Retropubic Versus Transobturator Midurethral Slings at Time of Colpocleisis.

IMPORTANCE: This study aimed to evaluate if there is a difference between outcomes when retropubic or transobturator midurethral sling surgery is performed at the time of colpocleisis. OBJECTIVES: The purpose of this study was to compare the surgical outcomes of the retropubic midurethral sling (RP-MUS) versus the transobturator midurethral sling (TO-MUS) in women who underwent concomitant colpocleisis, specifically 2-year MUS failure and 1-year lower urinary tract symptoms (LUTSs). A secondary aim was to identify factors associated with these surgical outcomes. STUDY DESIGN: All cases of concomitant MUS and colpocleisis within a closed, integrated health care delivery system were reviewed between April 1, 2010, and March 31, 2020. Postoperative MUS failure was defined as (1) postoperative stress urinary incontinence symptoms and/or (2) additional anti-incontinence surgery. Postoperative LUTSs were defined as (1) MUS lysis and/or (2) overactive bladder requiring management with a new treatment. RESULTS: Of the 558 women included, 454 (81%) received RP-MUS and 104 (19%) received TO-MUS. Cohort demographics were similar. Neither MUS failure (7% RP-MUS and 9% TO-MUS, P = 0.450) nor LUTSs (7% RP-MUS and 12% TO-MUS, P = 0.171) were significantly different between RP-MUS and TO-MUS. In multivariable analysis, age was found to be significantly associated with LUTSs (odds ratio 0.29, 95% confidence interval 0.09-0.93, P = 0.038 among 70-74-year-olds; odds ratio 0.28, 95% confidence interval 0.09-0.83, P = 0.022 among 75-79-year-olds). CONCLUSIONS: At the time of colpocleisis, both RP-MUS and TO-MUS were highly successful and associated with a low incidence of LUTSs, including MUS lysis. The findings of this large study support RP-MUS and TO-MUS as similarly effective anti-incontinence options at time of colpocleisis.

Pediatric Intensive Care Unit Early Mobility Program: Impact on Patient Functional Status.

INTRODUCTION: Patients admitted to the pediatric Intensive Care Unit (PICU) are frequently sedated, restrained, and placed on bed rest. These practices have known negative impacts including prolonged hospital stay and diminished functional status after discharge. The authors' objective was to investigate the impact of a PICU early mobility protocol on the frequency of orders for physical, occupational, and speech therapy (PT, OT, ST) and improvement in patient functional status. METHODS: Patients admitted in 2019 prior to the development of the PICU early mobility protocol were compared to those admitted in 2020 who underwent the protocol. Differences in clinical characteristics; PICU length of stay; rates of PT, OT, and ST orders; rates of bedside mobility activities; and functional status scores (FSSs) were assessed in bivariate and multivariate analyses. The protocol included early PT, OT, and ST order placement and frequent in-room mobility activities. RESULTS: Of the 384 patients included in the study, 216 (56%) were preprotocol patients, and 168 (44%) underwent the protocol. Patients in 2020 were more likely to receive a physical therapy order compared to their 2019 counterparts (79% vs 47%, p < 0.001). Patients in 2020 had a higher daily incidence of mobility activities compared to those in 2019 (4.88 activities vs 4.1 activities, p < 0.001). Changes in functional status scores were similar between the 2 groups. CONCLUSION: PICU early mobility was associated with increased physical, occupational, and speech therapy orders and daily mobility activities but was not associated with a reduction in functional morbidity at discharge or 3 months post-discharge.

Home Narrowband UV-B Treatment for Psoriasis: A Cohort Study.

This cohort study describes and identifies patient characteristics associated with use of in-office narrowband UV-B (NBUVB) or systemic therapy following home NBUVB machine receipt.

Gender-Affirming Mastectomy Trends and Surgical Outcomes in Adolescents.

Background: There are over 150,000 transgender adolescents in the United States, yet research on outcomes following gender-affirming mastectomy in this age group is limited. We evaluated gender-affirming mastectomy incidence, as well as postoperative complications, including regret, in adolescents within our integrated health care system. Methods: Gender-affirming mastectomies performed from January 1, 2013 - July 31, 2020 in adolescents 12-17 years of age at the time of referral were identified. The incidence of gender-affirming mastectomy was calculated by dividing the number of patients undergoing these procedures by the number of adolescents assigned female at birth ages 12-17 within our system at the beginning of each year and amount of follow-up time within that year. Demographic information, clinical characteristics (comorbidities, mental health history, testosterone use), surgical technique, and complications, including mention of regret, of patients who underwent surgery were summarized. Patients with and without complications were compared to evaluate for differences in demographic or clinical characteristics using chi-squared tests. Results: The incidence of gender-affirming mastectomy increased 13-fold (3.7 to 47.7 per 100,000 person-years) during the study period. Of the 209 patients who underwent surgery, the median age at referral was 16 years (range 12-17) and the most common technique was double-incision (85%). For patients with greater than 1-year follow-up (n=137, 65.6%), at least one complication was found in 7.3% (n=10), which included hematoma (3.6%), infection (2.9%), hypertrophic scars requiring steroid injection (2.9%), seroma (0.7%), and suture granuloma (0.7%); 10.9 % underwent revision (n=15). There were no statistically significant differences in patient demographics and clinical characteristics between those with and without complications (p>0.05). Two patients (0.95%) had documented postoperative regret but neither underwent reversal surgery at follow-up of 3 and 7 years postoperatively. Conclusion: Between 2013-2020, we observed a marked increase in gender-affirming mastectomies in adolescents. The prevalence of surgical complications was low and of over 200 adolescents who underwent surgery, only two expressed regret, neither of which underwent a reversal operation. Our study provides useful and positive guidance for adolescent patients, their families, and providers regarding favorable outcomes with gender-affirming mastectomy.

Differences in Surgical Complications for Stage 1 Phalloplasty With Concurrent Versus Asynchronous Hysterectomy in Transmasculine Patients.

Background The authors sought to compare the perioperative morbidity of Stage 1 phalloplasty with asynchronous vs concurrent hysterectomy among transmasculine patients. Methods This retrospective study included transmasculine patients undergoing Stage 1 phalloplasty with either asynchronous or concurrent hysterectomy at Kaiser Permanente Northern California from January 1, 2017, to September 9, 2019. The primary outcome was differences in surgical site infection rates. Secondary outcomes included perioperative and other postoperative complications. Comparisons of demographics and outcomes were made by F-tests and Fisher's exact tests. A p value of < 0.05 was considered statistically significant. Results Of 66 transmasculine patients undergoing Stage 1 phalloplasty, 32 (48%) had an asynchronous hysterectomy and 34 (52%) had a concurrent hysterectomy. Overall, surgical site infection rates were low, and there were no significant differences between groups. Patients who had undergone asynchronous hysterectomy had more neourethral complications with Stage 1 phalloplasty than those undergoing concurrent procedures (28% vs 3%, p < 0.05). There were no significant differences in estimated blood loss, length of stay, urinary tract infection, overactive bladder or narcotic use between groups. Conclusion Overall, there were no differences between groups in most postoperative complication rates. Although more neourethral complications were found in those undergoing asynchronous hysterectomy prior to Stage I phalloplasty, this may be partially explained by increasing surgeon experience over time given this difference did not remain statistically significant after the first year of the study period. Gynecologists seeking to provide comprehensive and inclusive care to transmasculine patients should take these findings into consideration when counseling patients planning genital gender affirmation surgery.

Improving Time to Molecular Testing Results in Patients With Newly Diagnosed, Metastatic Non-Small-Cell Lung Cancer.

PURPOSE: Next-generation sequencing (NGS) is a crucial component of evaluation of patients with newly diagnosed metastatic non-small-cell lung cancer (NSCLC) to determine appropriate first-line treatment. This quality improvement project aimed to reduce time to NGS results in patients with metastatic NSCLC. METHODS: We reviewed electronic medical records of patients with newly diagnosed, untreated metastatic NSCLC from December 2018 to August 2021 and determined the number of days from pathologic diagnosis to NGS results. We reviewed process maps for oncology, pathology, the Division of Research, and a NGS vendor to determine factors leading to preventable delays. Since November 2020, we created an automated, electronic weekly report to provide earlier identification of new pathologic diagnoses in patients with metastatic NSCLC. On June 2021, we worked with our NGS vendors to expand days of the week to accept specimens. RESULTS: Our interventions reduced the median time from pathologic diagnosis to NGS results from 24 (standard deviation [SD] 9) to 16 (SD 6) days. The median time from biopsy results to NGS order was reduced from 7 days to 1 day. The time from the specimen being sent from pathology to the NGS vendor was a median of 6 days in both cohorts. The total time from pathologic diagnosis to appropriate treatment was reduced from 33 (SD 18) to 22 (SD 8) days. CONCLUSION: NGS processing in a community setting can be complex. Using a systems focused approach to quality improvement is crucial in identifying the greatest barriers in an organization. We found that delays in time to NGS results can be reduced by improved communication and workflows among departments.

Intrauterine device, subdermal contraceptive, and depot medroxyprogesterone use among transmasculine and cisgender patients over a 10-year period.

OBJECTIVE: To describe use of three types of longer-acting contraception-intrauterine devices, subdermal contraceptives, and depot medroxyprogesterone-among transmasculine and cisgender women patients. STUDY DESIGN: A repeated cross-sectional study using electronic medical records of patients, age 18 to 45, receiving care within Kaiser Permanente Northern California between 2009 and 2019. Variations in demographics, clinical characteristics and contraception method uptake were assessed using t tests for continuous variables and chi-square tests for categorical variables for patients enrolled in 2019. A linear trend test for each group was used to assess the age-adjusted uptake of contraception methods by study year. RESULTS: The transmasculine group was younger, with a mean age of 27.3 years (±7.2) vs 32.5 years (±7.8) years, respectively p < 0.001. The transmasculine group used more tobacco, alcohol, and illicit drugs. The uptake of these contraception methods increased from 2009 to 2019 for both groups (transmasculine: 0.7% to 4.1%; cisgender: 5.6% to 6.7%) with a positive linear trend for both groups (p = 0.003 and p < 0.001, respectively). The change in uptake of any intrauterine device from 2009 to 2019 was greater for the transmasculine group (0.3% to 2.3% vs 3.3% to 3.5%). Etonogestrel implant uptake had a positive linear trend from 2009 to 2019 for both groups (transmasculine: 0% to 0.5%, p = 0.02, and cisgender 0.1% to 1.2%, p < 0.001). CONCLUSION: Annual uptake of these contraception methods increased significantly for both transmasculine and cisgender groups, and this increase was greater for the transmasculine patients. Uptake of these contraception methods was higher in the cisgender population. IMPLICATIONS: These findings suggest an improvement in use of long-term contraception and menstrual suppression medications for the transmasculine population. Further research is needed to understand these differences and identify a possible unmet need for intrauterine and subdermal contraceptives and depot medroxyprogesterone use among this often-marginalized population.

Improving Caregiver Health through Systematic Assessment and a Tailored Plan of Care.

Caregivers often experience strain and negative effects on their well-being. We tested the effects of a caregiver assessment and tailored care plan for caregivers of patients transitioning home from an inpatient rehabilitation facility (IRF), a study involving two groups: usual care (n = 225) (preimplementation) and intervention (postimplementation) (n = 215). Caregivers in the intervention group were assessed using the 25-item self-reported Preparedness Assessment for the Transition Home during the IRF stay. A tailored care plan was implemented in response to the assessment. Caregivers in both groups completed the Modified Caregiver Strain Index and Global Health Scale at 30- and 90-day postdischarge. After adjusting for baseline and demographics, caregivers in the intervention group reported lower strain (p < .01) and better overall health (p < .05) at 30-day post-IRF discharge, relative to usual care. Implementing a systematic caregiver assessment and tailored care plan in the IRF may mitigate the adverse effects of caregiving.

Breast cancer risk in BRCA mutation carriers after diagnosis of epithelial ovarian cancer is lower than in carriers without ovarian cancer.

OBJECTIVE: Evaluate the incidence and characteristics of breast cancers (BC) diagnosed following an epithelial ovarian cancer (EOC) diagnosis in women with pathogenic BRCA mutations. METHODS: Retrospective cohort study of all women in an integrated healthcare system with BRCA mutations diagnosed with EOC from 1/1/1997-12/31/2018. Primary outcome was rate of subsequent BC diagnosis. Secondary outcomes included risk factors associated with development of BC, median time to detection following EOC, and method of detection. RESULTS: There were 284 women with BRCA-associated EOC identified. Fifty-two women had risk-reducing mastectomy and were excluded. Of the 232 eligible women with a median follow-up of 5.6 years, 33 (14%) women were diagnosed with BC following EOC: 27 (11%) new cases and 6 (3%) recurrences. Twelve (36%) cases of BC were detected on screening mammogram, 4 (12%) on screening MRI, and 9 (27%) on work-up after presenting with a palpable lump. Twenty-nine (87%) were early stage (0-II) disease. Median interval from EOC to BC diagnosis was 80 months (IQR 32, 134) for new and 63 months (IQR 21, 94) for recurrent BCs. There was one death from breast cancer while 12 women died of ovarian cancer. CONCLUSIONS: Most BC following BRCA-associated EOC is early stage and not associated with mortality. Given BC rate similar to general population and median diagnosis at 6.6 years following ovarian cancer, increased BC screening may not be warranted in the early years after EOC diagnosis.

Patient-Reported Outcomes Integrated Within an Electronic Medical Record in Patients With Head and Neck Cancer.

PURPOSE: Patient-reported outcome (PRO) tools lead to clinical benefits, including improved overall survival for patients with cancer. However, routine implementation of PROs in clinical practice within the electronic medical record (EMR) by integrated health care delivery systems remains limited. We studied the use of a PRO tool for patients with head and neck cancer (HNC) integrated in an EMR at Kaiser Permanente in Northern California. METHODS: Between August 2017 and December 2019, patients with newly diagnosed HNC were surveyed at baseline, then every 3 months using the Functional Assessment of Cancer Therapy-General 7 and Functional Assessment of Cancer Therapy-Head and Neck (version 4). A medical assistant performed a baseline survey on diagnosis and then notified patients electronically per surveillance protocol. Patients who did not respond to online PRO surveys could complete them via telephone or in-person appointments with medical assistants. Abnormal findings on PRO surveys were referred to appropriate members of the care team or the treating Otolaryngology-Head and Neck Surgery physicians. RESULTS: Two hundred ninety patients received baseline surveys. Patients received up to a maximum of eight subsequent surveys. Of a total of 597 electronic surveys, 585 (97.9%) were completed. The percentage of patients completing each interval survey ranged from 92% to 100%. Multivariate Poisson regression analysis showed patients with English as their primary language and an online secure account were the most likely to complete surveys compared with those patients with non-English as a primary language and without an online account. CONCLUSION: PRO tools can be effectively used within the EMR for patients with HNC with a high response rate provided there is strong engagement from a dedicated member of the care team. This has important implications for designing clinical trials and symptom monitoring in clinical practices that incorporate EMRs.

Ovarian cancer surveillance in the clinical follow up of women with known BRCA1 or BRCA2 pathogenic variants in a large health care system.

OBJECTIVE: To assess CA 125 and transvaginal ultrasound surveillance in women with BRCA1 or BRCA2 pathogenic variants in a pragmatic clinical setting with>1 year follow up. METHODS: Retrospective cohort study in a large integrated health care system of women identified from 1/1/2003 to 12/31/2017 with a BRCA1 or BRCA2 pathogenic variant with at least one intact ovary. Demographic and clinical data were collected from date of genetic testing until oophorectomy, an ovarian cancer diagnosis, or 7/1/2019. Primary outcome was frequency and findings of CA 125 tests and ultrasounds performed; secondary outcome was epithelial ovarian cancers diagnosed. RESULTS: There were 1418 women, age ≥ 30 years with a BRCA1 or BRCA2 pathogenic variant with at least one intact ovary. Of the total of 1683 ultrasounds and 2437 CA 125 tests done, 1022 ultrasounds and 1709 CA 125 tests were performed for surveillance in 771 women followed >1 year. Of these women 241 (31%) women had no surveillance, and 530 (69%) women underwent any surveillance. Only 108 (20%) underwent regular surveillance. The number who underwent regular surveillance declined each year. Twenty-one women underwent surveillance indicated surgery with only 2 ovarian cancers found by surveillance. CONCLUSIONS: Many women with BRCA1 or BRCA2 pathogenic variants undergo ultrasound and CA 125 surveillance testing but abnormal surveillance testing led to diagnosis of ovarian cancer in only two cases. These findings question the use of CA 125 and ultrasound surveillance in the clinical setting for ovarian cancer detection in women with BRCA1 or BRCA2 pathogenic variants.

Prevalence, Characteristics, and Risk Factors of Moderate or High Hyperopia among Multiethnic Children 6 to 72 Months of Age: A Pooled Analysis of Individual Participant Data.

PURPOSE: To describe the prevalence, ocular characteristics, and associated risk factors of moderate to high hyperopia in early childhood. DESIGN: Pooled analysis of individual participant data from population-based studies. PARTICIPANTS: Six- to 72-month-old multiethnic children who participated in 4 population-based studies of pediatric eye diseases. METHODS: The pooled studies conducted comparable parental interviews and ocular examinations including cycloplegic autorefraction. Presence of hyperopia was defined based on cycloplegic refractive error in the worse eye. Multivariate analyses were performed to evaluate the association of potential risk factors with hyperopia risk. MAIN OUTCOME MEASURES: Prevalence and odds ratios of moderate to high hyperopia (≥4.0 diopters [D]). RESULTS: Cycloplegic refraction was completed in 15 051 children 6 to 72 months of age. Among these children, the overall prevalence of moderate to high hyperopia (≥4.0 D) in the worse eye was 3.2% (95% confidence interval, 2.9%-3.5%), accounting for 15.6% of all hyperopia (≥2.0 D). Among children with moderate to high hyperopia, both eyes were affected in 64.4%, 28.9% showed spherical anisometropia of 1.0 D or more, and 19.5% showed astigmatism of 1.5 D or more. Among 36- to 72-month-old children with moderate to high hyperopia, 17.6% wore glasses. Prevalence of moderate to high hyperopia was slightly less in 12- to 23-month-old children and was relatively stable in children 24 months of age and older. Non-Hispanic and Hispanic white race and ethnicity, family history of strabismus, maternal smoking during pregnancy, and being a participant in the United States studies were associated with a higher risk of moderate to high hyperopia (P < 0.05). CONCLUSIONS: By assembling similarly designed studies, our consortium provided robust estimates of the prevalence of moderate to high hyperopia in the general population and showed that in 6- to 72-month-old children, moderate to high hyperopia is not uncommon and its prevalence does not decrease with age. Risk factors for moderate to high hyperopia differ from those for low to moderate hyperopia (2.0-<4.0 D) in preschool children, with family history of strabismus and maternal smoking during pregnancy more strongly associated with moderate to high hyperopia than low to moderate hyperopia.

Factors Associated with Prevalent Diabetic Retinopathy in Chinese Americans: The Chinese American Eye Study.

OBJECTIVE: To identify factors associated with prevalent diabetic retinopathy (DR) among Chinese American adults with type 2 diabetes mellitus (T2DM), and to compare these factors to ones previously described for a population-based sample of Latinos with a higher DR prevalence. DESIGN: Population-based cross-sectional study. PARTICIPANTS: 4582 Chinese Americans aged 50 or older residing in Monterey Park, California. METHODS: Participants completed an in-home questionnaire on socio-demographic status and medical history, and a comprehensive clinical eye examination, using the same protocol implemented in the Los Angeles Latino Eye Study. Fundus photographs from 7 Early Treatment Diabetic Retinopathy fields were graded in a masked manner using a modified Airlie House grading system to assess presence and severity of DR. Logistic regression analyses based on a conceptual model of DR risk identified factors associated with prevalent DR. MAIN OUTCOME MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with DR and vision-threatening DR (VTDR). RESULTS: In total, 238 participants were diagnosed with any DR; 27 of these were classified as having VTDR. Both, any DR and VTDR showed statistically significant positive associations with T2DM duration (OR5-9 years = 1.24, OR10-14 years = 2.07, OR15+years = 3.99), glycosylated hemoglobin (HbA1c) (OR6.5-6.9% = 1.33, OR7-7.9% = 1.86, OR8%+ = 3.22), systolic blood pressure (SBP) (ORper 10mmHg+ = 1.19), and insulin treatment (ORinsulin+ = 2.44). For VTDR, we also found novel associations with antihypertensive drugs (OR: 0.18; 95% CI: 0.06-0.61) and statins (OR: 4.96; 95% CI: 1.60-16.41). Chinese Americans and Latinos had a nearly identical DR probability based on HbA1c and SBP. However, Latinos had a higher DR probability at every year of duration of T2DM (≥ 5 years). CONCLUSIONS: While we observed an overall lower DR prevalence in Chinese Americans than in Latinos (35.8% of individuals with TD2M in Chinese Americans versus 42.0% in Latinos), our data indicate that the impact of increasing HbA1c and SBP on DR probability is incrementally the same in both populations. However, increasing T2DM duration is associated with higher DR probability in Latinos than Chinese Americans, even after controlling for other known predictors. Novel factors associated with VTDR include antihypertensive drugs and statins. However, to determine if these drugs impact VTDR susceptibility, we need longitudinal data and more cases.

Evidence of a genetic link between endometriosis and ovarian cancer.

OBJECTIVE: To evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer. DESIGN: Pooled genetic analysis. SETTING: University hospital. PATIENT(S): Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Endometriosis-associated genetic variation and ovarian cancer. RESULT(S): There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected. CONCLUSION(S): By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions.

Population distribution of lifetime risk of ovarian cancer in the United States.

BACKGROUND: In U.S. women, lifetime risk of ovarian cancer is 1.37%, but some women are at a substantially lower or higher risk than this average. METHODS: We have characterized the distribution of lifetime risk in the general population. Published data on the relative risks and their variances for five well-accepted risk and protective factors for ovarian cancer, oral contraceptive use, parity, tubal ligation, endometriosis, and first-degree family history of ovarian cancer in conjunction with a genetic risk score using genome-wide significant common, low penetrance variants were used. The joint distribution of these factors (i.e., risk/protective factor profiles) was derived using control data from four U.S. population-based studies, providing a broad representation of women in the United States. RESULTS: A total of 214 combinations of risk/protective factors were observed, and the lifetime risk estimates ranged from 0.35% [95% confidence interval (CI), 0.29-0.42] to 8.78% (95% CI, 7.10-10.9). Among women with lifetime risk ranging from 4% to 9%, 73% had no family history of ovarian cancer; most of these women had a self-reported history of endometriosis. CONCLUSIONS: Profiles including the known modifiable protective factors of oral contraceptive use and tubal ligation were associated with a lower lifetime risk of ovarian cancer. Oral contraceptive use and tubal ligation were essentially absent among the women at 4% to 9% lifetime risk. IMPACT: This work demonstrates that there are women in the general population who have a much higher than average lifetime risk of ovarian cancer. Preventive strategies are available. Should effective screening become available, higher than average risk women can be identified.

Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.

OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.

Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer.

BACKGROUND: There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied. METHODS: Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic "risk score" was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk. RESULTS: Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest [95% confidence interval (CI), 1.48-1.84]. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet < 0.001), parity (Phet < 0.01), and tubal ligation (Phet = 0.041). CONCLUSIONS: The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted.

Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer.

HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

Prospective analysis of DNA damage and repair markers of lung cancer risk from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

Mutagen challenge and DNA repair assays have been used in case-control studies for nearly three decades to assess human cancer risk. The findings still engender controversy because blood was drawn after cancer diagnosis so the results may be biased, a type called 'reverse causation'. We therefore used Epstein-Barr virus-transformed lymphoblastoid cell lines established from prospectively collected peripheral blood samples to evaluate lung cancer risk in relation to three DNA repair assays: alkaline Comet assay, host cell reactivation (HCR) assay with the mutagen benzo[a]pyrene diol epoxide and the bleomycin mutagen sensitivity assay. Cases (n = 117) were diagnosed with lung cancer between 0.3 and 6 years after blood collection and controls (n = 117) were frequency matched on calendar year and age at blood collection, gender and smoking history; all races were included. Case and control status was unknown to laboratory investigators. In unconditional logistic regression analyses, statistically significantly increased lung cancer odds ratios (OR(adjusted)) were observed for bleomycin mutagen sensitivity as quartiles of chromatid breaks/cell [relative to the lowest quartile, OR = 1.2, 95% confidence interval (CI): 0.5-2.5; OR = 1.4, 95% CI: 0.7-3.1; OR = 2.1, 95% CI: 1.0-4.4, respectively, P(trend) = 0.04]. The magnitude of the association between the bleomycin assay and lung cancer risk was modest compared with those reported in previous lung cancer studies but was strengthened when we included only incident cases diagnosed more than a year after blood collection (P(trend) = 0.02), supporting the notion the assay may be a measure of cancer susceptibility. The Comet and HCR assays were unrelated to lung cancer risk.