Appearance Of Bone Metastases Research Articles

Newly Released Advances in the Molecular Mechanisms of Osseous Metastasis and Potential Therapeutic Strategies.

The appearance of bone metastases (BM) in individuals with advanced solid cancers (breast, prostate, lung) often worsens their quality of life and prognosis. Although none have been fully effective, several strategies have been used to combat BM. Hence, the need for new data that could be useful for treating bone metastasis. To this end, we reviewed the recent literature on the subject. About patients with prostate cancer, treatments with PIP5K1α inhibitors have been found to inhibit tumor invasion and metastasis, and G protein-coupled receptor class C group 5 member A (GPRC5A) could be a future therapeutic target. Regarding patients with breast cancer, we found the following: Asperolide A could be another curative drug; targeting transforming growth factor-beta (TGFβ) and bone morphogenetic protein (BMP) signaling pathways, along with osteoclast activity, could be a favorable therapeutic approach in the preclusion of osteolytic bone destruction; TRAF6 inhibitors such as 6877002 appear promising; aiming the BMP4-SMAD7 signaling axis is an innovative therapeutic approach; there is favorable proof for the plausible therapeutic utilization of bone aiming immunostimulatory MOF (BT-isMOF) nanoparticles, and inhibition of IL4R and macrophages could have therapeutic benefits. For lung cancer, the function of LIGHT in osteolytic osseous illness instigated by metastatic non-small cell lung cancer should be highlighted.

MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma.

Simple SummaryBone metastases cause substantial morbidity and implicate worse clinical outcomes for clear-cell renal cell carcinoma patients. MicroRNAs are small RNA molecules that modulate gene translation and are involved in the development of cancer and metastasis. We identified six microRNAs that are potentially specifically involved in metastasis to bone, of which two seem protective and four implicate a higher risk. This aids further understanding of the process of metastasizing to bone. Furthermore, these microRNA hold potential for biomarkers or therapeutic targets.Bone metastasis in clear-cell renal cell carcinoma (ccRCC) leads to substantial morbidity through skeletal related adverse events and implicates worse clinical outcomes. MicroRNAs (miRNA) are small non-protein coding RNA molecules with important regulatory functions in cancer development and metastasis. In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis. In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs. In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis. These miRNAs are potential biomarkers and attractive targets for miRNA inhibitors or mimics, which could lead to novel therapeutic possibilities for bone targeted treatment in metastatic ccRCC.

Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice.

Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective mouse models and treatment are necessary. High bone-metastatic variants of human breast cancer cells were selected in nude mice by cardiac injection. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases compared to only 20% with parental cells. Treatment with tumor-targeting Salmonella typhimurium A1-R completely prevented the appearance of bone metastasis of the high metastatic variant in nude mice (P < 0.001). After injection of the highly bone-metastatic breast cancer variant to the tibia of nude mice, S. typhimurium A1-R treatment significantly reduced tumor growth in the bone (P < 0.001). These data indicated that S. typhimurium A1-R is useful to prevent and inhibit breast cancer bone metastasis and should be of future clinical use for breast cancer in the adjuvant setting.

Prognostic role of early versus late onset of bone metastasis in patients with carcinoma of the ovary, peritoneum and fallopian tube

BackgroundBone metastases are a rare manifestation in the management of ovarian cancer and thought to be associated with a poor prognosis as sign of distant spread. Only few data exist on this rare condition. The present study aimed to more information on this very distinct patient collective. Patients and methodsA retrospective chart review was carried out including all patients who had been treated from 1994 to 2009 for histologically confirmed ovarian, peritoneal and fallopian tube cancer. Overall, 1717 cases were detected and screened. Patients with bone metastasis were identified and analyzed regarding survival as well as various clinical variables. ResultsA total of 26 women who had been diagnosed with bone metastases ante mortem could be identified, resulting in an incidence of 1.50%. The majority of patients presented multiple bone lesions (80.8%) and bone spread was symptomatic in 62.5% of the cases. Mean overall survival from primary diagnosis of EOC was 50.5 months (range: 2.5–142.5 months). Median overall survival after diagnosis of bone metastases was 7.2 months. When divided into two subsets depending on timepoint diagnosis of bone metastases, there was a significant difference in overall survival. The mean overall survival from primary diagnosis of EOC in the early-onset group (n = 8), defined as occurence of bone manifestation within 12 months, was 11.2 months. The mean overall survival in the late-onset group (n = 15) was 78.4 months (P = 0.000001). ConclusionsThe time interval from diagnosis to appearance of bone metastases is a prognostic factor in ovarian cancer. While early onset bone spread has a strong negative prognostic impact, late-onset bone diagnosis of bone metastases hardly influences the prognosis at all. This finding should be considered in the management of patients with bone metastases from ovarian cancer.

Establishing the nude mice bone metastasis model of lung adenocarcinoma and applying MicroCT into the observation

背景与目的骨转移占晚期肺癌的50%-70%。本研究以体外侵袭、迁移能力不同的肺腺癌细胞系A549、H1299、SPC-A-1、XL-2为基础建立肺腺癌骨转移裸小鼠模型，MicroCT观察骨转移情况。方法将50只6 w-8 w龄裸小鼠随机平均分为5组，4个实验组左心室分别注射相应四种细胞悬液（0.2 mL/只）；对照组左心室注射等量生理盐水。注射后第二周起定期对各组小鼠进行MicroCT扫描，当小鼠明显消瘦时此组观察结束，结束前行骨组织病理学检查；对各实验组出现的骨转移部位按中轴骨和四肢骨归类，比较这两种部位之间的转移率；根据各组出现骨转移所用平均时间、骨转移率，对各细胞系骨转移能力进行统计分析。结果经MicroCT、病理学检查确定，各实验组出现不同骨转移率，对照组小鼠无骨转移现象；各实验组中轴骨转移率均明显高于四肢骨，这与临床上肺癌骨转移规律一致，模型建立成功。各实验组间发生骨转移的小鼠数目及出现转移所用平均时间无明显差异。结论MicroCT能清晰地检测到骨质破坏，利于骨转移情况的判断；我们成功建立了肺腺癌骨转移模型，为以后探索出新的肺腺癌乃至肺癌骨转移临床预防和治疗方案提供基础；4种肺腺癌细胞系体外侵袭、迁移能力强弱不等，但体内骨转移能力没有明显差异，其原因还有待进一步的探索。

Overview of the latest treatments for castration-resistant prostate cancer

Over the past few years, we have developed an increased understanding of the molecular mechanisms that underlie prostate cancer progression and castration resistance and expanded our repertoire of therapeutic options for castration-resistant prostate cancer (CRPC). Four new agents (cabazitaxel, abiraterone acetate, enzalutamide, and radium-233) have been shown to prolong overall survival in patients with CRPC in the postchemotherapy setting. Targeting the androgen receptor pathway continues to have an important role in the treatment of CRPC, with abiraterone acetate and enzalutamide being the most exciting developments. Cabazitaxel is now considered the standard-of-care second-line chemotherapy for men with metastatic CRPC (mCRPC). Bone-targeted therapy is an active area of research, with denosumab being the first bone-targeted agent able to significantly delay the appearance of bone metastases in patients with CRPC and radium-223 being the first radiopharmaceutical agent to improve survival in patients with mCRPC.

Bisphosphonate-related osteonecrosis of jaw (BRONJ): an anti-angiogenic side-effect?

Bisphosphonates are recommended in the treatment of osteoporosis and some cancers, in which case they prevent the appearance of bone metastasis. The patients taking bisphosphonates are at increased risk of developing bisphosphonate-related osteonecrosis of jaw (BRONJ) which is characterised by the presence of an un-healing wound after dental surgery. BRONJ might represent an anti-angiogenic side effect. However, the real number of patients with BRONJ might be higher than currently recorded. Considering the differential diagnosis which includes various primary and secondary cancers, a correct histopathological diagnosis is very important. The morphological criteria for diagnosis of BRONJ are highlighted in this material.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1813972972323288

Encounter of cancer cells with bone. Management of bone metastasis arising from prostate cancer

Bone metastases and skeletal complications are major causes of morbidity in prostate cancer patients. Despite an osteoblastic appearance of bone metastases on imaging studies, patients have high osteoclast activity. Current evidence indicates that newer-generation nitrogen-containing bisphosphonates, particularly zoledronic acid, are potent inhibitors of bone resorption via suppression of osteoclast activity. Indeed, zoledronic acid has been reported to significantly decrease the risk of skeletal complications in men with castration-resistant prostate cancer and bone metastases. Additionally, an increased understanding of the pathogenesis of bone metastasis has resulted in the development of several bone-targeted therapies, including a monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand. In this paper, the current state and the future of bone metastases management from prostate cancer are outlined.

Osteoclast-targeted therapy for metastatic prostate cancer

Bone metastases and skeletal complications are major causes of morbidity in men with prostate cancer. Despite the osteoblastic appearance of bone metastases on imaging studies, patients with bone metastases have elevated markers of bone resorption, indicative of high osteoclast activity. Indeed, increased osteoclast activity is independently associated with higher risk of subsequent skeletal complications. Therapies aimed at reducing osteoclast activity would theoretically diminish disease-related skeletal complications, bone metastases and treatment-related fractures. Phase III clinical trials to address the role of osteoclast-targeted therapy in metastatic prostate cancer are reviewed here. Zoledronic acid, a potent bisphosphonate, significantly decreased the risk of skeletal complications in men with androgen-independent prostate cancer and bone metastases. Ongoing studies will evaluate the use of bisphosphonates or denosumab, a monoclonal antibody that inhibits the receptor activator of nuclear factor-κB ligand signaling in the prevention of bone metastases or skeletal complications. Additional studies are needed to determine the optimal timing, schedule and duration of bisphosphonate treatment in men with bone metastases. The results of these trials in the near future may herald further evolution in the targeting of osteoclasts and optimal supportive care in men with prostate cancer.

Metastasi ossee nel carcinoma della mammella: incremento della prevalenza di lesioni osteoaddensanti

It is well known that bone metastases from breast cancer usually show osteolytic changes. We retrospectively analysed the computed tomography (CT) appearance of bone metastases to quantify the distribution of lytic, mixed and sclerotic changes in a series of patients presenting with neoplastic bone involvement from breast cancer. Between 1996 and 2005, 468 women with a diagnosis of breast cancer were referred to our department for staging or follow-up CT examinations. Staging CT examinations detected systemic metastases in 142/468 patients, 60 of which had bone involvement. Patients with a second primary tumour or bone metabolic disorders were excluded from this retrospective analysis. In patients with bone metastases, CT identified 18 with osteolytic lesions (30%), 32 with osteosclerotic lesions (53.3%) and ten with mixed lesions (16.7%). Analysis of the cases observed for the first time during the 1996-2000 period showed osteolytic lesions in 53.6% (15/28), osteosclerotic lesions in 32.1% (9/28) and mixed lesions in 14.3% (4/28). Results were 9.4% (3/32), 71.9% (23/32) and 18.7% (6/32), respectively, for the same groups in the 2001-2005 period. Histological analysis of all cases included 81.9% of infiltrative ductal carcinoma, 11.2% of infiltrative lobular carcinoma, 3.7% of ductal lobular mixed carcinoma and 3% of medullar carcinoma. We found no statistically significant correlation between histological type of breast cancer and radiological appearance of bone metastasis. A significant difference between patients treated with or without zoledronic acid was observed, with a higher prevalence of osteosclerotic lesions in the former group of patients (p<0.05). We observed an increasing prevalence of osteosclerotic bone metastasis when comparing the 1996-2000 period with the 2001-2005 period. The significance of these distribution changes is not clear. However, we found a significant correlation of osteosclerotic lesions with zoledronic acid treatment. The advent of third generation bisphosphonates may have changed the CT appearance of bone metastasis from breast cancer.

CT Appearance of Bone Metastases Detected with FDG PET as Part of the Same PET/CT Examination

To retrospectively evaluate lesion findings at computed tomography (CT) performed as part of a combined positron emission tomography (PET)/CT examination in patients suspected of having metastatic bone lesions-lesions that were detected with fluorine 18 fluorodeoxyglucose (FDG) PET as part of the same examination-and to correlate the CT and FDG PET findings. This HIPAA-compliant study had institutional review board approval, and the need for patient informed consent was waived. Three hundred fifty-nine consecutive patients (191 male patients, 168 female patients; mean age, 56.9 years; age range, 8-92 years) underwent PET/CT. PET images were first reviewed by nuclear medicine physicians who had no clinical information regarding the presence or absence of bone metastasis by using a five-point grading system (0, a lesion was definitely negative for metastasis; 1, a lesion was probably negative; 2, a lesion was equivocal; 3, a lesion was probably positive; and 4, a lesion was definitely positive). For lesions assigned a grade of 3 or 4 at PET, CT characteristics such as the presence or absence of morphologic changes or accompanying findings (including bone destruction) were assessed by radiologists on the CT images obtained during the same imaging session. One hundred seventy-nine lesions in 55 patients were considered to be probable or definite bone metastases at PET. One hundred thirty-three of these lesions in 33 patients were clinically confirmed to be bone metastases at follow-up and/or histopathologic examination. CT revealed osteolytic changes in 41 (31%) and osteoblastic changes in 21 (16%) of the 133 lesions, but no or nonspecific changes were seen at CT in 49 (37%) and 22 lesions (17%), respectively. Of the 179 lesions suspected at PET, 46 ultimately proved to be nonosseous or false-positive for bone metastasis. Of these 46 lesions, 38 were not located in the bone but in adjacent tissues such as the pleura. CT images obtained as part of PET/CT scanning were useful in yielding the precise location of bone lesions and thus helping avoid misdiagnosis of bone metastasis; however, CT revealed morphologic changes in only half of the lesions assigned a grade of 3 or 4 at PET.

Correlation of the osteoblastic phenotype with prostate-specific antigen expression in metastatic prostate cancer: implications for paracrine growth.

The characteristic sclerotic appearance of bone metastases from prostate cancer is unexplained but could involve excess peritumoural activity of osteoblast mitogens such as the insulin-like growth factors (IGFs). Since prostatic metastases are distinguished by androgen-dependent secretion of prostate-specific antigen (PSA), a serine protease which cleaves extracellular IGF-binding proteins and thereby enhances the bioavailability of IGFs, the relationship was examined between tumour PSA expression and the osteoblastic phenotype. To this end, a cohort of 27 prostate cancer patients was evaluated to determine the relationship between serum PSA and radiographic bone lesion density at first presentation with metastatic disease. No linear correlation between absolute PSA levels and metastatic osteosclerosis was apparent. However, non-parametric statistical analysis revealed a highly significant link between low-PSA (<20 ng/ml) metastatic prostate cancer and osteolytic bone lesions (p<0.0001, chi(2)=21.5). This finding raises the possibility that the osteoblastic phenotype of prostate cancer derives in part from PSA-dependent proteolysis of IGF-binding proteins within bone matrix.

Role of Pamidronate Disodium in the Treatment of Metastatic Bone Disease

Bone metastases are a common feature of advanced neoplastic disease and are considered to be among the most frequent causes of pain and complications in oncologic patients. The main objective of the treatment of such patients is to control their symptoms and improve their quality of life. Pamidronate disodium is a second-generation bisphosphonate capable of inhibiting bone resorption (particularly osteoclast activity) without affecting bone remineralization. After a brief introduction concerning the pathophysiology of bone metastases and neoplastic bone pain, we herein present data on the clinical pharmacology and toxicity of bisphosphonates in general, and pamidronate in particular. We conclude by reviewing the literature on the use of pamidronate in phase II and III trials involving patients with metastatic bone disease. The paper is based on a review of articles published between 1984 and 1997 selected from the Cancerline and Medline databases. In the considered phase II and III studies involving patients with bone metastases (breast cancer and multiple myeloma in particular), pamidronate proved to be efficacious in reducing the incidence of pain and skeletal complications, decreasing the excretion of metabolic markers of bone resorption and improving the quality of life. Intravenous infusions of 60-90 mg over a period of 2 hr every 3-4 weeks did not cause any significant toxic effects and was easily managed. Pamidronate is a bisphosphonate that is efficacious in the treatment of symptomatic bone metastases and can be considered an important therapeutic option in association with systemic treatments, radiotherapy and normal supportive care, especially in patients with breast cancer and multiple myeloma. Further randomized studies are necessary to confirm the positive preliminary results in other neoplasms, analyze the cost/benefit ratio of the treatment, and verify the possibility that, in addition to being used for palliative purposes, pamidronate may also prevent or delay the appearance of bone metastases.

A heterogeneous pattern of progression in endocrine-treated patients with prostate cancer.

Prostatic carcinoma often shows different behavior in the primary site than in the metastases after endocrine treatment. The pattern of disease progression was evaluated in prostate cancer patients. Two hundred and sixty consecutive patients were observed following the initiation of endocrine treatment (11 patients with stage T1 disease, 42 with stage T2 70 with stage T3, 11 with N + M0 and 126 with stage M1 disease). Of the 117 patients whose disease progressed, 100 could be evaluated in terms of the pattern of disease progression. Twenty-two (64.7%) of the 34 patients with stage T1-3N0M0 showed a pattern of local progression. On the other hand, 56 (84.8%) of the 66 patients with stage N + or M1 experienced a pattern of distant progression. Patients with only distant progression numbered 36 cases and patients with local progression and distant progression numbered 20 cases. Most of the distant progressions appeared in bone site. Local progression was observed in only 30 (45.5%) patients with stage N + or M1 disease. In patients with localized disease (T1-3N0M0), both the interval to disease progression and the time to cancer death from the start of disease progression were significantly longer than those of patients with stage N + or M1. However, once bone metastasis occurred, the disease tended to progress rapidly. There was no significant difference between the interval to cancer death after the appearance of bone metastasis in patients with initially localized stages (T1-3N0M0) and the time to cancer death after disease progression in patients with metastatic disease (N + or M1). The study shows a heterogenous behavior of the prostatic tumor after endocrine treatment. This suggests that metastases and primary tumor have different clonal compositions. The study also supports the idea that there is a preferential environment for the growth of prostatic carcinoma cells in bone sites.

Computed tomography appearance of bone metastases of leiomyosarcoma.

Bone lesions in leiomyosarcoma are uncommon. When encountered, they are usually a late manifestation of disease seen in the setting of widespread systemic metastases. We present five cases of metastatic leiomyosarcoma, including one in which a bone lesion predated detection of a primary gastric leiomyosarcoma and one in which bone metastases signaled disease recurrence. Computed tomography in 14 of 16 osseous leiomyosarcomas demonstrated a lytic, non-expansile pattern.

Palliative radiotherapy for metastatic malignant melanoma: Brain metastases, bone metastases, and spinal cord compression

The records of all patients receiving palliative radiotherapy for malignant melanoma metastatic to brain, to bone, or with spinal cord compression were reviewed. The median survival of 77 patients with brain metastases from the initiation of radiotherapy was 14 weeks. A statistically improved survival was observed only in the 10 patients who underwent subtotal to total resection of a solitary brain metastasis prior to radiotherapy (median = 36 weeks). No improved survival was observed in the 12 patients with a solitary brain metastasis treated by radiotherapy alone (median = 16 weeks). Multivariate analysis revealed that fraction size, total dose, patient age, sex, and duration of the interval between initial diagnosis and appearance of brain metastases did not significantly influence survival, but the use of chemotherapy was associated with a decreased survival. Twenty six patients with symptomatic and radiographic evidence of 39 bone metastases showed a palliative response rate of 85%. 18 of 20 bony lesions treated with high-dose-per-fraction (≥400 cGy) and 15 of 19 bony lesions treated with conventional fractionation (≤300 cGy) were palliated. Total dose, patient age, sex, interval between initial diagnosis of malignant melanoma and the appearance of bone metastases, prior or concurrent chemotherapy, or lesion location did not significantly influence palliation. Seventeen patients were identified with symptomatic and myelographic evidence of spinal cord compression. Complete palliation was observed in 47% ( 8 17 ) and partial palliation was observed in 24% ( 4 17 ). The overall palliation response rate for neurologic symptoms due to spinal cord compression of 71% appeared to be independent of fraction size and total dose.

'For' or 'against' bone scintigraphy of patients with breast cancer.

Present opinions about the efficacy of bone scintigraphy of patients with breast cancer are widely different. The present article is an attempt to assess the possibilities of such a test through a retrospective analysis of bone scintigraphies of 422 patients with breast cancer made during the course of 6 years. The scintigrams were positive in 30.6% of the patients who have had symptoms from any part of their bone system and only in 6.1% of the patients with no complaints. The percentage of positive scintigrams varies from 14.3 to 42.1% depending on the stage of the cancer. All patients scanned before their operation had normal scintigrams; metastases in the bones appeared after the intervention. The time for the appearance of bone metastases in the different groups varies between 20.7 and 50.9 months. In conclusion we confirm those cases in which bone scintigraphy is applicable.

The course of metastatic disease originating from carcinoma of the prostate.

The purpose of this work was to study the time sequence and the patterns of the multistep spread of metastases. Fifty-one patients with stage D carcinoma of the prostate, previously treated for their primary tumor by surgery or radiotherapy combined with hormonal manipulation and for metastases by hormones and chemotherapy, were included in the study. The metastatic dissemination, characterized primarily by the appearance of bone metastases, could follow two distinct patterns: The first, characterized by sequential appearance of osteoblastic metastases, followed by the development of osteolytic bone lesions, and the second pattern, characterized by the simultaneous appearance of osteoblastic and osteolytic bone lesions. In cases with solely osteoblastic bone metastases, the lesions are hormone sensitive and long-lasting remissions could be obtained. The development of osteolytic bone lesions is usually accompanied by the recurrence of the primary tumor and appearance of metastases in other sites, such as the lymph nodes and lungs. Bone metastases became resistant to hormonal manipulation and with chemotherapy short remissions were obtained. The course of the terminal period is faster, with shorter survival times. The determination of serum acid and alkaline phosphatase levels seems to reflect the course of the disease during the initial period of the disease only, i.e. when bone metastases are sensitive to hormonal treatment.

Knochenläsionen und Metastasierungsmuster in einem experimentellen Plasmozytom der BALB/C-Maus (HIPA-Tumor)

The distribution of the metastases of an experimentally produced plasmocytoma (HIPA-tumor) was determined after intravenous, subcutaneous or intraperitoneal inoculation of a defined number of ascites tumor cells into isologous mice. After a latent period of about 17 days following intravenous inoculation osteolytic and osteoplastic metastases were common. These lesions were verified roentgenographically, histologically, and by maceration of gross specimens of bone. Bone metastases were rare after subcutaneous inoculation of neoplastic cells. Pulmonary metastases were equally common after intravenous or subcutaneous inoculation. Intraperitoneal inoculation did not produce extraperitoneal metastases. Incidence and morphological appearance of bone metastases agreed with those of other known experimental plasmocytomas. In contrast to the latter, HIPA-tumor did not give rise to splenic or hepatic metastases. The special position of the HIPA-tumor among murine plasmocytomas was discussed.