ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

Background: The standard surgical treatment of endometrial carcinoma (EC) consisting of total hysterectomy with bilateral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in EC in a multidisciplinary setting. While also addressing work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility sparing treatment. Objectives: To define recommendations for fertility-sparing treatment of patients with endometrial carcinoma. Materials and Methods: ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of EC (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives. Results: The multidisciplinary development group formulated 48 recommendations for fertility-sparing treatment of patients with endometrial carcinoma in four sections: patient selection, tumour clinicopathological characteristics, treatment and special issues. Conclusions: These recommendations provide guidance to professionals caring for women with endometrial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy, conservative surgery, and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario. What is new?: A collaboration was set up between the ESGO, ESHRE and ESGE, aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

Background: The standard surgical treatment of endometrial carcinoma (EC) consisting of total hysterectomy with bilateral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in EC in a multidisciplinary setting. While also addressing work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility sparing treatment. Objectives: To define recommendations for fertility-sparing treatment of patients with endometrial carcinoma. Materials and Methods: ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of EC (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives. Results: The multidisciplinary development group formulated 48 recommendations for fertility-sparing treatment of patients with endometrial carcinoma in four sections: patient selection, tumour clinicopathological characteristics, treatment and special issues. Conclusions: These recommendations provide guidance to professionals caring for women with endometrial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy, conservative surgery, and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario. What is new? A collaboration was set up between the ESGO, ESHRE and ESGE, aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

Radiology reporting of micturating cystourethrograms (MCUGs): What the paediatric urologists want to know.

BACKGROUND: Micturating cystourethrograms (MCUGs) are commonly requested to exclude vesicoureteric reflux (VUR) and bladder outlet obstruction (BOO). Useful additional information including timing and bladder volume at the start of reflux, urethral anomalies and post-void drainage can be obtained from the cystograms, but are not routinely reported by radiologists. OBJECTIVE: The study aim was to retrospectively review MCUG reports against a proposed reporting proforma, and then re-analyse the effect of the proforma on report quality. STUDY DESIGN: A retrospective analysis of paediatric MCUG reports was undertaken from two patient cohorts. Cohorts A (41 reports) and B (51 reports) comprised reports written before (2011-12) and following (2016-17) distribution of the standardised reporting proforma, respectively. Reports were assessed with respect to the parameters outlined on the standardised MCUG reporting proforma, including presence, grade and timing of VUR amongst others. Findings from both cohorts were compared and statistically analysed (p < 0.05 significant) to establish if the proforma influenced the content of reports. RESULTS: Statistically significant improvements were demonstrated in the reporting of: bladder outline normal/abnormal - reported in 92% after the proforma vs 56% before (p < 0.001); urethra normal/abnormal - 87% vs 68% (p = 0.033); contrast volume instilled - 84% vs 61% (p = 0.011); bladder emptying - 69% vs 17% (p < 0.001). In patients with VUR, reporting of VUR timing - 96% vs 33% (p < 0.001) and VUR grade - 91% vs 40% (p = 0.002) were also significantly improved. CONCLUSION: Implementation of a standardised MCUG reporting proforma produced substantial improvements in report quality and consistency, with statistically significant improvements noted in six of seven key features.

The prevalence of faecal incontinence in myotonic dystrophy type 1.

Faecal incontinence is recognised as a feature of myotonic dystrophy along with other symptoms of bowel dysfunction, but its prevalence is poorly defined. We have surveyed 152 unselected myotonic dystrophy patients. We identified issues with bowel control in 104 (68% of the study population). Forty-eight (32%) reported faecal incontinence in the 4 weeks prior to completion of the questionnaire. Fifty-six patients (37%) reported having to change their lifestyle because of incontinence issues at some point in the prior 4 weeks. This study shows a high frequency of life-changing symptoms in a large unselected, cohort of patients with myotonic dystrophy type 1, and highlights lower gastrointestinal symptoms as an important issue for further research.

Physician procedure volume and related adverse events after surgically induced abortion: a population-based cohort study.

BACKGROUND: Induced abortion is a common procedure performed by physicians with varying degrees of clinical experience. We aimed to determine whether a physician's procedure volume influences complications after induced abortion. METHODS: We obtained population-based retrospective data on surgically induced abortion procedures in Ontario between 2003 and 2015 from Ontario health administrative databases held at ICES. Physician procedure volume was defined as the number of surgically induced abortions performed in the 1-year period preceding the index procedure date, categorized as low (< 10th percentile of yearly volume) or higher (≥ 10th percentile). The primary outcome was a severe adverse event (maternal end organ damage, severe maternal morbidity, intensive care unit admission or death) within 42 days after an induced abortion. The secondary outcome was any adverse event within 42 days. RESULTS: Among 529 141 surgical abortion procedures, we found 850 severe adverse events (1.6 per 1000 procedures, 95% confidence interval [CI] 1.5-1.7), and 5664 any adverse events (10.7 per 1000 procedures, 95% CI 10.4-11.0). Severe adverse events occurred in 194 out of 52 889 procedures in the low-volume group (3.7 per 1000 procedures, 95% CI 3.2-4.2) compared with 656 out of 476 252 procedures in the higher-volume group (1.4 per 1000 procedures, 95% CI 1.3-1.5), an adjusted odds ratio (OR) of 1.91 (95% CI 1.41-2.59). The odds of any adverse event were also higher in the low-volume versus higher-volume group (adjusted OR 1.19, 95% CI 1.02-1.40). INTERPRETATION: Low physician procedure volumes are associated with an elevated risk of a complication after surgically induced abortion. Future investigation should compare processes of care between low- and higher-volume physicians to facilitate quality improvement in abortion care.

The search for the definition, etiology, and effective diagnosis of upper urinary tract obstruction: the Whitaker test then and now.

INTRODUCTION: Robert Whitaker, inspired by Dr William W Scott at the Brady Institute at Johns Hopkins and by Sir David Innes Williams at Great Ormond Street Hospital for Children in the late 1960s, spent much of his career exploring the meaning of persistent dilatation of the upper urinary tract, in an attempt to define obstruction and to find a means of diagnosing it accurately. OBJECTIVE: This is a historical review of Bob Whitaker's journey from his definition of obstruction to the inception of his eponymous test. RESULTS: In 1975, he proposed a theory to explain the pathophysiology behind obstructive hydronephrosis and megaureter. He was among the first pediatric urologists to observe that 'it is wrong… to assume that dilatation necessarily indicates obstruction', a statement that was widely stated and even appeared in the textbooks at the time. He defined obstruction as 'an increased pressure in the pelvicalyceal system of the kidney at normal physiological flow rates such that the renal function is adversely affected'. This realization led to the development of a percutaneous pressure-measuring technique at controlled flows, later referred to as the Whitaker test. It predated and later assisted in the interpretation of diuretic renograms. DISCUSSION: Whitaker questioned the etiology of 'hydronephrosis' and challenged other hypotheses proposed at the time, which often included causes of mechanical occlusion at the ureteropelvic junction (UPJ) or ureterovesical junction (UVJ). Whitaker's hypothesis is that 'obstruction' at UPJ and UVJ levels is not mechanical but the result of a failure of normal peristalsis to form and propagate a bolus. This, in turn, depends on the potentially abnormal distensibility of the renal pelvic and ureteric wall whether it be congenital or acquired. The aim of this review is to recall the history of the development of a technique to evaluate dilated upper urinary tracts and to re-evaluate various theories that might explain the etiology of the dilatation in the light of more recent evidence. Robert (or Bob, to his colleagues) Whitaker was among the founder members of the British Association of Paediatric Urologists, which now has more than 50 members, in 1992. Together with his colleagues Philip Ransley and David Thomas, Whitaker established the annual pediatric urology course for pediatric surgery and urology trainees in Cambridge, U.K., which still runs to this day. He retired from his surgical practice in 1990 and up until the present time has taught clinical anatomy in the Cambridge University School of Medicine.

The randomised uterine septum transsection trial (TRUST): design and protocol.

BACKGROUND: A septate uterus is a uterine anomaly that may affect reproductive outcome, and is associated with an increased risk for miscarriage, subfertility and preterm birth. Resection of the septum is subject of debate. There is no convincing evidence concerning its effectiveness and safety. This study aims to assess whether hysteroscopic septum resection improves reproductive outcome in women with a septate uterus. METHODS/DESIGN: A multi-centre randomised controlled trial comparing hysteroscopic septum resection and expectant management in women with recurrent miscarriage or subfertility and diagnosed with a septate uterus. The primary outcome is live birth, defined as the birth of a living foetus beyond 24 weeks of gestational age. Secondary outcomes are ongoing pregnancy, clinical pregnancy, miscarriage and complications following hysteroscopic septum resection. The analysis will be performed according to the intention to treat principle. Kaplan-Meier curves will be constructed, estimating the cumulative probability of conception leading to live birth rate over time. Based on retrospective studies, we anticipate an improvement of the live birth rate from 35% without surgery to 70% with surgery. To demonstrate this difference, 68 women need to be randomised. DISCUSSION: Hysteroscopic septum resection is worldwide considered as a standard procedure in women with a septate uterus. Solid evidence for this recommendation is lacking and data from randomised trials is urgently needed. TRIAL REGISTRATION: Dutch trial registry ( NTR1676 , 18th of February 2009).

Venous thromboembolism after induced abortion: a population-based, propensity-score-matched cohort study in Canada.

BACKGROUND: A woman's risk of venous thromboembolism during pregnancy is estimated to be two-to-six times higher than her risk when she is not pregnant. Such risk estimates are largely based on pregnancies that result in delivery of a newborn baby; no estimates exist for the risk of venous thromboembolism after induced abortion, another common pregnancy outcome. To fill this knowledge gap, we aimed to assess the risk of venous thromboembolism in women whose first pregnancy ended with induced abortion. METHODS: We did this propensity score-matched cohort study using data from the universal health-care system of Ontario, Canada. We included primigravid women who had an induced abortion between Jan 1, 2003, and Dec 31, 2015, and used a propensity score to match them to primigravid women who had a livebirth (1:1) or nulligravid women who were not pregnant on the procedure date of their matched counterpart and who did not conceive within 1 year afterwards (5:1). We excluded from our analysis women younger than 15 years or older than 49 years and individuals who had missing or invalid information about their sex, area of residence, residential income, or world region of origin. The primary outcome was risk of any venous thromboembolism within 42 days of the index date (defined as the date of an induced abortion, delivery date for livebirth, or for non-pregnant women the induced abortion date of their matched counterpart). We compared the rate of venous thromboembolism in primigravid women who had an induced abortion with the rate of venous thromboembolism in propensity-score-matched non-pregnant women and propensity-score-matched primigravid women whose pregnancy ended with a livebirth. We generated hazard ratios (HRs) of 42-day risk of venous thromboembolism after induced abortion using Cox proportional hazard models. FINDINGS: We identified 194 086 eligible women whose first pregnancy ended with induced abortion, of whom 176 001 (90·7%) could be matched with women whose first pregnancy ended in delivery of a newborn. These 176 001 women were also matched to 880 005 non-pregnant women. The rate of venous thromboembolism within 42 days of an induced abortion was 30·1 (95% CI 22·0-38·2) per 100 000 women compared with 13·5 (11·1-16·0) per 100 000 women in the non-pregnant group (HR 2·23, 95% CI 1·61-3·08). The HR was 0·16 (95% CI 0·12-0·22) when compared with the women in the livebirth cohort, whose venous thromboembolism rate within 42 days postpartum was 184·7 (95% CI 164·6-204·7) per 100 000 women. INTERPRETATION: The 42-day risk of venous thromboembolism after an induced abortion is double that of a matched non-pregnant woman, and is significantly lower than after a livebirth. This novel information can inform estimates of peri-procedural risk of venous thromboembolism after induced abortion. Clinicians could consider a lower threshold for ordering a diagnostic test to rule out venous thromboembolism after induced abortion than they would in a non-pregnant woman. FUNDING: Institute for Clinical Evaluative Sciences.

Intergenerational teen pregnancy: a population-based cohort study.

OBJECTIVE: To estimate the intergenerational association in teenage pregnancy, and whether there is a coupling tendency between a mother and daughter in how their teen pregnancies end, such as a termination of pregnancy (TOP) versus a live birth. DESIGN: Population-based cohort study. SETTING: Ontario, Canada. POPULATION: A total of 15 097 mothers and their 16 177 daughters. METHODS: Generalised estimating equations generated adjusted odds ratios (aOR) of a daughter experiencing a teen pregnancy in relation to the number of teen pregnancies her mother had. Multinomial logistic regression estimated the odds that a teen pregnancy ended with TOP among both mother and daughter. All models were adjusted for maternal age and world region of origin, the daughter's socio-demographic characteristics and comorbidities, mother-daughter cohabitation, and neighbourhood-level teen pregnancy rate. MAIN OUTCOME MEASURES: Teen pregnancy in the daughter, between ages 15 and 19 years, and also the nature of the daughter's teen pregnancy, categorised as (1) no teen pregnancy, (2) at least one teen pregnancy, all exclusively ending with a live birth, and (3) at least one teen pregnancy, with at least one teen pregnancy ending with a TOP. RESULTS: The proportion of daughters having a teen pregnancy among those whose mother had zero, one, two, or at least three teen pregnancies was 16.3, 24.9, 33.5 and 36.3%, respectively. The aOR of a daughter having a teen pregnancy was 1.42 (95% CI 1.25-1.61) if her mother had one, 1.97 (95% CI 1.71-2.26) if she had two, and 2.17 (95% CI 1.84-2.56) if her mother had three or more teen pregnancies, relative to none. If a mother had at least one teen pregnancy ending with TOP, then her daughter had an aOR of 2.12 (95% CI 1.76-2.56) for having a teen pregnancy also ending with TOP; whereas, if a mother had at least one teen pregnancy, all ending with a live birth, then her daughter had an aOR of 1.73 (95% CI 1.46-2.05) for that same outcome. CONCLUSION: There is a strong intergenerational occurrence of teenage pregnancy between a mother and daughter, including a coupling tendency in how the pregnancy ends. TWEETABLE ABSTRACT: Strong intergenerational association for teenage pregnancy between mother and daughter.

Intergenerational abortion tendency between mothers and teenage daughters: a population-based cohort study.

BACKGROUND: A teenage woman's sexual health practices may be influenced by her mother's experience. We evaluated whether there is an intergenerational tendency for induced abortion between mothers and their teenage daughters. METHODS: We conducted a retrospective population-based cohort study involving daughters born in Ontario between 1992 and 1999. We evaluated the daughters' data for induced abortions between age 12 years and their 20th birthday. We assessed each mother's history of induced abortion for the period from 4 years before her daughter's birth to 12 years after (i.e., when her daughter turned 12 years of age). We used Cox proportional hazard models to estimate a daughter's risk of having an induced abortion in relation to the mother's history of the same procedure. We adjusted hazard ratios (HRs) for maternal age and world region of origin, mental or physical health problems in the daughter, mother- daughter cohabitation, neighbourhood-level rate of teen induced abortion, rural or urban residence, and income quintile. RESULTS: A total of 431 623 daughters were included in the analysis. The cumulative probability of teen induced abortion was 10.1% (95% confidence interval [CI] 9.8%-10.4%) among daughters whose mother had an induced abortion, and 4.2% (95% CI 4.1%-4.3%) among daughters whose mother had no induced abortion, for an adjusted HR of 1.94 (95% CI 1.86-2.01). The adjusted HR of a teenaged daughter having an induced abortion in relation to number of maternal induced abortions was 1.77 (95% CI 1.69-1.85) with 1 maternal abortion, 2.04 (95% CI 1.91-2.18) with 2 maternal abortions, 2.39 (95% CI 2.19-2.62) with 3 maternal abortions and 2.54 (95% CI 2.33-2.77) with 4 or more maternal abortions, relative to none. INTERPRETATION: We found that the risk of teen induced abortion was higher among daughters whose mother had had an induced abortion. Future research should explore the mechanisms for intergenerational induced abortion.

To which countries do European psychiatric trainees want to move to and why?

BACKGROUND: There is a shortage of psychiatrists worldwide. Within Europe, psychiatric trainees can move between countries, which increases the problem in some countries and alleviates it in others. However, little is known about the reasons psychiatric trainees move to another country. METHODS: Survey of psychiatric trainees in 33 European countries, exploring how frequently psychiatric trainees have migrated or want to migrate, their reasons to stay and leave the country, and the countries where they come from and where they move to. A 61-item self-report questionnaire was developed, covering questions about their demographics, experiences of short-term mobility (from 3 months up to 1 year), experiences of long-term migration (of more than 1 year) and their attitudes towards migration. RESULTS: A total of 2281 psychiatric trainees in Europe participated in the survey, of which 72.0% have 'ever' considered to move to a different country in their future, 53.5% were considering it 'now', at the time of the survey, and 13.3% had already moved country. For these immigrant trainees, academic was the main reason they gave to move from their country of origin. For all trainees, the overall main reason for which they would leave was financial (34.4%), especially in those with lower (<500€) incomes (58.1%), whereas in those with higher (>2500€) incomes, personal reasons were paramount (44.5%). CONCLUSIONS: A high number of psychiatric trainees considered moving to another country, and their motivation largely reflects the substantial salary differences. These findings suggest tackling financial conditions and academic opportunities.

Heart Rate Variability in Obstetricians Working 14-Hour Call Compared to 24-Hour Call in Labour and Delivery.

INTRODUCTION: Obstetricians have stressful and demanding jobs that may impact their health. A physiological measurement of cardiac function which varies with stress is heart rate variability (HRV). By measuring the cyclic variations in R-R intervals, or beat-to-beat differences, HRV reflects the continuous interplay of the controlling forces in the autonomic nervous system. Studies have shown HRV to be reduced during periods of work-induced stress, including 24-hour shifts. OBJECTIVE: Our study aimed to determine if there was a correlation between length of shift worked and HRV. We hypothesised that working for a full 24-hour period is more stressful than a shorter, nighttime-only period, and HRV analyses were used to measure this objectively. METHODS: Obstetricians wore an HRV monitor for 24 hours during both a regular day followed by a 14-hour night shift and a continuous 24-hour shift in labour and delivery. The 24-hour samples were analysed using standard HRV measurements. HRV measurements obtained from each physician were then compared according to shift type, with each physician acting as his or her own comparator. RESULTS: There were no statistically significant differences in the most important measures of HRV between 24-hour periods which included either a 14-hour overnight shift or a continuous 24-hour shift on labour and delivery. CONCLUSION: We found no significant differences in key HRV measures in obstetricians working 14 hours versus 24 hours in labour and delivery. An anecdotal increase in physician awareness of his/her own health related to working conditions was noted during the study. Future studies should attempt to control for the hours prior to a night shift, assess associated endocrine variations, and focus upon HRV in the post-shift period.

Report on The Society for Fetal Urology panel discussion on the selection criteria and intervention for fetal bladder outlet obstruction.

INTRODUCTION: The Society for Fetal Urology panel section at the 2016 Fall Congress featured a multidisciplinary discussion on appropriate patient selection, the conservative versus surgical management, and postnatal renal outcome of fetuses with lower urinary tract obstruction (LUTO). SELECTION CRITERIA FOR INTERVENTION: Rodrigo Ruano shared his experience of prenatal intervention, presenting the outcome of 111 fetuses with severe LUTO treated with vesicoamniotic shunting (VAS) (n = 16), cystoscopy (n = 34) or no intervention (n = 61) in a non-randomized series. Multivariate analysis at the 6-month follow-up suggested a significantly higher probability of survival with fetal intervention versus no intervention. A clear trend for normal renal function was present in the fetal cystoscopy group, but not in the VAS group. In cases in which there was a postnatal diagnosis of posterior urethral valves (n = 57), fetal cystoscopy was effective in improving both the 6-month survival rate and renal function, while VAS was associated with an improvement in the 6-month survival rate. In an attempt to better define which fetuses would benefit from intervention, Michael Braun explained the proposed LUTO classification system that incorporates: (1) fetal urinary biomarkers of renal injury; (2) amniotic fluid levels as a surrogate for the severity of obstruction; and (3) imaging studies to identify signs of renal dysplastic or cystic changes. Intervention was not recommended in patients at low risk of either renal disease or pulmonary hypoplasia (Stage 1). Vesicoamniotic shunting was performed in patients at high risk of either progressive renal injury or pulmonary hypoplasia without evidence of severe pre-existing renal damage (Stage 2). For those patients, who at the time of evaluation had evidence of severe renal disease (Stage 3), fetal intervention was individualized and often based on bladder capacity and bladder refilling after vesicocentesis. He went on to present the nephrologic outcome of fetuses managed over the last 3 years utilizing the selection criteria. Craig Peters supported the concept of selective criteria and discussed the cautious viewpoint, namely: (1) the procedure may be unnecessary, as it is possible for patients to do well, in spite of severe prenatal obstruction; and (2) the risk of giving partial treatment by allowing the baby to survive to delivery with the daunting postnatal journey of renal and pulmonary insufficiency. CONCLUSION: Standardized patient selection utilizing a staging system is undoubtedly the way forward and will enable comparable long-term renal and bladder functional outcome studies.

Application of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement to publications on endoscopic treatment for vesicoureteral reflux.

OBJECTIVE: Following an increasing number of submissions on endoscopic treatment of vesicoureteral reflux (VUR), the Journal of Pediatric Urology sought to establish a quality guideline that would enable reviewers to select the best papers for publication in the journal. The "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) Statement, established in 2007, is a 22-item checklist designed to assist with clear reporting of observational studies. This checklist includes a description of methodological items and instructions on how to use them to transparently report observational studies. The aim of the present study was to apply the STROBE principle to observational studies about endoscopic management of VUR, and to establish a "check-list" to assist authors with good-quality submissions. STUDY DESIGN: The 22 STROBE criteria were listed and applied to publications on endoscopic treatment by utilizing examples from the current literature, with additional suggestions about how future studies could build upon the information already published on the subject. RESULTS: Based on this strategy, a checklist that is particular to endoscopic treatment studies was produced as a guideline for authors and reviewers. DISCUSSION: Application of the STROBE statement principles, in combination with key VUR data, will allow better quality submissions and a higher chance of positive reviews and acceptance rates.

Kruppel-like factor 4 signals through microRNA-206 to promote tumor initiation and cell survival.

Tumor cell heterogeneity poses a major hurdle in the treatment of cancer. Mammary cancer stem-like cells (MaCSCs), or tumor-initiating cells, are highly tumorigenic sub-populations that have the potential to self-renew and to differentiate. These cells are clinically important, as they display therapeutic resistance and may contribute to treatment failure and recurrence, but the signaling axes relevant to the tumorigenic phenotype are poorly defined. The zinc-finger transcription factor Kruppel-like factor 4 (KLF4) is a pluripotency mediator that is enriched in MaCSCs. KLF4 promotes RAS-extracellular signal-regulated kinase pathway activity and tumor cell survival in triple-negative breast cancer (TNBC) cells. In this study, we found that both KLF4 and a downstream effector, microRNA-206 (miR-206), are selectively enriched in the MaCSC fractions of cultured human TNBC cell lines, as well as in the aldehyde dehydrogenase-high MaCSC sub-population of cells derived from xenografted human mammary carcinomas. The suppression of endogenous KLF4 or miR-206 activities abrogated cell survival and in vivo tumor initiation, despite having only subtle effects on MaCSC abundance. Using a combinatorial approach that included in silico as well as loss- and gain-of-function in vitro assays, we identified miR-206-mediated repression of the pro-apoptotic molecules programmed cell death 4 (PDCD4) and connexin 43 (CX43/GJA1). Depletion of either of these two miR-206-regulated transcripts promoted resistance to anoikis, a prominent feature of CSCs, but did not consistently alter MaCSC abundance. Consistent with increased levels of miR-206 in MaCSCs, the expression of both PDCD4 and CX43 was suppressed in these cells relative to control cells. These results identify miR-206 as an effector of KLF4-mediated prosurvival signaling in MaCSCs through repression of PDCD4 and CX43. Consequently, our study suggests that a pluripotency factor exerts prosurvival signaling in MaCSCs, and that antagonism of KLF4-miR-206 signaling may selectively target the MaCSC niche in TNBC.