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Objective: We aimed to determine the incidence of major cardiovascular and cerebrovascular events in elderly patients with primary hyperparathyroidism (pHPT) and the impact of parathyroidectomy. Summary Background Data: pHPT is underdiagnosed and undertreated in the United States. It is associated with increased cardiovascular disease risk, but its association with cerebrovascular disease risk is not wellestablished. It is also unknown if parathyroidectomy reduces these risks. Methods: The incidence of major cerebrovascular and cardiovascular events in 108,869 patients with pHPT diagnosed in the Medicare database between 2008 and 2018 and a matched comparison group of 1,088,690 Medicare subjects was prospectively evaluated. We estimated hazard ratios (HR) for the association of pHPT and parathyroidectomy for the risk of these outcomes from Cox proportional hazards models. Survival curves were calculated to obtain 5-year disease-free survival estimates. Results: For patients with pHPT, five-year disease-free survival was lower, and HRs were higher than the comparison group for any outcome (75.9% vs. 78.4; HR 1.11, 95% confidence interval [CI] 1.09--1.13), major cerebrovascular events (84.5% vs. 86.3%; HR 1.14, 95% CI 1.12--1.17), and major cardiovascular events (87.7% vs. 88.8%; HR 1.06, 95% CI 1.03--1.08). However, in patients who had parathyroidectomy, the risks of major cerebrovascular and cardiovascular events did not differ from the comparison cohort. The lower risk in patients who had parathyroidectomy was maintained in subgroup analyses. Conclusions: Older patients with pHPT have an increased risk of major cerebrovascular and cardiovascular events compared with patients without the disease. Physicians treating older patients with primary hyperparathyroidism should consider parathyroidectomy. R.M.P. and N.N. contributed equally to the preparation of this manuscript. [ABSTRACT FROM AUTHOR]

Background: Epstein-Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL). Methods: Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case-control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models. Results: IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glycoprotein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types. Conclusions: Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis. [ABSTRACT FROM AUTHOR]

Shorter duration therapy for hepatitis C virus (HCV) infection might reduce treatment costs and increase the number of patients treated and cured. We determined factors associated with treatment response after an 8-week sofosbuvir-based therapy and developed a simple model to predict an individual's likelihood of treatment success. Among 2907 patients who received ledipasvir/sofosbuvir for 8 weeks, we determined failure rates by demographic and clinical characteristics, and IFNL4 -∆G/TT genotype. We estimated the average IFNL4 genotype-related treatment failure rate in major ancestry groups by applying our IFNL4 genotype results to genotype distributions from reference populations. We created a treatment response model based on three personal characteristics. Overall, 4.4% of the patients failed treatment. We observed significantly lower failure rates for persons <50 years (1.6%), females (2.6%), those carrying the IFNL4 -TT/TT genotype (1.8%), those with HCV RNA <5.8 log 10 copies/mL (2.0%) or HCV genotype-1B infection (2.6%). In a model based on ancestry, age and sex, the predicted probability of treatment failure ranged from 0.5% among females of East Asian ancestry <50 years of age to 8.5% among males of African ancestry age ≥65 years. Applying this algorithm at the point-of-care might facilitate HCV elimination, especially in low- and middle-income countries. [Display omitted] • Shorter therapy for HCV could increase the number of patients treated and cured. • We examined response to 8 weeks of ledipasvir/sofosbuvir in a large cohort. • Predictive factors included IFNL4 genotype, which varies markedly by ancestry. • A model based on ancestry, age and sex predicted treatment response. • This model might enhance efforts to eliminate hepatitis C virus. [ABSTRACT FROM AUTHOR]

Background: In Helicobacter pylori -driven gastric cancer, mucosal colonization induces chronic inflammation that may variably progress to cancer. Prospective studies of circulating inflammation-related proteins have suggested weak associations with gastric cancer risk. To assess potential utility as a screening tool in clinical settings, we examined circulating levels of a wide range of key inflammation molecules for associations with early-stage gastric cancer. Methods: We used pretreatment EDTA plasma from 239 individuals with early-stage noncardia gastric cancer (203 stage I and 36 stage II) and 256 age-frequency-matched H. pylori -seropositive cancer-free controls within the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Levels of 92 biomarkers were measured by proximity extension assays using Olink's Proseek Immuno-oncology Panel. Odds ratios (ORs) for association with gastric cancer risk were calculated for quantiles (two to four categories) of each biomarker from unconditional logistic regression models, adjusted for age, sex, smoking and alcohol consumption. Two-sided P values <0.05 were considered as significant. The false discovery rate (FDR) was used to correct for multiple comparisons. Results: Of 83 evaluable biomarkers, lower levels of TNFRSF12A (per quartile OR, 0.82; nominal P -trend = 0.02) and ADGRG1 (per quartile OR, 0.84; nominal P -trend = 0.03) were associated with early-stage gastric cancer but were not statistically significant after FDR correction. Conclusion: Our study did not identify any inflammation-related biomarkers that may be useful for early disease detection. To date, this is the first assessment of circulating inflammation-related proteins in early-stage gastric cancer. Given the complex inflammation processes preceding malignant transformation, further investigation of other biomarkers is warranted. [ABSTRACT FROM AUTHOR]

Background: Prolonged sitting and physical inactivity are associated with higher circulating levels of estrogens. It is unknown whether these risk factors are associated with circulating androgens/androgen metabolites, another set of hormones implicated in the etiology of cancers in postmenopausal women. Methods: We conducted a cross-sectional analysis of 1,782 postmenopausal women in the Women's Health Initiative Observational Study. Serum concentrations of 12 androgens/androgen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting time were self-reported at baseline. We performed linear regression to estimate geometric means (GM) of androgen/androgen metabolite concentrations (pmol/L) according to physical activity and sitting time, adjusting for potential confounders and stratified by menopausal hormone therapy (MHT) use. Results: Physical activity (≥15 vs. 0 MET-h/wk) was inversely associated with estrogen-to-androgen ratios among never/former MHT users (adj-GM = 37.5 vs. 49.6 unconjugated estrone:androstenedione; 20.2 vs. 30.3 unconjugated estradiol:testosterone; all Ptrend ≤ 0.03) but was not associated among current MHT users. Prolonged sitting (≥10 vs. ≤5 h/d) was positively associated with these ratios among both never/former (adj-GM = 44.2 vs. 38.3, Ptrend = 0.10; adj-GM = 23.4 vs. 20.2, Ptrend = 0.17; respectively) and current MHT users (adj-GM = 197 vs. 147; 105 vs. 75.5; respectively; all Ptrend ≤0.02), but the associations were statistically significant among current MHT users only. The associations persisted after adjustment for BMI. After adjustment for adrenal androgens, physical activity and sitting were not associated with androgen metabolites. Conclusions: Physical activity and sitting were associated with serum estrogen-to-androgen ratios but not androgen metabolites. Impact: This study contributes to our understanding of the link between physical activity, sitting, and cancer risk in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: Previous prospective studies of associations between circulating inflammation-related molecules and pancreatic cancer risk have included limited numbers of markers. Methods: We conducted a case-cohort study nested within the Japan Public Health Center-based Prospective Study Cohort II. We selected a random subcohort (n = 774) from a total of 23,335 participants aged 40 to 69 years who returned a questionnaire and provided blood samples at baseline. During the follow-up period from 1993 to 2010, we identified 111 newly diagnosed pancreatic cancer cases, including one case within the subcohort. Plasma concentrations of 62 inflammatory markers of chemokines, cytokines, and growth factors were measured by a Luminex fluorescent bead-based assay. Cox regression models were applied to estimate HR and 95% confidence intervals (CI) for pancreatic cancer risk for quartiles of marker levels adjusted for potential confounders. Results: The HR (95% CI) for the highest versus the lowest category of C-C motif ligand chemokine 8/monocyte chemoattractant protein 2 (CCL8/MCP2) was 2.03 (1.05-3.93; Ptrend = 0.048). After we corrected for multiple comparisons, none of the examined biomarkers were associated with pancreatic cancer risk at P-value <0.05. Conclusions: We found no significant associations between 62 inflammatory markers and pancreatic cancer risk. Impact: The suggestive association with circulating levels of leukocyte recruiting cytokine CCL8/MCP2 may warrant further investigation. [ABSTRACT FROM AUTHOR]

Background: The introduction of combination antiretroviral therapy (cART) has led to a significant reduction in Kaposi sarcoma (KS) incidence among people with HIV (PWH). However, it is unclear if incidence has declined similarly across key demographic and HIV transmission groups and the annual number of incident and prevalent KS cases remains unquantified. Methods: Using population-based registry linkage data, we evaluated temporal trends in KS incidence using adjusted Poisson regression. Incidence and prevalence estimates were applied to CDC HIV surveillance data, to obtain the number of incident (2008-2015) and prevalent (2015) cases in the United States. Results: Among PWH, KS rates were elevated 521-fold [95% confidence intervals (CI), 498-536] compared with the general population and declined from 109 per 100,000 person-years in 2000 to 47 per 100,000 person-years in 2015, at an annual percentage change of -6%. Rates declined substantially (Ptrend < 0.005) across all demographic and HIV transmission groups. Of the 5,306 new cases estimated between 2008 and 2015, 89% occurred among men who have sex with men. At the end of 2015, 1,904 PWH (0.20%) had been diagnosed with KS in the previous 5 years. Conclusions: A consistent gradual decline in KS incidence has occurred among PWH in the United States during the current cART era. This decrease is uniform across key demographic and HIV transmission groups, though rates remain elevated relative to the general population. [ABSTRACT FROM AUTHOR]

Background: Experimental studies suggest that iron overload might increase pancreatic cancer risk. We evaluated whether prediagnostic hemochromatosis and iron-overload diseases, including sideroblastic and congenital dyserythropoietic anemias, and non-alcoholic-related chronic liver disease (NACLD) were associated with pancreatic cancer risk in older adults. Methods: We conducted a population-based, case-control study within the U.S. Surveillance, Epidemiology, and End Results Program (SEER)-Medicare linked data. Incident primary pancreatic cancer cases were adults > 66 years. Controls were alive at the time cases were diagnosed and matched to cases (4:1 ratio) by age, sex, and calendar year. Hemochromatosis, iron-overload anemias, and NACLD were reported 12 or more months before pancreatic cancer diagnosis or control selection using Medicare claims data. Adjusted unconditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI) between hemochromatosis, sideroblastic and congenital dyserythropoietic anemias, NACLD, and pancreatic cancer. Results: Between 1992 and 2015, 80,074 pancreatic cancer cases and 320,296 controls were identified. Overall, we did not observe statistically significant associations between hemochromatosis, sideroblastic anemia, or congenital dyserythropoietic anemia and pancreatic cancer; however, sideroblastic anemia was associated with later primary pancreatic cancer (OR, 1.30; 95% CI, 1.03-1.64). NACLD was associated with first (OR, 1.10; 95% CI, 1.01-1.19), later (OR, 1.17; 95% CI, 1.02-1.35), and all (OR, 1.12; 95% CI, 1.04-1.20) pancreatic cancer. Conclusions: Overall hemochromatosis and iron-overload anemias were not associated with pancreatic cancer, whereas NACLD was associated with increased risk in this large study of older adults. Impact: These results partly support the hypothesis that iron-overload diseases increase pancreatic cancer risk. [ABSTRACT FROM AUTHOR]

Background: TNF inhibitors (TNFi) effectively treat rheumatoid arthritis but may increase patient risk of some malignancies, particularly lymphomas or skin cancers. Methods: We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to conduct a case-control study in patients with rheumatoid arthritis (2007-2015). Cases were individuals with a first cancer diagnosed in SEER registries (ages 66-99, 22 cancer sites, N = 10,263). Skin cancer cases [nonmelanoma skin cancer (NMSC, N = 501), basal cell carcinoma (BCC, N = 161), squamous cell carcinoma (SCC, N = 150)] and cancer-free controls (N = 30,475) were selected from Medicare beneficiaries residing in SEER areas. Cases and controls had prior Medicare claims-based evidence for rheumatoid arthritis, and TNFi exposure was ascertained from part B and part D claims. Logistic regression was used to estimate adjusted odds ratios (aOR). Results: TNFi exposure was present in 16.2% of controls and 12.8% to 33.7% of cancer cases, varying by site. TNFi use was associated with increased risk of NMSC overall (aOR 1.32, 95% confidence interval 1.06-1.63), non-Hodgkin lymphoma (NHL) overall (1.28, 1.06-1.56) and, specifically, follicular lymphoma (2.63, 1.63-4.24). TNFi exposure was not associated with other SEER cancer sites, BCC or SCC specifically, or other common NHL subtypes. Conclusions: Among older adults with rheumatoid arthritis, TNFi exposure was associated with elevated risk of NMSC and NHL, driven specifically by follicular lymphoma. Exposure was not associated with increased risk for other cancer sites. Impact: Our results support a role for TNF in lymphomagenesis. Given the association with NMSC, patients initiating TNFi therapy may benefit from skin cancer screening and sun protection measures. [ABSTRACT FROM AUTHOR]

Background: Anthropometric measures, including obesity, are important risk factors for breast and endometrial cancers in postmenopausal women. It is unknown whether these risk factors are associated with androgen metabolism, another risk factor for these cancers. Methods: Using baseline data from 1,765 postmenopausal women in the Women's Health Initiative Observational Study, we conducted a cross-sectional analysis examining associations between anthropometric measures [current body mass index (BMI), waist-to-hip ratio (WHR), height, and recalled BMI at age 18) and serum androgen metabolites. Twelve androgens/androgen metabolites were quantified using LC-MS/MS. Geometric means of androgen/androgen metabolite concentrations were estimated using linear regression, adjusting for potential confounders and stratified by hormone therapy (HT) use. Results: Regardless of HT use, higher current BMI (≥30 vs. <25 kg/m2) was associated with higher serum concentrations of dehydroepiandrosterone sulfate (DHEAS), 5α-reduced glucuronide metabolites [androsterone-glucuronide (ADT-G), 5α-androstane-3α,17β diol-3-glucuronide (3α-diol-3G), 3α-diol-17-glucuronide (3α-diol-17G)], and DHEAS:DHEA ratio (all P trend ≤ 0.02). BMI was also positively associated with unconjugated estrone:androstenedione and unconjugated estradiol:testosterone ratios among never/former HT users (all P trend < 0.001) but not among current users (P-int < 0.001). WHR was positively associated with adrenal androgens and 5α-reduced glucuronide metabolites in obese women only (BMI ≥ 30 kg/m2; all P-trend ≤ 0.01). BMI at age 18 was inversely associated with adrenal androgens (DHEA, DHEAS, androstenedione, testosterone) and 5α-reduced glucuronide metabolites in never/former HT users (all P trend < 0.06). Height was not associated with androgen metabolites. Conclusions: Current BMI is associated with androgen metabolism among postmenopausal women. Impact: This study contributes to our understanding of the link between obesity and cancer risk in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: The introduction of combination antiretroviral therapy (cART) has led to a significant reduction in Kaposi sarcoma (KS) incidence among people with HIV (PWH). However, it is unclear if incidence has declined similarly across key demographic and HIV transmission groups and the annual number of incident and prevalent KS cases remains unquantified. Methods: Using population-based registry linkage data, we evaluated temporal trends in KS incidence using adjusted Poisson regression. Incidence and prevalence estimates were applied to CDC HIV surveillance data, to obtain the number of incident (2008-2015) and prevalent (2015) cases in the United States. Results: Among PWH, KS rates were elevated 521-fold [95% confidence intervals (CI), 498-536] compared with the general population and declined from 109 per 100,000 person-years in 2000 to 47 per 100,000 person-years in 2015, at an annual percentage change of -6%. Rates declined substantially (Ptrend < 0.005) across all demographic and HIV transmission groups. Of the 5,306 new cases estimated between 2008 and 2015, 89% occurred among men who have sex with men. At the end of 2015, 1,904 PWH (0.20%) had been diagnosed with KS in the previous 5 years. Conclusions: A consistent gradual decline in KS incidence has occurred among PWH in the United States during the current cART era. This decrease is uniform across key demographic and HIV transmission groups, though rates remain elevated relative to the general population. [ABSTRACT FROM AUTHOR]

Background: While smokeless tobacco (ST) causes oral cancer and is associated with cardiovascular diseases, less is known about how its effects differ from other tobacco use. Biomarkers of potential harm (BOPH) can measure short-term health effects such as inflammation and oxidative stress. Methods: We compared BOPH concentrations [IL6, high-sensitivity C-reactive protein, fibrinogen, soluble intercellular adhesion molecule-1 (sICAM-1), and F2-isoprostane] across 3,460 adults in wave 1 of the Population Assessment of Tobacco and Health study (2013-2014) by tobacco use groups: primary ST users (current exclusive ST use among never smokers), secondary ST users (current exclusive ST use among former smokers), exclusive cigarette smokers, dual users of ST and cigarettes, former smokers, and never tobacco users. We estimated geometric mean ratios using never tobacco users, cigarette smokers, and former smokers as referents, adjusting for demographic and health conditions, creatinine (for F2-isoprostane), and pack-years in smoker referent models. Results: BOPH levels among primary ST users were similar to both never tobacco users and former smokers. Most BOPH levels were lower among ST users compared with current smokers. Compared with never tobacco users, dual users had significantly higher sICAM-1, IL6, and F2-isoprostane. However, compared with smokers, dual users had similar biomarker levels. Former smokers and secondary ST users had similar levels of all five biomarkers. Conclusions: ST users have lower levels of inflammatory and oxidative stress biomarkers than smokers. Impact: ST use alone and in combination with smoking may result in different levels of inflammatory and oxidative stress levels. [ABSTRACT FROM AUTHOR]

Background: Skin cancer screening is routinely performed for members of melanoma-prone families, but longitudinal studies evaluating the efficacy of surveillance in this high-risk population are lacking. Methods: We evaluated thickness for first primary melanomas diagnosed in melanoma-prone families (=2 individuals with melanoma) enrolled in NCT00040352 (NCI familial melanoma study) from 1976 through 2014; enrolled patients received routine skin cancer screening and education about skin self-exams. We used linear and ordinal logistic regression models adjusted for gender and age with a generalized estimating equations approach to report changes in thickness and tumor (T) stage over time, comparing outcomes for NCI cases diagnosed before (pre-study) versus after study participation (prospective) and for NCI cases versus nonfamilial cases [Surveillance, Epidemiology, and End Results (SEER) 9 registries]. Results: Tumor thickness was evaluated for 293 NCI (pre-study = 246; prospective = 47) patients. Compared with NCI pre-study cases, NCI prospective melanomas were thinner (0.6 vs. 1.1 mm; P < 0.001) and more likely to be T1 stage [39/47 (83%) vs. 98/246 (40%); P < 0.001]. Similar findings (P < 0.05) were observed for familial cases with and without germline CDKN2A and CDK4 mutations. Peters-Belson modeling suggested that calendar period effects of decreasing thickness in the general population (SEER 9) did not fully explain thickness trends in NCI families. Conclusions: Participation in a longitudinal surveillance program providing skin cancer screening and education about skin self-exams was associated with thinner melanomas for members of melanoma-prone families. [ABSTRACT FROM AUTHOR]

Background: CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes.Objective: We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1.Methods: We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and noncarriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family.Results: Histologic slides were evaluated for 290 melanomas (139 from 132 noncarriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, and 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in 10 of 15 invasive melanomas (67%) from POT1 carriers (P < .0001 vs noncarriers). This finding was independently confirmed by 3 expert melanoma dermatopathologists in 9 of 15 invasive melanomas (60%). In situ and invasive melanomas from CDKN2A and CDK4 carriers were histologically similar to melanomas from noncarriers.Limitations: Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1).Conclusion: Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoid differentiation in melanocytic tumors. [ABSTRACT FROM AUTHOR]

Background: Circulating inflammation proteins may be important mediators or markers of carcinogenic mechanisms. There have been few studies with limited numbers of analytes in patients with upper gastrointestinal (GI) tract tumors. We therefore evaluated risk associations of gastric and esophageal cancers with prediagnostic levels of a wide range of these molecules. Methods: We performed a case-cohort analysis within the Japan Public Health Center-Based Prospective Study Cohort II, including incident cases of gastric (n = 446) and esophageal (n = 68) cancers and a random subcohort (n = 774). A total of 64 biomarkers were measured in baseline plasma using Luminex bead-based assays. The median time between blood collection and diagnosis was 8.1 years for gastric cancer and 9.4 years for esophageal cancer. HRs for association with each marker were adjusted for potential confounders using Cox regression. Results: In separate models, sEGFR and TSLP were nominally associated with gastric cancer risk, and CRP, CXCL11/ITAC, and CCL15/MIP1D were associated with esophageal cancer. However, no association satisfied statistical significance after FDR correction. Associations did not differ by time from blood collection to cancer (<5 vs. =5 years). Conclusions: Our study failed to identify associations of circulating inflammation markers with risk of upper GI tract tumors. Impact: To date, this is the largest assessment of inflammation-related proteins with gastric and esophageal cancer risks. However, the evaluated molecules may not fully represent the complex inflammation processes preceding malignant transformation. Further investigation of other markers in prospective studies is warranted, as demonstration of associations may have important implications for prevention and treatment of these cancers. [ABSTRACT FROM AUTHOR]

Background: U.S. breast cancer incidence has been changing, as have distributions of risk factors, including body mass index (BMI), age at menarche, age at first live birth, and number of live births. Methods: Using data for U.S. women from large nationally representative surveys, we estimated risk factor distributions from 1980 to 2008. To estimate ecologic associations with breast cancer incidence, we fitted Poisson models to age- and calendar year-specific incidence data from the NCI's Surveillance, Epidemiology and End Results registries from 1980 to 2011. We then assessed the proportion of incidence attributable to specific risk factors by comparing incidence from models that only included age and calendar period as predictors with models that additionally included age- and cohort-specific categorized mean risk factors. Analyses were stratified by age and race. Results: Ecologic associations usually agreed with previous findings from analytic epidemiology. From 1980 to 2011, compared with the risk factor reference level, increased BMI was associated with 7.6% decreased incidence in women ages 40 to 44 and 2.6% increased incidence for women ages 55 to 59. Fewer births were associated with 22.2% and 3.99% increased incidence in women ages 40 to 44 and 55 to 59 years, respectively. Changes in age at menarche and age at first live birth in parous women did not significantly impact population incidence from 1980 to 2011. Conclusions: Changes in BMI and number of births since 1980 significantly impacted U.S. breast cancer incidence. Impact: Quantifying long-term impact of risk factor trends on incidence is important to understand the future breast cancer burden and inform prevention efforts. [ABSTRACT FROM AUTHOR]

Background: Although some familial cancer syndromes include biliary tract cancers (BTCs; cancers of the gallbladder, intrahepatic and extrahepatic bile ducts, and ampulla of Vater), the few studies that have examined the relationships between family history of cancer (FHC) and BTCs have reported inconclusive findings. The objective of this study was to investigate the associations of FHC with risk of BTC in the Biliary Tract Cancers Pooling Project (BiTCaPP). Methods: We used Cox proportional hazards regressions models to estimate HRs and 95% confidence intervals for associations between FHC (any, first-degree, in female relative, in male relative, relative with gastrointestinal cancer, and relative with hormonally related cancer) and BTC risk by anatomic site within the biliary tract, adjusting for sex and race/ethnicity. Sensitivity analyses were conducted that restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. Results: Data on FHC were available from 12 prospective studies within BiTCaPP, which collectively contributed 2,246 cases (729 gallbladder, 345 intrahepatic and 615 extrahepatic bile duct, and 385 ampulla of Vater cancers) with 21,706,107 person-years of follow-up. A marginal, inverse association between FHC and gallbladder cancer was driven to the null when analysis was restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. FHC was not associated with risk of BTC at the other anatomic sites. Conclusions: These findings do not support an association between FHC and BTCs. Impact: In a study of 1.5 million people, FHC is not a risk factor for BTCs. [ABSTRACT FROM AUTHOR]

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases. Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers. Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r² = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r² = 0.10), and then serum estrone and tissue estrone (r² = 0.09). There was no effect modification by Gleason score, race, or age. Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu. Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. [ABSTRACT FROM AUTHOR]

Background: Human immunodefieciency virus (HIV)-infected persons are living longer in the era of effective HIV treatment, resulting in an increasing cancer burden in this population. The combined effects of HIV and cancer on mortality are incompletely understood. Methods: We examined whether individuals with both HIV and cancer have excess mortality using data from the HIV/AIDS Cancer Match Study and the National Center for Health Statistics (1996-2010). We compared age, sex, and race-stratified mortality between people with and without HIV or one of the following cancers: lung, breast, prostate, colorectum, anus, Hodgkin lymphoma, or non-Hodgkin lymphoma. We utilized additive Poisson regression models that included terms for HIV, cancer, and an interaction for their combined effect on mortality. We report the number of excess deaths per 1,000 person-years for models with a significant interaction (P < 0.05). Results: For all cancers examined except prostate cancer, at least one demographic subgroup of HIV-infected cancer patients experienced significant excess mortality. Excess mortality was most pronounced at younger ages (30-49 years), with large excesses for males with lung cancer (white race: 573 per 1,000 person-years; non-white: 503) and non-Hodgkin lymphoma (white: 236; non-white: 261), and for females with Hodgkin lymphoma (white: 216; non-white: 136) and breast cancer (non-white: 107). Conclusions: In the era of effective HIV treatment, overall mortality in patients with both HIV and cancer was significantly higher than expected on the basis of mortality rates for each disease separately. Impact: These results suggest that HIV may contribute to cancer progression and highlight the importance of improved cancer prevention and care for the U.S. HIV population. [ABSTRACT FROM AUTHOR]

Background: Elevated keratinocyte carcinoma risk is present with several immune-related conditions, e.g., solid organ transplantation and non-Hodgkin lymphoma. Because many immune-related conditions are rare, their relationships with keratinocyte carcinoma have not been studied. Methods: We used Medicare claims to identify cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) cases in 2012, and controls matched on sex and age. All subjects were aged 65 to 95 years, of white race, and had attended =1 dermatologist visit in 2010-2011. Immune-related conditions were identified during 1999-2011 using Medicare claims. Associations were estimated with logistic regression, with statistical significance determined after Bonferroni correction for multiple comparisons. Results: We included 258,683 SCC and 304,903 BCC cases. Of 47 immune-related conditions, 21 and 9 were associated with increased SCC and BCC risk, respectively. We identified strongly elevated keratinocyte carcinoma risk with solid organ transplantation (SCC OR = 5.35; BCC OR = 1.94) and non-Hodgkin lymphoma (SCC OR = 1.62; BCC OR = 1.25). We identified associations with common conditions, e.g., rheumatoid arthritis [SCC OR = 1.06, 95% confidence interval (95% CI), 1.04-1.09] and Crohn's disease (SCC OR = 1.33, 95% CI, 1.27-1.39; BCC OR = 1.10, 95% CI, 1.05-1.15), and rare or poorly characterized conditions, e.g., granulomatosis with polyangiitis (SCC OR = 1.88; 95% CI, 1.61-2.19), autoimmune hepatitis (SCC OR = 1.81; 95% CI, 1.52-2.16), and deficiency of humoral immunity (SCC OR = 1.51, 95% CI, 1.41-1.61; BCC OR = 1.22, 95% CI, 1.14-1.31). Most conditions were more positively associated with SCC than BCC. Associations were generally consistent regardless of prior keratinocyte carcinoma history. Conclusions: Many immune-related conditions are associated with elevated keratinocyte carcinoma risk and appear more tightly linked to SCC. Impact: Immunosuppression or immunosuppressive treatment may increase keratinocyte carcinoma risk, particularly SCC. [ABSTRACT FROM AUTHOR]

Background: Obesity has been associated with substantially higher risk of inflammatory breast cancer (IBC) than other breast cancer. Here, we assess whether comorbidities of obesity, namely diabetes, abnormal glucose, dyslipidemia, and hypertension, are differentially related to risk of IBC and other breast cancers by tumor stage at diagnosis (localized/regional/distant/unstaged). Methods: We used linked SEER-Medicare data, with female breast cancer cases ages 66+ years identified by SEER registries (years 1992-2011). We divided first breast cancers into IBC (N = 2,306), locally advanced non-IBC (LABC; N = 10,347), and other (N = 197,276). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients alive and breast cancer free. We assessed exposures until 12 months before diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional logistic regression. Results: Diabetes was associated with increased risk of distant IBC (98.5% of IBC cases; OR 1.44; 99.9% CI 1.21-1.71), distant (OR 1.24; 99.9% CI, 1.09-1.40) and regional (OR 1.29 (99.9% CI, 1.14-1.45) LABC, and distant (OR 1.23; 99.9% CI, 1.10-1.39) and unstaged (OR 1.32; 99.9% CI, 1.18-1.47) other breast cancers. Dyslipidemia was associated with reduced risk of IBC (OR 0.80; 95% CI, 0.67-0.94) and other breast cancers except localized disease. Results were similar by tumor estrogen receptor status. Abnormal glucose levels and hypertension had little association with risk of any tumor type. Conclusions: Associations with diabetes and dyslipidemia were similar for distant stage IBC and other advanced tumors. Impact: If confirmed, such findings could suggest avenues for prevention. [ABSTRACT FROM AUTHOR]

Purpose Randomized trials have shown that intermittent androgen deprivation therapy for patients with advanced prostate cancer may improve sexual and physical functioning compared to continuous androgen deprivation therapy without compromising survival. To our knowledge it is unknown whether intermittent androgen deprivation therapy alters the risk of serious toxicities associated with continuous androgen deprivation therapy. Materials and Methods We performed a population based cohort study of 9,772 men 66 years old or older who were diagnosed with advanced prostate cancer from 2002 to 2011 and treated with androgen deprivation therapy. Intermittent androgen deprivation therapy was defined as a single 90-day interval between 2 androgen deprivation therapy sessions during which patients visited their physicians or underwent prostate specific antigen testing. Outcomes included acute myocardial infarction, stroke, heart failure, type 2 diabetes and fracture. We used Cox proportional hazard models to estimate the HRs of the comparative risk of serious toxicities between intermittent and continuous androgen deprivation therapy. Results A total of 2,113 (22%), 769 (9%) and 899 men (9%) had a new cardiovascular event, diabetes or fracture, respectively, within 5 years of starting androgen deprivation therapy. Compared to the continuous androgen deprivation therapy group, the intermittent therapy group was at lower risk for serious cardiovascular events (HR 0.64, 95% CI 0.53–0.77), particularly in reducing the risk of heart failure (HR 0.62, 95% CI 0.49–0.78) and fracture (HR 0.52, 95% CI 0.38–0.70, each p <0.0001). Conclusions Intermittent androgen deprivation therapy was associated with a lower risk of heart failure and fracture compared to continuous androgen deprivation therapy. This raises toxicity concerns for continuous relative to intermittent therapy and suggests that intermittent androgen deprivation therapy may represent a safer therapeutic choice in elderly men with advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Light and/or intermittent smokers have been the fastest growing segment of cigarette smokers in the United States over the past two decades. Defining their behavioral characteristics is a critical public health priority. Methods: Our sample included 78,229 U.S. adults from three pooled contemporary population-based surveys: the 2012 NHIS, 2012 NSDUH, and 2011-2012 NHANES. We classified current smokers into four categories (light and intermittent [LITS], light-daily, heavier-intermittent, and heavier-daily) and assessed smoking behaviors, illicit drug use, and mental health indicators using weighted analyses. Results: Analyses associated smoking categories with nicotine dependence, age of smoking initiation, race/ethnicity, and other demographic and behavioral factors. Compared with heavier-daily smokers, smokers who were LITS were most likely to have mild or no nicotine dependence (weighted odds ratio [OR], 16.92; 95% confidence interval [CI], 13.10-21.85), to start smoking cigarettes regularly after age 21 (OR, 3.42; 95% CI, 2.84-4.12), and to be Hispanic (OR, 5.38; 95% CI, 4.38-6.61). Additional significant results were found for other categories of smokers. Conclusions: Based on pooled data from three large national surveys, light and/or intermittent smokers differed in smoking, drug use, and mental health behaviors from heavier-daily, former, and never smokers. Notable differences by level of smoking frequency and intensity were observed for nicotine dependence, age of smoking initiation, and race/ethnicity. Impact: Our results may help focus preventive measures and policies for the growing number of light and/or intermittent smokers in the United States because smoking patterns vary by behavioral and socioeconomic factors. [ABSTRACT FROM AUTHOR]