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The Millennium Cohort Study, the US Department of Defense's largest and longest running study, was conceived in 1999 to investigate the effects of military service on service member health and well-being by prospectively following active duty, Reserve, and National Guard personnel from all branches during and following military service. In commemoration of the Study's 20th anniversary, this paper provides a summary of its methods, key findings, and future directions.Recruitment and enrollment of the first 5 panels occurred between 2001 and 2021. After completing a baseline survey, participants are requested to complete follow-up surveys every 3-5 years.Study research projects are categorized into 3 core portfolio areas (psychological health, physical health, and health-related behaviors) and several cross-cutting areas and have culminated in more than 120 publications to date. For example, some key Study findings include that specific military service-related factors (e.g., experiencing combat, serving in certain occupational subgroups) were associated with adverse health-related outcomes and that unhealthy behaviors and mental health issues may increase following the transition from military service to veteran status.The Study will continue to foster stakeholder relationships such that research findings inform and guide policy initiatives and health promotion efforts.

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Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis.Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls.Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85–0.99); CXCL3, 1.16 (1.05–1.29); IL6, 1.08 (1.00–1.17); MSR1, 0.90 (0.82–0.98); and MMP9, 0.91 (0.87–0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples.Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer.Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(2); 216–23. ©2012 AACR.

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PDF file - 99K, LocusZoom plots of the top two loci using stage 1 P values.

Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer.Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb).Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03–1.16] for the A/G genotype and 1.17 (95% CI, 1.05–1.30) for the G/G genotype (P = 1.6 × 10−4 in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P = 2.4 × 10−5).Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus.Impact: This study identified a potential genetic locus for endometrial cancer risk. Cancer Epidemiol Biomarkers Prev; 21(6); 980–7. ©2012 AACR.

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PDF file - 70K, Candidate inflammation genes selected for stage 1 study, Annotation of potentially functional SNPs in linkage disequilibrium (r2 > 0.2) with rs352038 (CXCL3) or rs3918249 (MMP9)

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PDF file, 123KB, Detailed Description of the Case and Control Sample Sets.

Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ���select and shrink for summary statistics��� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28���1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08���1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30���1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Introduction The primary objective of the current study was to assess factors associated with Human Papillomavirus (HPV) vaccine initiation and compliance in a cohort of active duty US military service members (SM). Materials and Methods We included active-duty participants aged 18-26 years from the Millennium Cohort Study, a longitudinal cohort study of over 200,000 military SMs. The eligible study population included 22,387 female SMs and 31,705 male SMs. Vaccination was assessed over the period 2006–2017. Logistic regression was used to estimate the odds of vaccine initiation and compliance (3 doses within a 1-year period) in relation to demographic, military, health, and behavioral characteristics. Results Among female SMs, 37.8% initiated the vaccine and 40.2% of initiators completed the series within a year. Among male SMs, 3.9% initiated the vaccine and 22.1% of initiators completed the series within a year. Differences by sociodemographic factors, deployment status, branch of service, occupation, and smoking status–but not by selected mental health conditions–were observed. Conclusion HPV vaccination uptake is subpar across all military service branches. Certain subgroups of SMs could be targeted to increase overall HPV vaccine coverage in the US military population.

Previous research suggests active duty service members (ADSM) experience higher rates of human papilloma virus infection and cervical dysplasia, which puts them at greater risk for cervical cancer. The current study examined crude rates and correlates of cervical cancer screening compliance in 2003-2015 among screening-eligible ADSM in the Millennium Cohort Study (MCS). Data were drawn from the MCS, Defense Manpower Data Center, and Military Health System Data Repository. Screening eligibility and compliance were calculated each year and initial analyses examined crude rates of compliance. Generalized estimating equations were calculated to determine whether sociodemographic, military, and mental/behavioral health covariates were associated with cervical cancer screening compliance. A majority of participants were 21-29 years old (79.4%), non-Hispanic White (60.6%), and enlisted (82.2%). Crude rates of cervical cancer screening compliance increased from 2003 (61.2%) to 2010 (83.1%), and then declined from 2010 to 2015 (59.8%). Older ADSM and those who had a history of deployment had lower odds of screening compliance. ADSM in the Air Force and those in healthcare occupations had higher odds of screening compliance. Study findings suggest that cervical cancer screening compliance is declining among ADSM. Interventions to improve screening should target groups with lower screening compliance.

The incidence of human papillomavirus (HPV) related cancers is growing in the United States. Active duty service members (ADSM) have higher rates of HPV infection than civilians and are therefore at greater risk of developing HPV-related cancers. The purpose of this commentary is to examine the burden of HPV-related cancers in ADSM. The current HPV vaccination and cervical cancer screening uptake rates of U.S. ADSM are presented, including a literature review of military-focused studies on HPV vaccination and cervical cancer screenings. We provide directions for future research, interventions, and policy recommendations to improve HPV-related cancer prevention among ADSM.

e19067 Background: The median survival for pts with LR-MDS is estimated to be 5–10 years. ESAs are utilized as first-line treatment for anemia in LR-MDS; however, real-world treatment patterns, clinical outcomes, and HCRU for pts with LR-MDS who reinitiated ESAs following previous discontinuation are not well-established. Methods: This was a retrospective study of pts with LR-MDS in a network of US community health systems who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019 and were followed through June 30, 2021. Pts were required to have discontinued (had a ≥ 3-week gap between treatment with epoetin alfa, or a ≥ 6-week gap between treatment with darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Outcomes included failure to achieve transfusion independence (TI), progression to acute myeloid leukemia (AML), overall survival (OS), number and type of health system visits, and medication use. TI was defined per IWG 2006 criteria in the subset of pts who had received ≥ 1 transfusion in the 8 weeks prior to ESA initiation. Results: There were 108 pts with confirmed LR-MDS who initiated ESA-based therapy. Pts had a median age of 79 years at diagnosis (interquartile range [IQR] 73–85), were predominantly male (58%), White (97%), and overweight or obese (52%). The median follow-up period was 17.0 months (IQR 7.2–34.7). The most used ESA was darbepoetin alfa (60%), followed by epoetin alfa (38%) and epoetin alfa-epbx (2%). Of the 33 pts who received a baseline transfusion, 52% did not achieve TI; 53% and 43% failed to achieve TI at 6 and 12 months, respectively. The majority of pts were repeatedly treated with ESAs (n = 61, 56%). Among these patients, 2% progressed to AML and 48% died during follow-up; median OS was 45 months. The median number of health system visits per patient-month was 3.2 (IQR 0.6–4.9); 89%, 62%, and 72% of pts had ≥ 1 outpatient, emergency department, or inpatient visit respectively, with median length of hospitalization of 12 days (IQR 4.8–27.8). Most pts (54%) received an antibiotic at least once during follow-up; overall, use of immunosuppressive therapy (2%) or iron chelation (3%) was rare. Conclusions: In this real-world study of community practice in the USA, reinitiation of ESA treatment after prior discontinuation in LR-MDS was prevalent. In these pts, poor clinical outcomes and frequent health system visits were observed. This study highlights the need to consider alternative treatment options for pts with LR-MDS.

1555 Background: It is a challenge to identify patients with myelodysplastic syndrome (MDS) using structured data from electronic health records (EHRs). Current claims-based algorithms incorporating diagnosis codes, clinical labs, and procedures have not been validated against an expert reference standard. A machine learning-based approach was investigated to identify erythropoietin-stimulating agent (ESA)-treated, lower-risk (LR)-MDS patients from structured EHR data. Methods: A sample of 1,549 patients from the Syapse Learning Health Network (SLHN) was identified as potential ESA-treated LR-MDS patients by a team of clinicians and epidemiologists based on diagnosis and medication data from multiple health systems’ EHRs and cancer registries. Of these, 404 (25%) were confirmed as ESA-treated LR-MDS patients through a review of patient records by certified cancer registrars (CTRs). The sample was divided into training and validation sets at a ratio of 80/20, stratified by the outcome. Age, sex, diagnosis codes corresponding to MDS and chronic kidney disease, medication (ESA, luspatercept, lenalidomide), clinical lab tests (hemoglobin, absolute neutrophils, platelet, blast percentage), and evidence of bone marrow biopsy were included as the predictive variables for the models. Gradient boosting machines with a nested cross-validation scheme were adopted to build the optimal model on the training set. Model acceptance was evaluated based on precision and recall on the validation set. The optimal model was then applied to the remaining unscreened SLHN patient population. Results: The optimal model identified an additional cohort of 157 patients based on the predicted likelihood. Among these, 69 (44%) were CTR-confirmed ESA-treated LR-MDS patients, all of whom were previously missed by the initial expert-determined selection criteria, as shown in the table. Conclusions: The application of machine learning methods increased the rate of ESA-treated MDS patient identification even after the expertly-determined population was depleted. This suggests the application of machine learning models using EHR data may improve the efficiency of MDS patient identification and screening efforts for research, quality improvement, and clinical care. [Table: see text]

To identify risk factors for surgical site infection and to define rates associated with cytoreductive surgery before and after implementation of an infection prevention bundle.We conducted a prospective quality improvement study. Patients who underwent ovarian, fallopian tube, or peritoneal cancer cytoreductive surgery at an academic tertiary care center from April 2014 to April 2016 were prospectively enrolled. Patient demographics, surgical variables, and surgical site infection rates were compared with a historical cohort after introduction of a 5-point infection prevention bundle, including: 1) preoperative and intraoperative skin preparation with 4% chlorhexidine and intraoperative vaginal preparation with 4% chlorhexidine; 2) preoperative use of oral antibiotics and mechanical bowel preparation; 3) appropriate timing of intraoperative antibiotics; 4) adoption of enhanced sterile surgical techniques for colon procedures and incisional closure; and 5) perioperative incision management.During the study period, 219 women underwent surgery: 91 prebundle and 128 treated in the postbundle period. Stage, body mass index, proportion of patients undergoing colon or upper abdominal surgery, and estimated blood loss were not different between the cohorts. Overall, the surgical site infection rate prebundle was 18 (20%); this was reduced to four (3%) postbundle (odds ratio [OR] 0.13, 95% CI 0.037-0.53; P.001). Patients who underwent a colon resection prebundle had an infection rate of 14 (33%) compared with three (7%) in the postbundle group (OR 0.14, 95% CI 0.037-0.53; P.001). Additionally, rates of surgical site infection-related hospital readmission were also lower in the postbundle (4/128 [3%]) compared with the prebundle group (12/91 [13%]; P=.005).Infection is common after ovarian cancer cytoreductive surgery. Implementation of a 5-point surgical site infection prevention bundle in women undergoing ovarian cancer operations was associated with dramatically decreased infection rates and lower hospital readmission rates.

Objective Our objectives were 1) to compare the efficacy of progestin therapy combined with metformin (Prog-Met) to Prog alone as primary fertility sparing treatment in women with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) or early-stage endometrioid carcinoma (EC), and 2) to analyze the proportion of women achieving live birth following treatment. Methods A retrospective cohort study of all reproductive-aged women with AH/IN or EC treated with Prog ± Met from 1999–2018 was conducted. Complete response (CR) was assessed and Kaplan-Meier analysis used to calculate time to CR. Comparison of potential response predictors was performed with multivariable Cox regression models. Results Ninety-two women met criteria; 59% (n = 54) were treated for AH/EIN and 41% (n = 38) for EC. Their median age, body mass index, and follow up time was 35 years, 37.7 kg/m2, and 28.4 months, respectively. Fifty-eight women (63%) received Prog and 34 (37%) received Prog-Met. Overall, 79% (n = 73) of subjects responded to treatment with a CR of 69% (n = 63). There was no difference in CR (p = 0.90) or time to CR (p = 0.31) between the treatment cohorts. Overall, 22% experienced a disease recurrence. On multivariable analysis, EC histology was the only covariate associated with a decreased Prog response (HR 0.48; p = 0.007). Only 17% of the cohort achieved a live-birth pregnancy, the majority of which required assisted reproductive technologies (81%) and occurred in the Prog treatment group. Conclusions Our study does not support the use of Prog-Met therapy for treatment of AH/EIN or EC. Additionally, fewer than 20% of women achieved a live-birth pregnancy during the study period, with most requiring ART.

Purpose/Objective In the United States over 40% of incident breast cancer diagnoses are in women over 65 years of age. Effective breast cancer treatments allow elderly patients to live long, healthy lives; questions regarding long-term quality of life are increasingly important. In women over 65, post-mastectomy breast reconstruction (PMBR) is uncommon with reported rates of 6-30%. The goal of this study is to report complication rates in elderly PMBR patients and to evaluate the impact of individual surgeons on PMBR in elderly patients. Material/methods We identified 19,417 Medicare beneficiaries diagnosed with localized breast cancer between 2005 and 2011 who underwent mastectomy. Medicare claims were used to identify PMBR, post-operative complications after PMBR (within 30 days of surgery), and long-term complications related to reconstruction (within three years following surgery). Mastectomy surgeon was identified from Medicare claims with surgeon characteristics identified through linkage to the American Medical Association (AMA) Masterfile. Multi-level, multivariable logistic models clustered by surgeon and geographic area were used to determine the impact of surgeons on the likelihood of reconstruction. The intraclass correlation coefficient (ICC) and median odds ratio (MOR) were used to describe the relative impact of the individual surgeon. The ICC estimates the proportion of variability explained by the surgeon on PMBR rates. The MOR quantifies the likelihood of a patient having a different PMBR outcome if the patient were to change surgeons (or geographic area); it is directly comparable to odds ratios. Odds ratios (OR) were used to describe the impact of fixed demographic and clinical covariates. Results Among the entire cohort, 1,234 (6.4%) patients underwent PMBR. The post-operative complication rate was 8.4% and the long-term complication rate was 19.9%. Eighteen percent of the variability in PMBR use was attributed to the individual surgeon (ICC 0.181). The MOR for surgeon was found to be 1.85 (95% CI [1.70,1.99]), indicating that a patient had an 85% chance of having a different outcome (receiving or not receiving PMBR) if the patient saw a different mastectomy surgeon. The MOR for geographic area indicated that a patient had a 32% chance of having a different outcome if the patient saw a surgeon in a different geographic area (1.32, 95% CI [1.17, 1.47]). Patients who were Asian, single, older, of lower socioeconomic status, and underwent radiation therapy were less likely to undergo PMBR. Patients who had pre-operative MRI or received chemotherapy were more likely to undergo PMBR. Patients who were treated by female surgeons or plastic surgeons were significantly more likely to undergo PMBR. Overall, the individual surgeon was the most predictive of PMBR, except for the use of pre-operative MRI and mastectomy surgeon's specialty being plastic surgery. Conclusion A small minority of older women undergo PMBR despite having low post-operative and long-term complication rates. The individual surgeon and geographic area significantly influences whether older breast cancer patients will undergo PMBR. Future research should focus on surgeon characteristics that may influence a patient's decision to undergo PMBR. Citation Format: Schoenbrunner AR, Fero KE, Boero IJ, Matsuno R, Kronstadt N, Lance S, Reid C, Wallace AM, Gosman AA, Murphy JD. Post mastectomy breast reconstruction in elderly women: Complications and the impact of individual surgeons [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-14-02.

Objectives Thirty-day readmission is used as a quality measure for patient care and Medicare-based hospital reimbursement. The primary study objective was to describe the 30-day readmission rate to an academic gynecologic oncology service. Secondary objectives were to identify risk factors and costs related to readmission. Methods This was a retrospective, concurrent cohort study of all surgical admissions to an academic, high volume gynecologic oncology service during a two-year period (2013–2014). Data were collected on patient demographics, medical comorbidities, psychosocial risk factors, and results from a hospital discharge screening survey. Mixed logistic regression was used to identify factors associated with 30-day readmission and costs of readmission were assessed. Results During the two-year study period, 1605 women underwent an index surgical admission. Among this population, a total of 177 readmissions (11.0%) in 135 unique patients occurred. In a surgical subpopulation with >1 night stay, a readmission rate of 20.9% was observed. The mean interval to readmission was 11.8days (SD 10.7) and mean length of readmission stay was 5.1days (SD 5.0). Factors associated with readmission included radical surgery for ovarian cancer (OR 2.87) or cervical cancer (OR 4.33), creation of an ostomy (OR 11.44), a Charlson score of ≥5 (OR 2.15), a language barrier (OR 3.36), a median household income in the lowest quartile (OR 6.49), and a positive discharge screen (OR 2.85). The mean cost per readmission was $25,416 (SD $26,736), with the highest costs associated with gastrointestinal complications at $32,432 (SD $32,148). The total readmission-related costs during the study period were $4,523,959. Conclusions Readmissions to a high volume gynecologic oncology service were costly and related to radical surgery for ovarian and cervical cancer as well as to medical, socioeconomic and psychosocial patient variables. These data may inform interventional studies aimed at decreasing unplanned readmissions in gynecologic oncology surgical populations.

Background The role of palliative care has expanded over the past several decades, although the oncology-specific regional evolution of this specialty has not been characterized at the population-based level. Methods This study defined the patterns of palliative care delivery using a retrospective cohort of patients with advanced cancer within the SEER-Medicare linked database. We identified 83,022 patients with metastatic breast, prostate, lung, and colorectal cancers. We studied trends between 2000 through 2009, and determined patient-level and regional-level predictors of palliative care delivery. Results Palliative care consultation rates increased from 3.0% in 2000 to 12.9% in 2009, with most consultations occurring in the last 4 weeks of life (77%) in the inpatient hospital setting. The rates of palliative care delivery were highest in the West (7.6%) and lowest in the South (3.2%). The likelihood of palliative care consultation increased with decreasing numbers of regional acute care hospital beds per capita. The use of palliative care consultation increased with increasing numbers of regional physicians. The use of palliative care decreased with increasing regional Medicare expenditure with a $1,387 difference per beneficiary between the first and fourth quartiles of palliative care use. Conclusions Geographic location influences a patient's options for palliative care in the United States. Although the overall rates of palliative care are increasing, future effort should focus on improving palliative care services in regions with the least access.

This cohort study evaluates the association of specific combat exposures with suicide attempts among active-duty members of the US Armed Forces., Key Points Question What is the association of combat exposure with suicide attempts among active-duty US service members who were deployed in support of the wars in Iraq and Afghanistan? Findings In this cohort study of 57 841 active-duty service members, high combat severity and certain combat experiences (ie, being attacked or ambushed, seeing dead bodies or human remains, and being directly responsible for the death of a noncombatant) were associated with suicide attempts. However, these associations were mostly accounted for by mental disorders, especially posttraumatic stress disorder. Meaning Results of this study suggest that certain types of combat experiences may have different implications for service members than other experiences, increasing these individuals’ risk of attempting suicide, either directly or indirectly through a mental disorder., Importance There is uncertainty about the role that military deployment experiences play in suicide-related outcomes. Most previous research has defined combat experiences broadly, and a limited number of cross-sectional studies have examined the association between specific combat exposure (eg, killing) and suicide-related outcomes. Objective To prospectively examine combat exposures associated with suicide attempts among active-duty US service members while accounting for demographic, military-specific, and mental health factors. Design, Setting, and Participants This cohort study analyzed data from the Millennium Cohort Study, an ongoing prospective longitudinal study of US service members from all military branches. Participants were enrolled in 4 phases from July 1, 2001, to April 4, 2013, and completed a self-administered survey at enrollment and every 3 to 5 years thereafter. The population for the present study was restricted to active-duty service members from the first 4 enrollment phases who deployed in support of the wars in Iraq and Afghanistan. Questionnaire data were linked with medical encounter data through September 30, 2015. Data analyses were conducted from January 10, 2017, to December 14, 2020. Exposures Combat exposure was examined in 3 ways (any combat experience, overall combat severity, and 13 individual combat experiences) using a 13-item self-reported combat measure. Main Outcomes and Measures Suicide attempts were identified from military electronic hospitalization and ambulatory medical encounter data using the International Classification of Diseases, Ninth Revision codes. Results Among 57 841 participants, 44 062 were men (76.2%) and 42 095 were non-Hispanic White individuals (72.8%), and the mean (SD) age was 26.9 (5.3) years. During a mean (SD) follow-up period of 5.6 (4.0) years, 235 participants had a suicide attempt (0.4%). Combat exposure, defined broadly, was not associated with suicide attempts in Cox proportional hazards time-to-event regression models after adjustments for demographic and military-specific factors; high combat severity and certain individual combat experiences were associated with an increased risk for suicide attempts. However, these associations were mostly accounted for by mental disorders, especially posttraumatic stress disorder. After adjustment for mental disorders, combat experiences with significant association with suicide attempts included being attacked or ambushed (hazard ratio [HR], 1.55; 95% CI, 1.16-2.06), seeing dead bodies or human remains (HR, 1.34; 95% CI, 1.01-1.78), and being directly responsible for the death of a noncombatant (HR, 1.81; 95% CI, 1.04-3.16). Conclusions and Relevance This study suggests that deployed service members who experience high levels of combat or are exposed to certain types of combat experiences (involving unexpected events or those that challenge moral or ethical norms) may be at an increased risk of a suicide attempt, either directly or mediated through a mental disorder.

Human papillomavirus (HPV) is the second most commonly diagnosed sexually transmitted infection in US service women, though the incidence has declined over the last decade, from 364.4 per 10,000 woman-years in 2007 to 90.0 per 10,000 woman-years in 2016. Despite the Department of Defense (DoD) routine vaccination recommendation for eligible service members age 17-26 years and provision of the vaccine free of charge, coverage remains low. During the years 2006-2011, only 22.5% of eligible women initiated the 3-dose series of the quadrivalent HPV vaccine, and it is not known whether receipt of the vaccine varies by demographic, military-specific, or other. We evaluated receipt of the HPV vaccine in a large cohort of active duty service women over the period 2001-2015. The women are part of the Millennium Cohort Study, which comprises over 200,000 current and past service members and is the largest longitudinal cohort of service members in military history. Briefly, participants were first enrolled in 2001 and complete follow-up questionnaires approximately every 3 years. Information on military experiences, lifestyle factors, and physical and mental health are collected at each time point. Additionally, participants can be linked to medical encounter, pharmacy, and national death data. Women who were active duty and age 18-26 years at the time of enrollment were included in the analysis. Medical encounter data and the military's central immunization database were used to identify women who had received at least one dose of the HPV (bivalent, quadrivalent, or nonavalent) vaccine. We used logistic regression to evaluate demographic, military, and health-related factors potentially related to receipt of the vaccine. There were n=14,591 women in our study cohort. Of these, n=4,867 (33.4%) had received at least one dose of the HPV vaccine. Women were less likely to be vaccinated if they were older (odds ratio [OR]=0.85, 95% confidence interval [95% CI]=0.77-0.93 for women age 25-26 years compared to women age 20-24 years), married at baseline (OR=0.79, 95% CI=0.73-0.86 compared to women who were never married), or smokers (OR=0.82, 95% CI=0.76-0.89). Women were more likely to be vaccinated if they were health care specialists (OR=1.43, 95% CI=1.30-1.57 compared to other occupations) or in the Air Force (OR=2.51, 95% CI=2.30-2.75 compared to Army). There were no differences by race, education, or military rank. In the general US population, non-white women are less likely to be vaccinated (41.5% of black, 44.7% of Hispanic or Latino, and 42.3% of Asian women compared to 52.2% in white women). However, in a setting where social determinants of health are in part addressed by equal access to vaccination, no racial differences were observed. Citation Format: Rayna K. Matsuno, Ben Porter, Steven Warner, Deborah B. Bookwalter, Natalie Wells. Human papillomavirus vaccination among US military service women [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C055.

Purpose: Ovarian cancer is a heterogeneous disease that can be divided into multiple subtypes with variable etiology, pathogenesis, and prognosis. We analyzed DNA methylation profiling data to identify biologic subgroups of ovarian cancer and study their relationship with histologic subtypes, copy number variation, RNA expression data, and outcomes. Experimental Design: A total of 162 paraffin-embedded ovarian epithelial tumor tissues, including the five major epithelial ovarian tumor subtypes (high- and low-grade serous, endometrioid, mucinous, and clear cell) and tumors of low malignant potential were selected from two different sources: The Polish Ovarian Cancer study, and the Surveillance, Epidemiology, and End Results Residual Tissue Repository (SEER RTR). Analyses were restricted to Caucasian women. Methylation profiling was conducted using the Illumina 450K methylation array. For 45 tumors array copy number data were available. NanoString gene expression data for 39 genes were available for 61 high-grade serous carcinomas (HGSC). Results: Consensus nonnegative matrix factorization clustering of the 1,000 most variable CpG sites showed four major clusters among all epithelial ovarian cancers. We observed statistically significant differences in survival (log-rank test, P = 9.1 × 10−7) and genomic instability across these clusters. Within HGSC, clustering showed three subgroups with survival differences (log-rank test, P = 0.002). Comparing models with and without methylation subgroups in addition to previously identified gene expression subtypes suggested that the methylation subgroups added significant survival information (P = 0.007). Conclusions: DNA methylation profiling of ovarian cancer identified novel molecular subgroups that had significant survival difference and provided insights into the molecular underpinnings of ovarian cancer. See related commentary by Ishak et al., p. 5729

Background: Pancreatic cancer is an aggressive disease characterized by early and relentless tumor spread, thus leading healthcare providers to consider it a “distant disease.” However, local pancreatic tumor progression can lead to substantial morbidity. This study defines the long-term morbidity from local and nonlocal disease progression in a large population-based cohort. Methods: A total of 21,500 Medicare beneficiaries diagnosed with pancreatic cancer in 2000 through 2011 were identified. Hospitalizations were attributed to complications of either local disease (eg, biliary disorder, upper gastrointestinal ulcer/bleed, pain, pancreas-related, radiation toxicity) or nonlocal/distant disease (eg, thromboembolic events, cytopenia, dehydration, nausea/vomiting/motility problem, malnutrition and cachexia, ascites, pathologic fracture, and chemotherapy-related toxicity). Competing risk analyses were used to identify predictors of hospitalization. Results: Of the total cohort, 9,347 patients (43.5%) were hospitalized for a local complication and 13,101 patients (60.9%) for a nonlocal complication. After adjusting for the competing risk of death, the 12-month cumulative incidence of hospitalization from local complications was highest in patients with unresectable disease (53.1%), followed by resectable (39.5%) and metastatic disease (33.7%) at diagnosis. For nonlocal complications, the 12-month cumulative incidence was highest in patients with metastatic disease (57.0%), followed by unresectable (56.8%) and resectable disease (42.8%) at diagnosis. Multivariable analysis demonstrated several predictors of hospitalization for local and nonlocal complications, including age, race/ethnicity, location of residence, disease stage, tumor size, and diagnosis year. Radiation and chemotherapy had minimal impact on the risk of hospitalization. Conclusions: Despite the widely known predilection of nonlocal/distant disease spread in pancreatic cancer, local tumor progression also leads to substantial morbidity and frequent hospitalization.

An outbreak of enterohaemorrhagic Escherichia coli O157 occurred in multiple prefectures of Japan in November 2009. We conducted two case–control studies with trace-back and trace-forward investigations to determine the source. The case definition was met by 21 individuals; 14 (66.7%) were hospitalised, but no haemolytic uraemic syndrome, acute encephalopathy or deaths occurred. Median age was 23 (range 12–48) years and 14 cases were male (66.7%). No significant associations with food were found in a case–control study by local public health centres, but our matched case–control study using Internet surveys found that beef hanging tender (or hanger steak), derived from the diaphragm of the cattle, was significantly associated with illness (odds ratio = 15.77; 95% confidence interval, 2.00–124.11). Pulsed-field gel electrophoresis analysis of isolates from patients and the suspected food showed five different patterns: two in faecal and food samples, and another three in patient faecal samples only, although there were epidemiological links to the meat consumed at the restaurants. Trace-back investigation implicated a common food processing company from outside Japan. Examination of the logistics of the meat processing company suggested that contamination did not occur in Japan. We concluded that the source of the outbreak was imported hanging tender. This investigation revealed that Internet surveys could be useful for outbreak investigations.

OBJECTIVES: Minimally invasive surgery (MIS) is a quality measure for endometrial cancer (EC) established by the Society of Gynecologic Oncology and the American College of Surgeons. Our study objective was to assess the proportion of EC cases performed by MIS at National Comprehensive Cancer Network (NCCN) centers and evaluate perioperative outcomes. METHODS: A retrospective cohort study of women who underwent surgical treatment for EC from 2013–2014 was conducted at four NCCN centers. Multivariable mixed logistic regression models analyzed factors associated with failure to perform MIS and perioperative complications. RESULTS: In total 1,621 patients were evaluated; 86.5% underwent MIS (robotic-assisted 72.5%, laparoscopic 20.9%, vaginal 6.6%). On multivariable analysis, factors associated with failure to undergo MIS were uterine size >12cm (Odds Ratio [OR]: 0.17, 95% CI 0.03–0.9), stage III (OR: 0.16, 95% CI 0.05–0.49) and IV disease (OR: 0.07, 95% CI 0.02–0.22). For stage I/II disease, complications occurred in 5.1% of MIS and 21.7% of laparotomy cases (p80% in EC care is feasible when performed at high volume centers.

Purpose: Palliative care’s role in oncology has expanded, but its effect on aggressiveness of care at the end of life has not been characterized at the population level. Methods: This matched retrospective cohort study examined the effect of an encounter with palliative care on health-care use at the end of life among 6,580 Medicare beneficiaries with advanced prostate, breast, lung, or colorectal cancer. We compared health-care use before and after palliative care consultation to a matched nonpalliative care cohort. Results: The palliative care cohort had higher rates of health-care use in the 30 days before palliative care consultation compared with the nonpalliative cohort, with higher rates of hospitalization (risk ratio [RR], 3.33; 95% CI, 2.87 to 3.85), invasive procedures (RR, 1.75; 95% CI, 1.62 to 1.88), and chemotherapy administration (RR, 1.61; 95% CI, 1.45 to 1.78). The opposite pattern emerged in the interval from palliative care consultation through death, where the palliative care cohort had lower rates of hospitalization (RR, 0.53; 95% CI, 0.44-0.65), invasive procedures (RR, 0.52; 95% CI, 0.45 to 0.59), and chemotherapy administration (RR, 0.46; 95% CI, 0.39 to 0.53). Patients with earlier palliative care consultation in their disease course had larger absolute reductions in health-care use compared with those with palliative care consultation closer to the end of life. Conclusion: This population-based study found that palliative care substantially decreased health-care use among Medicare beneficiaries with advanced cancer. Given the increasing number of elderly patients with advanced cancer, this study emphasizes the importance of early integration of palliative care alongside standard oncologic care.

Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (1% tumour cell nuclei), weak (1 to50%), or strong (≥50%). Associations with disease-specific survival were assessed.2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74).PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.Carraresi Foundation and others.

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ~25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours., National Institutes of Health (U.S.) (Grant 5U24CA143799-04), National Institutes of Health (U.S.) (Grant 5U24CA143835-04), National Institutes of Health (U.S.) (Grant 5U24CA143840-04), National Institutes of Health (U.S.) (Grant 5U24CA143843-04), National Institutes of Health (U.S.) (Grant 5U24CA143845-04), National Institutes of Health (U.S.) (Grant 5U24CA143848-04), National Institutes of Health (U.S.) (Grant 5U24CA143858-04), National Institutes of Health (U.S.) (Grant 5U24CA143866-04), National Institutes of Health (U.S.) (Grant 5U24CA143867-04), National Institutes of Health (U.S.) (Grant 5U24CA143882-04), National Institutes of Health (U.S.) (Grant 5U24CA143883-04), National Institutes of Health (U.S.) (Grant 5U24CA144025-04), National Institutes of Health (U.S.) (Grant U54HG003067-11), National Institutes of Health (U.S.) (Grant U54HG003079-10), National Institutes of Health (U.S.) (Grant U54HG003273-10)

Small-bowel cancer is uncommon and, accordingly, little is known about the epidemiology of this malignancy, especially by race and subtype.The objective of this analysis was to describe the distribution of small-bowel cancer in the United States by demographic, pathological, and clinical features.This study was retrospective in design.Data from 26 population-based cancer registries in the United States from 1995 to 2008 were used.Patients diagnosed with small-bowel cancer (topography codes C17.0-17.3 and C17.8-17.9) were included.The primary outcomes measured were race- and histology-specific incidence (age-adjusted rate trends and age-specific rates) of small-bowel cancer.A total of 56,223 men and women diagnosed with small-bowel cancer were identified. The overall age-adjusted incidence rates for small-bowel cancer were 26.1 in men and 17.7 in women. Neuroendocrine tumors were the most common histological types of small-bowel cancer in men and women, followed by carcinoma, lymphoma, and sarcoma. In comparison with whites, the rate of small-bowel cancer was 42% greater in black men, 46% greater in black women, 34% lower in Asian-Pacific Islander men, and 37% lower in Asian-Pacific Islander women. Rates of small-bowel cancer were 24% lower in Hispanic men and 15% lower in Hispanic women than rates in non-Hispanics. The excess of small-bowel cancer in blacks and the deficit in Asian-Pacific Islanders were attributable mainly to the incidence of adenocarcinoma and carcinoid tumors. The incidence of GI stromal tumor was significantly higher among Asian-Pacific Islanders.This is one of the largest studies of small-bowel cancer to date. These cancer registry data showed substantial racial and ethnic variation in the incidence of histological subtypes of small-bowel malignancy that suggest possible etiologic diversity and/or disparities in detection.

Effect of hydrogen-charging was investigated with respect to the tensile properties of three types of cast irons: JIS FCD400, FCD450 and FCD700. In this study, hydrogen charging led to a marked ductility loss in all the cast irons. The thermal desorption spectroscopy and the hydrogen microprint technique revealed that, in the hydrogen-charged specimens, most of solute hydrogen was diffusive and mainly segregated at graphite, graphite/matrix interface zone and pearlite. In the fracture process of non-charged specimen, neighboring graphites were interconnected with each other mainly by ductile dimple fracture. On the other hand, in the fracture process of hydrogen-charged specimen, the graphites were interconnected by cracks. The difference in the fracture morphology between the non-charged and the hydrogen-charged specimens is attributed to the presence of diffusive hydrogen in graphite and graphite/matrix interface. During early stage of fracture process in hydrogen-charged specimen, the interspace between graphite and matrix is filled with hydrogen gas, which leads to the ductility loss of matrix in the vicinity of graphite. Even after the initiation of crack from graphite, hydrogen is continuously outgassed from graphite and supplied to the crack tip. Therefore, concerning the hydrogen effect on the strength of cast irons, a role of subsurface graphite as a “local hydrogen supplier” should be taken into consideration.

Emerging data suggest that ovarian cancers differ by tumor grade. However, the reliability of microscopic grade from paraffin tissue in the general medical community and as reflected in population-based cancer registries is unknown. We examined grade agreement between two gynecologic pathologists and the Surveillance Epidemiology and End Results Residual Tissue Repository (SEER). Grade agreement was assessed with percent observer agreement and kappa coefficients for 664 invasive ovarian carcinomas, using previously defined three-tier and two-tier grading systems. A random subset of ovarian carcinomas was selected to compare intra- and inter-pathologist agreement. Five hundred and eighty-six of SEER’s 664 tumors were confirmed invasive. Percent agreement was 49 % with fair kappa coefficient = 0.25 (95 % CI: 0.20–0.30) for the 664 tumors. Agreement improved slightly when restricted to the 586 confirmed invasive cancers; it was better for high grade than low grade tumors, for two-tier than three-tier grading systems, and within (66 %) than between study pathologists (43 %). Grade was not a robust independent predictor of ovarian cancer-specific survival. Grade agreement was fair between SEER and study pathologists irrespective of grading system. Recorded grade in SEER should be used with caution and is probably not a reliable metric for ovarian cancer epidemiology.

To analyze contemporary U.S. use of minimally invasive surgery for the treatment of endometrial cancer and associated inpatient complications and costs.In this retrospective cohort study, the National Inpatient Sample database was analyzed in patients with nonmetastatic endometrial cancer who underwent hysterectomy during 2012-2013. Hierarchical multiple logistic regression and propensity score matching were used to compare complications among patients treated with open compared with minimally invasive hysterectomy surgery. Cost of care was also compared using generalized linear modeling.We identified 9,799 patients; 52.4% underwent open and 47.6% minimally invasive hysterectomy. Many patients (43.4%) were treated at low-volume hospitals (less than 10 endometrial cancer cases annually). Patients were less likely to undergo open surgery in high-volume compared with low-volume hospitals (51.8% compared with 58.1%, respectively; adjusted odds ratio [OR] 0.35, 95% confidence interval [CI] 0.13-0.94) and more likely to undergo open surgery in rural compared with urban teaching hospitals (75.6% compared with 51.1%, respectively; adjusted OR 14.34, 95% CI 9.66-21.27), government compared with nonprofit hospitals (61.3% compared with 51.1%, respectively; adjusted OR 1.66, 95% CI 1.15-2.39), and in patients of black (67.9%; OR 1.46, 95% CI 1.30-1.65) and "other" race (60.5%; adjusted OR 2.39, 95% CI 1.99-2.87) compared with white race (49.2%, referent). Open surgery was associated with increased perioperative complications (adjusted OR 2.80, 95% CI 2.48-3.17) and a $1,243 increase in cost per case compared with minimally invasive approaches (P.001). Using minimally invasive surgery for 80% of study patients may have averted 2,733 complications and saved approximately $19 million.Most U.S. women with endometrial cancer continue to be treated with open hysterectomy surgery despite increased complication rates and financial costs associated with this approach. A disparity in endometrial cancer surgical care exists that is affected by patient race and hospital geography and cancer volumes.

Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (P(trend) < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.

Effect of the hydrogen-charging on the uniaxial tensile behaviors of a ductile cast iron was investigated. It was found that the hydrogen-charging accelerated the process of crack growth from graphite in the uniaxial tensile loading condition. Further, the accelerated crack growth had a marked influence on the reduction of area at the final fracture (RA) of specimens. For instance, for the uncharged specimens, the RA was nearly constant irrespective of the strain rate. In contrast, for the hydrogen-charged specimens, the RA gradually decreased as the strain rate decreased. Thermal desorption spectroscopy and hydrogen microprint technique revealed that, in the hydrogen-charged specimen, most of solute hydrogen was diffusive one, which was mainly segregated at graphite, graphite/matrix interface zone and pearlite. Based on these experimental observations, we consider that the hydrogen-induced degradation behavior was caused mainly by a combination of the following three mechanisms: (i) supplement of hydrogen to the crack tip from graphite and graphite–matrix interface, (ii) hydrogen-enhanced pearlite cracking and, (iii) successive hydrogen-emission from graphite and additional hydrogen-supplement to the crack tip.