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PURPOSE: Based on prior reports demonstrating that neutral endopeptidase (NEP) inhibitors increase sperm motility, the goal of our studies was to identify endogenous seminal peptides that inhibit NEP and investigate their potential effect on sperm motility. METHODS: Peptidomic analysis was performed on human seminal fluid, identifying 22 novel peptides. One peptide, named RSIY-11, derived from semenogelin-1, was predicted through sequence analysis to be a substrate and/or potential inhibitor of NEP. Enzymatic analysis was conducted to determine the inhibitory constant (Ki) of RSIY-11 as an inhibitor of NEP. Total and progressive sperm motility was determined at baseline and 30 and 60 min following addition of RSIY-11 to seminal fluid in 59 patients undergoing an infertility workup at an urban medical center. Additionally, the effects of RSIY-11 on sperm motility were evaluated in 15 of the 59 patients that met criteria for asthenospermia. RESULTS: RSIY-11 was shown to act as a competitive inhibitor of NEP with a Ki of 18.4 ± 1.6 μM. Addition of RSIY-11 at concentrations of 0.75 μM, 7.5 μM, and 75 μM significantly increased sperm motility at all time points investigated, with increases of 6.1%, 6.9%, and 9.2% at 60 min, respectively. Additionally, within the subgroup of patients with asthenospermia, RSIY-11 at concentrations of 0.75 μM, 7.5 μM, and 75 μM significantly increased sperm motility at all time points investigated, with increases of 7.6%, 8.8%, and 10.6% at 60 min, respectively. CONCLUSIONS: RSIY-11 is a newly identified semenogelin-1-derived peptide present in seminal fluid. RSIY-11 acts as a potent competitive inhibitor of NEP, which when added to seminal fluid significantly increases sperm motility. RSIY-11 could play a potential role in the treatment for male factor infertility related to asthenospermia and improve intrauterine insemination outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10815-019-01524-8) contains supplementary material, which is available to authorized users.

INTRODUCTION AND OBJECTIVES:Recent evidence from pre-clinical models of prostate cancer (PCa) suggests that disruption of adrenergic signaling by beta-adrenergic receptor blockade inhibits PCa prog...

Background Cancers constitute a significant public health problem in Nigeria. Breast, cervix and prostate cancers are leading causes of cancer-related deaths. Changing diets, lifestyles, HIV/AIDS and macro-structural factors contribute to cancer morbidity and mortality. Poor health information linking cancer risk to individual behaviors, environmental pollutants and structural barriers undermine prevention/control efforts. Studies suggest increasing health literacy and empowering individuals to take preventive action will improve outcomes and mitigate impact on a weak health system. Methods We obtained qualitative data from 80 men, women, and young adults in 11 focus groups to assess beliefs, risk-perceptions, preventive behaviors and perceptions of barriers and facilitators to cancer control in Ibadan, Nigeria and conducted thematic analysis. Results Participants demonstrated awareness of cancers and mentioned several risk factors related to individual behaviors and the environment. Nonetheless, myths and misconceptions as well as micro, meso and macro level barriers impede prevention and control efforts. Conclusion Developing and implementing comprehensive context-relevant health literacy interventions in community settings are urgently needed. Copyright © 2016 John Wiley & Sons, Ltd.

The trillions of microbes that colonize our adult intestine are referred to as the gut microbiome (GMB). Functionally it behaves as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. While the relationship between the GMB and kidney stone disease (KSD) has not been investigated, dysbiosis of the GMB has been associated with diabetes, obesity and cardiovascular disease. In this pilot study we sought to identify unique changes in the GMB of kidney stone patients compared to patients without KSD. With an IRB-approved protocol we enrolled 29 patients into our pilot study. 23 patients were kidney stone formers and six were non-stone forming controls. Specimens were collected after a 6h fast and were flash frozen in dry ice and then stored at −80 °C. Microbiome: determination of bacterial abundance was by analysis of 16 s rRNA marker gene sequences using next generation sequencing. Sequencing of the GMB identified 178 bacterial genera. The five most abundant enterotypes within each group made up to greater than 50 % of the bacterial abundance identified. Bacteroides was 3.4 times more abundant in the KSD group as compared to control (34.9 vs 10.2 %; p = 0.001). Prevotella was 2.8 times more abundant in the control group as compared to the KSD group (34.7 vs 12.3 %; p = 0.005). In a multivariate analysis including age, gender, BMI, and DM, kidney stone disease remained an increased risk for high prevalence for Bacteroides (OR = 3.26, p = 0.033), whereas there was an inverse association with Prevotella (OR = 0.37, p = 0.043). There were no statistically significant differences in bacterial abundance levels for Bacteroides or Prevotella when comparing patients with and without DM, obesity (BMI >30), HTN or HLD. 11 kidney stone patients completed 24 h urine analysis at the time of this writing. Looking at the bacterial genuses with at least 4 % abundance in the kidney stone group, Eubacterium was inversely correlated with oxalate levels (r = −0.60, p

Streptococcus pyogenes infections have been associated with two autoimmune diseases of the CNS: Sydenham's chorea (SC) and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS). Despite the high frequency of pharyngeal streptococcus infections among children, only a small fraction develops SC or PANDAS. This suggests that several factors in combination are necessary to trigger autoimmune complications: specific S. pyogenes strains that induce a strong immune response toward the host nervous system; genetic susceptibility that predispose children toward an autoimmune response involving movement or tic symptoms; and multiple infections of the throat or tonsils that lead to a robust Th17 cellular and humoral immune response when untreated. In this review, we summarize the evidence for each factor and propose that all must be met for the requisite neurovascular pathology and behavioral deficits found in SC/PANDAS.

Introduction: Men of African descent have the highest burden of aggressive and lethal prostate cancer (PrCa). In Sub-Saharan Africa (SSA), PrCa accounts for 19% of all cancer-related deaths. However, there has been no large-scale PrCa survival studies in SSA. The objective of this study was to assess the feasibility of establishing a PrCa survival cohort in SSA, ascertain vital status and cause of death, determine willingness of PrCa patients to participate and evaluate feasibility of collecting tumor tissues and extract RNA. Methods: A total of 137 PrCa patients, who were initially enrolled in an ongoing PrCa genetic study across seven hospitals in West and South Africa (U01CA184374) in the MADCaP consortium, were followed from their cancer diagnosis and enrollment into the main study through date of death, date of last contact or end of follow-up: 12/31/2018. Follow-up was carried out by direct phone contact of patients and/or their next-of-kin and by reviewing medical records of follow-up hospital visits. PrCa patients alive at contact were invited to participate into the pilot study and completed a brief survey to assess their general health and symptoms as well as quality of life. Formalin-fixed, paraffin-embedded (FFPE) PrCa tissues from 20 patients were retrieved from pathology departments of four hospitals in West Africa. RNA extraction from tumor tissues was carried out using the Qiagen RNeasy® FFPE Kit in the Molecular Cytogenetic Core at Einstein (USA). Results: The average age of 137 PrCa patients was 68 years old (range 40-88), 70 (51%) and 41 (30%) of them were diagnosed with a Gleason score 8-10 cancer, or advanced tumor stage (T3/T4), and the median PSA at diagnosis was 100 ng/ml. Majority of patients received either radiation or hormone deprivation therapy; although there was variability across centers. During an average 20.3 months of follow-up, a total of 29 (21%) patients had died, and 23 (17%) were lost to follow-up; 69% of deaths were due to PrCa. Interestingly the majority of patients who died (62%) and those lost to follow-up (61%) had Gleason score 8-10 cancer. Among PrCa patients alive (N=85) at contact, 95% agreed to participate in the pilot study and completed the protocol. The median RNA yield of tumor samples was 645 ng (range 280-1,820 ng). Conclusions: This feasibility study demonstrated the ability to follow-up PrCa patients across several hospitals in West and South Africa and highlighted the advanced clinical characteristics of PrCa and relatively low survival among African men in SSA. Tumor samples also yielded sufficient RNA that can be used for molecular studies. Larger studies are needed to better understand the clinical and epidemiological risk factors for PrCa survival in SSA and to develop strategies to address survival bias and lost to follow-up. Studies of PrCa survival in Africa might also contribute to better understanding of PrCa racial disparities in the USA. Citation Format: Ilir Agalliu, Caroline Andrews, Akindele Olupelumi Adebiyi, Mohamed Jalloh, Maureen Joffe, Timothy R. Rebbeck, Ann Hsing. Pilot study of prostate cancer survival among African patients in the Men of African Descent and Cancer of the Prostate (MADCaP) Consortium [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3518.

Purpose Health research in low- and middle-income countries can generate novel scientific knowledge and improve clinical care, fostering population health improvements to prevent premature death. Project management is a critical part of the success of this research, applying knowledge, skills, tools, and techniques to accomplish required goals. Here, we describe the development and implementation of tools to support a multifaceted study of prostate cancer in Africa, focusing on building strategic and operational capacity. Methods Applying a learning organizational framework, we developed and implemented a project management toolkit (PMT) that includes a management process flowchart, a cyclical center-specific schedule of activities, periodic reporting and communication, and center-specific monitoring and evaluation metrics. Results The PMT was successfully deployed during year one of the project with effective component implementation occurring through periodic cycles of dissemination and feedback to local center project managers. A specific evaluation was conducted 1 year after study initiation to obtain enrollment data, evaluate individual quality control management plans, and undertake risk log assessments and follow-up. Pilot data obtained identified areas in which centers required mentoring, strengthening, and capacity development. Strategies were implemented to improve project goals and operational capacity through local problem solving, conducting quality control checks and following compliancy with study aims. Moving forward, centers will perform quarterly evaluations and initiate strengthening measures as required. Conclusion The PMT has fostered the development of both strategic and operational capacity across project centers. Investment in project management resources is essential to ensuring high-quality, impactful health research in low- and middle-income countries.

Background Opioid abuse is a growing epidemic in the United States, with opioid overdose becoming a leading cause of death. There is wide variation in prescription practices for post-operative opioids due to absence of guidelines. The purpose of this study is to examine postoperative opioid prescribing patterns after urogynecologic surgery and determine usage and management of opioid pills by patients. Materials and methods This is an observational, prospective study of female patients (N = 143) who underwent urogynecologic (prolapse or incontinence) surgery from June to December 2017 at a single academic center. Patients were surveyed regarding their pain medication use 30 days postoperatively. Survey questions included preoperative pain medication use, quantity of opioid pills consumed, need for additional opioid prescription, and management of remaining pills. T-test and one-way Anova were used for comparison of continuous variables and chi-squared test used for comparison of categorical variables. Results Of 143 eligible patients, 99 (69%) responded; 62% of respondent patients underwent vaginal surgery, 22% abdominal surgery with or without vaginal surgery, and 15% underwent other procedures. Postoperatively, 81.8% of patients were prescribed opioids. The average number of tablets prescribed ranged from 12.4 to 17.4 depending on the procedure. 54.3% of patients reported using less than half of their prescribed opioid prescription. Of the patients who had excess opioid tablets, only 8.6% reported discarding their opioids. Conclusion To date, no guidelines exist on prescribing opioids postoperatively. Opioids are overprescribed post-operatively with over half of patients using less than half of the opioids prescribed to them.

Importance Case-control studies show a possible relationship between oral bacteria and head and neck squamous cell cancer (HNSCC). Prospective studies are needed to examine the temporal relationship between oral microbiome and subsequent risk of HNSCC. Objective To prospectively examine associations between the oral microbiome and incident HNSCC. Design, Setting, and Participants This nested case-control study was carried out in 2 prospective cohort studies: the American Cancer Society Cancer Prevention Study II Nutrition Cohort (CPS-II) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Among 122 004 participants, 129 incident patient cases of HNSCC were identified during an average 3.9 years of follow-up. Two controls per patient case (n = 254) were selected through incidence density sampling, matched on age, sex, race/ethnicity, and time since mouthwash collection. All participants provided mouthwash samples and were cancer-free at baseline. Exposures Oral microbiome composition and specific bacterial abundances were determined through bacterial 16S rRNA gene sequencing. Overall oral microbiome composition and specific taxa abundances were compared for the case group and the control group, using PERMANOVA and negative binomial generalized linear models, respectively, controlling for age, sex, race, cohort, smoking, alcohol, and oral human papillomavirus-16 status. Taxa with a 2-sided false discovery rate (FDR)-adjustedP-value (q-value) Main Outcomes and Measures Incident HNSCC. Results The study included 58 patient cases from CPS-II (mean [SD] age, 71.0 [6.4] years; 16 [27.6%] women) and 71 patient cases from PLCO (mean [SD] age, 62.7 [4.8] years; 13 [18.3%] women). Two controls per patient case (n = 254) were selected through incidence density sampling, matched on age, sex, race/ethnicity, and time since mouthwash collection. Head and neck squamous cell cancer cases and controls were similar with respect to age, sex, and race. Patients in the case group were more often current tobacco smokers, tended to have greater alcohol consumption (among drinkers), and to be positive for oral carriage of papillomavirus-16. Overall microbiome composition was not associated with risk of HNSCC. Greater abundance of generaCorynebacterium(fold change [FC], 0.58; 95% confidence interval [CI], 0.41-0.80;q = .06) andKingella(FC, 0.63; 95% CI, 0.46-0.86;q = .08) were associated with decreased risk of HNSCC, potentially owing to carcinogen metabolism capacity. These findings were consistent for both cohorts and by cohort follow-up time. The observed relationships tended to be stronger for larynx cancer and for individuals with a history of tobacco use. Conclusions and Relevance This study demonstrates that greater oral abundance of commensalCorynebacteriumandKingellais associated with decreased risk of HNSCC, with potential implications for cancer prevention.

The objective of this study was to identify the independent effect of visceral fat on urine constituent excretion in a stone forming population. Using a database of 382 kidney stone patients with available visceral fat quantification, we created multiple linear regression models predicting changes in urinary solutes based on visceral fat area and body mass-index, divided by gender. Chi-square tests were used to compare stone composition by body mass-index and visceral fat area. Visceral fat predicts increases in urinary creatinine, sodium, and volume in men, but only urinary phosphate in women. In women, total body mass-index does not appear to modify this effect, but in men it is more pronounced in overweight patients for creatinine and volume only. Elevated visceral fat is associated with increased probability of uric acid stone composition. Different fat compartments likely effect urine composition in different ways. This effect appears to be different in men and women. Understanding and quantifying the effects of different fat compartments is probably important to understanding the metabolism of urolithiasis.

BACKGROUND: Evidence suggests that the risk of breast and prostate cancer is increased among those with a family history of the same disease and particularly among first-degree relatives. However, less is known about the relationship between breast and prostate cancer within families and particularly among minority populations. METHODS: Analyses of participants in the Women’s Health Initiative observational cohort who were free of breast cancer at the time of their baseline examination were conducted. Subjects were followed for breast cancer through August 31, 2009. A Cox proportional hazards regression modeling approach was used to estimate the risk of breast cancer associated with a family history of prostate cancer, breast cancer, and both among first-degree relatives. RESULTS: There were 78,171 eligible participants, and 3506 breast cancer cases were diagnosed during the study period. A family history of prostate cancer was associated with a modest increase in breast cancer risk after adjustments for confounders (adjusted hazard ratio [aHR], 1.14; 95% confidence interval [CI], 1.02-1.26). In a separate analysis examining the joint impact of both cancers, a family history of both breast and prostate cancer was associated with a 78% increase in breast cancer risk (aHR, 1.78; 95% CI, 1.45-2.19). Risk estimates associated with a family history of both breast and prostate cancer were higher among African American women (aHR, 2.34; 95% CI, 1.09-5.02) versus white women (aHR, 1.66; 95% CI, 1.33-2.08). CONCLUSIONS: These findings suggest that prostate cancer diagnosed among first-degree family members increases a woman’s risk of developing breast cancer. Future studies are needed to determine the relative contributions of genes and a shared environment to the risk for both cancers. Cancer 2015;000:000-000. V C 2015 American Cancer Society.

Background The follow-up rate, a standard index of the completeness of follow-up, is important for assessing the validity of a cohort study. A common method for estimating the follow-up rate, the “Percentage Method”, defined as the fraction of all enrollees who developed the event of interest or had complete follow-up, can severely underestimate the degree of follow-up. Alternatively, the median follow-up time does not indicate the completeness of follow-up, and the reverse Kaplan-Meier based method and Clark’s Completeness Index (CCI) also have limitations. Methods We propose a new definition for the follow-up rate, the Person-Time Follow-up Rate (PTFR), which is the observed person-time divided by total person-time assuming no dropouts. The PTFR cannot be calculated directly since the event times for dropouts are not observed. Therefore, two estimation methods are proposed: a formal person-time method (FPT) in which the expected total follow-up time is calculated using the event rate estimated from the observed data, and a simplified person-time method (SPT) that avoids estimation of the event rate by assigning full follow-up time to all events. Simulations were conducted to measure the accuracy of each method, and each method was applied to a prostate cancer recurrence study dataset. Results Simulation results showed that the FPT has the highest accuracy overall. In most situations, the computationally simpler SPT and CCI methods are only slightly biased. When applied to a retrospective cohort study of cancer recurrence, the FPT, CCI and SPT showed substantially greater 5-year follow-up than the Percentage Method (92%, 92% and 93% vs 68%). Conclusions The Person-time methods correct a systematic error in the standard Percentage Method for calculating follow-up rates. The easy to use SPT and CCI methods can be used in tandem to obtain an accurate and tight interval for PTFR. However, the FPT is recommended when event rates and dropout rates are high. Electronic supplementary material The online version of this article (10.1186/s12874-017-0436-z) contains supplementary material, which is available to authorized users.

Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4+ T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.

BackgroundSerum testosterone deficiency increases with aging. Age is also a major risk factor for prostate cancer (PrCa) and PCa tumors are more frequently diagnosed among men >65 years old. We evaluated the relationship between preoperative serum testosterone and clinical/ pathological features of PrCa in middle-aged and elderly patients.MethodsA total of 605 PrCa patients who underwent robotic-assisted radical prostatectomy between September 2010 and January 2013 at the University of Pennsylvania, and who had serum testosterone levels measured using Elecsys Testosterone II Immunoassay were included in this IRB-approved protocol. Androgen deficiency was determined as serum free testosterone (FT)

Urinary stone disease (USD) is a major health concern. There is a need for new treatment modalities. Recently, our group provided evidence for an association between the GMB composition and USD. The accessibility of the Gut Microbiome (GMB) makes it an attractive target for investigation and therefore, in these studies we have evaluated the extent to which the whole gut microbial community in fecal transplants can affect urinary stone risk parameters in an animal model. Fresh fecal pellets were collected from Zucker lean rats, homogenized in PBS (100 mg/mL), filtered through a 70 μm strainer and then orally gavaged into C57BL/6NTac germ‐free mice. Twenty‐four hours urine collections and GMB analysis were performed over time for 1 month. Kidney and gut tissue were harvested from transplanted mice for western blot analysis of expression levels of the Slc26a6 transporter involved in oxalate balance. Urinary calcium decreased after fecal transplant by 55% (P

Obesity is a risk factor for metabolic syndrome and urolithiasis, particularly uric acid stones. As estimated by visceral fat area, visceral obesity is a more specific measure of the risk of metabolic syndrome than body mass index. We investigated the effects of visceral fat area and other metabolic factors on uric acid stone formation in patients treated with percutaneous nephrolithotomy.We retrospectively reviewed the records of 269 patients who underwent percutaneous nephrolithotomy. Visceral fat area was measured in each patient on a CT axial slice at the umbilical level using the Aquarius iNtuition fat analysis tool. Analysis was performed to determine the effect of visceral fat area and other comorbidities on uric acid stone formation.Of the 269 patients analyzed there was no difference in baseline comorbidities between uric acid and nonuric acid stone formers. Patients with uric acid stones had a significantly higher mean visceral fat area (209.3 vs 161.9 cm², p = 0.001), and rates of hypertension (67.4% vs 47.3%) and coronary artery disease (14.3% vs 4.6%, each p = 0.011). On logistic regression analysis hypertension (OR 2.16, 95% CI 1.05-4.45, p = 0.04) and a high visceral fat area (OR 3.64, 95% CI 1.22-10.85, p = 0.02) were independent risk factors for uric acid stones.As a marker of visceral obesity, visceral fat area contributes to the risk of metabolic syndrome and urolithiasis. Uric acid stone formers showed a significantly higher hypertension rate and mean visceral fat area, which were independent risk factors for uric acid urolithiasis. Evaluating these characteristics in stone formers may facilitate a tailored metabolic assessment and treatment plan.

Introduction: Statins (HMG CoA reductase inhibitors) are a class of cholesterol lowering drugs that affect many intracellular pathways and have implications for chemopreventive activity against cancer. Epidemiological data on statins and breast cancer risk are conflicting. We analyzed updated data from the Women's Health Initiative (WHI) to assess the relationship between statins and breast cancer risk. Methods: This analysis included 154,587 post-menopausal women ages 50–79 years at baseline, in which 7,430 incident cases of invasive breast cancer were identified over an average of 10.8 (SD 3.3) years of follow-up. All cases of breast cancer were confirmed by review of medical records and pathology reports. Participants were asked to bring all current medications to their baseline visits and information on statin use was recorded. Statins were classified as lipophilic (lovastatin, simvastatin, fluvastatin) or hydrophilic (pravastatin and atorvastatin). Self and interviewer-administered questionnaires were used to collect information on other breast cancer risk factors. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses investigated the association of any statin use as well as, type of statin (lipophilic vs. hydrophilic), statin potency, and duration of use with breast cancer. To evaluate the effect of change in statin use over time, statin use was examined as a time-dependent exposure using updated information on statin use gathered during follow-up visits. Separate analyses were conducted by hormone receptor and HER2neu status, other tumor characteristics and use of postmenopausal hormone therapy. All statistical tests were two-sided. Results: Statins were used at baseline by 11,584 (7.5%) women in the cohort of whom 7,840 used lipophilic statins. The annualized rate of breast cancer was 0.42% among statin users and 0.42% among nonusers. The multivariable adjusted HR of breast cancer for statin users compared with non-users was 0.93 (95% C.I. 0.83–1.05), however for women using lipophilic statins the HR was 0.86 (95% CI, 0.74–1.00). Statin use for < 1 year was associated with a reduction in risk (HR 0.79, 95% C.I. 0.63–0.99) however there was no trend for overall duration of use. In the stratified analysis by tumor size, there was a marginal reduction in risk for tumors between 10 and 30 mm but not in smaller or larger tumors. There were no effect modifications by tumor stage, hormone receptor or HER2neu status, hormone therapy use, family history of breast cancer or body mass index. In the multivariable adjusted time-dependent model, the HR for simvastatin was 0.80 (95% CI, 0.64–0.99). Conclusion: Simvastatin was associated with a reduced risk of invasive breast cancer, and as a class, lipophilic statins were associated with a marginal benefit. This provides further evidence for possible class differences in statins with regard to chemo-preventive effects in breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-09.

Streptococcus pyogenes infections have been associated with two autoimmune diseases of the CNS: Sydenham’s chorea (SC) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS). Despite the high frequency of pharyngeal streptococcus infections among children, only a small fraction develops SC or PANDAS. This suggests that several factors in combination are necessary to trigger autoimmune complications: specific S. pyogenes strains that induce a strong immune response toward the host nervous system; genetic susceptibility that predispose children toward an autoimmune response involving movement or tic symptoms; and multiple infections of the throat or tonsils that lead to a robust Th17 cellular and humoral immune response when untreated. In this review, we summarize the evidence for each factor and propose that all must be met for the requisite neurovascular pathology and behavioral deficits found in SC/PANDAS.

INTRODUCTION AND OBJECTIVES: There is an ongoing debate on removing the label of cancer from Gleason 6 tumors. The aim of the study was to analyze long-term oncological outcomes in patients with pathologic Gleason 3+3 score after radical prostatectomy and to add further knowledge to the discussion. METHODS: We retrospectively analyzed the data of 2942 patients who underwent RP between January 1998 and 2010 and showed a Gleason score 3þ3 in final pathology. Biochemical recurrence (BCR)-free survival, metastasis-free survival (MFS) and cancer-specific survival (CSS) was reported. In multivariate regression analyses further prognosticators of oncological outcome in these patients were analyzed. RESULTS: Median follow-up was 80.7 months. 795 (27.1%) patients underwent lymph node dissection, whereas only one of these patients had positive lymph nodes. Mean preoperative PSA was 6.6 ng/ml, 9.1% of patients had a positive surgical margin and 94.4% had an organ-confined tumor. 198 patients (7.2%) recurred during the follow-up period, 15 (0.5%) patients developed metastasis and 7 (0.2%) patients died of their disease. Patients developing metastases had a significantly higher preoperative PSA (p1⁄40.03) and were more likely to harbor a non-organ-confined tumor (p

Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10(-6), 1.6 × 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10(-5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.

Study Type – Therapy (outcomes) Level of Evidence 2c What's known on the subject? and What does the study add? In addition to a higher prevalence and biological aggressiveness of prostate cancer, African-Americans tend towards narrower pelvises than Caucasians resulting in a potentially more difficult surgical dissection doing radical prostatectomy and increased positive surgical margins. In this study, there was no difference in urinary or sexual HRQL or overall satisfaction between African-Americans and Caucasians 2 years after radical prostatectomy, suggesting that the potential technical challenges of a narrower pelvis do not translate into poorer outcomes for African-Americans. OBJECTIVE • To determine if any differences exist in postoperative health-related quality-of-life (HRQL) outcomes, e.g. erectile function and continence, after radical prostatectomy (RP) in African-American (AA) vs Caucasian-American (CA) men. PATIENTS AND METHODS • Between October 2000 and July 2008, 1338 CA and 56 AA men underwent open RP by a single surgeon and signed informed consent to participate in a prospective longitudinal outcomes study. • The American Urological Association Symptom Score (AUA-SS) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) and a global assessment of satisfaction were self-administered at baseline and after RP 24 months. • Urinary, sexual, and satisfaction outcomes were compared at 24 months. RESULTS • AA men had significantly higher rates of hypertension and diabetes. • There were no other significant baseline differences in age, co-morbidities, body mass index, phosphodiesterase type 5 inhibitor use, preoperative prostate-specific antigen level, AUA-SS, and UCLA-PCI scores. • There were no differences in the percentage of men undergoing nerve-sparing procedures, estimated blood loss, transfusion rates, or complication rates between the groups. • At 24 months after RP the mean UCLA-PCI urinary and sexual function and bother scores and global satisfaction scores were similar between the groups. CONCLUSION • AA and CA men experience no significant differences in urinary and sexual HRQL or overall satisfaction after open RP when performed by a single experienced surgeon.

Genetic variation on the Y chromosome has not been convincingly implicated in prostate cancer risk. To comprehensively analyze the role of inherited Y chromosome variation in prostate cancer risk in individuals of European ancestry, we genotyped 34 binary Y chromosome markers in 3,995 prostate cancer cases and 3,815 control subjects drawn from four studies. In this set, we identified nominally significant association between a rare haplogroup, E1b1b1c, and prostate cancer in stage I (P = 0.012, OR = 0.51; 95% confidence interval 0.30–0.87). Population substructure of E1b1b1c carriers suggested Ashkenazi Jewish ancestry, prompting a replication phase in individuals of both European and Ashkenazi Jewish ancestry. The association was not significant for prostate cancer overall in studies of either Ashkenazi Jewish (1,686 cases and 1,597 control subjects) or European (686 cases and 734 control subjects) ancestry (Pmeta = 0.078), but a meta-analysis of stage I and II studies revealed a nominally significant association with prostate cancer risk (Pmeta = 0.010, OR = 0.77; 95% confidence interval 0.62–0.94). Comparing haplogroup frequencies between studies, we noted strong similarities between those conducted in the US and France, in which the majority of men carried R1 haplogroups, resembling Northwestern European populations. On the other hand, Finns had a remarkably different haplogroup distribution with a preponderance of N1c and I1 haplogroups. In summary, our results suggest that inherited Y chromosome variation plays a limited role in prostate cancer etiology in European populations but warrant follow-up in additional large and well characterized studies of multiple ethnic backgrounds. Electronic supplementary material The online version of this article (doi:10.1007/s00439-012-1139-5) contains supplementary material, which is available to authorized users.

Since 2012, US guidelines have recommended against prostate-specific antigen (PSA) screening for prostate cancer. However, evidence of screening benefit from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial and the European Randomized Study of Screening for Prostate Cancer has been inconsistent, due partly to differences in noncompliance and contamination. Using system dynamics modeling, we replicated the PLCO trial and extrapolated follow-up to 20 years. We then simulated 3 scenarios correcting for contamination in the PLCO control arm using Surveillance, Epidemiology, and End Results (SEER) incidence and survival data collected prior to the PSA screening era (scenario 1), SEER data collected during the PLCO trial period (1993-2001) (scenario 2), and data from the European trial's control arm (1991-2005) (scenario 3). In all scenarios, noncompliance was corrected using incidence and survival rates for men with screen-detected cancer in the PLCO screening arm. Scenarios 1 and 3 showed a benefit of PSA screening, with relative risks of 0.62 (95% confidence interval: 0.53, 0.72) and 0.70 (95% confidence interval: 0.59, 0.83) for cancer-specific mortality after 20 years, respectively. In scenario 2, however, there was no benefit of screening. This simulation showed that after correcting for noncompliance and contamination, there is potential benefit of PSA screening in reducing prostate cancer mortality. It also demonstrates the utility of system dynamics modeling for synthesizing epidemiologic evidence to inform public policy.

Cancers constitute a significant public health problem in Nigeria. Breast, cervix and prostate cancers are leading causes of cancer-related deaths. Changing diets, lifestyles, HIV/AIDS and macro-structural factors contribute to cancer morbidity and mortality. Poor health information linking cancer risk to individual behaviors, environmental pollutants and structural barriers undermine prevention/control efforts. Studies suggest increasing health literacy and empowering individuals to take preventive action will improve outcomes and mitigate impact on a weak health system.We obtained qualitative data from 80 men, women, and young adults in 11 focus groups to assess beliefs, risk-perceptions, preventive behaviors and perceptions of barriers and facilitators to cancer control in Ibadan, Nigeria and conducted thematic analysis.Participants demonstrated awareness of cancers and mentioned several risk factors related to individual behaviors and the environment. Nonetheless, myths and misconceptions as well as micro, meso and macro level barriers impede prevention and control efforts.Developing and implementing comprehensive context-relevant health literacy interventions in community settings are urgently needed.Copyright © 2016 John WileySons, Ltd.

Study Type – Outcomes (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? It is generally accepted in the medical community that total and intra-operative blood loss after RALP is significantly lower in comparison with ORRP. This has led to speculation that less bleeding results in better visualization of the operative field resulting in superior potency and continence. Blood loss (BL) during ORRP does not adversely impact clinical and functional outcomes irrespective of how BL is defined. Thus, the lower BL associated with RALP would not be expected to improve functional or oncological outcomes. OBJECTIVE • To determine the short- and long-term impact of blood loss (BL) on clinical, oncological and functional outcomes as well as complication rates after an open radical retropubic prostatectomy (ORRP). PATIENTS AND METHODS • Between 2000 and 2008, 1567 men who underwent an ORRP participated in our prospective longitudinal outcomes study. • Haematocrit (Hct) levels, transfusion rates, BL and complications were recorded prospectively. • Validated, self-administered quality-of-life (QoL) questionnaires were completed at baseline, 3, 6 and 12 months and yearly thereafter. • Urinary function and erectile dysfunction were assessed using AUA Symptom Score and the UCLA Prostate Cancer Index and analysis of variance (anova)/chi-square tests were used to compare clinical, BL, biochemical recurrence (BCR) and QoL outcomes amongst the three groups for continuous/categorical variables. RESULTS • The mean estimated BL was 742.7 (45 to 3500) mL and 5.4% and 3.8% received an autologous (AU) or allogeneic (AL) blood transfusions, respectively. • The average baseline, induction, postoperative and discharge Hct was 43.8%, 48.3%, 35.7% and 34.1%, respectively. • The estimated BL and the rate of change of Hct correlated moderately (r = 0.41, P

Exposure to endotoxin has been consistently associated with a reduced risk of lung cancer. However, there is a paucity of information regarding temporal aspects of this relationship. The objective of this study was to investigate the associations between contiguous windows of endotoxin exposure and risk of lung cancer.Data were reanalyzed from a case-cohort study (602 cases, 3,038 subcohort) of female textile workers in Shanghai, China. Cumulative endotoxin exposure was partitioned into two windows: ≥20 and20 years before risk. Exposure-response relations were examined using categorical and non-linear (semi-parametric) models, accounting for confounding by previous exposure windows.There was an inverse trend of decreasing risk of lung cancer associated with increasing levels of endotoxin exposure ≥20 years before risk (p trend = 0.02). Women in the highest two categories of cumulative exposures had hazard ratios of 0.78 (95% CI 0.60-1.03) and 0.77 (95% CI 0.58-1.02) for lung cancer, respectively, in comparison with unexposed textile workers. There was, however, a weaker association and not statistically significant between lung cancer and endotoxin exposure accumulated in the more recent window (20 years before risk).Results provide further evidence that endotoxin exposure that occurred 20 years or more before risk confers the strongest protection against lung cancer, indicating a possible early anti-carcinogenic effect. Further studies are needed to better understand the underlying biological mechanisms for this effect.

Study Type – Harm (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Erythropoletin-stimulating agents (ESAs) have been widely prescribed for treating anaemia secondary to advanced maligancies with the objective of reducing the need for red blood cell transfusions and improving the quality of life. However, the risk/benefit of ESAs has recently been questioned and metaanalyses showing that these agents are associated with an increased risk of mortality when chronically administered to patients with advanced/metastatic cancers. In this study we examined the impact of short-term preoperative utilization of ESAs on biochemical recurrence – free survival rates after open radical retropubic prostatectomy (ORRP). OBJECTIVE • To examine the impact of short-term preoperative utilization of erythropoietin-stimulating agents (ESAs) on biochemical recurrence (BCR)-free survival rates after open radical retropubic prostatectomy (ORRP) in light of the fact that the risk/benefit of ESAs has recently been questioned by the Food and Drug Administration (FDA) after reports showing a decreased survival. PATIENTS AND METHODS • From 2000 to 2008, 1567 patients underwent ORRP and 97.5% of these signed informed consent to participate in the New York University Prospective and Longitudinal Outcomes Study. • Of the remaining 1528 patients, 1317 (86%) received preoperative ESA (group 1) and 211 (14%) did not (group 2). • Patients were also classified as having low-, intermediate- or high-risk disease based on D’Amico risk categories. • Kaplan–Meier survival curves and Cox’s proportional hazard models were used to estimate BCR-free survival by ESA treatment. RESULTS • A significant difference was observed for BCR-free survival between the low- and intermediate/high-risk groups. • There were no statistically significant differences between groups 1 and 2 for BCR-free survival in the entire study populations and within risk groups. • In addition, Cox regression models showed no statistically significant differences in BCR-free survival according to preoperative ESA administration in the entire cohort as well as among the low- and intermediate/high-risk groups. CONCLUSIONS • The short-term use of ESAs as a preoperative blood management strategy for patients undergoing ORRP has no clinically relevant adverse effects on the biology of prostate cancer. • The present study supports the use of these agents before the procedure in patients undergoing surgery for localized disease.

Background Prostate cancer is a genetically complex disease with locus and disease heterogeneity. The RNASEL gene and HPCX locus have been implicated in hereditary prostate cancer; however, their contributions to sporadic forms of this malignancy remain uncertain.

Summary Axial muscles are innervated by motor neurons of the median motor column (MMC). In contrast to the segmentally restricted motor columns that innervate limb, body wall, and neuronal targets, MMC neurons are generated along the entire length of the spinal cord. We show that the specification of MMC fate involves a dorsoventral signaling program mediated by three Wnt proteins (Wnt4, Wnt5a, and Wnt5b) expressed in and around the floor plate. These Wnts appear to establish a ventralhigh to dorsallow signaling gradient and promote MMC identity and connectivity by maintaining expression of the LIM homeodomain proteins Lhx3/4 in spinal motor neurons. Elevation of Wnt4/5 activity generates additional MMC neurons at the expense of other motor neuron columnar subtypes, whereas depletion of Wnt4/5 activity inhibits the production of MMC neurons. Thus, two dorsoventral signaling pathways, mediated by Shh and Wnt4/5, are required to establish an early binary divergence in motor neuron columnar identity.

Transcription factor 7-like 2 (TCF7L2) is a high mobility group -box containing protein that is a critical member of the Wnt/β-catenin signaling pathway. In addition to its recently recognized role in diabetes, aberrant TCF7L2 expression has been implicated in cancer through regulation of cell proliferation and apoptosis by c-MYC and cyclin D. It has been hypothesized that germline variants within the TCF7L2 gene previously associated with diabetes may affect cancer risk through the Wnt/β-catenin signaling pathway. Specifically, the same risk allele of single nucleotide polymorphism (SNP) rs12255372 that is associated with diabetes (T allele) has recently been associated with an increased risk of breast cancer. Here, we investigated associations between rs12255372 and prostate cancer risk among 597 cases and 548 controls from a population-based study. We also evaluated prostate cancer progression/recurrence and prostate-specific mortality among these cases under long-term surveillance. The risk allele was associated with cancer progression/recurrence after primary treatment [hazard ratio (HR) =1.48, 95% confidence interval (CI) =1.01-2.19), but this association was attenuated when the model was further adjusted for Gleason score and tumor stage. There were no associations between this SNP and the risk of developing disease or prostate cancer-specific mortality. Our findings suggest that this variant in the TCF7L2 gene may enhance tumor progression or metastasis, but it does not contribute significantly to tumor initiation. These findings are of clinical importance for identification of patients that may develop more aggressive/recurrent disease after primary treatment.

Although prostate cancer screening by measurement of serum prostate-specific antigen (PSA) and digital rectal examination (DRE) is common in clinical practice, the impact of such screening on prostate cancer-specific mortality remains uncertain. Data from a population-based case–control study in King County, Washington, among men aged 50–64 years (706 cases, 645 controls) were used to examine the relationships between PSA and DRE screening and fatal prostate cancer and other-cause mortality. Incident cases were diagnosed in 1993–1996, identified via the Seattle-Puget Sound SEER cancer registry and followed for vital status through 1 June 2007. Controls were ascertained by random digit dialing and frequency age-matched to cases. The screening variable used in this analysis was self-reported receipt of one or more PSA and/or DRE tests performed as part of a routine checkup in the five-year period before diagnosis or reference date. A smaller proportion of men with fatal prostate cancer had one or more PSA and/or DRE screening tests compared to controls, resulting in an adjusted odds ratios (OR) of 0.38 (95% CI 0.19–0.77). There was no association, however, between PSA and/or DRE screening and other-cause mortality (OR = 1.02; 95% CI 0.51–2.02). Results of this study suggest a reduction in prostate cancer-specific mortality associated with PSA and/or DRE screening in middle-aged men. Findings should be interpreted cautiously, however, as results are based on observational data. Further, the study was not able to separate the relative efficacy of PSA versus DRE screening.

Objective The aim of this study was to examine associations of smoking at the time of diagnosis with the risk of prostate cancer death in a population-based cohort of men with prostate cancer. Methods Data were from 752 prostate cancer patients aged 40-64 years, who were enrolled in a case-control study and under long-term follow-up for mortality. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between smoking and prostate cancer-specific and other cause mortality. Results Compared to never smoking, smoking at the time of diagnosis was associated with a significant increase in risk of prostate cancer-specific mortality. After controlling for demographic characteristics, Gleason grade, stage at diagnosis, and primary treatment, the HR was 2.66 (95% CI: 1.10-6.43). Conclusions Smoking at the time of diagnosis, independent of key clinical prognostic factors, is associated with an increased risk of prostate cancer death.

Background: Family-based linkage studies, association studies, and studies of tumors have highlighted human chromosome 8q as a genomic region of interest for prostate cancer susceptibility loci. Recently, a locus at 8q24, characterized by both a single nucleotide polymorphism (SNP) and a microsatellite marker, was shown to be associated with prostate cancer risk in Icelandic, Swedish, and U.S. samples. Although the data were provocative, the U.S. samples were not population based, which precludes assessment of the potential contribution of this locus to prostate cancer incidence in the United States. Methods: We analyzed both markers in a population-based, case-control study of middle-aged men from King County, Washington. Results: Overall, there was a significant positive association between the A allele of the SNP rs1447295 and prostate cancer risk [odds ratio, 1.4; 95% confidence interval (95% CI), 1.1-2.0] but no significant association with the microsatellite DG8S737. However, significant associations were observed for both markers in men with high Gleason scores. Adjusting for age, first-degree family history of prostate cancer, and prostate cancer screening history, the adjusted odds ratios were 1.4 (95% CI, 1.1-1.8) for the A allele of the SNP and 1.9 (95% CI, 1.2-2.8) for the −10 allele of the microsatellite. Conclusions: These data suggest that the locus on chromosome 8q24 harbors a genetic variant associated with prostate cancer and that the microsatellite marker is a stronger risk factor for aggressive prostate cancers defined by poorly differentiated tumor morphology. (Cancer Epidemiol Biomarkers Prev 2007;16(4):809–14)

BACKGROUND Current research is inconclusive regarding the effect of obesity on outcomes after a prostate cancer diagnosis. The objective of this study was to examine associations between obesity and the risks of developing metastasis or prostate cancer-specific mortality in a population-based cohort of men with prostate cancer. METHODS Seven hundred fifty-two middle-aged men with prostate cancer who were enrolled in a case-control study and remain under long-term follow-up for disease progression and mortality formed the study cohort. Body mass index (BMI) in the year before diagnosis was obtained at the time of initial interview. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of prostate cancer metastasis and mortality associated with obesity, controlling for age, race, smoking status, Gleason score, stage at diagnosis, diagnostic prostate-specific antigen level, and primary treatment. RESULTS Obesity (BMI ≥30 kg/m2) was associated with a significant increase in prostate cancer mortality (HR, 2.64; 95% CI, 1.18–5.92). Among men who were diagnosed with local- or regional-stage disease, obesity also was associated with an increased risk of developing metastasis (HR, 3.61; 95% CI, 1.73–7.51). Associations generally were consistent across strata defined by Gleason score (2–6 or 7 [3 + 4] vs 7 [4 + 3] or 8–10), stage (local vs regional/distant for mortality), and primary treatment (androgen-deprivation therapy use: yes vs no). CONCLUSIONS Obesity at the time of diagnosis was associated with increased risks of prostate cancer metastasis and death. The increased risk of prostate cancer death or metastasis associated with obesity largely was independent of key clinical prognostic factors at diagnosis. Cancer 2007. © 2007 American Cancer Society.

BACKGROUND AND OBJECTIVES:Bronchiolitis, the most common reason for hospitalization in children younger than 1 year in the United States, has no proven therapies effective beyond supportive care. We aimed to investigate the effect of nebulized 3% hypertonic saline (HS) compared with nebulized normal saline (NS) on length of stay (LOS) in infants hospitalized with bronchiolitis.METHODS:We conducted a prospective, randomized, double-blind, controlled trial in an urban tertiary care children’s hospital in 227 infants younger than 12 months old admitted with a diagnosis of bronchiolitis (190 completed the study); 113 infants were randomized to HS (93 completed the study), and 114 to NS (97 completed the study). Subjects received 4 mL nebulized 3% HS or 4 mL 0.9% NS every 4 hours from enrollment until hospital discharge. The primary outcome was median LOS. Secondary outcomes were total adverse events, subdivided as clinical worsening and readmissions.RESULTS:Patient characteristics were similar in groups. In intention-to-treat analysis, median LOS (interquartile range) of HS and NS groups was 2.1 (1.2–4.6) vs 2.1 days (1.2–3.8), respectively, P = .73. We confirmed findings with per-protocol analysis, HS and NS groups with 2.0 (1.3–3.3) and 2.0 days (1.2–3.0), respectively, P = .96. Seven-day readmission rate for HS and NS groups were 4.3% and 3.1%, respectively, P = .77. Clinical worsening events were similar between groups (9% vs 8%, P = .97).CONCLUSIONS:Among infants admitted to the hospital with bronchiolitis, treatment with nebulized 3% HS compared with NS had no difference in LOS or 7-day readmission rates.

© 2015 Elsevier Inc.. Purpose: Many dietary factors have either proinflammatory or anti-inflammatory properties. We previously developed a dietary inflammatory index (DII) to assess the inflammatory potential of diet. In this study, we conducted a construct validation of the DII based on data from a food frequency questionnaire and three inflammatory biomarkers in a subsample of 2567 postmenopausal women in the Women's Health Initiative Observational Study. Methods: We used multiple linear and logistic regression models, controlling for potential confounders, to test whether baseline DII predicted concentrations of interleukin-6, high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor alpha receptor 2, or an overall biomarker score combining all three inflammatory biomarkers. Results: The DII was associated with the four biomarkers with beta estimates (95% confidence interval) comparing the highest with lowest DII quintiles as follows: interleukin-6: 1.26 (1.15-1.38), Ptrend< .0001; tumor necrosis factor alpha receptor 2: 81.43 (19.15-143.71), Ptrend=.004; dichotomized hs-CRP (odds ratio for higher vs. lower hs-CRP): 1.30 (0.97-1.67), Ptrend=.34; and the combined inflammatory biomarker score: 0.26 (0.12-0.40), Ptrend=.0001. Conclusions: The DII was significantly associated with inflammatory biomarkers. Construct validity of the DII indicates its utility for assessing the inflammatory potential of diet and for expanding its use to include associations with common chronic diseases in future studies.

Background Men of African descent have the highest incidence and mortality rates of prostate cancer (PrCa) worldwide. Notably, PrCa is increasing in Africa with Nigerian men being mostly affected. Thus, it is important to understand risk factors for PrCa in Nigeria and build capacity for cancer research. The goals of this study were to determine the feasibility of conducting an epidemiological study of PrCa and to obtain preliminary data on risk factors for PrCa in Nigeria. Methods A case–control study (50 cases/50 controls) was conducted at the University College Hospital (UCH) in Ibadan, Nigeria, between October 2011 and December 2012. Men aged 40 to 80 years were approached for the study and asked to provide informed consent and complete the research protocol. Logistic regression models were used to examine associations between demographic, social and lifestyle characteristics and risk of PrCa. Results The participation rate among cases and controls was 98% and 93%, respectively. All participants completed a questionnaire and 99% (50 cases/49 controls) provided blood samples. Cases had a median serum diagnostic PSA of 73 ng/ml, and 38% had a Gleason score 8–10 tumor. Family history of PrCa was associated with a 4.9-fold increased risk of PrCa (95% CI 1.0 - 24.8). There were statistically significant inverse associations between PrCa and height, weight and waist circumference, but there was no association with body mass index (kg/m2). There were no associations between other socio-demographic and lifestyle characteristics and PrCa risk. Conclusion This feasibility study demonstrated the ability to ascertain and recruit participants at UCH and collect epidemiological, clinical and biospecimen data. Our results highlighted the advanced clinical characteristics of PrCa in Nigerian men, and that family history of PrCa and some anthropometric factors were associated with PrCa risk in this population. However, larger studies are needed to better understand the epidemiological risk factors of PrCa in Nigeria.

Background Polymorphisms in glutathione S-transferase (GST) genes can increase oxidative stress, which may affect cancer prognosis. The aim of this study was to examine associations between GSTM1, T1, or P1 genetic variants and prostate cancer outcomes. Methods A population-based cohort of men (n = 752) from King County, Washington, diagnosed with prostate cancer in 1993–1996, and under long-term surveillance for mortality completed a follow-up survey about prostate cancer recurrence/progression. Cox PH models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for deaths from prostate cancer or other causes and prostate cancer recurrence/progression. Results There were 50 prostate cancer-specific deaths, 65 deaths from other causes, and 143 recurrence/progressions events during an average 9.6 years of follow-up. The adjusted HR for prostate cancer mortality was 3.8 (95% CI 1.6–8.9) among Caucasian men with the GSTM1-null genotype. There were no differences, however, in mortality from other causes or prostate cancer recurrence/progression between men with GSTM1-null versus not-null genotypes. The GSTT1 and GSTP1 genotypes were not associated with any of these outcomes. Discussion Results suggest that the GSTM1 genotype may be a useful biomarker to identify patients at higher risk for fatal prostate cancer. Prostate 66: 1535–1541, 2006. © 2006 Wiley-Liss, Inc.

BACKGROUND The glutathione S-transferase (GST) enzymes detoxify several carcinogens. Genetic polymorphisms in GSTM1, T1, and P1 (Ile105Val) have been associated with prostate cancer, however, results have been inconsistent across studies. METHODS Data from a population-based case-control study in King County, Washington, were used to further evaluate the relationships between these GST polymorphisms and prostate cancer. Incident cases (n = 590) were 40–64 years old, diagnosed from 1993 through 1996, and identified via the SEER cancer registry. Controls (n = 538) were identified via random digit dialing, and frequency age-matched to cases. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS Risk of prostate cancer was moderately increased among Caucasians with the GSTM1-null genotype (OR = 1.54; 95% CI 1.19–2.01). There were no associations for either GSTT1 or P1(Ile105Val). The association between the GSTM1-null genotype and prostate cancer was not different according to cancer aggressiveness defined by stage at diagnosis and Gleason score. Among GSTM1-null Caucasians, the relative risk of prostate cancer increased linearly with increasing pack-years of smoking (P-value for trend = 0.007), with the highest ORs observed for smokers of >30 pack-years. CONCLUSIONS Findings suggest that the GSTM1-null genotype defines a subgroup of men at higher risk of prostate cancer, particularly if they are heavy smokers. © 2005 Wiley-Liss, inc.

To analyze the perioperative outcomes and management considerations in patients with dialysis-dependent end-stage renal disease (ESRD) undergoing laparoscopic radical nephrectomy for renal-cell carcinoma (RCC).There were 224 consecutive laparoscopic radical nephrectomies reviewed. Of those, 37 patients with ESRD were identified and compared with 187 patients with sporadic RCC. Evaluable parameters included age, sex, race, side of surgery, medical comorbidities, body mass index, American Society of Anesthesiologist (ASA) scoring, and age adjusted Charlson Comorbidity Index. All complications occurring intraoperatively and within the first 30 days were classified as per the Clavien classification system. Presurgical workup and transplant considerations were evaluated. Demographic and clinical characteristics were compared using Student t tests and chi-square tests for categoric variables.Compared with non-ESRD patients, those with ESRD were younger and had smaller tumors. ASA was significantly higher in the ESRD group (P0.001). Mean blood loss was similar between ESRD patients and non-ESRD patients. Overall complication rates were higher in patients with ESRD. Pathologic characteristics of ESRD renal masses included a higher proportion of papillary RCC.Patients with RCC associated with ESRD tend to have a higher ASA class and lower grade tumors. In addition, this population is at increased risk of surgical complications and more likely to need transfusions. Careful preoperative preparation and intraoperative anesthetic management are crucial to minimize patient morbidity and improve outcomes.

Importance Patients with Parkinson disease (PD) who harbor LRRK2 G2019S mutations may have increased risks of nonskin cancers. However, the results have been inconsistent across studies. Objectives To analyze pooled data from 5 centers to further examine the association between LRRK2 G2019S mutation and cancer among patients with PD and to explore factors that could explain discrepancies. Design, Setting, and Participants Clinical, demographic, and genotyping data as well as cancer outcomes were pooled from 1549 patients with PD recruited across 5 movement disorders clinics located in Europe, Israel, and the United States. Associations between LRRK2 G2019S mutation and the outcomes were examined using mixed-effects logistic regression models to estimate odds ratios (ORs) and 95% CIs. Models were adjusted for age and ethnicity (Ashkenazi Jewish vs others) as fixed effects and study center as a random effect. Main Outcomes and Measures All cancers combined, nonskin cancers, smoking-related cancers, hormone-related cancers, and other types of cancer. Results The overall prevalence of the LRRK2 G2019S mutation was 11.4% among all patients with PD. Mutation carriers were younger at PD diagnosis and more likely to be women (53.1%) and of Ashkenazi Jewish descent (76.8%) in comparison with individuals who were not mutation carriers. The LRRK2 G2019S mutation carriers had statistically significant increased risks for nonskin cancers (OR, 1.62; 95% CI, 1.04-2.52), hormone-related cancers (OR, 1.87; 95% CI, 1.07-3.26) and breast cancer (OR, 2.34; 95% CI, 1.05-5.22) in comparison with noncarriers. There were no associations with other cancers. There were no major statistically significant differences in the results when the data were stratified by Ashkenazi Jewish ethnicity; however, there was some evidence of heterogeneity across centers. Conclusions and Relevance This multinational study from 5 centers demonstrates that LRRK2 G2019S mutation carriers have an overall increased risk of cancer, especially for hormone-related cancer and breast cancer in women. Larger prospective cohorts or family-based studies investigating associations between LRRK2 mutations and cancer among patients with PD are warranted to better understand the underlying genetic susceptibility between PD and hormone-related cancers.

Background: Exposure to metalworking fluids has been previously associated with prostate cancer mortality in a cohort of autoworkers. Our objective was to further explore this finding in a study of prostate cancer incidence in the same cohort, with reduced misclassification of outcome. Methods: We conducted a nested case-control study in the General Motors cohort of autoworkers. Incident cases of prostate cancer (n = 872) were identified via the Michigan Cancer Registry from 1985 through 2000. Controls were selected using incidence-density sampling with 5:1 ratio. Using cumulative exposure (mg/m 3 -years) as the dose metric, we first examined varying lengths of lags (0-25 years). Then, we evaluated consecutive windows of exposure: 25 or more years before risk age, and fewer than 25 years. We used penalized splines to model the relative risk as a smooth function of exposure, and adjusted for race and calendar year of diagnosis in a Cox model. Results: Risk of prostate cancer increased with exposure to soluble and straight fluids 25 years or more before risk age but not with exposure in the last 25 years. The relationship with soluble fluids was piecewise linear, with a small increase in risk at lower exposures followed by a steeper rise. By contrast, the relationship with straight fluids was linear, with a relative risk of 1.12 per 10 mg/m 3 -years of exposure (95% confidence interval = 1.04-1.20). Conclusions: Exposure to oil-based fluids, soluble and straight, is modestly associated with prostate cancer risk among autoworkers, with a latency period of at least 25 years.

Evidence suggests that the risk of breast and prostate cancer is increased among those with a family history of the same disease and particularly among first-degree relatives. However, less is known about the relationship between breast and prostate cancer within families and particularly among minority populations.Analyses of participants in the Women's Health Initiative observational cohort who were free of breast cancer at the time of their baseline examination were conducted. Subjects were followed for breast cancer through August 31, 2009. A Cox proportional hazards regression modeling approach was used to estimate the risk of breast cancer associated with a family history of prostate cancer, breast cancer, and both among first-degree relatives.There were 78,171 eligible participants, and 3506 breast cancer cases were diagnosed during the study period. A family history of prostate cancer was associated with a modest increase in breast cancer risk after adjustments for confounders (adjusted hazard ratio [aHR], 1.14; 95% confidence interval [CI], 1.02-1.26). In a separate analysis examining the joint impact of both cancers, a family history of both breast and prostate cancer was associated with a 78% increase in breast cancer risk (aHR, 1.78; 95% CI, 1.45-2.19). Risk estimates associated with a family history of both breast and prostate cancer were higher among African American women (aHR, 2.34; 95% CI, 1.09-5.02) versus white women (aHR, 1.66; 95% CI, 1.33-2.08).These findings suggest that prostate cancer diagnosed among first-degree family members increases a woman's risk of developing breast cancer. Future studies are needed to determine the relative contributions of genes and a shared environment to the risk for both cancers.

The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5′ of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53–0.67, P=9 × 10−18), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21–0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49–0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations., Genome-wide association studies (GWAS) have revealed gene variants associated with breast cancer, but their association with breast cancer development in Latinas is not clear. Here, the authors carry out a GWAS of breast cancer in Latinas and identify a significant protective variant of Indigenous American origin in the 6q25 region.