Ken Takeda

Myxoinflammatory fibroblastic sarcoma

Acral myxoinfl ammatory fi broblastic sarcoma (MIFS) was fi rst described in 1998 as a new entity in three independent reports by pathologists, Meis-Kindblom and Kindblom, Michal, and Montgomery et al. It occurs primarily in adults, with a peak incidence in the fourth and fi fth decades of life, and presents as a painless fi rm mass of the distal extremities, predominantly the hands and feet. Recently, proximally located MIFS has also been reported, and some authors have suggested dropping the adjective “acral” from the name of the tumor because of its possibly misleading nature. Histologically, MIFS is a poorly circumscribed and typically multinodular tumor. The most striking feature is infl ammatory infi ltration associated with a prominent myxoid matrix in variable proportions and the presence of bizarre virocyte or Reed-Sternberg-like cells and multivacuolated cells simulating lipoblasts. Surgical excision with a wide margin is considered the treatment of choice, as the tumor shows a high rate of local recurrence. Meis-Kindblom and Kindblom reported a 67% local recurrence rate within a median follow-up period of 5 years. However, the tumor is frequently diffi cult to diagnose correctly at the time of initial presentation because of its apparently benign nature, being a slowgrowing, small and painless mass in the distal extremity. As a result, there is a tendency for the tumor to be treated inadequately by referring physicians. Surgeons need to be mindful of MIFS, its nature, and the appropriate treatment necessary for this unique tumor. Case reports

Chromosomal and genetic imbalances in synovial sarcoma detected by conventional and microarray comparative genomic hybridization

Purpose: To analyze the relationship between chromosomal instabilities and clinicopathological factors in synovial sarcoma (SS). Methods: Twenty-two fresh-frozen SS were analyzed by metaphase comparative genomic hybridization (CGH). Additional microarray CGH was performed in 13 cases. Results: Fourteen patients with SYT–SSX1 rearrangements and nine patients with biphasic tumor subtypes had better prognosis than the eight patients with SYT–SSX2 rearrangements and 13 patients with monophasic subtypes, respectively. Gains (average 3.0) were more frequent than losses (average 1.0). Frequent gains were identified on chromosomal regions 2, 6q, 7, 8q, 12, 17q, 18q, and 21q, whereas frequent losses were over-lapped on chromosomes 1p31–p35, 3p, 6q, 16, and 17p. High-level gains were observed on chromosomes 1q21–q31, 7, 8, 12, 17q, 18q, and 21q. Thirteen monophasic and nine biphasic tumors had an average of 5.1 and 2.8 aberrations, respectively. Patients with tumors harboring numerous aberrations (≥3) had a worse clinical course. Microarray CGH more specifically detected genetic imbalances including gains in MDM2, MSH2, KCNK12, DCC, CDK2, ERBB3, SAS, and CDK4 and losses in HRAS, RASSF1, and CCND1. Gain of SAS was an important prognostic factor of SS. Conclusion: We have identified several factors influencing the prognosis of SS patients by metaphase and microarray CGH.

Construction of X-ray Dark-Field Imaging with a View Size of 80 mm Square and First Visualization of Human Articular Cartilage of Femoral Head under a Nearly Clinical Condition

Field size of 80 mm ×80 mm for X-ray dark-field (DFI) imaging at 35 keV using a 2.16-mm-thick 440 Laue diffraction analyzer has been achieved. Under this condition, only refracted X-rays from sample can transmit through this filter to form DFI while the beam that has not changed its direction is repelled to the diffraction direction. Its spatial resolution is 10 microns or better. An excised human femoral head in a water-filled vinyl bag simulating a clinical condition shows a high-contrast and high-spatial-resolution articular cartilage that has not been visualized by X-ray technique

MicroRNAs in soft tissue sarcomas: overview of the accumulating evidence and importance as novel biomarkers.

Sarcomas are distinctly heterogeneous tumors and a variety of subtypes have been described. Although several diagnostic explorations in the past three decades, such as identification of chromosomal translocation, have greatly improved the diagnosis of soft tissue sarcomas, the unsolved issues, including the limited useful biomarkers, remain. Emerging reports on miRNAs in soft tissue sarcomas have provided clues to solving these problems. Evidence of circulating miRNAs in patients with soft tissue sarcomas and healthy individuals has been accumulated and is accelerating their potential to develop into clinical applications. Moreover, miRNAs that function as novel prognostic factors have been identified, thereby facilitating their use in miRNA-targeted therapy. In this review, we provide an overview of the current knowledge on miRNA deregulation in soft tissue sarcomas, and discuss their potential as novel biomarkers and therapeutics.

Clinical significance of circulating miR-25-3p as a novel diagnostic and prognostic biomarker in osteosarcoma

Background Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma. Methods Global miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort. Results Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase. Conclusions Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients.

Circulating MicroRNA-92b-3p as a Novel Biomarker for Monitoring of Synovial Sarcoma

The lack of useful biomarkers is a crucial problem for patients with soft tissue sarcomas (STSs). Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel impact as biomarkers for patients with malignant diseases, but their significance in synovial sarcoma (SS) patients remains unknown. Initial global miRNA screening using SS patient serum and SS cell culture media identified a signature of four upregulated miRNAs. Among these candidates, miR-92b-3p secretion from SS cells was confirmed, which was embedded within tumour-derived exosomes rather than argonaute-2. Animal experiments revealed a close correlation between serum miR-92b-3p levels and tumour dynamics. Clinical relevance was validated in two independent clinical cohorts, and we subsequently identified that serum miR-92b-3p levels were significantly higher in SS patients in comparison to that in healthy individuals. Moreover, serum miR-92b-3p was robust in discriminating patients with SS from the other STS patients and reflected tumour burden in SS patients. Overall, liquid biopsy using serum miR-92b-3p expression levels may represent a novel approach for monitoring tumour dynamics of SS.

Favorable outcome after complete resection in elderly soft tissue sarcoma patients: Japanese Musculoskeletal Oncology Group study.

BACKGROUNDnThe surgical management of soft tissue sarcoma (STS) in elderly patients has only been addressed in a few studies. The objective of the current study was to assess surgical outcomes in patients with STS aged 70 years and older and the association of older age with the survival after complete resection.nnnMETHODSnA retrospective analysis was conducted in 158 elderly patients with localized STS who visited 11 institutions participating in Japanese Musculoskeletal Oncology Group between 1995 and 2006 and were treated by surgical resection. Univariate and multivariate analyses were performed to identify prognostic factors.nnnRESULTSnMedian follow-up period was 38 months. Histologically high-grade tumors were detected in 71% of the patients. Wide resection with adequate margins was performed in 66% of the cases. Systemic chemotherapy was performed in only 5 patients. Univariate analysis identified histological grade and gender as statistically significant prognostic factors for sarcoma-specific survival. Multivariate analysis did not identify significant prognostic factors for sarcoma-specific survival, although high grade sarcoma emerged as a potentially significant prognostic factor (P = 0.050). Local recurrence was detected in 19% of the patients. Multivariate analysis of local recurrence-free survival showed that tumor site and surgical margins were statistically significant prognostic factors.nnnCONCLUSIONSnOlder age was not identified as a prognostic factor for sarcoma-specific survival, which is not consistent with the findings of previous studies showing that older age was associated with decreased sarcoma-specific survival. Complete resection should be indicated and can lead to optimal treatment outcome for properly selected elderly patients.

Immunotherapy for Bone and Soft Tissue Sarcomas

Although multimodal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years. Immunotherapies have shown the effectiveness for several types of advanced tumors. Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas. Cytokine therapies with interleukin-2 or interferons have limited efficacy because of their cytotoxicities. Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year overall survival of patients. Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas. Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms. These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas. In this review, we provide an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discuss their potential as adjuvant therapies in combination with conventional therapies.

X-ray dark field imaging of human articular cartilage: Possible clinical application to orthopedic surgery

Despite its convenience and non-invasiveness on daily clinical use, standard X-ray radiography cannot show articular cartilage. We developed a novel type of X-ray dark field imaging (DFI), which forms images only by a refracted beam with very low background illumination. We examined a disarticulated distal femur and a shoulder joint with surrounding soft tissue and skin, both excised from a human cadaver at the BL20B2 synchrotron beamline at SPring-8. The field was 90 mm wide and 90 mm high. Articular cartilage of the disarticulated distal femur was obvious on DFI, but not on standard X-ray images. Furthermore, DFI allowed visualization in situ of articular cartilage of the shoulder while covered with soft tissue and skin. The gross appearance of the articular cartilage on the dissected section of the proximal humerus was identical to the cartilage shown on the DFI image. These results suggested that DFI could provide a clinically accurate method of assessing articular cartilage. Hence, DFI would be a useful imaging tool for diagnosing joint disease such as osteoarthritis.

Photodynamic Therapy with ATX-S10·Na(II) Inhibits Synovial Sarcoma Cell Growth

Photodynamic therapy (PDT) is an effective cancer treatment modality that allows selective destruction of malignant tumor cells. We asked whether PDT could inhibit inxa0vivo and inxa0vitro growth of synovial sarcoma cells. We analyzed PDT using ATX-S10·Na(II) and a diode laser for a synovial sarcoma cell line (SYO-1). Photodynamic therapy with ATX-S10·Na(II) showed an inxa0vitro cytotoxic effect on the cultured SYO-1 cells. The inxa0vitro effect of PDT depended on the treatment concentration of ATX-S10·Na(II) and the laser dose of irradiation. ATX-S10·Na(II) was detected in the tumor tissue specimens that were excised from nude mice bearing SYO-1 within 6xa0hours after intravenous injection, but it was eliminated from the tumor 12xa0hours after injection. Photodynamic therapy suppressed the tumor growth of nude mice bearing SYO-1, and high-dose irradiation induced no viable tumor cells in histologic specimens. Photodynamic therapy performed after marginal resection of the tumor of nude mice bearing SYO-1 reduced the rate of local recurrence of the tumor. Our results suggest PDT using ATX-S10·Na(II) and laser irradiation may be a potentially useful treatment for synovial sarcoma, especially to reduce the surgical margin and preserve critical anatomic structures adjacent to the tumor.