Pub Date : 2024-07-23DOI: 10.1101/2024.07.23.24310822
Chiara Maria Lavinia Loeffler, Hideaki Bando, Srividhya Sainath, Hannah Sophie Muti, Xiaofeng Jiang, Marko van Treeck, Nic Gabriel Reitsam, Zunamys I. Carrero, Tomomi Nishikawa, Toshihiro Misumi, Saori Mishima, Daisuke Kotani, Hiroya Taniguchi, Ichiro Takemasa, Takeshi Kato, Eiji Oki, Tanwei Yuan, Durgesh Wankhede, Sebastian Foersch, Hermann Brenner, Michael Hoffmeister, Yoshiaki Nakamura, Takayuki Yoshino, Jakob Nikolas Kather
Background: Although surgical resection is the standard therapy for stage II/III colorectal cancer (CRC), recurrence rates exceed 30%. Circulating tumor DNA (ctDNA) emerged as a promising recurrence predictor, detecting molecular residual disease (MRD). However, spatial information about the tumor and its microenvironment is not directly measured by ctDNA. Deep Learning (DL) can predict prognosis directly from routine histopathology slides. Methods: We developed a DL pipeline utilizing vision transformers to predict disease-free survival (DFS) based on histological hematoxylin & eosin (H&E) stained whole slide images (WSIs) from patients with resectable stage II-IV CRC. This model was trained on the DACHS cohort (n=1766) and independently validated on the GALAXY cohort (n=1555). Patients were categorized into high- or low-risk groups based on the DL-prediction scores. In the GALAXY cohort, the DL-scores were combined with the four-weeks post-surgery MRD status measured by ctDNA for prognostic stratification. Results: In GALAXY, the DL-model categorized 307 patients as DL high-risk and 1248 patients as DL low-risk (p<0.001; HR 2.60, CI 95% 2.11-3.21). Combining the DL scores with the MRD status significantly stratified both the MRD-positive group into DL high-risk (n=81) and DL low-risk (n=160) (HR 1.58 (CI 95% 1.17-2.11; p=0.002) and the MRD-negative group into DL high-risk (n=226) and DL low-risk (n=1088) (HR 2.37 CI 95% 1.73-3.23; p<0.001). Moreover, MRD-negative patients had significantly longer DFS when predicted as DL high-risk and treated with ACT (HR 0.48, CI 95% 0.27-0.86; p= 0.01), compared to the MRD-negative patients predicted as DL low-risk (HR=1.14, CI 95% 0.8-1.63; p=0.48). Conclusion: DL-based spatial assessment of tumor histopathology slides significantly improves the risk stratification provided by MRD alone. Combining histologic information with ctDNA yields the most powerful predictor for disease recurrence to date, with the potential to improve follow-up, withhold adjuvant chemotherapy in low-risk patients and escalate adjuvant chemotherapy in high-risk patients.
{"title":"HIBRID: Histology and ct-DNA based Risk-stratification with Deep Learning","authors":"Chiara Maria Lavinia Loeffler, Hideaki Bando, Srividhya Sainath, Hannah Sophie Muti, Xiaofeng Jiang, Marko van Treeck, Nic Gabriel Reitsam, Zunamys I. Carrero, Tomomi Nishikawa, Toshihiro Misumi, Saori Mishima, Daisuke Kotani, Hiroya Taniguchi, Ichiro Takemasa, Takeshi Kato, Eiji Oki, Tanwei Yuan, Durgesh Wankhede, Sebastian Foersch, Hermann Brenner, Michael Hoffmeister, Yoshiaki Nakamura, Takayuki Yoshino, Jakob Nikolas Kather","doi":"10.1101/2024.07.23.24310822","DOIUrl":"https://doi.org/10.1101/2024.07.23.24310822","url":null,"abstract":"Background: Although surgical resection is the standard therapy for stage II/III colorectal cancer (CRC), recurrence rates exceed 30%. Circulating tumor DNA (ctDNA) emerged as a promising recurrence predictor, detecting molecular residual disease (MRD). However, spatial information about the tumor and its microenvironment is not directly measured by ctDNA. Deep Learning (DL) can predict prognosis directly from routine histopathology slides. Methods: We developed a DL pipeline utilizing vision transformers to predict disease-free survival (DFS) based on histological hematoxylin & eosin (H&E) stained whole slide images (WSIs) from patients with resectable stage II-IV CRC. This model was trained on the DACHS cohort (n=1766) and independently validated on the GALAXY cohort (n=1555). Patients were categorized into high- or low-risk groups based on the DL-prediction scores. In the GALAXY cohort, the DL-scores were combined with the four-weeks post-surgery MRD status measured by ctDNA for prognostic stratification. Results: In GALAXY, the DL-model categorized 307 patients as DL high-risk and 1248 patients as DL low-risk (p<0.001; HR 2.60, CI 95% 2.11-3.21). Combining the DL scores with the MRD status significantly stratified both the MRD-positive group into DL high-risk (n=81) and DL low-risk (n=160) (HR 1.58 (CI 95% 1.17-2.11; p=0.002) and the MRD-negative group into DL high-risk (n=226) and DL low-risk (n=1088) (HR 2.37 CI 95% 1.73-3.23; p<0.001). Moreover, MRD-negative patients had significantly longer DFS when predicted as DL high-risk and treated with ACT (HR 0.48, CI 95% 0.27-0.86; p= 0.01), compared to the MRD-negative patients predicted as DL low-risk (HR=1.14, CI 95% 0.8-1.63; p=0.48). Conclusion: DL-based spatial assessment of tumor histopathology slides significantly improves the risk stratification provided by MRD alone. Combining histologic information with ctDNA yields the most powerful predictor for disease recurrence to date, with the potential to improve follow-up, withhold adjuvant chemotherapy in low-risk patients and escalate adjuvant chemotherapy in high-risk patients.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"166 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-22DOI: 10.1101/2024.07.22.24310623
Julie Marin, Paul Albin Bertoye, André Birgy, Samira Dziri, Mathilde Lescat
In microbiota research, whole stool sampling is the conventional approach but can be problematic or infeasible for certain patients. This study aims to validate the use of rectal swabbing as an alternative method for microbiota analysis and determine optimal storage conditions suitable for various clinical settings, including intensive care units. We evaluated different sampling techniques, conservation media and storage temperatures. Our findings indicated that rectal swabs yield microbiota diversity comparable to whole stool samples. Notably, storage conditions significantly impacted microbiota profiles, with increased E. coli and Enterococcus sp. quantifications observed at room temperature. Consequently, we recommend immediate refrigeration of rectal swabs to reliably assess aerobic and total microbiota, particularly for patients requiring urgent care such as antibiotic treatment.
{"title":"Validation of rectal swabbing for total and aerobic gut microbiota study","authors":"Julie Marin, Paul Albin Bertoye, André Birgy, Samira Dziri, Mathilde Lescat","doi":"10.1101/2024.07.22.24310623","DOIUrl":"https://doi.org/10.1101/2024.07.22.24310623","url":null,"abstract":"In microbiota research, whole stool sampling is the conventional approach but can be problematic or infeasible for certain patients. This study aims to validate the use of rectal swabbing as an alternative method for microbiota analysis and determine optimal storage conditions suitable for various clinical settings, including intensive care units. We evaluated different sampling techniques, conservation media and storage temperatures. Our findings indicated that rectal swabs yield microbiota diversity comparable to whole stool samples. Notably, storage conditions significantly impacted microbiota profiles, with increased <em>E. coli</em> and <em>Enterococcus sp.</em> quantifications observed at room temperature. Consequently, we recommend immediate refrigeration of rectal swabs to reliably assess aerobic and total microbiota, particularly for patients requiring urgent care such as antibiotic treatment.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-22DOI: 10.1101/2024.07.22.24310495
Axel Dignass, Irina Blumenstein, Carolina Schwedhelm, Katrin Strassen, Leonie Berger, Sophie Marquardt, Anna Seiffert, Nataliia Kulchytska, Ivonne Haensel, Alexa Benson, Agnes Kisser
Background: The treatment landscape for active ulcerative colitis (UC) is rapidly evolving and current real-world evidence on response to advanced therapy is limited. This study aimed to determine indicators of inadequate therapeutic response among patients with UC in Germany initiating advanced therapy. Methods: This retrospective analysis used German claims data (2015-2022) from adult patients (≥18 years). Prevalence and incidence of UC (ICD-10-GM: K51.X) were estimated. Inadequate response to therapy was evaluated in patients initiating advanced therapy based on eight predefined indicators observed for 12 months following index treatment prescription. Results: Mean UC patient age in 2016-2022 ranged from 49.6 to 51.5 years, 47.6%-48.3% were female. Administrative prevalence ranged from 0.45% in 2016 to 0.53% in 2022. Number of patients initiating advanced treatment ranged from 157 to 347 across the study years (3.2%-4.9% of overall treated study population). On average from 2016-2021, 78.8% had inadequate response in the 12 months following index treatment. Common indicators included prolonged use of corticosteroids (46.2%) and augmentation with conventional therapies (43.9%). Conclusions: Adult UC patients showed a high prevalence of inadequate response to advanced therapies. Our findings reveal a need for improved UC advanced therapy options, providing insight into inadequate response patterns. This may help identify patients who could benefit from a change in therapy to improve long-term outcomes.
{"title":"Evaluating Inadequate Therapy Response in Ulcerative Colitis Adult Patients: A Retrospective Analysis of German Health Claims Data on Advanced Therapy Initiation","authors":"Axel Dignass, Irina Blumenstein, Carolina Schwedhelm, Katrin Strassen, Leonie Berger, Sophie Marquardt, Anna Seiffert, Nataliia Kulchytska, Ivonne Haensel, Alexa Benson, Agnes Kisser","doi":"10.1101/2024.07.22.24310495","DOIUrl":"https://doi.org/10.1101/2024.07.22.24310495","url":null,"abstract":"Background: The treatment landscape for active ulcerative colitis (UC) is rapidly evolving and current real-world evidence on response to advanced therapy is limited. This study aimed to determine indicators of inadequate therapeutic response among patients with UC in Germany initiating advanced therapy.\u0000Methods: This retrospective analysis used German claims data (2015-2022) from adult patients (≥18 years). Prevalence and incidence of UC (ICD-10-GM: K51.X) were estimated. Inadequate response to therapy was evaluated in patients initiating advanced therapy based on eight predefined indicators observed for 12 months following index treatment prescription.\u0000Results: Mean UC patient age in 2016-2022 ranged from 49.6 to 51.5 years, 47.6%-48.3% were female. Administrative prevalence ranged from 0.45% in 2016 to 0.53% in 2022. Number of patients initiating advanced treatment ranged from 157 to 347 across the study years (3.2%-4.9% of overall treated study population). On average from 2016-2021, 78.8% had inadequate response in the 12 months following index treatment. Common indicators included prolonged use of corticosteroids (46.2%) and augmentation with conventional therapies (43.9%).\u0000Conclusions: Adult UC patients showed a high prevalence of inadequate response to advanced therapies. Our findings reveal a need for improved UC advanced therapy options, providing insight into inadequate response patterns. This may help identify patients who could benefit from a change in therapy to improve long-term outcomes.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"94 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-22DOI: 10.1101/2024.07.19.24310730
Ziqi Vincent Wang, Badwi B Boumelhem, Torsten Pennell, William W Bachovchin, Geraldine Ooi, Jacob George, Mohammed Eslam, Leon A Adams, Pieter van der Veken, Jack Hung-Sen Lai, Sarah Poplawski, Kate Brewer, Hui Emma Zhang, Geoffrey W McCaughan, Avik Majumdar, Mark D Gorrell
Objective: Metabolic fatty liver disease drives chronic liver injury leading to fibrosis. This study aimed to establish a model utilising serum circulating fibroblast activation protein (cFAP) to diagnose advanced fibrosis in patients with fatty liver disease. Design: Two retrospective cohorts recruited from tertiary hepatology clinics were studied as training (n=160) and external validation cohorts (n=342), with prevalence of histologic advanced fibrosis (F3/F4) of 20% and 11%, respectively. A marker of activated mesenchymal fibrogenic cells, cFAP, was measured using our single-step enzyme assay. A predictive model, FAP Index, containing age, type 2 diabetes, alanine transaminase and ordinal cFAP was developed using logistic regression. Diagnostic accuracy of FAP Index was assessed on a single and then sequential basis. Results: FAP Index AUROC was 0.875 (95% CI 0.813-0.938) in the training cohort and 0.841 (95% CI 0.776-0.906) in the validation cohort. Low cut-off -1.68 (Sensitivity 80.0%, negative predictive value 95.5%) and high cut-off +0.953 values (Specificity 97.7%, positive predictive value 88.9%) excluded and diagnosed advanced fibrosis, respectively. In the validation cohort, FAP Index then FIB-4 reduced indeterminate results by one-third compared to FIB-4 alone. Whereas FAP-Index followed by NFS (NAFLD Fibrosis Score) resulted in a reduction of indeterminate results by 70% compared to NFS alone. Conclusion: FAP Index is a novel, rapid, robust, inexpensive diagnostic tool for advanced fibrosis in metabolic fatty liver disease. Applying FAP Index followed by FIB-4 or NFS facilitates accurate risk-stratification of patients by greatly reducing the frequency of indeterminate results compared to FIB-4 or NFS alone, without compromising negative predictive value.
{"title":"Development and validation of a novel circulating fibroblast activation protein - based predictive model to improve fibrosis risk stratification in metabolic liver disease population","authors":"Ziqi Vincent Wang, Badwi B Boumelhem, Torsten Pennell, William W Bachovchin, Geraldine Ooi, Jacob George, Mohammed Eslam, Leon A Adams, Pieter van der Veken, Jack Hung-Sen Lai, Sarah Poplawski, Kate Brewer, Hui Emma Zhang, Geoffrey W McCaughan, Avik Majumdar, Mark D Gorrell","doi":"10.1101/2024.07.19.24310730","DOIUrl":"https://doi.org/10.1101/2024.07.19.24310730","url":null,"abstract":"Objective: Metabolic fatty liver disease drives chronic liver injury leading to fibrosis. This study aimed to establish a model utilising serum circulating fibroblast activation protein (cFAP) to diagnose advanced fibrosis in patients with fatty liver disease.\u0000Design:\u0000Two retrospective cohorts recruited from tertiary hepatology clinics were studied as training (n=160) and external validation cohorts (n=342), with prevalence of histologic advanced fibrosis (F3/F4) of 20% and 11%, respectively. A marker of activated mesenchymal fibrogenic cells, cFAP, was measured using our single-step enzyme assay. A predictive model, FAP Index, containing age, type 2 diabetes, alanine transaminase and ordinal cFAP was developed using logistic regression. Diagnostic accuracy of FAP Index was assessed on a single and then sequential basis.\u0000Results:\u0000FAP Index AUROC was 0.875 (95% CI 0.813-0.938) in the training cohort and 0.841 (95% CI 0.776-0.906) in the validation cohort. Low cut-off -1.68 (Sensitivity 80.0%, negative predictive value 95.5%) and high cut-off +0.953 values (Specificity 97.7%, positive predictive value 88.9%) excluded and diagnosed advanced fibrosis, respectively. In the validation cohort, FAP Index then FIB-4 reduced indeterminate results by one-third compared to FIB-4 alone. Whereas FAP-Index followed by NFS (NAFLD Fibrosis Score) resulted in a reduction of indeterminate results by 70% compared to NFS alone. Conclusion:\u0000FAP Index is a novel, rapid, robust, inexpensive diagnostic tool for advanced fibrosis in metabolic fatty liver disease. Applying FAP Index followed by FIB-4 or NFS facilitates accurate risk-stratification of patients by greatly reducing the frequency of indeterminate results compared to FIB-4 or NFS alone, without compromising negative predictive value.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-21DOI: 10.1101/2024.07.19.24310589
Luc Biedermann, Michael Doulberis, Philipp Schreiner, Ole Haagen Nielsen, Frans Olivier The, Stephan Brand, Sabine Burk, Petr Hurz, Pascal Juillerat, Claudia Krieger-Gruebel, Kristin Leu, Gabriel Leventhal, Benjamin Misselwitz, Silvie Scharl, Alain Schoepfer, Frank Seibold, Hans Herfarth, Gerhard Rogler
Background: In an open label pilot study dried bilberries were effective in inducing clinical, endoscopic and biochemical improvement in ulcerative colitis (UC) patients. Aim was the investigation of efficacy of anthocyanin rich extract (ACRE), the presumptive active ingredient of bilberries, in a controlled clinical trial in moderate-severe UC. Methods: We performed a multicenter randomized, placebo-controlled, double-blind study (planned initially for 100 patients; premature termination due to COVID-19 pandemic). Patients had moderate-severe active UC at screening (Mayo-score 6-12, endoscopic sub-score at least 2) and were randomized at baseline (verum: placebo, 2:1). Continuation of all UC-directed stable medical therapy was allowed. Primary endpoint was clinical response at week 8 (reduction of total Mayo-score at least 3 points). Biochemical (fecal calprotectin) and centrally-read endoscopic response were amongst the secondary endpoints. Results: Out of 48 patients screened in six Swiss trial centers, 34 were randomized. Eighteen ACRE and eight placebo patients could be analyzed in the Per-Protocol-Set. Half (9/18) of ACRE patients and 3/8 of placebo patients revealed clinical response at week 8 (CI 0.399-6.963; p=0.278). An improvement of the Mayo-score was observed in 77.8% of ACRE treated patients (62.5% of placebo). Fecal calprotectin dropped from 1049+/-1139 to 557+/-756μg/g feces in the ACRE but not in the placebo group (947+/-1039 to 1040+/-1179; p=0.035). Adverse events were rare. Conclusions: ACRE therapy was not significantly superior to placebo at inducing a clinical response. However, placebo response was unusual high. Moreover, there was a significant calprotectin decrease at end of treatment, indicative of ACRE biochemical efficacy in UC.
{"title":"A Multi-Center Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase IIa Study to Evaluate the Efficacy, Safety and Tolerability of an Anthocyanin Rich Extract (ACRE) in Patients with Ulcerative Colitis","authors":"Luc Biedermann, Michael Doulberis, Philipp Schreiner, Ole Haagen Nielsen, Frans Olivier The, Stephan Brand, Sabine Burk, Petr Hurz, Pascal Juillerat, Claudia Krieger-Gruebel, Kristin Leu, Gabriel Leventhal, Benjamin Misselwitz, Silvie Scharl, Alain Schoepfer, Frank Seibold, Hans Herfarth, Gerhard Rogler","doi":"10.1101/2024.07.19.24310589","DOIUrl":"https://doi.org/10.1101/2024.07.19.24310589","url":null,"abstract":"Background: In an open label pilot study dried bilberries were effective in inducing clinical, endoscopic and biochemical improvement in ulcerative colitis (UC) patients. Aim was the investigation of efficacy of anthocyanin rich extract (ACRE), the presumptive active ingredient of bilberries, in a controlled clinical trial in moderate-severe UC.\u0000Methods: We performed a multicenter randomized, placebo-controlled, double-blind study (planned initially for 100 patients; premature termination due to COVID-19 pandemic). Patients had moderate-severe active UC at screening (Mayo-score 6-12, endoscopic sub-score at least 2) and were randomized at baseline (verum: placebo, 2:1). Continuation of all UC-directed stable medical therapy was allowed. Primary endpoint was clinical response at week 8 (reduction of total Mayo-score at least 3 points). Biochemical (fecal calprotectin) and centrally-read endoscopic response were amongst the secondary endpoints. Results: Out of 48 patients screened in six Swiss trial centers, 34 were randomized. Eighteen ACRE and eight placebo patients could be analyzed in the Per-Protocol-Set. Half (9/18) of ACRE patients and 3/8 of placebo patients revealed clinical response at week 8 (CI 0.399-6.963; p=0.278). An improvement of the Mayo-score was observed in 77.8% of ACRE treated patients (62.5% of placebo). Fecal calprotectin dropped from 1049+/-1139 to 557+/-756μg/g feces in the ACRE but not in the placebo group (947+/-1039 to 1040+/-1179; p=0.035). Adverse events were rare.\u0000Conclusions: ACRE therapy was not significantly superior to placebo at inducing a clinical response. However, placebo response was unusual high. Moreover, there was a significant calprotectin decrease at end of treatment, indicative of ACRE biochemical efficacy in UC.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Pouchitis is the most common complication of restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). We previously reported the presence of anti-integrin αvβ6 antibodies in the serum of patients with UC. This study investigated the association between anti-integrin αvβ6 antibodies and the development of pouchitis in patients with UC. Methods Serum levels of anti-integrin αvβ6 antibodies were measured by enzyme-linked immunosorbent assay in 16 patients with UC who underwent RPC with IPAA. Integrin αvβ6 expression in the colonic, terminal ileal, and pouch epithelium was examined using immunohistochemistry and western blot analysis. Results Anti-integrin αvβ6 antibody levels in patients with UC were significantly decreased at 3, 9, and 12 months after RPC (P < 0.05). However, in patients who developed pouchitis, antibody levels remained high. The antibody levels at the time of RPC were significantly higher in patients who developed pouchitis compared to those who did not. Kaplan-Meier analysis revealed a significantly higher incidence of pouchitis in patients with antibody levels above the cutoff at the time of RPC. Although integrin αvβ6 was not expressed in the terminal ileal epithelium at the time of RPC, expression became positive in the pouch epithelium of patients with pouchitis. Conclusions The anti-integrin αvβ6 antibody levels in patients with UC were decreased after RPC, but remained high in patients who developed pouchitis. The antibody levels at the time of RPC may serve as a potential prognostic biomarker for predicting the risk of pouchitis in patients with UC.
{"title":"Anti-integrin αvβ6 antibodies predict pouchitis in patients with ulcerative colitis after restorative proctocolectomy with ileal pouch-anal anastomosis","authors":"Risa Nakanishi, Takeshi Kuwada, Masahiro Shiokawa, Yoshihiro Nishikawa, Sakiko Ota, Hajime Yamazaki, Takafumi Yanaidani, Kenji Sawada, Ayako Hirata, Muneji Yasuda, Ikuhisa Takimoto, Koki Chikugo, Masataka Yokode, Yuya Muramoto, Shimpei Matsumoto, Tomoaki Matsumoto, Norimitsu Uza, Tsutomu Chiba, Hiroshi Seno","doi":"10.1101/2024.07.07.24309941","DOIUrl":"https://doi.org/10.1101/2024.07.07.24309941","url":null,"abstract":"Background\u0000Pouchitis is the most common complication of restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). We previously reported the presence of anti-integrin αvβ6 antibodies in the serum of patients with UC. This study investigated the association between anti-integrin αvβ6 antibodies and the development of pouchitis in patients with UC.\u0000Methods\u0000Serum levels of anti-integrin αvβ6 antibodies were measured by enzyme-linked immunosorbent assay in 16 patients with UC who underwent RPC with IPAA. Integrin αvβ6 expression in the colonic, terminal ileal, and pouch epithelium was examined using immunohistochemistry and western blot analysis. Results\u0000Anti-integrin αvβ6 antibody levels in patients with UC were significantly decreased at 3, 9, and 12 months after RPC (P < 0.05). However, in patients who developed pouchitis, antibody levels remained high. The antibody levels at the time of RPC were significantly higher in patients who developed pouchitis compared to those who did not. Kaplan-Meier analysis revealed a significantly higher incidence of pouchitis in patients with antibody levels above the cutoff at the time of RPC. Although integrin αvβ6 was not expressed in the terminal ileal epithelium at the time of RPC, expression became positive in the pouch epithelium of patients with pouchitis.\u0000Conclusions\u0000The anti-integrin αvβ6 antibody levels in patients with UC were decreased after RPC, but remained high in patients who developed pouchitis. The antibody levels at the time of RPC may serve as a potential prognostic biomarker for predicting the risk of pouchitis in patients with UC.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141566883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-08DOI: 10.1101/2024.07.08.24309811
Ibrahim Al Bakir, Kit Curtius, George D Cresswell, Heather E Grant, Nadia Nasreddin, Kane Smith, Salpie Nowinski, Qingli Guo, Hayley L Belnoue-Davis, Jennifer Fisher, Theo Clarke, Christopher Kimberley, Maximilian Mossner, Philip D Dunne, Maurice B Loughrey, Ally Speight, James E East, Nicholas A Wright, Manuel Rodriguez-Justo, Marnix Jansen, Morgan Moorghen, Ann-Marie Baker, Simon J Leedham, Ailsa L Hart, Trevor A Graham
Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC), and this risk increases dramatically in those who develop low-grade dysplasia (LGD). However, there is currently no accurate way to risk-stratify patients with LGD, leading to both over- and under-treatment of cancer risk. Here we show that the burden of somatic copy number alterations (CNAs) within resected LGD lesions strongly predicts future cancer development. We performed a retrospective multi-centre validated case-control study of n=122 patients (40 progressors, 82 non-progressors, 270 LGD regions). Low coverage whole genome sequencing revealed CNA burden was significantly higher in progressors than non-progressors (p=2x10-6 in discovery cohort) and was a very significant predictor of CRC risk in univariate analysis (odds ratio = 36; p=9x10-7), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. The measurement of CNAs in LGD lesions is a robust, low-cost and rapidly translatable predictor of CRC risk in IBD that can be used to direct management and so prevent CRC in high-risk individuals whilst sparing those at low-risk from unnecessary intervention.
{"title":"Low coverage whole genome sequencing of low-grade dysplasia strongly predicts colorectal cancer risk in ulcerative colitis","authors":"Ibrahim Al Bakir, Kit Curtius, George D Cresswell, Heather E Grant, Nadia Nasreddin, Kane Smith, Salpie Nowinski, Qingli Guo, Hayley L Belnoue-Davis, Jennifer Fisher, Theo Clarke, Christopher Kimberley, Maximilian Mossner, Philip D Dunne, Maurice B Loughrey, Ally Speight, James E East, Nicholas A Wright, Manuel Rodriguez-Justo, Marnix Jansen, Morgan Moorghen, Ann-Marie Baker, Simon J Leedham, Ailsa L Hart, Trevor A Graham","doi":"10.1101/2024.07.08.24309811","DOIUrl":"https://doi.org/10.1101/2024.07.08.24309811","url":null,"abstract":"Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC), and this risk increases dramatically in those who develop low-grade dysplasia (LGD). However, there is currently no accurate way to risk-stratify patients with LGD, leading to both over- and under-treatment of cancer risk. Here we show that the burden of somatic copy number alterations (CNAs) within resected LGD lesions strongly predicts future cancer development. We performed a retrospective multi-centre validated case-control study of n=122 patients (40 progressors, 82 non-progressors, 270 LGD regions). Low coverage whole genome sequencing revealed CNA burden was significantly higher in progressors than non-progressors (p=2x10<sup>-6</sup> in discovery cohort) and was a very significant predictor of CRC risk in univariate analysis (odds ratio = 36; p=9x10<sup>-7</sup>), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. The measurement of CNAs in LGD lesions is a robust, low-cost and rapidly translatable predictor of CRC risk in IBD that can be used to direct management and so prevent CRC in high-risk individuals whilst sparing those at low-risk from unnecessary intervention.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141566882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-07DOI: 10.1101/2024.07.05.24310010
Chengbo Zeng, John Donlan, Teresa Indriolo, Lucinda Li, Enya Zhu, Joyce C Zhou, Malia E Armstrong, Kedie Pintro, Nora Horick, Raymond T Chung, Areej EI-Jawahri, Maria O Edelen, Nneka N Ufere
Background: The Hospital Anxiety and Depression Scale (HADS) demonstrates strong psychometric properties in many populations of patients with serious illness. However, its psychometric performance among patients with decompensated cirrhosis (DC) has not been examined. We investigated the reliability, validity, and responsiveness of the HADS for patients with DC. Methods: This observational study utilized data from patients with DC at enrollment and week 6 follow-up. Two hundred eighteen outpatients with DC were recruited from a liver transplant center, with 145 completing week 6 assessment. We evaluated psychological distress using HADS and Patient Health Questionnaire 9 (PHQ-9). Patients' health-related quality of life (HRQOL) was assessed using the Short-Form Liver Disease Quality of Life questionnaire. We examined reliability, floor/ceiling effects, structural validity, and known-groups validity for anxiety (HADS-Anxiety) and depression (HADS-Depression) subscales. We assessed the convergent validity with the PHQ-9. We predicted the change in HRQOL using the change in depression and anxiety. We also evaluated the internal responsiveness to changes in HRQOL for both HADS-Anxiety and HADS-Depression from baseline to week 6. Results: The HADS-Anxiety and HADS-Depression subscales showed strong internal consistency (Cronbach's alpha>0.8), adequate floor/ceiling effects (<15%), and excellent convergent validity with PHQ-9 (r>0.7). Both domains significantly predicted the changes in HRQOL longitudinally. Both HADS-Anxiety (1.8 [95% confidence interval [CI]: 0.5, 3.2]) and HADS-Depression (2.2 [95%CI: 1, 3.4]) showed responsiveness in patients with decreased HRQOL. Conclusions: The HADS is a reliable, valid, responsive tool for assessing anxiety and depression among patients with DC.
{"title":"Validation of the Hospital Anxiety and Depression Scale in Patients with Decompensated Cirrhosis","authors":"Chengbo Zeng, John Donlan, Teresa Indriolo, Lucinda Li, Enya Zhu, Joyce C Zhou, Malia E Armstrong, Kedie Pintro, Nora Horick, Raymond T Chung, Areej EI-Jawahri, Maria O Edelen, Nneka N Ufere","doi":"10.1101/2024.07.05.24310010","DOIUrl":"https://doi.org/10.1101/2024.07.05.24310010","url":null,"abstract":"Background: The Hospital Anxiety and Depression Scale (HADS) demonstrates strong psychometric properties in many populations of patients with serious illness. However, its psychometric performance among patients with decompensated cirrhosis (DC) has not been examined. We investigated the reliability, validity, and responsiveness of the HADS for patients with DC.\u0000Methods: This observational study utilized data from patients with DC at enrollment and week 6 follow-up. Two hundred eighteen outpatients with DC were recruited from a liver transplant center, with 145 completing week 6 assessment. We evaluated psychological distress using HADS and Patient Health Questionnaire 9 (PHQ-9). Patients' health-related quality of life (HRQOL) was assessed using the Short-Form Liver Disease Quality of Life questionnaire. We examined reliability, floor/ceiling effects, structural validity, and known-groups validity for anxiety (HADS-Anxiety) and depression (HADS-Depression) subscales. We assessed the convergent validity with the PHQ-9. We predicted the change in HRQOL using the change in depression and anxiety. We also evaluated the internal responsiveness to changes in HRQOL for both HADS-Anxiety and HADS-Depression from baseline to week 6. Results: The HADS-Anxiety and HADS-Depression subscales showed strong internal consistency (Cronbach's alpha>0.8), adequate floor/ceiling effects (<15%), and excellent convergent validity with PHQ-9 (r>0.7). Both domains significantly predicted the changes in HRQOL longitudinally. Both HADS-Anxiety (1.8 [95% confidence interval [CI]: 0.5, 3.2]) and HADS-Depression (2.2 [95%CI: 1, 3.4]) showed responsiveness in patients with decreased HRQOL.\u0000Conclusions: The HADS is a reliable, valid, responsive tool for assessing anxiety and depression among patients with DC.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141566884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-04DOI: 10.1101/2024.07.03.24309885
Mahmud Omar, Salih Nassar, Mohammad Omar, Mohammad Naffaa, Adi Lahat, Kassem Sharif
Background and Objective: Mendelian randomization (MR) has become an important tool in epidemiology, used to infer causal relationships diseases. This review aims to consolidate existing MR evidence concerning celiac disease (CeD). Methods: We systematically searched major databases up to May 2024, adhering to PRISMA guidelines. Only MR studies explicitly investigating CeD were included. We assessed the quality of each study based on the strength, independence, and exclusivity of the instrumental variables used. Results: From an initial pool of 207 articles, 35 met our inclusion criteria. These studies frequently addressed the relationship between CeD and autoimmune diseases like inflammatory bowel disease (IBD) and explored connections with gut microbiota, various cancers, and metabolic disorders. Significant findings highlight a robust bi-directional association between IBD and CeD and complex interactions with gut microbiota. Notably, many associations reported were near the threshold of clinical significance. Conclusion: This systematic review highlights the dual nature of current MR evidence on CeD. On one hand, we observe consistent associations between CeD, IBDs, and gut microbiota. On the other, there is a plethora of weaker associations that raise critical questions about their clinical and research significance. This work lays a solid foundation for deeper investigations into these weaker links, particularly in relation to lymphomas and psychiatric conditions. It calls for an expanded use of MR and other methodologies to explore under-researched areas.
{"title":"A Systematic Review of Mendelian Randomization Studies on Celiac Disease.","authors":"Mahmud Omar, Salih Nassar, Mohammad Omar, Mohammad Naffaa, Adi Lahat, Kassem Sharif","doi":"10.1101/2024.07.03.24309885","DOIUrl":"https://doi.org/10.1101/2024.07.03.24309885","url":null,"abstract":"Background and Objective: Mendelian randomization (MR) has become an important tool in epidemiology, used to infer causal relationships diseases. This review aims to consolidate existing MR evidence concerning celiac disease (CeD).\u0000Methods: We systematically searched major databases up to May 2024, adhering to PRISMA guidelines. Only MR studies explicitly investigating CeD were included. We assessed the quality of each study based on the strength, independence, and exclusivity of the instrumental variables used. Results: From an initial pool of 207 articles, 35 met our inclusion criteria. These studies frequently addressed the relationship between CeD and autoimmune diseases like inflammatory bowel disease (IBD) and explored connections with gut microbiota, various cancers, and metabolic disorders. Significant findings highlight a robust bi-directional association between IBD and CeD and complex interactions with gut microbiota. Notably, many associations reported were near the threshold of clinical significance.\u0000Conclusion: This systematic review highlights the dual nature of current MR evidence on CeD. On one hand, we observe consistent associations between CeD, IBDs, and gut microbiota. On the other, there is a plethora of weaker associations that raise critical questions about their clinical and research significance. This work lays a solid foundation for deeper investigations into these weaker links, particularly in relation to lymphomas and psychiatric conditions. It calls for an expanded use of MR and other methodologies to explore under-researched areas.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141549721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-03DOI: 10.1101/2024.07.01.24309778
Jerry D Gardner, George Triadafilopoulos
INTRODUCTION: Patients with chronic constipation exhibit symptoms and motility abnormalities that occur in combinations, but the nature of these combinations has not been characterized. METHODS: We calculated prevalences of combinations of symptoms (abdominal pain, infrequent defecation, incomplete evacuation, straining), abnormal motility test results (prolonged colonic transit time, low anal basal pressure, low anal squeeze pressure, poor rectal sensation, absent balloon expulsion), or both using data from 75 females and 91 males with chronic constipation. We calculated the Cluster Factor as observed prevalence of a combination of symptoms, abnormal test results or both divided by the prevalence of the combination due to chance. We calculated the conditional probabilities of combinations of symptoms, abnormal motility test results or both given the prevalence of other members of the same combination. RESULTS: Combinations of symptoms alone or abnormal motility test results alone in both males and females, and for combinations of symptoms plus abnormal motility test results in females, failed to cluster together beyond that attributable to chance alone. Males, however, showed significant clustering. Significant conditional probabilities with symptoms, and with symptoms plus abnormal motility test results was higher in males than females. Significant conditional probabilities with abnormal motility test results were not different between males and females. CONCLUSIONS: Gender-related differences in prevalences of combinations of symptoms and abnormal motility test results, of significant Cluster Factors, and of conditional probabilities indicate that chronic constipation in males reflects a fundamentally different disorder from that in females.
{"title":"DIFFERENT PHENOTYPES OF CHRONIC CONSTIPATION IN MALES AND FEMALES","authors":"Jerry D Gardner, George Triadafilopoulos","doi":"10.1101/2024.07.01.24309778","DOIUrl":"https://doi.org/10.1101/2024.07.01.24309778","url":null,"abstract":"INTRODUCTION: Patients with chronic constipation exhibit symptoms and motility abnormalities that occur in combinations, but the nature of these combinations has not been characterized.\u0000METHODS: We calculated prevalences of combinations of symptoms (abdominal pain, infrequent defecation, incomplete evacuation, straining), abnormal motility test results (prolonged colonic transit time, low anal basal pressure, low anal squeeze pressure, poor rectal sensation, absent balloon expulsion), or both using data from 75 females and 91 males with chronic constipation. We calculated the Cluster Factor as observed prevalence of a combination of symptoms, abnormal test results or both divided by the prevalence of the combination due to chance. We calculated the conditional probabilities of combinations of symptoms, abnormal motility test results or both given the prevalence of other members of the same combination.\u0000RESULTS: Combinations of symptoms alone or abnormal motility test results alone in both males and females, and for combinations of symptoms plus abnormal motility test results in females, failed to cluster together beyond that attributable to chance alone. Males, however, showed significant clustering. Significant conditional probabilities with symptoms, and with symptoms plus abnormal motility test results was higher in males than females. Significant conditional probabilities with abnormal motility test results were not different between males and females.\u0000CONCLUSIONS: Gender-related differences in prevalences of combinations of symptoms and abnormal motility test results, of significant Cluster Factors, and of conditional probabilities indicate that chronic constipation in males reflects a fundamentally different disorder from that in females.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141549722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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