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Introduction: Magnifying chromoendoscopy (MCE) and endoscopic ultrasonography (EUS) are often used as diagnostic tools to estimate the depth of invasion in early colorectal cancers (CRCs). The aim of this study was to compare MCE with EUS in distinguishing between slight submucosal invasion (invasion depth <1,000 μm) and massively submucosal invasion in patients with early CRCs, since slight submucosal invasion is currently considered as an indication for endoscopic resection and submucosal cancer with massively submucosal invasion should be surgically treated due to an increased risk of lymph node metastasis.

Methods: For this meta-analysis, relevant studies were identified from PubMed, Embase, and the Cochrane Library databases between the time of the establishment and April 2023. Data on the yield of tumors were extracted, pooled, and analyzed by STATA15.0 software. The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio in differentiating massive submucosal invasion from slight submucosal invasion were calculated for both diagnostic modalities.

Results: Twenty-six studies involving 12,586 lesions were included: sixteen were studies on MCE and 7 were studies on EUS and 3 were studies on both MCE and EUS. The pooled sensitivity of MCE was 0.78 (95% CI 0.72-0.83), the specificity was 0.95 (0.95% CI 0.91-0.97), the positive likelihood ratio was 15.4 (0.95% CI 8.7-27.4), and the negative likelihood ratio was 0.23 (0.95% CI 0.18-0.30). The pooled sensitivity of EUS was 0.88 (95% CI 0.81-0.93), the specificity was 0.87 (0.95% CI 0.80-0.91), the positive likelihood ratio was 6.7 (0.95% CI 4.4-10.3), and the negative likelihood ratio was 0.13 (0.95% CI 0.08-0.23).

Conclusion: The sensitivity tended to be higher in EUS than MCE for early CRCs with massively submucosal invasion, whereas the specificity was significantly lower in EUS than in MCE.

Introduction: Increased fecal protease activity, which may induce visceral hypersensitivity, has been observed in patients with irritable bowel syndrome (IBS). Serine proteases modulate FK506 binding protein (FKBP)-type peptidylprolyl cis-trans isomerase (PPIase) activity associated with immune and glucocorticoid receptor functions. The aim was to investigate whether camostat mesilate (CM), a serine protease inhibitor, modifies fecal bacterial function related to FKBP-type PPIases in patients with IBS.

Methods: Randomly assigned 16 patients with IBS received 200 mg po tid of CM and 16 patients received placebo for 14 days. Self-reported adequate relief (AR) as a primary endpoint, IBS Symptom Severity Scale (IBS-SSS), and colonic motor and pain thresholds to colorectal distention were assessed before and after treatment. The fecal bacterial content was inferred from 16S rRNA gene sequence data using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States and the Kyoto Encyclopedia of Genes and Genomes database.

Results: CM significantly increased the relative abundance of Streptococcus and the functional abundances of serine protease and FKBP-type PPIase FkpA, FklB and SlyD more than placebo after treatment. CM treatment was not superior to placebo in proportion of AR although colonic motor response partially changed.

Conclusion: CM modulated the fecal microbiome composition and functional potentials that are related to FKBP-type PPIase activity in IBS patients. These findings suggest that protease inhibitors may modify gut microbial function along with abnormal immunological and/or stress responses that underlie pathophysiology of IBS.

Background: The goal of surveillance after the endoscopic resection of colorectal tumors is to reduce colorectal cancer (CRC) incidence and mortality. Considering the effective use of the limited endoscopic capacity and the cost of surveillance, it is desirable to develop a surveillance program that is as minimal as possible. In Europe (European Society of Gastrointestinal Endoscopy [ESGE]) and the USA (Multi-Society Task Force [MSTF]), after the results of the National Polyp Study (NPS) were established, guidelines were developed that stratified risk based on initial endoscopy, and surveillance programs for each risk group were proposed. More than 10 years later, the "colonoscopy screening and surveillance guidelines" were developed with the basic principle of "aiming for zero CRC deaths during surveillance, bowel preservation, and emphasis on patient quality of life" as the guideline principles in Japan.

Summary: Randomized controlled trials to evaluate the appropriate surveillance intervals after endoscopic resection of colorectal tumors, the NPS, the Nottingham Study, and the Japan Polyp Study (JPS), are summarized. The ESGE, USMSTF, and Japanese guidelines compared low-risk adenoma, high-risk adenoma, advanced neoplasia, piecemeal resection, and serrated lesions by category.

Key messages: Surveillance guidelines based on risk stratification were developed in Japan. Guidelines are meaningful only when they are effectively utilized in clinical practice. They must also be revised based on new evidence. It is hoped that new knowledge will be accumulated, especially in Japan, on topics that are currently lacking.

Objectives: To explore the underlying variables and molecular pathways leading to pancreatic cancer liver metastasis.

Methods: Hs766T and Hs766T-L3 cells were used to create in vitro and in vivo pancreatic cancer liver metastasis models. DYRK2 involvement in pancreatic cancer metastasis was investigated using cell adhesion assays, wound healing assays, and migration and invasion assays. To examine the link between DYRK2 expression and epithelial-mesenchymal transition, Western blot, quantitative real-time PCR, immunofluorescence assays, and immunoprecipitation (IP) were utilized. We found that mice with DYRK2 overexpression had a lower incidence of liver metastasis compared to controls.

Results: DYRK2 expression decreased pancreatic cancer tumorigenic activities, including proliferation, migration, and invasion. By analyzing the expression levels of epithelial-mesenchymal transition markers and IP results after overexpressing DYRK2, we found that DYRK2 decreased Twist levels by increasing Twist ubiquitination, thereby inhibiting epithelial-mesenchymal transition.

Conclusions: Our findings provide theoretical and experimental support for the ongoing development of DYRK2-based targeted therapies for pancreatic cancer liver metastases.

Background: Endoscopic resection techniques for colorectal tumors are constantly evolving with improvements.

Summary: Over the past decade, there has been a paradigm shift toward cold polypectomy for the removal of small lesions (<10 mm), known as the "cold revolution". In recent years, underwater endoscopic mucosal resection (EMR) has emerged as an alternative to conventional EMR and has been gaining popularity for resection of intermediate and large-sized lesions (≥10 mm). Although colorectal endoscopic submucosal dissection (ESD) requires a high level of advanced skills, improvements in dissection techniques and devices have facilitated the procedure. In Japan, the safety and efficacy of ESD for resecting large lesions (≥20 mm) have been demonstrated in a large-scale, multicenter, prospective cohort study (CREATE-J). ESD is also being increasingly adopted in Western countries. As endoscopic resection continues to advance and include large and more complex defects, a variety of closure techniques and new devices are being developed. Meanwhile, the number of endoscopic resections for T1-colorectal cancer (T1-CRC), including those intended for total excisional biopsy, has been increasing owing to the aging population and improvements in endoscopic technique.

Key messages: This review provides a broad summary of endoscopic resection for colorectal tumors including advancements in closure techniques and devices for mucosal defects, as well as the potential role of endoscopic resection for patients with T1-CRC.

Introduction: This study aimed to train machine learning algorithms (MLAs) to detect advanced fibrosis (AF) in metabolic dysfunction-associated steatotic liver disease (MASLD) patients at the level of primary care setting and to explain the predictions to ensure responsible use by clinicians.

Methods: Readily available features of 618 MASLD patients followed up at a tertiary center were used to train five MLAs. AF was defined as liver stiffness ≥9.3 kPa, measured via 2-dimension shear wave elastography (n = 495) or liver biopsy ≥F3 (n = 123). MLAs were compared to Fibrosis-4 index (FIB-4) and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) on 540 MASLD patients from the primary care setting as validation. Feature importance, partial dependence, and shapely additive explanations (SHAPs) were utilized for explanation.

Results: Extreme gradient boosting (XGBoost) achieved an AUC = 0.91, outperforming FIB-4 (AUC = 0.78) and NFS (AUC = 0.81, both p < 0.05) with specificity = 76% versus 59% and 48% for FIB-4 ≥1.3 and NFS ≥-1.45, respectively (p < 0.05). Its sensitivity (91%) was superior to FIB-4 (79%). XGBoost confidently excluded AF (negative predictive value = 99%) with the highest positive predictive value (31%), superior to FIB-4 and NFS (all p < 0.05). The most important features were HbA1c and gamma glutamyl transpeptidase (GGT) with a steep increase in AF probability at HbA1c >6.5%. The strongest interaction was between AST and age. XGBoost, but not logistic regression, extracted informative patterns from ALT, low-density lipoprotein cholesterol, and alkaline phosphatase (p < 0.001). One-quarter of the false positives (FPs) were correctly reclassified with only one additional false negative based on the SHAP values of GGT, platelets, and ALT which were found to be associated with a FP classification.

Conclusions: An explainable XGBoost algorithm was demonstrated superior to FIB-4 and NFS for screening of AF in MASLD patients at the primary care setting. The algorithm also proved safe for use as clinicians can understand the predictions and flag FP classifications.

Background: Colorectal cancer (CRC) is a major concern because of its increasing incidence and mortality worldwide. Therefore, effective screening strategies are necessary to reduce its incidence.

Summary: In addition to fecal immunochemical tests and computed tomography colonography, screening colonoscopy is expected to significantly contribute to the reduction of CRC. However, the timing of colonoscopy for CRC screening is not well-defined because of the lack of sufficient data. Additionally, the effectiveness of colonoscopy is affected by various factors known as quality indicators (QIs), such as the performance of the endoscopist; therefore, there are concerns regarding quality assurance. The adenoma detection rate (ADR) is a well-known QI of colonoscopy. Substantial evidence has suggested that improving the ADR could reduce the incidence and mortality of postcolonoscopy CRC.

Key messages: Recent technological advancements have led to the development of image-enhanced endoscopy and the incorporation of artificial intelligence, and their ability to improve the ADR has been assessed. This review focused on screening colonoscopies and QIs and their ability to improve the ADR and incidence and mortality of CRC.

Introduction: Contrast-enhanced computed tomography (CE-CT) has been gaining attention as an initial investigation in the management of colonic diverticular bleeding (CDB), yet the role of CE-CT other than its diagnostic yield has not been adequately clarified. We aimed to determine whether the use of urgent CE-CT improves identification of stigmata of recent hemorrhage (SRH) in subsequently performed early colonoscopy (≤24 h of arrival) or other clinical outcomes of CDB.

Methods: We conducted a randomized, open-label, controlled trial at 23 institutions in Japan. Outpatients with suspected CDB were randomly assigned to undergo either urgent CE-CT followed by early colonoscopy (urgent-CE-CT + early-colonoscopy group) or early colonoscopy alone (early-colonoscopy group). The primary outcome was SRH identification. Secondary outcomes included successful endoscopic hemostasis, early (<30 days) and late (<1 year) rebleeding, length of hospital stay, and transfusion requirements.

Results: In total, 240 patients, mostly in a hemodynamically stable condition, were randomized. A contrast extravasation on CE-CT was observed in 20 of 115 patients (17.4%) in the urgent-CE-CT + early-colonoscopy group. SRH was identified in 23 of 115 patients (20.0%) in the urgent-CE-CT + early-colonoscopy group and 21 of 118 patients (17.8%) in the early-colonoscopy group (difference, 2.2; 95% confidence interval [CI], -7.9 to 12.3; p = 0.739). Successful endoscopic hemostasis was achieved in 21 patients in each group (18.3% and 17.8%, respectively) (difference, 0.5; 95% CI, -9.4 to 10.4; p = 1.000). There were also no significant differences between groups in early and late rebleeding, length of hospital stay, and transfusion requirements.

Conclusion: The use of urgent CE-CT before early colonoscopy did not improve SRH identification or other clinical outcomes in patients with suspected CDB in a hemodynamically stable condition. The routine use of urgent CE-CT as an initial investigation is not recommended in this population, also considering the low rate of extravasation-positive cases (UMIN registry number, UMIN000026865).

Background: Metabolic syndrome (MetS) is a cluster of cardiometabolic conditions that has been linked to high risk for cardiovascular disease, liver complications, and several malignancies. More recently, MetS has been associated with cognitive dysfunction.

Summary: Studies have shown an association with minimal cognitive impairment, progression to vascular dementia, and even Alzheimer's disease. MetS components have been individually explored, and glucose intolerance has the strongest association with impairment in several cognitive domains. Several hypotheses have been proposed regarding the pathophysiology underlying the MetS-cognitive dysfunction association, and even though insulin resistance plays a major role, more studies are needed to elucidate this topic. Moreover, several other factors contributing to this association have been identified. Liver disease and more specifically metabolic dysfunction-associated steatotic liver disease can on its own contribute to cognitive decline through systemic inflammation and higher ammonia levels. Gut dysbiosis that has also been identified in MetS can also lead to cognitive impairment through several mechanisms that result in neurotoxicity. Finally, there are several other factors that may modify the MetS-cognitive dysfunction relationship, such as lifestyle, diet, education status, and age. More recently, circadian syndrome was explored and was found to be even more strongly associated with cognitive impairment.

Key message: MetS is associated with cognitive decline. Certain cardiometabolic risk factors have a stronger association with cognitive impairment, and there are several factors that may modify this relationship. The aim of this review was to assess and summarize the existing body of evidence on the association between MetS and cognitive impairment and identify areas that necessitate further investigation.

Introduction: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we report the primary analysis of a phase 3 trial evaluating the efficacy and safety of etrasimod in patients from Japan with moderately to severely active UC.

Methods: Patients from Japan who completed the 12-week ELEVATE UC 12 induction trial could enroll in the 40-week ELEVATE UC 40 JAPAN maintenance trial for a combined 52-week treatment period. Patients in this Japan cohort continued their baseline assigned treatment (etrasimod 2 mg QD or placebo) from ELEVATE UC 12. Efficacy was assessed at week 12 and week 52. Treatment-emergent adverse events (TEAEs) pooled from both trials were assessed up to 52 weeks of exposure.

Results: The Japan cohort comprised 32 and 16 patients who received etrasimod and placebo, respectively. A numerically greater proportion of patients who received etrasimod versus placebo achieved clinical remission at week 12 (etrasimod: 14.3%; placebo: 7.1%) and week 52 (etrasimod: 25.0%; placebo: 7.1%); a similar trend was observed for all key secondary efficacy endpoints. TEAEs occurred in 84.4% (27/32) and 62.5% (10/16) of patients who received etrasimod and placebo, respectively. No new safety signals were detected.

Conclusion: In these induction and maintenance trials evaluating etrasimod in patients from Japan with UC, numerically higher proportions of patients who received etrasimod versus placebo achieved efficacy endpoints. Efficacy and safety findings were consistent with those from the global ELEVATE UC trial populations.