ABSTRACTThe role of the vitamin D receptor (VDR) in inflammatory bowel disease (IBD) is poorly described. The aim of this study was to examine the relationship between immunohistochemical VDR expression and IBD activity. The immunohistochemical expression of VDR was analysed in biopsies from active and inactive IBD in 28 patients (ulcerative colitis: 21, Crohn's disease: 7) and 12 non‐IBD controls. VDR expression did not change in active compared to inactive disease (p = 0.40 in epithelium and p = 0.29 in stroma). There was a trend for higher VDR expression in controls compared to IBD patients. No relationship was found between VDR expression and histologic inflammation (r = −0.19, p = 0.89 for epithelium and r = 0.13, p = 0.35 for stroma), colonoscopic picture and clinical and laboratory measures including serum 25(OH) vitamin D status (r = −0.91, p = 0.82). IBD disease activity did not correlate to VDR immunohistochemical expression, nor did it differ compared to controls. These results partly conflict with prior studies, but these have only shown modest correlations. Prospective studies investigating VDR activity between IBD and controls should be contemplated.

Abstract Aim Our goal was to describe a precision medicine program in a regional academic hospital, characterize features of included patients and present early data on clinical impact. Materials and methods We prospectively included 163 eligible patients with late-stage cancer of any diagnosis from June 2020 to May 2022 in the Proseq Cancer trial. Molecular profiling of new or fresh frozen tumor biopsies was done by WES and RNAseq with parallel sequencing of non-tumoral DNA as individual reference. Cases were presented at a National Molecular Tumor Board (NMTB) for discussion of targeted treatment. Subsequently, patients were followed for at least 7 months. Results 80% (N = 131) of patients had a successful analysis done, disclosing at least one pathogenic or likely pathogenic variant in 96%. A strongly or potentially druggable variant was found in 19% and 73% of patients, respectively. A germline variant was identified in 2.5%. Median time from trial inclusion to NMTB decision was one month. One third (N = 44) of patients who underwent molecularly profiling were matched with a targeted treatment, however, only 16% were either treated (N = 16) or are waiting for treatment (N = 5), deteriorating performance status being the primary cause of failure. A history of cancer among 1st degree relatives, and a diagnosis of lung or prostate cancer correlated with greater chance of targeted treatment being available. The response rate of targeted treatments was 40%, the clinical benefit rate 53%, and the median time on treatment was 3.8 months. 23% of patients presented at NMTB were recommended clinical trial participation, not dependent on biomarkers. Conclusions Precision medicine in end-stage cancer patients is feasible in a regional academic hospital but should continue within the frame of clinical protocols as few patients benefit. Close collaboration with comprehensive cancer centers ensures expert evaluations and equality in access to early clinical trials and modern treatment.

Double-stranded RNA (dsRNA) is produced during most viral infections, and immunohistochemical detection of dsRNA has been proposed as a potential screening marker for viral replication. The anti-dsRNA monoclonal antibody clone 9D5 is more sensitive than the established clone J2 but has not been validated in formalin-fixed paraffin-embedded (FFPE) tissue. This study aimed to test and compare the performance of the anti-dsRNA monoclonal antibodies, 9D5 and J2, in FFPE tissue using an automated staining platform. Archived clinical tissue samples with viral infections (n = 34) and uninfected controls (n = 30) were examined. Immunohistochemical staining for dsRNA (9D5 and J2) and virus-specific epitopes was performed. 9D5 provided a similar staining pattern but a higher signal-to-noise ratio than J2. The following proportions of virus-infected tissue samples were dsRNA-positive: SARS-CoV-2 (5/5), HPV (6/6), MCV (5/5), CMV (5/6), HSV (4/6), and EBV (0/6). Also, 18 of 30 uninfected samples were dsRNA positive, and an association between fixation time and intensity was observed. However, signals in all samples were markedly reduced by pretreatment with dsRNA-specific RNAse-III, indicating a specific reaction. In conclusion, dsRNA can be demonstrated in most viral infections with immunohistochemistry in FFPE tissue but with low clinical specificity. The antibody clone 9D5 performs better than clone J2.

BACKGROUND AND AIMS:Fatty acids (e.g. 16:1n-7) and desaturase indices (e.g. stearoyl-CoA desaturase, SCD) in plasma cholesteryl esters (CE) and phospholipids (PL) are used as biomarkers of dietary fat quality and lipid metabolism and are associated with disease outcomes. Endogenously produced circulating fatty acids are believed to reflect composition of the liver, yet little data exist to support such relationship. We investigated associations between circulating fatty acids and fatty acids within the liver. METHODS:Liver biopsies and blood were collected from n = 60 patients with non-alcoholic fatty liver disease. Fatty acids in CE, PL and triglycerides (TG) in plasma and liver were analyzed using gas chromatography. Associations were assessed using Spearman rank correlations. RESULTS:Overall, fatty acids and desaturase indices in plasma PL and TG showed moderate-strong correlations with fatty acids and desaturase indices in corresponding lipid fractions in liver. For plasma CE, 16:1n-7 and SCD were correlated with 16:1n-7 and SCD in liver CE. Noteworthy, fatty acids in plasma CE and PL also showed moderate-strong correlations with fatty acids in liver TG (e.g. r = 0.82-0.87 for 16:1n-7 and r = 0.77 for SCD). CONCLUSION:We demonstrate that fatty acids in circulating lipid fractions, including CE, TG and PL, reflects the composition of liver TG in humans, suggesting that circulating fatty acids might be useful biomarkers for the fatty acid composition of the liver. As liver tissue is rarely available in cohort studies, our findings could enhance our understanding of plasma fatty acids as markers of hepatic lipid metabolism and their links to metabolic diseases.

Cerebral cavernous malformation (CCM) is a neurovascular disease that results in various neurological symptoms. Thrombi have been reported in surgically resected CCM patient biopsies, but the molecular signatures of these thrombi remain elusive. Here, we investigated the kinetics of thrombi formation in CCM and how thrombi affect the vasculature and contribute to cerebral hypoxia. We used RNA sequencing to investigate the transcriptome of mouse brain endothelial cells with an inducible endothelial-specific Ccm3 knock-out (Ccm3-iECKO). We found that Ccm3-deficient brain endothelial cells had a higher expression of genes related to the coagulation cascade and hypoxia when compared with wild-type brain endothelial cells. Immunofluorescent assays identified key molecular signatures of thrombi such as fibrin, von Willebrand factor, and activated platelets in Ccm3-iECKO mice and human CCM biopsies. Notably, we identified polyhedrocytes in Ccm3-iECKO mice and human CCM biopsies and report it for the first time. We also found that the parenchyma surrounding CCM lesions is hypoxic and that more thrombi correlate with higher levels of hypoxia. We created an in vitro model to study CCM pathology and found that human brain endothelial cells deficient for CCM3 expressed elevated levels of plasminogen activator inhibitor-1 and had a redistribution of von Willebrand factor. With transcriptomics, comprehensive imaging, and an in vitro CCM preclinical model, this study provides experimental evidence that genes and proteins related to the coagulation cascade affect the brain vasculature and promote neurological side effects such as hypoxia in CCMs. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM.

Microorganisms are generally sensed by receptors recognizing microbial molecules, which evoke changes in cellular activities and gene expression. Bacterial pathogens induce secretion of the danger signal ATP as an early alert response of intestinal epithelial cells, initiating overt inflammation. However, what triggers ATP secretion during infection is unclear. Here we show that the inherently mechanosensitive plasma membrane channel PIEZO1 acts as a sensor for bacterial entry. PIEZO1 is mechanically activated by invasion-induced membrane ruffles upstream of Ca2+ influx and ATP secretion. Mimicking mechanical stimuli of pathogen uptake with sterile beads equally elicits ATP secretion. Chemical or genetic PIEZO1 inactivation inhibits mechanically induced ATP secretion. Moreover, chemical or mechanical PIEZO1 activation evokes gene expression in immune and barrier pathways. Thus, mechanosensation of invasion-induced plasma membrane distortion initiates immune signaling upon infection, independently of detection of microbial molecules. Hence, PIEZO1-dependent detection of infection is driven by physical signals instead of chemical ligands.

Background: The hepatic lipidome of patients with early stages of non-alcoholic fatty liver disease (NAFLD) has been fairly well-explored. However, studies on more progressive forms of NAFLD, i.e., liver fibrosis, are limited. Materials and methods: Liver fatty acids were determined in cholesteryl esters (CE), phospholipids (PL), and triacylglycerols (TAG) by gas chromatography. Cross-sectional associations between fatty acids and biopsy-proven NAFLD fibrosis (n = 60) were assessed using multivariable logistic regression models. Stages of fibrosis were dichotomized into none-mild (F0-1) or significant fibrosis (F2-4). Models were adjusted for body-mass index (BMI), age and patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409) (I148M) genotype. A secondary analysis examined whether associations from the primary analysis could be confirmed in the corresponding plasma lipid fractions. Results: PL behenic acid (22:0) was directly associated [OR (95% CI): 1.86 (1.00, 3.45)] whereas PL docosahexaenoic acid (22:6n-3) [OR (95% CI): 0.45 (0.23, 0.89)], TAG oleic acid (18:1n-9) [OR (95% CI): 0.52 (0.28, 0.95)] and 18:1n-9 and vaccenic acid (18:1n-7) (18:1) [OR (95% CI): 0.52 (0.28, 0.96)] were inversely associated with liver fibrosis. In plasma, TAG 18:1n-9 [OR (95% CI): 0.55 (0.31, 0.99)], TAG 18:1 [OR (95% CI): 0.54 (0.30, 0.97)] and PL 22:0 [OR (95% CI): 0.46 (0.25, 0.86)] were inversely associated with liver fibrosis. Conclusion: Higher TAG 18:1n-9 levels were linked to lower fibrosis in both liver and plasma, possibly reflecting an altered fatty acid metabolism. Whether PL 22:6n-3 has a protective role, together with a potentially adverse effect of hepatic 22:0, on liver fibrosis warrants large-scale studies.

Introduction Hepatocellular carcinoma (HCC) is a common cause of cancer-related death, often detected in the intermediate stage. The standard of care for intermediate-stage HCC is transarterial chemoembolisation (TACE), where idarubicin (IDA) is a promising drug. Despite the fact that TACE has been used for several decades, treatment success is unpredictable. This clinical trial has been designed believing that further improvement might be achieved by increasing the understanding of interactions between local pharmacology, tumour targeting, HCC pathophysiology, metabolomics and molecular mechanisms of drug resistance. Methods and analysis The study population of this single-centre clinical trial consists of adults with intermediate-stage HCC. Each tumour site will receive TACE with two different IDA doses, 10 and 15 mg, on separate occasions. Before and after each patient’s first TACE blood samples, tissue and liquid biopsies, and positron emission tomography (PET)/MRI will be performed. Blood samples will be used for pharmacokinetics (PK) and liver function evaluation. Tissue biopsies will be used for histopathology analyses, and culturing of primary organoids of tumour and non-tumour tissue to measure cell viability, drug response, multiomics and gene expression. Multiomics analyses will also be performed on liquid biopsies. PET/MRI will be used to evaluate tumour viability and liver metabolism. The two doses of IDA will be compared regarding PK, antitumour effects and safety. Imaging, molecular biology and multiomics data will be used to identify HCC phenotypes and their relation to drug uptake and metabolism, treatment response and survival. Ethics and dissemination Participants give informed consent. Personal data are deidentified. A patient will be withdrawn from the study if considered medically necessary, or if it is the wish of the patient. The study has been approved by the Swedish Ethical Review Authority (Dnr. 2021-01928) and by the Medical Product Agency, Uppsala, Sweden. Trial registration number EudraCT number: 2021-001257-31.

INTRODUCTION:Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC-UC) is considered a unique inflammatory bowel disease (IBD) entity. PSC diagnosis in an IBD individual entails a significantly higher risk of gastrointestinal cancer; however, biomarkers for identifying patients with UC at risk for PSC are lacking. We, therefore, performed a thorough PSC-UC biomarker study, starting from archived colonic tissue. METHODS:Proteins were extracted out of formalin-fixed paraffin-embedded proximal colon samples from PSC-UC (n = 9), UC (n = 7), and healthy controls (n = 7). Patients with IBD were in clinical and histological remission, and all patients with UC had a history of pancolitis. Samples were processed by the multienzyme digestion FASP and subsequently analyzed by liquid chromatography-tandem mass spectrometry. Candidate proteins were replicated in an independent cohort (n: PSC-UC = 16 and UC = 21) and further validated by immunohistochemistry. RESULTS:In the discovery step, 7,279 unique proteins were detected. The top 5 most differentiating proteins (PSC-UC vs UC) based on linear regression analysis were selected for replication. Of these, 1-acetylglycerol-3-phosphate O-acyltransferase 1 (AGPAT1) was verified as higher in PSC-UC than UC (P = 0.009) in the replication cohort. A difference on the group level was also confirmed by immunohistochemistry, showing more intense AGPAT1 staining in patients with PSC-UC compared with UC. DISCUSSION:We present AGPAT1 as a potential colonic biomarker for differentiating PSC-UC from UC. Our findings have possible implication for future PSC-IBD diagnostics and surveillance.

Abstract A 39-year-old male presented with deep venous thrombosis in the right lower limb. He had been experiencing increasing abdominal girth over several years, but this went undetected at the initial examination. Eighteen months later, a computed tomography was conducted, showing a huge retroperitoneal cyst (25 × 23 × 16 cm) lifting the right external iliac vessels. Complete surgical excision of the cyst was performed. The cyst was unilocular and contained 5 l of clear fluid. Histopathology examination found a thin cyst wall consisting of fibrous stromal tissue with a single-layer epithelium lining. Immunohistochemical staining revealed positivity for endothelial cell markers, CD31 and CD34, but negativity for the lymphatic marker podoplanin (D2–40), corresponding to a vascular origin, likely a venous malformation.

Background Nonalcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide. It is subdivided into nonalcoholic fatty liver (NAFL) and the more aggressive form, nonalcoholic steatohepatitis (NASH), which carries a higher risk of developing fibrosis and cirrhosis. There is currently no reliable non‐invasive method for differentiating NASH from NAFL. Purpose To investigate the ability of magnetic resonance imaging (MRI)‐based imaging biomarkers to diagnose NASH and moderate fibrosis as well as assess their repeatability. Study Type Prospective. Subjects Sixty‐eight participants (41% women) with biopsy‐proven NAFLD (53 NASH and 15 NAFL). Thirty participants underwent a second MRI in order to assess repeatability. Field Strength/Sequence 3.0 T; MR elastography ( MRE ) (a spin‐echo echo‐planar imaging [ SE‐EPI ] sequence with motion‐encoding gradients), MR proton density fat fraction ( PDFF ) and R2 * mapping (a multi‐echo three‐dimensional gradient‐echo sequence), T1 mapping (a single‐point saturation‐recovery technique), and diffusion‐weighted imaging ( SE‐EPI sequence). Assessment Quantitative MRI measurements were obtained and assessed alone and in combination with biochemical markers (cytokeratin‐18 [CK18] M30, alanine transaminase [ALT], and aspartate transaminase [AST]) using logistic regression models. Models that could differentiate between NASH and NAFL and between moderate to advanced fibrosis (F2–4) and no or mild fibrosis (F0–1), based on the histopathological results, were identified. Statistical Tests Independent samples t ‐test, Pearson's chi‐squared test, area under the receiver operating characteristic curve (AUROC), Spearman's correlation, intra‐individual coefficient of variation, and intraclass correlation coefficient (ICC). Statistical significance was set at P < 0.05. Results There was a significant difference between the NASH and NAFL groups with liver stiffness assessed with MRE, CK18 M30, and ALT, with an AUROC of 0.74, 0.76, and 0.70, respectively. Both MRE and PDFF contributed significantly to a bivariate model for diagnosing NASH (AUROC = 0.84). MRE could significantly differentiate between F2–4 and F0–1 (AUROC = 0.74). A model combining MRE with AST improved the diagnosis of F2–4 (AUROC = 0.83). The ICC for repeatability was 0.94 and 0.99 for MRE and PDFF, respectively. Data Conclusion MRE can potentially diagnose NASH and differentiate between fibrosis stages. Combining MRE with PDFF improves the diagnosis of NASH. Level of Evidence 2 Technical Efficacy Stage 2

To the Editor: Atypical flat lesions (AFLs) in the pancreas have been suggested a potential precursor to pancreatic ductal adenocarcinoma via acinar-to-ductal metaplasia (ADM) in mouse model studies. Still, the role of AFLs in human pancreatic cancer is unknown. Here, we present a case of KRAS-mutated pancreatic ductal adenocarcinoma arising from AFLs based on clear histopathological findings. This incidental finding highlights the need for further investigation of the prevalence and role of AFLs in human pancreatic ductal adenocarcinoma (PDAC) development. CASE REPORT A woman around 70 years old presented with abdominal pain and jaundice. No solid tumor was found on radiology, but suspicion of a malignant lesion was raised because of the presence of double duct sign,1 and the patient subsequently underwent pancreaticoduodenectomy. Perioperatively, the pancreas was soft in texture and absent of macroscopic tumor signs. Histopathological evaluation revealed KRAS-mutated PDAC with both a ductal growth pattern and a low differentiated growth pattern. The nonneoplastic pancreas was marked by chronic atrophic pancreatitis with extensive ADM positive for the ductal marker cytokeratin 7 (Fig. 1A). The metaplastic ductal epithelium consisted of inconspicuous cuboidal cells with centrally placed homogenous nuclei and a low proliferative activity indicated by less than 10% of Ki-67–positive nuclei (Fig. 1A). Only in 1 single acinus with ADM, pancreatic intraepithelial neoplasia (PanIN) grade I was observed.FIGURE 1: A, Acinar-to-ductal metaplasia and atypical flat lesions (AFLs) stained with hematoxylin and eosin, the ductal marker cytokeratin 7 (CK7), and the proliferation marker Ki-67. Acinar-to-ductal metaplasia exhibits small CK7-positive glands without dysplasia and with a low Ki-67 proliferation rate. The AFL displays irregular CK7-positive gland formations with highly pleomorphic epithelial cells and a high Ki-67 proliferation rate. Original magnification ×200. B, Overview over an acinus with AFL (right) and a magnification showing the transition into invasive growth into the surrounding stroma (left). Original magnifications ×50 and ×400. Scale bars, 200 μm. C, Theoretical progression from normal exocrine pancreas parenchyma into invasive ductal adenocarcinoma. Original magnifications ×50 (top panel) and ×400 (bottom panel). Scale bars, 200 μm.Several acini with metaplastic ductuli displayed dysplastic changes of the epithelium with pleomorphic hyperchromatic nuclei and a high proliferative activity with more than 50% of Ki-67–positive nuclei indicative of AFLs (Fig. 1A). In addition, some ducts showed back-to-back formations and shift toward a cribriform growth pattern. In 1 acinus with AFL, an outgrowth of a dysplastic gland into the surrounding connective tissue was detected as a clear sign of transition from AFL into infiltrative cancer growth (Fig. 1B). DISCUSSION Here, we present a case of PDAC that presents with extensive parenchymal atrophy and ADM as well as AFLs clearly progressing into infiltrating cancer. This case report shows that AFLs can progress to PDAC in human and probably via a sequence from chronic pancreatitis toward acinar atrophy and ADM (Fig. 1C). Acinar-to-ductal metaplasia is defined as the metaplastic transformation of pancreatic acinar cells into small intra-acinar ductal CK7-positive cells. It can be induced by stress and inflammation including pancreatitis, KRAS mutation, and epidermal growth factor receptor activation.2 In mice with KRAS mutation, ADM formation is an early event in PDAC progression.3 In humans, ADM is commonly found close to PanIN lesions, but its role in PDAC progression is not clear. Shi et al4 showed that ADM near PanIN lesions often shares the same KRAS mutation, whereas isolated ADM without adjacent PanIN foci is of wild-type KRAS. The authors argue against acinar cells being the cell of origin in PDAC but that ADM with KRAS mutations is more likely a retrograde expansion of PanIN lesions. An alternate interpretation is that ADMs that acquire a KRAS mutation develop into PanIN lesions.2 The latter has been experimentally supported in mouse models.5,6 We find it unlikely that the present PDAC case arose from PanIN lesions as only 1 low-grade PanIN was observed in an ADM area. Alternatively, human PDAC might arise from ADM via AFLs, which has been recently shown in mouse models.7,8 The presence of AFLs has also been demonstrated in human pancreas tissue, but without evidence of AFLs progressing into invasive carcinoma. Aichler et al8 reported the presence of AFLs in 3 familial pancreatic cancer cases but could not find AFLs in any sporadic PDAC case. On the contrary, Morita et al9 reviewed slides from 371 pancreatic specimens with different sporadic PDAC forms or benign lesions and identified AFLs in 18 cases. However, these findings do not clarify whether AFL is a precursor or only a bystander. In this case report, there is a clear progression from AFL into invasive carcinoma, which strongly suggests that AFL is the precursor lesion. In summary, this case report shows for the first time in humans that PDAC can arise from AFLs. The prevalence of AFLs and its pathophysiological role in pancreatic cancer need further investigation. Oskar Franklin, MD, PhDMikael Öman, MD, PhD Department of Surgical and Perioperative Sciences Umeå University Umeå, Sweden [email protected]Alkwin Wanders, MD, PhD Department of Biomedical Sciences Umeå University Umeå, Sweden Department of Pathology Clinical Cancer Research Center Aalborg University Hospital Aalborg, Denmark Department of Clinical Medicine Aalborg University Aalborg, Denmark

A healthy intestinal barrier prevents uptake of allergens and toxins, whereas intestinal permeability increases following chemotherapy and in many gastrointestinal and systemic diseases and disorders. Currently, there are no approved drugs that target and repair the intestinal epithelial barrier while there is a medical need for such treatment in gastrointestinal and related conditions. The objective of this single-pass intestinal perfusion study in rats was to investigate the preventive cytoprotective effect of three mucosal protective drugs—melatonin, misoprostol, and teduglutide—with different mechanisms of action on an acute jejunal injury induced by exposing the intestine for 15 min to the anionic surfactant, sodium dodecyl sulfate (SDS). The effect was evaluated by monitoring intestinal clearance of 51Cr-labeled ethylenediaminetetraacetate and intestinal histology before, during, and after luminal exposure to SDS. Our results showed that separate pharmacological pretreatments with luminal misoprostol and melatonin reduced acute SDS-induced intestinal injury by 47% and 58%, respectively, while their use in combination abolished this injury. This data supports further development of drug combinations for oral treatments of conditions and disorders related to a dysregulated or compromised mucosal epithelial barrier.

INTRODUCTION: Collagenous gastritis (CG), a rare disorder of unknown etiology, has been postulated to have immune-mediated mechanisms. We investigated (i) the incidence and prevalence of CG in a pediatric population; (ii) the clinical, endoscopic, and histologic characteristics of childhood-onset CG; and (iii) the evidence for autoimmunity and/or inflammatory activity in these patients. METHODS: Clinical, endoscopic, and histologic data were reviewed longitudinally in a population-based Swedish cohort of 15 patients with childhood-onset CG diagnosed in the period 2008–2019. A set of 11 autoantibodies, 4 blood inflammatory biomarkers, and the human leukocyte antigen DQ2/DQ8 genotype was analyzed cross-sectionally. RESULTS: The incidence rate of childhood-onset CG was 0.25/100,000 person-years, with an incidence rate ratio of girls to boys of 4.2 (95% confidence interval, 1.2–15). The prevalence of CG was 2.1/100,000 in children aged younger than 18 years. The endoscopic and histologic findings remained pathologic in all the examined patients during a median follow-up of 4.4 years. Many patients had heredity for autoimmune disorders (47%) and/or tested positive for autoantibodies (40%) or human leukocyte antigen DQ2/DQ8 (53%). No associated autoimmune comorbidities were observed. The serum levels of calprotectin and amyloid A were increased in 10/15 (67%) and 5/15 (33%) of the patients, respectively, whereas plasma C-reactive protein levels were normal in all, but 1 patient. DISCUSSION: The results indicate that childhood-onset CG is rare and has a chronic disease course. Although signs of autoimmune predisposition are frequent, early development of autoimmune comorbidities seems seldom. Serum calprotectin and amyloid A represent novel candidate biomarkers of inflammatory activity in CG (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A349).

Summary Background The vagus nerve provides essential parasympathetic innervation to the gastrointestinal system and is known to have anti‐inflammatory properties. Aims To explore the relationship between vagotomy and the risk of inflammatory bowel disease (IBD) and its major categories: Crohn's disease (CD) and ulcerative colitis (UC). Methods A matched cohort comprising 15 637 patients undergoing vagotomy was identified through the Swedish Patient Register from 1964 to 2010. Each vagotomised patient was matched for birth year and gender with 40 nonvagotomised individuals on the date of vagotomy. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for IBD using flexible parametric models adjusted for matching variables, year of vagotomy, birth country, chronic obstructive pulmonary disease and comorbidity index. Results We observed 119 (0.8%) patients with vagotomy developed IBD compared to 3377 (0.5%) IBD cases in nonvagotomised individuals. The crude incidence of IBD (per 1000 person‐years) was 0.38 for vagotomised patients and 0.25 for nonvagotomised individuals. We observed a time‐dependent elevated risk of IBD associated with vagotomy, for instance, the HR (95% CI) was 1.80 (1.40‐2.31) at year 5 and 1.49 (1.14‐1.96) at year 10 post‐vagotomy. The association appeared to be stronger for truncal than selective vagotomy and limited to CD (HR was 3.63 [1.94‐6.80] for truncal and 2.06 [1.49‐2.84] for selective vagotomy) but not UC (1.36 [0.71‐2.62] for truncal and 1.25 [0.95‐1.63] for selective vagotomy). Conclusions We found a positive association between vagotomy and later IBD, particularly for CD. The finding indirectly underlines the beneficial role of the vagal tone in IBD.

Background: Ulcerative colitis (UC) in patients with the severe disease primary sclerosing cholangitis (PSC) constitutes a distinct clinical phenotype (PSC-UC) with a high incidence of colorectal cancer. Today, PSC-UC diagnosis is built on clinical observations only. Tissue factor (TF) has a potential use in UC diagnostics, and also in colorectal cancer prognostication. Here we evaluate TF expression in an inflammatory bowel disease (IBD) cohort, with special focus on differences between UC and PSC-UC patients. Materials and methods: Colonic biopsies from UC (n = 23), PSC (n = 24), and healthy controls (n = 11) were stained for TF by immunohistochemistry. Mononuclear cell contribution to TF expression was verified using flow cytometry. Results: TF was distributed at three distinct colonic locations: in subepithelial pericryptal sheath cells, in mononuclear cells, and in the intestinal stroma. In contrast to UC-where inflammation was accompanied with TF up-regulation-PSC-UC activity remained low during inflammation. Stromal TF positivity was found exclusively in ongoing inflammation. Conclusion: Our study provides additional support for a divergent pathogenesis in PSC-UC, with an inflammatory environment that differs from classical UC. Stromal TF emerges as a new marker of colonic inflammation.