Mona El-Bahrawy

Primary Lesions of the Appendix in Patients Undergoing Surgery for Gynecological Tumors

Appendiceal neoplasms are an incidental finding in <1% of all appendicectomy specimens. Their incidence rates are largely based on appendectomies performed for appendicitis. Appendicectomy is often performed as part of cytoreductive surgery for gynecological malignancies. This is to reduce the risk of occult metastatic disease and to mitigate the morbidity of acute appendicitis in patients undergoing chemotherapy for cancers. The objective of this study was to investigate the incidence of primary lesions of the appendix in 2 cohorts of patients who underwent appendicectomy: patients who had surgery for mucinous neoplasms of the ovary and patients who had cytoreductive surgery for gynecological malignancies. This study looked at the histopathology reports of 581 patients covering both cohorts. Appendicectomy in the setting of mucinous neoplasms of the ovary was done in 187 patients and as part of cytoreductive surgery for gynecological malignancies in 182 patients. We used the updated 2019 WHO nomenclature to classify the appendiceal lesions. The 2 cohorts had an incidence of 13% (25/187) and 7% (12/182) of appendiceal lesions. The appendix was noted to be the frequent primary site of extraovarian mucinous tumor metastasis to the ovary with a frequency of 56% (14/25) in patients with mucinous ovarian tumors; the highest cited in literature to date. We also noted poor correlation between gross and microscopic confirmation of appendiceal lesions with 7% of all macroscopically normal appendices harboring an appendiceal pathology. The study highlights the importance of appendicectomy during surgery for ovarian mucinous neoplasms and as part of cytoreductive surgery for gynecological malignancies. It also signifies the importance of microscopic examination of the whole appendix, especially when no gross abnormality is detected.

Gene fusions in tumourigenesis with particular reference to ovarian cancer

Gene fusion, a genomic event that generates a novel gene from two independent genes, has long been known to be implicated in tumourigenesis and cancer progression. It has thus served as a diagnostic and prognostic biomarker in cancer, as well as an ideal therapeutic target in cancer therapy. Gene fusion can arise from chromosomal rearrangement and alternative splicing of transcripts, resulting in deregulation of proto-oncogenes or creation of an oncogenic novel gene. Largely facilitated by next generation sequencing technologies, a plethora of novel gene fusions have been identified in a variety of cancers, which leaves us the challenge of functionally characterising these candidate gene fusions. In this review, we summarise the molecular mechanisms, the oncogenic consequences and the therapeutic implications of verified gene fusions. We also discuss recent studies on gene fusions in both common and rare subtypes of ovarian tumours and how these findings can be translated to cancer therapies to benefit patients carrying these gene fusions.

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.