Hypercontractility of the cardiac sarcomere may be essential for the underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. Aficamten (CK-274) is a novel cardiac myosin inhibitor that was discovered from the optimization of indoline compound 1. The important advancement of the optimization was discovery of an Indane analogue (12) with a less restrictive structure-activity relationship that allowed for the rapid improvement of drug-like properties. Aficamten was designed to provide a predicted human half-life (t1/2) appropriate for once a day (qd) dosing, to reach steady state within two weeks, to have no substantial cytochrome P450 induction or inhibition, and to have a wide therapeutic window in vivo with a clear pharmacokinetic/pharmacodynamic relationship. In a phase I clinical trial, aficamten demonstrated a human t1/2 similar to predictions and was able to reach steady state concentration within the desired two-week window.

OBJECTIVES A bicuspid aortic valve (BAV) is characterized by variable phenotypic manifestations, as well as longitudinal evolution of valve dysfunction and ascending aorta dilatation. The present study investigated the impact of severe aortic stenosis (AS) on the flow patterns and wall shear stress (WSS) distribution in BAV patients with right-left (RL) and right-non-coronary (RN) cusp fusion types, and the study aimed to reveal whether aortic dysfunction could further alter intrinsic aortic haemodynamic aberrations generated by abnormal BAV cusp fusion patterns. METHODS Four-dimensional flow magnetic resonance imaging was performed in 120 BAV subjects and 20 tricuspid aortic valve controls. BAV patients were evenly categorized into 4 cohorts, including RL and RN BAV with no more than mild aortic dysfunction as well as RL and RN BAV-AS with isolated severe AS. RESULTS BAV subjects exhibited eccentric outflow jets resulting in regional WSS elevation at the right-anterior position of the ascending aorta in the RL group and the right-posterior location in the RN group (P < 0.005). The presence of severe AS resulted in accelerated outflow jets and more prominent flow and WSS eccentricity (P < 0.005) by marked helical (P = 0.014) and vortical flow formation (P < 0.005), as well as increased prevalence of tubular and transverse arch dilatation. The changes to the flow jet in BAV-AS subjects blurred the differences in peak flow velocity and WSS distribution between RL and RN BAV. Differences in the phenotypes of aortopathy were associated with changes in functional haemodynamic parameters such as flow displacement and WSS eccentricity. CONCLUSIONS Severe AS markedly exacerbated aortic flow aberrations in BAV patients and masked the existing distinct flow features deriving from RL and RN fusion types. Longitudinal studies are needed to investigate the evolution of ascending aortic dilatation relative to the interaction between intrinsic cusp fusion types and acquired severe valve dysfunction.

Objectives Our goal was to investigate the correlation between histopathology and diffusion parameters by utilising the most repeatable region-of-interest (ROI) strategy for diffusion parameters in rectal cancer on a 3T scanner. Methods 113 patients underwent DKI-MR and 66 of these patients received surgery without neoadjuvant chemoradiotherapy. Two readers independently measured the parameters using three slice protocols including single slice, three slices and whole-tumour slice (WTS), combined with one of two ROIs, including outline and round ROI. ANOVA, Kruskal-Wallis, a paired sample t-test, interclass correlation coefficient (ICC), Bland-Altman, Student’s t-tests, receiver operating characteristic curves and z statistic were used for statistical analysis. Results There were no significant differences among the three slice protocols in ADC values ( p = 0.822, 0.987), K values ( p = 0.842, 0.859) and D values ( p = 0.917, 0.988) using round and outline ROI, respectively. The ADC and D values derived from outline ROIs were higher than those from round ROIs (all p < 0.001 for ADC, all p < 0.001 for D), while K values derived from outline ROIs were lower than those from round ROIs ( p < 0.001, p = 0.001, p < 0.001) using three slice protocols, respectively. The WTS-outline ROI resulted in the best intra- and inter-observer ICC. Utilising the WTS-outline ROI method, the AUC for assessment of well-differentiated tumours was 0.871 by K and 0.809 by ADC; and the AUC for T2 was 0.768 by K. Conclusions The most repeatable strategy was the WTS-outline ROI method. In addition to DWI, DKI also have diagnostic value for rectal cancer histopathological characteristics utilising the WTS-outline ROI on a 3T scanner. Key Points • DKI using a 3T scanner is feasible for assessing rectal cancer. • ROI and slice protocol show considerable influence on DKI parameters. • DKI parameters exhibit excellent repeatability using whole-tumour slice-outline ROI on 3T scanner. • DKI has considerable diagnostic value for the estimation of rectal cancer characteristics.

PURPOSE We set out to explore the probability of MRI-detected extramural vascular invasion (mr-EMVI) before chemoradiation to predict responses to chemoradiation and survival in stage T3 rectal cancer patients. METHODS A total of 100 patients with T3 rectal cancer who underwent MRI examination and received neoadjuvant chemoradiation and surgery were enrolled. The correlation between mr-EMVI and other clinical factors were analyzed by chi-square. Logistic regression model was performed to select the potential factors influencing tumor responses to neoadjuvant chemoradiation. A Cox proportional hazards regression model was performed to explore potential predictors of survival. RESULTS The positive mr-EMVI result was more likely to be present in patients with a higher T3 subgroup (T3a+b = 7.1% vs. T3c+d = 90.1%, P < 0.001) and more likely in patients with mesorectal fascia involvement than in those without MRF (65% vs. 38.8%, P = 0.034). Compared with mr-EMVI (+) patients, more mr-EMVI (-) patients showed a good response (staged ≤ ypT2N0) (odds ratio [OR], 3.020; 95% confidence interval [CI], 1.071-8.517; P = 0.037). In univariate analysis, mr-EMVI (+) (hazard ratio [HR], 5.374; 95% CI, 1.210-23.872; P = 0.027) and lower rectal cancers (HR, 3.326; 95% CI, 1.135-9.743; P = 0.028) were significantly associated with decreased disease-free survival. A positive mr-EMVI status (HR, 5.727; 95% CI, 1.286-25.594; P = 0.022) and lower rectal cancers (HR, 3.137; 95% CI, 1.127-8.729; P = 0.029) also served as prognostic factors related to decreased disease-free survival in multivariate analysis. CONCLUSION The mr-EMVI status before chemoradiation is a significant prognostic factor and could be used for identifying T3 rectal cancer patients who might benefit from neoadjuvant chemoradiation.

Most patients with hypertrophic cardiomyopathy have single-gene autosomal dominant mutations in loci that encode for sarcomeric proteins. The aim of this study was to determine whether pathogenic mutations were present by whole-exome sequencing (WES) in two families with hypertrophic cardiomyopathy (HCM) that presented during adolescence. Blood samples and clinical data were collected from individuals in two families with HCM. DNA was extracted. Mutations were identified using whole-exome sequencing (WES), and the genotypes of family members were identified using Sanger sequencing. Compound heterozygous mutations in the MYBPC3 gene (c.659A > G, p.Tyr220Cys; c.772G > A, p.Glu258Lys,NM_000256, Family 1), (c.873delG, p. Ile292PhefsTer8; c.3G > A, p.Met1?, NM_000256, Family 2) were identified by WES. Patient 1 carried the maternally inherited c.659A > G mutation and the paternally inherited c.772G > A mutation. Patient 2 carried the maternally inherited frameshift mutation c.873delG and the paternally inherited mutation c.3G > A. Two families with HCM presenting during adolescence (age of onset is about 11 years old) demonstrated compound heterozygous mutations in the MYBPC3 gene. These findings suggested an association of MYBPC3 mutations with the early onset of symptoms and worsened prognoses. Our study highlights the importance of genetic screening of all family members in cases of HCM.

OBJECTIVES:Bicuspid aortic valve, characterized by valve malformation and risk for aortopathy, displays profound alteration in systolic aortic outflow and wall shear stress distribution. The present study performed 4-dimensional flow magnetic resonance imaging in patients with bicuspid aortic valve with right-left cusp fusion, focusing on the impact of valve function on hemodynamic status within the ascending aorta. METHODS:Four-dimensional flow magnetic resonance imaging was performed in 50 subjects with right-left bicuspid aortic valve and 15 age- and aortic size-matched controls with tricuspid aortic valve. Patients with bicuspid aortic valve were categorized into 3 groups according to their aortic valve function as follows: bicuspid aortic valve with no more than mild aortic valve dysfunction (bicuspid aortic valve control, n = 20), bicuspid aortic valve with severe aortic insufficiency (n = 15), and bicuspid aortic valve with severe aortic stenosis (n = 15). RESULTS:All patients with right-left bicuspid aortic valve exhibited peak wall shear stress at the right-anterior position of the ascending aorta (bicuspid aortic valve vs trileaflet aortic valve at the right-anterior position: 0.91 ± 0.23 N/m2 vs 0.43 ± 0.12 N/m2, P < .001) with no distinct alteration between bicuspid aortic valve with severe aortic insufficiency and bicuspid aortic valve with severe aortic stenosis. The predominance of dilatation involving the tubular ascending aorta (82%, type 2 aortopathy) persisted, with or without valve dysfunction. Compared with bicuspid aortic valve control subjects, the bicuspid aortic valve with severe aortic insufficiency group displayed universally elevated wall shear stress (0.75 ± 0.12 N/m2 vs 0.57 ± 0.09 N/m2, P < .01) in the ascending aorta, which was associated with elevated cardiac stroke volume (P < .05). The bicuspid aortic valve with severe aortic stenosis group showed elevated flow eccentricity in the form of significantly increased standard deviation of circumferential wall shear stress, which correlated with markedly increased peak aortic valve velocity (P < .01). CONCLUSIONS:The location of peak aortic wall shear stress and type of aortopathy remained homogeneous among patients with right-left bicuspid aortic valve irrespective of valve dysfunction. Severe aortic insufficiency or stenosis resulted in further elevated aortic wall shear stress and exaggerated flow eccentricity.

Objective: The objective of this study is to evaluate novel variations in a Chinese family of Han ethnicity, with arrhythmogenic right ventricular cardiomyopathy (ARVC) by the powerful technology of whole-exome sequencing (WES). Methods: Genomic DNA from representative family members was extracted and processed for WES via standardized methods. The exome sequence data were analyzed by Genome Analysis Toolkit software. Sanger sequencing was performed on DNA from the proband for genotype confirmation and from the other family members for familial co-segregation analysis. Results: A rare single nucleotide variant c.1592T>G (p.Phe531Cys) in exon 10 of desmoglein-2 (DSG2) was identified by WES in the affected individuals but not in the healthy control, which was confirmed by Sanger sequencing, suggesting that the mutation probably was a causal mutation for the familial disorder of ARVC. Conclusion: We identified a rare disease-causing mutation of the DSG2 gene associated with familial ARVC. The results might contribute to the early genetic analysis in inherited cardiomyopathies.

Bicuspid aortic valve (BAV) exhibits a clinical incline toward aortopathy, in which aberrant tensile and shear stress generated by BAV can induce differential expression of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs). Whether stenotic BAV, which exhibits additional eccentric high-velocity flow jet upon ascending aorta and further worsens circumferential systolic wall shear stress than BAV with echocardiographically normal aortic valve, can lead to unique plasma MMP/TIMP patterns is still unknown. According to their valvulopathy and aortic dilatation status, 93 BAV patients were included in the present study. Group A ( n = 37) and B ( n = 28) comprised severely stenotic patients with or without ascending aorta dilatation; Group C ( n = 12) and D ( n = 16) comprised echocardiographically normal BAV patients with or without ascending aorta dilatation. Plasma MMP/TIMP levels (MMP-1, -2, -3, -8, -9, -10, -13 and TIMP-1, -2, -4) were determined via a multiplex ELISA detection system in a single procedure. Among patients with isolated severe aortic stenosis, plasma levels of MMP-2 and -9 were significantly elevated when ascending aortic dilatation was present ( p = 0.001 and p = 0.002, respectively). MMP-2, however, remained as the single elevated plasma component among echocardiographically normal BAV patients with dilated ascending aorta ( p = 0.027). Multivariate analysis revealed that MMP-2 and MMP-9 could both serve as independent risk factor for aortic dilatation in the case of isolated severe stenosis ( p = 0.003 and p = 0.001, respectively), and MMP-2 in echocardiographically normal patients ( p = 0.002). In conclusion, BAV patients with isolated severe aortic stenosis demonstrated a distinct plasma MMP/TIMP pattern, which might be utilized as circulating biomarkers for early detection of aortic dilatation.

Development of multifunctional nanoprobes for tumor diagnosis is extremely important in the field of molecular imaging. In this study, the facile synthesis of lactobionic acid (LA)-targeted superparamagnetic iron oxide (Fe3O4) nanoparticles (NPs) with ultrahigh relaxivity for targeted magnetic resonance (MR) imaging of an orthotopic hepatocellular carcinoma (HCC) is reported. Polyethyleneimine (PEI)-stabilized Fe3O4 NPs prepared via a mild reduction route are sequentially coupled with fluorescein isothiocyanate and polyethylene glycol-LA (LA-PEG-COOH) segment, followed by acetylation of the remaining PEI surface amines. The formed LA-targeted Fe3O4 NPs are thoroughly characterized. It is shown that the developed multifunctional LA-targeted Fe3O4 NPs are colloidally stable and water-dispersible, display an ultrahigh r(2) relaxivity (579.89 x 10(-3) m (-1) s(-1)) and excellent hemocompatibility and cytocompatibility in the given concentration range, and can target HepG2 cells overexpressing asialoglycoprotein receptors as confirmed by in vitro cellular uptake assay, flow cytometry, and confocal microscopy. Most strikingly, the developed multifunctional LA-targeted Fe3O4 NPs can be used as a nanoprobe for targeted MR imaging of HepG2 cells in vitro and an orthotopic tumor model of HCC in vivo. With the ultrahigh r(2) relaxivity and the versatile PEI amine-mediated conjugation chemistry, a range of different Fe3O4 NP-based nanoprobes may be developed for theranostics of different types of cancer.

Object: The aim of this study was to assess the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI)-derived pharmacokinetic parameters between two contrast agents in a murine orthotopic pancreatic cancer model and to evaluate the tumor heterogenity and the potential association between kinetic parameters and angiogenic markers such as the microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression by immunohistochemistry.Materials and methods: Human pancreatic adenocarcinoma cell line MIAPaCa-2 was injected into the pancreas of BALB/C nu/nu mice. DCE-MRI was performed using Gd-DTPA and Gd-EOB-DTPA. Quantitative and semi-quantitative vascular parameters (K-trans, K-ep, v(e) and AUC) were calculated by using a dedicated postprocessing software program. Values were compared with tumor rim, tumor core and the entire tumor. The MVD and VEGF expressions between tumor rim and tumor core were also compared.Results: There were no significant differences in K-trns, K-ep, V-e, and AUC values of the three groups when using Gd-DTPA. However there were significant differences in K-trans, K-ep and AUC values of the three groups when using Gd-EOB-DTPA (P = 0.014, 0.022, 0.007, respectively), in addition, the K-trans and K-ep values of tumor core were significantly lower than those of the entire tumor (adjusted P = 0.014 and 0.027, respectively), the AUC values of core were significantly lower than those of the entire tumor and rim (adjusted P = 0.039 and 0.009, respectively). Immunohistology results revealed that MVD and VEGF expression in the tumor rim was significantly higher than that in the core. There was positive correlation between AUC and MVD, VEGF.Conclusion: The murine orthotopic pancreatic cancer model provides an ideal animal model to study human pancreatic cancer. It can more sensitively semi-quantitatively and quantitatively analyze tumor angiogenesis through selecting the albumin-binding contrast agent. (C) 2015 Elsevier Inc. All rights reserved.

Although the American College of Gastroenterology colorectal cancer screening guidelines highlight cigarette smoking as a risk factor, cigarette smoking is still an arguably underappreciated risk factor for this disease, especially for its subsites: colon cancer (CC) and rectal cancer (RC). A literature search of MEDLINE and EMBASE was performed up to 30 April 2013 for prospective cohort studies. A random-effects meta-analysis was carried out to estimate the summary relative risks (SRRs) and 95% confidence intervals (CIs) for the associations. A total of 24 prospective studies, which reported data for cigarette smoking and incidence of CC and RC separately, were included. Our analysis showed that, compared with never-smokers, current smokers had a higher risk of RC than CC (CC: SRR=1.09, 95% CI, 1.01–1.18; RC: SRR=1.24, 95% CI, 1.16–1.39; PRC vs. CC=0.034), whereas former smokers had a similar risk of CC and RC. Current smokers had a significantly higher risk of proximal CC than distal CC (P=0.035). This meta-analysis suggests that cigarette smoking is associated with an increased risk of both CC and RC, and that the magnitude of the association is stronger for RC than that for CC.

Background and aims: Quantification of the association between consumption of fruit and vegetables and risk of gastric cancer (GC) is controversial. We aimed to conduct a meta-analysis of cohort studies to evaluate the associations.Methods: Eligible studies published up to 31st August 2013 were retrieved via both computer searches of PubMed and EMBASE and a manual review of references. Random-effects models were used to calculate summary relative risk (SRR). Heterogeneity among studies was assessed using Cochran's Q and I-2 statistics.Results: A total of 17 articles (24 studies), were included in this meta-analysis. There were >2.4 million individuals (6632 GC events) with a median follow-up of 10 years. Based on the high versus low analysis, consumption of fruit, but not vegetables, may reduce risk of gastric cancer (fruit: SRR = 0.90, 95% confidence interval (CI): 0.83-0.98, P-heterogeneity = 0.450; vegetable: SRR = 0.96, 95% CI: 0.88-1.06, P-heterogeneity = 0.150). Meta regression analysis suggested that outcome (incidence versus mortality) and study quality (high versus low) contributed significantly to heterogeneity. The same results were also shown in the linear dose-response analysis (per 100-g/day) (fruit: SRR = 0.95, 95% CI: 0.91-0.99; vegetable: SRR = 0.96, 95% CI: 0.91-1.01). Significant inverse associations emerged in non-linear models for consumption of fruit (Pnon-linearity = 0.04), but not for consumption of vegetables (Pnon-linearity = 0.551).Conclusions: Findings from this meta-analysis indicate a significant protective effect for the consumption of fruit on GC risk, but not for the consumption of vegetables. (C) 2014 Elsevier Ltd. All rights reserved.

The aim of this study was to successfully establish an orthotopic murine model using two different human pancreatic adenocarcinoma cell lines and to propose a 3.0 tesla MRI protocol for noninvasive characterization of this model. SW1990 and MIAPaca-2 tumor cells were injected into the pancreas of BALB/C nu/nu mice. Tumor growth rate and morphological information were assessed by 3.0 tesla MRI (T1WI, T2WI and DCE-MRI) and immunohistology. Proliferation of SW1990 was significantly faster than that of MIAPaca-2 (P=0.000), but MIAPaca-2 mice had a significantly shorter survival than SW1990 mice (41 days and 44 days respectively, P=0.027). MRI could reliably monitor tumor growth in both cell lines: the tumors exhibiting a spherical growth pattern showed a high-intensity signal, and the SW1990 group developed significantly larger tumors compared with the MIAPaCa-2 group. There were no statistical differences between the two groups in which tumor size was assessed using electronic calipers and an MRI scan (P=0.680). Both tumors showed a slow gradual enhancement pattern. Immunohistochemistry demonstrated tumor tissues showing high expression of Ki-67. This model closely mimics human pancreatic cancer and permits monitoring of tumor growth and morphological information by noninvasive 3.0 tesla MRI studies reducing the number of mice required.

ABSTRACT The morphology of the trigeminal ganglion in human fetus was investigated by means of the tract‐tracing method using the lipophilic dye DiI‐C18‐(3) (1,1′‐double octadecane 3,3,3′3′‐tetramethyl indole carbonyl cyanine‐perchlorate), hematoxylin–eosin (HE) stain, and three‐dimensional computer reconstruction models. The trigeminal ganglion was flat in the dorsoventral direction, and DiI staining revealed that the trigeminal ganglion cells were somatotopically distributed in the ganglion in a way that reflected the mediolateral order of the three branches. Ganglion cells of the ophthalmic nerve were distributed in the anteromedial part of the trigeminal ganglion, those of the mandibular nerve were in the posterolateral part, and those of the maxillary nerve were localized in the intermediate part. DiI labeled both ganglion cells and nerve fibers in the trigeminal ganglion; the ganglion cells varied in size and appeared as round‐ or oval‐shaped, the neurites connected the cell soma, and some bipolar neurons were also observed. The number of embryonic trigeminal ganglion cells did not significantly change with gestational age, but the cell diameter, area, and perimeter significantly increased. The motor root leaves the pons, runs along the sensory root, passes the ventral surface of the ganglion, and finally runs together with the mandibular nerve. The findings reported here elucidate the morphology, development, and somatotopic organization of the trigeminal ganglion and reveal the trigeminal nerve motor root pathway along the trigeminal ganglion and mandibular nerve in the human fetus. Microsc. Res. Tech. 76:598–605, 2013 . © 2013 Wiley Periodicals, Inc.

Abstract Background: To provide a quantitative assessment of the association between body mass index (BMI) and the risk of gastric cancer, we summarized the evidence from prospective studies. Methods: Eligible studies published up to November 30, 2012, were retrieved via computer searches of MEDLINE and EMBASE as well as manual review of references. Summary relative risks (SRR) with their corresponding 95% confidence intervals (CI) were calculated using a random-effects model. Results: A total of 24 prospective studies of BMI and gastric cancer risk with 41,791 cases were included in our analysis. Overall, both overweight (BMI, 25–30 kg/m2) and obesity (BMI, ≥30 kg/m2) were not associated with risk of total gastric cancer (overweight: SRR, 1.01; 95% CI, 0.96–1.07; obesity: SRR, 1.06; 95% CI, 0.99–1.12). Furthermore, we found increased BMI was positively associated with the risk of gastric cardia cancer (GCC; SRR = 1.21 for overweight and 1.82 for obesity), but not with gastric non-cardia cancer (GNCC; SRR = 0.93 for overweight and SRR = 1.00 for obesity). Similar results were observed in a linear dose–response analysis. Conclusion: On the basis of meta-analysis of prospective studies, we find high BMI is positively associated with the risk of GCCs but not with GNCCs. Impact: (i) On the basis of more definite and quantitative evidence than previously available, we found that increasing BMI was not a clear risk factor for total gastric cancer. (ii) Increased BMI was positively associated with risk of GCC but not with GNCCs. Cancer Epidemiol Biomarkers Prev; 22(8); 1395–408. ©2013 AACR.

In recent years, increasing evidence has suggested a strong association between diabetes mellitus (DM) and hepatocellular carcinoma (HCC). To provide a quantitative assessment of this association, we performed a systematic review and meta-analysis of cohort studies. We collected studies through a literature search of Medline from January 1, 1966 and EMBASE from January 1, 1974, through July 31, 2010. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. A total of 25 cohort studies that met our inclusion and exclusion criteria were included in our analysis. Among these, 18 studies showed that DM was associated with an increased incidence of HCC (SRRs = 2.01, 95% CI: 1.612.51), compared with individuals without DM. There was a statistically significant heterogeneity among these studies (Q = 136.68, p < 0.001, I2 = 87.6%). Analyses subgrouped by controlling confounders revealed that the increased incidence of HCC was independent of geographic location, alcohol consumption, history of cirrhosis, or infections with hepatitis B (HBV) or hepatitis C virus (HCV). In addition, DM was also positively associated with HCC mortality (SRR = 1.56; 95% CI: 1.301.87), with no significant evidence of heterogeneity among studies (Q = 1.16, p = 0.56, I2 =0%). There were no significant publication bias (p = 0.79 for Egger's regression asymmetry test). These findings strongly support a positive association between DM and increased risk of HCC in both males and females.

Aims: To provide a quantitative assessment of the association between excess body weight (EBW) and the risk of primary liver cancer (PLC), we performed an updated meta-analysis of prospective observational studies.Methods: We searched PUBMED and EMBASE for studies of body mass index and the risk of PLC published through 15 th September 2011. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. The meta-regression and stratified methods were used to examine heterogeneity across studies.Results: A total of 26 prospective studies, including 25,337 PLC cases, were included in this analysis. Overall, excess body weight (EBW: body mass index (BMI) >= 25 kg/m(2)) and obesity (BMI >= 30 kg/m(2)) were associated with an increased risk of PLC, with significant heterogeneity (EBW: SRRs 1.48, 95% CIs 1.31-1.67, P-h < 0.001, I-2 = 83.6%; Obesity: SRRs 1.83, 95% CIs 1.59-2.11, P-h < 0.001, I-2 = 75.0%). Subgroup analyses revealed that the positive associations were independent of geographic locations, alcohol consumption, history of diabetes or infections with hepatitis B (HBV) and/or hepatitis C virus (HCV). Obese males had a higher risk of PLC than obese females did (P = 0.027). A stronger risk of PLC with EBW was observed for patients with HCV (but not HBV) infection or cirrhosis compared with the general population.Conclusions: Findings from this meta-analysis strongly support that EBW or obesity is associated with an increased risk of PLC in both males and females. (c) 2012 Elsevier Ltd. All rights reserved.

Data from epidemiological studies related to the association of cholecystectomy and pancreatic cancer (PaC) risk are inconsistent. We conducted a meta-analysis of observational studies to explore this relationship.