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OBJECTIVES: To examine if racial differences in cardiovascular health (CVH) are associated with cardiovascular disease (CVD) disparities among women with breast and gynecologic cancers. SAMPLE & SETTING: The sample consisted of 252 Black women and 93 White women without a self-reported history of cancer or CVD who developed a breast or gynecologic malignancy. Women who developed CVD before their cancer diagnosis were excluded. METHODS & VARIABLES: CVH was classified using metrics of the American Heart Association's Life's Simple 7 framework. Metrics were summed to create a total CVH score (0-7). Associations among race, ideal CVH (score of 5-7), and CVD incidence following cancer diagnosis were estimated with Cox proportional hazards models. RESULTS: Ideal CVH was similar between Black women (33%) and White women (37%). Race and CVH were not associated with CVD incidence. IMPLICATIONS FOR NURSING: In a small sample of women diagnosed with breast and gynecologic cancers, racial disparities in CVH and CVD incidence were not observed. Additional investigation of potential confounders relating to social determinants of health tied to the construct of race is warranted. [ABSTRACT FROM AUTHOR]

Endometrial cancer stage is a strong prognostic factor; however, the current stage classification does not incorporate transtubal spread as determined by intraluminal tumor cells (ILTCs). We examined relationships between ILTCs and survival outcomes according to histological subtype and stage and examined whether identification of ILTCs improves prognostic accuracy of endometrial cancer staging. We conducted a retrospective cohort study of women diagnosed with endometrial cancer at five academic hospitals between 2007 and 2012. Pathologists determined ILTC presence (no vs. yes) and location (free in lumen vs. attached to epithelial surface) based on pathology review of hematoxylin and eosin-stained sections of fallopian tubes. Associations between ILTCs with time to recurrence (TTR) and overall survival (OS) were examined with Cox proportional hazards models adjusted for other prognostic factors. Model discrimination metrics were used to assess the addition of ILTCs to stage for prediction of 5-year TTR and OS. In the overall study population (N = 1303), ILTCs were not independently associated with TTR (HR = 0.95, 95% CI = 0.69–1.32) or OS (HR = 0.97, 95% CI = 0.72–1.31). Among 805 women with stage I disease, ILTCs were independently associated with worse TTR (HR = 2.31, 95% CI = 1.06–5.05) and OS (HR = 2.16, 95% CI = 1.14–4.11). Upstaging early-stage cases with ILTCs present did not increase model discrimination. While our data do not suggest that endometrial cancer staging guidelines should be revised to include ILTCs, associations between ILTCs and reduced survival observed among stage I cases suggest this tumor feature holds clinical relevance for subgroups of endometrial cancer patients. • In endometrial cancer, the role of transtubal spread as determined by intraluminal tumor cell presence is controversial. • Presence of intraluminal tumor cells was not related to recurrence or overall survival in the overall study population. • Among women with stage 1 disease, intraluminal tumor cells were related to worse recurrence and overall survival. • Upstaging women with early-stage endometrial cancer with intraluminal tumor cells did not affect model discrimination. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer risk and survival have previously been associated with telomere length in peripheral blood leukocytes and tumor tissues. We quantitatively assessed these associations through a systematic review and meta-analysis. Following PRISMA guidelines, we identified relevant studies through database searches, and performed meta-analyses using random effects models. We found no association between telomere length in circulating leukocytes and the risk of developing colorectal cancer, however, shorter leukocyte telomeres were associated with a worse survival in patients with colorectal cancer. Therefore, telomere length may serve as a potential biomarker especially for colorectal cancer prognosis. Larger prospective cohort studies are needed to further confirm this potential association. (1) Background: Colorectal cancer risk and survival have previously been associated with telomere length in peripheral blood leukocytes and tumor tissue. A systematic review and meta-analysis of the literature was conducted. The PubMed, Embase, and Web of Science databases were searched through March 2022. (2) Methods: Relevant studies were identified through database searching following PRISMA guidelines. Risk estimates were extracted from identified studies; meta-analyses were conducted using random effects models. (3) Results: Fourteen studies were identified (eight on risk; six on survival) through systematic review. While no association was observed between circulating leukocyte telomere length and the risk of colorectal cancer [overall OR (95% CI) = 1.01 (0.82–1.24)], a worse survival for those with shorter telomeres in leukocytes and longer telomeres in tumor tissues was observed [Quartile1/Quartile2–4 overall HR (95% CI) = 1.41 (0.26–7.59) and 0.82 (0.69–0.98), respectively]. (4) Conclusions: Although there was no association with colorectal cancer risk, a poorer survival was observed among those with shorter leukocyte telomere length. Future larger studies evaluating a potentially non-linear relationship between telomeres and colorectal cancer are needed. [ABSTRACT FROM AUTHOR]

To determine associations between adoption of Medicaid expansion (ME) and changes in insurance status, early stage diagnosis, and cancer survival among women with endometrial carcinoma (EC). The National Cancer Database (NCDB) was queried for patients diagnosed with EC between the age 40–64 from 2004 to 2015. Difference-in-differences analysis quantified the impact of ME on the proportion of new EC diagnoses with insurance (vs. uninsured), the proportion diagnosed with stage I (vs. II-IV), and overall survival. 156,253 patients were included. Among 65,019 women living in ME states, ME is associated with an increase in the percent of EC cases who are insured of 1.4% (95% CI 0.9–2.0%, p < 0.0001), with strongest effects among Hispanic women, women in the lowest income quartile, and women in the second age quartile (age 53–57). There was no overall impact of ME on stage, though an increase of early stage diagnoses by 2.4% (95% CI 0.3–4.5%, p = 0.022) was observed among women age 53–57. There was a trend towards improved overall survival with ME, which was strongest in women age 53–57 (HR = 0.83, 95% CI 0.70–0.99, p = 0.037). Among women with EC, ME positively impacted insurance coverage, an important hurdle in accessing health care. In women aged 53–57, ME was associated with earlier stage at diagnosis and improved survival, suggesting that the magnitude of the improvement in insurance coverage may correlate with important clinical outcomes. Efforts should continue to understand the complexity of barriers to health care access and to develop effective strategies to surmount them. • Medicaid expansion improves insurance coverage for endometrial cancer patients. • Expansion improves coverage to a larger extent for some groups. • Some groups that experience a larger increase in coverage present at earlier stage. [ABSTRACT FROM AUTHOR]

Abstract In a prospective study of 31 925 men with 18 yr of follow-up, higher ejaculation frequency (EF) throughout adulthood was associated with lower rates of prostate cancer. To further explore this association, we evaluated whole transcriptome gene expression in the prostate tissue from study participants who developed prostate cancer between 1992 and 2004 (n = 157 tumor tissue, n = 85 adjacent normal). We tested for trends in gene expression according to the level of EF as self-reported in 1992 for ages 20–29 yr, 40–49 yr, and the year prior to the questionnaire, 1991. There were no associations between EF and gene expression in areas of tumor after accounting for multiple testing. In contrast, in the adjacent normal tissue, 409 genes and six pathways were differentially expressed at a false discovery rate ≤0.2 across categories of EF in 1991. These results suggest that ejaculation affects the expression of genes in the normal prostate tissue. The identified genes and pathways provide potential biological links between EF and prostate tumorigenesis. Patient summary To explore previous findings that men who ejaculate more frequently have lower risk of prostate cancer, we evaluated molecular alterations in the prostate tissue according to each man's frequency of ejaculation prior to diagnosis. We identified biological processes that could link ejaculation frequency and prostate cancer. Take Home Message Previous studies have found that men who ejaculate more frequently are at a lower risk of prostate cancer. We identify genes and biologic pathways that vary in the normal prostate tissue by ejaculation frequency and may link ejaculation and prostate tumor development. [ABSTRACT FROM AUTHOR]

Attempts to predict prognosis in cancer patients using high-dimensional genomic data such as gene expression in tumor tissue can be made difficult by the large number of features and the potential complexity of the relationship between features and the outcome. Integrating prior biological knowledge into risk prediction with such data by grouping genomic features into pathways and networks reduces the dimensionality of the problem and could improve prediction accuracy. Additionally, such knowledge-based models may be more biologically grounded and interpretable. Prediction could potentially be further improved by allowing for complex nonlinear pathway effects. The kernel machine framework has been proposed as an effective approach for modeling the nonlinear and interactive effects of genes in pathways for both censored and noncensored outcomes. When multiple pathways are under consideration, one may efficiently select informative pathways and aggregate their signals via multiple kernel learning (MKL), which has been proposed for prediction of noncensored outcomes. In this paper, we propose MKL methods for censored survival outcomes. We derive our approach for a general survival modeling framework with a convex objective function and illustrate its application under the Cox proportional hazards and semiparametric accelerated failure time models. Numerical studies demonstrate that the proposed MKL-based prediction methods work well in finite sample and can potentially outperform models constructed assuming linear effects or ignoring the group knowledge. The methods are illustrated with an application to 2 cancer data sets. [ABSTRACT FROM AUTHOR]

Objective Stage is a critical determinant of prognosis and treatment for endometrial cancer (EC) patients. Women who have had a tubal ligation for sterilization have improved EC survival, secondary to lower stage at presentation, suggesting that transtubal spread may represent an important route of metastasis. We evaluated detection of intraluminal tumor cells (ILTCs) in relation to tumor characteristics and survival. Methods One pathologist retrospectively evaluated hematoxylin and eosin sections of routinely collected fallopian tubes for ILTCs from 295 EC patients, masked to outcome. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between demographic (age, race) and clinical [FIGO 2009 stage, lymphovascular space invasion (LVSI), histological subtype] characteristics and ILTCs. Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations between ILTCs and recurrence-free survival (RFS) and EC-specific survival, overall and stratified by histological subtype or stage. Results In univariable logistic regression models, age (55–64 vs. ≥65: OR = 3.41, 95% CI = 1.48–7.84), stage (stage IV vs. stage I OR = 14.58, 95% CI = 5.27–40.35), LVSI (OR = 2.93, 95% CI = 1.42–6.04), and histological subtype (serous vs. low-grade endometrioid OR = 3.21, 95% CI = 1.08–9.58), were associated with ILTCs. Only age and stage remained significantly associated with ILTCs in adjusted models. ILTCs were significantly associated with lower EC-specific survival among women with serous EC or stage I disease; however, adjustment for age, stage, and histology attenuated these associations. Conclusion Our findings suggest that ILTCs are associated with adverse EC prognostic features and reduced survival in cases of early stage or serous histology. [ABSTRACT FROM AUTHOR]

Background Women with endometrial cancer (EC) are the second largest population of female cancer survivors in the United States. However, the outcomes of EC survivors, from the patient perspective, are not well-understood. Therefore, we conducted a systematic review of patient-reported outcomes (PROs) following an EC diagnosis. Methods We searched MEDLINE, EMBASE, Scopus, CINAHL, and reference lists to identify published observational studies that examined PROs among women with EC. Reviewers independently reviewed eligible full-text study articles and conducted data extraction. We qualitatively summarized included articles according to exposures [e.g. body mass index (BMI), treatment, etc.] or specific PROs (e.g. sexual function). Results Of 1722 unique studies, 102 full-text articles were reviewed, of which a total of 27 studies fulfilled the inclusion criteria. The most commonly used PRO questionnaires were the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) ( n = 9), Short Form 36 Questionnaire (SF-36, n = 8), the Functional Assessment of Cancer Therapy-General (FACT-G, n = 5), and the Female Sexual Function Index (FSFI, n = 4). Obesity was associated with lower quality of life (QOL) and physical functioning. Treatment type affected several outcomes. Laparoscopy generally resulted in better QOL outcomes than laparotomy. Likewise, vaginal brachytherapy was associated with better outcomes compared to external beam radiation. Sexual function outcomes were dependent on age, time since diagnosis, and having consulted a physician before engaging in sexual activities. In addition, a physical activity intervention was associated with improved sexual interest but not sexual function. Conclusions Our review provides insight into the experience of EC survivors from the patient perspective. Factors that contribute to QOL, such as pain, fatigue, emotional and social functioning, should be monitored following an EC diagnosis. [ABSTRACT FROM AUTHOR]

When a moderate number of potential predictors are available and a survival model is fit with regularization to achieve variable selection, providing accurate inference on the predicted survival can be challenging. We investigate inference on the predicted survival estimated after fitting a Cox model under regularization guaranteeing the oracle property. We demonstrate that existing asymptotic formulas for the standard errors of the coefficients tend to underestimate the variability for some coefficients, while typical resampling such as the bootstrap tends to overestimate it; these approaches can both lead to inaccurate variance estimation for predicted survival functions. We propose a two-stage adaptation of a resampling approach that brings the estimated error in line with the truth. In stage 1, we estimate the coefficients in the observed data set and in [Formula: see text] resampled data sets, and allow the resampled coefficient estimates to vote on whether each coefficient should be 0. For those coefficients voted as zero, we set both the point and interval estimates to [Formula: see text] In stage 2, to make inference about coefficients not voted as zero in stage 1, we refit the penalized model in the observed data and in the [Formula: see text] resampled data sets with only variables corresponding to those coefficients. We demonstrate that ensemble voting-based point and interval estimators of the coefficients perform well in finite samples, and prove that the point estimator maintains the oracle property. We extend this approach to derive inference procedures for survival functions and demonstrate that our proposed interval estimation procedures substantially outperform estimators based on asymptotic inference or standard bootstrap. We further illustrate our proposed procedures to predict breast cancer survival in a gene expression study. [ABSTRACT FROM AUTHOR]

Prostate tumors arise primarily in the peripheral zone (PZ) of the prostate, but 20–30% arise in the transition zone (TZ). Zone of origin may have prognostic value or reflect distinct molecular subtypes; however, it can be difficult to determine in practice. Using whole-genome gene expression, we built a signature of zone using normal tissue from five individuals and found that it successfully classified nine tumors of known zone. Hypothesizing that this signature captures tumor zone of origin, we assessed its relationship with clinical factors among 369 tumors of unknown zone from radical prostatectomies (RPs) and found that tumors that molecularly resembled TZ tumors showed lower mortality (P = 0.09) that was explained by lower Gleason scores (P = 0.009). We further applied the signature to an earlier study of 88 RP and 333 transurethral resection of the prostate (TURP) tumor samples, also of unknown zone, with gene expression on ~6000 genes. We had observed previously substantial expression differences between RP and TURP specimens, and hypothesized that this might be because RPs capture primarily PZ tumors, whereas TURPs capture more TZ tumors. Our signature distinguished these two groups, with an area under the receiver operating characteristic curve of 87% (P < 0.0001). Our findings that zonal differences in normal tissue persist in tumor tissue and that these differences are associated with Gleason score and sample type suggest that subtypes potentially resulting from different etiologic pathways might arise in these zones. Zone of origin may be important to consider in prostate tumor biomarker research. [ABSTRACT FROM AUTHOR]

To reduce costs and improve clinical relevance of genetic studies, there has been increasing interest in performing such studies in hospital-based cohorts by linking phenotypes extracted from electronic medical records (EMRs) to genotypes assessed in routinely collected medical samples. A fundamental difficulty in implementing such studies is extracting accurate information about disease outcomes and important clinical covariates from large numbers of EMRs. Recently, numerous algorithms have been developed to infer phenotypes by combining information from multiple structured and unstructured variables extracted from EMRs. Although these algorithms are quite accurate, they typically do not provide perfect classification due to the difficulty in inferring meaning from the text. Some algorithms can produce for each patient a probability that the patient is a disease case. This probability can be thresholded to define case-control status, and this estimated case-control status has been used to replicate known genetic associations in EMR-based studies. However, using the estimated disease status in place of true disease status results in outcome misclassification, which can diminish test power and bias odds ratio estimates. We propose to instead directly model the algorithm-derived probability of being a case. We demonstrate how our approach improves test power and effect estimation in simulation studies, and we describe its performance in a study of rheumatoid arthritis. Our work provides an easily implemented solution to a major practical challenge that arises in the use of EMR data, which can facilitate the use of EMR infrastructure for more powerful, cost-effective, and diverse genetic studies. [ABSTRACT FROM AUTHOR]

Integrating genomic information with traditional clinical risk factors to improve the prediction of disease outcomes could profoundly change the practice of medicine. However, the large number of potential markers and possible complexity of the relationship between markers and disease make it difficult to construct accurate risk prediction models. Standard approaches for identifying important markers often rely on marginal associations or linearity assumptions and may not capture non-linear or interactive effects. In recent years, much work has been done to group genes into pathways and networks. Integrating such biological knowledge into statistical learning could potentially improve model interpretability and reliability. One effective approach is to employ a kernel machine (KM) framework, which can capture nonlinear effects if nonlinear kernels are used (Scholkopf and Smola, 2002; Liu et al., 2007, 2008). For survival outcomes, KM regression modeling and testing procedures have been derived under a proportional hazards (PH) assumption (Li and Luan, 2003; Cai, Tonini, and Lin, 2011). In this article, we derive testing and prediction methods for KM regression under the accelerated failure time (AFT) model, a useful alternative to the PH model. We approximate the null distribution of our test statistic using resampling procedures. When multiple kernels are of potential interest, it may be unclear in advance which kernel to use for testing and estimation. We propose a robust Omnibus Test that combines information across kernels, and an approach for selecting the best kernel for estimation. The methods are illustrated with an application in breast cancer. [ABSTRACT FROM AUTHOR]

Background Although unopposed estrogen exposure is considered a major driver of endometrial carcinogenesis, chronic inflammation and insulin resistance and hyperinsulinemia are also major endometrial cancer risk factors. However, it is unclear whether diets with inflammatory or insulinemic potential are associated with risk of endometrial cancer. Methods We followed 48 330 women from the Nurses' Health Study (1984-2016) and 85 426 women from the Nurses' Health Study II (1989-2017). Using food frequency questionnaires, we calculated repeated measures of empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores, which characterize the potential of the whole diet to modulate circulating biomarkers of inflammation or C-peptide, respectively. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for type I endometrial cancer risk. Results We documented 1462 type I endometrial cancer cases over 2 823 221 person-years of follow-up. In the pooled multivariable-adjusted analyses, women in the highest compared with lowest quintiles were at higher risk of type I endometrial cancer (EDIP HRQ5vsQ1 = 1.46, 95% CI = 1.24 to 1.73; P trend <.001; EDIH HRQ5vsQ1 = 1.58, 95% CI = 1.34 to 1.87; P trend <.001). Additional adjustment for body mass index attenuated the associations (EDIP HR = 1.03, 95% CI = 0.87 to 1.22; EDIH HR = 1.01, 95% CI = 0.85 to 1.21), and mediation analyses showed that body mass index may explain 60.4% (95% CI = 37.4% to 79.6%; P <.001) and 71.8% (95% CI = 41.0% to 90.4%; P <.001) of the association of endometrial cancer with EDIP and EDIH, respectively. Conclusions In this large cohort study, higher dietary inflammatory and insulinemic potential were each associated with increased endometrial cancer incidence, and this association may be almost entirely mediated by adiposity. [ABSTRACT FROM AUTHOR]

Including previously genotyped controls in a genome-wide association study can provide cost-savings, but can also create design biases. When cases and controls are genotyped on different platforms, the imputation needed to provide genome-wide coverage will introduce differential measurement error and may lead to false positives. We compared genotype frequencies of two healthy control groups from the Nurses' Health Study genotyped on different platforms [Affymetrix 6.0 ( n = 1,672) and Illumina HumanHap550 ( n = 1,038)]. Using standard imputation quality filters, we observed 9,841 single-nucleotide polymorphisms (SNPs) out of 2,347,809 (0.4%) significant at the 5 × 10 level. We explored three methods for controlling for this Type I error inflation. One method was to remove platform effects using principal components; another was to restrict to SNPs of highest quality imputation; and a third was to genotype some controls alongside cases to exclude SNPs that are statistical artifact. The first method could not reduce the Type I error rate; the other two could dramatically reduce the error rate, although both required that a portion of SNPs be excluded from analysis. Ideally, the biases we describe would be eliminated at the design stage, by genotyping sufficient numbers of cases and controls on each platform. Researchers using imputation to combine samples genotyped on different platforms with severely unbalanced case-control ratios should be aware of the potential for inflated Type I error rates and apply appropriate quality filters. Every SNP found with genome-wide significance should be validated on another platform to verify that its significance is not an artifact of study design. [ABSTRACT FROM AUTHOR]

Simple Summary: Novel hormonal therapies (such as abiraterone and enzalutamide) and docetaxel are approved treatments for metastatic prostate cancer. Upfront use of these agents has been shown to improve overall survival. However, we do not know the real-world treatment patterns of these agents or the comparative effectiveness of these agents after treatment with a prior novel hormonal therapy in patients with metastatic prostate cancer. In this large study, we found that most patients with metastatic prostate cancer received only androgen deprivation therapy as upfront therapy without novel hormonal therapies or docetaxel. In patients treated with one novel hormonal therapy, alternate novel hormonal therapy was the most common next therapy and was associated with improved overall survival over docetaxel with the caveat of this being a non-randomized comparison. The study's limitations also include its retrospective design. Background: Both novel hormonal therapies and docetaxel are approved for treatment of metastatic prostate cancer (mPC; in castration sensitive or refractory settings). Present knowledge gaps include lack of real-world data on treatment patterns in patients with newly diagnosed mPC, and comparative effectiveness of novel hormonal therapies (NHT) versus docetaxel after treatment with a prior NHT. Methods: Herein we extracted patient-level data from a large real-world database of patients with mPC in United States. Utilization of NHT or docetaxel for mPC and comparative effectiveness of an alternate NHT versus docetaxel after one prior NHT was evaluated. Comparative effectiveness was examined via Cox proportional hazards model with propensity score matching weights. Each patient's propensity for treatment was modeled via random forest based on 22 factors potentially driving treatment selection. Results: The majority of patients (54%) received only androgen deprivation therapy for mPC. In patients treated with an NHT, alternate NHT was the most common next therapy and was associated with improved median overall survival over docetaxel (abiraterone followed by docetaxel vs. enzalutamide (8.7 vs. 15.6 months; adjusted hazards ratio; aHR 1.32; p = 0.009; and enzalutamide followed by docetaxel vs. abiraterone (9.7 vs. 13.2 months aHR 1.40; p = 0.009). Limitations of the study include retrospective design. [ABSTRACT FROM AUTHOR]

Disparities in adjuvant treatment between Black and White women with endometrial cancer (EC) are well documented and contribute to worse outcomes among Black women. However, factors leading to disparate treatment patterns are understudied. We examined whether patient refusal of adjuvant treatment (chemotherapy or radiation) differed between Black and White women and whether refusal differences mediate racial disparities in EC survival. We used the National Cancer Database (NCDB), a hospital-based registry covering ~70% of U.S. cancer diagnoses, to identify non-Hispanic Black (NHB) and non-Hispanic White (NHW) women diagnosed with EC from 2004 to 2015 who either received or refused chemotherapy or radiation. NCDB data are abstracted from medical records by tumor registrars. We used logistic regression to estimate adjusted odds ratios (aOR) of patient refusal of treatment associated with race, and accelerated failure time models to estimate differences in overall survival (OS) by race. We used causal mediation analysis to estimate how much of the difference in OS by race could be attributed to racial differences in treatment refusal. We considered the overall study populations as well as strata defined by histology, and adjusted for factors assessed at diagnosis, including age, comorbidity burden, insurance, hospital characteristics, stage, histology, and zip code-level income and education. We identified 49,518 women (83% NHW, 17% NHB) who received adjuvant chemotherapy and 12,710 women with documented refusal (90% NHW, 10% NHB). After adjusting for covariates, NHB women were more likely to refuse chemotherapy than NHW women (aOR=1.12, p=0.005), particularly among those with low-grade endometrioid (aOR = 1.22, p=0.02) or serous (aOR = 1.38, p<0.001) EC. Mean OS for NHB women was 43.5 months shorter than for NHW women. Of this disparity, 0.9 months of may be attributable to differences in chemotherapy refusal (p=0.01). Among women with serous EC, NHB race was associated with 17.6 months shorter OS, with 1 month potentially attributable to refusal differences (p=0.002). We identified 66,839 women (88% NHW, 12% NHB) receiving adjuvant radiation and 4,471 (88% NHW, 12% NHB) who refused. Among women with serous EC, NHB women were more likely to refuse radiation (OR = 1.39, p=0.01), and NHB women had mean OS 13.2 months shorter than NHW women, 0.4 months of which may be attributable to differences in treatment refusal (p=0.03). We observed differences in treatment refusal by race, and those differences may be responsible for up to 1 month of the OS disparity between NHW and NHB women. This represents a small fraction of the dramatic racial disparity in EC survival. While a better understanding of the reasons for patient treatment refusal and subsequent intervention may help improve outcomes for some women, other causes of disparate outcomes warrant further investigation. [ABSTRACT FROM AUTHOR]

In cancer studies, patients often experience two different types of events: a non-terminal event such as recurrence or metastasis, and a terminal event such as cancer-specific death. Identifying pathways and networks of genes associated with one or both of these events is an important step in understanding disease development and targeting new biological processes for potential intervention. These correlated outcomes are commonly dealt with by modeling progression-free survival, where the event time is the minimum between the times of recurrence and death. However, identifying pathways only associated with progression-free survival may miss out on pathways that affect time to recurrence but not death, or vice versa. We propose a combined testing procedure for a pathway's association with both the cause-specific hazard of recurrence and the marginal hazard of death. The dependency between the two outcomes is accounted for through perturbation resampling to approximate the test's null distribution, without any further assumption on the nature of the dependency. Even complex non-linear relationships between pathways and disease progression or death can be uncovered thanks to a flexible kernel machine framework. The superior statistical power of our approach is demonstrated in numerical studies and in a gene expression study of breast cancer. [ABSTRACT FROM AUTHOR]

Objective: Neuromyelitis optica spectrum disorders (NMOSD) represent rare autoimmune diseases of the central nervous system largely targeting optic nerve(s) and spinal cord. The present analysis used real-world data to identify clinical and epidemiological correlates of treatment change in patients with NMOSD. Methods: CIRCLES is a longitudinal, observational study of NMOSD conducted at 15 centers across North America. Patients with ≥ 60 days of follow-up and receiving on-study maintenance treatment were evaluated. The mean annual relapse rate (ARR) was estimated using negative binomial models; the likelihood of treatment change was estimated using Cox proportional hazards models. Relapses were included as time-varying covariates to estimate the relationship to treatment change. Results: Of 542 patients included, 171 (31.5%) experienced ≥ 1 relapse on the study and 133 patients (24.5%) had ≥ 1 change in the treatment regimen. Two categories of variables significantly correlated with the likelihood of treatment change: (1) relapse: any on-study relapse (hazard ratio [HR] = 2.91; p < 0.001), relapse phenotypes (HR range = 2.15–5.49; p < 0.001), and pre-study ARR > 0.75 (HR 2.28; p < 0.001); 2) disease phenotype: brain syndrome only vs transverse myelitis involvement at onset (HR 2.44; p = 0.008), disease duration < 1 vs > 5 years (HR 1.66; p = 0.028), or autoimmune comorbidity (HR 1.55; p = 0.015). A subset of these factors significantly correlated with shorter time to first rituximab discontinuation. Conclusions: In CIRCLES, relapse patterns and disease phenotype significantly correlated with changes in the maintenance treatment regimen. Such findings may facilitate the identification of patients with NMOSD who are likely to benefit from treatment change to reduce relapse risk or disease burden and enhance the quality of life. [ABSTRACT FROM AUTHOR]

Background Evidence suggests that ejaculation frequency may be inversely related to the risk of prostate cancer (PCa), a disease for which few modifiable risk factors have been identified. Objective To incorporate an additional 10 yr of follow-up into an original analysis and to comprehensively evaluate the association between ejaculation frequency and PCa, accounting for screening, clinically relevant disease subgroups, and the impact of mortality from other causes. Design, setting, and participants A prospective cohort study of participants in the Health Professionals Follow-up Study utilizing self-reported data on average monthly ejaculation frequency. The study includes 31 925 men who answered questions on ejaculation frequency on a 1992 questionnaire and followed through to 2010. The average monthly ejaculation frequency was assessed at three time points: age 20–29 yr, age 40–49 yr, and the year before questionnaire distribution. Outcome measurements and statistical analysis Incidence of total PCa and clinically relevant disease subgroups. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results and limitations During 480 831 person-years, 3839 men were diagnosed with PCa. Ejaculation frequency at age 40–49 yr was positively associated with age-standardized body mass index, physical activity, divorce, history of sexually transmitted infections, and consumption of total calories and alcohol. Prostate-specific antigen (PSA) test utilization by 2008, number of PSA tests, and frequency of prostate biopsy were similar across frequency categories. In multivariable analyses, the hazard ratio for PCa incidence for ≥21 compared to 4–7 ejaculations per month was 0.81 (95% confidence interval [CI] 0.72–0.92; p < 0.0001 for trend) for frequency at age 20–29 yr and 0.78 (95% CI 0.69–0.89; p < 0.0001 for trend) for frequency at age 40–49 yr. Associations were driven by low-risk disease, were similar when restricted to a PSA-screened cohort, and were unlikely to be explained by competing causes of death. Conclusions These findings provide additional evidence of a beneficial role of more frequent ejaculation throughout adult life in the etiology of PCa, particularly for low-risk disease. Patient summary We evaluated whether ejaculation frequency throughout adulthood is related to prostate cancer risk in a large US-based study. We found that men reporting higher compared to lower ejaculatory frequency in adulthood were less likely to be subsequently diagnosed with prostate cancer. [ABSTRACT FROM AUTHOR]

Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9–3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9–8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6–3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4–1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes. [ABSTRACT FROM AUTHOR]

Background: Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer.Methods: Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer-specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression.Results: Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight/obese men versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10-4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25).Conclusions: This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. Cancer 2017;123:4130-4138. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

To investigate the role of adiponectin receptor 2 (AdipoR2) in aggressive prostate cancer we used immunohistochemistry to characterize AdipoR2 protein expression in tumor tissue for 866 men with prostate cancer from the Physicians’ Health Study and the Health Professionals Follow-up Study. AdipoR2 tumor expression was not associated with measures of obesity, pathological tumor stage or prostate-specific antigen (PSA) at diagnosis. However, AdipoR2 expression was positively associated with proliferation as measured by Ki-67 expression quartiles (P-trend < 0.0001), with expression of fatty acid synthase (P-trend = 0.001), and with two measures of angiogenesis (P-trend < 0.1). An inverse association was observed with apoptosis as assessed by the TUNEL assay (P-trend = 0.006). Using Cox proportional hazards regression and controlling for age at diagnosis, Gleason score, year of diagnosis category, cohort and baseline BMI, we identified a statistically significant trend for the association between quartile of AdipoR2 expression and lethal prostate cancer (P-trend = 0.02). The hazard ratio for lethal prostate cancer for the two highest quartiles, as compared to the two lowest quartiles, of AdipoR2 expression was 1.9 (95% confidence interval [CI]: 1.2–3.0). Results were similar when additionally controlling for categories of PSA at diagnosis and Ki-67 expression quartiles. These results strengthen the evidence for the role of AdipoR2 in prostate cancer progression. [ABSTRACT FROM AUTHOR]

Gleason grade is universally used for pathologic scoring of the differentiation of prostate cancer. However, it is unknown whether prostate tumors arise well differentiated and then progress to less differentiated forms or if Gleason grade is an early and largely unchanging feature. Prostate-specific antigen (PSA) screening has reduced the proportion of tumors diagnosed at advanced stage, which allows assessment of this question on a population level. If Gleason grade progresses as stage does, one would expect a similar reduction in high-grade tumors. We studied 1,207 Physicians' Health Study and Health Professionals Follow-up Study participants diagnosed with prostate cancer from 1982 to 2004 and treated with prostatectomy. We compared the distribution of grade and clinical stage across the pre-PSA and PSA screening eras. We re-reviewed grade using the ISUP 2005 revised criteria. The proportion of advanced stage tumors dropped more than six-fold, from the earliest period (12/1982-1/1993), 19.9% stage ≥T3, to the latest (5/2000-12/2004), 3% stage T, none T4. The proportion of Gleason score ≥8 decreased substantially less, from 25.3% to 17.6%. A significant interaction between stage and diagnosis date predicting grade (P = 0.04) suggests that the relationship between grade and stage varies by time period. As the dramatic shift in stage since the introduction of PSA screening was accompanied by a more modest shift in Gleason grade, these findings suggest that grade may be established early in tumor pathogenesis. This has implications for the understanding of tumor progression and prognosis, and may help patients diagnosed with lower grade disease feel more comfortable choosing active surveillance. [ABSTRACT FROM AUTHOR]

A common treatment of advanced prostate cancer involves the deprivation of androgens. Despite the initial response to hormonal therapy, eventually all the patients relapse. In the present study, we sought to determine whether dietary polyunsaturated fatty acid (PUFA) affects the development of castration-resistant prostate cancer. Cell culture, patient tissue microarray, allograft, xenograft, prostate-specific Pten knockout and omega-3 desaturase transgenic mouse models in conjunction with dietary manipulation, gene knockdown and knockout approaches were used to determine the effect of dietary PUFA on castration-resistant Pten-null prostate cancer. We found that deletion of Pten increased androgen receptor (AR) expression and Pten-null prostate cells were castration resistant. Omega-3 PUFA slowed down the growth of castration-resistant tumors as compared with omega-6 PUFA. Omega-3 PUFA decreased AR protein to a similar extent in tumor cell cytosolic and nuclear fractions but had no effect on AR messenger RNA level. Omega-3 PUFA treatment appeared to accelerate AR protein degradation, which could be blocked by proteasome inhibitor MG132. Knockdown of AR significantly slowed down prostate cancer cell proliferation in the absence of androgens. Our data suggest that omega-3 PUFA inhibits castration-resistant prostate cancer in part by accelerating proteasome-dependent degradation of the AR protein. Dietary omega-3 PUFA supplementation in conjunction with androgen ablation may significantly delay the development of castration-resistant prostate cancer in patients compared with androgen ablation alone. [ABSTRACT FROM PUBLISHER]