Dataset Information

Complete Purging of Ewing Sarcoma Metastases from Human Ovarian Cortex Tissue Fragments by Inhibiting the mTORC1 Signaling Pathway.

ABSTRACT: Restoration of fertility by autologous transplantation of ovarian cortex tissue in former cancer patients may lead to the reintroduction of malignancy via the graft. Pharmacological ex vivo purging of ovarian cortex fragments prior to autotransplantation may reduce the risk of reseeding the cancer. In this study we have investigated the capacity of Everolimus (EVE), an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, to eradicate Ewing's sarcoma (ES) from ovarian tissue by a short-term ex vivo treatment. Exposure of experimentally induced ES tumor foci in ovarian tissue to EVE for 24 h completely eliminated the malignant cells without detrimental effects on follicle morphology, survival or early folliculogenesis. This indicates that effective purging of ovarian cortex tissue from contaminating ES tumor foci is possible by short-term exposure to EVE.

SUBMITTER: Peek R

PROVIDER: S-EPMC8509560 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Complete Purging of Ewing Sarcoma Metastases from Human Ovarian Cortex Tissue Fragments by Inhibiting the mTORC1 Signaling Pathway.

Peek Ronald R Eijkenboom Lotte L LL Braat Didi D M DDM Beerendonk Catharina C M CCM

Journal of clinical medicine 20210924 19

Restoration of fertility by autologous transplantation of ovarian cortex tissue in former cancer patients may lead to the reintroduction of malignancy via the graft. Pharmacological ex vivo purging of ovarian cortex fragments prior to autotransplantation may reduce the risk of reseeding the cancer. In this study we have investigated the capacity of Everolimus (EVE), an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, to eradicate Ewing's sarcoma (ES) from ovar ...[more]

PMID: 34640378

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Project description:BackgroundEwing sarcoma (ES) is sensitive to systemic therapy, including chemotherapy and anti-angiogenesis Tyrosine Kinase Inhibitors(aaTKIs). However, the prognosis of patients with metastatic disease remains poor. Recurrence or distant metastasis after a complete response (CR) or near-CR due to systemic therapy is not rare.MethodsWe reviewed data from 187 ES patients between 2014-2019 treated at a single institute in China. Patients with extensive lung/pleural metastases (L/Pmeta) who had a CR or near-CR after first- or second-line chemotherapy with or without aaTKIs were retrospectively enrolled. Event-free survival (EFS) and overall survival (OS) were determined using the Kaplan-Meier method. For patients who had L/P recurrence, images were reviewed to define the exact location of each recurrent lesion, compared with the primary L/P lesion before chemotherapy and summarized as the relapse pattern.ResultsSeventeen patients and 21 cases of CR/nCR (5 by VDC/IE, 3 by VIT, and 13 by AVI) were finally analyzed. Median follow-up for surviving patients was 39.6 (range, 14.5-60.9) months. Median EFS and OS were 9.3 (95% confidence interval [CI], 2.0-16.6) months and 37.5 (95% CI, 21.8-53.1) months, respectively. The 2-year EFS was 19% and the 2-year OS was 70.6%, respectively. Most patients (82.4%) received whole lung irradiation (WLI). Lung/pleural relapse occurred in 71.4% (15/21) of CR/nCR cases. Most notably, all recurrent lesions exactly coincided with the original metastatic lesions before chemotherapy (exactly in situ) in 9 of the 15 recurrent cases, which was thus the major relapse pattern, whereas 42.9% had distant metastases other than L/Pmeta.ConclusionsSurvival of ES patients with extensive L/Pmeta remains poor, even if they have a CR after systemic therapy. Recurrence exactly in situ is the major relapse pattern. WLI is not sufficient to prevent local recurrence in lung or pleura. More aggressive local treatment for metastatic lesions is warranted.

Project description:Adamantinoma-like Ewing sarcoma (ALES) has traditionally been considered a variant of Ewing sarcoma because it generally harbors EWSR1::FLI1 fusions despite showing diffuse positivity for keratins and p40. However, it has become increasingly recognized that different tumors can have identical translocations, including shared fusions between carcinomas and sarcomas, raising questions as to whether ALES might represent a separate entity. Using methylation profiling, we further explored the relationship between Ewing sarcoma and ALES. The archives of multiple institutions were searched for candidate cases of ALES. DNA methylation profiling was performed and results were compared to corresponding data from conventional Ewing sarcoma. Twelve cases of ALES (5 previously reported) were identified in 10 men and 2 women (aged 20-72 years; median age, 41.5 years). Cases included tumors arising in the parotid gland (3), sinonasal cavity (2), submandibular gland (2), thyroid gland (1), neck (1), gingiva (1), hypopharynx (1), and mandible (1). Histologic review consistently showed sheets and nests of basaloid cells within a fibromyxoid or hyalinized stroma. All tumors were positive for at least 1 keratin and CD99 expression, whereas all 10 cases tested were positive for p63 or p40; S100 protein expression was noted in 2 cases. Cases harbored either EWSR1::FLI1 fusions (n = 6), FUS::FLI1 fusions (n = 1), and/or EWSR1 rearrangements (n = 6). Methylation profiling was successful in 11/12 cases evaluated. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) of DNA methylation data revealed a distinct methylation cluster for all 11 cases, including the tumor with the FUS::FLI1 fusion, which clearly segregated them from the conventional Ewing sarcoma. Follow-up (n = 11, 1-154 months) revealed that 4 patients experienced recurrence and 6 developed metastatic disease. ALES demonstrates a distinct methylation signature from conventional Ewing sarcoma. This finding adds to the distinctive immunoprofile of ALES, suggesting that these 2 tumors should be considered distinct entities rather than histologic extremes of the same disease.

Dataset Information

Complete Purging of Ewing Sarcoma Metastases from Human Ovarian Cortex Tissue Fragments by Inhibiting the mTORC1 Signaling Pathway.

Publications

Complete Purging of Ewing Sarcoma Metastases from Human Ovarian Cortex Tissue Fragments by Inhibiting the mTORC1 Signaling Pathway.

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