Prafull Ghatage

Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma

Abstract Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial–mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Feasibility of ERAS guidelines for cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (CRS-HIPEC): An international multicenter study

Enhanced Recovery After Surgery (ERAS) protocols aim to optimize perioperative care and improve recovery after major surgery. While ERAS pathways are well established in several oncologic disciplines, their feasibility and consistency in the setting of cytoreductive surgery, with or without hyperthermic intraperitoneal chemotherapy (CRS ± HIPEC), remain uncertain due to the complexity and heterogeneity of these procedures. A prospective multicenter observational study was conducted across 10 expert CRS-HIPEC centers to assess the feasibility and real-world implementation of the ERAS Society guidelines for cytoreductive surgery, with or without hyperthermic intraperitoneal chemotherapy. Perioperative practices were compared before (PRE-ERAS) and after (POST-ERAS) structured ERAS guideline implementation. ERAS adherence, clinical outcomes, and predictors of 90-day postoperative complications and prolonged length of stay were analyzed using multivariable logistic regression models. In addition, a predefined subgroup analysis compared outcomes between ovarian and non-ovarian primary tumors. Between 2021 and 2022, 497 patients were included (PRE-ERAS: 288; POST-ERAS: 209). Baseline characteristics were similar except for more ovarian primaries in POST-ERAS (26.4% vs 44%, p = 0.004). POST-ERAS patients showed higher adherence to anemia screening (60% vs 69%, p = 0.042), carbohydrate loading (4% vs 30%, p 70% ERAS adherence (OR 0.19, 95% CI 0.06-0.54, p = 0.003) predicted fewer complications. Ovarian primary (OR 0.50, 95% CI 0.28-0.87, p = 0.016), >70% adherence (OR 0.33, 95% CI 0.12-0.82, p = 0.025), and POST-ERAS status (OR 0.61, 95% CI 0.37-0.99, p = 0.046) correlated with shorter LOS. ERAS implementation for CRS ± HIPEC shortened hospital stay but remained incomplete and was associated with increased readmissions, without reducing complication rates. These findings highlight the need to focus on a pragmatic set of high-impact ERAS elements to improve feasibility in complex cytoreductive surgery.