Metabolomics offers novel insights into metabolic alterations in colorectal cancer (CRC), including changes in amino acid profiles. Several studies have reported differences between CRC patients and controls, suggesting potential diagnostic utility. To evaluate evidence on amino acid alterations in CRC and advanced precursors across biological matrices and their potential as non-invasive biomarkers. A comprehensive search of MEDLINE, EMBASE, and Cochrane CENTRAL identifi ed 77 studies analysing amino acids in faeces, urine, serum, plasma, tissue, and saliva. Few studies included advanced adenomas and none assessed advanced serrated polyps. Results were heterogeneous across matrices, except for tissue, where most amino acids were consistently upregulated in CRC. Reported diagnostic performance varied widely (AUC 0.28–0.91), with limited external validation. Overall, amino acids show limited standalone diagnostic value but may enhance multi-metabolitepanels. Standardisation, inclusion of early lesions, and robust validation are essential for future biomarker research.

In Lynch syndrome, colonoscopy surveillance for colorectal cancer (CRC) is burdensome and post-colonoscopy CRCs still occur. Unlike the faecal immunochemical test (FIT), gut metabolomic alterations including amino-acids have shown potential as non-invasive biomarkers for detecting both advanced and non-advanced sporadic colorectal neoplasia. We aimed to evaluate the potential of faecal and urinary amino-acids to refine colonoscopy surveillance in Lynch syndrome. Individuals with Lynch syndrome collected faeces and urine 3 months before and 3-6 months after surveillance colonoscopy. Individuals with and without relevant neoplasia (defined as CRC, adenomas and advanced serrated polyps) were matched based on age, sex, smoking, and diet. Using liquid chromatography-tandem mass spectrometry and Random Forest classification, we assessed the diagnostic performance for relevant neoplasia of 20 faecal amino-acids (± positive FIT at 2.55 μg Hb/g faeces) and 20 urinary amino-acids. Among the 150 included individuals (118 collected faeces and 64 urine), 3% had CRC, 5% advanced adenomas, 3% advanced serrated polyps and 40% non-advanced adenomas at colonoscopy. In individuals with relevant neoplasia, faecal taurine and urinary citrulline, threonine and ornithine were elevated. Amino-acids showed 80% (faeces) and 88% (urine) sensitivity for relevant neoplasia, with higher specificity in urine (60%) than faeces (33%). Adding FIT-results to amino-acids outcomes did not improve diagnostic accuracy. After polypectomy, several faecal and urinary amino acids shifted towards levels of individuals without neoplasia. This exploratory study in Lynch syndrome highlights faecal and urinary amino acids as promising non-invasive biomarkers for postponing colonoscopy and follow-up after polypectomy, although these findings require external validation.

Metabolic processes play a role in cancer development, with faecal amino acids emerging as potential biomarkers for colorectal neoplasia. While fresh frozen tissue is preferred for metabolomic analysis, formalin-fixed paraffin-embedded (FFPE) tissue is more widely available. We aimed to evaluate amino acid profiles in FFPE tissue across different stages of the adenoma-carcinoma sequence. A panel of 20 amino acids was measured using liquid chromatography–tandem mass spectrometry. Fourteen amino acids were detected, with proline elevated in colorectal carcinoma versus advanced (FC 2.33, p = 0.04) and non-advanced adenomas (FC 2.42, p = 0.02). Despite analytical challenges, amino acid profiling in FFPE tissue is feasible.

Faecal amino acids are promising non-invasive diagnostic biomarkers, but stability remains unclear. This study examined whether storage conditions, sampling site within the sample, freeze-thaw cycles, and the OMNImet®·GUT device affect faecal amino acid concentrations. Faecal samples from three donors underwent various pre-analytical conditions. Amino acids were analysed through targeted liquid chromatography-tandem mass spectrometry. Most amino acids remained stable across sampling sites and freeze-thaw cycles. Storage at -20 °C preserved integrity, whereas 4 °C and 20 °C storage led to variations. The OMNImet®·GUT device stabilised some amino acids but showed inconsistencies. Pre-analytical conditions influence faecal amino acid concentrations. Standardisation is essential for biomarker reliability.

Post-colonoscopy colorectal cancer (CRC) rates and colonoscopy burden are considerable in Lynch syndrome. Urinary volatile organic compounds (VOCs) have shown promise as a patient-friendly alternative to faecal biomarkers for colorectal neoplasia detection. To evaluate the potential of urinary VOCs to guide optimal colonoscopy intervals in Lynch syndrome, we performed an exploratory prospective longitudinal study in urine collected by individuals with Lynch syndrome before and after colonoscopy. VOC patterns were analysed by field asymmetric ion mobility spectrometry (FAIMS) and gas chromatography-ion mobility spectrometry (GC-IMS) followed by machine learning algorithms. Gas chromatography time-of-flight mass spectrometry analysed the abundance of individual VOCs. Among 98 included individuals (median 51y, 58% female), 34 had relevant neoplasia at colonoscopy, including 28 non-advanced adenomas, 3 advanced adenomas, 2 CRCs, and 1 advanced serrated lesion. For GC-IMS, the respective sensitivity and negative predictive value for relevant neoplasia were 65% and 79% (70% specificity); for FAIMS, 74% and 75% (42% specificity). VOC patterns differed before and after polypectomy (AUC 0.84), while after polypectomy they resembled those of individuals without neoplasia (AUC 0.52). Non-advanced adenoma presence was associated with increased urinary abundance of decanoic acid (fatty acid). Diagnostic accuracy of urinary VOC patterns for relevant neoplasia was influenced by sample size and external confounders and was lower than for faecal VOC patterns among 50 individuals who had also collected faeces. Urinary VOCs hold promise as non-invasive biomarkers for postponing colonoscopy and for follow-up after polypectomy in Lynch syndrome, though large validation studies are needed that also assess stability and accuracy compared to faecal VOCs.

The intestinal microbiota plays a significant role in maintaining systemic and intestinal homeostasis, but can also influence diseases such as inflammatory bowel disease (IBD) and cancer. Certain bacterial species within the intestinal tract can chronically activate the immune system, leading to low-grade intestinal inflammation. As a result, plasma cells produce high levels of secretory antigen-specific immunoglobulin A (IgA), which coats the immunostimulatory bacteria. This IgA immune response against intestinal bacteria may be associated with the maintenance of homeostasis and health, as well as disease. Unraveling this dichotomy and identifying the immunostimulatory bacteria is crucial for understanding the relationship between the intestinal microbiota and the immune system, and their role in health and disease. IgA-SEQ technology has successfully identified immunostimulatory, IgA-coated bacteria from fecal material. However, the original technology is time-consuming and has limited downstream applications. In this study, we aimed to develop a next-generation, high-throughput, magnet-based sorting approach (ng-IgA-SEQ) to overcome the limitations of the original IgA-SEQ protocol. We show, in various settings of complexity ranging from simple bacterial mixtures to human fecal samples, that our magnetic 96-well plate-based ng-IgA-SEQ protocol is highly efficient at sorting and identifying IgA-coated bacteria in a high-throughput and time efficient manner. Furthermore, we performed a comparative analysis between different IgA-SEQ protocols, highlighting that the original FACS-based IgA-SEQ approach overlooks certain nuances of IgA-coated bacteria, due to the low yield of sorted bacteria. Additionally, magnetic-based ng-IgA-SEQ allows for novel downstream applications. Firstly, as a proof-of-concept, we performed metagenomic shotgun sequencing on 10 human fecal samples to identify IgA-coated bacterial strains and associated pathways and CAZymes. Secondly, we successfully isolated and cultured IgA-coated bacteria by performing the isolation protocol under anaerobic conditions. Our magnetic 96-well plate-based high-throughput next-generation IgA-SEQ technology efficiently identifies a great number of IgA-coated bacteria from fecal samples. This paves the way for analyzing large cohorts as well as novel downstream applications, including shotgun metagenomic sequencing, culturomics, and various functional assays. These downstream applications are essential to unravel the role of immunostimulatory bacteria in health and disease.

Background: identification and removal of advanced adenomas (AA) reduce colorectal cancer (CRC) incidence and potentially mortality. CRC screening often uses fecal immunochemical testing to select high-risk individuals for colonoscopy, despite its low sensitivity for AA and relatively high false-positivity rate. Previous studies have linked proteases to CRC development through their ability to facilitate angiogenesis and immunoregulation. This study aims to identify colorectal neoplasia-associated proteases and their substrates as a potential noninvasive screening test, introducing an innovative application of fecal protease profiling, which has previously been limited to tissue samples. Methods: eighteen fluorogenic substrates were designed based on literature. Proteolytic degradation of these substrates was measured in fecal samples of patients with CRC (n = 12), AA (n = 9), nonadvanced adenomas (n = 10), and controls (n = 14). Substrate degradation was correlated to a matched human proteome data set, and underlying proteases were identified based on their recognition patterns. Experiments with protease inhibitors and ZnCl2 were performed to further characterize the involved proteases. Results: in total, 7 of the 18 substrates tested showed a significantly decreased proteolytic degradation in feces from patients with any colorectal neoplasia compared to the control group. The l-aspartic acid-l-glutamic acid substrate (ED) showed significantly decreased degradation in AA and CRC patients. ED degradation significantly decreased with the addition of ZnCl2 and the cysteine protease inhibitor NEM. Conclusion: we successfully developed colorectal neoplasia-specific fluorogenic substrates, highlighting the ED substrate as a potential substrate for the detection of AA and CRC. Although the responsible proteases require further identification, our results suggest an association with calcium-dependent cysteine proteases.

INTRODUCTION:Colonoscopy surveillance for Lynch syndrome is burdensome and postcolonoscopy colorectal cancers (CRCs) still occur. The noninvasive fecal immunochemical test (FIT) might guide optimal colonoscopy intervals. METHODS:Prospective, multicenter observational study in which individuals with Lynch syndrome performed a quantitative FIT before high-quality surveillance colonoscopy. Diagnostic performance of FIT at various thresholds ≤20 μg Hb/g feces was assessed for relevant neoplasia, including advanced neoplasia (CRC, advanced adenomas [AAs] and advanced serrated lesions [ASLs]) and non-advanced adenomas (NAAs). RESULTS:Of the 217 included individuals (59% female, median age 51 years), 4 had CRC, 5 AA, 4 ASL, and 57 NAA as most relevant neoplasia. The lowest FIT positivity threshold (2.5 μg Hb/g feces, 14% positivity rate) maximized detection: 4/4 CRCs, 4/5 AA, 1/4 ASL, and 9/57 NAA were detected, resulting in a sensitivity and negative predictive value of, respectively, 89% and 99% for CRC plus AA, 69% and 97% for advanced neoplasia, and 26% and 72% for all relevant neoplasia (91% specificity for all groups). At equal sensitivity and negative predictive value, specificity for advanced neoplasia optimized to 94% at threshold 4.1 μg/g. Per 100 FITs at threshold 4.1 μg/g, 11 individuals would test positive and thus proceed to colonoscopy, 2 individuals with advanced neoplasia would be missed and 3 individuals would need colonoscopy to detect 1 advanced neoplasia. DISCUSSION:FIT at thresholds ≤4.1 μg Hb/g feces may be a promising strategy to postpone colonoscopy in approximately 9 of 10 individuals with Lynch syndrome. Large validation studies that also provide gene variant-specific outcomes should be prioritized.

Background: The faecal immunochemical test (FIT) suffers from suboptimal performance and participation in colorectal cancer (CRC) screening. Urinary volatile organic compounds (VOCs) may be a useful alternative. We aimed to determine the diagnostic po-tential of urinary VOCs for CRC/adenomas. By relating VOCs to known pathways, we aimed to gain insight into the pathophysiology of colorectal neoplasia.Methods: A systematic search was performed in PubMed, EMBASE and Web of Science. Original studies on urinary VOCs for CRC/adenoma detection with a control group were included. QUADAS-2 tool was used for quality assessment. Meta-analysis was per-formed by adopting a bivariate model for sensitivity/specificity. Fagan's nomogram estimated the performance of combined FIT-VOC. Neoplasm-associated VOCs were linked to pathways using the KEGG database.Results: Sixteen studies-involving 837 CRC patients and 1618 controls-were included; 11 performed chemical identification and 7 chemical fingerprinting. In all studies, urinary VOCs discriminated CRC from controls. Pooled sensitivity and specificity for CRC based on che-mical fingerprinting were 84% (95% CI 73-91%) and 70% (95% CI 63-77%), respectively. The most distinctive individual VOC was butanal (AUC 0.98). The estimated probability of having CRC following negative FIT was 0.38%, whereas 0.09% following negative FIT-VOC. Combined FIT-VOC would detect 33% more CRCs. In total 100 CRC-associated urinary VOCs were identified; particularly hydrocarbons, carboxylic acids, aldehydes/ketones and amino acids, and predominantly involved in TCA-cycle or alanine/aspartate/glutamine/glu-tamate/phenylalanine/tyrosine/tryptophan metabolism, which is supported by previous re-search on (colorectal)cancer biology. The potential of urinary VOCs to detect precancerous adenomas or gain insight into their pathophysiology appeared understudied. Conclusion: Urinary VOCs hold potential for non-invasive CRC screening. Multicentre va-lidation studies are needed, especially focusing on adenoma detection. Urinary VOCs eluci-date underlying pathophysiologic processes.(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

(1) Background: Colorectal cancer is the second commonest cause of cancer deaths worldwide; recently, volatile organic compounds (VOCs) have been proposed as potential biomarkers of this disease. In this paper, we aim to identify and review the available literature on the influence of mechanical bowel preparation on VOC production and measurement. (2) Methods: A systematic search for studies was carried out for articles relevant to mechanical bowel preparation and its effects on volatile organic compounds. A total of 4 of 1349 papers initially derived from the search were selected. (3) Results: Two studies with a total of 134 patients found no difference in measured breath VOC profiles after bowel preparation; one other study found an increase in breath acetone in 61 patients after bowel preparation, but no other compounds were affected. Finally, the last study showed the alteration of urinary VOC profiles. (4) Conclusions: There is limited data on the effect of bowel preparation on VOC production in the body. As further studies of VOCs are conducted in patients with symptoms of gastrointestinal disease, the quantification of the effect of bowel preparation on their abundance is required.

Sensor drift is a well-known disadvantage of electronic nose (eNose) technology and may affect the accuracy of diagnostic algorithms. Correction for this phenomenon is not routinely performed. The aim of this study was to investigate the influence of eNose sensor drift on the development of a disease-specific algorithm in a real-life cohort of inflammatory bowel disease patients (IBD). In this multi-center cohort, patients undergoing colonoscopy collected a fecal sample prior to bowel lavage. Mucosal disease activity was assessed based on endoscopy. Controls underwent colonoscopy for various reasons and had no endoscopic abnormalities. Fecal eNose profiles were measured using Cyranose 320®. Fecal samples of 63 IBD patients and 63 controls were measured on four subsequent days. Sensor data displayed associations with date of measurement, which was reproducible across all samples irrespective of disease state, disease activity state, disease localization and diet of participants. Based on logistic regression, corrections for sensor drift improved accuracy to differentiate between IBD patients and controls based on the significant differences of six sensors (p = 0.004; p < 0.001; p = 0.001; p = 0.028; p < 0.001 and p = 0.005) with an accuracy of 0.68. In this clinical study, short-term sensor drift affected fecal eNose profiles more profoundly than clinical features. These outcomes emphasize the importance of sensor drift correction to improve reliability and repeatability, both within and across eNose studies.

Background Screening for colorectal cancer (CRC) reduces its mortality but has limited sensitivity and specificity. Aims We aimed to explore potential biomarker panels for CRC and adenoma detection and to gain insight into the interaction between gut microbiota and human metabolism in the presence of these lesions.Methods This multicenter case-control cohort was performed between February 2016 and November 2019. Consecutive patients ≥18 years with a scheduled colonoscopy were asked to participate and divided into three age, gender, body-mass index and smoking status-matched subgroups: CRC (n = 12), adenomas (n = 21) and controls (n = 20). Participants collected fecal samples prior to bowel preparation on which proteome (LC-MS/MS), microbiota (16S rRNA profiling) and amino acid (HPLC) composition were assessed. Best predictive markers were combined to create diagnostic biomarker panels. Pearson correlation-based analysis on selected markers was performed to create networks of all platforms.Results Combining omics platforms provided new panels which outperformed hemoglobin in this cohort, currently used for screening (AUC 0.98, 0.95 and 0.87 for CRC vs controls, adenoma vs controls and CRC vs adenoma, respectively). Integration of data sets revealed markers associated with increased blood excretion, stress- and inflammatory responses and pointed toward downregulation of epithelial integrity.Conclusions Integrating fecal microbiota, proteome and amino acids platforms provides for new biomarker panels that may improve noninvasive screening for adenomas and CRC, and may subsequently lead to lower incidence and mortality of colon cancer.

The risk of recurrent dysplastic colonic lesions is increased following polypectomy. Yield of endoscopic surveillance after adenoma removal is low, while interval colorectal cancers occur. To longitudinally assess the dynamics of fecal microbiota and amino acids in the presence of adenomatous lesions and after their endoscopic removal. In this longitudinal case–control study, patients collected fecal samples prior to bowel preparation before scheduled colonoscopy and 3 months after this intervention. Based on colonoscopy outcomes, patients with advanced adenomas and nonadvanced adenomas (0.5–1.0 cm) who underwent polypectomy during endoscopy (n = 19) were strictly matched on age, body-mass index, and smoking habits to controls without endoscopic abnormalities (n = 19). Microbial taxa were measured by 16S RNA sequencing, and amino acids (AA) were measured by high-performance liquid chromatography (HPLC). Adenoma patients were discriminated from controls based on AA and microbial composition. Levels of proline (p = .001), ornithine (p = .02) and serine (p = .02) were increased in adenoma patients compared to controls but decreased to resemble those of controls after adenoma removal. These AAs were combined as a potential adenoma-specific panel (AUC 0.79(0.64–0.94)). For bacterial taxa, differences between patients with adenomas and controls were found (Bifidobacterium spp.↓, Anaerostipes spp.↓, Butyricimonas spp.↑, Faecalitalea spp.↑ and Catenibacterium spp.↑), but no alterations in relative abundance were observed after polypectomy. Furthermore, Faecalitalea spp. and Butyricimonas spp. were significantly correlated with adenoma-specific amino acids. We selected an amino acid panel specifically increased in the presence of adenomas and a microbial signature present in adenoma patients, irrespective of polypectomy. Upon validation, these panels may improve the effectiveness of the surveillance program by detection of high-risk individuals and determination of surveillance endoscopy timing, leading to less unnecessary endoscopies and less interval cancer.

The early prediction of changes in disease state allows timely treatment of patients with inflammatory bowel disease (IBD) to be performed, which improves disease outcome. The aim of this pilot study is to explore the potential of fecal volatile organic compound (VOC) profiles to predict disease course. In this prospective cohort, IBD patients were asked to collect two fecal samples and fill in a questionnaire at set intervals. Biochemically, active disease was defined by FCP ≥ 250 mg/g and remission was defined by FCP < 100 mg/g. Clinically, active disease was defined by a Harvey Bradshaw Index (HBI) ≥ 5 for Crohn’s disease or by a Simple Clinical Colitis Activity Index (SCCAI) ≥ 3 for ulcerative colitis. Clinical remission was defined by an HBI < 4 or SCCAI ≤ 2. Fecal VOC profiles were measured using gas chromatography-ion mobility spectrometry (GC-IMS). The fecal samples collected first were included for VOC analysis to predict disease state at the following collection. A total of 182 subsequently collected samples met the disease-state criteria. The fecal VOC profiles of samples displaying low FCP levels at the first measurements differed between patients preceding exacerbation versus those who remained in remission (AUC 0.75; p < 0.01). Samples with FCP levels at the first time point displayed different VOC profiles in patients preceding remission compared with those whose disease remained active (AUC 0.86; p < 0.01). Based on disease activity scores, there were no significant differences in any of the comparisons. Alterations in fecal VOC profiles preceding changes in FCP levels may be useful to detect disease-course alterations at an early stage. This could lead to earlier treatment, decreased numbers of complications, surgery and hospital admission.

LINKED CONTENTThis article is linked to Chandrapalan et al and Hanna & Cross papers. To view these articles, visit https://doi.org/10.1111/apt.16405 and https://doi.org/10.1111/apt.16471

Integrative multiomics data analysis provides a unique opportunity for the mechanistic understanding of colorectal cancer (CRC) in addition to the identification of potential novel therapeutic targets. In this study, we used public omics data sets to investigate potential associations between microbiome, metabolome, bulk transcriptomics and single cell RNA sequencing datasets. We identified multiple potential interactions, for example 5-aminovalerate interacting with Adlercreutzia; cholesteryl ester interacting with bacterial genera Staphylococcus, Blautia and Roseburia. Using public single cell and bulk RNA sequencing, we identified 17 overlapping genes involved in epithelial cell pathways, with particular significance of the oxidative phosphorylation pathway and the ACAT1 gene that indirectly regulates the esterification of cholesterol. These findings demonstrate that the integration of multiomics data sets from diverse populations can help us in untangling the colorectal cancer pathogenesis as well as postulate the disease pathology mechanisms and therapeutic targets.

SummaryBackgroundFaecal immunochemical test (FIT) is emerging as a valid test to rule‐out the presence of colorectal cancer (CRC). However, the accuracy of FIT is dependent on the cut‐off applied. An additional low‐cost test could improve further detection of CRC.AimsTo evaluate the efficacy of combined FIT and volatile organic compounds (VOC) in the detection of CRC within symptomatic populations.MethodsSystematic reviews on the diagnostic accuracy of FIT and VOC, for the detection of CRC, were updated. Meta‐analyses were performed adopting a bivariate model for sensitivity and specificity. Clinical utility of combined FIT and VOC was estimated using Fagan's nomogram. Post‐test probability of FIT negatives was used as a pre‐test probability for VOC.ResultsThe pooled sensitivity and specificity of FIT at 10 µg/g faeces, for the detection of CRC, were 0.914 (95% confidence interval [CI] = 0.894‐0.936) and 0.783 (CI = 0.850‐0.696), respectively. For VOC, the sensitivity was 0.837 (CI = 0.781‐0.881) and the specificity was 0.803 (CI = 0.870‐0.712). The area under the curve for FIT and VOC were 0.926 and 0.885, respectively. In a population with 5% CRC prevalence, the estimated probability of having CRC following a negative FIT was 0.5% and following both negative FIT and VOC was 0.1%.ConclusionsIn a FIT‐negative symptomatic population, VOC can be a good test to rule‐out the presence of CRC. The estimated probability reduction by 0.4% when both tests being negative offers adequate safety netting in primary care for the exclusion of CRC. The number needed to colonoscope to identify one CRC is eight if either FIT or VOC positive. Cost‐effectiveness and clinical accuracy of this approach will need further evaluation.

: Integrative multiomics data analysis provides a unique opportunity for the mechanistic understanding of colorectal cancer (CRC) in addition to the identification of potential novel therapeutic targets. In this study, we used public omics data sets to investigate potential associations between microbiome, metabolome, bulk transcriptomics and single cell RNA sequencing datasets. We iden-tified multiple potential interactions, for example 5-aminovalerate interacting with Adlercreutzia ; cholesteryl ester interacting with bacterial genera Staphylococcus , Blautia and Roseburia . Using public single cell and bulk RNA sequencing, we identified 17 overlapping genes involved in epithelial cell pathways, with particular significance of the oxidative phosphorylation pathway and the ACAT1 gene that indirectly regulates the esterification of cholesterol. These findings demonstrate that the integration of multiomics data sets from diverse populations can help us in untangling the colorectal cancer pathogenesis as well as postulate the disease pathology mechanisms and therapeutic targets.

BACKGROUND & AIMS: There are insufficient population-level data on the effects of primary sclerosing cholangitis (PSC) in patients with inflammatory bowel disease (IBD). METHODS: We identified incident cases of IBD, with PSC (PSC-IBD) and without, from April 2006 to April 2016 and collected data on outcomes through April 2019. We linked data from national health care registries maintained for all adults in England on hospital attendances, imaging and endoscopic evaluations, surgical procedures, cancer, and deaths. Our primary aim was to quantify the effects of developing PSC in patients with all subtypes of IBD and evaluate its effects on hepatopancreatobiliary disease, IBD-related outcomes, and all-cause mortality, according to sex, race, and age. RESULTS: Over 10 years, we identified 284,560 incident cases of IBD nationwide; of these, 2588 patients developed PSC. In all, we captured 31,587 colectomies, 5608 colorectal cancers (CRCs) 6608 cholecystectomies, and 41,055 patient deaths. Development of PSC was associated with increased risk of death and CRC (hazard ratios [HR5], 3.20 and 2.43, respectively; P < .001) and a lower median age at CRC diagnosis (59 y vs 69 y without PSC; P < .001). Compared to patients with IBD alone, patients with PSC-IBD had a 4-fold higher risk of CRC if they received a diagnosis of IBD at an age younger than 40 years; there was no difference between groups for patients diagnosed with IBD at an age older than 60 years. Development of PSC also increased risks of cholangiocarcinoma (HR, 28.46), hepatocellular carcinoma (HR, 21.00), pancreatic cancer (HR, 5.26), and gallbladder cancer (HR, 9.19) (P < .001 for all). Risk of hepatopancreatobiliary cancer-related death was lower among patients with PSC-IBD who received annual imaging evaluations before their cancer diagnosis, compared to those who did not undergo imaging (HR, 0.43; P = .037). The greatest difference in mortality between the PSC-IBD alone group vs the IBD alone group was for patients younger than 40 years (incidence rate ratio >7), in contrast to those who received a diagnosis of IBD when older than 60 years (incidence rate ratio, <1.5). Among patients with PSC-IBD we observed 173 first liver transplants. Liver transplantation and PSC-related events accounted for approximately 75% of clinical events when patients received a diagnosis of PSC at an age younger than 40 years vs 31% of patients who received a diagnosis when older than 60 years (P < .001). African Caribbean heritage was associated with increased risks of liver transplantation or PSC-related death compared with white race (HR, 2.05; P < .001), whereas female sex was associated with reduced risk (HR, 0.74; P = .025). CONCLUSIONS: In a 10-year, nationwide study, we confirmed that patients with PSC-IBD have increased risks of CRC, hepatopancreatobiliary cancers, and death compared to patients with IBD alone. In the PSC-IBD group, diagnosis of IBD at age younger than 40 years was associated with greater risks of CRC and all-cause mortality compared with diagnosis of IBD at older ages. Patients who receive a diagnosis of PSC at an age younger than 40 years, men, and patients of African Caribbean heritage have an increased incidence of PSC-related events.

BACKGROUND:Inflammatory bowel disease (IBD) is diagnosed and monitored using endoscopic assessment, which is invasive and costly. In this study, potential of faecal volatile organic compounds (VOC) analysis for IBD detection and identification of disease activity was evaluated.METHODS:IBD patients visiting outpatient clinics of participating tertiary hospitals were included. Active disease was defined as FCP ≥250 mg/g, remission as FCP <100 mg/g with Harvey Bradshaw Index <4 for Crohn's disease (CD) or Simple Clinical Colitis Activity Index <3 for ulcerative colitis (UC). Healthy controls (HC) were patients without mucosal abnormalities during colonoscopy. Faecal samples were measured using gas chromatography-ion mobility spectrometry.RESULTS:A total of 280 IBD patients collected 107 CDa, 84 CDr, 80 UCa and 63 UCr samples. Additionally, 227 HC provided one faecal sample. UC and CD were discriminated from HC with high accuracy (AUC (95%CI): UCa vs HC 0.96(0.94-0.99); UCr vs HC 0.95(0.93-0.98); CDa vs HC 0.96(0.94-0.99); CDr vs HC 0.95(0.93-0.98)). There were small differences between UC and CD (0.55(0.50-0.6)) and no differences between active disease and remission (UCa vs UCr 0.63(0.44-0.82); CDa vs CDr 0.52(0.39-0.65)).CONCLUSION:Our study outcomes imply that faecal VOC analysis holds potential for identifying biomarkers for IBD detection but not for monitoring disease activity.