Active plasma renin concentration throughout healthy and complicated pregnancy: a systematic review and meta-analysis.

BACKGROUND: Pregnancy is characterized by profound circulatory changes and compensatory adjustments in the renin-angiotensin-aldosterone system (RAAS). Differences in regulatory response may antedate or accompany vascular complicated pregnancy. We performed a systematic review and meta-analysis to delineate the trajectory of active plasma renin concentration (APRC) in healthy pregnancy and compare this to complicated pregnancy. METHODS: We performed a systematic review and meta-analysis on APRC during normotensive and hypertensive pregnancies, using PubMed (NCBI) and Embase (Ovid) databases. We included only studies reporting measurements during pregnancy together with a nonpregnant reference group measurement. Risk of bias was assessed with QUIPS. Ratio of the mean (ROM) and 95% confidence intervals (CI) of APRC values between pregnant and nonpregnant women were estimated for predefined intervals of gestational age using a random-effects model. Meta-regression was used to analyze APRC over time. RESULTS: In total, we included 18 studies. As compared to nonpregnant, APRC significantly increased as early as the first weeks of healthy pregnancy and stayed increased throughout the whole pregnancy (ROM 2.77; 95% CI 2.26-3.39). APRC in hypertensive complicated pregnancy was not significantly different from nonpregnancy (ROM 1.32; 95% CI 0.97-1.80). CONCLUSION: Healthy pregnancy is accompanied by a profound rise in APRC in the first trimester that is maintained until term. In hypertensive complicated pregnancy, this increase in APRC is not observed.

The effect of progestin therapy in advanced and recurrent endometrial cancer: A systematic review and meta-analysis.

BACKGROUND: Fifteen percent of patients with endometrial cancer (EC) have advanced stage disease or develop a recurrence. Progestins have been applied as systemic treatment for decades, but there is limited evidence on response prediction with biomarkers and toxicity. OBJECTIVES: To review the response and toxicity of progestin therapy and stratify response to progesterone receptor (PR) expression and tumour grade. SEARCH STRATEGY: We used the search terms 'Endometrial cancer', 'Progestins', 'Disease progression', 'Recurrence' and related terms in Pubmed, Embase and Cochrane databases. SELECTION CRITERIA: Studies on patients with advanced stage or recurrent EC treated with progestin monotherapy were included. Studies on adjuvant therapy, with fewer than ten cases and with sarcoma histology were excluded. DATA COLLECTION AND ANALYSIS: Evaluation for bias was performed with the Revised Cochrane RoB2 tool for randomised studies and the ROBINS-I tool for non-randomised studies. A random effects meta-analysis was performed with the overall response rate (ORR), clinical benefit rate and toxicity as primary outcome measures. MAIN RESULTS: Twenty-six studies (1639 patients) were included. The ORR of progestin therapy was 30% (95% CI 25-36), the clinical benefit rate was 52% (95% CI 42-61). In PR-positive EC, the ORR was 55%, compared with 12% in PR-negative disease (risk difference 43%, 95% CI 15-71). Severe toxicity occurred in 6.5%. CONCLUSIONS: Progestin therapy is a viable treatment option in patients with advanced stage and recurrent EC with low toxicity and high ORR in PR-positive disease. The role of PR expression in relation to progression-free survival and overall survival is unclear.

TUBectomy with delayed oophorectomy as an alternative to risk-reducing salpingo-oophorectomy in high-risk women to assess the safety of prevention: the TUBA-WISP II study protocol.

BACKGROUND: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy. PRIMARY OBJECTIVE: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk. STUDY HYPOTHESIS: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 (BRCA1) or 45-50 (BRCA2) years, compared with the current standard salpingo-oophorectomy at age 35-40 (BRCA1) or 40-45 (BRCA2) years, is non-inferior in regard to tubo-ovarian cancer risk. TRIAL DESIGN: In this international prospective preference trial, participants will choose between the novel salpingectomy with delayed oophorectomy and the current standard salpingo-oophorectomy. Salpingectomy can be performed after the completion of childbearing and between the age of 25 and 40 (BRCA1), 25 and 45 (BRCA2), or 25 and 50 (BRIP1, RAD51C, and RAD51D pathogenic variant carriers) years. Subsequent oophorectomy is recommended at a maximum delay of 5 years beyond the upper limit of the current guideline age for salpingo-oophorectomy. The current National Comprehensive Cancer Network (NCCN) guideline age, which is also the recommended age for salpingo-oophorectomy within the study, is 35-40 years for BRCA1, 40-45 years for BRCA2, and 45-50 years for BRIP1, RAD51C, and RAD51D pathogenic variant carriers. MAJOR INCLUSION/EXCLUSION CRITERIA: Premenopausal individuals with a documented class IV or V germline pathogenic variant in the BRCA1, BRCA2, BRIP1, RAD51C, or RAD51D gene who have completed childbearing are eligible for participation. Participants may have a personal history of a non-ovarian malignancy. PRIMARY ENDPOINT: The primary outcome is the cumulative tubo-ovarian cancer incidence at the target age: 46 years for BRCA1 and 51 years for BRCA2 pathogenic variant carriers. SAMPLE SIZE: The sample size to ensure sufficient power to test non-inferiority of salpingectomy with delayed oophorectomy compared with salpingo-oophorectomy requires 1500 BRCA1 and 1500 BRCA2 pathogenic variant carriers. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Participant recruitment is expected to be completed at the end of 2026 (total recruitment period of 5 years). The primary outcome is expected to be available in 2036 (minimal follow-up period of 10 years). TRIAL REGISTRATION NUMBER: NCT04294927.

Subjective outcomes 12 years after transvaginal mesh versus native tissue repair in women with recurrent pelvic organ prolapse; a randomized controlled trial.

INTRODUCTION AND HYPOTHESIS: The present study describes an extended follow-up study after 12 years and focusses on subjective outcomes of women who underwent surgery for recurrent pelvic organ prolapse in the randomized index study. METHODS: One hundred and ninety-four (194) women had been randomized in the original study and in the present study, 45 (47%) in the vaginal mesh repair versus 43 (43%) women with conventional vaginal native tissue repair completed the long-term questionnaires. The mesh used was a first-generation non-absorbable mesh kit. All types of conventional vaginal native tissue repairs were allowed, and additional vaginal native tissue repairs were allowed in the mesh group. The questionnaires as applied at baseline were used. The Patient Global Impression of Improvement questionnaire (PGI-I) was the primary outcome. RESULTS: At 12 years, 30 (71%) women in the mesh group versus 23 (59%) women in the native tissue repair group reported to be PGI-I (very) much improved (p=0.24). There were no differences found in any of the questionnaire domains. There was, however, a higher number of women who had had additional operations for recurrent pelvic organ prolapse, stress urinary incontinence, and/or exposure in the mesh group: 18 women (40%) in the mesh group versus 8 women (19%) in the native tissue repair group (p=0.03). CONCLUSIONS: There was no difference in subjective outcome between the groups, but there was a statistically significant higher number of women who had needed further operations. This study confirms that vaginal mesh should not be used in all women with recurrent pelvic organ prolapse.

First step in implementation of opportunistic salpingectomy for prevention of ovarian cancer: Current care and its determinants.

INTRODUCTION: Opportunistic salpingectomy (OS) refers to additional removal of the fallopian tubes during abdominal surgery performed for another medical indication, as prevention for ovarian cancer. As OS has been inconsistently implemented, its clinical practice varies worldwide. To reduce this variation, insight is required into current clinical practice and its determinants. Therefore, the study aim was to determine the implementation of counseling and performance of OS between 2015 and 2018, and its patient, surgical, physician, and hospital characteristics. MATERIAL AND METHODS: Retrospective study using electronic medical records from six different Dutch hospitals: two academic, two large teaching, and two non-teaching hospitals. Patients were considered eligible for OS if they underwent elective non-obstetric abdominal surgery for a gynecological indication from January 2015 through December 2018. Primary outcomes were uptake of counseling and performance of OS. Multilevel multivariable logistic regression analyses were conducted to identify characteristics associated with OS. RESULTS: A total of 3214 patients underwent elective non-obstetric abdominal surgery for a gynecological indication and were eligible for OS. Counseling on OS increased significantly from 2.9% in 2015 to 29.4% in 2018. In this period, 440 patients were counseled on OS, of which 95.9% chose OS. Performance of OS increased significantly from 6.9% in 2015 to 44.5% in 2018. Counseling for and performance of OS were more likely in patients who had surgery by laparoscopic approach, were counseled by a gynecological resident, or had more than three contact moments before surgery. Additionally, OS was less likely in patients who had vaginal surgery. CONCLUSIONS: Although the uptake of OS increased from 2015 to 2018, the majority of patients who were eligible for OS were not counseled and did not undergo OS. Its clinical practice varies on patient, surgery, and physician characteristics. Therefore, an implementation strategy tailored to associated determinants is recommended.

Maturation of GFR in Term-Born Neonates: An Individual Participant Data Meta-Analysis.

BACKGROUND: The evidence from individual studies to support the maturational pattern of GFR in healthy, term-born neonates is inconclusive. We performed an individual participant data (IPD) meta-analysis of reported measured GFR (mGFR) data, aiming to establish neonatal GFR reference values. Furthermore, we aimed to optimize neonatal creatinine-based GFR estimations. METHODS: We identified studies reporting mGFR measured by exogenous markers or creatinine clearance (CrCL) in healthy, term-born neonates. The relationship between postnatal age and clearance was investigated using cubic splines with generalized additive linear mixed models. From our reference values, we estimated an updated coefficient for the Schwartz equation (eGFR [ml/min per 1.73 m2]=(k×height [cm])/serum creatinine [mg/dl]). RESULTS: Forty-eight out of 1521 screened articles reported mGFR in healthy, term-born neonates, and 978 mGFR values from 881 neonates were analyzed. IPD were available for 367 neonates, and the other 514 neonates were represented by 41 aggregated data points as means/medians per group. GFR doubled in the first 5 days after birth, from 19.6 (95% CI, 14.7 to 24.6) to 40.6 (95% CI, 36.7 to 44.5) ml/min per 1.73 m2, and then increased more gradually to 59.4 (95% CI, 45.9 to 72.9) ml/min per 1.73 m2 by 4 weeks of age. A coefficient of 0.31 to estimate GFR best fitted the data. CONCLUSIONS: These reference values for healthy, term-born neonates show a biphasic increase in GFR, with the largest increase between days 1 and 5. Together with the re-examined Schwartz equation, this can help identify altered GFR in term-born neonates. To enable widespread implementation of our proposed eGFR equation, validation in a large cohort of neonates is required.

Risk factors for pelvic organ prolapse recurrence after sacrospinous hysteropexy or vaginal hysterectomy with uterosacral ligament suspension.

BACKGROUND: Given that the number of surgeries for pelvic organ prolapse is expected to increase worldwide, knowledge on risk factors for prolapse recurrence is of importance for developing preventive strategies and shared decision-making. OBJECTIVE: To identify risk factors for subjective and objective failure after either sacrospinous hysteropexy or vaginal hysterectomy with uterosacral ligament suspension over a period of 5 years after surgery. STUDY DESIGN: This was a secondary analysis of the 5-year follow-up of the SAVE-U trial. The SAVE-U trial was conducted in 4 Dutch hospitals. A total of 208 women with uterine prolapse stage ≥2 were randomized to sacrospinous hysteropexy or vaginal hysterectomy with uterosacral ligament suspension. For the current analysis, available annual 5-year follow-up data of 207 women were analyzed. Without missing values this analysis would have included 1035 measurements in total over the 5-year follow-up. Recurrences were analyzed as "events" using generalized linear mixed models because recurrences of anatomic failure and bothersome vaginal bulge symptoms fluctuated over time. The primary outcome was the composite outcome of failure defined as prolapse beyond the hymen, bothersome bulge symptoms, repeated surgery, or pessary use for recurrent prolapse. Secondary outcome measures were bothersome vaginal bulge symptoms, overall anatomic failure (Pelvic Organ Prolapse Quantification stage ≥2 in any compartment), apical compartment recurrence (Pelvic Organ Prolapse Quantification stage ≥2), anterior compartment recurrence (Pelvic Organ Prolapse Quantification stage ≥2), and posterior compartment recurrence (Pelvic Organ Prolapse Quantification stage ≥2). RESULTS: For the composite outcome of failure (164 events in 66 different women), statistically significant risk factors were: body mass index (odds ratio, 1.10 [per 1 kg/m2]; 95% confidence interval, 1.02-1.19; P=.02), smoking (odds ratio, 2.88; 95% confidence interval, 1.12-7.40; P=.03), and preoperative Pelvic Organ Prolapse Quantification point Ba (odds ratio, 1.23 [per 1 cm]; 95% confidence interval, 1.01-1.50; P=.04). When analyzing each surgical outcome measure separately, body mass index and Pelvic Organ Prolapse Quantification point Ba were risk factors for overall anatomic failure (462 events in 147 women; odds ratio, 1.15; 95% confidence interval, 1.07-1.25; P<.01 and odds ratio, 1.14; 95% confidence interval, 1.00-1.30; P=.05, respectively) and anterior compartment recurrence (385 events in 128 women; odds ratio, 1.11; 95% confidence interval, 1.02-1.22; P=.02 and odds ratio, 1.17; 95% confidence interval, 1.02-1.34; P=.02, respectively). Vaginal hysterectomy was a risk factor for posterior compartment recurrence when compared with sacrospinous hysteropexy (93 events in 40 women; odds ratio, 5.21; 95% confidence interval, 2.05-13.27; P<.01). Smoking was a risk factor for bothersome vaginal bulge symptoms (70 events in 41 women; odds ratio, 3.80; 95% confidence interval, 1.48-9.75; P=.01), and preoperative Pelvic Organ Prolapse Quantification stage 3 or 4 was significantly protective against bothersome bulge symptoms (odds ratio, 0.32; 95% confidence interval, 0.11-0.89; P=.03). CONCLUSION: Body mass index, smoking, and Pelvic Organ Prolapse Quantification point Ba were statistically significant risk factors for the composite outcome of failure (prolapse beyond the hymen, bothersome bulge symptoms, repeated surgery, or pessary use for recurrent prolapse) in the period of 5 years after surgery.

Risk factors for primary pelvic organ prolapse and prolapse recurrence: an updated systematic review and meta-analysis.

OBJECTIVE: To update a previously published systematic review and perform a meta-analysis on the risk factors for primary pelvic organ prolapse and prolapse recurrence. DATA SOURCES: PubMed and Embase were systematically searched. We searched from July 1, 2014 until July 5, 2021. The previous search was from inception until August 4, 2014. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and cross-sectional and cohort studies conducted in the Western developed countries that reported on multivariable analysis of risk factors for primary prolapse or prolapse recurrence were included. The definition of prolapse was based on anatomic references, and prolapse recurrence was defined as anatomic recurrence after native tissue repair. Studies on prolapse recurrence with a median follow-up of ≥1 year after surgery were included. METHODS: Quality assessment was performed with the Newcastle-Ottawa Scale. Data from the previous review and this review were combined into forest plots, and meta-analyses were performed where possible. If the data could not be pooled, "confirmed risk factors" were identified if ≥2 studies reported a significant association in multivariable analysis. RESULTS: After screening, 14 additional studies were selected-8 on the risk factors for primary prolapse and 6 on prolapse recurrence. Combined with the results from the previous review, 27 studies met the inclusion criteria, representing the data of 47,429 women. Not all studies could be pooled because of heterogeneity. Meta-analyses showed that birthweight (n=3, odds ratio, 1.04; 95% confidence interval, 1.02-1.06), age (n=3, odds ratio, 1.34; 95% confidence interval, 1.23-1.47), body mass index (n=2, odds ratio, 1.75; 95% confidence interval, 1.17-2.62), and levator defect (n=2, odds ratio, 3.99; 95% confidence interval, 2.57-6.18) are statistically significant risk factors, and cesarean delivery (n=2, pooled odds ratio, 0.08; 95% confidence interval, 0.03-0.20) and smoking (n=3, odds ratio, 0.59; 95% confidence interval, 0.46-0.75) are protective factors for primary prolapse. Parity, vaginal delivery, and levator hiatal area are identified as "confirmed risk factors." For prolapse recurrence, preoperative prolapse stage (n=5, odds ratio, 2.68; 95% confidence interval, 1.93-3.73) and age (n=2, odds ratio, 3.48; 95% confidence interval, 1.99-6.08) are statistically significant risk factors. CONCLUSION: Vaginal delivery, parity, birthweight, age, body mass index, levator defect, and levator hiatal area are risk factors, and cesarean delivery and smoking are protective factors for primary prolapse. Preoperative prolapse stage and younger age are risk factors for prolapse recurrence after native tissue surgery.

Cancer worry among BRCA1/2 pathogenic variant carriers choosing surgery to prevent tubal/ovarian cancer: course over time and associated factors.

OBJECTIVE: High cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this worry among BRCA1/2-PV carriers undergoing surgery to prevent ovarian cancer, and identified factors associated with high cancer worry. METHODS: Cancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose either novel risk-reducing salpingectomy with delayed oophorectomy or standard risk-reducing salpingo-oophorectomy. The Cancer Worry Scale was obtained before and 3 and 12 months after surgery. Cancer worry patterns were analysed using latent class growth analysis and associated factors were identified with regression analysis. RESULTS: Of all 577 BRCA1/2-PV carriers, 320 (57%) had high (≥ 14) cancer worry pre-surgery, and 54% had lower worry 12 months post-surgery than pre-surgery. Based on patterns over time, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56%), persistently high cancer worry (6%), and fluctuating, mostly declining, cancer worry (37%). Factors associated with persistently high cancer concerns were age below 35 (BRCA1) or 40 (BRCA2), unemployment, previous breast cancer, lower education and a more recent BRCA1/2-PV diagnosis. CONCLUSIONS: Some degree of cancer worry is considered normal, and most BRCA1/2-PV carriers have declining cancer worry after gynaecological risk-reducing surgery. However, a subset of these BRCA1/2-PV carriers has persisting major cancer concerns up to 1 year after surgery. They should be identified and potentially offered additional support. CLINICAL TRIAL REGISTRATION: The TUBA-study is registered at ClinicalTrials.gov since December 11th, 2014. Registration number: NCT02321228.

Practice pattern variation: treatment of pelvic organ prolapse in The Netherlands.

INTRODUCTION AND HYPOTHESIS: Great variety in clinical management of pelvic organ prolapse (POP) has been described over the last years. Practice pattern variation (PPV) reflects differences in care that cannot be explained by the underlying condition. We aim to explore whether PPV in management of POP in The Netherlands has changed between 2011 and 2017. METHODS: We conducted a multicenter cohort study, using prospective routinely collected benchmark data from LOGEX, a healthcare analytics company (Amsterdam, The Netherlands). Data of patients with a diagnosis POP from 50 hospitals (16 teaching and 34 non-teaching hospitals) were collected for the years 2011 and 2017. All treatments were categorized into three groups: conservative treatment, uterus-preserving or uterus-removing surgery. Using meta-analysis, we evaluated whether the proportions of conducted treatments changed over time and estimated the between-center variation (Cochran's Q), reflecting the PPV in 2011 and 2017. This variation was analyzed using F-tests. RESULTS: Compared to 2011, referral for POP in 2017 decreased by 16.2% (-4505 patients), and the percentage of hysterectomies decreased by 33.6% (p < 0.0001). The PPV of POP surgery decreased significantly by 47.2% (p = 0.0137) and of hysterectomies by 41.5% (p = 0.0316). CONCLUSIONS: We found a decline in PPV for POP surgery between 2011 and 2017. Furthermore, the number of surgical interventions decreased, which was mostly due to a decline of hysterectomies. This indicates a shift toward more conservative therapy and uterus preservation. A further reduction of PPV would be beneficial for the quality of health care.

Molecular Processes in Stress Urinary Incontinence: A Systematic Review of Human and Animal Studies.

Stress urinary incontinence (SUI) is a common and burdensome condition. Because of the large knowledge gap around the molecular processes involved in its pathophysiology, the aim of this review was to provide a systematic overview of genetic variants, gene and protein expression changes related to SUI in human and animal studies. On 5 January 2021, a systematic search was performed in Pubmed, Embase, Web of Science, and the Cochrane library. The screening process and quality assessment were performed in duplicate, using predefined inclusion criteria and different quality assessment tools for human and animal studies respectively. The extracted data were grouped in themes per outcome measure, according to their functions in cellular processes, and synthesized in a narrative review. Finally, 107 studies were included, of which 35 used animal models (rats and mice). Resulting from the most examined processes, the evidence suggests that SUI is associated with altered extracellular matrix metabolism, estrogen receptors, oxidative stress, apoptosis, inflammation, neurodegenerative processes, and muscle cell differentiation and contractility. Due to heterogeneity in the studies (e.g., in examined tissues), the precise contribution of the associated genes and proteins in relation to SUI pathophysiology remained unclear. Future research should focus on possible contributors to these alterations.

Early prediction of post-molar gestational trophoblastic neoplasia and resistance to methotrexate, based on a single serum human chorionic gonadotropin measurement.

BACKGROUND: Clinicians are unable to provide individualized counseling regarding risk of progression for patients with a complete hydatidiform mole (CHM). We developed nomograms enabling early prediction of post-molar gestational trophoblastic neoplasia (GTN) and resistance to methotrexate (MTX) based on a single serum human chorion gonadotropin (hCG) measurement. METHODS: We generated two nomograms with logistic regression: to predict post-molar GTN, and MTX resistance. For patients with high probability to progress to post-molar GTN or MTX resistance, we determined hCG cut-offs at 97.5% specificity to select patients for additional- or adjustments in current treatment. RESULTS: The nomograms had a good to excellent ability to distinguish either between patients with uneventful hCG regression versus progression to post molar GTN, or between patients cured by MTX versus patients in whom resistance would occur. At 97.5% specificity, we identified 66% (95%CI 56-75) of the 149 patients who would progress to post-molar GTN, four weeks after initial curettage. For patients treated with MTX, we identified 55% (95%CI 23-83) of the 43 patients who would become resistant, preceding their third course at 97.5% specificity. CONCLUSION: The nomograms and cut-off levels can be used to assist in counseling for patients diagnosed with CHM.

Evaluation of a patient decision aid for BRCA1/2 pathogenic variant carriers choosing an ovarian cancer prevention strategy.

OBJECTIVE: Risk-reducing surgery is advised to BRCA1/2 pathogenic variant (PV) carriers around the age of 40 years to reduce ovarian cancer risk. In the TUBA-study, a multicenter preference study (NCT02321228), BRCA1/2-PV carriers are offered a choice: the standard strategy of risk-reducing salpingo-oophorectomy or the novel strategy of risk-reducing salpingectomy with delayed oophorectomy. We evaluated feasibility and effectiveness of a patient decision aid for this choice. METHODS: Premenopausal BRCA1/2-PV carriers were counselled for risk-reducing surgical options in the TUBA-study; the first cohort was counselled without and the second cohort with decision aid. Evaluation was performed using digital questionnaires for participating women and their healthcare professionals. Outcome measures included actual choice, feasibility (usage and experiences) and effectiveness (knowledge, cancer worry, decisional conflict, decisional regret and self-estimated influence on decision). RESULTS: 283 women were counselled without and 282 women with decision aid. The novel strategy was chosen less frequently in women without compared with women with decision aid (67% vs 78%, p = 0.004). The decision aid was graded with an 8 out of 10 by both women and professionals, and 78% of the women would recommend this decision aid to others. Users of the decision aid reported increased knowledge about the options and increased insight in personal values. Knowledge on cancer risk, decisional conflict, decisional regret and cancer worry were similar in both cohorts. CONCLUSIONS: The use of the patient decision aid for risk-reducing surgery is feasible, effective and highly appreciated among BRCA1/2-PV carriers facing the decision between salpingo-oophorectomy or salpingectomy with delayed oophorectomy.

A tutorial on individualized treatment effect prediction from randomized trials with a binary endpoint.

Randomized trials typically estimate average relative treatment effects, but decisions on the benefit of a treatment are possibly better informed by more individualized predictions of the absolute treatment effect. In case of a binary outcome, these predictions of absolute individualized treatment effect require knowledge of the individual's risk without treatment and incorporation of a possibly differential treatment effect (ie, varying with patient characteristics). In this article, we lay out the causal structure of individualized treatment effect in terms of potential outcomes and describe the required assumptions that underlie a causal interpretation of its prediction. Subsequently, we describe regression models and model estimation techniques that can be used to move from average to more individualized treatment effect predictions. We focus mainly on logistic regression-based methods that are both well-known and naturally provide the required probabilistic estimates. We incorporate key components from both causal inference and prediction research to arrive at individualized treatment effect predictions. While the separate components are well known, their successful amalgamation is very much an ongoing field of research. We cut the problem down to its essentials in the setting of a randomized trial, discuss the importance of a clear definition of the estimand of interest, provide insight into the required assumptions, and give guidance with respect to modeling and estimation options. Simulated data illustrate the potential of different modeling options across scenarios that vary both average treatment effect and treatment effect heterogeneity. Two applied examples illustrate individualized treatment effect prediction in randomized trial data.

Imaging modalities for the detection of posterior pelvic floor disorders in women with obstructed defaecation syndrome.

BACKGROUND: Obstructed defaecation syndrome (ODS) is difficulty in evacuating stools, requiring straining efforts at defaecation, having the sensation of incomplete evacuation, or the need to manually assist defaecation. This is due to a physical blockage of the faecal stream during defaecation attempts, caused by rectocele, enterocele, intussusception, anismus or pelvic floor descent. Evacuation proctography (EP) is the most common imaging technique for diagnosis of posterior pelvic floor disorders. It has been regarded as the reference standard because of extensive experience, although it has been proven not to have perfect accuracy. Moreover, EP is invasive, embarrassing and uses ionising radiation. Alternative imaging techniques addressing these issues have been developed and assessed for their accuracy. Because of varying results, leading to a lack of consensus, a systematic review and meta-analysis of the literature are required. OBJECTIVES: To determine the diagnostic test accuracy of EP, dynamic magnetic resonance imaging (MRI) and pelvic floor ultrasound for the detection of posterior pelvic floor disorders in women with ODS, using latent class analysis in the absence of a reference standard, and to assess whether MRI or ultrasound could replace EP. The secondary objective was to investigate differences in diagnostic test accuracy in relation to the use of rectal contrast, evacuation phase, patient position and cut-off values, which could influence test outcome. SEARCH METHODS: We ran an electronic search on 18 December 2019 in the Cochrane Library, MEDLINE, Embase, SCI, CINAHL and CPCI. Reference list, Google scholar. We also searched WHO ICTRP and clinicaltrials.gov for eligible articles. Two review authors conducted title and abstract screening and full-text assessment, resolving disagreements with a third review author. SELECTION CRITERIA: Diagnostic test accuracy and cohort studies were eligible for inclusion if they evaluated the test accuracy of EP, and MRI or pelvic floor ultrasound, or both, for the detection of posterior pelvic floor disorders in women with ODS. We excluded case-control studies. If studies partially met the inclusion criteria, we contacted the authors for additional information. DATA COLLECTION AND ANALYSIS: Two review authors performed data extraction, including study characteristics, 'Risk-of-bias' assessment, sources of heterogeneity and test accuracy results. We excluded studies if test accuracy data could not be retrieved despite all efforts. We performed meta-analysis using Bayesian hierarchical latent class analysis. For the index test to qualify as a replacement test for EP, both sensitivity and specificity should be similar or higher than the historic reference standard (EP), and for a triage test either specificity or sensitivity should be similar or higher. We conducted heterogeneity analysis assessing the effect of different test conditions on test accuracy. We ran sensitivity analyses by excluding studies with high risk of bias, with concerns about applicability, or those published before 2010. We assessed the overall quality of evidence (QoE) according to GRADE. MAIN RESULTS: Thirty-nine studies covering 2483 participants were included into the meta-analyses. We produced pooled estimates of sensitivity and specificity for all index tests for each target condition. Findings of the sensitivity analyses were consistent with the main analysis. Sensitivity of EP for diagnosis of rectocele was 98% (credible interval (CrI)94%-99%), enterocele 91%(CrI 83%-97%), intussusception 89%(CrI 79%-96%) and pelvic floor descent 98%(CrI 93%-100%); specificity for enterocele was 96%(CrI 93%-99%), intussusception 92%(CrI 86%-97%) and anismus 97%(CrI 94%-99%), all with high QoE. Moderate to low QoE showed a sensitivity for anismus of 80%(CrI 63%-94%), and specificity for rectocele of 78%(CrI 63%-90%) and pelvic floor descent 83%(CrI 59%-96%). Specificity of MRI for diagnosis of rectocele was 90% (CrI 79%-97%), enterocele 99% (CrI 96%-100%) and intussusception 97% (CrI 88%-100%), meeting the criteria for a triage test with high QoE. MRI did not meet the criteria to replace EP. Heterogeneity analysis showed that sensitivity of MRI performed with evacuation phase was higher than without for rectocele (94%, CrI 87%-98%) versus 65%, CrI 52% to 89%, and enterocele (87%, CrI 74%-95% versus 62%, CrI 51%-88%), and sensitivity of MRI without evacuation phase was significantly lower than EP. Specificity of transperineal ultrasound (TPUS) for diagnosis of rectocele was 89% (CrI 81%-96%), enterocele 98% (CrI 95%-100%) and intussusception 96% (CrI 91%-99%); sensitivity for anismus was 92% (CrI 72%-98%), meeting the criteria for a triage test with high QoE. TPUS did not meet the criteria to replace EP. Heterogeneity analysis showed that sensitivity of TPUS performed with rectal contrast was not significantly higher than without for rectocele(92%, CrI 69%-99% versus 81%, CrI 58%-95%), enterocele (90%, CrI 71%-99% versus 67%, CrI 51%-90%) and intussusception (90%, CrI 69%-98% versus 61%, CrI 51%-86%), and was lower than EP. Specificity of endovaginal ultrasound (EVUS) for diagnosis of rectocele was 76% (CrI 54%-93%), enterocele 97% (CrI 80%-99%) and intussusception 93% (CrI 72%-99%); sensitivity for anismus was 84% (CrI 59%-96%), meeting the criteria for a triage test with very low to moderate QoE. EVUS did not meet the criteria to replace EP. Specificity of dynamic anal endosonography (DAE) for diagnosis of rectocele was 88% (CrI 62%-99%), enterocele 97% (CrI 75%-100%) and intussusception 93% (CrI 65%-99%), meeting the criteria for a triage test with very low to moderate QoE. DAE did not meet the criteria to replace EP. Echodefaecography (EDF) had a sensitivity of 89% (CrI 65%-98%) and specificity of 92% (CrI 72%-99%) for intussusception, meeting the criteria to replace EP but with very low QoE. Specificity of EDF for diagnosis of rectocele was 89% (CrI 60%-99%) and for enterocele 97% (CrI 87%-100%); sensitivity for anismus was 87% (CrI 72%-96%), meeting the criteria for a triage test with low to very low QoE. AUTHORS' CONCLUSIONS: In a population of women with symptoms of ODS, none of the imaging techniques met the criteria to replace EP. MRI and TPUS met the criteria of a triage test, as a positive test confirms diagnosis of rectocele, enterocele and intussusception, and a negative test rules out diagnosis of anismus. An evacuation phase increased sensitivity of MRI. Rectal contrast did not increase sensitivity of TPUS. QoE of EVUS, DAE and EDF was too low to draw conclusions. More well-designed studies are required to define their role in the diagnostic pathway of ODS.

The Natural History of Cervical Intraepithelial Neoplasia Grades 1, 2, and 3: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of the study was to obtain an updated overview of regression, persistence, and progression rates of conservatively managed cervical intraepithelial neoplasia grade 1 (CIN 1)/CIN 2/CIN 3. METHODS: Data sources were MEDLINE, Embase, and Cochrane (January 1, 1973-April 14, 2020). Two reviewers extracted data and assessed risk of bias. To estimate outcome rates, we pooled proportions of the individual study results using random-effects meta-analysis, resulting in point estimates and corresponding 95% CIs. Heterogeneity was quantified by the I2 and τ2 measures. RESULTS: Eighty-nine studies were included, 63 studies on CIN 1 (n = 6,080-8,767), 42 on CIN 2 (n = 2,909-3,830), and 7 on CIN 3 (n = 245-351). The overall regression, persistence, and progression to CIN 2 or worse and CIN 3 or worse rates for women with conservatively managed CIN 1 were 60% (95% CI = 55-65, I2 = 92%), 25% (95% CI = 20-30, I2 = 94%), 11% (95% CI = 8-13, I2 = 89%), and 2% (95% CI = 1-3, I2 = 82%), respectively. The overall regression, persistence, and progression rates for CIN 2 were 55% (95% CI = 50-60, I2 = 85%), 23% (95% CI = 19-28, I2 = 83%), and 19% (95% CI = 15-23, I2 = 88%), respectively. Finally, for CIN 3, these were 28% (95% CI = 17-41, I2 = 68%), 67% (95% CI = 36-91, I2 = 84%), and 2% (95% CI = 0-25, I2 = 95%), respectively. Cervical intraepithelial neoplasia grade 2 regression was significantly higher in women 30 years or younger and high-risk human papillomavirus-negative women (66%, 95% CI = 62-70, I2 = 76%; 94%, 95% CI = 84-99, I2 = 60%). Only 2/7,180 (0.03%) and 10/3,037 (0.3%) of the CIN 1 and CIN 2 cases progressed to cervical cancer. CONCLUSIONS: Most CIN 1/CIN 2 will regress spontaneously in less than 24 months, with the highest rates in high-risk human papillomavirus-negative and young women, whereas progression to cancer is less than 0.5%. Conservative management should be considered, especially in fertile women and with expected high compliance. Given the heterogeneity in regression rates of high-grade histology, this should be classified as CIN 2 or CIN 3 to guide management.

The relative risk of noncervical high-risk human papillomavirus-related (pre)malignancies after recurrent cervical intraepithelial neoplasia grade 3: A population-based study.

Women with cervical intraepithelial neoplasia grade 3 (CIN3) have a long-lasting increased risk for noncervical high-risk human papillomavirus (hrHPV)-related (pre)malignancies. The aim of our study was to estimate this risk in women with recurrent CIN3 compared to women without a history of CIN3 and women with a single episode of CIN3. Women with a CIN3 diagnosis between 1990 and 2010 were obtained from the Dutch Pathology Registry (PALGA) and matched with a control group of women without CIN3. Analysis has been conducted in a subset of women with recurrent CIN3, defined as reoccurrence minimally 2 years post-treatment. Cases of noncervical hrHPV-related (pre)malignancies of the anus, vulva, vagina and oropharynx were identified until 2015 and incidence rate ratios (IRRs) were estimated. Then, 1,797 women with recurrent CIN3 were included with a median age of 34 years (range 18-76) and 31,594 person-years of follow-up. Women with recurrent CIN3 had an increased risk of developing noncervical hrHPV-related (pre)malignancies compared to women without CIN3 with an IRR of 25.96 (95%CI 6.32-106.58). The IRR was 2.48 (95% CI 1.87-3.30) compared to women with a single episode of CIN3. Studies on posttreatment follow-up and prophylactic hrHPV vaccination are warranted.

The risk of cervical cancer after cervical intraepithelial neoplasia grade 3: A population-based cohort study with 80,442 women.

OBJECTIVE: To estimate the risk of cervical cancer in women with a history of cervical intraepithelial neoplasia (CIN) grade 3 and to review the compliance with post-treatment follow-up. METHODS: A population-based retrospective cohort study including 80,442 women with a median follow-up of 15.8 years, and 1,278,297 person years. Women with CIN3 between 1990 and 2010 were identified from the Dutch Pathology Registry (PALGA) and linked to the general female population from the Netherlands Cancer Registry. Cases of recurrent CIN3 and cervical cancer, defined as occurrence minimally two years post-treatment, were identified until 2016. Standardized incidence ratios (SIRs) were calculated for the risk of cervical cancer. RESULTS: 1554 women (1.9%) developed recurrent CIN3 and 397 women (0.5%) cervical cancer. Women with CIN3 were associated with a twofold increased risk of cervical cancer (SIR 2.29; 95%CI 2.07-2.52) compared with the general female population. Women aged ≥50 years during CIN3 diagnosis had a sevenfold and women with recurrent CIN3 a ninefold increased risk of developing cervical cancer. The increased risk up to 20 years of follow-up seems to be mostly attributable to ageing. 37.0% of women who developed cervical cancer after CIN3 did not complete the advised post-treatment follow-up. CONCLUSIONS: Women with CIN3 have a long-lasting twofold increased risk of developing cervical cancer, even when they complete the post-treatment follow-up and adhere to the regular screening program. This risk increases with CIN3 diagnosis at older age, further ageing during follow-up and in women with recurrent CIN3. Studies on optimizing follow-up strategies are warranted.

A tutorial on dynamic risk prediction of a binary outcome based on a longitudinal biomarker.

Dynamic risk predictions based on all available information are useful in timely identification of high-risk patients. However, in contrast with time to event outcomes, there is still a lack of studies that clearly demonstrate how to obtain and update predictions for a future binary outcome using a repeatedly measured biomarker. The aim of this study is to give an illustrative overview of four approaches to obtain such predictions: likelihood based two-stage method (2SMLE), likelihood based joint model (JMMLE), Bayesian two-stage method (2SB), and Bayesian joint model (JMB). We applied the approaches to provide weekly updated predictions of post-molar gestational trophoblastic neoplasia (GTN) based on age and repeated measurements of human chorionic gonadotropin (hCG). Discrimination and calibration measures were used to compare the accuracy of the weekly predictions. Internal validation of the models was conducted using bootstrapping. The four approaches resulted in the same predictive and discriminative performance in predicting GTN. A simulation study showed that the joint models outperform the two-stage methods when we increase the within- and the between-patients variability of the biomarker. The applicability of these models to produce dynamic predictions has been illustrated through a comprehensive explanation and accompanying syntax (R and SAS® ).

Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid-Refractory Acute Graft-versus-Host Disease.

Effective therapies for treating patients with steroid-refractory acute graft-versus-host-disease (SR-aGVHD), particularly strategies that reduce the duration of immunosuppression following remission, are urgently needed. The investigated immunotoxin combination consists of a mixture of anti-CD3 and anti-CD7 antibodies separately conjugated to recombinant ricin A (CD3/CD7-IT), which induces in vivo depletion of T cells and natural killer (NK) cells and suppresses T cell receptor activation. We conducted a phase I/II trial to examine the safety and efficacy of CD3/CD7-IT in 20 patients with SR-aGVHD; 17 of these patients (85%) had severe SR-aGVHD, and all 20 patients had visceral organ involvement, including 18 (90%) with gastrointestinal (GI) involvement and 5 (25%) with liver involvement. A validated 2-biomarker algorithm classified the majority of patients (11 of 20) as high risk. On day 28 after the start of CD3/CD7-IT therapy, the overall response rate was 60% (12 of 20), with 10 patients (50%) achieving a complete response. The 6-month overall survival rate was 60% (12 of 20), including 64% (7 of 11) classified as high risk by biomarkers. The 1-week course of treatment with CD3/CD7-IT caused profound but transient depletion of T cells and NK cells, followed by rapid recovery of the immune system with a diverse TCR Vß repertoire, and preservation of Epstein-Barr virus- and cytomegalovirus-specific T cell clones. Furthermore, our results indicate that CD3/CD7-IT appeared to be safe and well tolerated, with a relatively low prevalence of manageable and reversible adverse events, primarily worsening of hypoalbuminemia, microangiopathy, and thrombocytopenia. These encouraging results suggest that CD3/CD7-IT may improve patient outcomes in patients with SR-aGVHD.