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Bone Metastases (bone + metastase)
Kinds of Bone Metastases Selected AbstractsEarly (mucosal) gastric cancer with synchronous osteosclerotic bone metastases: a case reportEUROPEAN JOURNAL OF CANCER CARE, Issue 4 2010G. ANAGNOSTOPOULOS md ANAGNOSTOPOULOS G., SAKORAFAS G.H., KOSTOPOULOS P., MARGANTINIS G., TSIAKOS S. & PAVLAKIS G. (2010) European Journal of Cancer Care Early (mucosal) gastric cancer with synchronous osteosclerotic bone metastases: a case report Early gastric cancer (EGC) is defined as an adenocarcinoma confined to the gastric mucosa or submucosa, regardless of the presence of lymph node metastases. Early gastric cancer carries an excellent prognosis, with a 5-year survival rate at least 85% in most series. However, there are rare cases where distant metastases exist. Bone metastases are rare in gastric cancer; osteoblastic bone metastases are even rarer. We report a patient with EGC (mucosal) and synchronous osteosclerotic bone metastasis. To our knowledge, this is the first reported case of submucosal EGC with synchronous bone metastases. The patient was operated and he received adjuvant chemotherapy and radiotherapy. He died 18 months after gastric surgery from generalized disease. [source] Disseminated bony metastases following incidental gallbladder cancer detected after laparoscopic cholecystectomyHPB, Issue 4 2003F Youssef Background In patients with gallbladder cancer bony metastases are usually a late feature. Case outline A 47-year-old woman presented with a 2-month history of right upper quadrant pain. Ultrasound scan showed gallstones and a thick-walled gallbladder. Laparoscopic cholecystectomy was performed. Histopathology showed poorly differentiated adenocarcinoma infiltrating the muscular layer and vascular invasion. She was referred for further surgery. Staging CT scan of the abdomen showed no local residual disease. However Tc-99 bone scan suggested disseminated bony metastases, which were confirmed by bone trephine biopsy. The cancer progressed rapidly and the patient died 4 months after the diagnosis. Discussion Bone metastases can occur with early gallbladder cancer and a radioisotope bone scan can avoid unnecessary extensive liver surgery. [source] Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signalsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Toru Hiraga Abstract Imatinib mesylate (imatinib) is a potent and selective inhibitor of the tyrosine kinases, Bcr-Abl, c-Kit and platelet-derived growth factor receptors (PDGFRs). Recently, it has been reported that imatinib also targets the macrophage colony-stimulating factor (M-CSF) receptor c-Fms. M-CSF signals are essential for the differentiation of osteoclasts. Bone metastases of breast cancer are frequently associated with osteoclastic bone destruction. Furthermore, several lines of evidence suggest that osteoclasts play central roles in the development and progression of bone metastases. Thus, in the present study, we examined the effects of imatinib on bone metastases of breast cancer. Coimmunoprecipitation assays showed that imatinib inhibited the M-CSF-induced phosphorylation of c-Fms in osteoclast precursor cells as well as the PDGF-induced PDGFR phosphorylation in MDA-MB-231 human breast cancer cells. Imatinib also markedly reduced osteoclast formation in vitro. In contrast, those concentrations of imatinib did not affect osteoblast differentiation. We then examined the effects of imatinib on bone metastases of MDA-MB-231 cells in a nude mouse model. Radiographic and histomorphometric analyses demonstrated that imatinib significantly decreased bone metastases associated with the reduced number of osteoclasts. In support of the notion that the inhibition of c-Fms acts to suppress the development of bone metastases, we found that a specific inhibitor of c-Fms Ki20227 also decreased bone metastases. In conclusion, these results collectively suggest that imatinib reduced bone metastases, at least in part, by inhibiting osteoclastic bone destruction through the blockade of c-Fms signals. Our results also suggest that imatinib may have a protective effect against cancer treatment-induced bone loss. © 2008 Wiley-Liss, Inc. [source] Pathogenesis of osteoblastic bone metastases from prostate cancer,CANCER, Issue 6 2010Toni Ibrahim MD Abstract Prostate cancer is the second leading cause of cancer-related death in men. A typical feature of this disease is its ability to metastasize to bone. It is mainly osteosclerotic, and is caused by a relative excess of osteoblast activity, leading to an abnormal bone formation. Bone metastases are the result of a complex series of steps that are not yet fully understood and depend on dynamic crosstalk between metastatic cancer cells, cellular components of the bone marrow microenvironment, and bone matrix (osteoblasts and osteoclasts). Prostate cancer cells from primary tissue undergo an epithelial-mesenchymal transition to disseminate and acquire a bone-like phenotype to metastasize in bone tissue. This review discusses the biological processes and the molecules involved in the progression of bone metastases. Here we focus on the routes of osteoblast differentiation and activation, the crosstalk between bone cells and tumor cells, and the molecules involved in these processes that are expressed by both osteoblasts and tumor cells. Furthermore, this review deals with the recently elucidated role of osteoclasts in prostate cancer bone metastases. Certainly, to better understand the underlying mechanisms of bone metastasis and so improve targeted bone therapies, further studies are warranted to shed light on the probable role of the premetastatic niche and the involvement of cancer stem cells. Cancer 2010. © 2010 American Cancer Society. [source] Pharmacologic profile of zoledronic acid: A highly potent inhibitor of bone resorptionDRUG DEVELOPMENT RESEARCH, Issue 4 2002Jonathan R. Green Abstract Bisphosphonates are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclastic bone resorption (i.e., osteoporosis, Paget's disease, tumor-induced osteolysis). The nitrogen-containing bisphosphonate pamidronate is currently the standard treatment for hypercalcemia of malignancy (HCM) and skeletal complications of bone metastases. Zoledronic acid, a novel nitrogen-containing bisphosphonate with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates, including pamidronate, in both in vitro and in vivo preclinical models. Zoledronic acid inhibited ovariectomy-induced bone loss in adult monkeys and rats, and long-term treatment prevented skeletal turnover and subsequent bone loss, reduced cortical porosity, and increased mechanical strength. Zoledronic acid also significantly inhibited bone loss associated with arthritis, bone metastases, and prosthesis loosening. The increased potency of zoledronic acid vs. pamidronate has been demonstrated clinically: zoledronic acid (4 or 8 mg iv) was superior to pamidronate (90 mg iv) in normalizing corrected serum calcium in patients with HCM. In patients with bone metastases, low doses of zoledronic acid (, 2 mg) suppressed bone resorption markers , 50% below baseline, whereas pamidronate 90 mg yielded only 20 to 30% suppression. Importantly, the increased potency of zoledronic acid is not associated with an increased incidence of local (bone) or systemic adverse events. Zoledronic acid does not impair bone mineralization and, compared with pamidronate, has a greater renal and intestinal tolerability therapeutic index. Thus, based on preclinical assays and clinical data, zoledronic acid is the most potent bisphosphonate tested to date. Given its potency and excellent safety profile, zoledronic acid is now poised to become the new standard of treatment for HCM and metastatic bone disease. Drug Dev. Res. 55:210,224, 2002. © 2002 Wiley-Liss, Inc. [source] Early (mucosal) gastric cancer with synchronous osteosclerotic bone metastases: a case reportEUROPEAN JOURNAL OF CANCER CARE, Issue 4 2010G. ANAGNOSTOPOULOS md ANAGNOSTOPOULOS G., SAKORAFAS G.H., KOSTOPOULOS P., MARGANTINIS G., TSIAKOS S. & PAVLAKIS G. (2010) European Journal of Cancer Care Early (mucosal) gastric cancer with synchronous osteosclerotic bone metastases: a case report Early gastric cancer (EGC) is defined as an adenocarcinoma confined to the gastric mucosa or submucosa, regardless of the presence of lymph node metastases. Early gastric cancer carries an excellent prognosis, with a 5-year survival rate at least 85% in most series. However, there are rare cases where distant metastases exist. Bone metastases are rare in gastric cancer; osteoblastic bone metastases are even rarer. We report a patient with EGC (mucosal) and synchronous osteosclerotic bone metastasis. To our knowledge, this is the first reported case of submucosal EGC with synchronous bone metastases. The patient was operated and he received adjuvant chemotherapy and radiotherapy. He died 18 months after gastric surgery from generalized disease. [source] Efficacy of ibandronate for the treatment of skeletal events in patients with metastatic breast cancerEUROPEAN JOURNAL OF CANCER CARE, Issue 6 2009P. HERAS md HERAS P., KRITIKOS K., HATZOPOULOS A. & GEORGOPOULOU A.-P. (2009) European Journal of Cancer Care Efficacy of ibandronate for the treatment of skeletal events in patients with metastatic breast cancer Patients with breast carcinoma often develop bone metastases that carry a high risk of complications. A randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of ibandronate in patients with metastatic bone disease following breast cancer. The primary efficacy end point of the study was the proportion of patients who developed skeletal-related events (SREs, defined as pathologic fracture, spinal cord compression, radiation therapy to bone, change in anti-neoplastic therapy and surgery to bone). Secondary end points included time to first skeletal event, skeletal morbidity rate (events/year) and time to progression of bone lesions. In 150 patients (148,/2,) with breast carcinoma and bone metastases, treatment with intravenous ibandronate 6 mg over 15 min every 4 weeks for 24 months significantly reduced the proportion of patients who experienced an SRE compared with placebo (36% vs. 48%; P = 0.027). Time to first SRE was also delayed significantly (median 457 vs. 304 days; P = 0.007). Multiple event analysis showed that ibandronate reduced the risk of developing an SRE by 32% (hazard ratio = 0.69; 95% confidence interval 0.42,0.79; P = 0.003). In general, ibandronate was well tolerated with very rare grade 3 or 4 toxicity. In this study, ibandronate was shown to be significantly more effective than placebo as a treatment for metastatic bone disease from breast cancer using multiple end points. [source] Transcervical superior mediastinal lymphadenectomy in the management of papillary thyroid carcinomaHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 1 2003Mark L. C. Khoo FRCS Abstract Aim. Surgery is the treatment of choice for lymph node metastases in papillary thyroid carcinoma. When adequately treated by surgical extirpation, the presence of lymph node involvement does not seem to have a negative impact on cure rates or survival. Surgical lymphadenectomy for metastatic papillary thyroid carcinoma has been well described for both the central and the lateral compartments of the neck. Superior mediastinal lymphadenectomy, however, has only sporadically been mentioned. We describe our experience with transcervical superior mediastinal lymphadenectomy (TSML) that avoids the morbidity of the traditional sternal split. Materials and Methods. This retrospective analysis included 30 patients (24 women and 6 men; age range, 17,72 years) who underwent TSML by the senior author (JLF) for papillary carcinoma metastatic to the superior mediastinum between 1985 and 1999. Histopathologic examination confirmed positive nodes in all the mediastinal dissections. All patients received postoperative I131. Results. All the patients are alive after a median follow-up of 5 years (range, 1,14 years). Twenty-nine of 30 patients remain free of disease, whereas one patient is alive with lung and bone metastases. No patient has had local or regional relapse. The only significant complication was a high incidence of temporary (70%) and later permanent (50%) hypoparathyroidism. Conclusions. TSML is a safe and effective treatment for superior mediastinal metastases in papillary thyroid carcinoma. © 2002 Wiley Periodicals, Inc. Head Neck 24: 000,000, 2002 [source] Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signalsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Toru Hiraga Abstract Imatinib mesylate (imatinib) is a potent and selective inhibitor of the tyrosine kinases, Bcr-Abl, c-Kit and platelet-derived growth factor receptors (PDGFRs). Recently, it has been reported that imatinib also targets the macrophage colony-stimulating factor (M-CSF) receptor c-Fms. M-CSF signals are essential for the differentiation of osteoclasts. Bone metastases of breast cancer are frequently associated with osteoclastic bone destruction. Furthermore, several lines of evidence suggest that osteoclasts play central roles in the development and progression of bone metastases. Thus, in the present study, we examined the effects of imatinib on bone metastases of breast cancer. Coimmunoprecipitation assays showed that imatinib inhibited the M-CSF-induced phosphorylation of c-Fms in osteoclast precursor cells as well as the PDGF-induced PDGFR phosphorylation in MDA-MB-231 human breast cancer cells. Imatinib also markedly reduced osteoclast formation in vitro. In contrast, those concentrations of imatinib did not affect osteoblast differentiation. We then examined the effects of imatinib on bone metastases of MDA-MB-231 cells in a nude mouse model. Radiographic and histomorphometric analyses demonstrated that imatinib significantly decreased bone metastases associated with the reduced number of osteoclasts. In support of the notion that the inhibition of c-Fms acts to suppress the development of bone metastases, we found that a specific inhibitor of c-Fms Ki20227 also decreased bone metastases. In conclusion, these results collectively suggest that imatinib reduced bone metastases, at least in part, by inhibiting osteoclastic bone destruction through the blockade of c-Fms signals. Our results also suggest that imatinib may have a protective effect against cancer treatment-induced bone loss. © 2008 Wiley-Liss, Inc. [source] Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: Implication for breast cancer osteolytic bone metastasesINTERNATIONAL JOURNAL OF CANCER, Issue 5 2008Guojun Bu Abstract Most breast cancer metastases in bone form osteolytic lesions, but the mechanisms of tumor-induced bone resorption and destruction are not fully understood. Although it is well recognized that Wnt/,-catenin signaling is important for breast cancer tumorigenesis, the role of this pathway in breast cancer bone metastasis is unclear. Dickkopf1 (Dkk1) is a secreted Wnt/,-catenin antagonist. In the present study, we demonstrated that activation of Wnt/,-catenin signaling enhanced Dkk1 expression in breast cancer cells and that Dkk1 overexpression is a frequent event in breast cancer. We also found that human breast cancer cell lines that preferentially form osteolytic bone metastases exhibited increased levels of Wnt/,-catenin signaling and Dkk1 expression. Moreover, we showed that breast cancer cell-produced Dkk1 blocked Wnt3A-induced osteoblastic differentiation and osteoprotegerin (OPG) expression of osteoblast precursor C2C12 cells and that these effects could be neutralized by a specific anti-Dkk1 antibody. In addition, we found that breast cancer cell conditioned media were able to block Wnt3A-induced NF-kappaB ligand reduction in C2C12 cells. Finally, we demonstrated that conditioned media from breast cancer cells in which Dkk1 expression had been silenced via RNAi were unable to block Wnt3A-induced C2C12 osteoblastic differentiation and OPG expression. Taken together, these results suggest that breast cancer-produced Dkk1 may be an important mechanistic link between primary breast tumors and secondary osteolytic bone metastases. © 2008 Wiley-Liss, Inc. [source] Relevance of a new rat model of osteoblastic metastases from prostate carcinoma for preclinical studies using zoledronic acidINTERNATIONAL JOURNAL OF CANCER, Issue 4 2008François Lamoureux Abstract Animal models that mimic osteoblastic metastases associated with prostate carcinoma are required to improve the therapeutic options in humans. A new model was then developed and characterized in immunocompetent rats. The bisphosphonate zoledronic acid (ZOL) was tested to validate this model as a therapeutic application. Rat AT6-1 prostate tumor cells were characterized in vitro at the transcriptional (bone and epithelial markers) and functional (induction of mineralized nodules) levels. The bone lesions induced after their direct injection into the femur bone marrow were characterized by radiography, microscanner and histology analyses. ZOL effects were studied in vivo on bone lesion development and in vitro on AT6-1 cell proliferation, apoptosis and cell cycle analysis. Apart from epithelial markers, AT6-1 cells express an osteoblast phenotype as they express osteoblastic markers and are able to induce mineralized nodule formation in vitro. A disorganization of the trabecular bone at the growth zone level was observed in vivo after intraosseous AT6-1 cell injection as well as cortical erosion. The tumor itself is associated with bone formation as revealed by SEM analysis and polarized light microscopy. ZOL prevents the development of such osteoblastic lesions, related to a direct inhibitory effect on tumor cell proliferation independent of caspase 3 activation, but associated with cell cycle arrest. A new rat model of osteoblastic bone metastases was validated in immunocompetent rats and used to show the relevance of using ZOL in such lesions, as this compound shows bifunctional effects on both bone remodelling and tumor cell proliferation. © 2007 Wiley-Liss, Inc. [source] Apocrine carcinoma of the vulva in a band-like arrangement with inflammatory and telangiectatic metastasis via local lymphatic channelsINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 1 2003Takahiro Kiyohara MD Background Primary adenocarcinomas of the vulva have been classified as sweat gland carcinomas, extramammary Paget's disease, and primary breast carcinomas of the vulva. They share some common histopathologic features. Methods We describe a 72-year-old Japanese woman with apocrine carcinoma of the vulva and local lymphatic metastasis. Results The patient presented with a bruise on her inguinal area. Physical examination revealed a 4 cm × 7 cm, dark-red, irregularly elevated tumor on the left labium majora. Dome-shaped, flesh-colored, small papulovesicles were scattered on the abdomen, accompanied by erythema and induration. The lesion showed a band-like arrangement. General examination revealed multiple bone metastases, particularly in the spine. Microscopic examination revealed a moderately differentiated adenocarcinoma with signet ring cells. A few pagetoid clear cells were present in the hypertrophic epidermis. The peripheral papulovesicles demonstrated the same histopathologic view as in inflammatory and telangiectatic, metastatic breast carcinoma. Tumor cells were positive for various ductal and glandular markers. Estrogen and progesterone receptors were not expressed. Ultrastructural findings suggested differentiation towards apocrine or mammary glands because of the presence of an apocrine process and electron-dense mucous granules. The patient died in spite of combination chemotherapy and irradiation therapy. Conclusions We report a rare case of apocrine carcinoma of the vulva in a band-like arrangement with local lymphatic metastasis which showed the clinical and histopathologic characteristics of inflammatory and telangiectatic carcinoma. [source] Usefulness of single photon emission computed tomography imaging in the detection of lumbar vertebral metastases from prostate cancerINTERNATIONAL JOURNAL OF UROLOGY, Issue 6 2008Tetsuo Nozaki Objective: To determine whether single photon emission computed tomography (SPECT) is useful in the detection of prostate cancer bone metastases in the lumbar vertebrae. Methods: Thirty-nine patients (12 with benign prostatic hyperplasia, 27 with prostate cancer) were considered and submitted to bone SPECT. All of them had increased uptake in lumbar vertebrae on bone scintigraphy. In those with prostate cancer, definitive diagnosis of bone metastases was established by magnetic resonance imaging (MRI). SPECT axial images were classified into five accumulation patterns: mosaic, large hot, diffuse, peripheral, and articular (or pediculate). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of bone SPECT were calculated. Results: Overall, 116 vertebral lesions (49 metastatic, 67 degenerative) were studied. Mosaic, large hot and diffuse patterns were more frequently associated with metastatic lesions (84.2%, 70.3%, and 63.1% of the cases, respectively). On the other hand, peripheral and articular (or pediculate) patterns were mostly ascribed to degenerative lesions (100% and 87.5% of the cases, respectively). Sensitivity, specificity, PPV and NPV of bone SPECT were 95.9% (47/49), 73.1% (49/67), 72.3% (47/65), and 96.1% (49/51), respectively. Conclusions: Bone SPECT provides better accuracy than bone scintigraphy in differential diagnosis of lumbar vertebral lesions from prostate cancer. [source] Clinical experience of hormone therapy to bone metastatic prostate cancerINTERNATIONAL JOURNAL OF UROLOGY, Issue 5 2006MASAMI WAKISAKA Background:, A novel hormone therapy was instituted against prostate cancer with bone metastases and its therapeutic efficacy was investigated. Methods:, A total of 35 patients who had been pathologically diagnosed with carcinoma of the prostate between January 1994 and December 2003 were entered into the present study. Patients aged over 80 years were excluded from the study. As for the treatment methodology, diethylstilbestrol diphosphate (DES-P) at 500 mg/day was intravenously injected for 20,40 days, followed by monotherapy with an analog of luteinizing hormone-releasing hormone (LHRH). In all subjects, surgical castration was not conducted. The survival rate was analysed according to the method of Kaplan,Meier. Results:, One of the 35 patients was excluded from the study as this patient did not meet the inclusion criteria. There were four patients who dropped out of the study. On histology, 17 patients had moderately differentiated adenocarcinomas and 17 patients had poorly differentiated adenocarcinomas. As for the extent of disease (EOD), the patients were classified as with a score of 1 in 10 patients, 2 in 13 patients, 3 in 7 patients and 4 in 4 patients. The 5-year progression-free survival rate and overall survival rate were 24.3% and 60.6%, respectively. Conclusion:, Our new hormone therapy in the management of prostate cancer metastatic to the bone has demonstrated markedly superior therapeutic results compared to those so far obtained. [source] Remodeling and Vascular Spaces in BoneJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2007Erik Fink Eriksen Abstract In recent years, we have come to appreciate that the close association between bone and vasculature plays a pivotal role in the regulation of bone remodeling and fracture repair. In 2001, Hauge et al. characterized a specialized vascular structure, the bone remodeling compartment (BRC), and showed that the outer lining of this compartment was made up of flattened cells, displaying all the characteristics of lining cells in bone. A decrease in bone turnover leads to a decrease in surfaces covered with remodeling compartments, whereas increased turnover causes an increase. Immunoreactivity for all major osteotropic growth factors and cytokines including osteoprotegerin (OPG) and RANKL has been shown in the cells lining the BRC, which makes the BRC the structure of choice for coupling between resorption and formation. The secretion of these factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Reduction in BRC space brought about by antiresorptive therapies such as bisphosphonates reduce the number of skeletal events in advanced cancer, whereas an increase in BRC space induced by remodeling activators like PTH may increase the bone metastatic burden. The BRC has only been characterized in detail in trabecular bone; there is, however, evidence that a similar structure may exist in cortical bone, but further characterization is needed. [source] 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 LesionsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2001Olivier Peyruchaud Abstract 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. [source] A paradigm for the treatment of prostate cancer bone metastases based on an understanding of tumor cell,microenvironment interactionsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2005Robert D. Loberg Abstract The pliability of cancer cells to mutate into several different phenotypes in an attempt to find one that will survive and colonize at the metastatic site is a tremendous "hurdle" to overcome in designing novel cancer therapeutics. New targets of therapy are essential if we are to effectively overcome the evasiveness of cancer. The interaction between the tumor cell and the surrounding microenvironment creates a vicious cycle that perpetuates disease survival and progression. The future of cancer therapy resides in the ability to focus on the recruited and exploited relationships of the cancer cell with the host environment. These therapies target cancer cell growth early and interrupt the vicious cycle that is created by the tumor cells interacting with bone components by inhibiting osteoclasts, osteoblasts, stromal cells, and endothelial cells. They alter the bone microenvironment, creating a hostile "soil" that prevents the "seed" from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics. © 2005 Wiley-Liss, Inc. [source] SAPHO syndrome masquerading as metastatic bone diseaseJOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY, Issue 5 2005NH Theumann Summary A 46-year-old woman who had had a right mastectomy for breast carcinoma a month before underwent bone scintigraphy. The examination revealed multiple pelvic, vertebral and sternal hot spots suggestive of bone metastases. Standard X-rays and CT confirmed the presence of bony lesions but they were not typical of bone metastases. As the radiographic appearance was reminiscent of SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), bone biopsies were performed. Histology showed fibrosis and hyperostosis but no tumour cells. On further questioning, the patient revealed she had had palmar pustulosis and sacroiliitis some years earlier. The purpose of the case report is to show that accurate diagnosis of SAPHO syndrome requires careful clinical and radiological examinations. [source] Utility-adjusted analysis of the cost of palliative radiotherapy for bone metastasesJOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY, Issue 3 2003Michael B Barton Summary Palliative radiotherapy is effective in the treatment of bone metastases but is under-utilized, possibly because it is perceived to be expensive. We performed a cost-utility analysis of palliative radiotherapy for bone metastases, evaluating both the actual cost of radiotherapy as well as its impact on quality of life by adjusting for the variation in response to treatment. Hospital records between July 1991 and July 1996 were reviewed to ascertain the number of patients treated with palliative radiotherapy for bone metastases, the average number of fields of radiation delivered to each patient and the average duration of survival. Partial and complete response rates to palliative radiotherapy were obtained from a review of all published randomized controlled trials of radiation treatment of bone metastases. Utility values were assigned to the response rates, and an overall adjusted response rate to radiotherapy was derived. The cost of delivering a field of radiation was calculated. The total cost was divided by the total number of response months to give a utility-adjusted cost per month of palliative radiotherapy. The utility-adjusted cost per month of palliative radiotherapy of bone metastases was found to be AUS$ 100 per month or AUS$ 1200 per utility-adjusted life-year. This study demonstrates that, contrary to popular perception, palliative radiotherapy is a cost-effective treatment modality for bone metastases. [source] The role of surgery in breast cancer patients with isolated bone metastases at the time of diagnosisJOURNAL OF SURGICAL ONCOLOGY, Issue 2 2009Sevim Turanli MD Abstract Background Surgery for the primary tumor in breast cancer patients with synchronous isolated bone metastasis is applied for palliation. The aim was to determine whether surgical removal of the primary tumor provides a better survival and disease progression. Methods Forty-four patients were diagnosed between the dates June 2004 and January 2007 and these patients are classified according to the removal of the primary tumor or not. Patients and tumor characteristics, removal of the primary tumor, and response to systemic therapy are examined as the factors that were affecting overall survival and time to progression of the disease. Results The median follow-up time was 37.5 months. Mean time to progression and overall survival was longer for the patients who received surgery than the patients who did not (20.4 vs. 18.4 months and 57.6 vs. 44.5 months, respectively), but these were not significant (P,=,0.58, P,=,0.39). In multivariate analysis, response to systemic treatment [(P,=,0.03), hazard ratio,=,0.44, 95% confidence interval,=,0.20,0.93] was independent factor associated with overall survival. Conclusion The response to systemic therapy is the major factor on survival in the breast cancer patients with isolated bone metastasis. Excision of the primary tumor has no effect on time to progression and overall survival. J. Surg. Oncol. 2009;100:95,99. © 2009 Wiley-Liss, Inc. [source] A Bayesian hierarchical mixture model for platelet-derived growth factor receptor phosphorylation to improve estimation of progression-free survival in prostate cancerJOURNAL OF THE ROYAL STATISTICAL SOCIETY: SERIES C (APPLIED STATISTICS), Issue 1 2010Satoshi Morita Summary., Advances in understanding the biological underpinnings of many cancers have led increasingly to the use of molecularly targeted anticancer therapies. Because the platelet-derived growth factor receptor (PDGFR) has been implicated in the progression of prostate cancer bone metastases, it is of great interest to examine possible relationships between PDGFR inhibition and therapeutic outcomes. We analyse the association between change in activated PDGFR (phosphorylated PDGFR) and progression-free survival time based on large within-patient samples of cell-specific phosphorylated PDGFR values taken before and after treatment from each of 88 prostate cancer patients. To utilize these paired samples as covariate data in a regression model for progression-free survival time, and be cause the phosphorylated PDGFR distributions are bimodal, we first employ a Bayesian hierarchical mixture model to obtain a deconvolution of the pretreatment and post-treatment within-patient phosphorylated PDGFR distributions. We evaluate fits of the mixture model and a non-mixture model that ignores the bimodality by using a supnorm metric to compare the empirical distribution of each phosphorylated PDGFR data set with the corresponding fitted distribution under each model. Our results show that first using the mixture model to account for the bimodality of the within-patient phosphorylated PDGFR distributions, and then using the posterior within-patient component mean changes in phosphorylated PDGFR so obtained as covariates in the regression model for progression-free survival time, provides an improved estimation. [source] Ewing sarcoma bone metastases: ,You see one, you've seen them all'PEDIATRIC BLOOD & CANCER, Issue 5 2006(Commentary on Furth et al., page 607) No abstract is available for this article. [source] Structural studies of human alkaline phosphatase in complex with strontium: Implication for its secondary effect in bonesPROTEIN SCIENCE, Issue 7 2006Paola Llinas Abstract Strontium is used in the treatment of osteoporosis as a ranelate compound, and in the treatment of painful scattered bone metastases as isotope. At very high doses and in certain conditions, it can lead to osteomalacia characterized by impairment of bone mineralization. The osteomalacia symptoms resemble those of hypophosphatasia, a rare inherited disorder associated with mutations in the gene encoding for tissue-nonspecific alkaline phosphatase (TNAP). Human alkaline phosphatases have four metal binding sites,two for zinc, one for magnesium, and one for calcium ion,that can be substituted by strontium. Here we present the crystal structure of strontium-substituted human placental alkaline phosphatase (PLAP), a related isozyme of TNAP, in which such replacement can have important physiological implications. The structure shows that strontium substitutes the calcium ion with concomitant modification of the metal coordination. The use of the flexible and polarizable force-field TCPEp (topological and classical polarization effects for proteins) predicts that calcium or strontium has similar interaction energies at the calcium-binding site of PLAP. Since calcium helps stabilize a large area that includes loops 210,228 and 250,297, its substitution by strontium could affect the stability of this region. Energy calculations suggest that only at high doses of strontium, comparable to those found for calcium, can strontium substitute for calcium. Since osteomalacia is observed after ingestion of high doses of strontium, alkaline phosphatase is likely to be one of the targets of strontium, and thus this enzyme might be involved in this disease. [source] Pro-Opiomelanocortin Expression in a Metastatic Breast Carcinoma with Ectopic ACTH SecretionTHE BREAST JOURNAL, Issue 4 2004Marie-Françoise Pelte MD Abstract: Cushing's syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) secretion is rarely observed in breast carcinoma and only four cases have been previously published. We report here the case of a 50-year-old woman who presented with a history of diffuse bone pain associated with multiple hepatic, pulmonary, and bone metastases. A core needle biopsy specimen revealed an invasive ductal carcinoma in the right breast. The patient subsequently developed an ACTH-dependent paraneoplastic Cushing's syndrome and she died of arrhythmia and heart failure, despite treatment. At autopsy, immunohistochemical staining showed chromogranin A and ACTH positivity in the breast tumor and a lung metastasis. The mRNA expression of the pro-opiomelanocortin (POMC) gene was detected in tumoral cells by reverse transcriptase polymerase chain reaction (RT-PCR). This is the first case of Cushing's syndrome secondary to ectopic ACTH secretion where the presence of ACTH by immunohistochemistry and the expression of the POMC gene by RT-PCR have both been demonstrated in a breast carcinoma with metastases. The clinical history and the pathologic findings are presented with the methods and results of the molecular analysis. This case illustrates an example of ectopic ACTH syndrome in a breast carcinoma with neuroendocrine (NE) differentiation. This NE phenotype is directly related to the synthesis of ACTH by the tumoral cells. It should be kept in mind that an ectopic ACTH syndrome may be produced not only by small cell carcinoma or endocrine tumors but also by breast cancer. No relationship has been established between NE features and prognostic factors or patient outcome for this peculiar type of breast carcinoma. The demonstration of mRNA POMC in breast carcinoma with NE features suggests a depression and/or an activation of the POMC gene linked to the NE differentiation., [source] Osteonecrosis of the Mandible or Maxilla Associated with the use of New Generation BisphosphonatesTHE LARYNGOSCOPE, Issue 1 2006Matthew C. Farrugia DO Objective: The use of bisphosphonates is well established for the treatment of patients with metastatic bone disease, osteoporosis, and Paget's disease. Osteonecrosis of the mandible or maxilla associated with the use of bisphosphonates is a newly described entity never before discussed in the otolaryngology literature. In this paper, we review a series of patients diagnosed with osteonecrosis, all treated with new generation bisphosphonates. Our objective is to inform and educate others, particularly otolaryngologists/head and neck surgeons, about this drug induced entity, a condition that should be recognized early to avoid potential devastating consequences. Study Design: Retrospective chart review of a series of patients from a tertiary referral center. Methods: Pathology reports of specimens submitted from either the mandible or maxilla were reviewed from the previous 12 months. Any patient diagnosed with osteonecrosis without evidence of metastatic disease at that site was included; those with a previous history of radiation therapy were excluded. Each patient's medical history and profile were reviewed. Results: Twenty-three patients were identified with osteonecrosis of the mandible or maxilla. All of these were associated with the use of new generation bisphosphonates: zolendronate (Zometa, Novartis), pamidronate (Aredia, Novartis), and alendronate (Fosamax, Merck). Eighteen patients with known bone metastases had been treated with the intravenous form, whereas five patients with either osteoporosis or Paget's disease were using oral therapy. Patients typically presented with a nonhealing lesion, often times the result of previous dental intervention. Although the majority of these patients were treated with conservative surgical debridement, we present a case requiring a near total maxillectomy. Conclusions: Drug induced osteonecrosis of the mandible or maxilla has been recently recognized as a sequelae of treatment with the new generation of bisphosphonates. Most patients can be treated with conservative surgical debridement and cessation of bisphosphonate therapy, whereas a few may require radical surgical intervention. Other recommendations include regimented prophylactic care with an assessment of dental status before the administration of bisphosphonates, avoidance of dental procedures, and close monitoring of oral hygiene. [source] Kallikrein 4 is a potential mediator of cellular interactions between cancer cells and osteoblasts in metastatic prostate cancerTHE PROSTATE, Issue 4 2007Jin Gao Abstract BACKGROUND Prostate cancer (PCa) and bone cell interactions are critical in the metastatic phase. Kallikrein 4 (KLK4/hK4) is expressed in both PCa and mineralized tissues. We determined if KLK4/hK4 expression was associated with, and influenced by, the bone environment of metastatic PCa. METHODS Immunohistochemistry, in vitro co-culture, cell migration, and attachment assays. RESULTS hK4 was localized to tumor cells and osteoblasts in bone metastases. KLK4/hK4 increased in LNCaP and PC3 cells co-cultured with SaOs2 cells; SaOs2 KLK4/hK4 was unchanged. Co-culture did not affect cell proliferation but altered alkaline phosphatase activity/mRNA levels in SaOs2 cells. KLK4 -transfected PC3 cells had increased migration towards SaOs2 conditioned medium and greater attachment to the bone-matrix proteins, collagens I and IV. CONCLUSIONS hK4 expression and interaction with both tumor cells and osteoblasts suggests a role for hK4 in PCa bone metastasis. Whether this observation is unique to bone metastasis or reflects a role for hK4 in PCa metastasis generally is yet to be established. Prostate 67: 348,360, 2007. © 2007 Wiley-Liss, Inc. [source] Relaxin becomes upregulated during prostate cancer progression to androgen independence and is negatively regulated by androgensTHE PROSTATE, Issue 16 2006Vanessa C. Thompson Abstract BACKGROUND Relaxin is a potent peptide hormone normally secreted by the prostate. This study characterized relaxin expression during prostate cancer progression to androgen independence (AI), and in response to androgens. METHODS The prostate cancer cell line, LNCaP, was assayed by microarrays and confirmatory Northern analysis to assess changes in relaxin levels due to androgen treatment and in LNCaP xenografts following castration. Relaxin protein levels were examined by immunohistochemistry (IHC) in tissue microarrays of human prostate cancer samples following androgen ablation. RESULTS Relaxin levels decreased in a time and concentration-dependent manner due to androgens in vitro, and increased in xenografts post-castration. Relaxin increased in radical prostatectomy specimens after 6 months of androgen ablation and in AI tumors, was highest in bone metastases. CONCLUSIONS Relaxin is negatively regulated by androgens in vitro and in vivo, which correlates to clinical prostate cancer specimens following androgen ablation. The role of relaxin in angiogenesis and tissue remodeling suggests it may contribute to prostate cancer progression. Prostate © 2006 Wiley-Liss, Inc. [source] Prostate cancer expression of runt-domain transcription factor Runx2, a key regulator of osteoblast differentiation and functionTHE PROSTATE, Issue 1 2003Kristen D. Brubaker Abstract BACKGROUND Prostate cancer (CaP) bone metastases express numerous proteins associated with bone cells. Specific transcription factors, including Runx2, regulate the expression of many bone-related factors in osteoblasts. Expression of these transcription factors in CaP may be linked to the ability of CaP bone metastases to influence bone remodeling. METHODS CaP tissues and cell lines were analyzed for expression of Runx2 mRNA by RT-PCR and in situ hybridization, and protein by immunohistochemistry, Western blotting, and electrophoretic mobility shift assays (EMSA). RESULTS Runx2 mRNA and protein were detected in CaP tissues and cell lines. A specific Runx2: OSE2 complex could be formed with PC-3 nuclear extracts. CONCLUSIONS Expression of Runx2 in CaP may be the molecular switch that is associated with expression of various bone-specific factors in CaP. In turn, expression of these factors can influence bone remodeling and possibly play a role in the growth and survival of CaP in bone. Prostate 56: 13,22, 2003. © 2003 Wiley-Liss, Inc. [source] Evaluation of the safety, pharmacokinetics and treatment effects of an ,,,3 integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer and bone metastasesASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 1 2010Mark A ROSENTHAL Abstract Aim: This study aimed to evaluate the safety, pharmacokinetics and treatment effects of an ,,,3 integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer (HRPC) and bone metastases. Methods: A total of 21 patients with bone metastases and HRPC were randomized to receive MK-0429 200 mg b.i.d. or 1600 mg b.i.d. for 4 weeks. Toxicity, pharmacokinetics and markers of bone turnover and tumor activity were examined. Results: Nausea was the most common adverse event: one (200-mg group) and 11 (1600-mg group) patients. At 4 weeks, mean AUC0,12 h was 210 mmol*h (200-mg group) and 673 mmol*h (1600-mg group); mean Cmax values were 42 mmol/L (200-mg group) and 154 mmol/L (1600-mg group). Urinary cross-linked N-telopeptides of type I collagen to creatinine ratio (uNTx), a bone turnover biomarker, showed a change from baseline of ,43.4 percent (200-mg group) and ,34.1 percent (1600-mg group). There was an increase in serum prostate specific antigen (PSA), a marker for disease activity, of 54.1 percent (200-mg group) and 44.5 percent (1600-mg group). Conclusion: MK-0429 was generally well tolerated, with the most common side-effect being nausea. There was some evidence of an early reduction of bone turnover, indicating a potential for clinical use in the treatment of MBD although serum PSA was unexpectedly increased during the study. [source] Preserving bone health in patients with hormone-sensitive prostate cancer: the role of bisphosphonatesBJU INTERNATIONAL, Issue 11 2009Fred Saad Men with prostate cancer initiating androgen-deprivation therapy (ADT) may have multiple factors that threaten their skeletal health, including increased fracture risk from bone loss during ADT and the propensity to develop bone metastases, which may lead to skeletal-related events (SREs). Bisphosphonates have utility in oncology for patients with bone metastases to prevent bone loss during hormonal therapy and in the benign setting to treat osteoporosis. These agents have an emerging role in patients with hormone-sensitive prostate cancer (HSPC). Etidronate, alendronate, pamidronate, and zoledronic acid have all shown efficacy in preventing ADT-related bone loss. Alendronate and zoledronic acid have also been shown to increase bone mineral density vs baseline during ADT. Patients with bone metastases from HSPC who received 4 mg zoledronic acid every 3 or 4 weeks had a low incidence of skeletal complications, although controlled study data have not been reported. Bisphosphonate treatment in men with HSPC may be effective for the prevention of ADT-related bone loss, underscoring the importance of treating early to avoid SREs and potentially delay disease progression to metastatic bone disease. [source] | |||||||||||||||||||||||||||||||