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Background: Non‐invasive biomarkers may reduce post‐colonoscopy colorectal cancer (CRC) rates and colonoscopy overuse in Lynch syndrome. Unlike faecal immunochemical test (FIT), faecal volatile organic compounds (VOCs) may accurately detect both advanced and non‐advanced colorectal neoplasia. Aim: The aim of this study was to evaluate the potential of faecal VOCs—separately and with FIT—to guide optimal colonoscopy intervals in Lynch syndrome. Methods: Prospective longitudinal multicentre study in which individuals with Lynch syndrome collected faeces before and after high‐quality surveillance colonoscopy. VOC‐patterns were analysed using field asymmetric ion mobility spectrometry (FAIMS) and gas chromatography‐ion mobility spectrometry (GC‐IMS) followed by machine learning pipelines, and combined with FIT at 2.55 μg Hb/g faeces. Gas chromatography time‐of‐flight mass spectrometry analysed individual VOC abundance. Results: Among 200 included individuals (57% female, median 51 years), 62 had relevant neoplasia at colonoscopy: 3 CRC, 6 advanced adenoma (AA), 3 advanced serrated lesion (ASL), and 50 non‐advanced adenoma (NAA). Respective sensitivity and negative predictive value for CRC and AA (and also ASL in case of FAIMS) were 100% and 100% using FAIMS (54% specificity), and 89% and 99% using GC‐IMS (58% specificity). Respective sensitivity and specificity for any relevant neoplasia were 88% and 44% (FAIMS) and 84% and 28% (GC‐IMS); accuracy did not significantly improve upon VOC‐FIT. VOC‐patterns differed before and after polypectomy (AUC 0.70). NAA showed decreased faecal abundance of butanal, 2‐oxohexane, dimethyldisulphide and dimethyltrisulphide. Conclusions: In Lynch syndrome, faecal VOCs may be a promising strategy for postponing colonoscopy and for follow‐up after polypectomy. Our results serve as a stepping stone for large validation studies. Trial Registration: NL8749 [ABSTRACT FROM AUTHOR]

Aims: Conventional thiopurines (azathioprine and mercaptopurine) remain standard therapy to maintain steroid sparing remission in inflammatory bowel disease (IBD), but are regularly discontinued due to adverse drug reactions (ADRs). Measurement of the metabolites 6‐thioguanine nucleotides (6‐TGN), 6‐methylmercaptopurine ribonucleotides (6‐MMPR) and the 6‐MMPR/6‐TGN ratio, may predict the development of these ADRs. Our aim was to evaluate whether early thiopurine metabolite measurements were associated with clinical outcomes. Methods: A post‐hoc analysis was conducted of a multicentre, prospective, observational study on thiopurine‐induced hepatotoxicity. IBD patients who initiated thiopurine therapy were included and thiopurine metabolite concentrations were assessed after 7 days (±1) (T1). Patients were monitored for 12 weeks to document the occurrence of ADRs, early treatment discontinuation and effectiveness. Results: In total, 181 patients were evaluated. At T1, 6‐MMPR concentrations and 6‐TGN/6‐MMPR ratios were independently related to treatment discontinuation within 12 weeks after correction for sex, age and body mass index (BMI) (P =.034 and.002, respectively). The largest effects were observed for 6‐MMPR ≥3000 pmol/8 × 108 RBC and 6‐TGN/6‐MMPR ratio ≥17. Furthermore, 6‐MMPR concentrations and 6‐TGN/6‐MMPR ratios at T1 were independently related to skewed metabolism at steady state (Week 8, 6‐MMPR/‐6TGN ratio ≥11 and ≥20) (both P <.001). The occurrence of ADRs and effectiveness were not independently related to T1 thiopurine metabolite concentrations. Conclusions: Thiopurine metabolite concentrations at T1 were related to early treatment discontinuation and skewed metabolism at steady state, but not to effectiveness, helping to identify patients with a high risk of thiopurine treatment failure. [ABSTRACT FROM AUTHOR]

Abstract: The introduction of biological therapies has revolutionized inflammatory bowel disease (IBD) management. A critical consideration in developing these therapies is ensuring adequate drug concentrations at the site of action. While blood-based biomarkers have shown limited utility in optimizing treatment (except for TNF-alpha inhibitors and thiopurines), tissue drug concentrations may offer valuable insights. In antimicrobial therapies, tissue concentration monitoring is standard practice and could provide a new avenue for understanding the pharmacokinetics of biological and small-molecule therapies in IBD. Various methods exist for measuring tissue concentrations, including whole tissue sampling, MALDI-MSI, microdialysis, and fluorescent labeling. These techniques offer unique advantages, such as spatial drug-distribution mapping, continuous sampling, or cellular-level analysis. However, challenges remain, including sampling invasiveness, heterogeneity in tissue compartments, and a lack of standardized bioanalytical guidelines. Drug pharmacokinetics are influenced by multiple factors, including molecular properties, disease-induced changes in the gastrointestinal tract, and the timing of sample collection. For example, drug permeability, solubility, and interaction with transporters may vary between Crohn's disease and ulcerative colitis. Research into the tissue concentrations of drugs like anti-TNF agents, ustekinumab, vedolizumab, and tofacitinib has shown variable correlations with clinical outcomes, suggesting potential roles for tissue concentration monitoring in therapeutic drug management. Although routine clinical application is not yet established, exploring tissue drug concentrations may enhance understanding of IBD pharmacotherapy. [ABSTRACT FROM AUTHOR]

Background: Intracellular methotrexate polyglutamates (MTX‐PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX‐PG3 concentrations correlate with efficacy in patients with Crohn's disease (CD). Since RBCs are not involved in pathogenesis of CD and lack extended MTX metabolism, we determined MTX‐PGs accumulation in peripheral blood mononuclear cells (PBMCs: effector cells) and intestinal mucosa (target cells) and compared those with RBCs as a potential more precise biomarker. Methods: In a multicentre prospective cohort study, blood samples of patients with CD were collected during the first year of MTX therapy. Mucosal biopsies were obtained from non‐inflamed rectum and/or inflamed intestine. MTX‐PGs concentrations in mucosa, PBMCs and RBCs were measured by liquid chromatography–tandem mass spectrometry. Results: From 80 patients with CD, a total of 27 mucosal biopsies, 9 PBMC and 212 RBC samples were collected. From 12 weeks of MTX therapy onwards, MTX‐PG3 was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX‐PG1 (48%), which accounted for an 18 times higher concentration than in RBCs. Long‐chain MTX‐PGs were highly present in mucosa: 21% of MTX‐PGtotal was MTX‐PG5. MTX‐PG6 was measurable in all biopsies. Conclusions: MTX‐PG patterns differ between mucosa, PBMCs and RBCs of patients with CD. [ABSTRACT FROM AUTHOR]

Summary: Background: Data about the safety of allopurinol in pregnant women are sparsely reported. Aims: To investigate the risk of adverse pregnancy outcome and congenital abnormalities after in utero exposure to allopurinol in inflammatory bowel disease (IBD) pregnancies and in general. Methods: We collected safety data of patients with IBD who were treated with allopurinol during pregnancy between January 2013 and March 2022. Additionally, we performed a systematic review about the teratogenic potential of allopurinol. Results: We collected data from 42 allopurinol‐exposed pregnancies, including one twin pregnancy; in all women, allopurinol was combined with a thiopurine. Six pregnancies (14.3%) resulted in miscarriage and one in stillbirth at 32 weeks. A congenital anomaly was observed in one newborn (coarctation of the aorta discovered postpartum). Three pregnancies, including the twin pregnancy, ended in moderate preterm delivery and one in very preterm delivery. Five neonates (15.2%) were small for gestational age. From our literature search, we identified an additional 102 allopurinol‐exposed pregnancies resulting in 129 live births, including 36 infants from our cohort. Ten infants (7.8%) were born with a congenital anomaly. Two (1.6%) had a comparable pattern of multiple anomalies. The systematic review sub‐analysis including only infants born to mothers with IBD (n = 76) revealed that 2.6% of infants had congenital anomalies after in utero exposure to a low dose of allopurinol. Conclusions: Overall, the teratogenicity of allopurinol remains inconclusive. Children conceived by mothers treated for IBD with allopurinol/thiopurine co‐therapy do not seem to have an increased risk of congenital anomalies. [ABSTRACT FROM AUTHOR]

Early diagnosis and treatment of late-onset sepsis (LOS) is crucial for survival, but challenging. Intestinal microbiota and metabolome alterations precede the clinical onset of LOS, and the preterm gut is considered an important source of bacterial pathogens. Fecal volatile organic compounds (VOCs), formed by physiologic and pathophysiologic metabolic processes in the preterm gut, reflect a complex interplay between the human host, the environment, and microbiota. Disease-associated fecal VOCs can be detected with an array of devices with various potential for the development of a point-of-care test (POCT) for preclinical LOS detection. While characteristic VOCs for common LOS pathogens have been described, their VOC profiles often overlap with other pathogens due to similarities in metabolic pathways, hampering the construction of species-specific profiles. Clinical studies have, however, successfully discriminated LOS patients from healthy individuals using fecal VOC analysis with the highest predictive value for Gram-negative pathogens. This review discusses the current advancements in the development of a non-invasive fecal VOC-based POCT for early diagnosis of LOS, which may potentially provide opportunities for early intervention and targeted treatment and could improve clinical neonatal outcomes. Identification of confounding variables impacting VOC synthesis, selection of an optimal detection device, and development of standardized sampling protocols will allow for the development of a novel POCT in the near future. [ABSTRACT FROM AUTHOR]

Thiopurine treatment is regularly complicated by drug‐induced liver injury. It has been suggested that oxidative stress may play a synergistic role. To assess whether thiopurine‐induced liver injury coincides with increased oxidative stress and whether co‐administration with N‐acetylcysteine is protective, we performed a randomized open label crossover pilot study in inflammatory bowel disease patients with thiopurine‐induced increased serum liver tests. The study comprised four stages of 4 weeks. Patients received no additional therapy followed by N‐acetylcysteine 1200 mg twice a day, or the other way around, alongside ongoing thiopurine treatment. The third and fourth stages comprised a washout period and thiopurine reintroduction period. Nine patients completed the study, and the addition of N‐acetylcysteine decreased myeloperoxidase concentrations (33.6–24.5 pmol/L, p = 0.038). The other biomarkers remained unchanged, including thiopurine metabolites, xanthine oxidase activity, thiopurine S‐methyltransferase activity and serum liver enzyme activity tests. Reintroduction of thiopurines led to an increase of F2‐isoprostanes (101–157 ng/mmol, p = 0.038), but not of serum liver enzyme activity tests. Results suggests that thiopurines may increase oxidative stress and although the addition of N‐acetylcysteine led to a decrease in plasma myeloperoxidase concentrations, it does not protect from thiopurine‐induced increase of serum liver tests. [ABSTRACT FROM AUTHOR]