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HER2 is a predictive biomarker for HER2-targeted therapeutics. For antibody–drug conjugates (ADCs; e.g., trastuzumab emtansine (T-DM1)), HER2 is utilized as a transport gate for cytotoxic agents into the cell. ADC biomarkers may therefore be more complex, also reflecting the intracellular drug transport. Here we report on a positive correlation between the early endosome marker RAB5A and T-DM1 sensitivity in five HER2-positive cell lines. Correlation between RAB5A expression and T-DM1 sensitivity is confirmed in breast cancer patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial (NCT01042379), but not in the trastuzumab/paclitaxel control arm. The clinical correlation is further verified in patients from the KAMILLA trial (NCT01702571). In conclusion, our results suggest RAB5A as a predictive biomarker for T-DM1 response and outline proteins involved in endocytic trafficking as predictive biomarkers for ADCs., Antibody Drug Conjugates (ADCs) are emerging in the field of precision cancer medicine. Here, the authors suggest using endocytosis as a predictive biomarker for response

PURPOSETargeted therapeutics strongly depends on validated biomarkers in order to select patients most likely to benefit from the treatment. HER2 serves as a predictive biomarker for HER2-targeted tyrosine kinase inhibitors and monoclonal antibodies. HER2 may, however, also be utilized as a transport gate for delivery of cytotoxic agents into the cell, such as for HER2-targeted antibody drug conjugates (ADCs; e.g. trastuzumab emtansine (T-DM1)). The predictive biomarkers for such ADCs may be more complex, also reflecting the intracellular transport.METHODSFive HER2-positive breast and ovarian cancer cell lines were evaluated with respect to T-DM1 sensitivity and correlated to the expression levels of proteins involved in endocytic trafficking including RAB4A, RAB5A and RAB11A, with possible impact on ADC pharmacology. The results were confirmed in a clinical cohort consisting of patients from the adaptive breast cancer clinical trial I-SPY2 where pathological complete response (pCR) was correlated to the RNA expression level of RAB4A, RAB5A and RAB11A. A subset of the clinical KAMILLA trial including 19 patients was used as a verification cohort where semi-quantitative IHC of RAB5A was correlated to progression free survival (PFS).RESULTSThe early endosome marker RAB5A, was found to correlate positively to T-DM1 sensitivity in the cell line panel. Correlation between RAB5A expression and T-DM1 sensitivity (pCR) was confirmed in patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial, but not in the trastuzumab/paclitaxel control arm. The clinical correlation was verified in the patients from the KAMILLA trial where semi-quantitative RAB5A IHC staining correlated significantly positive to PFS.CONCLUSIONThe present results indicate that RAB5A is a predictive biomarker for T-DM1 and outline, for the first time, proteins involved in endocytic trafficking as predictive biomarkers for ADCs.

BackgroundColorectal cancer (CRC) screening reduces CRC incidence and mortality. However, current screening methods are either hampered by invasiveness or suboptimal performance, limiting their effectiveness as primary screening methods. To aid in the development of a non-invasive screening test with improved sensitivity and specificity, we have initiated a prospective biomarker study (CRCbiome), nested within a large randomized CRC screening trial in Norway. We aim to develop a microbiome-based classification algorithm to identify advanced colorectal lesions in screening participants testing positive for an immunochemical fecal occult blood test (FIT). We will also examine interactions with host factors, diet, lifestyle and prescription drugs. The prospective nature of the study also enables the analysis of changes in the gut microbiome following the removal of precancerous lesions.MethodsThe CRCbiome study recruits participants enrolled in the Bowel Cancer Screening in Norway (BCSN) study, a randomized trial initiated in 2012 comparing once-only sigmoidoscopy to repeated biennial FIT, where women and men aged 50–74 years at study entry are invited to participate. Since 2017, participants randomized to FIT screening with a positive test result have been invited to join the CRCbiome study. Self-reported diet, lifestyle and demographic data are collected prior to colonoscopy after the positive FIT-test (baseline). Screening data, including colonoscopy findings are obtained from the BCSN database. Fecal samples for gut microbiome analyses are collected both before and 2 and 12 months after colonoscopy. Samples are analyzed using metagenome sequencing, with taxonomy profiles, and gene and pathway content as primary measures. CRCbiome data will also be linked to national registries to obtain information on prescription histories and cancer relevant outcomes occurring during the 10 year follow-up period.DiscussionThe CRCbiome study will increase our understanding of how the gut microbiome, in combination with lifestyle and environmental factors, influences the early stages of colorectal carcinogenesis. This knowledge will be crucial to develop microbiome-based screening tools for CRC. By evaluating biomarker performance in a screening setting, using samples from the target population, the generalizability of the findings to future screening cohorts is likely to be high.Trial registrationClinicalTrials.govIdentifier:NCT01538550.

BackgroundColorectal cancer (CRC) screening reduces CRC incidence and mortality. However, current screening methods are either hampered by invasiveness or suboptimal performance, limiting their effectiveness as primary screening methods. To aid in the development of a non-invasive screening test with improved sensitivity and specificity, we have initiated a prospective biomarker study (CRCbiome), nested within a large randomized CRC screening trial in Norway. We aim to develop a microbiome-based classification algorithm to identify advanced colorectal lesions in screening participants testing positive for an immunochemical fecal occult blood test (FIT). We will also examine interactions with host factors, diet, lifestyle and prescription drugs. The prospective nature of the study also enables the analysis of changes in the gut microbiome following the removal of precancerous lesions.MethodsThe CRCbiome study recruits participants enrolled in the Bowel Cancer Screening in Norway (BCSN) study, a randomized trial initiated in 2012 comparing once-only sigmoidoscopy to repeated biennial FIT, where women and men aged 50-74 years at study entry are invited to participate. Since 2017, participants randomized to FIT screening with a positive test result have been invited to join the CRCbiome study. Self-reported diet, lifestyle and demographic data are collected prior to colonoscopy after the positive FIT-test (baseline). Screening data, including colonoscopy findings are obtained from the BCSN database. Fecal samples for gut microbiome analyses are collected both before and 2 and 12 months after colonoscopy. Samples are analyzed using metagenome sequencing, with taxonomy profiles, and gene and pathway content as primary measures. CRCbiome data will also be linked to national registries to obtain information on prescription histories and cancer relevant outcomes occurring during the 10 year follow-up period.DiscussionThe CRCbiome study will increase our understanding of how the gut microbiome, in combination with lifestyle and environmental factors, influences the early stages of colorectal carcinogenesis. This knowledge will be crucial to develop microbiome- based screening tools for CRC. By evaluating biomarker performance in a screening setting, using samples from the target population, the generalizability of the findings to future screening cohorts is likely to be high.Trial RegistrationClinicalTrials.gov Identifier: NCT01538550

Background Intraarticular corticosteroids (IACs) have been used to treat temporomandibular joint (TMJ) arthritis. However, prospective clinical studies with magnetic resonance imaging (MRI) scoring are lacking. The aim of this study was to examine efficacy and safety of a single IAC in the TMJ in adolescents with juvenile idiopathic arthritis (JIA) in a clinical setting. Methods In this Norwegian prospective multicenter pilot study 15 patients with JIA (mostly persistent oligoarthritis or RF negative polyarthritis categories) and a clinically and MRI-verified diagnosis of TMJ arthritis were treated with IACs and followed for 2 years. Demographics, systemic medication, general disease activity and outcome measures were recorded including a pain-index score and maximal incisal opening (MIO). Inflammation and bone damage scores were assessed, using two recently published MRI scoring systems with masked radiological evaluation. Results Among the 15 patients, 13 received a single IAC (5 bilateral), and 2 repeated IACs once unilaterally. Thus, the total number of IACs was 22. Median age was 15 years and the majority had an age not thought of as critical regarding mandibular growth retardation due to steroid injection. During the 2-year observation period systemic medication with disease modifying antirheumatic drugs (DMARDs) including biologics was initiated or adjusted in 10/15 (67%) patients. At the 2-months study visit after injection we observed a minimal improvement in MIO from median 44 (1st, 3rd quartiles; 36, 48) mm to 45 (43, 47) mm, p = 0.045 and decreased MRI mean additive inflammatory score from 4.4 ± 1.8 standard deviations (SD) to 3.4 ± 2.0, p = 0.040. From baseline to the 2-months follow-up pain improved in 6/11 patients but pain scores were not significantly improved. MRI-assessed damage increased in two patients with repeated IACs, and decreased in 3 patients but most of the patients were stable over the 2-year follow-up. Intra-rater repeatability of the MRI scoring system domains varied from poor to excellent. Conclusions In this pilot study of predominately single IACs to the TMJ in combination with systemic treatment we observed improvement in MRI-assessed inflammation, mostly stable condylar bone conditions and minimal clinical improvement in adolescents with JIA and TMJ arthritis. No severe side effects were seen.

Background Lifestyle factors may help to identify individuals at high-risk for colorectal cancer (CRC). Aims To examine the association between lifestyle, referral for follow-up colonoscopy and proximal neoplasia detection in CRC screening. Methods In this observational study, 14,832 individuals aged 50–74 years were invited to faecal immunochemical test (FIT) or sigmoidoscopy screening. Advanced lesions (AL), including advanced adenomas, advanced serrated lesions and CRC were divided according to location: distal-only, or proximal with or without distal AL. We collected information on smoking habit, body mass index and alcohol intake through a questionnaire. Results Out of 3,318 FIT and 2,988 sigmoidoscopy participants, 516 (16%) and 338 (11%), respectively, were referred for follow-up colonoscopy after a positive screening test. Two-hundred-and-fifty-six (4%) had distal-only and 119 (2%) proximal AL. In FIT participants, obesity and high alcohol intake were associated with proximal AL; odds ratio (95% confidence interval) 2.68 (1.36–5.26) and 2.16 (1.08–4.30), respectively. In sigmoidoscopy participants, current smoking was associated with proximal AL; 4.58 (2.24–9.38), and current smoking and obesity were associated with referral for colonoscopy; 2.80 (2.02–3.89) and 1.42 (1.01–2.00), respectively. Conclusion Current smoking, obesity and high alcohol intake were associated with screen-detected proximal colorectal AL. Current smoking and obesity were associated with referral for follow-up colonoscopy in sigmoidoscopy screening.

Background: Cancer screening provides an opportunity to increase awareness of cancer-preventive lifestyle behaviors such as nonsmoking, physical activity, low alcohol consumption, and a healthy diet. We tested the effect of standardized, individually tailored written feedback (TF), and a standard leaflet (SL) on 1-year lifestyle behaviors in a colorectal cancer screening setting. Methods: A total of 3,642 men and women aged 50–74 years invited to sigmoidoscopy screening were randomly assigned to: (i) TF; (ii) SL for cancer-preventive lifestyle behaviors; or (iii) control. Participants were mailed two self-reported lifestyle questionnaires (LSQ) 1 year apart. The TF intervention was based on the prescreening LSQ answers. We analyzed differences [with 95% confidence intervals (CI)] by comparing prescreening to 1-year follow-up of single cancer-preventive factors and the number of cancer-preventive lifestyle behaviors (range 0–4) between the groups by multivariable logistic regression and analysis of covariance (ANCOVA). Results: A total of 1,054 screening participants without neoplastic findings (29% of those invited to screening) were included in this study. Participants in the TF group increased their number of cancer-preventive lifestyle behaviors significantly compared with those in the control group by 0.11 (95% CI, 0.02 to 0.19). Overweight/obese individuals in the TF group had a −0.84 kg (95% CI, −1.47 to −0.22) larger reduction in body weight compared with the control group. Conclusions: TF at sigmoidoscopy screening led to small improvements in cancer-preventive behaviors. Impact: Colorectal cancer screening is a suitable setting for increasing awareness of cancer-preventive behavior.

When planning national screening programs, it is important to investigate potential changes in health behavior initiated by the screening. Knowledge of the consequences of different colorectal cancer (CRC) screening modalities for health behavior is limited. We aimed to investigate differences in 1-year health behavior changes after testing negative in CRC screening by one of two screening modalities. Participants of both sexes aged 50-74 years assigned randomly to five biennial rounds of fecal immunochemical test (FIT), one round of flexible sigmoidoscopy (FS), or no screening (control) were invited to complete a self-reported lifestyle questionnaire on smoking, body weight, physical activity, alcohol intake, and consumption of selected dietary items at baseline and at 1-year follow-up. In total, 1809 and 1327 individuals in the FIT and the FS arm, respectively, completed the lifestyle questionnaire, as did 1029 controls. We analyzed differences in 1-year health behavior changes between the arms at follow-up by analysis of covariance and logistic regression. Overall, 1-year changes in health behavior were moderate and probably of no clinical relevance. Participants with negative CRC screening test results in the first round of the FIT arm reduced their alcohol consumption significantly more than controls [-0.29 glass/week (95% confidence interval -0.54 to -0.04)]. Body weight decreased more in participants with negative screening test results in the FS than in the FIT arm [-0.31 kg (95% confidence interval -0.55 to -0.08)]. The present study did not suggest unfavorable short-term consequences in the health behavior of individuals who received a negative CRC screening test result from either a first round of FIT or a once-only FS screening.

Background/objectives The Oslo diet and antismoking study showed that counselling for a healthy lifestyle reduced lifelong coronary mortality in high-risk men. We explored whether the same counselling reduced also cancer risk. Methods The study randomly allocated males at high coronary risk to either a 5-year intervention for lifestyle changes (cholesterol-lowering dietary changes, weight loss and stopping smoking) or a control group (1 : 1) in 1972/73. We explored the incidence and mortality of all cancers and cancer forms related to smoking, BMI or diet up to 43 years after randomization. Results A total of 595 men in the intervention and 621 in the control group were included. At inclusion median age was 45 years, 588 (48.4%) subjects were overweight (BMI > 25 kg m-2 ) and 925 (76.1%) current smokers. The intervention did not reduce the risk of cancer after 43 years (adjusted hazard ratio (HR) 0.96, 95% confidence interval (CI) 0.80-1.15). In the first 25 years of follow-up, among the 1088 (89.5%) men who were overweight/obese and/or smokers, the intervention reduced the incidence of those cancer forms related to smoking, BMI or diet (including carcinoma of the respiratory, digestive and urinary tracts; adjusted HR 0.69; 95% CI 0.49-0.99). The intervention had no significant effect on incidence beyond 25 years, or on mortality. Conclusions The 5-year counselling for a healthy lifestyle did not reduce the overall cancer risk in the very long term. However, in the first 25 years, the counselling reduced the risk of relevant cancer types in overweight/obese subjects and smokers.

Irritable bowel syndrome (IBS) is often associated with other unexplained complaints like chronic fatigue syndrome (CFS), fibromyalgia and myalgic encephalopathy (ME). The pathogenesis of the relationship is unknown. Intestinal dysbiosis may be a common abnormality, but based on 1100 consecutive IBS patients examined over a nine years period, we hypothesize that the development of the disease, often from IBS to ME, actually manifests a "dysbiotic march". In analogy with "the atopic march" in allergic diseases, we suggest "a dysbiotic march" in IBS; initiated by extensive use of antibiotics during childhood, often before school age. Various abdominal complaints including IBS may develop soon thereafter, while systemic symptom like CFS, fibromyalgia and ME may appear years later.

Background: To reduce colorectal cancer (CRC) mortality through population-based screening programmes using faecal tests, it is important that individuals continue to participate in the repeated rounds of screening. We aimed to identify lifestyle predictors for discontinuation of faecal immunochemical test (FIT) screening after the first round, as well as lifestyle predictors for colorectal neoplasia detected in the second-round FIT screening. Methods: In this longitudinal study, we invited 6959 individuals aged 50–74 years from south-east Norway for a first round of FIT screening and to complete a self-reported lifestyle questionnaire on demographic factors, body mass index (BMI, kg m−2), smoking habits, physical activity, consumption of alcohol and dietary items. Two years later, we estimated the associations between these factors, non-participation and screening results in the second round of FIT screening using adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: Of the 3114 responders to the questionnaire who completed the first-round FIT and who were invited to participate in second-round FIT screening, 540 (17%) did not participate. The OR and (95% CI) for discontinuation of FIT screening after the first round was 1.61 (1.24–2.10) for current smoking compared with non-smoking; 2.01 (1.25–3.24) for BMI ≥ 35 kg m−2 compared with BMI 16.9–24.9 kg m−2 and 0.70 (0.52–0.94) for physical activity in the third quartile vs the first. Among participants, smoking, high BMI and high alcohol consumption were associated with an increased odds of detecting colorectal neoplasia (n=107). Conclusions: These results may indicate that Norwegian FIT screening participants who discontinue after the first round have lifestyle behaviours associated with increased risk of CRC.

Background & Aims The comparative effectiveness of sigmoidoscopy and fecal immunochemical testing (FIT) for colorectal cancer (CRC) screening is unknown. Methods Individuals aged 50–74 years living in Southeast Norway were randomly invited between 2012 and 2019 to either once-only flexible sigmoidoscopy or FIT screening every second year. Colonoscopy was recommended after sigmoidoscopy if any polyp of ≥10 mm, ≥3 adenomas, any advanced adenomas, or CRC was found or, subsequent to, FIT >15 μg hemoglobin/g feces. Data for this report were obtained after complete recruitment in both groups and included 2 full FIT rounds and part of the third round. Outcome measures were participation, neoplasia detection, and adverse events. Age-standardized detection rates and age-adjusted odds ratios (ORs) were calculated. Results We included 139,291 individuals: 69,195 randomized to sigmoidoscopy and 70,096 to FIT. The participation rate was 52% for sigmoidoscopy, 58% in the first FIT round, and 68% for 3 cumulative FIT rounds. Compared to sigmoidoscopy, the detection rate for CRC was similar in the first FIT round (0.25% vs 0.27%; OR, 0.92; 95% confidence interval [CI], 0.75–1.13) but higher after 3 FIT rounds (0.49% vs 0.27%; OR, 1.87; 95% CI, 1.54–2.27). Advanced adenoma detection rate was lower in the first FIT round compared to sigmoidoscopy at 1.4% vs 2.4% (OR, 0.57; 95% CI, 0.53–0.62) but higher after 3 cumulative FIT rounds at 2.7% vs 2.4% (OR, 1.14; 95% CI, 1.05–1.23). There were 33 (0.05%) serious adverse events in the sigmoidoscopy group compared to 47 (0.07%) in the FIT group (P = .13). Conclusions Participation was higher and more CRC and advanced adenomas were detected with repeated FIT compared to sigmoidoscopy. The risk of perforation and bleeding was comparable. Clinicaltrials.gov, Number: NCT01538550.

Irritable bowel syndrome (IBS) is often accompanied by extra-intestinal symptoms, including fatigue and musculoskeletal pain. The present study aimed to investigate whether these symptoms were associated with markers of enterocyte disintegrity, endotoxemia and inflammation. Patients with IBS were recruited consecutively from our outpatient clinic (n=94) and compared with a group of healthy controls (n=20). Habitual symptoms were assessed using the IBS Severity Scoring System, the Fatigue Impact Scale and Visual Analogue Scales for measuring musculoskeletal pain. A lactulose challenge test was performed to induce post-prandial symptoms, and blood samples were obtained prior to and 90 min following lactulose ingestion to determine levels of intestinal fatty acid binding protein (iFABP), lipopolysaccharide (LPS), the LPS co-receptor soluble cluster of differentiation (sCD) 14, monocyte chemoattractant protein-1 (MCP-1) and calprotectin. Habitual symptom scores were high among the included patients, and lactulose ingestion induced significantly more symptoms in the patient group compared with the healthy control group (P=0.0001). Serum levels of iFABP were reduced in IBS patients compared with healthy controls, prior to and following lactulose ingestion (P=0.0002 and P=0.0001, respectively). Following lactulose ingestion, iFABP levels decreased in IBS patients (P=0.0001) and in healthy controls (P=0.02). Fasting levels of LPS, sCD14, MCP-1 and calprotectin were not significantly different between IBS patients and healthy controls. However, following lactulose ingestion, LPS levels increased in healthy controls (P=0.03), whereas MCP-1 levels decreased in IBS patients (P=0.008). Intestinal and extra-intestinal symptom severities were not correlated with levels of circulating biomarkers. No assessed biomarker in the present study appeared to be associated with symptom development in IBS patients. However, the implications of the low levels of iFABP observed require further investigation.

BACKGROUND: Allergy immunotherapy targets the immunological cause of allergic rhinoconjunctivitis and allergic asthma and has the potential to alter the natural course of allergic disease.OBJECTIVE: The primary objective was to investigate the effect of the SQ grass sublingual immunotherapy tablet compared with placebo on the risk of developing asthma.METHODS: A total of 812 children (5-12 years), with a clinically relevant history of grass pollen allergic rhinoconjunctivitis and no medical history or signs of asthma, were included in the randomized, double-blind, placebo-controlled trial, comprising 3 years of treatment and 2 years of follow-up.RESULTS: There was no difference in time to onset of asthma, defined by prespecified asthma criteria relying on documented reversible impairment of lung function (primary endpoint). Treatment with the SQ grass sublingual immunotherapy tablet significantly reduced the risk of experiencing asthma symptoms or using asthma medication at the end of trial (odds ratio = 0.66, P < .036), during the 2-year posttreatment follow-up, and during the entire 5-year trial period. Also, grass allergic rhinoconjunctivitis symptoms were 22% to 30% reduced (P < .005 for all 5 years). At the end of the trial, the use of allergic rhinoconjunctivitis pharmacotherapy was significantly less (27% relative difference to placebo, P < .001). Total IgE, grass pollen-specific IgE, and skin prick test reactivity to grass pollen were all reduced compared to placebo.CONCLUSIONS: Treatment with the SQ grass sublingual immunotherapy tablet reduced the risk of experiencing asthma symptoms and using asthma medication, and had a positive, long-term clinical effect on rhinoconjunctivitis symptoms and medication use but did not show an effect on the time to onset of asthma.

The relation of gastrointestinal (GI) complaints to IgE-mediated allergy is not well understood. Increased numbers of “IgE-armed” mast cells have been observed in duodenal mucosa of patients with functional GI complaints. To explore whether total IgE and atopic sensitization were associated with functional GI complaints. Levels of serum total and specific IgE and GI complaints were measured in 161 patients and in a general population sample of 478 persons. Standard inhalant allergens were measured in the patient group, and selected inhalant allergens in the general population. GI complaints were assessed by two standardized questionnaires. The associations between GI complaints and total IgE were analyzed in multiple regression models. GI complaints were positively associated with higher total IgE levels (all: b = 0.028, p = 0.012; patient group: b = 0.038, p = 0.072; general population: b = 0.038, p = 0.005), but negatively associated with atopic sensitization (all: b = −11.256, p = 0.181; patient group: b = −85.667, p

// Olga Ostrup 1, 2, * , Vegar Johansen Dagenborg 1, 9, * , Einar Andreas Rodland 1, 2 , Veronica Skarpeteig 2 , Laxmi Silwal-Pandit 2 , Krzysztof Grzyb 5 , Audun Elnaes Berstad 7 , Asmund Avdem Fretland 4, 8, 9 , Gunhild Mari Maelandsmo 1, 10 , Anne-Lise Borresen-Dale 2, 9 , Anne Hansen Ree 6, 9 , Bjorn Edwin 4, 8, 9 , Vigdis Nygaard 1, * and Kjersti Flatmark 1, 3, 9, * 1 Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway 2 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway 3 Department of Gastroenterological Surgery, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway 4 Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway 5 Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway 6 Department of Oncology, Akershus University Hospital, Lorenskog, Norway 7 Department of Radiology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway 8 The Intervention Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway 9 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway 10 Department of Pharmacy, University of Tromso - The Arctic University of Norway, Tromso, Norway * These authors have contributed equally to this work Correspondence to: Kjersti Flatmark, email: kjersti.flatmark@rr-research.no Keywords: colorectal liver metastases, genomic profiling, neoadjuvant chemotherapy, immunogenic cell death Received: February 23, 2017 Accepted: June 26, 2017 Published: July 18, 2017 ABSTRACT Background: Metastatic colorectal cancer (CRC) is associated with highly variable clinical outcome and response to therapy. The recently identified consensus molecular subtypes (CMS1-4) have prognostic and therapeutic implications in primary CRC, but whether these subtypes are valid for metastatic disease is unclear. We performed multi-level analyses of resectable CRC liver metastases (CLM) to identify molecular characteristics of metastatic disease and evaluate the clinical relevance. Methods: In this ancillary study to the Oslo-CoMet trial, CLM and tumor-adjacent liver tissue from 46 patients were analyzed by profiling mutations (targeted sequencing), genome-wide copy number alteration (CNAs), and gene expression. Results: Somatic mutations and CNAs detected in CLM were similar to reported primary CRC profiles, while CNA profiles of eight metastatic pairs suggested intra-patient divergence. A CMS classifier tool applied to gene expression data, revealed the cohort to be highly enriched for CMS2. Hierarchical clustering of genes with highly variable expression identified two subgroups separated by high or low expression of 55 genes with immune-related and metabolic functions. Importantly, induction of genes and pathways associated with immunogenic cell death (ICD) was identified in metastases exposed to neoadjuvant chemotherapy (NACT). Conclusions: The uniform classification of CLM by CMS subtyping may indicate that novel class discovery approaches need to be explored to uncover clinically useful stratification of CLM. Detected gene expression signatures support the role of metabolism and chemotherapy in shaping the immune microenvironment of CLM. Furthermore, the results point to rational exploration of immune modulating strategies in CLM, particularly by exploiting NACT-induced ICD.

Postprandial dyspepsia is common and may be associated with abnormal intragastric distribution of food. We aimed to determine the effect of body position on gastric emptying, meal distribution, and postprandial perceptions in healthy subjects.Eight adolescents (4 females and 4 males aged 14 years) were investigated using three-dimensional ultrasonography. The subjects were studied twice in a random order: once in the right lateral recumbent (RLR) position and once in the left lateral recumbent (LLR) position. Postprandial perceptions, gastric volumes, and antral areas were recorded immediately after the ingestion of 500 ml of a low-caloric meat soup over 4 min, and at 10 and 20 min following the meal.Postprandial perceptions (epigastric pain, nausea, and fullness) were more pronounced in the RLR position compared to the LLR position, particularly at the end of the meal ingestion (p0.01). Gastric volumes were significantly smaller in the RLR position compared to the LLR position at 10 min (p0.01) and 20 min (p0.05). Antral areas were significantly wider in the RLR position compared to the LLR position at 10 min (p0.05) and 20 min (p0.01).Postprandial perceptions are more pronounced, gastric emptying is faster, and antral area is wider in the RLR position compared to the LLR position. The results suggest that lying on the left side after a meal may be a measure to reduce postprandial dyspeptic sensations.

Background Postprandial discomfort following intake of poorly absorbable, but fermentable carbohydrates is a common complaint in patients with irritable bowel syndrome (IBS). We used lactulose as a model substance for this group of symptom triggering carbohydrates, aiming to visualize the intestinal response in IBS patients compared to healthy controls. Methods Patients with IBS according to Rome III criteria (n = 52) and healthy controls (n = 16) underwent a lactulose challenge test. By using magnetic resonance imaging, we measured small bowel water content (SBWC), and distension (diameter) of the distal ileum and the colon, both in fasting state and 1 h after ingestion of 10 g lactulose. We recorded symptoms after lactulose ingestion. Key Results Lactulose provoked significantly more symptoms in IBS patients than in healthy controls (p

Taste ability is known to be impaired in elderly and even more so in acutely hospitalized elderly people. To our knowledge, no study has investigated the association between taste impairment and mortality. Our aim was to examine this association in acutely hospitalized older people. In a prospective study, 200 acutely hospitalized elderly people ≥70 years of age were included between November 2009 and October 2010 at the Oslo University Hospital, Norway. Exclusion criteria were cognitive impairment, nursing home residency, and terminal diseases. Comorbidity was registered with the Cumulative Illness Rating Scale, in addition to recording of age, gender, smoking, education, and number of medications. Taste ability was assessed quantitatively with the "taste strips method" in 174 patients (mean age: 84 years). Mortality until 1 January 2012 was obtained from hospital records. Fifty-six patients died during the observation period. The relative risk of death in total taste score quartile 4 compared with total taste score quartile 1 was 0.31 (95% confidence interval [95% CI]: 0.14-0.69, P = 0.004), after adjusting for age, gender, smoking, education, and Cumulative Illness Rating Scale. Adjusted 1-year mortality decreased from 30% in total taste score quartile 1 to 9% in total taste score quartile 4. Thus, impaired taste appears to be strongly associated with mortality in acutely hospitalized elderly people.

In 10 duodenal ulcer patients gastric juice was aspirated every 10 min for 20 min before and 200 min after sham feeding. One antacid tablet or placebo was given 80 min after the sham feeding. Analyses of the aspirates showed that antacids reduced mean hydrogen ion activity and pepsin concentration significantly for 40 and 60 min, respectively, and increased phospholipid concentration for 30 min, compared with placebo. Highest mean pH was 2.52. The percentage of pH readings at or above pH levels of 2, 3, and 4 during the 2 h period following antacid administration was 29, 10, and 2%, respectively. No significant differences between antacid and placebo were found regarding intragastric concentrations of bile acids and prostaglandin E2. When one antacid tablet was administered 80 min after a real meal, the effect on intragastric pH was similarly weak, but lasted slightly longer. Acid neutralization' alone can hardly explain the ulcer-healing effect of low-dose antacids. Antacid-induced increase in intragastric concentration of phospholipids is a new and potentially important observation.

Background: In metastatic colorectal cancer, only the microsatellite instable (MSI) subgroup of cases has so far demonstrated major responses to immune checkpoint inhibition. Increased infiltration of T lymphocytes in presumed non-responsive tumors has been shown to facilitate response to immune checkpoint inhibition. Cytotoxic chemotherapy might induce immunogenic cell death and cause infiltration of immune cells, turning “cold” tumors into “hot”. In this work we investigated whether standard-of-care neoadjuvant chemotherapy (NACT) would influence T-cell infiltration in the tumor microenvironment of colorectal liver metastases (CLM) in a substudy of patients included in the OSLO-COMET trial (n=280; NCT01516710). Materials and methods: Patients (n=92; bearing 144 metastatic tumors) had resectable CLM, and of these, 45 patients received NACT, in most cases fluoropyrimidine-based, with the addition of oxaliplatin (n=36) or irinotecan (n=8). Quantification of total T-cells (Ttot), cytotoxic T-cells, T-helper cells, and regulatory T-cells was performed by immunohistochemical staining of serial sections with antibodies against CD3, CD8, CD4, and FOXP3, respectively. Hotspots from the invasive margin (IM), intratumoral region (IT), and adjacent liver tissue (NLi) were analyzed. T-cell density was reported as number of T-cells/mm2. Results: The density of Ttot in the IM region (median 2360 cells/mm2) was 7 times greater than in the IT region (319 cells/mm2) and 13 times greater than in the NLi region (183 cells/mm2), with similar findings for T-cell subtypes. Comparing patients that had received NACT to patients that had not, there was no difference in T-cell infiltration in the IM and NLi regions, but a non-significant trend towards increased T-cell density was detected in the IT region after NACT, exemplified by Ttot 353 vs 292 cells/mm2 (p=0.2). Exploring the influence of the time interval between NACT completion and surgery by receiver operating characteristic curve analysis, 9.5 weeks was identified as the time point that separated the cases most clearly by T-cell density. Interestingly, cases with a shorter than 9.5-week interval had a significantly higher intratumoral T-cell count than cases with the longer interval; with median Ttot 491 vs 236 cells cells/mm2; p Conclusion: The main finding of this work was that NACT administration was associated with a transient increase of intratumoral T-cell density in CLM, potentially promoting an MSI-like tumor immune phenotype. The results suggest that when exploring combinations of cytotoxic therapy and immune checkpoint inhibition, the timing of individual treatment components may be essential. To further optimize treatment schedules, biomarkers reflecting T-cell infiltration may be a useful tool for tailoring personalized therapy. Citation Format: Kjersti Flatmark, audun E. Berstad, Vegar Dagenborg, Bjørn Edwin, Åsmund A. Fretland, Krzysztof Grzyb, Eirik Høye, Marius Lund-Iversen, Serena E. Marshall, Anne H. Ree, Sheraz Yaqub. Neoadjuvant chemotherapy promotes a transient increase of intratumoral T-cell density in colorectal liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4967.

SUMMARY Background: Spiramycin (Rovamycin) is a well-established macrolide antibiotic with good anti-Helicobacter pylori activity in vitro. It is acid-stable and found in high concentration in various body fluids and cells after oral administration. Its anti-H. pylori activity in vivo has not yet been tested. Methods: Twenty-five consecutive patients with endoscopically verified peptic ulcer and a positive biopsy urease test were given spiramycin tables 1.5 MIU instead of oxytetracycline 500 mg q.d.s. in our triple therapy regimen with bismuth subnitrate suspension 10 mL (150 mg bismuth subnitrate) q.d.s. and metronidazole 400 mg t.d.s. for 10 days. Bismuth was taken between meals and spiramycin and metronidazole with meals. Re-endoscopy and 14C-urea breath test were performed 4 weeks after completion of therapy. Those who were H. pylori negative according to the breath test returned for 1-year follow-up. Results: Per protocol analysis at 4 weeks showed that 21 out of 23 patients were H. pylori negative and had healed ulcers. These 21 patients were persistingly H. pylori negative and had no ulcers at 1-year follow-up. H. pylori eradication and ulcer healing rates were thus 91.3%; 95 % confidence interval from 72.0% to 98.9%. Side-effects limiting daily activity were significantly less frequent than we have experienced previously using oxytetracycline in triple therapy. Conclusions: Spiramycin appears to be an alternative to tetracycline in the triple therapy of H. pylori infection. Further studies to position spiramycin as an anti-H. pylori drug are warranted.

A substantial minority of patients with gastro-oesophageal reflux disease (GERD) are infected with Helicobacter pylori, but there is controversy as to whether these patients should be treated for their infection. We hypothesized that H. pylori eradication increases gastro-oesophageal acid reflux in such patients with time.Thirty-five consecutive H. pylori-infected patients (16 M and 19 F) with mild or moderate reflux oesophagitis were enrolled. Twenty-four-hour intra-oesophageal (n = 35) and intragastric (n = 12) pH-metry was recorded before and 15 months after H. pylori eradication. Gastric biopsy specimens from the antrum and corpus were obtained from 10 consecutive patients before and 15 months after H. pylori eradication.Fifteen months after eradication of H. pylori there was a significant decrease in percentage time oesophageal pH4 in the recumbent position only (P = 0.04). Despite a marked reduction in the severity of gastritis, there was no significant change in gastric acidity, total intra-oesophageal acid exposure or symptom score. Heartburn improved in 12, worsened in 7. and remained unchanged in 16 patients (P = 0.36) without any significant relationship to individual changes in acid exposure (P = 0.60).H. pylori eradication does not increase gastric acidity or gastro-oesophageal acid reflux in patients with mild to moderate reflux oesophagitis over the first 15 months.

To investigate the association between adherence to health recommendations and detection of advanced colorectal neoplasia (ACN) in colorectal cancer (CRC) screening.A total of 14832 women and men were invited to CRC screening, 6959 in the fecal immunochemical test arm and 7873 in the flexible sigmoidoscopy arm. These were also sent a self-reported lifestyle questionnaire to be completed prior to their first CRC screening. A lifestyle score was created to reflect current adherence to healthy behaviors in regard to smoking, body mass index, physical activity, alcohol consumption and food consumption, and ranged from zero (poorest) to six (best). Odds ratios (ORs) and 95%CIs were calculated using multivariable logistic regression to evaluate the association between the single lifestyle variables and the lifestyle score and the probability of detecting ACN.In all 6315 women and men completed the lifestyle questionnaire, 3323 (53%) in the FIT arm and 2992 (47%) in the FS arm. This was 89% of those who participated in screening. ACN was diagnosed in 311 (5%) participants of which 25 (8%) were diagnosed with CRC. For individuals with a lifestyle score of two, three, four, and five-six, the ORs (95%CI) for the probability of ACN detection were 0.82 (0.45-1.16), 0.43 (0.28-0.73), 0.41 (0.23-0.64), and 0.41 (0.22-0.73), respectively compared to individuals with a lifestyle score of zero-one. Of the single lifestyle factors, adherence to non-smoking and moderate alcohol intake were associated with a decreased probability of ACN detection compared to being a smoker or having a high alcohol intake 0.53 (0.42-0.68) and 0.63 (0.43-0.93) respectively.Adopted healthy behaviors were inversely associated with the probability of ACN detection. Lifestyle assessment might be useful for risk stratification in CRC screening.

doi: 10.1111/j.1741-2358.2011.00607.x Association between oral health and body cell mass in hospitalised elderly Objective: To examine whether oral health in hospitalised elderly was associated with body cell mass (BCM) measured with Bioimpedance spectroscopy. Background: Body cell mass is the tissue producing the metabolic work necessary for all body functions. BCM is mainly muscle tissue. Low BCM is associated with diseases, ageing and poor nutritional status. Reduced oral health is also associated with these parameters; thus, BCM and oral health may be related. Methods: Body cell mass was measured using Bioimpedance spectroscopy in 138 acutely hospitalised elderly ≥70 years. The number of own teeth, posterior occluding tooth pairs and decayed teeth were registered. Oral hygiene was registered with Mucosal–Plaque Score, an index based on assessment of plaque accumulation and mucosal/gingival inflammation. Mini Nutritional Assessment-Short Form, body mass index and handgrip strength were used as nutritional indicators. Comorbidity was assessed with Cumulative Index Rating Scale. Results: Mean age was 83.2 ± 5.9 years, ranging from 70 to 101 years. Dentition status was significantly and positively associated with BCM. Reduced oral hygiene was significantly associated with low BCM. These findings remained significant after adjusting for confounders. Conclusion: These results show that compromised oral health was significantly associated with reduced BCM in hospitalised elderly.

The biliopancreatic diversion with duodenal switch can be performed by different combinations of restriction and malabsorption. The aim of this study was to evaluate weight loss and potential side effects for two variants of the procedure. All patients eligible for a 2-year follow-up (n = 182) was included in the study. Thirty-five patients (group A) had a gastric remnant with a volume of approximately 200 ml, an alimentary limb (AL) of 250 cm, and a common channel (CC) of 100 cm, while 147 patients (group B) had a gastric remnant of 100–120 ml, an AL of 40%, and a CC of 10% of the small bowel length. Preoperative variables, such as body mass index (BMI), sex, age, and factors that might influence weight loss, and postoperative weight loss and side effects were registered and compared. Preoperatively, the BMI was 50.6 in group A and 52.1 in group B (ns), with no difference in age, sex, or variables that might influence weight loss. At 2 years, the BMI was 33.1 in group A (n = 34) and 28.5 in group B (n = 119) with an adjusted difference in weight loss of 5.6 BMI units between the groups (p

Jørgen Valeur1,2, Mette Helvik Morken1, Elisabeth Norin3, Tore Midtvedt3, Arnold Berstad1,21Institute of Medicine, University of Bergen, Bergen, Norway; 2Department of Medicine, Haukeland University Hospital, Bergen, Norway; 3Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, SwedenPurpose: Enterometabolic disturbances may cause meal-related symptoms. We performed a functional evaluation of the intestinal microflora in patients with unexplained, self-reported food hypersensitivity by measuring fecal short-chain fatty acids (SCFAs).Patients and methods: Thirty-five consecutive patients with self-reported food hypersensitivity and 15 healthy volunteers of similar age, gender, and body mass index collected all feces for 72 hours. Fecal concentrations of acetic, propionic, n-butyric, i-butyric, n-valeric, i-valeric, n-caproic, and i-caproic acids were analyzed by gas-liquid chromatography. Concentrations and excretions (output) of SCFAs in patients and controls were compared and related to gastrointestinal symptoms.Results: Despite nonsignificant differences between patients and controls for both total and individual SCFA concentrations and excretions, n-butyric acid comprised a higher (P = 0.035) and acetic acid a lower (P = 0.012) proportion of total SCFA in patients compared to controls. There were no significant correlations between symptom scores and concentrations or excretions of individual or total SCFAs, but the proportion of n-butyric acid was significantly higher in patients with severe symptoms compared to patients with moderate symptoms (P = 0.016).Conclusion: The results indicate an enterometabolic disturbance in patients with self-reported food hypersensitivity. Higher proportions of n-butyric acid may be related to abdominal symptom generation, but may also protect against organic bowel disease. Further studies are needed to clarify these aspects.Keywords: butyrate, dysbiosis, gut microbiota, irritable bowel syndrome, short-chain fatty acids

OBJECTIVE. Intestinal infection with Giardia lamblia may lead to therapy-resistant, long-lasting post-giardiasis irritable bowel syndrome (IBS). We report two open pilot studies aiming to treat this condition, using either antibiotics or bacterio-therapy. MATERIAL AND METHODS. Twenty-eight patients with persistent abdominal symptoms, following clearance of G. lamblia infection, were investigated. Eighteen received treatment with rifaximin plus metronidazole (8-10 days) whereas 10 received a suspension of live faecal flora, installed into the duodenum during gastro-duodenoscopy. Customary abdominal symptoms and symptoms following a lactulose breath test were quantified by questionnaires. Hydrogen and methane production after lactulose were analysed in expired air and excretion of fat and short-chain fatty acids (SCFAs) was examined in faeces. RESULTS. As compared with pre-treatment values, total customary symptom scores were barely significantly reduced (p = 0.07) after antibiotics, but were highly significantly reduced (p = 0.0009) after bacterio-therapy. However, symptom improvement following bacterio-therapy did not persist 1 year later. Hydrogen breath excretion was slightly reduced after antibiotics, but not after bacterio-therapy. Compared with healthy persons, faecal excretion of fat was significantly increased in Giardia-cured patients. SCFAs were increased in the bacterio-therapy group, and were not influenced by therapy. CONCLUSIONS. Both antibiotics and bacterio-therapy were ineffective with respect to cure of post-giardiasis IBS. High faecal excretion of fat and SCFAs suggests that intestinal malabsorption of fat and carbohydrates may play a role in the IBS-like complaints of these patients.

Significant reductions were registered in the plasma levels of prekallikrein proactivator (pro-PKA), prekallikrein (PK), and high molecular weight kininogen (HMWK) 3-5 min. after the intravenous injection into rats of serotonin (0.02-0.20 mg/kg) or noradrenaline (0.02 mg/kg), whereas adrenaline (0.02 mg/kg) showed no effect, and tyramine (3.0 mg/kg) only slightly lowered the parameters mentioned. Pretreatment with reserpine (1.5 mg/kg) injected intraperitoneally 24 hours before dextran (10 mg/100 g) inhibited the dextran-induced lowering of pro-PKA and PK, but not the lowering of HMWK, while the effects of serotonin (0.13 mg/kg) were not influenced. After pretreatment of the rats with guanethidine (150 mg and 150 mg/kg respectively 48 hours and 24 hours before dextran) the dextran-induced reductions in the levels of pro-PKA and PK took place to the same extent as in control rats. while the lowering of HMWK was abolished. Pretreatment with reserpine protected against dextran-induced oedemas, whereas pretreatment with guanethidine did not. It is concluded that catecholamines are probably not important in the initial phase of the dextran reaction in the rat, whereas serotonin seems to be an essential factor at this stage, as it is known to be during the fully developed dextran reaction. The results indicate that HMWK is not essential in connection with the early events of the dextran reaction, whereas the parameters pro-PKA and PK seem to be of primary importance during this phase.

Irritable bowel syndrome (IBS) is associated with unexplained medical symptoms, and the degree of somatic comorbidity may indicate whether the aetiology of IBS is predominantly psychological or biological in origin. The purpose of this study was to examine the comorbidity and quality of life of patients with IBS following infection with Giardia lamblia.Sixty-seven consecutive patients with persistent abdominal symptoms, initiated by an acute infection with G. lamblia, completed questionnaires for scoring of subjective health complaints (SHC) and quality of life (Short-form Nepean Dyspepsia Index (SF-NDI)). The scores were compared with corresponding scores in persons from the general population (n=70).Compared with controls, each of the two groups of patients, those with present (n=17) and those with cured (n=50) G. lamblia infection, had significantly higher scores (p0.0001) on SHC. However, subscores on somatic comorbidity (musculoskeletal pain) were low and similar to those in the general population (OR 1.2 (0.51-2.73)). Quality of life was substantially impaired in the patients; sum scores 30.0+/-8.0 (mean+/-SD) and 31.7+/-9.3 in the patient groups and 13.5+/-6.8 in the general population (p0.0001).Patients with post-giardiasis IBS suffer very little somatic comorbidity, suggesting that the aetiology of this form of postinfective IBS is predominantly biological in origin and may thus differ from the more common, non-postinfective forms of IBS. The combination of persisting abdominal symptoms and psychological distress might be a perpetuating factor contributing to low quality of life.

Objective – To identify possible associations between white matter lesions (WML) and cognition in patients with memory complaints, stratified in groups with normal and low cerebrospinal fluid (CSF) Aβ42 values. Material and Methods – 215 consecutive patients with subjective memory complaints were retrospectively included. Patients were stratified into two groups with normal (n = 127) or low (n = 88) CSF Aβ42 levels (cut-off is 450 ng/l). Cognitive scores from the Mini-Mental State Examination (MMSE) and the Neurobehavioral Cognitive Status Examination (Cognistat) were used as continuous dependent variables in linear regression. WML load was used as a continuous independent variable and was scored with a visual rating scale. The regression model was corrected for possible confounding factors. Results – WML were significantly associated with MMSE and all Cognistat subscores except language (repetition and naming) and attention in patients with normal CSF Aβ42 levels. No significant associations were observed in patients with low CSF Aβ42. Conclusions – WML were associated with affection of multiple cognitive domains, including delayed recall and executive functions, in patients with normal CSF Aβ42 levels. The lack of such associations for patients with low CSF Aβ42 (i.e. with evidence for amyloid deposition), suggests that amyloid pathology may obscure cognitive effects of WML.

The aim of this study was to examine the lifestyle of adult patients with abdominal discomfort (i.e., diarrhea, bloating, pain, and irregular defecation) self-attributed to food hypersensitivity and compare it with controls to see if the patients had a special lifestyle explaining their symptoms. Forty-six participants in this study were adult ethnic Norwegians referred by general practitioners to the Centre for Occupational and Environmental Allergy at Haukeland University Hospital because of gastrointestinal complaints, which the patients or their doctors suspected could be due to food allergy. They were compared with 70 age- and sex-matched volunteer controls from the general population. All participants filled out an extensive questionnaire focusing on different lifestyle aspects. One hundred percent of the patients and 43% of the controls (p < .0001) reported hypersensitivity to at least one food item. Significantly, fewer patients than controls reported daily consumption of milk (p = .004), coffee (p = .02), and alcohol (p = .008) for the past year. Among consumers, the participants used less milk (P = .002) and coffee (P = .04) than controls. Eating habits, meal patterns, quality of sleep, the amount of exercise, and use of painkillers were similar in both groups. There were small differences in lifestyle between the patients and the controls. Patients with gastrointestinal complaints self-attributed to food hypersensitivity used less milk, coffee, and alcohol, but none of those differences explain their symptoms. Such lifestyle would rather be expected to lessen symptoms, and we postulate that it is the consequence of their food intolerance and not its cause.

Background: Two-dimensional ultrasonography has shown a widened gastric antrum in patients with non-ulcer dyspepsia (NUD) and erosive prepyloric changes (EPC). Methods: In this study, volumes of gastric antrum and gallbladder were estimated with three-dimensional (30) ultrasonography before and after ingestion of 500 ml meat soup in 17 NUD with EPC patients and in 18 healthy subjects. A mechanical ultrasound scanner, coupled to a stepping motor, tilted the transducer through an angle of 51° or 88° while recording a total of 95 or 81 images, respectively. Volume estimation was performed digitally after interactive manual contour tracing and organ reconstruction in three dimensions. Results: Antral volumes were larger in NUD patients than in healthy controls (P = 0.001). Fasting gallbladder volumes were similar in the two groups. Postprandial antral filling was more pronounced in patients than in healthy subjects (P = 0.02). whereas gallbladder emptying was more pronounced in healthy subjects than in patients (P = 0.05). The soup induced dyspeptic symptoms in 15 NUD patients, but only had this effect in two healthy subjects (P < 0.001). Conclusion: Patients with NUD and EPC are characterized by abnormal antral filling, reduced gallbladder emptying, and dyspeptic symptoms in response to ingestion of meat soup.

Antral hypomotility and impaired gastric accommodation in patients with functional dyspepsia have been ascribed to vagal dysfunction. We investigated whether vagal stimulation by sham feeding would improve meal-induced gastric motor function in these patients. Fourteen healthy volunteers and 14 functional dyspepsia patients underwent a drink test twice, once with and once without simultaneous sham feeding. After ingesting 500 mL clear meat soup (20 kcal, 37 degrees C) in 4 min, sham feeding was performed for 10 min by chewing a sugar-containing chewing gum while spitting out saliva. Using two- and three-dimensional ultrasound, antral motility index (contraction amplitude x frequency) and intragastric volumes were estimated. Without sham feeding, functional dyspepsia patients had lower motility index than healthy volunteers (area under curve 8.0 +/- 1.2 vs 4.4 +/- 1.0 min(-1), P = 0.04). In functional dyspepsia patients, but not in healthy volunteers, motility index increased and intragastric volume tended to increase by sham feeding (P = 0.04 and P = 0.06 respectively). The change in motility index was negatively correlated to the change in pain score (r = -0.59, P = 0.007). In functional dyspepsia patients, vagal stimulation by sham feeding improves antral motility in response to a soup meal. The result supports the view that impaired vagal stimulation is implicated in the pathogenesis of gastric motility disturbances in functional dyspepsia.

Carbohydrate malabsorption causes more symptoms in patients with functional gastrointestinal disorders than in healthy individuals. The purpose of this study was to investigate whether this could be explained by differences in ileal brake hormone secretion.Eighteen consecutive patients with functional abdominal complaints, referred to our clinic for investigation of self-reported food hypersensitivity, were included in the study and compared with 15 healthy volunteers. All subjects ingested a mixture of 25 g fructose and 5 g sorbitol. Pulmonary hydrogen and methane excretion and plasma glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) levels were measured during the next 3 h. Both habitual and post-test symptoms were assessed.Malabsorption of fructose and sorbitol was present in 61% of the patients and 73% of the controls. Nevertheless, the patients experienced significantly more symptoms following carbohydrate challenge, and 78% of the patients claimed that the challenge replicated their habitual gastrointestinal complaints. No significant differences in gas excretion or GLP-1 and PYY levels were found between patients and controls or between symptomatic and asymptomatic carbohydrate malabsorbers. A weak correlation between hydrogen excretion and PYY levels was demonstrated in non-producers of methane.Neither intestinal gas production nor ileal brake hormone secretion seems to play a role in the symptomatology of carbohydrate intolerance in patients with self-reported food hypersensitivity. Other mechanisms related to bacterial fermentation may be involved and should be investigated further.

Ragnhild Undseth,1 Greta Jakobsdottir,2 Margareta Nyman,2 Arnold Berstad,3 Jørgen Valeur3 1Department of Radiology, Lovisenberg Diaconal Hospital, Oslo, Norway; 2Food for Health Science Centre, Lund University, Lund, Sweden; 3Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway Background: Ingestion of low-digestible carbohydrates triggers symptoms in patients with irritable bowel syndrome (IBS). These carbohydrates become substrates for microbial fermentation in the colon, yielding short-chain fatty acids (SCFAs) that are readily absorbed. Aiming to compare colonic fermentation in patients with IBS and healthy controls, we analyzed the concentrations of SCFA in serum at fasting and 90 minutes following ingestion of an unabsorbable, but fermentable carbohydrate, lactulose. Methods: Patients with IBS according to Rome III criteria (n=22) and healthy controls (n=20) ingested 10 g lactulose dissolved in water. Symptoms were graded by questionnaires and SCFA were analyzed using hollow fiber-supported liquid membrane extraction coupled with gas chromatography. Results: Lactulose induced more symptoms in patients with IBS than in healthy controls (P=0.0001). Fasting serum levels of SCFA did not differ between patients with IBS and controls. However, the postprandial levels of total SCFA (P=0.0002), acetic acid (P=0.005), propionic acid (P=0.0001), and butyric acid (P=0.01) were significantly lower in patients with IBS compared with healthy controls. There was no correlation between the levels of serum SCFA and symptom severity. Conclusion: Low-serum levels of SCFA after lactulose ingestion may indicate impaired colonic fermentation in patients with IBS. Conceivably, this disturbance is related to symptom generation, but the mechanism is not clear. Keywords: fermentation, FODMAP, irritable bowel syndrome, microbiota, short-chain fatty acids&nbsp

Background: Participation in cancer screening programmes might cause worries in the population outweighting the benefits of reduced mortality. The present study aimed to investigate possible psychological harm of participation in a colorectal cancer (CRC) screening pilot in Norway. Methods: In a prospective, randomised trial participants (aged 50–74 years) were invited to either flexible sigmoidoscopy (FS) screening, faecal immunochemical test (FIT), or no screening (the control group; 1 : 1: 1). Three thousand two hundred and thirteen screening participants (42% of screened individuals) completed the Hospital Anxiety and Depression Scale questionnaire as well as the SF-12—a health-related quality of life (HRQOL) questionnaire when invited to screening and when receiving the screening result. A control group was invited to complete the questionnaires only. Two thousand six hundred and eighteen control participants (35% of invited individuals) completed the questionnaire. Results: A positive screening result did not increase participants' level of anxiety or depression, or decrease participants' level of HRQOL. Participants who received a negative result reported decreased anxiety and improvement on some HRQOL dimensions. However, no change was considered to be of clinical relevance. Conclusion: The current study showed no clinically relevant psychological harm of receiving a positive CRC screening result or of participating in FS or FIT screening, in a Norwegian population.

Objective. A new distension paradigm, by which the gastric volume response to ramp-tonic distension can be analysed in detail, has been developed. The aim of this study was to investigate the applicability of this new paradigm in man, and to compare pressure-induced gastric accommodation in healthy volunteers (HV) and patients with functional dyspepsia (FD). Material and methods. Ten HV, and 11 FD patients were examined twice; once in the fasting state and once postprandially. Intragastric bag pressure was raised from 1 to 12 mmHg in 4 min (ramp phase) and then kept constant for 5 min (tonic phase). Results. Compared to HV, fasting FD patients had lower gastric accommodation rates (0.99 /0.2 versus 2.59 /0.4 ml/s, p /0.002), lower maximum volume (2399 /39 versus 4289 /64 ml, p /0.01) and a longer accommodation time (1579 /26 versus 929 /15 s, p /0.03). A test meal prior to distension tended to normalize the response in FD patients. Conclusions. This new barostat paradigm allowed detailed analysis of short-term pressureinduced accommodation in man. Impaired gastric distension-induced accommodation is a novel abnormality in FD.

Owing to lack of objective measures, the diagnosis of food hypersensitivity may be difficult. The aim of this study was to investigate whether the intestinal response to direct provocation in patients with food hypersensitivity could be recognized by ultrasound.Thirty-two patients with chronic abdominal complaints, self-attributed to food hypersensitivity/allergy were included in the study. Via a nasoduodenal tube, the duodenal mucosa was challenged with the suspected food item dissolved in 10 ml water or saline. Using external ultrasound, the sonographic features (wall thickness and diameter of the duodenal bulb and jejunum, peristalsis activity and luminal fluid) were recorded before and during one hour after challenge.Sonographic changes were observed after challenge in 14 (44%) of the 32 patients. A positive sonographic response (increased wall thickness, diameter, peristalsis and/or luminal fluid) was significantly related to a positive skin prick test (p = 0.008) and a positive double-blind placebo-controlled food challenge (p = 0.03). A significant correlation was found between provocation-induced symptoms and wall thickness of the duodenal bulb (r = 0.50, p = 0.004) or the jejunum (r = 0.42, p = 0.02). Intra- and interobserver variation of the tracing procedure showed low values.Responses of the proximal small intestines to direct provocation (swelling of the wall and exudation of fluid into the lumen) could be visualized by transabdominal ultrasound. This new provocation test could be helpful in the evaluation of patients with food hypersensitivity.

Background/Aims: We investigated whether increasing the efferent vagal activity by insulin-induced hypoglycemia would enhance gastric emptying and volumes in healthy subjects. Methods: Twenty healthy volunteers (10 males) were examined with and without vagal stimulation by insulin-induced hypoglycemia using a glucose clamp technique. Stomach function was tested by drinking meat soup (0.04 kcal ml–1) at a rate of 100 ml min–1 until maximal capacity. Intragastric volume at maximal drinking capacity was determined by three-dimensional ultrasound. Respiratory sinus arrhythmia (RSA) was used as an index of cardiac vagal activity and plasma pancreatic polypeptide (PP) as a measure of gastric vagal activity, and skin conductance (SC) as a measure of sympathetic tone. Results: Insulin-induced hypoglycaemia increased drinking capacity (p = 0.002), gastric emptying (p = 0.02), PP (p = 0.004) and SC (p = 0.004), while intragastric volume was unchanged (p = 0.7) and RSA decreased (p = 0.03). Conclusion: Enhancement of gastric vagal activity by insulin-induced hypoglycemia increased drinking capacity and gastric emptying similarly, resulting in an unchanged intragastric volume. Enhanced efferent vagal activity to the stomach (as measured by PP) was not associated by enhanced cardiac vagal activity (as measured by RSA), possibly a consequence of stress-induced sympathetic activation during the procedure.

We investigated the effect of prior acute stress on colonic permeability induced by a chemical irritant known to induce symptoms similar to inflammatory bowel disease in rodents. Adult male rats (n = 12) were stressed by a single session of ten unpredictable, uncontrollable foot shocks, and half were home cage controls (n = 12). Twenty-nine days later, half of each treatment group was exposed to 4% DSS (dextran sulphate sodium) solution in their drinking water for 48 hours while half received pure water over two periods separated by 17 days. After food deprivation overnight and light isoflurane anaesthesia the following morning, the animals were given a colonic infusion of 2000 nCi (nanocurie) 51CrEDTA (51Cr-labelled ethylenediaminetetraacetic acid) and then placed individually in metabolic cages for a six hours continuous urine collection. Radioactivity in urine was measured by a gamma counter and percentage recovery of 51CrEDTA calculated as an indicator of colonic mucosal permeability. Results concluded that pre-shocked animals exposed to DSS showed significantly higher mucosal permeability than the pre-shocked animals given water, and the non-shocked animals given either DSS or water. Pre-shock in combination with two exposures to a chemical irritant separated by 17 days had a pronounced effect on colonic permeability, indicating that stress should be considered a possible initiating or contributory factor to increased intestinal permeability related to a mucosal challenge.

2276 - 8 Irritable bowel syndrome is a commonly occurring symptom complex of unknown cause. The condition is characterised by gastrointestinal problems, but is often accompanied by functional disorders in several organ systems. Disruption of the intestinal flora may be a causal factor, and this possibility should be further researched, not least as a basis for treatment.

The aim of this study was to elucidate the relationship between duodenal ulcer (DU) disease and psychological symptoms.Sixty-four Helicobacter pylori-positive patients with frequently relapsing DUs (patient group 1) were compared with 78 control subjects without dyspepsia, starting 2 years before and ending 10 years after eradication of H. pylori. Seven non-relapsing and untreated patients (patient group 2) were also followed-up.The relapse rate was reduced from 100% per year in the two years before anti-H. pylori treatment to 0.3% per year after treatment in patient group 1. The reinfection rate was 0.7% per year. Anxiety and neuroticism were high at inclusion, but had normalized at the 10-year follow-up in relapse-free patients. There was no increase of gastro-oesophageal reflux symptoms during the 10 years after H. pylori eradication.Normalization of anxiety and neuroticism following cure of DU disease supports the view that the increased anxiety and neuroticism are consequences, and not causes, of the disease.

Background: Rheumatic joint pain is a common extra-intestinal complication of inflammatory bowel disease (IBD). Because the high ratio of n-6 to n-3 fatty acids (FAs) of the Western diet might promote rheumatic disorders, we sought to compare the effects of short-term duodenal administration of n-3-rich seal oil and n-6-rich soy oil on IBD-related joint pain. Methods: Nineteen patients with IBD-related joint pain were included in the study; 9 had Crohn disease and 10 had ulcerative colitis. Ten millilitres seal oil (n = 10) or soy oil (n = 9) was self-administered through a nasoduodenal feeding tube 3 times daily for 10 days. Results: Compared with soy oil treatment, seal oil significantly reduced the duration of morning stiffness (P = 0.024), number of tender joints (P = 0.035), intensity of pain (P = 0.025) and the doctor’s scoring of rheumatic disease activity (P = 0.025) at the end of the 10-day treatment period. Analysis of the effects as area under the curve (area between the curve and baseline, zero) for the entire period from start of treatment until 6 months’ post-treatment suggested a long-lasting beneficial effect of seal oil administration on joint pain, whereas soy oil tended (not significantly) to aggravate the condition. Consistently, the serum ratios of n-6 to n-3 FAs (P 0.01) and arachidonic acid to eicosapentaenoic acid (P 0.01) were reduced after treatment with seal oil. Conclusion: The results suggest distinctive, differential prolonged effects on IBD-related joint pain of short-term duodenal administration of n-3-rich seal oil (significant improvement) and n-6-rich soy oil (tendency to exacerbation).

Drinking capacity is often reduced in functional dyspepsia. Drink tests may therefore have diagnostic potential. A simple drink test in combination with ultrasonography was applied in this study, the aim being to find the best drink for this test.On separate days, 10 patients with functional dyspepsia (FD) and 10 healthy controls (C) drank three different test meals (Nutridrink 150 kcal/100 mL, meat soup 4 kcal/100 mL and water) at a rate of 100 mL/min until maximal drinking capacity. Intragastric volume at maximal drinking capacity was determined using 3-dimensional ultrasonography.Drinking capacity (P0.05) and intragastric volume (P0.01) were significantly lower in patients than in the controls with the meat soup meal, but not with Nutridrink or water. Gastric emptying distinguished significantly (P0.05) between patients and controls only with Nutridrink. Gastric emptying of Nutridrink was significantly correlated to the rate by which nausea was induced (P = 0.02), while gastric emptying of meat soup was significantly negatively correlated to the rate by which fullness was induced (P0.05). Receiver operating characteristic (ROC) analysis indicated that optimal discrimination between patients and controls was obtained by the combined test results of symptoms per intragastric volume using meat soup as the test meal.For the non-invasive diagnosis of functional dyspepsia by a rapid drink test in combination with ultrasonography, a meat soup meal is preferable compared to Nutridrink or water.

It is known that patients with peptic ulcer disease (PUD) often have an unhealthy lifestyle that results in increased mortality because of smoking-related diseases. No thorough study has been done to see what changes, if any, the patient makes to lifestyle after eradication of Helicobacter pylori.One-hundred-and-eighty-three patients were enrolled in an open-endoscopy setting; 58% had PUD and 42% gastritis and/or duodenitis (G/D). They filled out a lifestyle questionnaire before the start of anti-Helicobacter therapy and again 1 year later.The prevalence of food intolerance decreased from 71% to 44% among patients with PUD (P0.0001) and from 76% to 63% among patients with G/D (P = 0.09). Tolerance improved for coffee, orange juice, fried foods, spicy foods and fruits. There was no significant change in smoking or alcohol consumption after eradication. Coffee and tea consumption was unchanged. Milk consumption decreased from 4.2 dL/day to 3.3 (P = 0.01). The number of meals decreased from 3.5/day to 3.4 (P = 0.005) and snacking from 1.3 snacks/day to 1.1 (P = 0.02). Consumption of fruit increased from 4.0 to 4.3 times/week (P = 0.04), but the frequency of meat, fish, vegetables, spicy foods, salty foods, sweets and cakes did not change. The time spent on each meal was unchanged. There was no change in the time spent exercising. There were few significant differences between PUD and G/D patients.Food was better tolerated, but there were no major changes in lifestyle after eradication of H. pylori. Patients therefore do not abuse the privilege of a more tolerant digestion by indulging in a more unhealthy lifestyle.

Two pilot studies were performed to determine whether aluminium-containing antacids may have a place in the treatment of Helicobacter pylori infection. The urease activity of H. pylori is cytopathic to gastric epithelium, and inhibition of this enzyme may have therapeutic potential. In the first study 24 subjects, 12 of which were infected with H. pylori, were given 1 tablet of chewable aluminium hydroxide-containing antacids 10 min before a 14C-urea breath test. Gastric urease activity was suppressed by 33.3% (p = 0.02) in the H. pylori-positive subjects (none became negative) within 40 min after administration of the tablet. Gastric H. pylori infection can be effectively eradicated by triple regimens containing bismuth salts, tetracycline, and metronidazole. Owing to adverse effects of this treatment and concern for possible neurotoxicity of bismuth, a bismuth substitute is warranted. Hence, in the second study, 20 subjects infected with H. pylori were treated with 1 antacid tablet 4 times daily between meals, plus 500 mg oxytetracycline and 200 mg metronidazole 4 times daily with meals for 2 weeks. Individual H. pylori status was assessed by the 14C-urea breath test. Four weeks after cessation of treatment, H. pylori was eradicated in 45% (9 of 20) of the subjects (95% confidence interval, 23.1-68.5%). Thirty per cent (6 of 20) observed one or more adverse effect regarded as moderate or severe, of which loose stools and headache were the most common.(ABSTRACT TRUNCATED AT 250 WORDS)