Risk-reducing salpingectomy with delayed oophorectomy to prevent ovarian cancer in women with an increased inherited risk: insights into an alternative strategy.

Epithelial ovarian cancer (EOC) is the most lethal type of gynaecological cancer, due to lack of effective screening possibilities and because the disease tends to metastasize before onset of symptoms. Women with an increased inherited risk for EOC are advised to undergo a risk-reducing salpingo-oophorectomy (RRSO), which decreases their EOC risk by 96% when performed within guideline ages. However, it also induces premature menopause, which has harmful consequences. There is compelling evidence that the majority of EOCs originate in the fallopian tube. Therefore, a risk-reducing salpingectomy with delayed oophorectomy (RRS with DO) has gained interest as an alternative strategy. Previous studies have shown that this alternative strategy has a positive effect on menopause-related quality of life and sexual health when compared to the standard RRSO. It is hypothesized that the alternative strategy is non-inferior to the standard RRSO with respect to oncological safety (EOC incidence). Three prospective studies are currently including patients to compare the safety and/or quality of life of the two distinct strategies. In this article we discuss the background, opportunities, and challenges of the current and alternative strategy.

Regularized parametric survival modeling to improve risk prediction models.

We propose to combine the benefits of flexible parametric survival modeling and regularization to improve risk prediction modeling in the context of time-to-event data. Thereto, we introduce ridge, lasso, elastic net, and group lasso penalties for both log hazard and log cumulative hazard models. The log (cumulative) hazard in these models is represented by a flexible function of time that may depend on the covariates (i.e., covariate effects may be time-varying). We show that the optimization problem for the proposed models can be formulated as a convex optimization problem and provide a user-friendly R implementation for model fitting and penalty parameter selection based on cross-validation. Simulation study results show the advantage of regularization in terms of increased out-of-sample prediction accuracy and improved calibration and discrimination of predicted survival probabilities, especially when sample size was relatively small with respect to model complexity. An applied example illustrates the proposed methods. In summary, our work provides both a foundation for and an easily accessible implementation of regularized parametric survival modeling and suggests that it improves out-of-sample prediction performance.

The effect of opportunistic salpingectomy for primary prevention of ovarian cancer on ovarian reserve: a systematic review and meta-analysis.

BACKGROUND: Opportunistic salpingectomy (OS) is an attractive method for primary prevention of ovarian cancer. Although OS has not been associated with a higher complication rate, it may be associated with earlier onset of menopause. OBJECTIVE: To provide a systematic review and meta-analysis of the effect of OS on both age at menopause and ovarian reserve. METHODS: A search was conducted in the Cochrane Library, Embase and MEDLINE databases from inception until March 2022. We included randomized clinical trials and cohort studies investigating the effect of OS on onset of menopause and/or ovarian reserve through change in anti-Müllerian hormone (AMH), antral follicle count (AFC), estradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH). Data was extracted independently by two researchers. Random-effects meta-analyses were conducted to estimate the pooled effect of OS on ovarian reserve. RESULTS: The initial search yielded 1047 studies. No studies were found investigating the effect of OS on age of menopause. Fifteen studies were included in the meta-analysis on ovarian reserve. Meta-analyses did not result in statistically significant differences in mean change in AMH (MD -0.07 ng/ml, 95%CI -0.18;0.05), AFC (MD 0.20 n, 95 % CI -4.91;5.30), E2 (MD 3.97 pg/ml, 95%CI -0.92;8.86), FSH (MD 0.33mIU/ml, 95%CI -0.15;0.81) and LH (MD 0.03mIU/ml; 95%CI -0.47;0.53). CONCLUSION: Our study shows that OS does not result in a significant reduction of ovarian reserve in the short term. Further research is essential to confirm the absence of major effects of OS on menopausal onset since clear evidence on this subject is lacking. Registration number PROSPERO CRD42021260966.

Diagnostic test accuracy of magnetic resonance imaging and pelvic floor ultrasound for diagnosis of levator ani muscle avulsion.

OBJECTIVE: To estimate the diagnostic test accuracy of magnetic resonance imaging (MRI) and pelvic floor ultrasound for levator ani muscle (LAM) avulsion in a general parous population, with view to establishing if ultrasound could substitute for MRI to diagnose LAM avulsion. METHODS: This was a cross-sectional study of 135 women 4 years after their first delivery. Signs and symptoms of pelvic floor dysfunction were assessed using validated methods. All women underwent four-dimensional transperineal ultrasound (TPUS), three-dimensional endovaginal ultrasound (EVUS) and MRI. Images were acquired at rest, on pelvic floor muscle contraction (PFMC) and on maximum Valsalva maneuver, and analyzed by two blinded observers. Predefined cut-off values were used to diagnose LAM avulsion. In the absence of a reference standard, latent class analysis (LCA) was used to establish diagnostic test characteristics for LAM avulsion as the primary outcome measure. Secondary outcomes were kappa (κ) agreement between imaging techniques, intraclass correlation coefficients (ICC) for hiatal measurements at rest, on PFMC and on maximum Valsalva maneuver, and the association of LAM avulsion with signs and symptoms of pelvic floor dysfunction. RESULTS: The prevalence of LAM avulsion was 23.0% for MRI, 11.1% for TPUS and 17.8% for EVUS. The prevalence of LAM avulsion using LCA was 15.7%. The sensitivity for LAM avulsion of TPUS (71% (95% CI, 50-90%)) and EVUS (91% (95% CI, 74-100%)) was lower than that of MRI (100% (95% CI, 84-100%)). The specificity of TPUS (100% (95% CI, 97-100%)) and EVUS (95% (95% CI, 91-99%)) was higher than that of MRI (91% (95% CI, 85-97%)). MRI and EVUS had high predictive values for the assessment of major LAM avulsion (positive predictive value (PPV), 95% and negative predictive value (NPV), 100%; PPV, 100% and NPV, 98%, respectively), while TPUS had high predictive values for minor LAM avulsion (PPV, 100% and NPV, 95%). Major LAM avulsion on MRI and EVUS was associated with anterior vaginal wall prolapse, which was not found for TPUS. The agreement in the diagnosis of LAM avulsion (κ, 0.69) and hiatal measurements (ICC, 0.60-0.81) was highest between MRI and EVUS. CONCLUSIONS: Pelvic floor ultrasound can be implemented as a triage test to assess parous women for LAM avulsion because of its high specificity. Ultrasound cannot substitute for MRI because of its lower sensitivity. The predictive ability of ultrasound is moderate for the presence, and very good for the absence, of LAM avulsion. A positive test should be confirmed by a different observer or imaging technique. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Stop routine screening for associated malignancies in cutaneous noninvasive vulvar Paget disease?

BACKGROUND: Vulvar Paget disease (VPD) is extremely rare and thought to be associated with other malignancies. OBJECTIVES: To evaluate the risk of developing breast, intestinal and urological malignancies in patients with VPD compared with the general population, and in particular to focus on the risk of malignancy in patients with cutaneous noninvasive VPD. METHODS: Data on the oncological history of patients with any type of VPD between 2000 and 2015 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. Follow-up data and a control group from the general population were obtained from the Netherlands Cancer Registry. After correction for age and calendar year at time of diagnosis, standardized incidence ratios (SIRs) for the first 3 years after VPD diagnosis were estimated with 95% confidence intervals (CIs). RESULTS: We identified 199 patients with a first diagnosis of VPD [164 noninvasive, 35 (micro)invasive] between 2000 and 2015. The SIR of developing an associated malignancy in the first 3 years after diagnosis was 4·67 (95% CI 2·66-7·64). This was due mainly to the high incidence of intestinal malignancies among patients with secondary VPD. Subgroup analysis for cutaneous noninvasive VPD did not reveal a significantly increased risk for associated malignancies: SIR 2·08 (95% CI 0·76-4·62). CONCLUSIONS: Of our patients with VPD, 76·9% were diagnosed with cutaneous noninvasive VPD, and this group has no increased risk for developing malignancies of the breast, intestine or urological tract. Our study suggests that routine screening for these malignancies in patients diagnosed with cutaneous noninvasive VPD may not be necessary.

The efficacy of ultrasound in the follow up after a negative sentinel lymph node in women with vulvar cancer: a prospective single-centre study.

OBJECTIVE: To determine the efficacy of the addition of an ultrasound of the groins in routine follow up of women with vulvar squamous cell carcinoma (SCC) after a negative sentinel lymph node (SLN). DESIGN: Prospective single-centre study. SETTING: A tertiary expert oncology centre for the treatment of vulvar cancer. POPULATION: All women with vulvar SCC with a negative SLN, treated between 2006 and 2014. METHODS: We prospectively collected data of 139 women with vulvar SCC treated with an SLN procedure. We analysed data of 76 patients with a negative SLN. Three-monthly follow-up visits consisted of physical examination combined with an ultrasound of the groins by a radiologist. MAIN OUTCOME MEASURES: The diagnostic value of ultrasound in the follow up of women with vulvar SCC with a negative SLN during the first 2 years after treatment. RESULTS: During a routine visit, two asymptomatic isolated groin recurrences were detected. Both patients were treated by inguinofemoral lymphadenectomy and adjuvant radiotherapy and are alive without evidence of disease 39 and 120 months after diagnosis. In total, 348 ultrasounds and 29 fine-needle aspiration were performed. The sensitivity of ultrasound to detect a groin metastasis was 100% (95% CI 16-100%), and specificity was 92% (95% CI 89-95%). CONCLUSIONS: Routine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences. Further research is necessary to determine the exact role of ultrasound in the follow up of patients with vulvar SCC with a negative SLN. TWEETABLE ABSTRACT: Routine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences.

Volume-controlled versus short drainage after inguinofemoral lymphadenectomy in vulvar cancer patients: A Dutch nationwide prospective study.

OBJECTIVE: Inguinofemoral lymphadenectomy for patients with vulvar squamous cell carcinoma is associated with a high incidence of postoperative wound complications, which may be influenced by inguinal drain management. The aim of this nationwide prospective study (MAMBO: Morbidity And Measurement of the BOdy) was to assess the feasibility and the incidence of complications after volume-controlled versus short drainage. METHODS: The MAMBO study consisted of two observational studies in all eight oncology centers in the Netherlands, conducted between 2012 and 2016. In the first study, the drain was removed when the production was <30ml/24h, except in the first 48h, and after a maximum of 28days (MAMBO-IA). In the second study, the drain was removed five days postoperatively regardless of production (MAMBO-IB). We assessed the complications within eight weeks after surgery using logistic regression to compare the incidence of one or more complications between the two drainage protocols, adjusting for possible confounders. RESULTS: We included 77 patients (139 groins) for volume-controlled drainage and 64 patients (112 groins) for short drainage. Volume-controlled drainage was associated with significant less lymphocele formation. Moreover, we found no difference in wound infection or primary wound breakdown. The estimated incidence of one or more complications was 46% per groin after volume-controlled drainage versus 75% after short drainage, (RD 29% (95% CI 8, 49) p=0.006). CONCLUSIONS: This prospective study shows that volume-controlled drainage is associated with significantly less complications compared to short drainage. We therefore recommend volume-controlled drainage after inguinofemoral lymphadenectomy in patients with vulvar squamous cell carcinoma.

High-risk human papillomavirus detection in self-sampling compared to physician-taken smear in a responder population of the Dutch cervical screening: Results of the VERA study.

In 2017 the cervical cancer screening program in The Netherlands will be revised. Cervical smears will primarily be tested for the presence of high-risk human papillomavirus (hrHPV) instead of cytology, and vaginal self-sampling will be offered to non-responders. This includes a potential risk that part of the women who would otherwise opt for a cervical smear will wait for self-sampling. However, self-sampling for hrHPV in a responder population has never been studied yet. The aim of this study was to investigate the applicability and accuracy of self-sampling in detecting hrHPV in a screening responder population. A total of 2049 women, aged 30-60years, participating in the screening program in The Netherlands were included from April 2013 to May 2015. After they had their cervical smear taken, women self-collected a cervicovaginal sample with a brush-based device, the Evalyn Brush. Both the cervical smear and self-sample specimen were tested with the COBAS 4800 HPV platform. The hrHPV prevalence was 8.0% (95% CI 6.9-9.2) among the physician-taken samples, and 10.0% (95% CI 8.7-11.3) among the self-samples. There was 96.8% (95% CI 96.0-97.5) concordance of hrHPV prevalence between self-samples and physician-taken samples. Women in our study evaluated self-sampling as convenient (97.1%), user-friendly (98.5%), and 62.8% preferred self-sampling over a physician-taken sampling for the next screening round. In conclusion, self-sampling showed high concordance with physician-taken sampling for hrHPV detection in a responder screening population and highly acceptable to women. Implementation of HPV-self-sampling for the responder population as a primary screening tool may be considered.

Implementing targeted expectant management in fertility care using prognostic modelling: a cluster randomized trial with a multifaceted strategy.

STUDY QUESTION: What is the effectiveness of a multifaceted implementation strategy compared to usual care on improving the adherence to guideline recommendations on expectant management for couples with unexplained infertility? SUMMARY ANSWER: The multifaceted implementation strategy did not significantly increase adherence to guideline recommendations on expectant management compared to care as usual. WHAT IS KNOWN ALREADY: Intrauterine insemination (IUI) with or without ovarian hyperstimulation has no beneficial effect compared to no treatment for 6 months after the fertility work-up for couples with unexplained infertility and a good prognosis of natural conception. Therefore, various professionals and policy makers have advocated the use of prognostic profiles and expectant management in guideline recommendations. STUDY DESIGN, SIZE, DURATION: A cluster randomized controlled trial in 25 clinics in the Netherlands was conducted between March 2013 and May 2014. Clinics were randomized between the implementation strategy (intervention, n = 13) and care as usual (control, n = 12). The effect of the implementation strategy was evaluated by comparing baseline and effect measurement data. Data collection was retrospective and obtained from medical record research and a patient questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 544 couples were included at baseline and 485 at the effect measurement (247 intervention group/238 control group). MAIN RESULTS AND THE ROLE OF CHANCE: Guideline adherence increased from 49 to 69% (OR 2.66; 95% CI 1.45-4.89) in the intervention group, and from 49 to 61% (OR 2.03; 95% CI 1.38-3.00) in the control group. Multilevel analysis with case-mix adjustment showed that the difference of 8% was not statistically significant (OR 1.31; 95% CI 0.67-2.59). The ongoing pregnancy rate within six months after fertility work-up did not significantly differ between intervention and control group (25% versus 27%: OR 0.72; 95% CI 0.40-1.27). LIMITATIONS REASONS FOR CAUTION: There is a possible selection bias, couples included in the study had a higher socio-economic status than non-responders. How this affects guideline adherence is unclear. Furthermore, when powering for this study we did not take into account the unexpected improvement of adherence in the control group. WIDER IMPLICATIONS OF THE FINDINGS: Generalization of our results to other countries with recommendations on expectant management might be questionable because barriers for expectant management can be very different in other countries. Furthermore, due to a large variation in improved adherence rate in the intervention group it will be interesting to further analyse the process of implementation in each clinic with a process evaluation on professionals and couples' exposure to and experiences with the strategy. STUDY FUNDING/COMPETING INTEREST(S): Supported by Netherlands Organisation for Health Research and Development (ZonMW, project number 171203005). No competing interests. TRIAL REGISTRATION NUMBER: Dutch trial Register, www.trialregister.nl NTR3405. TRIAL REGISTRATION DATE: 19 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: 10 July 2012.

Can the FIGO 2000 scoring system for gestational trophoblastic neoplasia be simplified? A new retrospective analysis from a nationwide dataset.

BACKGROUND: Worldwide introduction of the International Fedaration of Gynaecology and Obstetrics (FIGO) 2000 scoring system has provided an effective means to stratify patients with gestational trophoblastic neoplasia to single- or multi-agent chemotherapy. However, the system is quite elaborate with an extensive set of risk factors. In this study, we re-evaluate all prognostic risk factors involved in the FIGO 2000 scoring system and examine if simplification is feasible. PATIENTS AND METHODS: Between January 2003 and December 2012, 813 patients diagnosed with gestational trophoblastic neoplasia were identified at the Trophoblastic Disease Centre in London and scored using the FIGO 2000. Multivariable analysis and stepwise logistic regression were carried out to evaluate whether the FIGO 2000 scoring system could be simplified. RESULTS: Of the eight FIGO risk factors only pre-treatment serum human chorionic gonadotropin (hCG) levels exceeding 10 000 IU/l (OR = 5.0; 95% CI 2.5-10.4) and 100 000 IU/l (OR = 14.3; 95% CI 4.7-44.1), interval exceeding 7 months since antecedent pregnancy (OR = 4.1; 95% CI 1.0-16.2), and tumor size of over 5 cm (OR = 2.2; 95% CI 1.3-3.6) were identified as independently predictive for single-agent resistance. In addition, increased risk was apparent for antecedent term pregnancy (OR = 3.4; 95% CI 0.9-12.7) and the presence of five or more metastases (OR = 3.5; 95% CI 0.4-30.4), but patient numbers in these categories were relatively small. Stepwise logistic regression identified a simplified risk scoring model comprising age, pretreatment serum hCG, number of metastases, antecedent pregnancy, and interval but omitting tumor size, previous failed chemotherapy, and site of metastases. With this model only 1 out 725 patients was classified different from the FIGO 2000 system. CONCLUSION: Our simplified alternative using only five of the FIGO prognostic factors appears to be an accurate system for discriminating patients requiring single as opposed to multi-agent chemotherapy. Further work is urgently needed to validate these findings.

The added value of hysterectomy in the management of gestational trophoblastic neoplasia.

BACKGROUND: Despite the undoubted effectiveness of chemotherapeutic treatment in gestational trophoblastic neoplasia (GTN), problems related to toxicity of chemotherapy and chemo-resistant disease have led to reconsideration of the use of hysterectomy. Aim of the present study was to evaluate indications for and outcome of hysterectomy in patients with GTN in a nation-wide cohort. METHODS: Between 1977 and 2012, we identified all patients diagnosed with GTN and treated with hysterectomy from the Dutch national databases. Demographics, clinical characteristics and follow-up were recorded retrospectively. RESULTS: One hundred and nine patients (16.5% of all registered patients with GTN) underwent hysterectomy as part of their management for GTN. The majority of patients was classified as low-risk disease (74.3%), post-molar GTN (73.5%) and disease confined to the uterus (65.1%). After hysterectomy, complete remission was achieved in 66.2% of patients with localized disease and in 15.8% of patients with metastatic disease. For patients with localized disease, treated with primary hysterectomy, treatment duration was significantly shorter (mean 3.2weeks and 8.0weeks respectively, p=0.01) with lower number of administered chemotherapy cycles (mean 1.5 and 5.8 respectively, p<0.01) than patients in a matched control group. CONCLUSION: In selected cases, a hysterectomy may be an effective means to either reduce or eliminate tumor bulk. Primary hysterectomy should mainly be considered in older patients with localized disease and no desire to preserve fertility, whereas patients with chemotherapy-resistant disease may benefit from additional hysterectomy, especially when disease is localized. For patients with widespread metastatic disease, the benefit of hysterectomy lies in the removal of chemotherapy-resistant tumor bulk with subsequent effect on survival.

Reactivation of Latent HPV Infections After Renal Transplantation.

Female renal transplant recipients (RTRs) have an increased risk for developing human papillomavirus (HPV)-related (pre)malignant lesions of the genital tract. This study aims to assess the genital prevalence of HPV before and after renal transplantation (RT). In female patients who were counseled for RT at the Radboud University Medical Center Nijmegen, the Netherlands, gynecological examination was performed at first visit, and 1 and 2 years later. HPV self-sampling and questionnaires on sexual behavior were performed every 3 months. In 65 patients who underwent RT, the high-risk human papillomavirus (hrHPV) prevalence as assessed with the highly sensitive SPF10 -LiPA25 test increased significantly from 19% before to 31% after RT (p = 0.045). Based upon the clinically validated Cobas 4800 HPV test, the hrHPV prevalence increased from 10% before to 14% after RT (p = 0.31). During follow-up, no changes in sexual behavior were reported. Thirty-three patients who did not undergo RT showed a hrHPV prevalence of 21% at study entry and of 27% after 12 months with the sensitive test, and a stable prevalence of 16% with the clinically validated test. The results of this study indicate that activation of latent HPV infections may contribute to the increased risk of HPV-related (pre)malignant lesions in female RTRs.

Decision-making in female fertility preservation is balancing the expected burden of fertility preservation treatment and the wish to conceive.

STUDY QUESTION: What are the decisive factors in fertility preservation (FP) decision-making in young women scheduled for gonadotoxic therapy? SUMMARY ANSWER: FP decision-making in young women scheduled for gonadotoxic therapy is mainly based on weighing two issues: the intensity of the wish to conceive a child in the future and the expected burden of undergoing FP treatment. WHAT IS KNOWN ALREADY: Future fertility is of importance for young cancer patients whose reproductive function is being threatened by oncological therapy. To prevent or reduce severe psychological effects of infertility as well as feelings of regret about their FP decision after cancer treatment, the quality of fertility preservation counselling (FPC) should be improved. To improve care, those issues forming a decisive factor in FP decision-making for patients should be clarified, as these issues deserve extensive discussion during FPC. Until now, decisive factors have not been isolated from the complex interplay of all aspects of FP that women contemplate during FP decision-making. STUDY DESIGN, SIZE, DURATION: By using a mixed methods methodology, a questionnaire developed after qualitative research involving a selected group of five women who previously received FPC was retrospectively sent to eligible patients (n = 143) who had received FPC (1999 - July 2013) and to whom at least one FP option was offered. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients had received FPC at a university hospital in the Netherlands, in a setting where financial factors do not play a role in FP. They were aged ≥16 years and were scheduled for gonadotoxic treatment. The relationship between patients' baseline characteristics, their attributed importance to 28 relevant importance items and their FP choices was investigated. MAIN RESULTS AND THE ROLE OF CHANCE: After five interviews, 28 importance items for FP decision-making were identified and included in our questionnaire. Of these 28 importance items, 24 items could be clustered into seven importance themes. A total of 87 patients (61%) responded to our questionnaire. After performing a multivariable logistic regression analysis, proceeding with FP was related to higher attributed importance during FP decision-making to the theme 'Wish to conceive (in the future)' (odds ratio (OR) 10.8, 95% confidence interval (CI) 3.5-34.4) and the item 'Having a stable partner relationship' (OR 2.0, 95% CI 1.0-4.1), while higher attributed importance to the theme 'Expected burden of FP' during FP decision-making (OR 0.08, 95% CI 0.02-0.3) more often resulted in refraining from treatment. LIMITATIONS, REASONS FOR CAUTION: Besides possible recall and selection bias, the fact that this study was performed in Dutch patients aged ≥16 years counselled in a single centre, where finance was not an additional consideration, possibly limits the generalizability of our results to a broader European population of cancer patients. Furthermore, we are not able to draw conclusions about the causality of the associations observed in our study. WIDER IMPLICATIONS OF THE FINDINGS: The wish to conceive and the expected burden of FP treatment should be discussed carefully with patients during FP decision-making, either by the referring healthcare provider or by reproductive medicine specialist. Prospective research is needed to explore the causality of the associations found in this study. Furthermore, in order to deliver high quality patient-centred care, the development of tools to explore patients' wish to conceive (for example in different age categories) and tools to provide clear information about the burden of FP treatments (using the preferred information channels suggested by patients) is needed. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Radboud Institute for Health Sciences (research school affiliated to the Radboud university medical center). The authors have declared no conflicts of interest with respect to this work.

Clitoral involvement of squamous cell carcinoma of the vulva: localization with the worst prognosis.

OBJECTIVE: The overall 5-year survival of patients with vulvar squamous cell carcinoma (SCC) is 70%. The clinical impression is that localization of SCC on the clitoris may lead to worse prognosis. The aim of this study is to assess the disease specific survival (DSS) in patients with clitoral SCC compared to patients with SCC without clitoral involvement. METHODS: All consecutive patients with primary vulvar SCC treated with surgery at the Department of Gynaecologic Oncology at the Radboud university medical centre (Radboudumc) between March 1988 and January 2012, were analysed. The clinical and histopathological characteristics and DSS rates of patients with (N = 72) and without clitoral SCC (N = 275) were compared. Furthermore, patients with clitoral involvement were compared to patients with perineal SCCs (N = 52) and other central SCCs without clitoral and/or perineal involvement (N = 117). RESULTS: Patients with clitoral SCC more often had larger and deeper invaded tumours, lymphovascular space involvement (LVSI), positive surgical margins and a higher percentage of positive lymph nodes. Kaplan-Meier survival analyses showed worse DSS in patients with a clitoral SCC compared to patients without clitoral involvement. Multivariable analysis showed that not clitoral involvement, but invasion depth, differentiation grade and lymph node status are independent prognostic factors. CONCLUSIONS: Patients with clitoral SCC have worse survival compared to patients without clitoral involvement. This is probably caused by unfavourable histopathological characteristics of the tumour rather than the localization itself. Prospective studies are needed to further assess the influence of localization of the vulvar SCC on prognosis.

Cervicovaginal HPV infection in female renal transplant recipients: an observational, self-sampling based, cohort study.

Immunosuppressive treatment of organ transplant recipients is associated with an increase in the occurrence of human papillomavirus (HPV) related anogenital (pre)malignancies. This cohort study investigated the genotype-specific prevalence of HPV infections in a large cohort of female renal transplant recipients (RTRs). Participants self-collected a cervicovaginal sample for detection and genotyping of HPV. Besides, they completed a questionnaire regarding sociodemographic variables, medical data and sexual behavior. Anogenital screening was offered to all HPV-positive participants. A total number of 218 female RTRs was included. The prevalence of mucosal HPV infections was 27.1% and 17.4% for high risk HPV in particular. The studied cohort showed a broad range of HPV genotypes and multiple HPV genotypes were found in 27.1% of HPV-positive patients. Seven participants were identified with occult premalignant anogenital lesions. In conclusion, this study shows a high point-prevalence of HPV in female RTRs (age-matched West-European general population: 9-10%) with a shift in the distribution of genotypes as compared with the general population. Moreover, a substantial number of patients with occult premalignancies was identified. The introduction of self-sampling for HPV positivity can help in early detection of (pre)malignant anogenital lesions in this vulnerable population.

The natural history of levator avulsion one year following childbirth: a prospective study.

OBJECTIVE: To explore the natural history of levator avulsion in primipara 1 year postpartum and correlate this to pelvic floor dysfunction (PFD). DESIGN: Observational longitudinal cohort study. SETTING: District General University Hospital. POPULATION OR SAMPLE: Nullipara at 36 weeks of gestation, 3 months and 1 year postpartum. METHODS: Validated methods assessed muscle strength, prolapse, ultrasound measurements of levator hiatus and avulsion, and questionnaires for sexual function, and urinary and anal incontinence. Pattern differences over time were evaluated using linear mixed models. MAIN OUTCOME MEASURES: Natural history of levator avulsion and relationship with PFD. RESULTS: Of the 269 nullipara, 191 returned at 3 months and 147 (55%) at 1 year postpartum; 109 had a vaginal delivery and 38 had a caesarean delivery. Sixty-two percent (n = 13/21; 95% CI 41-79%) of levator avulsions diagnosed 3 months postpartum were no longer evident at 1 year. Following vaginal delivery, nine women (8%, 95% CI 4.2-15.1%) had persistent levator avulsion. Most changes in PFD occurred between the antenatal and first postnatal visit, without improvement at 1 year. Women with persistent levator avulsion had significantly worse deterioration patterns of muscle strength, hiatus measurements and vaginal symptoms (loose vagina/lump sensation). However, evidence of PFD was also related to no longer evident levator avulsion. CONCLUSIONS: Sixty-two percent of levator avulsions were no longer evident 1 year postpartum. Partial avulsion has a tendency to improve over time, which seems to be less common for complete levator avulsions. Women with no longer evident and persistent levator avulsion had PFD, with worse patterns in presence of persistent avulsion.

Deciding about fertility preservation after specialist counselling.

STUDY QUESTION: How do female patients experience fertility preservation (FP) consultation (FPC) with a specialist in reproductive medicine and subsequent decision-making on FP? SUMMARY ANSWER: Most patients had positive experiences with FPC, but negative experiences were found to be associated with decisional conflict and decision regret. WHAT IS KNOWN ALREADY: When confronted with a need for gonadotoxic treatment, girls and young women will have to make an irreversible decision with regard to FP. Patients may experience decisional conflict and develop regret about their decision during follow-up. Patients' opportunities to ask questions during FPC and their knowledge about FP have been inversely related to decisional conflict. STUDY DESIGN, SIZE, DURATION: A questionnaire on experiences with FPC, designed after qualitative research, was retrospectively distributed to 108 patients to whom FP was offered after FPC between July 2008 and July 2013. Aiming to minimize recall bias, we defined a subgroup of patients counselled since 2011 who had not yet tried to conceive after FPC. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were aged ≥16 years and had either cancer or a benign disease that required gonadotoxic therapy. They received FPC in a single university hospital in the Netherlands. Apart from patients' experiences, patients' characteristics, decisional conflict and decision regret were assessed. MAIN RESULTS AND ROLE OF CHANCE: A total of 64 patients (59.3%) responded to the questionnaire. Patients generally had positive experiences with FPC, but indicated room for improvement. Negative experiences were associated with decisional conflict regarding the FP decision (not enough time for counselling: P < 0.0001; not having the opportunity to ask all questions during FPC: P < 0.0001; not feeling supported by the counsellor during decision-making: P = 0.0003; not all applicable options were discussed: P = 0.0001; benefits and disadvantages of FP options were not clearly explained: P = 0.0005). Decisional conflict was correlated to decision regret (P < 0.0001). In the subgroup of patients counselled after 2011 who had not tried to conceive (n = 33), similar results as for the total study population were found for the association of patient experiences with decisional conflict. LIMITATIONS, REASONS FOR CAUTION: Given our retrospective design, we were not informed about the causality of the associations observed. We studied Dutch patients who were counselled in a single centre and were at least 16 years old when filling in the questionnaire. This may limit the generalizability of our data to other settings and populations. WIDER IMPLICATIONS OF THE FINDINGS: More attention should be paid to improving FPC care. Interventions aiming at improving patients' comprehension of the topic of FP and their feelings of being supported in decision-making are advisable. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Radboud Institute for Health and an unconditional grant from Merck Serono. The authors have declared no conflicts of interest with respect to this work.

External validation of three prognostic models for overall survival in patients with advanced-stage epithelial ovarian cancer.

BACKGROUND: For various malignancies, prognostic models have shown to be superior to traditional staging systems in predicting overall survival. The purpose of this study was to validate and compare the performance of three prognostic models for overall survival in patients with advanced-stage epithelial ovarian cancer. METHODS: A multi-institutional epithelial ovarian cancer database was used to identify patients and to evaluate the predictive performance of two nomograms, a prognostic index and FIGO (International Federation of Obstetrics and Gynecology) stage. All patients were treated for advanced-stage epithelial ovarian cancer between January 1996 and January 2009 in 11 hospitals in the eastern part of The Netherlands. RESULTS: In total, 542 patients were found to be eligible. Overall performance did not differ between the three prognostic models and FIGO stage. The discriminative performance for Chi's model was moderately good (c indices 0.65 and 0.68) and for the models of Gerestein and Teramukai reasonable (c indices between 0.60 and 0.62). The c indices of FIGO stage ranged between 0.54 and 0.62. After recalibration, the three models showed almost perfect calibration, whereas calibration of FIGO stage was reasonable. CONCLUSION: The three prediction models showed general applicability and a reasonably well-predictive performance, especially in comparison to FIGO stage. To date, there are no studies available that analyse the impact of these prognostic models on decision-making and patient outcome. Therefore, the usefulness of these models in daily clinical practice remains to be investigated.

Breast cancer risk prediction model: a nomogram based on common mammographic screening findings.

OBJECTIVES: To develop a prediction model for breast cancer based on common mammographic findings on screening mammograms aiming to reduce reader variability in assigning BI-RADS. METHODS: We retrospectively reviewed 352 positive screening mammograms of women participating in the Dutch screening programme (Nijmegen region, 2006-2008). The following mammographic findings were assessed by consensus reading of three expert radiologists: masses and mass density, calcifications, architectural distortion, focal asymmetry and mammographic density, and BI-RADS. Data on age, diagnostic workup and final diagnosis were collected from patient records. Multivariate logistic regression analyses were used to build a breast cancer prediction model, presented as a nomogram. RESULTS: Breast cancer was diagnosed in 108 cases (31 %). The highest positive predictive value (PPV) was found for spiculated masses (96 %) and the lowest for well-defined masses (10 %). Characteristics included in the nomogram are age, mass, calcifications, architectural distortion and focal asymmetry. CONCLUSION: With our nomogram we developed a tool assisting screening radiologists in determining the chance of malignancy based on mammographic findings. We propose cutoff values for assigning BI-RADS in the Dutch programme based on our nomogram, which will need to be validated in future research. These values can easily be adapted for use in other screening programmes. KEY POINTS: • There is substantial reader variability in assigning BI-RADS in mammographic screening. • There are no strict guidelines linking mammographic findings to BI-RADS categories. • We developed a model (nomogram) predicting the presence of breast cancer. • Our nomogram is based on common findings on positive screening mammograms. • The nomogram aims to assist screening radiologists in assigning BI-RADS categories.