Bone marrow adipocytes induce cancer-associated fibroblasts and immune evasion, enhancing invasion and drug resistance.

Bone metastasis occurs frequently in cancer patients. Conventional therapies have limited therapeutic outcomes, and thus, exploring the mechanisms of cancer progression in bone metastasis is important to develop new effective therapies. In the bone microenvironment, adipocytes are the major stromal cells that interact with cancer cells during bone metastasis. However, the comprehensive functions of bone marrow adipocytes in cancer progression are not yet fully understood. To address this, we investigated the role of bone marrow adipocytes on cancer cells, by focusing on an invasive front that reflects the direct effects of stromal cells on cancer. In comprehensive histopathological and genetic analysis using bone metastasis specimens, we examined invasive fronts in bone metastasis and compared invasive fronts with adipocyte-rich bone marrow (adipo-BM) to those with hematopoietic cell-rich bone marrow (hemato-BM) as a normal counterpart of adipocytes. We found morphological complexity of the invasive front with adipo-BM was significantly higher than that with hemato-BM. Based on immunohistochemistry, the invasive front with adipo-BM comparatively had a significantly increased cancer-associated fibroblast (CAF) marker-positive area and lower density of CD8+ lymphocytes compared to that with hemato-BM. RNA sequencing analysis of primary and bone metastasis cancer revealed that bone metastasized cancer cells acquired drug resistance-related gene expression phenotypes. Clearly, these findings indicate that bone marrow adipocytes provide a favorable tumor microenvironment for cancer invasion and therapeutic resistance of bone metastasized cancers through CAF induction and immune evasion, providing a potential target for the treatment of bone metastasis.

A multicentre retrospective study on extra-thoracic solitary fibrous tumour: preoperative MRI findings predict intraoperative findings and postoperative prognosis.

OBJECTIVE: The present study investigated the relationships between the preoperative and operative findings of solitary fibrous tumour (SFT) and between preoperative findings and prognosis. METHODS: We reviewed 50 SFT patients treated at our musculoskeletal oncology hospital group. We analyzed preoperative clinical findings, particularly MRI imaging findings, and intraoperative information as well as the relationship between preoperative findings and outcomes. RESULTS: Mean age was 48.9 years and the mean follow-up was 51.8 months. Prior to surgery, needle biopsy was performed on 27 patients and open biopsy on 14. T2-weighted images showed a high signal intensity in 24 patients and heterogeneous signal intensity in 20. Tumours had polylobular contours in 17 patients and smooth and round contours in 27. Collateral feeding vessels were detected in 22 patients. Gd-enhanced MRI was performed on 23 patients, and showed 15 with homogeneous enhancement and 8 with heterogeneous enhancement. Surgical times were significantly longer in patients with a retroperitoneal origin, a tumour of 10 cm or more, and polylobular-type tumours. Intraoperative blood loss was significantly greater in patients with a retroperitoneal origin and heterogeneous Gd-MRI-enhanced tumours. In histopathological evaluations, surgical margins were positive in 12 patients. Local recurrence was observed in one patient. Distant metastasis was noted in eight patients, four of whom had pulmonary metastases. Positive surgical margins were more common in polylobular-type tumours. Distant metastases were more likely to appear in patients with observable collateral feeding vessels and heterogeneous Gd-MRI enhancement. CONCLUSION: The present results suggest that preoperative clinical findings in SFT patients predict longer surgical times and the risk of increased intraoperative blood loss. Moreover, the risk of a positive surgical margin and postoperative distant metastases may be predicted based on preoperative MRI.

Intraoperative extracorporeal irradiation for giant sarcoma-infiltrated calvarium: a case report.

Large bone defects that occur after resection of calvarial tumours are commonly remedied using titanium meshes or bone prostheses. However, these methods have several problems. While intraoperative extracorporeal radiotherapy for bone flaps could avoid these problems, there have been only a few reports wherein meningiomas were treated with 120 Gy irradiation. Moreover, no reports are available on calvarial metastasis of sarcoma, and the therapeutic radiation dose remains uncertain. Here, we report a case of giant calvarial metastasis of myxoid liposarcoma treated with intraoperative extracorporeal radiotherapy at a dose of 50 Gy. The treatment resulted in successful tumour control followed by favourable bone reconstruction.

Clinical analysis of multimodal treatment for localized synovial sarcoma: A multicenter retrospective study.

INTRODUCTION: Several prognostic factors for survival in synovial sarcoma have been proposed, but the role of adjuvant chemotherapy and radiotherapy is a matter of debate. The study aim was to clarify the effect of high-dose ifosfamide-containing chemotherapy and adjuvant radiotherapy for patients with localized synovial sarcoma. MATERIALS AND METHODS: Five tertiary musculoskeletal oncology hospitals participated in this retrospective study. The records of the patient diagnosed with synovial sarcoma without metastasis at diagnosis from 1990 to 2011 have been collected and reviewed. Overall, distant failure-free, and local failure-free survivals were calculated, and prognostic factors for each survival were evaluated by performing univariate and multivariate analyses. RESULTS: A total of 162 patients were enrolled in this study with a median follow-up period of 67 months (range, 5-267 months) for all surviving patients. The 5-year overall, distant failure-free, and local failure-free survival rates were 79.7%, 66.3%, and 98.4%, respectively. Univariate analyses demonstrated that high-dose ifosfamide-containing chemotherapy was significantly associated with better overall (p = 0.014) and distant failure-free survival (p = 0.0043) than that of low-dose or no ifosfamide-containing chemotherapy if we analyzed only patients with tumors >5 cm in size. Addition of radiotherapy was not a significant prognostic factor for overall survival in the univariate and multivariate analyses, but it did improve the overall survival of the patients with R1 resection (p = 0.053). CONCLUSION: Patients with localized synovial sarcoma >5 cm in size had better overall and distant failure-free survival after receiving adjuvant chemotherapy containing high-dose ifosfamide comparing to low-dose or no ifosfamide-containing chemotherapy. The addition of adjuvant radiotherapy was beneficial for the patients who received R1 resection. Alternatively, adjuvant radiotherapy could be avoided for patients who achieved an R0 margin.

Perioperative Adriamycin plus ifosfamide vs. gemcitabine plus docetaxel for high-risk soft tissue sarcomas: randomised, phase II/III study JCOG1306.

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.

Standardization of evaluation method and prognostic significance of histological response to preoperative chemotherapy in high-grade non-round cell soft tissue sarcomas.

BACKGROUND: Preoperative chemotherapy is widely applied to high-grade localized soft tissue sarcomas (STSs); however, the prognostic significance of histological response to chemotherapy remains controversial. This study aimed to standardize evaluation method of histological response to chemotherapy with high agreement score among pathologists, and to establish a cut-off value closely related to prognosis. METHODS: Using data and specimens from the patients who had registered in the Japan Clinical Oncology Group study, JCOG0304, a phase II trial evaluating the efficacy of perioperative chemotherapy with doxorubicin (DOX) and ifosfamide (IFO), we evaluated histological response to preoperative chemotherapy at the central review board. RESULTS: A total of 64 patients were eligible for this study. The percentage of viable tumor area ranged from 0.1% to 97.0%, with median value of 35.7%. Regarding concordance proportion between pathologists, the weighted kappa coefficient (κ) score in all patients was 0.71, indicating that the established evaluation method achieved substantial agreement score. When the cut-off value of the percentage of the residual tumor area was set as 25%, the p-value for the difference in overall survival showed the minimum value. Hazard ratio of the non-responder with percentage of the residual tumor < 25%, to the responder was 4.029 (95% confidence interval 0.893-18.188, p = 0.070). CONCLUSION: The standardized evaluation method of pathological response to preoperative chemotherapy showed a substantial agreement in the weighted κ score. The evaluation method established here was useful for estimating of the prognosis in STS patients who were administered perioperative chemotherapy with DOX and IFO. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).

A randomized phase III trial of denosumab before curettage for giant cell tumor of bone. JCOG1610.

OBJECTIVES: The aim of JCOG1610 (randomized controlled phase III trial) was to confirm the superiority of preoperative denosumab to curettage with adjuvant local therapy for patients with giant cell tumor of bone without possible post-operative large bone defect. METHODS: The primary endpoint was relapse-free survival and the total sample size was set at 106 patients. Patient accrual began in October 2017. However, the accrual was terminated in December 2020 due to a recommendation from the Data and Safety Monitoring Committee because of poor patient accrual. Now, we report the descriptive results obtained in this study. RESULTS: A total of 18 patients had been registered from 13 Japanese institutions at the time of termination on December 2020. Eleven patients were assigned to Arm A (curettage and adjuvant local therapy) and 7 to Arm B (preoperative denosumab, curettage and adjuvant local therapy). Median follow-up period was 1.6 (range: 0.5-2.8) years. Protocol treatment was completed in all but one patient in Arm A who had a pathological fracture before surgery. All patients in Arm B were treated with five courses of preoperative denosumab. Relapse-free survival proportions in Arm A and B were 90.0% (95% confidence interval: 47.3-98.5) and 100% (100-100) at 1 year, and 60.0% (19.0-85.5) and 62.5% (14.2-89.3) at 2 years, respectively [hazard ratio (95% confidence interval): 1.51 (0.24-9.41)]. CONCLUSION: In terms of relapse-free survival, the superiority of preoperative denosumab was not observed in patients with giant cell tumor of bone without possible post-operative large bone defect.

Ten-year follow-up results of perioperative chemotherapy with doxorubicin and ifosfamide for high-grade soft-tissue sarcoma of the extremities: Japan Clinical Oncology Group study JCOG0304.

BACKGROUND: Soft-tissue sarcomas (STS) are rare malignant tumors those are resistant to chemotherapy. We have previously reported the 3-year follow-up result on the efficacy of perioperative chemotherapy with doxorubicin (DXR) and ifosfamide (IFM) for high-risk STS of the extremities (JCOG0304). In the present study, we analyzed the 10-year follow-up results of JCOG0304. METHODS: Patients with operable, high-risk STS (T2bN0M0, AJCC 6th edition) of the extremities were treated with 3 courses of preoperative and 2 courses of postoperative chemotherapy, which consisted of 60 mg/m2 of DXR plus 10 g/m2 of IFM over a 3-week interval. The primary study endpoint was progression-free survival (PFS) estimated by Kaplan-Meier methods. Prognostic factors were evaluated by univariable and multivariable Cox proportional hazards model. RESULTS: A total of 72 patients were enrolled between March 2004 and September 2008, with 70 of these patients being eligible. The median follow-up period was 10.0 years for all eligible patients. Local recurrence and distant metastasis were observed in 5 and 19 patients, respectively. The 10-year PFS was 65.7% (95% CI: 53.4-75.5%) with no PFS events being detected during the last 5 years of follow-up. The 10-year overall survival was 78.1% (95% CI: 66.3-86.2%). Secondary malignancy was detected in 6 patients. The subgroup analysis demonstrated that there was significant difference in survival with regard to primary tumor size. CONCLUSIONS: Only a few long-term results of clinical trials for perioperative chemotherapy treatment of STS have been reported. Our results demonstrate that the 10-year outcome of JCOG0304 for patients with operable, high-risk STS of the extremities was stable and remained favorable during the last 5 years of follow-up. TRIAL REGISTRATION: This trial was registered at the UMIN Clinical Trials Registry as C000000096 on August 30, 2005.

Prospective comparison of various radiological response criteria and pathological response to preoperative chemotherapy and survival in operable high-grade soft tissue sarcomas in the Japan Clinical Oncology Group study JCOG0304.

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).

Efficacy of Trabectedin in Patients with Advanced Translocation-Related Sarcomas: Pooled Analysis of Two Phase II Studies.

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 (<1,000/µL, ≥1,000/µL) or number of previous chemotherapy regimens (0, 1, 2, ≥3 regimens), and a Weibull parametric model was used to estimate the numerical relationship between lymphocyte count and PFS and OS. RESULTS: Median PFS and OS in overall patients were 5.6 (95% confidence interval [CI]: 4.1-7.3) and 17.5 months (95% CI: 12.6-23.6), respectively. PFS in the myxoid and round-cell liposarcoma (MRCL) group (7.4 months [95% CI: 5.6-11.1]) was longer than in the other subtypes. The response rate was also highest in the MRCL group. Median OS was longer in patients with baseline lymphocyte counts ≥1,000/µL than in those with counts of <1,000/µL, but median PFS was not different between the two subgroups. CONCLUSION: Our updated and pooled data showed that trabectedin exerted prolonged disease control and antitumor effects in patients with advanced TRS, especially in MRCL. We consider that the subgroup analyses also provide important information for trabectedin treatment in patients with TRS. IMPLICATIONS FOR PRACTICE: The progression-free survival (PFS) for the integrated data of 66 patients with translocation-related sarcomas (TRSs) in two phase II studies of trabectedin 1.2 mg/m2 was 5.6 months (95% confidence interval: 4.1-7.3). PFS and response rate in myxoid/round-cell liposarcoma was longer than that of other subtypes. The overall survival (OS) in all TRS subtypes was similar to previous data of TRS patients. In subgroup analysis, the patients with baseline lymphocyte count ≥1,000/µL exhibited better OS, although PFS was not different by baseline lymphocyte count. Our data are considered important information for trabectedin treatment in TRS patients.

Impact of geriatric factors on surgical and prognostic outcomes in elderly patients with soft-tissue sarcoma.

OBJECTIVE: Patients aged ≥65 years requiring surgery for soft-tissue sarcoma are a concern in an aging society. We aimed to reveal the association of clinical/geriatric factors with survival period or postoperative events in such patients who underwent surgery. METHODS: We enrolled patients aged ≥65 years who underwent surgery for localized soft-tissue sarcoma at five institutions. We retrospectively collected clinical/geriatric factors and laboratory data, and analyzed their association with outcomes using univariate and multivariate analyses. RESULTS: Among the 202 patients included, mean age at presentation was 73 years. Surgical margin was R0 in 139 patients (69%). The Eastern Cooperative Oncology Group performance status was ≥2 in 15 (7%). Thirty patients (15%) showed thinness (body mass index <18.49 kg/cm2). High-sensitivity-modified Glasgow prognostic score ≥1 was seen in 52 patients (26%). Multivariate analysis showed that R1 surgical margin was significantly correlated with poor sarcoma-specific survival (hazard ratio for R1 vs. R0, 3.17; P = 0.001) and event-free survival (hazard ratio for R1 vs. R0, 2.56; P < 0.001). Higher Eastern Cooperative Oncology Group performance status was significantly associated with poor sarcoma-specific survival (hazard ratio for ≥2 vs. 0 or 1, 2.15; P = 0.038), and higher sensitivity-modified Glasgow prognostic score was significantly associated with poor event-free survival (hazard ratio for ≥1 vs. 0, 1.74; P = 0.046). Severe thinness (body mass index <16.00) was a risk factor for postoperative events (odds ratio for body mass index <16.00 vs. ≥16.00, 8.15, P = 0.010). CONCLUSIONS: Negative surgical margin was associated with better survival. Coexisting conditions had an impact on outcomes in elderly soft-tissue sarcoma patients.

Factors associated with the decision of operative procedure for proximal femoral bone metastasis: Questionnaire survey to institutions participating the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group.

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.

Results of sub-analysis of a phase 2 study on trabectedin treatment for extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: The randomized phase 2 study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121850 (May 31, 2012).

Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study.

BACKGROUND: Trabectedin binds to the minor groove of DNA and blocks DNA repair machinery. Preclinical data have shown that trabectedin also modulates the transcription of the oncogenic fusion proteins of translocation-related sarcomas. We aimed to assess the efficacy and safety of trabectedin as second-line therapy or later for patients with advanced translocation-related sarcoma. METHODS: We did a multicentre randomised open-label study in Japan. Eligible patients had pathological diagnosis of translocation-related sarcoma, were aged 19 years or older, were unresponsive or intolerant to standard chemotherapy regimens, no more than four previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0 or 1, adequate bone marrow reserve, renal and liver functions, and had measurable lesions. Patients were randomly assigned (1:1) by the minimisation method to receive either trabectedin (1·2 mg/m(2) given via a central venous line over 24 h on day 1 of a 21 day treatment cycle) or best supportive care, which was adjusted centrally by pathological subtype. Investigators, patients, and the sponsor were unmasked to the treatment assignment. Progression-free survival and objective responses were assessed by a masked central radiology imaging review. Efficacy was assessed by masked central radiology imaging review. The primary endpoint was progression-free survival for the full analysis set population. Follow-up is ongoing for the patients under study treatment. The study is registered with Japan Pharmaceutical Information Center, number JapicCTI-121850. FINDINGS: Between July 11, 2012, and Jan 20, 2014, 76 patients were enrolled and allocated to receive either trabectedin (n=39) or best supportive care (n=37). After central review to confirm pathological subtypes, 73 patients (37 in the trabectedin group and 36 in the best supportive care group) were included in the primary efficacy analysis. Median progression-free survival of the trabectedin group was 5·6 months (95% CI 4·1-7·5) and the best supportive care group was 0·9 months (0·7-1·0). The hazard ratio (HR) for progression-free survival of trabectedin versus best supportive care was 0·07 (90% CI 0·03-0·14 and 95% CI 0·03-0·16) by a Cox proportional hazards model (p<0·0001). The most common drug-related adverse events for patients treated with trabectedin were nausea (32 [89%] of 36), decreased appetite (21 [58%]), decreased neutrophil count (30 [83%]), increased alanine aminotransferase (24 [67%]), and decreased white blood cell count (20 [56%]). INTERPRETATION: Trabectedin significantly reduced the risk of disease progression and death in patients with advanced translocation-related sarcoma after standard chemotherapy such as doxorubicin, and should be considered as a new therapeutic treatment option for this patient population. FUNDING: Taiho Pharmaceutical Co., Ltd.

Development and external validation of nomograms predicting distant metastases and overall survival after neoadjuvant chemotherapy and surgery for patients with nonmetastatic osteosarcoma: A multi-institutional study.

BACKGROUND: In this era of individualized cancer treatment, data that could be applied to predicting the survival of patients with osteosarcoma are still limited because of the rarity of the disease and the difficulty in accumulating a sufficient number of patients. Therefore, a multi-institutional collaboration was implemented to develop and externally validate nomograms that would predict metastasis-free survival (MFS) and overall survival (OAS) for patients with nonmetastatic osteosarcoma. METHODS: This study retrospectively examined 1070 patients treated with neoadjuvant chemotherapy and surgery for nonmetastatic osteosarcoma. Data from Japanese patients (n = 557) were used to develop multivariate nomograms based on Cox regression. Six clinical and pathologic variables were built into nomograms estimating the probability of MFS and OAS 3 and 5 years after diagnosis. The model was internally validated for discrimination and calibration with bootstrap resampling and was externally validated with an independent patient cohort from Korea (n = 513). RESULTS: A patient's age, tumor site, and histologic response were found to have a stronger influence on MFS and OAS in the model than sex, tumor size, or pathologic fracture. The nomograms and calibration plots based on these results well predicted the probability of MFS (concordance index, 0.631) and OAS (concordance index, 0.679). The concordance indices for external validation were 0.682 for MFS and 0.665 for OAS. CONCLUSIONS: The nomograms were externally validated and verified to be useful for the prediction of MFS and OAS and for the assessment of the postoperative prognosis. They can be used for counseling patients and for establishing appropriate surveillance strategies after surgery.

Prognostic Value of Relevant Clinicopathologic Variables in Epithelioid Sarcoma: A Multi-Institutional Retrospective Study of 44 Patients.

BACKGROUND: Epithelioid sarcoma (ES) is an extremely rare soft tissue sarcoma. Recently, the proximal variant has been reported to be a more aggressive subtype; however, as most reports of ES have involved small case series, the actual prognostic implications remain unclear. We investigated the clinicopathological features of patients with ES to identify the prognostic factors that influence survival. METHODS: We retrospectively analyzed the clinicopathological features of 44 patients with ES who had been treated at our institutions between 1991 and 2011. Among these patients, 26 were diagnosed histologically as having classic-type ES, whereas the remaining 18 had proximal-type ES. Thirty-three of the patients, all without distant metastases, underwent curative surgery, and the remaining 11 with distant metastases (M1) received palliative treatment. RESULTS: The proximal subtype was significantly correlated with a proximal tumor location, distant metastases at presentation, presence of rhabdoid cells, a higher tumor grade, and vascular invasion. The overall survival (OS) rate at 5 years for the 44 patients was 45 %. A superficial tumor location and lymph node metastases (N1) at presentation were independently predictive of local recurrence-free survival (LRFS), and N1 and M1 tumors were independently predictive of distant metastasis-free survival and OS, respectively. The proximal subtype was associated with unfavorable LRFS and OS, although not to a statistically significant degree. CONCLUSIONS: Proximal-type ES has significantly more aggressive clinicopathological features than classic-type ES, and lymph node or distant metastasis has the most critical impact on prognosis.

Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities (JCOG0304).

OBJECTIVE: The efficacy of perioperative chemotherapy for soft tissue sarcomas is controversial and only a few prospective studies of pre-operative chemotherapy for soft tissue sarcomas in the extremities have been reported. We therefore carried out Phase II study of perioperative chemotherapy for patients with soft tissue sarcomas in the extremities. METHODS: Patients with Stage III non-round cell soft tissue sarcomas in the extremities were eligible. The patients were treated with pre-operative chemotherapy consisting doxorubicin 60 mg/m(2) and ifosfamide 10 g/m(2) for three courses. After the tumor resection, two additional courses of the same regimen were carried out. RESULTS: A total of 72 patients were enrolled and 70 patients were eligible. The median age of the patients was 49 years. The major pathological subtypes were synovial sarcoma in 20 and undifferentiated pleomorphic sarcoma in 17 patients. The protocol treatments were completed in 74% of the eligible cases. The 2 and 5-year progression-free survival rates were 75.7% (95% CI, 63.9-84.1%) and 63.8% (95% CI, 51.3-73.9%), respectively. The 5-year overall survival was 82.6% (95% CI, 71.3-89.7%). There was no treatment-related death. Grade 3 or 4 hematological toxicities (leukopenia and neutropenia) were observed in most of the patients. CONCLUSIONS: Although the toxicities of the regimen were significant, pre-operative chemotherapy followed by post-operative chemotherapy using doxorubicin and high-dose ifosfamide was feasible. The outcome of the trial for the patients with high-grade soft tissue sarcomas in the extremities was favorable, and this regimen is promising for further investigation. This trial was registered at the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) as C000000096.

Prognostic factors in elderly osteosarcoma patients: a multi-institutional retrospective study of 86 cases.

BACKGROUND: The occurrence of osteosarcoma in elderly patients has recently been increasing, and the outcome is poor. This multi-institutional retrospective study was conducted to investigate clinical features and prognostic factors in patients older than 40 years with osteosarcoma. METHODS: Patients with conventional high-grade osteosarcoma older than 40 years were recruited to this study. Secondary osteosarcoma arising from Paget's disease or irradiated bones was excluded. Information on tumor- and treatment-related factors was collected and statistically analyzed. The median follow-up was 57 months (range 8-244 months) for all surviving patients. RESULTS: A total of 86 patients were enrolled in this study. The median age at diagnosis was 61 years. Surgery and chemotherapy were conducted in 73 and 63 % of all patients, respectively. The 5-year overall and event-free survival rates were 38.8 and 34.0 %, respectively. Tumor site (extremity 57.9 %; axial 19.0 %; p < 0.0001), metastasis at diagnosis (yes 12.2 %; no 48.3 %; p < 0.0091), and definitive surgery (yes 56.2 %; no 10.6 %; p < 0.0001) were associated with overall survival. Although patients without metastasis who received definitive surgery were regarded as good candidates for chemotherapy, the addition of chemotherapy did not have any impact on the outcome (yes 63.4 %; no 65.2 %; p = 0.511). CONCLUSIONS: The present study revealed the distinct clinical features, such as the high incidence of truncal tumors or metastasis at diagnosis, in patients older than 40 years with osteosarcoma. Additionally, prognostic factor analyses revealed that tumor site, metastasis at diagnosis, definitive surgery, and surgical margins were significant prognostic factors, whereas chemotherapy did not influence survival.

Effect of Tranilast on the Frequency of Invasive Treatment for Extra-Abdominal Desmoid Fibromatosis.

BACKGROUND: Active surveillance (AS) has been suggested for managing extra-abdominal desmoid fibromatosis (EADF), but a substantial percentage of such patients transitioned to invasive secondary treatments. The anti-keloid medication tranilast is frequently used in Japan but its effectiveness for EADF is not well understood. METHODS: We retrospectively analyzed the medical records of EADF patients treated with tranilast between January 2009 and March 2021. EADF has been reported to shrink spontaneously, so the effects of all drugs must be compared with AS. To assess the effect of tranilast, we compared the clinical courses of patients receiving tranilast with those managed by AS (as identified in a systematic review). A systematic review of AS outcomes was conducted on July 22, 2021, in accordance with PRISMA guidelines. The primary endpoint was rate of conversion to secondary treatment. Secondary endpoints were progression-free survival, objective response rate (ORR), disease control rate (DCR), and adverse events. The rates of conversion to secondary treatment, ORRs, and DCRs were compared between the two groups by using the Fisher exact test. RESULTS: Eighteen patients who received tranilast as initial treatment for EADF were included. Two patients (11.1%) underwent surgical resection for treatment of tumor growth and persistent pain. The rate of conversion to secondary treatment was significantly lower for tranilast than for a pure AS approach (40.1%; p = 0.01). ORR and DCR did not differ between groups. CONCLUSIONS: Tranilast was better than AS for initial management of EADF.

Fluorodeoxyglucose positron emission tomography (FDG/PET) shows the effect of carbon-ion radiotherapy (CIRT); with pathologic confirmation.

Response evaluation of carbon-ion radiotherapy poses a diagnostic challenge. Due to its functional aspects, fluorodeoxyglucose positron emission tomography (FDG/PET) has a role in the diagnosis of photon radiation therapy. In addition, several studies suggested that FDG/PET may be useful to select the optimal site for performing a diagnostic biopsy. Here, we report a 73-year-old female in which FDG/PET was effective in determining the recurrence of liposarcoma and the therapeutic effect. Based on the results of FDG/PET, we could make a pathologic definitive diagnosis and selectively performing carbon-ion radiotherapy for active tumors.