Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets—a narrative review

Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future

Polycystic ovary syndrome and postpartum depression: A systematic review and meta-analysis of observational studies

Objective: To estimate the risk of postpartum depression (PPD) in women with polycystic ovary syndrome (PCOS) and assess related moderators. Methods: Observational studies reporting on PPD rates in women with vs. without PCOS were identified in Embase/Medline/PsychInfo/Cinhail in 03/2021 since data inception. Quality of studies was evaluated using the Newcastle-Ottawa-Scale. The primary outcome was the odds ratio (OR, 95% confidence intervals [95%CI]) of PPD in women with vs. without PCOS. Meta-regression analyses included the effects of age, body mass index, percent smokers, history of depression, preterm delivery, hypertension during pregnancy, gestational diabetes and cesarian section as well as subgroup analyses based on the assessment methods for PCOS and PPD. Sensitivity analyses after excluding poor quality studies and cross-sectional studies and sequentially excluding each study were performed. Results: One study was rated as good, two as fair and three as low-quality. In six studies (n = 934,922), 44,167 women with PCOS were at increased PPD risk compared to 890,755 women without PCOS (OR= 1.45, 95%CI= 1.18 to 1.79, p< 0.001). When excluding one study that underestimated PCOS prevalence, we estimated an OR of 1.59 (95%CI= 1.56 to 1.62, p< 0.001) with reduced heterogeneity (I2= 45.3%). Higher ORs of PPD in women with PCOS were moderated by lower percentage of preterm delivery (co-efficient -0.07, 95%CI= -0.1 to -0.04, p< 0.001). After excluding low-quality studies yielded an OR of 1.58 (95%CI= 1.56 to 1.59, p< 0.001) with heterogeneity dropping (I2= 14.0%). Limitations: The methodological heterogeneity of available studies. Conclusions: Women with PCOS are at elevated PPD risk with risk moderators requiring further research. Keywords: Mood disorders; Perinatal mental health; Polycystic ovarian syndrome; Postpartum depression; Preterm delivery

Fertility, pregnancy and neonatal outcomes of patients with adenomyosis: a systematic review and meta-analysis.

This study aimed to investigate the association of adenomyosis with fertility, pregnancy and neonatal outcomes. An electronic search was conducted using the MEDLINE, PubMed and Cochrane databases up to April 2020. Seventeen observational studies were included. Adenomyosis was significantly associated with a lower clinical pregnancy rate (odds ratio [OR] 0.69; 95% confidence interval [CI] 0.51-0.94) and higher miscarriage rate (OR 2.17; 95% CI 1.25-3.79) after treatment with assisted reproductive technology (ART). The lower clinical pregnancy rate was more significant in the subgroup of patients with short down-regulation protocols. Similar associations were recorded after age adjustment. Adenomyosis was also significantly associated with an increased risk of pre-eclampsia, preterm delivery, Caesarean section, fetal malpresentation, small for gestational age infancy and post-partum haemorrhage, which was confirmed after correction for age and mode of conception. In conclusion, adenomyosis is associated with negative effects on fertility after ART. The potentially protective role of the ultra-long down-regulation protocols needs further evaluation in randomized controlled studies. Adenomyosis is also associated (independently of the mode of conception) with adverse pregnancy and neonatal outcomes. Proper counselling prior to ART and close monitoring of pregnancy in patients with adenomyosis should be recommended

Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets — a narrative review

Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.</p

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London