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Background osteosarcoma is a rare, primary malignant bone tumour with limited available treatments for advanced or recurrent disease, resulting in a poor prognosis for patients. TAS-115 is a novel tyrosine kinase inhibitor under investigation in a phase I study in patients with solid tumours. We report data of osteosarcoma patients in the expansion cohort of this ongoing study. Patients and methods an analysis of this multicentre, open-label study was performed 6 months after the final patient was enrolled, and included patients aged ≥15 years, with unresectable or recurrent osteosarcoma, and who had refractory to standard therapy or for whom no standard therapy was available. TAS-115 650 mg/day was orally administered in a 5 days on/2 days off schedule. Results a total of 20 patients with osteosarcoma were enrolled. The most common adverse drug reactions (ADRs) were neutrophil count decreased (75%), aspartate aminotransferase increased (50%), and platelet count decreased (50%); 85% of patients had grade ≥ 3 ADRs. Long-term disease control (>1 year) with TAS-115 was achieved in three patients. The best overall response was stable disease (50%); no patient achieved a complete or partial response. Median progression-free survival was 3 months; 4-month and 12-month progression-free rates were 42% and 31%, respectively. Conclusion the safety and tolerability of TAS-115 and long-term disease stability for patients with unresectable or recurrent osteosarcoma were confirmed in this study, suggesting that TAS-115 is a promising novel therapy for advanced osteosarcoma patients. Trial registration number: JapicCTI-132333 (registered on November 8, 2013)., (© 2021. The Author(s).)

TAS-115 is a novel MET, VEGFR, FMS and PDGFR inhibitor, developed to improve the continuity of drug administration with a relatively short half-life. We assessed its tolerability, safety, pharmacokinetics, efficacy, and pharmacodynamics in patients with solid tumors. This open-label, dose-escalation phase I study of TAS-115 consisted of three parts: part 1 (TAS-115 was administered orally once daily [SID]); part 2 and an expansion part (SID in a 5 days on/2 days off [5-on/2-off] schedule for 21 days per cycle). In part 1 (200-800 mg SID administered to 21 patients), systemic exposure after single administration increased almost dose-proportionally. Three dose-limiting toxicities (DLTs) were observed in three patients: grade 3 rash (650 mg), thrombocytopenia with bleeding, and rash (800 mg). The maximum tolerated dose (MTD) was determined as 650 mg SID. In part 2, the 5-on/2-off schedule was evaluated at the MTD to improve treatment exposure. No DLTs were observed and no patients required treatment interruption in cycle 1. During part 2 and the expansion part (N = 61), grade ≥3 treatment-related adverse events were reported in 47 patients, with neutropenia (24.6%), hypophosphatemia (21.3%), anemia, and thrombocytopenia (14.8% each), and leukocytopenia (11.5%) occurring in ≥10% of patients. The best overall response was stable disease in 31 of 82 patients (37.8%). An apparent reduction in fluorodesoxyglucose-uptake and bone scan index was observed in some patients. TAS-115 was generally well tolerated, with manageable toxicities and recommended phase II dose was estimated as 650 mg SID, 5-on/2-off. Furthermore, promising antitumor activity was observed.

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).

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 < 0.001)., Conclusion: The recurrence rate of GCTB was still high after curettage, especially in Campanacci grade III, and improvements in the therapeutic strategy are needed in this cohort. There is a possibility that a sufficient dose of preoperative denosumab can reduce recurrence after curettage. Recently, we have started a clinical trial, JCOG1610, to investigate the efficacy of preoperative denosumab in patients who can be treated with curettage in GCTB.

Synovial sarcoma (SS) is an aggressive soft tissue tumour with poor prognosis. Using five human SS cell lines, we examined the cytotoxic effects of trabectedin (ET-743; Yondelis(®)), a novel marine natural product, which was approved in Europe for the treatment of soft tissue sarcomas (STS). The significant growth inhibitory effects were observed in all SS cell lines below nanomolar concentration of trabectedin. Furthermore, trabectedin significantly suppressed the tumour growth in xenograft models. Flow cytometer analysis in vitro and immunohistochemical analysis in vivo revealed its effect of cell cycle inhibition and apoptosis induction. We also examined the expression of ERCC1, 5 and BRCA1 in SS cell lines and clinical samples, and majority of them showed highly trabectedin-sensitive pattern as previously reported in other cancers. Our preclinical data indicated that trabectedin could be a promising therapeutic option for patients with SS.

Background: Clear cell sarcoma (CCS) is a therapeutically unresolved, aggressive, soft tissue sarcoma (STS) that predominantly affects young adults. This sarcoma is defined by t(12;22)(q13;q12) translocation, which leads to the fusion of Ewing sarcoma gene (EWS) to activating transcription factor 1 (ATF1) gene, producing a chimeric EWS-ATF1 fusion gene. We established a novel CCS cell line called Hewga-CCS and developed an orthotopic tumor xenograft model to enable comprehensive bench-side investigation for intensive basic and preclinical research in CCS with a paucity of experimental cell lines., Methods: Hewga-CCS was derived from skin metastatic lesions of a CCS developed in a 34-year-old female. The karyotype and chimeric transcript were analyzed. Xenografts were established and characterized by morphology and immunohistochemical reactivity. Subsequently, the antitumor effects of pazopanib, a recently approved, novel, multitargeted, tyrosine kinase inhibitor (TKI) used for the treatment of advanced soft tissue sarcoma, on Hewga-CCS were assessed in vitro and in vivo., Results: Hewga-CCS harbored the type 2 EWS-ATF1 transcript. Xenografts morphologically mimicked the primary tumor and expressed S-100 protein and antigens associated with melanin synthesis (Melan-A, HMB45). Pazopanib suppressed the growth of Hewga-CCS both in vivo and in vitro. A phospho-receptor tyrosine kinase array revealed phosphorylation of c-MET, but not of VEGFR, in Hewga-CCS. Subsequent experiments showed that pazopanib exerted antitumor effects through the inhibition of HGF/c-MET signaling., Conclusions: CCS is a rare, devastating disease, and our established CCS cell line and xenograft model may be a useful tool for further in-depth investigation and understanding of the drug-sensitivity mechanism.

We examined efficacy of the mTOR inhibitor RAD001 to seek novel therapies for synovial sarcoma (SS). Although RAD001 had significant anti-tumor effects, its sensitivity differed among cell lines. Phospho-receptor tyrosine kinase (RTK) array analyses revealed c-MET phosphorylation in highly mTOR inhibitor-sensitive cells and PDGFRα (which induces intrinsic resistance to mTOR inhibitor) activation in less sensitive cells. Combined treatment with RAD001 and the PDGFR inhibitor pazopanib showed anti-tumor effects in xenograft models with less sensitive cells. Thus, evaluating activated RTKs in clinical samples may predict sensitivity to mTOR inhibitors, raising the possibility of a tailored therapy for SS., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A 70-year-old Japanese man was re-admitted because of relapse of adenocarcinoma of the lung. He received daily administration of gefitinib as second-line chemotherapy. He was given a diagnosis of drug-induced lung disease due to gefitinib on day 6 because of hypoxemia and ground glass opacities in the bilateral lung fields. There was no response to corticosteroid pulse therapy. Continuous administration of sivelestat was intravenously added from day 9. Although mechanical ventilation was required for 10 days, lung infiltrates and hypoxia gradually improved. Sivelestat and corcicosteroid was apparently effective in this case and may be useful treatment for drug-induced lung disease due to gefitinib.

A 41-year-old man with productive cough was admitted to our hospital. His chest roentgenogram showed multiple small nodules in the bilateral lung fields. The nodules were revealed as intrapulmonary metastases of the adenocarcinoma of the lung. Systemic chemotherapy with paclitaxel and carboplatin was not effective, and continuous oral gefitinib therapy was initiated. Twenty-one days later, spontaneous pneumothorax was found in the left lung, and four days after that, in the right lung as well. The extent of the pneumothorax was slight; therefore, he recovered without drainage within several days. Spontaneous pneumothorax, especially bilateral pneumothorax, is a rare complication of chemotherapy for lung cancer.