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Background This randomised phase II/III trial aimed to determine whether perioperative chemotherapy with gemcitabine plus docetaxel (GD) is non-inferior to the standard Adriamycin plus ifosfamide (AI) in terms of overall survival (OS) in patients with soft tissue sarcoma (STS). Methods Patients with localised high-risk STS in the extremities or trunk were randomised to receive AI or GD. The treatments were repeated for three preoperative and two postoperative courses. The primary endpoint was OS. Results Among 143 enrolled patients who received AI (70 patients) compared to GD (73 patients), the estimated 3-year OS was 91.4% for AI and 79.2% for GD (hazard ratio 2.55, 95% confidence interval: 0.80–8.14, P = 0.78), exceeding the prespecified non-inferiority margin in the second interim analysis. The estimated 3-year progression-free survival was 79.1% for AI and 59.1% for GD. The most common Grade 3–4 adverse events in the preoperative period were neutropenia (88.4%), anaemia (49.3%), and febrile neutropenia (36.2%) for AI and neutropenia (79.5%) and febrile neutropenia (17.8%) for GD. Conclusions Although GD had relatively mild toxicity, the regimen—as administered in this study—should not be considered a standard treatment of perioperative chemotherapy for high-risk STS in the extremities and trunk. Clinical trial registration jRCTs031180003.

Background/Aim: Although smoking history is predictive of poor pulmonary metastasis-free survival (PMFS) in patients with epithelial tumors, the impact of smoking history on PMFS in those with soft-tissue sarcoma (STS) is not known. Patients and Methods: Patients undergoing treatment for STS at our institutes between 2008 and 2017 were enrolled. Patients were excluded if they had metastatic lesion, or had a histopathological classification demonstrating small round-cell sarcoma. The impact of smoking history on PMFS and overall survival was examined with multivariate analysis using a Cox proportional hazards model. Results: A total of 250 patients were retrospectively reviewed. Patients with smoking history had worse PMFS on multivariate analysis (hazard ratio=2.00, 95% confidence interval=1.12-3.60). On the other hand, smoking history did not significantly affect overall survival (hazard ratio=1.26, 95% confidence interval=0.61-2.58). Conclusion: Patients with STS need to be followed-up by frequent clinical assessments if they have a smoking history.

Background Hemarthrosis after total knee arthroplasty (TKA) is a relatively rare complication. Although most cases are effectively treated with conservative therapy, some cases require angiographic embolization or surgical intervention. Angiosarcoma is a rare malignant tumor derived from the vascular endothelium with neovascular hyperplasia and mainly arises in the skin and superficial soft tissue, and less frequently in deep soft tissue and bone. Although malignant neoplasms such as angiosarcoma in the vicinity of orthopedic implants were reported, the causal relationship between development of the malignant tumor and the orthopedic implant is widely debated in the literature. Case presentation We report the case of a 68-year-old female with angiosarcoma that developed in the knee joint 2 years after revision TKA. The patient exhibited severe persistent bleeding, which reached 1000–1400 ml per day for 4 months. Histological analysis of the synovial tissue in the knee joint showed large cells with nuclear atypia. Immunohistochemical staining showed cells that were positive for CD31, CD34, and D2-40, and she was diagnosed with angiosarcoma. The patient underwent an amputation at the level of the thigh, and her general condition immediately improved after the operation. The patient did not exhibit bleeding from the site of amputation, and no local recurrence or distant metastases were detected 1 year after the amputation. Conclusions To the best of our knowledge, this represents the first report of angiosarcoma 2 years after revision TKA. Further careful follow up is needed, given the high-grade malignancy.

Background: Hepatic metastasis of soft tissue sarcoma is rare compared to lung metastasis, and the literature is scarce. We examined the risk of hepatic metastasis according to the site of occurrence and histological type. Methods: From a Hospital-based Cancer Registry, 658 patients registered between 2007 and 2017 with soft tissue sarcomas were evaluated. The exclusion criteria were gastrointestinal stromal tumors, tumors of unknown origin, and follow-up periods of less than 1 month. SPSS 25 was used for statistical analysis. Results: The risk of hepatic metastasis was significantly higher in the retroperitoneum (HR, 5.981; 95% CI, 2.793-12.808) and leiomyosarcoma (HR, 4.303; 95% CI, 1.782-10.390). Multivariate analysis showed that the risk of hepatic metastasis as first distant metastasis was high in leiomyosarcoma (HR, 4.546; 95% CI, 2.275-9.086) and retroperitoneal onset (HR, 4.588; 95% CI, 2.280-9.231). The 2-year survival rate after hepatic metastasis was 21.7%. Conclusions: The onset of hepatic metastasis indicates a poor prognosis. However, hepatic metastasis from retroperitoneal sarcoma and leiomyosarcoma may be the first distant metastasis in some cases. For retroperitoneal sarcoma and leiomyosarcoma, additional screening for hepatic metastasis such as contrast CT should be considered during staging and follow-up after treatment., Article, Cancer medicine 17(17) : 6159-6165(2020)

Malignant peripheral nerve sheath tumor (MPNST) often does not respond well to chemotherapy and develops against a background of NF1. The purpose of our study was to examine the efficacy of pazopanib against MPNST. Our study was designed as a physician-initiated phase II clinical trial in patients with advanced MPNST. Patients were registered from 11 large hospitals. The primary endpoint was set to clarify the clinical benefit rate (CBR) at 12 weeks according to response evaluation criteria in solid tumors (RECIST). Progression-free survival (PFS), overall survival (OS) and the CBR based on modified Choi evaluation at week 12 were set as secondary endpoints along with treatment-related safety. The study enrolled 12 patients. Median age was 49 years. Seven had Grade 2 and five Grade 3 according to the FNCLCC evaluation. Median follow-up period was 10.6 months. CBR at 12 weeks was both 50.0% (RECIST and Choi). The median PFS was 5.4 months for both RECIST and Choi, and the median OS was 10.6 months. Of special interest, the median PFS was 2.9 months for patients with FNCLCC Grade 2 and 10.2 months for Grade 3 (both RECIST and Choi). Grade 4 adverse events of neutropenia and lipase elevation were noted in one patient each. The results of this pazopanib therapy were generally better than those of any of the other single molecular targeted therapies reported previously. Although accumulation of more cases remains necessary, we conclude pazopanib treatment for MPNST to be a safe and promising treatment after doxorubicin-based chemotherapy.

The currently approved dose of pazopanib (800mg) is being re-examined owing to its adverse effects. The aim of this study was to evaluate the relationships among starting or maintenance doses of pazopanib, estimated pazopanib C-min, and other clinical factors, including albumin and a-1 acid glycoprotein levels, in soft-tissue sarcoma and renal cell carcinoma. We also determined whether therapeutic drug monitoring of pazopanib concentrations may be used to improve its therapeutic efficacy and prevent adverse effects. Forty patients who received pazopanib for renal cancer or soft-tissue sarcoma at the Hokkaido Cancer Center were evaluated prospectively. C-min, for pazopanib was calculated based on the measured values from the plasma samples. The efficacy and time to treatment failure were then assessed. The pazopanib maintenance doses were 200 (n=4), 400 (n=34), 600 (n=4), and 800mg (m = 1). Most patients (65%) who received a 400 mg dose had an effective pazopanib concentration (>= 20//g/mL), whereas 35% of patients who received the 400mg dose had ineffective concentrations (

The time course of the response to each drug is important to avoid inappropriate termination of treatment by misjudging tumor progression; however, little is known about soft tissue sarcoma (STS) regarding this matter. This study aimed to perform a time‐lapse analysis of tumor response in patients with STS treated with trabectedin from 2 phase II clinical trials. We examined 66 patients with translocation‐related sarcoma registered in 2 Japanese phase II clinical trials. All patients previously received standard therapy before the administration of trabectedin at 1.2 mg/m2 every 3 weeks. Imaging evaluation was performed according to the study protocol. The sum of the maximum diameters of the target lesions was calculated and analyzed over time. Among the 66 patients, 9 (13.6%) showed partial response (PR) to trabectedin. Histological diagnoses of these 9 responders comprised 6 myxoid liposarcoma, 2 synovial sarcoma, and a mesenchymal chondrosarcoma. The median period from treatment initiation to the first PR was 123 (range, 34‐328) days. The pattern of tumor response to trabectedin showed an increasing tendency in size in the initial stage, usually followed by a size decrease with repeated administration. STS response to trabectedin was characterized as delayed and potentially persistent. Clinicians treating STS with trabectedin should know the features of the response pattern to avoid interrupting the treatment before maximal efficacy is achieved., Among 66 patients with translocation‐related sarcoma, 9 showed partial response to trabectedin, and 5 of the 9 responders (56%) fulfilled the criteria for partial response later than 100 days from treatment initiation. Tumor response to trabectedin was characterized as delayed and stabilized by the detailed time‐lapse analysis of tumor size.

Background Primary osteosarcoma in elderly patients are rare malignant tumors. Its optimal treatment has not yet been determined. Methods This retrospective study included 104 patients aged >50 years with resectable, non-metastatic osteosarcoma treated by the members of the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group. The effects of adjuvant chemotherapy were estimated by comparing outcomes in patients who received surgery plus chemotherapy with those who underwent surgery alone. Results Median age at presentation was 59 years. Neoadjuvant and adjuvant chemotherapy was administered to 83 (79.8%) patients. Patients who underwent surgery plus chemotherapy and those who underwent surgery alone had 5-year overall survival (OS) rates of 68.6% and 71.7%, respectively (p = 0.780), and 5-year relapse free survival (RFS) rates of 48.2% and 43.6%, respectively (p = 0.64). Univariate analysis showed that resection with wide margins was significantly correlated with better prognosis. Conclusions The addition of chemotherapy to surgery did not improve OS or RFS in patients aged >50 years with resectable, non-metastatic osteosarcoma. Surgery with wide margins was only significantly prognostic of improved survival. The effect of chemotherapy in elderly osteosarcoma patients was unclear.

Purpose Survival time after bisphosphonate use has been increasingly recognized to be associated with the incidence of medication-related osteonecrosis of the jaw (MRONJ); however, this has not been elucidated sufficiently in the literature. This study aimed to clarify the incidence of MRONJ and the corresponding survival rate of patients treated with zoledronic acid (ZA) for each type of cancer and obtain useful information for the oral management of cancer. Methods We evaluated 988 patients who were administered ZA at our hospital; among them, 862 patients with metastatic bone tumors or myeloma were included. Results The median survival time (MST) after ZA initiation was 35, 34, 8, 41, 12, and 6 months for patients with breast, prostrate, lung, myeloma, renal, and other cancers, respectively. Patients with cancers that had a short survival time (lung and other cancers [MST = 8 and 6 months, respectively] and cancers with MST

Granular cell tumors (GCTs) are rare mesenchymal tumors that exhibit a characteristic morphology and a finely granular cytoplasm. The genetic alterations responsible for GCT tumorigenesis had been unknown until recently, when loss-of-function mutations of ATP6AP1 and ATP6AP2 were described. Thus, we performed whole-exome sequencing, RNA sequencing, and targeted sequencing of 51 GCT samples. From these genomic analyses, we identified mutations in genes encoding vacuolar H+ -ATPase (V-ATPase) components, including ATP6AP1 and ATP6AP2, in 33 (65%) GCTs. ATP6AP1 and ATP6AP2 mutations were found in 23 (45%) and 2 (4%) samples, respectively, and all were truncating or splice site mutations. In addition, seven other genes encoding V-ATPase components were also mutated, and three mutations in ATP6V0C occurred on the same amino acid (isoleucine 136). These V-ATPase component gene mutations were mutually exclusive, with one exception. These results suggest that V-ATPase function is impaired in GCTs not only by loss-of-function mutations of ATP6AP1 and ATP6AP2 but also through mutations of other subunits. Our findings provide additional support for the hypothesis that V-ATPase dysfunction promotes GCT tumorigenesis.

The usefulness of adjuvant chemotherapy for high-grade osteosarcoma was established by two randomized, controlled trials conducted in the 1980s, which used six drugs, doxorubicin, cisplatin, high-dose methotrexate, bleomycin, cyclophosphamide and actinomycin D. Since then, development has been promoted in the direction of introducing preoperative chemotherapy, changing post-operative adjuvant chemotherapy according to histological effects, adding ifosfamide as a key drug and strengthening adjuvant chemotherapy. No clinical trials, however, have shown the effectiveness of study treatment, and the improvement of treatment results during that time has been slight, although the JCOG0905 study is now going to verify the effectiveness of introducing ifosfamide for patients who experienced limited preoperative therapeutic effects. We are desperately looking for a breakthrough.

Previous studies have not clearly identified a prognostic factor for desmoid tumours (DT). Whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics. CTNNB1 mutations with specific hotspots were identified in 56 cases (87.5%). A copy number loss in chromosome 6 (chr6) was identified in 14 cases (21.9%). Clustering based on the mRNA expression profiles was predictive of the patients' prognoses. The risk score generated by the expression of a three-gene set (IFI6, LGMN, and CKLF) was a strong prognostic marker for recurrence-free survival (RFS) in our cohort. In risk groups stratified by the expression of IFI6, the hazard ratio for recurrence-free survival in the high-risk group relative to the low-risk group was 12.12 (95% confidence interval: 1.56–94.2; p = 8.0 × 106). In conclusion, CTNNB1 mutations and a chr6 copy number loss are likely the causative mutations underlying the tumorigenesis of DT while the gene expression profiles may help to differentiate patients who would be good candidates for wait-and-see management and those who might benefit from additional systemic or radiation therapies.

Alveolar soft part sarcoma (ASPS), epithelioid sarcoma (ES), and clear cell sarcoma (CCS) are known to be chemoresistant tumors. The aim of this study was to investigate the effect of pazopanib on these chemoresistant tumors. This study is designed as a single‐arm, multicenter, investigator‐initiated phase II trial. Patient enrollment was undertaken between July 2016 and August 2018 at 10 hospitals participating in the Japanese Musculoskeletal Oncology Group. The primary end‐point is the CBR (CBR, including complete or partial response and stable disease) at 12 weeks after treatment with pazopanib according to RECIST. Eight patients were enrolled within the period. The histological subtypes were 5 ASPS, 2 ES, and 1 CCS. The median follow‐up period was 22.2 (range, 4.9‐24.9) months. All patients initially received pazopanib 800 mg once daily. The CBRs were 87.5% (7 of 8) and 75.0% (6 of 8) according to RECIST and Choi criteria at 12 weeks after pazopanib treatment, respectively. The CBRs at 12 weeks according to RECIST were 80.0%, 100.0%, and 100.0% in ASPS, ES, and CCS, respectively. Partial response was observed in 1 ASPS according to RECIST and 3 ASPS and 1 ES according to Choi criteria at 12 weeks after pazopanib treatment. This study documented antitumor activity of pazopanib, especially in ASPS. These results support the frontline use of pazopanib for ASPS. Prospective data collection is desired using both RECIST and Choi criteria for these rare chemoresistant tumors., This prospective study, carried out among the Japanese reference centers for treatment of sarcomas, confirmed the value of pazopanib in patients with metastatic or unresectable chemoresistant sarcomas (alveolar soft part sarcoma, epithelioid sarcoma, and clear cell sarcoma). Pazopanib showed antitumor activity in most patients with alveolar soft part sarcoma according to RECIST and Choi criteria. These results support the frontline use of pazopanib for alveolar soft part sarcoma.

The genomic characteristics of dedifferentiated liposarcoma (DDLPS) that are associated with clinical features remain to be identified. Here, we conduct integrated whole exome and RNA sequencing analysis in 115 DDLPS tumors and perform comparative genomic analysis of well-differentiated and dedifferentiated components from eight DDLPS samples. Several somatic copy-number alterations (SCNAs), including the gain of 12q15, are identified as frequent genomic alterations. CTDSP1/2-DNM3OS fusion genes are identified in a subset of DDLPS tumors. Based on the association of SCNAs with clinical features, the DDLPS tumors are clustered into three groups. This clustering can predict the clinical outcome independently. The comparative analysis between well-differentiated and dedifferentiated components identify two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation. This large-scale genomic analysis reveals the mechanisms underlying the development and progression of DDLPS and provides insights that could contribute to the refinement of DDLPS management., Understanding the genomic features of dedifferentiated liposarcoma (DDLPS) is likely to uncover new options for management. Here, the authors reveal three prognostic groups, and highlight molecular markers associated with malignant transformation.

Background Soft tissue sarcomas (STS) are rare malignant tumors. The efficacy of preoperative chemotherapy for STS is evaluated using various tumor size-based radiological response criteria. However, it is still unclear which set of criteria would show the best association with pathological response and survival of the patients with STS. Methods We compared radiological responses to preoperative chemotherapy for operable STS by the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST, World Health Organization criteria, Japanese Orthopaedic Association criteria, and modified Choi criteria and analyzed the association with pathological response and survival using the data from the Japan Clinical Oncology Group (JCOG) study JCOG0304, a phase II clinical trial evaluating the efficacy of perioperative chemotherapy for STS in the extremities. Results Seventy eligible patients in JCOG0304 were analyzed. The results demonstrated that none of the size-based radiological response criteria showed significant association with pathological response to preoperative chemotherapy for STS. The difference between overall survival of the patients assessed as partial response and stable disease/progressive disease by RECIST was not significant (hazard ratio 1.37, p = 0.63), and calculated C-index was 0.50. All other response criteria also could not exhibit significant association between radiological responses and survival. Conclusion In the present study, none of the radiological response criteria analyzed demonstrated association of response to preoperative chemotherapy with pathological response or survival of the patients with operable STS. Further prospective investigation is required to develop criteria to evaluate not only tumor shrinkage but biological effects of preoperative chemotherapy for the patients with localized STS. Trial registration UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).

In regular IVF, a portion of oocytes exhibit abnormal numbers of pronuclei (PN) that is considered as abnormal fertilization, and they are routinely discarded. However, it is known that abnormal ploidy still does not completely abandon embryo development and implantation. To explore the potential of cytoplasm from those abnormally fertilized oocytes, we developed a novel technique for the transfer of large cytoplasm between pronuclear-stage mouse embryos, and assessed its impact. A large volume of cytoplast could be efficiently transferred in the PN stage using a novel two-step method of pronuclear-stage cytoplasmic transfer (PNCT). PNCT revealed the difference in the cytoplasmic function among abnormally fertilized embryos where the cytoplasm of 3PN was developmentally more competent than 1PN, and the supplementing of fresh 3PN cytoplasm restored the impaired developmental potential of postovulatory “aged” oocytes. PNCT-derived embryos harbored significantly higher mitochondrial DNA copies, ATP content, oxygen consumption rate, and total cells. The difference in cytoplasmic function between 3PN and 1PN mouse oocytes probably attributed to the proper activation via sperm and may impact subsequent epigenetic events. These results imply that PNCT may serve as a potential alternative treatment to whole egg donation for patients with age-related recurrent IVF failure.

TPS11580 Background: Soft tissue sarcomas (STS) are a rare type of malignancy, which comprises of a variety of histologies. Chemotherapy is the standard treatment for patients with advanced STS. Doxorubicin alone or in combination with ifosfamide is widely accepted as the first-line chemotherapy for advanced STS. While a combination with gemcitabine and docetaxel is regarded as a standard regimen of the second-line chemotherapy after failure of doxorubicin-based first-line regimen, the efficacy is not sufficient. Trabectedin, eribulin, and pazopanib are the candidates of the second-line chemotherapy for advanced STS, although there is no clear evidence showing which is better among those agents. The purpose of this clinical trial conducted by Bone and Soft Tissue Tumor Study Group of Japan Clinical Oncology Group (JCOG) is to determine the most promising regimen among trabectedin, eribulin and pazopanib as the test arm regimen in the future phase III trial of the second-line treatment for patients with advanced STS. Methods: The study, JCOG1802, is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 IV, every 3 weeks), eribulin (1.4 mg/m2 IV, days 1 and 8, every 3 weeks) and pazopanib (800 mg PO, everyday) for patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. Eligibility criteria include 16 year-old or older, unresectable and/or metastatic STS, an exacerbation within 6 months prior to registration, histological diagnosis of STS other than Ewing sarcoma, well-differentiated liposarcoma and myxoid liposarcoma, a history of chemotherapy for STS other than doxorubicin-based regimen, ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2, and sufficient organ function. Primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. To select the most promising regimen in median PFS (3 months in the worst regimen and 4 months in the best regimen) with a probability of at least 80%, a total of 120 patients will be enrolled from 37 institutions in Japan. After JCOG1802, a subsequent phase III trial comparing the winner of this study and a combination of gemcitabine and docetaxel will be planned. The study was activated at December 5, 2019 and 22 of planned 120 patients have been enrolled as of February 15, 2021. Clinical trial information: jRCTs031190152.

Granular cell tumors (GCTs) are rare mesenchymal tumors that exhibit a characteristic morphology and a finely granular cytoplasm. The genetic alterations responsible for GCT tumorigenesis had been unknown until recently, when loss-of-function mutations of ATP6AP1 and ATP6AP2 were described. Thus, we performed whole-exome sequencing, RNA sequencing, and targeted sequencing of 51 GCT samples. From these genomic analyses, we identified mutations in genes encoding vacuolar H

Background Leiomyosarcoma of bone (LMSoB) is a rare malignant bone tumor. This multicenter retrospective study was conducted to investigate the diagnosis and the clinical outcome of primary LMSoB in Japan. Methods Forty-eight patients (average age: 52 years [range 14–88 years]) with primary LMSoB who were treated at registered institutes in Japan between 1991 and 2014 were recruited. The median follow-up period was 44 months (range: 2–273). Results The 5-year overall survival rates and disease-free survival rates were 78.3% and 44.9%, respectively. Surgical treatment was performed in 42 patients, and R0 resection was achieved in 31 patients. Neoadjuvant chemotherapy was administered in 18 patients. The most common regimen (cisplatin-based chemotherapy) was administered in 15 patients, however, no patient achieved a good response in both radiological and histological evaluations. The presence of metastasis at the first visit and a lack of definitive surgery were significantly correlated with poor overall survival, and the surgical margin was a significant prognostic factor for disease-free survival. Conclusions This study is the largest LMSoB case series ever reported. Surgical treatment with wide margins was the only treatment that proved to be effective, whereas adjuvant chemotherapy in the present setting did not improve the overall survival. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

Purpose To evaluate the results of carbon ion radiation therapy administered to 188 patients with unresectable primary sacral chordomas. Patients and methods One hundred eighty-eight patients were treated with carbon ion radiation therapy at a single institute between 1996 and 2013 and retrospectively analyzed. The median age was 66 years. The highest proximal invasion reached past S2 level in 137 patients. The median clinical target volume was 345 cm(3). One hundred six patients received 67.2 gray equivalents (GyE)/16 fractions (fr), 74 patients received 70.4 GyE/16 fr, 7 patients received 73.6 GyE/16 fr, and 1 patient received 64.0 GyE/16 fr. Results The median follow-up period was 62 months (range, 6.8-147.5 months). Seventy percent of patients were followed for 5 years or until death. The 5-year local control, overall survival, and disease-free survival rates were 77.2%, 81.1%, and 50.3%, respectively. Forty-one patients had a local recurrence. Sex, tumor volume, level of proximal invasion, and irradiated dose were unrelated to local control. There was grade 3 toxicity of the peripheral nerves in 6 patients and grade 4 toxicity of the skin in 2 patients. Ambulation remained in 97% of patients. Conclusions Carbon ion radiation therapy was safe and effective for unresectable chordoma and provided good local control and survival while preserving ambulation.

Aim Our randomised phase II study showed the clinical benefit of trabectedin compared with best supportive care (BSC) in patients with advanced translocation-related sarcomas after the failure of standard chemotherapy. The aim of the present study was to evaluate efficacy and safety of trabectedin in the identical patients crossed over to trabectedin after disease progression in the BSC arm of the randomised study. Patients and methods This was a single-arm study of the BSC patients of the randomised study in whom disease progressed. Trabectedin (1.2 mg/m 2 ) was administered over 24 h on day 1 of a 21-d treatment cycle. The efficacy and safety of trabectedin after BSC were evaluated and retrospectively compared with the results of the randomised study. Results Thirty patients crossed over to trabectedin. Median progression-free survival (PFS) was 7.3 months (95% confidence interval [CI]: 2.9–9.1) after crossover compared with 0.9 months (95% CI: 0.9–1.0) at BSC in the randomised study. PFS in the present study was comparable to that of the trabectedin arm in the randomised study. The number of patients with growth modulation index ≥1.33 was 25 (86%). Individual tumour volume was decreased in 11 patients after crossover. Adverse drug reactions (ADRs) were observed in 27 patients (96.4%). ADRs of grade III–IV were mainly bone marrow suppression and abnormal liver functions. Conclusion Trabectedin was revealed to be effective and well tolerated in the identical patients crossed over to trabectedin after disease progression in BSC. The present study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121853.

Synovial sarcoma accounts for almost 10% of all soft tissue sarcomas, and its prognosis is poor with 5-year survival rates at 36%. Thus, new treatments and therapeutic targets for synovial sarcoma are required. Tumor-initiating cells have been defined by the ability for self-renewal and multipotent differentiation, and they exhibit higher tumorigenic capacity, chemoresistance and radiation resistance, expecting to be a new therapeutic target. In synovial sarcoma, the presence of such stemness remains largely unclear; thus, we analyzed whether synovial sarcoma possessed tumor-initiating cells and explored specific markers, and we discovered that synovial sarcoma cell lines possessed heterogeneity by way of containing a sphere-forming subpopulation highly expressing NANOG, OCT4 and SOX2. By expression microarray analysis, CXCR4 was identified to be highly expressed in the sphere subpopulation and correlated with stem-cell-associated markers. Inhibition of CXCR4 suppressed the cell proliferation of synovial sarcoma cell lines in vitro. The tumor-initiating ability of CXCR4-positive cells was demonstrated by xenograft propagation assay. CXCR4-positive cells showed higher tumorigenicity than negative ones and possessed both self-renewal and multipotent differentiation ability. Immunohistochemical analysis of 39 specimens of synovial sarcoma patients revealed that CXCR4 strongly correlated with poor prognosis of synovial sarcoma. Thus, we conclude that CXCR4 is the marker of synovial sarcoma-initiating cells, a new biomarker for prognosis and a new potential therapeutic target.

11504 Background: Our previous phase II study for high-grade soft tissue sarcomas (STS), JCOG0304, suggested long-term favorable effects of perioperative adriamycin plus ifosfamide (AI) on survival of STS patients. We have also reported in 2015 ASCO Annual Meeting that a phase II/III trial to confirm the non-inferiority of perioperative gemcitabine plus docetaxel (GD) to AI for high-grade STS (JCOG1306) had been started. We herein report the results of JCOG1306 at the early termination by the preplanned second interim analysis. Methods: Patients with operable, FNCLCC grade 2/3 STS primary tumor (T2bN0M0 or anyTN1M0, AJCC 7th edition) or first local recurrent tumor in the extremities or trunk were randomized to AI or GD. Chemotherapy consisted of adriamycin 60 mg/m2 plus ifosfamide 10 g/m2 for AI or gemcitabine 1,800 mg/m2 plus docetaxel 70 mg/m2 for GD. The treatments were repeated for 3 courses preoperatively and 2 courses postoperatively in a 3-week interval. The primary endpoint in phase III part was overall survival (OS). Planned sample size was 140 with a one-sided alpha of 0.1, power of 0.7 and a non-inferiority margin of 8% at 3-year OS, assuming 3-year OS of AI to be 85% and that of GD as 87%. The patient accrual has started in February 2014 and finished in September 2018. Results: A total of 143 patients were enrolled and included in the efficacy analysis. Seventy and 73 patients were assigned to AI and GD, respectively. At the second interim-analysis on December 2019, the estimated 2-year OS was 94.3 % (95% confidence interval (CI) 83.4–98.1) in AI and 91.6 % (80.9–96.4) in GD (hazard ratio (HR) 2.55, 95% CI 0.67–9.78). The estimated 2-year progression-free survival was 81.9 % (95% CI: 69.5–89.7) in AI and 64.0 % (51.1–74.4) in GD (HR 2.32, 95% CI 1.22–4.39). There were no treatment-related deaths in both groups. The most common Grade 3 or higher adverse events in AI were neutropenia (88.4%), anemia (49.3%), and febrile neutropenia (36.2%), whereas those in GD were neutropenia (79.5%), febrile neutropenia (17.8%), and alanine aminotransferase (9.6%). Based on the result of this analysis, the Data Monitoring and Safety Committee of JCOG recommended terminating the study since the point estimate of HR was above the pre-specified allowable HR of 1.61. Conclusions: Although the toxicities were modest in GD, non-inferiority of GD to AI could not be confirmed. In the perioperative chemotherapy for high-grade STS in the extremities and trunk, AI remains the standard regimen. Clinical trial information: UMIN000013175 .

A randomized phase III trial was planned to commence in October 2017. Resectable giant cell tumor of bone (GCTB) without possible postoperative large bone defect has been treated by curettage with local adjuvant treatment, with the local recurrence rate found to be as high as 24.6-30.8%. The aim of this study is to confirm the superiority of preoperative denosumab for patients with GCTB without possible postoperative large bone defect. A total of 106 patients will be accrued from 34 Japanese institutions over 5 years. The primary endpoint is relapse-free survival (RFS). Secondary endpoints include overall survival, joint-preserved survival, local RFS, metastasis-free survival, adverse events, serious adverse events, surgical and postoperative complications, and discontinuation of denosumab. This trial is conducted by the Bone and Soft Tissue Tumor Study Group in the Japan Clinical Oncology Group and has been registered in the UMIN Clinical Trials Registry as UMIN000029451 [http://www.umin.ac.jp/ctr/index.htm].

A randomized Phase II/III trial was planned to commence in March 2014. Perioperative chemotherapy with adriamycin plus ifosfamide is the current standard treatment for T2bN0M0 high-grade non-round cell soft tissue sarcoma. The purpose of this study is to confirm the non-inferiority of perioperative chemotherapy with gemcitabine and docetaxel to adriamycin plus ifosfamide for patients with T2bN0M0 or any TN1M0 non-round cell soft tissue sarcoma in the extremities and body wall. A total of 140 patients will be accrued from 28 Japanese institutions over 6 years. The primary endpoint in the Phase II part is the proportion of completion of pre-operative chemotherapy without progressive disease and overall survival in the Phase III part. The secondary endpoints are progression-free survival, response rate of pre-operative chemotherapy, pathological response rate, proportion of preservation of diseased limbs, disease control rate and proportion of adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000013175 [http://www.umin.ac.jp/ctr/index.htm].

Background Pathological fracture of the proximal femur is a main cause of cancer patients losing their ability to walk. Although both osteosynthetic devices (predominantly intramedullary nails) and prosthetic replacement have been widely performed for treatment, controversies exist regarding which procedure should be used for the various conditions. In order to decide the eligibility criteria of a planned randomized prospective study about the treatment of pathological fractures of the proximal femur, we assessed the factors affecting the selection of operative procedures using questionnaires sent to the members of the Bone and Soft Tissue Tumor Study Group (BSTTSG) of the Japan Clinical Oncology Group (JCOG). Methods Questionnaire surveys to evaluate (1) the priority levels of the factors, (2) the equipoise range of each factor in situations where either procedure could be applied, (3) risk and benefit of each procedure, and (4) the degree of bone destruction affecting the selection of operative procedures, were sent to 26 institutions. Results Over 80% of the institutions answered. Orthopaedic surgeons of BSTTSG decided on the procedure according to the following factors in descending order: life expectancy, performance status before fracture, the degree of bone destruction, walking ability before fracture, general complications, the number of bone metastases in other sites, and the visceral metastasis status. With regard to bone destruction, (1) the involvement of the head, neck, calcar, and intertrochanteric region, (2) transverse destruction >1/2, and (3) soft-tissue tumor extension, were the factors that led to the choice of prosthesis treatment. Conclusions Using these identified factors, the inclusion criteria for the prospective randomized study of the surgical treatment of metastatic bone tumors of the proximal femur were optimized. The evaluation system about the bone destruction of metastases needs to be refined through the following prospective randomized study.

The tensor fascia lata (TFL) flap is used to reconstruct various anatomical structures in different regions of the body. We herein describe the use of TFL flaps for a variety of indications, and discuss the results of such procedures with respect to postoperative complications in oncology patients. We reviewed 15 oncology patients who were treated with TFL flaps. The lesions were located in the groin in five patients, the lower abdomen in five, and the buttocks, ischium, shoulder, thigh and upper abdomen in one patient each. Abdominal wall reconstruction was performed in nine patients. Three patients underwent resection of femoral vessels and the tumor in the groin, followed by a vascular graft implant. In these patients, the combined flaps were transferred to reconstruct the defects. Nine patients developed complications. No total flap loss occurred in any patient. Postoperative complications, such as necrosis in the distal part of the flap (33 %) and ventral hernias (11 %) were seen, but these percentages were comparable to those seen in previous reports. Our review shows that the TFL flap is useful to reconstruct the defects in various anatomical sites in oncology patients.

The posterior thigh flap is a reliable flap owing to the dependability of the inferior gluteal artery. Its utility for the reconstruction of sacral, perineal, ischial, pelvic, trochanteric and vulvar defects is well established. We herein describe the use of the flap for a variety of indications, and discuss the results with respect to postoperative complications in oncology patients. We reviewed nine oncology patients who were treated with pedicled posterior thigh flaps. We assessed the use of this treatment by recording the site of the defect, the type of flap used, and the presence or absence of previous surgical procedures, radiation therapy and postoperative complications. Defects after resection of soft tissue sarcomas were the most common condition (n = 4), followed by skin cancers (n = 2), gastrointestinal cancers (n = 2) and radiation osteomyelitis (n = 1). Six patients (66 %) developed complications; three (33 %) were major and three (33 %) were minor. There was one case of total necrosis of the flap and two cases of partial necrosis. In oncology patients, the posterior thigh flap is an excellent choice for the reconstruction of sacral, ischial, pelvic or buttock defects, since it does not cause any donor site morbidity.

Trabectedin is reported to be particularly effective against translocation-related sarcoma. Recently, a randomized phase 2 study in patients with translocation-related sarcomas unresponsive or intolerable to standard chemotherapy was conducted, which showed clinical benefit of trabectedin compared with best supportive care (BSC). Extraskeletal myxoid chondrosarcoma (EMCS) and Mesenchymal chondrosarcoma (MCS) are very rare malignant soft tissue sarcomas, and are associated with translocations resulting in fusion genes. In addition, the previous in vivo data showed that trabectedin affect tumor necrosis and reduction in vascularization in a xenograft model of a human high-grade chondrosarcoma. The aim of the present analysis was to clarify the efficacy of trabectedin for EMCS and MCS subjects in the randomized phase 2 study. Five subjects with EMCS and MCS received trabectedin treatment in the randomized phase 2 study. Three MCS subjects were allocated to the BSC group. Objective response and progression-free survival (PFS) were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by central radiology imaging review. The median follow-up time of the randomized phase 2 study was 22.7 months, and one subject with MCS was still receiving trabectedin treatment at the final data cutoff. The median PFS was 12.5 months (95 % CI: 7.4–not reached) in the trabectedin group, while 1.0 months (95 % CI: 0.3–1.0 months) in MCS subjects of the BSC group. The six-month progression-free rate was 100 % in the trabectedin group. One subject with MCS showed partial response, and the others in the trabectedin group showed stable disease. Overall survival of EMCS and MCS subjects was 26.4 months (range, 10.4–26.4 months) in the trabectedin group. At the final data cutoff, two of five subjects were still alive. This sub-analysis shows that trabectedin is effective for patients with EMCS and MCS compared with BSC. The efficacy results were better than previously reported data of TRS. These facts suggest that trabectedin become an important choice of treatment for patients with advanced EMCS or MCS who failed or were intolerable to standard chemotherapy. The randomized phase 2 study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121850 (May 31, 2012).

This analysis updates the results of two phase II studies of translocation‐related sarcomas to evaluate the efficacy of trabectedin against histological subtype and analyze overall survival., Background. Trabectedin is reported as effective, especially against translocation‐related sarcomas (TRSs) after failure of or intolerance to standard chemotherapy. We conducted two phase II studies of TRS, confirming high efficacy of 1.2 mg/m2 trabectedin. The updated data of 66 patients in these studies was integrated to evaluate the efficacy of trabectedin against each histological subtype, and analyze final overall survival (OS). Methods. Trabectedin was administered on day one of a 21‐day cycle. Efficacy was assessed using progression‐free survival (PFS), OS, and best overall response. An analysis of OS and PFS was performed for subgroups divided by baseline lymphocyte count (

The survival of patients with osteosarcoma has improved dramatically due to the introduction of effective systemic chemotherapy. The key standard drugs for osteosarcoma chemotherapy are methotrexate, doxorubicin, and cisplatin, and multi-institutional trials based on these drugs have been conducted in Japan since the 1990s. However, there have been no nationwide data on treatment outcome, especially with regard to survival and prognostic factors. In this chapter, therefore, we present data from a large nationwide cohort of patients with osteosarcoma treated at 11 referral centers in Japan during the period 1990–2010 with special reference to survival and relevant prognostic factors. The 3-, 5-, and 10-year metastasis-free survival and overall survival rates for the 529 patients were 70 %, 64 %, and 62 % and 88 %, 83 %, and 77 %, respectively. The prognosis for patients with osteosarcoma in Japan was comparable to, or slightly better than, those reported in other countries. International collaboration should also be conducted in Asian countries including Japan to improve the outcome further and find the optimal treatment for osteosarcoma.

Adjuvant chemotherapy is a standard treatment for osteosarcoma, which was verified by two randomized controlled trials (RCTs). Preoperative chemotherapy and limb-preserving procedure have been developed in the USA since around 1970 and in Japan since around 1980. In addition, histologic evaluation concerned with the rate of necrosis of excised tumors after preoperative chemotherapy has been tried, and it has been reported that patients with higher rate of necrosis result in better survival. Neoadjuvant chemotherapy for osteosarcoma (NECO) study tried to improve survival of the patients with lower rate of necrosis, called as “poor responders,” by the changes or addition of chemotherapeutic agents on the basis of the histologic evaluation in Japan, and the study found the possibility to rescue poor responders. Such strategies, however, have not been verified by RCT yet. Now additional effects of ifosfamide (IFO) to postoperative chemotherapy for poor responders after preoperative chemotherapy and surgery are just tested by two RCTs.

Leiomyosarcoma of bone (LMSoB) is a rare malignant bone tumor. This multicenter retrospective study was conducted to investigate the diagnosis and the clinical outcome of primary LMSoB in Japan.Forty-eight patients (average age: 52 years [range 14-88 years]) with primary LMSoB who were treated at registered institutes in Japan between 1991 and 2014 were recruited. The median follow-up period was 44 months (range: 2-273).The 5-year overall survival rates and disease-free survival rates were 78.3% and 44.9%, respectively. Surgical treatment was performed in 42 patients, and R0 resection was achieved in 31 patients. Neoadjuvant chemotherapy was administered in 18 patients. The most common regimen (cisplatin-based chemotherapy) was administered in 15 patients, however, no patient achieved a good response in both radiological and histological evaluations. The presence of metastasis at the first visit and a lack of definitive surgery were significantly correlated with poor overall survival, and the surgical margin was a significant prognostic factor for disease-free survival.This study is the largest LMSoB case series ever reported. Surgical treatment with wide margins was the only treatment that proved to be effective, whereas adjuvant chemotherapy in the present setting did not improve the overall survival. J. Surg. Oncol. 2016;114:495-500. © 2016 Wiley Periodicals, Inc.

BACKGROUND Because the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large‐scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real‐life, postmarketing surveillance data. METHODS Patients received pazopanib with the objective of treating local recurrence (n = 20), metastasis (n = 104), and both (n = 32). The patient median age was 53.8 years. The primary objective of this study was to clarify the efficacy of pazopanib for patients with STS. RESULTS The median treatment duration was 28.7 weeks, and the average dose intensity of pazopanib was 609 mg. Adverse events occurred in 127 patients (81.4%). In addition to the main common toxicities, such as hypertension and liver disorder, pneumothorax (n = 11) and thrombocytopenia (n = 16) also were observed. The median progression‐free survival for all patients was 15.4 weeks. The median progression‐free survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 18.6 weeks, 16.4 weeks, 15.3 weeks, and 8 weeks, respectively. The median survival for all patients was 11.2 months. The median survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 20.1 months, 10.6 months, 9.5 months, and 7.3 months, respectively. CONCLUSIONS There were apparent differences in the efficacy of pazopanib treatment among histologic types of STS. Pazopanib treatment is a new treatment option; however, adverse events like pneumothorax and thrombocytopenia, which did not occur frequently in the PALETTE study (pazopanib for metastatic soft‐tissue sarcoma), should be taken into consideration. Cancer 2016;122:1408‐16. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society., Clinical outcomes of 156 Japanese patients with relapsed soft tissue sarcoma receive pazopanib treatment are investigated. There are apparent differences in the efficacy of pazopanib treatment among histologic types of soft tissue sarcoma.

Background Giant cell tumor of bone (GCTB) is an intermediate tumor known to be locally aggressive, but rarely metastasizing. To plan a prospective study of GCTB, we performed a questionnaire survey for institutions participating in the Bone and Soft Tissue Tumor Study Group (BSTTSG) in the Japan Clinical Oncology Group (JCOG) in 2015. Methods We reviewed 158 consecutive patients with primary GCTB treated with curettage without perioperative denosumab from 2008 to 2010 in Japan. We investigated local and distant recurrence rates after definitive curettage. We also investigated the recurrence rate after treatment with preoperative and/or postoperative denosumab with curettage in recent years. There were 40 patients treated with perioperative denosumab, and the factors affecting recurrence in them were investigated. Results Answers were available from 24 of 30 institutions (80.0%) participating in JCOG BSTTSG. Thirty (19.0%) and 4 (2.5%) of 158 patients developed local and distant recurrence after curettage without perioperative denosumab from 2008 to 2010, respectively. Campanacci grade and embolization before surgery were significantly associated with increasing incidence of local recurrence after curettage (p = 0.034 and p = 0.022, respectively). In patients treated with perioperative desnosumab, 120 mg denosumab was administered subcutaneously for a median 6 (2–41) and 6 (1–14) times in preoperative and postoperative settings, respectively. The recurrence rates were 6 of 21 (28.6%), 2 of 9 (22.2%), and 0 of 10 (0.0%) in the preoperative, postoperative, and both pre- and postoperative denosumab treatment groups, respectively. With all of the preoperative treatments, administration exceeding five times was significantly associated with a decreased incidence of local recurrence after curettage (p