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OBJECTIVE: To compare the effect of tibolone to conjugated estrogens with medroxyprogesterone-acetate (CEE + MPA) on breast density, as a predictor for breast cancer risk, in women with a high risk of breast and ovarian cancer. METHODS: Women aged 30-50 (N = 114) who had undergone risk-reducing salpingo-oophorectomy (RRSO) were randomized to tibolone or CEE + MPA. RESULTS: Breast density decreased 46% after RRSO in untreated women, 39% after treatment with tibolone, and 17% after treatment with CEE + MPA; the decrease in breast density after CEE + MPA was significantly different compared with that of untreated women (P = 0.017). CONCLUSIONS: A decline in breast density is seen after premenopausal RRSO despite the use of both CEE + MPA or tibolone, although lower breast density is seen after tibolone use.

Background Vulvar lichen sclerosus (VLS) occurring in children and adolescents may have repercussions throughout life. Objective We sought to assess the evidence available on the long-term consequences of juvenile VLS. Methods Multiple databases were searched for studies containing long-term follow-up information on children or adolescents up to age 18 years with VLS. Articles were classified by level of evidence and the specific aspects of VLS studied. Results In all, 37 studies met the inclusion criteria, giving information on the long-term consequences of VLS, of which 13 were cohort studies and 24 were case reports or series. These publications show that signs and symptoms persist after puberty and beyond, scarring and permanent architectural changes occur, treatment is effective with regard to symptoms, and long-term quality of life is affected. Findings suggest a possible relationship with risk of malignancy. The included publications had low-level evidence. Limitations Meta-analysis was not possible because the studies had different focuses. Very few patients were followed into adulthood. Conclusions There is low-level evidence suggesting long-term repercussions of juvenile VLS. Studies following children and adolescents with VLS into adulthood are needed to better understand the course of this disease and its repercussions on adult vulvar health.

STUDY QUESTION Do children conceived by ART have an increased risk of cancer?SUMMARY ANSWER Overall, ART-conceived children do not appear to have an increased risk of cancer.WHAT IS KNOWN ALREADY Despite the increasing use of ART, i.e. IVF or ICSI worldwide, information about possible long-term health risks for children conceived by these techniques is scarce.STUDY DESIGN, SIZE, DURATION A nationwide historical cohort study with prospective follow-up (median 21 years), including all live-born offspring from women treated with subfertility treatments between 1980 and 2001.PARTICIPANTS/MATERIALS, SETTING, METHODS All offspring of a nationwide cohort of subfertile women (OMEGA study) treated in one of the 12 Dutch IVF clinics or two fertility clinics. Of 47 690 live-born children, 24 269 were ART-conceived, 13 761 naturally conceived and 9660 were conceived naturally or through fertility drugs, but not by ART. Information on the conception method of each child and potential confounders were collected through the mothers' questionnaires and medical records. Cancer incidence was ascertained through linkage with The Netherlands Cancer Registry from 1 January 1989 until 1 November 2016. Cancer risk in ART-conceived children was compared with risks in naturally conceived children from subfertile women (hazard ratios [HRs]) and with the general population (standardized incidence ratios [SIRs]).MAIN RESULTS AND THE ROLE OF CHANCE The median follow-up was 21 years (interquartile range (IQR): 17-25) and was shorter in ART-conceived children (20 years, IQR: 17-23) compared with naturally conceived children (24 years, IQR: 20-30). In total, 231 cancers were observed. Overall cancer risk was not increased in ART-conceived children, neither compared with naturally conceived children from subfertile women (HR: 1.00, 95% CI 0.72-1.38) nor compared with the general population (SIR = 1.11, 95% CI: 0.90-1.36). From 18 years of age onwards, the HR of cancer in ART-conceived versus naturally conceived individuals was 1.25 (95% CI: 0.73-2.13). Slightly but non-significantly increased risks were observed in children conceived by ICSI or cryopreservation (HR = 1.52, 95% CI: 0.81-2.85; 1.80, 95% CI: 0.65-4.95, respectively). Risks of lymphoblastic leukemia (HR = 2.44, 95% CI: 0.81-7.37) and melanoma (HR = 1.86, 95% CI: 0.66-5.27) were non-significantly increased for ART-conceived compared with naturally conceived children.LIMITATIONS, REASONS FOR CAUTION Despite the large size and long follow-up of the cohort, the number of cancers was rather small for subgroup analyses as cancer in children and young adults is rare.WIDER IMPLICATIONS OF THE FINDINGS Overall, ART-conceived children do not appear to have an increased cancer risk after a median follow-up of 21 years. This large study provides important results, enabling physicians to better inform couples considering ART about the long-term safety of ART for their children. However, larger studies with prolonged follow-up are needed to investigate cancer risk in adults and in children conceived by ICSI and/or from cryopreserved embryos.STUDY FUNDING/COMPETING INTEREST(S) This work was supported by The Dutch Cancer Society (NKI 2006-3631) which funded the OMEGA-women's cohort and Children Cancer Free (KIKA;147) which funded the OMEGA-offspring cohort. We declare no competing interests.

Despite inconclusive evidence, concerns that assisted reproductive technology may be associated with increased risk of ovarian cancer remain. Significant increases in gonadotropin levels and disruption of ovarian epithelium have been proposed as mechanisms to explain this potential association. Several studies investigating this have suggested the observed increased risk in those undergoing assisted reproductive technology (ART) may be more related to nulliparity and subfertility than the treatment itself.This nationwide retrospective cohort study with prospective follow-up aimed to determine long-term ovarian cancer risk among women treated with ART compared with women in the general population and compared with subfertile women not treated with ART. Also investigated was whether unsuccessful ART and successful ART leading to childbirth had different effects on ovarian cancer risk. Women treated with ART between 1983 and 2000 identified in the OMEGA-1 (OvariuMstimulatie En Gynecologische Aandoenginen-1) cohort were included in this analysis. The OMEGA-1 cohort included women starting ovarian stimulation for ART in in vitro fertilization (IVF) clinics in the Netherlands, as well as a comparison cohort of subfertile ART-native women. Eligible women entered into the study cohort on the date of first ART or first clinic visit for subfertility evaluation. Cancer diagnosis data were obtained through the population-based Netherlands Cancer Registry between 1989 and July 2018. Ovarian cancer incidence in the ART and non-ART cohorts were compared, and standardized incidence ratios (SIRs) were calculated based on the observed and expected numbers of tumors in each cohort.The final study cohort consisted of 30,625 ART-treated women and 9988 non-ART-treated women with a median follow-up of 24 years. A total of 158 ovarian cancers were observed in the follow-up period, 158 of which were invasive and 100 borderline. Ovarian cancer risk was increased in the ART group (SIR = 1.43; 95% confidence interval [CI], 1.18-1.71) but not in the non-ART group (SIR = 1.15; 95% CI, 0.81-1.59; P = 0.25) compared with the general population. Nulliparous women had a 2-fold increased risk of ovarian cancer compared with the general population, and each subfertility diagnosis was associated with an increase in ovarian cancer risk in ART-treated women but not in non-ART-treated women. When comparing the ART group and non-ART group and adjusting for age at start and parity, the hazards ratio (HR) for ovarian cancer was 1.02 (95% CI, 0.70-1.50), and this did not increase after more ART cycles. A decreased risk of ovarian cancer was associated with a larger number of successful ART cycles (1 successful ART cycle HR = 0.54; 95% CI, 0.35-0.87; >= 2 cycles HR = 0.37; 95% CI, 0.18-0.73; P = 0.001); however, a larger number of unsuccessful cycles was not associated with a greater risk. Borderline ovarian cancers were more common among both ART and non-ART women compared with the general population (SIR = 2.20; 95% CI, 1.66-2.86; SIR = 1.84; 95% CI, 1.05-2.99, respectively), and more common in ART-treated women compared with non-ART women (HR, 1.84; 95% CI, 1.08-3.14); however, risk did not increase with more ART cycles or follow-up time.The results of this study show an increased risk of ovarian cancer among ART-treated women compared with the general population, but not compared with subfertile women not treated with ART and is attributed to nulliparity.

Objective To investigate the effect of second uterine curettage on the number of chemotherapy courses and relapse rate in low-risk postmolar gestational trophoblastic neoplasia. Methods In a phase III trial, patients with low risk gestational trophoblastic neoplasia were randomised (1:1) to a second curettage or no curettage group before methotrexate treatment. Eligibility criteria were serum human chorionic gonadotropin (hCG) level 5,000 international units/L or less and fit for treatment with methotrexate. Exclusion criteria were previous uterine perforation and life-threatening bleeding. With a two-sided 5% significance level and a power of 99%, a sample size of 44 patients per group was necessary to detect a mean reduction in 2.3 chemotherapy courses. The primary outcome was the number of chemotherapy courses required for hCG normalization. Secondary outcomes were needed for second-line treatment, toxicity, relapse rates, and variables associated with number of chemotherapy courses. Results From October 2011 through February 2016, 89 patients entered the study at the Mansoura Trophoblastic Clinic; in each group, 43 patients were included in the intention-to-treat analyses. Surgical complications did not occur. The mean number of chemotherapy courses required to reach hCG normalization was 4.4±2.2 SD in the control group vs 3.8±2.3 SD in the intervention group (P=.14). Groups were comparable in terms of second-line treatment needed to reach hCG normalization, and relapse within the first year. Only hCG levels related to the number of chemotherapy cycles required for hCG normalization. Conclusion Second uterine curettage did not reduce the number of chemotherapy courses required or affect relapse rate in patients with low-risk postmolar gestational trophoblastic neoplasia. Clinical trials registration Dutch Trial Registry, NTR3390.

Cancer stem–like cells (CSC) may be critical to maintain the malignant behavior of solid and hematopoietic cancers. Recently, patients with endometrial cancer whose tumors expressed high levels of aldehyde dehydrogenase (ALDH), a detoxifying enzyme characteristic of many progenitor and stem cells, exhibited a relative reduction in survival compared with patients with low levels of ALDH. Given evidence of its role as a CSC marker, we hypothesized that high level of ALDH activity (ALDHhi) in a tumor might positively correlate with the presence of stem- and progenitor-like tumor cells in this disease setting. In support of this hypothesis, ALDH could be used to enrich for CSC in endometrial cancer cell lines and primary tumors, as illustrated by the increased tumor-initiating capacity of ALDHhi cells in immunodeficient mice. ALDHhi cells also exhibited greater clonogenic and organoid-forming capacity compared with ALDHlo cells. Notably, the number of ALDHhi cells in tumor cell lines and primary tumors inversely correlated with differentiation grade. Expression analysis revealed upregulation of IL6 receptor subunits and signal transducers CD126 and GP130 in ALDHhi endometrial cancer cells. Accordingly, targeted inhibition of the IL6 receptor and its downstream effectors JAK1 and STAT3 dramatically reduced tumor cell growth. Overall, our results provide a preclinical rationale to target IL6 or its effector functions as a novel therapeutic option in endometrial cancer. Cancer Res; 75(17); 3608–22. ©2015 AACR.

Background: Breast cancer risk is temporarily increased after a full-term pregnancy and declines thereafter, possibly due to increased levels of gonadal and placental hormones during pregnancy. Inconsistent results, however, have been reported after twin pregnancies with higher hormone levels. Among women treated with in vitro fertilisation (IVF), for whom the number of embryos available for implantation is known, we recently observed that a multiple birth after implantation of all transferred embryos is associated with higher levels of vascular endothelial growth factor (VEGF). As VEGF is involved in breast cancer progression, we studied the effects of embryo implantation and a multiple birth on breast cancer risk in a nationwide Dutch cohort of IVF-treated women. Methods: We performed a cohort analysis among 12,589 women who had been treated with IVF between 1983 and 1995 and completed a risk factor questionnaire between 1997 and 1999. Data on IVF treatment were obtained from medical records. Breast cancer cases were ascertained through linkage with the population-based Netherlands Cancer Registry. Breast cancer risks associated with singleton and multiple births were estimated with Cox regression. Findings: There were 1688 women (13.4%) with multiples, 6027 (47.9%) with singletons and 4874 (38.7%) nulliparous women. Breast cancer occurred in 317 women of whom 57 had multiples. Breast cancer risk was 1.44 times higher in mothers of multiples than in mothers of singletons (95% confidence interval (CI) 1.06-1.97). Risk was highest in women who gave birth to multiples from all embryos transferred (adjusted hazard ratio (HR) 1.86, 95% CI 1.01-3.43), and lower for those with multiples after incomplete embryo implantation (adjusted HR 1.31, 95% CI 0.76-2.25). Interpretation: A woman's potential to implant all transferred embryos may be associated with breast cancer risk. Further research is needed to confirm our results and to identify the underlying biological mechanisms. (C) 2014 Elsevier Ltd. All rights reserved.

Background In view of the increased risk of developing breast (BC) cancer, BRCA mutation carriers are offered intensive surveillance or risk reducing mastectomy (RRM) and/or salpingo-ovariectomy (RRSO). It is insufficiently clear how to counsel mutation carriers who have been treated for OC, and it may be questioned whether RRM is indicated. It is possible that BC risk, both of primary (PBC) and contralateral BC (CBC), may be modified by the treatment given for OC mostly including surgery and platinum-based chemotherapy. Further, the BC risk has to be weighted against the risk of death after OC. So far, there are no data available on the PBC or CBC risk after OC in BRCA mutation carriers. Patients and Methods From the database of the institutional Family Cancer Clinic (FCC), we selected BRCA-associated OC patients either without (n= 79, at risk of PBC) or with a history of unilateral BC (n=37, at risk of CBC). Controls were BRCA mutation carriers without OC, either without (n=351) or with a history of unilateral BC (n=294). Follow-up started at OC diagnosis, and for controls at date of first visit at the FCC or the 35th birthday. Exclusion criteria were: other malignancy besides epithelial OC or BC, inadequate follow-up data, bilateral breast cancer or mastectomy. Data analyses were performed using t- and chi-squared tests, and Kaplan-Meier survival method with death prior to BC as competing risk event. Results Only six OC patients (5.1%) did not receive chemotherapy as part of primary therapy for OC, five at risk of PBC and one at risk of CBC. Chemotherapy schedules were mainly platinum-based (92%). RRSO was performed in 45% of the controls. The risks of PBC at 2, 5, and 10 years in BRCA-associated OC patients were 3%, 6% and 11%, respectively, versus 6%, 16% and 28% in unaffected BRCA mutation carriers (p=0.03). The mortality rate at those time points in the OC group was 13%, 33% and 61%, respectively, versus 1%, 2% and 2% in unaffected mutation carriers (p In patients with a history of unilateral BC, the risks of CBC at 2, 5, and 10 years in OC patients were 0%, 7% and 7%, respectively, versus 6%, 16% and 34% in the BC patients without OC (p=0.06). The mortality rate at similar time points was 19%, 34%, and 55%, respectively, in the OC group versus 4%, 11%, and 21% for the non-OC patients (p Conclusions The risk of developing a PBC or CBC was much lower in BRCA mutation carriers with a history of OC than in mutation carriers without OC. Also, since the 10-year mortality rate after ovarian cancer was 55–60% and the risk of developing a PBC or CBC at the highest was 11% over the same time period, our data suggest that intensive breast cancer surveillance strategies for the BRCA-associated ovarian cancer group might be reconsidered, while risk reducing mastectomy is not indicated unless in specific cases requiring careful consideration in a multisciplinary setting. Further studies in larger groups are warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-04.

Contains fulltext : 89638.pdf (Publisher’s version ) (Closed access) BACKGROUND: Urinary incontinence (UI) and anal incontinence (AI) are complaints with impact on quality of life (QOL). Few data are available on prevalence of double incontinence (DI) in the general female population. OBJECTIVE: To determine prevalence of UI, AI, and DI, their associations with age, parity, and effects on QOL. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study on a general female population, aged 45-85 years. MEASUREMENTS: Validated questionnaires measuring pelvic floor dysfunction and QOL. A short questionnaire was used for non-responders. Analyses were performed with Chi-square tests, ANOVA, and logistic regression. RESULTS: Response rate was 62.7% (1,869/2,979); 59% of non-responders filled in the short questionnaire (620/1,051). No significant differences in stress urinary incontinence, vaginal bulging, solid stool incontinence and parity were found between responders and non-responders. DI with and without flatal incontinence were reported by 7.7% and 35.4%, respectively. Women with urge urinary incontinence (UUI) alone had an OR of 4.3 (95% CI 2.4-7.9) for liquid stool incontinence, 1.6 (95% CI 0.5-4.9) for solid stool incontinence and 2.4 for flatal incontinence (95% CI 1.5-3.8). Women with AI had an OR of 5.8 (95% CI 1.8-18.2) for UUI. Women with DI including flatus reported significantly poorer QOL. Limitation of the study was the lack of objective clinical validation of symptoms, which may have influenced the real prevalence data. CONCLUSIONS: Most important relation was found between UUI and liquid stool incontinence (OR 4.3). We recommend that clinicians take the history of patients with UUI or mixed urinary incontinence to exclude the co-existence of AI. 01 april 2010

Introduction and hypothesis Major levator ani abnormalities (LAA) may lead to abnormal pelvic floor muscle contraction (pfmC) and secondarily to stress urinary incontinence (SUI), prolapse, or fecal incontinence (FI). Methods A retrospective observational study included 352 symptomatic patients to determine prevalence of LAA in underactive pfmC and the relationship with symptoms. On 2D/3D transperineal ultrasound, PfmC was subjectively assessed as underactive (UpfmC) or normal (NpfmC) and quantified. LAA, defined as a complete avulsion of the pubic bone, was analyzed using tomographic ultrasound imaging. Results LAA were found in 53.8% of women with UpfmC versus 16.1% in NpfmC (P

Objective: Treatment in advanced stage epithelial ovarian cancer (EOC) is based on primary cytoreductive surgery followed by platinum-based chemotherapy Successful cytoreduction to minimal residual tumour burden is the most important determinant of prognosis. However, extensive surgical procedures to achieve maximal debulking are inevitably associated with postoperative morbidity and mortality. The objective of this study is to determine predictors of 30-day morbidity after primary cytoreductive surgery for advanced stage EOC. Methods: All patients in the South Western part of the Netherlands who underwent primary cytoreductive surgery for advanced stage EOC between January 2004 and December 2007 were identified from the Rotterdam Cancer Registry database. All peri- and postoperative complications within 30 days after surgery were registered and classified according to the definitions of the National Surgical Quality Improvement Programme (NSQIP). To investigate independent predictors of 30-day morbidity, a Cox proportional hazards model with backward stepwise elimination was utilised. The identified predictors were entered into a nomogram. Results: Two hundred and ninety-three patients entered the study protocol. optimal cytoreduction was achieved in 136 (46%) patients. 30-day morbidity was seen in 99 (34%) patients. Postoperative morbidity could be predicted by age (P = 0.007; odds ratio [OR] 1.034), WHO performance status (P = 0.046; OR 1.757), extent of surgery (P = 0.1308; OR = 2.101), and operative time (P = 0.017; OR 1.007) with an optimism corrected c-statistic of 0.68. Conclusion: 30-day morbidity could be predicted by age, WHO performance status, operative time and extent of surgery. The generated nomogram could be valuable for predicting operative risk in the individual patient. (C) 2009 Elsevier Ltd. All rights reserved.

Contains fulltext : 89827.pdf (Publisher’s version ) (Closed access) INTRODUCTION AND HYPOTHESIS: This study aims to examine the relationship between pelvic floor muscle function (PFMF) and pelvic organ prolapse (POP) in a general female population. METHODS: Cross-sectional study on women aged 45-85 years. Validated questionnaires were used to assess pelvic floor muscle function. POP and PFMF were evaluated with vaginal examination. For statistical analysis chi-squared test for trend and analysis of variance were used. RESULTS: Response rate to the questionnaire was 62.7% (1,869/2,979). No significant differences were found in muscle strength and endurance during voluntary muscle contraction between the POP stages. Women with POP stages I and II were significantly less able to achieve effective involuntary muscle contraction during coughing (38.3% and 37.7%) than women without POP (75.2%). CONCLUSION: Involuntary contraction of the PFM during coughing (that resulted in stabilization of the perineum) was significantly weaker in the women with POP stage I and II than in the women without POP. 01 maart 2010

Objectives:Treatment of patients with an advanced-stage epithelial ovarian cancer (EOC) is based on cytoreductive surgery and platinum-based chemotherapy. Amount of residual disease after primary cytoreductive surgery is an important prognostic factor.The objectives of the present study were to evaluate the accuracy and reproducibility of preoperative clinical judgment of residual disease after primary cytoreductive surgery and to compare the predictive performance of the offhand assessment to the predictive performance of prediction models.Materials and Methods:Fifteen observers (5 gynecologic oncologists, 5 gynecologists, and 5 senior residents) were offered preoperative data of 20 patients with advanced-stage EOC who underwent primary cytoreductive surgery. The observers were asked to predict residual disease after cytoreductive surgery (≤1 or >1 cm). Their estimation was compared with the performance of 2 prediction models.Results:Overall, suboptimal cytoreduction was predicted with a sensitivity of 50% and a specificity of 56%. The intraclass correlation coefficient was 0.27.χ2 test showed no significant difference in prediction of suboptimal cytoreduction between the different subgroups and prediction models.Conclusions:Clinical judgment of residual disease after primary cytoreductive surgery in patients with advanced-stage EOC shows limited accuracy. Given the poor interobserver reproducibility, prediction models could attribute to uniform treatment decisions and improve counseling.

Residual disease after cytoreductive surgery is an important prognostic factor in patients with advanced stage epithelial ovarian cancer (EOC). Aggressive surgical procedures necessary to achieve maximal cytoreduction are inevitably associated with postoperative morbidity and mortality. To determine causes of postoperative mortality (POM) after surgery for EOC all postoperative deaths in the southwestern part of the Netherlands over a 17-year period were identified and analysed by reviewing medical notes. Between 1989 and 2005, 2434 patients underwent cytoreductive surgery for EOC. Sixty-seven patients (3.1%) died within 30 days after surgery. Postoperative mortality increased with age from 1.5% (26/1765) for the age group 20-69 to 6.6% (32/486) for the age group 70-79 and 9.8% (18/183) for patients aged 80 years or older. Pulmonary failure (18%) and surgical site infection (15%) were the most common causes of death. Only a quarter of deaths resulted from surgical site complications. Our results suggest that causes of postoperative mortality after surgery for EOC are very heterogeneous. Given the impact of general complications, progress in preoperative risk assessment, preoperative preparation and postoperative care seem essential to reduce the occurrence of fatal complications.

Objective Prognosis in women with ovarian cancer mainly depends on International Federation of Gynecology and Obstetrics stage and the ability to perform optimal cytoreductive surgery. Since ovarian cancer has a heterogeneous presentation and clinical course, predicting progression-free survival (PFS) and overall survival (OS) in the individual patient is difficult. The objective of this study was to determine predictors of PFS and OS in women with advanced stage epithelial ovarian cancer (EOC) after primary cytoreductive surgery and first-line platinum-based chemotherapy. Design Retrospective observational study. Setting Two teaching hospitals and one university hospital in the south-western part of the Netherlands. Population Women with advanced stage EOC. Methods All women who underwent primary cytoreductive surgery for advanced stage EOC followed by first-line platinum-based chemotherapy between January 1998 and October 2004 were identified. To investigate independent predictors of PFS and OS, a Cox’ proportional hazard model was used. Nomograms were generated with the identified predictive parameters. Main outcome measures The primary outcome measure was OS and the secondary outcome measures were response and PFS. Results A total of 118 women entered the study protocol. Median PFS and OS were 15 and 44 months, respectively. Preoperative platelet count (P = 0.007), and residual disease

Objective. Accurate estimation of the risk of postoperative mortality (POM) is essential for the decision whether or not to perform cytoreductive surgery in a patient with advanced stage ovarian cancer. To ascertain modern reference figures, a systematic review of studies reporting POM after primary cytoreductive surgery for advanced stage epithelial ovarian cancer (EOC) was performed. Materials and methods. A Medline search was performed to retrieve papers on primary cytoreductive surgery for advanced stage EOC. Twenty-three papers met the inclusion criteria and were reviewed. Results. According to population-based studies, POM after primary cytoreductive surgery for EOC is 3.7% on average. Single centre studies report an average rate of 2.5%. The overall mean POM is 2.8%. POM is more frequent for elderly women and after extensive procedures. Accurate information on age-specific and procedure-specific rates could not be obtained. Conclusion. POM rates after surgery for EOC are satisfactorily low. There is a clear need for reliable reference figures for mortality after debulking surgery in the elderly. (C) 2009 Elsevier Inc. All rights reserved.

Aims: To test the face validity and reliability of a new digital pelvic floor muscle function (PFMF) assessment scheme that was designed on the basis of the recently standardized terminology of the International Continence Society. Methods: Study participants comprised 41 women, age 18–85 years. Data on age and parity were obtained. Face validity of the new assessment scheme was tested by three senior and one junior pelvic physiotherapists, using the Delphi technique. PFMF of each woman was assessed four times by three specially trained pelvic physiotherapists. Examiners were blinded to parity and other findings. To test reliability, Kappa (K) was used for the dichotomous variables and Weighted Kappa (Kw) for the items with more than two categories. Results: Mean age of the women was 41 years (SD 10.5); 14 were nulliparous (34.1%), 6 primiparous (14.6%), and 21 multiparous (51.2%). The new assessment scheme showed satisfactory face validity and intra-observer reliability but low inter-observer reliability. Conclusions: The new assessment scheme based on the terminology of the ICS showed satisfactory face validity and intra-observer reliability. It can therefore be considered suitable for use in clinical practice. More detailed redefinition of the described outcome measures is necessary to improve the inter-observer reliability. Neurourol. Urodynam. 28:295–300, 2009. 2008 Wiley-Liss, Inc.

Tamoxifen is used as adjuvant treatment for postmenopausal breast cancer patients. The mechanism of action of tamoxifen in breast cancer patients is that tamoxifen inhibits growth of cancer cells by competitive antagonism for estrogens at the estrogen receptor (ER). In the endometrium, tamoxifen has an effect that varies with the ambient concentration of estrogen: in premenopausal women (high estrogen levels), tamoxifen displays an estrogen-antagonistic effect, while in postmenopausal women (low estrogen levels), tamoxifen displays an estrogen-agonistic mode of action. Here, using microarray technology we have compared estrogen signaling with tamoxifen signaling in the human endometrium. It was observed that on the one hand tamoxifen-treatment results in modulation of expression of specific genes (370 genes)and on the other hand tamoxifen-treatment results in modulation of a set of genes which are also regulated by estrogen treatment (142 genes). Upon focusing on regulation of proliferation, we found that tamoxifen-induced endometrial proliferation is largely accomplished by using the same set of genes as are regulated by estradiol. So, as far as regulation of proliferation goes, tamoxifen seems to act as estrogen agonist. Furthermore, tamoxifen-specific gene regulation may explain why tamoxifen-induced endometrial tumors behave more aggressively than sporadic endometrial tumors. (C) 2008 Elsevier Ltd. All rights reserved.

Previous studies have shown that both exogenous and endogenous estrogens and progestogens increase the risk of breast cancer. it has been suggested that in vitro fertilization (IVF) procedures may increase breast cancer risk. This risk could be could be due to a temporary decrease in estradiol and progesterone levels (during down-regulation of the natural cycle), as well as strongly elevated levels (during stimulation phase). Results of previous studies investigating breast cancer risk after IVF treatment were inconclusive because of limited follow-up. Recent studies have reported no increased risk of this cancer after IVT at a mean follow-up of 8 and 16 years. This historical cohort (OMEGA) study quantified long-term risk of breast cancer after ovarian stimulation for IVF. The aim of the study was to compare the long-term risk of breast cancer among a nationwide cohort of women receiving ovarian stimulation for IVF with that of women receiving other fertility treatments and those in the general population. The study was conducted in 12 IVF clinics in the Netherlands. The cohort was composed of 19,158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women who started other fertility treatments between 1980 and 1995 (non-IVF group) Data were obtained from all 12 IVF clinics. There was complete follow-up through December 2013 for 96% of the cohort. At end of follow-up, the median age was 53.8 years in the IVF group and 55.3 years in the non-IVF group. Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was obtained from medical records and mailed questionnaires. First invasive and in situ breast cancer incidence among women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Risk of breast cancer in the IVF group was compared with risk in the non-IVF group (hazard ratios [HRs]) and the general population (standardized incidence ratios [SIRs]). In the total cohort, the mean age at baseline was 32.8 years, and the mean number of IVF cycles was 3.6. After a median follow-up of 21.1 years, 839 of the cohort had invasive breast cancer, and 109 had in situ breast cancer. Compared with the general population, breast cancer risks were not increased either in the IVF group (SIR, 1.01; 95% confidence interval [CI], 0.93-1.09) or the non-IVF group (SIR, 1.00; 95% CI, 0.88-1.15). At the age of 55 years, cumulative incidence rates of breast cancer were 3.0% in the IVF group and 2.9% in the non-IVF group (P = 0.85). With longer time since treatment (>= 20 years), the SIR did not increase in the IVF group (SIR, 0.92; 95% CI, 0.73-1.15) or in the non-IVF group (SIR, 1.03; 95% CI, 0.82-1.29). Women with 7 or more IVF cycles had a significantly decreased risk of breast cancer than did women who were treated with 1 to 2 IVF cycles; the HR was 0.55, with a 95% CI of 0.39 to 0.77. The risk was also significantly lower (HR, 0.77; 95% CI, 0.61-0.96) after poor response to the first IVF cycle ( = 4 collected oocytes). These data show that IVT treatment did not increase the risk of breast cancer in a cohort of women undergoing fertility treatment in the Netherlands between 1980 and 1995 when compared with women who received non-IVF treatment or those in the general population after a median follow-up of 21 years. These findings are consistent with those from recent reviews showing no significant increase in long-term risk of breast cancer among IVF-treated women.

Women with severe menopausal symptoms can, at their request, be treated effectively with hormone therapy. Good information about the advantages and disadvantages of hormone therapy should precede this decision. For women with breast cancer or an inherited increased risk of breast cancer and severe, often therapy-related climacteric symptoms, a high degree of reticence is appropriate in relation to hormone therapy. If the quality of life is seriously affected in these often-young women with these iatrogenic climacteric complaints, then careful consideration must be given to the various treatment modalities.

Objective To evaluate the supplementary value of adding hyperthermia to radiotherapy in patients with primary vaginal cancer. Study design Cohort of 44 patients diagnosed with primary vaginal cancer between 1990 and 2002 was assessed. Survival rates and median survival of patients with primary vaginal cancer undergoing radiotherapy with and without hyperthermia were compared. Hyperthermia was solely added to radiotherapy in case of a tumor size >4 cm in diameter for FIGO stage III disease. Results The calculated overall 5-year survival of primary vaginal cancer was 63%. In comparison to histologic high grade tumors, higher survival rates for histologic low grade tumors were calculated. For FIGO stage III of disease, the addition of hyperthermia to radiotherapy for tumors >4 cm in diameter resulted similar survival rates and median survival when compared to those achieved by radiotherapy as monotherapy in tumors of Conclusions The addition of hyperthermia to radiotherapy might result in better survival rates in primary vaginal cancer for tumors >4 cm in diameter. The supplementary effect of hyperthermia to radiotherapy may be a feasible and beneficial approach in the treatment of vaginal cancer.

Objectives The aim of this study was to evaluate whether the efficiency of the current diagnostic work up following postmenopausal bleeding could be improved by diagnostic strategies that take into account characteristics of the women in addition to the currently recommended transvaginal measurement of endometrial thickness to determine for subsequent histological assessment. Design Multicenter, prospective cohort study. Setting A university hospital and seven teaching hospitals in the Netherlands. Sample Consecutive women not using hormone replacement therapy, presenting with postmenopausal bleeding. Methods Five hundred and forty women underwent transvaginal sonography, and in case of endometrial thickness (double layer) above 4 mm, subsequent endometrial sampling was performed. Presence of carcinoma was ruled out by the absence of abnormalities in histological specimen or by an uneventful follow up of at least 6 months. Main outcome measures Probability of endometrial carcinoma was estimated by multivariable logistic regression models. For each diagnostic strategy, we calculated diagnostic accuracy (area under receiver operating characteristic curve [AUC]), negative predictive value (NPV) and the number of diagnostic procedures. Results A strategy with transvaginal sonography alone with a fixed threshold incorrectly classified 0.7% of the women as nonmalignant (NPV: 99.3% [98.5–100%]), with 97% sensitivity and 56% specificity. A strategy integrating characteristics of the women with transvaginal sonography could result in less false reassurances (NPV: 99.6% [99.2–100%]), with only marginal decrease in diagnostic procedures, or a minor increase in false reassurances (NPV: 99.0% [98.3–100%]), with a substantial reduction (15–20%) in the procedures. AUCs associated with these strategies could improve from 0.76 (0.73–0.79) for transvaginal sonography alone to 0.90 (0.87–0.93) for the integrated strategy. Conclusion Taking into account the characteristics of the women could increase the efficiency of the diagnostic work up for postmenopausal bleeding.

Contains fulltext : 51607.pdf (Publisher’s version ) (Closed access) BRCA1/2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/2 mutation carriers. In this multicentre, observational, follow-up study we examined medical record data of a consecutive series of 888 BRCA1/2 mutation carriers who started annual screening with transvaginal ultrasonography and serum CA125 between 1993 and 2005. The women were annually screened for 75% of their total period of follow-up. Compliance decreased with longer follow-up. Five of the 10 incident cancers were interval tumours, diagnosed in women with a normal screening result within 3-10 months before diagnosis. No difference in stage distribution between incident screen-detected and interval tumours was found. Eight of the 10 incident cancers were stage III/IV (80%). Cancers diagnosed in unscreened family members had a similar stage distribution (77% in stage III/IV). The observed number of cases detected during screening was not significantly higher than expected (Standardized Incidence Ratio (SIR): 1.5, 95% confidence interval: 0.7-2.8). For the subgroup that was fully compliant to annual screening, a similar SIR was found (1.6, 95% confidence interval: 0.5-3.6). Despite annual gynaecological screening, a high proportion of ovarian cancers in BRCA1/2 carriers are interval cancers and the large majority of all cancers are diagnosed in advanced stages. Therefore, it is unlikely that annual screening will reduce mortality from ovarian cancer in BRCA1/2 mutation carriers.

Objective: The value of follow-up after treatment for endometrial cancer will be discussed. Study design: We evaluated our clinical experience, including mode of detection, of patients with recurrent endometrial cancer treated in the Erasmus Medical Centre in Rotterdam over a 20-year period. Clinical data and histopathological features from 64 patients were analyzed. Survival was analyzed with a Kaplan-Meier curve. Results: Twenty-two patients had a local recurrence, 30 had a distant recurrence and 12 had simultaneous local and distant recurrent disease. Ninety-five percent of the local recurrences and 67% of the distant recurrences were detected within three years. Twenty-seven patients had a screen-detected recurrence, 34 had an interval screening recurrence and two had a chance finding recurrence. The overall survival rate at two years was 70% and at five years 53%. Patients with a screen-detected recurrence had a 5-year survival rate of 62%, while patients with interval screening and chance finding recurrences had a 5-year survival rate of 47%. Conclusion: A follow-up program in the first three years after primary treatment of endometrial cancer is useful in detecting recurrent disease. We have no reason to use a different program of follow-up in patients with low risk primary disease.

Aim of the study Results on tumour characteristics and survival of hereditary breast cancer (BC), especially on BRCA2-associated BC, are inconclusive. The prognostic impact of the classical tumour and treatment factors in hereditary BC is insufficiently known. Methods We selected 103 BRCA2-, 223 BRCA1- and 311 non-BRCA1/2 BC patients (diagnosis 1980–2004) from the Rotterdam Family Cancer Clinic. To correct for longevity bias, analyses were also performed while excluding index patients undergoing DNA testing ⩾2 years after BC diagnosis. As a comparison group, 759 sporadic BC patients of comparable age at and year of diagnosis were selected. We compared tumour characteristics, the occurrence of ipsilateral recurrence (LRR) and contralateral BC (CBC) as well as distant disease-free (DDFS), BC-specific (BCSS) and overall survival (OS) between these groups. By multivariate modelling, the prognostic impact of tumour and treatment factors was investigated separately in hereditary BC. Results We confirmed the presence of the particular BRCA1-phenotype. In contrast, tumour characteristics of BRCA2-associated BC were similar to those of non-BRCA1/2 and sporadic BC, with the exception of a high risk of CBC (3.1% per year) and oestrogen-receptor (ER)-positivity (83%). No significant differences between BRCA2-associated BC and other BC subgroups were found with respect to LRR, DDFS, BCSS and OS. Independent prognostic factors for BC-specific survival in hereditary BC (combining the three subgroups) were tumour stage, adjuvant chemotherapy, histologic grade, ER status and a prophylactic (salpingo-)oophorectomy. Conclusions Apart from the frequent occurrence of contralateral BC and a positive ER-status, BRCA2-associated BC did not markedly differ from other hereditary or sporadic BC. Our observation that tumour size and nodal status are prognostic factors also in hereditary BC implies that the strategy to use these factors as a proxy for ultimate mortality appears to be valid also in this specific group of patients.

Objectives: Suboptimal debulking (>1 cm residual tumor) results in poor survival rates for patients with an advanced stage of ovarian cancer. The purpose of this study was to develop a prediction model, based on simple preoperative parameters, for patients with an advanced stage of ovarian cancer who are at risk of suboptimal cytoreduction despite maximal surgical effort. Methods: Retrospective analysis of 187 consecutive patients with a suspected clinical diagnosis of advanced-stage ovarian cancer undergoing upfront debulking between January 1998 and December 2003. Preoperative parameters were Karnofsky performance status, ascites and serum concentrations of CA 125, hemoglobin, albumin, LDH and blood platelets. The main outcome parameter was residual tumor >1 cm. Univariate and multivariate logistic regression was employed for testing possible prediction models. A clinically applicable graphic model (nomogram) for this prediction was to be developed. Results: Serum concentrations of CA 125 and blood platelets in the group with residual tumor >1 cm were higher in comparison to the optimally cytoreduced group (p < 0.0001 and 1 cm based on serum levels of CA 125 and albumin was established. Conclusion: Postoperative residual tumor despite maximal surgical effort can be predicted by preoperative CA 125 and serum albumin levels. With a nomogram based on these two parameters, probability of postoperative residual tumor in each individual patient can be predicted. This proposed nomogram may be valuable in daily routine practice for counseling and to select treatment modality.

OBJECTIVE: To determine the incidence of parametrial involvement in a select group of patients with early cervical cancer. METHODS: We retrospectively reviewed the records of patients with cervical cancer and a maximum tumor diameter of 2 cm, infiltration depth

Background. The purpose of this study is to determine: 1. the effect of treatment for Hodgkin's lymphoma on ovarian function, and 2. the interventions to relieve postmenopausal symptoms. Methods. Seventy-seven consecutive patients treated between 1989 and 2003 in the Rotterdam region for Hodgkin's lymphoma stages I and II were approached for this study. A questionnaire consisting of 45 questions was carried out to evaluate premature menopausal symptoms, hormonal replacement therapy and use of contraception, menstrual cycle, and subsequent pregnancies. Results. After informed consent 67 patients were willing to participate in the study and 66 patients filled in a questionnaire. After antitumor treatment 13 patients developed treatment-related premature ovarian failure, 35 patients had a spontaneous cycle, and 18 patients could not be classified as they used hormonal contraception. Women who developed treatment-related premature ovarian failure had a significantly higher mean age at the start of treatment for Hodgkin's lymphoma than women who remained premenopausal (p

The pleomorphic adenoma of the vulva is an extremely scarce diagnosis. This form of neoplasm is more frequently observed in other topographic sites of the human body. Treatment modalities largely derive from experiences with the pleomorphic adenoma located in these other sites. As a result of similarity with other tumors and scarcity of the neoplasm, the diagnosis of pleomorphic adenoma of the vulva is easily missed in daily routine practice. Recurrences of this neoplasm are frequently observed with an estimated incidence of malignant transformation of 25%. Addressing this previously mentioned issue, an extensive surgical excision and long-term follow-up is advocated. This report is illustrated by the case of a 66-year-old woman who was admitted to our hospital with a pleomorphic adenoma of the vulva, diagnosed by pathologic assessments following surgical excision. As a result of the rarity of this diagnosis, characteristics and treatment of extravulvar in addition to vulvar localizations of the pleomorphic adenoma are reviewed.

In advanced endometrial cancer, the importance of peritoneal cytology and optimal surgical cytoreduction remain subjects of discussion. We evaluated our clinical experience of 67 patients with FIGO stage III and IV endometrial cancer treated in the Erasmus Medical Centre in Rotterdam over a 20-year period with an emphasis on stage IIIA disease based on positive cytology only and optimal cytoreduction. Lymphadenectomy was not routinely performed and peritoneal cytology was examined in 74% of the patients. Stage IIIA disease was found in 33 patients, 10 of whom had positive cytology only. Analysis showed that incidence of recurrence and survival rates of patients with stage IIIA disease based on positive cytology only were comparable with stage IIIA disease based on other factors. In 50 patients, it was possible to remove all macroscopic tumor, whereas in 17 patients, an optimal cytoreduction was not achievable. The 2- and 5-year survival rates after optimal cytoreduction were 82.2% and 65.6%; where this could not be achieved, these figures were 50.8% and 40.6%. In advanced endometrial cancer patients, positive peritoneal cytology seems an important prognostic factor in stage IIIA disease if lymph node status is unknown. Survival is improved if optimal surgical cytoreduction is achievable.

Background. Peripheral primitive neuroectodermal tumor (PNET) of the cervix uteri is extremely rare. Between 1987 and 2002, there have been eight cases described in the English literature. The treatment policies in these eight cases differed considerably, partly due to the rarity of the disease and to differing time periods of diagnosis and treatment. Case. At the end of 2002, a 21-year-old woman presented with a PNET of the cervix uteri at our institute, the Erasmus Medical Center. For the appropriate treatment in this case, we reviewed the literature and decided that the treatment should be different from the local surgical treatment followed by additional treatments as most of the earlier reports describe. Conclusion. In view of the current knowledge of PNET belonging to the family of Ewing's sarcoma, and the improvement of treatment outcome in these tumors due to dose-intensive neo-adjuvant chemotherapy, patients with PNET of the cervix should be treated in accordance to the protocol for bony Ewing's sarcoma with multimodality therapy by means of induction chemotherapy, surgery, and consolidation chemotherapy.

Objective Women at high risk of ovarian cancer are currently offered two options: either surveillance or prophylactic bilateral salpingo-oophorectomy. The efficacy and outcome of surveillance remain unclear. Methods We performed a retrospective study. Between 1994 and 2000, we screened 383 high-risk women, of which 152 were BRCA1/2 mutation carriers. Surveillance consisted of annual gynecological examination, transvaginal ultrasound, and serum CA125 measurement. Exploratory or prophylactic surgery was performed in selected cases. Results There were no screen-detected primary ovarian cancers. Abnormal results at surveillance were observed in 74 (19.3%) of women; in 47 (63.5%), the abnormalities disappeared spontaneously. Exploratory surgery was performed in 20 (27.0%) women in whom one malignancy was found (metastatic breast cancer in the ovary). A rising CA125 value prompted further (non-surgical) evaluation in three women with a history of breast cancer: recurrent breast cancer was diagnosed in two women; in the third, a chondrosarcoma was found. 133 women opted for prophylactic bilateral salpingo-oophorectomy, whereby two unexpected malignancies were found (fallopian tube cancer and metastatic breast cancer). One interval primary ovarian cancer occurred, presenting as papillary serous carcinoma of the peritoneum 14 months after prophylactic bilateral salpingo-oophorectomy. Complications of prophylactic surgery were encountered in 15 (11.5%) women. Conclusions Ovarian cancer surveillance has limited sensitivity, and a high number of false positive findings. This can lead to unnecessary surgical interventions, possibly resulting in surgery-related complications. It is important to inform high-risk women of these limitations. For now, prophylactic bilateral salpingo-oophorectomy remains the optimal risk-reducing strategy for women at high risk.

BACKGROUND. Patients with advanced cervical carcinoma are treated routinely with radiotherapy and cisplatin-containing chemotherapy. It has been shown that hyperthermia can improve the results of both radiotherapy and cisplatin. In the current study, the feasibility and efficacy of the combination of all three modalities was studied in previously untreated patients with cervical carcinoma. METHODS. Patients with advanced cervical carcinoma were registered prospectively in the U.S., Norway, and the Netherlands. External-beam radiotherapy and brachytherapy were administered for a biologically effective dose ! 86.7 gray. At least 4 courses of weekly cisplatin (40 mg/m 2 ) and 4 sessions of weekly locoregional hyperthermia were added to radiotherapy. RESULTS. Sixty-eight patients with a median age of 45 years were enrolled. Fulldose radiotherapy was delivered to all patients according to plan. At least 4 courses of chemotherapy were received by 97% of patients, and at least 4 courses of hyperthermia treatment were received by 93% of patients. Toxicity was fully comparable to that described for chemoradiotherapy alone, and the median total treatment time was 45 days. Complete remission was achieved by 61 patients (90%). After a median follow-up of 538 days, 74% of patients remained alive without signs of recurrence, and the overall survival rate was 84%. CONCLUSIONS. The combination of full-dose radiotherapy, chemotherapy, and hyperthermia was feasible and effective in a multicenter international setting among patients with advanced cervical carcinoma. A Phase III study comparing this novel triplet with standard chemoradiation, designed to show at least a 15% improvement in overall survival, has been launched. Cancer 2005;104:763‐70. © 2005 American Cancer Society.

Background. To evaluate the effectiveness of intravaginal electrical stimulation (ES) of the pelvic floor for urinary incontinence in elderly women, and to determine whether ES of the pelvic floor is a preferable treatment for urinary incontinence in elderly women. Methods. Postmenopausal women (age 65 years or older) were enrolled in a randomized clinical trial and underwent every-other-day ES of the pelvic floor, or a daily Kegel exercise (KE) program. Objective outcome variables were: (1) Urinary leakage (during a standardized PAD test), (2) pelvic muscle strength (measured by a perineometer), and (3) detrusor instability (on ambulant urodynamic registration). Subjective outcome variables were women's subjective assessment of change in urinary symptoms based on the PRAFAB score. Twenty-four women treated with ES and 11 women treated with Kegel exercises completed the 8-week study program. The Chi-square test was used for statistical analysis. Results. No significant improvement in objective outcome var...

Background Our aim was to examine whether women who had a low number of retrieved oocytes at their first IVF attempt reach the menopausal transition and/or the natural menopause earlier than women of similar ages with a high number of retrieved oocytes. Methods We conducted a retrospective cohort study among women in The Netherlands who received IVF treatment between 1983 and 1995. For the present study, we selected all cohort members who had a regular menstrual cycle at the time of the first visit to the gynaecologist (n = 4601). After a median follow-up of 5.5 years, 3871 (84%) women still had a regular menstrual cycle pattern, 547 (12%) women had entered the menopausal transition (i.e. no menses for 3-11 months, use of HRT or irregular menstrual cycles) and 27 (1%) women had reached natural menopause. We examined whether the quantity and the quality of the retrieved oocytes were related to an early menopausal transition and early menopause. The live birth rate per embryo transfer was used as indicative of the quality of the oocytes. Results The age-adjusted odds ratio (OR) for having entered the menopausal transition/natural menopause for women with a poor response (0-3 oocytes) at their first IVF attempt was 3.1 [95% confidence interval (CI) 2.4-3.8] compared with women with a normal response (>3 oocytes). Women who were stimulated with gonadotrophins during IVF treatment but did not undergo an IVF puncture because of an anticipated poor response (cancelled IVF cycle) had an age-adjusted OR of 3.2 (95% CI 2.3-4.3). There was no significant difference in the odds of reaching the menopausal transition/natural menopause, after adjustment for age and the number or retrieved oocytes, between women who did and did not have a live birth following their first embryo transfer (OR = 1.3; 95% CI 0.95-1.7). Conclusions These results indicate that a low remaining quantity of oocytes, as reflected by a low number of retrieved oocytes at first IVF treatment, is an important predictor of the risk of an early menopausal transition/natural menopause. The quality of the oocytes did not affect the risk of an early menopausal transition/natural menopause once the number of retrieved oocytes had been taken into account. Our findings support the concept that the number of remaining follicles in the ovaries is one of the main aspects of reproductive ageing.

Purpose: To explore long-term psychosocial consequences of carrying a BRCA1/2 mutation and to identify possible risk factors for long-term psychological distress. Patients and Methods: Five years after genetic test disclosure, 65 female participants (23 carriers, 42 noncarriers) of our psychological follow-up study completed a questionnaire and 51 participants were interviewed. We assessed general and hereditary cancer-related distress, risk perception, openness to discuss the test result with relatives, body image and sexual functioning. Results: Carriers did not differ from noncarriers on several distress measures and both groups showed a significant increase in anxiety and depression from 1 to 5 years follow-up. Carriers having undergone prophylactic surgery (21 of 23 carriers) had a less favorable body image than noncarriers and 70% reported changes in the sexual relationship. A major psychological benefit of prophylactic surgery was a reduction in the fear of developing cancer. Predictors of long-term distress were hereditary cancer-related distress at blood sampling, having young children, and having lost a relative to breast/ovarian cancer. Long-term distress was also associated with less open communication about the test result within the family, changes in relationships with relatives, doubting about the validity of the test result, and higher risk perception. Conclusion: Our findings support the emerging consensus that genetic predisposition testing for BRCA1/2 does not pose major mental health risks, but our findings also show that the impact of prophylactic surgery on aspects such as body image and sexuality should not be underestimated, and that some women are at risk for high distress, and as a result, need more attentive care.

Summary Background Transgenerational effects of diethylstilbestrol (DES) have been reported in animals, but effects in human beings are unknown. Alerted by two case reports, we aimed to establish the risk of hypospadias in the sons of women who were exposed to DES in utero. Methods We did a cohort study of all sons of a Dutch cohort of 16 284 women with a diagnosis of fertility problems. We used a mailed questionnaire assessing late effects of fertility treatment to identify boys with hypospadias. We compared the prevalence rate of hypospadias between boys with and without maternal DES exposure in utero. Findings 16 284 mothers (response rate 67%) reported 8934 sons. The mothers of 205 boys reported DES exposure in utero. Four of these children were reported to have hypospadias. In the remaining 8729 children, only eight cases of hypospadias were reported (prevalence ratio 21·3 [95% CI 6·5–70·1]). All cases of hypospadias were medically confirmed. Maternal age or fertility treatment did not affect the risk of hypospadias. Children conceived after assisted reproductive techniques such as in-vitro fertilisation were not at increased risk of hypospadias compared with children conceived naturally (1·8, 0·6–5·7). Interpretation Our findings suggest an increased risk of hypospadias in the sons of women exposed to DES in utero. Although the absolute risk of this anomaly is small, this transgenerational effect of DES warrants additional studies.

This review summarises preclinical and clinical data on effects of endogenous and exogenous estrogens on probability of breast cancer diagnosis, and on the course and efficacy of breast cancer therapies. The data indicate that higher endogenous estrogen exposure (e.g. pregnancy, early menarche and late menopause, estrogen levels in future breast cancer patients, obesity) or exogenous estrogens (oral contraceptives; hormone replacement therapies) may be associated with an increased probability of breast cancer diagnosis. However, there is little evidence that estrogens have deleterious effects on the course of breast cancer. Moreover, increased incidence of breast cancer diagnosis after prolonged hormone replacement therapy (HRT) use seems to be associated with clinically less advanced disease. In studies assessing both diagnosis and mortality, HRT is frequently associated with reduced mortality compared to never users. The interaction of progestagens and estrogens on the probability of breast cancer diagnosis is complex and dependent on type of progestagens and regimens employed. Efficacy of current treatment modalities for breast cancer (surgery, irradiation, adjuvant therapy or chemotherapy) is not negatively influenced by estrogens at concentrations considerably higher than those attained with current HRT preparations. Although it cannot be excluded that estrogens increase the probability of breast cancer diagnosis, available data fail to demonstrate that, once breast cancer has been diagnosed, estrogens worsen prognosis, accelerate the course of the disease, reduce survival or interfere with the management of breast cancer. It may therefore be concluded that the prevalent opinion that estrogens and estrogen treatment are deleterious for breast cancer, needs to be revisited. However, results of ongoing prospective, randomised clinical trials with different HRT regimens in healthy women or breast cancer survivors are needed to provide more definite conclusions about risks and benefits of HRT.

Objective: to assess the interaction between postmenopausal hormone replacement therapy (HRT) and various reproductive risk factors for breast cancer such as early menarche, late menopause, late first delivery and nulliparity. Design: three cohort studies and fourteen case control studies, published between 1975 and 1997, provided relative risks (RRs) of HRT use in women with, as well as in those without, a reproductive risk factor for breast cancer. Methods: using an additive RR model reported before, we investigated whether the RR for breast cancer in women with a combination of HRT and a given reproductive risk factor result from a simple addition of RRs of HRT on the one hand, and of the pre-existing reproductive risk factor on the other hand, or that synergism between both risk factors occurs. Results: simple addition of RRs was shown in the case of early menarche and late menopause. Less increase of risk, suggesting antagonism, was found for both late first delivery and nulliparity in combination with HRT use. Conclusion: we could not observe any synergistic effect of the combined risks of any of the following reproductive risk factors for breast cancer: early menarche, late menopause, late first delivery or nulliparity on the one hand, with the risk resulting from HRT use on the other hand. Therefore, as far as the risk of breast cancer is concerned, the use of HRT appears not to be highly detrimental in women with a reproductive breast cancer risk factor, as it results in not more than a simple addition of risks at the most.

Item does not contain fulltext BACKGROUND: Recent studies suggested an improved overall survival (OS) for BRCA2- versus BRCA1-associated epithelial ovarian cancer (EOC), whereas the impact of chemotherapy is not yet clear. In a nationwide cohort, we examined the results of primary treatment, progression-free survival (PFS), treatment-free interval (TFI), and OS of BRCA1 versus BRCA2 EOC patients. METHODS: Two hundred and forty-five BRCA1- and 99 BRCA2-associated EOC patients were identified through all Dutch university hospitals. Analyses were carried out with the Pearson's Chi-square test, Kaplan-Meier, and Cox regression methods. RESULTS: BRCA1 patients were younger at EOC diagnosis than BRCA2 patients (51 versus 55 years; P < 0.001), without differences regarding histology, tumor grade, and International Federation of Gynecology and Obstetrics (FIGO) stage. Complete response rates after primary treatment, including chemotherapy, did not differ between BRCA1 (86%) and BRCA2 patients (90%). BRCA1 versus BRCA2 patients had a shorter PFS (median 2.2 versus 3.9 years, respectively; P = 0.006), TFI (median 1.7 versus 2.8 years; P = 0.009), and OS (median 6.0 versus 9.7 years; P = 0.04). Differences could not be explained by age at diagnosis, FIGO stage or type of treatment. CONCLUSIONS: PFS and OS were substantially longer in BRCA2- than in BRCA1-associated EOC patients. While response rates after primary treatment were similarly high in both groups, TFI, as surrogate for chemosensitivity, was significantly longer in BRCA2 patients.

Objectives To measure progress against endometrioid endometrial carcinoma (EEC) in the Netherlands by analyzing trends in incidence, survival and mortality simultaneously. Study design Descriptive study of incidence, survival and mortality rates of women with EEC in the Netherlands. Rates were age-standardized to the European standard population. Population-based data were extracted from the nationwide Dutch Cancer Registry (NCR) between 1989 and 2009. Mortality data since 1989 came from Statistics Netherlands. European age standardized incidence rates were calculated according to age, histology and stage. Five year relative survival estimates were calculated in four periods. Optimal progress against cancer is defined as decreasing incidence and/or improving survival accompanied by declining mortality. Results 80% of the 32,332 patients newly diagnosed with a corpus uteri malignancy had an EEC. The incidence of EEC rose significantly from 11/100,000 to 15/100,000, being most pronounced in women with FIGO stage IB and in the group with grade 1&2 tumours (P

The experience from using different hormonal trials in 33 ovarian cancer patients, who were beyond the stage of standard therapies and experimental cytotoxic therapies in a single institution, are reported. Agents used were progestins, an antiestrogen (tamoxifen), an antiandrogen (flutamide) and a GnRH-agonist (decapeptyl). Twenty-one patients completed at least 8 weeks of treatment. Two patients obtained an objective response (10%): one partial response on tamoxifen for 6 months and one complete response on decapeptyl for 38 + months. Two further patients achieved disease stabilizations on tamoxifen and flutamide for 6 and 8 months respectively. Although the objective response rate with hormonal therapies is limited in these circumstances the absence of important toxicities favor their use. It is suggested to further study this in patients who do not reach a complete response after standard induction chemotherapy, particularly in those with well-differentiated tumors.

BACKGROUND: The objective of this study was to assess the incidence of primary breast cancer (PBC) and contralateral breast cancer (CBC) in patients who had BRCA1/BRCA2-associated epithelial ovarian cancer (OC). METHODS: From the database of the Rotterdam Family Cancer Clinic, patients who had BRCA-associated OC without a history of unilateral breast cancer (BC) (at risk of PBC; n = 79) or with a history of unilateral BC (at risk of CBC; n = 37) were selected. The control groups consisted of unaffected BRCA mutation carriers (n = 351) or mutation carriers who had a previous unilateral BC (n = 294), respectively. The risks of PBC and CBC were calculated using the Kaplan-Meier survival method with death considered as a competing risk event. RESULTS: Women with BRCA-associated OC had lower 2-year, 5-year, and 10-year risks of PBC (3%, 6%, and 11%, respectively) compared with unaffected mutation carriers (6%, 16%, and 28%, respectively; P = .03), although they had a considerably higher mortality rate at similar time points (13%, 33%, and 61%, respectively, vs 1%, 2%, and 2%, respectively; P < .001). In BRCA mutation carriers with a previous unilateral BC, the 2-year, 5-year, and 10-year risks of CBC were nonsignificantly lower in patients with OC than in those without OC (0%, 7%, and 7%, respectively, vs 6%, 16%, and 34%, respectively; P = .06), whereas the mortality rate was higher in patients with OC (19%, 34%, and 55%, respectively, vs 4%, 11%, and 21%, respectively; P < .001). CONCLUSIONS: Patients with BRCA-associated OC had a lower risk of developing a subsequent PBC or CBC than mutation carriers without OC, whereas the risk of dying from OC was greater than the risk of developing BC. These data may facilitate more tailored counseling for this patient subgroup, although confirmative studies are warranted. Cancer 2013. © 2012 American Cancer Society.

The effect of chemotherapy on the different components of uterine and ovarian carcinosarcoma is largely unknown. This report describes six patients with advanced carcinosarcoma, five of whom received 4 cycles of doxorubicin and ifosfamide (AI) directed at the sarcomatous component of the tumor. Responses in these five patients at second-look laparotomy were: one complete response, two partial responses (persistence of only the carcinomatous component), one stable disease, and one progressive disease (both components still present in both cases). Thereafter 4 cycles of a cisplatin-based regimen were scheduled. Response to the cisplatin-containing regimen was only evaluated clinically. The sixth patient (with no macroscopic disease left after initial surgery) received 6 cycles of a cisplatin-based chemotherapy from the onset and was found to be in complete response at relaparotomy. Median progression-free survival for all patients was 15 months and median survival 21 months. A literature survey showed that carcinosarcoma differs from adult soft tissue sarcomas with respect to responsiveness to chemotherapy. Cisplatin and ifosfamide are active as single agents, whereas the response to single-agent doxorubicin seems to be lower. The data suggest, however, that superior response rates and increased survival times are achieved with cisplatin/doxorubicin-based chemotherapy. The sensitivity of carcinosarcoma to cisplatin supports the recent view that carcinosarcoma of the female genital tract is possibly a high grade carcinoma with metaplastic sarcomatous elements.

Background Because it is insufficiently clear whether BRCA-associated epithelial ovarian cancer (EOC) is more chemosensitive than sporadic EOC, we examined response to chemotherapy, progression-free survival (PFS) and overall survival (OS) in BRCA1- and BRCA2-associated versus sporadic EOC patients. Methods Data about patient characteristics, response to and outcome after primary therapy, including chemotherapy, were collected from 99 BRCA1, 13 BRCA2 and 222 sporadic patients. Analyses were carried out using a chi-square test and Kaplan–Meier and Cox regression methods. Results Complete response (CR) or no evidence of disease (NED) was observed in 87% of the BRCA1 patients, progressive disease (PD) in 2%, being 71% and 15%, respectively, in sporadic EOC patients (P = 0.002). In BRCA2 patients, 92% had CR/NED, and none PD (P = 0.27). Median PFS in BRCA1, BRCA2 and sporadic patients was 2.1 [95% confidence interval (CI) 1.9–2.5] years (P = 0.006), 5.6 (95% CI 0.0–11.5) years (P = 0.008) and 1.3 (95% CI 1.1–1.5) years, respectively. Median OS in the three groups was 5.9 (95% CI 4.7–7.0) years (P 10 years (P = 0.008), and 2.9 (95% CI 2.2–3.5) years, respectively. A trend for a longer PFS and OS in BRCA2 compared with BRCA1 patients was observed. Conclusion Compared with sporadic EOC patients, both BRCA1- and BRCA2-associated patients have improved outcomes after primary therapy, including chemotherapy.

Contains fulltext : 98452.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To estimate the prevalence and identify the factors associated with previous pelvic organ prolapse (POP) and/or incontinence surgery. STUDY DESIGN: In a cross-sectional study, all women who were aged 45-85 years and registered in eight general practices were invited to participate. They completed standardised questionnaires (the urinary distress inventory (UDI) and the defaecatory distress inventory (DDI)) and answered questions on previous pelvic floor surgery. RESULTS: Out of 2979 women eligible for this study, 1380 women were included. Previous surgery had been performed in 119 women. The prevalence of surgery increased with age, with a prevalence of 20.3% in the age group 76-85 years. Pelvic floor symptoms were more prevalent in women who had undergone previous surgery, with higher UDI and DDI scores. Factors associated with previous surgery were age, higher BMI, POP symptoms during pregnancy and previous hernia surgery. CONCLUSION: In The Netherlands, approximately one in five women will undergo surgery for POP and/or incontinence during her lifetime. The women who underwent surgery were more likely to have symptoms of pelvic floor dysfunction than those who did not undergo surgery.

Contains fulltext : 98453.pdf (Publisher’s version ) (Closed access) INTRODUCTION AND HYPOTHESIS: To study the prevalence and risk factors of overactive bladder (OAB) symptoms and its relationship with symptoms of pelvic organ prolapse (POP). METHODS: This is a cross-sectional study including women aged between 45 and 85 years, registered in eight general practices. All women were asked to self complete the validated Dutch translated questionnaires. All symptoms were dichotomized as present or absent based on responses to each symptom and degree of bother. RESULTS: Forty-seven percent of the women filled out the questionnaire. Prevalence of urgency was 34% and the prevalence of any OAB symptoms 49%. Prevalence of OAB symptoms increased with advancing age. Symptoms of POP were an independent risk factor for symptomatic OAB. Other risk factors were continence and prolapse surgery in the past, age above 75, overweight, postmenopausal status and smoking. CONCLUSIONS: The prevalence of any OAB symptoms was 49%. POP symptoms were an independent risk factor for symptomatic OAB.