PURPOSE After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet... Show morePURPOSE After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO.METHODS Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study.RESULTS From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO.CONCLUSION BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events. Show less
Steenbeek, M.P.; Harmsen, M.G.; Hoogerbrugge, N.; Jong, M.A. de; Maas, A.H.E.M.; Prins, J.B.; ... ; Hullu, J.A. de 2021
IMPORTANCE Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk... Show moreIMPORTANCE Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause.OBJECTIVE To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant.DESIGN, SETTING, AND PARTICIPANTS A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible.INTERVENTIONS Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications.MAIN OUTCOMES AND MEASURES Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes.RESULTS A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P < .001) points higher during 1 year after RRSO than after RRS. After RRSO with hormone replacement therapy, the difference was 3.6 points (95% CI, 2.3-4.8; P < .001) compared with RRS.CONCLUSIONS AND RELEVANCE Results of this nonrandomized controlled trial suggest that patients have better menopause-related quality of life after RRS than after RRSO, regardless of hormone replacement therapy. An international follow-up study is currently evaluating the oncologic safety of this therapy. Show less
Wenzel, H.H.B.; Kruitwagen, R.F.P.M.; Nijman, H.W.; Bekkers, R.L.M.; Gorp, T. van; Kroon, C.D. de; ... ; Aa, M.A. van der 2020
Introduction Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying... Show moreIntroduction Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short-term surgical complications and to evaluate its possible predictors in women with early-stage cervical cancer.Material and methods Women diagnosed with early-stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also excluded. Occurrence of intraoperative and postoperative complications and type of complications, developing within 30 days after surgery, were prospectively registered. Multivariable logistic regression analysis was used to identify predictors of surgical complications.Results A total of 472 women were selected, of whom 166 (35%) developed surgical complications within 30 days after radical hysterectomy. The most frequent complications were urinary retention with catheterization in 73 women (15%) and excessive perioperative blood loss >1000 mL in 50 women (11%). Open surgery (odds ratio [OR] 3.42; 95% CI 1.73-6.76), chronic pulmonary disease (OR 3.14; 95% CI 1.45-6.79), vascular disease (OR 1.90; 95% CI 1.07-3.38), and medical center (OR 2.83; 95% CI 1.18-6.77) emerged as independent predictors of the occurrence of complications. Body mass index (OR 0.94; 95% CI 0.89-1.00) was found as a negative predictor of urinary retention. Open surgery (OR 36.65; 95% CI 7.10-189.12) and body mass index (OR 1.15; 95% CI 1.08-1.22) were found to be independent predictors of excessive perioperative blood loss.Conclusions Short-term surgical complications developed in 35% of the women after radical hysterectomy for early-stage cervical cancer in the Netherlands, a nation with centralized surgical care. Comorbidities predict surgical complications, and open surgery is associated with excessive perioperative blood loss. Show less
Linden, M. van der; Oonk, M.H.M.; Doorn, H.C. van; Bulten, J.; Dorst, E.B.L. van; Fons, G.; ... ; Hullu, J.A. de 2019
Background: Vulvar Paget disease (VPD) is a rare skin disorder that is considered premalignant.Objective: To assess the clinical course, treatment schedules, and effect of invasion and treatment on... Show moreBackground: Vulvar Paget disease (VPD) is a rare skin disorder that is considered premalignant.Objective: To assess the clinical course, treatment schedules, and effect of invasion and treatment on recurrence and survival in patients with VPD.Methods: Data on women with VPD were retrieved from the medical files and pathology reports in all Dutch tertiary university medical centers. Disease-free survival and 5-year disease-specific survival were estimated by using Kaplan-Meier curves.Results: Data on 113 patients whose VPD was diagnosed between 1991 and 2016 were analyzed; 77% had noninvasive VPD. Most of the women (65%) underwent a surgical procedure. Recurrences were reported in 40%. Of the women with noninvasive VPD, 8% developed invasion. There were no disease-specific deaths reported in the women with noninvasive VPD. The 5-year disease-specific survival rate was greater than 98% in noninvasive and microinvasive VPD, but significantly worse in invasive VPD (50% [P < .0005]).Limitations: The main limitations of this study are its retrospective character and the fact that original pathology samples were not available for reassessment.Conclusions: VPD is extremely rare, and the recurrence rates are high. Most patients have noninvasive VPD, which does not affect survival and should be considered a chronic disorder with limited invasive potential. In cases of invasive disease, survival decreases significantly. Show less
Promoter methylation is a gene-and cancer type-specific epigenetic event that plays an important role in tumour development. As endometrioid (endometrioid endometrial carcinoma, EEC) and serous... Show morePromoter methylation is a gene-and cancer type-specific epigenetic event that plays an important role in tumour development. As endometrioid (endometrioid endometrial carcinoma, EEC) and serous endometrial cancers (uterine papillary serous carcinoma, UPSC) exhibit different clinical, histological and molecular genetic characteristics, we hypothesized that these differences may be reflected in epigenetic phenomena as well. Identification of a panel of methylation biomarkers could be helpful in a correct histological classification of these two subtypes, which solely on the basis of morphology is not always easy. Methylation-specific multiplex ligation-dependent probe amplification was used to assess the extent of promoter methylation of different tumour suppressor genes in EEC and UPSC. Methylation results were correlated with histology and survival. The median cumulative methylation index of all genes was significantly higher in EEC (124) than in UPSC (93) (P<0.001). Promoter methylation of CDH13 and MLH1 was more frequently present in EEC, while CDKN2B and TP73 were more frequently methylated in UPSC. Almost 90% of EEC and 70% of UPSC could be predicted by CDH13 and TP73. In EEC, methylation of MLH1 was associated with a shorter disease-free survival (DFS; P<0.0001) and overall survival (OS; P=0.005). In a multivariate model, MLH1 methylation emerged as an additional prognostic factor to stage for DFS (P=0.002). In conclusion, promoter methylation is more common in EEC than UPSC. A panel of methylation biomarkers could be useful to distinguish between the two histological subtypes of endometrial cancer. Furthermore, methylation of MLH1 may have prognostic value in EEC. Endocrine-Related Cancer (2010) 17 663-673 Show less
