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Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7–4·8) for pazopanib compared with 1·6 months (0·9–1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24–0·40; p<0·0001). Overall survival was 12·5 months (10·6–14·8) with pazopanib versus 10·7 months (8·7–12·8) with placebo (HR 0·86, 0·67–1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. GlaxoSmithKline.

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. 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/m2 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. 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%]). 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. Taiho Pharmaceutical Co., Ltd.

Background/Objectives: Surgery remains the mainstay of treatment for retroperitoneal sarcoma (RPS); however, definitive therapeutic strategies for patients with insufficient surgical margins and unresectable disease owing to locally advanced RPS remain unclear. Carbon ion radiotherapy (CIRT) has been employed in patients with unresectable RPS. This study aimed to evaluate the effectiveness of CIRT in this patient population. Methods: A retrospective analysis was conducted in 76 patients with unresectable RPS treated with CIRT. Of these, 95% had a confirmed prognosis until 2022. In 74 patients, the prescribed relative biological effectiveness dose was 70.4 Gy, delivered in 16 fractions over 4 weeks. Respiratory gating was used, and spot scanning irradiation has been performed in all patients since 2016. Results: The 3- and 5-year overall survival rates for the entire cohort were 68.3% and 49.4%, respectively, with a median overall survival time of 58.1 months. The 3- and 5-year local control rates were 79.0% and 72.0%, respectively. Among 47 naïve patients with treatment-naïve tumors, the 3- and 5-year abdominal recurrence-free survival rates were 51.1% and 29.1%, respectively. Late adverse events of grade 3 or higher occurred in 4 (5.2%) patients. Conclusions: CIRT represents a definitive treatment option for patients with unresectable RPS. In the future, multicenter studies should be conducted to evaluate the effectiveness of CIRT for RPS in larger patient cohorts.

Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with a poor prognosis and, thus, novel therapeutic strategies for SS are urgently required. In the present study, we investigated the functional and therapeutic relevance of hepatocyte growth factor (HGF)/c‐MET signaling in SS. Both HGF and c‐MET were highly expressed in Yamato‐SS cells, resulting in activation of c‐MET and its downstream AKT and extracellular signal‐regulated kinase signaling pathways, whereas c‐MET was expressed but not activated in SYO‐1 or HS‐SY‐II cells. c‐MET‐activated Yamato‐SS cells showed higher anchorage‐independent growth ability and less sensitivity to chemotherapeutic agents than did c‐MET‐inactivated SYO‐1 or HS‐SY‐II cells. INC280, a selective c‐MET inhibitor, inhibited growth of Yamato‐SS cells both in vitro and in vivo but not that of SYO‐1 or HS‐SY‐II cells. INC280 induced cell cycle arrest and apoptosis, and blocked phosphorylation of c‐MET and its downstream effectors in Yamato‐SS cells. Co‐expression of HGF and c‐MET in SS clinical samples correlated with a poor prognosis in patients with SS. Taken together, activation of HGF/c‐MET signaling in an autocrine fashion leads to an aggressive phenotype in SS and targeting of this signaling exerts superior antitumor effects on c‐MET‐activated SS. HGF/c‐MET expression status is a potential biomarker for identification of SS patients with a worse prognosis who can benefit from c‐MET inhibitors. HGF/c‐MET signaling is a promising therapeutic target in a subset of patients with SS. Inhibition of this signaling could be a novel strategy in future clinical practice for treatment of refractory SS.

Background Limb-salvage reconstruction for periacetabular malignant tumors is one of the most challenging problems in orthopaedic oncology. Reconstructive options include resection arthroplasty, endoprosthesis, allograft, recycled autobone graft, arthrodesis, and pseudarthrosis. However, no standard procedure exists because of rarity and clinical variability of the disease. We previously developed a megaprosthetic system with a constrained total hip mechanism (C-THA). Questions/purposes We evaluated (1) survival of patients and C-THA; (2) postoperative function; and (3) complications. Methods We retrospectively reviewed 25 patients with primary periacetabular tumors treated using C-THA between 1985 and 2009. There were 18 male and seven female patients with a median age of 44 years (range, 16–72 years). They included 11 chondrosarcomas, eight osteosarcomas, two giant cell tumors of bone (one locally aggressive benign, one malignant), and others in four. Surgical margin was wide in 18 patients, marginal in five, and intralesional in two. The minimum postoperative followup for survivors was 32 months (median, 163 months; range, 32–285 months). Results The 10-year overall survival rate of all patients was 47%. C-THA implants survived in 19 of 25 patients at last followup. Twenty-one patients acquired ambulatory activity. There were seven local recurrences, resulting in hemipelvectomy in one patient. Postoperative complications included deep infection in eight of the 25 patients, dislocation in four, and aseptic loosening in two, necessitating five revision surgeries and three implant removals. Conclusions Our observations suggest C-THA using an acetabular reconstruction cup is a useful reconstructive option after resection of periacetabular malignant tumors despite frequent postoperative complications. Level of Evidence Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Through the development of the first molecular targeted drug in this niche field, pazopanib became the first approved molecular targeted drug for non-adipocytic soft tissue sarcoma, after publication of the results of a randomised, double-blind, placebo-controlled phase 3 trial (PALLETTE).3 Although oral pazopanib resulted in significant efficacy in progression-free survival compared with placebo, it is more commonly used as a second-line treatment following previous chemotherapy (such as doxorubicin). In soft tissue sarcomas, several rare histological subtypes have specific fusion genes, including clear cell sarcoma (EWSR1–ATF1), synovial sarcoma (SS18–SSX), alveolar rhabdomyosarcoma (PAX3, PAX7–FOXO1), myxoid liposarcoma (FUS–DDIT3), Ewing family tumours (EWSR1–FLI1, ERG, ETV, and FEV), alveolar soft part sarcoma (ASPL–TFE3), inflammatory myofibroblastic tumour (TMP3, TMP4–ALK), infantile fibrosarcoma (ETV6–NTRK3), Ewing sarcoma-like small blue round cell tumour (CIC–DUX4), and solitary fibrous tumour (NAB2–STAT6).8 Although these fusion genes were identified decades ago, the molecular mechanism is still not used as a drug development target. Similar to the approval of pembrolizumab for microsatellite instability-high tumours,9 it might be necessary to investigate the oncogenetic signalling pathway of each rare entity and develop a new statistical strategy for clinical trials in these rare populations. [...]for specific entities, the first-line drug might change from doxorubicin to molecular targeted drugs.

Approximately 60–70% of EWSR1 -negative small blue round cell sarcomas harbour a rearrangement of CIC , most commonly CIC-DUX4 . CIC-DUX4 sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The CIC-DUX4 fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a DUX4 pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both in vitro and in vivo . Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. Our model will be a useful modality for investigating the molecular pathology and therapy of CDS.

Carbon ion radiotherapy is known for its high‐precision dose distribution and high biological effectiveness. We evaluated the results of carbon ion radiotherapy in 128 patients with unresectable localized axial soft tissue sarcoma at a single institution. The patients’ median age was 54 years, and the median follow‐up period was 49.4 (range 6.4‐146.4) months. The median tumor volume was 356 cm3. The 5‐year local control, overall survival, and disease‐free survival rates were 65%, 46%, and 39%, respectively. In the univariate analysis, tumor volume, local control, and incidences of metastases were significantly related to overall survival. In the multivariate analysis, tumor volume and local control were significantly related to overall survival. We did not find any factors related to local control. Five patients required surgical intervention because of adverse events in the bones. Carbon ion radiotherapy may be a treatment option for unresectable axial soft tissue sarcoma. The result of carbon ion radiotherapy in 128 patients with unresectable localized axial soft tissue sarcoma was evaluated. Carbon ion radiotherapy will be a treatment option for unresectable axial soft tissue sarcoma.

Synovial sarcoma (SS) is a malignant soft‐tissue tumor characterized by the recurrent chromosomal translocation SS18–SSX. Vascular endothelial growth factor (VEGF)‐targeting anti‐angiogenic therapy has been approved for soft‐tissue sarcoma, including SS; however, the mechanism underlying the VEGF signal for sarcomagenesis in SS is unclear. Here, we show that SS18–SSX directs the VEGF signal outcome to cellular growth from differentiation. Synovial sarcoma cells secrete large amounts of VEGF under spheroid culture conditions in autocrine fashion. SS18–SSX knockdown altered the VEGF signaling outcome, from proliferation to tubular differentiation, without affecting VEGF secretion, suggesting that VEGF signaling promoted cell growth in the presence of SS18–SSX. Thus, VEGF inhibitors blocked both host angiogenesis and spheroid growth. Simultaneous treatment with VEGF and chemokine (C‐X‐C motif) (CXC) ligand 12 and CXC receptor 4 inhibitors and/or ifosfamide effectively suppressed tumor growth both in vitro and in vivo. SS18–SSX directs the VEGF signal outcome from endothelial differentiation to spheroid growth, and VEGF and CXC receptor 4 are critical therapeutic targets for SS. This study showed link between SS18‐SSX and VEGF signal contributing tumor growth, and presented novel combined therapeutic approach on synovial sarcoma.