Cancer-Associated Mutations in Endometriosis without Cancer.

BACKGROUND: Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis. METHODS: We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations. RESULTS: Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions. CONCLUSIONS: We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.

Chronic pelvic pain in an interdisciplinary setting: 1-year prospective cohort.

BACKGROUND: Chronic pelvic pain affects ∼15% of women, and presents a challenging problem for gynecologists due to its complex etiology involving multiple comorbidities. Thus, an interdisciplinary approach has been proposed for chronic pelvic pain, where these multifactorial comorbidities can be addressed by different interventions at a single integrated center. Moreover, while cross-sectional studies can provide some insight into the association between these comorbidities and chronic pelvic pain severity, prospective longitudinal cohorts can identify comorbidities associated with changes in chronic pelvic pain severity over time. OBJECTIVE: We sought to describe trends and factors associated with chronic pelvic pain severity over a 1-year prospective cohort at an interdisciplinary center, with a focus on the role of comorbidities and controlling for baseline pain, demographic factors, and treatment effects. STUDY DESIGN: This was a prospective 1-year cohort study at an interdisciplinary tertiary referral center for pelvic pain and endometriosis, which provides minimally invasive surgery, medical management, pain education, physiotherapy, and psychological therapies. Exclusion criteria included menopause or age >50 years. Sample size was 296 (57% response rate at 1 year; 296/525). Primary outcome was chronic pelvic pain severity at 1 year on an 11-point numeric rating scale (0-10), which was categorized for ordinal regression (none-mild 0-3, moderate 4-6, severe 7-10). Secondary outcomes included functional quality of life and health utilization. Baseline comorbidities were endometriosis, irritable bowel syndrome, painful bladder syndrome, abdominal wall pain, pelvic floor myalgia, and validated questionnaires for depression, anxiety, and catastrophizing. Multivariable ordinal regression was used to identify baseline comorbidities associated with the primary outcome at 1 year. RESULTS: Chronic pelvic pain severity decreased by a median 2 points from baseline to 1 year (6/10-4/10, P < .001). There was also an improvement in functional quality of life (42-29% on the pain subscale of the Endometriosis Health Profile-30, P < .001), and a reduction in subjects requiring a physician visit (73-36%, P < .001) or emergency visit (24-11%, P < .001) in the last 3 months. On multivariable ordinal regression for the primary outcome, chronic pelvic pain severity at 1 year was independently associated with a higher score on the Pain Catastrophizing Scale at baseline (odds ratio, 1.10; 95% confidence interval, 1.00-1.21, P = .04), controlling for baseline pain, treatment effects (surgery), age, and referral status. CONCLUSION: Improvements in chronic pelvic pain severity, quality of life, and health care utilization were observed in a 1-year cohort in an interdisciplinary setting. Higher pain catastrophizing at baseline was associated with greater chronic pelvic pain severity at 1 year. Consideration should be given to stratifying pelvic pain patients by catastrophizing level (rumination, magnification, helplessness) in research studies and in clinical practice.

Prospective Cohort of Deep Dyspareunia in an Interdisciplinary Setting.

INTRODUCTION: Deep dyspareunia is a common symptom in women, including in half of women with endometriosis, but little is known about its response to treatment and predictors of persistent deep dyspareunia over time. AIM: To follow up deep dyspareunia severity over a 1-year prospective cohort at an interdisciplinary center, and to identify baseline predictors of more persistent deep dyspareunia at 1 year. METHODS: Prospective 1-year cohort study at a tertiary referral center for pelvic pain and endometriosis, where a range of interdisciplinary treatments are provided at a single center (surgical, hormonal, physical, and psychological therapies). Exclusion criteria were menopause, age >50 years, and never previously sexually active. Primary outcome (deep dyspareunia severity) and secondary outcome (sexual quality of life) were followed up over 1 year. Ordinal logistic regression was performed, controlling for baseline severity of deep dyspareunia, to identify baseline predictors of deep dyspareunia severity at 1 year. MAIN OUTCOME MEASURE: Primary outcome was severity of deep dyspareunia on an 11-point numeric rating scale (0-10), categorized into absent-mild (0-3), moderate (4-6), and severe (7-10); secondary outcome was sexual quality of life measured by the Endometriosis Health Profile-30. RESULTS: 1-year follow-up was obtained for 278 subjects (56% response rate at 1 year; 278/497). Severity of deep dyspareunia improved over the 1 year (McNemar test, P < .0001): the proportion of patients in the severe category decreased from 55.0% to 30.4%, the moderate category remained similar from 17.7% to 25.0%, and the absent-mild category increased from 27.3% to 44.6%. Sexual quality of life also improved (56% to 43% on the sex subscale of the Endometriosis Health Profile-30) (Welch t test, P < .001). On ordinal regression, severity of deep dyspareunia at 1 year was independently associated with younger age (OR = 0.94, 95% CI = 0.91-0.97, P = .008), and with a higher baseline depression score on the Patient Health Questionnaire-9 (OR = 1.07, 95% CI = 1.03-1.11, P = .01). CLINICAL IMPLICATIONS: Clinicians should consider employing an interdisciplinary approach for deep dyspareunia, and screening for and treating depression symptoms in these women. STRENGTH & LIMITATIONS: Strengths of the study include its prospective nature, and assessment of deep dyspareunia specifically (as opposed to superficial dyspareunia). Limitations include non-randomized design, and the patients lost to follow-up over the 1 year. CONCLUSION: Over 1 year in an interdisciplinary setting, improvements were observed in deep dyspareunia and sexual quality of life, but younger women and those with more severe depression at baseline had more persistent deep dyspareunia at 1 year. Yong PJ, Williams C, Bodmer-Roy S, et al. Prospective Cohort of Deep Dyspareunia in an Interdisciplinary Setting. J Sex Med 2018;15:1765-1775.

Drivers of maternity care in high-income countries: can health systems support woman-centred care?

In high-income countries, medical interventions to address the known risks associated with pregnancy and birth have been largely successful and have resulted in very low levels of maternal and neonatal mortality. In this Series paper, we present the main care delivery models, with case studies of the USA and Sweden, and examine the main drivers of these models. Although nearly all births are attended by a skilled birth attendant and are in an institution, practice, cadre, facility size, and place of birth vary widely; for example, births occur in homes, birth centres, midwifery-led birthing units in hospitals, and in high intervention hospital birthing facilities. Not all care is evidenced-based, and some care provision may be harmful. Fear prevails among subsets of women and providers. In some settings, medical liability costs are enormous, human resource shortages are common, and costs of providing care can be very high. New challenges linked to alteration of epidemiology, such as obesity and older age during pregnancy, are also present. Data are often not readily available to inform policy and practice in a timely way and surveillance requires greater attention and investment. Outcomes are not equitable, and disadvantaged segments of the population face access issues and substantially elevated risks. At the same time, examples of excellence and progress exist, from clinical interventions to models of care and practice. Labourists (who provide care for all the facility's women for labour and delivery) are discussed as a potential solution. Quality and safety factors are informed by women's experiences, as well as medical evidence. Progress requires the ability to normalise birth for most women, with integrated services available if complications develop. We also discuss mechanisms to improve quality of care and highlight areas where research can address knowledge gaps with potential for impact. Evaluation of models that provide woman-centred care and the best outcomes without high costs is required to provide an impetus for change.

Multifactorial contributors to the severity of chronic pelvic pain in women.

BACKGROUND: Chronic pelvic pain affects ∼15% of women, and is associated with significant societal cost and impact on women's health. Identifying factors involved in chronic pelvic pain is challenging due to its multifactorial nature and confounding between potential factors. For example, while some women with endometriosis have chronic pelvic pain, there may be comorbid conditions that are implicated in the chronic pelvic pain rather than the endometriosis itself. OBJECTIVE: We sought to explore multifactorial variables independently associated with the severity of chronic pelvic pain in women. STUDY DESIGN: We used baseline cross-sectional data from an ongoing prospective cohort, collected from patient online questionnaires, physical examination, and physician review of medical records. Participants were recruited from a tertiary referral center for endometriosis and chronic pelvic pain in Vancouver, British Columbia, Canada, from December 2013 through April 2015. Exclusion criteria included menopausal status or age >50 years. Primary outcome was self-reported severity of chronic pelvic pain in the last 3 months (0-10 numeric rating scale). Potential associated factors ranged from known pain conditions assessed by standard diagnostic criteria, validated psychological questionnaires, musculoskeletal physical exam findings, as well as pain-related, reproductive, medical/surgical, familial, demographic, and behavioral characteristics. Mann-Whitney, Kruskal-Wallis, or Spearman test were used to identify variables with an association with the primary outcome (P < .05), followed by multivariable linear regression to control for confounding and to identify independent associations with the primary outcome (P < .05). RESULTS: Overall, 656 women were included (87% consent rate), of whom 55% were diagnosed with endometriosis. The following factors were independently associated with higher severity of chronic pelvic pain: abdominal wall pain (P = .005), pelvic floor tenderness (P = .004), painful bladder syndrome (P = .019), higher score on Pain Catastrophizing Scale (P < .001), adult sexual assault (P = .043), higher body mass index (P = .023), current smoking (P = .049), and family history of chronic pain (P = .038). Severity of chronic pelvic pain was similar between women with and without endometriosis. CONCLUSION: Multifactorial variables independently associated with severity of chronic pelvic pain were identified, ranging from myofascial/musculoskeletal, urological, family history, and psycho-social factors. Continued research is required to validate these factors and to determine whether any are potentially modifiable for the management of chronic pelvic pain.

Anatomic Sites and Associated Clinical Factors for Deep Dyspareunia.

INTRODUCTION: Deep dyspareunia negatively affects women's sexual function. There is a known association between deep dyspareunia and endometriosis of the cul-de-sac or uterosacral ligaments in reproductive-age women; however, other factors are less clear in this population. AIM: To identify anatomic sites and associated clinical factors for deep dyspareunia in reproductive-age women at a referral center. METHODS: This study involved the analysis of cross-sectional baseline data from a prospective database of 548 women (87% consent rate) recruited from December 2013 through April 2015 at a tertiary referral center for endometriosis and/or pelvic pain. Exclusion criteria included menopausal status, age at least 50 years, previous hysterectomy or oophorectomy, and not sexually active. We performed a standardized endovaginal ultrasound-assisted pelvic examination to palpate anatomic structures for tenderness and reproduce deep dyspareunia. Multivariable regression was used to determine which tender anatomic structures were independently associated with deep dyspareunia severity and to identify clinical factors independently associated with each tender anatomic site. MAIN OUTCOME MEASURE: Severity of deep dyspareunia on a numeric pain rating scale of 0 to 10. RESULTS: Severity of deep dyspareunia (scale = 0-10) was independently associated with tenderness of the bladder (b = 0.88, P = .018), pelvic floor (levator ani) (b = 0.66, P = .038), cervix and uterus (b = 0.88, P = .008), and cul-de-sac or uterosacral ligaments (b = 1.39, P < .001), but not with the adnexa (b = -0.16, P = 0.87). The number of tender anatomic sites was significantly correlated with more severe deep dyspareunia (Spearman r = 0.34, P < .001). For associated clinical factors, greater depression symptom severity was specifically associated with tenderness of the bladder (b = 1.05, P = .008) and pelvic floor (b = 1.07, P < .001). A history of miscarriage was specifically associated with tenderness of the cervix and uterus (b = 2.24, P = .001). Endometriosis was specifically associated with tenderness of the cul-de-sac or uterosacral ligaments (b = 3.54, P < .001). CONCLUSIONS: In reproductive-age women at a tertiary referral center, deep dyspareunia was independently associated not only with tenderness of the cul-de-sac and uterosacral ligaments but also with tenderness of the bladder, pelvic floor, and cervix and uterus. Yong PJ, Williams C, Yosef A, et al. Anatomic Sites and Associated Clinical Factors for Deep Dyspareunia. Sex Med 2017;5:e184-e195.