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Abstract Background Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD. Methods We induced acute or chronic colitis in BALB/c mice by one or four cycles of 3% dextran sulphate sodium (DSS), respectively. Mice were treated by daily gavages of various dosages of 6-tioguanine, azathioprine, or by phosphate buffered saline (PBS) starting the first day of DSS or after two cycles of DSS, respectively. We monitored the efficacy and toxicity by measuring the weight change and serum alanine aminotransferase (ALT) activity and by disease severity and histology, at the end of the experiment. Moreover, we measured cytokine production after colon fragment cultivation by enzyme-linked immunoabsorbent assay and numbers of apoptotic cells in the spleen by flow cytometry. Results 6-TG is effective in the treatment of acute DSS-induced colitis in a dose-dependent manner and 40 μg of 6-TG is significantly more effective in the treatment of acute colitis than both AZA and PBS. This effect is accompanied by decrease of IL-6 and IFN-γ production in colon. We did not observe histological abnormalities in liver samples from control (PBS) or 6-TG treated mice. However, liver samples from most mice treated with AZA showed mild, yet distinct signs of hepatotoxicity. In chronic colitis, all thiopurine derivatives improved colitis, 20 μg of 6-TG per dose was superior. High doses of 6-TG led to significant weight loss at the end of the therapy, but none of the thiopurine derivatives increased levels of serum ALT. Both thiopurine derivatives reduced the proportion of apoptotic T helper cells, but a high production of both IL-6 and TGF-β was observed only in colon of AZA-treated mice. Conclusions Use of 6-TG in the treatment of experimental colitis in mice appears superior to AZA administration and placebo. In contrast to 6-TG, the use of AZA resulted in histological liver abnormalities.

Summary: Background: Low‐dose thiopurine‐allopurinol (LDTA) combination therapy is a commonly applied optimisation strategy in IBD patients with a skewed thiopurine metabolism. Aim: To assess continued LDTA maintenance treatment at annual intervals and explore risk factors for treatment cessation Methods: Adult IBD patients treated with LDTA between 2009 and 2016 were retrospectively included. Data on the incidence of clinical and laboratory adverse events (AEs), including hepatotoxicity and myelotoxicity resulting in imposing LDTA therapy cessation and associated risk factors were collected. Results: In total, 221 IBD patients (46% male, median age 42 years) were included. Maintenance LDTA treatment was continued in 78% of patients at 1 year (n = 145), 66% at 2 years (n = 83), 57% at 3 years (n = 52) and 52% at 4 years (n = 33). Treatment in patients receiving LDTA therapy for AEs during thiopurine monotherapy was more often continued than in patients initiating LDTA for other indications (eg, ineffectiveness of thiopurine monotherapy, routinely discovered skewed metabolism) (P = 0.016). Myelotoxicity during thiopurine monotherapy resolved in 87% and hepatotoxicity in 86% after median of 1.2 and 1.4 months after LDTA initiation. Cumulative incidence of AEs during LDTA resulting in therapy cessation within total follow‐up of 449 treatment‐years was 7% for clinical AEs, 4% for myelotoxicity and 1% for hepatotoxicity. Conclusion: LDTA therapy is a safe and beneficial optimisation strategy in IBD patients. Continued maintenance LDTA treatment is 52% after 4 years of treatment and most commonly affected by ineffectiveness of LDTA rather than LDTA‐attributed toxicity. LDTA optimisation strategy is most advantageous in patients failing thiopurine monotherapy due to AEs. [ABSTRACT FROM AUTHOR]

Background: Off‐label prescribing is encountered across various fields of medicine and creates alternative treatment options, but is associated with unknown safety risks. The use of off‐label drugs for the treatment of patients with inflammatory bowel diseases (IBD) has not been characterised before. Aim: To assess the proportion and characteristics of off‐label prescribing for IBD in tertiary care centres in the Netherlands. Methods: A prospective database of IBD patients from all Dutch university hospitals was used to collect data on drug prescriptions for IBD and demographics. Drugs were classified as off‐label if they were unlicensed for Crohn's disease and/or ulcerative colitis by the Medicines Evaluation Board. Uni‐ and multivariable analyses were used to identify patient‐specific characteristics predictive of increased off‐label use. Results: For the induction and/or maintenance treatment of 4583 IBD patients, 12 651 historical and current drug records were available in the database. Of these, 2374 (19%) were considered off‐label prescriptions. Out of 4583 IBD patients, 1477 (32%) were exposed to off‐label drugs. Commonly prescribed off‐label IBD drugs were mercaptopurine (18%), beclomethasone (12%), thioguanine (4%) and allopurinol (3%). Non‐thiopurine/methotrexate off‐label drugs were prescribed in 243 patients (6%), including biological agents or tofacitinib in 47 IBD patients (1%). Off‐label prescriptions were more common in ulcerative colitis than Crohn's disease (37% vs 29%, P < 0.001). Smokers and patients that received ≥5 drug types during their disease course were more likely to be exposed to off‐label drugs (smoking 33% vs 27% and multiple drug use 66% vs 22%, both P < 0.001). Conclusion: About one‐fifth of prescriptions for IBD were off‐label and one‐third of IBD patients, especially ulcerative colitis patients, were exposed to off‐label drugs. [ABSTRACT FROM AUTHOR]

Background: Esophagectomy or pancreaticoduodenectomy is the standard surgical approach for patients with tumors of the esophagus or pancreatic head. Postoperative mortality is strongly correlated with the occurrence of anastomotic leakage (AL). Delay in diagnosis leads to delay in treatment, which ratifies the need for development of novel and accurate non-invasive diagnostic tests for detection of AL. Urinary volatile organic compounds (VOCs) reflect the metabolic status of an individual, which is associated with a systemic immunological response. The aim of this study was to determine the diagnostic accuracy of urinary VOCs to detect AL after esophagectomy or pancreaticoduodenectomy. Methods: In the present study, urinary VOCs of 63 patients after esophagectomy (n = 31) or pancreaticoduodenectomy (n = 32) were analyzed by means of field asymmetric ion mobility spectrometry. AL was defined according to international study groups. Results: AL was observed in 15 patients (24%). Urinary VOCs of patients with AL after pancreaticoduodenectomy could be distinguished from uncomplicated controls, area under the curve 0.85 (95% CI 0.76–0.93), sensitivity 76%, and specificity 77%. However, this was not observed following esophagectomy, area under the curve 0.51 (95% CI 0.37–0.65). Conclusion: In our study population AL following pancreaticoduodenectomy could be discriminated from uncomplicated controls by means of urinary VOC analysis, NTC03203434. [ABSTRACT FROM AUTHOR]

Introduction: The fecal volatolome, which is composed of fecal volatile organic compounds (VOCs), seems to hold potential as non-invasive biomarker for the detection of colorectal cancer (CRC) and its precursor lesions advanced adenomas (AA). The potential of the fecal volatolome has been subject of various studies using either chemical analytical or pattern-recognition techniques. The available literature on the potential of the fecal volatolome as CRC and AA biomarker was reviewed.Methods: A systematic literature search was conducted in PubMed, Embase, the Cochrane Library, Google Scholar and ResearchGate using the following keywords: Colorectal Cancer, Advanced Adenoma, Volatile Organic Compound, Metabolome, Gas Chromatrography-Mass Spectrometry, Selected-Ion Flow-Tube Mass Spectrometry, eNose, and Fecal Biomarkers.Results: Eighty-eight titles or abstracts were identified from the search, of which 11 papers describing the potential of the fecal volatolome for CRC detection were selected. In these studies, different techniques were used for the headspace analyses of fecal VOCs, limiting the possibility to compare outcomes. Increased levels of amino acids and short chain fatty acids, and decreased levels of bile acids and polyol alcohols in the gas phase of feces were observed repeatedly. All selected papers reported high diagnostic value for the detection of both CRC and AA based on fecal VOCs.Conclusion: Based on the included studies, fecal VOC analyses seem promising for future screening of CRC and AA, with potentially improved test performances allowing for earlier detection of AA and CRC and consequently earlier initiation of treatment, possibly reducing morbidity and mortality rates next to lower rates of (unnecessary) colonoscopies. [ABSTRACT FROM AUTHOR]

Fecal volatile organic compound (VOC) analysis has shown great potential as a noninvasive diagnostic biomarker for a variety of diseases. Before clinical implementation, the factors influencing the outcome of VOC analysis need to be assessed. Recent studies found that the sampling conditions can influence the outcome of VOC analysis. However, the dietary influences remains unknown, especially in (preterm) infants. Therefore, we assessed the effects of feeding composition on fecal VOC patterns of preterm infants (born at <30 weeks gestation). Two subgroups were defined: (1) daily intake >75% breastmilk (BM) feeding and (2) daily intake >75% formula milk (FM) feeding. Fecal samples, which were collected at 7, 14 and 21 days postnatally, were analyzed by an electronic nose device (Cyranose 320®). In total, 30 preterm infants were included (15 FM, 15 BM). No differences in the fecal VOC patterns were observed at the three predefined time-points. Combining the fecal VOC profiles of these time-points resulted in a statistically significant difference between the two subgroups although this discriminative accuracy was only modest (AUC [95% CI]; p-value; sensitivity; and specificity of 0.64 [0.51⁻0.77]; 0.04; 68%; and 51%, respectively). Our results suggest that the influence of enteral feeding on the outcome of fecal VOC analysis cannot be ignored in this population. Furthermore, in both subgroups, the fecal VOC patterns showed a stable longitudinal course within the first month of life. [ABSTRACT FROM AUTHOR]

Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease. [ABSTRACT FROM AUTHOR]