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Background: Understanding factors associated with opioid dispensing in cancer patients is important for developing tailored guidelines and ensuring equitable access to pain management. We examined patterns and predictors of opioid dispensing among older cancer patients from 2008 to 2015. Methods: We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database linked to Medicare claims. We included the most common cancer types among patients aged 66–95 years. Opioids dispensed within 30 days before and 120 days after cancer diagnosis were assessed. We used logistic regression models to examine trends, adjusted odds ratios (aORs), and 95% confidence intervals (CIs) for opioid dispensing, considering patient demographics, geography, cancer stage, comorbidities, and treatment options. Models were stratified by sex. Results: A total of 211,759 cancer patients aged 66–95 years were included in the study. For cancers combined, non‐Hispanic Black men had a significantly lower odds of receiving opioids during the 120 days post‐diagnosis (aOR = 0.89, 95% CI = 0.84–0.94) compared to non‐Hispanic White men. Factors such as pre‐diagnosis opioid dispensing, age, geography, cancer stage, comorbidities, and type of cancer treatment were associated with opioid dispensing during the 120 days post‐diagnosis. Surgery had the strongest association, with men undergoing surgery being 4.4 times more likely to receive opioids within 120 days post‐diagnosis (aOR = 4.41, 95% CI = 4.23–4.60), while women had an odds ratio of 2.72 (95% CI = 2.62–2.83). Chemotherapy and radiotherapy were also positively associated with opioid dispensing, with less pronounced estimates. Conclusions: We observed significant variations in opioid dispensing among cancer patients aged 66‐95 years across cancer types and demographic and clinical factors. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East‐Asian hospital‐based case–control study. We identified 16 IgG antibodies significantly elevated in EBV‐positive cHL compared with controls, defining an "East‐Asian antibody signature of EBV‐positive cHL." We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case–control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the "East‐Asian antibody signature of EBV‐positive cHL" exhibited significant associations with cHL in the European population. Conversely, we assessed the "European antibody signature of EBV‐positive cHL" identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East‐Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East‐Asian population. This cross‐comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti‐EBV IgG antibodies (LMP‐1, TK, BALF2, BDLF3, and BBLF1), found in both population‐specific antibody signatures, represent a "core signature of EBV‐positive cHL." Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV‐positive cHL independent of population‐specific factors. [ABSTRACT FROM AUTHOR]

Thyroid cancer more commonly affects women than men and is the third most frequently diagnosed cancer among women of reproductive age. We conducted a nested case–control study within the Finnish Maternity Cohort to evaluate pre‐diagnostic sex steroid and thyroid function markers in relation to subsequent maternal papillary thyroid cancer. Cases (n = 605) were women ages 18–44 years, who provided an early‐pregnancy (<20 weeks gestation) blood sample and were diagnosed with papillary thyroid cancer up to 11 years afterward. Controls (n = 1185) were matched to cases 2:1 by gestational age, mother's age, and date at blood draw. Odds ratios (ORs) for the associations of serum thyroid peroxidase antibodies (TPO‐Ab), thyroglobulin antibodies (Tg‐Ab), thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), progesterone, and estradiol with papillary thyroid cancer were estimated using conditional logistic regression. TPO‐Ab and Tg‐Ab positivity (>95th percentile among controls) were associated with more than 3‐fold (OR = 3.32, 95% confidence interval [CI] 2.33–4.72) and 2‐fold (OR = 2.03, 95% CI 1.41–2.93) increased odds of papillary thyroid cancer, respectively. These associations were similar by time since blood draw, parity, gestational age, smoking status, and age and stage at diagnosis. In models excluding TPO‐Ab or Tg‐Ab positivity, TPO‐Ab (quartile 4 vs. 1: OR = 1.66, 95% CI 1.17–2.37, p‐trend =.002) and Tg‐Ab (quartile 4 vs. 1: OR = 1.74, 95% CI 1.22–2.49, p‐trend =.01) levels were positively associated with papillary thyroid cancer. No associations were observed for estradiol, progesterone, TSH, fT3, or fT4 overall. Our results suggest that thyroid autoimmunity in early pregnancy may increase the risk of maternal papillary thyroid cancer. [ABSTRACT FROM AUTHOR]

Our work was motivated by the question whether, and to what extent, well‐established risk factors mediate the racial disparity observed for colorectal cancer (CRC) incidence in the United States. Mediation analysis examines the relationships between an exposure, a mediator and an outcome. All available methods require access to a single complete data set with these three variables. However, because population‐based studies usually include few non‐White participants, these approaches have limited utility in answering our motivating question. Recently, we developed novel methods to integrate several data sets with incomplete information for mediation analysis. These methods have two limitations: (i) they only consider a single mediator and (ii) they require a data set containing individual‐level data on the mediator and exposure (and possibly confounders) obtained by independent and identically distributed sampling from the target population. Here, we propose a new method for mediation analysis with several different data sets that accommodates complex survey and registry data, and allows for multiple mediators. The proposed approach yields unbiased causal effects estimates and confidence intervals with nominal coverage in simulations. We apply our method to data from U.S. cancer registries, a U.S.‐population‐representative survey and summary level odds‐ratio estimates, to rigorously evaluate what proportion of the difference in CRC risk between non‐Hispanic Whites and Blacks is mediated by three potentially modifiable risk factors (CRC screening history, body mass index, and regular aspirin use). [ABSTRACT FROM AUTHOR]

Gut barrier dysfunction can result in the liver being exposed to an elevated level of gut‐derived bacterial products via portal circulation. Growing evidence suggests that systemic exposure to these bacterial products promotes liver diseases including hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). However, prospective studies have not examined the association between biomarkers of gut barrier dysfunction and HCC risk in a population of hepatitis B or C viral (HBV/HCV) carriers. We investigated whether prediagnostic, circulating biomarkers of gut barrier dysfunction were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)‐HBV and REVEAL‐HCV cohorts from Taiwan. REVEAL‐HBV included 185 cases and 161 matched controls, and REVEAL‐HCV 96 cases and 96 matched controls. The biomarkers quantitated were immunoglobulin A (IgA), IgG, and IgM against lipopolysaccharide (LPS) and flagellin, soluble CD14 (an LPS coreceptor), and LPS‐binding protein (LBP). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarker levels and HCC were calculated using multivariable‐adjusted logistic regression. A doubling of the circulating levels of antiflagellin IgA or LBP was associated with a 76% to 93% increased risk of HBV‐related HCC (OR per one unit change in log2 antiflagellin IgA = 1.76, 95% CI: 1.06‐2.93; OR for LBP = 1.93, 95% CI: 1.10‐3.38). None of the other markers were associated with an increased risk of HBV‐related or HCV‐related HCC. Results were similar when cases diagnosed in the first 5 years of follow‐up were excluded. Our findings contribute to understanding the interplay of gut barrier dysfunction and primary liver cancer etiology. [ABSTRACT FROM AUTHOR]

In the United States, renal cell carcinoma (RCC) incidence and the prevalence of obesity, an established risk factor for RCC, have been increasing for several decades. RCC is more common among older individuals. We sought to quantify the contribution of excess adiposity to the rising incidence of RCC among individuals 60 years or older. National Institutes of Health‐American Association of Retired Persons Diet and Health Study data (n = 453 859 participants, enrolled in 1995‐1996, age at enrollment 50‐71 years) were used to estimate multivariable‐adjusted hazard ratios (HRs) for RCC across body mass index categories and HRs associated with smoking. Population attributable fractions (PAFs) were calculated using estimated HRs and annual overweight/obesity prevalence from the National Health Interview Survey (1985‐2008). PAF estimates were combined with RCC incidence from Surveillance, Epidemiology and End Results‐13 to calculate annual percent changes in RCC incidence attributable (and unrelated) to overweight/obesity. We found that between 1995 and 2018, among individuals aged 60 years and older, PAF for overweight/obesity increased from 18% to 29% for all RCCs. In comparison, the PAF for smoking declined from 12% to 9%. RCC incidence increased 1.8% per year (95% confidence interval [CI] 1.5%‐2.1%) overall, while RCC incidence attributable to overweight/obesity increased 3.8% per year (95%CI 3.5%‐4.2%) and RCC incidence unrelated to overweight/obesity increased 1.2% per year (95% CI 0.9%‐1.4%). In conclusion, overweight/obesity appears to have contributed importantly to the rising incidence of RCC in the United States since the mid‐1990s. Public health interventions focused on reducing overweight and obesity could help substantially in curbing this trend. [ABSTRACT FROM AUTHOR]

We propose and study structured time‐dependent inverse regression (STIR), a novel sufficient dimension reduction model, to analyze longitudinally measured, correlated biomarkers in relation to an outcome. The time structure is accommodated in an inverse regression model for the markers that can be applied both to equally and unequally spaced time points for each sample. The inverse regression structure also naturally accommodates retrospectively sampled markers, that is, markers measured in case‐control studies. We estimate the corresponding linear combinations of the markers, the reduction, using least squares. We show that under additional distributional assumptions the reduction contains sufficient information about the outcome. In extensive simulations the STIR linear combinations perform well in predictive models based on samples of realistic size. A Wald‐type test for association of a particular marker with outcome at any time point based on the STIR reduction has better power overall than assessing associations based on logistic or linear regression models that include all longitudinally measured markers as independent predictors. As illustrations we estimate the STIR reductions for a cohort study of diabetes and hyperlipidemia and a case‐control study of brain cancer with multiple longitudinally measured biomarkers. We assess the STIR reductions' predictive performance and identify outcome‐associated biomarkers. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is highly fatal, and its incidence is increasing in the United States. Population‐based registry studies suggest associations between a few autoimmune conditions and PC risk, albeit based on a relatively small number of cases. We conducted a population‐based, nested case‐control study to examine the associations between autoimmune conditions and PC risk within the Surveillance, Epidemiology, and End Results Program (SEER)‐Medicare population. Incident primary malignant PC cases (n = 80 074) were adults ≥66 years and diagnosed between 1992 and 2015. Controls (n = 320 296) were alive at the time cases were diagnosed and frequency‐matched to cases (4:1 ratio) by age, sex, and year of diagnosis. We used multivariable‐adjusted, unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 45 autoimmune conditions identified from Medicare claims. Eight autoimmune conditions including ankylosing spondylitis (OR = 1.45; 95% CI: 1.14‐1.84), Graves' disease (OR = 1.18; 95% CI: 1.03‐1.34), localized scleroderma (OR = 1.27; 95% CI: 1.06‐1.52), pernicious anemia (OR = 1.08; 95% CI: 1.02‐1.14), primary sclerosing cholangitis (OR = 1.37; 95% CI: 1.18‐1.59), pure red cell aplasia (OR = 1.31; 95% CI: 1.16‐1.47), type 1 diabetes (OR = 1.11; 95% CI: 1.07‐1.15), and ulcerative colitis (OR = 1.18; 95% CI: 1.07‐1.31) were associated with increased PC risk (false discovery rate‐adjusted P values <.10). In subtype analyses, these conditions were associated with pancreatic ductal adenocarcinoma, whereas only ulcerative colitis was associated with pancreatic neuroendocrine tumors. Our results support the hypothesis that autoimmune conditions may play a role in PC development. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) is among the most common viral infections after solid organ transplantation (SOT). Associations of CMV with cancer risk among SOT recipients have been incompletely evaluated. Methods: The authors used linked data from the US SOT registry and 32 cancer registries. Poisson regression was used to compare cancer incidence across CMV risk groups based on donor (D) and recipient (R) immunoglobulin G (IgG) serostatus: high risk (R‐negative/D‐positive), moderate risk (R‐positive), and low risk (R‐negative/D‐negative). Results: In total, 247,318 SOT recipients were evaluated during 2000–2017 (R‐negative/D‐positive, 20.3%; R‐positive, 62.9%; R‐negative/D‐negative, 16.8%). CMV‐seropositive recipients were older, more racially/ethnically diverse, and had lower socioeconomic status than CMV‐seronegative recipients. Compared with R‐negative/D‐negative recipients, recipients in the R‐negative/D‐positive and R‐positive groups had a lower incidence of diffuse large B‐cell lymphoma (DLBCL; R‐negative/D‐positive: adjusted incidence rate ratio [aIRR], 0.74; 95% confidence interval [CI], 0.59–0.91; R‐positive: aIRR, 0.83; 95% CI, 0.69–1.00). CMV serostatus modified the association between Epstein–Barr virus (EBV) status and DLBCL (p =.0006): DLBCL incidence was increased for EBV R‐negative/D‐positive recipients (aIRR, 3.46; 95% CI, 1.50–7.95) among CMV R‐negative/D‐negative recipients but not among the other CMV risk groups. Compared with recipients who were CMV R‐negative/D‐negative, those who were R‐negative/D‐positive had a lower incidence of small intestine cancer (aIRR, 0.23; 95% CI, 0.09–0.63), and R‐positive recipients had a higher incidence of lung cancer (aIRR, 1.24; 95% CI, 1.05–1.46). CMV status was not associated with risk for other cancers. Conclusions: CMV status was not associated with risk for most cancers among SOT recipients. The inverse association with DLBCL may reflect the protective effects of CMV prophylaxis or treatment with off‐target efficacy against EBV infection (the major cause of lymphoma in SOT recipients). Cancer is a major adverse outcome of solid organ transplantation (SOT), and prior donor and recipient cytomegalovirus (CMV) infections are common; however, associations of CMV with cancer risk among SOT recipients have been incompletely evaluated. In this analysis of 247,318 SOT recipients, an inverse association between risk of CMV infection and diffuse large B‐cell lymphoma was observed; however, CMV status was not associated with risk for most other cancers. [ABSTRACT FROM AUTHOR]

Validation of risk prediction models in independent data provides a more rigorous assessment of model performance than internal assessment, for example, done by cross-validation in the data used for model development. However, several differences between the populations that gave rise to the training and the validation data can lead to seemingly poor performance of a risk model. In this paper we formalize the notions of "similarity" or "relatedness" of the training and validation data, and define reproducibility and transportability. We address the impact of different distributions of model predictors and differences in verifying the disease status or outcome on measures of calibration, accuracy and discrimination of a model. When individual level information from both the training and validation data sets is available, we propose and study weighted versions of the validation metrics that adjust for differences in the risk factor distributions and in outcome verification between the training and validation data to provide a more comprehensive assessment of model performance. We provide conditions on the risk model and the populations that gave rise to the training and validation data that ensure a model's reproducibility or transportability, and show how to check these conditions using weighted and unweighted performance measures. We illustrate the method by developing and validating a model that predicts the risk of developing prostate cancer using data from two large prostate cancer screening trials. [ABSTRACT FROM AUTHOR]

Immunity may play a role in preventing cancer progression. We studied associations of immune‐related conditions with cancer‐specific mortality among older adults in the United States. We evaluated 1 229 443 patients diagnosed with 20 common cancer types (age 67‐99, years 1993‐2013) using Surveillance Epidemiology and End Results‐Medicare data. With Medicare claims, we ascertained immune‐related medical conditions diagnosed before cancer diagnosis (4 immunosuppressive conditions [n = 3380 affected cases], 32 autoimmune conditions [n = 155 766], 3 allergic conditions [n = 101 366]). For each cancer site, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cancer‐specific mortality associated with each condition, applying a Bonferroni cutoff for significance (P < 5.1 × 10−5). Bayesian metaanalysis methods were used to detect patterns across groups of conditions and cancers. We observed 21 associations with cancer‐specific mortality at the Bonferroni threshold. Increased cancer‐specific mortality was observed with rheumatoid arthritis for patients with melanoma (aHR 1.51, 95% CI 1.31‐1.75) and breast cancer (1.24, 1.15‐1.33)), and with hemolytic anemia for bladder cancer (2.54, 1.68‐3.82). Significant inverse associations with cancer‐specific mortality were observed for allergic rhinitis (range of aHRs: 0.84‐0.94) and asthma (0.83‐0.95) for cancers of the lung, breast, and prostate. Cancer‐specific mortality was nominally elevated in patients with immunosuppressive conditions for eight cancer types (aHR range: 1.27‐2.36; P‐value range: 7.5 × 10−5 to 3.1 × 10−2) and was strongly associated with grouped immunosuppressive conditions using Bayesian metaanalyses methods. For older patients with several cancer types, certain immunosuppressive and autoimmune conditions were associated with increased cancer‐specific mortality. In contrast, inverse associations with allergic conditions may reflect enhanced immune control of cancer. [ABSTRACT FROM AUTHOR]

Background: Solid organ transplant recipients have an elevated risk of cancer. Quantifying the life‐years lost (LYL) due to cancer provides a complementary view of the burden of cancer distinct from other metrics and may identify subgroups of transplant recipients who are most affected. Methods: Linked transplant and cancer registry data were used to identify incident cancers and deaths among solid organ transplant recipients in the United States (1987‐2014). Data on LYL due to cancer within 10 years posttransplant were derived using mean survival estimates from Cox models. Results: Among 221,962 transplant recipients, 13,074 (5.9%) developed cancer within 10 years of transplantation. During this period, the mean LYL due to cancer were 0.16 years per transplant recipient and 2.7 years per cancer case. Cancer was responsible for a loss of 1.9% of the total life‐years expected in the absence of cancer in this population. Lung recipients had the highest proportion of total LYL due to cancer (0.45%) followed by heart recipients (0.29%). LYL due to cancer increased with age, from 0.5% among those aged birth to 34 years at transplant to 3.2% among those aged 50 years and older. Among recipients overall, lung cancer was the largest contributor, accounting for 24% of all LYL due to cancer, and non‐Hodgkin lymphoma had the next highest contribution (15%). Conclusions: Transplant recipients have a shortened lifespan after developing cancer. Lung cancer and non‐Hodgkin lymphoma contribute strongly to LYL due to cancer within the first 10 years after transplant, highlighting opportunities to reduce cancer mortality through prevention and screening. Transplantation recipients have a shortened lifespan after developing cancer. Lung cancer and non‐Hodgkin lymphoma contribute strongly to life‐years lost due to cancer, highlighting opportunities to reduce cancer mortality in this population through prevention and screening. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME), including immune cells, cancer‐associated fibroblasts, endothelial cells, adjacent normal cells, and others, plays a crucial role in influencing tumor behavior and progression. Here, we characterized the TME in 83 primary renal tumors and matched metastatic or recurrence tissue samples (n = 15) from papillary renal cell carcinoma (pRCC) types 1 (n = 20) and 2 (n = 49), collecting duct carcinomas (CDC; n = 14), and high‐grade urothelial carcinomas (HGUC; n = 5). We investigated 10 different markers of immune infiltration, vasculature, cell proliferation, and epithelial‐to‐mesenchymal transition by using machine learning image analysis in conjunction with immunohistochemistry. Marker expression was compared by Mann–Whitney and Kruskal–Wallis tests and correlations across markers using Spearman's rank correlation coefficient. Multivariable Poisson regression analysis was used to compare marker expression between histological types, while accounting for variation in tissue size. Several immune markers showed different rates of expression across histological types of renal carcinoma. Using pRCC1 as reference, the incidence rate ratio (IRR) of CD3+ T cells (IRR [95% confidence interval, CI] = 2.48 [1.53–4.01]) and CD20+ B cells (IRR [95% CI] = 4.38 [1.22–5.58]) was statistically significantly higher in CDC. In contrast, CD68+ macrophages predominated in pRCC1 (IRR [95% CI] = 2.35 [1.42–3.9]). Spatial analysis revealed CD3+ T‐cell and CD20+ B‐cell expressions in CDC to be higher at the proximal (p < 0.0001) and distal (p < 0.0001) tumor periphery than within the central tumor core. In contrast, expression of CD68+ macrophages in pRCC2 was higher in the tumor center compared to the proximal (p = 0.0451) tumor periphery and pRCC1 showed a distance‐dependent reduction, from the central tumor, in CD68+ macrophages with the lowest expression of CD68 marker at the distal tumor periphery (p = 0.004). This study provides novel insights into the TME of rare kidney cancer types, which are often understudied. Our findings of differences in marker expression and localization by histological subtype could have implications for tumor progression and response to immunotherapies or other targeted therapies. [ABSTRACT FROM AUTHOR]

Typically, case-control studies to estimate odds-ratios associating risk factors with disease incidence only include newly diagnosed cases. Recently proposed methods allow incorporating information on prevalent cases, individuals who survived from disease diagnosis to sampling, into cross-sectionally sampled case-control studies under parametric assumptions for the survival time after diagnosis. Here we propose and study methods to additionally use prospectively observed survival times fromprevalent and incident cases to adjust logistic models for the time between diagnosis and sampling, the backward time, for prevalent cases. This adjustment yields unbiased odds-ratio estimates from case-control studies that include prevalent cases.We propose a computationally simple two-step generalized method-of-moments estimation procedure. First, we estimate the survival distribution assuming a semiparametric Cox model using an expectation-maximization algorithm that yields fully efficient estimates and accommodates left truncation for prevalent cases and right censoring. Then, we use the estimated survival distribution in an extension of the logistic model to three groups (controls, incident, and prevalent cases), to adjust for the survival bias in prevalent cases. In simulations, under modest amounts of censoring, odds-ratios from the two-step procedure were equally efficient as those estimated from a joint logistic and survival data likelihood under parametric assumptions. This indicates that utilizing the cases' prospective survival data lessens model dependencies and improves precision of association estimates for case-control studies with prevalent cases. We illustrate the methods by estimating associations between single nucleotide polymorphisms and breast cancer risk using controls, and incident and prevalent cases sampled from the US Radiologic Technologists Study cohort. [ABSTRACT FROM AUTHOR]

Epidemiologic studies conducted to quantify the impact of radiation dose d on an outcome typically model the hazard ratio (HR) for association using a linear term, HR(d)=1+βd, via a linear excess relative risk (ERR) model, based on biological considerations. To study associations of risk of a second cancer with radiation treatment for a first cancer, several nested case‐control designs to estimate β have been proposed that use refined doses received by different locations in the organ of interest. Here we first evaluated the small sample bias in maximum likelihood estimates of β for the linear ERR model using location‐specific radiation doses in simulations. As we found substantial upward bias for studies of realistic sample sizes (more than 50% relative bias for studies with 75 cases), we also proposed and investigated several approaches to correct this bias. We studied first and second order jackknife bias corrections and we derived a modified set of score functions under retrospective case‐control sampling, from which we directly obtained bias‐corrected estimates. In simulations based on doses from a study of stomach cancer among testicular cancer survivors and synthetically generated data, neither the first nor second order jackknife bias correction performed well. Estimates based on the modified score equations corrected the bias much better, albeit not completely, and were numerically much more stable. [ABSTRACT FROM AUTHOR]

Summary: Background: Clinical and experimental studies suggest immunologic proteins contribute to hepatocellular carcinoma (HCC) development. Aim: To evaluate circulating immunologic markers and HCC risk. Methods: From a Taiwanese cohort of chronically hepatitis B virus (HBV)‐infected individuals followed over time (REVEAL‐HBV), we sampled 175 who developed HCC, 117 cirrhosis only, and 165 non‐cirrhotic controls. From a similar Taiwanese cohort of chronically hepatitis C virus (HCV)‐infected individuals (REVEAL‐HCV), we included 94 individuals who developed HCC, 68 cirrhosis only and 100 non‐cirrhotic controls. We compared pre‐diagnostic plasma levels of 102 markers in HCC cases to non‐cirrhotic and cirrhotic controls using polytomous logistic regression. A priori markers included insulin‐like growth factor binding protein‐3 (IGFBP‐3), intercellular adhesion molecule 1 (ICAM‐1) and interleukin 6 (IL‐6). P‐values for other markers were corrected for multiple testing (false discovery rate = 10%). Results: In both REVEAL‐HBV and REVEAL‐HCV, increasing levels of ICAM‐1 were associated with increased risk of HCC compared to non‐cirrhotic controls (P‐trend 0.02 and 0.001, respectively). In both REVEAL‐HBV and REVEAL‐HCV, two novel markers [C‐X‐C motif chemokine 11 (CXCL11) and hepatocyte growth factor (HGF)] were positively associated [strongest odds ratioquartile 4 versus 1 (OR) 4.55 for HGF in HCV], while two [complement factor H related 5 (CFHR5) and stem cell factor (SCF)] were negatively associated (strongest ORQ4vQ1 0.14 for SCF in HCV) with development of HCC compared to non‐cirrhotic controls. Conclusions: We confirmed the association for ICAM‐1 and identified 4 additional proteins associated with HBV‐ and HCV‐related HCC. These findings highlight the importance of immunologic processes in HBV‐ and HCV‐related HCC. [ABSTRACT FROM AUTHOR]

Background: Although stratifying individuals with respect to nasopharyngeal carcinoma (NPC) risk with Epstein-Barr virus-based markers is possible, the performance of diagnostic methods for detecting lesions among screen-positive individuals is poorly understood.Methods: The authors prospectively evaluated 882 participants aged 30 to 70 years who were enrolled between October 2014 and November 2018 in an ongoing, population-based NPC screening program and had an elevated NPC risk. Participants were offered endoscopy and magnetic resonance imaging (MRI), and lesions were identified either by biopsy at a follow-up endoscopy or further contact and linkage to the local cancer registry through December 31, 2019. The diagnostic performance characteristics of endoscopy and MRI for NPC detection were investigated.Results: Eighteen of 28 identified NPC cases were detected by both methods, 1 was detected by endoscopy alone, and 9 were detected by MRI alone. MRI had significantly higher sensitivity than endoscopy for NPC detection overall (96.4% vs 67.9%; Pdifference = .021) and for early-stage NPC (95.2% vs 57.1%; P = .021). The sensitivity of endoscopy was suggestively lower among participants who had previously been screened in comparison with those undergoing an initial screening (50.0% vs 81.2%; P = .11). The authors observed a higher overall referral rate by MRI versus endoscopy (17.3% vs 9.1%; P < .001). Cases missed by endoscopy had early-stage disease and were more commonly observed for tumors originating from the pharyngeal recess.Conclusions: MRI was more sensitive than endoscopy for NPC detection in the context of population screening but required the referral of a higher proportion of screen-positive individuals. The sensitivity of endoscopy was particularly low for individuals who had previously been screened. [ABSTRACT FROM AUTHOR]

Despite evidence suggesting the utility of Epstein-Barr virus (EBV) markers to stratify individuals with respect to nasopharyngeal carcinoma (NPC) risk in NPC high-risk regions, no validated NPC risk prediction model exists. We aimed to validate an EBVbased NPC risk score in an endemic population undergoing screening for NPC. This prospective study was embedded within an ongoing NPC screening trial in southern China initiated in 2008, with 51 235 adult participants. We assessed the score's discriminatory ability (area under the receiver-operator-characteristics curve, AUC). A new model incorporating the EBV score, sex and family history was developed using logistic regression and internally validated using cross-validation. AUCs were compared. We also calculated absolute NPC risk combining the risk score with population incidence and competing mortality data. A total of 151 NPC cases were detected in 2008 to 2016. The EBV-based score was highly discriminating, with AUC = 0.95 (95% CI = 0.93-0.97). For 90% specificity, the score had 87.4% sensitivity (95% CI = 81.0-92.3%). As specificity increased from 90% to 99%, the positive predictive value increased from 2.4% (95% CI = 1.9-3.0%) to 12.5% (9.9-15.5%). Correspondingly, the number of positive tests per detected NPC case decreased from 272 (95% CI = 255-290) to 50 (41-59). Combining the score with other risk factors (sex, firstdegree family history of NPC) did not improve AUC. Men aged 55 to 59 years with the highest risk profile had the highest 5-year absolute NPC risk of 6.5%. We externally validated the discriminatory accuracy of a previously developed EBV score in a high-risk population. Adding nonviral risk factors did not improve NPC prediction [ABSTRACT FROM AUTHOR]

Background: Despite the high incidence and mortality of prostate cancer (PCa) in the Unites States, few risk factors have been consistently linked with these PCa outcomes. Assessing proxies of reproductive factors may offer insights into PCa pathogenesis. In this study, we examined fatherhood status as a proxy of fertility in relation to total, nonaggressive, aggressive, and fatal PCa. Methods: We examined participants of two cohorts, the NIH‐AARP Diet and Health (NIH‐AARP) Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals of associations between fatherhood status and number of children sired in relation to PCa incidence. Results: Fatherhood status (one or more children vs. childless) was positively associated with total PCa risk in NIH‐AARP or PLCO, but was not statistically significant (p = 0.06 and 0.55, respectively). Number of children sired indicated a slightly elevated risk of total PCa, but HRs were rarely significant and were of a fairly constant magnitude with no discernable trend relative to the childless referent group. Associations were similar for nonaggressive and aggressive PCa. The trend test for fatal PCa was statistically significant in NIH‐AARP (ptrend < 0.01), despite none of the individual categorical point estimates reaching this threshold. Conclusion: This study provides tentative evidence that fathering children is associated with a slightly increased PCa risk. Future research should strive to assess better proxies of reproductive function in relation to aggressive and fatal PCa to provide more specific evidence for this putative relationship. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the dominant histologic type of liver cancer, accounting for 75% of cases. Growing evidence suggests that the cross‐talk between the gut microbiome and metabolome (ie, gut‐liver axis) are related to the development of hepatic inflammation, and ultimately, HCC. Bile acids are metabolites, derived from cholesterol and synthesized in the liver, which may have a critical role in regulation of the gut‐liver axis. We investigated whether prediagnostic circulating bile acids were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)‐Hepatitis B Virus (HBV) and REVEAL‐Hepatitis C Virus (HCV) cohorts from Taiwan. Fifteen bile acids were quantitated using liquid chromatography, from 185 cases and 161 matched controls in REVEAL‐HBV and 96 cases and 96 matched controls in REVEAL‐HCV. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between bile acid levels and HCC were calculated using multivariable‐adjusted logistic regression. Higher levels of glycine and taurine conjugated primary bile acids were associated with a 2‐ to 8‐fold increased risk of HBV‐ (eg, glycocholic acid ORQ4vsQ1 = 3.38, 95% CI: 1.48‐7.71, Ptrend <.003) and HCV‐related HCC (eg, OR = 8.16, 95% CI: 2.21‐30.18, Ptrend <.001). However, higher levels of the secondary bile acid deoxycholic acid were inversely associated with HBV‐related HCC risk (OR = 0.41, 95% CI: 0.19‐0.88, Ptrend =.02). Our study provides evidence that higher concentrations of bile acids—specifically, conjugated primary bile acids—are associated with increased HCC risk. However, our study does not support the hypothesis that higher levels of secondary bile acids increase liver cancer risk; indeed, deoxycholic acid may be associated with a decreased HCC risk. What's new? The bacteria in the gut convert bile acids into secondary bile acids. In rodents, these acids increase the risk of hepatocellular carcinoma (HCC). In this study, however, the authors found that the same does not apply to humans. Instead, primary bile acids are associated with an increased risk, at least in patients with hepatitis B or C viral infection. Secondary bile acids, such as deoxycholic acid, may even decrease HCC risk. The human microbiome is intricately linked with hepatic metabolic processes, known as the gut‐liver axis, and the present study highlights the need to examine this cross‐talk between the microbiome and metabolome. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy type I (DM1) is an autosomal dominant multisystem disorder characterized by myotonia and muscle weakness. Type 2 diabetes (T2D) and cancer have been shown to be part of the DM1 phenotype. Metformin, a well‐established agent for the management of T2D, is thought to have cancer‐preventive effects in the general population. In our study, we aimed to assess the association between T2D, metformin use and the risk of cancer in DM1 patients. We identified a cohort of 913 DM1 patients and an age‐, sex‐ and clinic‐matched cohort of 12,318 DM1‐free controls from the UK Clinical Practice Research Datalink, a large primary care records database. We used Cox regression models to assess cancer risk in T2D patients who were metformin users or nonusers compared to patients without T2D. Separate analyses were conducted for DM1 patients and controls. T2D was more prevalent in DM1 than in controls (8% vs. 3%, p < 0.0001). DM1 patients with T2D, compared to those without T2D, were more likely to develop cancer (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 1.18–10.97; p = 0.02), but not if they were treated with metformin (HR = 0.43, 95% CI = 0.06–3.35; p = 0.42). Among controls, we observed no significant associations between T2D and cancer risk in either users or nonusers of Metformin (HR = 1.28, 95% CI = 0.91–1.79; p = 0.16 and HR = 1.13, 95% CI = 0.72–1.79; p = 0.59, respectively). These results show an association between T2D and cancer risk in DM1 patients and may provide new insights into the possible benefits of Metformin use in DM1. What's new? Recent evidence suggests that myotonic dystrophy type I (DM1), an inherited nucleotide repeat disorder, is a cancer predisposition syndrome. However, the underlying pathological mechanisms and cancer‐predisposing risk factors remain unknown. Here, type 2 diabetes (T2D) and metformin were investigated for potential associations with cancer risk in DM1 patients. T2D was found to be more prevalent in DM1 patients than controls. DM1 patients with T2D were at increased risk of developing cancer. By contrast, cancer risk was not elevated in DM1‐T2D patients taking metformin. Further investigation of metformin use and cancer in DM1 patients could yield important insights into DM1‐related cancer prevention. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is the predominant histologic subtype of esophageal cancer worldwide. Measurements of circulating inflammation‐related biomarkers may inform etiology or provide noninvasive signatures for early diagnosis. We therefore examined levels of inflammation molecules for associations with ESCC risk. Using a case–cohort study designed within the Japan Public Health Center‐based Prospective Study, we measured baseline plasma levels of 92 biomarkers using a multiplex assay in a subcohort of 410 randomly selected participants and 66 participants with incident ESCC (including four cases that occurred in the subcohort). ESCC hazard ratios (HRs) were calculated for 2–4 quantiles of each biomarker by Cox proportional hazards regression models with age as the time metric, adjusted for sex, smoking and alcohol use. Twenty analytes were undetectable in nearly all samples. Of the remaining 72, 12 biomarkers (FGF19, ST1A1, STAMBP, AXIN1, CASP8, NT3, CD6, CDCP1, CD5, SLAMF1, OPG and CSF1) were associated with increased ESCC risk (ptrend < 0.05) with HRs per quantile 1.28–1.65. Seven biomarkers (CXCL6, CCL23, CXCL5, TGFA, CXCL1, OSM and CCL4) were inversely associated with HRs 0.57–0.72. FGF19, CASP8, STAMBP, ST1A1 and CCL‐4 met statistical significance with false discovery rate correction. Associations did not differ <5 vs. ≥5 years between blood collection and ESCC diagnosis. CASP8, STAMBP and ST1A1 were strongly correlated (p < 0.05). Our study expands the range of inflammation molecules associated with the development of this highly lethal neoplasia. Correlations among these novel biomarkers suggest a possible shared pathway. These findings need replication and could further delineate ESCCs molecular mechanisms of carcinogenesis. What's new?: Chronic inflammation has long been considered an important contributor to carcinogenesis. Circulating levels of inflammation‐related biomarkers may thus provide valuable information regarding cancer etiology, and may eventually aid in the early diagnosis of some cancers. In this study, the authors identified five such proteins that are associated with esophageal squamous cell carcinoma (ESCC) risk. These biomarkers may improve our understanding of ESCC etiology, enhance non‐invasive, molecular diagnostic panels, and may provide potential therapeutic targets. [ABSTRACT FROM AUTHOR]

The humoral immune response to Epstein–Barr virus (EBV) in classical Hodgkin lymphoma (cHL) stratified by EBV tumor status is unclear. We examined IgG and IgA antibody responses against 202 protein sequences representing 86 EBV proteins using a microarray and sera from 139 EBV‐positive cHL cases, 70 EBV‐negative cHL cases and 141 population‐based controls frequency matched to EBV‐positive cHL cases on sex and age by area (UK, Denmark and Sweden). We leveraged existing data on the proportion of circulating B‐cells infected by EBV and levels of serum CCL17, a chemokine secreted by cHL tumor cells, from a subset of the cHL cases in the UK. Total IgG but not IgA response level was significantly different between EBV‐positive cHL cases and controls. The distinct serological response included significant elevations in 16 IgG antibodies and 2 IgA antibodies, with odds ratioshighest vs. lowest tertile > 3 observed for the following EBV proteins: LMP1 (oncogene), BcLF1 (VCAp160, two variants) and BBLF1 (two variants). Our cHL IgG signature correlated with the proportion of circulating EBV‐infected B‐cells, but not serum CCL17 levels. We observed no differences in the anti‐EBV antibody profile between EBV‐negative cHL cases and controls. BdRF1(VCAp40)‐IgG and BZLF1(Zta)‐IgG were identified as the serological markers best able to distinguish EBV‐positive from EBV‐negative cHL tumors. Our results support the hypothesis that differences in the EBV antibody profile are specific to patients with EBV‐positive cHL and are not universally observed as part of a systematically dysregulated immune response present in all cHL cases. What's new? Previous studies of Epstein–Barr virus in classical Hodgkin lymphoma (cHL) have been limited to only a few antibodies or protein complexes. In this study, the authors used a new protein microarray technology to measure both IgG and IgA antibody responses against far more EBV proteins. They found systemic differences in the EBV antibody profile in cHL cases, which are both specific to EBV‐positive tumors, and include immune aberrations that reflect exposure to multiple stages of the viral life cycle. Evidence of increased, systemic exposure to EBV lytic‐cycle activity supports a role for ongoing viral activity in tumor pathogenesis. [ABSTRACT FROM AUTHOR]

The decision curve plots the net benefit (NB) of a risk model for making decisions over a range of risk thresholds, corresponding to different ratios of misclassification costs. We discuss three methods to estimate the decision curve, together with corresponding methods of inference and methods to compare two risk models at a given risk threshold. One method uses risks (R) and a binary event indicator (Y) on the entire validation cohort. This method makes no assumptions on how well‐calibrated the risk model is nor on the incidence of disease in the population and is comparatively robust to model miscalibration. If one assumes that the model is well‐calibrated, one can compute a much more precise estimate of NB based on risks R alone. However, if the risk model is miscalibrated, serious bias can result. Case–control data can also be used to estimate NB if the incidence (or prevalence) of the event (Y=1) is known. This strategy has comparable efficiency to using the full (R,Y) data, and its efficiency is only modestly less than that for the full (R,Y) data if the incidence is estimated from the mean of Y. We estimate variances using influence functions and propose a bootstrap procedure to obtain simultaneous confidence bands around the decision curve for a range of thresholds. The influence function approach to estimate variances can also be applied to cohorts derived from complex survey samples instead of simple random samples. [ABSTRACT FROM AUTHOR]

Summary: Primary central nervous system lymphoma (PCNSL) risk is highly increased in immunosuppressed individuals, such as those with human immunodeficiency virus infection and solid organ transplant recipients, but rates are increasing among immunocompetent older adults (age ≥65 years). We utilized data from a large, nationally‐representative cohort of older adults in the United States and found that PCNSL is significantly associated with systemic lupus erythematosus, polyarteritis nodusa, autoimmune hepatitis, myasthenia gravis and uveitis. Immunosuppressive drugs given to treat these conditions may increase PCNSL risk, but these associations cannot explain the observed temporal increase in PCNSL rates, given the low prevalence of these conditions. [ABSTRACT FROM AUTHOR]

Our knowledge of epidemiologic risk factors for ovarian cancer supports a role for androgens in the pathogenesis of this disease; however, few studies have examined associations between circulating androgens and ovarian cancer risk. Using highly sensitive LC–MS/MS assays, we evaluated associations between pre‐diagnostic serum levels of 12 androgens, including novel androgen metabolites that reflect androgen activity in tissues, and ovarian cancer risk among postmenopausal women in a nested case–control study in the Women's Health Initiative (WHI) Observational Study (OS). We frequency‐matched 169 ovarian cancer cases to 410 controls from women enrolled in WHI‐OS who were not using menopausal hormones at enrollment/blood draw. We estimated associations overall and by subtype (n = 102 serous/67 non‐serous) using multivariable adjusted logistic regression. Androgen/androgen metabolite levels were not associated with overall ovarian cancer risk. In analyses by subtype, women with increased levels of androsterone‐glucuronide (ADT‐G) and total 5‐α reduced glucuronide metabolites (markers of tissue‐level androgenic activity) were at increased risk of developing non‐serous ovarian cancer: ADT‐G tertile (T)3 versus T1 odds ratio [OR] (95% confidence interval [CI]) 4.36 (1.68–11.32), p‐heterogeneity 0.002; total glucuronide metabolites 3.63 (1.47–8.95), 0.002. Risk of developing serous tumors was unrelated to these markers. ADT‐G and total glucuronide metabolites, better markers of tissue‐level androgenic activity in women than testosterone, were associated with an increased risk of developing non‐serous ovarian cancer. Our work demonstrates that sex steroid metabolism is important in the etiology of non‐serous ovarian cancers and supports a heterogeneous hormonal etiology across histologic subtypes of ovarian cancer. What's new?: Sex steroids play a role in ovarian carcinogenesis but associations between circulating androgen levels and ovarian cancer risk are inconsistent. Using mass spectrometry, the authors focused on 5α‐reduced androgen metabolites that cannot be metabolized into estrogen and therefore better reflect androgenic activity in tissues. They found androsterone‐glucuronide levels associated with increased risk of non‐serous tumors, the less frequent cancer form, pointing to unique subtype‐specific influences of androgens in ovarian malignancies. [ABSTRACT FROM AUTHOR]

Background: Solid organ transplant recipients have an elevated risk of cancer. Quantifying deaths attributable to cancer can inform priorities to reduce cancer burden.Methods: Linked transplantation and cancer registry data were used to identify incident cancers and deaths among solid organ transplant recipients in the United States (1987-2014). Population-attributable fractions (PAFs) of deaths due to cancer and corresponding cancer-attributable mortality rates were estimated using Cox models.Results: Among 221,962 solid organ transplant recipients, 15,012 developed cancer. Approximately 13% of deaths (PAF, 13.2%) were attributable to cancer, corresponding to a cancer-attributable mortality rate of 516 per 100,000 person-years. Lung cancer was the largest contributor to mortality (PAF, 3.1%), followed by non-Hodgkin lymphoma (NHL; PAF, 1.9%), colorectal cancer (PAF, 0.7%), and kidney cancer (PAF, 0.5%). Cancer-attributable mortality rates increased with age at transplantation, reaching 1229 per 100,000 person-years among recipients aged ≥65 years. NHL was the largest contributor among children (PAF, 4.1%) and lung cancer was the largest contributor among recipients aged ≥50 years (PAFs, 3.7%-4.3%). Heart recipients had the highest PAF (16.4%), but lung recipients had the highest cancer-attributable mortality rate (1241 per 100,000 person-years). Overall, mortality attributable to cancer increased steadily with longer time since transplantation, reaching 15.7% of deaths (810 per 100,000 person-years) at ≥10 years after transplantation. Comparison of cancer-attributable mortality rates with specified causes of death indicated that some deaths recorded as other causes might instead be caused by cancer or its treatment.Conclusions: Cancer is a substantial cause of mortality among solid organ transplant recipients, with major contributions reported from lung cancer and NHL. Cancer-attributable mortality increases with age and time since transplantation, and therefore cancer deaths will become an increasing burden as recipients live longer. [ABSTRACT FROM AUTHOR]

Background: In the United States, incidence and mortality rates of hepatocellular carcinoma (HCC) are increasing in older individuals. Chronic infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) are important causes of HCC; however, the contribution of viral hepatitis to recent trends in HCC incidence among older Americans is unclear.Methods: Data from the Surveillance, Epidemiology, and End Results-Medicare linkage (SEER-Medicare) for the years 2001 through 2013 were used to identify HCC cases among individuals aged ≥66 years and Medicare files were used to assess the HCV and HBV status of these HCC cases. Age-standardized incidence rates of HCV-attributable, HBV-attributable, and HCV/HBV-unrelated HCC were estimated overall and by age group, sex, and race/ethnicity. The authors also calculated annual percent changes (APCs) in HCC incidence.Results: Between 2001 and 2013, a total of 15,300 HCC cases occurred in this population. Overall HCC rates increased 43% from 16.3 to 23.3 per 100,000 population (APC, 3.40% per year), whereas HCV-attributable HCC rates nearly doubled from 4.2 to 8.2 per 100,000 population (APC, 5.62% per year). HCC rates increased more slowly for HBV-attributable HCC (1.3 to 1.8 per 100,000 population; APC, 3.17% per year) and HCV/HBV-unrelated HCC (11.3 to 14.1 per 100,000 population; APC, 2.35% per year). The percentage of HCC cases with evidence of HCV infection increased from 25.7% in 2001 through 2004 to 32.3% in 2011 through 2013, whereas the percentage with HBV remained stable at 8%. In 2013, higher rates for both HCV-attributable and HBV-attributable HCC were noted among individuals aged 66 to 75 years, men, and individuals of Asian ancestry.Conclusions: Among Americans aged ≥66 years, HCC rates increased rapidly between 2001 and 2013. Although HCV-attributable cases contributed substantially to this increase, rates of HBV-attributable and HCV/HBV-unrelated HCC also rose during this period. [ABSTRACT FROM AUTHOR]

Objectives: Recent evidence showed that myotonic dystrophy type I (DM1) patients are at increased risk of certain cancers, but the risk of benign tumors is unknown. We compared the risk of benign tumors in DM1 patients with matched DM1‐free individuals and assessed the association between benign tumors and subsequent cancers. Methods: We identified 927 DM1 patients and 13,085 DM1‐free individuals matched on gender, birth‐year, clinic, and clinic‐registration year from the UK Clinical Practice Research Datalink, a primary care records database. We used Cox regression models for statistical analyses. Results: DM1 patients had elevated risks of thyroid nodules (Hazard Ratio [HR] = 10.4; 95% Confidence Interval [CI] = 3.91–27.52; P < 0.001), benign tumors of the brain or nervous system (HR = 8.4; 95% CI = 2.48–28.47; P < 0.001), colorectal polyps (HR = 4.3; 95% CI = 1.76–10.41; P = 0.001), and possibly uterine fibroids (HR = 2.7; 95% CI = 1.22–5.88; P = 0.01). Pilomatricomas and salivary gland adenomas occurred almost exclusively in DM1 patients (Fisher's exact P < 0.001). The HR for colorectal polyps was elevated in DM1 males but not in females (HR = 8.2 vs. 1.3, respectively; P‐heterogeneity < 0.001), whereas endocrine and brain tumors occurred exclusively in females. The data suggested an association between benign tumors and subsequent cancer in classic DM1 patients (HR = 2.7; 95% CI = 0.93–7.59; P = 0.07). Interpretation: Our study showed a similar site‐specific benign tumor profile to that previously reported for DM1‐associated cancers. The possible association between benign tumors and subsequent cancer in classic DM1 patients warrants further investigation as it may guide identifying patients at elevated risk of cancer. Our findings underscore the importance of following population‐based screening recommendations in DM1 patients, for example, for colorectal cancer. [ABSTRACT FROM AUTHOR]

Extensive mammographic density (MD), a well‐established breast cancer risk factor, is a radiological representation of stromal and epithelial breast tissue content. In studies conducted predominantly among Caucasian women, histologic measures of reduced terminal duct lobular unit (TDLU) involution have been correlated with extensive MD, but independently associated with breast cancer risk. We therefore examined associations between TDLU measures and MD among Chinese women, a low‐risk population but with high prevalence of dense breasts. Diagnostic pre‐treatment digital mammograms were obtained from 144 breast cancer cases at a tertiary hospital in Beijing and scored using the Breast Imaging Reporting and Data System (BI‐RADS) density classification. TDLU features were assessed using three standardized measures (count/100 mm2, span [μm], and acini count/TDLU) in benign tissues. Associations between each of TDLU measures and MD were examined using generalized linear models for TDLU count and span and polytomous logistic regression for acini count with adjustment for potential confounders stratified by age. Among women ≥50 years, 63% had dense breasts; cases with dense breasts (BI‐RADS, c‐d) had greater TDLU count (21.1 [SE = 2.70] vs. 9.0 [SE = 1.83]; p = 0.0004), longer span (480.6 μm [SE = 24.6] vs. 393.8 μm [SE = 31.8]; p = 0.03), and greater acini count (ORtrend = 16.1; 95%CI = 4.08–63.1; ptrend < 0.0001) compared to those with non‐dense breasts (BI‐RADS, a‐b). Among women <50 years, 91% had dense breasts, precluding our ability to detect associations. Our findings are consistent with previously reported associations between extensive MD and reduced TDLU involution, supporting the hypothesis that breast cancer risk associated with extensive MD may be related to the amount of "at‐risk" epithelium. What's new? Women with extensively dense breasts carry a heightened cancer risk, a finding well established in the Caucasian population. Here, the authors confirmed this finding in Chinese women by examining the involution of the aging breast, specifically of the terminal duct lobular unit, in relationship to the mammographic density. This extension to an Asian population underscores the model that a higher amount of "at‐risk" epithelium due to reduced involution link extensive breast density with breast cancer risk. [ABSTRACT FROM AUTHOR]

Summary: Hepatocellular carcinoma (HCC) incidence is high in The Gambia, and hepatitis B virus (HBV) infection is the main cause. People coinfected with HBV and hepatitis D virus (HDV) have an even greater risk of HCC and cirrhosis. Using a new HDV quantitative microarray antibody capture (Q‐MAC) assay, we evaluated the association between HDV infection and HCC or cirrhosis among participants in The Gambia Liver Cancer Study. In this case‐control study, cases had HCC (n = 312) or cirrhosis (n = 119). Controls (n = 470) had no clinical evidence of liver disease and normal serum alpha‐foetoprotein. Participants were previously tested for hepatitis B surface antigen (HBsAg); we tested HBsAg+ specimens by HDV Q‐MAC, western blot and RNA assays. We evaluated separate cut‐offs of the Q‐MAC assay for predicting anti‐HDV and RNA positivity. Q‐MAC correctly identified 29/29 subjects who were western blot‐positive (sensitivity = 100%, specificity = 99.4%) and 16/17 who were RNA‐positive (sensitivity = 94.1%, specificity = 100%). Compared to controls, cases more often had HBV monoinfection (HBsAg+/HDV RNA−; 54.1% vs 17.0%; odds ratio [OR] = 6.28; P < 0.001) or HBV‐HDV coinfection (HBsAg+/HDV RNA+; 3.9% vs 0%; P < 0.001). Risk estimates (for HCC or cirrhosis) based on HDV antibody status and adjusted for covariates (demographics, alcohol, smoking, body mass index, anti‐HCV and aflatoxin B1 exposure) yielded consistent results for both HBV monoinfection (adjusted OR = 8.29; 95% confidence interval = 5.74‐11.98) and HBV‐HDV coinfection (adjusted OR = 30.66; 95% confidence interval = 6.97‐134.95). In this Gambian population, HDV Q‐MAC had high sensitivity and specificity for both anti‐HDV and HDV RNA. HDV infection contributed to the high risk of HCC in The Gambia. [ABSTRACT FROM AUTHOR]

Background: Biliary tract cancers (BTCs) are rare but deadly cancers (gallbladder cancer [GBC], intrahepatic cholangiocarcinoma [ICC], extrahepatic cholangiocarcinoma [ECC], and ampulla of Vater cancer [AVC]). A recent US study reported increasing GBC incidence among people younger than 45 years and blacks; however, it did not examine trends for other biliary tract sites. Methods: This study characterized demographic differences in BTC incidence rates and time trends by anatomic site. Population‐based North American Association of Central Cancer Registries data were used to calculate age‐adjusted incidence rates, incidence rate ratios (IRRs), and estimated annual percent changes (eAPCs) for 1999‐2013 by site and demographic group. For sites with significant differences in eAPC by age group, IRRs were compared by age group. Results: GBC incidence rates declined among women (eAPC, –0.5%/y; P = .01) and all racial/ethnic groups except for non‐Hispanic blacks, among whom rates increased (1.8%/y; P < .0001). Although GBC rates increased among 18‐ to 44‐year‐olds (eAPC, 1.8%/y; P = .01), they decreased among people 45 years old or older (–0.4%/y; P = .009). Sex (P < .0001) and racial/ethnic differences (P = .003 to.02) in GBC incidence were larger for younger people than older people. During this period, ICC (eAPC, 3.2%/y; P < .0001) and ECC rates (1.8%/y; P = .001) steadily increased across sex and racial/ethnic groups. Although AVC incidence rates increased among younger adults (eAPC, 1.8%/y; P = .03) but not older adults (–0.20%/y; P = .30), sex and racial/ethnic IRRs did not differ by age. Conclusions: Differential patterns of BTC rates and temporal trends have been identified by anatomic site and demographic groups. These findings highlight the need for large pooling projects to evaluate BTC risk factors by anatomic site. Significant and novel variations in biliary tract cancer incidence rates and trends are identified across anatomic sites by demographic group among adults in the United States between 1999 and 2013. Differences in sex‐ and race/ethnicity‐specific gallbladder cancer incidence rate ratios are larger among younger adults than older adults, and this may reflect underlying differences in the prevalence of and trends in risk factors by demographic group. [ABSTRACT FROM AUTHOR]

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2‐pathway rather than the competing 16‐pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty‐four women in a WHIOS case–control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2‐, 4‐, or 16‐pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2‐methoxyestrone, 4‐methoxyestrone and unconjugated estriol). The relative concentrations of 2‐ and 4‐pathway EM did not differ between the MHT users (2‐pathway EM comprised 15% and 4‐pathway EM <2% of the total), but 16‐pathway EM were lower in E alone users (p = 0.036). Ratios of 2‐ and 4‐pathway EM compared to 16‐pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE‐alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2‐ vs. the competing 16‐pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI. What's new? The Women's Health Initiative discovered that women taking conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) together increased their risk of breast cancer, but surprisingly, taking CEE alone reduced the risk of cancer. Here, the authors investigate the mechanism involved. To trace the pathway of CEE metabolism, they measured 15 different estrogen metabolites, using serum from women in the WHI Observational Study. In women taking estrogen alone, they found more activity in the "2‐pathway" over the "16‐pathway" of estrogen metabolism, which leads to reduced cancer risk. Those taking estrogen and progestin together showed more activity in the "16‐pathway," associated with higher cancer risk. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that people with autoimmune conditions may be at increased risk of hepatobiliary tumors. In the present study, we evaluated associations between autoimmune conditions and hepatobiliary cancers among adults aged ≥66 in the United States. We used Surveillance, Epidemiology, and End Results (SEER)‐Medicare data (1992–2013) to conduct a population‐based, case–control study. Cases (n = 32,443) had primary hepatobiliary cancer. Controls (n = 200,000) were randomly selected, cancer‐free adults frequency‐matched to cases by sex, age and year of selection. Using multivariable logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations with 39 autoimmune conditions identified via Medicare claims. We also conducted separate analyses for diagnoses obtained via inpatient versus outpatient claims. Sixteen conditions were associated with at least one hepatobiliary cancer. The strongest risk estimates were for primary biliary cholangitis with hepatocellular carcinoma (OR: 31.33 [95% CI: 23.63–41.56]) and primary sclerosing cholangitis with intrahepatic cholangiocarcinoma (7.53 [5.73–10.57]), extrahepatic cholangiocarcinoma (5.59 [4.03–7.75]), gallbladder cancer (2.06 [1.27–3.33]) and ampulla of Vater cancer (6.29 [4.29–9.22]). Associations with hepatobiliary‐related conditions as a group were observed across nearly all cancer sites (ORs ranging from 4.53 [95% CI: 3.30–6.21] for extrahepatic cholangiocarcinoma to 7.18 [5.94–8.67] for hepatocellular carcinoma). Restricting to autoimmune conditions diagnosed via inpatient claims, 6 conditions remained associated with at least one hepatobiliary cancer, and several risk estimates increased. In the outpatient restricted analysis, 12 conditions remained associated. Multiple autoimmune conditions are associated with hepatobiliary cancer risk in the US Medicare population, supporting a shared immuno‐inflammatory etiology to these cancers. What's new? Growing evidence suggests that people with autoimmune conditions may be at increased risk of hepatobiliary tumors. This large, longitudinal study investigated associations between hepatobiliary cancers and 39 autoimmune conditions. There was a 1.1‐ to 31.3‐fold increased risk of hepatobiliary cancer after diagnosis of a range of different autoimmune diseases, and novel associations were observed. The magnitude of associations was particularly strong for primary biliary cholangitis, primary sclerosing cholangitis, pure red cell aplasia and immune thrombocytopenic purpura. Findings support an immuno‐inflammatory etiology. Further research is needed to assess the need for additional cancer monitoring in individuals with certain autoimmune conditions. [ABSTRACT FROM AUTHOR]

Blood levels of inflammation‐related markers may reveal molecular pathways contributing to carcinogenesis. To date, prospective associations with colorectal cancer (CRC) risk have been based on few studies with limited sets of analytes. We conducted a case‐cohort study within the Japan Public Health Center‐based Prospective Study Cohort II, comparing 457 incident CRC cases during median 18 years follow‐up with a random subcohort of 774 individuals. Baseline plasma levels of 62 cytokines, soluble receptors, acute‐phase proteins, and growth factor markers were measured using Luminex bead‐based assays. We estimated hazard ratios (HRs) associating each marker with CRC risk by Cox proportional hazards models adjusted for potential confounders. Subanalyses compared cases by years after blood draw (<5 vs. ≥5) and anatomical subsite (colon vs. rectum). Linear trends in quantiles of four C‐C motif ligand (CCL) chemokines, one C‐X‐C motif ligand (CXCL) chemokine, and a soluble receptor were nominally associated with CRC risk based on ptrend < 0.05, but none met false discovery rate corrected statistical significance. HRs for the 4th vs. 1st quartile were: 1.69 for CCL2/MCP1, 1.61 for soluble tumor necrosis factor receptor 2, 1.39 for CCL15/MIP1D, 1.35 for CCL27/CTACK, 0.70 for CXCL6/GCP2 and 0.61 for CCL3/MIP1A. Among cases diagnosed 5+ years after enrollment, CCL2/MCP1, CCL3/MIP1A and CXCL6/GCP2 retained nominal statistical significance. There were no significant differences in associations between colon and rectum. Our findings implicate chemokine alterations in colorectal carcinogenesis, but require replication for confirmation. Noninvasive chemokine assays may have potential application in colorectal cancer screening and etiologic research. What's new? Chronic inflammatory bowel diseases are known risk factors for colorectal cancer (CRC) but few prospective studies with limited sets of markers have investigated the association of circulating inflammatory markers and CRC risk. Here the authors performed a comprehensive analysis of 62 circulating markers and identified five chemokines associated with CRC risk. No differences between colon and rectum cancers were observed suggesting that tests for these chemokines may be useful screening tools for both colon and rectal cancers. [ABSTRACT FROM AUTHOR]

Due to treatment with immunosuppressive medications, solid organ transplant recipients have elevated risk for Kaposi sarcoma (KS), which is caused by human herpesvirus 8 (HHV8). Other risk factors for KS are poorly understood. We linked the United States solid organ transplant registry with 17 population‐based cancer registries to ascertain KS incidence among 244,964 transplant recipients from 1987–2014. To compare incidence rates of KS according to patient and transplant characteristics, we calculated incidence rate ratios (IRRs) using Poisson regression. To compare associations of KS with other skin cancers occurring before or within 12 months of KS diagnosis, we computed odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. All statistical tests were two‐sided. We identified 163 KS cases during follow‐up. Among transplant recipients, we found significantly increased risk of KS associated with male sex (IRR = 1.87; 95%CI:1.32,2.71), nonwhite race (IRR = 2.67; 95%CI:1.92,3.72), non‐US citizenship (IRR = 2.10; 95%CI:1.19,3.47), lung transplant (IRR = 2.22; 95%CI:1.03,4.24, vs. kidney), and older age at transplant. KS risk decreased significantly with time since transplant and recent calendar year, however, no specific induction or maintenance medication was associated with KS. KS incidence was not significantly associated with ambient ultraviolet radiation (IRR = 1.32 95%CI:0.87,2.02, tertile 3 vs. 1). KS incidence has decreased in recent calendar years. In a cross‐sectional sample, we found cutaneous squamous cell carcinoma was associated with KS (OR = 4.83; 95%CI:1.30,14.69). KS risk factors included those potentially associated with HHV8 infection and increased immunosuppression. Our findings suggest that transplant recipients with a non‐KS skin cancer may also be at high KS risk. What's new? Due to treatment with immunosuppressive medications, solid organ transplant recipients are at elevated risk for cancers caused by oncogenic viruses, such as Kaposi sarcoma (KS). In this large population‐based study of transplant recipients, factors potentially linked to HHV8 infection or greater immunosuppression were associated with increased KS risk. While no specific medications were significantly associated with KS risk, recent transplant recipients had reduced KS risk, suggesting possible improvements in drug‐prescribing patterns. The findings also suggest that transplant recipients with non‐KS skin cancers may constitute an additional high‐risk group for KS, underscoring the need for skin cancer screening in this population. [ABSTRACT FROM AUTHOR]

Background and Aim: Inflammation plays a role in the development of both gallstones and gallbladder cancer; however, few studies have investigated the association of circulating inflammation proteins with risk of gallstones. Methods: This study measured 13 cytokines (including 10 interleukins [ILs]) that have been associated with cancer in serum samples collected from 150 gallstone patients and 149 population‐based controls from Shanghai, China, in 1997–2001. This study estimated the associations of each cytokine, categorized into quartiles and coded as a trend, with risk of gallstones using logistic regression models adjusted for potential confounders. Results: Higher levels of IL‐6, IL‐10, IL‐12 (p70), and IL‐13 were associated with increased risk of gallstones (i.e. Ptrend < 0.003, Bonferroni corrected), with odds ratios (ORs) that ranged from ORhighest quartile [Q4] versus lowest quartile [Q1] = 3.2 (95% confidence interval: 1.4, 7.5) for IL‐13 to ORQ4 versus Q1 = 5.7 (95% confidence interval: 2.5, 13.5) for IL‐12 (p70). In a regression model including all four ILs, only IL‐12 retained statistical significance (P < 0.05). Conclusion: This study found four circulating ILs that were associated with gallstones. Future studies are needed to validate the findings and evaluate the common pathway or mechanism in the development of gallbladder diseases associated with these cytokine signatures. [ABSTRACT FROM AUTHOR]

Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin‐like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 and 2012 (75% premenopausal), serum concentrations of IGF‐I and binding protein (IGFBP)‐3 were quantified using enzyme‐linked immunosorbent assay. Hematoxilyn and eosin‐stained tissue sections were assessed for numbers of TDLUs (“TDLU count”). Zero‐inflated Poisson regression models with a robust variance estimator were used to estimate relative risks (RRs) for association of IGF measures (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. AA (vs. Caucasian) women had higher age‐adjusted mean levels of serum IGF‐I (137 vs. 131 ng/mL, p = 0.07) and lower levels of IGFBP‐3 (4165 vs. 4684 ng/mL, p < 0.0001). Postmenopausal IGFBP‐3 was inversely associated with TDLU count among AA (RRT3vs.T1 = 0.49, 95% CI = 0.28–0.84, p‐trend = 0.04) and Caucasian (RRT3vs.T1=0.64, 95% CI = 0.42–0.98, p‐trend = 0.04) women. In premenopausal women, higher IGF‐I:IGFBP‐3 ratios were associated with higher TDLU count in Caucasian (RRT3vs.T1=1.33, 95% CI = 1.02–1.75, p‐trend = 0.04), but not in AA (RRT3vs.T1=0.65, 95% CI = 0.42–1.00, p‐trend = 0.05), women. Our data suggest a role of the IGF system, particularly IGFBP‐3, in TDLU involution of the normal breast, a breast cancer risk factor, among Caucasian and AA women. [ABSTRACT FROM AUTHOR]

The female preponderance of many autoimmune diseases suggests a possible hormonal etiology. Little research exists on systemic and organ‐specific autoimmune diseases and risk of breast cancer by tumor estrogen receptor (ER)‐ and progesterone receptor (PR)‐ status. Here, we evaluate associations between selected systemic and organ‐specific autoimmune diseases and breast cancer risk overall and by tumor ER‐ and PR‐status. We used linked Surveillance, Epidemiology and End Results (SEER)‐Medicare data, with first female breast cancer cases ages ≥66 years identified by SEER registries (years 1992–2011; N = 209,929). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients who were alive and breast cancer‐free. We assessed exposures until 12 months before breast cancer diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional and multinomial logistic regression. We found reduced breast cancer risk among those with rheumatoid arthritis (OR = 0.84; 99.9% CI 0.79–0.89), systemic lupus erythematosus (OR = 0.82; 99.9% CI 0.70–0.97) and pernicious anemia (OR = 0.90; 99.9% CI 0.83–0.97) and increased risk among those with psoriasis (OR = 1.16; 99.9% CI 1.06–1.27). Statistically significant alterations in risk for rheumatoid arthritis were limited to ER‐positive (+) breast cancer, whereas those for the other three conditions were further limited to ER+/PR+ breast cancer. However, only differences for rheumatoid arthritis by ER‐status were statistically significant (p‐heterogeneity = 0.0001). The reasons for these associations need to be investigated in future studies accounting for host characteristics and autoimmune disease treatment. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy type 1 (DM1) is an inherited multisystem neuromuscular disorder caused by a CTG trinucleotide repeat expansion in the DMPK gene. Recent evidence documents that DM1 patients have an increased risk of certain cancers, but whether skin cancer risks are elevated is unclear. Using the U.K. Clinical Practice Research Datalink (CPRD), we identified 1,061 DM1 patients and 15,119 DM1‐free individuals matched on gender, birth year (±2 years), attending practice and registration year (±1 year). We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of DM1 diagnosis with skin cancer risk using Cox proportional hazards models, for all skin cancers combined and by histological subtype. Follow‐up started at the latest of the age at practice registration, DM1 diagnosis/control selection or January 1st 1988, and ended at the earliest of the age at first skin cancer diagnosis, death, transfer out of the practice, last date of data collection or the end of the CPRD record (October 31, 2016). During a median follow‐up of 3.6 years, 35 DM1 patients and 108 matched DM1‐free individuals developed a skin cancer. DM1 patients had an increased risk of skin cancer overall (HR = 5.44, 95% CI = 3.33‐8.89, p < 0.0001), and basal cell carcinoma (BCC) (HR = 5.78, 95% CI = 3.36‐9.92, p < 0.0001). Risks did not differ by gender, or age at DM1 diagnosis (p‐heterogeneity > 0.5). Our data confirm suggested associations between DM1 and skin neoplasms with the highest risk seen for BCC. Patients are advised to minimize ultraviolet light exposure and seek medical advice for suspicious lesions. [ABSTRACT FROM AUTHOR]

Background: Human papillomavirus 16 (HPV16) E6 antibodies may be an early marker of the diagnosis and recurrence of human papillomavirus-driven oropharyngeal cancer (HPV-OPC).Methods: This study identified 161 incident oropharyngeal cancer (OPC) cases diagnosed at the University of Pittsburgh (2003-2013) with pretreatment serum. One hundred twelve had preexisting clinical HPV testing with p16 immunohistochemistry and HPV in situ hybridization (87 were dual-positive [HPV-OPC], and 25 were dual-negative [HPV-negative]); 62 had at least 1 posttreatment serum sample. Eighty-six of the 161 tumors were available for additional HPV16 DNA/RNA testing (45 were dual-positive [HPV16-OPC], and 19 were dual-negative [HPV16-negative). HPV16 E6 antibody testing was conducted with multiplex serology. The following were evaluated: 1) the sensitivity and specificity of HPV16 E6 serology for distinguishing HPV-OPC and HPV16-OPC from HPV-negative OPC, 2) HPV16 E6 antibody decay after treatment with linear models accommodating correlations in variance estimates, and 3) pre- and posttreatment HPV16 E6 levels and the risk of recurrence with Cox proportional hazards models.Results: Seventy-eight of 87 HPV-OPCs were HPV16 E6-seropositive (sensitivity, 89.7%; 95% confidence interval [CI], 81.3%-95.2%), and 24 of 25 HPV-negative OPCs were HPV16 E6-seronegative (specificity, 96.0%; 95% CI, 79.6%-99.9%). Forty-two of 45 HPV16-OPCs were HPV16 E6-seropositive (sensitivity, 93.3%; 95% CI, 81.7%-98.6%), and 18 of 19 HPV16-negative OPCs were HPV16 E6-seronegative (specificity, 94.7%; 95% CI, 74.0%-99.9%). Posttreatment HPV16 E6 antibody levels did not decrease significantly from the baseline (P = .575; median follow-up, 307 days) and were not associated with the risk of recurrence. However, pretreatment HPV16 E6 seropositivity was associated with an 86% reduced risk of local/regional recurrence (hazard ratio, 0.14; 95% CI, 0.03-0.68; P = .015).Conclusions: HPV16 E6 antibodies may have potential clinical utility for the diagnosis and/or prognosis of HPV-OPC. Cancer 2017;123:4382-90. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Meta-analysis can average estimates of multiple parameters, such as a treatment's effect on multiple outcomes, across studies. Univariate meta-analysis (UVMA) considers each parameter individually, while multivariate meta-analysis (MVMA) considers the parameters jointly and accounts for the correlation between their estimates. The performance of MVMA and UVMA has been extensively compared in scenarios with two parameters. Our objective is to compare the performance of MVMA and UVMA as the number of parameters, p, increases. Specifically, we show that (i) for fixed-effect (FE) meta-analysis, the benefit from using MVMA can substantially increase as p increases; (ii) for random effects (RE) meta-analysis, the benefit from MVMA can increase as p increases, but the potential improvement is modest in the presence of high between-study variability and the actual improvement is further reduced by the need to estimate an increasingly large between study covariance matrix; and (iii) when there is little to no between-study variability, the loss of efficiency due to choosing RE MVMA over FE MVMA increases as p increases. We demonstrate these three features through theory, simulation, and a meta-analysis of risk factors for non-Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]

We compare the calibration and variability of risk prediction models that were estimated using various approaches for combining information on new predictors, termed 'markers', with parameter information available for other variables from an earlier model, which was estimated from a large data source. We assess the performance of risk prediction models updated based on likelihood ratio (LR) approaches that incorporate dependence between new and old risk factors as well as approaches that assume independence ('naive Bayes' methods). We study the impact of estimating the LR by (i) fitting a single model to cases and non-cases when the distribution of the new markers is in the exponential family or (ii) fitting separate models to cases and non-cases. We also evaluate a new constrained maximum likelihood method. We study updating the risk prediction model when the new data arise from a cohort and extend available methods to accommodate updating when the new data source is a case-control study. To create realistic correlations between predictors, we also based simulations on real data on response to antiviral therapy for hepatitis C. From these studies, we recommend the LR method fit using a single model or constrained maximum likelihood. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is associated with cancer risk and increases the risk of Barrett esophagus, which is the precursor lesion of esophageal adenocarcinoma (EA), primarily in the absence of gastroesophageal reflux disease (GERD). However, to the authors' knowledge, little is known regarding whether MetS is associated with the risk of EA.Methods: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, the authors evaluated whether MetS was associated with EA. A total of 3167 cases of EA were compared with individually matched population controls (5:1); a subset of 575 EA cases were able to be individually matched with 575 Barrett esophagus controls. MetS was defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in the period 1 to 3 years before the diagnosis of EA or control selection. Unconditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. Potential effect modification by GERD symptoms and sex was examined in stratified models.Results: EA was found to be significantly associated with MetS (odds ratio, 1.16; 95% confidence interval, 1.06-1.26) compared with population controls. In males, the association was restricted to those individuals without prior GERD; however, in females, MetS was found to be associated with EA regardless of GERD status. Effect modification by sex was observed (P for interaction = .01). MetS was not found to be associated with EA risk when compared with Barrett esophagus controls.Conclusions: In this older population, MetS was found to be associated with an increased risk of EA in males without GERD and females regardless of GERD status. Given the lack of an association when compared with Barrett esophagus controls, MetS may impact EA risk by primarily increasing the risk of the precursor lesion, Barrett esophagus. Cancer 2017;123:657-665. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per-allele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant ( p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 ( PEX14), rs11242675 ( FOXQ1) and rs6001930 ( MKL1) were associated with higher TDLU count ( p = 0.047, 0.045 and 0.031, respectively); rs1353747 ( PDE4D) and rs6472903 ( 8q21.11) were associated with higher acini count per TDLU ( p = 0.007 and 0.027, respectively); and rs1353747 ( PDE4D) and rs204247 ( RANBP9) were associated with the product of TDLU and acini counts ( p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility. [ABSTRACT FROM AUTHOR]

Obesity is a strong risk factor for developing endometrial cancer and cardiovascular disease (CVD); consequently, understanding CVD mortality among endometrial cancer survivors is important. We analyzed Surveillance, Epidemiology and End Results Program data for 157,496 endometrial cancer cases diagnosed between 1988 and 2012. We calculated standardized mortality ratios (SMRs) for CVD and all-cause mortality comparing endometrial cancer cases and general population women. We categorized women into one of three prognostic groups (excellent, intermediate and poor) based on tumor characteristics. Cumulative incidence function curves were plotted to visualize absolute mortality risk in the presence of competing risks. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression for cause-specific mortality. Deaths were as follows: endometrial cancer 40.6%, CVD 20.5%, other cancers 18.7% and other causes 20.3%. Women with endometrial cancer were more likely to die from CVD (age-adjusted SMR = 8.8, 95% CI = 8.7-9.0) and all causes (age-adjusted SMR = 15.9, 95% CI = 15.8-16.0) compared to general population women. In case-only analyses, higher CVD mortality was associated with older age, Black ethnicity and lack of surgical treatment. Poor prognosis cancers (non-endometrioid histology and late stage) were related to higher mortality from each cause, with the highest HRs observed for endometrial cancer-specific mortality. Among women diagnosed with excellent prognosis tumors (endometrioid, well-differentiated and early stage), absolute risk of CVD mortality surpassed endometrial cancer-specific mortality 5 years after diagnosis. Women diagnosed with common forms of endometrial cancer have a high CVD burden. After diagnosis, cardiovascular health should be emphasized for these women to reduce mortality. [ABSTRACT FROM AUTHOR]

Inflammation is proposed to increase risk of developing endometrial cancer, but few prospective epidemiologic studies have investigated the relationship between circulating inflammation markers and endometrial cancer risk. In a nested case-control study within the PLCO Screening Trial we measured serum levels of 64 inflammation-related biomarkers in 284 incident endometrial cancer cases and 284 matched controls. Using multivariable logistic regression inflammation markers were evaluated individually and combined into a cross-validated inflammation score. Of 64 markers, 22 were associated with endometrial cancer risk at p < 0.05 and 17 of 22 markers remained associated after multiple testing corrections. After adjusting for BMI and estradiol, SERPINE1 [quartile(Q)4 vs. Q1 odds ratio (OR) (95% confidence interval (CI)), p trend = 2.43 (0.94-6.29), 0.03] and VEGFA [2.56 (1.52-4.30), 0.0002] were positively associated with endometrial cancer risk, while CCL3 [0.46 (0.27-0.77), 0.01], IL13 [0.55 (0.33-0.93), 0.01], IL21 [0.52 (0.31-0.87), 0.01], IL1B [0.51 (0.30-0.86), 0.01] and IL23 [0.60 (0.35-1.03), 0.02] were inversely associated with risk. We observed large differences in ORs across BMI-inflammation score categories. Endometrial cancer risk was most pronounced among obese women with the highest inflammation score tertile (T) [10.25 (3.56-29.55) vs. normal BMI/T1]. Several inflammation markers were prospectively associated with endometrial cancer, including adipokines, pro- and anti-inflammatory cytokines, angiogenic factors and acute phase proteins. Inverse associations with anti-inflammatory markers (IL13, IL21), other inflammation markers/mediators (CCL3, IL1B, IL23), and a robust positive association between VEGFA and endometrial cancer risk were independent of BMI and estradiol, suggesting that these factors may influence risk through other mechanisms. [ABSTRACT FROM AUTHOR]

A small proportion of individuals infected with Epstein-Barr virus (EBV) develop nasopharyngeal carcinoma (NPC). Timing of initial exposure could alter immunological responses to primary EBV infection and explain variation in cancer risk later in life. We measured early life family structure as a proxy for the timing of primary EBV infection to examine whether earlier age at infection alters NPC risk. We utilized data from 480 NPC cases and 1,291 unaffected siblings from Taiwanese NPC multiplex families (≥ 2 family members with NPC, N = 2,921). Information on birth order within the family was derived from questionnaires. We utilized logistic regression models to examine the association between birth order and NPC, accounting for correlations between relatives. Within these high-risk families, older siblings had an elevated risk of NPC. Compared with being a first-born child, the risk (95% CIs) of NPC associated with a birth order of two, three, four and five or more was 1.00 (0.71, 1.40), 0.88 (0.62, 1.24), 0.74 (0.53, 1.05) and 0.60 (0.43, 0.82), respectively ( P for trend = 0.002). We observed no associations between NPC risk and the number of younger siblings or cumulative infant-years exposure. These associations were not modified by underlying genetic predisposition or family size. We observed that early life family structure was important for NPC risk in NPC multiplex families, with older siblings having a greater risk of disease. Future studies focusing on more direct measures of the immune response to EBV in early childhood could elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Several studies have reported bidirectional inverse associations between cancer and Alzheimer's disease ( AD) . This study evaluates these relationships in a Medicare population. Using Surveillance, Epidemiology, and End Results ( SEER) linked to Medicare data, 1992-2005, we evaluated cancer risks following AD in a case-control study of 836,947 cancer cases and 142,869 controls as well as AD risk after cancer in 742,809 cancer patients and a non-cancer group of 420,518. We applied unconditional logistic regression to estimate odds ratios ( ORs) and Cox proportional hazards models to estimate hazards ratios ( HRs). We also evaluated cancer in relation to automobile injuries as a negative control to explore potential study biases. In the case-control analysis, cancer cases were less likely to have a prior diagnosis of AD than controls ( OR = 0.86; 95% CI = 0.81-0.92). Cancer cases were also less likely than controls to have prior injuries from automobile accidents to the same degree ( OR = 0.83; 95% CI = 0.78-0.88). In the prospective cohort, there was a lower risk observed in cancer survivors, HR = 0.87 (95% CI = 0.84-0.90). In contrast, there was no association between cancer diagnosis and subsequent automobile accident injuries ( HR = 1.03; 95% CI = 0.98-1.07). That cancer risks were similarly reduced after both AD and automobile injuries suggest biases against detecting cancer in persons with unrelated medical conditions. The modestly lower AD risk in cancer survivors may reflect underdiagnosis of AD in those with a serious illness. This study does not support a relationship between cancer and AD. [ABSTRACT FROM AUTHOR]