FECAL IMMUNOCHEMICAL TEST TO DETECT COLORECTAL NEOPLASIA IN LYNCH SYNDROME - A PROSPECTIVE MULTICENTER STUDY.

OBJECTIVES: Colonoscopy surveillance for Lynch syndrome is burdensome and post-colonoscopy colorectal cancers (CRCs) still occur. The non-invasive fecal immunochemical test (FIT) might guide optimal colonoscopy intervals. METHODS: Prospective, multi-center observational study in which individuals with Lynch syndrome performed a quantitative FIT prior to 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 [AA] and advanced serrated lesions [ASL]) and non-advanced adenomas (NAA). RESULTS: Of the 217 included individuals (59% female, median age 51y), 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 (NPV) 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 NPV, 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. CONCLUSIONS: FIT at thresholds ≤ 4.1 µg Hb/g feces may be a promising strategy to postpone colonoscopy in approximately 9 out of 10 individuals with Lynch syndrome. Large validation studies that also provide gene variant-specific outcomes should be prioritized.

Multicentre study and systematic review: Allopurinol exposure during pregnancy.

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.

Integration of stool microbiota, proteome and amino acid profiles to discriminate patients with adenomas and colorectal cancer.

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 potential of fecal microbiota and amino acids to detect and monitor patients with adenoma.

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.

Switching TNFα inhibitors: Patterns and determinants.

The aim of this study was to assess switching patterns and determinants for switching in patients initiating TNFα inhibitor (TNFα-i) treatment. Patients were included who started TNFα-i treatment between July 1, 2012 and December 31, 2017, from three Dutch hospitals, and were diagnosed with rheumatic diseases (RD), inflammatory bowel disease (IBD), or psoriasis. Outcomes were switching, defined as initiating another biological; switching patterns including multiple switches until the end of follow-up; determinants for first switch, assessed using multivariate logistic regression. A total of 2228 patients were included (median age 43.3 years, 57% female), of which 52% (n = 1155) received TNFα-i for RD, 43% (n = 967) for IBD, and 5% (n = 106) for psoriasis. About 16.6% of RD patients, 14.5% of IBD patients, and 16.0% of psoriasis patients switched at least once, mainly to another TNFα-i. TNFα-i dose escalation (OR 13.78, 95% CI 1.40-135.0) and high-dose corticosteroids initiation (OR 3.62, 95% CI 1.10-12.15) were determinants for switching in RD patients. TNFα-i dose escalation (OR 8.22, 95% CI 3.76-17.93), immunomodulator initiation/dose escalation (OR 2.13, 95% CI 1.04-4.34), high-dose corticosteroids initiation (OR 6.91, 95% CI 2.81-17.01) and serum concentration measurement (OR 5.44, 95% CI 2.74-10.79) were determinants for switching in IBD patients. Switching biological treatment occurred in about one in six patients. RD patients with TNFα-i dose escalation and/or high-dose corticosteroids initiation were more likely to switch. IBD patients with TNFα-i or immunomodulator initiation/dose escalation, high-dose corticosteroids initiation or serum concentration measurement were more likely to switch. These findings might help clinicians anticipating switching in TNFα-i treatment.

The faecal scent of inflammatory bowel disease: Detection and monitoring based on volatile organic compound analysis.

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.

The influence of lifestyle factors on fecal volatile organic compound composition as measured by an electronic nose.

INTRODUCTION: Fecal volatile organic compounds (VOCs) are gaseous metabolic products which are increasingly considered potential non-invasive biomarkers for the detection of various (gastrointestinal) diseases. The influence of lifestyle factors on fecal VOC patterns remains unexplored but is of importance prior to implementation of VOC analysis as a diagnostic tool. The aim of this study was to investigate the effects of age, gender, body mass index, smoking status, dietary preferences, medication use and co-morbidity on fecal VOC patterns. METHODS: For this study, fecal samples of patients undergoing a colonoscopy were collected prior to endoscopy. All participants completed a questionnaire on lifestyle factors, co-morbidity and medication use. Patients without colonic abnormalities were included in this study. Fecal VOC patterns were analyzed by means of an electronic nose (eNose) device (Cyranose® 320). RESULTS: From the 1039 participants willing to participate in the initial study, 211 were eligible as controls. All unique lifestyle variables investigated in this study affected the fecal VOC composition. The strongest influences were caused by low BMI, a vegetarian diet and an active smoking status, whereas the least influence was found for the variables gender, age > 55 years and previous smokers. DISCUSSION: Age, gender, BMI, smoking habits, dietary preferences, co-morbidity and medication use all have unique effects on fecal VOC composition. Future studies should carefully consider this influence on VOC outcome when defining VOC signatures as biomarker for diagnostic purposes.