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Cell Communication and Signaling : CCS Mar 2024Tryptophan (Trp) metabolism plays a crucial role in influencing the development of digestive system tumors. Dysregulation of Trp and its metabolites has been identified... (Review)
Review
Tryptophan (Trp) metabolism plays a crucial role in influencing the development of digestive system tumors. Dysregulation of Trp and its metabolites has been identified in various digestive system cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers. Aberrantly expressed Trp metabolites are associated with diverse clinical features in digestive system tumors. Moreover, the levels of these metabolites can serve as prognostic indicators and predictors of recurrence risk in patients with digestive system tumors. Trp metabolites exert their influence on tumor growth and metastasis through multiple mechanisms, including immune evasion, angiogenesis promotion, and drug resistance enhancement. Suppressing the expression of key enzymes in Trp metabolism can reduce the accumulation of these metabolites, effectively impacting their role in the promotion of tumor progression and metastasis. Strategies targeting Trp metabolism through specific enzyme inhibitors or tailored drugs exhibit considerable promise in enhancing therapeutic outcomes for digestive system tumors. In addition, integrating these approaches with immunotherapy holds the potential to further enhance treatment efficacy.
Topics: Humans; Tryptophan; Gastrointestinal Neoplasms; Liver
PubMed: 38462620
DOI: 10.1186/s12964-024-01552-7 -
Journal of Pediatric Gastroenterology... Dec 2023The objective of this study was to evaluate the efficacy and safety of budesonide oral suspension (BOS) in adolescents with eosinophilic esophagitis (EoE).
OBJECTIVES
The objective of this study was to evaluate the efficacy and safety of budesonide oral suspension (BOS) in adolescents with eosinophilic esophagitis (EoE).
METHODS
This post hoc analysis pooled data from two 12-week, randomized, double-blind, placebo-controlled studies of BOS 2.0 mg twice daily (b.i.d.) (phase 2, NCT01642212; phase 3, NCT02605837) in patients aged 11-17 years with EoE and dysphagia. Efficacy endpoints included histologic (≤6, ≤1, and <15 eosinophils per high-power field [eos/hpf]), dysphagia symptom (≥30% reduction in Dysphagia Symptom Questionnaire [DSQ] scores from baseline), and clinicopathologic (≤6 eos/hpf and ≥30% reduction in DSQ scores from baseline) responses at week 12. Change from baseline to week 12 in peak eosinophil counts, DSQ scores, EoE Histology Scoring System (EoEHSS) grade (severity) and stage (extent) total score ratios (TSRs), and total EoE Endoscopic Reference Scores (EREFS) were assessed. Safety outcomes were also examined.
RESULTS
Overall, 76 adolescents were included (BOS, n = 45; placebo, n = 31). Significantly more patients who received BOS than placebo achieved histologic responses (≤6 eos/hpf: 46.7% vs 6.5%; ≤1 eos/hpf: 42.2% vs 0.0%; <15 eos/hpf: 53.3% vs 9.7%; P < 0.001) and a clinicopathologic response (31.1% vs 3.2%; P = 0.003) at week 12. More BOS-treated than placebo-treated patients achieved a dysphagia symptom response at week 12 (68.9% vs 58.1%; not statistically significant P = 0.314). BOS-treated patients had significantly greater reductions in EoEHSS grade and stage TSRs ( P < 0.001) and total EREFS ( P = 0.021) from baseline to week 12 than placebo-treated patients. BOS was well tolerated, with no clinically meaningful differences in adverse events versus placebo.
CONCLUSIONS
BOS 2.0 mg b.i.d. significantly improved most efficacy outcomes in adolescents with EoE versus placebo.
Topics: Adolescent; Humans; Budesonide; Deglutition Disorders; Eosinophilic Esophagitis; Esophagoscopy; Suspensions; Treatment Outcome; Child; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic
PubMed: 37718471
DOI: 10.1097/MPG.0000000000003948 -
Cardiovascular and Interventional... Sep 2023The purpose of the study was to investigate outcome after pediatric transjugular intrahepatic portosystemic shunt (TIPS) with respect to survival MATERIAL AND METHODS:... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The purpose of the study was to investigate outcome after pediatric transjugular intrahepatic portosystemic shunt (TIPS) with respect to survival MATERIAL AND METHODS: After searching for studies on TIPS in children in Ovid, Medline, Embase, Scopus and Cochrane published between 2000 and 2022, individual patient data were retrieved from five retrospective cohorts. Overall survival (OS) and transplant-free survival (TFS) were calculated using Kaplan-Meier analysis and log-rank test and compared to the indication (ascites vs. variceal bleeding) as well as to the level of obstruction (pre-hepatic vs. hepatic vs. post-hepatic). Additionally, TIPS patency was analyzed.
RESULTS
n = 135 pediatric patients were included in the final analysis. Indication for pediatric TIPS creation was heterogeneous among the included studies. TIPS patency decreased from 6 to 24 months, subsequent pediatric liver transplantation was performed in 22/135 (16.3%) of cases. The presence of ascites was related with poorer TFS (HR 2.3, p = 0.023), while variceal bleeding was not associated with impaired survival. Analysis of the level of obstruction (pre-hepatic, hepatic and post-hepatic) failed to prove significantly reduced OS for post-hepatic obstruction (HR 3.2, p = 0.092) and TFS (HR 1.3, p = 0.057). There was no difference in OS and TFS according to age at time of TIPS placement.
CONCLUSIONS
The presence of ascites associates with impaired survival after TIPS in children, with no differences in survival according to the age of the child. Interventional shunt procedures can be considered feasible for all ages.
LEVEL OF EVIDENCE
Level 2a.
Topics: Humans; Child; Hypertension, Portal; Portasystemic Shunt, Transjugular Intrahepatic; Treatment Outcome; Retrospective Studies; Ascites; Hepatic Encephalopathy; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Liver Cirrhosis
PubMed: 37532945
DOI: 10.1007/s00270-023-03520-z -
Lipids in Health and Disease Feb 2024The roles of serum lipids on digestive system cancer (DSC) risk were still inconclusive. In this study, we systematically assessed indicative effects of signature...
Appraising associations between signature lipidomic biomarkers and digestive system cancer risk: novel evidences from a prospective cohort study of UK Biobank and Mendelian randomization analyses.
BACKGROUND
The roles of serum lipids on digestive system cancer (DSC) risk were still inconclusive. In this study, we systematically assessed indicative effects of signature lipidomic biomarkers (high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG)) on DSC (oesophagus, stomach, colorectal, liver, gallbladder, and pancreas cancers) risk.
METHODS
HDL-C, LDL-C, and TG concentration measurements were respectively analyzed with enzyme immunoinhibition, enzymatic selective protection, and GPO-POD methods in AU5800 supplied from Beckman Coulter. The diagnoses of DSCs were coded using International Classification of Diseases, Tenth Revision (ICD-10) codes updated until October 2022 in the UK Biobank (UKB). In this study, we assessed phenotypic association patterns between signature lipidomic biomarkers and DSC risk using restricted cubic splines (RCSs) in multivariable-adjusted Cox proportional hazards regression models. Moreover, linear and nonlinear causal association patterns of signature lipidomic biomarkers with DSC risk were determined by linear and nonlinear Mendelian randomization (MR) analyses.
RESULTS
A median follow-up time of 11.8 years was recorded for 319,568 participants including 6916 DSC cases. A suggestive independent nonlinear phenotypic association was observed between LDL-C concentration and stomach cancer risk (P < 0.05, P < 0.05). Meanwhile, a remarkable independent linear negative phenotypic association was demonstrated between HDL-C concentration and stomach cancer risk (P > 0.05, P < 0.008 (0.05/6 outcomes, Bonferroni-adjusted P)), and suggestive independent linear positive associations were observed between HDL-C concentration and colorectal cancer risk, and between TG concentration and gallbladder cancer risk (P > 0.05, P < 0.05). Furthermore, based on nonlinear and linear MR-based evidences, we observed an suggestive independent negative causal association (hazard ratio (HR) per 1 mmol/L increase: 0.340 (0.137-0.843), P = 0.020) between LDL-C and stomach cancer risk without a nonlinear pattern (Quadratic P = 0.901, Cochran Q P = 0.434). Meanwhile, subgroup and stratified MR analyses both supported the category of LDL-C ≥ 4.1 mmol/L was suggestively protective against stomach cancer risk, especially among female participants (HR: 0.789 (0.637-0.977), P = 0.030) and participants aged 60 years or older (HR: 0.786 (0.638-0.969), P = 0.024), and the category of TG ≥ 2.2 mmol/L concluded to be a suggestive risk factor for gallbladder cancer risk in male participants (HR: 1.447 (1.020-2.052), P = 0.038) and participants aged 60 years or older (HR: 1.264 (1.003-1.593), P = 0.047).
CONCLUSIONS
Our findings confirmed indicative roles of signature lipidomic biomarkers on DSC risk, notably detecting suggestive evidences for a protective effect of high LDL-C concentration on stomach cancer risk, and a detrimental effect of high TG concentration on gallbladder cancer risk among given participants.
Topics: Humans; Male; Female; Cholesterol, LDL; Prospective Studies; Mendelian Randomization Analysis; Gallbladder Neoplasms; Stomach Neoplasms; UK Biobank; Biological Specimen Banks; Lipidomics; Risk Factors; Triglycerides; Cholesterol, HDL; Biomarkers
PubMed: 38419059
DOI: 10.1186/s12944-024-02053-9 -
The Turkish Journal of Gastroenterology... Nov 2023Autoimmune hepatitis (AIH) is a rare, immune-mediated liver disease. It has a heterogeneous nature with varied clinical presentations. The management of patients with...
Diagnosis and Treatment of Autoimmune Hepatitis: Questions, Answers, and Illustrative Cases: Endorsed by Autoimmune Liver Diseases Special Interest Group, Turkish Association for the Study of Liver.
Autoimmune hepatitis (AIH) is a rare, immune-mediated liver disease. It has a heterogeneous nature with varied clinical presentations. The management of patients with AIH is challenging in many ways. The main difficulties are inexperience due to the rarity of the disease, diagnostic confusion in controversial areas such as variant/overlap cases, acute presentations, the presence of non-alcoholic fatty liver disease or drug-induced liver injury features, and the long and complex course of treatment. Here, we provide a clear, concise, and visualized review regarding the diagnosis and treatment of AIH, including illustrative cases.
Topics: Humans; Hepatitis, Autoimmune; Public Opinion; Liver Diseases; Chemical and Drug Induced Liver Injury
PubMed: 37947207
DOI: 10.5152/tjg.2023.23242 -
Clinical Nutrition (Edinburgh, Scotland) Apr 2024Albumin is a relatively small molecule with a radius of 7.5 nm and a molecular weight of 65 kDa. It is the most abundant protein in plasma, accounting for 60-75% of...
Albumin is a relatively small molecule with a radius of 7.5 nm and a molecular weight of 65 kDa. It is the most abundant protein in plasma, accounting for 60-75% of its oncotic pressure. Its concentration in plasma is merely one static measurement reflecting a dynamic and complex system of albumin physiology, and is the net result of several different processes, one or more of which may become deranged by disease or its treatment. It is also unsurprising that hypoalbuminaemia has proved to be an indicator of morbidity and mortality risk since the underlying conditions which cause it, including protein energy malnutrition, crystalloid overload, inflammation, and liver dysfunction are themselves risk factors. In some cases, its underlying cause may require treatment but mostly it is just a parameter to be monitored and used as one measure of clinical progress or deterioration. While malnutrition, associated with a low protein intake, may be a contributory cause of hypoalbuminaemia, in the absence of inflammation and/or dilution with crystalloid its development in response to malnutrition alone is slow compared with the rapid change caused by inflammatory redistribution or dilution with crystalloids. Other significant causes include liver dysfunction and serous losses. These causal factors may occur singly or in combination in any particular case. Treatment is that of the underlying causes and associated conditions such as a low plasma volume, not of hypoalbuminaemia per se.
Topics: Humans; Hypoalbuminemia; Clinical Relevance; Albumins; Inflammation; Malnutrition; Crystalloid Solutions; Liver Diseases
PubMed: 38394971
DOI: 10.1016/j.clnu.2024.02.018 -
Gastroenterology Sep 2023At least 20%-30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure-associated liver disease (IFALD), for which...
BACKGROUND & AIMS
At least 20%-30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure-associated liver disease (IFALD), for which there are few therapeutic options. SEFA-6179 is a first-in-class structurally engineered medium-chain fatty acid analogue that acts through GPR84, PPARα, and PPARγ agonism. We hypothesized that SEFA-6179 would prevent biochemical and histologic liver injury in a preterm piglet model of IFALD.
METHODS
Preterm Yorkshire piglets were delivered by cesarean section, and parenteral nutrition was provided for 14 days via implanted central venous catheters. Animals were treated with either medium-chain triglyceride vehicle control or SEFA-6179.
RESULTS
Compared to medium-chain triglyceride vehicle at day of life 15, SEFA-6179 prevented biochemical cholestasis (direct bilirubin: 1.9 vs <0.2 mg/dL, P = .01; total bilirubin: 2.7 vs 0.4 mg/dL, P = .02; gamma glutamyl transferase: 172 vs 30 U/L, P = .01). SEFA-6179 also prevented steatosis (45.6 vs 13.9 mg triglycerides/g liver tissue, P = .009), reduced bile duct proliferation (1.6% vs 0.5% area cytokeratin 7 positive, P = .009), and reduced fibrosis assessed by a masked pathologist (median Ishak score: 3 vs 1, P = 0.007). RNA sequencing of liver tissue demonstrated that SEFA-6179 broadly impacted inflammatory, metabolic, and fibrotic pathways, consistent with its in vitro receptor activity (GPR84/PPARα/PPARγ agonist).
CONCLUSIONS
In a preterm piglet model of IFALD, SEFA-6179 treatment prevented biochemical cholestasis and steatosis and reduced bile duct proliferation and fibrosis. SEFA-6179 is a promising first-in-class therapy for the prevention and treatment of IFALD that will be investigated in an upcoming phase II clinical trial.
Topics: Pregnancy; Animals; Female; Swine; Intestinal Failure; Cesarean Section; PPAR alpha; PPAR gamma; Liver; Liver Diseases; Intestinal Diseases; Cholestasis; Liver Failure; Bilirubin; Fatty Acids; Fibrosis; Triglycerides
PubMed: 37263310
DOI: 10.1053/j.gastro.2023.05.035 -
Biomedicine & Pharmacotherapy =... Jan 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide. Its occurrence and progression involve the process... (Review)
Review
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide. Its occurrence and progression involve the process from simple hepatic steatosis to metabolic dysfunction associated steatohepatitis (MASH), which could develop into advanced liver fibrosis, cirrhosis, or hepatocellular carcinoma (HCC). Growing evidences support that the pathogenesis and progression of MASLD are closely related to immune system dysfunction. This review aims to summarize the association of MASLD with immune disorders and the prospect of using immunotherapy for MASLD.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Metabolic Diseases; Fatty Liver; Liver Cirrhosis
PubMed: 38147736
DOI: 10.1016/j.biopha.2023.116069 -
Revista de Gastroenterologia de Mexico... 2024Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized advanced cancer management. Nevertheless, the generalized use of these medications has led to... (Review)
Review
Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized advanced cancer management. Nevertheless, the generalized use of these medications has led to an increase in the incidence of adverse immune-mediated events and the liver is one of the most frequently affected organs. Liver involvement associated with the administration of immunotherapy is known as immune-mediated hepatitis (IMH), whose incidence and clinical characteristics have been described by different authors. It often presents as mild elevations of amino transferase levels, seen in routine blood tests, that spontaneously return to normal, but it can also manifest as severe transaminitis, possibly leading to the permanent discontinuation of treatment. The aim of the following review was to describe the most up-to-date concepts regarding the epidemiology, diagnosis, risk factors, and progression of IMH, as well as its incidence in different types of common cancers, including hepatocellular carcinoma. Treatment recommendations according to the most current guidelines are also provided.
Topics: Humans; Hepatitis; Carcinoma, Hepatocellular; Immunotherapy; Hepatitis A; Liver Neoplasms
PubMed: 38485561
DOI: 10.1016/j.rgmxen.2023.12.001 -
Digestive and Liver Disease : Official... Apr 2024The systemic treatment of hepatocellular carcinoma (HCC) is changing rapidly. After a decade of tyrosine kinase inhibitors (TKIs), as the only therapeutic option for the... (Review)
Review
The systemic treatment of hepatocellular carcinoma (HCC) is changing rapidly. After a decade of tyrosine kinase inhibitors (TKIs), as the only therapeutic option for the treatment of advanced HCC, in the last few years several phase III trials demonstrated the efficacy of immune checkpoint inhibitors (ICIs). The combination of the anti-PD-L1 atezolizumab and the anti-vascular endothelial growth factor (VEGF) bevacizumab demonstrated the superiority over sorafenib and currently represents the standard of care treatment for advanced HCC. In addition, the combination of durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) proved to be superior to sorafenib, and in the same trial durvalumab monotherapy showed non-inferiority compared to sorafenib. However, early reports suggest an influence of HCC etiology in modulating the response to these drugs. In particular, a lower effectiveness of ICIs has been suggested in patients with non-viral HCC (in particular non-alcoholic fatty liver disease). Nevertheless, randomized controlled trials available to date have not been stratified for etiology and data suggesting a possible impact of etiology in the outcome of patients managed with ICIs derive from subgroup not pre-specified analyses. In this review, we aim to examine the potential impact of HCC etiology on the response to immunotherapy regimens for HCC.
Topics: Humans; Carcinoma, Hepatocellular; Sorafenib; Liver Neoplasms; Digestive System Diseases; Immunotherapy
PubMed: 37758610
DOI: 10.1016/j.dld.2023.08.062