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BACKGROUND: Plant-rich diets are associated with lower cardiometabolic risks and longer survival in the general population, but their association with mortality in cancer survivors is still unclear. OBJECTIVES: We aimed to examine the associations of 3 postdiagnostic plant-based diet indices with all-cause mortality in omnivorous long-term colorectal cancer (CRC) survivors. METHODS: Diet was assessed with FFQs at a median of 6 years after diagnosis in 1404 CRC survivors (56% male; median age, 69 years) in a Northern German prospective cohort study. An overall, a healthful plant-based, and an unhealthful plant-based diet index were derived by scoring intakes of animal foods reversely and intakes of healthy (whole grains, vegetables, fruits, legumes, nuts, oils, tea/coffee) and less healthy plant foods (refined grains, fruit juices, sugar-sweetened beverages, potatoes, sweets/desserts) positively or reversely, depending on the index. Vital status follow-up was conducted via population registries. Cox proportional hazards regression was applied to estimate HRs for all-cause mortality according to plant-based diet adherence. RESULTS: Within 7 years (median) after diet assessment, 204 deaths occurred. The overall plant-based diet index displayed a significant, inverse association with all-cause mortality (HR per 10-point increase in diet index, 0.72; 95% CI, 0.57–0.91). Although not statistically significant, higher healthful plant-based diet scores showed a strong tendency towards lower mortality (HR, 0.82; 95% CI, 0.67–1.01). The unhealthful plant-based diet index was associated with higher mortality, but lost statistical significance after multivariable adjustment (HR, 1.19; 95% CI, 0.96–1.48). A subgroup analysis revealed that the tendency towards a positive association of the unhealthful plant-based diet with mortality was restricted to less physically active individuals (

Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian ancestry (10–20%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany (n = 3702) and one admixed Latin American cohort from Chile (n = 1076). We detected 2936 large and rare CNVs events (size > 100 kb, frequency

ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (pCTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

Pro-inflammatory dietary factors have been shown to be associated with the incidence of a range of cancers. However, there are many fewer studies on the association between the inflammatory potential of diet and survival after cancer diagnosis. We examined the association between post-diagnosis dietary inflammatory index (DII®) scores and all-cause mortality in long-term survivors of colorectal cancer (CRC). DII scores were calculated from dietary data of 1,404 CRC survivors collected at a median of 6 years after CRC diagnosis. Using multivariable-adjusted Cox proportional hazards regression models, hazard ratios (HR) and 95% confidence intervals (CI) were estimated for the association of DII scores, modeled continuous and in quartiles, with all-cause mortality. After a median follow-up time of 7 years (after dietary assessment), 204 study participants had died. Overall, in the fully adjusted model there was a suggestion of a positive association between DII score and all-cause mortality (HRDIIquartile4vs1 : 1.36; 95% CI: 0.88-2.09 and HRDIIcontinuous : 1.08; 95% CI: 0.97-1.20). However, in subgroup analyses, we found significant differences in individuals with metastatic disease (HRDIIcontinuous : 1.34; 95% CI: 1.07-1.67) and the absence of stoma (HRDIIcontinuous : 1.15; 95% CI: 1.02-1.29). Overall, the post-diagnosis DII was not statistically significantly associated with all-cause mortality in CRC long-term survivors; however, there was suggestive evidence of an association in select subgroups.

Die extrakorporale ileokolische Anastomose im Rahmen einer laparoskopisch assistierten rechtsseitigen Hemikolektomie gilt aktuell noch als das Standardverfahren in der klinischen Praxis. Durch die technische Weiterentwicklung der minimalinvasiven Chirurgie und der zunehmenden Standardisierung laparoskopischer Prozeduren wird die intrakorporale Anastomosentechnik immer haufiger angewendet. In ersten klinischen Studien zeigt sich, dass die Technik von einem geschulten Laparoskopiker sicher und mit vergleichbarem Ergebnis zur extrakorporalen Ileokolostomie durchgefuhrt werden kann. Hierbei kommt uberwiegend die isoperistaltische latero-laterale Stapler-Ileotransversostomie zur Anwendung. Kleinere Hautschnitte, eine verkurzte klinische Liegezeit und eine beschleunigte Rehabilitation sind haufig genannte Vorteile der Laparoskopie. Die Anforderungen an die manuellen Fertigkeiten und die technischen Kenntnisse des Operateurs sind hoch.

ObjectiveHaemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.DesignWe conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.ResultsWe demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.ConclusionHEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Hemorrhoidal disease (HEM) affects a large fraction of the population but its etiology including suspected genetic predisposition is poorly understood. We conducted a GWAS meta-analysis of 218,920 HEM patients and 725,213 controls of European ancestry, demonstrating modest heritability and genetic correlation with several other diseases from the gastrointestinal, neuroaffective and cardiovascular domains. HEM polygenic risk scores validated in 180,435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harboring genes whose expression is enriched in blood vessels and gastrointestinal tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses of affected tissue from HEM patients highlighted HEM gene co-expression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organization of the extracellular matrix. We conclude HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Bacterial sensing by intestinal tumor cells contributes to tumor growth through cell-intrinsic activation of the calcineurin-NFAT axis, but the role of this pathway in other intestinal cells remains unclear. Here, we found that myeloid-specific deletion of calcineurin in mice activated protective CD8

BackgroundAlthough lifestyle modifications are an integral part of treatment and prevention of hemorrhoidal disease, it is largely unknown how lifestyle factors like diet and physical activity are characterized in patients with a history of advanced and invasively treated hemorrhoidal disease.MethodsIn a Northern German cross-sectional study, clinical characteristics and dietary and physical activity data of 386 patients were assessed via questionnaires at median 10 years after their first invasive hemorrhoidal treatment. Food and nutrient intake and physical activity levels of the hemorrhoid patients were compared with general population controls. Additionally, within the hemorrhoid patient cohort, dietary intake and physical activity were related to clinical characteristics using logistic regression analyses.resultsWhereas in men, there were no statistically significant differences in food intake between hemorrhoids patients and controls, women with a history of hemorrhoids had a significantly higher consumption of potatoes, nuts and animal fat, and a lower consumption of fruits, compared to women from the control group. Hemorrhoid patients reported slightly more gardening activities and less TV watching than controls. Within the hemorrhoid patient cohort, hemorrhoid grade, type of first therapy, need for further treatment, patients’ compliance for another surgery if necessary and current anal afflictions revealed individual associations with fiber, alcohol, animal fat and potato consumption and the amounts of home repair activities and sleeping time.ConclusionsAlthough we could identify some statistically significant differences in dietary and physical activity behavior between hemorrhoid patients and controls and observed associations between clinical characteristics and lifestyle factors, some findings are, in parts, still inconsistent. Whether patients are following lifestyle recommendations as part of conservative hemorrhoid treatment and tertiary prevention and which patients are more adherent than others (e.g., high-grade vs. low-grade) needs further investigation.

Personalized treatment vs. standard of care is much debated, especially in clinical practice. Here we investigated whether overall survival differences in metastatic colorectal cancer patients are explained by tumor mutation profiles or by treatment differences in real clinical practice. Our retrospective study of metastatic colorectal cancer patients of confirmed European ancestry comprised 54 Americans and 54 gender-matched Germans. The Americans received standard of care, and on treatment failure, 35 patients received individualized treatments. The German patients received standard of care only. Tumor mutations, tumor mutation burden and microsatellite status were identified by using the FoundationOne assay or the IDT Pan-Cancer assay. High-risk patients were identified according to the mutational classification by Schell and colleagues. Results: Kaplan&ndash, Meier estimates show the high-risk patients to survive 16 months longer under individualized treatments than those under only standard of care, in the median (p &lt, 0.001). Tumor mutation profiles stratify patients by risk groups but not by country. Conclusions: High-risk patients appear to survive significantly longer (p &lt, 0.001) if they receive individualized treatments after the exhaustion of standard of care treatments. Secondly, the tumor mutation landscape in Americans and Germans is congruent and thus warrants the transatlantic exchange of successful treatment protocols and the harmonization of guidelines.

ZusammenfassungDie akute Cholezystitis ist eine Inflammation der Gallenblase und wird zu ca. 90% der Fälle durch eine Cholelithiasis getriggert. Gallensteinassoziierte Erkrankungen gehören zu den teuersten im Bereich der Gastroenterologie und haben somit eine hohe volkswirtschaftliche Relevanz. Der Entstehungsprozess von Gallensteinen ist multifaktoriell. Mit steigendem Alter steigt das Risiko für das Gallensteinleiden. Insbesondere die kohlenhydrat- und fettreiche Ernährung sowie der Mangel an körperlicher Bewegung in der westlichen Welt sind an der Entstehung von Gallensteinen beteiligt. Als weiterer wichtiger Risikofaktor konnten genetische Varianten in Cholesterintransportern identifiziert werden. Die Diagnose erfolgt durch die Kombination aus Anamnese, körperlichem Untersuchungsbefund, abdomineller Sonografie sowie laborchemischen Infektparametern. Typisch sind kolikartige Schmerzen im rechten Oberbauch, die länger als 6 Stunden anhalten, Fieber bzw. Leukozytose und ein Gallenblasenwandödem im Ultraschall in Kombination mit einem positiven Murphy-Zeichen. Die Therapie der Wahl stellt die frühzeitige laparoskopische Cholezystektomie dar.

Background Despite rising incidence rates of colorectal malignancies, only a few prognostic tools have been implemented in proven clinical routine. Cell division and proliferation play a significant role in malignancies. In terms of colorectal cancer, the impact of proliferation associated proteins is controversially debated. The aim of our study was to examine the expression of topoisomerase II α and minichromosome maintenance protein 6 and to correlate these findings with the clinical data. Methods Tissue samples of 619 patients in total were stained using the antibodies Ki-S4 and Ki-MCM6 targeting topoisomerase II α as well as minichromosome maintenance protein 6. The median rate of proliferation was correlated with clinical and follow up data. Results The expression rate of minichromosome maintenance protein 6 is significantly higher than the proportion of topoisomerase II α in tumour cells (p

Solid tumors are characterized by global metabolic alterations which contribute to their growth and progression. Altered gene expression profiles and plasma lipid composition suggested a role for metabolic reprogramming in colorectal cancer (CRC) development. However, a conclusive picture of CRC-associated lipidome alterations in the tumor tissue has not emerged. Here, we determined molar abundances of 342 species from 20 lipid classes in matched biopsies of CRC and adjacent normal mucosa. We demonstrate that in contrast to previous reports, CRC shows a largely preserved lipidome composition that resembles that of normal colonic mucosa. Important exceptions include increased levels of lyso-phosphatidylinositols in CRC and reduced abundance of ether phospholipids in advanced stages of CRC. As such, our observations challenge the concept of widespread alterations in lipid metabolism in CRC and rather suggest changes in the cellular lipid profile that are limited to selected lipids involved in signaling and the scavenging of reactive oxygen species.

Pro-inflammatory dietary factors have been shown to be associated with the incidence of a range of cancers. However, there are many fewer studies on the association between the inflammatory potential of diet and survival after cancer diagnosis. We examined the association between post-diagnosis dietary inflammatory index (DII®) scores and all-cause mortality in long-term survivors of colorectal cancer (CRC). DII scores were calculated from dietary data of 1,404 CRC survivors collected at a median of 6 years after CRC diagnosis. Using multivariable-adjusted Cox proportional hazards regression models, hazard ratios (HR) and 95% confidence intervals (CI) were estimated for the association of DII scores, modeled continuous and in quartiles, with all-cause mortality. After a median follow-up time of 7 years (after dietary assessment), 204 study participants had died. Overall, in the fully adjusted model there was a suggestion of a positive association between DII score and all-cause mortality (HR

Latin Americans and Chilean Amerindians have the highest prevalence of gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however, they only explain a small portion of the genetic component of the disease. Here, we performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Chilean Latinos with Mapuche Native American ancestry. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Top-10 candidate variants surpassing the suggestive cutoff of P −5 in the discovery cohort were genotyped in an independent replication sample composed of 1,643 individuals. Variants with positive replication were further examined in two European GSD populations and a Chilean GBC cohort. We consistently replicated the association of ABCG8 gene with GSD (rs11887534, P = 3.24 × 10−8, OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 × 10−7, OR = 1.40) as a novel candidate gene for the disease in admixed Chilean Latinos. ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 was significantly decreased in gallbladder (P = 0.015) and duodenal mucosa (P = 0.001) of GSD individuals compared to healthy controls, where according to GTEx data in the small intestine, the presence of the risk allele contributes to the observed effect. We conclude that ABCG8 and TRAF3 genes are associated with GSD and GBC in admixed Latinos and that decreased TRAF3 levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.

BackgroundLatin Americans and Chilean Amerindians have the highest prevalence of cholesterol gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however they only explain a small portion of the population-attributable risk of the disease.MethodsWe performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Latinos with Mapuche Native American Ancestry, followed by a replication analysis of 10 candidate single nucleotide polymorphisms (SNPs) with suggestive genome-wide significance (P−5) in 1,643 individuals. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Logistic regression analyses were adjusted for age, sex, BMI, Type 2 Diabetes and Amerindian ancestry. Associated variants were further examined in two large GSD European populations and in a Chilean gallbladder cancer (GBC) cohort. We determined the expression levels of a novel GSD-candidate gene in normal and GSD-tissue samples.ResultsWe consistently replicated theABCG8gene (rs11887534; P=3.24×10−8, OR=1.74) associated with GSD in admixed Latinos and identified a novel candidate signal within theTRAF3gene on chromosome 14 (rs12882491; P=1.11×10−7, OR=1.40).ABCG8andTRAF3variants also conferred risk to GBC. Gene expression analyses indicated thatTRAF3levels were significantly decreased in the gallbladder (P=0.015) and the duodenal mucosa (P=0.001) of affected GSD individuals compared to healthy controls.ConclusionsWe confirmedABCG8and identifiedTRAF3both associated with GSD and GBC in admixed Latinos. Decreased TRAF3 expression levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.

ObjectiveHomozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.DesignWe analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.ResultsThe Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (pConclusionThe Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.

Background Lifestyle recommendations for cancer survivors are warranted to improve survival. In this study, we aimed to examine the association of total physical activity, different types of physical activity, hours of sleeping at day and night, and hours spent watching television (TV) with all-cause mortality in long-term colorectal cancer (CRC) survivors. Methods We assessed physical activity in 1376 CRC survivors (44% women; median age, 69 years) at median 6 years after CRC diagnosis using a validated questionnaire. Multivariable-adjusted Cox regression models were used to estimate hazard ratios (HRs) for all-cause mortality according to categories of physical activities, sleep duration, and TV watching. Results During a median follow-up time of 7 years, 200 participants had died. Higher total physical activity was significantly associated with lower all-cause mortality (HR: 0.53; 95% CI: 0.36–0.80, 4th vs. 1st quartile). Specifically, sports, walking, and gardening showed a significant inverse association with all-cause mortality (HR: 0.34; 95% CI: 0.20–0.59, HR: 0.65; 95% CI: 0.43–1.00, and HR: 0.62; 95% CI: 0.42–0.91, respectively for highest versus lowest category). Individuals with ≥2 h of sleep during the day had a significantly increased risk of all-cause mortality compared to individuals with no sleep at day (HR: 2.22; 95% CI: 1.43–3.44). TV viewing of ≥4 h per day displayed a significant 45% (95% CI: 1.02–2.06) higher risk of dying compared to ≤2 h per day of watching TV. Conclusions Physical activity was inversely related to all-cause mortality; specific activity types might be primarily responsible for this association. More hours of sleep during the day and a higher amount of TV viewing were each associated with higher all-cause mortality. Based on available evidence, it is reasonable to recommend CRC survivors to engage in regular physical activity. Electronic supplementary material The online version of this article (10.1186/s12885-017-3697-3) contains supplementary material, which is available to authorized users.

Summary Concerns have been raised that mammalian target of rapamycin inhibitors in pediatric transplant recipients might interfere with longitudinal bone growth by inhibition of growth factor signaling and growth plate chondrocyte proliferation. We therefore undertook a prospective nested, case-control study on longitudinal growth over 2 years in steroid-free pediatric renal transplant recipients. Fourteen patients on a steroid-free maintenance immunosuppressive regimen consisting of low-dose everolimus (EVR) in conjunction with low-dose cyclosporine (CsA) were compared to a matched cohort of 14 steroid-free patients on a standard dose mycophenolate mofetil (MMF) regimen in conjunction with a standard dose calcineurin inhibitor (CNI). The mean change in height standard deviation (SD) score in the first study year was 0.31 ± 0.71 SD score in the EVR group compared to 0.31 ± 0.64 SD score in the MMF group (P = 0.20). For the entire study period of 2 years, the change in height SD score in the EVR group was 0.43 ± 0.81 SDS compared to 0.75 ± 0.85 SDS in the MMF group (P = 0.32). The percentage of prepubertal patients experiencing catch-up growth, defined as an increase in height SD score ≥0.5 in 2 years, was similar in the EVR group (5/8, 65%) and the MMF group (6/8, 75%; P = 1.00). Longitudinal growth over 2 years in steroid-free pediatric patients on low-dose EVR and CsA is not different to that of a matched steroid-free control group on an immunosuppressive regimen with standard-dose CNI and MMF. Hence, low-dose EVR does not appear to negatively impact short-term growth in pediatric renal transplant recipients.

INTRODUCTION: Data on the efficacy and safety of everolimus in pediatric renal transplantation compared to other immunosuppressive regimens are scarce. PATIENTS/METHODS: We therefore performed a multicenter, observational, matched cohort study over 4 years post-transplant in 35 patients on everolimus plus low-dose cyclosporine, who were matched (1:2) with a control group of 70 children receiving a standard-dose calcineurin-inhibitor- and mycophenolate mofetil-based regimen. RESULTS: Corticosteroids were withdrawn in 83% in the everolimus vs. 39% in the control group (p