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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 towards 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) has been demonstrated in a large-scale, multicenter, prospective cohort study (CREATE-J). ESD is 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 also 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.

Background This study aimed to train machine learning algorithms(MLAs) to detect advanced fibrosis(AF) in 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 NAFLD fibrosis score(NFS) on 540 MASLD patients from the primary care setting as validation. Feature importance, partial dependence, and shapely additive explanations(SHAP) 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% vs. 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 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, LDL-c,and ALP(p<0.001). One quarter of the false positives (FP) 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: Tumor-associated macrophages, which are part of the tumor microenvironment, are a major factor in cancer progression. However, a complete understanding of the regulatory mechanism of M2 polarization of macrophages (Mø) in liver cancer is yet to be established. This study aimed to investigate the potential mechanism by which NEIL3 influenced M2 Mø polarization in liver cancer.

Methods: Bioinformatics analysis analyzed NEIL3 expression and its enriched pathways in liver cancer tissue, as well as its correlation with pathway genes. The upstream transcription factor of NEIL3, TFAP2A, was predicted and its expression in liver cancer tissue was analyzed. The binding relationship between the two was analyzed by dual-luciferase reporter and chromatin immunoprecipitation experiments. qRT-PCR assessed NEIL3 and TFAP2A levels in liver cancer cells. Cell viability was detected by CCK-8, while CD206 and CD86 expression was detected by immunofluorescence. IL-10 and CCR2 expressions were assessed using qRT-PCR, and M2 Mø quantity was detected using flow cytometry. Reagent kits tested glutamine (Gln) consumption, α-ketoglutarate, and glutamate content, as well as NADPH/NADP+ and GSH/GSSG ratios. Expression of Gln transport proteins was detected using Western blot. An animal model was established to investigate the influence of NEIL3 expression on liver cancer growth.

Results: NEIL3 was highly expressed in liver cancer and promoted Mø M2 polarization through Gln metabolism. TFAP2A was identified as the upstream transcription factor of NEIL3 and was highly expressed in liver cancer. Rescue experiments presented that overexpression of NEIL3 reversed the suppressive effect of TFAP2A knockdown on Mø M2 polarization in liver cancer. In vivo experiments demonstrated that the knockdown of NEIL3 could significantly repress the growth of xenograft tumors.

Conclusion: This study suggested that the TFAP2A/NEIL3 axis promoted Mø M2 polarization through Gln metabolism, providing a theoretical basis for immune therapy targeting the liver cancer TME.

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.

Introduction: The research field of artificial intelligence (AI) in medicine and especially in gastroenterology is rapidly progressing with the first AI tools entering routine clinical practice, for example, in colorectal cancer screening. Contrast-enhanced ultrasound (CEUS) is a highly reliable, low-risk, and low-cost diagnostic modality for the examination of the liver. However, doctors need many years of training and experience to master this technique and, despite all efforts to standardize CEUS, it is often believed to contain significant interrater variability. As has been shown for endoscopy, AI holds promise to support examiners at all training levels in their decision-making and efficiency.

Methods: In this systematic review, we analyzed and compared original research studies applying AI methods to CEUS examinations of the liver published between January 2010 and February 2024. We performed a structured literature search on PubMed, Web of Science, and IEEE. Two independent reviewers screened the articles and subsequently extracted relevant methodological features, e.g., cohort size, validation process, machine learning algorithm used, and indicative performance measures from the included articles.

Results: We included 41 studies with most applying AI methods for classification tasks related to focal liver lesions. These included distinguishing benign versus malignant or classifying the entity itself, while a few studies tried to classify tumor grading, microvascular invasion status, or response to transcatheter arterial chemoembolization directly from CEUS. Some articles tried to segment or detect focal liver lesions, while others aimed to predict survival and recurrence after ablation. The majority (25/41) of studies used hand-picked and/or annotated images as data input to their models. We observed mostly good to high reported model performances with accuracies ranging between 58.6% and 98.9%, while noticing a general lack of external validation.

Conclusion: Even though multiple proof-of-concept studies for the application of AI methods to CEUS examinations of the liver exist and report high performance, more prospective, externally validated, and multicenter research is needed to bring such algorithms from desk to bedside.

Introduction: Exocrine pancreatic insufficiency (EPI) is caused by multiple clinical conditions such as cystic fibrosis and chronic pancreatitis (CP). Standard management of EPI includes pancreatic enzyme replacement therapy (PERT) along with consultation with a dietitian. While PERTs have been on the market for several decades, newer publications on their clinical efficacy and safety raised the need for a comprehensive review of the literature. We aimed to identify the available evidence on the clinical efficacy and safety of treatments for EPI to understand the current treatment landscape and unmet need in patients with EPI.

Methods: A systematic literature review (SLR) was conducted in Embase, Medline, and Evidence-Based Medicine databases from 2010 to 2022; conference proceedings from 2020 to 2022 were also searched. Articles were screened independently by two reviewers at abstract and full-text stage against predefined eligibility criteria.

Results: We identified 26 journal publications and two conference abstracts, reporting on 22 randomized control trials, four observational studies, and two single-arm interventional studies. The most reported treatment was pancrelipase, specifically Creon® (n = 12). Fourteen studies reported coefficient of fat absorption (CFA) results. Across studies, patients experienced a considerable increase in CFA post-initiation of treatment regardless of intervention or timepoint. Mean change in CFA ranged from 7.5% in patients with CP who received placebo to 36% in patients with CP treated with Creon®. Ten studies reported coefficient of nitrogen absorption (CNA). Where reported, pancrelipase (including Creon®) increased CNA levels in EPI patients compared to placebo. Only one study compared PERT brands head-to-head: no significant differences were reported in the CNA-72 h values (Creon® 82.0% [SE: 1.2] vs. Zenpep® 80.9% [SE: 1.2]). Loss of body weight and low body mass index (BMI) are important features of EPI. Overall, treatment with PERT increased BMI and body weight, or limited their decline, with increases ranging from 0.1 to 6.1 kg. Based on the 18 studies that reported safety outcomes, PERT was considered safe and well tolerated.

Conclusions: This SLR confirmed that PERT is an effective and tolerable treatment option for patients with EPI. However, nutritional parameters and health-related quality of life data were sparsely reported, and future clinical trials should look to incorporate these data given their importance in clinical practice and patient outcomes.