchyma were used to inform a cylindrical vessel geometry using the Geant4 general purpose Monte Carlo (MC) toolkit with the Geant4-DNA low energy physics models. Energy deposition was evaluated as a radial function and the resulting phase spaces were superimposed on a DNA model to estimate double-strand break (DSB) yields for representative β- and α-emitters, 177Lu and 212Pb. Relative biological effectiveness (RBE) values were determined by only evaluating DNA damage due to physical interactions. RESULTS: 177Lu produced 2.69 ± 0.08 DSB per GbpGy, without significant variation from the lumen of the vessel to a radius of 100 µm. The DSB yield of 212Pb included two local maxima produced by the 6.1 MeV and 8.8 MeV α-emissions from decay products, 212Bi and 212Po, with yields of 7.64 ± 0.12 and 9.15 ± 0.24 per GbpGy, respectively. Given its higher DSB yield 212Pb may be more effective for short range targeting of early micrometastatic lesions than 177Lu. CONCLUSION: MC simulation of a model of early brain metastases provides invaluable insight into the potential efficacy of α-, β- and AE-emitting radionuclides for TRT. 212Pb, which has the attributes of a theranostic radionuclide since it can be used for SPECT imaging, showed a favorable dose profile and RBE 192. Dosimetric evaluation of radionuclides for VCAM-1-targeted radionuclide therapy of early brain metastases. PubMed Falzone, Nadia; Ackerman, Nicole L; Rosales, Liset de la Fuente; Bernal, Mario A; Liu, Xiaoxuan; Peeters, Sarah Gja; Soto, Manuel Sarmiento; Corroyer-Dulmont, Aurélien; Bernaudin, Myriam; Grimoin, Elisa; Touzani, Omar; Sibson, Nicola R; Vallis, Katherine A 2018-01-01 Brain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this study was to use a model of early brain metastasis to evaluate the efficacy of α-emitting radionuclides, 149Tb, 211At, 212Pb, 213Bi and 225Ac; β-emitting radionuclides, 90Y, 161Tb and 177Lu; and Auger electron (AE)-emitters 67Ga, 89Zr, 111In and 124I, for targeted radionuclide therapy (TRT). Histologic sections and two photon microscopy of mouse brain parenchyma were used to inform a cylindrical vessel geometry using the Geant4 general purpose Monte Carlo (MC) toolkit with the Geant4-DNA low energy physics models. Energy deposition was evaluated as a radial function and the resulting phase spaces were superimposed on a DNA model to estimate double-strand break (DSB) yields for representative β- and α-emitters, 177Lu and 212Pb. Relative biological effectiveness (RBE) values were determined by only evaluating DNA damage due to physical interactions. 177Lu produced 2.69 ± 0.08 DSB per GbpGy, without significant variation from the lumen of the vessel to a radius of 100 µm. The DSB yield of 212Pb included two local maxima produced by the 6.1 MeV and 8.8 MeV α-emissions from decay products, 212Bi and 212Po, with yields of 7.64 ± 0.12 and 9.15 ± 0.24 per GbpGy, respectively. Given its higher DSB yield 212Pb may be more effective for short range targeting of early micrometastatic lesions than 177Lu. MC simulation of a model of early brain metastases provides invaluable insight into the potential efficacy of α-, β- and AE-emitting radionuclides for TRT. 212Pb, which has the attributes of a theranostic radionuclide since it can be used for SPECT imaging, showed a favorable dose profile and RBE. 193. Liver metastases MedlinePlus Metastases to the liver; Metastatic liver cancer; Liver cancer - metastatic; Colorectal cancer - liver metastases; Colon cancer - liver metastases; Esophageal cancer - liver metastases; Lung cancer - liver metastases; Melanoma - liver metastases 194. Single-dose half-body irradiation for the palliation of multiple bone metastases from solid tumors: a preliminary report SciTech Connect Salazar, O.M.; Rubin, P.; Hendrickson, F.R.; Poulter, C.; Zagars, G.; Feldman, M.I.; Asbell, S.; Doss, L. 1981-06-01 The on-going protocol of the Radiation Therapy Oncology Group RTOG number 78-10, which tests escalating single doses of half-body irradiation (HBI) for the palliation of multiple bone metastases, has accrued 108 patients as of August 1980. Of these, 91 patients are evaluable at this time. Lower half-body irradiation (LHBI) was given to 52 patients and another 12 patients received mid-body irradiation (MBI); both LHBI and MBI were targeted to receive escalating doses of 800 rad (27 patients,), 900 rad (25 patients), and 1000 rad (12 patients). The latter test dose still required another 13 patients for completion. The remaining 27 patients received upper half-body irradiation (UHBI) with single doses of 600 rad (24 patients), 700 rad (3 patients), and 800 rad (no patients). The 700 rad test dose just opened for accrual and patients will not enter the 800 rad category until the lower dose closes with approximately 25 patients. Of the 91 evaluable patients, 36% had breast, 35% prostate, and 18% lung primary tumors. Seventy patients (77%) had pain relief after HBI, 21% actually had complete subjective responses. Of all relieved patients, 50% achieved pain relief within two days after HBI and after a week, almost 80% had achieved relief. The duration of pain relief was substantial and persisted for 70% of the patient's remaining life. The technique has been well tolerated with minimal toxicity and no treatment-related fatalities were reported in the doses employed. Increasing the dose from 600 rad to 800 rad was beneficial, but 800 rad on (to 900 rad or 1000 rad) has not produced better symptomatic responses and may result in increased toxicity. HBI appears to be highly effective in achieving results similar to conventional (2 to 3 week) radiation with localized fields. 195. Intra-individual comparison of Tc-99m-MDP bone scan and the PSMA-ligand Tc-99m-MIP-1427 in patients with osseous metastasized prostate cancer. PubMed Rathke, Hendrik; Afshar-Oromieh, Ali; Giesel, Frederik L; Kremer, Christophe; Flechsig, Paul; Haufe, Sabine; Mier, Walter; Holland-Letz, Tim; de Bucourt, Maximilian; Armor, Thomas; Babich, John; Haberkorn, Uwe; Kratochwil, Clemens 2018-01-25 To evaluate the detection rate of bone metastases obtained with the PSMA targeting tracer 99m Tc-MIP-1427 as opposed to the conventional bone scan with 99m Tc-MDP in a collective of advanced stage patients with known osseous metastasized prostate cancer. Methods: 21 Patients with known metastatic disease were staged with both, conventional bone scan and PSMA-ligand scintigraphy, within a time-frame of <10 days. Imaging included planar whole-body scans and SPECT or SPECT/CT with two bed positions 3 h after injection of either 500-750 MBq 99m Tc-MIP-1427 or 600-750 MBq 99m Tc-MDP. Lesions were scored: typical tumor, equivocal (benign/malignant), or normal within a standard reporting schema divided into defined anatomical regions. Blind and consensus reads were performed with sequential un-blinding: first planar scans, then SPECT/CT, then best valuable comparator including MRI, PET/CT and follow-up exams. Results: 11 patients had PSMA-positive visceral metastases which were predictably not diagnosed with conventional bone scan. However, SPECT/CT was required to distinguish between soft tissue uptake and overlapping bone. 4 patients had extensive MDP negative bone marrow lesions. 7 patients had superscan character in bone scan; in contrast, extent of red marrow involvement was more evident by PSMA-scan. Only 3 patients had completely equal results in the bone-scan and PSMA-scan. Also more suspicious lesions were detected in 16 patients using PSMA-scan in comparison to bone-scan. In two patients (about 10 %) a PSMA-negative tumor phenotype was present. Conclusion: PSMA-scanning presented a clearly advantage versus bone-scans by reducing the number of equivocal findings, in most patients. SPECT/CT is pivotal to differentiate between benign (e.g. degenerative changes), bone metastases and extra-osseous tumor lesions. Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc. 196. Impact of a dedicated palliative radiation oncology service on the use of single fraction and hypofractionated radiation therapy among patients with bone metastases. PubMed Skamene, Sonia; Agarwal, Isha; Makar, Maggie; Krishnan, Monica; Spektor, Alex; Hertan, Lauren; Mouw, Kent W; Taylor, Allison; Noveroske Philbrick, Sarah; Balboni, Tracy 2017-11-30 Radiation therapy (RT) is frequently used to palliate symptomatic bone metastases. While high quality literature has shown that for uncomplicated bone metastases, shorter radiotherapy courses are just as effective as longer courses for the treatment of pain, shorter courses remain under-utilized. We aimed to assess the impact of a dedicated palliative radiation oncology service on the frequency of single fraction RT (SF-RT) and hypofractionated radiation (hypo-RT) (≤5 fractions) among patients with bone metastases. We identified 2,086 instances of palliative radiation (RT) for complicated and uncomplicated bone metastases between April 10, 2008 and September 17, 2014. We used multivariable logistic regression analysis (MVA) to estimate the association of the Supportive and Palliative Radiation Oncology (SPRO) service with the likelihood of receiving SF-RT or hypoRT after controlling for age, sex, tumor type, and treatment site. Prior to SPRO's implementation on July 1, 2011, the proportion of SF-RT and hypo-RT for bone metastases was 6.4% and 27.6% respectively. After SPRO's implementation, the proportion of SF-RT and hypo-RT increased to 22.3% (P<0.001) and 53.5% (P<0.001) respectively. In MVA, patients were more likely to receive SF-RT [odds ratio (OR) =3.3, 95% confidence interval (CI) =2.4-4.7, P<0.001], and hypo-RT (OR =2.5, 95% CI =2.0-3.1, P<0.001) after SPRO's implementation. Compared to sites without a dedicated palliative service, patients receiving care at the SPRO affiliated department were more likely to receive SF-RT (OR =1.9, 95% CI =1.1-3.2, P=0.02) and hypo-RT (OR =1.5, 95% CI =1.1-2.0, P=0.004) for bone metastases. After SPRO's implementation, the average number of RT courses delivered for bone metastases increased from 17.4 to 25.6 per month, (+8.3, 95% CI =4.99-11.55, P<0.001). Despite greater SF-RT and hypo-RT, the average total fractions per month of palliative RT for bone metastases increased from 163.5 pre-SPRO to 166.8 post-SPRO, though 197. Patterns of Practice in Palliative Radiotherapy for Painful Bone Metastases: Impact of a Regional Rapid Access Clinic on Access to Care SciTech Connect Wu, Jackson S.Y., E-mail:
[email protected]; Kerba, Marc; Wong, Rebecca K.S. 2010-10-01 Purpose: External beam radiotherapy (RT) is commonly indicated for the palliation of symptomatic bone metastases, but there is evidence of underutilization of this treatment modality in palliative care for cancer populations. This study was conducted to investigate factors that influenced the use of palliative RT services at a regional comprehensive cancer center. Methods and Materials: A cohort of patients with radiographically confirmed bone metastases and first-time users of palliative RT between 2003 and 2005 was retrospectively reviewed from the time of initial diagnosis of bone metastases to death or last follow-up. Type of radiation treatment service provider used (rapid accessmore » or routine access) and patient-, tumor-, and treatment-related factors were analyzed for their influences on the number of treatment courses given over the duration of disease. Results: A total of 887 patients received 1,354 courses of palliative RT for bone metastases at a median interval of 4.0 months between courses. Thirty-three percent of patients required more than one RT course. Increased age and travel distance reduced the likelihood and number of treatment courses, while service through a rapid access clinic was independently associated with an increase in subsequent use of palliative RT. Conclusions: A rapid access service model for palliative RT facilitated access to RT. Travel distance and other factors remained substantial barriers to use of palliative RT services. The pattern of practice suggests an unmet need for symptom control in patients with bone metastases.« less 198. Patterns of Practice in Palliative Radiotherapy for Painful Bone Metastases: Impact of a Regional Rapid Access Clinic on Access to Care SciTech Connect Wu, Jackson S.Y.; Kerba, Marc; Wong, Rebecca K.S.; Mckimmon, Erin; Eigl, Bernhard; Hagen, Neil A. 2010-10-01 Purpose: External beam radiotherapy (RT) is commonly indicated for the palliation of symptomatic bone metastases, but there is evidence of underutilization of this treatment modality in palliative care for cancer populations. This study was conducted to investigate factors that influenced the use of palliative RT services at a regional comprehensive cancer center. Methods and Materials: A cohort of patients with radiographically confirmed bone metastases and first-time users of palliative RT between 2003 and 2005 was retrospectively reviewed from the time of initial diagnosis of bone metastases to death or last follow-up. Type of radiation treatment service provider used (rapid access or routine access) and patient, tumor-, and treatment-related factors were analyzed for their influences on the number of treatment courses given over the duration of disease. Results: A total of 887 patients received 1,354 courses of palliative RT for bone metastases at a median interval of 4.0 months between courses. Thirty-three percent of patients required more than one RT course. Increased age and travel distance reduced the likelihood and number of treatment courses, while service through a rapid access clinic was independently associated with an increase in subsequent use of palliative RT. Conclusions: A rapid access service model for palliative RT facilitated access to RT. Travel distance and other factors remained substantial barriers to use of palliative RT services. The pattern of practice suggests an unmet need for symptom control in patients with bone metastases. 199. Healthcare resource use and costs associated with renal impairment in US patients with bone metastases from solid tumors. PubMed Qian, Yi; Arellano, Jorge; Bhowmik, Debajyoti; Thomson, Erin; Smith, David M; Hechmati, Guy; Song, Xue 2017-04-01 Introduction During cancer progression, more than half of patients develop renal insufficiency, including chronic kidney disease. The primary and secondary objectives of this study were to estimate healthcare resource use and costs, respectively, associated with renal impairment in patients with bone metastases from solid tumors in the United States. Methods and materials This was a retrospective, observational cohort study conducted using administrative claims data for individuals with solid tumors and bone metastases. Control patients were matched to renal impairment patients using propensity scores (ratio up to 3:1) based on demographics, clinical characteristics, and baseline costs. Average per-patient per-year healthcare resource utilization and costs (total costs and cost components; 2013 dollars) were reported. Results In total, 2616 renal impairment patients were matched to 7211 control patients. Renal impairment patients had greater healthcare resource use compared with controls, including a greater mean number of hospital admissions (4.4 versus 2.1), longer average stay per hospital admission (7.4 versus 6.5 days), as well as greater mean number of physician office visits (22.9 versus 18.8), emergency department visits (3.1 versus 2.0), and hospital-based outpatient visits (18.8 versus 16.0) compared with control patients. Total costs were > $50,000 higher among renal impairment patients ($142,267 versus $88,839; P < 0.001), with hospital costs accounting for $72,557 for renal impairment patients, and $27,858 for control patients ( P < 0.001). Conclusion The healthcare resource use and costs associated with renal impairment in patients with bone metastases from solid tumors is high; efforts to reduce renal impairment in this population, including the potential avoidance of nephrotoxic agents, are warranted. 200. Medical treatment of breast cancer bone metastasis: from bisphosphonates to targeted drugs. PubMed Erdogan, Bulent; Cicin, Irfan 2014-01-01 Breast cancer bone metastasis causing severe morbidity is commonly encountered in daily clinical practice. It causes pain, pathologic fractures, spinal cord and other nerve compression syndromes and life threatening hypercalcemia. Breast cancer metastasizes to bone through complicated steps in which numerous molecules play roles. Metastatic cells disrupt normal bone turnover and create a vicious cycle to which treatment efforts should be directed. Bisphosphonates have been used safely for more than two decades. As a group they delay time to first skeletal related event and reduce pain, but do not prevent development of bone metastasis in patients with no bone metastasis, and also do not prolong survival. The receptor activator for nuclear factor κB ligand inhibitor denosumab delays time to first skeletal related event and reduces the skeletal morbidity rate. Radionuclides are another treatment option for bone pain. New targeted therapies and radionuclides are still under investigation. In this review we will focus on mechanisms of bone metastasis and its medical treatment in breast cancer patients. « 8 9 10 11 12 » « 9 10 11 12 13 » 201. Effectiveness of 18F-FDG-PET/CT vs Bone Scintigraphy in Treatment Response Assessment of Bone Metastases in Breast Cancer. PubMed Al-Muqbel, Kusai M; Yaghan, Rami J 2016-05-01 The aim of the study was to examine the effectiveness of fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) versus bone scintigraphy (BS) in treatment response assessment of bone metastases in breast cancer.The medical records of breast cancer patients with metastatic bone disease were reviewed retrospectively in our hospital from the period of January 2003 until April 2014. We included in our study patients evaluated by BS and/or 18F-FDG-PET/CT. Group 1 included patients who underwent pre- and post-treatment BS. Group 2 included patients who underwent pre- and post-treatment 18F-FDG-PET/CT scans. Group 3 included patients who underwent pretreatment BS and post-treatment both modalities. Functional and structural bone changes were monitored on pre- and post-treatment scans.Group 1 included 71 patients, average age of 49.5 y (range 28-73 y). Post-treatment results were as follows: 34% stable disease, 43% progressed disease, 19% improved disease, 3% resolved disease, and 2% relapsed disease. Group 2 included 32 patients, average age 53.2 y (ranges between 37 and 78 y). Post-treatment results were as follows: 3% stable disease, 15% progressed disease, 15% improved disease, 53% resolved disease, and 14% relapsed disease. After treatment, the total symptomatic/imaging concordance rate was 51% in BS and 83% in 18FFDG-PET/CT. Structurally, most patients with newly diagnosed metastatic bone disease had predominantly osteolytic lesions, which became mixed or osteoblastic after treatment as noted on CT images of responders. Group 3 included 8 patients, average age 48.9 y (ranges 32-64 y). Five patients had stable disease according to BS. 18F-FDG-PET/CT was concordant in 3/5 patients and discordant in 2/5 patients. Three patients had progressed disease on BS with concordant findings on 18F-FDG-PET/CT.18F-FDG-PET/CT was found a powerful tool in treatment response assessment of bone metastases in breast cancer and consistent 202. External beam radiotherapy for palliation of painful bone metastases: pooled data bioeffect dose response analysis of dose fractionation NASA Astrophysics Data System (ADS) Naveen, T.; Supe, Sanjay S.; Ganesh, K. M.; Samuel, Jacob 2009-01-01
Bone metastases develop in up to 70% of newly diagnosed cancer patients and result in immobility, anxiety, and depression, severely diminishing the patients quality of life. Radiotherapy is a frequently used modality for bone metastasis and has been shown to be effective in reducing metastatic bone pain and in some instances, causing tumor shrinkage or growth inhibition. There is controversy surrounding the optimal fractionation schedule and total dose of external beam radiotherapy, despite many randomized trials and overviews addressing the issue. This study was undertaken to apply BED to clinical fractionation data of radiotherapeutic management of bone metastases in order to arrive at optimum BED values for acceptable level of response rate. A computerised literature search was conducted to identify all prospective clinical studies that addressed the issue of fractionation for the treatment of bone metastasis. The results of these studies were pooled together to form the database for the analysis. A total of 4111 number of patients received radiation dose ranging from 4 to 40.5 Gy in 1 to 15 fractions with dose per fraction ranging from 2 to 10 Gy. Single fraction treatments were delivered in 2013 patients and the dose varied from 4 to 10 Gy. Multifraction treatments were delivered in 2098 patients and the dose varied from 15 to 40.5 Gy. The biological effective dose (BED) was evaluated for each fractionation schedule using the linear quadratic model and an α/β value of 10 Gy. Response rate increased significantly beyond a BED value of 14.4 Gy (p < 0.01). Based on our analysis and indications from the literature about higher retreatment and fracture rate of single fraction treatments, minimum BED value of 14.4 Gy is recommended. 203. Study of a new bone-targeting titanium implant-bone interface. PubMed Liu, Xiangning; Zhang, Ye; Li, Shaobing; Wang, Yayu; Sun, Ting; Li, Zejian; Cai, Lizhao; Wang, Xiaogang; Zhou, Lei; Lai, Renfa New strategies involving bone-targeting titanium (Ti) implant-bone interface are required to enhance bone regeneration and osseointegration for orthopedic and dental implants, especially in osteoporotic subjects. In this study, a new dual-controlled, local, bone-targeting delivery system was successfully constructed by loading tetracycline-grafted simvastatin (SV)-loaded polymeric micelles in titania nanotube (TNT) arrays, and a bone-targeting Ti implant-bone interface was also successfully constructed by implanting the delivery system in vivo. The biological effects were evaluated both in vitro and in vivo. The results showed that Ti surfaces with TNT-bone-targeting micelles could promote cytoskeletal spreading, early adhesion, alkaline phosphatase activity, and extracellular osteocalcin concentrations of rat osteoblasts, with concomitant enhanced protein expression of bone morphogenetic protein (BMP)-2. A single-wall bone-defect implant model was established in normal and ovariectomized rats as postmenopausal osteoporosis models. Microcomputed tomography imaging and BMP-2 expression in vivo demonstrated that the implant with a TNT-targeting micelle surface was able to promote bone regeneration and osseointegration in both animal models. Therefore, beneficial biological effects were demonstrated both in vitro and in vivo, which indicated that the bone-targeting effects of micelles greatly enhance the bioavailability of SV on the implant-bone interface, and the provision of SV-loaded targeting micelles alone exhibits the potential for extensive application in improving local bone regeneration and osseointegration, especially in osteoporotic subjects. 204. Study of a new bone-targeting titanium implant–bone interface PubMed Central Liu, Xiangning; Zhang, Ye; Li, Shaobing; Wang, Yayu; Sun, Ting; Li, Zejian; Cai, Lizhao; Wang, Xiaogang; Zhou, Lei; Lai, Renfa 2016-01-01 New strategies involving bone-targeting titanium (Ti) implant–bone interface are required to enhance bone regeneration and osseointegration for orthopedic and dental implants, especially in osteoporotic subjects. In this study, a new dual-controlled, local, bone-targeting delivery system was successfully constructed by loading tetracycline-grafted simvastatin (SV)-loaded polymeric micelles in titania nanotube (TNT) arrays, and a bone-targeting Ti implant–bone interface was also successfully constructed by implanting the delivery system in vivo. The biological effects were evaluated both in vitro and in vivo. The results showed that Ti surfaces with TNT–bone-targeting micelles could promote cytoskeletal spreading, early adhesion, alkaline phosphatase activity, and extracellular osteocalcin concentrations of rat osteoblasts, with concomitant enhanced protein expression of bone morphogenetic protein (BMP)-2. A single-wall bone-defect implant model was established in normal and ovariectomized rats as postmenopausal osteoporosis models. Microcomputed tomography imaging and BMP-2 expression in vivo demonstrated that the implant with a TNT-targeting micelle surface was able to promote bone regeneration and osseointegration in both animal models. Therefore, beneficial biological effects were demonstrated both in vitro and in vivo, which indicated that the bone-targeting effects of micelles greatly enhance the bioavailability of SV on the implant–bone interface, and the provision of SV-loaded targeting micelles alone exhibits the potential for extensive application in improving local bone regeneration and osseointegration, especially in osteoporotic subjects. PMID:27932879 205. Pain Palliation in Patients with Bone Metastases Using Magnetic Resonance-Guided Focused Ultrasound with Conformal Bone System: A Preliminary Report PubMed Central Joo, Bio; Lee, Soo Hyeon; Choi, Hye Jin; Lim, Seung Tack; Rha, Sun Young; Rachmilevitch, Itay; Lee, Young Han; Suh, Jin-Suck 2015-01-01 Purpose We evaluated the safety and effectiveness of the Magnetic Resonance-guided Focused Ultrasound (MRgFUS) with the ExAblate Conformal Bone System for the palliation of painful bone metastases. Materials and Methods Our Institutional Review Board approved this study, and all patients gave informed consent prior to enrollment. A total of six painful metastatic bone lesions in five patients were treated using MRgFUS with the ExAblate Conformal Bone System for pain palliation. The follow-up sessions were at 3 days, 2 weeks, 1, 2, and 3 months, and 1 year after treatment. Efficacy was evaluated by the changes in visual analog scale (VAS) scores. At 3-months and 1-year follow-ups, unenhanced computed tomography and contrast-enhanced MR imaging examinations were performed. All adverse events were assessed to evaluate treatment safety. Results All patients showed significant pain relief within 2 weeks. Two patients experienced complete pain reduction that lasted for 1 year. Two other patients showed pain relief measured as VAS scores of 2 and 4 on their last follow-up. Although the remaining patient had experienced significant pain relief in two lesions, the VAS score re-increased on his last follow-up. The size of the enhancing soft tissue mass in metastatic lesions decreased, and new bone formation was seen on follow-up images. Although adverse events were not serious, non-specific leg pain and second degree skin burn were noted. Conclusion MRgFUS was demonstrated to be effective palliative treatment within 2 weeks in selected patients with painful bone metastases. PMID:25684002 206. Pain palliation in patients with bone metastases using magnetic resonance-guided focused ultrasound with conformal bone system: a preliminary report. PubMed Joo, Bio; Park, Mi-Suk; Lee, Soo Hyeon; Choi, Hye Jin; Lim, Seung Tack; Rha, Sun Young; Rachmilevitch, Itay; Lee, Young Han; Suh, Jin-Suck 2015-03-01 We evaluated the safety and effectiveness of the Magnetic Resonance-guided Focused Ultrasound (MRgFUS) with the ExAblate Conformal Bone System for the palliation of painful bone metastases. Our Institutional Review Board approved this study, and all patients gave informed consent prior to enrollment. A total of six painful metastatic bone lesions in five patients were treated using MRgFUS with the ExAblate Conformal Bone System for pain palliation. The follow-up sessions were at 3 days, 2 weeks, 1, 2, and 3 months, and 1 year after treatment. Efficacy was evaluated by the changes in visual analog scale (VAS) scores. At 3-months and 1-year follow-ups, unenhanced computed tomography and contrast-enhanced MR imaging examinations were performed. All adverse events were assessed to evaluate treatment safety. All patients showed significant pain relief within 2 weeks. Two patients experienced complete pain reduction that lasted for 1 year. Two other patients showed pain relief measured as VAS scores of 2 and 4 on their last follow-up. Although the remaining patient had experienced significant pain relief in two lesions, the VAS score re-increased on his last follow-up. The size of the enhancing soft tissue mass in metastatic lesions decreased, and new bone formation was seen on follow-up images. Although adverse events were not serious, non-specific leg pain and second degree skin burn were noted. MRgFUS was demonstrated to be effective palliative treatment within 2 weeks in selected patients with painful bone metastases. 207. Impact of target point deviations on control and complication probabilities in stereotactic radiosurgery of AVMs and metastases. PubMed Treuer, Harald; Kocher, Martin; Hoevels, Moritz; Hunsche, Stefan; Luyken, Klaus; Maarouf, Mohammad; Voges, Jürgen; Müller, Rolf-Peter; Sturm, Volker 2006-10-01 Determination of the impact of inaccuracies in the determination and setup of the target point in stereotactic radiosurgery (SRS) on the expectable complication and control probabilities. Two randomized samples of patients with arteriovenous malformation (AVM) (n=20) and with brain metastases (n=20) treated with SRS were formed, and the probability for complete obliteration (COP) or complete remission (CRP), the size of the 10 Gy-volume in the brain tissue (VOI10), and the probability for radiation necrosis (NTCP) were calculated. The dose-effect relations for COP and CRP were fitted to clinical data. Target point deviations were simulated through random vectors and the resulting probabilities and volumes were calculated and compared with the values of the treatment plan. The decrease of the relative value of the control probabilities at 1mm target point deviation was up to 4% for AVMs and up to 10% for metastases. At 2 mm the median decrease was 5% for AVMs and 9% for metastases. The value for the target point deviation, at which COP and CRP decreased about 0.05 in 90% of the cases, was 1.3 mm. The increase of NTCP was maximally 0.0025 per mm target point deviation for AVMs and 0.0035/mm for metastases. The maximal increase of VOI10 was 0.7 cm(3)/mm target point deviation in both patient groups. The upper limit for tolerable target point deviations is at 1.3mm. If this value cannot be achieved during the system test, a supplementary safety margin should be applied for the definition of the target volume. A better accuracy level is desirable, in order to ensure optimal chances for the success of the treatment. The target point precision is less important for the minimization of the probability of radiation necroses. 208. Biochemical markers of bone turnover in patients with spinal metastases after resistance training under radiotherapy--a randomized trial. PubMed Rief, Harald; Omlor, Georg; Akbar, Michael; Bruckner, Thomas; Rieken, Stefan; Förster, Robert; Schlampp, Ingmar; Welzel, Thomas; Bostel, Tilman; Roth, Heinz Jürgen; Debus, Jürgen 2016-03-17 To compare the effects of resistance training versus passive physical therapy on bone turnover markers (BTM) in the metastatic bone during radiation therapy (RT) in patients with spinal bone metastases. Secondly, to evaluate an association of BTM to local response, skeletal-related events (SRE), and number of metastases. In this randomized trial, 60 patients were allocated from September 2011 to March 2013 into one of the two arms: resistance training (Arm A) or passive physical therapy (Arm B) with thirty patients in each arm during RT. Biochemical markers such as pyridinoline (PYD), desoxy-pyridinoline (DPD), bone alkaline phosphatase (BAP), total amino-terminal propeptide of type I collagen (PINP), beta-isomer of carboxy-terminal telopeptide of type I collagen (CTX-I), and cross-linked N-telopeptide of type I collagen (NTX) were analyzed at baseline, and three months after RT. Mean change values of PYD and CTX-I were significantly lower at 3 months after RT (p = 0.035 and p = 0.043) in Arm A. Importantly, all markers decreased in both arms, except of PYD and CTX-I in arm B, although significance was not reached for some biomarkers. In arm A, the local response was significantly higher (p = 0.003) and PINP could be identified as a predictor for survivors (OR 0.968, 95%CI 0.938-0.999, p = 0.043). BAP (OR 0.974, 95%CI 0.950-0.998, p = 0.034) and PINP (OR 1.025, 95%CI 1.001-1.049, p = 0.044) were related with an avoidance of SRE. In this group of patients with spinal bone metastases, we were able to show that patients with guided resistance training of the paravertebral muscles can influence BTM. PYD and CTX-I decreased significantly in arm A. PINP can be considered as a complementary tool for prediction of local response, and PINP as well as BAP for avoidance of SRE. Clinical trial identifier NCT 01409720. August 2, 2011. 209. FDG avid breast cancer bone metastases silent on CT and scintigraphy: a case report with radiologic-pathologic correlation. PubMed Jeong, Daniel; Bui, Marilyn; Peterson, Daniel; Montilla-Soler, Jaime; Gage, Kenneth L 2017-10-01 Bone is the one of the most common distant metastatic sites in breast cancer. Routine initial breast cancer staging evaluation typically includes computed tomography (CT) and skeletal scintigraphy while 18F fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) is reserved for clinically high-risk cases. Since FDG PET-CT is not routinely performed during staging or surveillance evaluations, it is important for radiologists and clinicians to appreciate the limitations of bone metastasis detection on CT and scintigraphy. We present a case of bony metastases of invasive ductal carcinoma of the breast which were not detected on diagnostic CT or skeletal scintigraphy but were metabolically active on FDG PET-CT and evident on magnetic resonance. We provide a review of the literature and radiologic-pathologic correlation to explain the discordant imaging findings. 210. The use of collagen-based scaffolds to simulate prostate cancer bone metastases with potential for evaluating delivery of nanoparticulate gene therapeutics. PubMed Fitzgerald, Kathleen A; Guo, Jianfeng; Tierney, Erica G; Curtin, Caroline M; Malhotra, Meenakshi; Darcy, Raphael; O'Brien, Fergal J; O'Driscoll, Caitriona M 2015-10-01 Prostate cancer bone metastases are a leading cause of cancer-related death in men with current treatments offering only marginally improved rates of survival. Advances in the understanding of the genetic basis of prostate cancer provide the opportunity to develop gene-based medicines capable of treating metastatic disease. The aim of this work was to establish a 3D cell culture model of prostate cancer bone metastasis using collagen-based scaffolds, to characterise this model, and to assess the potential of the model to evaluate delivery of gene therapeutics designed to target bone metastases. Two prostate cancer cell lines (PC3 and LNCaP) were cultured in 2D standard culture and compared to 3D cell growth on three different collagen-based scaffolds (collagen and composites of collagen containing either glycosaminoglycan or nanohydroxyapatite). The 3D model was characterised for cell proliferation, viability and for matrix metalloproteinase (MMP) enzyme and Prostate Specific Antigen (PSA) secretion. Chemosensitivity to docetaxel treatment was assessed in 2D in comparison to 3D. Nanoparticles (NPs) containing siRNA formulated using a modified cyclodextrin were delivered to the cells on the scaffolds and gene silencing was quantified. Both prostate cancer cell lines actively infiltrated and proliferated on the scaffolds. Cell culture in 3D resulted in reduced levels of MMP1 and MMP9 secretion in PC3 cells. In contrast, LNCaP cells grown in 3D secreted elevated levels of PSA, particularly on the scaffold composed of collagen and glycosaminoglycans. Both cell lines grown in 3D displayed increased resistance to docetaxel treatment. The cyclodextrin.siRNA nanoparticles achieved cellular uptake and knocked down the endogenous GAPDH gene in the 3D model. In conclusion, development of a novel 3D cell culture model of prostate cancer bone metastasis has been initiated resulting, for the first time, in the successful delivery of gene therapeutics in a 3D in vitro model 211. A Simple and Effective Daily Pain Management Method for Patients Receiving Radiation Therapy for Painful Bone Metastases SciTech Connect Andrade, Regiane S.; UPMC Radiation Oncology Outreach Program; Proctor, Julian W., E-mail:
[email protected] 2010-11-01 Purpose: The incidence of painful bone metastases increases with longer survival times. Although external beam radiation therapy (EBRT) is an effective palliative treatment, it often requires several days from the start of treatment to produce a measurable reduction in pain scores and a qualitative amelioration of patient pain levels. Meanwhile, the use of analgesics remains the best approach early on in the treatment course. We investigated the role of radiation therapists as key personnel for collecting daily pain scores to supplement assessments by physician and oncology nursing staff and manage pain more effectively during radiation treatment. Methods and Materials: Dailymore » pain scores were obtained by the radiation therapists for 89 patients undertaking a total of 124 courses of EBRT for bone metastases and compared with pretreatment pain scores. The majority of patients (71%) were treated to 30 Gy (range, 20-37.5) in 10 fractions (range, 8-15 fractions). Results: One hundred nineteen treatment courses (96%) were completed. Pain scores declined rapidly to 37.5%, 50%, and 75% of the pretreatment levels by Days 2, 4, and 10, respectively. Pain was improved in 91% of patients with only 4% of worse pain at the end of treatment. Improved pain scores were maintained in 83% of patients at 1-month follow-up, but in 35% of them, the pain was worse than at the end of treatment. Conclusions: Collection of daily pain scores by radiation therapists was associated with an effective reduction in pain scores early on during EBRT of painful osseous metastases.« less 212. (153)Sm-EDTMP for pain relief of bone metastases from prostate and breast cancer and other malignancies. PubMed Correa-González, Luis; Arteaga de Murphy, Consuelo; Pichardo-Romero, Pablo; Pedraza-López, Martha; Moreno-GarcÃa, Claudia; Correa-Hernández, Luis 2014-05-01 Approximately 85% of patients with cancer suffer severe metastatic bone pain for which radionuclide therapy has been employed for pain palliation. We undertook this study to evaluate the pain relief effect of (153)Sm-EDTMP in Mexican patients with severe and painful bone metastases from mainly prostate, breast, and renal cancer and other malignancies. Patients (277) with intense sustained pain caused by bone metastases were referred to the Nuclear Medicine Department of the Oncology Hospital of the Mexican Social Security Institute. The patients had to have acceptable physical conditions, a previous positive (99m)Tc-MDP scan and blood values within normal range. (153)Sm-EDTMP was prepared at the Instituto Nacional de Investigaciones Nucleares (ININ) and 37 MBq/kg of body weight was injected intravenously. Pain palliation was evaluated with a visual analogue scale (VAS) and a verbal rating scale (VRS) before treatment and 3 and 12 weeks after treatment was started. The age interval of the patients was 24-92 years with a mean age of 64 ± 12 years. Mean values for hemoglobin, leukocyte and platelet counts did not statistically differ at zero time, 3 and 12 weeks after treatment. Pain intensity and relief assessment were statistically different: 9.1 ± 0.61 units initially; 4.2 ± 1.3 units 3 weeks later (54%) and after 12 weeks the pain diminished to 2.4 ± 1.4 units (74%) in the pain relief score scales. (153)Sm-EDTMP was readily available, safe and well tolerated. We conclude that (153)Sm-EDTMP was an adequate palliative agent and was the best option for our Mexican patients to relieve their severe metastatic bone pain. Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved. 213. Inducing targeted failure in cadaveric testing of 3-segment spinal units with and without simulated metastases. PubMed Groenen, Karlijn H J; Janssen, Dennis; van der Linden, Yvette M; Kooloos, Jan G M; Homminga, Jasper; Verdonschot, Nico; Tanck, Esther 2018-01-01 We propose an experimental setup and protocol able to induce targeted failure of the middle vertebra in 3-segment spinal units and to capture the specimens' deformation in their postfailure state. Sixteen 3-segment spinal units with and without artificial metastases were destructively tested in axial compression using one of two failure criteria; either: (A) A clear drop in force (>10-15% of peak force) (n = 4); or (B) A minimum displacement of 5 mm (n = 12). Subsequently, the specimens were fully fixated in polymethylmethacrylate (PMMA), thereby preserving their post-failure state. Pre- and post-experiment computed tomography (CT) scans were acquired to determine the occurrence of failure in one of the vertebral bodies. All specimens were successfully fixated in their post-failure state. When applying failure criterion A, two specimens showed signs of failure. When applying failure criterion B, all specimens showed signs of failure; in 9 out of 12 specimens this occurred in the middle vertebrae only. In conclusion, this research provides an experimental setup and protocol able to induce targeted failure of 3-segment spinal units and to capture the specimens' deformation in their post-failure state. Furthermore, this study illustrates the importance of an adequate failure criterion for successful simulation of vertebral fractures in an experimental setup. Copyright © 2017 IPEM. Published by Elsevier Ltd. All rights reserved. 214. Patient, Caregiver, and Nurse Preferences for Treatments for Bone Metastases from Solid Tumors. PubMed Qian, Yi; Arellano, Jorge; Hauber, A Brett; Mohamed, Ateesha F; Gonzalez, Juan Marcos; Hechmati, Guy; Gatta, Francesca; Harrelson, Stacey; Campbell-Baird, Cynthia 2016-08-01 Bone-targeted agents (BTAs) used for the prevention of skeletal-related events (SREs) associated with metastatic bone disease possess different attributes that factor into treatment decisions. The aim of this study was to evaluate preferences of patients, caregivers, and nurses for features of BTAs used to prevent SREs in patients with a self-reported physician diagnosis of bone metastasis from solid tumors. Patients (n = 187), primary caregivers (n = 197), or nurses (n = 196) completed a web-enabled discrete-choice experiment (10-question survey) in which they chose between pairs of hypothetical profiles of BTAs. Each profile was defined by six key treatment attributes, including efficacy and safety (two each) and route/frequency of administration and cost (one each). The relative importance of treatment attributes and levels was estimated. The most important treatment attribute for patients and nurses was out-of-pocket cost, and for caregivers, treatment-related risk of renal impairment. Risk of renal impairment was the second most important attribute for patients and nurses, while time until first SRE was the third most important attribute for all respondents. For nurses, risk of osteonecrosis of the jaw was least important, and for patients and caregivers, mode of administration was least important. Respondents considered hypothetical medications; therefore, their decisions may not have the same consequences as actual decisions. The perspectives of patients, caregivers, and nurses are integral when making treatment decisions about BTAs to prevent SREs associated with solid tumors. Identifying the relative importance of attributes of BTAs will aid in the proper selection of therapy in this setting, which may improve patient outcomes. 215. Determining the Incidence of Pain Flare Following Palliative Radiotherapy for Symptomatic Bone Metastases: Results From Three Canadian Cancer Centers SciTech Connect Hird, Amanda; Chow, Edward Zhang Liying; Wong, Rebecca; Wu, Jackson; Sinclair, Emily; Danjoux, Cyril; Tsao, May; Barnes, Elizabeth; Loblaw, Andrew 2009-09-01 Purpose: To determine the incidence of pain flare following radiotherapy (RT) for painful bone metastases. Materials and Methods: Patients with bone metastases treated with RT were eligible. Worst pain scores and analgesic consumption were collected before, daily during, and for 10 days after treatment. Pain flare was defined as a 2-point increase in the worst pain score (0-10) compared to baseline with no decrease in analgesic intake, or a 25% increase in analgesic intake with no decrease in worst pain score. Pain flare was distinguished from progression of pain by requiring the worst pain score and analgesic intake return to baseline levels after the increase/flare (within the 10-day follow-up period). Results: A total of 111 patients from three cancer centers were evaluable. There were 50 male and 61 female patients with a median age of 62 years (range, 40-89 years). The primary cancers were mainly breast, lung, and prostate. Most patients received a single 8 Gy (64%) or 20 Gy in five fractions (25%). The overall pain flare incidence was 44/111 (40%) during RT and within 10 days following the completion of RT. Patients treated with a single 8 Gy reported a pain flare incidence of 39% (27/70) and, with multiple fractions, 41% (17/41). Conclusion: More than one third of the enrolled patients experienced a pain flare. Identifying at-risk individuals and managing potential pain flares is crucial to achieve an optimal level of care. 216. Diagnostic performance of11C-choline PET/CT and bone scintigraphy in the detection of bone metastases in patients with prostate cancer. PubMed Kitajima, Kazuhiro; Fukushima, Kazuhito; Yamamoto, Shingo; Kato, Takashi; Odawara, Soichi; Takaki, Haruyuki; Fujiwara, Masayuki; Yamakado, Koichiro; Nakanishi, Yukako; Kanematsu, Akihiro; Nojima, Michio; Hirota, Shozo 2017-08-01 The aim of this study was to compare 11C-choline PET/CT and bone scintigraphy (BS) for detection of bone metastases in patients with prostate cancer. Twenty-one patients with histologically proven prostate cancer underwent 11C-choline PET/CT and BS before (n = 4) or after (n = 17) treatment. Patient-, region-, and lesion-based diagnostic performances of bone metastasis of both 11C-choline PET/CT and BS were evaluated using a five-point scale by two experienced readers. Bone metastases were present in 11 (52.4%) of 21 patients and 48 (32.7%) of 147 regions; 111 lesions were found to have bone metastases. Region-based analysis showed that the sensitivity, specificity, accuracy, and area under the receiver-operating-characteristic curves (AUC) of 11C-choline PET/CT were 97.9%, 99.0%, 98.6%, and 0.9989, respectively; those of BS were 72.9%, 99.0%, 90.5%, and 0.8386, respectively. Sensitivity, accuracy, and AUC significantly differed between the two methods (McNemar test, p = 0.0015, p = 0.0015, and p < 0.0001, respectively). 11C-choline PET/CT detected 110/111 metastatic lesions (99.1%); BS detected 85 (76.6%) (p < 0.0001). According to the CT morphological type, the visualization rates of 11C-choline-PET/BS were 100%/90.3% for the blastic type, 91.7%/8.3% for the lytic type, 100%/100% for the mixed type, and 100%/53.3% for the invisible type, respectively. Significant differences in blastic, lytic, and invisible types were observed between the two methods (p = 0.013, p = 0.0044, and p = 0.023, respectively). In conclusion, 11C-choline PET/CT had greater sensitivity and accuracy than BS for detection of bone involvement in patients with prostate cancer. 217. Prostate cancer in patients from rural and suburban areas--PSA value, Gleason score and presence of metastases in bone scan. PubMed Szot, Wojciech; Kostkiewicz, Magdalena; ZajÄ…c, Joanna; Owoc, Alfred; Bojar, Iwona 2014-01-01 Prostate cancer is the second most common neoplasm among men both worldwide and in Poland. In prostate cancer, bone metastasis is related to a poorer prognosis. A diagnosis of metastatic bone disease is important in prostate cancer patients prior to therapy. Prostate specific antigen (PSA) serum value is used both as a screening tool and for staging of prostate cancer. To evaluate whether there is a link between symptoms presented by patients, pain in particular, and the presence, number and location of bone metastases as assessed by bone scan scintigraphy in concordance with PSA values and Gleason scores. A group of 186 patients (aged: 68.38±6.16) diagnosed with prostate cancer, from rural and suburban areas of MaÅ‚opolska province, that was directed for bone scan scintigraphy to the Nuclear Medicine Dept, John Paul II Hospital in Kraków. Analysis of all laboratory findings (including PSA value) and a biopsy were performed. Then, bone scan scintigraphy was done with the use of methylene disphosphonate (MDP) labeled with Tc-99m. In patients with a Gleason value≤7 and a PSA value≤20 ng/ml, the cutoff value for a negative bone scan with a confidence interval of 0.95 was established at a PSA value below 10 ng/ml (p<0.01). Correlations were established between PSA value and presence of metastases in bone scan (r=0.45, p=0.05), the number of metastases (r=0.66, p<0.01), and their presence in particular body regions. The correlation between PSA value and both presence and number of metastases confirms the usefulness of bone scan scintigraphy in prostate cancer staging. The cutoff value for negative bone scan with a 95% confidence interval was established at PSA=10 ng/ml. 218. EORTC QLQ-BM22 quality of life evaluation and pain outcome in patients with bone metastases from breast cancer treated with zoledronic acid. PubMed Yeh, Dah-Cherng; Chen, Dar-Ren; Chao, Tsu-Yi; Chen, Shin-Cheh; Wang, Hwei-Chung; Rau, Kun-Ming; Feng, Yin-Hsun; Chang, Yuan-Ching; Lee, Kuan-Der; Ou-Yang, Fu; Kuo, Wen-Hung; Chang, King-Jen; Lin, Yung-Chang; Tseng, Ling-Ming; Hou, Ming-Feng 2014-01-01 We assessed the effect of zoledronic acid on quality of life (QOL) and pain outcome in breast cancer patients with bone metastases using the European Organization for Research and Treatment of Cancer bone metastases module (EORTC QLQ-BM22). Three hundred sixty-six breast cancer patients receiving zoledronic acid for bone metastases from 13 Centers were prospectively enrolled. QOL was evaluated using the EORTC QLQ-BM22 and pain outcome were measured monthly with a Visual Analog Scale (VAS) score for 24 months. No significant change of functional scale (functional interference and psychosocial aspects) of the EORTC QLQ-BM22 was reported. Significant reduction of the symptom scale was noted after treatment compared with the baseline. The painful site subscale was significantly reduced during the first 12 months, with the exception the 6-month follow-up of point. Pain characteristics subscale was also significantly lower from the 2-month time point onwards. VAS scores indicated a significant reduction in pain over the course of the study to the 22-month time point follow-up compared to the baseline. Zoledronic acid treatment improved QOL of breast cancer patients with bone metastases by relieving bone pain. Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved. 219. Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics. PubMed Bollig-Fischer, Aliccia; Michelhaugh, Sharon K; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adele; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep 2015-06-10 Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n = 4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments. 220. Metastases in immune-mediated dormancy: a new opportunity for targeting cancer. PubMed Romero, Irene; Garrido, Federico; Garcia-Lora, Angel M 2014-12-01 The aim of any anticancer treatment is to avoid, control, or eliminate disseminated tumor cells. Clinical and experimental evidence has revealed that metastases can remain in a latency state, that is, metastasis dormancy. Three mechanisms are thought to be involved in cancer dormancy: cellular dormancy, angiogenic dormancy, and immune-mediated dormancy. Here, we review the mechanisms and cells involved in immune-mediated cancer dormancy and discuss current and future immunotherapeutic strategies. Recent results indicate that the immune system can restrain disseminated cancer cells, promoting their permanent dormancy. CD8(+) T lymphocytes play a relevant role in maintaining immune equilibrium with metastatic dormant cells, and MHC class I surface expression on tumor cells may also be involved. Natural killer (NK) cells have an activator function that triggers a cytotoxic T lymphocyte (CTL) response. Furthermore, immune dormancy promotes cancer cell growth arrest and angiogenic control. Immunotherapeutic interventions in metastatic dormancy may help to control or eradicate cancer disease. Treatments that activate or increase the CTL immune response or reverse cancer cell-induced CTL immunosuppression might be useful to restrain or destroy metastatic cells. These objectives may be achieved by recovering or increasing MHC class I surface expression on cancer cells or even by activating NK cells. Immune-mediated metastasis dormancy provides an opportunity for targeting cancer in novel immune treatments. ©2014 American Association for Cancer Research. « 9 10 11 12 13 » « 10 11 12 13 14 » 221. Musculoskeletal Complications and Bone Metastases in Breast Cancer Patients Undergoing Estrogen Deprivation Therapy DTIC Science & Technology 2015-10-01 subsequent bone destruction often result in severe bone pain, fragility fractures, nerve compression syndromes , and hypercalcemia of malignancy resulting...include body composition by DXA, osteolytic lesion area by X -ray, changes in bone by µCT, serum levels of 17β-estradiol and inflammatory cytokines by...Five weeks after inoculation, osteolytic lesion area increased by 110% (Figure 9, p.01, X -Ray) and tumor burden in bone assessed by histology 222. Local and targeted drug delivery for bone regeneration. PubMed Newman, Maureen R; Benoit, Danielle Sw
2016-08-01 While experimental bone regeneration approaches commonly employ cells, technological hurdles prevent translation of these therapies. Alternatively, emulating the spatiotemporal cascade of endogenous factors through controlled drug delivery may provide superior bone regenerative approaches. Surgically placed drug depots have clinical indications. Additionally, noninvasive systemic delivery can be used as needed for poorly healing bone injuries. However, a major hurdle for systemic delivery is poor bone biodistribution of drugs. Thus, peptides, aptamers, and phosphate-rich compounds with specificity toward proteins, cells, and molecules within the regenerative bone microenvironment may enable the design of targeted carriers with bone biodistribution greater than that achieved by drug alone. These carriers, combined with osteoregenerative drugs and/or stimuli-sensitive linkers, may enhance bone regeneration while minimizing off-target tissue effects. Copyright © 2016 Elsevier Ltd. All rights reserved. 223. Single fraction conventional external beam radiation therapy for bone metastases: a systematic review of randomised controlled trials. PubMed Dennis, Kristopher; Makhani, Leila; Zeng, Liang; Lam, Henry; Chow, Edward 2013-01-01 To determine the optimal dose of single fraction conventional palliative radiation therapy for the relief of pain caused by bone metastases. Ovid version of EMBASE and EMBASE Classic, MEDLINE, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials were searched for relevant randomised controlled trials. Pain response data were standardised according to the clinical trial endpoints recommended by the International Bone Metastases Consensus Working Party. From 2696 references we selected 26 articles for review. These described 24 trials that cumulatively randomised 3233 patients to 28 single fraction arms: two arms received 4 Gy, one 5 Gy, one 6 Gy, twenty-two 8 Gy, one 10 Gy and one 8-15 Gy. Eighty-four percent of all patients received 8 Gy and this imbalance precluded formal modelling analyses for different doses. Efficacy endpoints and pain assessment times varied. In general, higher doses produced better pain response rates. The overall (OR) and complete (CR) pain response rates for different doses according to available intention-to-treat (ITT) and assessable patient (A) figures were: 4 Gy [OR(ITT)=23-47%, OR(A)=44-47%, CR(ITT)=15-18%, CR(A)=15-26%], 5 Gy [OR(A)=72%, CR(A)=55%], 6 Gy [OR(ITT&A)=65%, CR(ITT&A)=21%], 8 Gy [OR(ITT)=21-81%, OR(A)=31-93%, CR(ITT)=9-52%, CR(A)=14-57%], 10 Gy [OR(A)=84%, CR(A)=39%]. In trials that directly compared different single fraction doses, 8 Gy was statistically superior to 4 Gy. 8 Gy was by far the most commonly administered single fraction dose within 24 randomised trials of conventional radiation therapy for the palliation of bone metastases. 8 Gy should be the standard dose against which future treatments are compared due to its reproducible pain response rate and its established safe profile. The optimal dose for the relief of pain remains an open question, however, 8 Gy produced statistically superior pain response rates compared to 4 Gy in trials directly comparing those doses 224. Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases. PubMed Xie, Jipan; Namjoshi, Madhav; Wu, Eric Q; Parikh, Kejal; Diener, Melissa; Yu, Andrew P; Guo, Amy; Culver, Kenneth W 2011-10-01 Bone metastases are common in patients with hormone-refractory prostate cancer. In a study of autopsies of patients with prostate cancer, 65%-75% had bone metastases. Bone metastases place a substantial economic burden on payers with estimated total annual costs of $1.9 billion in the United States. Skeletal-related events (SREs), including pathologic fractures, spinal cord compression, surgery to bone, and radiation to bone, affect approximately 50% of patients with bone metastases. They are associated with a decreased quality of life and increased health care costs. Zoledronic acid is an effective treatment in preventing SREs in solid tumors and multiple myeloma. Recently, denosumab was FDA-approved for prevention of SREs in patients with bone metastases from solid tumors. A Phase 3 clinical trial (NCT00321620) demonstrated that denosumab had superior efficacy in delaying first and subsequent SREs compared with zoledronic acid. However, the economic value of denosumab has not been assessed in patients with hormone-refractory prostate cancer. To compare the cost-effectiveness of denosumab with zoledronic acid in the treatment of bone metastases in men with hormone-refractory prostate cancer. An Excel-based Markov model was developed to assess costs and effectiveness associated with the 2 treatments over a 1- and 3-year time horizon. Because the evaluation was conducted from the perspective of a U.S. third-party payer, only direct costs were included. Consistent with the primary outcome in the Phase 3 trial, effectiveness was assessed based on the number of SREs. The model consisted of 9 health states defined by SRE occurrence, SRE history, disease progression, and death. A hypothetical cohort of patients with hormone-refractory prostate cancer received either denosumab 120 mg or zoledronic acid 4 mg at the model entry and transitioned among the 9 health states at the beginning of each 13-week cycle. Transition probabilities associated with experiencing the first 225. Course of Quality of Life After Radiation Therapy for Painful Bone Metastases: A Detailed Analysis From the Dutch Bone Metastasis Study SciTech Connect Westhoff, Paulien G.; Verdam, Mathilde G.E.; Oort, Frans J.; Jobsen, Jan J.; Vulpen, Marco van; Leer, Jan Willem H.; Marijnen, Corrie A.M.; Graeff, Alexander de; Linden, Yvette M. van der 2016-08-01 Purpose: To study the course of quality of life (QoL) after radiation therapy for painful bone metastases. Patients and Methods: The Dutch Bone Metastasis Study randomized 1157 patients with painful bone metastases between a single fraction of 8 Gy and 6 fractions of 4 Gy between 1996 and 1998. The study showed a comparable pain response of 74%. Patients filled out weekly questionnaires for 13 weeks, then monthly for 2 years. In these analyses, physical, psychosocial, and functional QoL domain scores and a score of general health were studied. Mixed modeling was used to model the course of QoL and to study the influence of several characteristics. Results: In general, QoL stabilized after 1 month. Psychosocial QoL improved after treatment. The level of QoL remained stable, steeply deteriorating at the end of life. For most QoL domains, a high pain score and intake of opioids were associated with worse QoL, with small effect sizes (−0.11 to −0.27). A poor performance score was associated with worse functional QoL, with a medium effect size (0.41). There is no difference in QoL between patients receiving a single fraction of 8 Gy and 6 fractions of 4 Gy, except for a temporary worsening of physical QoL after 6 fractions. Conclusion: Although radiation therapy for painful bone metastases leads to a meaningful pain response, most domains of QoL do not improve after treatment. Only psychosocial QoL improves slightly after treatment. The level of QoL is related to the actual survival, with a rather stable course of QoL for most of the remaining survival time and afterward a sharp decrease, starting only a few weeks before the end of life. Six fractions of 4 Gy lead to a temporary worse physical QoL compared with a single fraction of 8 Gy. 226. Course of Quality of Life After Radiation Therapy for Painful Bone Metastases: A Detailed Analysis From the Dutch Bone Metastasis Study SciTech Connect Westhoff, Paulien G., E-mail:
[email protected]; Department of Radiotherapy, Radboud University Medical Center, Nijmegen; Verdam, Mathilde G.E. 2016-08-01 Purpose: To study the course of quality of life (QoL) after radiation therapy for painful bone metastases. Patients and Methods: The Dutch Bone Metastasis Study randomized 1157 patients with painful bone metastases between a single fraction of 8 Gy and 6 fractions of 4 Gy between 1996 and 1998. The study showed a comparable pain response of 74%. Patients filled out weekly questionnaires for 13 weeks, then monthly for 2 years. In these analyses, physical, psychosocial, and functional QoL domain scores and a score of general health were studied. Mixed modeling was used to model the course of QoL and to study the influence ofmore » several characteristics. Results: In general, QoL stabilized after 1 month. Psychosocial QoL improved after treatment. The level of QoL remained stable, steeply deteriorating at the end of life. For most QoL domains, a high pain score and intake of opioids were associated with worse QoL, with small effect sizes (−0.11 to −0.27). A poor performance score was associated with worse functional QoL, with a medium effect size (0.41). There is no difference in QoL between patients receiving a single fraction of 8 Gy and 6 fractions of 4 Gy, except for a temporary worsening of physical QoL after 6 fractions. Conclusion: Although radiation therapy for painful bone metastases leads to a meaningful pain response, most domains of QoL do not improve after treatment. Only psychosocial QoL improves slightly after treatment. The level of QoL is related to the actual survival, with a rather stable course of QoL for most of the remaining survival time and afterward a sharp decrease, starting only a few weeks before the end of life. Six fractions of 4 Gy lead to a temporary worse physical QoL compared with a single fraction of 8 Gy.« less 227. [Diagnostic performance of bone scintigraphy and (11)C-Choline PET/CT in the detection of bone metastases in patients with biochemical recurrence of prostate cancer]. PubMed Garcia, J R; Moreno, C; Valls, E; Cozar, P; Bassa, P; Soler, M; Alvarez-Moro, F J; Moragas, M; Riera, E 2015-01-01 To compare bone scan (BS) with (11)C-Choline PET/CT for the detection of bone metastases in patients with biochemical recurrence of prostate cancer (PC). A total of 169 patients with biochemical recurrence of PC(PSA:2.4-58 ng/ml) who were referred for both exams (0-15 days-in-between) were included. Lesion-detection-rate per patients and lesions were analyzed for both BS and (11)C-Choline PET/CT. Metastasis diagnosis was reached by: biopsy, CT/(18)F-Fluoride PET/MRI confirmation, or evidence of progression in subsequent imaging procedures. A total of 91 lesions were found to be active in BS and/or (11)C-choline PET/CT (40 patients), with 78 of which were metastatic. BS detected 38 blastic, 2 lytic and 10 non-CT-evident lesions. (11)C-Choline PET/CT detected 41 blastic, 4 lytic and 29 non-CT-evident lesions. BS and (11)C-Choline PET/CT sensitivities were 65.4% and 96.1%; specificities ere 38.5 and 92.3% (χ(2) 8.27, p<0.04). Both imaging techniques were negative in 118 patients. Tracer avid lesions were found in 51 patients: with 30/51 being BS and (11)C-Choline PET/CT concordant; in 21/51 patients had discordant lesions (kappa 0.712, p=0.00). Lesions were absolutely discordant in 10/19 patients,: 5 FN BS, 2 FP BS (degenerative changes; dysplasia), 1 FN (11)C-Choline PET/CT (blastic), 1 FP (11)C-Choline PET/CT (degenerative), 1 out of field-of-view lesion with (11)C-Choline PET/CT (tibia alone). (11)C-Choline PET/CT showed extraosseous involvement in 26/51 patients with bone metastases: 9 local recurrences, 5 infra-diaphragmatic-lymph-nodes, 2 supra-diaphragmatic, 5 local and infra-diaphragmatic, 4 infra- and supra-diaphragmatic, 1 supra-diaphragmatic and lung metastases. (11)C-Choline PET/CT yielded better sensitivity and specificity than BS for the detection of bone involvement in patients with biochemical recurrence of PC and allowed extraosseous restaging, with an impact in the clinical management of these patients. Copyright © 2014 Elsevier España, S.L.U. and 228. Musculoskeletal Complications and Bone Metastases in Breast Cancer PatientsUndergoing Estrogen Deprivation Therapy DTIC Science & Technology 2016-10-01 treated with vehicle or AI (letrozole; Let). An OVX+Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three...metastases. Five weeks after tumor cell inoculation, tumor-induced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let-Zol mice...OVX) is sufficient to cause skeletal muscle weakness in mice 6- weeks post-surgery. I am currently examining whether estrogen deprivation-induced 229. [Radiotherapy in the management of painful bone metastases at The National Institute of Oncology in Morocco: data from one year follow-up of 86 patients]. PubMed Lachgar, Amine; Toulba, Ahmedou; Kebdani, Tayeb; Elgueddari, Brahim Khalil; Benjaafar, Noureddine 2015-01-01 Radiation therapy plays an essential role in the management of pain caused by bone metastases Objectives: Evaluate the effect of radiation for the relief of pain caused by bone metastases. We conducted a prospective study of 86 patients suffering from pain associated with bone metastases treated at our department by external radiotherapy between September 2010 and December 2011. Patients recorded pain severity in the numeric rating scale and analgesic requirements before, at the end of irradiation, then weekly for a month, and every month for a year. The median age of patients was 54 years (28-75 years). There were 45 (52.3%) women and 41 (47.7%) men. Radiotherapy was delivered in a multifraction schedule to a total dose of 30 Gy in 72% of patients or in a single fraction of 8 Gy in 28% of patients. A favorable analgesic response was observed in 59 (68.6%) patients with 8 (9.3%) complete responses and 51 (59.3%) partial responses. The median time-to-response was 2 weeks (0-7 weeks), and the median duration of pain relief was 22 weeks (9-46 weeks). Radiotherapy is effective in relieving pain associated with bone metastases in the majority of patients. 230. Determining the Incidence of Pain Flare Following Palliative Radiotherapy for Symptomatic Bone Metastases: Results From Three Canadian Cancer Centers SciTech Connect Hird, Amanda; Chow, Edward; Zhang Liying 2009-09-01 Purpose: To determine the incidence of pain flare following radiotherapy (RT) for painful bone metastases. Materials and Methods: Patients with bone metastases treated with RT were eligible. Worst pain scores and analgesic consumption were collected before, daily during, and for 10 days after treatment. Pain flare was defined as a 2-point increase in the worst pain score (0-10) compared to baseline with no decrease in analgesic intake, or a 25% increase in analgesic intake with no decrease in worst pain score. Pain flare was distinguished from progression of pain by requiring the worst pain score and analgesic intake return tomore » baseline levels after the increase/flare (within the 10-day follow-up period). Results: A total of 111 patients from three cancer centers were evaluable. There were 50 male and 61 female patients with a median age of 62 years (range, 40-89 years). The primary cancers were mainly breast, lung, and prostate. Most patients received a single 8 Gy (64%) or 20 Gy in five fractions (25%). The overall pain flare incidence was 44/111 (40%) during RT and within 10 days following the completion of RT. Patients treated with a single 8 Gy reported a pain flare incidence of 39% (27/70) and, with multiple fractions, 41% (17/41). Conclusion: More than one third of the enrolled patients experienced a pain flare. Identifying at-risk individuals and managing potential pain flares is crucial to achieve an optimal level of care.« less 231. Radium-223 dichloride therapy in breast cancer with osseous metastases PubMed Central Takalkar, Amol; Paryani, Bhavna; Adams, Scott; Subbiah, Vivek 2015-01-01 Osseous metastases occur frequently in patients with breast cancer. Few options exist for bone targeted therapy for hormone refractory patients with breast cancer with progressive bone metastases. We present a case of breast cancer with osseous metastases but no visceral metastases. The patient had been treated with surgery, chemotherapy, radiation and hormonal therapy, but still had extensive symptomatic osseous metastases. She received radium-223 dichloride, a therapeutic radiopharmaceutical Food and Drug Administration (FDA) approved for castration resistant prostate cancer with bone metastases. She tolerated the therapy well with no significant adverse effects. She had an excellent response with significant pain relief obviating need for regular analgaesics. Her tumour markers also dropped significantly. Osseous metastases assessed with F-18 fluorodeoxy glucose (FDG) positron emission tomography/CT (PET/CT) and F-18 sodium fluoride (NaF) bone PET/CT) scans at baseline, after two and six cycles, also showed interval improvement in the lesions. Radium-223 dichloride could potentially be a safe and useful therapeutic option in this setting. PMID:26581701 232. CyberKnife stereotactic radiosurgery and stereotactic ablative radiation therapy of patients with prostate cancer bone metastases. PubMed Napieralska, A; Miszczyk, L; Stapor-Fudzinska, M 2016-01-01 The aim of the study was to evaluate the effectiveness and toxicity of CyberKnife (CK) stereotactic radiosurgery (SRS) and stereotactic ablative radiation therapy (SABR) of patients with prostate cancer bone metastases. Analysis of prognostic and predictive factors was also performed. Material consisted of 51 patients with 71 bone oligometastases treated using CK SRS/SABR. In half of the patients single lesion was treated, in half 2-5 lesions. Median PSA concentration at the time of metastasis detection was 5.75 ng/ml. Total dose of 645Gy (median 20) was delivered with 1-5 fractions of 6-15 Gy (median 9). Biologic equivalent dose (BED) (α/β=1.6) over 100 Gy was delivered to 45 lesions (63%) in 38 patients (75%). In statistical analysis Kaplan-Meier method, log-rank test and the Cox proportional hazard model were used. One-, two- and three-year overall survival (OS) was 90%, 76% and 70%, respectively. All patients having PSA concentration lower that 1 ng/ml at last control lived at least three years. One-, two- and three- year local control (LC) was 97%, 70% and 30%. Patients with PSA below 20 ng/ml at the time of metastasis detection had better local control of lesions and lower PSA at the last control. Median of PSA concentration after CK based SRS/SABR remains stable during first 12 months of follow-up, dropped during the next months and at last control was comparable to initial level. Median PSA at last control in patients without disease progression was 1.67ng/ml and 20 patients had PSA below 1.0ng/ml. At the last control 59% of patients had no other metastases. Rapid pain decrease was observed in analysed group and during each control about 90% of patients had pain relief. No major toxicity was observed, 3 patients suffered from fracture of irradiated bone.SRS/SABR of prostate cancer bone oligometastases provides good LC of lesions, excellent pain control without additional toxicity. Patients with PSA concentration below 20ng/ml at the time of metastasis 233. Targeted Therapy as an Alternative to Whole-Brain Radiotherapy in EGFR-Mutant or ALK-Positive Non-Small-Cell Lung Cancer With Brain Metastases. PubMed MartÃnez, Pablo; Mak, Raymond H; Oxnard, Geoffrey R 2017-09-01 Is up-front whole-brain radiotherapy required to treat multiple brain metastases from non-small-cell lung cancer when highly active targeted therapies are available? Patients with EGFR-mutant or ALK-positive non-small-cell lung cancer with brain metastases now have the potential to achieve a prolonged survival. Through use of highly active targeted therapies, whole-brain radiotherapy can be safely postponed, diminishing toxic effects that could impair quality of life. 234. Magnetic resonance imaging of osteosarcoma using a bis(alendronate)-based bone-targeted contrast agent. PubMed Ge, Pingju; Sheng, Fugeng; Jin, Yiguang; Tong, Li; Du, Lina; Zhang, Lei; Tian, Ning; Li, Gongjie 2016-12-01 Magnetic resonance (MR) is currently used for diagnosis of osteosarcoma but not well even though contrast agents are administered. Here, we report a novel bone-targeted MR imaging contrast agent, Gd 2 -diethylenetriaminepentaacetate-bis(alendronate) (Gd 2 -DTPA-BA) for the diagnosis of osteosarcoma. It is the conjugate of a bone cell-seeking molecule (i.e., alendronate) and an MR imaging contrast agent (i.e., Gd-DTPA). Its physicochemical parameters were measured, including pK a , complex constant, and T 1 relaxivity. Its bone cell-seeking ability was evaluated by measuring its adsorption on hydroxyapatite. Hemolysis was investigated. MR imaging and biodistribution of Gd 2 -DTPABA and Gd-DTPA were studied on healthy and osteosarcoma-bearing nude mice. Gd 2 -DTPA-BA showed high adsorption on hydroxyapatite, the high MR relaxivity (r 1 ) of 7.613mM -1 s -1 (2.6 folds of Gd-DTPA), and no hemolysis. The MR contrast effect of Gd 2 -DTPA-BA was much higher than that of Gd-DTPA after intravenous injection to the mice. More importantly, the MR imaging of osteosarcoma was significantly improved by Gd 2 -DTPA-BA. The signal intensity of Gd 2 -DTPA-BA reached 120.3% at 50min, equal to three folds of Gd-DTPA. The bone targeting index (bone/blood) of Gd 2 -DTPA-BA in the osteosarcoma-bearing mice was very high to 130 at 180min. Furthermore, the contrast enhancement could also be found in the lung due to metastasis of osteosarcoma. Gd 2 -DTPA-BA plays a promising role in the diagnoses of osteosacomas, including the primary bone tumors and metastases. Copyright © 2016 Elsevier Masson SAS. All rights reserved. 235. Bone turnover markers in women with early stage breast cancer who developed bone metastases. A prospective study with multivariate logistic regression analysis of accuracy. PubMed Lumachi, Franco; Basso, Stefano M M; Camozzi, Valentina; Tozzoli, Renato; Spaziante, Roberto; Ermani, Mario 2016-09-01 The skeleton is the most common site of metastasis for breast cancer and the periodic measurement of circulating bone turnover markers (BTMs) can be useful. The aim of this study was to prospectively evaluate the diagnostic accuracy of a panel of BTMs in the early detection of bone metastases (BMs). We reviewed the medical records of 297 postmenopausal women with early stage luminal-type invasive ductal carcinoma (IDC). Twenty-six patients who developed isolated BMs during follow-up and 24 randomly selected controls were studied. The two groups were matched according to age, final disease staging, and follow-up. All patients underwent periodic measurement of total and bone-specific (BSAP) alkaline phosphatase, CTX, ICTP, osteocalcin, NTX, PINP, and TRACP5b. Only BSAP, CTX, PINP, and TRACP5b were significantly (p<0.05) associated with the group, and the logistic regression analysis excluded CTX from the model. The AUC (ROC curve) for TRACP5b alone, which was the most accurate marker, and for the combination of BSAP+PINP+TRACP5b was 0.784 (95% CI: 0.651-0.916) and 0.889 (95% CI: 0.798-0.981), respectively. According to our results, the measurement of these three markers together should be performed in all postmenopausal patients with luminal-type IDC, when an early diagnosis of BMs is required. Copyright © 2016 Elsevier B.V. All rights reserved. 236. Prostate Cancer Skeletal Metastases: Pathobiology and Interventions DTIC Science & Technology 2005-02-01 bone resorption. Skeletal metastases are often associated with significant complications including severe bone pain, impaired mobility , pathological...cancellous bone but not in osteoarthritis . J Bone Miner Res 2001; 16(6): 1015-1027. Mechanisms of Bone Resorption in Prostate Cancer Skeletal...prostate mobility , pathological fracture, spinal cord carcinoma metastasis with skeletal metastases compression, and symptomatic hypercalcemia 237. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases PubMed Central Himelstein, Andrew L.; Foster, Jared C.; Khatcheressian, James L.; Roberts, John D.; Seisler, Drew K.; Novotny, Paul J.; Qin, Rui; Go, Ronald S.; Grubbs, Stephen S.; Oâ €™Connor, Tracey; Velasco, Mario R.; Weckstein, Douglas; O’Mara, Ann; Loprinzi, Charles L.; Shapiro, Charles L. 2017-01-01 IMPORTANCE Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. OBJECTIVE To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. DESIGN, SETTING, PARTICIPANTS Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; followup concluded in April 2014. INTERVENTIONS; Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. MAIN OUTCOMES AND MEASURES; The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7%as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0–10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0–4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). RESULTS Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiplemyeloma), 795 completed the study at 2 years. A total of 260 238. Targeting of α(v)-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer. PubMed van der Horst, Geertje; van den Hoogen, Christel; Buijs, Jeroen T; Cheung, Henry; Bloys, Henny; Pelger, Rob C M; Lorenzon, Giocondo; Heckmann, Bertrand; Feyen, Jean; Pujuguet, Philippe; Blanque, Roland; Clément-Lacroix, Philippe; van der Pluijm, Gabri 2011-06-01 Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelialmesenchymal transition (EMT). Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the non-peptide α(v)-integrin antagonist GLPG0187 dose-dependently increased the E-cadherin/vimentin ratio, rendering the cells a more epithelial, sessile phenotype. In addition, GLPG0187 dose-dependently diminished the size of the aldehyde dehydrogenase high subpopulation of prostate cancer cells, suggesting that α(v)-integrin plays an important role in maintaining the prostate cancer stem/progenitor pool. Our data show that GLPG0187 is a potent inhibitor of osteoclastic bone resorption and angiogenesis in vitro and in vivo. Real-time bioluminescent imaging in preclinical models of prostate cancer demonstrated that blocking Î ±(v)-integrins by GLPG0187 markedly reduced their metastatic tumor growth according to preventive and curative protocols. Bone tumor burden was significantly lower in the preventive protocol. In addition, the number of bone metastases/mouse was significantly inhibited. In the curative protocol, the progression of bone metastases and the formation of new bone metastases during the treatment period was significantly inhibited. In conclusion, we demonstrate that targeting of integrins by GLPG0187 can inhibit the de novo formation and progression of bone metastases in prostate cancer by antitumor (including inhibition of EMT and the size of the prostate cancer stem cell population), antiresorptive, and antiangiogenic mechanisms. 239. Beta-catenin/TCF Pathway and Castrate Resistant Progression in Osteoblastic Bone Metastases DTIC Science & Technology 2010-06-01 Initial x-ray analysis of the first successful tumor development 6 weeks after injection of MDA PCa 118 cells transfected with si- bcat or si-control...suggested that bone mass increases in the bones injected with MDA PCa 118 cells transfected with si-controls but not in those injected with si- bcat ...confirm the findings of x-ray analysis (Fig. 1). We then repeated this study by injecting MDA PCa 118 cells transfected with si- bcat or si- control 240. Iodine-131-labeled diphosphonates for palliative treatment of bone metastases: II. Preliminary clinical results with iodine-131 BDP3 SciTech Connect Eisenhut, M.; Berberich, R.; Kimmig, B. 1986-08-01 The kinetics, dosimetry, and response of iodine-131 alpha-amino-(4-hydroxybenzylidene)-diphosphonate ((/sup 131/I)BDP3) treatment were investigated with patients who had pain symptoms from bone metastases of various primary carcinoma. The blood clearance of (/sup 131/I)BDP3 was rapid. More than 90% disappeared from the blood pool at 2 hr after injection. The excretion of the activity occurred solely through the kidneys and mean total-body retention at 48 hr was 48.6%. The urinary activity showed a metabolite which must be formed by an in vivo cleavage reaction of a phosphorus-carbon bond. The uptake of in vivo cleaved (/sup 131/I)iodide in the unblocked thyroid was approximatelymore » 0.5%. The effective half-life of (/sup 131/I)BDP3 in metastatic bone (median 182 hr; range 177-205 hr) proved to be longer than in unaffected areas (145 hr; 140-165 hr). Palliative therapies were performed with 18 patients. They received doses ranging between 6 and 48 mCi (/sup 131/I)BDP3. The response was 44% complete pain relief, 6% substantial pain relief, 22% minimal improvement, and 28% no change. The duration of response ranged between 1 and 8 wk.« less « 10 11 12 13 14 » « 11 12 13 14 15 » 241. Iodine-131-labeled diphosphonates for palliative treatment of bone metastases: II. Preliminary clinical results with iodine-131 BDP3 SciTech Connect Eisenhut, M.; Berberich, R.; Kimmig, B.; Oberhausen, E. 1986-08-01 The kinetics, dosimetry, and response of iodine-131 alpha-amino-(4-hydroxybenzylidene)-diphosphonate ((/sup 131/I)BDP3) treatment were investigated with patients who had pain symptoms from bone metastases of various primary carcinoma. The blood clearance of (/sup 131/I)BDP3 was rapid. More than 90% disappeared from the blood pool at 2 hr after injection. The excretion of the activity occurred solely through the kidneys and mean total-body retention at 48 hr was 48.6%. The urinary activity showed a metabolite which must be formed by an in vivo cleavage reaction of a phosphorus-carbon bond. The uptake of in vivo cleaved (/sup 131/I)iodide in the unblocked thyroid was approximately 0.5%. The effective half-life of (/sup 131/I)BDP3 in metastatic bone (median 182 hr; range 177-205 hr) proved to be longer than in unaffected areas (145 hr; 140-165 hr). Palliative therapies were performed with 18 patients. They received doses ranging between 6 and 48 mCi (/sup 131/I)BDP3. The response was 44% complete pain relief, 6% substantial pain relief, 22% minimal improvement, and 28% no change. The duration of response ranged between 1 and 8 wk. 242. ¹â·â·Lu-EDTMP for treatment of bone pain in patients with disseminated skeletal metastases. PubMed Shinto, Ajit S; Shibu, Deepu; Kamaleshwaran, Koramadai Karuppusamy; Das, Tapas; Chakraborty, Sudipta; Banerjee, Sharmila; Thirumalaisamy, Palanisamy; Das, Pravin; Veersekar, Ganesh 2014-03-01 (177)Lu-labeled ethylenediaminetetramethylene phosphonic acid ((177)Lu-EDTMP) is an agent that concentrates in areas of enhanced osteoblastic activity. The potential of (177)LuEDTMP for palliation of metastatic bone pain has been documented in the recent literature. The objective of the present work was to study the efficacy and safety of the agent after administration to a limited number of patients. Ten patients (median age, 68.5 y) with disseminated skeletal metastases received a single bolus infusion of (177)Lu-EDTMP (3.7 GBq). All patients had painful bone metastases in more than one anatomic region that were not relieved by narcotic analgesics. The efficacy of the agent was studied by following pain scores assessed at baseline and at 4, 8, and 12 wk after therapy, by using Karnofsky indices and mobility scores, and by determining the requirement for analgesics at baseline and 4 wk after therapy. The toxicity of the agent was assessed by analyzing complete blood counts. A significant reduction in the mean pain score was noted in all patients. The initial mean pain score of 8.44 dropped to 5.73 within 1 mo of treatment. Six patients who required analgesics for pain management had either reduced or completely withdrawn from their use by 4 wk. Compared with initial scans, scans obtained 1 mo after therapy also showed a decreased uptake of the radiotracer. The mobility scores of all patients were higher at 4 wk. The mean Karnofsky performance score of all patients was initially 45 and increased markedly to 69 at 4 wk. None of the patients experienced blood-related toxicity. (177)LuEDTMP, with only low bone marrow toxicity, provided significant pain relief to patients and considerably increased their mobility, resulting in an overall improvement in the quality of life. The results of the preliminary clinical studies indicate that (177)Lu-EDTMP can be considered an effective and safe therapeutic radiopharmaceutical for pain palliation of patients with disseminated
243. Bone-targeting dendrimer for the delivery of methotrexate and treatment of bone metastasis. PubMed Yamashita, Shugo; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira 2018-02-06 We developed a bone-targeting dendrimer for the delivery of anti-tumour agents and effective treatment of bone metastasis, in which alendronate (ALN), a bone-targeting moiety, is covalently bonded to a polyethylene glycol (PEG)-conjugated polyamidoamine (PAMAM) dendrimer (PEG-PAMAM-ALN). Approximately 7.0 and 21.9% of the administered doses of [ 111 In]PAMAM and PEG-PAMAM-ALN accumulated in the bones within 180 min after intravenous injection in mice, respectively. [ 3 H]-labelled methotrexate (MTX) rapidly disappeared from the blood, and bone distribution was found to be only 1.1% of the administered dose at 180 min. In contrast, 21.5% of the administered dose of [ 3 H]MTX-loaded PEG-PAMAM-ALN accumulated in the bones at 180 min after intravenous injection in mice, which was approximately 20-fold higher than that of [ 3 H]MTX. In a bone metastatic tumour mouse model, in which B16-BL6/Luc cells were injected into the left ventricle of female C57BL/6 mice, the growth of metastatic tumour in the bones was significantly inhibited by intravenous injection of MTX-loaded PEG-PAMAM-ALN. These findings indicate that PEG-PAMAM-ALN is a promising bone-targeting carrier for the delivery of anti-tumour agents and treatment of bone metastasis. 244. Comparison of ¹â¸F-fluoride PET/CT, ¹â¸F-FDG PET/CT and bone scintigraphy (planar and SPECT) in detection of bone metastases of differentiated thyroid cancer: a pilot study. PubMed Ota, Naotoshi; Kato, Katsuhiko; Iwano, Shingo; Ito, Shinji; Abe, Shinji; Fujita, Naotoshi; Yamashiro, Keiichi; Yamamoto, Seichi; Naganawa, Shinji 2014-02-01 We compared the efficacies of ¹â¸F-fluoride positron emission tomography (¹â¸F-fluoride PET)/CT, ¹â¸F-fludeoxyglucose PET (¹â¸F-FDG PET)/CT, and â¹â¹mTc bone scintigraphy [planar and single photon emission CT (SPECT)] for the detection of bone metastases in patients with differentiated thyroid carcinoma (DTC). We examined 11 patients (8 females and 3 males; mean age 6 standard deviation, 61.968.7 years) with DTC who had been suspected of having bone metastases after total thyroidectomy and were hospitalized to be given ¹³¹I therapy. Bone metastases were verified either when positive findings were obtained on both ¹³¹I scintigraphy and CT or when MRI findings were positive if MRI was performed. Metastases were confirmed in 24 (13.6%) of 176 bone segments in 9 (81.8%) of the 11 patients. The sensitivities of ¹â¸F-fluoride PET/CT and â¹â¹mTc bone scintigraphy (SPECT) were significantly higher than those of ¹â¸F-FDG PET/CT and â¹â¹mTc bone scintigraphy (planar) (p,0.05). The accuracies of ¹â¸F-fluoride PET/CT and mTc bone scintigraphy (SPECT) were significantly higher than that of â¹â¹mTc bone scintigraphy (planar) (p,0.05). The sensitivity and accuracy of ¹â¸F-fluoride PET/CT for the detection of bone metastases of DTC are significantly higher than those of â¹â¹mTc bone scintigraphy (planar). However, the sensitivity and accuracy of â¹â¹mTc bone scintigraphy (planar) are improved near to those of ¹â¸F-fluoride PET/CT when SPECT is added to a planar scan. The sensitivity of ¹â¸F-FDG PET/CT is significantly lower than that of 18F-fluoride PET/CT or â¹â¹mTc bone scintigraphy (SPECT). 245. Sexual selection targets cetacean pelvic bones. PubMed Dines, James P; Otárola-Castillo, Erik; Ralph, Peter; Alas, Jesse; Daley, Timothy; Smith, Andrew D; Dean, Matthew D 2014-11-01 Male genitalia evolve rapidly, probably as a result of sexual selection. Whether this pattern extends to the internal infrastructure that influences genital movements remains unknown. Cetaceans (whales and dolphins) offer a unique opportunity to test this hypothesis: since evolving from land-dwelling ancestors, they lost external hind limbs and evolved a highly reduced pelvis that seems to serve no other function except to anchor muscles that maneuver the penis. Here, we create a novel morphometric pipeline to analyze the size and shape evolution of pelvic bones from 130 individuals (29 species) in the context of inferred mating system. We present two main findings: (1) males from species with relatively intense sexual selection (inferred by relative testes size) tend to evolve larger penises and pelvic bones compared to their body length, and (2) pelvic bone shape has diverged more in species pairs that have diverged in inferred mating system. Neither pattern was observed in the anterior-most pair of vertebral ribs, which served as a negative control. This study provides evidence that sexual selection can affect internal anatomy that controls male genitalia. These important functions may explain why cetacean pelvic bones have not been lost through evolutionary time. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution. 246. Sexual selection targets cetacean pelvic bones PubMed Central Dines, J. P.; Otárola-Castillo, E.; Ralph, P.; Alas, J.; Daley, T.; Smith, A. D.; Dean, M. D. 2014-01-01 Male genitalia evolve rapidly, probably as a result of sexual selection. Whether this pattern extends to the internal infrastructure that influences genital movements remains unknown. Cetaceans (whales and dolphins) offer a unique opportunity to test this hypothesis: since evolving from land-dwelling ancestors, they lost external hind limbs and evolved a highly reduced pelvis which seems to serve no other function except to anchor muscles that maneuver the penis. Here we create a novel morphometric pipeline to analyze the size and shape evolution of pelvic bones from 130 individuals (29 species) in the context of inferred mating system. We present two main findings: 1) males from species with relatively intense sexual selection (inferred by relative testes size) have evolved relatively large penises and pelvic bones compared to their body size, and 2) pelvic bone shape diverges more quickly in species pairs that have diverged in inferred mating system. Neither pattern was observed in the anterior-most pair of vertebral ribs, which served as a negative control. This study provides evidence that sexual selection can affect internal anatomy that controls male genitalia. These important functions may explain why cetacean pelvic bones have not been lost through evolutionary time. PMID:25186496 247. IKK inhibition by BMS-345541 suppresses breast tumorigenesis and metastases by targeting GD2+ cancer stem cells. PubMed Battula, Venkata Lokesh; Nguyen, Khoa; Sun, Jeff; Pitner, Mary Kathryn; Yuan, Bin; Bartholomeusz, Chandra; Hail, Numsen; Andreeff, Michael 2017-06-06 We have identified that the ganglioside GD2 is a marker for breast cancer stem cells (BCSCs), and that targeting the enzyme GD3 synthase (GD3S, which regulates GD2 biosynthesis) reduces breast tumorigenesis. The pathways regulating GD2 expression, and their anomalous functions in BCSC, are unclear. Proteomic analysis of GD2+ and GD2cells from breast cancer cell lines revealed the activation of NFκB signaling in GD2+ cells. Dose- and time-dependent suppression of NFκB signaling by the small molecule inhibitor BMS-345541 reduced GD2+ cells by > 90%. Likewise, BMS-345541 inhibited BCSC GD3S expression, mammosphere formation, and cell migration/invasion in vitro. Breast tumor-bearing mice treated with BMS-345541 showed a statistically significant decrease in tumor volume and exhibited prolonged survival compared to control mice, with a median survival of 78 d for the BMS-345541-treated group vs. 58 d for the controls. Moreover, in an experimental metastases model, treatment with BMS-345541 reduced the lung metastases by > 5-fold. These data suggest that GD2 expression and function,and NFκB signaling, are related, and they control BCSCs tumorigenic characteristics. Thus, the suppression of NFκB signaling by BMS-345541 is a potentially important advance in controlling breast cancer growth and metastases. 248. IKK inhibition by BMS-345541 suppresses breast tumorigenesis and metastases by targeting GD2+ cancer stem cells PubMed Central Battula, Venkata Lokesh; Nguyen, Khoa; Sun, Jeff; Pitner, Mary Kathryn; Yuan, Bin; Bartholomeusz, Chandra; Hail, Numsen; Andreeff, Michael 2017-01-01 We have identified that the ganglioside GD2 is a marker for breast cancer stem cells (BCSCs), and that targeting the enzyme GD3 synthase (GD3S, which regulates GD2 biosynthesis) reduces breast tumorigenesis. The pathways regulating GD2 expression, and their anomalous functions in BCSC, are unclear. Proteomic analysis of GD2+ and GD2cells from breast cancer cell lines revealed the activation of NFκB signaling in GD2+ cells. Dose- and time-dependent suppression of NFκB signaling by the small molecule inhibitor BMS-345541 reduced GD2+ cells by > 90%. Likewise, BMS-345541 inhibited BCSC GD3S expression, mammosphere formation, and cell migration/invasion in vitro. Breast tumor-bearing mice treated with BMS-345541 showed a statistically significant decrease in tumor volume and exhibited prolonged survival compared to control mice, with a median survival of 78 d for the BMS-345541-treated group vs. 58 d for the controls. Moreover, in an experimental metastases model, treatment with BMS-345541 reduced the lung metastases by > 5-fold. These data suggest that GD2 expression and function, and NFκB signaling, are related, and they control BCSCs tumorigenic characteristics. Thus, the suppression of NFκB signaling by BMS-345541 is a potentially important advance in controlling breast cancer growth and metastases. PMID:28415808 249. Radiotherapy for Brain Metastases From Renal Cell Carcinoma in the Targeted Therapy Era: The University of Rochester Experience. PubMed Bates, James E; Youn, Paul; Peterson, Carl R; Usuki, Kenneth Y; Walter, Kevin A; Okunieff, Paul; Milano, Michael T 2017-10-01 Radiotherapy remains the standard approach for brain metastases from renal cell carcinoma (RCC). Kinase inhibitors (KI) have become standard of care for metastatic RCC. They also increase the radiosensitivity of various tumor types in preclinical models. Data are lacking regarding the effect of KIs among RCC patients undergoing radiotherapy for brain metastases. We report our experience of radiotherapy for brain metastatic RCC in the era of targeted therapy and analyzed effects of concurrent KI therapy. We retrospectively analyzed 25 consecutive patients who received radiotherapy for brain metastases from RCC with whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or both. Kaplan-Meier rates of overall survival (OS) and brain progression-free survival (BPFS) were calculated and univariate analyses performed. Lower diagnosis-specific graded prognostic assessment (DS-GPA) score and multiple intracranial metastases were associated with decreased OS and BPFS on univariate analysis; DS-GPA is also a prognostic factor on multivariate analysis. There was no significant difference in OS or BPFS for SRS compared with WBRT or WBRT and SRS combined. The concurrent use of KI was not associated with any change in OS or BPFS. This hypothesis-generating analysis suggests among patients with brain metastatic RCC treated with the most current therapies, those selected to undergo SRS did not experience significantly different survival or control outcomes than those selected to undergo WBRT. From our experience to date, limited in patient numbers, there seems to be neither harm nor benefit in using concurrent KI therapy during radiotherapy. Given that most patients progress systemically, we would recommend considering KI use during brain radiotherapy in these patients. 250. Somatic mutation detection using various targeted detection assays in paired samples of circulating tumor DNA, primary tumor and metastases from patients undergoing resection of colorectal liver metastases. PubMed 2016-12-01 Assessing circulating tumor DNA (ctDNA) is a promising method to evaluate somatic mutations from solid tumors in a minimally-invasive way. In a group of twelve metastatic colorectal cancer (mCRC) patients undergoing liver metastasectomy, from each patient DNA from cell-free DNA (cfDNA), the primary tumor, metastatic liver tissue, normal tumoradjacent colon or liver tissue, and whole blood were obtained. Investigated was the feasibility of a targeted NGS approach to identify somatic mutations in ctDNA. This targeted NGS approach was also compared with NGS preceded by mutant allele enrichment using synchronous coefficient of drag alteration technology embodied in the OnTarget assay, and for selected mutations with digital PCR (dPCR). All tissue and cfDNA samples underwent IonPGM sequencing for a CRC-specific 21-gene panel, which was analyzed using a standard and a modified calling pipeline. In addition, cfDNA, whole blood and normal tissue DNA were analyzed with the OnTarget assay and with dPCR for specific mutations in cfDNA as detected in the corresponding primary and/or metastatic tumor tissue. NGS with modified calling was superior to standard calling and detected ctDNA in the cfDNA of 10 patients harboring mutations in APC, ATM, CREBBP, FBXW7, KRAS, KMT2D, PIK3CA and TP53. Using this approach, variant allele frequencies in plasma ranged predominantly from 1 to 10%, resulting in limited concordance between ctDNA and the primary tumor (39%) and the metastases (55%). Concordance between ctDNA and tissue markedly improved when ctDNA was evaluated for KRAS, PIK3CA and TP53 mutations by the OnTarget assay (80%) and digital PCR (93%). Additionally, using these techniques mutations were observed in tumor-adjacent tissue with normal morphology in the majority of patients, which were not observed in whole blood. In conclusion, in these mCRC patients with oligometastatic disease NGS on cfDNA was feasible, but had limited sensitivity to detect all somatic mutations present 251. Dosimetry and toxicity of Samarium-153-EDTMP administered for bone pain due to skeletal metastases SciTech Connect Bayouth, J.E.; Macey, D.J.; Kasi, L.P. 1994-01-01 Palliation of bone pain in patients with cancer metastatic to bone is being evaluated in several cancer centers by the administration of the bone-seeking phosphonate ethylenediaminetetramethylenephosphonic acid (EDTMP) chelated with the beta particle-emitting radionuclide {sup 153}Sm. In this study {sup 153}Sm-EDTMP was intravenously injected into 19 patients over a 1-min period. Patients received up to four injections of 18.5 MBq (0.5 mCi) or 37 MBq (1.0mCi) per kilogram of body weight. Skeletal retention was calculated from urinary excretion. No uptake of {sup 153}Sm-EDTMP in nonskeletal tissues was observed in whole-body gamma camera images. The mean skeletal uptake for all patients was 54% {plus_minus} 16% of the injected dose (%ID). This resulted in the bone marrow receiving 89 cGy/GBq {plus_minus} 27 cGy/GBq (3.28 cGy/mCi {plus_minus} 0.99 cGy/mCi), with calculated marrow doses ranging from 27 cGy to 338 cGy. For each patient, the estimated radiation absorbed dose to the marrow was correlated to the percent decrease in platelet number, ranging from 7.4% to 78.9%. Since the deviation of uptake between the four injections for a given patient (7.6% ID) was less than the deviation for all patients (16% ID), the initial dose may be used to estimate the skeletal uptake for the remaining doses. These radiation dose estimates permit patients at risk to be identified prior to reaching myelotoxicity and develop dose-response models. Thirteen patients (68%) reported significant pain relief from this radionuclide therapy. Bone pain appears to be alleviated by {sup 153}Sm-EDTMP with limited red marrow doses and no toxic effects in other organs. 15 refs., 8 figs., 2 figs. 252. Heterogeneity in primary colorectal cancer and its corresponding metastases: a potential reason of EGFR-targeted therapy failure? PubMed Li, Zhongqi; Jin, Ketao; Lan, Huanrong; Teng, Lisong 2011-01-01 Epidermal growth factor receptor (EGFR)-targeted therapy represents an important approach in metastatic colorectal cancer (CRC) therapy. However, a number of CRC patients show intrinsic or acquired resistance to EGFR-targeted therapy. EGFR antibody therapy is established in CRC patients with wild-type KRAS. However, up to half of these patients do not respond to this therapy. This phenomenon implied some potential mechanisms of resistance to EGFR inhibitors might exist. One of the potential reasons to explain this phenomenon is heterogeneity of CRC. The heterogeneity of CRC has been well described at the morphological, molecular and genomic levels. This review discussed the potential relationship of heterogeneity, including intratumor heterogeneity of CRC and heterogeneity in primary CRC and its corresponding metastases, to EGFR-targeted therapy failure. 253. Comparison of the EORTC QLQ-BM22 and the BOMET-QOL quality of life questionnaires in patients with bone metastases. PubMed Bedard, Gillian; Zeng, Liang; Poon, Michael; Lam, Henry; Lauzon, Natalie; Chow, Edward 2014-06-01 Bone metastases are a common complication of advanced cancer and often result in a decrease in patients' quality of life. Very few specific modules have been created to accurately assess quality of life in this patient group. The purpose of this study was to compare two questionnaires, the European Organization for Research and Treatment of Cancer quality of life questionnaire for patients with bone metastases (EORTC QLQ-BM22) and the bone metastases quality of life questionnaire (BOMET-QOL. A literature search was conducted in Medline, Health and Psychosocial Instruments, Embase and Embase Classic to identify studies that discussed the development, validation and reliability of the (EORTC) QLQBM22 and the BOMET-QOL. Studies that discussed the development and validity of the questionnaire along with studies using these tools were included. Both questionnaires were developed in collaboration with patients and health-care professionals. The QLQ-BM22 is over twice the length of the BOMET-QOL, with 22 questions as compared to 10. The QLQ-BM22 has four subscales while the BOMET-QOL has no subscales. The QLQ-BM22 gives a more in-depth analysis of symptoms and well-being and includes issues such as mobility, side effects, complications of treatment and dependency. The BOMET-QOL is shorter and gives an overall assessment of pain and mobility. Scoring, item format, organization and response options vary between the questionnaires but the recall period for both is the previous week. Both questionnaires have been determined valid and reliable. The QLQ-BM22 and the BOMET-QOL are designed specifically for patients with bone metastases and each has strengths and weaknesses. Use of one over the other is ultimately dependent on trial design and investigators' goals. © 2013 Wiley Publishing Asia Pty Ltd. 254. Targeting subchondral bone for treating osteoarthritis: what is the evidence? PubMed Central Tat, Steeve Kwan; Lajeunesse, Daniel; Pelletier, Jean-Pierre; Martel-Pelletier, Johanne 2016-01-01 Over the past few decades, significant progress has been made with respect to new concepts about the pathogenesis of osteoarthritis (OA). This article summarises some of the knowledge we have today on the involvement of the subchondral bone in OA. It provides substantial evidence that changes in the metabolism of the subchondral bone are an integral part of the OA disease process and that these alterations are not merely secondary manifestations, but are part of a more active component of the disease. Thus, a strong rationale exists for therapeutic approaches that target subchondral bone resorption and/or formation, and data evaluating the drugs targeting bone remodelling raise the hope that new treatment options for OA may become available. PMID:20129200 255. Stereotactic Radiosurgery of the Postoperative Resection Cavity for Brain Metastases: Prospective Evaluation of Target Margin on Tumor Control SciTech Connect Choi, Clara Y.H.; Chang, Steven D.; Gibbs, Iris C.; Adler, John R.; Harsh, Griffith R.; Lieberson, Robert E.; Soltys, Scott G. 2012-10-01 Purpose: Given the neurocognitive toxicity associated with whole-brain irradiation (WBRT), approaches to defer or avoid WBRT after surgical resection of brain metastases are desirable. Our initial experience with stereotactic radiosurgery (SRS) targeting the resection cavity showed promising results. We examined the outcomes of postoperative resection cavity SRS to determine the effect of adding a 2-mm margin around the resection cavity on local failure (LF) and toxicity. Patients and Methods: We retrospectively evaluated 120 cavities in 112 patients treated from 1998-2009. Factors associated with LF and distant brain failure (DF) were analyzed using competing risks analysis, with death as a competing risk. The overall survival (OS) rate was calculated by the Kaplan-Meier product-limit method; variables associated with OS were evaluated using the Cox proportional hazards and log rank tests. Results: The 12-month cumulative incidence rates of LF and DF, with death as a competing risk, were 9.5% and 54%, respectively. On univariate analysis, expansion of the cavity with a 2-mm margin was associated with decreased LF; the 12-month cumulative incidence rates of LF with and without margin were 3% and 16%, respectively (P=.042). The 12-month toxicity rates with and without margin were 3% and 8%, respectively (P=.27). On multivariate analysis, melanoma histology (P=.038) and number of brain metastases (P=.0097) were associated with higher DF. The median OS time was 17 months (range, 2-114 months), with a 12-month OS rate of 62%. Overall, WBRT was avoided in 72% of the patients. Conclusion: Adjuvant SRS targeting the resection cavity of brain metastases results in excellent local control and allows WBRT to be avoided in a majority of patients. A 2-mm margin around the resection cavity improved local control without increasing toxicity compared with our prior technique with no margin. 256. Carcinoma of the prostate: the treatment of bone metastases by radioactive phosphorus (TSP) SciTech Connect Ariel, I.M.; Hassouna, H. 1985-01-01 The administration of radioactive phosphorus and testosterone benefitted two-thirds of thirty patients with prostate cancer treated. Subjective relief of bone pain occurred in 73% of cases and measurable objective improvement occurred in 50%. Hematopoietic depression occurred in 30% of the patients necessitating readmission to hospital for transfusion. This method of treatment is advocated for patients with widespread osseous metastasis, especially those with severe pain. 257. Biological Differences Between Prostate Cancer Cells that Metastasize to Bone Versus Soft Tissue Sites DTIC Science & Technology 2004-12-01 initial hormones prior to hormone deprivation ranged from 0 to 144 months. Patients survived in the no. death (year) diagnosis Treatment * chemotherapy...biomarkers and genes. Comparisons were made between patients as well as within the same patient . No consistent differences were found between bone and soft...within the same patient . An appreciation of this heterogeneity is critical to evaluating diagnostic and prognostic biomarkers as well as designing 258. {sup 188}Rhenium-HEDP in the Treatment of Pain in Bone Metastases SciTech Connect Gaudiano, J.; Savio, E.; Robles, A.; Muniz, S.; Leon, A.; Verdera, S.; Martinez, G.; Hermida, J.C.; Knapp, F.F., Jr. 1999-01-18 Systemic use of radiopharmaceuticals is a recognized alternative method for the treatment of pain in patients with multiple bone metastasis. A new option, {sup 188}Re-HEDP is proposed, using generator-obtained {sup 188}Rhenium ({beta} energy = 2.1 MeV, {gamma} energy = 155 keV, half-life = 16.9 hours). After establishing parameters of biodistribution, dosimetry and image acquisition in mice, rats and rabbits, Phase I and II studies were conducted on 12 patients with multiple metastasis from carcinomas, with pain surpassing other analgesic options. More than 50% pain relief was found in 91% of the patients, with total relief during a variable period in 41% of them allowing opiate and other analgesic drugs to be decreased or withdrawn, and showing a lower bone marrow contribution to total absorbed dose than that reported for other similar radiopharmaceuticals. Further study of this option is recommended in order to determine higher dose protocols without toxic bone marrow reaction possibilities. 259. Bone tissue engineering and regenerative medicine: targeting pathological fractures. PubMed Nguyen, Duong T; Burg, Karen J L 2015-01-01 Patients with bone diseases have the highest risk of sustaining fractures and of suffering from nonunion bone healing due to tissue degeneration. Current fracture management strategies are limited in design and functionality and do not effectively promote bone healing within a diseased bone environment. Fracture management approaches include pharmaceutical therapy, surgical intervention, and tissue regeneration for fracture prevention, fracture stabilization, and fracture site regeneration, respectively. However, these strategies fail to accommodate the pathological nature of fragility fractures, leading to unwanted side effects, implant failures, and nonunions. To target fragility fractures, fracture management strategies should include bioactive bone substitutes designed for the pathological environment. However, the clinical outcome of these materials must be predictable within various disease environments. Initial development of a targeted treatment strategy should focus on simulating the physiological in vitro bone environment to predict clinical effectiveness of the engineered bone. An in vitro test system can facilitate reduction of implant failures and non-unions in fragility fractures. © 2014 Wiley Periodicals, Inc. 260. Visceral and bone metastases of a WHO grade 2 meningioma: A case report and review of the literature. PubMed Paix, A; Waissi, W; Antoni, D; Adeduntan, R; Noël, G 2017-02-01 Meningiomas represent the most common tumours of the central nervous system in adults. Risk factors include ionizing radiation, female hormones exposure, head trauma, cell phone use, breast cancer and family history of meningioma. Despite complete surgical resection, natural history of meningiomas often includes local recurrence but very few metastatic meningiomas have been reported. Here, we report the case of a metastatic meningioma. A 43-year-old woman was firstly treated for a symptomatic parietal meningioma WHO grade II by surgical resection followed by an irradiation of the surgical bed. After surgical resection and irradiation, the patient recovered incompletely. Two months after the end of the radiation treatment, the patient presented at the emergency unit for sciatic pain revealing bone metastases that has been histologically confirmed. Moreover, imaging led to the diagnosis of liver and lungs metastasis. Despite lack of guidelines for metastatic meningioma, few treatments have been used and published for recurrent and multiple meningioma management. In case studies, some partial responses have been seen with mifepristone and improved progression-free survival rates have been obtained with hydroxyurea and sunitinib. Metastasis in meningioma is very uncommon and no specific management has been described. Hydroxyurea, sunitinib and mifepristone could be options if no clinical trial data is available. Copyright © 2017. Published by Elsevier SAS. « 11 12 13 14 15 » « 12 13 14 15 16 » 261. Would Larger Radiation Fields Lead to a Faster Onset of Pain Relief in the Palliation of Bone Metastases? SciTech Connect Chow, Edward; Makhani, Leila; Culleton, Shaelyn 2009-08-01 Purpose: Hemibody irradiation has been shown to relieve bony metastatic pain within 24-48 hours of treatment, whereas for local external beam radiation, onset of pain relief is 1-4 weeks after radiation. The primary objective of this study is to examine whether there is a relationship between the areas of radiation treatment and onset of pain relief. Methods and Materials: From Jan 1999 to Jan 2002, a total of 653 patients with symptomatic bone metastases were treated with external beam radiation. Pain scores and analgesic consumption were recorded at baseline and Weeks 1, 2, 4, 8, and 12. The areas ofmore » radiation treatment for all patients were calculated, then correlated with the response and analyzed in various ways. We first compared pain score alone with mean radiation field size. Second, we combined pain score and analgesic consumption. Last, we implemented the International Consensus end points for pain score and analgesic intake. Results: Assessment of 653 patients showed no significant correlation comparing pain scores alone with radiation field area, with the exception of Week 4 for partial responders. Again, no significant correlation was found when combining both analgesic intake and pain score against radiation field size. Even when implementing the International Consensus end point definitions for radiation response, the only significant correlation between radiation field size and response was observed in Week 2 for partial response. Conclusion: There was no statistical significance between mean areas of radiation treatment with the onset of pain relief.« less 262. Would Larger Radiation Fields Lead to a Faster Onset of Pain Relief in the Palliation of Bone Metastases? SciTech Connect Chow, Edward Makhani, Leila; Culleton, Shaelyn; Makhani, Nadiya; Davis, Lori; Campos, Sarah; Sinclair, Emily 2009-08-01 Purpose: Hemibody irradiation has been shown to relieve bony metastatic pain within 24-48 hours of treatment, whereas for local external beam radiation, onset of pain relief is 1-4 weeks after radiation. The primary objective of this study is to examine whether there is a relationship between the areas of radiation treatment and onset of pain relief. Methods and Materials: From Jan 1999 to Jan 2002, a total of 653 patients with symptomatic bone metastases were treated with external beam radiation. Pain scores and analgesic consumption were recorded at baseline and Weeks 1, 2, 4, 8, and 12. The areas of radiation treatment for all patients were calculated, then correlated with the response and analyzed in various ways. We first compared pain score alone with mean radiation field size. Second, we combined pain score and analgesic consumption. Last, we implemented the International Consensus end points for pain score and analgesic intake. Results: Assessment of 653 patients showed no significant correlation comparing pain scores alone with radiation field area, with the exception of Week 4 for partial responders. Again, no significant correlation was found when combining both analgesic intake and pain score against radiation field size. Even when implementing the International Consensus end point definitions for radiation response, the only significant correlation between radiation field size and response was observed in Week 2 for partial response. Conclusion: There was no statistical significance between mean areas of radiation treatment with the onset of pain relief. 263. Enhancing Quality of Life for Breast Cancer Patients with Bone Metastases DTIC Science & Technology 2007-03-01 the knee flexed, a small incision was made at the joint and the patella carefully moved to expose the distal end of the femur. Using a sterile 26G...weighed and the hind limbs scrubbed with betadine followed by 70% ethanol. With the knee flexed, a small incision was made at the joint and the patella...tumor-bearing limbs had a 50% chance of failing through either the bone or the ligaments of the knee . This suggests that at early time points the 264. Impact of Using Audit Data to Improve the Evidence-Based Use of Single-Fraction Radiation Therapy for Bone Metastases in British Columbia SciTech Connect Olson, Robert A.; Tiwana, Manpreet; Barnes, Mark; Cai, Eric; McGahan, Colleen; Roden, Kelsey; Yurkowski, Emily; Gentles, Quinn; French, John; Halperin, Ross; Olivotto, Ivo A. 2016-01-01 Purpose: To assess the impact of a population-based intervention to increase the consistency and use of single-fraction radiation therapy (SFRT) for bone metastases. Methods and Materials: In 2012, an audit of radiation therapy prescriptions for bone metastases in British Columbia identified significant interphysician and -center (26%-73%) variation in the use of SFRT. Anonymous physician-level and identifiable regional cancer center SFRT use data were presented to all radiation oncologists, together with published guidelines, meta-
analyses, and recommendations from practice leaders. The use of SFRT for bone metastases from 2007 through 2011 was compared with use of SFRT in 2013, to assess the impact of the audit and educational intervention. Multilevel logistic regression was used to assess the relationship between the usage of SFRT and the timing of the radiation while controlling for potentially confounding variables. Physician and center were included as group effects to account for the clustered structure of the data. Results: A total of 16,898 courses of RT were delivered from 2007 through 2011, and 3200 courses were delivered in 2013. The rates of SFRT use in 2007, 2008, 2009, 2010, 2011, and 2013 were 50.5%, 50.9%, 48.3%, 48.5%, 48.0%, and 59.7%, respectively (P<.001). Use of SFRT increased in each of 5 regional centers: A: 26% to 32%; B: 36% to 56%; C: 39% to 57%; D: 49% to 56%; and E: 73% to 85.0%. Use of SFRT was more consistent; 3 of 5 centers used SFRT for 56% to 57% of bone metastases RT courses. The regression analysis showed strong evidence that the usage of SFRT increased after the 2012 intervention (odds ratio 2.27, 95% confidence interval 2.06-2.50, P<.0001). Conclusion: Assessed on a population basis, an audit-based intervention increased utilization of SFRT for bone metastases. The intervention reversed a trend to decreasing SFRT use, reduced costs, and improved patient convenience. This suggests that dissemination of programmatic quality 265. Impact of Using Audit Data to Improve the Evidence-Based Use of Single-Fraction Radiation Therapy for Bone Metastases in British Columbia SciTech Connect Olson, Robert A., E-mail:
[email protected]; University of Northern British Columbia, Prince George, British Columbia; University of British Columbia, Vancouver, British Columbia 2016-01-01 Purpose: To assess the impact of a population-based intervention to increase the consistency and use of single-fraction radiation therapy (SFRT) for bone metastases. Methods and Materials: In 2012, an audit of radiation therapy prescriptions for bone metastases in British Columbia identified significant interphysician and -center (26%-73%) variation in the use of SFRT. Anonymous physician-level and identifiable regional cancer center SFRT use data were presented to all radiation oncologists, together with published guidelines, metaanalyses, and recommendations from practice leaders. The use of SFRT for bone metastases from 2007 through 2011 was compared with use of SFRT in 2013, to assess themore » impact of the audit and educational intervention. Multilevel logistic regression was used to assess the relationship between the usage of SFRT and the timing of the radiation while controlling for potentially confounding variables. Physician and center were included as group effects to account for the clustered structure of the data. Results: A total of 16,898 courses of RT were delivered from 2007 through 2011, and 3200 courses were delivered in 2013. The rates of SFRT use in 2007, 2008, 2009, 2010, 2011, and 2013 were 50.5%, 50.9%, 48.3%, 48.5%, 48.0%, and 59.7%, respectively (P<.001). Use of SFRT increased in each of 5 regional centers: A: 26% to 32%; B: 36% to 56%; C: 39% to 57%; D: 49% to 56%; and E: 73% to 85.0%. Use of SFRT was more consistent; 3 of 5 centers used SFRT for 56% to 57% of bone metastases RT courses. The regression analysis showed strong evidence that the usage of SFRT increased after the 2012 intervention (odds ratio 2.27, 95% confidence interval 2.06-2.50, P<.0001). Conclusion: Assessed on a population basis, an audit-based intervention increased utilization of SFRT for bone metastases. The intervention reversed a trend to decreasing SFRT use, reduced costs, and improved patient convenience. This suggests that dissemination of programmatic 266. Impact of Using Audit Data to Improve the Evidence-Based Use of Single-Fraction Radiation Therapy for Bone Metastases in British Columbia. PubMed Olson, Robert A; Tiwana, Manpreet; Barnes, Mark; Cai, Eric; McGahan, Colleen; Roden, Kelsey; Yurkowski, Emily; Gentles, Quinn; French, John; Halperin, Ross; Olivotto, Ivo A 2016-01-01 To assess the impact of a population-based intervention to increase the consistency and use of single-fraction radiation therapy (SFRT) for bone metastases. In 2012, an audit of radiation therapy prescriptions for bone metastases in British Columbia identified significant interphysician and -center (26%-73%) variation in the use of SFRT. Anonymous physician-level and identifiable regional cancer center SFRT use data were presented to all radiation oncologists, together with published guidelines, meta-analyses, and recommendations from practice leaders. The use of SFRT for bone metastases from 2007 through 2011 was compared with use of SFRT in 2013, to assess the impact of the audit and educational intervention. Multilevel logistic regression was used to assess the relationship between the usage of SFRT and the timing of the radiation while controlling for potentially confounding variables. Physician and center were included as group effects to account for the clustered structure of the data. A total of 16,898 courses of RT were delivered from 2007 through 2011, and 3200 courses were delivered in 2013. The rates of SFRT use in 2007, 2008, 2009, 2010, 2011, and 2013 were 50.5%, 50.9%, 48.3%, 48.5%, 48.0%, and 59.7%, respectively (P<.001). Use of SFRT increased in each of 5 regional centers: A: 26% to 32%; B: 36% to 56%; C: 39% to 57%; D: 49% to 56%; and E: 73% to 85.0%. Use of SFRT was more consistent; 3 of 5 centers used SFRT for 56% to 57% of bone metastases RT courses. The regression analysis showed strong evidence that the usage of SFRT increased after the 2012 intervention (odds ratio 2.27, 95% confidence interval 2.06-2.50, P<.0001). Assessed on a population basis, an audit-based intervention increased utilization of SFRT for bone metastases. The intervention reversed a trend to decreasing SFRT use, reduced costs, and improved patient convenience. This suggests that dissemination of programmatic quality indicators in oncology can lead to increased utilization 267. 223Ra-dichloride response in a patient with Paget disease and bone metastases secondary to castration-resistant prostate cancer. PubMed GarcÃa Cañamaque, Lina; Rioja Parada, Cristina; GarcÃa De la Peña, Paloma 2017-11-15 Paget disease is commonly asymptomatic and discovered when an imaging test is performed for another clinical indication or when elevated serum alkaline phosphatase is found. Bone pain usually appears late in the disease process and is only present in a minority of patients. For diagnosis, X-ray and bone scan are the most recommended imaging methods; radionuclide imaging of the skeleton has become the standard, since it is the most sensitive test for detecting increased bone activity. For treatment, either bisphosphonates or calcitonin are recommended. We present a 74-year-old patient diagnosed with prostate cancer in 2001 who developed bone metastases concomitant with a Paget bone disease. This patient received treatment with Ra-223, having stable disease in bone scan and no relevant toxicities. There is no clinical experience with Ra-223 and Paget disease, since it is characterized classically as a high bone turnover disease and therefore there is no rationale to administer a drug that has a high bone affinity. Nevertheless, Ra-223 is not contraindicated. 268. Impact of targeted PPAR gamma disruption on bone remodeling USDA-ARS?s Scientific Manuscript database Peroxisome proliferator-activated receptor gamma (PPAR gamma), known as the master regulator of adipogenesis, has been regarded as a promising target for new anti-osteoporosis therapy due to its role in regulating bone marrow mesenchymal stem/progenitor cell (BMSC) lineage commitment. However, the p... 269. Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration PubMed Central Gu, Wenyi; Wu, Chengtie; Chen, Jiezhong; Xiao, Yin 2013-01-01 Nanotechnology is a vigorous research area and one of its important applications is in biomedical sciences. Among biomedical applications, targeted drug delivery is one of the most extensively studied subjects. Nanostructured particles and scaffolds have been widely studied for increasing treatment efficacy and specificity of present treatment approaches. Similarly, this technique has been used for treating bone diseases including bone regeneration. In this review, we have summarized and highlighted the recent advancement of nanostructured particles and scaffolds for the treatment of cancer bone metastasis, osteosarcoma, bone infections and inflammatory diseases, osteoarthritis, as well as for bone regeneration. Nanoparticles used to deliver deoxyribonucleic acid and ribonucleic acid molecules to specific bone sites for gene therapies are also included. The investigation of the implications of nanoparticles in bone diseases have just begun, and has already shown some promising potential. Further studies have to be conducted, aimed specifically at assessing targeted delivery and bioactive scaffolds to further improve their efficacy before they can be used clinically. PMID:23836972 270. Antibody-Mediated Targeting of Alpha PDGF Receptor to Inhibit the Progression of Skeletal Micro-Metastases DTIC Science & Technology 2011-10-01 metastasesâ€. Orlando FL. Presentations University of Illinois at Chicago – Department of Biopharmaceutical Sciences. College of Pharmacy...cancer [J]. European Urology, 2004, 45(1):26-34. Bagi CM. Targeting of therapeutic agents to bone to treat metastatic cancer [J]. Adv Drug Deliv 271. Beta-catenin/TCF Signaling and Castrate-Resistant Progression of Osteoblastic Bone Metastases DTIC Science & Technology 2009-06-01 were first transiently transfected with either beta-catenin–specific siRNA (si- bcat ) or non-targeted siRNA (si-control). At 24 hours after the...when coculturing was performed with MDA PCa 118 cells with beta-catenin knockdown (PMO co si- bcat -118b), the increase in PMO cell proliferation was...unchanged, and thus PMOs were cocultured in the presence of the same number of si-control-118b or si- bcat -118 cells. This then supports the idea that beta 272. Use of Single- versus Multiple-Fraction Palliative Radiation Therapy for Bone Metastases: Population-Based Analysis of 16,898 Courses in a Canadian Province SciTech Connect Olson, Robert A.; Tiwana, Manpreet S.; Barnes, Mark; Kiraly, Andrew; Beecham, Kwamena; Miller, Stacy; Hoegler, David; Olivotto, Ivo 2014-08-01 Purpose: There is abundant evidence that a single fraction (SF) of palliative radiation therapy (RT) for bone metastases is equivalent to more protracted and costly multiple fraction courses. Despite this, there is low utilization of SFRT internationally. We sought to determine the utilization of SFRT in a population-based, publicly funded health care system. Methods and Materials: All consecutive patients with bone metastases treated with RT during 2007 to 2011 in British Columbia (BC) were identified. Associations between utilization of SFRT and patient and provider characteristics were investigated. Results: A total of 16,898 courses of RT were delivered to 8601 patients. SFRT was prescribed 49% of the time. There were positive relationships among SFRT utilization and primary tumor group (P<.001; most commonly in prostate cancer), worse prognosis (P<.001), increasing physician experience (P<.001), site of metastases (P<.001; least for spine metastases), and area of training (P<.001; most commonly for oncologists trained in the United Kingdom). There was wide variation in the prescription of SFRT across 5 regional cancer centers, ranging from 25.5% to 73.4%, which persisted after controlling for other, potentially confounding factors (P<.001). Conclusions: The large variability in SFRT utilization across BC Cancer Agency (BCCA) cancer centers suggests there is a strong cultural effect, where physicians' use of SFRT is influenced by their colleagues' practice. SFRT use in BC was similar to that in other Canadian and western European reports but strikingly higher than in the United States. Further work is needed to standardize SFRT prescribing practices internationally for this common indication for RT, with the potential for huge health system cost savings and substantial improvements in patients' quality of life. 273. Use of Single- versus Multiple-Fraction Palliative Radiation Therapy for Bone Metastases: Population-Based Analysis of 16,898 Courses in a Canadian Province SciTech Connect Olson, Robert A., E-mail:
[email protected]; University of Northern British Columbia, Prince George, British Columbia; University of British Columbia, Vancouver, British Columbia 2014-08-01 Purpose: There is abundant evidence that a single fraction (SF) of palliative radiation therapy (RT) for bone metastases is equivalent to more protracted and costly multiple fraction courses. Despite this, there is low utilization of SFRT internationally. We sought to determine the utilization of SFRT in a population-based, publicly funded health care system. Methods and Materials: All consecutive patients with bone metastases treated with RT during 2007 to 2011 in British Columbia (BC) were identified. Associations between utilization of SFRT and patient and provider characteristics were investigated. Results: A total of 16,898 courses of RT were delivered to 8601 patients.more » SFRT was prescribed 49% of the time. There were positive relationships among SFRT utilization and primary tumor group (P<.001; most commonly in prostate cancer), worse prognosis (P<.001), increasing physician experience (P<.001), site of metastases (P<.001; least for spine metastases), and area of training (P<.001; most commonly for oncologists trained in the United Kingdom). There was wide variation in the prescription of SFRT across 5 regional cancer centers, ranging from 25.5% to 73.4%, which persisted after controlling for other, potentially confounding factors (P<.001). Conclusions: The large variability in SFRT utilization across BC Cancer Agency (BCCA) cancer centers suggests there is a strong cultural effect, where physicians' use of SFRT is influenced by their colleagues' practice. SFRT use in BC was similar to that in other Canadian and western European reports but strikingly higher than in the United States. Further work is needed to standardize SFRT prescribing practices internationally for this common indication for RT, with the potential for huge health system cost savings and substantial improvements in patients' quality of life.« less 274. Use of single- versus multiple-fraction palliative radiation therapy for bone metastases: population-based analysis of 16,898 courses in a Canadian province. PubMed Olson, Robert A; Tiwana, Manpreet S; Barnes, Mark; Kiraly, Andrew; Beecham, Kwamena; Miller, Stacy; Hoegler, David; Olivotto, Ivo 2014-08-01 There is abundant evidence that a single fraction (SF) of palliative radiation therapy (RT) for bone metastases is equivalent to more protracted and costly multiple fraction courses. Despite this, there is low utilization of SFRT internationally. We sought to determine the utilization of SFRT in a population-based, publicly funded health care system. All consecutive patients with bone metastases treated with RT during 2007 to 2011 in British Columbia (BC) were identified. Associations between utilization of SFRT and patient and provider characteristics were investigated. A total of 16,898 courses of RT were delivered to 8601 patients. SFRT was prescribed 49% of the time. There were positive relationships among SFRT utilization and primary tumor group (P<.001; most commonly in prostate cancer), worse prognosis (P<.001), increasing physician experience (P<.001), site of metastases (P<.001; least for spine metastases), and area of training (P<.001; most commonly for oncologists trained in the United Kingdom). There was wide variation in the prescription of SFRT across 5 regional cancer centers, ranging from 25.5% to 73.4%, which persisted after controlling for other, potentially confounding factors (P<.001). The large variability in SFRT utilization across BC Cancer Agency (BCCA) cancer centers suggests there is a strong cultural effect, where physicians' use of SFRT is influenced by their colleagues' practice. SFRT use in BC was similar to that in other Canadian and western European reports but strikingly higher than in the United States. Further work is needed to standardize SFRT prescribing practices internationally for this common indication for RT, with the potential for huge health system cost savings and substantial improvements in patients' quality of life. Copyright © 2014 Elsevier Inc. All rights reserved. 275. Defining the Optimal Planning Target Volume in Image-Guided Stereotactic Radiosurgery of Brain Metastases: Results of a Randomized Trial SciTech Connect Kirkpatrick, John P., E-mail:
[email protected]; Department of Surgery, Duke University, Durham, North Carolina; Wang, Zhiheng 2015-01-01 Purpose: To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. Methods and Materials: Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board–approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diametersmore » less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator–based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS). Results: Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non–small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change 276. High-Linear Energy Transfer Irradiation Targeted to Skeletal Metastases by the Alpha Emitter Ra-223: Adjuvant or Alternative to Conventional Modalities? SciTech Connect Bruland, Oyvind S.; Nilsson, Sten; Fisher, Darrell R.; Larsen, Roy H. 2006-10-15 The bone-seeking, alpha-particle emitting radiopharmaceutical Alpharadin, 223RaCl2 (t1/2 = 11.4 days) is under clinical development as a novel treatment for skeletal metastases from breast and prostate cancer. This paper summarizes the current status of preclinical and clinical research on 223RaCl2. Potential advantages of 223Ra to that of external beam irradiation or registered beta-emitting bone-seekers are discussed. Published data of 223Ra dosimetry in mice and a therapeutic study in a skeletal metastases model in nude rats have indicated significant therapeutic potential of bone-seeking alpha-emitters. This paper provides short-term and long-term results from the first clinical single dosage trial. We present data from a repeated dosage study of five consecutive injections of 50 kBq/kg bodyweight, once every third week, or two injections of 125 kBq/kg bodyweight, six weeks apart. Furthermore, preliminary results are given for a randomized phase II trial involving 64 patients with hormone-refractory prostate cancer and painful skeletal metastases who received four monthly injections of 223Ra or saline as an adjuvant to external beam radiotherapy. Also presented are preliminary dose estimates for 223Ra in humans. Results indicate that repeated dosing is feasible and that opportunities are available for combined treatment strategies. 277. Significance of hormone receptor status in comparison of 18F -FDG-PET/CT and 99mTc-MDP bone scintigraphy for evaluating bone metastases in patients with breast cancer: single center experience. PubMed Teke, Fatma; Teke, Memik; Inal, Ali; Kaplan, Muhammed Ali; Kucukoner, Mehmet; Aksu, Ramazan; Urakci, Zuhat; Tasdemir, Bekir; Isikdogan, Abdurrahman 2015-01-01 Fluorine-18 deoxyglucose positron emission tomography computed tomography (18F-FDG-PET/ CT) and bone scintigraphy (BS) are widely used for the detection of bone involvement. The optimal imaging modality for the detection of bone metastases in hormone receptor positive (+) and negative (-) groups of breast cancer remains ambiguous. Sixtytwo patients with breast cancer, who had undergone both 18F-FDG-PET/CT and BS, being eventually diagnosed as having bone metastases, were enrolled in this study. 18F-FDGPET/CT had higher sensitivity and specificity than BS. Our data showed that 18F-FDG- PET/CT had a sensitivity of 93.4% and a specificity of 99.4%, whiel for BS they were 84.5%, and 89.6% in the diagnosis of bone metastases. κ statistics were calculated for 18F-FDGPET/CT and BS. The κ-value was 0.65 between 18F-FDG-PET/CT and BS in all patients. On the other hand, the κ-values were 0.70 in the hormone receptor (+) group, and 0.51 in hormone receptor (-) group. The κ-values suggested excellent agreement between all patient and hormone receptor (+) groups, while the κ-values suggested good agreement in the hormone receptor (-) group. The sensitivity and specificity for 18F-FDG-PET/CT were higher than BS in the screening of metastatic bone lesions in all patients. Similarly 18F-FDG-PET/CT had higher sensitivity and specificity in hormone receptor (+) and (-) groups. 278. Doxorubicin-poly (ethylene glycol)-alendronate self-assembled micelles for targeted therapy of bone metastatic cancer PubMed Central Ye, Wei-liang; Zhao, Yi-pu; Li, Huai-qiu; Na, Ren; Li, Fei; Mei, Qi-bing; Zhao, Ming-gao; Zhou, Si-yuan 2015-01-01 In order to increase the therapeutic effect of doxorubicin (DOX) on bone metastases, a multifunctional micelle was developed by combining pH-sensitive characteristics with bone active targeting capacity. The DOX loaded micelle was self-assembled by using doxorubicin-poly (ethylene glycol)-alendronate (DOX-hyd-PEG-ALN) as an amphiphilic material. The size and drug loading of DOX loaded DOX-hyd-PEG-ALN micelle was 114 nm and 24.3%. In pH 5.0 phosphate buffer solution (PBS), the micelle released DOX significantly faster than in pH 7.4 PBS. In addition, with the increase of incubation time, more red DOX fluorescence was observed in tumor cells and trafficked from cytoplasm to nucleus. The IC50 of DOX loaded DOX-hyd-PEG-ALN micelle on A549 cells was obviously lower than that of free DOX in 48 h. Furthermore, the in vivo image experimental results indicated that a larger amount of DOX was accumulated in the bone metastatic tumor tissue after DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered, which was confirmed by histological analysis. Finally, DOX loaded DOX-hyd-PEG-ALN micelle effectively delayed the tumor growth, decreased the bone loss and reduced the cardiac toxicity in tumor-bearing nude mice as compared with free DOX. In conclusion, DOX loaded DOX-hyd-PEG-ALN micelle had potential in treating bone metastatic tumor. PMID:26419507 279. Overall survival and the response to radiotherapy among molecular subtypes of breast cancer brain metastases treated with targeted therapies. PubMed Miller, Jacob A; Kotecha, Rupesh; Ahluwalia, Manmeet S; Mohammadi, Alireza M; Chao, Samuel T; Barnett, Gene H; Murphy, Erin S; Vogelbaum, Michael A; Angelov, Lilyana; Peereboom, David M; Suh, John H 2017-06-15 The current study was conducted to investigate survival and the response to radiotherapy among patients with molecular subtypes of breast cancer brain metastases treated with or without targeted therapies. Patients diagnosed with breast cancer brain metastases at a single tertiary care institution were included. The primary outcome was overall survival, whereas secondary outcomes included the cumulative incidences of distant intracranial failure, local failure, and radiation necrosis. Competing risks regression was used to model secondary outcomes. Within the study period, 547 patients presented with 3224 brain metastases and met inclusion criteria. Among patients with human epidermal growth factor receptor 2 (HER2)-amplified disease, 80% received HER2 antibodies and 38% received HER2/epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The median survival was significantly shorter in the basal cohort (8.4 months), and progressively increased in the luminal A (12.3 months), HER2-positive (15.4 months), and luminal B (18.8 months) cohorts (P<.001). Among patients with HER2-amplified disease, the median survival was extended with the use of both HER2 antibodies (17.9 months vs 15.1 months; P†‰= .04) and TKIs (21.1 months vs 15.4 months; P = .03). The 12-month cumulative incidences of local failure among molecular subtypes were 6.0% in the luminal A cohort, 10.3% in the luminal B cohort, 15.4% in the HER2-positive cohort, and 9.9% in the basal cohort (P = .01). Concurrent HER2/epidermal growth factor receptor TKIs with stereotactic radiosurgery significantly decreased the 12-month cumulative incidence of local failure from 15.1% to 5.7% (P<.001). Molecular subtypes appear to be prognostic for survival and predictive of the response to radiotherapy. TKIs were found to improve survival and local control, and may decrease the rate of distant failure. To preserve neurocognition, these results support a paradigm of upfront radiosurgery and HER2 280. Targeting Bone Marrow Lymphoid Niches In Acute Lymphoblastic Leukemia PubMed Central Uy, Geoffrey L.; Hsu, Yen-Michael S.; Schmidt, Amy P.; Stock, Wendy; Fletcher, Theresa R.; Trinkaus, Kathryn M.; Westervelt, Peter; DiPersio, John F.; Link, Daniel C. 2015-01-01 In acute lymphoblastic leukemia (ALL) the bone marrow microenvironment provides growth and survival signals that may confer resistance to chemotherapy. Granulocyte colonystimulating factor (G-CSF) potently inhibits lymphopoiesis by targeting stromal cells that comprise the lymphoid niche in the bone marrow. To determine whether lymphoid niche disruption by G-CSF sensitizes ALL cells to chemotherapy, we conducted a pilot study of G-CSF in combination with chemotherapy in patients with relapsed or refractory ALL. Thirteen patients were treated on study; three patients achieved a complete remission (CR/CRi) for an overall response rate of 23%. In the healthy volunteers, G-CSF treatment disrupted the lymphoid niche, as evidenced by reduced expression of CXCL12, interleukin-7, and osteocalcin. However, in most patients with relapsed/refractory ALL expression of these genes was markedly suppressed at baseline. Thus, although G-CSF treatment was associated with ALL cell mobilization into the blood, and increased apoptosis of bone marrow resident ALL cells, alterations in the bone marrow microenvironment were modest and highly variable. These data suggest that disruption of lymphoid niches by G-CSF to sensitize ALL cells to chemotherapy may be best accomplished in the consolidation where the bone marrow microenvironment is more likely to be normal. PMID:26467815 « 12 13 14 15 16 » « 13 14 15 16 17 » 281. Use of Neoadjuvant Chemotherapy Plus Molecular Targeted Therapy in Colorectal Liver Metastases: A Systematic Review and Meta-analysis. PubMed Sabanathan, Dhanusha; Eslick, Guy D; Shannon, Jenny 2016-12-01 Surgery remains the standard of care for patients with colorectal liver metastases (CLMs), with a 5-year survival rate approaching 35%. Perioperative chemotherapy confers a survival benefit in selected patients with CLMs. The use of molecular targeted therapy combined with neoadjuvant chemotherapy for CLMs, however, remains controversial. We reviewed the published data on combination neoadjuvant chemotherapy and molecular targeted therapy for resectable and initially unresectable CLMs. A literature search of the Medline and PubMed databases was conducted to identify studies of neoadjuvant chemotherapy plus molecular targeted therapy in the management of resectable or initially unresectable CLMs. We calculated the pooled proportion and 95% confidence intervals using a random effects model for the relationship of the combination neoadjuvant treatment on the overall response rate and performed a systematic review of all identified studies. The analysis was stratified according to the study design. The data from 11 studies of 908 patients who had undergone systemic chemotherapy plus targeted therapy for CLM were analyzed. The use of combination neoadjuvant therapy was associated with an overall response rate of 68% (95% confidence interval, 63%-73%), with significant heterogeneity observed in the studies (I2 = 89.35; P < .001). Of the 11 studies, 4 used a combination that included oxaliplatin, 2 included irinotecan, and 5 included a combination of both. Also, 7 studies used cetuximab and 4 bevacizumab. The overall progression-free survival was estimated at 14.4 months. Current evidence suggests that neoadjuvant chemotherapy plus molecular targeted agents for CLM confers high overall response rates. Combination treatment might also increase the resectability rates in initially unresectable CLM. Further studies are needed to examine the survival outcomes, with a focus on the differential role of molecular targeted therapy in the neoadjuvant versus adjuvant setting 282. The Risk of Misdiagnosing the Primary Site Responsible for Bone Metastases in Patients With Chronic Lymphocytic Leukemia and a Second Primary Carcinoma PubMed Central Hatoum, Georges; Meshkin, Cyrus; Alkhunaizi, Sufana; Levene, Richard; Formoso-Onofrio, Julie 2015-01-01 Chronic lymphocytic leukemia (CLL) is a common malignancy which may coexist with other primary cancers. CLL is rarely the cause of solitary bone lesions; such lesions in the context of CLL are believed to result from either Richter’s transformation or metastasis from another primary malignancy. Renal cell carcinoma (RCC), on the other hand, is a malignancy which frequently metastasizes to bone and may cause an osteolytic solitary bone lesion. The origin of a solitary bone lesion in a patient with multiple potential primary malignancies has prognostic implications and affects treatment protocol, and as such must be diagnosed accurately. We describe a patient with CLL and a history of RCC who is found to have an incidental solitary bone lesion of the T11 vertebra. After two separate CT-guided biopsies revealed various lymphoid cell predominance and no evidence of RCC, treatment with low dose external beam radiation therapy (EBRT) was employed. Post-therapy MRI showed further propagation of the lesion. Surgical corpectomy was subsequently performed and postoperative pathology of the lesion was consistent with RCC. The patient was treated with bisphosphonates and a higher dose of EBRT. Our case illustrates the importance of surgical excisional biopsy for accurately diagnosing the primary source metastatic to the bone in a patient with CLL and another potential primary cancer. PMID:29147427 283. A Prospective Study Comparing99mTc-Hydroxyethylene-Diphosphonate Planar Bone Scintigraphy and Whole-Body SPECT/CT with18F-Fluoride PET/CT and18F-Fluoride PET/MRI for Diagnosing Bone Metastases. PubMed Löfgren, Johan; Mortensen, Jann; Rasmussen, Sine H; Madsen, Claus; Loft, Annika; Hansen, Adam E; Oturai, Peter; Jensen, Karl Erik; Mørk, Mette Louise; Reichkendler, Michala; Højgaard, Liselotte; Fischer, Barbara M 2017-11-01 We prospectively evaluated and compared the diagnostic performance of 99m Tc-hydroxyethylene-diphosphonate ( 99m Tc-HDP) planar bone scintigraphy (pBS), 99m Tc-HDP SPECT/CT, 18 F-NaF PET/CT, and 18 F-NaF PET/MRI for the detection of bone metastases. Methods: One hundred seventeen patients with histologically proven malignancy referred for clinical pBS were prospectively enrolled. pBS and whole-body SPECT/CT were performed followed by 18 F-NaF PET/CT within 9 d. 18 F-NaF PET/MRI was also performed in 46 patients. Results: Bone metastases were confirmed in 16 patients and excluded in 101, which was lower than expected. The number of equivocal scans was significantly higher for pBS than for SPECT/CT and PET/CT (18 vs. 5 and 6, respectively; P = 0.004 and 0.01, respectively). When equivocal readings were excluded, no statistically significant difference in sensitivity, specificity, positive predictive value, negative predictive value, or overall accuracy were found when comparing the different imaging techniques. In the per-patient analysis, equivocal scans were either assumed positive for metastases ("pessimistic analysis") or assumed negative for metastases ("optimistic analysis"). The percentages of misdiagnosed patients for the pessimistic analysis were 21%, 15%, 9%, and 7% for pBS, SPECT/CT, PET/CT, and PET/MRI, respectively. Corresponding figures for the optimistic analysis were 9%, 12%, 5%, and 7%. In those patients identified as having bone metastases according to the reference standard, SPECT/CT, 18 F-NaF PET/CT, and PET/MRI detected additional lesions compared with pBS in 31%, 63%, and 71%, respectively. Conclusion: 18 F-NaF PET/CT and whole-body SPECT/CT resulted in a significant reduction of equivocal readings compared with pBS, which implies an improved diagnostic confidence. However, the clinical benefit of using, for example, 18 F-NaF PET/CT or PET/MRI as compared with SPECT/CT and pBS in this patient population with a relatively low prevalence of bone 284. Targeting Extracellular Matrix Glycoproteins in Metastases for Tumor-Initiating Cell Therapy DTIC Science & Technology 2016-04-01 enhancing nanomedicine delivery to OPN-rich targets. a. Preparation of Osteopontin(OPN)-targeting carrier (under Objective 1). Lipid nanoparticles ...phosphocholine), and/or PEGDSPE (Polyethylene glycol-distearoyl-glycero-phosphoethanolamine). These nanoparticles were conjugated with OPN-antibody using SATA...as conjugation agent. The OPNtargeting lipid nanoparticles (OPN-LN) showed no visible aggregation and precipitation at 37 oC in 72 hours. OPN-LN 285. Quality of Life After Palliative Radiation Therapy for Patients With Painful Bone Metastases: Results of an International Study Validating the EORTC QLQ-BM22
SciTech Connect Zeng Liang; Chow, Edward; Bedard, Gillian; Zhang, Liying; Fairchild, Alysa; Vassiliou, Vassilios; Alm El-Din, Mohamed A.; Jesus-Garcia, Reynaldo; Kumar, Aswin; Forges, Fabien; Tseng, Ling-Ming; Hou, Ming-Feng; Chie, Wei-Chu; Bottomley, Andrew 2012-11-01 Purpose: Radiation therapy (RT) is an effective method of palliating painful bone metastases and can improve function and reduce analgesic requirements. In advanced cancer patients, quality of life (QOL) is the primary outcome of interest over traditional endpoints such as survival. The purpose of our study was to compare bone metastasis-specific QOL scores among patients who responded differently to palliative RT. Methods and Materials: Patients receiving RT for bone metastases across 6 countries were prospectively enrolled from March 2010-January 2011 in a trial validating the QLQ-BM22 and completed the QLQ-BM22 and the core measure (QLQ-C30) at baseline and after 1 month. Pain scores and analgesic intake were recorded, and response to RT was determined according to the latest published guidelines. The Kruskal-Wallis nonparametric and Wilcoxon rank sum tests compared changes in QOL among response groups. A Bonferroni-adjusted P<.003 indicated statistical significance. Results: Of 79 patients who received palliative RT, 59 were assessable. Partial response, pain progression, and indeterminate response were observed in 22, 8, and 29 patients, respectively; there were no patients with a complete response. Patients across all groups had similar baseline QOL scores apart from physical functioning (patients who progressed had better initial functioning). One month after RT, patients who responded had significant improvements in 3 of 4 QLQ-BM22 domains (painful site, P<.0001; painful characteristic, P<.0001; and functional interference, P<.0001) and 3 QLQ-C30 domains (physical functioning, P=.0006; role functioning, P=.0026; and pain, P<.0001). Patients with progression in pain had significantly worse functional interference (P=.0007) and pain (P=.0019). Conclusions: Patients who report pain relief after palliative RT also have better QOL with respect to bone metastasis-specific issues. The QLQ-BM22 and QLQC30 are able to discriminate among patients with varying 286. Rapid bone repair in a patient with lung cancer metastases to the spine using a novel herbal medicine: A case report. PubMed Pu, Rong; Zhao, Qianhong; Li, Zhimei; Zhang, Lingyan; Luo, Xiaolu; Zeren, Yangji; Yu, Cui; Li, Xianyong 2016-09-01 The prognosis of lung carcinoma with metastasis to the bone, particularly to the spine, is poor. Chemotherapy and radiotherapy are established treatments for metastatic bone disease, but their effectiveness is unsatisfactory and bone repair following their use is slow and difficult. Medicine prepared from herbal extracts may be an alternative treatment option. The present study discusses the case of a 59-year-old patient diagnosed with squamous cell lung cancer (T2N3M1) in which first-line chemotherapy using docetaxel plus cisplatin failed. Heavy multiple bone metastases were detected in the T9 vertebra and sixth left rib, resulting in a high risk of pathological fracture. Eastern Cooperative Oncology Group (ECOG) and numerical rating scale (NRS) scores of pain were 2 and 4, respectively. A second-line treatment was chosen consisting of biological intracontrol treatment (BICT) plus bisphosphonates administered over 40 days. BICT is a therapy involving the use of herbal extracts (including ginseng, herba agrimoniae, hairyvein agrimonia herb, white flower patrinia herb and arginine) and palliative care. A partial positive response was reached following use of this regimen, particularly with regard to bone repair. A computed tomography scan revealed a 90% reduction in the broken area of the rib cage and T9 vertebra. The bone repair was rapid and almost complete. In addition, growth of the primary tumor in the right pulmonary hilar and metastasis in the mediastinal lymph nodes were stabilized following treatment. ECOG and NRS scores were decreased to 1 and 0, respectively, leading to an improved quality of life. Based on these results, the present study suggests that this herbal medicine-based regimen promotes bone repair and inhibits tumor growth, with low toxicity. However, the mechanism by which herbal medicine promotes rapid bone repair is unclear. Further studies are required to determine whether cells in the tumor microenvironment are stimulated to undergo re 287. Bone Marrow Metastases: T2-weighted Dixon Spin-Echo Fat Images Can Replace T1-weighted Spin-Echo Images. PubMed Maeder, Yaël; Dunet, Vincent; Richard, Raphael; Becce, Fabio; Omoumi, Patrick 2018-03-01 Purpose To test the potential of Dixon T2-weighted fat-only sequences to replace T1-weighted sequences for the detection of bone metastases, with the hypothesis that diagnostic performance with an alternative magnetic resonance (MR) imaging protocol (sagittal spin-echo Dixon T2-weighted fat-only and water-only imaging) would not be inferior to that with the standard protocol (sagittal spin-echo T1-weighted and spin-echo Dixon T2-weighted water-only imaging). Materials and Methods A total of 121 consecutive whole-spine MR imaging examinations (63 men; mean age ± standard deviation, 61.4 years ± 11.8) performed for suspected vertebral bone metastases were included in this retrospective, institutional review board-approved study. Quantitative image analysis was performed for 30 randomly selected spine levels. Qualitative analysis was performed separately by two musculoskeletal radiologists, who registered the number of metastases for each spine level. Areas under the curve with the protocols were compared on the basis of nonparametric receiver operating characteristic curve estimations by using a noninferiority test on paired data, with a best valuable comparator as a reference. Interobserver and interprotocol agreement was assessed by using κ statistics. Results Contrast-to-noise ratio was significantly higher on the alternative protocol images than on the standard protocol images (181.1 [95% confidence interval: 140.4, 221.7] vs 84.7 [95% confidence interval: 66.3, 103.1] respectively; P < .001). Diagnostic performance was not significantly inferior with the alternative protocol than with the standard protocol for both readers in a per-patient analysis (sensitivity, 97.9%-98.9% vs 93.6%-97.9%; specificity, 85.2%-92.6% vs 92.6%-96.3%; area under the curve, 0.92-0.96 vs 0.95, respectively; all P ≤ .02) and a per-spine level analysis (all P < .01). Interobserver and interprotocol agreement was good to very good (κ = 0.70-0.81). Conclusion Dixon T2-weighted fat 288. Assessment of the risk factors for impending fractures following radiotherapy for long bone metastases using CT scan-based virtual simulation: a retrospective study. PubMed Tatar, Zuzana; Soubrier, Martin; Dillies, Anne Françoise; Verrelle, Pierre; Boisgard, Stéphane; Lapeyre, Michel 2014-10-16 Radiotherapy for long bone metastases (RTLB) can be complicated by fractures, which considerably increase morbidity and mortality. The aim of this study was to analyze the risk factors for impending fractures following radiotherapy for long bone metastases (RTLB) using CT scan-based virtual simulation. Forty-seven (47) patients were treated with RTLB (18 lung, 11 breast, 10 prostate and 8 other cancers) for a period of 18 months. Two doctors analyzed the CT images prior to radiation therapy. The impending fractures were then monitored and the correlation between bone scan parameters and fracture occurrence was analyzed. The male gender ratio was 0.57 and the mean age 62.8 (33-93) years. The average size of the metastatic lesions was 32 (8-87) x 2 (6-81) x 52 (7-408) mm with cortical involvement (CI) in 66% of cases. The site was in the upper third of the bone in 92% of cases (28 femoral, 17 humeral and two tibial). Ten fractures occurred: two during RTLB, seven after one month and one after 6.6 months. The fractured lesions measured 48 (17-87) x 34 (12-66) x 76 (38-408) mm. The predictive parameters for fracture were osteolytic (39% vs. 10%; p=0.02) and permeative lesions (42% vs. 0%; p<0.0005), a Mirels score ≥9 (42% vs. 0%; p<0.0005), circumferential CI ≥30% (71% vs. 0%, p < 0.00001), CI ≥45 mm in height (67% vs. 0%, p<0.00001) and CI in thickness =100% (40% vs. 0%; p=0.0008). In the multivariate analysis, circumferential CI ≥30% was the only predictive parameter for fracture (p=0.00035; OR=62; CI 95%: 6.5-595). Overall survival was 91% and 40% at one month and twelve months respectively. Prophylactic primary fixation surgery should always be considered when the circumferential CI ≥30%. 289. Presence of bone marrow micro-metastases in stage I-III colon cancer patients is associated with worse disease-free and overall survival. PubMed Viehl, Carsten T; Weixler, Benjamin; Guller, Ulrich; Dell-Kuster, Salome; Rosenthal, Rachel; Ramser, Michaela; Banz, Vanessa; Langer, Igor; Terracciano, Luigi; Sauter, Guido; Oertli, Daniel; Zuber, Markus 2017-05-01 The prognostic significance of bone marrow micro-metastases (BMM) in colon cancer patients remains unclear. We conducted a prospective cohort study with long-term follow-up to evaluate the relevance of BMM as a prognostic factor for disease free (DFS) and overall survival (OS) in stage I-III colon cancer patients. In this prospective multicenter cohort study 144 stage I-III colon cancer patients underwent bone marrow aspiration from both iliac crests prior to open oncologic resection. The bone marrow aspirates were stained with the pancytokeratin antibody A45-B/B3 and analyzed for the presence of epithelial tumor cells. DFS and OS were analyzed using a Cox proportional hazard model and robust standard errors to account for clustering in the multicenter setting. Median overall follow-up was 6.2 years with no losses to follow-up, and 7.3 years in patients who survived. BMM were found in 55 (38%) patients. In total, 30 (21%) patients had disease recurrence and 56 (39%) patients died. After adjusting for known prognostic factors, BMM positive patients had a significantly worse DFS (hazard ratio [HR] 1.33; 95% confidence interval [95% CI]: 1.02-1.73; P = 0.037) and OS (HR 1.30; 95% CI: 1.09-1.55; P = 0.003) compared to BMM negative patients. Bone marrow micro-metastases occur in over one third of stage I-III colon cancer patients and are a significant, independent negative prognostic factor for DFS and OS. Future trials should evaluate whether node-negative colon cancer patients with BMM benefit from adjuvant chemotherapy. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. 290. Assessment of National Practice for Palliative Radiation Therapy for Bone Metastases Suggests Marked Underutilization of Single-Fraction Regimens in the United States SciTech Connect Rutter, Charles E.; Yu, James B.; Wilson, Lynn D.; Park, Henry S. 2015-03-01 Purpose: To characterize temporal trends in the application of various bone metastasis fractionations within the United States during the past decade, using the National Cancer Data Base; the primary aim was to determine whether clinical practice in the United States has changed over time to reflect the published randomized evidence and the growing movement for value-based treatment decisions. Patients and Methods: The National Cancer Data Base was used to identify patients treated to osseous metastases from breast, prostate, and lung cancer. Utilization of single-fraction versus multiple-fraction radiation therapy was compared according to demographic, disease-related, and health care system details. Results: We included 24,992 patients treated during the period 2005-2011 for bone metastases. Among patients treated to non-spinal/vertebral sites (n=9011), 4.7% received 8 Gy in 1 fraction, whereas 95.3% received multiple-fraction treatment. Over time the proportion of patients receiving a single fraction of 8 Gy increased (from 3.4% in 2005 to 7.5% in 2011). Numerous independent predictors of single-fraction treatment were identified, including older age, farther travel distance for treatment, academic treatment facility, and non-private health insurance (P<.05). Conclusions: Single-fraction palliative radiation therapy regimens are significantly underutilized in current practice in the United States. Further efforts are needed to address this issue, such that evidence-based and cost-conscious care becomes more commonplace. 291. Assessment of national practice for palliative radiation therapy for bone metastases suggests marked underutilization of single-fraction regimens in the United States. PubMed Rutter, Charles E; Yu, James B; Wilson, Lynn D; Park, Henry S 2015-03-01 To characterize temporal trends in the application of various bone metastasis fractionations within the United States during the past decade, using the National Cancer Data Base; the primary aim was to determine whether clinical practice in the United States has changed over time to reflect the published randomized evidence and the growing movement for valuebased treatment decisions. The National Cancer Data Base was used to identify patients treated to osseous metastases from breast, prostate, and lung cancer. Utilization of singlefraction versus multiple-fraction radiation therapy was compared according to demographic, disease-related, and health care system details. We included 24,992 patients treated during the period 2005-2011 for bone metastases. Among patients treated to non-spinal/vertebral sites (n=9011), 4.7% received 8 Gy in 1 fraction, whereas 95.3% received multiplefraction treatment. Over time the proportion of patients receiving a single fraction of 8 Gy increased (from 3.4% in 2005 to 7.5% in 2011). Numerous independent predictors of single-fraction treatment were identified, including older age, farther travel distance for treatment, academic treatment facility, and non-private health insurance (P<.05). Singlefraction palliative radiation therapy regimens are significantly underutilized in current practice in the United States. Further efforts are needed to address this issue, such that evidencebased and cost-conscious care becomes more commonplace. Copyright © 2015 Elsevier Inc. All rights reserved. 292. Biological 18[F]-FDG-PET image-guided dose painting by numbers for painful uncomplicated bone metastases: A 3-arm randomized phase II trial. PubMed Berwouts, Dieter; De Wolf, Katrien; Lambert, Bieke; Bultijnck, Renée; De Neve, Wilfried; De Lobel, Lizzy; Jans, Lennart; Goetghebeur, Els; Speleers, Bruno; Olteanu, Luiza A M; Madani, Indira; Goethals, Ingeborg; Ost, Piet 2015-05-01 Antalgic radiotherapy for bone metastases might be improved by implementing biological information in the radiotherapy planning using (18)F-FDG-PET-CT based dose painting by numbers (DPBN). Patients with uncomplicated painful bone metastases were randomized (1:1:1) and blinded to receive either 8Gy in a single fraction with conventionally planned radiotherapy (arm A) or 8Gy in a single fraction with DPBN (dose range between 610Gy and 10Gy) (arm B) or 16Gy in a single fraction with DPBN (dose range between 1410Gy and 18Gy) (arm C). The primary endpoint was overall pain response at 1month. The phase II trial was designed to select the experimental arm with sufficient promise of efficacy to continue to a phase III trial. Forty-five patients were randomized. Eight (53%), 12 (80%) and 9 patients (60%) had an overall response to treatment in arm A, B and C, respectively. The estimated odds ratio of overall response for arm B vs. A is 3.5 (95% CI: 0.44-17.71, p=0.12). The estimated odds ratio of arm C vs. A is 1.31 (95% CI: 0.31-5.58, p=0.71). A single fraction of 8Gy with DPBN will be further evaluated in a phase III-trial. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved. 293. Skeletal metastases from hepatoma: frequency, distribution, and radiographic features SciTech Connect Kuhlman, J.E.; Fishman, E.K.; Leichner, P.K.; Magid, D.; Order, S.E.; Siegelman, S.S. 1986-07-01 Over the past 6 years, the authors evaluated 300 patients with hepatoma as part of phase 1 and 2 treatment protocol trials. Analysis of the available clinical data and radiographic studies revealed 22 patients (7.3%) with skeletal metastases demonstrated by radiography, computed tomography (CT), and/or nuclear scintigraphy. The plain film appearance of skeletal metastases from hepatoma was osteolytic in all cases. CT scanning best demonstrated the expansile, destructive nature of these metastases, which were often associated with large, bulky soft-tissue masses. Skeletal metastases from hepatomas demonstrated increased radiotracer uptake on standard bone scans and were gallium avid, similar to the hepatoma itself. In addition, they could be targeted therapeutically with I-131 antiferritin immunoglobulin. The most frequent sites of skeletal metastases were the ribs, spine, femur, pelvis, and humerus. An initial symptom in ten patients was skeletal pain corresponding to the osseous metastases. In five patients, pathologic fractures of the proximal femur or humerus developed and required total hip replacement or open-reduction internal fixation. Patients with long-standing cirrhosis or known hepatocellular carcinoma who also have skeletal symptoms should be evaluated for possible osseous metastases. 294. Bone marrow involvement identifies a subgroup of advanced Ewing sarcoma patients with fatal outcome irrespective of therapy in contrast to curable patients with multiple bone metastases but unaffected marrow PubMed Central Thiel, Uwe; Wawer, Angela; von Luettichau, Irene; Bender, Hans-Ulrich; Blaeschke, Franziska; Grunewald, Thomas G.P.; Steinborn, Marc; Röper, Barbara; Bonig, Halvard; Klingebiel, Thomas; Bader, Peter; Koscielniak, Ewa; Paulussen, Michael; Dirksen, Uta; Juergens, Heribert; Kolb, Hans-Jochem; Burdach, Stefan E.G. 2016-01-01 Purpose Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols. Design Of 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996. MetaEICESS 1992 consisted of induction chemotherapy, whole body imaging directed radiotherapy to the primary tumor and metastases, tandem high-dose chemotherapy and autologous rescue. In MetaEICESS 2007 this treatment was complemented by allogeneic stem cell transplantation. EICESS 1992 comprised induction chemotherapy, local therapy to the primary tumor only followed by consolidation chemotherapy. Results In MetaEICESS 8/18 patients survived in complete remission vs. 2/26 in EICESS 1992 (p<0.05). Survival did not differ between MetaEICESS 2007 and MetaEICESS 1992. Three MetaEICESS patients died of complications, all in MetaEICESS 1992. After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without BM involvement, in contrast to 0/5 patients with BM involvement. This was confirmed in a multivariate analysis. There was no correlation between BM involvement and the number of metastases at diagnosis. Conclusion The MetaEICESS protocols yield long-term disease-free survival in patients with advanced Ewing sarcoma. Allogeneic stem cell transplantation was not associated with increased death of complications. Bone marrow involvement is a risk factor distinct from multiple bone metastases. PMID:27486822 295. Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer. PubMed Thompson, Michelle L; Jimenez-Andrade, Juan M; Chartier, Stephane; Tsai, James; Burton, Elizabeth A; Habets, Gaston; Lin, Paul S; West, Brian L; Mantyh, Patrick W 2015-09-01 Tumor cells frequently metastasize to bone where they can generate cancer-induced bone pain (CIBP) that can be difficult to fully control using available therapies. Here, we explored whether PLX3397, a high-affinity small molecular antagonist that binds to and inhibits phosphorylation of colony-stimulating factor-1 receptor, the tyrosine-protein kinase c-Kit, and the FMS-like tyrosine kinase 3, can reduce CIBP. These 3 targets all regulate the proliferation and function of a subset of the myeloid cells including macrophages, osteoclasts, and mast cells. Preliminary experiments show that PLX3397 attenuated inflammatory pain after formalin injection into the hind paw of the rat. As there is an inflammatory component in CIBP, involving macrophages and osteoclasts, the effect of PLX3397 was explored in a prostate model of CIBP where skeletal pain, cancer cell proliferation, tumor metastasis, and bone remodeling could be monitored in the same animal. Administration of PLX3397 was initiated on day 14 after prostate cancer cell injection when the tumor was well established, and tumor-induced bone remodeling was first evident. Over the next 6 weeks, sustained administration of PLX3397 attenuated CIBP behaviors by approximately 50% and was equally efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. Developing a better understanding of potential effects that analgesic therapies have on the tumor itself may allow the development of therapies that not only better control the pain but also positively impact disease progression and overall survival in patients with bone cancer. 296. Targeted Inhibition of Prostate Cancer Metastases with an RNA Aptamer to Prostate-specific Membrane Antigen PubMed Central Dassie, Justin P; Hernandez, Luiza I; Thomas, Gregory S; Long, Matthew E; Rockey, William M; Howell, Craig A; Chen, Yani; Hernandez, Frank J; Liu, Xiu Ying; Wilson, Mary E; Allen, Lee-Ann; Vaena, Daniel A; Meyerholz, David K; Giangrande, Paloma H 2014-01-01 Cell-targeted therapies (smart drugs), which selectively control cancer cell progression with limited toxicity to normal cells, have been developed to effectively treat some cancers. However, many cancers such as metastatic prostate cancer (PC) have yet to be treated with current smart drug technology. Here, we describe the thorough preclinical characterization of an RNA aptamer (A9g) that functions as a smart drug for PC by inhibiting the enzymatic activity of prostate-specific membrane antigen (PSMA). Treatment of PC cells with A9g results in reduced cell migration/invasion in culture and metastatic disease in vivo. Importantly, A9g is safe in vivo and is not immunogenic in human cells. Pharmacokinetic and biodistribution studies in mice confirm target specificity and absence of non-specific on/off-target effects. In conclusion, these studies provide new and important insights into the role of PSMA in driving carcinogenesis and demonstrate critical endpoints for the translation of a novel RNA smart drug for advanced stage PC. PMID:24954476 297. Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). PubMed Wirth, Manfred; Tammela, Teuvo; Cicalese, Virgilio; Gomez Veiga, Francisco; Delaere, Karl; Miller, Kurt; Tubaro, Andrea; Schulze, Matthias; Debruyne, Frans; Huland, Hartwig; Patel, Anup; Lecouvet, Frederic; Caris, Christien; Witjes, Wim 2015-03-01 Patients with high-risk localised prostate cancer (PCa) are at risk of developing bone metastases (BMs). Zoledronic acid (ZA) significantly reduces the incidence of skeletal complications in castration-resistant metastatic PCa versus placebo. To investigate ZA for the prevention of BMs in high-risk localised PCa. Randomised open-label multinational study with patients having at least one of the following: prostate-specific antigen ≥20 ng/ml, node-positive disease, or Gleason score 8-10. Standard PCa therapy alone or combined with 4mg ZA intravenously every 3 mo for ≤4 yr. BMs were assessed using locally evaluated bone-imaging procedures (BIPs), with subsequent blinded central review. Patients with BMs, time to BMs, overall survival, and adverse events were compared between treatment groups. A total of 1393 of 1433 randomised patients were used for intentionto-treat (ITT) efficacy analyses, with 1040 patients with BIP-BM outcome status at 4±0.5 yr. The local urologist/radiologist diagnosed BIP-BMs in 88 of 515 patients (17.1%) in the ZA group and 89 of 525 patients (17.0%) in the control group (chi-square test: p=0.95), with a difference between proportions of 0.1% (95% confidence interval [CI], -4.4 to 4.7) in favour of the control group. In the ITT population (n=1393), the Kaplan-Meier estimated proportion of BMs after a median follow-up of 4.8 yr was 14.7% in the ZA group versus 13.2% in the control group (log-rank: p=0.65). Low hot spot numbers on bone scans were confirmed as metastases with additional imaging. Central reviews of BIPs were possible only on a subset of patients. ZA administered every 3 mo was demonstrated to be ineffective for the prevention of BMs in high-risk localised PCa patients at 4 yr. Zoledronic acid administered every 3 mo was demonstrated to be ineffective for the prevention of bone metastases in high-risk nonmetastatic PCa patients at 4 yr. The ZEUS trial is registered in the Dutch trial register www.trialregister.nl and the 298. Disseminated bone metastases from occult thyroid cancer effectively treated with debulking surgery and a single dosimetry-guided administration of radioiodine. PubMed Borsò, Elisa; Boni, Giuseppe; Mazzarri, Sara; Cocciaro, Ardico; Gambacciani, Carlo; Traino, Antonio C; Manca, Giampiero; Grosso, Mariano; Scatena, Cristian; Ortenzi, Valerio; Vannozzi, Riccardo; Marzola, Maria Cristina; Rubello, Domenico; Mariani, Giuliano 2015-01-01 In this paper we report on a successful management of multiple bone metastases from differentiated thyroid cancer. In 2007, a 75-year-old female patient, previously referred for thyroidectomy for multinodular goiter, underwent surgical removal of a lumbar mass with histological findings of metastasis from well differentiated thyroid cancer. After surgery, serum thyroglobulin (sTg) was 204.4 ng/mL. A diagnostic/dosimetric (123)I WBS was performed, following stimulation by rTSH. Serial WBSs were acquired, along with SPECT/CT and bone scan for localization of lesions. sTg raised to 3.810 ng/mL, and (123)I WBS showed thyroid remnants and numerous areas with high iodine-uptake corresponding to skeletal sites, the two largest loading on the skull, with osteolytic pattern. Calculated radiation absorbed dose for skull lesions, determined by mean of MIRD methodology, was 63.5 mGy/MBq. The patient underwent surgical removal of the two major skull lesions. Successively, 100 mCi (131)I was administered after stimulation by rTSH, with stimulated sTg 297 ng/mL. After 8 months, diagnostic WBS was negative both for remnants and metastases and rTSH-stimulated Tg was 0.6 ng/mL. To date, the patient has maintained sTg values <1 ng/mL during L-T4 suppressive therapy and after rTSH stimulations. In this unusual case of extensive bone cancerous involvement with high iodine avidity, a multidisciplinary approach based on surgery and dosimetry-guided radiometabolic therapy allowed to accurately assess the patient, execute a small number of treatments and achieve a complete remission of the disease in a very short time, with no additive morbidity. Copyright © 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved. 299. Chapter 13: Carbonic Anhydrase IX as an Imaging and Therapeutic Target for Tumors and Metastases PubMed Central Tafreshi, Narges K.; Lloyd, Mark C.; Bui, Marilyn M.; Gillies, Robert J.; Morse, David L. 2014-01-01 Carbonic anhydrase IX (CAIX) which is a zinc containing metalloprotein, efficiently catalyzes the reversible hydration of carbon dioxide. It is constitutively up-regulated in several cancer types and has an important role in tumor progression, acidification and metastasis. High expression of CAIX generally correlates with poor prognosis and is related to a decrease in the disease-free interval following successful therapy. Therefore, it is considered as a prognostic indicator in oncology. In this review, we describe CAIX regulation and its role in tumor hypoxia, acidification and metastasis. In addition, the molecular imaging of CAIX and its potential for use in cancer detection, diagnosis, staging, and for use in following therapy response is discussed. Both antibodies and small molecular weight compounds have been used for targeted imaging of CAIX expression. The use of CAIX expression as an attractive and promising candidate marker for systemic anticancer therapy is also discussed. PMID:24146382 300. Cost-effectiveness analysis of single fraction of stereotactic body radiation therapy compared with single fraction of external beam radiation therapy for palliation of vertebral bone metastases. PubMed Kim, Hayeon; Rajagopalan, Malolan S; Beriwal, Sushil; Huq, M Saiful; Smith, Kenneth J 2015-03-01 Stereotactic body radiation therapy (SBRT) has been proposed for the palliation of painful vertebral bone metastases because higher radiation doses may result in superior and more durable pain control. A phase III clinical trial (Radiation Therapy Oncology Group 0631) comparing single fraction SBRT with single fraction external beam radiation therapy (EBRT) in palliative treatment of painful vertebral bone metastases is now ongoing. We performed a cost-effectiveness analysis to compare these strategies. A Markov model, using a 1-month cycle over a lifetime horizon, was developed to compare the cost-effectiveness of SBRT (16 or 18 Gy in 1 fraction) with that of 8 Gy in 1 fraction of EBRT. Transition probabilities, quality of life utilities, and costs associated with SBRT and EBRT were captured in the model. Costs were based on Medicare reimbursement in 2014. Strategies were compared using the incremental cost-effectiveness ratio (ICER), and effectiveness was measured in quality-adjusted life years (QALYs). To account for uncertainty, 1-way, 2-way and probabilistic sensitivity analyses were performed. Strategies were evaluated with a willingness-to-pay (WTP) threshold of $100,000 per QALY gained. Base case pain relief after the treatment was assumed as 20% higher in SBRT. Base case treatment costs for SBRT and EBRT were $9000 and $1087, respectively. In the base case analysis, SBRT resulted in an ICER of $124,552 per QALY gained. In 1-way sensitivity analyses, results were most sensitive to variation of the utility of unrelieved pain; the utility of relieved pain after initial treatment and median survival were also sensitive to variation. If median survival is ≥11 months, SBRT cost <$100,000 per QALY gained. SBRT for palliation of vertebral bone metastases is not cost-effective compared with EBRT at a $100,000 per QALY gained WTP threshold. However, if median survival is ≥11 months, SBRT costs ≤$100,000 per QALY gained, suggesting that selective SBRT use in « 13 14 15 16 17 » « 14 15 16 17 18 » 301. Quality of Life After Palliative Radiation Therapy for Patients With Painful Bone Metastases: Results of an International Study Validating the EORTC QLQ-BM22 SciTech Connect Zeng Liang; Chow, Edward, E-mail:
[email protected]; Bedard, Gillian 2012-11-01 Purpose: Radiation therapy (RT) is an effective method of palliating painful bone metastases and can improve function and reduce analgesic requirements. In advanced cancer patients, quality of life (QOL) is the primary outcome of interest over traditional endpoints such as survival. The purpose of our study was to compare bone metastasis-specific QOL scores among patients who responded differently to palliative RT. Methods and Materials: Patients receiving RT for bone metastases across 6 countries were prospectively enrolled from March 2010-January 2011 in a trial validating the QLQ-BM22 and completed the QLQ-BM22 and the core measure (QLQ-C30) at baseline and after 1more » month. Pain scores and analgesic intake were recorded, and response to RT was determined according to the latest published guidelines. The Kruskal-Wallis nonparametric and Wilcoxon rank sum tests compared changes in QOL among response groups. A Bonferroni-adjusted P<.003 indicated statistical significance. Results: Of 79 patients who received palliative RT, 59 were assessable. Partial response, pain progression, and indeterminate response were observed in 22, 8, and 29 patients, respectively; there were no patients with a complete response. Patients across all groups had similar baseline QOL scores apart from physical functioning (patients who progressed had better initial functioning). One month after RT, patients who responded had significant improvements in 3 of 4 QLQ-BM22 domains (painful site, P<.0001; painful characteristic, P<.0001; and functional interference, P<.0001) and 3 QLQ-C30 domains (physical functioning, P=.0006; role functioning, P=.0026; and pain, P<.0001). Patients with progression in pain had significantly worse functional interference (P=.0007) and pain (P=.0019). Conclusions: Patients who report pain relief after palliative RT also have better QOL with respect to bone metastasis-specific issues. The QLQ-BM22 and QLQC30 are able to discriminate among patients with 302. [Surgery of brain metastases]. PubMed Métellus, P; Reyns, N; Voirin, J; Menei, P; Bauchet, L; Faillot, T; Loiseau, H; Pallud, J; Guyotat, J; Mandonnet, E 2015-02-01 Surgical excision of brain metastases has been well evaluated in unique metastases. Two randomized phase III trial have shown that combined with adjuvant whole brain radiotherapy, it significantly improves overall survival. However, even in the presence of multiple brain metastases, surgery may be useful. Also, even in lesions amenable to radiosurgery, surgical resection is preferred when tumors displayed cystic or necrotic aspect with important edema or when located in highly eloquent areas or cortico-subcortically. Furthermore, surgery may have a diagnostic role, in the absence of histological documentation of the primary disease, to rule out a differential diagnosis (brain abscess, lymphoma, primary tumor of the central nervous system or radionecrosis). Finally, the biological documentation of brain metastatic disease might be useful in situations where a specific targeted therapy can be proposed. Selection of patients who will really benefit from surgery should take into account three factors, clinical and functional status of the patient, systemic disease status and characteristics of intracranial metastases. Given the improved overall survival of cancer patients partially due to the advent of effective targeted therapies on systemic disease, a renewed interest has been given to the local treatment of brain metastases. Surgical resection currently represents a valuable tool in the armamentarium of brain metastases but has also become a diagnostic and decision tool that can affect therapeutic strategies in these patients. Copyright © 2015. Published by Elsevier SAS. 303. Economic Analysis of Radiation Therapy Oncology Group (RTOG) 97-14: Multiple versus single fraction radiation treatment of patients with Bone Metastases PubMed Central Konski, Andre; James, Jennifer; Hartsell, William; Leibenhaut, Mark H.; Janjan, Nora; Curran, Walter; Roach, Mack; Watkins-Bruner, Deborah 2010-01-01 Introduction RTOG 97-14 concluded a single fraction of radiation was as effective in relieving pain as multiple fractions in the treatment of patients with bone metastases. A statistically significant higher re-treatment rate, however, was noted in patients undergoing a single fraction treatment. The purpose of the analysis was to determine if multiple fraction treatment is cost-effective in treating patients with bone metastasis by preventing further re-treatment. Methods & Material A Markov model was used to evaluate the costeffectiveness of 30 Gy in 10 fractions compared to 8 Gy in 1 fraction. Transition probabilities, cost and utilities were obtained from the clinical trial. Costs and outcomes were not discounted because of the short-time line for the study. Results The expected mean cost and quality adjusted survival in months for patients receiving 8 Gy in 1 fraction and 30 Gy in
10 fractions was $998 and 7.26 months and $2,316 and 9.53 months, respectively. The incremental cost-effectiveness ratio (ICER) was $6973/quality-adjusted life year. The results were sensitive to the utility of the post-treatment state for both single and multiple fraction treatment. Conclusion Single fraction treatment was the less expensive treatment in the treatment of patients with bone metastasis treated on RTOG 97-14. PMID:19546803 304. Assessment of National Practice for Palliative Radiation Therapy for Bone Metastases Suggests Marked Underutilization of Single-Fraction Regimens in the United States SciTech Connect Rutter, Charles E., E-mail:
[email protected]; Yale Cancer Center, New Haven, Connecticut; Yu, James B. 2015-03-01 Purpose: To characterize temporal trends in the application of various bone metastasis fractionations within the United States during the past decade, using the National Cancer Data Base; the primary aim was to determine whether clinical practice in the United States has changed over time to reflect the published randomized evidence and the growing movement for value-based treatment decisions. Patients and Methods: The National Cancer Data Base was used to identify patients treated to osseous metastases from breast, prostate, and lung cancer. Utilization of single-fraction versus multiple-fraction radiation therapy was compared according to demographic, disease-related, and health care system details. Results: Wemore » included 24,992 patients treated during the period 2005-2011 for bone metastases. Among patients treated to non-spinal/vertebral sites (n=9011), 4.7% received 8 Gy in 1 fraction, whereas 95.3% received multiple-fraction treatment. Over time the proportion of patients receiving a single fraction of 8 Gy increased (from 3.4% in 2005 to 7.5% in 2011). Numerous independent predictors of single-fraction treatment were identified, including older age, farther travel distance for treatment, academic treatment facility, and non-private health insurance (P<.05). Conclusions: Single-fraction palliative radiation therapy regimens are significantly underutilized in current practice in the United States. Further efforts are needed to address this issue, such that evidence-based and cost-conscious care becomes more commonplace.« less 305. Chemotherapy and targeted therapy for patients with initially unresectable colorectal liver metastases, focusing on conversion hepatectomy and long-term survival. PubMed Beppu, Toru; Miyamoto, Yuji; Sakamoto, Yasuo; Imai, Katsunori; Nitta, Hidetoshi; Hayashi, Hiromitsu; Chikamoto, Akira; Watanabe, Masayuki; Ishiko, Takatoshi; Baba, Hideo 2014-06-01 Eight years have passed since the introduction of chemotherapy (chemo) and targeted therapy regimens for colorectal liver metastases (CRLM). This study aimed to clarify the effectiveness of chemo and targeted therapy in facilitating conversion hepatectomy and improving long-term survival in Japanese patients with CRLM. A total of 199 patients with CRLM were treated between May 2005 and August 2012. Initial therapies for these patients included straightforward hepatic resection (n = 48; 24 %), induction chemotherapy (n = 148; 74 %), and radiofrequency ablation (n = 3; 2 %). In 56 of 137 patients (40.1 %) with initially unresectable CRLM, 7.5 courses of chemo and targeted therapy downsized and converted tumors to resectable tumors. The 5-year cumulative overall survival (OS) rate and the median survival time were significantly higher for the resectable CRLM than for the unresectable CRLM (54.6 vs. 5.3 % and 77.3 vs. 21.3 months, respectively; P < .0001). Multivariate analysis revealed that conversion hepatectomy (hazard ratio [HR] 0.19; P < .001) and responder to chemo and targeted therapy (HR 0.46; P < .01) were independent prognostic factors for OS. Multivariate analysis also revealed that left-sided colon or rectal cancer (odds ratio [OR] 8.4; P < .05), H1/H2 metastases (OR 7.3; P < .05), no extrahepatic metastases (OR 52.6; P < .001), and responder to chemo and targeted therapy (OR 6.1; P < .05) were significant predictors of conversion hepatectomy. A chemo and targeted therapy can facilitate conversion hepatectomy and allow for an excellent prognosis in patients with initially unresectable CRLM. 306. Lung metastases MedlinePlus Metastases to the lung; Metastatic cancer to the lung; Lung cancer - metastases ... Metastatic tumors in the lungs are cancers that developed at other places in the body (or other parts of the lungs). They then spread through the bloodstream or lymphatic ... 307. Contrast-Enhanced Computed Tomography Evaluation of Hepatic Metastases in Breast Cancer Patients Before and After Cytotoxic Chemotherapy or Targeted Therapy. PubMed He, Hongying; Cai, Chunyan; Charnsangavej, Chusilp; Theriault, Richard L; Green, Marjorie; Quraishi, Mohammad A; Yang, Wei T 2015-11-01 To evaluate change in size vs computed tomography (CT) density of hepatic metastases in breast cancer patients before and after cytotoxic chemotherapy or targeted therapy. A database search in a single institution identified 48 breast cancer patients who had hepatic metastases treated with either cytotoxic chemotherapy alone or targeted therapy alone, and who had contrast-enhanced CT (CECT) scans of the abdomen at baseline and within 4 months of initiation of therapy in the past 10 years. Two radiologists retrospectively evaluated CT scans and identified up to 2 index lesions in each patient. The size (centimeters) of each lesion was measured according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and CT density (Hounsfield units) was measured by drawing a region of interest around the margin of the entire lesion. The percent change in sum of lesion size and mean CT density on pre- and post-treatment scans was computed for each patient; results were compared within each treatment group. Thirty-nine patients with 68 lesions received cytotoxic chemotherapy only; 9 patients with 15 lesions received targeted therapy only. The mean percent changes in sum of lesion size and mean CT density were statistically significant within the cytotoxic chemotherapy group before and after treatment, but not significant in the targeted therapy group. The patients in the targeted therapy group tend to have better 2-year survival. The patients who survived at 2 years tend to have more decrease in tumour size in the cytotoxic chemotherapy group. Cytotoxic chemotherapy produced significant mean percent decrease in tumour size and mean CT density of hepatic metastases from breast cancer before and after treatment, whereas targeted therapy did not. Nonetheless, there is a trend that the patients in the targeted therapy group had better 2-year survival rate. This suggests that RECIST is potentially inadequate in evaluating tumour response in breast cancer liver 308. Targeted delivery of mesenchymal stem cells to the bone. PubMed Yao, Wei; Lane, Nancy E 2015-01-01 Osteoporosis is a disease of excess skeletal fragility that results from estrogen loss and aging. Age related bone loss has been attributed to both elevated bone resorption and insufficient bone formation. We developed a hybrid compound, LLP2A-Ale in which LLP2A has high affinity for the α4β1 integrin on mesenchymal stem cells (MSCs) and alendronate has high affinity for bone. When LLP2A-Ale was injected into mice, the compound directed MSCs to both trabecular and cortical bone surfaces and increased bone mass and bone strength. Additional studies are underway to further characterize this hybrid compound, LLP2A-Ale, and how it can be utilized for the treatment of bone loss resulting from hormone deficiency, aging, and inflammation and to augment bone fracture healing. This article is part of a Special Issue entitled "Stem Cells and Bone". Copyright © 2014 Elsevier Inc. All rights reserved. 309. Targeting G-Protein Signaling for the Therapeutics of Prostate Tumor Bone Metastases and the Associated Chronic Bone Pain DTIC Science & Technology 2015-09-01 inflammation, opioid receptor-dependent analgesia and morphine -induced antinociceptive tolerance and dependence, without causing overt side effects ...relief from pain due to the development of tolerance upon chronic use, and also have serious side effects . Thus, it is imperative to develop novel...resistant to most of the current anti-cancer treatments, and the currently used pain therapeutic medications or analgesics often do not provide effective 310. Early detection of bone metastases in a murine model using fluorescent human breast cancer cells: application to the use of the bisphosphonate zoledronic acid in the treatment of osteolytic lesions. PubMed Peyruchaud, O; Winding, B; Pécheur, I; Serre, C M; Delmas, P; Clézardin, P 2001-11-01 A very common metastatic site for human breast cancer is bone. The traditional bone metastasis model requires human MDA-MB-231 breast carcinoma cell inoculation into the left heart ventricle of nude mice. MDA-MB-231 cells usually develop osteolytic lesions 3-4 weeks after intracardiac inoculation in these animals. Here, we report a new approach to study the formation of bone metastasis in animals using breast carcinoma cells expressing the bioluminescent jellyfish protein (green fluorescent protein [GFP]). We first established a subclone of MDA-MB-231 cells by repeated in vivo passages in bone using the heart injection model. On stable transfection of this subclone with an expression vector for GFP and subsequent inoculation of GFP-expressing tumor cells (B02/GFP.2) in the mouse tail vein, B02/GFP.2 cells displayed a unique predilection for dissemination to bone. Externally fluorescence imaging of live animals allowed the detection of fluorescent bone metastases approximately 1 week before the occurrence of radiologically distinctive osteolytic lesions. The number, size, and intensity of fluorescent bone metastases increased progressively with time and was indicative of breast cancer cell progression within bone. Histological examination of fluorescent long bones from B02/GFP.2-bearing mice revealed the occurrence of profound bone destruction. Treatment of B02/GFP.2-bearing mice with the bisphosphonate zoledronic acid markedly inhibited the progression of established osteolytic lesions and the expansion of breast cancer cells within bone. Overall, this new bone metastasis model of breast cancer combining both fluorescence imaging and radiography should provide an invaluable tool to study the effectiveness of pharmaceutical agents that could suppress cancer colonization in bone. 311. CT-guided percutaneous screw fixation plus cementoplasty in the treatment of painful bone metastases with fractures or a high risk of pathological fracture. PubMed Pusceddu, Claudio; Fancellu, Alessandro; Ballicu, Nicola; Fele, Rosa Maria; Sotgia, Barbara; Melis, Luca 2017-04-01 To evaluate the feasibility and effectiveness of computed tomography (CT)-guided percutaneous screw fixation plus cementoplasty (PSFPC), for either treatment of painful metastatic fractures or prevention of pathological fractures, in patients who are not candidates for surgical stabilization. Twenty-seven patients with 34 metastatic bone lesions underwent CTguided PSFPC. Bone metastases were located in the vertebral column, femur, and pelvis. The primary end point was the evaluation of feasibility and complications of the procedure, in addition to the length of hospital stay. Pain severity was estimated before treatment and 1 and 6 months after the procedure using the visual analog scale (VAS). Functional outcome was assessed by improved patient walking ability. All sessions were completed and well tolerated. There were no complications related to either incorrect positioning of the screws during bone fixation or leakage of cement. All patients were able to walk within 6 h after the procedure and the average length of hospital stay was 2 days. The mean VAS score decreased from 7.1 (range, 4-9) before treatment to 1.6 (range, 0-6), 1 month after treatment, and to 1.4 (range 0-6) 6 months after treatment. Neither loosening of the screws nor additional bone fractures occurred during a median follow-up of 6 months. Our results suggest that PSFPC might be a safe and effective procedure that allows the stabilization of the fracture and the prevention of pathological fractures with significant pain relief and good recovery of walking ability, although further studies are required to confirm this preliminary experience. 312. Epidermal growth factor receptor mutations should be considered as a prognostic factor for survival of patients with pathological fractures or painful bone metastases from non-small cell lung cancer. PubMed Willeumier, J J; van der Hoeven, N M A; Bollen, L; Willems, L N A; Fiocco, M; van der Linden, Y M; Dijkstra, P D S 2017-04-01 This study aims to assess first, whether mutations in the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (kRAS) genes are associated with overall survival (OS) in patients who present with symptomatic bone metastases from non-small cell lung cancer (NSCLC) and secondly, whether mutation status should be incorporated into prognostic models that are used when deciding on the appropriate palliative treatment for symptomatic bone metastases. We studied 139 patients with NSCLC treated between 2007 and 2014 for symptomatic bone metastases and whose mutation status was known. The association between mutation status and overall survival was analysed and the results applied to a recently published prognostic model to determine whether including the mutation status would improve its discriminatory power. The median OS was 3.9 months (95% confidence interval (CI) 2.1 to 5.7). Patients with EGFR (15%) or kRAS mutations (34%) had a median OS of 17.3 months (95% CI 12.7 to 22.0) and 1.8 months (95% CI 1.0 to 2.7), respectively. Compared with EGFR-positive patients, EGFR-negative patients had a 2.5 times higher risk of death (95% CI 1.5 to 4.2). Incorporating EGFR mutation status in the prognostic model improved its discriminatory power. Survival prediction models for patients with symptomatic bone metastases are used to determine the most appropriate (surgical) treatment for painful or fractured lesions. This study shows that NSCLC should not be regarded as a single entity in such models. Cite this article: Bone Joint J 2017;99-B:516-21. ©2017 The British Editorial Society of Bone & Joint Surgery. 313. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. PubMed Himelstein, Andrew L; Foster, Jared C; Khatcheressian, James L; Roberts, John D; Seisler, Drew K; Novotny, Paul J; Qin, Rui; Go, Ronald S; Grubbs, Stephen S; O'Connor, Tracey; Velasco, Mario R; Weckstein, Douglas; O'Mara, Ann; Loprinzi, Charles L; Shapiro, Charles L 2017-01-03 Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. Randomized, openlabel clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4week dosing group and 253 patients (28.6%) in 314. Impact of dynamic changes to a bone metastases pathway in a large, integrated, National Cancer Institute-designated comprehensive cancer center network. PubMed Gebhardt, Brian J; Rajagopalan, Malolan S; Gill, Beant S; Heron, Dwight E; Rakfal, Susan M; Flickinger, John C; Beriwal, Sushil 2015-01-01 Studies suggest equivalent pain relief from bone metastases after radiation therapy with >10-fraction regimens and shorter courses. Although American Society for Radiation Oncology evidence-based guidelines and the Choosing Wisely campaign endorse single-fraction treatments and caution against the use of extended courses, publications report single-fraction utilization rates below 5%. We evaluated the impact of our bone metastasis clinical pathway on the adoption of short-course palliative radiation in a large, integrated radiation oncology network. We implemented a clinical pathway for the management of bone metastases in 2003 that required the entry of management decisions into an online tool that subjected off-pathway choices to peer review beginning in 2009. In 2014, the pathway was modified to encourage single-fraction treatments, and the use of >10 fractions was considered off pathway. Data were obtained from 16 integrated sites (4 academic, 12 community) from 2003 through 2014. Multivariate logistic regression was conducted to establish factors associated with treatment with a single fraction and with >10 fractions. In this study, 12,678 unique courses were delivered. From 2003 to 2008, the single-fraction utilization rate was 7.6%. This increased to 10.9% from 2009 to 2013 and to 15.8% in 2014. The odds ratios for single-fraction use were 1.59 (95% confidence interval [CI], 1.391.81) and 2.58 (95% CI, 2.11-3.15) for 2009-2013 and 2014, respectively. Academic physicians were more likely to treat with a single fraction (odds ratio, 5.00; 95% CI, 4.38-5.71). Use of >10-fraction regimens significantly decreased from 18.6% in 2003-2008 to 15.2% in 2009-2013 and 9.7% in 2014. Although our single-fraction utilization rate was initially in line with national rates (7.6%), the adoption rate increased to >15%. The use of >10-fraction regimens decreased significantly, predominantly among community practices. By 2014, >90% of courses were delivered with <10 fractions 315. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study PubMed Central Fizazi, Karim; Carducci, Michael; Smith, Matthew; Damião, Ronaldo; Brown, Janet; Karsh, Lawrence; Milecki, Piotr; Shore, Neal; Rader, Michael; Wang, Huei; Jiang, Qi; Tadros, Sylvia; Dansey, Roger; Goessl, Carsten 2011-01-01 Summary Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castrationresistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1 316. NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases PubMed Central Lin, T.-h.; Pajarinen, J.; Lu, L.; Nabeshima, A.; Cordova, L.A.; Yao, Z.; Goodman, S.B. 2017-01-01 Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bonehealing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system. PMID:28215222 317. Effect of a High Bone Turnover State Induced by Estrogen Deficiency on the Development and Progression of Breast Cancer Bone Metastases DTIC Science & Technology 2008-04-01 therapy on BMD in athymic versus immunocompetent mice. 15. SUBJECT TERMS Aromatase inhibitors, letrozole, breast cancer, ovariectomy 16...athymic mice. Our previously reported data showed variable effects on bone mineral density (BMD) in this mouse model after ovariectomy (OVX) and...and Mineral Research, Honolulu, Hawaii, 2007. Ovariectomy Decreases Bone Mass in Young and Old Female Athymic Mice. W. Kozlow, K. Mohammad, C. R 318. Systemic therapy for brain metastases. PubMed Venur, Vyshak Alva; Karivedu, Vidhya; Ahluwalia, Manmeet S 2018-01-01 Central nervous system metastases cause grave morbidity in patients with advanced malignancies. Lung cancer, breast cancer, and melanoma are the three most common causes of brain metastases. Although the exact incidence of brain metastases is unclear, there appears to be an increasing incidence which has been attributed to longer survival, better control of systemic disease, and better imaging modalities. Until recently surgical resection of solitary or symptomatic brain metastases, and radiation therapy (either whole-brain radiation therapy or stereotactic radiation) were the mainstay of treatment for patients with brain metastases. The majority of traditional chemotherapies have shown limited activity in the central nervous system, which has been attributed to the blood-brain barrier and the molecular structure of the used agents. The discovery of driver mutations and drugs targeting these mutations has changed the treatment landscape. Several of these targeted small-molecule tyrosine kinase inhibitors do cross the blood-brain barrier and/or have shown activity in the central nervous system. Another major advance in the care of brain metastases has been the advent of new immunotherapeutic agents, for which initial studies have shown intracranial activity. In this chapter, we will review the unique challenges in the treatment of brain metastases. The pertinent clinical studies of chemotherapy in brain metastases will be discussed. The currently reported clinical trials and evidence for use of targeted therapies and immunotherapeutic agents will be emphasized. Copyright © 2018 Elsevier B.V. All rights reserved. 319. RANKL: A therapeutic target for bone destruction in rheumatoid arthritis. PubMed Tanaka, Sakae; Tanaka, Yoshiya; Ishiguro, Naoki; Yamanaka, Hisashi; Takeuchi, Tsutomu 2018-01-01 Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Recent studies have indicated the critical involvement of osteoclasts in bone destruction in RA. The osteoclast differentiation factor receptor activator of NF-κB ligand (RANKL), which belongs to the tumor necrosis factor superfamily, plays a critical role in osteoclast differentiation and bone destruction in RA. Denosumab, an antibody against human RANKL, efficiently suppressed the progression of bone erosion in RA patients in randomized controlled studies, and is considered as a putative therapeutic option for preventing bone destruction in RA. 320. Estrogen Regulates Bone Turnover by Targeting RANKL Expression in Bone Lining Cells. PubMed Streicher, Carmen; Heyny, Alexandra; Andrukhova, Olena; Haigl, Barbara; Slavic, Svetlana; Schüler, Christiane; Kollmann, Karoline; Kantner, Ingrid; Sexl, Veronika; Kleiter, Miriam; Hofbauer, Lorenz C; Kostenuik, Paul J; Erben, Reinhold G 2017-07-25 Estrogen is critical for skeletal homeostasis and regulates bone remodeling, in part, by modulating the expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for bone resorption by osteoclasts. RANKL can be produced by a variety of hematopoietic (e.g. T and B-cell) and mesenchymal (osteoblast lineage, chondrocyte) cell types. The cellular mechanisms by which estrogen acts on bone are still a matter of controversy. By using murine reconstitution models that allow for selective deletion of estrogen receptoralpha (ERα) or selective inhibition of RANKL in hematopoietic vs. mesenchymal cells, in conjunction with in situ expression profiling in bone cells, we identified bone lining cells as important gatekeepers of estrogen-controlled bone resorption. Our data indicate that the increase in bone resorption observed in states of estrogen deficiency in mice is mainly caused by lack of ERα-mediated suppression of RANKL expression in bone lining cells. « 14 15 16 17 18 » « 15 16 17 18 19 » 321. Biomaterial-mediated strategies targeting vascularization for bone repair. PubMed GarcÃa, José R; GarcÃa, Andrés J 2016-04-01 Repair of non-healing bone defects through tissue engineering strategies remains a challenging feat in the clinic due to the aversive microenvironment surrounding the injured tissue. The vascular damage that occurs following a bone injury causes extreme ischemia and a loss of circulating cells that contribute to regeneration. Tissue-engineered constructs aimed at regenerating the injured bone suffer from complications based on the slow progression of endogenous vascular repair and often fail at bridging the bone defect. To that end, various strategies have been explored to increase blood vessel regeneration within defects to facilitate both tissue-engineered and natural repair processes. Developments that induce robust vascularization will need to consolidate various parameters including optimization of embedded therapeutics, scaffold characteristics, and successful integration between the construct and the biological tissue. This review provides an overview of current strategies as well as new developments in engineering biomaterials to induce reparation of a functional vascular supply in the context of bone repair. 322. Metabolic activity in bone metastases of breast and prostate cancer were similar as studied by 18F-FDG PET/CT. The role of 99mTc-MDP. PubMed Pietrzak, Agata; Czepczynski, Rafal; Wierzchoslawska, Ewa; Cholewinski, Witold 2017-01-01 The aim of this study was to compare the metabolic activity of metastatic foci from breast and prostate cancer patients as scanned by fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and by technetium-99m methyl diphosphonate (99mTc-MDP) bone scan (BS). Forty one patients were studied, divided into 2 groups based on histologically confirmed diagnosis: a) Breast cancer group, 23 women, mean age: 61±12 years, range: 37-79 years and, b) Prostate cancer group, 18 men, mean age 68±8 years, range: 52-82 years. Another group of 17 non cancer atherosclerotic subjects 9 women and 8 men, of mean age and age range similar to the above were also studied for comparison. The R index (the total count rate in bone metastases divided by the total count rate in a contralateral area), the maximum semi-quantitative standardized uptake value (SUVmax) of BS lesions and the mean number of metastases were evaluated. For the metastatic findings in the PET/CT scans the automatic method of contouring with 50% background cut-off was used, while for the 99mTc-MDP BS metastases were delineated manually. The mean R index of the bone metastatic foci studied by 18F-FDG PET/CT was 1.89±0.69 for Groups I and II patients. There was no significant difference of the R index between prostate cancer and breast cancer metastases (1.95±0.86 vs 1.83±0.52). The average SUVmax value was significantly higher in breast cancer patients than in prostate cancer patients (5.15±2.54 vs 4.01±1.71; P<0.05). There was no significant correlation in both cancer groups between R index and SUVmax values. The number of metastatic foci diagnosed by the 99mTc-MDP BS scan was much less than by the 18F-FDG PET/CT. No significant correlation was noticed in the metabolic activity-glucose utilization of metastatic bone foci between breast and prostate cancer cases. This observation validates the independent value of analyzed diagnostic methods and suggests negligible influence 323. Incorporating target registration error into robotic bone milling NASA Astrophysics Data System (ADS) Siebold, Michael A.; Dillon, Neal P.; Webster, Robert J.; Fitzpatrick, J. Michael 2015-03-01 Robots have been shown to be useful in assisting surgeons in a variety of bone drilling and milling procedures. Examples include commercial systems for joint repair or replacement surgeries, with in vitro feasibility recently shown for mastoidectomy. Typically, the robot is guided along a path planned on a CT image that has been registered to the physical anatomy in the operating room, which is in turn registered to the robot. The registrations often take advantage of the high accuracy of fiducial registration, but, because no real-world registration is perfect, the drill guided by the robot will inevitably deviate from its planned path. The extent of the deviation can vary from point to point along the path because of the spatial variation of target registration error. The allowable deviation can also vary spatially based on the necessary safety margin between the drill tip and various nearby anatomical structures along the path. Knowledge of the expected spatial distribution of registration error can be obtained from theoretical models or experimental measurements and used to modify the planned path. The objective of such modifications is to achieve desired probabilities for sparing specified structures. This approach has previously been studied for drilling straight holes but has not yet been generalized to milling procedures, such as mastoidectomy, in which cavities of more general shapes must be created. In this work, we present a general method for altering any path to achieve specified probabilities for any spatial arrangement of structures to be protected. We validate the method via numerical simulations in the context of mastoidectomy. 324. Interactive local super-resolution reconstruction of whole-body MRI mouse data: a pilot study with applications to bone and kidney metastases. PubMed Dzyubachyk, Oleh; Khmelinskii, Artem; Plenge, Esben; Kok, Peter; Snoeks, Thomas J A; Poot, Dirk H J; Löwik, Clemens W G M; Botha, Charl P; Niessen, Wiro J; van der Weerd, Louise; Meijering, Erik; Lelieveldt, Boudewijn P F
2014-01-01 In small animal imaging studies, when the locations of the micro-structures of interest are unknown a priori, there is a simultaneous need for full-body coverage and high resolution. In MRI, additional requirements to image contrast and acquisition time will often make it impossible to acquire such images directly. Recently, a resolution enhancing post-processing technique called super-resolution reconstruction (SRR) has been demonstrated to improve visualization and localization of micro-structures in small animal MRI by combining multiple low-resolution acquisitions. However, when the field-of-view is large relative to the desired voxel size, solving the SRR problem becomes very expensive, in terms of both memory requirements and computation time. In this paper we introduce a novel local approach to SRR that aims to overcome the computational problems and allow researchers to efficiently explore both global and local characteristics in whole-body small animal MRI. The method integrates state-of-the-art image processing techniques from the areas of articulated atlas-based segmentation, planar reformation, and SRR. A proof-of-concept is provided with two case studies involving CT, BLI, and MRI data of bone and kidney tumors in a mouse model. We show that local SRR-MRI is a computationally efficient complementary imaging modality for the precise characterization of tumor metastases, and that the method provides a feasible high-resolution alternative to conventional MRI. 325. Fluorodeoxyglucose Uptake on Positron Emission Tomography Is a Useful Predictor of Long-Term Pain Control After Palliative Radiation Therapy in Patients With Painful Bone Metastases: Results of a Single-Institute Prospective Study SciTech Connect Tahara, Takatoshi, E-mail:
[email protected]; Fujii, Shinya; Ogawa, Toshihide 2016-02-01 Purpose: To determine whether fluorodeoxyglucose positron emission tomography (FDG-PET) before and after palliative radiation therapy (RT) can predict long-term pain control in patients with painful bone metastases. Methods and Materials: Thirty-one patients with bone metastases who received RT were prospectively included. Forty painful metastatic treatment fields were evaluated. All patients had undergone pre-RT and post-RT PET/CT scanning. We evaluated the relationships between the pre-RT, post-RT, and changes in maximum standardized uptake value (SUV{sub max}) and the pain response, and between SUV{sub max} and pain relapse of the bone metastases in the treatment field. In addition, we compared the SUV{sub max}more » according to the length of time from the completion of RT to pain relapse of the bone metastases. Results: Regarding the pain response at 4 weeks after the completion of RT, there were 36 lesions of 27 patients in the responder group and 4 lesions of 4 patients in the nonresponder group. Changes in the SUV{sub max} differed significantly between the responder and nonresponder groups in both the early and delayed phases (P=.0292 and P=.0139, respectively), but no relationship was observed between the pre-RT and post-RT SUV{sub max} relative to the pain response. The responder group was evaluated for the rate of relapse. Thirty-five lesions of 26 patients in the responder group were evaluated, because 1 patient died of acute renal failure at 2 months after RT. Twelve lesions (34%) showed pain relapse, and 23 lesions (66%) did not. There were significant differences between the relapse and nonrelapse patients in terms of the pre-RT (early/delayed phases: P<.0001/P<.0001), post-RT (P=.0199/P=.0261), and changes in SUV{sub max} (P=.0004/P=.004). Conclusions: FDG-PET may help predict the outcome of pain control in the treatment field after palliative RT for painful bone metastases.« less 326. Fluorodeoxyglucose Uptake on Positron Emission Tomography Is a Useful Predictor of Long-Term Pain Control After Palliative Radiation Therapy in Patients With Painful Bone Metastases: Results of a Single-Institute Prospective Study SciTech Connect Tahara, Takatoshi; Fujii, Shinya; Ogawa, Toshihide; Michimoto, Koichi; Fukunaga, Takeru; Tanino, Tomohiko; Uchida, Nobue; Matsuki, Tsutomu; Sakamoto, Hiroaki 2016-02-01 Purpose: To determine whether fluorodeoxyglucose positron emission tomography (FDG-PET) before and after palliative radiation therapy (RT) can predict long-term pain control in patients with painful bone metastases. Methods and Materials: Thirty-one patients with bone metastases who received RT were prospectively included. Forty painful metastatic treatment fields were evaluated. All patients had undergone pre-RT and post-RT PET/CT scanning. We evaluated the relationships between the pre-RT, post-RT, and changes in maximum standardized uptake value (SUV{sub max}) and the pain response, and between SUV{sub max} and pain relapse of the bone metastases in the treatment field. In addition, we compared the SUV{sub max} according to the length of time from the completion of RT to pain relapse of the bone metastases. Results: Regarding the pain response at 4 weeks after the completion of RT, there were 36 lesions of 27 patients in the responder group and 4 lesions of 4 patients in the nonresponder group. Changes in the SUV{sub max} differed significantly between the responder and nonresponder groups in both the early and delayed phases (P=.0292 and P=.0139, respectively), but no relationship was observed between the pre-RT and post-RT SUV{sub max} relative to the pain response. The responder group was evaluated for the rate of relapse. Thirty-five lesions of 26 patients in the responder group were evaluated, because 1 patient died of acute renal failure at 2 months after RT. Twelve lesions (34%) showed pain relapse, and 23 lesions (66%) did not. There were significant differences between the relapse and nonrelapse patients in terms of the pre-RT (early/delayed phases: P<.0001/P<.0001), post-RT (P=.0199/P=.0261), and changes in SUV{sub max} (P=.0004/P=.004). Conclusions: FDG-PET may help predict the outcome of pain control in the treatment field after palliative RT for painful bone metastases. 327. A rare case of nasopharyngeal carcinoma with widespread CNS metastases. PubMed Rafee, S; Elamin, Y Y; Cronin, K; Brennan, S; Osman, N 2014-06-01 Nasopharyngeal cancer is unique among head and neck cancers. Despite definitive treatment, there is a high rate of recurrence, most commonly in the bone, lung or liver. Brain metastases and particularly, leptomeningeal carcinomatosis are extremely rare. We present a case of recurrent nasopharyngeal carcinoma with brain metastases and leptomeningeal carcinomatosis in the absence of local recurrence and systemic metastases. 328. Multimodal Partial-Volume Correction: Application to 18F-Fluoride PET/CT Bone Metastases Studies. PubMed Grecchi, Elisabetta; O'Doherty, Jim; Veronese, Mattia; Tsoumpas, Charalampos; Cook, Gary J; Turkheimer, Federico E 2015-09-01 (18)F-fluoride PET/CT offers the opportunity for accurate skeletal metastasis staging, compared with conventional imaging methods. (18)F-fluoride is a bone-specific tracer whose uptake depends on osteoblastic activity. Because of the resulting increase in bone mineralization and sclerosis, the osteoblastic process can also be detected morphologically in CT images. Although CT is characterized by high resolution, the potential of PET is limited by its lower spatial resolution and the resulting partial-volume effect. In this context, the synergy between PET and CT presents an opportunity to resolve this limitation using a novel multimodal approach called synergistic functional-structural resolution recovery (SFSRR). Its performance is benchmarked against current resolution recovery technology using the point-spread function (PSF) of the scanner in the reconstruction procedure. The SFSRR technique takes advantage of the multiresolution property of the wavelet transform applied to both functional and structural images to create a high-resolution PET image that exploits the structural information of CT. Although the method was originally conceived for PET/MR imaging of brain data, an ad hoc version for whole-body PET/CT is proposed here. Three phantom experiments and 2 datasets of metastatic bone (18)F-fluoride PET/CT images from primary prostate and breast cancer were used to test the algorithm performances. The SFS-RR images were compared with the manufacturer's PSF-based reconstruction using the standardized uptake value (SUV) and the metabolic volume as metrics for quantification. When compared with standard PET images, the phantom experiments showed a bias reduction of 14% in activity and 1.3 cm(3) in volume estimates for PSF images and up to 20% and 2.5 cm(3) for the SFS-RR images. The SFS-RR images were characterized by a higher recovery coefficient (up to 60%) whereas noise levels remained comparable to those of standard PET. The clinical data showed an 329. Effect of a High Bone Turnover State Induced by Estrogen Deficiency on the Development and Progression of Breast Cancer Bone Metastases DTIC Science & Technology 2009-04-01 female BALBc/ICR Swiss immunocompetent mice were treated with ovariectomy (OVX), sham surgery, the AI letrozole (5 mg/kg/day) or control. Ten weeks...breast cancer, ovariectomy , metastasis, bisphosphonates, mouse model 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES...previously reported data showed variable effects on bone mineral density (BMD) in this mouse model after ovariectomy (OVX) and treatment with the aromatase 330. The Role of Osteocytes in Targeted Bone Remodeling: A Mathematical Model PubMed Central Graham, Jason M.; Ayati, Bruce P.; Holstein, Sarah A.; Martin, James A. 2013-01-01 Until recently many studies of bone remodeling at the cellular level have focused on the behavior of mature osteoblasts and osteoclasts, and their respective precursor cells, with the role of osteocytes and bone lining cells left largely unexplored. This is particularly true with respect to the mathematical modeling of bone remodeling. However, there is increasing evidence that osteocytes play important roles in the cycle of targeted bone remodeling, in serving as a significant source of RANKL to support osteoclastogenesis, and in secreting the bone formation inhibitor sclerostin. Moreover, there is also increasing interest in sclerostin, an osteocyte-secreted bone formation inhibitor, and its role in regulating local response to changes in the bone microenvironment. Here we develop a cell population model of bone remodeling that includes the role of osteocytes, sclerostin, and allows for the possibility of RANKL expression by osteocyte cell populations. We have aimed to give a simple, yet still tractable, model that remains faithful to the underlying system based on the known literature. This model extends and complements many of the existing mathematical models for bone remodeling, but can be used to explore aspects of the process of bone remodeling that were previously beyond the scope of prior modeling work. Through numerical simulations we demonstrate that our model can be used to explore theoretically many of the qualitative features of the role of osteocytes in bone biology as presented in recent literature. PMID:23717504 331. Is there any significance of lung cancer histology to compare the diagnostic accuracies of (18)F-FDG-PET/CT and (99m)Tc-MDP BS for the detection of bone metastases in advanced NSCLC? PubMed Inal, Ali; Kaplan, Muhammed Ali; Kucukoner, Mehmet; Urakcı, Zuhat; Dostbil, Zeki; Komek, Hail; Onder, Hakan; Tasdemir, Bekir; Isıkdogan, Abdurrahman 2014-01-01 Bone scintigraphy (BS) and fluorine-18 deoxyglucose positron emission tomography computed tomography ((18)F-FDG-PET/CT) are widely used for the detection of bone involvement. The optimal imaging modality for the detection of bone metastases in histological subgroups of non-small cell lung cancer (NSCLC) remains ambiguous. The aim of this study was to compare the efficacy of (18)F-FDG-PET/C and 99mTc-methylene diphosphonate ((99m)Tc-MDP) BS in the detection of bone metastases of patients in NSCLC. Specifically, we compared the diagnostic accuracies of these imaging techniques evaluating bone metastasis in histological subgroups of NSCLC. Fifty-three patients with advanced NSCLC, who had undergone both (18)F-FDG-PET/CT and BS and were eventually diagnosed as having bone metastasis, were enrolled in this retrospective study. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of (18)F-FDG-PET/CT and BS were 90.4%, 99.4%, 98.1%, 96.6%, 97.0% and 84.6%, 93.1%, 82.5%, 93.2, 90.8%, respectively. The κ statistics were calculated for (18)F-FDG-PET/CT and BS. The κ-value was 0.67 between (18)F-FDG-PET/CT and BS in all patients. On the other hand, the κ-value was 0.65 in adenocarcinoma, and 0.61 in squamous cell carcinoma between (18)F-FDG-PET/CT and BS. The κ-values suggested excellent agreement between all patients and histological subgroups of NSCLC. (18)F-FDG-PET/CT was more favorable than BS in the screening of metastatic bone lesions, but the trend did not reach statistical significance in all patients and histological subgroups of NSCLC. Our results need to be validated in prospective and larger study clinical trials to further clarify this topic. 332. Targeting Neuropilin-1 in Prostate Cancer Bone Metastasis DTIC Science & Technology 2010-04-01 soft tissues, forming mixed osteo- blastic and osteolytic lesions in mouse skeleton [19,21,22]. The ARCaPM-C2 subclone, derived from metastatic bone...proliferation and migration, an underlying mechanism for angiogen- esis during tumor progression. However, neither exo - genous human VEGF165 (Figure 2b) nor 333. Does response rate of chemotherapy with molecular target agents correlate with the conversion rate and survival in patients with unresectable colorectal liver metastases?: A systematic review. PubMed Okuno, M; Hatano, E; Nishino, H; Seo, S; Taura, K; Uemoto, S 2017-06-01 This study aimed to evaluate whether the response rate of chemotherapy with molecular target agents correlates with the conversion rate, R0 resection rate, and survival in patients with initially unresectable colorectal liver metastases (CRLM). We reviewed the literature of prospective, controlled trials of systemic chemotherapy for patients with unresectable liver-only CRLM, including resectable extrahepatic metastases. Pearson's correlation coefficients were calculated. A total of 26 patient groups from 18 studies were reviewed. The response rate was significantly correlated with the conversion rate (r = 0.66) and R0 resection rate (r = 0.43) in overall patients. In subgroup analysis, only the conversion rate in patients with chemotherapy only (r = 0.75) and anti-EGFR therapy (r = 0.78) were significantly strongly correlated with the response rate. A non-significant strong trend toward correlation between response and conversion rates was observed in patients with bevacizumab (r = 0.73, p = 0.10). The regression line in the scatter plot of patients using bevacizumab showed a less steep slope. This indicated that conversion rates were relatively less affected by response rates under anti-VEGF therapy compared with the other patient groups. The response rate in chemotherapy-only patients was significantly correlated with median progression-free survival (r = 0.61) and overall survival (r = 0.66). Chemotherapy without molecular target agents and with anti-EGFR agents shows similar results of correlation between response and conversion/R0 resection rates. Under antiVEGF therapy, conversion would be expected, even with a relatively lower response rate. Copyright © 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. 334. Use of intravenous bisphosphonates in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems. PubMed Oster, Gerry; Lamerato, Lois; Glass, Andrew G; Richert-Boe, Kathryn E; Lopez, Andrea; Chung, Karen; Richhariya, Akshara; Dodge, Tracy; Wolff, Greg G; Balakumaran, Arun; Edelsberg, John 2014-05-01 The purpose of this paper is to document the use of intravenous (IV) bisphosphonates for prevention of skeletal-related events (SREs) in patients with bone metastases (BM) due to breast cancer (BC), lung cancer (LC), or prostate cancer (PC). Using data from two large US health systems, we identified all patients aged ≥ 18 years with primary BC, LC, or PC and newly diagnosed BM between 1/1/1995 and 12/31/2009. Starting with the diagnosis of BM, we reviewed medical and administrative records for evidence of receipt of IV bisphosphonates (zoledronic acid or pamidronate) and occurrence of SREs. Initiation of IV bisphosphonates prior to occurrence of an SRE was designated "primary prophylaxis"; use following an SRE was designated "secondary prophylaxis". We identified a total of 1,193 patients with newly diagnosed BM, including 400 with BC, 332 with LC, and 461 with PC. Use of IV bisphosphonates was substantially higher in BC (55.8 % of all patients) than in LC (14.8 %) or PC (20.2 %). Use of IV bisphosphonates was fairly evenly split between primary and secondary prophylaxis in BC (26.3 vs. 29.5 %, respectively) and PC (10.6 vs 9.5 %); in LC, however, primary prophylaxis was much less common than secondary prophylaxis (4.8 vs 9.9 %). Almost one half of all patients with BM due to BC, and substantially more with LC and PC, do not receive IV bisphosphonates. Among patients receiving such therapy, treatment often is not initiated until after the occurrence of an SRE. Our study suggests that IV bisphosphonates may be substantially underutilized in patients with BM due to these common cancers. 335. Treatment and prevention of bone complications from prostate cancer. PubMed Lee, Richard J; Saylor, Philip J; Smith, Matthew R 2011-01-01 Bone metastases and skeletal complications are major causes of morbidity in prostate cancer patients. Despite the osteoblastic appearance of bone metastases on imaging studies, patients have elevated serum and urinary markers of bone resorption, indicative of high osteoclast activity. Increased osteoclast activity is independently associated with higher risk of subsequent skeletal complications, disease progression, and death. Osteoclast-targeted therapies are therefore a rational approach to reduction of risk for disease-related skeletal complications, bone metastases, and treatment-related fractures. This review focuses on recent advances in osteoclast-targeted therapy in prostate cancer. Bisphosphonates have been extensively studied in men with prostate cancer. Zoledronic acid significantly decreased the risk of skeletal complications in men with castration-resistant prostate cancer and bone metastases, and it is FDA-approved for this indication. Denosumab is a human monoclonal antibody that binds and inactivates RANKL, a critical mediator of osteoclast differentiation, activation, and survival. Recent global phase 3 clinic trials demonstrated an emerging role for denosumab in the treatment of prostate cancer bone metastases and prevention of fractures associated with androgen deprivation therapy. Copyright © 2010 Elsevier Inc. All rights reserved. 336. Cancer to bone: a fatal attraction PubMed Central Weilbaecher, Katherine N.; Guise, Theresa A.; McCauley, Laurie K. 2013-01-01 When cancer metastasizes to bone, considerable pain and deregulated bone remodelling occurs, greatly diminishing the possibility of cure. Metastasizing tumour cells mobilize and sculpt the bone microenvironment to enhance tumour growth and to promote bone invasion. Understanding the crucial components of the bone microenvironment that influence tumour localization, along with the tumour-derived factors that modulate cellular and protein matrix components of bone to favour tumour expansion and invasion, is central to the pathophysiology of bone metastases. Basic findings of tumour–bone interactions have uncovered numerous therapeutic opportunities that focus on the bone microenvironment to prevent and treat bone metastases. PMID:21593787 337. 18F-FDG PET/CT is a prognostic biomarker in patients affected by bone metastases from breast cancer in comparison with 18F-NaF PET/CT. PubMed Piccardo, A; Puntoni, M; Morbelli, S; Massollo, M; Bongioanni, F; Paparo, F; Altrinetti, V; Gonella, R; Gennari, A; Iacozzi, M; Sambuceti, G; DeCensi, A 2015-01-01 To compare 18F-FDG PET/CT and 18F-NaF PET/CT with respect to disease prognostication and outcome in patients affected by bone metastases from breast cancer (BC). We retrospectively investigated 32 women with BC and documented bone metastases. Semi-quantitative parameters were applied to 18F-FDG PET/CT and 18F-Na PET/CT in order to evaluate disease extent and tumour metabolism. We used time-to-event analyses (Kaplan Meier and COX proportional hazard methods) to estimate progression-free (PFS) and overall survival (OS) in order to assess the independent prognostic value of 18F-FDG PET/CT and 18F-Na PET/CT. The sensitivity of 18F-NaF PET/CT (100%) was higher (p < 0.05) than that of 18F-FDG PET/CT (72% and 72%). None of the 18F-FDG PET/CT-negative patients showed disease progression at the end of follow-up. After adjustment for age, Ki-67 levels, presence of visceral metastases, hormone therapy, duration of bone disease and response to first-line therapy, only 18F-FDG SUV mean [HR 15.7, 95% confidence interval (CI) 1.15-214.5] and 18F-FDG whole-body bone metabolic burden (WB-B-MB) (HR 16.9; 95%CI 1.87-152.2) were independently and significantly associated with OS. None of the 18F-NaF PET/CT parameters were associated with OS. None of the conventional clinical prognostic parameters remained significantly associated with OS after the inclusion of PET/CT parameters in the model. 18F-FDG PET/CT is independently associated with OS in BC patients with bone metastases and its prognostic impact seems to be higher than conventional clinical and biological prognostic factors. Although 18F-NaF PET/CT has a higher diagnostic sensitivity than 18F-FDG PET/CT, it is not independently associated with OS. 338. Understanding and Targeting Epigenetic Alterations in Acquired Bone Marrow Failure DTIC Science & Technology 2016-07-01 epigenetic regulation of gene transcription or in RNA splicing. This includes mutations in ASXL1, TET2, and EZH2 as well as mutations in the RNA splicing...2017). 15. SUBJECT TERMS ASXL1; Bone marrow failure; Myelodysplastic Syndrome; RNA splicing; SF3B1; SRSF2; TET2 16. SECURITY CLASSIFICATION OF...and RNA splicing factors has highlighted the fact that a number of these genes encode enzymes and/or result in alterations in enzymatic function 339. Antibody-Mediated Targeting of Alpha PDGF Receptor to Inhibit the Progression of Skeletal Micro-Metastases DTIC Science & Technology 2012-10-01 of any dimer formation following treatment of cells with bone marrow and subsequent cell - surface receptor cross-linking (Fig. 2). Thus, we hypothesize...potential to prostate cancer cells ; b) Provide pre-clinical evidence that antibodies against this receptor can impair metastatic progression in the...expression of this receptor if PC3-N cells confers full metastatic potential to these cells and allows them to progress at the skeletal levels in a manner 340. Health resource utilization associated with skeletal-related events in patients with bone metastases: Results from a multinational retrospective – prospective observational study – a cohort from 4 European countries PubMed Central Hoefeler, H.; Duran, I.; Hechmati, G.; Garzon Rodriguez, C.; Lüftner, D.; Ashcroft, J.; Bahl, A.; Atchison, C.; Wei, R.; Thomas, E.; Lorusso, V. 2014-01-01 Background Skeletal-related events (SREs; pathologic fracture, radiation or surgery to bone, spinal cord compression) frequently occur in patients with advanced cancer with bone metastases/lesions. Limited data on the associated patient and economic burden are available to aid in resource planning and evaluating treatment options. Methods Patients with bone metastases/lesions secondary to breast, lung or prostate cancer or multiple myeloma; with at least one SRE within 97 days prior to enrollment; life expectancy of at least 6 months; and Eastern Cooperative Oncology Group performance status 0, 1 or 2 were recruited. Information on health resource utilization (HRU; including number/duration of hospitalizations, outpatient visits, procedures), attributed by investigators to be associated with a SRE, was collected retrospectively for up to 97 days prior to enrollment and prospectively for up to 18–21 months. Results A total of 631 patients contributing 1282 SREs, were enrolled across Germany, Italy, Spain and the United Kingdom. Approximately a third of all SREs required an inpatient stay. Mean duration of inpatient stay for patients with SREs requiring one ranged from 8.4 to 41.1 days across all countries and SRE types. Conclusion All types of SREs are associated with substantial HRU burden. Preventing SREs by using the best therapeutic options available may help to reduce the burden to patients and healthcare systems. PMID:26909296 « 15 16 17 18 19 » « 16 17 18 19 20 » 341. Targeting cellular senescence prevents age-related bone loss in mice. PubMed Farr, Joshua N; Xu, Ming; Weivoda, Megan M; Monroe, David G; Fraser, Daniel G; Onken, Jennifer L; Negley, Brittany A; Sfeir, Jad G; Ogrodnik, Mikolaj B; Hachfeld, Christine M; LeBrasseur, Nathan K; Drake, Matthew T; Pignolo, Robert J; Pirtskhalava, Tamar; Tchkonia, Tamara; Oursler, Merry Jo; Kirkland, James L; Khosla, Sundeep 2017-09-01 Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities. 342. Effect of athletic fatigue damage and the associated bone targeted remodeling in the rat ulna. PubMed Hao, Li; Rui-Xin, Li; Biao, Han; Bin, Zhao; Bao-Hui, Hao; Ying-Jie, Liu; Xi-Zheng, Zhang 2017-08-08 Fatigue damage of the long bones is prevalent in running athletes and military recruits due to vigorous mid- and long-term physical activity. The current study attempted to know the features of bony athletic fatigue damage and to explore the mechanism of fatigue damage repair through bone targeted remodeling process. Right ulnae of the Wistar rats were fatigue loaded on an INSTRON 5865 to construct the athletic fatigue damage model, and several time points (i.e. experimental days: 0, 7, 13 and 19) were selected to simulate physiological status, preliminary, mid-term and perennial stage during continuous high-intensive training, respectively. The multi-level responses of rat ulnae under the athletic fatigue loading, including cellular protein expression, micro damage or micro-crack and macro mechanical properties, were tested and statistically analyzed. Wistar rats, subjected to the athletic fatigue loading protocol, experienced a decrease of ulna fatigue mechanical properties and an active bone resorption of the loaded ulnae in the early stage, whereafter, a hyperactive bone formation and significant improvements of ulnae fatigue mechanical properties were detected. However, a deterioration of quasi-static mechanical properties in the subsequent period implied limitations of bone remodeling to maintain the bearing capacity of bone during long-term strenuous exercise. In summary, after athletic fatigue loading, bone targeted remodeling is activated and proceeds to repair fatigue damage, but only to a certain extent. 343. Chemotherapy plus targeted drugs in conversion therapy for potentially resectable colorectal liver metastases: a meta-analysis. PubMed Wang, Lu; Sun, Yinan; Zhao, Ben; Zhang, Huixian; Yu, Qianqian; Yuan, Xianglin 2016-08-23 To evaluate the safety and efficiency of the conversion therapy: chemotherapy plus anti-epidermal growth factor Receptor (EGFR) or anti-vascular endothelial growth factor receptor (VEGFR) monoclonal antibodies (MoAbs) with different rat sarcoma (RAS) status in patients with potentially resectable colorectal liver metastases (CRLM). Randomized controlled trials (RCTs) were identified and the association between RAS mutation and clinical outcome in CRLM patients treated with anti-EGFR or anti-VEGFR MoAbs was investigated. Searches were performed for data recorded between January 2005 and August 2015 in the Cochrane Library, MEDLINE, PubMed, and EMBASE. Objective response rates (ORR), conversion resection rates (CRR), R0 resection rates (R0R) and rate ratios (RR) were used to assess the strength of the association between different RAS status, MoAbs and conversion efficiency. In the conversion therapy, ORR and RR were associated with patients with wild type RAS and different MoAbs. Patients treated with MoAbs: anti-VEGFR or anti-EGFR drugs, resulted in higher ORR, (RR=1.53, 95% confidence interval [CI]: 1.27-1.84, P < 0.05). Furthermore, anti-EGFR regimens displayed higher ORR compared with anti-VEGFR regimens in CRLM patients, (RR=1.15, 95%CI: 1.04-1.26, P < 0.05). However, CRLM patients with mutant type RAS did not benefit from anti-EGFR therapy, (RR=0.91, 95%CI: 0.76-1.08, P<0.05) and wild type RAS patients displayed higher ORR with anti-EGFR therapy, (RR=1.56, 95%CI: 1.16-2.01, P <0.05). In addition, the patients achieved higher resection rates (RR=1.67, 95%CI: 1.00-2.81, P ≤ 0.05) and R0 resection (RR=1.85, 95%CI: 1.04-3.27, P < 0.05). We noted that the addition of MoAbs (antiEGFR or anti-VEGFR) to standard chemotherapy could improve conversion efficiency for patients with potentially resectable CRLM patients, and anti-EGFR therapies maybe more effective than anti-VEGFR therapies. RAS status is a potential predictive marker of the clinical benefit resulting 344. Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non-small cell lung cancer treated with radiotherapy for brain metastases. PubMed Mak, Kimberley S; Gainor, Justin F; Niemierko, Andrzej; Oh, Kevin S; Willers, Henning; Choi, Noah C; Loeffler, Jay S; Sequist, Lecia V; Shaw, Alice T; Shih, Helen A 2015-02-01 We determined the impact of genetic alterations in EGFR, ALK, or KRAS on survival after radiotherapy for brain metastases in non-small cell lung cancer (NSCLC). Of 172 genotyped NSCLC patients treated with radiotherapy for brain metastases in 2005-2012, 54 had cancers with EGFR mutations, 12 had ALK rearrangements, 38 had KRAS mutations, and 68 were wild-type (WT). Overall survival (OS) was determined. Median follow-up was 8.6 months. Median OS was 13.6 months for patients with EGFR mutations and 26.3 months for patients with ALK rearrangements, in contrast to 5.7 months for KRAS-mutant patients and 5.5 months for WT patients (P = .001). On multivariate analysis, adjusting for receipt of targeted therapy after cranial radiotherapy, ALK rearrangements were associated with improved OS (HR, 0.31; 95% CI, 0.13-0.74; P = .008). EGFR mutations were not significantly associated with improved OS on multivariate analysis (HR, 0.71; 95% CI, 0.37-1.38; P = .3). KRAS mutations were also not associated with improved OS (HR, 0.93; 95% CI, 0.59-1.47; P = .8). Receipt of targeted therapy after cranial radiotherapy was independently associated with improved OS (HR, 0.30; 95% CI, 0.17-0.54; P < .001). Receipt of chemotherapy after cranial radiotherapy, number of brain metastases, extracranial metastases, age, and performance status were also associated with OS. NSCLC patients with genetic alterations in ALK have improved survival outcomes after radiotherapy for brain metastases compared with EGFR, KRAS, or WT. Subsequent receipt of targeted therapy was associated with additional improvement in OS. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for NeuroOncology. All rights reserved. For permissions, please e-mail:
[email protected]. 345. Characteristics and Prognostic Factors for Patients With HER2-overexpressing Breast Cancer and Brain Metastases in the Era of HER2-targeted Therapy: An Argument for Earlier Detection.
PubMed Morikawa, Aki; Wang, Rui; Patil, Sujata; Diab, Adi; Yang, Jonathan; Hudis, Clifford A; McArthur, Heather L; Beal, Kathryn; Seidman, Andrew D 2017-12-21 Although brain metastases (BM) are associated with poor prognosis, patients with human epidermal growth factor receptor 2 (HER2) overexpressing (HER2 + ) breast cancer (BC) with BM who are treated with anti-HER2 therapy have a relatively longer survival after BM diagnosis compared with other subtypes and HER2 + patients previously untreated with anti-HER2 therapy. It is unclear if previously reported prognostic factors are applicable to patients with HER2 + BC in the era of HER2-targeted therapy. We evaluated 100 consecutive patients with HER2 + BC with BM who underwent radiation therapy as primary BM treatment from January 2001 to December 2011 at Memorial Sloan Kettering Cancer Center by retrospective review. Patient characteristics at the time of BM diagnosis and their associations with time from BM to death were evaluated by Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models. Significantly better survival from BM was noted for patients with higher performance status, fewer BM lesions, continued use of HER2-targeted therapy after BM diagnosis, and better controlled extracranial metastatic disease. Absence of neurologic symptoms at BM diagnosis was significantly associated with fewer lesions, decreased use of whole brain radiotherapy, and longer survival in univariate and multivariate analysis (multivariate hazard ratio, 3.69; 95% confidence interval, 1.698.07). Our finding supports the continued use of HER2-targeted therapy after BM diagnosis. In addition, future research on the clinical impact of detecting asymptomatic BM in patients with HER2 + BC, in terms of improving prognosis, quality of life, and avoidance of whole brain radiotherapy, is warranted. Copyright © 2017 Elsevier Inc. All rights reserved. 346. Anatomic and functional imaging in the diagnosis of spine metastases and response assessment after spine radiosurgery. PubMed Soliman, Moaaz; Taunk, Neil K; Simons, Robert E; Osborne, Joseph R; Kim, Michelle M; Szerlip, Nicholas J; Spratt, Daniel E 2017-01-01 Spine stereotactic radiosurgery (SSRS) has recently emerged as an increasingly effective treatment for spinal metastases. Studies performed over the past decade have examined the role of imaging in the diagnosis of metastases, as well as treatment response following SSRS. In this paper, the authors describe and review the utility of several imaging modalities in the diagnosis of spinal metastases and monitoring of their response to SSRS. Specifically, we review the role of CT, MRI, and positron emission tomography (PET) in their ability to differentiate between osteoblastic and osteolytic lesions, delineation of initial bony pathology, detection of treatment-related changes in bone density and vertebral compression fracture after SSRS, and tumor response to therapy. Validated consensus guidelines defining the imaging approach to SSRS are needed to standardize the diagnosis and treatment response assessment after SSRS. Future directions of spinal imaging, including advances in targeted tumor-specific molecular imaging markers demonstrate early promise for advancing the role of imaging in SSRS. 347. Crosstalk between bone niche and immune system: osteoimmunology signaling as a potential target for cancer treatment. PubMed Criscitiello, Carmen; Viale, Giulia; Gelao, Lucia; Esposito, Angela; De Laurentiis, Michele; De Placido, Sabino; Santangelo, Michele; Goldhirsch, Aron; Curigliano, Giuseppe 2015-02-01 There is a well recognized link between the bone and the immune system and in recent years there has been a major effort to elucidate the multiple functions of the molecules expressed in both bone and immune cells. Several molecules that were initially identified and studied in the immune system have been shown to have essential functions also in the bone. An interdisciplinary field embracing immune and bone biology has been brought together and called "osteoimmunology". The co-regulation of the skeletal and immune systems strikingly exemplifies the extreme complexity of such an interaction. Their interdependency must be considered in designing therapeutic approaches for either of the two systems. In other words, it is necessary to think of the osteoimmune system as a complex physiological unit. Denosumab was originally introduced to specifically target bone resorption, but it is now under evaluation for its effect on the long term immune response. Similarly, our current and still growing knowledge of the intimate link between the immune system and bone will be beneficial for the safety of drugs targeting either of these integrated systems. Given the large number of molecules exerting functions on both the skeletal and immune systems, osteoimmunological understanding is becoming increasingly important. Both bone and immune systems are frequently disrupted in cancer; and they may be crucial in regulating tumor growth and progression. Some therapies - such as bisphosphonates and receptor activator of NF-κB ligand (RANKL) targeted drugs - that aim at reducing pathologic osteolysis in cancer may interact with the immune system, thus providing potential favorable effects on survival. Copyright © 2014 Elsevier Ltd. All rights reserved. 348. Potential synergistic implications for stromal-targeted radiopharmaceuticals in bone-metastatic prostate cancer PubMed Central Sartor, Oliver 2011-01-01 Genetic heterogeneity and chemotherapy-resistant ‘stem cells' represent two of the most pressing issues in devising new strategies for the treatment of advanced prostate cancer. Though curative strategies have long been present for men with localized disease, metastatic prostate cancer is currently incurable. Though substantial improvements in outcomes are now possible through the utilization of newly approved therapies, novel combinations are clearly needed. Herein we describe potentially synergistic interactions between bone stromal-targeted radiopharmaceuticals and other therapies for treatment of bone-metastatic prostate cancer. Radiation has long been known to synergize with cytotoxic chemotherapies and recent data also suggest the possibility of synergy when combining radiation and immune-based strategies. Combination therapies will be required to substantially improve survival for men with castrate-resistant metastatic prostate cancer and we hypothesize that bone-targeted radiopharmaceuticals will play an important role in this process. PMID:21499278 349. Novel modeling of cancer cell signaling pathways enables systematic drug repositioning for distinct breast cancer metastases. PubMed Zhao, Hong; Jin, Guangxu; Cui, Kemi; Ren, Ding; Liu, Timothy; Chen, Peikai; Wong, Solomon; Li, Fuhai; Fan, Yubo; Rodriguez, Angel; Chang, Jenny; Wong, Stephen T C 2013-10-15 A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease. ©2013 AACR. 350. Mechanism and Function of Monoclonal Antibodies Targeting Siglec-15 for Therapeutic Inhibition of Osteoclastic Bone Resorption* PubMed Central Stuible, Matthew; Moraitis, Anna; Fortin, Annie; Saragosa, Stefan; Kalbakji, Aida; Filion, Mario; Tremblay, Gilles B. 2014-01-01 The use of monoclonal antibodies to target functionally important cell-surface proteins on bone-resorbing osteoclasts represents a promising approach for treatment of cancerassociated bone loss and other skeletal pathologies. Previously, we identified Siglec-15, a little studied sialic acid-binding receptor, as a candidate target that is highly up-regulated during osteoclast differentiation induced by the cytokine receptor activator of NF-κB ligand (RANKL). In this report, we confirm that Siglec-15 is localized to the plasma membrane where it can be targeted by monoclonal antibodies to inhibit differentiation of functional osteoclasts in vitro. Furthermore, we found that treatment of mice with these antibodies led to a marked increase in bone mineral density, consistent with inhibition of osteoclast activity. Interestingly, osteoblast numbers were maintained despite the anti-resorptive activity. At the molecular level, Siglec-15 interacts with the adapter protein DAP12 and can induce Akt activation when clustered on the osteoclast cell surface, which likely represents its normal signaling function. Importantly, we discovered that monoclonal antibodies induce rapid internalization, lysosomal targeting, and degradation of Siglec-15 by inducing receptor dimerization. This study defines a key regulatory node that controls osteoclast differentiation and activity downstream of RANKL and supports further development of Siglec-15 antibodies as a novel class of bone loss therapeutics. PMID:24446437 351. Targeted Therapies for Myeloma and Metastatic Bone Cancers DTIC Science & Technology 2010-09-01 used at 100 fold excess over NP content. The common sugar sucrose was also effective. Data for sucrose was given in previous reports. (Fig 1-5...0.024(0.010) 0.064(0.012) 0.085(0.015) Skull 0.253(0.050) 0.215(0.084) 0.216(0.040) 0.251(0.010) Upper Spine 0.197(0.052) 0.183(0.080) 0.403(0.104...ID/ organ 4-5-2010 Targeted PEG Control Mean (SEM) Calvaria 0.039(0.008) 0.025(0.000) 0.032(0.012) 0.090 Skull 0.173(0.024) 0.192(0.000 352. Risk of Leptomeningeal Disease in Patients Treated With Stereotactic Radiosurgery Targeting the Postoperative Resection Cavity for Brain Metastases SciTech Connect Atalar, Banu; Modlin, Leslie A.; Choi, Clara Y.H.; Adler, John R.; Gibbs, Iris C.; Chang, Steven D.; Harsh, Griffith R.; Li, Gordon; Nagpal, Seema; Hanlon, Alexandra; Soltys, Scott G. 2013-11-15 Purpose: We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients. Methods and Materials: We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), and histology (lung, colon, breast, melanoma, gynecologic, other). Results: With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (P=.004). Conclusions: In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology. 353. Dose response of bone-targeted enzyme replacement for murine hypophosphatasia PubMed Central Yadav, Manisha C.; Lemire, Isabelle; Leonard, Pierre; Boileau, Guy; Blond, Laurent; Beliveau, Martin; Cory, Esther; Sah, Robert L.; Whyte, Michael P.; Crine, Philippe; Millán, José Luis 2011-01-01 Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD10, renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2−/−) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2−/− mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2 mg/kg for 43 days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED80 (the dose prevents the bone defects in 80% of mice) was 3.2, 2.8 and 2.9 mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PPi concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials. PMID:21458605 354. Bone as a Possible Target of Chemical Toxicity of Natural Uranium in Drinking Water PubMed Central Kurttio, Päivi; Komulainen, Hannu; Leino, Aila; Salonen, Laina; Auvinen, Anssi; Saha, Heikki 2005-01-01 Uranium accumulates in bone, affects bone metabolism in laboratory animals, and when ingested in drinking water increases urinary excretion of calcium and phosphate, important components in the bone structure. However, little is known about bone effects of ingested natural uranium in humans. We studied 146 men and 142 women 26–83 years of age who for an average of 13 years had used drinking water originating from wells drilled in bedrock, in areas with naturally high uranium content. Biochemical indicators of bone formation were serum osteocalcin and amino-terminal propeptide of type I procollagen, and a marker for bone resorption was serum type I collagen carboxy-terminal telopeptide (CTx). The primary measure of uranium exposure was uranium concentration in drinking water, with additional information on uranium intake and uranium concentration in urine. The data were analyzed separately for men and women with robust regression (which suppresses contributions of potential influential observations) models with adjustment for age, smoking, and estrogen use. The median uranium concentration in drinking water was 27 μg/L (interquartile range, 6–116 μg/L). The median of daily uranium intake was 36 μg (7–207 μg) and of cumulative intake 0.12 g (0.02–0.66 g). There was some suggestion that elevation of CTx (p = 0.05) as well as osteocalcin (p = 0.19) could be associated with increased uranium exposure (uranium in water and intakes) in men, but no similar relationship was found in women. Accordingly, bone may be a target of chemical toxicity of uranium in humans, and more detailed evaluation of bone effects of natural uranium is warranted. PMID:15626650 355. Cost-Effectiveness Analysis of Single Fraction of Stereotactic Body Radiation Therapy Compared With Single Fraction of External Beam Radiation Therapy for Palliation of Vertebral Bone Metastases SciTech Connect Kim, Hayeon; Rajagopalan, Malolan S.; Beriwal, Sushil; Huq, M. Saiful; Smith, Kenneth J. 2015-03-01 Purpose: Stereotactic body radiation therapy (SBRT) has been proposed for the palliation of painful vertebral bone metastases because higher radiation doses may result in superior and more durable pain control. A phase III clinical trial (Radiation Therapy Oncology Group 0631) comparing single fraction SBRT with single fraction external beam radiation therapy (EBRT) in palliative treatment of painful vertebral bone metastases is now ongoing. We performed a cost-effectiveness analysis to compare these strategies. Methods and Materials: A Markov model, using a 1-month cycle over a lifetime horizon, was developed to compare the cost-effectiveness of SBRT (16 or 18 Gy in 1 fraction) with that of 8 Gy in 1 fraction of EBRT. Transition probabilities, quality of life utilities, and costs associated with SBRT and EBRT were captured in the model. Costs were based on Medicare reimbursement in 2014. Strategies were compared using the incremental cost-effectiveness ratio (ICER), and effectiveness was measured in quality-adjusted life years (QALYs). To account for uncertainty, 1-way, 2-way and probabilistic sensitivity analyses were performed. Strategies were evaluated with a willingness-to-pay (WTP) threshold of $100,000 per QALY gained. Results: Base case pain relief after the treatment was assumed as 20% higher in SBRT. Base case treatment costs for SBRT and EBRT were $9000 and $1087, respectively. In the base case analysis, SBRT resulted in an ICER of $124,552 per QALY gained. In 1-way sensitivity analyses, results were most sensitive to variation of the utility of unrelieved pain; the utility of relieved pain after initial treatment and median survival were also sensitive to variation. If median survival is ≥11 months, SBRT cost <$100,000 per QALY gained. Conclusion: SBRT for palliation of vertebral bone metastases is not cost-effective compared with EBRT at a $100,000 per QALY gained WTP threshold. However, if median survival is ≥11 months, SBRT costs ≤$100 356. Cost-Effectiveness Analysis of Single Fraction of Stereotactic Body Radiation Therapy Compared With Single Fraction of External Beam Radiation Therapy for Palliation of Vertebral Bone Metastases SciTech Connect Kim, Hayeon, E-mail:
[email protected]; Rajagopalan, Malolan S.; Beriwal, Sushil 2015-03-01 Purpose: Stereotactic body radiation therapy (SBRT) has been proposed for the palliation of painful vertebral bone metastases because higher radiation doses may result in superior and more durable pain control. A phase III clinical trial (Radiation Therapy Oncology Group 0631) comparing single fraction SBRT with single fraction external beam radiation therapy (EBRT) in palliative treatment of painful vertebral bone metastases is now ongoing. We performed a cost-effectiveness analysis to compare these strategies. Methods and Materials: A Markov model, using a 1-month cycle over a lifetime horizon, was developed to compare the cost-effectiveness of SBRT (16 or 18 Gy in 1 fraction)more » with that of 8 Gy in 1 fraction of EBRT. Transition probabilities, quality of life utilities, and costs associated with SBRT and EBRT were captured in the model. Costs were based on Medicare reimbursement in 2014. Strategies were compared using the incremental cost-effectiveness ratio (ICER), and effectiveness was measured in quality-adjusted life years (QALYs). To account for uncertainty, 1-way, 2-way and probabilistic sensitivity analyses were performed. Strategies were evaluated with a willingness-to-pay (WTP) threshold of $100,000 per QALY gained. Results: Base case pain relief after the treatment was assumed as 20% higher in SBRT. Base case treatment costs for SBRT and EBRT were $9000 and $1087, respectively. In the base case analysis, SBRT resulted in an ICER of $124,552 per QALY gained. In 1-way sensitivity analyses, results were most sensitive to variation of the utility of unrelieved pain; the utility of relieved pain after initial treatment and median survival were also sensitive to variation. If median survival is ≥11 months, SBRT cost <$100,000 per QALY gained. Conclusion: SBRT for palliation of vertebral bone metastases is not cost-effective compared with EBRT at a $100,000 per QALY gained WTP threshold. However, if median survival is ≥11 months, SBRT costs â 357. Neoadjuvant chemotherapy (NCT) plus targeted agents versus NCT alone in colorectal liver metastases patients: A systematic review and meta-analysis. PubMed Cui, Chun-Hui; Huang, Shu-Xin; Qi, Jia; Zhu, Hui-Juan; Huang, Zong-Hai; Yu, Jin-Long 2015-12-22 To assess the efficacy of neoadjuvant chemotherapy (NCT) plus targeted agents versus NCT alone for the treatment of colorectal liver metastases (CRLM) patients. Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). All clinical studies were independently identified by two authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), hepatic resection and R0 hepatic resection rate were extracted and analyzed using Comprehensive MetaAnalysis software (Version 2.0). A total of 40 cohorts with 2099 CRLM patients were included: 962 patients were treated with NCT alone, 602 with NCT plus anti-epidermal growth-factor receptor (EGFR)-monoclonal antibodies (MoAbs) and 535 with NCT plus bevacizumab. Pooled ORR was significantly higher for NCT plus bevacizumab or anti-EGFR-MoAbs than NCT alone [relative risk (RR) 1.53, 95% CI 1.30-1.80; p < 0.001; RR 1.53, 95% CI: 1.27-1.83, p < 0.001; respectively]. NCT plus bevacizumab significantly improved R0 hepatic resection rate (RR 1.61, 95% CI: 1.27-2.04, p < 0.001), but not for overall hepatic resection rate (RR 1.26, 95% CI: 0.81-1.94, p = 0.30). While hepatic resection and R0 hepatic resection rate was comparable between NCT plus anti-EGFR-MoAbs and NCT alone (p = 0.42 and p = 0.37, respectively). In comparison with NCT alone, NCT plus bevacizumab significantly improve ORR and R0 hepatic resection rate but not for hepatic resection rate. Our findings support the need to compare NCT plus bevacizumab with NCT alone in the neoadjuvant setting in large prospective trials due to its higher hepatic resection rate and R0 hepatic resection rate in CRLM patients. 358. Magnetic resonance-guided focused ultrasound surgery for treatment of painful osseous metastases NASA Astrophysics Data System (ADS) Hurwitz, Mark; Machtinger, Ronit; Fennessy, Fiona 2011-03-01 Magnetic resonance guided focused ultrasound surgery (MRgFUS) is an emerging technology that can non-invasively heat and ablate targeted tissue utilizing ultrasound energy. Use of MR imaging for treatment guidance provides several key advantages over more widely used ultrasound guidance for focused ultrasound ablation. MR allows for precise targeting, detailed beam path visualization, real time non-invasive temperature measurement, and treatment feedback to ensure therapeutic goals are achieved. In the realm of oncology, management of painful bone metastases is a common and daunting clinical problem. The Insightec ExAblate System has been shown in phase I/II trials for treatment of bone metastases to have an excellent safety profile and high rates of pain response. An international multi-center phase III trial for patients with painful bone metastases or multiple myeloma who are not candidates for radiation therapy is currently open. Patients are randomized 3:1 to MRgFUS or sham treatment with crossover to study treatment allowed for sham failures. The primary study endpoint is assessment of pain control over 3 months following treatment. In addition safety, quality of life, cost effectiveness analysis, and patient perceived clinical benefit are also being assessed. Details of the MRgFUS system, technical and clinical therapeutic parameters, use of real time non-invasive MR thermometry, and examples of patient treatments with use of MRgFUS to treat bone metastases will be discussed. New directions in use of MRgFUS including an update on development of a new mobile applicator and integration of MRgFUS in multimodality oncologic care will also be presented. 359. Normal Collagen and Bone Production by Gene-targeted Human Osteogenesis Imperfecta iPSCs PubMed Central Deyle, David R; Khan, Iram F; Ren, Gaoying; Wang, Pei-Rong; Kho, Jordan; Schwarze, Ulrike; Russell, David W 2012-01-01 Osteogenesis imperfecta (OI) is caused by dominant mutations in the type I collagen genes. In principle, the skeletal abnormalities of OI could be treated by transplantation of patientspecific, bone-forming cells that no longer express the mutant gene. Here, we develop this approach by isolating mesenchymal cells from OI patients, inactivating their mutant collagen genes by adeno-associated virus (AAV)-mediated gene targeting, and deriving induced pluripotent stem cells (iPSCs) that were expanded and differentiated into mesenchymal stem cells (iMSCs). Gene-targeted iMSCs produced normal collagen and formed bone in vivo, but were less senescent and proliferated more than bone-derived MSCs. To generate iPSCs that would be more appropriate for clinical use, the reprogramming and selectable marker transgenes were removed by Cre recombinase. These results demonstrate that the combination of gene targeting and iPSC derivation can be used to produce potentially therapeutic cells from patients with genetic disease. PMID:22031238 360. Animal Models of Bone Metastasis PubMed Central Rosol, Thomas J.; Tannehill-Gregg, Sarah H.; LeRoy, Bruce E.; Mandl, Stefanie; Contag, Christopher H. 2011-01-01 vascular patterns in the metaphyses of long bones and rapid bone turnover in young animals in the pathogenesis of metastasis in experimental models are uncertain. Improvements in the imaging of experimental animals in vivo using fluorescent markers or light emitted from luciferase have led to increased sensitivity of detection and more accurate quantification of bone metastases. For example, imaging of human prostate carcinoma PC-3M cells transfected with luciferase, following injection into the left ventricle, has demonstrated that there is rapid localization of tumor cells to bones and other organs, such as the kidneys and lungs. CONCLUSIONS Animal models of metastasis have supported drug development and have been useful for identification of metastasis suppressor and promoter genes as novel targets for the development of novel therapies. Further refinement of these models will involve spatiotemporal analysis of the metastatic process by imaging and use of image data to stage disease and guide tissue sampling for gene expression profiling via gene array technology. In the future, integrated analyses of these models will be needed to understand the complexities of this important disease process. PMID:15043188 « 16 17 18 19 20 » « 17 18 19 20 21 » 361. [Lymph node and distant metastases of thyroid gland cancer. Metastases in the thyroid glands]. PubMed Schmid, K W 2015-11-01 The different biological features of the various major entities of thyroid cancer, e.g. papillary, follicular, poorly differentiated, anaplastic and medullary, depend to a large extent on their different metastatic spread. Papillary thyroid cancer (PTC) has a propensity for cervical lymphatic spread that occurs in 20-50 % of patients whereas distant metastasis occurs in < 5 % of cases. Cervical lymphadenopathy may be the first symptom particularly of (micro) PTC. In contrast follicular thyroid cancer (FTC) has a marked propensity for vascular but not lymphatic invasion and 10-20 % of FTC develop distant metastases. At the time of diagnosis approximately one third of medullary thyroid cancer (MTC) cases show lymph node metastases, in 10-15 % distant metastases and 25 % develop metastases during the course of the disease. Poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) spread via both lymphatic and vascular invasion. Thus distant metastases are relatively uncommon in DTC and when they occur, long-term stable disease is the typical clinical course. The major sites of distant metastases are the lungs and bone. Metastases to the brain, breasts, liver, kidneys, muscle and skin are relatively rare or even rare. The thyroid gland itself can be a site of metastases from a variety of other tumors. In autopsy series of patients with disseminated cancer disease, metastases to the thyroid gland were found in up to 10 % of cases. Metastases from other primary tumors to the thyroid gland have been reported in 1.4-3 % of patients who have surgery for suspected cancer of the thyroid gland. The most common primary cancers that metastasize to the thyroid gland are renal cell (48.1 %), colorectal (10.4 %), lung (8.3 %) and breast cancer (7.8 %) and surprisingly often sarcomas (4.0 %). 362. Feasibility and performance of novel software to quantify metabolically active volumes and 3D partial volume corrected SUV and metabolic volumetric products of spinal bone marrow metastases on 18F-FDG-PET/CT. PubMed Torigian, Drew A; Lopez, Rosa Fernandez; Alapati, Sridevi; Bodapati, Geetha; Hofheinz, Frank; van den Hoff, Joerg; Saboury, Babak; Alavi, Abass 2011-01-01 Our aim was to assess feasibility and performance of novel semi-automated image analysis software called ROVER to quantify metabolically active volume (MAV), maximum standardized uptake value-maximum (SUV(max)), 3D partial volume corrected mean SUV (cSUV(mean)), and 3D partial volume corrected mean MVP (cMVP(mean)) of spinal bone marrow metastases on fluorine-18 fluorodeoxyglucose-positron emission tomography/computerized tomography ((18)F-FDG-PET/CT). We retrospectively studied 16 subjects with 31 spinal metastases on FDG-PET/CT and MRI. Manual and ROVER determinations of lesional MAV and SUV(max), and repeated ROVER measurements of MAV, SUV(max), cSUV(mean) and cMVP(mean) were made. Bland-Altman and correlation analyses were performed to assess reproducibility and agreement. Our results showed that analyses of repeated ROVER measurements revealed MAV mean difference (D)=-0.03±0.53cc (95% CI(-0.22, 0.16)), lower limit of agreement (LLOA)=-1.07cc, and upper limit of agreement (ULOA)=1.01cc; SUV(max) D=0.00±0.00 with LOAs=0.00; cSUV(mean) D=-0.01±0.39 (95% CI(-0.15, 0.13)), LLOA=-0.76, and ULOA=0.75; cMVP(mean) D=-0.52±4.78cc (95% CI(-2.23, 1.23)), LLOA=-9.89cc, and ULOA=8.86cc. Comparisons between ROVER and manual measurements revealed volume D= -0.39±1.37cc (95% CI (-0.89, 0.11)), LLOA=-3.08cc, and ULOA=2.30cc; SUV(max) D=0.00±0.00 with LOAs=0.00. Mean percent increase in lesional SUV(mean) and MVP(mean) following partial volume correction using ROVER was 84.25±36.00% and 84.45±35.94% , respectively. In conclusion, it is feasible to estimate MAV, SUV(max), cSUV(mean), and cMVP(mean) of spinal bone marrow metastases from (18)F-FDG-PET/CT quickly and easily with good reproducibility via ROVER software. Partial volume correction is imperative, as uncorrected SUV(mean) and MVP(mean) are significantly underestimated, even for large lesions. This novel approach has great potential for practical, accurate, and precise combined structural-functional PET 363. High-fat diet enhances and monocyte chemoattractant protein-1 deficiency reduces bone loss in mice with pulmonary metastases of Lewis lung carcinoma USDA-ARS?s Scientific Manuscript database Bone is adversely affected by metastasis and metastasis-associated complications. Obesity is a risk factor for both bone and cancer. Adipose tissue is an endocrine organ that produces pro-inflammatory adipokines, such as monocyte chemotactic protein-1 (MCP-1), that contribute to obesity and obesit... 364. Identification of Rorβ targets in cultured osteoblasts and in human bone SciTech Connect Roforth, Matthew M. Khosla, Sundeep Monroe, David G. 2013-11-01 Highlights: •We examine the gene expression patterns controlled by Rorβ in osteoblasts. •Genes involved in extracellular matrix regulation and proliferation are affected. †¢Rorβ mRNA levels increase in aged, human bone biopsies. •Rorβ may affect osteoblast activity by modulation of these pathways. -- Abstract: Control of osteoblastic bone formation involves the cumulative action of numerous transcription factors, including both activating and repressive functions that are important during specific stages of differentiation. The nuclear receptor retinoic acid receptor-related orphan receptor β (Rorβ) has been recently shown to suppress the osteogenic phenotype in cultured osteoblasts, and is highly upregulated in bone marrow-derived osteogenic precursors isolated from aged osteoporotic mice, suggesting Rorβ is an important regulator of osteoblast function. However the specific gene expression patterns elicited by Rorβ are unknown. Using microarray analysis, we identified 281 genes regulated by Rorβ in an MC3T3-E1 mouse osteoblast cell model (MC3T3-Rorβ-GFP). Pathway analysis revealed alterations in genes involved in MAPK signaling, genes involved in extracellular matrix (ECM) regulation, and cytokine-receptor interactions. Whereas the identified Rorβ-regulated ECM genes normally decline during osteoblastic differentiation, they were highly upregulated in this nonmineralizing MC3T3-Rorβ-GFP model system, suggesting that Rorβ may exert its anti-osteogenic effects through ECM disruption. Consistent with these in vitro findings, the expression of both RORβ and a subset of RORβ-regulated genes were increased in bone biopsies from postmenopausal women (73 ± 7 years old) compared to premenopausal
women (30 ± 5 years old), suggesting a role for RORβ in human age-related bone loss. Collectively, these data demonstrate that Rorβ regulates known osteogenic pathways, and may represent a novel therapeutic target for age-associated bone loss. 365. Tumor-expressed adrenomedullin accelerates breast cancer bone metastasis. PubMed Siclari, Valerie A; Mohammad, Khalid S; Tompkins, Douglas R; Davis, Holly; McKenna, C Ryan; Peng, Xianghong; Wessner, Lisa L; Niewolna, Maria; Guise, Theresa A; Suvannasankha, Attaya; Chirgwin, John M 2014-12-02 osteoclast activity. The results identify AM as a target for therapeutic intervention against bone metastases. Adrenomedullin potentiates osteolytic responses in bone to metastatic breast cancer cells. Small-molecule antagonists can effectively block bone-mediated responses to tumor-secreted adrenomedullin, and such agents warrant development for testing in vivo. 366. Lung cancer-derived Dickkopf1 is associated with bone metastasis and the mechanism involves the inhibition of osteoblast differentiation SciTech Connect Chu, Tianqing; Teng, Jiajun; Jiang, Liyan; Zhong, Hua; Han, Baohui 2014-01-17 Highlights: •DKK1 level was associated with NSCLC bone metastases. •Lung tumor cells derived DKK1 inhibited osteoblast differentiation. •Lung tumor cells derived DKK1 modulates β-catenin and RUNX2. -- Abstract: Wnt/β-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferably metastasizes to skeleton. But the role of them in bone dissemination is poorly understood. This study aims to define the role of DKK1 in lung cancer bone metastases and investigate the underlying mechanism. Our results demonstrated that DKK1 over-expression was a frequent event in non-small-cell lung cancer (NSCLC) blood samples, and serous DKK1 level was much higher in bone metastatic NSCLC compared to non-bone metastatic NSCLC. We also found that conditioned medium from DKK1 over-expressing lung cancer cells inhibited the differentiation of osteoblast, determined by alkaline phosphatase activity and osteocalcin secretion, whereas the conditioned medium from DKK1 silencing lung cancer cells exhibited the opposite effects. Mechanistically, DKK1 reduced the level of β-catenin and RUNX2, as well as inhibiting the nuclear translocation of β-catenin. Taken together, these results suggested that lung cancer-produced DKK1 may be an important mechanistic link between NSCLC and bone metastases, and targeting DKK1 may be an effective method to treat bone metastase of NSCLC. 367. Novel targets for the prevention of osteoporosis - lessons learned from studies of metabolic bone disorders. PubMed Henriksen, Kim; Thudium, Christian Schneider; Christiansen, Claus; Karsdal, Morten Asser 2015-01-01 Osteoporosis is a major health care problem, and whereas efficacious treatments for vertebral fracture reduction are available for osteoporosis patients, these therapies are still limited with respect to capacity for restoration of bone loss, as well as efficacy on non-vertebral fractures, such as hip fractures, which are the source of morbidity and mortality. Studies of rare bone diseases in humans, such as osteopetrosis, sclerosteosis, pycnodysostosis and more, have shed light on a series of drug targets in bone that have the potential to result in therapies for osteoporosis with novel mechanisms of action, and the potential to improve the standard of care substantially. We focus on how they are separated from classic treatments for osteoporosis, in terms of novel modes of action, additional beneficial effects on bone turnover and importantly also safety. We focus on the status of anti-sclerostin antibodies, novel parathyroid hormone-related protein analogs, inhibitors of cathepsin K and ClC-7 in osteoclasts, all of which are currently in development. There is a good possibility that the treatment of osteoporosis will be greatly improved within the coming years; however, with numerous effective and safe drugs already available careful attention to the safety of these novel candidates is crucial. 368. Bone as target organ for metals: the case of f-elements. PubMed Vidaud, Claude; Bourgeois, Damien; Meyer, Daniel 2012-06-18 The skeleton is a target organ for most metals. This leads to their bioaccumulation, either as storage of useful oligoelements or as a protection against damage by toxic elements. The different events leading to their accumulation in this organ, under constant remodeling, are not fully understood, nor the full subsequent impact on bone metabolism. This lack of knowledge is particularly true for lanthanides and actinides, whose use has been increasing over recent decades. These metals, known as f-elements, present chemical similarities and differences. After a comparison of the biologically relevant physicochemical properties of lanthanides and actinides, and a brief reminder of the main events of bone metabolism, this review considers the results published over the past decade regarding the interaction between bones and f-elements. Emphasis will be given to the molecular events, which constitute the basis of the most recent toxicological studies in this domain but still need further investigation. Ionic exchanges with the inorganic matrix, interactions with bone proteins, and cellular mechanism disturbances are mainly considered in this review. 369. Reliability of the Bony Anatomy in Image-Guided Stereotactic Radiotherapy of Brain Metastases SciTech Connect Guckenberger, Matthias; Baier, Kurt; Guenther, Iris 2007-09-01 Purpose: To evaluate whether the position of brain metastases remains stable between planning and treatment in cranial stereotactic radiotherapy (SRT). Methods and Materials: Eighteen patients with 20 brain metastases were treated with single-fraction (17 lesions) or hypofractionated (3 lesions) image-guided SRT. Median time interval between planning and treatment was 8 days. Before treatment a cone-beam CT (CBCT) and a conventional CT after application of i.v. contrast were acquired. Setup errors using automatic bone registration (CBCT) and manual soft-tissue registration of the brain metastases (conventional CT) were compared. Results: Tumor size was not significantly different between planning and treatment. The three-dimensionalmore » setup error (mean {+-} SD) was 4.0 {+-} 2.1 mm and 3.5 {+-} 2.2 mm according to the bony anatomy and the lesion itself, respectively. A highly significant correlation between automatic bone match and soft-tissue registration was seen in all three directions (r {>=} 0.88). The three-dimensional distance between the isocenter according to bone match and soft-tissue registration was 1.7 {+-} 0.7 mm, maximum 2.8 mm. Treatment of intracranial pressure with steroids did not influence the position of the lesion relative to the bony anatomy. Conclusion: With a time interval of approximately 1 week between planning and treatment, the bony anatomy of the skull proved to be an excellent surrogate for the target position in image-guided SRT.« less 370. Improved detection of bone metastases from lung cancer in the thoracic cage using 5- and 1-mm axial images versus a new CT software generating rib unfolding images: comparison with standard ¹â¸F-FDG-PET/CT. PubMed Homann, Georg; Mustafa, Deedar F; Ditt, Hendrik; Spengler, Werner; Kopp, Hans-Georg; Nikolaou, Konstantin; Horger, Marius 2015-04-01 To evaluate the performance of a dedicated computed tomography (CT) software called "bone reading" generating rib unfolded images for improved detection of rib metastases in patients with lung cancer in comparison to readings of 5- and 1-mm axial CT images and (18)F-Fluordeoxyglucose positron emission tomography/computed tomography (FDGPET/CT). Ninety consecutive patients who underwent (18)F-FDG-PET/CT and chest CT scanning between 2012 and 2014 at our institution were analyzed retrospectively. Chest CT scans with 5- and 1-mm slice thickness were interpreted blindly and separately focused on the detection of rib metastases (location, number, cortical vs. medullary, and osteoblastic vs. sclerotic). Subsequent image analysis of unfolded 1 mm-based CT rib images was performed. For all three data sets the reading time was registered. Finally, results were compared to those of FDG-PET. Validation was based on FDG-PET positivity for osteolytic and mixed osteolytic/osteoblastic focal rib lesions and follow-up for sclerotic PETnegative lesions. A total of 47 metastatic rib lesions were found on FDG-PET/CT plus another 30 detected by CT bone reading and confirmed by follow-up CT. Twenty-nine lesions were osteolytic, 14 were mixed osteolytic/osteoblastic, and 34 were sclerotic. On a patient-based analysis, CT (5 mm), CT (1 mm), and CT (1-mm bone reading) yielded a sensitivity, specificity, and accuracy of 76.5/97.3/93, 81.3/97.3/94, and 88.2/95.9/92, respectively. On segment-based (unfolded rib) analysis, the sensitivity, specificity, and accuracy of the three evaluations were 47.7/95.7/67, 59.5/95.8/77, and 94.8/88.2/92, respectively. Reading time for 5 mm/1 mm axial images and unfolded images was 40.5/50.7/21.56 seconds, respectively. The use of unfolded rib images in patients with lung cancer improves sensitivity and specificity of rib metastasis detection in comparison to 5- and 1-mm CT slice reading. Moreover, it may reduce the reading time. Copyright © 2015 AUR 371. Extraneural metastases of anaplastic oligodendroglial tumors. PubMed Volavsek, Metka; Lamovec, Janez; Popović, Mara 2009-01-01 Extraneural metastases of malignant gliomas are rare. According to the literature, they tend to appear in glioblastoma patients, but are exceptionally rare in anaplastic oligodendroglioma. We report on an anaplastic oligodendroglioma and an anaplastic oligoastrocytoma that metastasized to cervical lymph nodes and bones. Both patients were women aged 54 and 30 years, and the metastases appeared following craniotomy. In the first patient, metastases to cervical lymph nodes developed one year after surgery, and, despite adjuvant therapy, recurred in the same location several times. Fine needle aspiration biopsy (FNAB) of the cervical lymph node prior to neck dissection suggested a possible metastatic primitive neuroepithelial tumor. In the second case, metastases to the sacrum and femur developed after surgery for a recurrent anaplastic oligoastrocytoma. Our two cases reconfirm a rare but definite ability not only of glioblastoma but also of anaplastic oligodendroglioma, namely to metastasize to extraneural sites. It is important to bear this in mind, particularly in cases when the history of primary brain tumor is unavailable. In such instances, the correct diagnosis of the metastatic lesion may be extremely difficult if not impossible. 372. Designing calcium phosphate-based bifunctional nanocapsules with bone-targeting properties NASA Astrophysics Data System (ADS) Khung, Yit-Lung; Bastari, Kelsen; Cho, Xing Ling; Yee, Wu Aik; Loo, Say Chye Joachim 2012-06-01 Using sodium dodecyl sulphate micelles as template, hollow-cored calcium phosphate nanocapsules were produced. The surfaces of the nanocapsule were subsequently silanised by a polyethylene glycol (PEG)-based silane with an N-hydroxysuccinimide ester end groups which permits for further attachment with bisphosphonates (BP). Characterisations of these nanocapsules were investigated using Field Emission Scanning Electron Microscopy (FESEM), Transmission Electron Microscopy, Fourier Transform Infra-Red Spectroscopy, Xray diffraction, X-ray photoelectron spectroscopy and Dynamic Light Scattering. To further validate the bone-targeting potential, dentine discs were incubated with these functionalised nanocapsules. FESEM analysis showed that these surface-modified nanocapsules would bind strongly to dentine surfaces compared to non-functionalised nanocapsules. We envisage that respective components would give this construct a bifunctional attribute, whereby (1) the shell of the calcium phosphate nanocapsule would serve as biocompatible coating aiding in gradual osteoconduction, while (2) surface BP moieties, acting as targeting ligands, would provide the bone-targeting potential of these calcium phosphate nanocapsules. 373. Murine models of breast cancer bone metastasis PubMed Central Wright, Laura E; Ottewell, Penelope D; Rucci, Nadia; Peyruchaud, Olivier; Pagnotti, Gabriel M; Chiechi, Antonella; Buijs, Jeroen T; Sterling, Julie A 2016-01-01 Bone metastases cause significant morbidity and mortality in late-stage breast cancer patients and are currently considered incurable. Investigators rely on translational models to better understand the pathogenesis of skeletal complications of malignancy in order to identify therapeutic targets that may ultimately prevent and treat solid tumor metastasis to bone. Many experimental models of breast cancer bone metastases are in use today, each with its own caveats. In this methods review, we characterize the bone phenotype of commonly utilized human- and murine-derived breast cell lines that elicit osteoblastic and/or osteolytic destruction of bone in mice and report methods for optimizing tumor-take in murine models of bone metastasis. We then provide protocols for four of the most common xenograft and syngeneic inoculation routes for modeling breast cancer metastasis to the skeleton in mice, including the intra-cardiac, intra-arterial, orthotopic and intra-tibial methods of tumor cell injection. Recommendations for in vivo and ex vivo assessment of tumor progression and bone destruction are provided, followed by discussion of the strengths and limitations of the available tools and translational models that aid investigators in the study of breast cancer metastasis to bone. PMID:27867497 374. Animal Models of Bone Metastasis PubMed Central Simmons, J. K.; Hildreth, B. E.; Supsavhad, W.; Elshafae, S. M.; Hassan, B. B.; Dirksen, W. P.; Toribio, R. E.; Rosol, T. J. 2015-01-01 Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone. PMID:26021553 375. Magnetic resonance-guided focused ultrasound for the treatment of painful bone metastases: role of apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) MRI in the assessment of clinical outcome. PubMed Anzidei, Michele; Napoli, Alessandro; Sacconi, Beatrice; Boni, Fabrizio; Noce, Vincenzo; Di Martino, Michele; Saba, Luca; Catalano, Carlo 2016-12-01 To assess the correlation between functional MRI, including ADC values obtained from DWI and DCE, and clinical outcome in patients with bone metastases treated with MRgFUS. Twenty-three patients with symptomatic bone metastases underwent MRgFUS treatment (ExAblate 2100 system InSightec) for pain palliation. All patients underwent clinical and imaging follow-up examinations at 1, 3 and 6 months after treatment. Visual Analog Scale (VAS) score was used to evaluate treatment efficacy in terms of pain palliation while ADC maps obtained by DWI sequences, and DCE data were used for quantitative assessment of treatment response at imaging. Spearman Correlation Coefficient Test was calculated to assess the correlation between VAS, ADC and DCE data. All treatments were performed successfully without adverse events. On the basis of VAS score, 16 (69.6 %) patients were classified as complete clinical responders, 6 (26.1 %) as partial responders and only one (4.3 %) was classified as a non-responder. The mean VAS score decreased from 7.09 ± 1.8 at baseline to 2.65 ± 1.36 at 1 month, 1.04 ± 1.91 at 3 months and 1.09 ± 1.99 at 6 months (p < 0.001). Baseline mean ADC value of treated lesions was 1.05 ± 0.15 mm 2 /s, increasing along follow-up period (1.57 ± 0.27 mm 2 /s 1st month; 1.49 ± 0.3 mm 2 /s 3rd month; 1.45 ± 0.32 mm 2 /s 6th month, p < 0.001). Non perfused volume (NPV) was 46.4 at 1 month, 45.2 at 3 months and 43.8 at 6 months. Spearman Coefficient demonstrated a statistically significant negative correlation between VAS and ADC values (Ï = -0.684; p = 0.03), but no significant correlation between VAS and NPV (Ï = 0.02216, p = 0.9305). Among other DCE data, Ktrans significantly changed in complete responders (3 months Ktrans = 2.14/min; -ΔKt = 52.65 % p < 0.01) and was not significantly different in partial responders (3 months Ktrans 0.042/min; ΔKt = 11.39 % p > 0.01). In patients with painful bone 376. Challenging the current approaches to multiple myeloma-related bone disease: from bisphosphonates to target therapy. PubMed Tassone, P; Tagliaferri, P; Rossi, M; Calimeri, T; Bulotta, A; Abbruzzese, A; Caraglia, M; Neri, P 2009-11-01 Bone disease (BD) is the hall-mark clinical feature of multiple myeloma (MM), accounting up to 60% of patients with bone pain at diagnosis and 60% with a pathologic fracture during the course of their disease. Experimental models, which recapitulate in vivo the human bone marrow microenvironment (HBMM) in immunodeficient mice have been recently developed as valuable tool for the study of MM pathophysiology as well as the experimental treatment of BD. At present, bisphosphonates are the mainstay treatment of MM-related BD. The growing information on the cellular and molecular bases of BD as well as the availability of novel anti-resorptive agents, such as the IgG1-anti-RANKL (AMG 161) Denosumab, are now depicting a new scenario where the treatment will be afforded by the use of different agents. Furthermore the availability of highthroughput molecular profiling approaches, including DNA microarrays and proteomics, is likely to provide new platforms for patients stratification and treatment individualization on specific targets. It is now the right time for a therapeutical approach which is rationally based on the complexity of the biopathology of MM-related BD. 377. Development of Controlled Drug Delivery Systems for Bone Fracture-Targeted Therapeutic Delivery: A Review. PubMed Wang, Yuchen; Newman, Maureen R; Benoit, Danielle S W 2018-02-19 Impaired fracture healing is a major clinical problem that can lead to patient disability, prolonged hospitalization, and significant financial burden. Although the majority of fractures heal using standard clinical practices, approximately 10% suffer from delayed unions or non-unions. A wide range of factors contribute to the risk for nonunions including internal factors, such as patient age, gender, and comorbidities, and external factors, such as the location and extent of injury. Current clinical approaches to treat nonunions include bone grafts and low-intensity pulsed ultrasound (LIPUS), which realizes clinical success only to select patients due to limitations including donor morbidities (grafts) and necessity of fracture reduction (LIPUS), respectively. To date, therapeutic approaches for bone regeneration rely heavily on protein-based growth factors such as INFUSE, an FDA-approved scaffold for delivery of bone morphogenetic protein 2 (BMP-2). Small molecule modulators and RNAi therapeutics are under development to circumvent challenges associated with traditional growth factors. While preclinical success has shown promise experimentally, drug delivery has become a major hurdle stalling clinical translation. Therefore, this review overviews current therapies employed to stimulate fracture healing pre-clinically and clinically, including a focus on drug delivery systems for growth factors, parathyroid hormone (PTH), small molecules, and RNAi therapeutics, as well as recent advances and future promise of fracture-targeted drug delivery. Copyright © 2018. Published by Elsevier B.V. 378. Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models. PubMed Benito, Juliana; Ramirez, Marc S; Millward, Niki Zacharias; Velez, Juliana; Harutyunyan, Karine G; Lu, Hongbo; Shi, Yue-Xi; Matre, Polina; Jacamo, Rodrigo; Ma, Helen; Konoplev, Sergej; McQueen, Teresa; Volgin, Andrei; Protopopova, Marina; Mu, Hong; Lee, Jaehyuk; Bhattacharya, Pratip K; Marszalek, Joseph R; Davis, R Eric; Bankson, James A; Cortes, Jorge E; Hart, Charles P; Andreeff, Michael; Konopleva, Marina 2016-04-01 To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxiaactivated prodrug TH-302 in leukemia models. Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models. Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. ©2015 American Association for Cancer Research. 379. Single-fraction radiotherapy versus multifraction radiotherapy for palliation of painful vertebral bone metastases-equivalent efficacy, less toxicity, more convenient: a subset analysis of Radiation Therapy Oncology Group trial 97-14. PubMed Howell, David D; James, Jennifer L; Hartsell, William F; Suntharalingam, Mohan; Machtay, Mitchell; Suh, John H; Demas, William F; Sandler, Howard M; Kachnic, Lisa A; Berk, Lawrence B 2013-02-15 The Radiation Therapy Oncology Group (RTOG) trial 97-14 revealed no difference between radiation delivered for painful bone metastases at a dose of 8 gray (Gy) in 1 fraction (single-fraction radiotherapy [SFRT]) and 30 Gy in 10 fractions (multifraction radiotherapy [MFRT]) in pain relief or narcotic use 3 months after randomization. SFRT for painful vertebral bone metastases (PVBM) has not been well accepted, possibly because of concerns about efficacy and toxicity. In the current study, the authors evaluated the subset of patients that was treated specifically for patients with PVBM. PVBM included the cervical, thoracic, and/or lumbar spine regions. Among patients with PVBM, differences in retreatment rates and in pain relief, narcotic use, and toxicity 3 months after randomization were evaluated. Of 909 eligible patients, 235 (26%) had PVBM. Patients with and without PVBM differed in terms of the percentage of men (55% vs 47%, respectively; P = .03) and the proportion of patients with multiple painful sites (57% vs 38%, respectively; P < .01). Among those with PVBM, more patients who received MFRT had multiple sites treated (65% vs 49% for MFRT vs SFRT, respectively; P = .02). There were no statistically significant treatment differences in terms of pain relief (62% vs 70% for MFRT vs SFRT, respectively; P = .59) or freedom from narcotic use (24% vs 27%, respectively; P = .76) at 3 months. Significant differences in acute grade 2 through 4 toxicity (20% vs 10% for MFRT vs SFRT, respectively; P = .01) and acute grade 2 through 4 gastrointestinal toxicity (14% vs 6%, respectively; P = .01) were observed at 3 months, with lower toxicities seen in the patients treated with SFRT. Late toxicity was rare. No myelopathy was recorded. SFRT produced higher 3-year retreatment rates (5% vs 15%; P = .01). Results for the subset of patients with PVBM in the RTOG 94-17 randomized controlled trial were comparable to those for the entire population. SFRT produced less acute 380. Alendronate-decorated biodegradable polymeric micelles for potential bone-targeted delivery of vancomycin. PubMed Cong, Yingying; Quan, Changyun; Liu, Meiqing; Liu, Jie; Huang, Gang; Tong, Guoquan; Yin, Yihua; Zhang, Chao; Jiang, Qing 2015-01-01 Osteomyelitis is a bone infection disease which is caused by bacteria or other germs, and could cause serious impact on the health and working capacity of the patients. Alendronate (ALN) can chelate strongly with the calcium ion of hydroxyapatite (HA) which is commonly used to treat osteoporosis. Nanomedicine has attracted a lot of attention in that the nanosized carrier can deliver drug molecules to specific site of interest with the aid of targeting moiety and achieve sustained release, resulting in improved therapeutic effect and reduced side effect. In this study, micelles self-assembled from poly(lactic acid-co-glycolic acid)-block-poly(ethylene glycol)-alendronate (PLGA-PEG-ALN) copolymer were prepared for bone-targeted delivery of vancomycin (Van). The chemical structure of PLGA-PEG-ALN was confirmed by proton nuclear magnetic resonance ((1)H-NMR) spectroscopy. The formation of the nanoparticles was characterized by dynamic light scattering, transmission electronic microscopy as well as the critical micelle concentration measurement. Release profiles from the micelles revealed that the conjugation of ALN to the surface of micelle did not pose adverse effect on the drug-loading capacity and release behaviors. The cytotoxicity of Van-loaded PLGA-PEG-ALN micelles as well as the blank micelles was evaluated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay toward rat bone marrow stromal cells (rBMSCs) and human embryonic hepatocytes (L02 cells), and results showed that this Van-loaded micelle possesses appropriate cytotoxicity and is safe in the potential treatment of osteomyelitis. The in vitro affinity of PLGA-PEG-ALN micelles to the HA was also confirmed in vitro. The antibacterial effect of Van-loaded PLGA-PEGALN micelles was tested against Staphylococcus aureus (SA) which is the main pathogenic bacteria in osteomyelitis, and the results showed that the Van-loaded micelles can effectively inhibit the growth of SA. These results « 17 18 19 20 21 » « 18 19 20 21 22 » 381. Aspartic acid-based modified PLGA-PEG nanoparticles for bone targeting: in vitro and in vivo evaluation. PubMed Fu, Yin-Chih; Fu, Tzu-Fun; Wang, Hung-Jen; Lin, Che-Wei; Lee, Gang-Hui; Wu, Shun-Cheng; Wang, Chih-Kuang 2014-11-01 Nanoparticles (NP) that target bone tissue were developed using PLGA-PEG (poly(lactic-co-glycolic acid)-polyethylene glycol) diblock copolymers and bone-targeting moieties based on aspartic acid, (Asp)(n(1,3)). These NP are expected to enable the transport of hydrophobic drugs. The molecular structures were examined by (1)H NMR or identified using mass spectrometry and Fourier transform infrared (FT-IR) spectra. The NP were prepared using the water miscible solvent displacement method, and their size characteristics were evaluated using transmission electron microscopy (TEM) and dynamic light scattering. The bone targeting potential of the NP was evaluated in vitro using hydroxyapatite affinity assays and in vivo using fluorescent imaging in zebrafish and rats. It was confirmed that the average particle size of the NP was <200 nm and that the dendritic Asp3 moiety of the PLGA-PEG-Asp3 NP exhibited the best apatite mineral binding ability. Preliminary findings in vivo bone affinity assays in zebrafish and rats indicated that the PLGA-PEG-ASP3 NP may display increased bone-targeting efficiency compared with other PLGA-PEG-based NP that lack a dendritic Asp3 moiety. These NP may act as a delivery system for hydrophobic drugs, warranting further evaluation of the treatment of bone disease. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. 382. Upregulation of Claudin-4, CAIX and GLUT-1 in distant breast cancer metastases. PubMed Jiwa, Laura S; van Diest, Paul J; Hoefnagel, Laurien D; Wesseling, Jelle; Wesseling, Pieter; Moelans, Cathy B 2014-11-22 Several studies have shown that the immunophenotype of distant breast cancer metastases may differ significantly from that of the primary tumor, especially with regard to differences in the level of hormone receptor protein expression, a process known as receptor conversion. This study aimed to compare expression levels of several membrane proteins between primary breast tumors and their corresponding distant metastases in view of their potential applicability for molecular imaging and drug targeting. Expression of Claudin-4, EGFR, CAIX, GLUT-1 and IGF1R was assessed by immunohistochemistry on tissue microarrays composed of 97 paired primary breast tumors and their distant (non-bone) metastases. In both the primary cancers and the metastases, Claudin-4 was most frequently expressed, followed by GLUT-1, CAIX and EGFR.From primary breast cancers to their distant metastases there was positive to negative conversion, e.g. protein expression in the primary tumor with no expression in its paired metastasis, in 6%, 19%, 12%, 38%, and 0% for Claudin-4 (n.s), GLUT-1 (n.s), CAIX (n.s), EGFR (n.s) and IGF1R (n.s) respectively. Negative to positive conversion was seen in 65%, 47%, 43%, 9% and 0% of cases for Claudin-4 (p = 0.049), GLUT-1 (p = 0.024), CAIX (p = 0.002), EGFR (n.s.) and IGF1R (n.s.) respectively. Negative to positive conversion of Claudin-4 in the metastasis was significantly associated with tumor size (p = 0.015), negative to positive conversion of EGFR with negative PR status (p = 0.046) and high MAI (p = 0.047) and GLUT-1 negative to positive conversion with (neo)adjuvant chemotherapy (p = 0.039) and time to metastasis formation (p = 0.034). CAIX and GLUT-1 expression in the primary tumor were significantly associated with high MAI (p = 0.008 and p = 0.038 respectively). Claudin-4 is frequently expressed in primary breast cancers but especially in their metastases and is thereby an attractive membrane bound molecular imaging and drug target. Conversion in 383. Emerging Treatments for Choroidal Metastases PubMed Central Chen, Connie J.; McCoy, Allison N.; Brahmer, Julie; Handa, James T. 2015-01-01 It has been over a century since Perls described the first case of choroidal metastasis. For the next six decades only 230 cases were described in the literature. Today, however, ocular metastasis is recognized as the most common intraocular malignancy. Thanks to recent advances in treatment options for metastatic disease, patients are living longer, and choroidal metastases will become an increasingly important issue for oncologists and ophthalmologists alike. We summarize the current knowledge of choroidal metastases and examine their emerging systemic and local therapies. Targeted therapies for metastatic lung, breast, and colon cancer—the most common causes of choroidal metastases—are reviewed in detail with the goal of identifying the most effective treatment strategies. PMID:22117885 384. Targeting gene expression during the early bone healing period in the mandible: A base for bone tissue engineering. PubMed Beck-Broichsitter, Benedicta E; Werk, Anneke N; Smeets, Ralf; Gröbe, Alexander; Heiland, Max; Cascorbi, Ingolf; Wiltfang, Jörg; Häsler, Robert; Becker, Stephan T 2015-10-01 Although bone tissue engineering techniques have become more and more sophisticated than in the past, natural bone healing mechanisms have not been sufficiently considered for further improvement of these techniques so far. We used an established animal model with transcriptome analysis to generate an unbiased picture of early bone healing to support tissue engineering concepts. In 30 Wistar rats, a 3-mm bone defect was created in the mandibular angle. Tissue was sampled at 5, 10, and 15 days, and the former defect area was excised to undergo transcriptome analysis after RNA extraction. Five differentially expressed genes were further evaluated with reverse transcription-polymerase chain reaction (rt-
PCR). Transcriptome analysis revealed 2467 significantly over- and under-expressed transcripts after 5 days and 2265 after 15 days of bone healing, respectively. Validation via rtPCR confirmed overexpression of osteoactivin, angiopoietin-like factor-4, and metallomatrix proteinase-9 and underexpression of mastcellprotease-10 and proteoglycane-2 in comparison to values in the control group. This systematic genome-wide transcriptome analysis helps to decipher the physiological mechanisms behind physiological bone healing. The exemplary depiction of 5 genes demonstrates the great complexity of metabolic processes during early bone healing. Here, BMP-2 signaling pathways and local hypoxia play decisive roles in bone formation. Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved. 385. The RANKL/RANK system as a therapeutic target for bone invasion by oral squamous cell carcinoma (Review). PubMed Jimi, Eijiro; Shin, Masashi; Furuta, Hiroyuki; Tada, Yukiyo; Kusukawa, Jingo 2013-03-01 Squamous cell carcinomas (SCCs) of the gingiva frequently invade the mandible or maxilla; this invasion is associated with a worse prognosis. The bone destruction associated with carcinomal invasion is mediated by osteoclasts rather than directly by the carcinoma. Therefore, if the cellular and molecular mechanisms by which oral SCC regulates bone invasion were known, it could inform the development of new therapeutic targets. Recently, dysregulation of the functional equilibrium in the receptor activator of NF-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) triad has been shown to be responsible for osteolysis associated with the development of malignant tumors in bone sites. Furthermore, the administration of OPG or soluble RANK prevents bone metastasis by cancer cells. In this review, we discuss recent findings indicating that bone invasion by oral SCC is mediated via RANKL/RANK and may be successfully prevented by RANKL inhibition. 386. Targeting A-type K(+) channels in primary sensory neurons for bone cancer pain in a rat model. PubMed Duan, Kai-Zheng; Xu, Qian; Zhang, Xiao-Meng; Zhao, Zhi-Qi; Mei, Yan-Ai; Zhang, Yu-Qiu 2012-03-01 Cancer pain is one of the most severe types of chronic pain, and the most common cancer pain is bone cancer pain. The treatment of bone cancer pain remains a clinical challenge. Here, we report firstly that A-type K(+) channels in dorsal root ganglion (DRG) are involved in the neuropathy of rat bone cancer pain and are a new target for diclofenac, a nonsteroidal anti-inflammatory drug that can be used for therapy for this distinct pain. There are dynamically functional changes of the A-type K(+) channels in DRG neurons during bone cancer pain. The A-type K(+) currents that mainly express in isolectin B4-positive small DRG neurons are increased on post-tumor day 14 (PTD 14), then faded but still remained at a higher level on PTD 21. Correspondingly, the expression levels of A-type K(+) channel Kv1.4, Kv3.4, and Kv4.3 showed time-dependent changes during bone cancer pain. Diclofenac enhances A-type K(+) currents in the DRG neurons and attenuates bone cancer pain in a dose-dependent manner. The analgesic effect of diclofenac can be reversed or prevented by A-type K(+) channel blocker 4-AP or pandinotoxin-Kα, also by siRNA targeted against rat Kv1.4 or Kv4.3. Repeated diclofenac administration decreased soft tissue swelling adjacent to the tumor and attenuated bone destruction. These results indicate that peripheral A-type K(+) channels were involved in the neuropathy of rat bone cancer pain. Targeting A-type K(+) channels in primary sensory neurons may provide a novel mechanism-based therapeutic strategy for bone cancer pain. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. 387. Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration. PubMed Stiers, Pieter-Jan; van Gastel, Nick; Carmeliet, Geert 2016-09-05 Bone tissue engineering is a promising therapeutic alternative for bone grafting of large skeletal defects. It generally comprises an ex vivo engineered combination of a carrier structure, stem/progenitor cells and growth factors. However, the success of these regenerative implants largely depends on how well implanted cells will adapt to the hostile and hypoxic host environment they encounter after implantation. In this review, we will discuss how hypoxia signalling may be used to improve bone regeneration in a tissue-engineered construct. First, hypoxia signalling induces angiogenesis which increases the survival of the implanted cells as well as stimulates bone formation. Second, hypoxia signalling has also angiogenesis-independent effects on mesenchymal cells in vitro, offering exciting new possibilities to improve tissue-engineered bone regeneration in vivo. In addition, studies in other fields have shown that benefits of modulating hypoxia signalling include enhanced cell survival, proliferation and differentiation, culminating in a more potent regenerative implant. Finally, the stimulation of endochondral bone formation as a physiological pathway to circumvent the harmful effects of hypoxia will be briefly touched upon. Thus, angiogenic dependent and independent processes may counteract the deleterious hypoxic effects and we will discuss several therapeutic strategies that may be combined to withstand the hypoxia upon implantation and improve bone regeneration. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved. 388. (123)I-BZA2 as a melanin-targeted radiotracer for the identification of melanoma metastases: results and perspectives of a multicenter phase III clinical trial. PubMed Cachin, Florent; Miot-Noirault, Elisabeth; Gillet, Brigitte; Isnardi, Vanina; Labeille, Bruno; Payoux, Pierre; Meyer, Nicolas; Cammilleri, Serge; Gaudy, Caroline; Razzouk-Cadet, Micheline; Lacour, Jean Philippe; Granel-Brocard, Florence; Tychyj, Christelle; Benbouzid, Fathalah; Grange, Jean Daniel; Baulieu, Françoise; Kelly, Antony; Merlin, Charles; Mestas, Danielle; Gachon, Françoise; Chezal, Jean Michel; Degoul, Françoise; D'Incan, Michel 2014-01-01 Our group has developed a new radiopharmaceutical, (123)I - N-(2-diethylaminoethyl)-2-iodobenzamide ((123)I-BZA2), a benzamide derivative able to bind to melanin pigment in melanoma cells. In a prospective and multicentric phase III clinical study, the value of (18)F-FDG PET/CT and (123)I-BZA2 scintigraphy was compared for melanoma staging. Patients with a past history of cutaneous or ocular melanoma were included from 8 hospitals. (18)F-FDG imaging was performed according to a standard PET protocol. Whole-body, static planar, and SPECT/CT (if available) images were acquired 4 h after injection of a 2 MBq/kg dose of (123)I-BZA2. (18)F-FDG and (123)I-BZA2 sensitivity and specificity for the diagnosis of melanoma metastasis were calculated and compared on both a lesion basis and a patient basis. True-positive and true-negative lesion status was determined after 6 mo of clinical follow-up or according to lesion biopsies (if available). Melanin content in biopsies was evaluated with the standard Fontana-Masson silver method and was correlated with (123)I-BZA2 uptake. Based on statistical analysis, the number of inclusions was estimated at 186. In all, 87 patients were enrolled from 2008 to 2010. Of these, 45 (52%) had metastases. A total of 338 imaging abnormalities were analyzed; 86 lesions were considered metastases, and 20 of 25 lesion biopsies found melanoma metastases. In a patient-based analysis, the sensitivity of (18)F-FDG for diagnosis of melanoma metastases was higher than that of (123)I-BZA2, at 87% and 39%, respectively (P < 0.05). For specificity, (18)FFDG and (123)I-BZA2 were not statistically different, at 78% and 94%, respectively. In a lesion-based analysis, the sensitivity of (18)F-FDG was statistically higher than that of (123)I-BZA2 (80% vs. 23%, P < 0.05). The specificity of (18)F-FDG was lower than that of (123)I-BZA2 (54% vs. 86%, P < 0.05). According to biopsy analysis, only 9 of 20 metastatic lesions (45%) were pigmented with high melanin 389. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. PubMed Langdahl, Bente; Ferrari, Serge; Dempster, David W 2016-12-01 The adult skeleton is renewed by remodeling throughout life. Bone remodeling is a process where osteoclasts and osteoblasts work sequentially in the same bone remodeling unit. After the attainment of peak bone mass, bone remodeling is balanced and bone mass is stable for one or two decades until age-related bone loss begins. Age-related bone loss is caused by increases in resorptive activity and reduced bone formation. The relative importance of cortical remodeling increases with age as cancellous bone is lost and remodeling activity in both compartments increases. Bone modeling describes the process whereby bones are shaped or reshaped by the independent action of osteoblast and osteoclasts. The activities of osteoblasts and osteoclasts are not necessarily coupled anatomically or temporally. Bone modeling defines skeletal development and growth but continues throughout life. Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at the long bones with aging. Existing and upcoming treatments affect remodeling as well as modeling. Teriparatide stimulates bone formation, 70% of which is remodeling based and 20-30% is modeling based. The vast majority of modeling represents overflow from remodeling units rather than de novo modeling. Denosumab inhibits bone remodeling but is permissive for modeling at cortex. Odanacatib inhibits bone resorption by inhibiting cathepsin K activity, whereas modeling-based bone formation is stimulated at periosteal surfaces. Inhibition of sclerostin stimulates bone formation and histomorphometric analysis demonstrated that bone formation is predominantly modeling based. The bone-mass response to some osteoporosis treatments in humans certainly suggests that nonremodeling mechanisms contribute to this response and bone modeling may be such a mechanism. To date, this has only been demonstrated for teriparatide, however, it is clear that 390. WISP1/CCN4: A Potential Target for Inhibiting Prostate Cancer Growth and Spread to Bone PubMed Central Sonn, Robert; Kilts, Tina M.; de Castro, Luis F.; Maeda, Azusa; Fisher, Larry W.; Robey, Pamela G.; Berendsen, Agnes D.; Li, Li; McCartney-Francis, Nancy; Brown, Aaron C.; Crawford, Nigel P. S.; Molinolo, Alfredo; Jain, Alka; Fedarko, Neal S.; Young, Marian F. 2013-01-01 Prostate cancer (PC) is a leading cause of death in men however the factors that regulate its progression and eventual metastasis to bone remain unclear. Here we show that WISP1/CCN4 expression in prostate cancer tissues was up-regulated in early stages of the disease and, further, that it correlated with increased circulating levels of WISP1 in the sera of patients at early stages of the disease. WISP1 was also elevated in the mouse prostate cancer model TRAMP in the hypoplastic diseased tissue that develops prior to advanced carcinoma formation. When the ability of anti-WISP1 antibodies to reduce the spread of PC3-Luc cells to distant sites was tested it showed that twice weekly injections of antiWISP1 antibodies reduced the number and overall size of distant tumors developed after intracardiac (IC) injection of PC3-Luc cells in mice. The ability of antibodies against WISP1 to inhibit growth of PC3-Luc cancer cells in mice was also evaluated and showed that twice weekly injections of anti-WISP1 antibodies reduced local tumor growth when examined in xenografts. To better understand the mechanism of action, the migration of PC3-Luc cells through membranes with or without a Matrigelâ„¢ barrier showed the cells were attracted to WISP1, and that this attraction was inhibited by treatment with anti-WISP1 antibodies. We also show the expression of WISP1 at the bone-tumor interface and in the stroma of early grade cancers suggested WISP1 expression is well placed to play roles in both fostering growth of the cancer and its spread to bone. In summary, the up-regulation of WISP1 in the early stages of cancer development coupled with its ability to inhibit spread and growth of prostate cancer cells makes it both a potential target and an accessible diagnostic marker for prostate cancer. PMID:23977121 391. Indian hedgehog gene is a target of the bone morphogenetic protein signaling pathway. PubMed Seki, Kenji; Hata, Akiko 2004-04-30 Bone morphogenetic proteins (BMPs), a large subgroup of the transforming growth factor-beta family of growth factors, are key mediators of many fundamental processes in embryonic development. The BMP target genes mediating these effects and the mechanism of their selective regulation are poorly characterized. In this study, we used a chromatin immunoprecipitation-based gene cloning method to identify BMP target genes in a mouse embryonic carcinoma cell line. We identified the Indian hedgehog (Ihh) gene as a target of BMP signaling. Both reporter and reverses transcription-PCR assays revealed that Ihh is up-regulated in embryonic cells upon BMP treatment. The BMP response element of the Ihh promoter contains multiple GC-rich motifs known as the "Mad/Medea binding box" found in the Drosophila tinman gene and in the mouse Id1 gene. DNA binding studies revealed that Smad4 binds to these GC-rich motifs. These findings indicate that BMP stimulates Ihh expression. We also suggest expression of the Ihh gene, which contains multiple Smad binding sites, might be finely regulated by a gradient of BMP concentrations. 392. Bone metastasis and the metastatic niche PubMed Central Ren, Guangwen; Esposito, Mark; Kang, Yibin 2015-01-01 The bone marrow has been long known to host a unique environment amenable to colonization by metastasizing tumor cells. Yet, the underlying molecular interactions within this specialized microenvironment which give rise to the high incidence of bone metastasis in breast and prostate cancer patients have long remained uncharacterized. With the recent description of the bone metastatic “niche,†considerable focus has been placed on understanding how the bone stroma contributes to each step of metastasis. Discoveries within this field have demonstrated that when cancer cells home to the niche in which hematopoietic and mesenchymal stem/progenitor cells normally reside, a bidirectional crosstalk emerges between the tumor cells and the bone metastatic stroma. This communication modulates every step of cancer cell metastasis to the bone, including the initial homing and seeding, formation of micrometastases, outgrowth of macrometastases, and the maintenance of long-term dormancy of disseminated tumor cells in bone. In clinical practice, targeting the bone metastatic niche is evolving into a promising avenue for the prevention of bone metastatic relapse, therapeutic resistance, and other aspects of cancer progression. Here, we review the current knowledge concerning the role of the bone metastatic niche in bone metastasis. PMID:26275789 393. Development of a bone targeted thermosensitive liposomal doxorubicin formulation based on a bisphosphonate modified non-ionic surfactant. PubMed Song, Heliang; Zhang, Jiabing; Liu, Xinrong; Deng, Tongming; Yao, Peng; Zhou, Shaobing; Yan, Weili 2016-09-01 Bone is among the most common sites of metastasis in cancer patients, so it is an urgent need to develop drug delivery systems targeting tumor bone metastasis with the feature of controlled release. This study aimed to delivery of thermosensitive liposomal doxorubicin to bone for tumor metastasis treatment. First, Brij78 (polyoxyethylene stearyl ether) was conjugated with Pamidronate (Pa). By incorporating Pa-Brij78 to DPPC/Chol liposomes, we developed Pa surface functionalized liposomes. The Pa-Brij78/DPPC/Chol liposomes (PB-liposomes) exhibited a stronger binding affinity to hydroxyapatite (HA), a major component of bone, than Brij78/DPPC/Chol liposomes (B-liposomes). Doxorubicin (Dox) was then encapsulated in PB-liposomes and the results demonstrated complete release of Dox from PB-liposomes or the complex of HA/PB-liposomes within 10 min at 42 °C. Next, human lung cancer A549 cells were treated with the thermosensitive complex of HA/PB-liposomes/Dox to mimic tumor bone metastasis treatment through bone targeted delivery of therapeutic agents. Pre-incubation of HA/PB-liposomes/Dox with mild heat at 42 °C induced subsequent higher cytotoxicity to A549 cells than incubation of the same complex at 37 °C, suggesting more active drug release triggered by heat. In conclusion, we synthesized a novel surfactant Pa-Brij78 and it has the potential to be used for development of a bone targeted thermosensitive liposome formulation for treatment of tumor bone metastasis. 394. Development of imaging probes for bone cancer in animal models. A systematic review. PubMed Fernandes, Renata Salgado; Dos Santos Ferreira, Diego; de Aguiar Ferreira, Carolina; Giammarile, Francesco; Rubello, Domenico; de Barros, André Luis Branco 2016-10-01 Bone is a dynamic tissue that is constantly remodeled throughout the lifetime to ensure the integrity of the skeleton. Primary cancer cells disseminate into circulation, often extravasating to bone, where they interact with the bone marrow to grow and proliferate, disrupting the bone homeostasis. Although primary bone tumors account for less than 0.2% of all cancers, bone is a common site for the development of metastases, as its microenvironment provides the necessary conditions for the growth and proliferation of cancer cells. Metastases to the skeletal system are observed in up to 70% of all cancer patients and the growth of disseminated tumor metastases is a major cause of mortality. As widely known, a non-invasive diagnosis of bone tumors at early stages is of great importance to provide insights that will help on the decision of therapy regimen, improving treatment outcomes. Early diagnosis of bone metastases is also an important step for establishing palliative care as they may cause serious endocrine, hematologic, neurologic and orthopedic complications as well as intolerable pain. Therefore, development of new imaging techniques, imaging moieties, and animal models to mimic these bone conditions, play an important role in improving the clinical outcome of this disease. In this review, we will briefly describe the advantages and disadvantages of the currently available imaging techniques that aim at identifying bone tumors. In addition, we will provide an update on the animal models applicable at mimicking bone tumor characteristics, as well as describe recent advances on the development of new imaging probes, in the preclinical settings including targeted nanoparticles and radiopharmaceuticals. Copyright © 2016 Elsevier Masson SAS. All rights reserved. 395. [Radiotherapy for brain metastases]. PubMed Latorzeff, I; Antoni, D; Gaudaire-Josset, S; Feuvret, L; Tallet-Richard, A; Truc, G; Noël, G 2016-09-01 Radiotherapy for brain metastases has become more multifaceted. Indeed, with the improvement of the patient's life expectancy, side effects must be undeniably avoided and the retreatments or multiple treatments are common. The cognitive side effects should be warned and the most modern techniques of radiation therapy are used regularly to reach this goal. The new classifications of patients with brain metastases help guiding treatment more appropriately. Stereotactic radiotherapy has supplanted whole brain radiation therapy both for patients with metastases in place and for those who underwent surgery. Hippocampus protection is possible with intensity-modulated radiotherapy. Its relevance in terms of cognitive functioning should be more clearly demonstrated but the requirement, for using it, is increasingly strong. While addressing patients in palliative phase, the treatment of brain metastases is one of the localisations where technical thinking is the most challenging. Copyright © 2016. Published by Elsevier SAS. 396. Distinct bone morphogenetic proteins activate indistinguishable transcriptional responses in nephron epithelia including Notch target genes. PubMed Larman, Barry W; Karolak, Michele J; Lindner, Volkhard; Oxburgh, Leif 2012-01-01 Endogenous Bone Morphogenetic Protein (BMP) signaling plays a significant role in the kidney's recovery from acute injury and exogenous administration of BMP7 has therapeutic potential in numerous rodent models of renal injury and disease. However, in the healthy kidney endogenous BMP7 ligand is vigorously counteracted by extracellular antagonists such as USAG1 and CHRDL1. Little is known about the degree of BMP signaling and the ligands driving it in the healthy adult kidney. In this study we characterize basal BMP signaling in the healthy tubular nephron, and show that BMP2 is expressed in proximal nephron epithelial cells. Comparative gene profiling of proximal tubule cell responses to BMP2 and BMP7 does not reveal any qualitative difference, suggesting that identical BMP gene targets may be activated in healthy and injured organs. Interestingly, our gene profiling analysis shows that BMP signaling activates a number of Notch regulated transcription factors, including HEY1. As in other biological systems, HEY1 functions as a negative feedback regulator of BMP2 expression in the proximal tubule. In summary, this work reveals endogenous BMP signaling patterns in the healthy human and mouse kidneys, and identifies novel gene targets, some of which are involved in the complex regulation of BMP signaling in the adult kidney. Copyright © 2011 Elsevier Inc. All rights reserved. 397. Distinct Bone Morphogenetic Proteins activate indistinguishable transcriptional responses in nephron epithelia including Notch target genes PubMed Central Larman, Barry W.; Karolak, Michele J.; Lindner, Volkhard; Oxburgh, Leif 2011-01-01 Endogenous Bone Morphogenetic Protein (BMP) signaling plays a significant role in the kidney’s recovery from acute injury and exogenous administration of BMP7 has therapeutic potential in numerous rodent models of renal injury and disease. However, in the healthy kidney endogenous BMP7 ligand is vigorously counteracted by extracellular antagonists such as USAG1 and CHRDL1. Little is known about the degree of BMP signaling and the ligands driving it in the healthy adult kidney. In this study we characterize basal BMP signaling in the healthy tubular nephron, and show that BMP2 is expressed in proximal nephron epithelial cells. Comparative gene profiling of proximal tubule cell responses to BMP2 and BMP7 does not reveal any qualitative difference, suggesting that identical BMP gene targets may be activated in healthy and injured organs. Interestingly, our gene profiling analysis shows that BMP signaling activates a number of Notch regulated transcription factors, including HEY1. As in other biological systems, HEY1 functions as a negative feedback regulator of BMP2 expression in the proximal tubule. In summary, this work reveals endogenous BMP signaling patterns in the healthy human and mouse kidney, and identifies novel gene targets, some of which are involved in the complex regulation of BMP signaling in the adult kidney. PMID:21945409 398. Therapeutic Targeting of TRPV1 for the Treatment of Chronic Pain Associated with Prostate Cancer Bone Metastasis DTIC Science & Technology 2013-07-30 1 AD_________________ Award Number: W81XWH-11-1-0333 TITLE: Therapeutic Targeting of TRPV1 for the...TITLE AND SUBTITLE Therapeutic Targeting of TRPV1 for the Treatment of Chronic Pain 5a. CONTRACT NUMBER Associated with Prostate Cancer Bone...specific inflammatory factors, IL-6 and TNF-α, PTHrP and ET-1 on upregulation of TRPV1 channel function/expression, and nociceptor sensitization 399. Prostate-specific membrane antigen (PSMA) expression in breast cancer and its metastases. PubMed Kasoha, Mariz; Unger, Clara; Solomayer, Erich-Franz; Bohle, Rainer M; Zaharia, Claudia; Khreich, Fadi; Wagenpfeil, Stefan; Juhasz-Böss, Ingolf 2018-02-10 The present study was undertaken to investigate the expression of prostate-specific membrane antigen (PSMA) in normal breast tissues, in cancerous breast tissues and in distant metastases from patients with breast cancer. Immunohistochemical analysis was performed to determine PSMA expression and angiogenic activity using anti-PSMA mAb and antiCD31 mAb respectively. Immunofluorescence staining was applied to confirm the exact co-localization of PSMA and CD31. We observed different patterns of PSMA expression between normal and cancerous tissues. Normal breast tissues showed PSMA expression only in normal glandular cells. However, primary breast tumors and distant metastases showed PSMA expression in tumor cells and in tumor-associated neovasculature. PSMA score group status in primary breast tumors was significantly associated with histologic type and tumor grade (p = 0.026 and p = 0.004 respectively). Distant metastases showed higher PSMA expression in tumor-associated neovasculature comparing with primary tumors. Moreover, brain tumor-associated neovasculture had significantly higher expression of PSMA comparing with bone tumor-associated neovasculture. The localized binding of PSMA mAb to the neovasculature endothelium was confirmed with the double Immunofluorescence staining. 68 Ga-PSAM imaging of a patient with metastatic breast cancer showed strong tracer uptake in all known skeletal metastases. To the best of our knowledge, this study is the second one that has assessed PSMA expression in a large number of breast cancer patients. Our findings showed that PSMA is particularly expressed in tumor-associated neovasculature of breast tumors and its distant metastases, thus enhancing the evidence on the potential usefulness of PSMA as a therapeutic vascular target. 400. An Approach for the Identification of Targets Specific to Bone Metastasis Using Cancer Genes Interactome and Gene Ontology Analysis PubMed Central Vashisht, Shikha; Bagler, Ganesh 2012-01-01 Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a ‘Cancer Genes Network’, a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of ‘Cancer Genes Network’, have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer. PMID:23166660 « 18 19 20 21 22 » « 19 20 21 22 23 » 401. Targeted delivery of rhBMP-2 Improves Bone Formation in Type I Diabetes PubMed Central de Santana, Ronaldo Barcellos; Trackman, Phillip C. 2015-01-01 Purpose Bone formation and healing are diminished in experimental type I diabetes. The present study investigated whether controlled local release of a Bone Morphogenetic Protein (rhBMP-2) stimulates bone defect healing in diabetes, due to its anabolic effects on bone. Material and Methods Bilateral experimental circular bone defects were created in the temporal bones of 64 BALB/cByJ mice. Defects were treated with acellular collagen sponges (ACS), 0.4 µg or 1.8 µg of rhBMP-2 per defect, while untreated defects served as controls. The effects of rhBMP-2 on calvaria defect healing over a 14 day healing period in diabetic and non-diabetic mice were determined histomorphometrically. Results Diabetes inhibited bone formation in both untreated and BMP-treated bone defects. Controlled local release of rhBMP-2 significantly stimulates bone formation in diabetic animals to near normal levels, and enhances bone regeneration in normal animals. Conclusions rhBMP-2 may be beneficial in treating deficient intramembranous bone formation in diabetes. PMID:26009923 402. Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial. PubMed Parker, Christopher C; Coleman, Robert E; Sartor, Oliver; Vogelzang, Nicholas J; Bottomley, David; Heinrich, Daniel; Helle, Svein I; O'Sullivan, Joe M; FossÃ¥, Sophie D; Chodacki, AleÅ¡; Wiechno, PaweÅ‚; Logue, John; Seke, Mihalj; Widmark, Anders; Johannessen, Dag Clement; Hoskin, Peter; James, Nicholas D; Solberg, Arne; Syndikus, Isabel; Kliment, Jan; Wedel, Steffen; Boehmer, Sibylle; Dall'Oglio, Marcos; Franzén, Lars; Bruland, Øyvind S; Petrenciuc, Oana; Staudacher, Karin; Li, Rui; Nilsson, Sten 2017-07-10 In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment. To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection. Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr. All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics. During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary nontreatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up. Final long-term safety 403. Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference-based bone anabolic strategy. PubMed Liang, Chao; Guo, Baosheng; Wu, Heng; Shao, Ningsheng; Li, Defang; Liu, Jin; Dang, Lei; Wang, Cheng; Li, Hui; Li, Shaohua; Lau, Wing Ki; Cao, Yu; Yang, Zhijun; Lu, Cheng; He, Xiaojuan; Au, D W T; Pan, Xiaohua; Zhang, Bao-Ting; Lu, Changwei; Zhang, Hongqi; Yue, Kinman; Qian, Airong; Shang, Peng; Xu, Jiake; Xiao, Lianbo; Bian, Zhaoxiang; Tan, Weihong; Liang, Zicai; He, Fuchu; Zhang, Lingqiang; Lu, Aiping; Zhang, Ge 2015-03-01 Currently, major concerns about the safety and efficacy of RNA interference (RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific delivery systems for osteogenic siRNAs. Here we screened the aptamer CH6 by cell-SELEX, specifically targeting both rat and human osteoblasts, and then we developed CH6 aptamerfunctionalized lipid nanoparticles (LNPs) encapsulating osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA (CH6-LNPs-siRNA). Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 gene silencing, which promoted bone formation, improved bone microarchitecture, increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents. These results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level. 404. Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference–based bone anabolic strategy PubMed Central Liang, Chao; Guo, Baosheng; Wu, Heng; Shao, Ningsheng; Li, Defang; Liu, Jin; Dang, Lei; Wang, Cheng; Li, Hui; Li, Shaohua; Lau, Wing Ki; Cao, Yu; Yang, Zhijun; Lu, Cheng; He, Xiaojuan; Au, DWT; Pan, Xiaohua; Zhang, Bao-Ting; Lu, Changwei; Zhang, Hongqi; Yue, Kinman; Qian, Airong; Shang, Peng; Xu, Jiake; Xiao, Lianbo; Bian, Zhaoxiang; Tan, Weihong; Liang, Zicai; He, Fuchu; Zhang, Lingqiang; Lu, Aiping; Zhang, Ge 2017-01-01
Currently, major concerns about the safety and efficacy of RNA interference (RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific delivery systems for osteogenic siRNAs. Here we screened the aptamer CH6 by cell-SELEX, specifically targeting both rat and human osteoblasts, and then we developed CH6 aptamerâ €“functionalized lipid nanoparticles (LNPs) encapsulating osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA (CH6-LNPs-siRNA). Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 gene silencing, which promoted bone formation, improved bone microarchitecture, increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents. These results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level. PMID:25665179 405. DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo PubMed Central Isaac, J; Erthal, J; Gordon, J; Duverger, O; Sun, H-W; Lichtler, A C; Stein, G S; Lian, J B; Morasso, M I 2014-01-01 Human mutations and in vitro studies indicate that DLX3 has a crucial function in bone development, however, the in vivo role of DLX3 in endochondral ossification has not been established. Here, we identify DLX3 as a central attenuator of adult bone mass in the appendicular skeleton. Dynamic bone formation, histologic and micro-computed tomography analyses demonstrate that in vivo DLX3 conditional loss of function in mesenchymal cells (Prx1-Cre) and osteoblasts (OCN-Cre) results in increased bone mass accrual observed as early as 2 weeks that remains elevated throughout the lifespan owing to increased osteoblast activity and increased expression of bone matrix genes. Dlx3OCN-conditional knockout mice have more trabeculae that extend deeper in the medullary cavity and thicker cortical bone with an increased mineral apposition rate, decreased bone mineral density and increased cortical porosity. Trabecular TRAP staining and site-specific Q-PCR demonstrated that osteoclastic resorption remained normal on trabecular bone, whereas cortical bone exhibited altered osteoclast patterning on the periosteal surface associated with high Opg/Rankl ratios. Using RNA sequencing and chromatin immunoprecipitation-Seq analyses, we demonstrate that DLX3 regulates transcription factors crucial for bone formation such as Dlx5, Dlx6, Runx2 and Sp7 as well as genes important to mineral deposition (Ibsp, Enpp1, Mepe) and bone turnover (Opg). Furthermore, with the removal of DLX3, we observe increased occupancy of DLX5, as well as increased and earlier occupancy of RUNX2 on the bone-specific osteocalcin promoter. Together, these findings provide novel insight into mechanisms by which DLX3 attenuates bone mass accrual to support bone homeostasis by osteogenic gene pathway regulation. PMID:24948010 406. Lung cancer-derived Dickkopf1 is associated with bone metastasis and the mechanism involves the inhibition of osteoblast differentiation. PubMed Chu, Tianqing; Teng, Jiajun; Jiang, Liyan; Zhong, Hua; Han, Baohui 2014-01-17 Wnt/β-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferably metastasizes to skeleton. But the role of them in bone dissemination is poorly understood. This study aims to define the role of DKK1 in lung cancer bone metastases and investigate the underlying mechanism. Our results demonstrated that DKK1 over-expression was a frequent event in non-small-cell lung cancer (NSCLC) blood samples, and serous DKK1 level was much higher in bone metastatic NSCLC compared to non-bone metastatic NSCLC. We also found that conditioned medium from DKK1 over-expressing lung cancer cells inhibited the differentiation of osteoblast, determined by alkaline phosphatase activity and osteocalcin secretion, whereas the conditioned medium from DKK1 silencing lung cancer cells exhibited the opposite effects. Mechanistically, DKK1 reduced the level of β-catenin and RUNX2, as well as inhibiting the nuclear translocation of β-catenin. Taken together, these results suggested that lung cancer-produced DKK1 may be an important mechanistic link between NSCLC and bone metastases, and targeting DKK1 may be an effective method to treat bone metastase of NSCLC. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved. 407. Extraneural metastases of medulloblastoma: desmoplastic variants may have prolonged survival. PubMed Young, Robert J; Khakoo, Yasmin; Yhu, Stephen; Wolden, Suzanne; De Braganca, Kevin C; Gilheeney, Stephen W; Dunkel, Ira J 2015-04-01 Extraneural metastases from CNS medulloblastoma are rare and poorly described. The purpose of this study is to describe the clinical and radiological characteristics of a large single institution series of patients with medulloblastoma who developed extraneural metastases. We retrospectively reviewed a departmental database over a 20 year period for all patients with medulloblastoma who developed extraneural metastases. Chart and imaging reviews were performed, and overall survival (OS) estimated by the Kaplan-Meier method. We found 14 patients with medulloblastoma and extraneural metastases. The median age at initial diagnosis was 16.3 years (range, 3.2-44.2), and the most common subtype was desmoplastic (n = 6, 42.9%). After initial gross total resection, most patients received radiation therapy alone (n = 10, 71.4%). Metastases to bone were most common (n = 11, 78.6%) followed by metastases to bone marrow (n = 6, 42.9%), usually to the spine. The median time from initial diagnosis to first extraneural metastasis was 1.5 years (range, 0.2-17.4), and the median OS from extraneural metastasis to death was 3.3 years (range, 0-18). The Kaplan-Meier estimate of 5 year OS from extraneural metastasis diagnosis was 40.0% (95% CI, 20.2-79.2). Extraneural metastases from medulloblastoma may rarely develop after initial diagnosis to involve bone and bone marrow. We found that desmoplastic variant extraneural tumors had longer survival than nondesmoplastic variants, suggesting that histopathological and more recent molecular subtyping have important roles in determining the prognosis of medulloblastoma patients. © 2014 Wiley Periodicals, Inc. 408. Stereotactic Radiosurgery for Treatment of Brain Metastases. PubMed Badiyan, Shahed N; Regine, William F; Mehta, Minesh 2016-08-01 Brain metastases are the most common intracranial malignancy. Incidence of brain metastases has risen as systemic therapies have improved and patients with metastatic disease live longer. Whole-brain radiation therapy, for many years, has been the standard treatment approach. Stereotactic radiosurgery has become an increasingly popular option because of its relatively short, convenient, and noninvasive treatment course. Although recently published data have renewed interest in use of whole-brain radiation therapy or systemic therapies for control of micrometastatic disease, stereotactic radiosurgery continues to be an important modality, capable of delivering ablative doses of radiation for long-term control of macroscopic disease. The purpose of this review is to explore the different paradigms for incorporation of stereotactic radiosurgery into management of brain metastases. Current uses for stereotactic radiosurgery include delivery as a boost with whole-brain radiation therapy; alone for patients with a limited number of brain metastases; in pre- or postoperative settings; and in combination with systemic, targeted, and immune-based therapies. Mature prospective data on use of stereotactic radiosurgery in combination with whole-brain radiation therapy is available; however, prospective, randomized data on stereotactic radiosurgery for patients with a greater number of brain metastases, its use in pre- and postoperative settings, and its use in combination with systemic therapies are limited. Data from ongoing and future studies are needed to define the appropriate use of stereotactic radiosurgery in these settings. Copyright © 2016 by American Society of Clinical Oncology. 409. A novel bone targeting delivery system carrying phytomolecule icaritin for prevention of steroid-associated osteonecrosis in rats. PubMed Chen, Shihui; Zheng, Lizhen; Zhang, Jiayong; Wu, Heng; Wang, Nan; Tong, Wenxue; Xu, Jiankun; Huang, Le; Zhang, Yifeng; Yang, Zhijun; Lin, Ge; Wang, Xinluan; Qin, Ling 2018-01-01 One of the effective strategies for prevention of steroid-associated osteonecrosis (SAON) is to inhibit bone resorption and fat formation and promote bone formation at osteonecrotic sensitive skeletal sites. We identified a novel phytomolecule that showed positive effects on osteogenesis, anti-bone resorption and anti-adipogenesis in vitro and also developed a bone-targeting delivery system (BTDS) for in vivo experimental study. The study investigated if our innovative synthesized BTDS carrying this phytomolecule would be able to effectively prevent SAON in a rat model. SAON was induced by combined injections of lipopolysaccharide and methylprednisolone. SAON rats were divided into four groups, one SAON untreated control group and three SAON treatment groups with different types of delivery systems (Asp8-liposome-icaritin, liposome-icaritin and Asp8-liposome) for two weeks. SAON lesions were identified and osteoclasts activity, osteogenesis and adipogenesis at these sites were evaluated by immunohistochemistry. Ex vitro study was also designed to evaluate the osteogenic and adipogenic potential of the isolated bone marrow stromal cells (BMSCs) via real-time PCR and histochemical staining. Our results showed that as a bone surface-specific BTDS, Asp8-liposome-icaritin effectively prevented steroids-treated rats from SAON with significantly decreased osteocytes apoptosis, downregulated osteoclatsogenesis and up-regulated osteogenesis. However, both liposome-icaritin and Asp8-liposome treatment did not show significant efficacy for SAON prevention. In summary, this proof-concept-study showed for the first time that the innovative Asp8-liposome-icaritin BTDS was effective for prevention of SAON in terms of bone resorption prevention, adipogenesis suppression, and bone-formation enhancement. Copyright © 2017 Elsevier Inc. All rights reserved. 410. Results of thoracotomy in osteogenic sarcoma with pulmonary metastases. PubMed Central Carter, S R; Grimer, R J; Sneath, R S; Matthews, H R 1991-01-01 BACKGROUND Resection of pulmonary metastases may be followed by long term survival and now that it is an accepted method of treatment for patients with osteogenic sarcoma indicators of favourable prognosis are needed to aid the assessment of suitability for resection. This study compares the survival rates of patients who did and did not undergo resection of their pulmonary metastases and relates them to prognostic indicators. METHODS The study population was the 43 patients with osteosarcoma who developed pulmonary metastases out of the 111 patients with osteosarcoma treated by the Birmingham bone tumour treatment service during 1977-83. All patients who developed metastases confined to the lungs were considered for resection, thoracotomy being advised for all patients (provided that they were fit enough) who had metastases thought to be resectable even if they were multiple. RESULTS Of the 18 patients who did not have a thoracotomy, 15 died of disseminated disease after a mean interval of eight months; one patient died of cardiomyopathy and two are alive after 26 and eight months. Of the 25 patients who underwent thoracotomy in an attempt to resect metastases, three were found to have inoperable disease and died after a mean interval of 5.4 months from thoracotomy. Overall, after thoracotomy (repeated if necessary) there was a 20% survival at five years from the first thoracotomy. When survival was assessed with respect to the disease free interval and the number and bilaterality of the metastases no significant relationships were found. There was, however, a significant relation between survival and the position of metastases, patients with metastases confined to one lobe of the lung having a mean survival of 29.5 months, compared with 13.7 months in patients with disease in more than one lobe. CONCLUSION Thus patients who had a thoracotomy survived longer from the time of diagnosis of pulmonary metastasis than those not undergoing thoracotomy; metastases 411. Skin metastases from lung cancer: a case report. PubMed Pajaziti, Laura; Hapçiu, Syzana Rexhepi; Dobruna, Shkendije; Hoxha, Naim; Kurshumliu, Fisnik; Pajaziti, Artina 2015-04-11 Lung cancer is one of the most frequent malignancies, with high mortality rates. It can metastasize in almost all organs, but more often invades hilar nodes, liver, adrenal glands, bones and brain. There are various data on the incidence of lung cancer metastases in the skin. In 1-12% of patients with lung cancer are developed skin metastases. Metastases in the skin may be the first sign of lung cancer. Forty-five years old Albanian male, smoker, was admitted to our department with multiple nodules localized in the skin of the head, neck, back and chest. The nodules measuring 5-15 millimeters in greatest dimension were round and skin-colored, with telangiectasias, firm and tender. They appeared in an eruptive form about two weeks before being admitted at our hospital. In addition, the patient exhibited signs of weight loss, anorexia and fatigue. Excisional biopsy was performed to one of the lesions. Histopathology confirmed metastatic nature of the lesion namely, malignant tumor of neuroendocrine phenotype consistent with small-cell carcinoma. Chest X-ray and computed tomography revealed an expansive process in the 7(th) segment of the left lung, left hilar and mediastinal lymphadenopathy and a suspicious initial secondary deposit in the left adrenal gland. The patient was referred to the department of oncology for further treatment. After the third cycle of chemotherapy, the magnetic resonance imaging revealed brain metastases. The patient passed away four months after the diagnosis of lung cancer first presented with skin metastases. Metastases in skin may be the first sign of lung cancer. Although rare appearing, we should raise suspicion in cases of atypical lesions in the skin not only of the smokers, but also of the non-smokers. Skin metastases from small-cell lung carcinoma are a poor prognostic indicator. The appearance of multiple skin metastases with other internal metastases shorten the survival time. 412. Poly aspartic acid peptide-linked PLGA based nanoscale particles: potential for bone-targeting drug delivery applications. PubMed Jiang, Tao; Yu, Xiaohua; Carbone, Erica J; Nelson, Clarke; Kan, Ho Man; Lo, Kevin W-H 2014-11-20 Delivering drugs specifically to bone tissue is very challenging due to the architecture and structure of bone tissue. Poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) hold great promise for the delivery of therapeutics to bone tissue. The goal of the present research was to formulate a PLGA-based NP drug delivery system for bone tissue exclusively. Since poly-aspartic acids (poly-Asp) peptide sequence has been shown to bind to hydroxyapatite (HA), and has been suggested as a molecular tool for bone-targeting applications, we fabricated PLGA-based NPs linked with poly-Asp peptide sequence. Nanoparticles made of methoxy - poly(ethylene glycol) (PEG)-PLGA and maleimide-PEGPLGA were prepared using a water-in-oil-in-water double emulsion and solvent evaporation method. Fluorescein isothiocyanate (FITC)-tagged poly-Asp peptide was conjugated to the surface of the nanoparticles via the alkylation reaction between the sulfhydryl groups at the N-terminal of the peptide and the CC double bond of maleimide at one end of the polymer chain to form thioether bonds. The conjugation of FITC-tagged poly-Asp peptide to PLGA NPs was confirmed by NMR analysis and fluorescent microscopy. The developed nanoparticle system is highly aqueous dispersible with an average particle size of ∼80 nm. In vitro binding analyses demonstrated that FITC-poly-Asp NPs were able to bind to HA gel as well as to mineralized matrices produced by human mesenchymal stem cells and mouse bone marrow stromal cells. Using a confocal microscopy technique, an ex vivo binding study of mouse major organ ground sections revealed that the FITC-poly-Asp NPs were able to bind specifically to the bone tissue. In addition, proliferation studies indicated that our FITC-poly-Asp NPs did not induce cytotoxicity to human osteoblast-like MG63 cell lines. Altogether, these promising results indicated that this nanoscale targeting system was able to bind to bone tissue specifically and might have a great 413. Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta. PubMed Jacobsen, Christina M; Barber, Lauren A; Ayturk, Ugur M; Roberts, Heather J; Deal, Lauren E; Schwartz, Marissa A; Weis, MaryAnn; Eyre, David; Zurakowski, David; Robling, Alexander G; Warman, Matthew L 2014-10-01 The cell surface receptor low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5(p.A214V) ) that is orthologous to a human HBM-causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5(+/p.A214V) mice to Col1a2(+/p.G610C) mice, which model human type IV OI. We found that Col1a2(+/p.G610C) ;Lrp5(+/p.A214V) offspring had significantly increased bone mass and strength compared to Col1a2(+/p.G610C) ;Lrp5(+/+) littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2(+/p.G610C) mice with a monoclonal antibody that inhibits sclerostin activity (Scl-Ab). We found that antibody-treated mice had significantly increased bone mass and strength compared to vehicle-treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI. © 2014 American Society for Bone and Mineral Research. 414. Osteoclastic miR-214 targets TRAF3 to contribute to osteolytic bone metastasis of breast cancer PubMed Central Liu, Jin; Li, Defang; Dang, Lei; Liang, Chao; Guo, Baosheng; Lu, Cheng; He, Xiaojuan; Cheung, Hilda Y. S.; He, Bing; Liu, Biao; Li, Fangfei; Lu, Jun; Wang, Luyao; Shaikh, Atik Badshah; Jiang, Feng; Lu, Changwei; Peng, Songlin; Zhang, Zongkang; Zhang, Bao-Ting; Pan, Xiaohua; Xiao, Lianbo; Lu, Aiping; Zhang, Ge 2017-01-01 The role of osteoclastic miRNAs in regulating osteolytic bone metastasis (OBM) of breast cancer is still underexplored. Here, we examined the expression profiles of osteoclastogenic miRNAs in human bone specimens and identified that miR-214-3p was significantly upregulated in breast cancer patients with OBM. Consistently, we found increased miR-214-3p within osteoclasts, which was associated with the elevated bone resorption, during the development of OBM in human breast cancer xenografted nude mice (BCX). Furthermore, genetic ablation of osteoclastic miR-214-3p in nude mice prevent the development of OBM. Conditioned medium from MDA-MB-231 cells dramatically stimulated miR-214-3p expression to promote osteoclast differentiation. Mechanistically, a series of in vitro study showed that miR-214-3p directly targeted Traf3 to promote osteoclast activity and bone-resorbing activity. In addition, osteoclast-specific miR-214-3p knock-in mice showed remarkably increased bone resorption when compared to the littermate controls, which was attenuated after osteoclast-targeted treatment with Traf3 3′UTR-containing plasmid. In BCX nude mice, osteoclast-targeted antagomir-214-3p delivery could recover the TRAF3 protein expression and attenuate the development of OBM, respectively. Collectively, inhibition of osteoclastic miR-214-3p may be a potential therapeutic strategy for breast cancer patients with OBM. Meanwhile, the intraosseous TRAF3 could be a promising biomarker for evaluation of the treatment response of antagomir214-3p. PMID:28071724 415. Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis. PubMed Lee, Changki; Whang, Young Mi; Campbell, Preston; Mulcrone, Patrick L; Elefteriou, Florent; Cho, Sun Wook; Park, Serk In 2018-02-01 Prostate cancer characteristically induces osteoblastic bone metastasis, for which no therapies are available. A dual kinase inhibitor of c-Met and VEGFR-2 (cabozantinib) was shown to reduce prostate cancer growth in bone, with evidence for suppressing osteoblastic activity. However, c-Met and VEGFR2 signaling in osteoblasts in the context of bone metastasis remain unclear. Here we show using cultured osteoblasts that hepatocyte growth factor (HGF) and VEGF-A increased receptor activator of NFκB ligand (RANKL) and M-CSF, two essential factors for osteoclastogenesis. Insulin-like growth factor-1 (IGF1) also increased RANKL and M-CSF via c-Met transactivation. The conditioned media from IGF1-, HGF-, or VEGFA-treated osteoblasts promoted osteoclastogenesis that was reversed by inhibiting c-Met and/or VEGFR2 in osteoblasts. In vivo experiments used cabozantinibresistant prostate cancer cells (PC-3 and C4-2B) to test the effects of c-Met/VEGFR2 inhibition specifically in osteoblasts. Cabozantinib (60 mg/kg, 3 weeks) suppressed tumor growth in bone and reduced expression of RANKL and M-CSF and subsequent tumor-induced osteolysis. Collectively, inhibition of c-Met and VEGFR2 in osteoblasts reduced RANKL and M-CSF expression, and associated with reduction of tumor-induced osteolysis, suggesting that c-Met and VEGFR2 are promising therapeutic targets in bone metastasis. Copyright © 2017 Elsevier B.V. All rights reserved. 416. Heterotopic bone induction via BMP signaling: Potential therapeutic targets for fibrodysplasia ossificans progressiva. PubMed Katagiri, Takenobu; Tsukamoto, Sho; Kuratani, Mai 2017-07-25 More than 50years ago, Marshal M. Urist detected "heterotopic bone-inducing activity" in demineralized bone matrix. This unique activity was referred to as "bone morphogenetic protein (BMP)" because it was sensitive to trypsin digestion. Purification of the bone-inducing activity from demineralized bone matrix using a bone-inducing assay in vivo indicated that the original "BMP" consisted of a mixture of new members of the transforming growth factor-β (TGF-β) family. The establishment of new in vitro assay systems that reflect the bone-inducing activity of BMPs in vivo have revealed the functional receptors and downstream effectors of BMPs. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic bone formation in soft tissues similar to the event induced by the transplantation of BMPs in skeletal muscle. In patients with FOP, genetic mutations have been identified in the ACVR1 gene, which encodes the BMP receptor ALK2. The mutations in ALK2 associated with FOP are hypersensitive to type II receptor kinases. Recently, activin A, a non-osteogenic member of the TGF-β family, was identified as the ligand of the mutant ALK2 in FOP, and various types of signaling inhibitors for mutant ALK2 are currently under development to establish effective treatments for FOP. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved. 417. Targeting the LRP5 pathway improves bone properties in a mouse model of Osteogenesis Imperfecta PubMed Central Jacobsen, Christina M.; Barber, Lauren A.; Ayturk, Ugur M.; Roberts, Heather J.; Deal, Lauren E.; Schwartz, Marissa A.; Weis, MaryAnn; Eyre, David; Zurakowski, David; Robling, Alexander G.; Warman, Matthew L. 2014-01-01 The cell surface receptor low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5p.A214V) that is orthologous to a human HBM-causing mutation have increased bone mass and strength. Osteogenesis Imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5+/p.A214V mice to Col1a2+/p.G610C mice, which model human type IV OI. We found that Col1a2+/p.G610C;Lrp5+/p.A214V offspring had significantly increased bone mass and strength compared to Col1a2+/p.G610C;Lrp5+/+ littermates. The improved bone properties were not due to altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2+/p.G610C mice with a monoclonal antibody that inhibits sclerostin activity (Scl-Ab). We found that antibody treated mice had significantly increased bone mass and strength compared to vehicle treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI. PMID:24677211 418. Resident stromal cell-derived MMP-9 promotes the growth of colorectal metastases in the liver microenvironment. PubMed Gorden, D Lee; Fingleton, Barbara; Crawford, Howard C; Jansen, Duco E; Lepage, Martin; Matrisian, Lynn M 2007-08-01 Colorectal cancer, the second leading cause of cancer deaths in the United States, has a high probability of metastasizing to the liver. Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases that are implicated in cancer metastasis and many aspects of tumor progression. Using a splenic injection experimental metastasis model, mice that are genetically deficient in MMP-9 demonstrated a nearly 2-fold decrease in liver weight compared with wild type (WT) mice following injection with MC38 syngeneic colorectal cancer cells. Bioluminesence imaging data demonstrates an early negative effect on tumor growth in MMP-9 null mice when compared with WT controls. Reconstitution of the bone marrow in MMP-9-/- mice with cells competent to produce MMP-9 did not recapitulate the WT phenotype of overwhelming burden of metastatic disease in the liver. In situ hybridization revealed the presence of MMP-9 mRNA in both MC38 tumor cells and in surrounding stromal cells, and immunostaining with anti MMP-9 was consistent with MMP9 expression by resident liver Kupffer cells. Stromal-derived MMP-9 contributes to the establishment and growth of colorectal metastases in the liver. Stromal MMP-9 was derived from resident cells, most likely Kupffer cells, as opposed to infiltrating bone marrow-derived cells and the effect of stromal MMP-9 was independent of expression of MMP-9 by tumor cells. Stromal-derived MMP-9 may represent an important target for selective inhibition in the treatment of metastases. (c) 2007 Wiley-Liss, Inc. 419. Targeting survivin as a potential new treatment for chondrosarcoma of bone PubMed Central de Jong, Y; van Oosterwijk, J G; Kruisselbrink, A B; Briaire-de Bruijn, I H; Agrogiannis, G; Baranski, Z; Cleven, A H G; Cleton-Jansen, A-M; van de Water, B; Danen, E H J; Bovée, J V M G 2016-01-01 Chondrosarcomas are malignant cartilage-forming bone tumors, which are intrinsically resistant to chemo- and radiotherapy, leaving surgical removal as the only curative treatment option. Therefore, our aim was to identify genes involved in chondrosarcoma cell survival that could serve as a target for therapy. siRNA screening for 51 apoptosis-related genes in JJ012 chondrosarcoma cells identified BIRC5, encoding survivin, as essential for chondrosarcoma survival. Using immunohistochemistry, nuclear as well as cytoplasmic survivin expression was analyzed in 207 chondrosarcomas of different subtypes. Nuclear survivin has been implicated in cell-cycle regulation while cytoplasmic localization is important for its anti-apoptotic function. RT–PCR was performed to determine expression of the most common survivin isoforms. Sensitivity to YM155, a survivin inhibitor currently in phase I/II clinical trial for other tumors, was examined in 10 chondrosarcoma cell lines using viability assay, apoptosis assay and cell-cycle analysis. Survivin expression was found in all chondrosarcoma patient samples. Higher expression of nuclear and cytoplasmic survivin was observed with increasing histological grade in central chondrosarcomas. Inhibition of survivin using YM155 showed that especially TP53 mutant cell lines were sensitive, but no caspase 3/7 or PARP cleavage was observed. Rather, YM155 treatment resulted in a block in S phase in two out of three chondrosarcoma cell lines, indicating that survivin is more involved in cell-cycle regulation than in apoptosis. Thus, survivin is important for chondrosarcoma survival and chondrosarcoma patients might benefit from survivin inhibition using YM155, for which TP53 mutational status can serve as a predictive biomarker. PMID:27159675 420. Characterizing and Targeting Bone Marrow-Derived Inflammatory Cells in Driving the Malignancy and Progression of Childhood Astrocytic Brain Tumors DTIC Science & Technology 2015-09-01 Medical College New York, NY 10065-4805 REPORT DATE: September 2015 TYPE OF REPORT: Annual Report PREPARED FOR: U.S. Army Medical Research and...REPORT DATE September 2015 2. REPORT TYPE Annual 3. DATES COVERED 1 Sep 2014 - 31 Aug 2015 4. TITLE AND SUBTITLE Characterizing and Targeting Bone...med.cornell.edu doi: 10.1158/0008-5472.CAN-13-1072 2013 American Association for Cancer Research. Cancer Research www.aacrjournals.org 1011 on September 11, 2015 « 19 20 21 22 23 » « 20 21 22 23 24 » 421. Carboxy-terminal telopeptide (CTX) and amino-terminal propeptide (PINP) of type I collagen as markers of bone metastases in patients with non-small cell lung cancer. PubMed Lumachi, Franco; Santeufemia, Davide A; Del Conte, Alessandro; Mazza, Francesco; Tozzoli, Renato; Chiara, Giordano B; Basso, Stefano M M 2013-06-01 The early diagnosis of non-small cell lung carcinoma (NSCLC) is difficult, and 30-40% of patients with NSCLC develop bone metastases (BMs) during the course of their disease. Because the delayed demonstration of skeletal involvement may seriously affect survival, there is a need for early diagnosis of BMs. Unfortunately, the sensitivity of common serum tumor markers is low and they are used mainly for monitoring the efficacy of therapy and detection of recurrence. The aim of this study was to evaluate the utility of a panel of serum biomarkers in patients with NSCLC and BMs. Sixteen patients (11 males, 5 females; median age=64 years, range 54-68 years) with NSCLC and BMs (cases), and 18 age- and stage-matched patients without BMs (controls) underwent measurement of serum carboxy-terminal telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase isoform type 5b (TRAP5b) and amino-terminal propeptide of type I collagen (PINP), carcinoembryonic antigen (CEA) and fragments of cytokeratin 19 (CYFRA 21-1. CTX (443.7 ± 945.1 vs. 402.7 ± 28.4 pg/ml, p=0.003) and PINP (75.9 ± 11.4 vs. 64.1 ± 7.5 μg/l, p=0.001) were significantly higher in patients with BMs, while the mean value of the other markers did not differ (p=NS) between cases and controls. The sensitivity, specificity and accuracy were 73.3%, 86.7% and 79.4% for CTX; 55.5%, 62.5% and 58.8% for CEA; 65.0%, 78.6% and 70.6% for CYFRA; 30.4%, 76.2% and 67.6% for TRAP5b; and 72.2%, 81.2% and 76.5% for PINP, respectively. The area under the receiver operating characteristic curve (AUC) for CTX was 0.68. In conclusion, CTX and PINP measurement can be useful in monitoring patients with NSCLC during follow-up, with the aim of detecting BMs early. 422. Comparison of hybrid68Ga-PSMA-PET/CT and99mTc-DPD-SPECT/CT for the detection of bone metastases in prostate cancer patients: Additional value of morphologic information from low dose CT. PubMed Janssen, Jan-Carlo; Meißner, Sebastian; Woythal, Nadine; Prasad, Vikas; Brenner, Winfried; Diederichs, Gerd; Hamm, Bernd; Makowski, Marcus R 2018-02-01 This study compared 68 Gallium-prostate-specific-membrane-antigen based Positron-emission-tomography ( 68 Ga-PSMA-PET) and 99metastable technetium-3,3-diphospho-1,2propanedicarbonacid ( 99m Tc-DPD-SPECT) in performing skeletal staging in prostate cancer (PC) patients and evaluated the additional value of the information from low-dosecomputed tomography (CT). In this retrospective study, 54 patients who received 68 Ga-PSMA-PET/CT and 99m Tc-DPD-SPECT/CT within 80 days were extracted from our database. Osseous lesions were classified as benign, malignant or equivocal. Lesion, region and patient based analysis was performed with and without CT fusion. The reference standard was generated by defining a best valuable comparator (BVC) containing information from all available data. In the patient based analysis, accuracies measured as "areaunder-the-curve" (AUC) for 68 Ga-PSMA-PET, 99m Tc-SPECT, 68 Ga-PSMA-PET/CT and 99m Tc-SPECT/CT were 0.97-0.96, 0.86-0.83, 1.00 and 0.83, respectively (p<0.05) (ranges = optimistic vs. pessimistic view). Region based analysis resulted in the following sensitivities and specificities: 91.8-97.7%, 100-99.5% (PET); 61.2-70.6%, 99.8-98.3% (SPECT); 97.7%, 100% (PET/CT), 69.4% and 98.3% (SPECT/CT) (p<0.05). The amount of correct classifications of equivocal lesions by CT was significantly higher in PET (100%) compared to SPECT (52.4%) (p<0.05). 68 Ga-PSMA-PET outperforms 99m Tc-DPD-SPECT in detecting bone metastases in PC patients. Additional information from lowdose-CT resulted in a significant reduction in equivocal lesions in both modalities, however 68 Ga-PSMA-PET benefited most. • Ga-PSMA-PET outperforms 99m Tc-DPDSPECT in skeletal staging in prostate cancer patients • Proportion of equivocal decisions was significantly reduced by CT-fusion in both modalities • Ga-PSMA-PET benefits more from CT information, compared to 99m Tc-DPD-SPECT. 423. SU-F-T-57: Delivered Activity Accuracy of Radium 223 Dichloride Injections, When Being Administrated for Castration Resistant Prostate Cancer, Symptomatic Bone Metastases. The Impact of Residual Activity in the Spent Syringe and Dispensing Accuracy of Ra 223 SciTech Connect Jennings, G 2016-06-15
Purpose: To quantify the delivered activity accuracy of Radium 223 dichloride injections, when being administrated for castration – resistant prostate cancer, symptomatic bone metastases. The impact of residual activity in the spent syringe and dispensing accuracy of Ra 223. Methods: The administration is by slow intravenous injection over 1 minute followed by double flushing of the 10 mL syringe and IV with saline. Eighty (80) procedures was used to investigate variations in the activity from the amount prescribed (µCi) = 1.35 × Patient weight Kg. The Activity dispensed into a 10mL syringe using a NIST traceable Capintec CRC-25R Chamber and a cross calibrated capintec CRC-15R to measure activity in the syringe immediately before and after administration Results: The patients weight range from 121Ib to 235lb and doses ranging 74.25 µCi to 144.2 µCi. The deviation of dispensed dose vs Prescribed dose average +2.1% with a range of −1.1% to +5.7%. The Dose measured before administration ranges 79.3 µCi to 154.9 µCi. Deviation from the dispensed dose was show to average +2.9% with a range of −0.8% to +7.3%. The average residual dose post injection was 2.5 µCi or 2.2% of the pre injection activity. Ranging from 0.9 µCi to 6.2 µCi, 0.7% to 5.4% respectively. Subtracting the residual activity from that measured activity before injection and comparing it to prescription dose was shown to have an average variation of +2.7% with a range of −0.8% to 7.4%. Conclusion: The case resulted in the 6.2 µCi maximum residual dose had two syringes. A small, 82.8 µCi activity, case resulted in the 7.4% maximum variation in measures less residual verses prescription dose. The average +2.1 % dispenses activity of Ra 223 over the prescription dosage was seen to counteract the average 2.2% residual dosage found to remain in the syringe. 424. SU-F-T-57: Delivered Activity Accuracy of Radium 223 Dichloride Injections, When Being Administrated for Castration Resistant Prostate Cancer, Symptomatic Bone Metastases. The Impact of Residual Activity in the Spent Syringe and Dispensing Accuracy of Ra 223 SciTech Connect Jennings, G 2016-06-15 Purpose: To quantify the delivered activity accuracy of Radium 223 dichloride injections, when being administrated for castration – resistant prostate cancer, symptomatic bone metastases. The impact of residual activity in the spent syringe and dispensing accuracy of Ra 223. Methods: The administration is by slow intravenous injection over 1 minute followed by double flushing of the 10 mL syringe and IV with saline. Eighty (80) procedures was used to investigate variations in the activity from the amount prescribed (µCi) = 1.35 × Patient weight Kg. The Activity dispensed into a 10mL syringe using a NIST traceable Capintec CRC-25R Chamber andmore » a cross calibrated capintec CRC-15R to measure activity in the syringe immediately before and after administration Results: The patients weight range from 121Ib to 235lb and doses ranging 74.25 µCi to 144.2 µCi. The deviation of dispensed dose vs Prescribed dose average +2.1% with a range of −1.1% to +5.7%. The Dose measured before administration ranges 79.3 µCi to 154.9 µCi. Deviation from the dispensed dose was show to average +2.9% with a range of −0.8% to +7.3%. The average residual dose post injection was 2.5 µCi or 2.2% of the pre injection activity. Ranging from 0.9 µCi to 6.2 µCi, 0.7% to 5.4% respectively. Subtracting the residual activity from that measured activity before injection and comparing it to prescription dose was shown to have an average variation of +2.7% with a range of −0.8% to 7.4%. Conclusion: The case resulted in the 6.2 µCi maximum residual dose had two syringes. A small, 82.8 µCi activity, case resulted in the 7.4% maximum variation in measures less residual verses prescription dose. The average +2.1 % dispenses activity of Ra 223 over the prescription dosage was seen to counteract the average 2.2% residual dosage found to remain in the syringe.« less 425. Intracranial dural metastases. PubMed Nayak, Lakshmi; Abrey, Lauren E; Iwamoto, Fabio M 2009-05-01 : Intracranial dural metastases (IDM) are found at autopsy in 9% of patients with advanced systemic cancer. However, to the authors' knowledge, IDM have not been studied systematically in the modern neuroimaging era. The objective of the current study was to evaluate the demographics, clinical presentation, imaging, treatment, and prognosis of patients with IDM. : The current study was a retrospective review of 122 patients with IDM diagnosed at Memorial Sloan-Kettering Cancer Center between 1999 and 2006. Patients with concurrent brain or leptomeningeal metastases were excluded. : Sixty-one percent of the patients were women; the median age at diagnosis was 59 years, the median Karnofsky performance scale (KPS) at diagnosis was 80, and the median time to IDM diagnosis from initial cancer diagnosis was 37 months. Breast (34%) and prostate (17%) cancers were the most frequent primary tumors associated with IDM. Fifty-six percent of patients had a single dural metastasis. On imaging, 70% had metastases of the overlying skull, 44% had dural tail metastases, 53% had vasogenic edema, and 34% had brain invasion. Direct extension from skull metastases was the most common mode of spread. Eighty-three percent of patients had active systemic disease at the time of IDM diagnosis. A lower KPS and lung cancer were associated with worse overall survival. Surgical resection and chemotherapy improved progression-free survival, but only resection was found to be associated with improved overall survival. : IDM affect a significant proportion of cancer patients. KPS and status of systemic cancer should guide treatment decisions. Cancer 2009. (c) 2009 American Cancer Society. 426. NADPH oxidases are critical targets for prevention of ethanol-induced bone loss USDA-ARS?s Scientific Manuscript database The molecular mechanisms through which chronic alcohol consumption induce bone loss and osteoporosis are largely unknown. Ethanol increases expression and activates NADPH (nicotinamide adenine dinucleotide phosphate) oxidase enzymes (Nox) in osteoblasts leading to accumulation of reactive oxygen spe... 427. Wnt Signaling in Prostate Cancer Bone Metastases DTIC Science & Technology 2015-09-01 Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Ace-1-Dkk-1, a canine prostate cancer overexpressing Dkk-1 is used in this study to investigate how...Dkk-1 expression in prostate cancer could change the metastatic phenotype and tumor growth in vivo. Ace-1-Dkk-1, a canine prostate cancer 428. Wnt Signaling in Prostate Cancer Bone Metastases DTIC Science & Technology 2016-11-01 dehydrated , embedded, sectioned into slides and stained with hematoxylin/eosin. Results: Macroscopically, all the animals at the dose of 1000 mg/kg/day...Biosciences IMID - 4 POLY-LACTIC-CO- GLYCOLIC ACID (PLGA) NANOPARTICLE DELIVERY OF SWINE INFLUENZA VIRUS VACCINE PROVIDES HETEROLOGOUS PROTECTION...to reduce mortality in calves between 11 and 21 days of age with watery diarrhea in the absence of systemic signs of dehydration or depression. If 429. Development of a Bifunctional Aptamer Targeting the Transferrin Receptor and Epithelial Cell Adhesion Molecule (EpCAM) for the Treatment of Brain Cancer Metastases. PubMed Macdonald, Joanna; Henri, Justin; Goodman, Lynda; Xiang, Dongxi; Duan, Wei; Shigdar, Sarah 2017-04-19 The treatment of brain disorders is greatly hindered by the presence of the blood-brain barrier, which restricts the overwhelming majority of small molecules from entering the brain. A novel approach by which to overcome this barrier is to target receptor mediated transport mechanisms present on the endothelial cell membranes. Therefore, we fused an aptamer that binds to epithelial cell adhesion molecule-expressing cancer cells to an aptamer targeting the transferrin receptor. This generated a proof of concept bifunctional aptamer that can overcome the blood-brain barrier and potentially specifically target brain disorders. The initial fusion of the two sequences enhanced the binding affinity of both aptamers while maintaining specificity. Additionally, mutations were introduced into both binding loops to determine their effect on aptamer specificity. The ability of the aptamer to transcytose the blood-brain barrier was then confirmed in vivo following a 1 nmol injection. This study has shown that through the fusion of two aptamer sequences, a bifunctional aptamer can be generated that has the potential to be developed for the specific treatment of brain disorders. 430. Melanoma Brain Metastases: Current Areas of Investigation and Future Directions. PubMed Glitza Oliva, Isabella; Tawbi, Hussein; Davies, Michael A Metastases to the central nervous system (CNS) are one of the most common and lethal complications of metastatic melanoma. Historically, melanoma patients with CNS metastases have had dismal outcomes and very limited treatment options. However, the development of more effective targeted, immune, and radiation therapies is now leading to promising new investigations and strategies. Optimizing the development and testing of such strategies will benefit from an improved understanding of the unique molecular features of these tumors and the influence of the brain microenvironment. Accounting for unique clinical features and challenges of CNS metastases will also be critical to making significant clinical impact in patients. 431. Targeted reversion of induced pluripotent stem cells from patients with human cleidocranial dysplasia improves bone regeneration in a rat calvarial bone defect model. PubMed Saito, Akiko; Ooki, Akio; Nakamura, Takashi; Onodera, Shoko; Hayashi, Kamichika; Hasegawa, Daigo; Okudaira, Takahito; Watanabe, Katsuhito; Kato, Hiroshi; Onda, Takeshi; Watanabe, Akira; Kosaki, Kenjiro; Nishimura, Ken; Ohtaka, Manami; Nakanishi, Mahito; Sakamoto, Teruo; Yamaguchi, Akira; Sueishi, Kenji; Azuma, Toshifumi 2018-01-22 Runt-related transcription factor 2 (RUNX2) haploinsufficiency causes cleidocranial dysplasia (CCD) which is characterized by supernumerary teeth, short stature, clavicular dysplasia, and osteoporosis. At present, as a therapeutic strategy for osteoporosis, mesenchymal stem cell (MSC) transplantation therapy is performed in addition to drug therapy. However, MSC-based therapy for osteoporosis in CCD patients is difficult due to a reduction in the ability of MSCs to differentiate into osteoblasts resulting from impaired RUNX2 function. Here, we investigated whether induced pluripotent stem cells (iPSCs) properly differentiate into osteoblasts after repairing the RUNX2 mutation in iPSCs derived from CCD patients to establish normal iPSCs, and whether engraftment of osteoblasts derived from properly reverted iPSCs results in better regeneration in immunodeficient rat calvarial bone defect models. Two cases of CCD patient-derived induced pluripotent stem cells (CCD-iPSCs) were generated using retroviral vectors (OCT3/4, SOX2, KLF4, and c-MYC) or a Sendai virus SeVdp vector (KOSM302L). Reverted iPSCs were established using programmable nucleases, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-derived RNA-guided endonucleases, to correct mutations in CCD-iPSCs. The mRNA expressions of osteoblast-specific markers were analyzed using quantitative reverse-transcriptase polymerase chain reaction. iPSCs-derived osteoblasts were transplanted into rat calvarial bone defects, and bone regeneration was evaluated using microcomputed tomography analysis and histological analysis. Mutation analysis showed that both contained nonsense mutations: one at the very beginning of exon 1 and the other at the initial position of the nuclear matrix-targeting signal. The osteoblasts derived from CCD-iPSCs (CCD-OBs) expressed low levels of several osteoblast differentiation markers, and transplantation of these osteoblasts into calvarial bone defects created in rats with 432. RGD peptide conjugated liposomal drug delivery system for enhance therapeutic efficacy in treating bone metastasis from prostate cancer. PubMed Wang, Fangfang; Chen, Lei; Zhang, Rui; Chen, Zhongping; Zhu, Li 2014-12-28 Targeting αvβ3 integrin is particularly promising for the treatment of bone metastases by targeting integrin-rich tumor cells and by inhibiting integrin-involved bone metastases. In this work, a liposomal drug delivery system conjugated with cyclic arginine-glycine-aspartic acid-tyrosine-lysine peptide (cRGDyk) as αvβ3 integrin ligand was thus developed to improve therapeutic efficacy in a mice model of bone metastasis from prostate cancer. The resultant liposomes were characterized in terms of size, morphology, zeta potential, stability, drug encapsulation percentage and loading efficiency, and drug release. Compared with free cisplatin and cRGDyk-free liposomes, cRGDyk conjugated liposomes showed significantly higher cellular uptake and higher cytotoxicity of loaded cisplatin, as evidenced by in vitro cell experiments. In vivo results revealed that free cisplatin and free cRGDyk could relieve tumor-induced pain but had no contributions to tumor regression and overall survival improvement. cRGDyk-free liposomal drug system with prolonged blood circulation time could accumulated in the tumor sites in the bone through enhanced permeability and retention (EPR) effects and however, did not exhibit desirable therapeutic efficacy superior to free cisplatin and free cRGDyk. This strongly suggested that ERP effects were not effective in treating metastases. By taking advantages of targeted drug delivery and synergistic antitumor activity of cRGDyk and loaded cisplatin, cRGDyk conjugated liposomal drug system could inhibit osteoclastic and osteoblastic bone lesions, relieve pain, and improve overall survival. Inspired by their enhanced therapeutic efficacy and low organ toxicity, cRGDyk conjugated liposomes could serve as an effective drug system for targeted and synergistic therapy of bone metastases. Copyright © 2014 Elsevier B.V. All rights reserved. 433. Local delivery of nitric oxide: targeted delivery of therapeutics to bone and connective tissues. PubMed Nichols, Scott P; Storm, Wesley L; Koh, Ahyeon; Schoenfisch, Mark H 2012-09-01 Non-invasive treatment of injuries and disorders affecting bone and connective tissue remains a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several important roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair. Copyright © 2012 Elsevier B.V. All rights reserved. 434. Factors Influencing the Central Nervous System Distribution of a Novel Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GSK2126458: Implications for Overcoming Resistance with Combination Therapy for Melanoma Brain Metastases PubMed Central Vaidhyanathan, Shruthi; Wilken-Resman, Brynna; Ma, Daniel J.; Parrish, Karen E.; Mittapalli, Rajendar K.; Carlson, Brett L.; Sarkaria, Jann N. 2016-01-01 Small molecule inhibitors targeting the mitogen-activated protein kinase pathway (Braf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) have had success in extending survival for patients with metastatic melanoma. Unfortunately, resistance may occur via cross-activation of alternate signaling pathways. One approach to overcome resistance is to simultaneously target the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. Recent reports have shown that GSK2126458 [2,4-difluoroN-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl) benzenesulfonamide], a dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor, can overcome acquired resistance to Braf and mitogen-activated protein kinase kinase inhibitors in vitro. These resistance mechanisms may be especially important in melanoma brain metastases because of limited drug delivery across the blood–brain barrier. The purpose of this study was to investigate factors that influence the brain distribution of GSK2126458 and to examine the efficacy of GSK2126458 in a novel patient-derived melanoma xenograft (PDX) model. Both in vitro and in vivo studies indicate that GSK2126458 is a substrate for Pglycoprotein (P-gp) and breast cancer resistance protein (Bcrp), two dominant active efflux transporters in the blood–brain barrier. The steady-state brain distribution of GSK2126458 was 8-fold higher in the P-gp/Bcrp knockout mice compared with the wild type. We also observed that when simultaneously infused to steady state, GSK212658, dabrafenib, and trametinib, a rational combination to overcome mitogen-activated protein kinase inhibitor resistance, all had limited brain distribution. Coadministration of elacridar, a P-gp/Bcrp inhibitor, increased the brain distribution of GSK2126458 by approximately 7-fold in wild-type mice. In the PDX model, GSK2126458 showed efficacy in flank tumors but was ineffective in intracranial melanoma. These results show 435. Concurrent antitumor and bone-protective effects of everolimus in osteotropic breast cancer. PubMed Browne, Andrew J; Kubasch, Marie L; Göbel, Andy; Hadji, Peyman; Chen, David; Rauner, Martina; Stölzel, Friedrich; Hofbauer, Lorenz C; Rachner, Tilman D 2017-08-09 The mammalian target of rapamycin inhibitor everolimus is approved as an antitumor agent in advanced estrogen receptor-positive breast cancer. Surrogate bone marker data from clinical trials suggest effects on bone metabolism, but the mode of action of everolimus in bone biology remains unclear. In this study, we assessed potential bone-protective effects of everolimus in the context of osteotropic tumors. The effects of everolimus on cancer cell viability in vitro and on tumor growth in vivo were assessed. Everolimus-regulated osteoclastogenesis and osteoblastogenesis were also assessed in vitro before we assessed the bone-protective effect of everolimus in a model where bone loss was induced in ovariectomized (OVX) mice. Finally, the role of everolimus in the progression of osteolytic bone disease was assessed in an intracardiac model of breast cancer bone metastases. At low concentrations (1 nM) in vitro, everolimus reduced the viability of human and murine cancer cell lines and impaired the osteoclastogenesis of osteoclast progenitors as assessed by quantitative real-time polymerase chain reaction and counting tartrate-resistant acid phosphatase-positive, multinucleated osteoclasts (p < 0.001). Everolimus had little or no deleterious effect on osteoblastogenesis in vitro, with concentrations of 1 and 10 nM increasing the messenger RNA expression of osteoblast marker genes (p ≤ 0.05) and leaving mineralization in differentiated human mesenchymal stem cells unchanged. Everolimus treatment (1 mg/kg body weight/day) prevented the bone loss observed in OVX mice and concurrently inhibited the metastatic growth of MDA-MB-231 cells by 70% (p < 0.002) while preserving bone mass in an intracardiac model of bone metastasis. These results underline the antitumor effects of everolimus and highlight its bone-protective efficacy, warranting further research on the potential implications on bone health in populations prone to osteoporosis and bone metastases 436. Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis A model for compartment-specific androgen action in the skeleton PubMed Central Wiren, Kristine M.; Semirale, Anthony A.; Zhang, Xiao-Wei; Woo, Adrian; Tommasini, Steven M.; Price, Christopher; Schaffler, Mitchell B.; Jepsen, Karl J. 2008-01-01 Androgens are anabolic hormones that affect many tissues, including bone. However, an anabolic effect of androgen treatment on bone in eugonadal subjects has not been observed and clinical trials have been disappointing. The androgen receptor (AR) mediates biological responses to androgens. In bone tissue, both AR and the estrogen receptor (ER) are expressed. Since androgens can be converted into estrogen, the specific role of the AR in maintenance of skeletal homoeostasis remains controversial. The goal of this study was to use skeletally targeted overexpression of AR in differentiated osteoblasts as a means of elucidating the specific role(s) for AR transactivation in the mature bone compartment. Transgenic mice overexpressing AR under the control of the 2.3-kb α1(I)-collagen promoter fragment showed no difference in body composition, testosterone, or 17β-estradiol levels. However, transgenic males have reduced serum osteocalcin, CTx and TRAPC5b levels, and a bone phenotype was observed. In cortical bone, high-resolution microcomputed tomography revealed no difference in periosteal perimeter but a significant reduction in cortical bone area due to an enlarged marrow cavity. Endocortical bone formation rate was also significantly inhibited. Biomechanical analyses showed decreased whole bone strength and quality, with significant reductions in all parameters tested. Trabecular morphology was altered, with increased bone volume comprised of more trabeculae that were closer together but not thicker. Expression of genes involved in bone formation and bone resorption was significantly reduced. The consequences of androgen action are compartment-specific; anabolic effects are exhibited exclusively at periosteal surfaces, but in mature osteoblasts androgens inhibited osteogenesis with detrimental effects on matrix quality, bone fragility and whole bone strength. Thus, the present data demonstrate that enhanced androgen signaling targeted to bone results in low bone 437. Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo. PubMed Kroon, Jan; Buijs, Jeroen T; van der Horst, Geertje; Cheung, Henry; van der Mark, Maaike; van Bloois, Louis; Rizzo, Larissa Y; Lammers, Twan; Pelger, Rob C; Storm, Gert; van der Pluijm, Gabri; Metselaar, Josbert M 2015-06-01 The inflammatory tumor microenvironment, and more specifically the tumor-associated macrophages, plays an essential role in the development and progression of prostate cancer towards metastatic bone disease. Tumors are often characterized by a leaky vasculature, which - combined with the prolonged circulation kinetics of liposomes - leads to efficient tumor localization of these drug carriers, via the so-called enhanced permeability and retention (EPR) -effect. In this study, we evaluated the utility of targeted, liposomal drug delivery of the glucocorticoid dexamethasone in a model of prostate cancer bone metastases. Tumor-bearing Balb-c nu/nu mice were treated intravenously with 0.2-1.0-5.0†‰mg/kg/week free- and liposomal DEX for 3-4 weeks and tumor growth was monitored by bioluminescent imaging. Intravenously administered liposomes localize efficiently to bone metastases in vivo and treatment of established bone metastases with (liposomal) dexamethasone resulted in a significant inhibition of tumor growth up to 26 days after initiation of treatment. Furthermore, 1.0 mg/kg liposomal dexamethasone significantly outperformed 1.0 mg/kg free dexamethasone, and was found to be well-tolerated at clinicallyrelevant dosages that display potent anti-tumor efficacy. Liposomal delivery of the glucocorticoid dexamethasone inhibits the growth of malignant bone lesions. We believe that liposomal encapsulation of dexamethasone offers a promising new treatment option for advanced, metastatic prostate cancer which supports further clinical evaluation. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc. 438. Revisiting bone targeting potential of novel hydroxyapatite based surface modified PLGA nanoparticles of risedronate: Pharmacokinetic and biochemical assessment. PubMed Rawat, Purnima; Ahmad, Iqbal; Thomas, Shindu C; Pandey, Shweta; Vohora, Divya; Gupta, Sarika; Ahmad, Farhan Jalees; Talegaonkar, Sushama 2016-06-15 Hydroxyapatite based biodegradable mPEG-PLGA nanoparticles of risedronate (mPEG-PLGA-RIS-HA) were prepared by water miscible dialysis method for synergistic treatment of osteoporosis. The bone targeting potential of prepared nanoparticles was evaluated by performing the cell viability study and protein estimation in pre-osteoblast cell line (MC3T3E1). Biochemical and in-vivo pharmacokinetic studies on osteoporotic rat model treated with different formulations were performed. Under the biochemical study ALP, TRAP, HxP and Calcium levels were determined. Osteoporotic model treated with prepared nanoparticles indicated significant effect on bone. Pharmacokinetic studies revealed 6fold and 4-fold increase in the relative bioavailability after intravenous and oral administration of nanoparticles respectively as compared to marketed formulation confirming better effective drug transport. Biochemical investigations also showed a significant change in biomarker level which ultimately lead to bone formation/resorption. A stability analysis has also been carried out according to ICH guidelines (Q1AR2) and shelf life was found to be 1year and 4 months for the prepared formulation. Thus the results of present studies indicated that mPEG-PLGA-RIS-HA NPs has a great potential for sustained delivery of RIS for the treatment and prevention of osteoporosis and to minimize the adverse effects of RIS typically induced by its oral administration. Copyright © 2016 Elsevier B.V. All rights reserved. 439. CT-Guided Radiofrequency Ablation in Patients with Hepatic Metastases from Breast Cancer SciTech Connect Jakobs, Tobias F., E-mail:
[email protected]; Hoffmann, Ralf-Thorsten; Schrader, Angelika 2009-01-15 The purpose of this study was to evaluate technical success, technique effectiveness, and survival following radiofrequency ablation for breast cancer liver metastases and to determine prognostic factors. Forty-three patients with 111 breast cancer liver metastases underwent CT-guided percutaneous radiofrequency (RF) ablation. Technical success and technique effectiveness was evaluated by performing serial CT scans. We assessed the prognostic value of hormone receptor status, overexpression of human epidermal growth factor receptor 2 (HER2), and presence of extrahepatic tumor spread. Survival rates were calculated using the Kaplan-Meier method. Technical success was achieved in 107 metastases (96%). Primary technique effectiveness was 96%. During follow-upmore » local tumor progression was observed in 15 metastases, representing a secondary technique effectiveness of 86.5%. The overall time to progression to the liver was 10.5 months. The estimated overall median survival was 58.6 months. There was no significant difference in terms of survival probability with respect to hormone receptor status, HER2 overexpression, and presence of isolated bone metastases. Survival was significantly lower among patients with extrahepatic disease, with the exception of skeletal metastases. We conclude that CT-guided RF ablation of liver metastases from breast cancer can be performed with a high degree of technical success and technique effectiveness, providing promising survival rates in patients with no visceral extrahepatic disease. Solitary bone metastases did not negatively affect survival probability after RF ablation.« less 440. Colorectal Liver Metastases PubMed Central Haddad, Ashraf J.; Bani Hani, Murad; Pawlik, Timothy M.; Cunningham, Steven C. 2011-01-01 The diagnosis and management of CRLM is complex and requires a multidisciplinary team approach for optimal outcomes. Over the past several decades, the 5-year survival following resection of CRLM has increased and the criteria for resection have broadened substantially. Even patients with multiple, bilateral CRLM, previously thought unresectable, may now be candidates for resection. Two-stage hepatectomy, repeat curative-intent hepatectomy, and even selected resection of extrahepatic metastases have further increased the number of patients who may be treated with curative intent. Multiple liver-directed therapies exist to treat unresectable, incurable patients with adequate survival benefit and morbidity rates. PMID:22312501 « 20 21 22 23 24 » « 21 22 23 24 25 » 441. [Histological and molecular analysis of brain metastases]. PubMed Lechapt Zalcman, E; Bazille, C; Rousseau, A; Burel-Vandenbos, F; Pierga, J-Y 2015-02-01 The first step in the diagnosis of a metastatic brain lesion is to exclude a primary central nervous sytem tumour, followed by verification or identification of the primary tumor site, in order to guide the clinician to specific therapy. In addition to morphological features, ancillary immunohistochemical study is most effective for the evaluation of a metastatic neoplasm of unknown primary. Although the main principles are same, there are slight variations in the approach to the secondary lesion in the central nervous system versus other regions. Indeed, immunohistochemical approach focuses on the most common tumor types associated with secondary brain colonization: lung cancer, breast cancer and melanoma. Several studies have reported that targeted therapies are capable of reducing brain metastases in melanoma or non-small cell lung cancer, sometimes with a high dramatic response. These results have clearly impacted routine neuropathological practice. It is likely that molecular subtyping of central nervous system metastases will play an increasing role in the future. In accordance with the recommendations of Inca (French national cancer institute), the pathologist develops appropriate strategies for molecular and immunohistochemical analysis, in order to provide results as soon as possible. This article summarizes the diagnosic approach to brain metastases, with a focus on the recent emergence of targeted therapies. Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved. 442. Receptor-Targeted, Magneto-Mechanical Stimulation of Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells PubMed Central Hu, Bin; El Haj, Alicia J; Dobson, Jon 2013-01-01 Mechanical cues are employed to promote stem cell differentiation and functional tissue formation in tissue engineering and regenerative medicine. We have developed a Magnetic Force Bioreactor (MFB) that delivers highly targeted local forces to cells at a pico-newton level, utilizing magnetic micro- and nano-particles to target cell surface receptors. In this study, we investigated the effects of magnetically targeting and actuating specific two mechanical-sensitive cell membrane receptors—platelet-derived growth factor receptor α (PDGFRα) and integrin ανβ3. It was found that a higher mineral-to-matrix ratio was obtained after three weeks of magneto-mechanical stimulation coupled with osteogenic medium culture by initially targeting PDGFRα compared with targeting integrin ανβ3 and non-treated controls. Moreover, different initiation sites caused a differentiated response profile when using a 2-day-lagged magneto-mechanical stimulation over culture periods of 7 and 12 days). However, both resulted in statistically higher osteogenic marker genes expression compared with immediate magneto-mechanical stimulation. These results provide insights into important parameters for designing appropriate protocols for ex vivo induced bone formation via magneto-mechanical actuation. PMID:24065106 443. Metastatic Prostate Cancer and the Bone: Significance and Therapeutic Options. PubMed Gartrell, Benjamin A; Coleman, Robert; Efstathiou, Eleni; Fizazi, Karim; Logothetis, Christopher J; Smith, Matthew R; Sonpavde, Guru; Sartor, Oliver; Saad, Fred 2015-11-01 Skeletal involvement is common in metastatic prostate cancer (PCa) and is associated with skeletal-related events (SREs). The interaction of PCa with the bone microenvironment contributes to self-perpetuating progression of cancer in bone. Bone-targeted agents (BTAs) are available for use in metastatic castration-resistant prostate cancer (mCRPC). To review the biology of bone metastases in PCa and to review the clinical trial data for BTAs in PCa. A literature search was conducted in October 2014. Keywords included clinical trial, prostate cancer, denosumab, bisphosphonates, zoledronic acid, radium-223, bone turnover markers, skeletal-related events, and symptomatic skeletal events. The biology of bone metastases in PCa is summarized. Data supporting the use of BTAs in PCa are reviewed, and issues related to the combination and sequencing of available agents are discussed. The osteoclast-targeted agents zoledronic acid and denosumab decrease SREs in mCRPC, and the α-emitting radiopharmaceutical agent radium-223 improves survival and decreases symptomatic skeletal events. Limited data are available to guide the sequence and combination of BTAs with disease-modifying agents, although data support the use of osteoclast-targeted drugs with chemotherapy, androgen-targeted agents, and radium-223. Zoledronic acid does not reduce SREs when started prior to castration resistance, although osteoclast-targeted agents do improve outcomes when used in patients with asymptomatic to minimally symptomatic chemotherapy-naive mCRPC. The optimal sequence of radium223 with chemotherapy is uncertain, although data suggest the efficacy and tolerability of radium-223 is similar with either sequence. Clinical trials evaluating the combination of BTAs with other agents are under way. The optimization of sequence and combination strategies will guide the best use of available agents. The literature pertaining to bone metastases in prostate cancer (PCa) was reviewed, and the current 444. Solitary Adrenal Metastases from Breast Invasive Ductal Carcinoma. PubMed Stroescu, Cezar; Gilca, Iulian; Chirita, DragoÅŸ; Poenaru, Radu; PuÅŸcaÅŸu, Ana; Pescaru, Diana; Birceanu, Adelina; NiÅ£ipir, Cornelia; Copcă, Narcis 2017-01-01
The usual neoplastic dissease involving suprarenal glands are adrenal metastaes. The majority of suprarenal metastatic disease arise from lung cancer, followed by the stomach and colon cancer, oesophagus, the liver/bile ducts cancer and renal cell carcinoma. Invasive mammary carcinoma usually spreads to the bones, lungs, lymph nodes, liver and the brain. Adrenal gland metastases from invasive no special type carcinoma represents an extremly low rate number of cases. We discuss about a 66 year old patient who presented with a solitary adrenal metastases from triple negative breast invasive carcinoma. The patient underwent total left adrenalectomy in June 2016. No further adjuvants therapies were performed. At the time of writing the patient is in good condition, without any evidence of recurrence. The role of surgical and adjuvant therapy in treating adrenal metastases after breast cancer in survival rate will be determined in future studies. Celsius. 445. Bone biopsy protocol for advanced prostate cancer in the era of precision medicine. PubMed Sailer, Verena; Schiffman, Marc H; Kossai, Myriam; Cyrta, Joanna; Beg, Shaham; Sullivan, Brian; Pua, Bradley B; Lee, Kyungmouk Steve; Talenfeld, Adam D; Nanus, David M; Tagawa, Scott T; Robinson, Brian D; Rao, Rema A; Pauli, Chantal; Bareja, Rohan; Beltran, Luis S; Sigaras, Alexandros; Eng, Kenneth Wa; Elemento, Olivier; Sboner, Andrea; Rubin, Mark A; Beltran, Himisha; Mosquera, Juan Miguel 2018-03-01 Metastatic biopsies are increasingly being performed in patients with advanced prostate cancer to search for actionable targets and/or to identify emerging resistance mechanisms. Due to a predominance of bone metastases and their sclerotic nature, obtaining sufficient tissue for clinical and genomic studies is challenging. Patients with prostate cancer bone metastases were enrolled between February 2013 and March 2017 on an institutional review board-approved protocol for prospective image-guided bone biopsy. Bone biopsies and blood clots were collected fresh. Compact bone was subjected to formalin with a decalcifying agent for diagnosis; bone marrow and blood clots were frozen in optimum cutting temperature formulation for next-generation sequencing. Frozen slides were cut from optimum cutting temperature cryomolds and evaluated for tumor histology and purity. Tissue was macrodissected for DNA and RNA extraction, and whole-exome sequencing and RNA sequencing were performed. Seventy bone biopsies from 64 patients were performed. Diagnostic material confirming prostate cancer was successful in 60 of 70 cases (85.7%). The median DNA/RNA yield was 25.5 ng/μL and 16.2 ng/μL, respectively. Whole-exome sequencing was performed successfully in 49 of 60 cases (81.7%), with additional RNA sequencing performed in 20 of 60 cases (33.3%). Recurrent alterations were as expected, including those involving the AR, PTEN, TP53, BRCA2, and SPOP genes. This prostate cancer bone biopsy protocol ensures a valuable source for high-quality DNA and RNA for tumor sequencing and may be used to detect actionable alterations and resistance mechanisms in patients with bone metastases. Cancer 2018;124:1008-15. © 2017 American Cancer Society. © 2017 American Cancer Society. 446. Epigenetic Pathways Regulating Bone Homeostasis: Potential Targeting for Intervention of Skeletal Disorders PubMed Central Gordon, Jonathan A. R.; Montecino, Martin A.; Aqeilan, Rami I.; Stein, Janet L.; Stein, Gary S.; Lian, Jane B. 2014-01-01 Epigenetic regulation utilizes different mechanisms to convey heritable traits to progeny cells that are independent of DNA sequence, including DNA silencing, post-translational modifications of histone proteins and the post-transcriptional modulation of RNA transcript levels by non-coding RNAs. Although long non-coding RNAs have recently emerged as important regulators of gene imprinting, but their functions during osteogenesis are as yet unexplored. In contrast, microRNAs (miRNAs) are well characterized for their control of osteogenic and osteoclastic pathways; thus, further defining how gene regulatory networks essential for skeleton functions are coordinated and finely tuned through the activities of miRNAs. Roles of miRNAs are constantly expanding as new studies uncover associations with skeletal disorders. The distinct functions of epigenetic regulators and evidence for integrating their activities to control normal bone gene expression and bone disease will be presented. In addition, potential for using “signature microRNAs†to identify, manage and therapeutically treat osteosarcoma will be discussed in this review. PMID:25260661 447. Bone Marrow Metastasis Is an Early Stage of Bone Metastasis in Breast Cancer Detected Clinically by F18-FDG-PET/CT Imaging PubMed Central 2017-01-01 Objective To determine the value of 18F-FDG PET/CT in detection of bone marrow (BM) metastasis in breast cancer which is considered an early stage of bone metastasis. Patients and Methods Retrospectively, breast cancer patients with bone metastasis were included. BM metastasis was considered if the lesion was PET positive/CT occult while bone metastasis was considered if the lesion was PET positive/ CT positive. BM metastases were observed sequentially on F18-FDG PET/CT. Results We included 35 patients. Eighteen patients (51%) had BM metastases in addition to other bone metastases. BM metastases comprised 24% of all lesions. Posttreatment scan was performed on 26/35 patients. Twentythree percent of BM metastases had resolved completely without causing bone destruction after treatment. Sixty-five percent of BM metastases had converted into bone metastases after treatment. Twelve percent of BM metastases had persisted after treatment. Conclusion This retrospective study showed clinically by 18F-FDG PET/CT imaging that BM metastasis is an early stage of bone metastasis in breast cancer. Interestingly, 18F-FDG-PET/CT showed that early eradication of individual BM metastasis by systemic treatment precluded development of bone metastasis. However, more research is needed to study the impact of an early diagnosis of BM metastases on treatment outcome. PMID:28884133 448. Bone Marrow Metastasis Is an Early Stage of Bone Metastasis in Breast Cancer Detected Clinically by F18-FDG-PET/CT Imaging. PubMed Al-Muqbel, Kusai M 2017-01-01 To determine the value of 18F-FDG PET/CT in detection of bone marrow (BM) metastasis in breast cancer which is considered an early stage of bone metastasis. Retrospectively, breast cancer patients with bone metastasis were included. BM metastasis was considered if the lesion was PET positive/CT occult while bone metastasis was considered if the lesion was PET positive/ CT positive. BM metastases were observed sequentially on F18-FDG PET/CT. We included 35 patients. Eighteen patients (51%) had BM metastases in addition to other bone metastases. BM metastases comprised 24% of all lesions. Posttreatment scan was performed on 26/35 patients. Twenty-three percent of BM metastases had resolved completely without causing bone destruction after treatment. Sixty-five percent of BM metastases had converted into bone metastases after treatment. Twelve percent of BM metastases had persisted after treatment. This retrospective study showed clinically by 18F-FDG PET/CT imaging that BM metastasis is an early stage of bone metastasis in breast cancer. Interestingly, 18F-FDG-PET/CT showed that early eradication of individual BM metastasis by systemic treatment precluded development of bone metastasis. However, more research is needed to study the impact of an early diagnosis of BM metastases on treatment outcome. 449. Robotic Radiosurgery for Adrenal Gland Metastases PubMed Central Heidorn, Sarah-Charlotta; Kremer, Nikolaus; Muacevic, Alexander; Fürweger, Christoph 2017-01-01 Introduction The purpose of this study was to investigate the safety and efficacy of CyberKnife (CK) robotic radiosurgery for treatment of adrenal metastases. Methods We performed a retrospective analysis of 23 patients with adrenal metastases who had been treated with CK between October 2006 and December 2015. Fifteen patients received chemotherapy prior to radiosurgery, all patients underwent computer tomography (CT) fluoroscopically guided percutaneous placement of one to three gold fiducials into the adrenal gland. Nineteen patients were selected for single-fraction radiosurgery with a median dose of 22 Gy, four patients were treated in three fractions with a median dose of 13.5 Gy. Results Median follow-up time was 23.6 months. Four patients (17%) experienced local relapse during the evaluation period with a mean time of 19 months to tumor progression. The actuarial local tumor control rate was 95% after one year and 81% after two years. Three of the four patients with local recurrence were retreated with CK radiosurgery. Dynamic tumor tracking enabled accurate treatment with correlation errors less than 2 mm, despite extensive respiration-induced target motion up to 22 mm. Apart from nausea directly after treatment in five patients, we observed no early or late treatment-related side effects. Conclusions Single fraction robotic radiosurgery for adrenal gland metastases is a safe and effective treatment option for patients who are not eligible for surgical resection. PMID:28451479 450. The effect of a multicomponent dual-modality exercise program targeting osteoporosis on bone health status and physical function capacity of postmenopausal women. PubMed Tolomio, Silvia; Ermolao, Andrea; Lalli, Alberto; Zaccaria, Marco 2010-01-01 Exercise is important for the prevention of osteoporosis and the reduction of fracture risk because it improves muscle mass and strength, besides improving balance. We evaluated the effect of a specific exercise program on bone mass and quality and physical function capacity in postmenopausal women with low bone mineral density. Participants (N = 125) underwent a bone mass (Dual X-ray Absorptiometry), bone quality (osteosonography), and physical functional capacity assessment. Fifty-eight of them took part in an 11-month exercise program (E), that included a multicomponent (strength, aerobic capacity, balance, joint mobility) dual-modality (on ground and in the water; alternating group and homebased exercise periods) exercise regimen. The others represented a control group (C) that did not exercise. After the exercise program all participants were reevaluated. After the training program: femoral neck T-score significantly improved in E; C significantly decreased all bone quality (osteosonography) parameters, whereas E showed no differences; E significantly improved all the physical function capacity parameters, while most of them decreased or did not change in C. A specific exercise program targeting osteoporosis improves physical function capacity, reduces physiological bone loss, and maintains bone quality in low bone mineral density postmenopausal women. 451. Influence of the location and number of metastases in the survival of metastatic prostatic cancer patients. PubMed Guijarro, A; Hernández, V; de la Morena, J M; Jiménez-Valladolid, I; Pérez-Fernández, E; de la Peña, E; Llorente, C 2017-05-01 The prognosis of patients diagnosed with metastatic prostate cancer seems to be modulated by factors such as the number and site of metastases. Our objective is to evaluate survival outcomes according to the number and site of metastases in our series of metastatic patients over the last 15 years. A retrospective analysis was performed on patients diagnosed between 1998 and 2014. We analyzed overall survival and progression-free survival, depending on the number and location of metastases on patients with newly diagnosed metastatic prostate cancer. Other potential prognostic factors were also evaluated: age, clinical stage, PSA at diagnosis, Gleason, PSA nadir, time till PSA nadir and first-line or second-line treatment after progression. We analyzed a series of 162 patients. The mean age was 72.7yr (SD: 8.5). The estimated median overall survival was 3.9 yr (95% CI 2.65.2). The overall survival in patients with only lymph node metastases was 7 yr (95% CI 4.1-9.7), 3.9 (95%CI 2.3-5.5) in patients with only bone metastases, 2.5 yr (95% CI 2-2.3) in lymph nodes and bone metastases, and 2.2 yr (95% CI 1.4-3) in patients with visceral metastases (P<.001). In multivariate analysis, the location of metastasesis significantly associated with overall survival and progression-free survival. The number of metastases showed no association with survival. The site of metastases has a clear impact on both overall survival and progression-free survival. Patients with only lymph node involvement had a better prognosis. The number of metastases showed no significant impact on survival in our series. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved. 452. Leukoencephalopathy After Stereotactic Radiosurgery for Brain Metastases SciTech Connect Trifiletti, Daniel M.; Lee, Cheng-Chia; Schlesinger, David; Larner, James M.; Xu, Zhiyuan; Sheehan, Jason P. 2015-11-15 Purpose: Although the use of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases has increased dramatically during the past decade to avoid the neurocognitive dysfunction induced by whole brain radiation therapy (WBRT), the cumulative neurocognitive effect of numerous SRS sessions remains unknown. Because leukoencephalopathy is a sensitive marker for radiation-induced central nervous system damage, we studied the clinical and dosimetric predictors of SRS-induced leukoencephalopathy. Methods and Materials: Patients treated at our institution with at least 2 sessions of SRS for brain metastases from 2007 to 2013 were reviewed. The pre- and post-SRS magnetic resonance imaging sequences were reviewed and graded for white matter changes associated with radiation leukoencephalopathy using a previously validated scale. Patient characteristics and SRS dosimetric parameters were reviewed for factors that contributed to leukoencephalopathy using Cox proportional hazards modeling. Results: A total of 103 patients meeting the inclusion criteria were identified. The overall incidence of leukoencephalopathy was 29% at year 1, 38% at year 2, and 53% at year 3. Three factors were associated with radiation-induced leukoencephalopathy: (1) the use of WBRT (P=.019); (2) a higher SRS integral dose to the cranium (P=.036); and (3) the total number of intracranial metastases (P=.003). Conclusions: Our results have established that WBRT plus SRS produces leukoencephalopathy at a much higher rate than SRS alone. In addition, for patients who did not undergo WBRT before SRS, the integral dose was associated with the development of leukoencephalopathy. As the survival of patients with central nervous system metastases increases and as the neurotoxicity of chemotherapeutic and targeted agents becomes established, these 3 potential risk factors will be important to consider. 453. Leukoencephalopathy After Stereotactic Radiosurgery for Brain Metastases SciTech Connect Trifiletti, Daniel M., E-mail:
[email protected]; Lee, Cheng-Chia; Schlesinger, David 2015-11-15 Purpose: Although the use of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases has increased dramatically during the past decade to avoid the neurocognitive dysfunction induced by whole brain radiation therapy (WBRT), the cumulative neurocognitive effect of numerous SRS sessions remains unknown. Because leukoencephalopathy is a sensitive marker for radiation-induced central nervous system damage, we studied the clinical and dosimetric predictors of SRS-induced leukoencephalopathy. Methods and Materials: Patients treated at our institution with at least 2 sessions of SRS for brain metastases from 2007 to 2013 were reviewed. The pre- and post-SRS magnetic resonance imaging sequences were reviewedmore » and graded for white matter changes associated with radiation leukoencephalopathy using a previously validated scale. Patient characteristics and SRS dosimetric parameters were reviewed for factors that contributed to leukoencephalopathy using Cox proportional hazards modeling. Results: A total of 103 patients meeting the inclusion criteria were identified. The overall incidence of leukoencephalopathy was 29% at year 1, 38% at year 2, and 53% at year 3. Three factors were associated with radiation-induced leukoencephalopathy: (1) the use of WBRT (P=.019); (2) a higher SRS integral dose to the cranium (P=.036); and (3) the total number of intracranial metastases (P=.003). Conclusions: Our results have established that WBRT plus SRS produces leukoencephalopathy at a much higher rate than SRS alone. In addition, for patients who did not undergo WBRT before SRS, the integral dose was associated with the development of leukoencephalopathy. As the survival of patients with central nervous system metastases increases and as the neurotoxicity of chemotherapeutic and targeted agents becomes established, these 3 potential risk factors will be important to consider.« less 454. Radium-223: From Radiochemical Development to Clinical Applications in Targeted Cancer Therapy SciTech Connect Bruland, Oyvind S.; Jonasdottir, Thora J.; Fisher, Darrell R.; Larsen, Roy H. 2008-09-15 The radiochemical properties of radium-223 (223Ra, T1/2 = 11.4 d) render this alpha-emitting radionuclide promising for targeted cancer therapy. Together with its short-lived daughters, each 223Ra decay produces four alpha-particle emissions—which enhance therapy effectiveness at the cellular level. In this paper, we review the recently published data reported for pre-clinical and clinical use of 223Ra in cancer treatment. We have evaluated two distinct chemical forms of 223Ra in vivo: 1) cationic 223Ra as dissolved RaCl2, and 2) liposome-encapsulated 223Ra. Cationic 223Ra seeks metabolically active osteoblastic bone and tumor lesions with high uptake and strong binding affinity based on its similarities to calcium. Based on these properties, we have advanced the clinical use of 223Ra for treating bone metastases from late-stage breast and prostate cancer. The results show impressive anti-tumor activity and improved overall survival in hormone-refractory prostate cancer patients with bone metastases. In other studies, we have evaluated the biodistribution and tumor uptake of liposomally encapsulated 223Ra in mice with human osteosarcoma xenografts, and in dogs with spontaneous osteosarcoma and associated soft tissue metastases. Results indicate excellent biodistributions in both species. In dogs, we found considerable uptake of liposomal 223Ra in cancer metastases in multiple organs, resulting in favorable tumor-to-normal soft tissue ratios. Collectively, these findings show an outstanding potential for 223Ra as a therapeutic agent. 455. Targeting Angiogenesis-Dependent Calcified Neoplasms Using Combined Polymer Therapeutics PubMed Central Segal, Ehud; Pan, Huaizhong; Ofek, Paula; Udagawa, Taturo; KopeÄková, Pavla; KopeÄek, JindÅ™ich; Satchi-Fainaro, Ronit 2009-01-01 Background There is an immense clinical need for novel therapeutics for the treatment of angiogenesis-dependent calcified neoplasms such as osteosarcomas and bone metastases. We developed a new therapeutic strategy to target bone metastases and calcified neoplasms using combined polymer-bound angiogenesis inhibitors. Using an advanced “living polymerization†technique, the reversible addition-fragmentation chain transfer (RAFT), we conjugated the aminobisphosphonate alendronate (ALN), and the potent antiangiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer through a Glycine-Glycine-Proline-Norleucine linker, cleaved by cathepsin K, a cysteine protease overexpressed at resorption sites in bone tissues. In this approach, dual targeting is achieved. Passive accumulation is possible due to the increase in molecular weight following polymer conjugation of the drugs, thus extravasating from the tumor leaky vessels and not from normal healthy vessels. Active targeting to the calcified tissues is achieved by ALN's affinity to bone mineral. Methods and Finding The anti-angiogenic and antitumor potency of HPMA copolymer-ALN-TNP-470 conjugate was evaluated both in vitro and in vivo. We show that free and conjugated ALN-TNP-470 have synergistic anti-angiogenic and antitumor activity by inhibiting proliferation, migration and capillary-like tube formation of endothelial and human osteosarcoma cells in vitro. Evaluation of anti-angiogenic, antitumor activity and body distribution of HPMA copolymer-ALN-TNP-470 conjugate was performed on severe combined immunodeficiency (SCID) male mice inoculated with mCherry-labeled MG-63-Ras human osteosarcoma and by modified Miles permeability assay. Our targeted bi-specific conjugate reduced VEGF-induced vascular hyperpermeability by 92% and remarkably inhibited osteosarcoma growth in mice by 96%. Conclusions This is the first report to describe a new concept of a narrowly-dispersed combined polymer therapeutic 456. The Osteogenic Niche Promotes Early-Stage Bone Colonization of Disseminated Breast Cancer Cells PubMed Central Wang, Hai; Yu, Cuijuan; Gao, Xia; Welte, Thomas; Muscarella, Aaron M.; Tian, Lin; Zhao, Hong; Zhao, Zhen; Du, Shiyu; Tao, Jianning; Lee, Brendan; Westbrook, Thomas F.; Wong, Stephen T. C.; Jin, Xin; Rosen, Jeffrey M.; Osborne, C. Kent; Zhang, Xiang H.-F. 2014-01-01 Summary Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We further elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human datasets analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. Significance In advanced stages, breast cancer bone metastases are driven by paracrine crosstalk among cancer cells, osteoblasts, and osteoclasts, which constitute a vicious osteolytic cycle. Current therapies targeting this process limit tumor progression, but do not improve patient survival. On the other hand, bone micrometastases may remain indolent for years before activating the vicious cycle, providing a therapeutic opportunity to prevent macrometastases. Here, we show that bone colonization is initiated in a microenvironment niche exhibiting active osteogenesis. Cancer and osteogenic cells form heterotypic adherens junctions, which enhance mTOR activity and drive early-stage bone colonization prior to osteolysis. These results reveal a strong connection between osteogenesis and micrometastasis and suggest potential therapeutic targets to prevent bone macrometastases. PMID:25600338 457. Novel Approaches to Breast Cancer Prevention and Inhibition of Metastases DTIC Science & Technology 2013-10-01 Ras- driven transformation, we performed a near-genome wide screen for genes that control tumor progression. Using this system we have functionally...take the RANKL/RANK system into human breast cancer patients to provide a novel prognostic marker for breast cancer risk and a molecular rationale for...derived cell lines and that the RANKL/RANK system can function as a soil factor that controls bone metastases of epithelial tumors7, a finding that 458. Cryotherapy for liver metastases. PubMed Bala, Malgorzata M; Riemsma, Robert P; Wolff, Robert; Kleijnen, Jos 2013-06-05 Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. In cryoablation, liquid nitrogen or argon gas is delivered to the liver tumour, guided by ultrasound using a specially designed probe. Ice crystal formation during the rapid freezing process causes destruction of cellular structure and kills the tumour cells. To study the beneficial and harmful effects of cryotherapy compared with no intervention, other ablation methods, or systemic treatments in patients with liver metastases. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012. We included all randomised clinical trials assessing the beneficial and harmful effects of cryotherapy and its comparators, irrespective of the location of the primary tumour. We extracted relevant information on participant characteristics, interventions, study outcomes, and data on the outcomes for our review, as well as information on the design and methodology of the trials. Bias risk assessment of and data extraction from the trials fulfilling the inclusion criteria were done by one author and checked by a second author. One randomised clinical trial fulfilled the inclusion criteria of the review. The trial was judged as a trial with high risk of bias due to the unclear report on the generation of the allocation sequence and allocation concealment, blinding, incomplete outcome data and the selective outcome reporting domain. The trial included 123 consecutive patients with solitary or multiple unilobar or bilobar liver metastases who were randomised into two groups, 63 459. miR-34a Blocks Osteoporosis and Bone Metastasis by Inhibiting Osteoclastogenesis and Tgif2 PubMed Central Krzeszinskia, Jing Y.; Wei, Wei; Huynh, HoangDinh; Jin, Zixue; Wang, Xunde; Chang, Tsung-Cheng; Xie, Xian-Jin; He, Lin; Mangala, Lingegowda S.; Lopez-Berestein, Gabriel; Sood, Anil K.; Mendell, Joshua T.; Wan, Yihong 2014-01-01 The bone resorbing osteoclasts significantly contribute to osteoporosis and cancer bone metastases1-3. MicroRNAs (miRNAs) play important roles in physiology and disease4,5, and present tremendous therapeutic potential6. Nonetheless, how miRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is down-regulated during osteoclast differentiation. Osteoclastic miR-34a over-expressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify Tgif2 (transforming growth factor-beta-induced factor 2) as an essential direct miR-34a target that is proosteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers. PMID:25043055 460. [Brain metastases imaging]. PubMed Delmaire, C; Savatovsky, J; Boulanger, T; Dhermain, F; Le Rhun, E; Météllus, P; Gerber, S; Carsin-Nicole, B; Petyt, G 2015-02-01 The therapeutic management of brain metastases depends upon their diagnosis and characteristics. It is therefore imperative that imaging provides accurate diagnosis, identification, size and localization information of intracranial lesions in patients with presumed cerebral metastatic disease. MRI exhibits superior sensitivity to CT for small lesions identification and to evaluate their precise anatomical location. The CT-scan will be made only in case of MRI's contraindication or if MRI cannot be obtained in an acceptable delay for the management of the patient. In clinical practice, the radiologic metastasis evaluation is based on visual image analyses. Thus, a particular attention is paid to the imaging protocol with the aim to optimize the diagnosis of small lesions and to evaluate their evolution. The MRI protocol must include: 1) non-contrast T1, 2) diffusion, 3) T2* or susceptibility-weighted imaging, 4) dynamic susceptibility contrast perfusion, 5) FLAIR with contrast injection, 6) T1 with contrast injection preferentially using the 3D spin echo images. The role of the nuclear medicine imaging is still limited in the diagnosis of brain metastasis. The Tc-sestamibi brain imaging or PET with amino acid tracers can differentiate local brain metastasis recurrence from radionecrosis but still to be evaluated. Copyright © 2015. Published by Elsevier SAS. « 21 22 23 24 25 » « 21 22 23 24 25 » 461. Novel treatment strategies for brain tumors and metastases PubMed Central El-Habashy, Salma E.; Nazief, Alaa M.; Adkins, Chris E.; Wen, Ming Ming; El-Kamel, Amal H.; Hamdan, Ahmed M.; Hanafy, Amira S.; Terrell, Tori O.; Mohammad, Afroz S.; Lockman, Paul R.; Nounou, Mohamed Ismail 2015-01-01 This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following strategies: the development of new drug entities that specifically target the brain cells, the blood–brain barrier and the tumor cells, tailor-designing a novel carrier system that is able to perform multitasks and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a US FDA approved drug with a targeting moiety, diagnostic moiety or PK modifying moiety, or the use of innovative nontraditional approaches such as genetic engineering, stem cells and vaccinations. Until now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are actively ongoing to take brain tumor targeting, and novel and targeted CNS delivery systems to potential clinical application. PMID:24998288 462. Targeted disruption of BMP signaling through type IA receptor (BMPR1A) in osteocyte suppresses SOST and RANKL, leading to dramatic increase in bone mass, bone mineral density and mechanical strength. PubMed Kamiya, Nobuhiro; Shuxian, Lin; Yamaguchi, Ryosuke; Phipps, Matthew; Aruwajoye, Olumide; Adapala, Naga Suresh; Yuan, Hui; Kim, Harry K W; Feng, Jian Q 2016-10-01 Recent studies suggest a critical role of osteocytes in controlling skeletal development and bone remodeling although the molecular mechanism is largely unknown. This study investigated BMP signaling in osteocytes by disrupting Bmpr1a under the Dmp1-promoter. The conditional knockout (cKO) mice displayed a striking osteosclerotic phenotype with increased trabecular bone volume, thickness, number, and mineral density as assessed by X-ray and micro-CT. The bone histomorphometry, H&E, and TRAP staining revealed a dramatic increase in trabecular and cortical bone masses but a sharp reduction in osteoclast number. Moreover, there was an increase in BrdU positive osteocytes (2-5-fold) and osteoid volume (~4-fold) but a decrease in the bone formation rate (~85%) in the cKO bones, indicating a defective mineralization. The SEM analysis revealed poorly formed osteocytes: a sharp increase in cell numbers, a great reduction in cell dendrites, and a remarkable change in the cell distribution pattern. Molecular studies demonstrated a significant decrease in the Sost mRNA levels in bone (>95%), and the SOST protein levels in serum (~85%) and bone matrices. There was a significant increase in the β-catenin (>3-fold) mRNA levels as well as its target genes Tcf1 (>6-fold) and Tcf3 (~2-fold) in the cKO bones. We also showed a significant decrease in the RANKL levels of serum proteins (~65%) and bone mRNA (~57%), and a significant increase in the Opg mRNA levels (>20-fold) together with a significant reduction in the Rankl/Opg ratio (>95%), which are responsible for a sharp reduction in the cKO osteoclasts. The values of mechanical strength were higher in cKO femora (i.e. max force, displacement, and work failure). These results suggest that loss of BMP signaling specifically in osteocytes dramatically increases bone mass presumably through simultaneous inhibition of RANKL and SOST, leading to osteoclast inhibition and Wnt activation together. Finally, a working hypothesis is 463. Cutaneous metastases secondary to pancreatic cancer PubMed Central Horino, Kei; Takamori, Hiroshi; Ikuta, Yoshiaki; Nakahara, Osamu; Chikamoto, Akira; Ishiko, Takatoshi; Beppu, Toru; Baba, Hideo 2012-01-01 AIM: To evaluate prognoses after cutaneous metastases, derived from pancreatic cancer. METHODS: We treated two patients with cutaneous metastases from pancreatic cancer. We reviewed 40 reported patients in addition to our cases and analyzed clinical features of cutaneous metastases from pancreatic cancer. RESULTS: The median survival time (MST) was 5 mo after diagnoses of cutaneous metastases. The cumulative 2-year survival rate was 3.5%. The most frequent site of cutaneous metastases was the umbilicus. The MST of patients who were treated with chemotherapy or chemoradiotherapy (CRT) was 6.5 mo, which was statistically longer in comparison to patients without treatment. Prognoses of cutaneous metastases are similar to other metastatic sites from pancreatic cancer. Receiving chemotherapy or CRT was the only prognostic factor of cutaneous metastases from pancreatic cancer. CONCLUSION: The prognoses of cutaneous metastases are similar to other metastatic pancreatic cancers. Receiving chemotherapy or CRT was the only prognostic factor of cutaneous metastases from pancreatic cancer. PMID:22844548 464. [18F]MEL050 as a melanin-targeted PET tracer: Fully automated radiosynthesis and comparison to18F-FDG for the detection of pigmented melanoma in mice primary subcutaneous tumors and pulmonary metastases. PubMed Rizzo-Padoin, Nathalie; Chaussard, Michael; Vignal, Nicolas; Kotula, Ewa; Tsoupko-Sitnikov, Vadim; Vaz, Sofia; Hontonnou, Fortune; Liu, Wang-Qing; Poyet, Jean-Luc; Vidal, Michel; Merlet, Pascal; Hosten, Benoit; Sarda-Mantel, Laure
2016-12-01 Melanoma is a highly malignant cutaneous tumor of melanin-producing cells. MEL050 is a synthetic benzamide-derived molecule that specifically binds to melanin with high affinity. Our aim was to implement a fully automated radiosynthesis of [ 18 F]MEL050, using for the first time, the AllInOneâ„¢ synthesis module (Trasis), and to evaluate the potential of [ 18 F]MEL050 for the detection of pigmented melanoma in mice primary subcutaneous tumors and pulmonary metastases, and to compare it with that of [ 18 F]FDG. Automated radiosynthesis of [ 18 F]MEL050, including HPLC purification and formulation, were performed on an AllInOneâ„¢ synthesis module. [ 18 F]MEL050 was synthesized using a one-step bromine-for-fluorine nucleophilic heteroaromatic substitution. Melanoma models were induced by subcutaneous (primary tumor) or intravenous (pulmonary metastases) injection of B16-F10-luc2 cells in NMRI mice. The maximum percentage of [ 18 F]MEL050 Injected Dose per g of lung tissue (%ID/g Max) was determined on PET images, compared to [ 18 F]FDG and correlated to in vivo bioluminescence imaging. The automated radiosynthesis of [ 18 F]MEL050 required an overall radiosynthesis time of 48min, with a yield of 13-18% (not-decay corrected) and radiochemical purity higher than 99%. [ 18 F]MEL050 PET/CT images were concordant with bioluminescence imaging, showing increased radiotracer uptake in all primary subcutaneous tumors and pulmonary metastases of mice. PET quantification of radiotracers uptake in tumors and muscles demonstrated similar tumor-to-background ratio (TBR) with [ 18 F]MEL050 and [ 18 F]FDG in subcutaneous tumors and higher TBR with [ 18 F]MEL050 than with [ 18 F]FDG in pulmonary metastases. We successfully implemented the radiosynthesis of [ 18 F]MEL050 using the AllInOneâ„¢ module, including HPLC purification and formulation. In vivo PET/CT validation of [ 18 F]MEL050 was obtained in mouse models of pigmented melanoma, where higher [ 18 F]MEL050 uptake was observed 465. Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis. PubMed Nakajima, Kosei; Kho, Dhong Hyo; Yanagawa, Takashi; Harazono, Yosuke; Hogan, Victor; Chen, Wei; Ali-Fehmi, Rouba; Mehra, Rohit; Raz, Avraham 2016-03-15 Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including tartrate-resistant acid phosphatase, and reduced the number of mature osteoclasts. Structurally, the 158-175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and colocalized with myosin-2A along the surface of cell-cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche. ©2016 American Association for Cancer Research. 466. Unsanctifying the sanctuary: challenges and opportunities with brain metastases PubMed Central Puhalla, Shannon; Elmquist, William; Freyer, David; Kleinberg, Lawrence; Adkins, Chris; Lockman, Paul; McGregor, John; Muldoon, Leslie; Nesbit, Gary; Peereboom, David; Smith, Quentin; Walker, Sara; Neuwelt, Edward 2015-01-01 While the use of targeted therapies, particularly radiosurgery, has broadened therapeutic options for CNS metastases, patients respond minimally and prognosis remains poor. The inability of many systemic chemotherapeutic agents to penetrate the blood-brain barrier (BBB) has limited their use and allowed brain metastases to become a burgeoning clinical challenge. Adequate preclinical models that appropriately mimic the metastatic process, the BBB, and blood-tumor barriers (BTB) are needed to better evaluate therapies that have the ability to enhance delivery through or penetrate into these barriers and to understand the mechanisms of resistance to therapy. The heterogeneity among and within different solid tumors and subtypes of solid tumors further adds to the difficulties in determining the most appropriate treatment approaches and methods of laboratory and clinical studies. This review article discusses therapies focused on prevention and treatment of CNS metastases, particularly regarding the BBB, and the challenges and opportunities these therapies present. PMID:25846288 467. Stereotactic radiosurgery of brain metastases. PubMed Specht, Hanno M; Combs, Stephanie E 2016-09-01 Brain metastases are a common problem in solid malignancies and still represent a major cause of morbidity and mortality. With the ongoing improvement in systemic therapies, the expectations on the efficacy of brain metastases directed treatment options are growing. As local therapies against brain metastases continue to evolve, treatment patterns have shifted from a palliative "one-treatment-fits-all" towards an individualized, patient adapted approach. In this article we review the evidence for stereotactic radiation treatment based on the current literature. Stereotactic radiosurgery (SRS) as a local high precision approach for the primary treatment of asymptomatic brain metastases has gained wide acceptance. It leads to lasting tumor control with only minor side effects compared to whole brain radiotherapy, since there is only little dose delivered to the healthy brain. The same holds true for hypofractionated stereotactic radiotherapy (HFSRT) for large metastases or for lesions close to organs at risk (e.g. the brainstem). New treatment indications such as neoadjuvant SRS followed by surgical resection or postoperative local therapy to the resection cavity show promising data and are also highlighted in this manuscript. With the evolution of local treatment options, optimal patient selection becomes more and more crucial. This article aims to aid decision making by outlining prognostic factors, treatment techniques and indications and common dose prescriptions. 468. The effect of distant metastases sites on survival in de novo stage-IV breast cancer: A SEER database analysis. PubMed Wu, San-Gang; Li, Hui; Tang, Li-Ying; Sun, Jia-Yuan; Zhang, Wen-Wen; Li, Feng-Yan; Chen, Yong-Xiong; He, Zhen-Yu 2017-06-01 To investigate the effect of distant metastases sites on survival in patients with de novo stage-IV breast cancer. From 2010 to 2013, patients with a diagnosis of de novo stage-IV breast cancer were identified using the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox regression analyses were performed to analyze the effect of distant metastases sites on breast cancer-specific survival and overall survival. A total of 7575 patients were identified. The most common metastatic sites were bone, followed by lung, liver, and brain. Patients with hormone receptor+/human epidermal growth factor receptor 2- and hormone receptor+/human epidermal growth factor receptor 2+ status were more prone to bone metastases. Lung and brain metastases were common in hormone receptor-/human epidermal growth factor receptor 2+ and hormone receptor-/human epidermal growth factor receptor 2- subtypes, and patients with hormone receptor+/ human epidermal growth factor receptor 2+ and hormone receptor-/human epidermal growth factor receptor 2+ subtypes were more prone to liver metastases. Patients with liver and brain metastases had unfavorable prognosis for breast cancer-specific survival and overall survival, whereas bone and lung metastases had no effect on patient survival in multivariate analyses. The hormone receptor-/human epidermal growth factor receptor 2- subtype conferred a significantly poorer outcome in terms of breast cancer-specific survival and overall survival. hormone receptor+/human epidermal growth factor receptor 2+ disease was associated with the best prognosis in terms of breast cancer-specific survival and overall survival. Patients with liver and brain metastases were more likely to experience poor prognosis for breast cancer-specific survival and overall survival by various breast cancer subtypes. Distant metastases sites have differential impact on clinical outcomes in stage-IV breast cancer. Follow-up screening for brain and 469. The critical role of the ZNF217 oncogene in promoting breast cancer metastasis to the bone. PubMed Bellanger, Aurélie; Donini, Caterina F; Vendrell, Julie A; Lavaud, Jonathan; Machuca-Gayet, Irma; Ruel, Maëva; Vollaire, Julien; Grisard, Evelyne; GyÅ‘rffy, Balázs; Bièche, Ivan; Peyruchaud, Olivier; Coll, Jean-Luc; Treilleux, Isabelle; Maguer-Satta, Véronique; Josserand, Véronique; Cohen, Pascale A 2017-05-01 Bone metastasis affects >70% of patients with advanced breast cancer. However, the molecular mechanisms underlying this process remain unclear. On the basis of analysis of clinical datasets, and in vitro and in vivo experiments, we report that the ZNF217 oncogene is a crucial mediator and indicator of bone metastasis. Patients with high ZNF217 mRNA expression levels in primary breast tumours had a higher risk of developing bone metastases. MDA-MB-231 breast cancer cells stably transfected with ZNF217 (MDA-MB-231ZNF217) showed the dysregulated expression of a set of genes with bone-homing and metastasis characteristics, which overlapped with two previously described 'osteolytic bone metastasis' gene signatures, while also highlighting the bone morphogenetic protein (BMP) pathway. The latter was activated in MDA-MB-231-ZNF217 cells, and its silencing by inhibitors (Noggin and LDN-193189) was sufficient to rescue ZNF217-dependent cell migration, invasion or chemotaxis towards the bone environment. Finally, by using noninvasive multimodal in vivo imaging, we found that ZNF217 increases the metastatic growth rate in the bone and accelerates the development of severe osteolytic lesions. Altogether, the findings of this study highlight ZNF217 as an indicator of the emergence of breast cancer bone metastasis; future therapies targeting ZNF217 and/or the BMP signalling pathway may be beneficial by preventing the development of bone metastases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 470. Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition. PubMed Kubista, Bernd; Schoefl, Thomas; Mayr, Lisa; van Schoonhoven, Sushilla; Heffeter, Petra; Windhager, Reinhard; Keppler, Bernhard K; Berger, Walter 2017-04-12 Osteosarcoma is the most frequent primary malignant bone tumor. Although survival has distinctly increased due to neoadjuvant chemotherapy in the past, patients with metastatic disease and poor response to chemotherapy still have an adverse prognosis. Hence, development of new therapeutic strategies is still of utmost importance. Anticancer activity of KP46 against osteosarcoma cell models was evaluated as single agent and in combination approaches with chemotherapeutics and Bcl-2 inhibitors using MTT assay. Underlying mechanisms were tested by cell cycle, apoptosis and autophagy assays. KP46 exerted exceptional anticancer activity at the nanomolar to low micromolar range, depending on the assay format, against all osteosarcoma cell models with minor but significant differences in IC 50 values. KP46 treatment of osteosarcoma cells caused rapid loss of cell adhesion, weak cell cycle accumulation in S-phase and later signs of apoptotic cell death. Furthermore, already at sub-cytotoxic concentrations KP46 reduced the migratory potential of osteosarcoma cells and exerted synergistic effects with cisplatin, a standard osteosarcoma chemotherapeutic. Moreover, the gallium compound induced signs of autophagy in osteosarcoma cells. Accordingly, blockade of autophagy by chloroquine but also by the Bcl-2 inhibitor obatoclax increased the cytotoxic activity of KP46 treatment significantly, suggesting autophagy induction as a protective mechanism against KP46. Together, our results identify KP46 as a new promising agent to supplement standard chemotherapy and possible future targeted therapy in osteosarcoma. 471. WNT5A and Its Receptors in the Bone-Cancer Dialogue. PubMed Thiele, Stefanie; Rachner, Tilman D; Rauner, Martina; Hofbauer, Lorenz C 2016-08-01 Wnt signaling is critical for tumorigenesis and skeletal remodeling. However, its contribution to the formation of metastatic bone lesions remains poorly defined. One major challenge of unraveling its role in cancer progression is the high complexity of Wnt signaling, which includes numerous ligands, receptors, and inhibitors, with intricate biological effects and specific signaling pathways depending on the cellular context. In this perspective, we summarize the role of the noncanonical Wnt ligand WNT5A in the development and metastatic process of osteotropic cancer entities. We focus on its tumor-suppressive function in breast cancer, tumor promoting effects in melanoma, and ambiguous role in prostate cancer, and discuss potential challenges and opportunities that may be associated with targeting Wnt signaling for cancer therapy and treatment of bone metastases. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research. 472. [Imaging diagnostics of bone sarcomas]. PubMed Krämer, J A; Gübitz, R; Beck, L; Heindel, W; Vieth, V 2014-06-01 Bone tumors and especially bone sarcomas are rare lesions of the skeletal system in comparison to the much more frequently occurring bone metastases. Despite the relative rarity they are important differential diagnoses of bone lesions. The aim of this article is to give the reader an insight into the fundamentals of the primary imaging of bone sarcomas and to illustrate this with the help of two examples (e.g. osteosarcoma and chondrosarcoma). The foundation of the imaging of bone sarcomas is the radiograph in two planes. This method delivers important information on bone tumors. This information should be analyzed with the help of the Lodwick classification, the configuration of periosteal reactions and a possible reaction of the cortex. A possible tumor matrix and the localization within the skeleton or within long bones also provide important information for differential diagnostic delimitation. Magnetic resonance imaging (MRI) with specific adapted bone tumor sequences allows an exact local staging of a bone sarcoma. In addition to local imaging a compartmental MRI which illustrates the entire extent of tumor-bearing bone and the adjacent joints should be performed to rule out possible skip lesions. The most common distant metastases of osteosarcoma and chondrosarcoma occur in the lungs; therefore, a computed tomography (CT) of the chest is part of staging. Other imaging methods, such as CT of the tumor, positron emission tomography CT (PET-CT), bone scan and whole body MRI supplement the imaging depending on tumor type. 473. CD169(+) macrophages mediate pathological formation of woven bone in skeletal lesions of prostate cancer. PubMed Wu, Andy C; He, Yaowu; Broomfield, Amy; Paatan, Nicoll J; Harrington, Brittney S; Tseng, Hsu-Wen; Beaven, Elizabeth A; Kiernan, Deirdre M; Swindle, Peter; Clubb, Adrian B; Levesque, Jean-Pierre; Winkler, Ingrid G; Ling, Ming-Tat; Srinivasan, Bhuvana; Hooper, John D; Pettit, Allison R 2016-06-01 Skeletal metastases present a major clinical challenge for prostate cancer patient care, inflicting distinctive mixed osteoblastic and osteolytic lesions that cause morbidity and refractory skeletal complications. Macrophages are abundant in bone and bone marrow and can influence both osteoblast and osteoclast function in physiology and pathology. Herein, we examined the role of macrophages in prostate cancer bone lesions, particularly the osteoblastic response. First, macrophage and lymphocyte distributions were qualitatively assessed in patient's prostate cancer skeletal lesions by immunohistochemistry. Second, macrophage functional contributions to prostate tumour growth in bone were explored using an immune-competent mouse model combined with two independent approaches to achieve in vivo macrophage depletion: liposome encapsulated clodronate that depletes phagocytic cells (including macrophages and osteoclasts); and targeted depletion of CD169(+) macrophages using a suicide gene knock-in model. Immunohistochemistry and histomorphometric analysis were performed to quantitatively assess cancer-induced bone changes. In human bone metastasis specimens, CD68(+) macrophages were consistently located within the tumour mass. Osteal macrophages (osteomacs) were associated with pathological woven bone within the metastatic lesions. In contrast, lymphocytes were inconsistently present in prostate cancer skeletal lesions and when detected, had varied distributions. In the immune-competent mouse model, CD169(+) macrophage ablation significantly inhibited prostate cancer-induced woven bone formation, suggesting that CD169(+) macrophages within pathological woven bone are integral to tumour-induced bone formation. In contrast, panphagocytic cell, but not targeted CD169(+) macrophage depletion resulted in increased tumour mass, indicating that CD169(-) macrophage subset(s) and/or osteoclasts influenced tumour growth. In summary, these observations indicate a prominent role 474. Brain Metastases from Endometrial Carcinoma PubMed Central Piura, Ettie; Piura, Benjamin 2012-01-01 This paper will focus on knowledge related to brain metastases from endometrial carcinoma. To date, 115 cases were documented in the literature with an incidence of 0.6% among endometrial carcinoma patients. The endometrial carcinoma was usually an advanced-stage and high-grade tumor. In most patients (~90%), brain metastasis was detected after diagnosis of endometrial carcinoma with a median interval from diagnosis of endometrial carcinoma to diagnosis of brain metastases of 17 months. Brain metastasis from endometrial carcinoma was either an isolated disease limited to the brain only (~50%) or part of a disseminated disease involving also other parts of the body (~50%). Most often, brain metastasis from endometrial carcinoma affected the cerebrum (~75%) and was solitary (~60%). The median survival after diagnosis of brain metastases from endometrial carcinoma was 5 months; however, a significantly better survival was achieved with multimodal therapy including surgical resection or stereotactic radiosurgery followed by whole brain radiotherapy (WBRT) and/or chemotherapy compared to WBRT alone. It is suggested that brain imaging studies should be considered in the routine follow up of patients with endometrial carcinoma and that the search for a primary source in females with brain metastases of unknown primary should include endometrial biopsy. PMID:22523707 475. Codelivery of Ponatinib and SAR302503 by Active Bone-Targeted Polymeric Micelles for the Treatment of Therapy-Resistant Chronic Myeloid Leukemia. PubMed Mu, Chao-Feng; Xiong, Yang; Bai, Xue; Sheng, Yun-Jie; Cui, Jiajun 2017-01-03 Point mutations in the BCR-ABL1 domain and primitive chronic myelogenous leukemia (CML) cells existing in the bone marrow environment insensitive to tyrosine kinase inhibitors (TKIs) have become two major challenges in the CML therapy. In this study, combined TKI ponatinib and JAK2 inhibitor SAR302503 short-term treatment effectively suppressed growth and promoted apoptosis of BaF3/T315I cells in cytokine-containing medium in vitro. SAR302503 prevented cytokine-dependent resistance to ponatinib via inhibition of JAK2/STAT5 phosphorylation. Codelivery of ponatinib and SAR302503 by active bone-targeted polymeric micellar formulation greatly increased the drug accumulation in medullary cavity. The therapeutic efficacy of bone-targeted formulation was demonstrated in BaF3/T315I cells inoculated murine model with no dose-limited toxicity detectable in health mice. Thus, the intravenous injectable bone-homing ponatinib and SAR302503 micellar formulation represents a promising strategy for the treatment of therapyresistant CML. 476. Quantifying Interobserver Variation in Target Definition in Palliative Radiotherapy SciTech Connect Grabarz, Daniel; Panzarella, Tony; Bezjak, Andrea 2011-08-01 Purpose: To describe the degree of interobserver and intraobserver variability in target and field definition when using three-dimensional (3D) volume- vs. two-dimensional (2D) field-based planning. Methods and Materials: Standardized case scenario and diagnostic imaging for 9 palliative cases (3 bone metastases, 3 palliative lung cancer, and 3 abdominal pelvis soft-tissue disease) were presented to 5 study radiation oncologists. After a decision on what the intended anatomic target should be, observers created two sets of treatment fields, first using a 2D field-based and then a 3D volume-based planning approach. Percent overlap, under-coverage, and over-coverage were used to describe interobserver and intraobservermore » variations in target definition. Results: The degree of interobserver variation for 2D and 3D planning was similar with a degree of overlap of 76% (range, 56%-85%) and 74% (range, 55%-88%), respectively. When comparing the treatment fields defined by the same observer using the two different planning methods, the mean degree of overlap was 78%; over-coverage, 22%; and under-coverage, 41%. There was statistically significantly more under-coverage when field-based planning was used for bone metastases (33%) vs. other anatomic sites (16%) (p = 0.02). In other words, 2D planning is more likely to result in geographic misses in bone metastases compared with other areas. Conclusions: In palliative radiotherapy clinically significant interobserver and intraobserver variation existed when using both field- and volume-based planning approaches. Strategies that would reduce this variability deserve further investigation.« less 477. Quantifying Interobserver Variation in Target Definition in Palliative Radiotherapy SciTech Connect Grabarz, Daniel; Panzarella, Tony; Bezjak, Andrea; Mclean, Michael; Elder, Christine; Wong, Rebecca K.S. 2011-08-01 Purpose: To describe the degree of interobserver and intraobserver variability in target and field definition when using three-dimensional (3D) volume- vs. two-dimensional (2D) field-based planning. Methods and Materials: Standardized case scenario and diagnostic imaging for 9 palliative cases (3 bone metastases, 3 palliative lung cancer, and 3 abdominal pelvis soft-tissue disease) were presented to 5 study radiation oncologists. After a decision on what the intended anatomic target should be, observers created two sets of treatment fields, first using a 2D field-based and then a 3D volume-based planning approach. Percent overlap, under-coverage, and over-coverage were used to describe interobserver and intraobserver variations in target definition. Results: The degree of interobserver variation for 2D and 3D planning was similar with a degree of overlap of 76% (range, 56%-85%) and 74% (range, 55%-88%), respectively. When comparing the treatment fields defined by the same observer using the two different planning methods, the mean degree of overlap was 78%; over-coverage, 22%; and under-coverage, 41%. There was statistically significantly more under-coverage when field-based planning was used for bone metastases (33%) vs. other anatomic sites (16%) (p = 0.02). In other words, 2D planning is more likely to result in geographic misses in bone metastases compared with other areas. Conclusions: In palliative radiotherapy clinically significant interobserver and intraobserver variation existed when using both field- and volume-based planning approaches. Strategies that would reduce this variability deserve further investigation. 478. Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow Microenvironment PubMed Central Remédio, Leonor; Carvalho, Tânia; Caiado, Francisco; Bastos-Carvalho, Ana; Martins, Diana; Duarte, António; Yagita, Hideo; Dias, Sergio 2012-01-01 Delta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31+, VE-Cadherin+ and c-kit+ vessel density, and also increased megakaryocytes, whereas CD105+, VEGFR3+, SMA+ and lectin+ vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b+), decreased B (B220+) and T (CD3+) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting. PMID:23285048 479. Targeted alpha anticancer therapies: update and future prospects PubMed Central Allen, Barry J; Huang, Chen-Yu; Clarke, Raymond A 2014-01-01 Targeted alpha therapy (TAT) is an emerging option for local and systemic cancer treatment. Preclinical research and clinical trials show that alpha-emitting radionuclides can kill targeted cancer cells while sparing normal cells, thus reducing toxicity. 223RaCl2 (Xofigo®) is the first alpha emitting radioisotope to gain registration in the US for palliative therapy of prostate cancer bone metastases by indirect physiological targeting. The alpha emitting radioisotopes 211At, 213Bi, 225Ac and 227Th are being used to label targeting vectors such as monoclonal antibodies for specific cancer therapy indications. In this review, safety and tolerance aspects are considered with respect to microdosimetry, specific energy, Monte Carlo model calculations, biodosimetry, equivalent dose and mutagenesis. The clinical efficacy of TAT for solid tumors may also be enhanced by its capacity for tumor anti-vascular (TAVAT) effects. This review emphasizes key aspects of TAT research with respect to the PAI2-uPAR complex and the monoclonal antibodies bevacizumab, C595 and J591. Clinical trial outcomes are reviewed for neuroendocrine tumors, leukemia, glioma, melanoma, non-Hodgkins lymphoma, and prostate bone metastases. Recommendations and future directions are proposed. PMID:25422581 480. Sclerotic Vertebral Metastases: Pain Palliation Using Percutaneous Image-Guided Cryoablation SciTech Connect Costa de Freitas, Ricardo Miguel Menezes, Marcos Roberto de; Cerri, Giovanni Guido; Gangi, Afshin 2011-02-15 Cryoablative therapies have been proposed to palliate pain from soft-tissue or osteolytic bone tumors. A case of a patient with painful thoracic and sacral spine sclerotic metastases successfully treated by image-guided percutaneous cryoablation with the aid of insulation techniques and thermosensors is reported in this case report. « 21 22 23 24 25 » « 21 22 23 24 25 » 481. The challenge of targeting metastasis. PubMed Fidler, Isaiah J; Kripke, Margaret L 2015-12-01 Metastases that are resistant to conventional therapy are the major cause of death from cancer. In most patients, metastasis has already occurred by the time of diagnosis. Thus, the prevention of metastasis is unlikely to be of therapeutic benefit. The biological heterogeneity of metastases presents a major obstacle to treatment. However, the growth and survival of metastases depend on interactions between tumor cells and host homeostatic mechanisms. Targeting these interactions, in addition to the tumor cells, can produce synergistic therapeutic effects against existing metastases. 482. Spinal metastases: Is stereotactic body radiation therapy supported by evidences? PubMed De Bari, Berardino; Alongi, Filippo; Mortellaro, Gianluca; Mazzola, Rosario; Schiappacasse, Luis; Guckenberger, Matthias 2016-02-01 Stereotactic body radiotherapy (SBRT) is becoming widely adopted in the treatment of primary and secondary tumors. Spinal bone metastases are frequently discovered in cancer patients, and in the past have been usually treated with a palliative goal. Nevertheless, in some particular clinical settings, such as oligometastatic patients and/or those with a long life expectancy, spinal SBRT could be considered a valid therapeutic option to obtain long-lasting palliation and, when possible, with a curative goal. This review aims to summarize available clinical and dosimetric data of published studies about spinal SBRT. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved. 483. Sphingosine 1-phosphate signaling in bone remodeling: multifaceted roles and therapeutic potential. PubMed Meshcheryakova, Anastasia; Mechtcheriakova, Diana; Pietschmann, Peter 2017-07-01 Sphingolipids belong to a complex class of lipid molecules that are crucially involved in the regulation of important biological processes including proliferation, migration and apoptosis. Given the significant progress made in understanding the sphingolipid pathobiology of several diseases, sphingolipid-related checkpoints emerge as attractive targets. Recent data indicate the multifaceted contribution of the sphingolipid machinery to osteoclast - osteoblast crosstalk, representing one of the pivotal interactions underlying bone homeostasis. Imbalances in the interplay of osteoblasts and osteoclasts might lead to bone-related diseases such as osteoporosis, rheumatoid arthritis, and bone metastases. Areas covered: We summarize and analyze the progress made in bone research in the context of the current knowledge of sphingolipid-related mechanisms regulating bone remodeling. Particular emphasis was given to bioactive sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs). Moreover, the mechanisms of how dysregulations of this machinery cause bone diseases, are covered. Expert opinion: In the context of bone diseases, pharmacological interference with sphingolipid machinery may lead to novel directions in therapeutic strategies. Implementation of knowledge derived from in vivo animal models and in vitro studies using pharmacological agents to manipulate the S1P/S1PRs axes suggests S1PR2 and S1PR3 as potential drug targets, particularly in conjunction with technology for local drug delivery. 484. Sphingosine 1-phosphate signaling in bone remodeling: multifaceted roles and therapeutic potential PubMed Central Meshcheryakova, Anastasia; Mechtcheriakova, Diana; Pietschmann, Peter 2017-01-01 ABSTRACT Introduction: Sphingolipids belong to a complex class of lipid molecules that are crucially involved in the regulation of important biological processes including proliferation, migration and apoptosis. Given the significant progress made in understanding the sphingolipid pathobiology of several diseases, sphingolipid-related checkpoints emerge as attractive targets. Recent data indicate the multifaceted contribution of the sphingolipid machinery to osteoclast – osteoblast crosstalk, representing one of the pivotal interactions underlying bone homeostasis. Imbalances in the interplay of osteoblasts and osteoclasts might lead to bone-related diseases such as osteoporosis, rheumatoid arthritis, and bone metastases. Areas covered: We summarize and analyze the progress made in bone research in the context of the current knowledge of sphingolipid-related mechanisms regulating bone remodeling. Particular emphasis was given to bioactive sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs). Moreover, the mechanisms of how
dysregulations of this machinery cause bone diseases, are covered. Expert opinion: In the context of bone diseases, pharmacological interference with sphingolipid machinery may lead to novel directions in therapeutic strategies. Implementation of knowledge derived from in vivo animal models and in vitro studies using pharmacological agents to manipulate the S1P/S1PRs axes suggests S1PR2 and S1PR3 as potential drug targets, particularly in conjunction with technology for local drug delivery. PMID:28524744 485. Metastasizing Esthesioneuroblastoma in a Dog. PubMed Siudak, K; Klingler, M; Schmidt, M J; Herden, C 2015-07-01 A 7-year-old Afghan hound presented with a history of disorientation, loss of vision, and seizures. Magnetic resonance imaging helped identify a mass at the level of the main olfactory bulb that compressed and displaced adjacent tissues in the cribriform plate into the nasal cavity and nasopharynx. Bony structures were osteolytic. After removing almost 80% of the mass, the tumor recurred a few months later. Due to severe respiratory distress and subsequent to an ultrasound diagnosis of a liver tumor, the dog was euthanized. In addition to the nasal mass, a single nodule in the liver and multiple nodules in the lung were present. All masses had similar cell morphology and were diagnosed as metastasizing esthesioneuroblastoma. The neoplastic cells expressed neuron-specific enolase and chromogranin A, and a few cells within the nasal mass were positive for cytokeratin. This is the first description of a canine esthesioneuroblastoma with distant metastases. © The Author(s) 2014. 486. Bone graft MedlinePlus Autograft - bone; Allograft - bone; Fracture - bone graft; Surgery - bone graft; Autologous bone graft ... Fuse joints to prevent movement Repair broken bones (fractures) that have bone loss Repair injured bone that ... 487. Bone Is a Major Target of PTH/PTHrP Receptor Signaling in Regulation of Fetal Blood Calcium Homeostasis PubMed Central Hirai, Takao; Kobayashi, Tatsuya; Nishimori, Shigeki; Karaplis, Andrew C.; Goltzman, David 2015-01-01 The blood calcium concentration during fetal life is tightly regulated within a narrow range by highly interactive homeostatic mechanisms that include transport of calcium across the placenta and fluxes in and out of bone; the mechanisms of this regulation are poorly understood. Our findings that endochondral bone-specific PTH/PTHrP receptor (PPR) knockout (KO) mice showed significant reduction of fetal blood calcium concentration compared with that of control littermates at embryonic day 18.5 led us to focus on bone as a possibly major determinant of fetal calcium homeostasis. We found that the fetal calcium concentration of Runx2 KO mice was significantly higher than that of control littermates, suggesting that calcium flux into bone had a considerable influence on the circulating calcium concentration. Moreover, Runx2:PTH double mutant fetuses showed calcium levels similar to those of Runx2 KO mice, suggesting that part of the fetal hypocalcemia in PTH KO mice was caused by the increment of the mineralized bone mass allowed by the formation of osteoblasts. Finally, Rank:PTH double mutant mice had a blood calcium concentration even lower than that of the either Rank KO or PTH KO mice alone at embryonic day 18.5. These observations in our genetic models suggest that PTH/PTHrP receptor signaling in bones has a significant role of the regulation of fetal blood calcium concentration and that both placental transport and osteoclast activation contribute to PTH's hypercalcemic action. They also show that PTH-independent deposition of calcium in bone is the major controller of fetal blood calcium level. PMID:26052897 488. Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms. PubMed Sedghizadeh, Parish P; Sun, Shuting; Junka, Adam F; Richard, Eric; Sadrerafi, Keivan; Mahabady, Susan; Bakhshalian, Neema; Tjokro, Natalia; Bartoszewicz, Marzenna; Oleksy, Monika; Szymczyk, Patrycja; Lundy, Mark W; Neighbors, Jeffrey D; Russell, R Graham G; McKenna, Charles E; Ebetino, Frank H 2017-03-23 Osteomyelitis is a major problem worldwide and is devastating due to the potential for limb-threatening sequelae and mortality. Osteomyelitis pathogens are bone-attached biofilms, making antibiotic delivery challenging. Here we describe a novel osteoadsorptive bisphosphonate-ciprofloxacin conjugate (BV600022), utilizing a "target and release" chemical strategy, which demonstrated a significantly enhanced therapeutic index versus ciprofloxacin for the treatment of osteomyelitis in vivo. In vitro antimicrobial susceptibility testing of the conjugate against common osteomyelitis pathogens revealed an effective bactericidal profile and sustained release of the parent antibiotic over time. Efficacy and safety were demonstrated in an animal model of periprosthetic osteomyelitis, where a single dose of 10 mg/kg (15.6 μmol/kg) conjugate reduced the bacterial load by 99% and demonstrated nearly an order of magnitude greater activity than the parent antibiotic ciprofloxacin (30 mg/kg, 90.6 μmol/kg) given in multiple doses. Conjugates incorporating a bisphosphonate and an antibiotic for bone-targeted delivery to treat osteomyelitis biofilm pathogens constitute a promising approach to providing high bone-antimicrobial potency while minimizing systemic exposure. 489. Applying quality by design principles to the small-scale preparation of the bone-targeting therapeutic radiopharmaceutical rhenium-188-HEDP. PubMed Lange, Rogier; Ter Heine, Rob; van der Gronde, Toon; Selles, Suzanne; de Klerk, John; Bloemendal, Haiko; Hendrikse, Harry 2016-07-30 Rhenium-188-HEDP ((188)Re-HEDP) is a therapeutic radiopharmaceutical for treatment of osteoblastic bone metastases. No standard procedure for the preparation of this radiopharmaceutical is available. Preparation conditions may influence the quality and in vivo behaviour of this product. In this study we investigate the effect of critical process parameters on product quality and stability of (188)Re-HEDP. A stepwise approach was used, based on the quality by design (QbD) concept of the ICH Q8 (Pharmaceutical Development) guideline. Potential critical process conditions were identified. Variables tested were the elution volume, the freshness of the eluate, the reaction temperature and time, and the stability of the product upon dilution and storage. The impact of each variable on radiochemical purity was investigated. The acceptable ranges were established by boundary testing. With 2ml eluate, adequate radiochemical purity and stability were found. Nine ml eluate yielded a product that was less stable. Using eluate stored for 24h resulted in acceptable radiochemical purity. Complexation for 30min at room temperature, at 60°C and at 100°C generated appropriate and stable products. A complexation time of 10min at 90°C was too short, whereas heating 60min resulted in products that passed quality control and were stable. Diluting the end product and storage at 32.5°C resulted in notable decomposition. Two boundary tests, an elution volume of 9ml and a heating time of 10min, yielded products of inadequate quality or stability. The product was found to be instable after dilution or when stored above room temperature. Our findings show that our previously developed preparation method falls well within the proven acceptable ranges. Applying QbD principles is feasible and worthwhile for the small-scale preparation of radiopharmaceuticals. Copyright © 2016 Elsevier B.V. All rights reserved. 490. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis DTIC Science & Technology 2014-10-01 models. We further hypothesize that RIT in combination with low dose WBRT will not only achieve effective treatment of brain metastases but also...measurements of vascular perfusion revealed significantly lower tumor perfusion in metastases as compared to the contralateral normal brain. The...probe for sensitive detection of brain metastases in mice. 9 Fig. 5 PS-targeted PET imaging of brain metastases. A. A mouse bearing multiple MDA 491. Molecular insights into melanoma brain metastases. PubMed Westphal, Dana; Glitza Oliva, Isabella C; Niessner, Heike 2017-06-01 Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune-checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain-specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163-75. © 2017 American Cancer Society. © 2017 American Cancer Society. 492. Morphological and phenotypical features of ovarian metastases in breast cancer patients. PubMed Peters, Inge T A; van der Steen, Merle A; Huisman, Bertine W; Hilders, Carina G J M; Smit, Vincent T H B M; Vahrmeijer, Alexander L; Sier, Cornelis F M; Trimbos, J Baptist; Kuppen, Peter J K 2017-03-21 Autotransplantation of frozen-thawed ovarian tissue is a method to preserve ovarian function and fertility in patients undergoing gonadotoxic therapy. In oncology patients, the safety cannot yet be guaranteed, since current tumor detection methods can only exclude the presence of malignant cells in ovarian fragments that are not transplanted. We determined the need for a novel detection method by studying the distribution of tumor cells in ovaries from patients with breast cancer. Furthermore, we examined which cell-surface proteins are suitable as a target for non-invasive tumor-specific imaging of ovarian metastases from invasive breast cancer. Using the nationwide database of the Dutch Pathology Registry (PALGA), we identified a cohort of 46 women with primary invasive breast cancer and ovarian metastases. The localization and morphology of ovarian metastases were determined on hematoxylin-and-eosin-stained sections. The following cell-surface markers were immunohistochemically analyzed: E-cadherin, epithelial membrane antigen (EMA), human epidermal growth receptor type 2 (Her2/neu), carcinoembryonic antigen (CEA), αvβ6 integrin and epithelial cell adhesion molecule (EpCAM). The majority of ovarian metastases (71%) consisted of a solitary metastasis or multiple distinct nodules separated by uninvolved ovarian tissue, suggesting that ovarian metastases might be overlooked by the current detection approach. Combining the targets E-cadherin, EMA and Her2/neu resulted in nearly 100% detection of ductal ovarian metastases, whereas the combination of EMA, Her2/neu and EpCAM was most suitable to detect lobular ovarian metastases. Examination of the actual ovarian transplants is recommended. A combination of targets is most appropriate to detect ovarian metastases by tumor-specific imaging. 493. Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector PubMed Central Nakamura-Takahashi, Aki; Miyake, Koichi; Watanabe, Atsushi; Hirai, Yukihiko; Iijima, Osamu; Miyake, Noriko; Adachi, Kumi; Nitahara-Kasahara, Yuko; Kinoshita, Hideaki; Noguchi, Taku; Abe, Shinichi; Narisawa, Sonoko; Millán, Jose Luis; Shimada, Takashi; Okada, Takashi 2016-01-01 Hypophosphatasia (HPP) is an inherited disease caused by genetic mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). This results in defects in bone and tooth mineralization. We recently demonstrated that TNALP-deficient (Akp2−/−) mice, which mimic the phenotype of the severe infantile form of HPP, can be treated by intravenous injection of a recombinant adeno-associated virus (rAAV) expressing bone-targeted TNALP with deca-aspartates at the C-terminus (TNALP-D10) driven by the tissuenonspecific CAG promoter. To develop a safer and more clinically applicable transduction strategy for HPP gene therapy, we constructed a self-complementary type 8 AAV (scAAV8) vector that expresses TNALP-D10 via the muscle creatine kinase (MCK) promoter (scAAV8-MCK-TNALP-D10) and examined the efficacy of muscle-directed gene therapy. When scAAV8-MCK-TNALP-D10 was injected into the bilateral quadriceps of neonatal Akp2−/− mice, the treated mice grew well and survived for more than 3 months, with a healthy appearance and normal locomotion. Improved bone architecture, but limited elongation of the long bone, was demonstrated on X-ray images. Micro-CT analysis showed hypomineralization and abnormal architecture of the trabecular bone in the epiphysis. These results suggest that rAAV-mediated, muscle-specific expression of TNALP-D10 represents a safe and practical option to treat the severe infantile form of HPP. PMID:26904710 494. Targeting RANKL for reduction of bone loss around unstable implants: OPG-Fc compared to alendronate in a model for mechanically induced loosening. PubMed Aspenberg, Per; Agholme, Fredrik; Magnusson, Per; Fahlgren, Anna 2011-02-01 Orthopedic joint prostheses may loosen because of localized bone resorption. Despite initial optimism, there are no reports showing that bisphosphonates can stop the progression of prosthetic loosening once it has begun. This might be due to the strong resorptive stimulus, which continuously recruits new osteoclasts. Therefore, we hypothesized that a treatment targeting osteoclast recruitment would be more efficacious than a treatment reducing osteoclast activity. We used a previously described rat model for instability-induced bone resorption, and compared OPG-Fc with alendronate at a clinically relevant or an extreme dose. A titanium plate was osseointegrated at the rat tibial surface. Instability was simulated by a piston, moving perpendicularly to the bone surface. Piston movement induced bone loss via hydrostatic pressure or fluid flow. Rats were randomized to 5 groups (total n=56), of which 4 were subjected to instability and one was stable. The unstable groups were injected with either high-dose OPG-Fc (10 mg/kg, twice weekly), a high dose of alendronate (20 μg /kg/day), an extreme dose of alendronate (200 μg/kg/day) or saline. Significant protection against resorption could only be shown for OPG-Fc and the extreme alendronate dose. Both alendronate doses reduced serum levels of tartrate-resistant acid phosphatase isoform 5b to a similar extent, demonstrating that the lower dose was able to reduce resorption in the normally remodeling skeleton, although not in the osteolytic lesions caused by instability. Osteoclast numbers in the lesion were increased by the lower bisphosphonate dose and reduced by OPG-Fc. The results suggest the possibility of targeting osteoclast recruitment via the RANKL system in patients with impending prosthetic loosening. Copyright © 2010 Elsevier Inc. All rights reserved. 495. Calvaria and orbital metastases of pulmonary adenosquamous carcinoma in a cat: a diagnostic challenge. PubMed Binanti, Diana; Zani, Davide Danilo 2015-04-01 An 11-year-old cat with a 4-month history of lethargy, inappetence, dysphagia, partial mandibular paralysis and weight loss, was euthanized due to the rapid deterioration of his condition. Post-mortem radiographic examination revealed severe bone lysis of the left zygomatic arch, temporal and parietal bones. Magnetic resonance imaging of the head showed a large isointense mass of the left side of the skull associated with extensive lysis of the parietal and temporal bones and destruction of the adjacent tympanic bulla. Gross and histological examinations revealed a pulmonary adenosquamous carcinoma of the left lung, with metastases to the spleen, liver, mesenteric lymph nodes, mesentery, diaphragm, abdominal aorta, left orbit and calvaria. No limb or digit metastases were detected. 496. Cerebellar metastases of recurrent phyllodes tumor breast; a rare phenomenon reflecting the unpredictable outcome. PubMed Singh, Jyotsna; Majumdar, Kaushik; Gupta, Rahul; Batra, Vineeta Vijay 2015-01-01 Carcinomas of lung, breast, colon, kidney, and malignant melanomas are the most common malignancies that metastasize to the central nervous system (CNS). Phyllodes tumor is a rare fibroepithelial tumor of the breast, often having unpredictable recurrences, with increasing histological grade and distant metastasis. Malignant forms exist, which may develop distant metastases usually to the lung, pleura, bone, and liver. CNS metastasis of phyllodes tumor is rare and associated with a poor prognosis, with resistance to chemotherapy and radiation. We present a rare case of cerebellar metastasis in recurrent phyllodes tumor breast with subsequent rapid downhill course. 497. Gallium, a promising candidate to disrupt the vicious cycle driving osteolytic metastases. PubMed Strazic-Geljic, Ivana; Guberovic, Iva; Didak, Blanka; Schmid-Antomarchi, Heidy; Schmid-Alliana, Annie; Boukhechba, Florian; Bouler, Jean-Michel; Scimeca, Jean-Claude; Verron, Elise 2016-09-15 Bone metastases of breast cancer typically lead to a severe osteolysis due to an excessive osteoclastic activity. On the other hand, the semi-metallic element gallium (Ga) displays an inhibitory action on osteoclasts, and therefore on bone resorption, as well as antitumour properties. Thus, we explored in vitro Ga effects on osteoclastogenesis in an aggressive bone metastatic environment based on the culture of pre-osteoclast RAW 264.7 cells with conditioned medium from metastatic breast tumour cells, i.e. the breast tumour cell line model MDA-MB-231 and its bone-seeking clone MDA-231BO. We first observed that Ga dose-dependently inhibited the tumour cells-induced osteoclastic differentiation of RAW 264.7 cells. To mimic a more aggressive environment where pro-tumourigenic factors are released from bone matrix due to osteoclastic resorption, metastatic breast tumour cells were stimulated with TGF-β, a mayor cytokine in bone metastasis vicious cycle. In these conditions, we observed that Ga still inhibited cancer cells-driven osteoclastogenesis. Lastly, we evidenced that Ga affected directly and strongly the proliferation/viability of both cancer cell lines, as well as the expression of major osteolytic factors in MDA-231BO cells. With the exception of two small scale clinical studies from 1980s, this is the first time that antitumour properties of Ga have been specifically studied in the context of bone metastases. Our data strongly suggest that, through its action against the vicious cycle involving bone cells and tumour cells, Ga represents a relevant and promising candidate for the local treatment of bone metastases in patients with breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved. 498. Stereotactic Body Radiation Therapy in Spinal Metastases SciTech Connect Ahmed, Kamran A.; Stauder, Michael C.; Miller, Robert C. 2012-04-01 Purpose: Based on reports of safety and efficacy, stereotactic body radiotherapy (SBRT) for treatment of malignant spinal tumors was initiated at our institution. We report prospective results of this population at Mayo Clinic. Materials and Methods: Between April 2008 and December 2010, 85 lesions in 66 patients were treated with SBRT for spinal metastases. Twenty-two lesions (25.8%) were treated for recurrence after prior radiotherapy (RT). The mean age of patients was 56.8 {+-} 13.4 years. Patients were treated to a median dose of 24 Gy (range, 10-40 Gy) in a median of three fractions (range, 1-5). Radiation was delivered withmore » intensity-modulated radiotherapy (IMRT) and prescribed to cover 80% of the planning target volume (PTV) with organs at risk such as the spinal cord taking priority over PTV coverage. Results: Tumor sites included 48, 22, 12, and 3 in the thoracic, lumbar, cervical, and sacral spine, respectively. The mean actuarial survival at 12 months was 52.2%. A total of 7 patients had both local and marginal failure, 1 patient experienced marginal but not local failure, and 1 patient had local failure only. Actuarial local control at 1 year was 83.3% and 91.2% in patients with and without prior RT. The median dose delivered to patients who experienced local/marginal failure was 24 Gy (range, 18-30 Gy) in a median of three fractions (range, 1-5). No cases of Grade 4 toxicity were reported. In 1 of 2 patients experiencing Grade 3 toxicity, SBRT was given after previous radiation. Conclusion: The results indicate SBRT to be an effective measure to achieve local control in spinal metastases. Toxicity of treatment was rare, including those previously irradiated. Our results appear comparable to previous reports analyzing spine SBRT. Further research is needed to determine optimum dose and fractionation to further improve local control and prevent toxicity.« less 499. Stereotactic radiotherapy for large solitary brain metastases. PubMed Feuvret, L; Vinchon, S; Martin, V; Lamproglou, I; Halley, A; Calugaru, V; Chea, M; Valéry, C A; Simon, J-M; Mazeron, J-J 2014-03-01 To assess effectiveness and toxicity levels of stereotactic radiation therapy without whole brain radiation therapy in patients with solitary brain metastases larger than 3cm. Between June 2007 and March 2009, 12 patients received fractionated stereotactic radiation therapy and 24 patients underwent stereotactic radiosurgery. For the fractionated stereotactic radiation therapy group, 3×7.7Gy were delivered to the planning target volume (PTV); median volume and diameter were 29.4 cm(3) and 4.4cm, respectively. For the stereotactic radiosurgery group, 14Gy were delivered to the PTV; median volume and diameter were 15.6 cm(3) and 3.7cm, respectively. Median follow-up was 218 days. For the fractionated stereotactic radiation therapy group, local control rates were 100% at 360 days and 64% at 720 days; for the stereotactic radiosurgery group, rates were 58% at 360 days and 48% at 720 days (P=0.06). Median survival time was 504 days for the fractionated stereotactic radiation therapy group and 164 days for the stereotactic radiosurgery group (P=0.049). Two cases of grade 2 toxicity were observed in the fractionated stereotactic radiation therapy group, and 6 cases of grade 1-2 toxicity, in the stereotactic radiosurgery group. This study provides data to support that fractionated stereotactic radiation therapy without whole brain radiation therapy with a margin dose of 3 fractions of 7.7Gy for treatment of solitary large brain metastases is efficient and well-tolerated. Because of the significant improvement in overall survival, this schedule should be assessed in a randomized trial. Copyright © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved. 500. [Complete remission of endobronchial, parenchymal and hilar lymphatic lung metastases of prostatic carcinoma after anti-androgenic hormotherapy]. PubMed Morrone, N; Volpe, V L; Dourado, A M; Coletta, E N 1996-01-01 A 65 year old male Negro had respiratory and urinary symptoms for the last 5 months. The work-up disclosed a prostatic carcinoma with metastases in bones, bronchus, lung parenchyma and hilar lymphnodes. Prostatic and bronchial biopsies revealed carcinoma; specific prostatic antigen was detected in both. A prostatectomy with bilateral orchiectomy was performed followed by anti-androgenic hormotherapy. Complete remission of metastatic bronchial, lung parenchyma and lymphatic lesions was observed; bone lesions did not change. lung and bronchial metastases of prostatic carcinoma may resemble primitive bronchial tumor; complete remission with anti-androgenic therapy is possible, saving the patient from unnecessary radio and/or chemotherapy. « 21 22 23 24 25 » Some links on this page may take you to non-federal websites. Their policies may differ from this site. Privacy and Security