Treatment-induced pathologic necrosis is an independent predictor of both local recurrence and overall survival in patients who receive neoadjuvant therapy for high-grade extremity soft tissue sarcomas. A complete pathologic response (> or = 95% pathologic necrosis) correlated with a significantly lower rate of local recurrence and improved overall survival.

Ifosfamide-based chemotherapy was associated with an improved DSS in adult patients with high-risk, primary, extremity, synovial sarcoma and should be considered in the treatment of such patients.

Liposarcoma (LPS) is the most common type of soft tissue sarcoma accounting for 20% of all adult sarcomas. Due to absence of clinically effective treatment options in inoperable situations and resistance to chemotherapeutics, a critical need exists to identify novel therapeutic targets. We analyzed LPS genomic landscape using SNP arrays, whole exome sequencing and targeted exome sequencing to uncover the genomic information for development of specific anti-cancer targets. SNP array analysis indicated known amplified genes (MDM2, CDK4, HMGA2) and important novel genes (UAP1, MIR557, LAMA4, CPM, IGF2, ERBB3, IGF1R). Carboxypeptidase M (CPM), recurrently amplified gene in well-differentiated/de-differentiated LPS was noted as a putative oncogene involved in the EGFR pathway. Notable deletions were found at chromosome 1p (RUNX3, ARID1A), chromosome 11q (ATM, CHEK1) and chromosome 13q14.2 (MIR15A, MIR16-1). Significantly and recurrently mutated genes (false discovery rate < 0.05) included PLEC (27%), MXRA5 (21%), FAT3 (24%), NF1 (20%), MDC1 (10%), TP53 (7%) and CHEK2 (6%). Further, in vitro and in vivo functional studies provided evidence for the tumor suppressor role for Neurofibromin 1 (NF1) gene in different subtypes of LPS. Pathway analysis of recurrent mutations demonstrated signaling through MAPK, JAK-STAT, Wnt, ErbB, axon guidance, apoptosis, DNA damage repair and cell cycle pathways were involved in liposarcomagenesis. Interestingly, we also found mutational and copy number heterogeneity within a primary LPS tumor signifying the importance of multi-region sequencing for cancer-genome guided therapy. In summary, these findings provide insight into the genomic complexity of LPS and highlight potential druggable pathways for targeted therapeutic approach.

Background. This report describes the unusually high response rate of metastatic synovial sarcoma to high dose ifosfamide (14–18 g/m2) when that drug was used to treat 13 consecutive patients with recurrent metastatic synovial sarcoma before surgery (or thoracotomies) to provide optimal salvage therapy for these patients. Patients and Methods. Thirteen patients with recurrent or pulmonary metastatic synovial sarcoma seen at the Cedars‐Sinai Comprehensive Cancer Center (Los Angeles, CA) from April, 1989 through January, 1993 were treated with high dose ifosfamide (14–18 g/m2). Ifosfamide was infused at the dose of 2 g/m2 over a 4‐hour bolus infusion, followed by 2‐g/m2 24‐hour continuous infusions of ifosfamide, for a total of 14 or 18 g/m2 (6–8 days). Mesna (Mesnex, Bristol‐Myers Oncology, Princeton, NJ) was infused with the ifosfamide at equimolar doses. Supplemental sodium bicarbonate (180 mEq) was given daily to prevent severe acidosis. Nine of the thirteen patients were treated with prior chemotherapy for their primary tumors. Prior chemotherapy consisted of doxorubicin (Adriamycin, Adria Labs, Dublin, OH) in all patients and doxorubicin combined with cisplatin in eight of them. Results. All 13 patients had objective responses to high dose ifosfamide chemotherapy. There were nine partial responses and four complete responses. Five of the patients died of disease at 20–40 months (median, 27 months) from initial therapy. Eight patients have survived from 2 to 43 months (median, 20 months) from initial therapy, and three of these patients are disease free. Those patients surviving disease free had successful surgical removal of their residual metastatic disease after chemotherapy. Conclusion. Metastatic synovial sarcoma appears to be particularly sensitive to high dose ifosfamide chemotherapy. This experience suggests that there is a role for high dose ifosfamide chemotherapy in preoperative and postoperative adjuvant chemotherapy for primary synovial sarcoma, which is usually always a high grade malignant lesion with a poor prognosis after surgery alone.

Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators facilitating the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET protein inhibitor, has antiproliferative activity against many cancers, mainly through inhibition of c-MYC and upregulation of p21. In this research, we investigated the use of JQ1 for human osteosarcoma (OS) treatment. JQ1 significantly inhibited the proliferation and survival of OS cells inducing G1 cell cycle arrest, premature senescence, but little effect on apoptosis. Interestingly, c-MYC protein levels in JQ1-treated cells remained unchanged, whereas the upregulation of p21 protein was still observable. Although effective in vitro, JQ1 alone failed to reduce the size of the MNNG/HOS xenografts in immunocompromised mice. To overcome the resistance of OS cells to JQ1 treatment, we combined JQ1 with rapamycin, an mammalian target of rapamycin (mTOR) inhibitor. JQ1 and rapamycin synergistically inhibited the growth and survival of OS cells in vitro and in vivo. We also identified that RUNX2 is a direct target of bromodomain-containing protein 4 (BRD4) inhibition by JQ1 in OS cells. Chromatin immunoprecipitation (ChIP) showed that enrichment of BRD4 protein around RUNX2 transcription start sites diminished with JQ1 treatment in MNNG/HOS cells. Overexpression of RUNX2 protected JQ1-sensitive OS cells from the effect of JQ1, and siRNA-mediated inhibition of RUNX2 sensitized the same cells to JQ1. In conclusion, our findings suggest that JQ1, in combination with rapamycin, is an effective chemotherapeutic option for OS treatment. We also show that inhibition of RUNX2 expression by JQ1 partly explains the antiproliferative activity of JQ1 in OS cells.

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BACKGROUND: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of 50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2-and 5-year survival rates were determined. RESULTS: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2-and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;123:90-7.

Background. The effectiveness of adjuvant chemotherapy in soft tissue sarcomas remains a matter of controversy. The authors reviewed their experience with 14 patients with localized disease treated with intensive doxorubicin‐cisplatin‐ifosfamide‐based chemotherapy. Methods. Fourteen patients with newly diagnosed nonmetastatic synovial sarcoma seen between 1985 and 1992 received intensive chemotherapy and local radiation therapy before surgical resection, followed in most patients by intensive postoperative chemotherapy. Chemotherapy included high‐dose cisplatin and doxorubicin or high‐dose ifosfamide (14 g/m2) and cisplatin with doxorubicin. Results. One (7%) patient had a local recurrence during the study interval and remains free of disease 35 months after re‐excision and a second course of intensive chemotherapy. All other 13(93%) patients remained continuously free of disease after a median follow‐up of 37 months (range, 6–85 months). There were no deaths. General toxicity was the reason cited by seven patients who elected not to receive postoperative chemotherapy. For the remaining seven patients who elected to continue treatment, there were only two hospitalization admissions for neutropenia and fever. There was no significant cardiotoxicity, nephrotoxicity, or neurotoxicity. Conclusion. Additional studies using new intensive systemic adjuvant therapies are needed to determine whether the encouraging results of this experience can be translated into prolonged disease‐free and overall survival.