45 research outputs found

    Causality and functional relevance of BRCA1 and BRCA2 pathogenic variants in non-high-grade serous ovarian carcinomas

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    The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non-HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high-grade endometrioid (3/20; 15%), low-grade endometrioid (1/40; 2.5%), low-grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re-evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight ‘anomalous’ cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first ‘anomalous’ non-HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53-abnormal high-grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53-wildtype low-grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non-causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high-grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype-directed sequencing. Furthermore, in-depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2-related cancers. Molecular tumour pathology - and tumour genetic

    Loss of HLA class I and mismatch repair protein expression in sporadic endometrioid endometrial carcinomas

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    Tumor cells can escape from cytotoxic T-cell responses by downregulation of human leukocyte antigen (HLA) class I molecules expressed at the cell surface which has been associated with a deficient mismatch repair (MMR) system in colorectal carcinomas. Our study investigated the association between expression of MMR proteins and HLA class I in sporadic endometrioid endometrial carcinomas (EC). In a consecutively selected cohort of 486 EC patients, MMR proteins (MLH1, MSH2 and MSH6) and HLA class I (HLA-A, -B, -C or beta 2m) were investigated by immunohistochemistry. Expression levels of MMR proteins and HLA class I were compared between low-grade and high-grade ECs. HLA class I expression was compared between tumors with loss (negative immunostaining of =1 MMR protein) and expression of MMR proteins. Associations between previously determined numbers of intratumoral CD8+ T-lymphocytes and expression of MMR proteins and HLA class I and the influence on survival was determined. ECs with loss of MMR protein expression (33.5%) more frequently have loss of HLA-B/C (37.3%), compared to ECs with MMR protein expression (25.5%, p = 0.007). Patients with loss of MMR proteins have a worse disease-specific survival compared to patients with expression (p = 0.039). CD8+ T-lymphocytes have a positive influence on disease-free and disease-specific survival in the total EC cohort but not in patients with loss of MMR protein expression. In conclusion, our results indicate that loss of MMR protein expression is related to selective downregulation of HLA class I which contributes to immune escape in EC with an abnormal MMR system

    Implementing an advanced laparoscopic procedure by monitoring with a visiting surgeon

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    Study Objective: To investigate the feasibility of safely implementing a total laparoscopic hysterectomy (LH) in established gynecologists' practices with on-site coaching and monitoring of the learning curve by an experienced visiting surgeon. Design: Multicenter prospective feasibility and implementation study (Canadian Task Force classification II-2). Setting: Eleven general gynecologists in 8 hospitals (1 university hospital and 7 regional hospitals) participated. Patients: Laparoscopic hysterectomy was performed in 83 patients during the learning curve, and in 83 patients after the learning curve. Interventions: During the learning curve, an experienced visiting laparoscopist was available for coaching during each LH. A competence score was marked on an Objective Structured Assessment of Technical Skills (OSATS) form. Complications were recorded intraoperatively and postoperatively for 6 weeks after surgery in all patients. Measurements and Main Results: Nine of 11 gynecologists reached the competence score of at least 28 points during the study, from January 2005 to January 2007. A major complication occurred in 3 of 83 LH procedures (4%) performed during the learning curve, and in 5 of 83 LH procedures (6%) performed after the learning curve (p = .72). Conclusion: The concept of a visiting surgeon for on-site coaching and monitoring of established gynecologists during the learning curve of an advanced laparoscopic procedure using Objectively Structured Assessment of Technical Skills is feasible. According to the observed complication rate during and after the learning curve, on-site coaching is a useful tool when implementing a new laparoscopic technique in established gynecologists' practices. Journal of Minimally Invasive Gynecology (2010) 17, 771-778 (C) 2010 AAGL. All rights reserved

    Role of endocervical curettage in the preoperative staging of endometrial carcinoma

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    Objective, The presence of cervical involvement is important to establish a rational treatment for endometrial cancer patients. We investigated the value of preoperative endocervical curettage (ECC) in predicting cervical involvement. Methods. Preoperative ECC of 290 patients with clinical stage I epithelial endometrial cancer was compared with histopathology of the uterus. Results, Amongst all ECCs, 245 (84.5%) were negative and 45 (15.5%) were positive for endometrial cancer. in the uterine specimen, cervical involvement was found in 20% (58/290). PPV and NPV of ECC were 86.7% and 92.2%. False negative and false positive ECC occurred in 6.6% and 2.1%, Of all patients with positive ECC, 46.7% had FIGO stage II disease and 46.7% had extra uterine tumor spread (FIGO III, IV). Conclusion. ECC is an acceptable diagnostic tool to predict the presence or absence of cervical involvement in early stage endometrial cancer patients. (C) 2008 Elsevier Inc. All rights reserved
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