Opportunistic Salpingectomy Between 2017 and 2020: A Descriptive Analysis.

OBJECTIVES: Opportunistic salpingectomy (OS) is the removal of fallopian tubes during another pelvic surgery for the purpose of ovarian cancer prevention. Herein, we describe the rates of OS at the time of hysterectomy and tubal sterilization between 2017 and 2020. METHODS: This study uses the Canadian Institute of Health Information's Discharge Abstract Database and National Ambulatory Care Reporting System for all Canadian provinces and territories except for Quebec between the fiscal years 2017 and 2020. A descriptive analysis on all people aged 15 years and older who had hysterectomies or tubal sterilizations was conducted to determine the proportion of hysterectomies that included bilateral salpingectomy (OS) and the proportion of tubal sterilizations that were OS compared to tubal ligation. RESULTS: There were 174 006 people included in the study. The proportion of hysterectomies that included OS increased from 31.7% in 2017 to 39.9% by 2020. With respect to tubal sterilizations, rates of OS increased from 26.3% of all tubal sterilizations in 2017 to 42.5% in 2020. British Columbia remained the jurisdiction with the highest rates of OS, but rates increased significantly in many jurisdictions, particularly at the time of tubal sterilization. CONCLUSION: The rates of OS have continued to increase in all Canadian jurisdictions following the official Society of Obstetricians and Gynaecologists of Canada recommendation to consider OS in 2015. Assuming that all tubal ligations could have been OS and 75% of hysterectomies with ovarian conservation could have included OS, our data indicate 76 932 missed opportunities for ovarian cancer prevention.

Delayed versus Immediate Cord Clamping in Preterm Infants.

BACKGROUND: The preferred timing of umbilical-cord clamping in preterm infants is unclear. METHODS: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. RESULTS: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. CONCLUSIONS: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088 .).

Examining indicators of early menopause following opportunistic salpingectomy: a cohort study from British Columbia, Canada.

BACKGROUND: The fallopian tube may often be the site of origin for the most common and lethal form of ovarian cancer, high-grade serous ovarian cancer. As a result, many colleges of obstetrics and gynecology, which include the American College of Obstetricians and Gynecologists, are recommending surgical removal of the fallopian tube (bilateral salpingectomy) at the time of other gynecologic surgeries (particularly hysterectomy and tubal sterilization) in women at general population risk for ovarian cancer, collectively referred to as opportunistic salpingectomy. Previous research has illustrated no increased risk of complications after opportunistic salpingectomy. However, most studies that have examined potential hormonal consequences of opportunistic salpingectomy have had limited follow-up time and have focused on surrogate hormonal markers. OBJECTIVE: We examine whether there are differences in physician visits for menopause and filling a prescription for hormone replacement therapy among women who undergo opportunistic salpingectomy in the population of British Columbia, Canada. STUDY DESIGN: We identified all women who were ≤50 years old in British Columbia who underwent opportunistic salpingectomy from 2008-2014. We compared women who underwent opportunistic salpingectomy at hysterectomy with women who underwent hysterectomy alone and women who underwent opportunistic salpingectomy for sterilization with women who underwent tubal ligation. We used Cox Proportional hazards models to model time to physician visits for menopause and for filling a prescription for hormone replacement therapy. We calculated adjusted hazards ratios for these outcomes and adjusted for other gynecologic conditions, surgical approach, and patient age. We performed an age-stratified analysis (<40, 40-44, 45-49 years) and conducted a sensitivity analysis that included only women with ≥5 years of follow up. RESULTS: We included 41,413 women in the study. There were 6861 women who underwent hysterectomy alone, 6500 who underwent hysterectomy with opportunistic salpingectomy, 4479 who underwent hysterectomy with bilateral salpingo-oophorectomy, 18,621 who underwent tubal ligation, and 4952 who underwent opportunistic salpingectomy for sterilization. In women who underwent opportunistic salpingectomy, there was no difference in time to the first physician visit related to menopause for both women who underwent hysterectomy with opportunistic salpingectomy (adjusted hazard ratio, 0.98; 95% confidence interval, 0.88-1.09) and women who underwent opportunistic salpingectomy for sterilization (adjusted hazard ratio, 0.92; 95% confidence interval, 0.77-1.10). There was also no difference in time to filling a prescription for hormone replacement therapy for women who underwent hysterectomy with opportunistic salpingectomy or opportunistic salpingectomy for sterilization (adjusted hazard ratio, 0.82; 95% confidence interval, 0.72-0.92; and adjusted hazard ratio, 1.00; 95% confidence interval, 0.89-1.12; respectively). In contrast, we report significantly increase hazards for time to physician visit for menopause (adjusted hazard ratio, 1.95; 95% confidence interval, 1.78, 2.13) and filling a prescription for hormone replacement therapy (adjusted hazard ratio, 3.80; 95% confidence interval, 3.45, 4.18) among women who underwent hysterectomy with bilateral salpingo-oophorectomy. There were no increased hazards for physician visits for menopause or initiation of hormone replacement therapy among women who underwent opportunistic salpingectomy in any of the age-stratified analyses, nor among women with at least 5 years of follow up. CONCLUSION: Our results reveal no indication of an earlier age of onset of menopause among the population of women who underwent hysterectomy with opportunistic salpingectomy and opportunistic salpingectomy for sterilization as measured by physician visits for menopause and initiation of hormone replacement therapy. Our findings are reassuring, given that earlier age at menopause is associated with increased mortality rates, particularly from cardiovascular disease.

Extending the safety evidence for opportunistic salpingectomy in prevention of ovarian cancer: a cohort study from British Columbia, Canada.

BACKGROUND: Recent evidence has suggested that the fallopian tube may often be the site of origin for the most common and lethal form of ovarian cancer. As a result, many Colleges of Obstetrics and Gynecology, including the American College of Obstetricians and Gynecology, are recommending surgical removal of the fallopian tube (bilateral salpingectomy) at the time of other gynecologic surgeries (particularly hysterectomy and tubal sterilization) in women at general population risk for ovarian cancer, collectively referred to as opportunistic salpingectomy. OBJECTIVE: Previous research with the use of hospital data has indicated good perioperative safety of opportunistic salpingectomy, but no data on minor complications have been presented. Herein, we examine whether women who undergo opportunistic salpingectomy are at increased risk of minor complications after surgery. STUDY DESIGN: We identified all women in British Columbia who underwent opportunistic salpingectomy between 2008 and 2014 and examined all physician visits in the 2 weeks after discharge from the hospital. We compared women who underwent opportunistic salpingectomy at hysterectomy with women who underwent hysterectomy alone and women who underwent opportunistic salpingectomy for sterilization with women who underwent tubal ligation. We examined visits for surgical infection, surgical complication, orders for laboratory tests, and orders for imaging (x-ray, ultrasound scan, or computed tomography scan) and whether women who underwent opportunistic salpingectomy were more likely to fill a prescription for an antibiotic or analgesic in the 2 weeks after discharge from the hospital. We calculated adjusted odds ratios for these outcomes, adjusting for other gynecologic conditions, surgical approach, and patient age. RESULTS: We included 49,275 women who had undergone a hysterectomy alone, a hysterectomy with opportunistic salpingectomy, a hysterectomy with bilateral salpingo-oophorectomy, a tubal ligation, or an opportunistic salpingectomy for sterilization. In women who had undergone opportunistic salpingectomy, there was no increased risk for physician visits for surgical infection, surgical complication, ordering a laboratory test, or ordering imaging in the 2 weeks after discharge. There was no increased risk of filling a prescription for an antibiotic. However, women who underwent opportunistic salpingectomy were at approximately 20% increased odds of filling a prescription for an analgesic in the 2 weeks after discharge from the hospital (adjusted odds ratio, 1.23; 95% confidence interval, 1.15-1.32 for hysterectomy with opportunistic salpingectomy; adjusted odds ratio, 1.21; 95% confidence interval, 1.14-1.29 for opportunistic salpingectomy for sterilization). CONCLUSION: We report no differences in minor complications between women who undergo opportunistic salpingectomy and women who undergo hysterectomy alone or tubal ligation, except for a slightly increased likelihood of filling a prescription for analgesic medication in the immediate 2 weeks after discharge.

Changing Clinical Practice: Evaluation of Implementing Recommendations for Opportunistic Salpingectomy in British Columbia and Ontario.

OBJECTIVE: The aim of the study was to explore the factors that contributed to the adoption of opportunistic salpingectomies (removal of fallopian at the time of hysterectomy or in lieu of tubal ligation) by gynecologic surgeons in British Columbia (where a knowledge translation initiative took place) and in Ontario (a comparator where no knowledge translation initiative took place). We aimed to understand why the knowledge translation initiative undertaken by OVCARE in British Columbia resulted in such a dramatic uptake in opportunistic salpingectomy. METHODS: We undertook a qualitative evaluation of clinicians' decisions about whether or not they should adopt the practice of opportunistic salpingectomy based on interviews with gynecologic surgeons in British Columbia and Ontario (n = 28). The analysis draws from the Consolidated Framework for Implementation Research. RESULTS: Regional cohesion combined with practice change information exposure and thought leader support were important in explaining differences in adoption levels between participants. The British Columbian knowledge translation campaign was successful because provincial thought leaders exposed gynecologic surgeons to recommendations through multiple sources within a highly socially cohesive environment wherein clinicians felt pressure to adopt the recommendations. In both provinces, high adopters often believed that the workload and surgical risk associated with the adoption was low and the potential benefit-because of limited ovarian cancer detection and treatment options-was high. CONCLUSION: This research points to the important role that local professional networks can play in encouraging clinicians to change their practice by creating a cohesive regional environment where clinicians are repeatedly exposed to important information and supported in their practice change by local thought leaders.

Outcomes of Conservative Management of High Grade Squamous Intraepithelial Lesions in Young Women.

OBJECTIVE: The aim of the study was to determine regression rates of cervical intraepithelial neoplasia (CIN) 2 and 3 in women younger than 24 years, followed conservatively for up to 24 months. MATERIALS AND METHODS: This is a retrospective chart review of colposcopy patients in clinic database based on the following: (1) younger than 24 years at first visit; (2) first visit January 1, 2010, to May 31, 2013, and at least 1 follow-up visit after diagnosis; (3) histologic diagnosis of CIN2+; and (4) optimal conservative management (observation for up to 24 months or to 24 years, whichever occurred first). Patient information and clinical/pathologic data were extracted from charts to examine patient characteristics and treatment outcomes, CIN2+ regression rates, median times to regression for CIN2 versus CIN3 (Kaplan-Meier survival analysis), and predictors of regression (multivariate logistic regression analysis). RESULTS: A total of 154 women met criteria. The most severe histological diagnoses were CIN2 in 99 (64.3%), CIN3 in 51 (33.1%), and adenocarcinoma in situ in 4 (2.6%). Adenocarcinoma in situ was immediately treated. In follow-up, CIN2 regressed to CIN1 or negative in 74 women (74.7%)-median time to regression, 10.8 months. Cervical intraepithelial neoplasia 3 regressed in 11 women (21.6%)-median time to regression not reached (last follow-up censored at 52.7 months). Cervical intraepithelial neoplasia 2 on biopsy, low grade referral Pap, and younger age predicted regression. Overall, 49 women (31.8%) were treated. CONCLUSIONS: Conservative management should continue to be recommended to young women with CIN2. Rigorous retention mechanisms are required to ensure that these women return for follow-up.

Muscle magnetic resonance imaging in congenital myasthenic syndromes.

INTRODUCTION: In this study we investigated muscle magnetic resonance imaging in congenital myasthenic syndromes (CMS). METHODS: Twenty-six patients with 9 CMS subtypes and 10 controls were imaged. T1-weighted (T1w) and short-tau inversion recovery (STIR) 3-Tesla MRI images obtained at thigh and calf levels were scored for severity. RESULTS: Overall mean the T1w score was increased in GFPT1 and DPAGT1 CMS. T1w scans of the AChR-deficiency, COLQ, and CHAT subjects were indistinguishable from controls. STIR images from CMS patients did not differ significantly from those of controls. Mean T1w score correlated with age in the CMS cohort. CONCLUSIONS: MRI appearances ranged from normal to marked abnormality. T1w images seem to be especially abnormal in some CMS caused by mutations of proteins involved in the glycosylation pathway. A non-selective pattern of fat infiltration or a normal-appearing scan in the setting of significant clinical weakness should suggest CMS as a potential diagnosis. Muscle MRI could play a role in differentiating CMS subtypes. Muscle Nerve 54: 211-219, 2016.

The Long-term Efficacy and Safety of Fecal Microbiota Transplant for Recurrent, Severe, and Complicated Clostridium difficile Infection in 146 Elderly Individuals.

OBJECTIVES: Clostridium difficile infection (CDI) in the elderly has a higher prevalence, greater morbidity and mortality, and lower response to conventional treatment than the general population. Fecal microbiota transplant (FMT) is highly effective therapy for CDI but has not been studied specifically in the elderly. This study aims to determine the long-term efficacy and safety of FMT for recurrent (RCDI), severe (SCDI), and complicated (CCDI) CDI in elderly patients. METHODS: A multicenter, long-term follow-up study was performed with demographic, pre-FMT, and post-FMT data collected from elderly patients with RCDI, SCDI, and CCDI, through a 47-item questionnaire. Outcome measures included primary and secondary cure rates, early (<12 wk) and late (≥12 wk) recurrence rates, and adverse events (AEs), including post-FMT diagnoses. RESULTS: Of 168 eligible patients, 146 patients met the inclusion criteria. Of these, 68.5% were women. The mean (range) age was 78.6 (65 to 97) years and the follow-up period was 12.3 (1 to 48) months. FMT was performed for RCDI in 89 (61%), SCDI in 45 (30.8%), and CCDI in 12 (8.2%) patients. The primary and secondary cure rates were 82.9% and 95.9%, respectively. Early and late recurrences occurred in 25 and 6 patients, respectively. AEs included CDI-negative diarrhea in 7 (4.8%) and constipation in 4 (2.7%) patients. Serious AEs, recorded in 6 patients, were hospital admissions for CDI-related diarrhea, one of which culminated in death. New diagnoses post-FMT included microscopic colitis (2), Sjogren syndrome (1), follicular lymphoma (1), contact dermatitis and idiopathic Bence-Jones proteinuria (1), and laryngeal carcinoma (1)-all, however, were associated with predisposing factors. CONCLUSIONS: FMT is a safe and effective treatment option for RCDI, SCDI, and CCDI in elderly patients.

Mutations in GFPT1 that underlie limb-girdle congenital myasthenic syndrome result in reduced cell-surface expression of muscle AChR.

Mutations in GFPT1 underlie a congenital myasthenic syndrome (CMS) characterized by a limb-girdle pattern of muscle weakness. Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is a key rate-limiting enzyme in the hexosamine biosynthetic pathway providing building blocks for the glycosylation of proteins and lipids. It is expressed ubiquitously and it is not readily apparent why mutations in this gene should cause a syndrome with symptoms restricted to muscle and, in particular, to the neuromuscular junction. Data from a muscle biopsy obtained from a patient with GFPT1 mutations indicated that there were reduced endplate acetylcholine receptors. We, therefore, further investigated the relationship between identified mutations in GFPT1 and expression of the muscle acetylcholine receptor. Cultured myotubes derived from two patients with GFPT1 mutations showed a significant reduction in cell-surface AChR expression (Pt1 P < 0.0001; Pt2 P = 0.0097). Inhibition of GFPT1 enzymatic activity or siRNA silencing of GFPT1 expression both resulted in reduced AChR cell-surface expression. Western blot and gene-silencing experiments indicate this is due to reduced steady-state levels of AChR α, δ, ε, but not ß subunits rather than altered transcription of AChR-subunit RNA. Uridine diphospho-N-acetylglucosamine, a product of the hexosamine synthetic pathway, acts as a substrate at an early stage in the N-linked glycosylation pathway. Similarity between CMS due to GFPT1 mutations and CMS due to DPAGT1 mutations would suggest that reduced endplate AChR due to defective N-linked glycosylation is a primary disease mechanism in this disorder.

Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates.

Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed whole-exome sequencing to determine the underlying defect in a group of individuals with an inherited limb-girdle pattern of myasthenic weakness. We identify DPAGT1 as a gene in which mutations cause a congenital myasthenic syndrome. We describe seven different mutations found in five individuals with DPAGT1 mutations. The affected individuals share a number of common clinical features, including involvement of proximal limb muscles, response to treatment with cholinesterase inhibitors and 3,4-diaminopyridine, and the presence of tubular aggregates in muscle biopsies. Analyses of motor endplates from two of the individuals demonstrate a severe reduction of endplate acetylcholine receptors. DPAGT1 is an essential enzyme catalyzing the first committed step of N-linked protein glycosylation. Our findings underscore the importance of N-linked protein glycosylation for proper functioning of the neuromuscular junction. Using the DPAGT1-specific inhibitor tunicamycin, we show that DPAGT1 is required for efficient glycosylation of acetylcholine-receptor subunits and for efficient export of acetylcholine receptors to the cell surface. We suggest that the primary pathogenic mechanism of DPAGT1 mutations is reduced levels of acetylcholine receptors at the endplate region. These individuals share clinical features similar to those of congenital myasthenic syndrome due to GFPT1 mutations, and their disorder might be part of a larger subgroup comprising the congenital myasthenic syndromes that result from defects in the N-linked glycosylation pathway and that manifest through impaired neuromuscular transmission.

Experiencing Health Advocacy During Cervical Cancer Awareness Week: A National Initiative for Obstetrics and Gynaecology Residents.

OBJECTIVE: The Royal College of Physicians and Surgeons of Canada requires that residents demonstrate competence in health advocacy (HA). We sought to develop and implement a national educational module for obstetrics and gynaecology residents to address the role of HA. This pilot program was centred on cervical cancer prevention, which lends itself to applying the principles of advocacy. METHODS: An educational module was developed and disseminated to all obstetrics and gynaecology residency programs in Canada. The module describes options for HA involving cervical dysplasia screening, such as an outreach clinic or a forum for public/student education, which were to be implemented during Cervical Cancer Awareness Week. The measures of success were the number of programs implementing the curriculum, number of residents who participated, diversity of projects implemented, individuals (patients or learners) reached by the program, and the overall experience of the trainees. RESULTS: Three programs implemented the curriculum in 2011, one in 2012, and seven in 2013. After three years, the module has involved seven of 16 medical schools, over 100 residents, and thousands of women either directly or indirectly. Additionally, attributes of HA experienced by the residents were identified: teamwork, leadership, increased systems knowledge, increased social capital within the community, creativity, innovation, and adaptability. CONCLUSION: We have demonstrated that an educational module can be implemented nationally, helping our residents fulfill their HA requirements. Other specialties could use this module in building HA into their own programs.

Objectif : Le Collège royal des médecins et chirurgiens du Canada exige que les résidents fassent preuve de compétence dans le rôle de promoteur de la santé (PS ou promotion de la santé). Nous avons cherché à élaborer et à mettre en œuvre, à l'intention des résidents en obstétrique-gynécologie, un module pédagogique national traitant de ce rôle de PS. Ce programme pilote était centré sur la prévention du cancer du col utérin, soit un sujet se prêtant bien à l'application des principes de la promotion de la santé. Méthodes : Un module pédagogique a été élaboré et transmis à tous les programmes de résidence en obstétrique-gynécologie au Canada. Ce module décrit les options de PS mettant en jeu le dépistage de la dysplasie cervicale (telles qu'une clinique visant l'élargissement de la population desservie ou un forum d'éducation visant le public / la population étudiante) qui devaient être mises en œuvre au cours de la Semaine de sensibilisation au cancer du col de l'utérus. La réussite a été mesurée en fonction du nombre de programmes mettant en œuvre le curriculum, du nombre de résidents y ayant participé, de la diversité des projets mis en œuvre, de la nature des personnes (patientes ou apprenants) atteintes par le programme et de l'expérience globale des stagiaires. Résultats : Trois programmes ont mis en œuvre le curriculum en 2011, un programme l'a fait en 2012 et sept l'ont fait en 2013. Après trois ans, le module s'est attiré la participation directe ou indirecte de sept des 16 facultés de médecine, de plus de 100 résidents et de milliers de femmes. De plus, les attributs de la PS vécus par les résidents ont été identifiés : travail d'équipe, leadership, connaissances accrues au sujet des systèmes, capital social accru au sein de la communauté, créativité, innovation et adaptabilité. Conclusion : Nous avons démontré qu'un module pédagogique, visant à aider nos résidents à répondre à leurs exigences en matière de PS, peut être mis en œuvre à l'échelle nationale. D'autres spécialités pourraient utiliser ce module pour incorporer la PS dans leurs programmes respectifs.

Impact of Neighborhood Environments on Health Consciousness, Information Seeking, and Attitudes among US-Born and Non-US-Born Free Clinic Patients.

OBJECTIVES: This study examined the impact of neighborhood environments on health consciousness, information seeking, and attitudes among uninsured free clinic patients to better understand the specific needs of the population for health promotion and prevention efforts. METHODS: US-born English-speaking, non-US-born English-speaking, and Spanish-speaking free clinic patients completed a self-administered survey using reliable measures in autumn 2014 (N = 769). RESULTS: The results of this study suggest that social cohesion is positively associated with health consciousness, information seeking, and attitudes. Lower levels of available healthy food in the community were associated with higher levels of health consciousness. Although Spanish speakers reported lower levels of the availability of healthy food, social cohesion, and access to the Internet or text messaging compared with US-born or non-US-born English speakers, they were more likely to be health conscious and have higher levels of health information seeking. Spanish speakers as well as non-US-born English speakers, were more likely to attend health education classes compared with US-born English speakers. CONCLUSIONS: Health education programs for free clinic patients should include strategies to increase social cohesion. Health education programs should consider the diverse needs of these individual populations to maximize the effectiveness of the programs for free clinic patients.

A functional proteogenomic analysis of endometrioid and clear cell carcinomas using reverse phase protein array and mutation analysis: protein expression is histotype-specific and loss of ARID1A/BAF250a is associated with AKT phosphorylation.

BACKGROUND: Ovarian cancer is now recognized as a number of distinct diseases primarily defined by histological subtype. Both clear cell ovarian carcinomas (CCC) and ovarian endometrioid carcinomas (EC) may arise from endometriosis and frequently harbor mutations in the ARID1A tumor suppressor gene. We studied the influence of histological subtype on protein expression with reverse phase protein array (RPPA) and assessed proteomic changes associated with ARID1A mutation/BAF250a expression in EC and CCC. METHODS: Immunohistochemistry (IHC) for BAF250a expression was performed on 127 chemotherapy-naive ovarian carcinomas (33 CCC, 29 EC, and 65 high-grade serous ovarian carcinomas (HGSC)). Whole tumor lysates were prepared from frozen banked tumor samples and profiled by RPPA using 116 antibodies. ARID1A mutations were identified by exome sequencing, and PIK3CA mutations were characterized by MALDI-TOF mass spectrometry. SAM (Significance Analysis of Microarrays) was performed to determine differential protein expression by histological subtype and ARID1A mutation status. Multivariate logistic regression was used to assess the impact of ARID1A mutation status/BAF250a expression on AKT phosphorylation (pAKT). PIK3CA mutation type and PTEN expression were included in the model. BAF250a knockdown was performed in 3 clear cell lines using siRNA to ARID1A. RESULTS: Marked differences in protein expression were observed that are driven by histotype. Compared to HGSC, SAM identified over 50 proteins that are differentially expressed in CCC and EC. These included PI3K/AKT pathway proteins, those regulating the cell cycle, apoptosis, transcription, and other signaling pathways including steroid hormone signaling. Multivariate models showed that tumors with loss of BAF250a expression showed significantly higher levels of AKT-Thr308 and AKT-Ser473 phosphorylation (p < 0.05). In 31 CCC cases, pAKT was similarly significantly increased in tumors with BAF250a loss on IHC. Knockdown of BAF250a by siRNA in three CCC cell lines wild type for ARID1A showed no increase in either pAKT-Thr308 or pAKT-S473 suggesting that pAKT in tumor tissues is indirectly regulated by BAF250a expression. CONCLUSIONS: Proteomic assessment of CCC and EC demonstrates remarkable differences in protein expression that are dependent on histotype, thereby further characterizing these cancers. AKT phosphorylation is associated with ARID1A/BAF250a deficient tumors, however in ovarian cancers the mechanism remains to be elucidated.

Opportunistic salpingectomy: uptake, risks, and complications of a regional initiative for ovarian cancer prevention.

OBJECTIVE: The purpose of this study was to assess the uptake and perioperative safety of bilateral salpingectomy (BS) as an ovarian cancer risk-reduction strategy in low-risk women after a regional initiative that was aimed at general gynecologists in the province of British Columbia, Canada. STUDY DESIGN: This population-based retrospective cohort study evaluated 43,931 women in British Columbia from 2008-2011 who underwent hysterectomy that was performed with and without BS or bilateral salpingo-oophorectomy or who underwent surgical sterilization by means of BS or tubal ligation. Parameters that were examined include patient age, operating time, surgical approach, indication, length of hospital stay, and perioperative complications. RESULTS: There was an increase in the uptake of hysterectomy with BS (5-35%; P < .001) and BS for sterilization (0.5-33%; P < .001) over the study period, particularly in women <50 years old. Minimal additional surgical time is required for hysterectomy with BS (16 minutes; P < .001) and BS for sterilization (10 minutes; P < .001) compared with hysterectomy alone or tubal ligation, respectively. No significant differences were observed in the risks of hospital readmission or blood transfusions in women who underwent hysterectomy with BS (adjusted odds ratio [aOR], 0.91; 95% confidence interval [CI], 0.75-1.10; and aOR, 0.86; 95% CI, 0.67-1.10, respectively) or BS for sterilization (aOR, 0.8; 95% CI, 0.56-1.21; and aOR, 0.75; 95% CI, 0.32-1.73, respectively). From 2008-2011 the proportion of hysterectomies with BS performed by open laparotomy decreased from 77-44% with uptake in laparoscopic, vaginal, and combined procedures (P < .001). CONCLUSION: After our 2010 educational initiative, there has been a shift in surgical paradigm in our province. This cancer prevention approach does not increase the risk of operative/perioperative complications and appears both feasible and safe.

Congenital myasthenic syndromes due to mutations in ALG2 and ALG14.

Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed linkage analysis, whole-exome and whole-genome sequencing to determine the underlying defect in patients with an inherited limb-girdle pattern of myasthenic weakness. We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome. Through analogy with yeast, ALG14 is thought to form a multiglycosyltransferase complex with ALG13 and DPAGT1 that catalyses the first two committed steps of asparagine-linked protein glycosylation. We show that ALG14 is concentrated at the muscle motor endplates and small interfering RNA silencing of ALG14 results in reduced cell-surface expression of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells. ALG2 is an alpha-1,3-mannosyltransferase that also catalyses early steps in the asparagine-linked glycosylation pathway. Mutations were identified in two kinships, with mutation ALG2p.Val68Gly found to severely reduce ALG2 expression both in patient muscle, and in cell cultures. Identification of DPAGT1, ALG14 and ALG2 mutations as a cause of congenital myasthenic syndrome underscores the importance of asparagine-linked protein glycosylation for proper functioning of the neuromuscular junction. These syndromes form part of the wider spectrum of congenital disorders of glycosylation caused by impaired asparagine-linked glycosylation. It is likely that further genes encoding components of this pathway will be associated with congenital myasthenic syndromes or impaired neuromuscular transmission as part of a more severe multisystem disorder. Our findings suggest that treatment with cholinesterase inhibitors may improve muscle function in many of the congenital disorders of glycosylation.

The fallopian tube as the origin of high grade serous ovarian cancer: review of a paradigm shift.

Research published over the past 10 years has suggested that most "ovarian cancer," and specifically the high-grade serous carcinoma (HGSC) subtype of ovarian cancer, actually originates in the fallopian tube. In this review, we examine the evidence supporting the tubal origin hypothesis for HGSC, and discuss the clinical implications of our improved understanding of the pathogenesis of ovarian cancer. We searched Medline R and Medline in-process and non-indexed citations from inception to December 15, 2012, to identify all English or French language articles discussing the origins of HGSC. Articles and findings were summarized descriptively. A step-wise transformation from normal epithelium to a lesion with the ability to invade and metastasize has been demonstrated within the fallopian tube. Intraepithelial or early invasive carcinoma of the fallopian tube is frequently identified in BRCA mutation carriers who undergo prophylactic risk-reducing salpingo-oophorectomy. In both BRCA mutation carriers and women from the general population, pre-invasive changes within the fimbriated end of the fallopian tube appear in association with early HGSC. Molecular and genetic studies, as well as in vitro and animal models, have also supported a tubal origin for HGSC. Whether the removal of fallopian tubes (salpingectomy) at the time of pelvic surgery for other reasons will lead to reductions in mortality from ovarian cancer is currently unknown, but it is an important area for future clinical research.

Les recherches publiées au cours des 10 dernières années ont laissé entendre que la plupart des « cancers de l'ovaire ¼ (et plus particulièrement le sous-type « carcinome séreux de haut grade histologique ¼ [CSHG] du cancer de l'ovaire) trouvent en fait leur origine dans la trompe de Fallope. Dans le cadre de cette analyse, nous examinons les données soutenant l'hypothèse de l'origine tubaire du CSHG et nous discutons des implications cliniques de notre compréhension améliorée de la pathogenèse du cancer de l'ovaire. Nous avons mené des recherches dans Medline R et dans les citations en traitement et non répertoriées de Medline en vue d'en tirer tous les articles publiés en anglais ou en français discutant des origines du CSHG, et ce, du début de notre étude jusqu'au 15 décembre 2012. Les articles et les constatations ont été résumés de façon descriptive. Une transformation progressive de l'épithélium normal en lésion ayant la capacité d'envahir les tissus voisins et de produire des métastases a été démontrée au sein de la trompe de Fallope. La présence d'un carcinome intraépithélial ou invasif précoce de la trompe de Fallope est fréquemment identifiée chez les porteuses de la mutation BRCA qui subissent une salpingo-ovariectomie prophylactique d'atténuation du risque. Tant chez les porteuses de la mutation BRCA que chez les femmes de la population générale, des modifications préinvasives affectant la frange ovarienne se manifestent en association avec l'apparition d'un CSHG précoce. Des études moléculaires et génétiques (ainsi que des études in vitro et menées sur des modèles animaux) ont également soutenu l'hypothèse de l'origine tubaire du CSHG. Bien que nous ne disposions toujours pas d'une réponse à la question de savoir si le retrait des trompes de Fallope (salpingectomie) au moment d'une chirurgie pelvienne effectuée pour d'autres raisons mène à une baisse du taux de mortalité attribuable au cancer de l'ovaire, elle demeure néanmoins un domaine d'intérêt important pour les futures recherches cliniques.

Clinical features of congenital myasthenic syndrome due to mutations in DPAGT1.

BACKGROUND: A newly defined congenital myasthenic syndrome (CMS) caused by DPAGT1 mutations has recently been reported. While many other CMS-associated proteins have discrete roles localised to the neuromuscular junction, DPAGT1 is ubiquitously expressed, modifying many proteins, and as such is an unexpected cause of isolated neuromuscular involvement. METHODS: We present detailed clinical characteristics of five patients with CMS caused by DPAGT1 mutations. RESULTS: Patients have prominent limb girdle weakness and minimal craniobulbar symptoms. Tubular aggregates on muscle biopsy are characteristic but may not be apparent on early biopsies. Typical myasthenic features such as pyridostigmine and 3, 4- diaminopyridine responsiveness, and decrement on repetitive nerve stimulation are present. CONCLUSIONS: These patients mimic myopathic disorders and are likely to be under-diagnosed. The descriptions here should facilitate recognition of this disorder. In particular minimal craniobulbar involvement and tubular aggregates on muscle biopsy help to distinguish DPAGT1 CMS from the majority of other forms of CMS. Patients with DPAGT1 CMS share similar clinical features with patients who have CMS caused by mutations in GFPT1, another recently identified CMS subtype.

Slow channel congenital myasthenic syndrome responsive to a combination of fluoxetine and salbutamol.

INTRODUCTION: Slow channel congenital myasthenic syndrome is a dominant disorder characterized by prolonged acetylcholine receptor ion-channel activation. METHODS: Molecular genetic techniques, electrophysiology, and binding studies in human embryonic kidney (HEK) 293 cells determined mutant function and expression levels. Patient response to treatment was measured by quantitative myasthenic gravis and Medical Research Council grade strength scores. RESULTS: We report an unusual case due to heteroallelic mutations in CHRNE. The slow channel mutation, p.εS278del, is accompanied by a severe low-expression mutation, p.εR217L, on the second allele. Expression studies and cosegregation of p.εS278del with the disorder in the patient's offspring demonstrate robust expression of the p.εS278del mutation. The patient showed modest benefits from standard treatment with fluoxetine, but there was dramatic improvement when salbutamol was combined with fluoxetine. CONCLUSIONS: This case suggests that salbutamol, which is beneficial in some other congenital myasthenic syndromes, might also be considered in addition to fluoxetine in slow channel syndrome.

Risk-reducing salpingectomy in Canada: a survey of obstetrician-gynaecologists.

OBJECTIVE: Performing risk-reducing salpingectomy (RRS) at the time of hysterectomy or as a method of tubal ligation has been suggested as a way to reduce the incidence of high grade serous carcinoma (HGSC) of the ovary, since this type of cancer is hypothesized to originate in the fallopian tube. We conducted a survey of Canadian obstetrician-gynaecologists to better understand the uptake and knowledge of implementing this procedure, and to identify barriers to doing so. METHODS: An anonymous, web-based survey using both quantitative and qualitative methods was sent to obstetrician-gynaecologist members of the Society of Obstetricians and Gynaecologists of Canada and the Society of Gynecologic Oncology of Canada. The survey contained questions about demographics, knowledge and beliefs about RRS, and possible barriers to its implementation in women at average risk for ovarian cancer. RESULTS: One hundred ninety-two physicians responded to the survey, a response rate of 25%. Respondents varied in their duration in practice, came from all provinces, and spent a large proportion of their time practising gynaecology. Ninety percent of respondents had heard of RRS; however, 37% were unaware of the evidence supporting the hypothesis that HGSC originates in the fallopian tube, and 38% were unsure whether there would be any population benefit from performing RRS at the time of other gynaecologic surgery. Multiple barriers to implementation were identified. CONCLUSION: Most Canadian obstetrician-gynaecologists responding to our survey were aware of RRS as a possible method to prevent ovarian cancer in women at average risk; however, barriers still exist to widespread implementation. Further research is needed to quantify the population benefit of this procedure.

Objectif : La tenue d'une salpingectomie de réduction du risque (SRR) au moment d'une hystérectomie ou comme moyen de procéder à une ligature des trompes a été suggérée à titre de façon de réduire l'incidence du carcinome séreux de grade élevé (CSGE) de l'ovaire, puisque l'on soupçonne que ce type de cancer trouve son origine dans la trompe de Fallope. Nous avons mené un sondage auprès d'obstétriciens-gynécologues canadiens afin de déterminer leurs connaissances sur le sujet, de mieux comprendre les facteurs qui influencent leurs opinions quant à cette intervention et de cerner les obstacles à la mise en œuvre de cette dernière. Méthodes : Nous avons fait parvenir un sondage Web anonyme utilisant des méthodes tant quantitatives que qualitatives aux obstétriciens-gynécologues étant membres de la Société des obstétriciens et gynécologues du Canada et de la Société de gynéco-oncologie du Canada. Ce sondage contenait des questions au sujet des caractéristiques démographiques des répondants, de leurs connaissances et de leurs opinions quant à la SRR, ainsi qu'au sujet des obstacles possibles à la mise en œuvre de cette dernière chez des femmes exposées à un risque moyen de cancer de l'ovaire. Résultats : Le nombre de répondants au sondage a été de 192, soit un taux de réponse de 25 %. La durée de pratique variait d'un répondant à l'autre : ils provenaient de toutes les provinces et passaient une grande partie de leur temps à pratiquer la gynécologie. Quatre-vingt-dix pour cent des répondants avaient entendu parler de la SRR; toutefois, 37 % n'étaient pas au courant des données soutenant l'hypothèse selon laquelle le CSGE trouve son origine dans la trompe de Fallope et 38 % demeuraient indécis quant à la question de savoir si la tenue d'une SRR au moment de l'exécution d'une autre chirurgie gynécologique pouvait entraîner quelque avantage que ce soit au niveau populationnel. De multiples obstacles à la mise en œuvre ont été identifiés. Conclusion : La plupart des obstétriciens-gynécologues canadiens ayant répondu à notre sondage connaissaient le potentiel de la SRR à titre de méthode de prévenir le cancer de l'ovaire chez les femmes exposées à des risques moyens; toutefois, il existe toujours des obstacles à la mise en œuvre à grande échelle de cette intervention. La tenue d'autres recherches s'avère requise pour en quantifier les avantages au niveau populationnel.

Cervical PEComa: Challenges in diagnosis and prognosis of a rare neoplasm.

•Cervical PEComas are rare neoplasms which present a diagnostic challenge.•Large tumour size is an important clinical prognosticator in cervical PEComa.•All reported cases of cervical PEComa classified as benign by Folpe criteria behaved in benign fashion clinically.•Tumours ≤ 4 cm may be assessed with cone biopsy, and simple hysterectomy considered if no adverse pathologic features.•Molecular characterization and linkage with coordinated rare tumour registries may identify novel treatments.