Proteins in stool as biomarkers for non-invasive detection of colorectal adenomas with high risk of progression.

Screening to detect colorectal cancer (CRC) in an early or premalignant state is an effective method to reduce CRC mortality rates. Current stool-based screening tests, e.g. fecal immunochemical test (FIT), have a suboptimal sensitivity for colorectal adenomas and difficulty distinguishing adenomas at high risk of progressing to cancer from those at lower risk. We aimed to identify stool protein biomarker panels that can be used for the early detection of high-risk adenomas and CRC. Proteomics data (LC-MS/MS) were collected on stool samples from adenoma (n = 71) and CRC patients (n = 81) as well as controls (n = 129). Colorectal adenoma tissue samples were characterized by low-coverage whole-genome sequencing to determine their risk of progression based on specific DNA copy number changes. Proteomics data were used for logistic regression modeling to establish protein biomarker panels. In total, 15 of the adenomas (15.8%) were defined as high risk of progressing to cancer. A protein panel, consisting of haptoglobin (Hp), LAMP1, SYNE2, and ANXA6, was identified for the detection of high-risk adenomas (sensitivity of 53% at specificity of 95%). Two panels, one consisting of Hp and LRG1 and one of Hp, LRG1, RBP4, and FN1, were identified for high-risk adenomas and CRCs detection (sensitivity of 66% and 62%, respectively, at specificity of 95%). Validation of Hp as a biomarker for high-risk adenomas and CRCs was performed using an antibody-based assay in FIT samples from a subset of individuals from the discovery series (n = 158) and an independent validation series (n = 795). Hp protein was significantly more abundant in high-risk adenoma FIT samples compared to controls in the discovery (p = 0.036) and the validation series (p = 9e-5). We conclude that Hp, LAMP1, SYNE2, LRG1, RBP4, FN1, and ANXA6 may be of value as stool biomarkers for early detection of high-risk adenomas and CRCs. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study.

OBJECTIVES: Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs). DESIGN: NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies. RESULTS: NKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo. CONCLUSION: NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.

Thioguanine Therapy in Inflammatory Bowel Diseases. A Practical Guide.

Thiopurine-derivates azathioprine and mercaptopurine are frequently used to maintain remission in inflammatory bowel diseases (IBD). Despite their efficacy, more than 50% of patients discontinue therapy, mainly due to the development of adverse events. Thioguanine is an alternative thiopurine and has been conditionally licensed in The Netherlands as IBD treatment for patients after conventional thiopurine therapy failure. In this review we will provide practical information on initiating and maintaining thioguanine therapy in IBD and provide information concerning safety issues and future perspectives. The thioguanine toxicity profile is relatively mild and the reported incidence of nodular regenerative hyperplasia related to thioguanine use seems comparable to conventional thiopurines and the background incidence in IBD patients. Routine monitoring of laboratory parameters and adverse events is recommended, comparable to the monitoring of patients on conventional thiopurine therapy.

Faecal microbiota transplantation for Clostridioides difficile infection: Four years' experience of the Netherlands Donor Feces Bank.

BACKGROUND: The Netherlands Donor Feces Bank provides standardized ready-to-use donor faecal suspensions for faecal microbiota transplantation treatment of patients with recurrent Clostridioides difficile infection. OBJECTIVE: The purpose of this study was evaluation of safety, feasibility and outcome of faecal microbiota transplantation facilitated by a national stool bank. METHODS: The methods used included: observational cohort study of donors and recipients of faecal suspensions; assessment of donor screening and patient selection performed by an expert panel of medical microbiologists, gastroenterologists and infectious disease specialists; and patient outcome evaluated at different timepoints after faecal microbiota transplantation. RESULTS: Of 871 volunteers who registered as a potential faeces donor, 16 (2%) became active donors. Nine donors stopped or were excluded after a mean donation period of 5.7 months. In 2016-2019, 47 (27%) of 176 requests for faecal microbiota transplantations were deemed not indicated by the expert panel. In total, 129 patients with recurrent C. difficile infection were treated with 143 faecal suspensions in 40 different hospitals. The cure rate at two months after a single infusion was 89% (107/120). Of 84 patients, long-term follow-up (median 42 weeks) was available and sustained cure was achieved in 61 (73%). Early C. difficile infection relapses (within two months after faecal microbiota transplantation) and late recurrences (after more than two months) occurred more frequently in patients who received non-C. difficile antibiotics within three weeks after faecal microbiota transplantation and in moderately to severely immunocompromised patients. Of 21 patients with C. difficile infection after faecal microbiota transplantation, 14 were cured with anti-C. difficile antibiotics and seven with a second transplantation. No faecal microbiota transplantation-related serious adverse events were observed, but gastro-intestinal complaints (nausea, abdominal pain or diarrhoea) persisted in 32% of the treated patients at long-term follow-up. CONCLUSION: Faecal suspensions provided by a centralized stool bank, supported by a multidisciplinary expert team, resulted in effective, appropriate and safe application of faecal microbiota transplantation for recurrent C. difficile infection. LEVEL OF EVIDENCE: Level II, prospective cohort study.

Risks for lymphoma and gastrointestinal carcinoma in patients with newly diagnosed adult-onset celiac disease: Consequences for follow-up: Celiac disease, lymphoma and GI carcinoma.

BACKGROUND: The association between celiac disease (CD) and the development of lymphoid and gastrointestinal (GI) malignancies have been reported. However, data are scarce yet needed to develop evidence-based follow-up programs. OBJECTIVE: The objective of this article is to assess relative (RR) and absolute risks of lymphoma and GI carcinoma for newly diagnosed patients. METHODS: A case-control design to determine RR was performed with cases (lymphoma or GI carcinoma) and controls (melanoma or basal cell carcinoma) diagnosed 1994-2014, retrieved from the Dutch nationwide population-based pathology database (PALGA). Within this population, individuals with histologically proven CD before or simultaneously diagnosed with the malignancy were identified. RESULTS: A total of 349/301,425 cases (0.1%) and 282/576,971 (0.05%) controls were diagnosed with CD. Risk of T-cell lymphoma, predominantly enteropathy-associated T-cell lymphoma (EATL), was strongly associated with CD diagnosis (RR = 35.8 (95% CI 27.1-47.4)). Although most often synchronously diagnosed, T-cell lymphoma RR ≥ 1 year after CD diagnosis was still elevated (RR = 12.7 (95% CI 7.6-21.3)). Other CD-associated malignancies were small bowel adenocarcinoma (RR = 11.9 (95% CI 8.2-17.2)) and esophageal squamous cell carcinoma (RR = 3.5 (95% CI 2.1-5.8)). Absolute risks were relatively low. Other types of lymphomas and GI carcinomas were not associated with CD. CONCLUSION: Increased risk for specific malignancies in CD should alert physicians for EATL (both intestinal and extraintestinal) and small bowel adenocarcinoma in patients with CD diagnosed at age ≥ 50 years.

High inter-individual variability of serum xanthine oxidoreductase activity in IBD patients.

OBJECTIVES: Thiopurines play an essential role in the management of inflammatory bowel diseases (IBD, i.e. Crohn's disease and ulcerative colitis). Over the past decade, several strategies to optimize treatment with thiopurines have been evaluated, including co-administration of allopurinol, a xanthine-oxidoreductase (XO) inhibitor, to low-dose thiopurine therapy. We aimed to assess the inter-individual variability of XO-activity between IBD-patients. METHODS: We assessed XO activity in serum of IBD-patients of two medical centers in The Netherlands using the Amplex® Red Xanthine/Xanthine Oxidase Assay Kit, which measures the superoxide formation in a coupled reaction to the red-fluorescent oxidation product, resofurine. RESULTS: We observed a high inter-individual variability of XO-activity in 119 patients, with a median activity of 16 µU/ml/hour (range 1-85 µU/ml/hour). The XO-activity was influenced by gender (male 19.5 vs. female 14.0 µU/ml/hour, p < 0.01), patient's age (Pearson's correlation r = 0.21, p = 0.02) and duration of IBD (r = 0.23, p = 0.01). The XO activity was not affected by the type of IBD, smoking status, body mass index or (type of) thiopurine use (p > 0.05). CONCLUSIONS: There is a high inter-individual variability of XO-activity in IBD-patients; XO-activity is positively associated with male gender and patient's age.

Anal plugs and retrograde colonic irrigation are helpful in fecal incontinence or constipation.

AIM: To evaluate the feasibility, clinical effect and predicting factors for favorable outcome of treatment with anal plugs in fecal incontinence and retrograde colonic irrigation (RCI) in patients with fecal incontinence or constipation. METHODS: Patients who received treatment with an anal plug or RCI between 1980 and 2005 were investigated with a questionnaire. RESULTS: Of the 201 patients (93 adults, 108 children), 101 (50%) responded. Adults: anal plugs (8), five stopped immediately, one stopped after 20 mo and two used it for 12-15 mo. RCI (40, 28 fecal incontinence, 12 constipation), 63% are still using it (mean 8.5 years), 88% was satisfied. Younger adults (< 40 years) were more satisfied with RCI (94% vs 65%, P = 0.05). Children: anal plugs (7), 5 used it on demand for an average of 2.5 years with satisfactory results, one stopped immediately and one after 5 years. RCI (26 fecal incontinence, 22 constipation), 90% are still using it (mean time 6.8 years) and felt satisfied. Children tend to be more satisfied (P = 0.001). Besides age, no predictive factors for success were found. There was no difference in the outcome between patients with fecal incontinence or constipation. CONCLUSION: RCI is more often applied than anal plugs and is helpful in patients with fecal incontinence or constipation, especially for younger patients. Anal plugs can be used incidentally for fecal incontinence, especially in children.

Nodular regenerative hyperplasia rarely leads to liver transplantation: A 20-year cohort study in all Dutch liver transplant units.

BACKGROUND: Nodular regenerative hyperplasia is an uncommon liver condition associated with several autoimmune disorders and drugs. The clinical symptoms of nodular regenerative hyperplasia vary from asymptomatic to severe complications of portal hypertension (nodular regenerative hyperplasia-syndrome). OBJECTIVE: The purpose of this study was to identify the prognosis and optimal management, as well as the role of liver transplantation, in nodular regenerative hyperplasia. METHODS: The pathology databases of all three Dutch liver transplant units were retrospectively scrutinised for explanted livers diagnosed with nodular regenerative hyperplasia or without clear diagnosis. Pre- and post-transplantation clinical, biochemical, radiological and histological information was obtained from electronic and paper records. RESULTS: In total, 1886 patients received a liver transplant. In 255 patients, nodular regenerative hyperplasia could not be excluded. After detailed chart review, the native livers of 11 patients (0.6%) (82% male, median age: 44 years) displayed nodular regenerative hyperplasia. Seven patients (64%) had underlying disorders or drug exposure which possibly caused nodular regenerative hyperplasia. Laboratory and imaging abnormalities were present in all patients but did not contribute to the diagnosis of nodular regenerative hyperplasia. Five-year survival was 73% (median follow-up: four years, range: 2-248 months). CONCLUSION: Nodular regenerative hyperplasia is a rare finding in patients, predominantly young males, transplanted for end-stage liver disease with unknown aetiology. Nonetheless, liver transplantation may have an important role in end-stage nodular regenerative hyperplasia-syndrome.

Splenic volume differentiates complicated and non-complicated celiac disease.

BACKGROUND: Studies in small groups of patients indicated that splenic volume (SV) may be decreased in patients with celiac disease (CD), refractory CD (RCD) type II and enteropathy-associated T-cell lymphoma (EATL). OBJECTIVE: The objective of this article is to evaluate SV in a large cohort of uncomplicated CD, RCD II and EATL patients and healthy controls. METHODS: The retrospective cohort consisted of 77 uncomplicated CD (of whom 39 in remission), 29 RCD II, 24 EATL and 12 patients with both RCD II and EATL. The control group included 149 healthy living kidney donors. SV was determined on computed tomography. RESULTS: The median SV in the uncomplicated CD group was significantly larger than in controls (202 cm3 (interquartile range (IQR): 154-275) versus 183 cm3 (IQR: 140-232), p = 0.02). After correction for body surface area, age and gender, the ratio of SV in uncomplicated CD versus controls was 1.28 (95% confidence interval: 1.20-1.36; p < 0.001). The median SV in RCD II patients (118 cm3 (IQR 83-181)) was smaller than the median SV in the control group (p < 0.001). CONCLUSION: This study demonstrates large inter-individual variation in SV. SV is enlarged in uncomplicated CD. The small SV in RCD II may be of clinical relevance considering the immune-compromised status of these patients.

How I treat my inflammatory bowel disease-patients with thiopurines?

Thiopurines are essential drugs to maintain remission in patients with inflammatory bowel disease (IBD). Thiopurines used in IBD are azathioprine (2.0-2.5 mg/kg), mercaptopurine (1.0-1.5 mg/kg) and thioguanine (0.2-0.3 mg/kg). However, mainly due to numerous adverse events associated with thiopurine use, almost 50% of the patients have to discontinue conventional thiopurine treatment. Extensive monitoring and the application of several treatment strategies, such as split-dose administration, co-administration with allopurinol or dose reduction/increase, may increase the chance of successful therapy. With this review, we provide practical information on how thiopurines are initiated and maintained in two thiopurine research centers in The Netherlands. We provide clinical information concerning safety issues, indications and management of therapy that may serve as a guide for the administration of thiopurines in IBD patients in daily practice.

Auto immune hepatitis.

To provide an update of the latest trends in epidemiology, clinical course, diagnostics, complications and treatment of auto immune hepatitis (AIH). A search of the MEDLINE database was performed using the search terms: "auto immune hepatitis", "clinical presentation", "symptoms", "signs", "diagnosis", "auto antibodies", "laboratory values", "serology", "histopathology", "histology", "genetics", "HLA genes", "non-HLA genes", "environment", "epidemiology", "prevalence", "incidence", "demographics", "complications", "HCC", "PBC", "PSC", "corticosteroid", "therapy", "treatment", "alternative treatment". English-language full-text articles and abstracts were considered. Articles included reviews, meta-analysis, prospective retrospective studies. No publication date restrictions were applied. AIH is an immune meditated progressive inflammatory liver disease that predominantly affects middle-aged females but may affect people of all ages. The clinical spectrum of AIH is wide, ranging from absent or mild symptoms to fulminant hepatic failure. The aetiology of AIH is still unknown, but is believed to occur as the consequence of an aberrant immune response towards an un-known trigger in a genetically susceptible host. In the absence of a gold standard, diagnosis is based on the combination of clinical, biochemical and histopathological criteria. Immunosuppressive treatment has been the cornerstone of treatment since the earliest description of the disease in 1950 by Waldenström. Such treatment is often successful at inducing remission and generally leads to normal life expectancy. Nevertheless, there remain significant areas of unmet aetiological a clinical needs including fundamental insight in disease pathogenesis, optimal therapy, duration of treatment and treatment alternatives in those patients unresponsive to standard treatment regimens.

Efficacy of thioguanine treatment in inflammatory bowel disease: A systematic review.

AIM: To critically assess the available literature regarding the efficacy of thioguanine treatment in inflammatory bowel disease (IBD) patients, irrespective of the (hepato-) toxicity profile. METHODS: A systematic literature search of the MEDLINE database using PubMed was performed using the keywords "thioguanine", "6-TG", "thioguanine", "inflammatory bowel disease", "IBD", "Crohn's disease", "Ulcerative colitis" and "effectiveness" in order to identify relevant articles published in English starting from 2000. Reference lists of the included articles were cross-checked for missing articles. Reviewed manuscripts concerning the effectiveness of thioguanine treatment in IBD were reviewed by the authors and the data were extracted. Data were subsequently analyzed with descriptive statistics. Due to the lack of standardized outcomes, a formal meta-analysis was not performed. RESULTS: A total of 11 applicable studies were found that involved the effectiveness of thioguanine therapy in IBD. Eight studies were conducted in a prospective manner, in the remaining three studies, data was collected retrospectively. In total, 353 IBD-patients (225 patients with Crohn's disease, 119 with ulcerative colitis and nine with unclassified IBD) with prior azathioprine/mercaptopurine resistance and/or intolerance (n = 321) or de novo thioguanine administration (n = 32) were included for analysis, of which 228 (65%) had clinical improvement on thioguanine therapy, based on standard IBD questionnaires, biochemical parameters or global physician assessments. Short-term results were based on 268 treatment years (median follow-up 9 mo, range 3-22 mo) with a median daily dose of 20 mg (range 10-80 mg). Discontinuation, mostly due to adverse events, was reported in 72 patients (20%). CONCLUSION: The efficacy of thioguanine therapy in IBD patients intolerant to conventional thiopurine therapy is observed in 65%, with short term adverse events in 20% of patients.

Video capsule endoscopy in celiac disease: current clinical practice.

OBJECTIVE: A complete examination of the small intestine is possible by video capsule endoscopy (VCE). The aim of this study was to evaluate current indications for performing VCE in celiac disease. METHODS: In all 84 celiac disease patients on a gluten-free diet who had undergone VCE were enrolled at five centers in Europe. The indications, findings and clinical impact of VCE were recorded by a structured questionnaire. VCE was also carried out in 34 consecutive patients with untreated celiac disease (controls) in another center. RESULTS: Out of the 84 patients, 34 had overt symptoms and small intestinal histology compatible with refractory celiac disease. VCE was normal in 9 patients, and 7 had only proximal and one distal atrophy, 14 had intestinal ulcer and 2 an intestinal stricture. VCE was used in the adjustment of immunosuppressive treatment in 9 patients. In the remaining 50 patients, a VCE was performed because of less severe symptoms, 31 of which had an earlier histological recovery. The VCE showed proximal small bowel atrophy in 21 and distal atrophy in 3 patients, and 3 ulcers were seen. In this group the patients received mainly advice with a view to achieving better dietary compliance. Of the 34 newly detected celiac patients, 4 were normal, 27 proximal and 3 had distal small intestinal atrophy in the VCE. CONCLUSIONS: VCE has a definite impact on the management of refractory sprue. In the remaining patients with established celiac disease, the procedure plays a more limited role.

Differences in taste between three polyethylene glycol preparations: a randomized double-blind study.

BACKGROUND AND AIM: Patients suffering from chronic constipation require long-term, regular therapy with laxatives. Literature regarding patient preference and acceptance in polyethylene glycol preparations is scarce. Therefore, this research aimed to identify preference between the three polyethylene glycol 3350, namely Molaxole(®), Movicol(®), and Laxtra Orange(®). Furthermore, taste is one of the most important factors leading to patients' adherence, particularly when the treatment lasts for a long time. METHODS: In this randomized, cross-over double-blind study, 100 volunteers were recruited by advertisement. The volunteers were invited to taste the preparations and grade the taste using a five-point hedonic scale (extremely poor taste [1] to extremely good taste [5]). The volunteers were then asked to choose the most palatable preparation. RESULTS: One hundred volunteers with a mean age of 35 years (range 20-61) were randomized (76 females). Molaxole(®), Movicol(®), and Laxtra Orange(®) had a mean hedonic score of 2.76 (SD: 0.82), 2.81 (SD: 0.76) and 3.12 (SD: 0.82) respectively. The hedonic taste score for Laxtra Orange(®) was significantly better than Molaxole(®) (P = 0.001) and Movicol(®) (P = 0.001). No difference was found between Molaxole(®) and Movicol(®) (P = 0.61). Molaxole(®) was the most preferred preparation for 19 volunteers (19%), Movicol(®) for 24 volunteers (25%) and Laxtra Orange(®) for 55 volunteers (56%). Two volunteers had no preference. The order in which volunteers tested the preparations had no influence on the taste results. No significant differences in age or gender were observed. CONCLUSION: Laxtra Orange(®) was most palatable preparation. This may have implications for adherence in patients with chronic constipation.

Indian task force for celiac disease: current status.

There are limited data on celiac disease (CD) from India. The limited knowledge about CD in India might be attributed to several factors. The first meeting of the Indian Task Force for Celiac Disease was held in the Asian Institute of Gastroenterology, Hyderabad, India in December 2008. The objectives of the meeting were to focus research on prevalence of CD in the wheat-eating Northern vs the rice-eating Southern Indian population, low-budget serological assays to study the underprivileged population, to involve other medical subspecialties in CD, to suggest proper legislation regarding wheat food labeling, and to organize affordable food substitutes for patients with celiac disease.