Therapy Of Bone Metastases Research Articles

223Ra-dichloride therapy of bone metastasis: optimization of SPECT images for quantification

Background223Ra imaging is crucial to evaluate the successfulness of the therapy of bone metastasis of castration-resistant prostate cancer (CRPC). The goals of this study were to establish a quantitative tomographic 223Ra imaging protocol with clinically achievable conditions, as well as to investigate its usefulness and limitations.We performed several experiments using the Infinia Hawkeye 4 gamma camera (GE) and physical phantoms in order to assess the optimal image acquisition and reconstruction parameters, such as the windows setting, as well as the iteration number and filter of the reconstruction algorithm. Then, based on the MIRD pamphlet 23, we used a NEMA phantom and an anthropomorphic TORSO® phantom to calibrate the gamma camera and investigate the accuracy of quantification.ResultsExperiences showed that the 85 keV ± 20%, 154 keV ± 10%, and 270 keV ± 10% energy windows are the most suitable for 223Ra imaging.The study with the NEMA phantom showed that the OSEM algorithm with 2 iterations, 10 subsets, and the Butterworth filter offered the best compromise between contrast and noise. Moreover, the calibration factors for different sphere sizes (26.5 ml, 11.5 ml, and 5.6 ml) were constant for 223Ra concentrations ranging between 6.5 and 22.8 kBq/ml. The values found are 73.7 cts/s/MBq, 43.8 cts/s/MBq, and 43.4 cts/s/MBq for 26.5 ml, 11.5 ml, and 5.6 ml sphere, respectively. For concentration lower than 6.5 kBq/ml, the calibration factors exhibited greater variability pointing out the limitations of SPECT/CT imaging for quantification.By the use of a TORSO® phantom, we simulated several tumors to normal tissue ratios as close as possible to clinical conditions. Using the calibration factors obtained with the NEMA phantom, for 223Ra concentrations higher than 8 kBq/ml, we were able to quantify the activity with an error inferior to 18.8% in a 5.6 ml lesion.ConclusionsAbsolute quantitative 223Ra SPECT imaging appears feasible once the dimension of the target is determined. Further evaluation should be needed to apply the calibration factor-based quantitation to clinical 223Ra SPECT/CT imaging. This will open the possibility for patient-specific 223Ra treatment planning and therapeutic outcome prediction in patients.

The role of GDF15 in bone metastasis of lung adenocarcinoma cells.

Lung cancer is the most common malignant tumor in China. It often metastasizes to bone, thereby significantly shortening the lives of patients, and reducing their quality of life. However, the efficacy of treatment for bone metastasis of lung cancer at this stage is very limited. The development and clinical application of molecular‑targeted drugs for the effective targeted therapy of bone metastasis of lung cancer are urgently required. The growth differentiation factor 15 (GDF15) gene which may be associated with bone metastasis of lung cancer, was screened out by whole‑genome sequencing. In the present study, we used a recombinant GDF15 lentivirus technique to upregulate the expression of GDF15 in lung adenocarcinoma A549 cells, and the results revealed that GDF15 could inhibit the proliferation, migration and invasion, while promoting apoptosis of A549 cells. In addition, GDF15 significantly decreased the number and sites of lung metastases and bone metastases in vivo compared to the control group. Finally, it was revealed that Smad2 and phospho‑Smad2 protein expression was lower in the GDF15‑overexpressing A549 cells. This result indicated that the tumor suppressive effect of GDF15 may be related to the TGF‑β/Smad signaling pathway, although more studies are still required for confirmation. In summary, GDF15 inhibited the growth and bone metastasis of lung adenocarcinoma A549 cells, and this effect may be achieved through the TGF‑β/Smad signaling pathway.

Drug delivery system for therapy for bone metastasis

Drug delivery system for therapy for bone metastasis

Strontium-89 Chloride Delivery for Painful Bone Metastasis in Patients with History of Previous Radiation

Re-irradiation of previously irradiated site must be done with careful consideration to minimizing dose to organs at risk. In particular, re-irradiation of the spine carries significant morbidity due to risk of myelitis. Strontium-89 chloride (Sr-89) is widely used for treatment of painful bone metastasis. The purpose of this study is to evaluate pain response and safety of Sr-89 administration for painful bone metastasis in the setting of prior radiation. After institutional review board approval, records of patients who received Sr-89 injection for painful bone metastasis in previously irradiated sites were retrospectively reviewed. Patients with follow-up of less than 1 month were excluded from analysis. Efficacy of pain control was evaluated with the verbal rating scale (VRS), documentation of the analgesic dose employing the World Health Organization (WHO) pain relief ladder. Adverse events were measured using CTCAE v4.0. Twenty-three patients met study inclusion criteria, of which 12 were male and 11 were female. Median age at treatment was 69 years (50-83). Primary sites were lung (n=11), prostate (n=3), breast (n=2), uterine cervix (n=2), kidney (n=1), and other (n=4). Median follow-up was 8 (1-49) months. Twelve patients treated with SR-89 had prior history of palliative radiation therapy for bone metastasis. The remainder had received radiation for non-bony metastasis as follows: concurrent chemo-radiotherapy (CCRT) for lung cancer (n=7), post-operative radiotherapy to regional lymph nodes of breast cancer (n=1), pre-operative CCRT for rectal cancer (n=1), radical CCRT for cervical cancer (n=1), and radiotherapy to tumor bed for recurrent prostate cancer (n=1). Prior to administration of Sr-89, the VRS grade of 0/1/2/3 was n=1/5/12/5, respectively. Analgesic score 0/1/2/3/4/5/6 was n=3/9/2/4/3/1/1, respectively. After administration of Sr-89, VRS grade didn’t change in 3 patients, and improved in 20; 17 occurred after 1 month, 2 after 2 months, and 1 after 3 months. Analgesic score didn’t change in 15 but improved in 8 patients; 4 after 1 month, 2 after 2 months, 2 after 3 months. In two patients neither the VRS nor the analgesic score improved and in two patients the VRS improved but the analgesic score increased, hence difficult to evaluate efficacy of SR-89. This made the response rate of evaluable patients 90.1%. Flare phenomenon was observed in 3 patients, but all were controlled with analgesic and improved within one week. No grade 2 or worse adverse events was observed. Administration of strontium-89 chloride to patients with painful bone metastasis at previously irradiated sites is an effective and safe treatment options for palliation of symptoms at the end of life.

Abstract B050: The role of activated beta-catenin/Wnt signaling in the progression of castration resistance of prostate cancer in bone

Abstract Bone metastases typically develop in patients with advanced prostate cancer (PCa). These metastases are osteoblastic (bone-forming) and constitute the main cause of morbidity and mortality. Androgen deprivation is commonly used to treat bone metastases of PCa, but responses to such therapy are short, and eventually the disease progresses to a castration-resistant form. Bone is the primary site of castration-resistant PCa (CRPC) progression. Further development of therapies for bone metastases of PCa requires an understanding of the mechanisms underlying the growth of CRPC in bone. Clinical and laboratory-based investigations have implicated a role for PCa cell-bone cell interaction in the growth of PCa and have demonstrated that osteoblasts produce factors that favor the growth and survival of PCa cells. Collectively, these observations strongly suggest that PCa cells interact with osteoblasts and that this interaction contributes to the growth of PCa in bone. Recently, a study showed 18% of patients with metastatic CRPC harbored alterations in the Wnt canonical pathway, including hotspot mutations of β-catenin (β-cat), the molecular node of the Wnt canonical pathway, that leads to pathway activation. This report is in agreement with previous publications of β-cat nuclear accumulation, an indirect measure of Wnt-canonical pathway activation, in 20 to 40% of advanced PCas. We previously reported that a patient-derived xenograft (PDX) MDA-PCa-118b (118b) developed in our lab harbors a β-cat mutation (D32G) and has an activated Wnt canonical pathway. 118b induces an osteoblastic reaction when it is implanted in the bone of mice in vivo. In vitro, 118b induces osteoblast proliferation in coculture. In contrast, the PCa cell line, PC3, induces osteolytic lesions in vivo and in vitro inhibits osteoblast proliferation in coculture. Strikingly, expression of β-cat mutated at D32G in PC3 cells reverses the osteoblast inhibitory effect of PC3 cells, resulting in increased proliferation of osteoblasts when grown in coculture. We therefore hypothesize that β-cat/Wnt signaling in PCa cells mediates the PCa-bone interaction that favors PCa growth in bone. Our future studies are focusing on studying the importance of β-cat mutations recently identified in patients with metastatic CRPC and determining whether these mutations also result in an osteoblastic phenotype, which in turn supports growth of prostate cancer in bone. Additionally, we are screening our collection of PCa PDX lines for increased β-cat expression through immunohistochemistry and will sequence DNA from PDX lines that demonstrate increased nuclear β-cat expression to test for activating mutations in β-cat. Our aim is to gain insight into the mechanism of the paracrine interaction between PCa cells and bone that supports the growth of PCa bone lesions, with the ultimate goal of developing therapies to block these interactions and reducing the morbidity and mortality associated with metastatic disease. Citation Format: Justin M. Roberts, Estefania Labanca, Peter Shepherd, Jun Yang, Michael W. Starbuck, Nora M. Navone. The role of activated beta-catenin/Wnt signaling in the progression of castration resistance of prostate cancer in bone [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B050.

Abstract 38: Mitophagy deficiency promotes osteolytic bone metastasis in breast cancer

Abstract Introduction: Metastasis of breast cancer to the bone is a common complication and occurs in 65-80% of late-stage patients. Specifically, the development of osteolytic bone lesions increases patient morbidity and mortality with debilitating skeletal complications. Mitophagy is a selective form of autophagy that removes damaged or excessive mitochondria in response to various metabolic stresses. However, the role of mitophagy in development of cancer remains largely unclear. The Janus-faced role of mitophagy during tumorigenesis leads to a novel challenge when targeting it for cancer therapies. This study focuses on the role of mitophagy deficiency in breast cancer osteolytic bone metastasis, and explores the potential of rescuing mitophagy deficiency as possible therapeutic targets for metastatic disease. Methods: Specific single-guide RNAs (sgRNAs) were used to deplete ULK1 expression in breast cancer cell lines. Mitophagy was monitored by detecting Tom20 and Hsp60. In addition, mitochondrial DNA (mtDNA) was used to further confirm the reduction of mitochondrial mass. For bone metastasis studies, luciferase-tagged tumor cells were injected into the left cardiac ventricle of anesthetized female nude mice. Metastatic progression was monitored by bioluminescence imaging (BLI). Micro-CT imaging was used to detect bone volume, cortical wall thickness, trabecular thickness and number in mice of tibia. TRAP assay was used to detect osteoclast differentiation assays. Results: We found that the core Atg protein ULK1 was not only expressed at low level in breast cancer, but also required for hypoxia-induced mitophagy. ULK1-related mitophagy deficiency promoted the formation of metastatic osteolytic lesions in experimental bone metastasis mouse model with MDA-MB-231 cells. TRAP staining revealed that mature osteoclasts significantly increased in RAW264.7 cells treated with CM from ULK1-knockout breast cancer cells. In addition, MEK inhibitor trametinib was sufficient to upregulate the expression of ULK1 and reduced the release of cytokines, which is key to osteoclast differentiation via triggering mitophagy, thereby effectively blocking breast cancer osteolytic bone metastasis. Conclusion: In conclusion, we demonstrate the functional importance of mitophagy defect in breast cancer for promoting osteolytic bone metastasis. We also provide strong preclinical evidence for using MEK-ERK pathway inhibitors to disrupt ERK kinase-involved ULK1 degradation and induce mitophagy as a breast cancer bone metastasis therapy. Citation Format: Rong Deng, Hai-Liang Zhang, Rui-Zhao Cai, Jun Tang, Xiao-Feng Zhu. Mitophagy deficiency promotes osteolytic bone metastasis in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 38.

Choosing Wisely at the End of Life: Use of Shorter Courses of Palliative Radiation Therapy for Bone Metastasis

American Society for Radiation Choosing Wisely guidelines recommend ≤10 fractions of radiation therapy (RT) for bone metastasis, with consideration for 1 fraction in patients with a poor prognosis. The purpose of this analysis was to evaluate characteristic differences in guideline concordance to fractionation regimens in a modern cohort of older patients with a diagnosis of bone metastasis. Medicare beneficiaries aged ≥65 years treated with RT for bone metastasis from 2012 to 2015 were identified. Guideline-concordant RT fractionation was defined in the entire cohort as ≤10 fractions. Utilization of 1 fraction versus ≥2 fractions was analyzed in deceased patients. Patient demographic, disease, and facility characteristics associated with shorter fractionation were analyzed. In 569 patients treated with RT, the median age at diagnosis was 73 years. The most common cancer types were lung (37%), genitourinary (26%), breast (15%), and gastrointestinal (10%). Among all patients, 34%, 30%, and 36% received 1 fraction, 2 to 10 fractions, and ≥11 fractions, respectively. In comparison with receipt of 1 to 10 fractions, receipt of ≥11 fractions was associated with a $1467 increase in per-patient cost to Medicare during the calendar quarter of RT. Almost two-thirds of patients who died within 30 days of RT completion were treated with >1 fraction. Although guideline concordance was high overall, a large number of patients received longer courses of RT at the end of life. Strong consideration should be made for utilization of shorter courses, particularly in patients with a limited prognosis.

Recent advances on the progressive mechanism and therapy in castration-resistant prostate cancer.

BackgroundAlthough there have been great advances in mechanisms and therapeutic methods of prostate cancer, the mortality rate of prostate cancer remains high. The castration-resistant prostate cancer (CRPC), which develops from hormone-sensitive prostate cancer, foreshadows a more dismal outcome. Concomitant with the researches in the mechanism of CRPC and therapy for CRPC, more and more landmark progress has been made in recent years.MethodsA number of clinical and experimental studies were reviewed to indicate the novel advancement in the progressive mechanism and therapy of CRPC.ResultsThe androgen receptor (AR) is still a vital driver in the progression of CRPC, while other multiple mechanisms also contribute to this progression, such as tumor immunity, cancer stem cells, epithelial–mesenchymal transition and DNA repair disorder. In terms of the therapeutic methods of CRPC, chemotherapy with drugs, such as docetaxel, has been the first-line therapy for CRPC for many years. Besides, newer agents, which target some of the above mechanisms, show additional overall survival benefits for CRPC patients. These therapies include drugs targeting the androgen axis pathway (androgen synthesis, androgen receptor splice variants, coactivators of AR and so on), PI3K-AKT pathway, WNT pathway, DNA repair, rearrangement of ETS gene, novel chemotherapy and immunotherapy, bone metastasis therapy and so on. Understanding these novel findings on the mechanisms of CRPC and the latest potential CRPC therapies will direct us for further exploration of CRPC.ConclusionThrough comprehensive consideration, the predominant mechanism of CRPC might be the AR signal axis concomitant with tumor microenvironment, stress, immunity, tumor microenvironment and so on. For CRPC therapy, targeting the AR axis pathway and chemotherapy are the first-line treatments at present. However, with the advancements in CRPC therapy made by the researchers, other novel potential methods will occupy more and more important position in the treatment of CRPC, especially the therapies targeting the tumor microenviroment, tumor immunity and DNA repair and so on.

Amorphous, Smart, and Bioinspired Polyphosphate Nano/Microparticles: A Biomaterial for Regeneration and Repair of Osteo-Articular Impairments In-Situ.

Using femur explants from mice as an in vitro model, we investigated the effect of the physiological polymer, inorganic polyphosphate (polyP), on differentiation of the cells of the bone marrow in their natural microenvironment into the osteogenic and chondrogenic lineages. In the form of amorphous Ca-polyP nano/microparticles, polyP retains its function to act as both an intra- and extracellular metabolic fuel and a stimulus eliciting morphogenetic signals. The method for synthesis of the nano/microparticles with the polyanionic polyP also allowed the fabrication of hybrid particles with the bisphosphonate zoledronic acid, a drug used in therapy of bone metastases in cancer patients. The results revealed that the amorphous Ca-polyP particles promote the growth/viability of mesenchymal stem cells, as well as the osteogenic and chondrogenic differentiation of the bone marrow cells in rat femur explants, as revealed by an upregulation of the expression of the transcription factors SOX9 (differentiation towards osteoblasts) and RUNX2 (chondrocyte differentiation). In parallel to this bone anabolic effect, incubation of the femur explants with these particles significantly reduced the expression of the gene encoding the osteoclast bone-catabolic enzyme, cathepsin-K, while the expression of the tartrate-resistant acid phosphatase remained unaffected. The gene expression data were supported by the finding of an increased mineralization of the cells in the femur explants in response to the Ca-polyP particles. Finally, we show that the hybrid particles of polyP complexed with zoledronic acid exhibit both the cytotoxic effect of the bisphosphonate and the morphogenetic and mineralization inducing activity of polyP. Our results suggest that the Ca-polyP nano/microparticles are not only a promising scaffold material for repairing long bone osteo-articular damages but can also be applied, as a hybrid with zoledronic acid, as a drug delivery system for treatment of bone metastases. The polyP particles are highlighted as genuine, smart, bioinspired nano/micro biomaterials.

Breast Osteoblast-like Cells: A Reliable Early Marker for Bone Metastases From Breast Cancer

BackgroundThe development of bone metastasis from breast cancer results from a functional interaction between tumor cells and osteoclasts or osteoblasts. The main aim of this study was therefore to test the hypothesis that the appearance of breast osteoblast-like cells (BOLCs) in primary mammary lesions is a precursor (and hence an early predictor) of the formation of breast cancer metastases to bone. Patients and MethodsIn this study, we collected 64 breast infiltrating carcinomas, 50 breast benignant lesions, and 10 biopsies of bone metastasis selected from patients with infiltrated carcinoma. Immunohistochemical, western blot, and ultrastructural analysis allowed us to investigate the presence of BOLCs in breast cancer lesions and metastatic sites. ResultsWe established the presence of a high amount of breast cancer cells that underwent mesenchymal transformation in infiltrating carcinomas. In addition, our results demonstrated that the microenvironment of breast cancer is very similar to the microenvironment of bone. We noted a significantly higher expression of BMP-2/4 and PTX3 in breast-infiltrating carcinomas compared with benign lesions. Moreover, we also identified numerous BOLCs positive to RANKL and Vitamin D receptor. Thanks to ultrastructural analysis, we also revealed the presence of BOLCs at the metastatic site. ConclusionsThe identification of breast cancer cells with high affinity for a bone environment opens new perspectives on prevention and therapy of bone metastases from breast.

Impact of a clinical pathway tool on appropriate palliative radiation therapy for bone metastases.

97 Background: Clinical pathways increase compliance with treatment guidelines, improve outcomes, and reduce costs. Guidelines recommend single fraction radiation therapy (SFRT) for palliation of uncomplicated bone metastases, but implementation is variable. We examined the effects of a clinical pathway tool on appropriate SFRT rates in an academic radiation oncology practice. Methods: Clinical pathways increase compliance with treatment guidelines, improve outcomes, and reduce costs. Guidelines recommend single fraction radiation therapy (SFRT) for palliation of uncomplicated bone metastases, but implementation is variable. We examined the effects of a clinical pathway tool on appropriate SFRT rates in an academic radiation oncology practice. Results: The final pathway was used in 38% of 723 bone metastases radiation prescription made since March 2016, with appropriate SFRT rates rising from 18% prior to implementation to 48% post-launch in cases where the pathway was used (p < 0.01). There was no increase in the appropriate SFRT rate for cases treated after March 2016 but not entered into the pathway tool as compared to cases prior to pathway tool implementation. Major reasons for rejecting recommendations included disagreement with life expectancy prognostication and patient convenience. The pathway increased physicians’ confidence regarding compliance with treatment guidelines and made it easier to find well-supported treatment recommendations. Workflow disruptions and the inability to handle nuanced situations emerged as limitations. Conclusions: Our experience demonstrates the utility of clinical pathway decision support for bone metastases in complex academic settings. Pathway use significantly increased appropriate care, more than doubling appropriate treatment rates relative to a synchronous group. Next steps include increasing the pathway’s ease of use, refining its prognostic abilities, and measuring related value effects.

RETRACTED ARTICLE: Epigenetic regulation of HGF/Met receptor axis is critical for the outgrowth of bone metastasis from breast carcinoma

Our translational research deals with the influence of microenvironment on the phenotype and colonization of bone metastases from breast carcinoma, and on pre-metastatic niche formation. The aim of the present study was to clarify the origin of hepatocyte growth factor (HGF), ligand of Met receptor, the control of the axis HGF/Met by DNA methylation, and its importance for the nexus supportive cells-metastatic cells and for metastasis outgrowth. In bone metastasis of the 1833-xenograft model, DNA methyltransferase blockade using the chemotherapic drug 5-aza-2′-deoxycytidine (decitabine) strongly reduced the expression of HGF/Met receptor axis and of E-cadherin, with decrease of metastasis wideness and osteolysis, prolonging mice survival. Thus, DNA methylation events acted as commanders of breast carcinoma cells metastatizing to bone influencing the epithelial phenotype. HGF emerged as a bone-marrow stimulus, and the exosomes seemed to furnish HGF to metastatic cells. In fact, decitabine treatment similarly affected some markers of these microvesicles and HGF, indicating that its supply to recipient cells was prevented. Notably, in bone metastasis the hypomethylation of HGF, Met and E-cadherin promoters did not appear responsible for their elevated expression, but we suggest the involvement of hypermethylated regulators and of Wwox oncosuppressor, the latter being affected by decitabine. Wwox expression increased under decitabine strongly localizing in nuclei of bone metastases. We hypothesize a role of Wwox in Met activity since in vitro Wwox overexpression downregulated the level of nuclear-Met protein fragment and Met stability, also under long exposure of 1833 cells to decitabine. HGF enhanced phosphoMet and the activity in nuclei, an effect partially prevented by decitabine. Altogether, the data indicated the importance to target the tumor microenvironment by blocking epigenetic mechanisms, which control critical events for colonization such as HGF/Met axis and Wwox, as therapy of bone metastasis.

CURRENT CAPABILITIES AND PROSPECTS OF CHEMORADIOTHERAPY FOR MEDULLARY THYROID CANCER (A LITERATURE REVIEW)

Medullary thyroid cancer (MTC) is characterized by the most aggressive course among differentiated thyroid carcinomas and is accompanied by early and extensive metastasis. Up to 60 % of patients with MTC already have disseminated forms of the disease (stage III– IV) by the moment of diagnosis. Overall five-year and ten-year survival of patients with MTC is 85–89 and 73–75 %, respectively, whereas five-year survival rate in patients with stage III–IV MTC is significantly lower and does not exceed 5–10 %. Therefore, treatment of disseminated forms of MTC is an extremely important problem in clinical oncology. The article gives an overview of Russian and foreign publications on the effectiveness of radiation and drug therapy for generalized MTC. Particular attention is paid to modern promising treatment strategies used for this category of patients, such as radionuclide therapy of bone metastases and targeted therapy with tyrosine kinase inhibitors.

Results of Palliative Radiation Therapy for Bone Metastasis From Hepatocellular Carcinoma: A Dose-Response Relationship

Results of Palliative Radiation Therapy for Bone Metastasis From Hepatocellular Carcinoma: A Dose-Response Relationship

Diffuse Large B-Cell Lymphoma Complicated by Small Bowel Obstruction after Radiotherapy: a Case Study

ABSTRACT Although the spleen is frequently involved in disseminated non-Hodgkin’s lymphoma (NHL), splenic presentation as the initial or only site of disease is uncommon. Treatment modalities include surgery, chemotherapy, and radiation therapy. The priority of cancer follow up is to perform surveillance for recurrent cancer and evaluation of treatment response. Side effects of treatment are frequently missed or overlooked. A 66-year-old woman was presented to our hospital with a month history of spleen enlargement. On physical examination the spleen was palpated at Schuffner 2. Abdominal MSCT scan was suggestive of lymphoma. Surgery revealed adhesion and obstruction of the stomach. Biopsy and gastrojejunostomy shunting were done, but splenectomy was difficult. The pathology anatomy findings confirmed the diagnosis of diffuse non Hodgkin’s lymphoma large B-cell type. Immunohistochemistry showed positive CD3 and CD20. She underwent 6 cycles of rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone (RCHOP) chemotherapy. CT evaluation done 7 months later revealed that the hilus lienalis lymph nodes and spleen has decrease in size. However, a lumbosacral x-ray done due to back pain revealed metastasis on her 1st and 2nd lumbal spine. After a single fraction of radiotherapy, nausea, vomiting and abdominal distension occurred. A 3 position abdominal x-ray revealed signs of small bowel obstruction. After surgery she has received 9 cycles of zoledronic acid and remained in good condition and ambulatory. Splenic presentation as the initial or only site of non-Hodgkin’s lymphoma (NHL) is uncommon. Acute small bowel obstruction and fistula due to palliative radiation therapy for bone metastasis needs prompt and appropriate treatment.

A DOTA based bisphosphonate with an albumin binding moiety for delayed body clearance for bone targeting

Radiolabeled bisphosphonates are commonly used in the diagnosis and therapy of bone metastases. Blood clearance of bisphosphonates is usually fast and only 30%–50% of the injected activity is retained in the skeleton, while most of the activity is excreted by the urinary tract. A longer blood circulation may enhance accumulation of bisphosphonate compounds in bone metastases. Therefore, a chemically modified macrocyclic bisphosphonate derivative with an additional human albumin binding entity was synthesized and pharmacokinetics of its complex was evaluated. The DOTA-bisphosphonate conjugate BPAMD was compared against the novel DOTAGA-derived albumin-binding bisphosphonate DOTAGA(428-d-Lys)MBP (L1). The ligands were labeled with 68Ga(III) and were evaluated in in vitro binding studies to hydroxyapatite (HA) as well as to human serum albumin. The compounds were finally compared in in vivo PET and ex vivo organ distribution studies in small animals over 6h. Binding studies revealed a consistent affinity of both bisphosphonate tracers to HA. Small animal PET and ex vivo organ distribution studies showed longer blood retention of [68Ga]L1. [68Ga]BPAMD is initially more efficiently bound to the bone but skeletal accumulation of the modified compound and [68Ga]BPAMD equalized at 6h p.i. Ratios of femur epiphyseal plate to ordinary bone showed to be more favorable for [68Ga]L1 than for [68Ga]BPAMD due to the longer circulation time of the new tracer. Thus, the chemical modification of BPAMD toward an albumin-binding bisphosphonate, L1, resulted in a novel PET tracer which conserves advantages of both functional groups within one and the same molecule. The properties of this new diagnostic tracer are expected to be preserved in 177Lu therapeutic agent with the same ligand (a theranostic pair).

Basigin-2 upregulated by receptor activator of NF-κB ligand enhances lung cancer-induced osteolytic lesions.

BackgroundLung cancer bone metastasis causes poor prognosis. Basigin-2, a novel cancer-associated biomarker, is upregulated in lung cancer and has been linked with tumor progression. But little is known about the role of basigin-2 in lung cancer bone metastasis and osteolytic lesion.MethodsBasigin-2 expression was evaluated in biopsy tissue specimens of 20 lung cancer patients with bone metastases via immunohistochemistry. Invasion assay and MTT proliferation assay were performed to test the invasion and proliferation of lung cancer cell after modulated basigin-2 expression. The osteoclastic activity of basigin-2 was detected in tibia cancer model by injected of lung cancer cells. The regulation role of receptor activator of NF-κB ligand (RANKL) on basigin-2 and its downstream molecules were measured by real-time quantitative RT-PCR, gelatin zymography and western blot analysis.ResultsWe found that basigin-2 was highly expressed in lung cancer bone metastases. Then, we demonstrated that basigin-2 could promote lung cancer cells invasion, metastasis and proliferation through upregulating metalloproteinases-2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF) expression. The lung cancer cells overexpressing basigin-2 strongly induced the osteolytic lesions in immunodeficient mice, which were reduced by treatment with basigin-2 blocking antibody. Furthermore, we explored the enhanced basigin-2 molecular mechanism in lung cancer bone metastasis. Our results indicated the RANKL, pivotal for the control of bone resorption, could increase basigin-2 and its downstream molecules MMP-2, MMP-9 and VEGF expression in vitro.ConclusionsBasigin-2 upregulated by RANKL induces MMPs and VEGF, which may increase lung cancer cell metastasis ability and support osteoclastic activity. Thus, our data suggest important roles for basigin-2 in lung cancer-induced osteolytic lesion and implicate this protein potential application as a target for lung cancer bone metastasis therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0302-9) contains supplementary material, which is available to authorized users.

Therapy for bone metastasis from different cancers ⁎

Abstract The bone is the most common target organ of cancer metastasis. Bone metastasis leads to considerable morbidity due to skeletal-related events (SREs). These include bone pain, hypercalcemia, pathologic fractures, and compression of the spinal cord. Cancers such as those of the lung, breast, prostate, and kidney are more likely to cause SREs than other cancer types. Additionally, some blood cancers, including multiple myeloma and lymphoma, frequently cause SREs. In this article, we review the conventional therapies for metastatic bone disease, including drug therapy, radiotherapy, and surgery. Among osteoclast-targeting agents, bisphosphonates and nuclear factor kappa-B ligand inhibitors are the most widely used agents to prevent cancer-related bone loss. Unsealed radioisotopes are also considered promising in cancer therapy. Currently, iodine-131, strontium-89, and radium-223 are available for the treatment of bone metastasis. However, the treatments for blood cancers with SREs are different from those of other cancers. In those cases, new classes of agents including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors have shown remarkable efficacy. We also discuss the potential development of new therapies for these diseases.

Dexamethasone Versus Placebo in the Prophylaxis of Radiation-induced Pain Flare Following Palliative Radiation Therapy for Bone Metastases: A Double-blind Randomized, Controlled, Superiority Trial

Dexamethasone Versus Placebo in the Prophylaxis of Radiationinduced Pain Flare Following Palliative Radiation Therapy for Bone Metastases: A Double-blind Randomized, Controlled, Superiority Trial E. Chow, R. Meyer, K. Ding, A. Nabid, P. Chabot, G. Coulombe, S. Ahmed, J. Kuk, A.R. Dar, A. Mahmud, A.M. Fairchild, C. Wilson, J.S. Wu, K. Dennis, M. Brundage, C. de Angelis, and R. Wong; Sunnybrook Health Sciences Centre-Odette Cancer Centre, Toronto, ON, Canada, Juravinski Hospital and Cancer Centre and McMaster University, Hamilton, ON, Canada, NCIC Clinical Trials Group, Cancer Research Institute, Queen’s University, Kingston, ON, Canada, CHUS, Sherbrooke, QC, Canada, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada, Hopital Notre-Dame du CHUM, Montreal, QC, Canada, CancerCare Manitoba, Winnipeg, MB, Canada, McMaster University, Hamilton, ON, Canada, London Regional Cancer Program, London, ON, Canada, Cancer Centre of Southeastern Ontario, Kingston, ON, Canada, Cross Cancer Institute, Edmonton, AB, Canada, University of Calgary, Calgary, AB, Canada, The Ottawa Cancer Centre, Ottawa, ON, Canada, Queen’s University, Kingston, ON, Canada, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada, Princess Margaret Hospital, Toronto, ON, Canada

THE EFFECT OF RADIATION THERAPY FOR BONE METASTASIS IN URINARY ORGAN CANCER.

(Objective) Bone metastasis symptoms are complications that greatly reduce the quality of life (QOL) of cancer patients. We report a retrospective study on the efficacy of radiation therapy for patients with bone metastasis in urinary organ cancer. (Subjects and methods) Subjects are comprised of 17 patients; total irradiated areas consist of 25 sites. There are 5 patients diagnosed with renal cell carcinoma, 1 patient with bladder cancer and 11 patients with prostatic cancer. All of them have undergone radiation therapy for bone metastasis in urinary organ cancer between April 2007 and March 2014 in the Department of Urology, Kanazawa Medical University. The mean age of the patients was 66.7 years old. We looked at irradiated areas, exposure dose and changes of symptom in all patients. (Results) Irradiated areas are thoracolumbar vertebrae (14 sites), cranial base (2 sites), pubic bone (1 site), ilium bone (2 sites), sacral bone (1 site), rib bone (1 site) and hip joint (1 site). The mean exposure dose of one area is 37.5 Gy (13.5-60). 19 irradiated sites which were previously reported to have sharp pain have gained improvement at 16 sites. These 16 sites have comparatively lesser pain or no pain. 8 cases in acknowledgment of walk difficulty, it was with 7 cases walking alone possibility again. (Conclusion) This study showed that radiation therapy have significant improvement in terms of symptoms and QOL for the patients with bone metastasis in urinary organ cancer.