Faecal Volatile Organic Compounds to Detect Colorectal Neoplasia in Lynch Syndrome-A Prospective Longitudinal Multicentre Study.

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.

Fecal Immunochemical Test to Detect Colorectal Neoplasia in Lynch Syndrome: A Prospective Multicenter Study.

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.

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.

Discontinuation of infliximab treatment in patients with inflammatory bowel disease who retransitioned to originator and those who remained on biosimilar.

Background: Many patients with inflammatory bowel disease (IBD) have transitioned from an infliximab originator to a biosimilar. However, some patients retransition to the originator (i.e. stop biosimilar and reinitiate the originator). Whether this sign of potential unsatisfactory treatment response is specifically related to the infliximab biosimilar or the patient and/or the disease including patients' beliefs on the biosimilar is unclear. Objectives: We aimed to compare the risk of and reasons for infliximab discontinuation between retransitioned patients and those remaining on biosimilar. Design: Non-interventional, multicentre cohort study. Methods: IBD patients who transitioned from infliximab originator to biosimilar between January 2015 and September 2019 in two Dutch hospitals were eligible for this study. Retransitioned patients (retransitioning cohort) were matched with patients remaining on biosimilar (biosimilar remainder cohort). Reasons for discontinuation were categorised as the unwanted response (i.e. loss of effect or adverse events) or remission. Risk of unwanted discontinuation was compared using Cox proportional hazards models. Results: Patients in the retransitioning cohort (n = 44) were younger (median age 39.9 versus 44.0 years), more often female (65.9% versus 48.9%) and had shorter dosing intervals (median 48.5 versus 56.0 days) than in the biosimilar remainder cohort (n = 127). Infliximab discontinuation due to unwanted response was 22.7% in the retransitioning and 13.4% in the biosimilar remainder cohort, and due to remission was 2.3% and 9.4%, respectively. Retransitioned patients are at increased risk of discontinuing due to unwanted response compared with biosimilar remainder patients (adjusted HR 3.7, 95% CI: 1.0-13.9). Patients who retransitioned due to an increase in objective disease markers had higher discontinuation rates than patients who retransitioned due to symptoms only (66.7% versus 23.7%). Conclusion: Retransitioned patients are at increased risk of infliximab discontinuation due to unwanted response. Retransitioning appeared related to the patient and/or disease and not the product. Clinicians might switch patients opting for retransitioning to other treatment regimens.

Exposure to Thioguanine During 117 Pregnancies in Women With Inflammatory Bowel Disease.

BACKGROUND: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. METHODS: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. RESULTS: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. CONCLUSION: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes.

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.

Lower Risk of Recurrence with a Higher Induction Dose of Mesalazine and Longer Duration of Treatment in Ulcerative Colitis: Results from the Dutch, Non-Interventional, IMPACT Study.

BACKGROUND AND AIMS: The dose and duration of mesalazine treatment for ulcerative colitis (UC) is a potentially important determinant of effectiveness, with evidence suggesting that continuing the induction dose for 6-12 months may improve outcomes; however, real-world data are lacking. We assessed mesalazine use in Dutch clinical practice, including how differences in dose and duration affected UC outcomes. METHODS: Adults with mild-to-moderate UC who received oral prolonged-release mesalazine de novo or had a dose escalation for an active episode were followed for 12 months in this non-interventional study (ClinicalTrials.gov identifier: NCT02261636). The primary endpoint was time from start of treatment to dose reduction (TDR). Secondary endpoints included recurrence rate, adherence, and work productivity. RESULTS: In total, 151 patients were enrolled, of whom 108 (71.5%) were newly diagnosed with UC. The majority (120; 79.5%) received a dose of ≥4 g/day. Nearly one-third (48; 31.8%) underwent dose reduction, with mean TDR being 8.3 months. Disease extent and endoscopic appearance did not influence duration of induction therapy, while TDR increased with higher baseline UCDAI scores. TDR was longer in patients without (mean 8.8 months) than with (4.1 months) recurrence, although not significantly (p=0.09). Patients on ≥4 g/day had a significantly lower chance of recurrence versus those on 2-<4 g/day (26.6% vs 62.5%, respectively; p=0.04). Longer treatment duration was associated with significantly reduced recurrence risk [hazard ratio >6 months vs 3-6 months: 0.19 (95%CI: 0.08-0.46); p<0.05], particularly for those on ≥4 g/day [0.15 (0.06-0.40) vs 0.26 (0.01-11.9) for 2-<4 g/day). Patients reported significantly increased work productivity, which was maintained throughout follow-up. CONCLUSIONS: Mesalazine was effective induction therapy, with treatment duration not meaningfully influenced by disease extent and endoscopic appearance at initiation. A higher induction dose of oral mesalazine (≥4 g/day) and longer duration of treatment (>6 months) was associated with a lower recurrence risk.

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 From Reference Infliximab to Biosimilar CT-P13 Did Not Change Quality of Life in Stable Inflammatory Bowel Disease Patients.

Background: Quality of life (QoL) data for patients with inflammatory bowel disease switched from the reference infliximab to biosimilar CT-P13 is lacking. This study aims to demonstrate noninferiority for QoL and efficacy after switching. Methods: OoL and clinical efficacy were measured prior to and after 2, 4, and 6 CT-P13 infusions. Results: One hundred seventy-eight patients were included. Noninferiority was established for QoL [ratio 97.95% (95% confidence interval 95.93 to 100.01)] and efficacy [difference -0.02 (95% confidence interval -0.68 to 0.64)]. Five patients reported 6 nonrelated, serious adverse events. Conclusions: Switching from reference infliximab to CT-P13 did not affect the QoL or disease activity and was well tolerated.

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.

Budesonide with multi-matrix technology as second-line treatment for ulcerative colitis: evaluation of long-term cost-effectiveness in the Netherlands.

AIMS: Budesonide with multi-matrix technology (MMX) is an oral corticosteroid, shown to have high topical activity against ulcerative colitis (UC) while maintaining low systemic bioavailability with few adverse events. The aim of this study was to evaluate the cost-effectiveness of budesonide MMX versus commonly used corticosteroids, in the second-line treatment of active mild-to-moderate UC in the Netherlands. MATERIALS AND METHODS: An eight-state Markov model with an 8 week cycle length captured remission, four distinct therapy stages, hospitalization, possible colectomy and mortality. Remission probability for budesonide MMX was based on the CORE-II study. Population characteristics were derived from the Dutch Inflammatory Bowel Disease South Limburg cohort (n = 598) and included patients with proctitis (39%), left-sided (42%) and extensive disease (19%). Comparators (topical budesonide foam and enema, oral budesonide and prednisolone) were selected based on current Dutch clinical practice. Treatment effects were evaluated by network meta-analysis using a Bayesian framework. Cost-effectiveness analysis was performed over a 5 year time horizon from a societal perspective, with costs, health-state and adverse event utilities derived from published sources. Outcomes were weighted by disease extent distribution and corresponding comparators. RESULTS: Budesonide MMX was associated with comparable quality-adjusted life year (QALY) gain versus foam and oral formulations (+0.01 QALYs) in the total UC population, whilst being cost-saving (EUR 366 per patient). Probabilistic sensitivity analysis evaluated an 86.6% probability of budesonide MMX being dominant (cost-saving with QALY gain) versus these comparators. Exploratory analysis showed similar findings versus prednisolone. LIMITATIONS: Differing definitions of trial end-points and remission across trials meant indirect comparison was not ideal. However, in the absence of head-to-head clinical data, these comparisons are reasonable alternatives and currently offer the only comparison of second-line UC treatments. CONCLUSIONS: In the present analysis, budesonide MMX was shown to be cost-effective versus comparators in the total UC population, for the second-line treatment of active mild-to-moderate UC in the Netherlands.