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MicroRNAs (miRNAs) have emerged as key players in cancer progression and metastatic initiation yet their importance in regulating prostate cancer (PCa) metastasis to bone has begun to be appreciated. We employed multimodal strategy based on in-house PCa clinical samples, publicly available TCGA cohorts, a panel of cell lines, in silico analyses, and a series of in vitro and in vivo assays to investigate the role of miR-466 in PCa. Expression analyses revealed that miR-466 is under-expressed in PCa compared to normal tissues. Reconstitution of miR-466 in metastatic PCa cell lines impaired their oncogenic functions such as cell proliferation, migration/invasion and induced cell cycle arrest, and apoptosis compared to control miRNA. Conversely, attenuation of miR-466 in normal prostate cells induced tumorigenic characteristics. miR-466 suppressed PCa growth and metastasis through direct targeting of bone-related transcription factor RUNX2. Overexpression of miR-466 caused a marked downregulation of integrated network of RUNX2 target genes such as osteopontin, osteocalcin, ANGPTs, MMP11 including Fyn, pAkt, FAK and vimentin that are known to be involved in migration, invasion, angiogenesis, EMT and metastasis. Xenograft models indicate that miR-466 inhibits primary orthotopic tumor growth and spontaneous metastasis to bone. Receiver operating curve and Kaplan-Meier analyses show that miR-466 expression can discriminate between malignant and normal prostate tissues; and can predict biochemical relapse. In conclusion, our data strongly suggests miR-466-mediated attenuation of RUNX2 as a novel therapeutic approach to regulate PCa growth, particularly metastasis to bone. This study is the first report documenting the anti-bone metastatic role and clinical significance of miR-466 in prostate cancer.

Purpose: Advanced metastatic prostate cancer (PCa) is a fatal disease, with only palliative therapeutic options. Though almost 80% of cases of metastatic PCa present bone metastasis, our current understanding of the molecular mechanisms that govern this metastatic dissemination remains fragmentary. The main objective of the present study was to identify microRNA (miRNA) genes that regulate metastatic PCa., Experimental Design: miRNA expression profiling was done in human prostate cell lines to identify dysregulated miRNA components of advanced PCa. miR-203 expression was assessed in prostate carcinoma cell lines and clinical specimens by real-time PCR and in situ hybridization. To assess the biological significance of miR-203, miR-203 was reexpressed in bone metastatic PCa cell lines followed by in vitro and in vivo functional assays., Results: miR-203 expression is specifically attenuated in bone metastatic PCa suggesting a fundamental antimetastatic role for this miRNA. Reintroduction of miR-203 in bone metastatic PCa cell lines suppresses metastasis via inhibition of several critical steps of the metastatic cascade including epithelial-mesenchymal transition, invasion, and motility. Ectopic miR-203 significantly attenuated the development of metastasis in a bone metastatic model of PCa. Importantly, miR-203 regulates a cohort of pro-metastatic genes including ZEB2, Bmi, survivin, and bone-specific effectors including Runx2, a master regulator of bone metastasis., Conclusions: miR-203 is an "antimetastatic" miRNA in PCa that acts at multiple steps of the PCa metastatic cascade via repression of a cohort of prometastatic targets. miR-203 may be an attractive target for therapeutic intervention in advanced PCa., (©2011 AACR.)

Introduction: In the reconstruction of extensive bone defects after massive resection of malignant musculoskeletal tumors, the clinical results of moderately heat-treated autogenous bone graft have rarely been documented. We evaluated the remodelling and healing process of moderately heat-treated autogenous bone graft by means of imaging features., Materials and Methods: The subjects of this study were 19 patients with bone and soft-tissue tumors treated by heat-treated bone graft at our institution between 1992 and 2001, the mean follow-up period was 4.8+/-2.8 years (range 1-9 years). The remodelling and healing process of heat-treated bone graft was evaluated by means of radiography, bone scintigraphy, and MRI., Results: The mean period to obtain bone union between host bone and grafted bone was 9.4 months. Infection was noted in 1 patient, and fracture was present in 2 patients. In 6 patients, pseudoarthrosis was found. Bone scintigraphy showed an increased uptake at the host-graft junction in the period between 3 and 36 months (median 10.7 months) postoperatively. A gradually increased diffuse uptake on the grafted side was evident at an average of 29.1 months (range 19-41 months) postoperatively. High signal intensity on T2-weighted images was observed in the early period after surgery, and iso-intense or low signal intensity became evident after an average of 28.3 months. A gradually increased diffuse uptake on scintigraphy and iso-intense or low signal intensity on T2-weighted images indicated remodelling of the grafted bone., Conclusion: Bone union of a moderately heat-treated autogenous bone graft was noted at about 9 months, and its remodelling was proceeding at about 30 months. This method will be useful for bone defects after massive resection of soft-tissue and bone tumors.

We evaluated the number of steps, activities of daily life (ADL) score, Enneking score, active range of motion and muscle strength by muscle manual testing for function in lower limbs after reconstructive procedures in surgical treatment of tumors. The 56 patients with 20 malignant bone tumors and 36 malignant soft-tissue tumors averaged 7119 +/- 3563 steps per day, or 69.8% of the control group. The average ADL score of patients was 14.0 +/- 4.1 points (70.0%), and the average Enneking score 20.4 +/- 6.0 points (68.0%). The scores of the bone tumor group were lower than those of the soft-tissue tumor group. These scores were not correlated with the range of motion. The number of steps and ADL score were correlated with Enneking score (coefficient 0.52 and 0.84, respectively). The number of steps and the ADL score appear to be useful, as is Enneking score.

Low-grade intraosseous osteosarcoma is an uncommon bone tumor that is characterized by minimum cytological atypism and a much better prognosis than conventional osteosarcoma. This report describes a patient who had a low-grade osteosarcoma that mimicked fibrous dysplasia (FD). The tumor had an area of high-grade sarcoma at the initial diagnosis. Ten years after incomplete resection of FD-like tumor, local recurrence with areas of high-grade tumor developed. This case illustrates the potential of dedifferentiation in low-grade intraosseous osteosarcoma.

Background: Several reports have shown peritumoral edema accompanying primary bone tumors demonstrated by magnetic resonance imaging (MRI). However, the mechanism of this inflammatory reaction is still unclear. The authors postulated that the reaction was caused by some chemical mediators including prostanoids, because several investigators have observed that some types of bone tumors synthesize prostanoids. Therefore, the authors compared MRI findings and tumor prostaglandin (PG) levels., Methods: The subjects were 29 patients with primary bone tumor or tumor-like conditions: chondroblastoma (n = 5); chondrosarcoma, including rare variants (n = 8); giant cell tumor (n = 6); osteochondroma (n = 5); osteoblastoma (n = 2); Ewing's sarcoma (n = 2); and eosinophilic granuloma (n = 1). T1- and T2-weighted spin echo images were obtained in all but one patient before surgery. The tumor concentration of prostaglandin E2, 6-keto-PGF1 alpha, and thromboxane B2 were measured by radioimmunoassay., Results: MRI distinctly showed bone marrow edema in 9 and soft tissue edema in 12 of the 28 patients examined. These findings were significantly correlated with the PG levels. Moreover, the PG levels were correlated with the histologic classifications (P < 0.001). In particular, the chondroblastomas showed prominent concentrations of PGs compared with other cartilaginous tumors or giant cell tumors., Conclusions: Although peritumoral edema accompanying benign and malignant bone tumors is not necessarily related to one single pathophysiologic mechanism, these results suggest that PG production was an important cause of the inflammatory reaction that was revealed by MRI. Recognition of this phenomenon is advantageous not only for strict diagnostic purposes but also for understanding the characteristic features of individual primary bone tumors.

Internal fixation or endoprosthetic replacement of a long bone metastatic lesion was performed using adriamycin-containing bone cement (methylmethacrylate) after resection or curettage of the lesion in 25 patients (27 limbs). Survival rate, limb function, and local recurrence rate were retrospectively evaluated in this patient cohort. Survival rate was 53% at 12 months and 30% at 24 months, which was better than in previous reports. One patient showed local recurrence radiographically. Postoperatively, none of the patients developed infection, delayed wound healing, myelo-suppression attributed to adriamycin, and 74% of the patients were able to walk outdoors.

A case of malignant hemangioendothelioma of the left calcaneus associated with unique system manifestations is reported here. The severe toxic manifestations included: high fever, anemia, leukocytosis, coagulation abnormalities, and other signs. Because of poor response to many antibiotic regimens, the confusion of diagnosis, and severe coagulation abnormalities with clinical signs that the life of the patient was endangered, below the knee amputation was performed. Pathological studies revealed a malignant hemangioendothelioma. A review of the case suggests that the signs and symptoms were possibly due to an immune response to the tumor rather than to secondary infection, although the latter possibility cannot be completely excluded.

Objective: The objective of this study was to evaluate the inflammatory reaction accompanying chondroblastoma and to define the value of the finding in clinical practice., Design: We reviewed the clinical, radiographic, and magnetic resonance (MR) findings in six patients with histologically proven chondroblastoma., Results: In all cases, MR imaging showed marrow and soft tissue edema. In four of six cases, periosteal reaction related to intra-osseous edema was more clearly demonstrated on MR imaging than on radiographs. Follow-up MR studies after surgery were available in three patients and all showed disappearance of inflammatory responses such as marrow and soft tissue edema, and reactive synovitis., Conclusion: We propose that these inflammatory reactions of chondroblastomas are important signs for detecting residual tumor in recurrences after surgery, as well as for making a precise diagnosis. The MR changes may also be valuable in demonstrating eradication of the tumor.

A retrospective investigation was performed on the significance of dose intensity in preoperative chemotherapy for osteosarcoma. In this paper, we studied 29 patients, who had classical stage II-B osteosarcoma and received preoperative treatment consisting of high dose methotrexate (HD-MTX) and/or cisplatinum (CDDP) between 1985 and 1991. Preoperative dose intensity was calculated in the following two ways. 1. Total dose of MTX and CDDP administered during initial five weeks: MTX (g)/10/m2 + CDDP(mg)/100/m2 2. Dose intensity of MTX and CDDP from initiation of treatment (I) to resumption of postoperative chemotherapy (R): MTX (g)/10/m2 + CDDP (mg)/100/m2 / days from (I) to (R)/ideal period of new regimen (63 days) Continuous disease free survival rate (CDFR) was significantly higher in the group receiving preoperative chemotherapy at higher dose intensity (> 3.0). Supplementary administration of adriamycin (ADR) to CDDP/MTX was not favorable in the preoperative stage, because it put off the following therapy and diminished the dose intensity. Since July 1989, we have tried a short intensive preoperative chemotherapy regimen: weekly two cycles of CDDP 100 mg/m2 intravenously, followed by weekly two cycles of HD-MTX 10g/m2. Surgery was scheduled six weeks after beginning treatment, and postoperative chemotherapy was started three weeks after surgery. Twenty patients have been treated by this regimen to date. All patients remain disease free, and six are CDF beyond 24 months.

Between 1988 and 1993, 16 cases of osteoid osteoma were examined by magnetic resonance imaging (MRI). MRI clearly visualized the extent of inflammation in the bone marrow and soft parts that is difficult to observe with other diagnostic techniques. The degree of inflammation varied among the patients. This might be associated with the anatomical relationship between the nidus and the cortex. The high sensitivity of MRI, unfortunately, may lead to an erroneous interpretation in lesions accompanied by inflammatory responses of the bone marrow or soft parts, such as osteoid osteoma. However, these reactions on MRI may offer a key to the pathogenesis of osteoid osteoma, a unique bone neoplasm.