Comparative Assessment of Antitumor Effects and Autophagy Induction as a Resistance Mechanism by Cytotoxics and EZH2 Inhibition in INI1-Negative Epithelioid Sarcoma Patient-Derived Xenograft.

Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline- and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin-ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin-ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.

PD-L1 assessment in pediatric rhabdomyosarcoma: a pilot study.

BACKGROUND: Rhabdomyosarcomas (RMSs) are the most frequent soft tissue sarcoma in children and adolescents, defined by skeletal muscle differentiation and the status of FOXO1 fusions. In pediatric malignancies, in particular RMS, scant and controversial observations are reported about PD-L1 expression as a putative biomarker and few immune checkpoint clinical trials are conducted. METHODS: PD-L1 assessment was evaluated by immunohistochemistry (IHC) utilizing two anti-PDL1 antibodies, in a pilot cohort of 25 RMS. Results were confirmed in primary and commercial RMS cell lines by cytofluorimetric analysis and IHC. RESULTS: PD-L1 expression was detectable, by both anti-PD-L1 antibodies, in the immune contexture of immune cells infiltrating and/or surrounding the tumor, in 15/25 (60%) RMS, while absent expression was observed in neoplastic cells. Flow cytometry analysis and PD-L1 IHC of commercial and primary RMS cell lines confirmed a very small percentage of PD-L1 positive-tumor cells, under the detection limits of conventional IHC. Interestingly, increased PD-L1 expression was observed in the immune contexture of 4 RMS cases post chemotherapy compared to their matched pre-treatment samples. CONCLUSION: Here we identify a peculiar pattern of PD-L1 expression in our RMS series with scanty positive-tumor cells detected by flow cytometry, and recurrent expression in the immune cells surrounding or infiltrating the tumor burden.

High-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria.

PURPOSE: To compare radiologic response as defined according to both Response Evaluation Criteria in Solid Tumors (RECIST) and the new Choi criteria recently proposed for gastrointestinal stromal tumors with pathologic response in high-grade soft-tissue sarcomas (STSs) treated with preoperative chemotherapy and radiation therapy. MATERIALS AND METHODS: The institutional ethical committee approved the trial in which patients were enrolled. Signed informed consent was obtained. Thirty-seven patients (21 men, 16 women; mean age, 44.2 years) enrolled in a collaborative randomized trial on preoperative chemotherapy and radiation therapy in localized high-risk STS at a single institution were selected for this retrospective analysis. Tumor response to preoperative treatment was assessed by using both RECIST and Choi criteria at computed tomography (CT) and was adapted to be used at magnetic resonance (MR) imaging. Pathologic response was assessed as either good or very good. Sensitivity, specificity, and predictive value of RECIST and Choi criteria were calculated with pathologic response as the reference standard and were reported with 95% confidence intervals. RESULTS: For 28 patients without synovial sarcomas, sensitivity of RECIST versus adapted Choi criteria was 32.0% versus 88.0% for good response and 41.2% versus 82.4% for very good response, respectively; specificity for pathologic response was 100% versus 100% for not a good response and 90.9% versus 27.3% for not a very good response, respectively. In synovial sarcoma, the nontreatment-related neoplastic cystic component of the tumor was a major obstacle for both RECIST and Choi criteria. CONCLUSION: In STS treated with chemotherapy and radiation therapy, tumor size may be insufficient to render actual tumor response. Tumor attenuation at CT or tumor contrast material enhancement at MR imaging may complement tumor size, thus making Choi criteria more predictive of pathologic response.