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In this issue of I BJOG i , Kremer and colleagues present a comprehensive review on the role of hypermethylation of host cell genes in cervical carcinogenesis and discuss the complexity of the literature surrounding different human DNA methylation tests (Kremer et al. I BJOG i 2020; https://doi.org/10.1111/1471-0528.16395). Novel triage tests that improve the accuracy of detecting women at true risk of high-grade lesions are essential and DNA methylation offers potential. [Extracted from the article]

OC24.01: Use of intraoperative ultrasound during fertility-sparing endoscopic surgery This was a prospective analysis of all women with a gynecological pathology who underwent intraoperative ultrasound-guided surgical management, with both curative and fertility-sparing aims. One woman recurred post-operatively with her third recurrence, who previously had bilateral disease and non-invasive implants with microinvasive disease and micropapillary pattern. [Extracted from the article]

The article presents a case study of a 73-year-old woman presented with umbilical and vaginal metastasis. It says that the patient underwent various procedures such as laparotomy, histology and external beam radiotherapy. It tackles possible mechanisms of cancer cell implantation such as the penetration of malignant cells in the uterine wall and the cell exfoliation through fallopian tubes. It adds that patients' survival rate depends on the time of diagnosis and treatment regime.

Summary: Struma ovarii is an ovarian teratoma that comprises 2-5% of all ovarian teratomas. Malignant transformation of struma ovarii occurs in less than 5% of all cases, and metastatic disease is even rarer. We report two cases initially diagnosed with benign struma ovarii that presented malignant transformation, specifically highly differentiated follicular carcinoma of the ovary (HDFCO), some years after the first diagnosis. Case 1 concerns a 37-year-old female featuring HDFCO of the right ovary with multiple metastatic foci, who was diagnosed with benign struma ovarii 14 years ago. Case 2 concerns a 26-year-old female diagnosed with HDFCO of the left ovary. This patient was initially diagnosed with benign struma ovarii 6 years ago that recurred 4 years after the diagnosis. Both patients were treated with surgery, adjunctive total thyroidectomy, and radioactive iodine (131I) therapy., Learning Points: Malignant transformation of struma ovarii is very rare (<5%). Diagnosis of HDFCO without extra ovarian dissemination is difficult due to the resemblance of its histological appearance with normal thyroid tissue. There is no consensus on the postoperative treatment of malignant struma ovarii (MSO). Clinical and histological features of MSO should be assessed for the postoperative treatment decisions. TSH suppression and thyroglobulin level measurements are necessary for patient follow-up.

Background: This study aims to evaluate the strength of the association between frailty and intraoperative/postoperative complications in patients undergoing minimally invasive surgery (MIS) for endometrial cancer., Methods: In this retrospective observational multicenter cohort study, frailty was defined beforehand by a modified frailty index (mFI) score of ≥3. Multiple logistic regressions were performed to investigate possible preoperative predictors-including frailty, age, and body mass index-of intraoperative and early (within 30 days from surgery) or delayed (beyond 30 days from surgery) postoperative complications., Results: The study involved 577 women, of whom 6.9% (n = 40) were frail with an mFI ≥ 3, while 93.1% (n = 537) were non-frail with an mFI of 0-2. Frail women had a significantly higher rate of intraoperative complications (7.5% vs. 1.7%, p = 0.01), with odds 4.54 times greater (95% CI: 1.18-17.60, p = 0.028). There were no differences in the rate of early postoperative complications (15% vs. 6.9%, p = 0.06) and delayed postoperative complications (2.5% vs. 3.9%, p = 0.65) for frail versus non-frail patients. The odds of early postoperative complications increased by 0.7% (95% CI: 1.00-1.15) for every one-unit increase in age ( p = 0.032)., Conclusions: Frailty was associated with a significantly higher risk of intraoperative complications in older women undergoing MIS for endometrial cancer. Likewise, increasing age was an independent predictor of early postoperative complications. Our findings support the practice of assessing frailty before surgery to optimize perioperative management in this patient population.

Ovarian cancer (OC) represents one of the most lethal cancers in women. The aim of surgical treatment is complete cytoreduction in advanced stages and a surgical staging in early stages. Although the guidelines still suggest laparotomy as the standard approach, in recent years minimally invasive surgery (MIS) has become increasingly popular in the treatment of OC, especially in early stages, because the 5-year relative survival exceeds 90% and the patients' quality of life cannot be overshadowed. However, MIS has been demonstrated to have a role even in advanced stages, in the prediction of optimal cytoreduction, identification patients who may benefit from neoadjuvant chemotherapy, and, more recently, in the interval debulking surgery, as in selected cases of secondary cytoreduction for recurrent ovarian cancer. The aim of this review is to describe the MIS (especially robotic surgery), with its advantages and pitfalls, in the treatment of OC., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

(1) Background: Highly differentiated follicular carcinoma of ovarian origin (HDFCO) is an extremely uncommon neoplasm, associated with struma ovarii. There are scarce cases reported in the literature and, subsequently, no reliable conclusions on its pathophysiology, treatment, and prognosis can be drawn. The goal of this study is to enrich the literature on the topic by adding our own experience with a case, and simultaneously accumulate all cases published up to date. (2) Methods: The present review was performed in accordance with the guidelines for systematic reviews and meta-analyses (PRISMA). PubMed (1966-2022), Scopus (2004-2022), and Clinicaltrials.gov databases were screened for relevant articles published up to July 2022. (3) Results: Twenty patients with HDFCO were identified. The included patients were aged 47.15 years (range 24-74). The predominant origin was ovarian (60%) and extraperitoneal spread was confirmed in 15% of the cases. Surgical treatment varied from conservative to radical (35.3% vs. 41.2%, respectively) and the administration of supplementary therapy and thyroidectomy was not universal. Combined thyroidectomy/radioactive iodine therapy was applied in just 62.5% of the reported cases. There was one patient who demonstrated disease recurrence and lives with the disease. No disease related morbidity was reported. (4) Conclusions: HDFCO represents a low-grade malignant tumor, whose rarity does not allow for reliable conclusions. Standard treatment including complete surgical excision and supplementary treatment seems to offer a favorable prognosis in selected cases.

Study Question: Does fertility treatment (FT) significantly increase the incidence of breast, ovarian, endometrial or cervical cancer?, Summary Answer: Overall, FT does not significantly increase the incidence of breast, ovarian or endometrial cancer and may even reduce the incidence of cervical cancer., What Is Known Already: Infertility affects more than 14% of couples. Infertility and nulliparity are established risk factors for endometrial, ovarian and breast cancer, yet the association with FT is more contentious., Study Design, Size, Duration: A literature search was carried out using Cochrane Library, EMBASE, Medline and Google Scholar up to December 2019. Peer-reviewed studies stating cancer incidence (breast, ovarian, endometrial or cervical) in FT and no-FT groups were identified. Out of 128 studies identified, 29 retrospective studies fulfilled the criteria and were included (n = 21 070 337)., Participants/materials, Setting, Methods: In the final meta-analysis, 29 studies were included: breast (n = 19), ovarian (n = 19), endometrial (n = 15) and cervical (n = 13), 17 studies involved multiple cancer types and so were included in each individual cancer meta-analysis. Primary outcome of interest was cancer incidence (breast, ovarian, endometrial and cervical) in FT and no-FT groups. Secondary outcome was cancer incidence according to specific fertility drug exposure. Odds ratio (OR) and random effects model were used to demonstrate treatment effect and calculate pooled treatment effect, respectively. A meta-regression and eight sub-group analyses were performed to assess the impact of the following variables, maternal age, infertility, study size, outliers and specific FT sub-types, on cancer incidence., Main Results and the Role of Chance: Cervical cancer incidence was significantly lower in the FT group compared with the no-FT group: OR 0.68 (95% CI 0.46-0.99). The incidences of breast (OR 0.86; 95% CI 0.73-1.01) and endometrial (OR 1.28; 95% CI 0.92-1.79) cancers were not found to be significantly different between the FT and no-FT groups. Whilst overall ovarian cancer incidence was not significantly different between the FT and no-FT groups (OR 1.19; 95% CI 0.98-1.46), separate analysis of borderline ovarian tumours (BOT) revealed a significant association (OR 1.69; 95% CI 1.27-2.25). In further sub-group analyses, ovarian cancer incidence was shown to be significantly higher in the IVF (OR 1.32; 95% CI 1.03-1.69) and clomiphene citrate (CC) treatment group (OR 1.40; 95% CI 1.10-1.77), respectively when compared with the no-FT group. Conversely, the incidences of breast (OR 0.75; 95% CI 0.61-0.92) and cervical cancer (OR 0.58; 95% CI 0.38-0.89) were significantly lower in the IVF treatment sub-group compared to the no-FT group., Limitations, Reasons for Caution: The large, varied dataset spanning a wide study period introduced significant clinical heterogeneity. Thus, results have to be interpreted with an element of caution. Exclusion of non-English citations, unpublished work and abstracts, in order to ensure data accuracy and reliability was maintained, may have introduced a degree of selection bias., Wider Implications of the Findings: The results for breast, ovarian, endometrial and cervical cancer are reassuring, in line with previously published meta-analyses for individual cancers but the association between IVF and CC treatment and an increase in ovarian cancer incidence requires additional work to understand the potential mechanism driving this association. In particular, focusing on (i) discriminating specific treatments effects from an inherent risk of malignancy; (ii) differential risk profiles among specific patient sub-groups (refractory treatment and obesity); and (iii) understanding the impact of FT outcomes on cancer incidence., Study Funding/competing Interest(s): This study did not receive any funding. The authors have no financial, personal, intellectual and professional conflicts of interest to declare., Prospero Registration Number: CRD42019153404., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Vaginal ovarian cystectomy has not gained wide acceptance owing to the potential difficulty in entering the cul-de-sac. We review the current evidence on vaginal approaches to benign ovarian cysts. Outcome measures of interest included time to return to work, patient satisfaction, surgical complications and length of hospital stay. Ten studies were included in this review and involving 525 patients. Vaginal ovarian cystectomy is overall safe and feasible in appropriately selected cases with no evidence of intrapelvic adhesions or endometriosis. These findings will need to be validated in appropriately powered studies, before reliable conclusions can be drawn. Furthermore, we emphasize the importance of ultrasound both preoperatively for case selection optimization and intraoperatively, as a means of guidance during posterior culdotomy., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript., (© 2020 Srdjan Saso.)

Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory m/z features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings., Competing Interests: Competing interest statement: Waters Corporation provided supplies and maintenance for the mass spectrometry equipment used. Z.T. serves as a paid consultant for Waters Corporation. J.B. is employed by Waters Corporation., (Copyright © 2020 the Author(s). Published by PNAS.)

Background: Methylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus (HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detecting high-grade cervical intra-epithelial neoplasia (CIN)., Methods: We performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted in duplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effects binary regression model were applied to determine pooled effect estimates., Findings: 44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (≥CIN2/high-grade squamous intra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72·7% (47·8-92·2))) vs. low-grade CIN (≤CIN1/low-grade squamous intra-epithelial lesion (LSIL) (44·4% (95%CI:16·0-74·1))). Pooled difference in mean methylation level was significantly higher in ≥CIN2/HSIL vs. ≤CIN1/LSIL for HPV16 L1 (11·3% (95%CI:6·5-16·1)). Pooled odds ratio of HPV16 L1 methylation was 5·5 (95%CI:3·5-8·5) for ≥CIN2/HSIL vs. ≤CIN1/LSIL (p < 0·0001). HPV16 L1/L2 genes performed best in predicting CIN2 or worse (pooled sensitivity 77% (95%CI:63-87), specificity 64% (95%CI:55-71), area under the curve (0·73 (95%CI:0·69-0·77))., Interpretation: Higher HPV methylation is associated with increased disease severity, whilst HPV16 L1/L2 genes demonstrated high diagnostic accuracy to detect high-grade CIN in HPV16 positive women. Direct clinical use is limited by the need for a multi-genotype and standardised assays. Next-generation multiplex HPV sequencing assays are under development and allow potential for rapid, automated and low-cost methylation testing., Funding: NIHR, Genesis Research Trust, Imperial Healthcare Charity, Wellcome Trust NIHR Imperial BRC, European Union's Horizon 2020., (Copyright © 2019. Published by Elsevier B.V.)

Aim: Since the first natural orifice transluminal endoscopic surgery procedure, renewed interest has arisen in further developing and advancing minimal access surgery. We introduce a natural orifice endoscopic approach for a bilateral salpingo-oophorectomy., Patients & Methods: Using the vagina as a natural orifice, we performed a transvaginal laparoscopic salpingo-oophorectomy to remove bilateral adnexa in patients with a strong family history of ovarian and/or breast cancer and those positive for BRCA1/2 mutation., Results: Total 36 women underwent transvaginal laparoscopic salpingo-oophorectomy. Conversion to routine laparoscopy was required in eight patients to complete the operation. No peri-operative complications were noted., Conclusion: We describe a novel approach in gynecological surgery. Our technique proved to be safe and efficient with the advantage of avoiding any abdominal scars., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript., (© 2019 Srdjan Saso.)

Introduction: Splenectomy-induced thrombocytosis and leukocytosis may obscure the early diagnosis of post-operative infection or sepsis. In trauma patients after splenectomy, a platelet-to-white blood cell ratio of <20 has been shown to reliably differentiate post-operative sepsis from transient physiological responses., Objective: To determine whether the platelet-to-white blood cell ratio can be applied to differentiate between reactive post-operative changes and latent infection., Methods: All consecutive patients with ovarian cancer who underwent splenectomy between January 2013 and October 2018 in two large European gynecological cancer centers were retrospectively evaluated. Main outcome measures were white blood cell count, platelet count, and platelet-to-white blood cell ratio on post-operative days 1, 5, and 7. These were correlated with surgical outcome and morbidity according to the Clavien-Dindo classification. A binomial logistic regression was applied to assess the predictive value of day 5 platelet-to-white blood cell ratio, white blood cell count, and platelet count for predicting grade III post-operative sepsis., Results: Ninety-five patients with ovarian cancer (mean age 54 years, range 18-75) were identified. Seventeen patients (17.9%) developed a grade III post-operative sepsis. In all post-operative patients, mean white blood cell count on day 5 decreased (from 15.4×10 3 /μL to 11.4×10 3 /μL), while the mean platelet count rose (from 260.7×10 3 /μL to 385.3×10 3 /μL). A high platelet count (>313×10 3 /μL) failed to show any predictive value (OR=0.94; 95% CI 0.30 to 3.0; p=0.921). A low platelet-to-white blood cell ratio (<26) (OR=3.49; 95% CI 1.18 to 10.32; p=0.0241) and high white blood cell count (>14.5×10 3 /μL) on day 5 (OR=11.0; 95% CI 3.3 to 36.2; p<0.001) were significant for predicting sepsis. Despite a significant OR, the sensitivity and specificity were low; day 5 platelet-to-white blood cell ratio at a cut-off point of 26 achieved a sensitivity of 72% and specificity of 53% (area under the curve 0.637, 95% CI 0.480 to 0.796) in predicting grade III post-operative sepsis., Conclusions: Platelet-to-white blood cell ratio after cytoreductive surgery for ovarian cancer with splenectomy does not appear to have a strong predictive value in differentiating between sepsis and reactive splenectomy-induced changes. Leukocytosis, in combination with clinical assessment, may remain the most useful tool for prediction of sepsis after cytoreductive surgery with splenectomy., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Evaluate postoperative hepatic-function in patients with advanced ovarian cancer (OC) who underwent extensive right upper-quadrant (RUQ) cytoreduction in primary, relapsed or interval settings., Methods: We retrospectively reviewed all patients with OC who underwent liver resection, mobilization and/or diaphragmatic-stripping between 01/2013 and 12/2016. Postoperative liver enzyme function (LFTs), assessed by alanine transaminase (ALT), alkaline phosphatase (ALP) and bilirubin (Bil), was correlated with postoperative complications., Results: 132 patients were identified. 81 patients (61%) underwent upfront, 25(19%) interval and 26(20%) secondary cytoreduction. The surgical procedures were right diaphragmatic peritoneal stripping (81/132;61%), full-thickness resection (42/132;32%), liver-capsule resection (85/132;64%), porta-hepatis tumor resection (11/132;8%) and partial hepatectomy (5/132;4%). 74%(98/132) of patients increased their LFTs postoperatively with a peak at 24-hours. Highest ALT median was 1.7-fold of upper normal limit (UNL), with the highest ALT value rising up to 28-fold UNL on the 1st postoperative day (PoD)(range 6-1792 IU/L). Median value of highest ALP was within normal, with the highest ALP value rising up to 4-fold UNL on PoD 5(range 22-512 IU/L). Median value of highest Bilirubin level was also within normal, with highest Bilirubin level rising up to 6-fold UNL on PoD 5(range: 2-120 μmol/L). Mean LFT-normalization time was 7 days (range: 3-14 days). No significant morbidity was directly linked to LFT deterioration, apart from one case (0.8%) of fatal fulminant hepatic-failure., Conclusion: RUQ-cytoreduction is almost always associated with a transient LFT-increase, with no significant clinical implications and spontaneous normalization within the first postoperative week. Due to the existing risk of fulminant liver failure, albeit rare and difficult to predict, postoperatively elevated LFTs should be monitored, until normalization. Large prospective studies are required to assess the predictive value of LFTs and other risk factors for postoperative hepatic failure in patients with OC undergoing extensive RUQ-cytoreduction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: Extracellular matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are involved in the breakdown of fetal membranes before delivery. Our aim was to investigate the occurrence of any polymorphism on genes coding for MMPs 1-3 and TIMP 2 in preterm laboring patients as a potential source of this phenomenon. This question has not been studied before., Methodology & Results: A prospective population study was performed in a Greek university hospital. Group A (control) included 66 women with no symptoms of premature labor. Group B (research) comprised 66 women, exhibiting signs of threatened preterm labor. No statistically significant difference in polymorphism, both in the distribution of genotype as well as allele frequencies, was detected between the two groups. This also applied to gestational age less or greater than 32 weeks., Conclusion: Gene polymorphisms of MMP 1-3 and TIMP 2 are not associated with premature rupture of membranes/contractions, as well as gestational age at preterm labor., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.