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Background: Myxoid liposarcoma is a histological subtype of liposarcoma particularly sensitive to trabectedin. In clinical use this drug does not cause cumulative toxicity, allowing prolonged treatment, generally until disease progression. No other effective therapies are available for trabectedin-resistant patients., Methods: Through repeated in vivo treatment in athymic nude mice, we have obtained a patient-derived xenograft with acquired resistance to trabectedin., Results: At basal level, the morphology of the resistant and sensitive models did not differ, in keeping with the finding that the transcriptional profiles of the resistant and sensitive tumours were very similar. After trabectedin treatment adipogenesis was induced in the parental xenograft but not in the resistant one, as assessed by pathological and molecular analysis. A defective transcription-coupled-nucleotide excision repair in the resistant tumour due to mutation of the UVSSA gene may be implicated in the mechanism of resistance., Conclusions: This is the first in vivo model of myxoid liposarcoma with acquired resistance to trabectedin. Although further studies are necessary to characterise the resistance mechanisms, this is a useful tool for studying new therapeutic strategies to overcome trabectedin resistance in patients.

Trabectedin has been approved for second-line treatment of soft tissue sarcomas. However, its efficacy to target sarcoma initiating cells has not been addressed yet. Here, we used pioneer models of myxoid/round cell liposarcoma (MRCLS) and undifferentiated pleomorphic sarcoma (UPS) developed from transformed human mesenchymal stromal/stem cells (MSCs) to evaluate the effect of trabectedin in the cell type responsible for initiating sarcomagenesis and their derived cancer stem cells (CSC) subpopulations. We found that low nanomolar concentrations of trabectedin efficiently inhibited the growth of sarcoma-initiating cells, induced cell cycle arrest, DNA damage and apoptosis. Interestingly, trabectedin treatment repressed the expression of multiple genes responsible for the development of the CSC phenotype, including pluripotency factors, CSC markers and related signaling pathways. Accordingly, trabectedin induced apoptosis and reduced the survival of CSC-enriched tumorsphere cultures with the same efficiency that inhibits the growth of bulk tumor population. In vivo, trabectedin significantly reduced the mitotic index of MRCLS xenografts and inhibited tumor growth at a similar extent to that observed in doxorubicin-treated tumors. Combination of trabectedin with campthotecin (CPT), a chemotherapeutic drug that shows a robust anti-tumor activity when combined with alkylating agents, resulted in a very strong synergistic inhibition of tumor cell growth and highly increased DNA damage and apoptosis induction. Importantly, the enhanced anti-tumor activity of this combination was also observed in CSC subpopulations. These data suggest that trabectedin and CPT combination may constitute a novel strategy to effectively target both the cell-of-origin and CSC subpopulations in sarcoma., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Mediastinal liposarcomas (LPS) are rare tumours. We report a case of primary myxoid LPS in a 22-year-old woman suffering from cough, dyspnoea on exercise and asthenia for 3 weeks. Thoracic MRI showed a large tumour on the right side. After neoadjuvant chemotherapy, a complete resection was performed, followed by adjuvant thoracic irradiation. Eighteen months after the diagnosis, no sign of recurrence was detected. Mediastinal LPS include a heterogeneous group of bulky tumours, the progression of which depends on the histological type. The prognosis is dominated by the operability of the tumour. Adjuvant therapies are not established., (Copyright © 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Myxoid liposarcoma (ML) is the most common type of liposarcoma. It has been classified as an intermediate grade tumor with a definite metastatic potential but a relatively indolent natural history. Little is known about its sensitivity to chemotherapy., Method: The authors reviewed their experience with chemotherapy in ML from 1986 to 1992. The patient population was identified through a search of the database maintained by the Department of Melanoma-Sarcoma Medical Oncology of the M.D. Anderson Cancer Center., Results: Forty-four patients each with a histologically confirmed diagnosis of ML were identified. Twenty-one were treated with chemotherapy. The median age was 45 years (31-69 years); there were 14 men and 7 women. The ML in 19 patients was in the lower extremity, one in the head and neck, and one pelvic. The median size of the primary tumor was 15 cm (range, 7-48 cm) in maximum dimension. Of the 18 patients who received doxorubicin- and dacarbazine-based chemotherapy as a frontline regimen [median of 3 (2-9) cycles] and were evaluable for response, 8 (1 completed response, 7 partial responses) achieved an objective response (44%, 95% confidence interval 21-67%). Two of the remaining three patients who were also treated with a similar regimen were not evaluable for response (one received chemotherapy postoperatively, and the other received concomitant radiation and doxorubicin), and the third patient received ifosfamide as frontline chemotherapy because of a significant cardiac history. Seven patients received chemotherapy in the neoadjuvant setting, 13 for recurrent or metastatic disease, and 1 postoperatively after complete tumor resection. At the last follow-up, 10 patients were alive with no evidence of disease, 3 were alive with disease, and 8 had died. The median follow-up was 51 months (range, 6-199 months) from diagnosis., Conclusion: The authors conclude that doxorubicin- and dacarbazine-based chemotherapy is effective in the treatment of ML.