Metabolic liver cancer: associations of rare and common germline variants in one-carbon metabolism and DNA methylation genes.

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in the overall sample and among non-Hispanic whites. The results show that among non-Hispanic whites, presence of rare functional variants in ABCC2 was associated with 7-fold higher risk of metabolic HCC (OR = 6.92, 95% CI: 2.38-20.15, P = 0.0004), and this association remained significant when analyses were restricted to functional rare variants observed in ≥2 participants (cases 3.2% versus controls 0.0%, P = 1.02 × 10-5). In the overall multiethnic sample, presence of rare functional variants in ABCC2 was nominally associated with metabolic HCC (OR = 3.60, 95% CI: 1.52-8.58, P = 0.004), with similar nominal association when analyses were restricted to functional rare variants observed in ≥2 participants (cases 2.9% versus controls 0.2%, P = 0.006). A common variant in PNPLA3 (rs738409[G]) was associated with higher HCC risk in the overall sample (P = 6.36 × 10-6) and in non-Hispanic whites (P = 0.0002). Our findings indicate that rare functional variants in ABCC2 are associated with susceptibility to metabolic HCC in non-Hispanic whites. PNPLA3-rs738409 is also associated with metabolic HCC risk.

Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Development of a Novel Comprehensive Hepatocellular Carcinoma Outcome Prognostic Scoring System With Integration of Imaging Features.

BACKGROUND: Accurate prognostic stratification of hepatocellular carcinoma (HCC) is vital for clinical trial enrollment and treatment allocation. Multiple scoring systems have been created to predict patient survival, but no standardized scoring systems account for radiologic tumor features. We sought to create a generalizable scoring system for HCC which incorporates standardized radiologic tumor features and more accurately predicts overall survival (OS) than established systems. METHODS: Clinicopathologic parameters were collected from a prospectively collected cohort of patients with HCC treated at a single institution. Imaging studies were evaluated for tumor characteristics. Patients were randomly divided into a training set for identification of covariates that impacted OS and a validation set. Cox models were used to determine the association of various factors with OS and a scoring system was created. RESULTS: We identified 383 patients with HCC with imaging and survival outcomes, n = 255 in the training set and 128 in the validation cohort. Factors associated with OS on multivariate analysis included: tumor margin appearance on CT or MRI (hazard ratio [HR] 1.37, 95% CI, 1.01-1.88) with infiltrative margins portending worse outcomes than encapsulated margins, massive tumor morphology (HR 1.64, 95% CI, 1.06-2.54); >2 lesions (HR 2.06, 95% CI, 1.46-2.88), Child-Turcotte-Pugh class C (HR 3.7, 95% CI, 2.23-6.16), and portal vein thrombus (HR 2.41, 95% CI, 1.71-3.39). A new scoring system was developed and more predictive of OS than other well-established systems. CONCLUSIONS: Incorporation of standardized imaging characteristics to established clinical and lab predictors of outcome resulted in an improved predictive scoring system for patients with HCC.

Incidence and Geographical Distribution of Adrenocortical Carcinoma: Retrospective Analysis of a State Cancer Registry.

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare malignancy without established association with environmental risk factors. ACC incidence is stable based on large surgical databases while referral centers data reported increasing number of cases seen. We studied ACC incidence and distribution at a county level to find potential ACC "hot spots" that could be linked to environmental exposures. METHODS: A retrospective analysis of Texas Cancer Registry that included ACC patients diagnosed between 2000 and 2018. County-level heatmaps were created and compared with breast, prostate, and lung cancer. RESULTS: We identified 448 ACC cases during the study period. Cases were registered in 110 of the 254 counties (43.3%) in Texas, representing 92.74% of the total population. The median incidence was 23 new cases/y (range 14-33). The mean population-adjusted ACC incidence rate was 0.104 per 100 000 per year (standard deviation 0.005; 95% CI, 0.092-0.116). Seven counties (6.3%) accounted for 215 (48.0%) cases, with more than 10 cases each and median standardized incidence ratio (SIR) of 0.1 (range, 0.0-0.9). One hundred three counties (93.7%) accounted for the remaining 233 cases (52%), with fewer than 10 cases per county. The highest standardized incidence ratios were found in counties with a median population of fewer than 14 000 residents and with only one reported case. CONCLUSION: Our analysis is the first report to create ACC heatmap and could not detect any geographic clustering of ACC in Texas. The incidence of ACC remained stable and consistent with data from other large databases.

Clinical and Prognostic Biomarker Value of Blood-Circulating Inflammatory Cytokines in Hepatocellular Carcinoma.

INTRODUCTION: Circulating inflammatory cytokines play critical roles in tumor-associated inflammation and immune responses. Recent data have suggested that several interleukins (ILs) mediate carcinogenesis in hepatocellular carcinoma (HCC). However, the predictive and prognostic value of circulating ILs is yet to be validated. Our study aimed to evaluate the association of the serum ILs with overall survival (OS) and clinicopathologic features in a large cohort of HCC patients. METHODS: We prospectively collected data and serum samples from 767 HCC patients treated at the University of Texas MD Anderson Cancer Center between 2001 and 2014, with a median follow-up of 67.4 months (95% confidence interval [CI]: 52.5, 83.3). Biomarker association with OS was evaluated by the log-rank method. RESULTS: The median OS in this cohort was 14.2 months (95% CI: 12, 16.1 months). Clinicopathologic features were more advanced, and OS was significantly inferior in patients with high circulating levels of IL1-R1, IL-6, IL-8, IL-10, IL-15, IL-16, and IL-18. CONCLUSION: Our study shows that several serum IL levels are valid prognostic biomarker candidates and potential targets for therapy in HCC.

Pain, Analgesic Use, and Patient Satisfaction With Spinal Versus General Anesthesia for Hip Fracture Surgery : A Randomized Clinical Trial.

BACKGROUND: The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported. OBJECTIVE: To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia. DESIGN: Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505). SETTING: 46 U.S. and Canadian hospitals. PARTICIPANTS: Patients aged 50 years or older undergoing hip fracture surgery. INTERVENTION: Spinal or general anesthesia. MEASUREMENTS: Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care. RESULTS: A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups. LIMITATION: Missing outcome data and multiple outcomes assessed. CONCLUSION: Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institute.

International multicenter validation of GES score for HCC risk stratification in chronic hepatitis C patients.

We have recently demonstrated the ability of a simple predictive model (GES) score to determine the risk of hepatocellular carcinoma (HCC) after using direct-acting antivirals. However, our results were restricted to Egyptian patients with hepatitis C virus (HCV) genotype 4. Therefore, we studied a large, independent cohort of multiethnic populations through our international collaborative activity. Depending on their GES scores, patients are stratified into low risk (≤ 6/12.5), intermediate risk (> 6-7.5/12.5), and high risk (> 7.5/12.5) for HCC. A total of 12,038 patients with chronic HCV were analyzed in this study, of whom 11,202 were recruited from 54 centers in France, Japan, India, the U.S., and Spain, and the remaining 836 were selected from the Gilead-sponsored randomized controlled trial conducted across the U.S., Europe, Canada, and Australia. Descriptive statistics and log-rank tests. The performance of the GES score was evaluated using Harrell's C-index (HCI). The GES score proved successful at stratifying all patients into 3 risk groups, namely low-risk, intermediate-risk, and high-risk. It also displayed significant predictive value for HCC development in all participants (p < .0001), with HCI ranging from 0.55 to 0.76 among all cohorts after adjusting for HCV genotypes and patient ethnicities. The GES score can be used to stratify HCV patients into 3 categories of risk for HCC, namely low-risk, intermediate-risk, and high-risk, irrespective of their ethnicities or HCV genotypes. This international multicenter validation may allow the use of GES score in individualized HCC risk-based surveillance programs.

Dietary N-Nitroso Compounds and Risk of Hepatocellular Carcinoma: A USA-Based Study.

BACKGROUND AND AIMS: N-nitroso compounds (NOCs) are among the most potent dietary carcinogens. N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), and N-nitrosopiperidine (NPIP) are abundant in foods and carcinogenic to the liver. We investigated the relationship between dietary NOCs and HCC risk. APPROACH AND RESULTS: In this large, hospital-based, case-control study of 827 pathologically or radiologically confirmed HCC cases and 1,013 controls, NOC intake was calculated by linking food frequency questionnaire-derived dietary data with a comprehensive NOC concentration database. Multivariable-adjusted ORs and 95% CIs of HCC by quartiles of NOC consumption were estimated using logistic regression models, with the lowest quartile as the referent. We further investigated joint effects of consuming the highest quartile of NOCs that were associated with increased HCC risk and hepatitis, diabetes, or alcohol drinking on HCC risk. After adjustment for confounding factors, higher intake of NDEA from plant sources (ORQ4 vs. Q1  = 1.58; 95% CI = 1.03-2.41), NDMA from plant sources (ORQ4 vs. Q1  = 1.54; 95% CI = 1.01-2.34), and NPIP (ORQ4 vs. Q1  = 2.52; 95% CI = 1.62-3.94) was associated with increased HCC risk. No association was observed for nitrate or total NOC intake and HCC risk. Higher consumption of HCC-inducing NOCs and positive hepatitis virus status jointly increased the risk of developing HCC. CONCLUSIONS: In conclusion, though some of our findings may indicate the presence of reverse causation owing to lower meat intake among cases with chronic liver diseases before HCC diagnosis, the potent dietary HCC carcinogens, NDEA, NDMA, and NPIP, and their enhanced carcinogenic effects among chronic carriers of hepatitis virus warrant further prospective investigation.

HepatoScore-14: Measures of Biological Heterogeneity Significantly Improve Prediction of Hepatocellular Carcinoma Risk.

BACKGROUND AND AIMS: Therapeutic, clinical trial entry and stratification decisions for hepatocellular carcinoma (HCC) are made based on prognostic assessments, using clinical staging systems based on small numbers of empirically selected variables that insufficiently account for differences in biological characteristics of individual patients' disease. APPROACH AND RESULTS: We propose an approach for constructing risk scores from circulating biomarkers that produce a global biological characterization of individual patient's disease. Plasma samples were collected prospectively from 767 patients with HCC and 200 controls, and 317 proteins were quantified in a Clinical Laboratory Improvement Amendments-certified biomarker testing laboratory. We constructed a circulating biomarker aberration score for each patient, a score between 0 and 1 that measures the degree of aberration of his or her biomarker panel relative to normal, which we call HepatoScore. We used log-rank tests to assess its ability to substratify patients within existing staging systems/prognostic factors. To enhance clinical application, we constructed a single-sample score, HepatoScore-14, which requires only a subset of 14 representative proteins encompassing the global biological effects. Patients with HCC were split into three distinct groups (low, medium, and high HepatoScore) with vastly different prognoses (medial overall survival 38.2/18.3/7.1 months; P < 0.0001). Furthermore, HepatoScore accurately substratified patients within levels of existing prognostic factors and staging systems (P < 0.0001 for nearly all), providing substantial and sometimes dramatic refinement of expected patient outcomes with strong therapeutic implications. These results were recapitulated by HepatoScore-14, rigorously validated in repeated training/test splits, concordant across Myriad RBM (Austin, TX) and enzyme-linked immunosorbent assay kits, and established as an independent prognostic factor. CONCLUSIONS: HepatoScore-14 augments existing HCC staging systems, dramatically refining patient prognostic assessments and therapeutic decision making and enrollment in clinical trials. The underlying strategy provides a global biological characterization of disease, and can be applied broadly to other disease settings and biological media.

Dietary Intake of Fatty Acids and Risk of Pancreatic Cancer: A Case-Control Study.

BACKGROUND: Epidemiological findings on dietary fat intake and risk of pancreatic cancer (PanC) are inconsistent. OBJECTIVES: This study aimed to determine the association between types of dietary fat intake and PanC. METHODS: We conducted a hospital-based case-control study in 957 pathologically confirmed PanC cases and 938 cancer-free controls. Cases and controls were frequency matched by age, sex, and race. Dietary information was collected using a self-administered validated FFQ. Unconditional logistic regression models were used to estimate the ORs and 95% CIs of PanC risk by quintiles of fat intake with the lowest quintile as referent and with adjustment for other risk factors and dietary factors. RESULTS: We observed no difference in (median) intake of total fat standardized for energy among cases versus controls. The multivariable-adjusted OR (95% CI) of the highest versus the lowest quintile of intake (ORQ5 compared with Q1) was 2.51 (1.68-3.72) for fat from animal sources and 0.41 (0.29-0.58) for fat from plant sources. Intakes of total MUFA, total PUFA, and linoleic (n-6) and long chain n-3 fatty acids were inversely associated with PanC (ORQ5 compared with Q1 and 95% CI: 0.55 [0.36-0.82], 0.59 [0.42-0.82], 0.64 [0.43-0.84], and 0.60 [0.42-0.84], respectively). Arachidonic acid (n-6) and several SFAs were positively associated with PanC. CONCLUSION: Although some observed associations with pancreatic cancer risk could be explained by reverse causation, the potential protective associations with intakes of largely plant-derived PUFAs and MUFAs and fish-derived long chain n-3 PUFAs warrant further prospective investigation.

Epigallocatechin gallate ameliorates tetrahydrochloride-induced liver toxicity in rats via inhibition of TGFß / p-ERK/p-Smad1/2 signaling, antioxidant, anti-inflammatory activity.

Chronic liver disease is a worldwide health problem. Carbon tetra hydrochloride is an environmental toxin which is regarded as highly toxic and a potential human carcinogen. It can cause liver damage through the generation of metabolites and production of free radicals. Green tea contains catechins such as Epigallocatechin gallate which has been found to reduce the inflammation, oxidative stress, and fibrosis in experimental animal models. Hence, it represents a good source to prevent or ameliorate several chronic diseases. Silymarin is extracted from milk thistle seeds and has been found to be an effective agent to reduce the oxidative stress and free radical production and thereby exert protective effects in chronic liver conditions. The present study was planned to keep in view the above-mentioned facts. We included thirty rats in our study and divided them into five groups, each having six rats and the study continued for 8 weeks. Group I received normal saline; Group 2 received i.p. CCl4 injections; Group 3 received CCl4 i.p. injection and Epigallocatechin gallate (EGCG) oral gavage, Group 4 received CCl4 i.p. injection and silymarin by oral gavage; and Group 5 received CCl4 i.p. injection and combined EGCG + silymarin by oral gavage. The study found that in group 2, CCl4 induced significant elevation of ALT and MDA and reduced GSH thereby signifying increased oxidative stress. CCl4 also significantly increased inflammatory (TNFα, NFκB, IL1ß, and TGFß) as well as fibrotic markers (p-ERK and p-Smad1/2 protein expression). EGCG and silymarin significantly reversed the previously mentioned parameters either alone or in combination; however, the effect was more pronounced in case of EGCG. We conclude that EGCG and silymarin possess liver protective effects through their antioxidant, anti-inflammatory, and antifibrotic action.

Dexmedetomidine for reduction of atrial fibrillation and delirium after cardiac surgery (DECADE): a randomised placebo-controlled trial.

BACKGROUND: Atrial fibrillation and delirium are common consequences of cardiac surgery. Dexmedetomidine has unique properties as sedative agent and might reduce the risk of each complication. This study coprimarily aimed to establish whether dexmedetomidine reduces the incidence of new-onset atrial fibrillation and the incidence of delirium. METHODS: A randomised, placebo-controlled trial was done at six academic hospitals in the USA. Patients who had had cardiac surgery with cardiopulmonary bypass were enrolled. Patients were randomly assigned 1:1, stratified by site, to dexmedetomidine or normal saline placebo. Randomisation was computer generated with random permuted block size 2 and 4, and allocation was concealed by a web-based system. Patients, caregivers, and evaluators were all masked to treatment. The study drug was prepared by the pharmacy or an otherwise uninvolved research associate so that investigators and clinicians were fully masked to allocation. Participants were given either dexmedetomidine infusion or saline placebo started before the surgical incision at a rate of 0·1 µg/kg per h then increased to 0·2 µg/kg per h at the end of bypass, and postoperatively increased to 0·4 µg/kg per h, which was maintained until 24 h. The coprimary outcomes were atrial fibrillation and delirium occurring between intensive care unit admission and the earlier of postoperative day 5 or hospital discharge. All analyses were intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT02004613 and is closed. FINDINGS: 798 patients of 3357 screened were enrolled from April 17, 2013, to Dec 6, 2018. The trial was stopped per protocol after the last designated interim analysis. Among 798 patients randomly assigned, 794 were analysed, with 400 assigned to dexmedetomidine and 398 assigned to placebo. The incidence of atrial fibrillation was 121 (30%) in 397 patients given dexmedetomidine and 134 (34%) in 395 patients given placebo, a difference that was not significant: relative risk 0·90 (97·8% CI 0·72, 1·15; p=0·34). The incidence of delirium was non-significantly increased from 12% in patients given placebo to 17% in those given dexmedetomidine: 1·48 (97·8% CI 0·99-2·23). Safety outcomes were clinically important bradycardia (requiring treatment) and hypotension, myocardial infarction, stroke, surgical site infection, pulmonary embolism, deep venous thrombosis, and death. 21 (5%) of 394 patients given dexmedetomidine and 8 (2%) of 396 patients given placebo, had a serious adverse event as determined by clinicians. 1 (<1%) of 391 patients given dexmedetomidine and 1 (<1%) of 387 patients given placebo died. INTERPRETATION: Dexmedetomidine infusion, initiated at anaesthetic induction and continued for 24 h, did not decrease postoperative atrial arrhythmias or delirium in patients recovering from cardiac surgery. Dexmedetomidine should not be infused to reduce atrial fibrillation or delirium in patients having cardiac surgery. FUNDING: Hospira Pharmaceuticals.

Epidemiological risk factors for adrenocortical carcinoma: A hospital-based case-control study.

Adrenocortical carcinoma (ACC) is a rare malignancy whose risk factors are unclear. We explored the association of ACC risk with exposure to selected environmental factors, with a focus on cigarette smoking. We conducted a hospital-based case-control study at The University of Texas MD Anderson Cancer Center. Cases (n = 432) patients with ACC treated at MD Anderson, and controls (n = 1,204) were healthy and genetically unrelated spouses of patients at MD Anderson who had cancers not associated with smoking. Information on the subjects' demographic features and selected risk factors was collected using a structured, validated questionnaire and medical records review. Unconditional logistic regression was used to calculate adjusted odds ratios (AORs) via the maximum-likelihood method. Cases had a younger mean (± standard deviation) age than did controls (47.0 ± 0.7 and 60.0 ± 0.3 years, respectively), and the majority of cases were female (60.6%) and non-Hispanic white (82.4%). We found a markedly increased risk of ACC among male cigarette smokers, with an AOR = 1.8 (95% confidence interval [CI] =1.2-2.9), but not among female smokers (AOR = 1.1, 95% CI = 0.7-1.6). Family history of cancer was associated with increased risk of ACC (AOR = 2.8, 95% CI 1.9-4.3) and in both men and women, whereas alcohol consumption was associated with reduced risk in men (AOR = 0.2, 95% CI = 0.1-0.3) but not women (AOR = 0.7, 95% CI = 0.5-1.1). Understanding these risk factors and their underlying mechanisms may help prevent ACC in susceptible individuals and eventually identify new therapeutic options for ACC.

Impact of Integrating Insulin-Like Growth Factor 1 Levels into Model for End-Stage Liver Disease Score for Survival Prediction in Hepatocellular Carcinoma Patients.

BACKGROUND: Liver reserve affects survival in hepatocellular carcinoma (HCC). Model for End-Stage Liver Disease (MELD) score is used to predict overall survival (OS) and to prioritize HCC patients on the transplantation waiting list, but more accurate models are needed. We hypothesized that integrating insulin-like growth factor 1 (IGF-1) levels into MELD score (MELD-IGF-1) improves OS prediction as compared to MELD. METHODS: We measured plasma IGF-1 levels in training (n = 310) and validation (n = 155) HCC cohorts and created MELD-IGF-1 score. Cox models were used to determine the association of MELD and MELD-IGF-1 with OS. Harrell's c-index was used to compare the predictive capacity. RESULTS: IGF-1 was significantly associated with OS in both cohorts. Patients with an IGF-1 level of ≤26 ng/mL in the training cohort and in the validation cohorts had significantly higher hazard ratios than patients with the same MELD but IGF-1 >26 ng/mL. In both cohorts, MELD-IGF-1 scores had higher c-indices (0.60 and 0.66) than MELD scores (0.58 and 0.60) (p < 0.001 in both cohorts). Overall, 26% of training and 52.9% of validation cohort patients were reclassified into different risk groups by MELD-IGF-1 (p < 0.001). CONCLUSIONS: After independent validation, the MELD-IGF-1 could be used to risk-stratify patients in clinical trials and for priority assignment for patients on liver transplantation waiting list.

Bayesian copy number detection and association in large-scale studies.

BACKGROUND: Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging due to biological and technical sources of heterogeneity that vary across the genome within and between samples. METHODS: We developed an approach called CNPBayes to identify latent batch effects in genome-wide association studies involving copy number, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. RESULTS: Applying a hidden Markov model (HMM) to identify CNVs in a large multi-site Pancreatic Cancer Case Control study (PanC4) of 7598 participants, we found CNV inference was highly sensitive to technical noise that varied appreciably among participants. Applying CNPBayes to this dataset, we found that the major sources of technical variation were linked to sample processing by the centralized laboratory and not the individual study sites. Modeling the latent batch effects at each CNV region hierarchically, we developed probabilistic estimates of copy number that were directly incorporated in a Bayesian regression model for pancreatic cancer risk. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Suppressor Candidate 3 (TUSC3). CONCLUSIONS: Laboratory effects may not account for the major sources of technical variation in genome-wide association studies. This study provides a robust Bayesian inferential framework for identifying latent batch effects, estimating copy number, and evaluating the role of copy number in heritable diseases.

Retrospective analysis of long-term outcome 10 years after liver transplantation for Wilson disease: experience over three decades.

We evaluated long-term outcomes for patients with Wilson disease (WD) after liver transplantation (LT) and searched for risk factors for poor survival. Retrospective analysis of UNOS/OPTN data identified 156 pediatric and 515 adult cases of LT for WD between 1987 and 2016. Comparison cases were 10 442 pediatric and 104 874 adult non-WD transplant recipients. Survival was calculated using Kaplan-Meier analysis. Recipient, donor, and surgical variables were compared by Cox regression. Survival rates 3, 5, and 10 years after LT for adult WD patients (87.5%, 85.4%, and 80.5%, respectively) were significantly higher than those for non-WD patients (P < 0.001); survival rates for pediatric WD patients (90.5%, 89.7%, and 86.5%, respectively) did not differ significantly from non-WD patients. Graft survival in adult and pediatric patients followed similar trends. Regression analysis identified older age, female gender, and use of life support at the time of transplant as risk factors for decreased survival for adults with WD, and younger age, male gender, obesity, and high serum creatinine at the time of transplant as risk factors for poor survival in pediatric recipients with WD. Presentation with fulminant liver failure was not associated with survival in WD patients. No donor characteristic predicted poor survival. Long-term patient and graft survival after LT is excellent for both adult and pediatric WD patients.

Dietary N-nitroso compounds and risk of pancreatic cancer: results from a large case-control study.

N-nitroso compounds (NOCs) are among the most potent dietary and pancreatic carcinogens. N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) are the most prevalent NOCs identified in foods. Using a validated and comprehensive N-nitroso database developed to estimate total NOCs and important individual NOCs from food intake, we investigated dietary exposure to NOCs in relation to pancreatic cancer in a large matched case-control study. Self-administered food frequency questionnaires were collected from 957 pathologically confirmed pancreatic ductal adenocarcinoma cases and 938 frequency-matched controls. For each food item, frequency of intake and portion size in grams was multiplied by the estimated NOC concentration from the N-nitroso database. Multiple unconditional logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CIs) for pancreatic cancer risk by quartiles of NOCs and major food group contributors to NOCs, with the lowest quartile as referent. Following adjustment for confounders, we observed significant positive associations for NDEA (ORQ4 versus Q1 = 2.28, 95% CI = 1.71-3.04, Ptrend < 0.0001) and NDMA from plant sources (ORQ4 versus Q1 = 1.93, 95% CI = 1.42-2.61, Ptrend < 0.0001) with pancreatic cancer. The major food groups related to NDEA and NDMA intakes in this population were fermented cheese, pizza, grains, seafood and beer. No associations of intake of nitrate or total NOCs were observed; nitrite was inversely associated with pancreatic cancer. Although some of our findings probably reflect reverse causation bias due to lower meat intake in cases with latent disease, biologically plausible findings for pancreatic carcinogens, NDEA and NDMA, warrant further prospective investigation.

Vitamin C and Vitamin E Mitigate the Risk of Pancreatic Ductal Adenocarcinoma from Meat-Derived Mutagen Exposure in Adults in a Case-Control Study.

BACKGROUND: Previous studies have found that meat-derived mutagens increase, and vitamin C or E decrease, the risk of pancreatic cancer. OBJECTIVE: The aim of this study was to determine whether intake of vitamin C or E modulates the association between meat-derived mutagen exposure and risk of pancreatic cancer. DESIGN: We conducted a case-control study in 1321 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 1061 healthy controls (aged 28-88 y). Cases and controls were frequency-matched by age, sex, and race/ethnicity. Mutagen intake was assessed using a meat preparation questionnaire. Intakes of vitamin C, E, and other dietary components were assessed via a food-frequency questionnaire in a subset of 811 cases and 818 controls. ORs and 95% CIs were estimated in multivariable-adjusted logistic regression models. RESULTS: The risk of PDAC was not associated with meat intake but was associated with consumption of well-done grilled or barbecued chicken (OR: 1.57; 95% CI: 1.18, 2.09; P = 0.001). Intake of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline was associated with increased PDAC risk (Ptrend = 0.047). Participants in the highest, as compared with the lowest, quintile of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (PhIP) intake experienced a 38% increased risk of PDAC (95% CI: 1.00, 1.90; P = 0.048). Intakes of total vitamin C or E from food and supplements or from supplements alone were each inversely associated with PDAC risk. Stratified analyses showed differential associations for PhIP intake and PDAC risk, such that risk increased among individuals with lower intake of vitamin C or E and decreased among those with higher vitamin intake. Significant interactions of dietary vitamin C, dietary vitamin E, and total vitamin E with PhIP intake were detected (Pinteraction = 0.023, <0.001, and 0.013, respectively). CONCLUSIONS: Consistent with experimental evidence, this study of 811 cases and 818 controls has shown that high intake of dietary vitamin C or E mitigates the risk of PhIP-related PDAC.

Automated Volumetric Assessment of Hepatocellular Carcinoma Response to Sorafenib: A Pilot Study.

PURPOSE: This pilot study evaluates the feasibility of automated volumetric quantification of hepatocellular carcinoma (HCC) as an imaging biomarker to assess treatment response for sorafenib. METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, a training database of manually labeled background liver, enhancing and nonenhancing tumor tissue was established using pretherapy and first posttherapy multiphasic computed tomography images from a registry of 13 HCC patients. For each patient, Hounsfield density and geometry-based feature images were generated from registered multiphasic computed tomography data sets and used as the input for a random forest-based classifier of enhancing and nonenhancing tumor tissue. Leave-one-out cross-validation of the dice similarity measure was applied to quantify the classifier accuracy. A Cox regression model was used to confirm volume changes as predictors of time to progression (TTP) of target lesions for both manual and automatic methods. RESULTS: When compared with manual labels, an overall classification accuracy of dice similarity coefficient of 0.71 for pretherapy and 0.66 posttherapy enhancing tumor labels and 0.45 for pretherapy and 0.59 for posttherapy nonenhancing tumor labels was observed. Automated methods for quantifying volumetric changes in the enhancing lesion agreed with manual methods and were observed as a significant predictor of TTP. CONCLUSIONS: Automated volumetric analysis was determined to be feasible for monitoring HCC response to treatment. The information extracted using automated volumetrics is likely to reproduce labor-intensive manual data and provide a good predictor for TTP. Further work will extend these studies to additional treatment modalities and larger patient populations.

Genetic polymorphisms associated with pancreatic cancer survival: a genome-wide association study.

Previous findings on the association of genetic factors and pancreatic cancer survival are limited and inconsistent. In a two-stage study, we analyzed the existing genome-wide association study dataset of 868 pancreatic cancer patients from MD Anderson Cancer Center in relation to overall survival using Cox regression. Top hits were selected for replication in another 820 patients from the same institution using the Taqman genotyping method. Functional annotation, pathway analysis and gene expression analysis were conducted using existing software and databases. We discovered genome-wide significant associations of patient survival with three imputed SNPs which, in complete LD (r2 = 1), were intronic SNPs of the PAIP2B (rs113988120) and DYSF genes (rs112493246 and rs138529893) located on Chromosome 2. The variant alleles were associated with a 3.06-fold higher risk of death [95% confidence interval (CI) = 2.10-4.47, p=6.4 × 10-9] after adjusting for clinical factors. Eleven SNPs were tested in the replication study and the association of rs113988120 with survival was confirmed (hazard ratio: 1.57, 95% CI: 1.13-2.20,  p=0.008). In silico analysis found rs1139988120 might lead to altered motif. This locus is in LD (D' = 0.77) with three eQTL SNPs near or belong to the NAGK and MCEE genes. According to The Cancer Genome Atlas data and our previous RNA-sequencing data, the mRNA expression level of PAIP2B but not NAGK, MCEE or DYSF was significantly lower in pancreatic tumors than in normal adjacent tissues. Additional validation efforts and functional studies are warranted to demonstrate whether PAIP2B is a novel tumor suppressor gene and a potential therapeutic target for pancreatic cancer.