Systematic Review and Meta-analysis

[Posted 10/Nov/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: While the overall efficacy and safety of tofacitinib in moderate-severe UC is consistent with clinical trial data, the dose dependent increase in AEs highlights the significance of early dose de-escalation. Rate of clinical response after tofacitinb induction was similar in biologic naive and biologic experienced patients.

BACKGROUND: The objective of our systematic review and meta-analysis was to evaluate the effectiveness and safety of tofacitinib in the treatment of moderate-severe ulcerative colitis (UC).

DETAILS: Authors searched Medline, Embase, Web of Science, and Cochrane Central to identify articles and abstracts reporting efficacy or safety data on tofacitinib use in UC. Primary outcome assessed was remission. Secondary outcomes included clinical response, steroid free remission, and adverse events (AEs). A total of 26 studies were included. The rates of remission were 29.81% [95% confidence interval (CI): 22.37%-37.25%, I²: 90%] at week 8, 32.27% (95% CI: 27.67%-36.88%, I²: 42%) at 6 months and 38.03% (95% CI: 33.59%-42.48%, I²: 0%) at 1-year. Clinical response rates were 59.41% (95% CI: 55.03%-63.94%, I²: 61%) at week 8, 48.99% (95% CI: 36.92%-61.06%, I²: 91%) at 6 months and 50.87% (95% CI: 42.16%-59.58%, I²: 67%) at 1-year. Odds ratio of clinical response at week 8 in biologic naive versus biologic experienced patients was 1.59 (95% CI: 0.54-4.63). Pooled incidence rate for serious infections, major adverse cardiovascular events, and nonmelanotic squamous cell malignancies across all doses was 4.41 per 100-patient years (PYs) (95% CI: 2.32-8.38 per 100-PY, I²: 78%), 0.91 per 100-PY (95% CI: 0.43-1.93 per 100-PY, I²: 37%) and 0.91 per 100-PY (95% CI: 0.61-1.34 per 100-PY, I²: 0%), respectively. Higher dose was associated with an increased frequency of AEs.

Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Source: Taneja, V., El-Dallal, M., Haq, Z., et al. (2022). Effectiveness and Safety of Tofacitinib for Ulcerative Colitis: Systematic Review and Meta-analysis. J Clin Gastro. 2022; 56(10): e323-e333. Published: November/December, 2022. DOI: 10.1097/MCG.0000000000001608.

[Posted 18/Mar/2024]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

KEY FINDINGS: By using integrative scRNA-seq, spatial transcriptomic analysis and functional assays, authors have uncovered a stem-like cell cluster marked with PTPRO and ASCL2 as the metastatic culprit, whose subpopulations show further different liver or ovary organotropism.

BACKGROUND: Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain largely undiscovered.

DETAILS: Authors performed single-cell RNA sequencing and spatial transcriptomic analysis in primary colorectal cancer (CRC) and metastases in the liver (lCRC) or ovary (oCRC). Authors also conducted immunofluorescence staining and functional experiments to examine the mechanism. Integrative analyses of epithelial cells reveal a stem-like cell cluster with high protein tyrosine phosphatase receptor type O (PTPRO) and achaete scute-like 2 (ASCL2) expression as the metastatic culprit. This cell cluster comprising distinct subpopulations shows distinct liver or ovary metastatic preference. Population 1 (P1) cells with high delta-like ligand 4 (DLL4) and MAF bZIP transcription factor A (MAFA) expression are enriched in primary CRC and oCRC, thus may be associated with ovarian metastasis. P3 cells having a similar expression pattern as cholangiocytes are found mainly in primary CRC and lCRC, presuming to be likely the culprits that specifically metastasise to the liver. Stem-like cells interacted with cancer-associated fibroblasts and endothelial cells via the DLL4-NOTCH signalling pathway to metastasise from primary CRC to the ovary. In the oCRC microenvironment, myofibroblasts provide cancer cells with glutamine and perform a metabolic reprogramming, which may be essential for cancer cells to localise and develop in the ovary.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Li, R., Liu, X., Huang, X., et al. (2024). Single-Cell Transcriptomic Analysis Deciphers Heterogenous Cancer Stem-Like Cells in Colorectal Cancer and Their Organ-Specific Metastasis. Gut. 2024; 73(3): 470-484 .Published: March, 2024. DOI: 10.1136/gutjnl-2023-330243.

[Posted 15/Jan/2024]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: The study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.

BACKGROUND: Early gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq).

DETAILS: scRNA-seq was conducted on 95,551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed. Integrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5+ stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5+ stem cells during EGCA malignant progression.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Wang Z., Wang Q., Chen C., et al. (2023). NNMT Enriches for AQP5+ Cancer Stem Cells to Drive Malignant Progression in Early Gastric Cardia Adenocarcinoma. Gut. 2024; 73: 63-77. Published: November, 2023. DOI: 10.1136/gutjnl-2022-328408.

A Meta-Analysis.

[Posted 26/Sep/2023]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: The research provides evidence that EDGE for endoscopic retrograde cholangiopancreatography yields good treatment outcomes in patients with RYGBs. The AE rate is significantly lower with 20-mm versus 15-mm LAMS; thus, the former is likely preferable.

BACKGROUND: Endoscopic ultrasound-directed trans-gastric retrograde cholangiopancreatography (EDGE) is a new procedure for treating pancreaticobiliary diseases in patients with Roux-en-Y gastric bypass (RYGB). The aim of this meta-;analysis was to determine the overall outcomes and safety of EDGE.

DETAILS: Authors performed a computerized search of the main databases, including PubMed, EMBASE, Cochrane Library, and Science Citation Index, through October 2022. The main outcome measures examined in the meta-analysis were technical and clinical success rates and overall adverse event (AE) rate, especially the lumen-apposing metal stent (LAMS) dislodgement rate. AE rates were assessed according to LAMS size (15 vs. 20 mm), number of stages (single vs. two) and access route (gastrogastric vs. jejuno-gastric). Fourteen trials with a total of 574 patients who had undergone 585 EDGE procedures were included in this study. The cumulative technical and clinical success and AE rates were 98%, 94%, and 14%, respectively. The commonest AE was LAMS dislodgement (rate 4%). The overall AE rate was lower in the 20-mm LAMS than in the 15-mm LAMS group (odds ratio [OR]=5.79; 95% confidence interval [CI]: 2.35 to 14.29). There were no significant differences in AE rate between number of stages (OR=1.36; 95% CI: 0.51 to 3.64) or differing access routes (OR=1.03; 95% CI 0.48 to 2.22).

Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Source: Tong, S., Tianjie, C., Jing, W., et al. (2023). Endoscopic-Directed Trans-Gastric Retrograde Cholangiopancreatography in Patients With Roux-en-Y gastric Bypasses: A Meta-Analysis. Journal of Clinical Gastroenterology. 2023; 57(9): 871-878. Published: September, 2023. DOI: 10.1097/MCG.0000000000001864.

Lessons for the Adult Gastroenterologist

[Posted 18/Aug/2023]

AUDIENCE: Gastroenterology, Pediatric, Internal Medicine

KEY FINDINGS: The present review addresses the epidemiology, clinical features, diagnostic testing, treatment, prognosis, and transplant outcomes of 4 hallmark childhood cholestatic liver diseases: biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, and bile acid synthesis disorders.

BACKGROUND: Children with cholestatic liver diseases are increasingly living into adulthood, thanks to innovations in medical and surgical therapies. The excellent outcomes observed in pediatric liver transplantation for diseases, such as biliary atresia, have transformed the life trajectory of children born with once-fatal liver diseases.

DETAILS: The evolution of molecular genetic testing, has helped expedite the diagnosis of other cholestatic disorders, improving the clinical management, disease prognosis, and family planning for inherited disorders, such as progressive familial intrahepatic cholestasis and bile acid synthesis disorders. The expanding list of therapeutics, including bile acids and the newer ileal bile acid transport inhibitors, has also helped slow the progression of disease and improve the quality of life for certain diseases, like Alagille syndrome. More and more children with cholestatic disorders are expected to require care from adult providers familiar with the natural history and potential complications of these childhood diseases. The aim of this review is to bridge the gap between pediatric and adult care in children with cholestatic disorders.

Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Source: Chan, A. P. and Venick, R. S. (2023). Childhood Cholestatic Liver Diseases that Persist Into Adulthood : Lessons for the Adult Gastroenterologist. Journal of Clinical Gastroenterology. 2023; 57(7): 686-693. Published: August, 2023. DOI: 10.1097/MCG.0000000000001850.

A Diet Intervention In Pre-Diabetes

[Posted 20/Jul/2023]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: The findings support the role of gut microbiome in modulating the effects of dietary modifications on cardiometabolic outcomes, and advance the concept of precision nutrition strategies for reducing comorbidities in pre-diabetes.

BACKGROUND: Aim of the study is to explore the interplay between dietary modifications, microbiome composition and host metabolic responses in a dietary intervention setting of a personalised postprandial-targeting (PPT) diet versus a Mediterranean (MED) diet in pre-diabetes.

DETAILS: In a 6-month dietary intervention, adults with pre-diabetes were randomly assigned to follow an MED or PPT diet (based on a machine-learning algorithm for predicting postprandial glucose responses). Data collected at baseline and 6 months from 200 participants who completed the intervention included: dietary data from self-recorded logging using a smartphone application, gut microbiome data from shotgun metagenomics sequencing of faecal samples, and clinical data from continuous glucose monitoring, blood biomarkers and anthropometrics. PPT diet induced more prominent changes to the gut microbiome composition, compared with MED diet, consistent with overall greater dietary modifications observed. Particularly, microbiome alpha-diversity increased significantly in PPT (p=0.007) but not in MED arm (p=0.18). Post hoc analysis of changes in multiple dietary features, including food-categories, nutrients and PPT-adherence score across the cohort, demonstrated significant associations between specific dietary changes and species-level changes in microbiome composition. Furthermore, using causal mediation analysis we detect nine microbial species that partially mediate the association between specific dietary changes and clinical outcomes, including three species (from Bacteroidales, Lachnospiraceae, Oscillospirales orders) that mediate the association between PPT-adherence score and clinical outcomes of hemoglobin A1c (HbA1c), high-density lipoprotein cholesterol (HDL-C) and triglycerides. Finally, using machine-learning models trained on dietary changes and baseline clinical data, we predict personalised metabolic responses to dietary modifications and assess features importance for clinical improvement in cardiometabolic markers of blood lipids, glycaemic control and body weight.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Ben-Yacov, O., Godneva, A., Rein, M., et al. (2023). Gut Microbiome Modulates The Effects Of A Personalised Postprandial-Targeting (PPT) Diet On Cardiometabolic Markers: A Diet Intervention In Pre-Diabetes. Gut. 2023; 72(8): 1486-1496. Published: August, 2023.