Background:Benign portal vein thrombosis (PVT) presents considerable technical challenges for portal vein reconstruction (PVR) during liver transplantation (LT). This study aimed to evaluate the surgical outcomes, safety profile, and clinical feasibility of ectopic physiological portal vein reconstruction (EPPVR) at non-hilar area for patients with complex benign PVT. Methods:We conducted a retrospective observational cohort study analyzing intraoperative parameters, postoperative complications, and survival outcomes in liver transplant recipients with benign PVT. Among 120 enrolled patients, 10 cases (8.3%) underwent EPPVR, including three varicose vein reconstructions (VVRs), one anterior transpancreatic bridge reconstruction, and five "pull-out" portal vein reconstructions (POPVRs) beneath the pancreas. Results:Compared with conventional orthotopic physiological portal vein reconstruction (OPPVR), EPPVR was associated with significantly longer anhepatic phase (154.50±45.43 vs. 79.77±34.56 mins, P<0.001) and greater intraoperative blood loss (1,930.00±1,515.15 vs. 766.36±707.50 mL, P=0.001). Postoperatively, the EPPVR group demonstrated markedly higher rates of elevated ascitic fluid amylase (60.0% vs. 5.5%, P<0.001) and required more frequent portal vein stent implantation in surviving patients (37.5% vs. 3.9%, P=0.008). Other complication rates and perioperative survival rate were comparable between these two groups. The above trends remained consistent in the subgroup analysis of patients with Yerdel grade 2-4 PVT, although the difference in stent implantation rates lost statistical significance (37.5% vs. 10.3%, P=0.15). Conclusions:Although EPPVR was associated with elevated perioperative risks, it did not decrease the perioperative survival rate in PVT patients. This reconstruction approach may represent a feasible alternative for complex PVT cases requiring non-standard reconstruction approaches, contingent upon thorough preoperative assessment and surgical planning.
Background: In many clinical trials, the outcome variables are often binary (or categorical), and the main interest is to investigate any relationship between these categorical outcomes and intervention strategies for measuring the effect size and strength of association. The two frequently applied statistical methods used for this purpose are the relative risk (RR) and odds ratio (OR). The aim of this paper is to explore the fundamental concepts, definitions, computational methods, interpretations, differences, and lastly the relationship between RR and OR in the context of gastroesophageal reflux disease (GERD) following two bariatric (weight loss) procedures, namely laparoscopic vertical sleeve gastrectomy (LVSG) vs. laparoscopic Roux-en-Y gastric bypass (LRYGB). Methods: From January 2015 to March 2024, several electronic databases were searched for randomized controlled trials (RCTs) comparing LVSG and LRYGB and their effects on postoperative GERD at 5-year follow-up. Computation of OR and RR was undertaken to determine this impact, the differences in the effect size and strength of association between these two methods, and to demonstrate the differences between these two concepts. Results: Our analysis has demonstrated that GERD is far more common in patients' population following a LVSG compared to LRYGB. The RR for GERD is 4.96 times higher for the LVSG cohort compared to the LRYGB group. Similarly, the OR has revealed that the odds of GERD for LVSG patients is 6.4 times that of LRYGB patients at 5-year follow-up. Conclusions: Although both OR and RR have demonstrated a large effect size and strong association for GERD following LVSG compared to LRYGB, the OR strength of association is more convincing. The results suggest the primary use of OR is the right approach, as it is showing greater strength of association between exposure, i.e., LVSG, and outcome, i.e., GERD at 5-year follow-up in our analysis.
Background:Lymph node metastasis is a key determinant of prognosis and adjuvant treatment in rectal cancer and is currently staged according to the American Joint Committee on Cancer (AJCC) 8th edition pathological N (pN) classification, which is based solely on the number of metastatic lymph nodes. However, prognostic heterogeneity exists among patients within the same pN category, particularly when lymph node retrieval is inadequate. Alternative nodal metrics, including the lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS), have been proposed to improve risk stratification. Methods:This retrospective study included 170 patients with histologically confirmed rectal adenocarcinoma who underwent curative resection. Cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method, and differences among groups were assessed with the log-rank test. Multivariate Cox proportional hazards models were employed to identify independent prognostic factors. Model performance was evaluated using the area under the curve (AUC), Akaike information criterion (AIC), and chi-square trend and likelihood ratio tests. Results:All three classification systems-pN, LNR, and LODDS-were significantly associated with CSS (log-rank P<0.001 for all). In multivariable analysis, each nodal classification system was independently associated with CSS after adjustment for covariates. Among them, LNR showed the slightly higher discriminative ability, with the highest AUC at 3 years (0.664), followed by pN (AUC =0.662) and LODDS (AUC =0.603). Prognostic performance improved notably in patients with ≥12 lymph nodes retrieved. Conclusions:pN, LNR, and LODDS are independent prognostic indicators in rectal cancer. Among them, LNR demonstrates slightly higher prognostic performance and may serve as a more effective tool for risk stratification than the AJCC 8th edition pN classification or LODDS, particularly when lymph node retrieval is adequate.
Background: Gallbladder cancer (GBC) exhibits significant heterogeneity in postoperative prognosis, and the traditional tumor-nodes-metastasis (TNM) staging system has limitations in individualized survival prediction. This study aimed to develop and validate a nomogram integrating preoperative systemic status, ultrasonographic features, and postoperative pathological parameters for quantitatively predicting the overall survival (OS) of GBC patients after surgery, to aid clinical risk stratification and decision-making. Methods: Clinicopathological data of 61 GBC patients who underwent surgical treatment at Peking Union Medical College Hospital (PUMCH) between August 2008 and December 2022 were retrospectively collected. Univariate and multivariate Cox proportional hazards regression models were employed to screen for independent prognostic factors. The model was optimized based on the Akaike Information Criterion (AIC), and a nomogram for predicting 1-year, 3-year, and 5-year OS was constructed. Internal validation was performed using the Bootstrap method (500 resamples). The model's discrimination and calibration were comprehensively assessed using the concordance index (C-index), time-dependent receiver operating characteristic (ROC) curves, and calibration curves. The optimal cutoff value for the risk score was determined using the maximal selected rank statistics (MaxStat) method. Results: During the median follow-up period, 54.1% of patients died. Multivariate Cox regression analysis identified four independent adverse prognostic factors: elevated American Society of Anesthesiologists (ASA) classification [grade III vs. grade I: hazard ratio (HR) =9.68, 95% confidence interval (CI): 2.46-38.01, P=0.001], preoperative low serum albumin (Alb) (per 1 g/L decrease: HR =1.10, P=0.03), lymph node metastasis (N1/N2 vs. N0: HR =4.72, 95% CI: 1.90-11.74, P<0.001), and hyperechoic tumor appearance on ultrasonography (hyperechoic vs. hypoechoic: HR =7.69, 95% CI: 1.35-43.70, P=0.02). The nomogram constructed based on these factors demonstrated excellent discrimination (C-index =0.733). The area under the curve (AUC) values for predicting 1-year, 3-year, and 5-year survival rates were 0.882, 0.845, and 0.840, respectively. Calibration curves showed high agreement between predicted probabilities and actual observations. The risk stratification system divided patients into low-risk and high-risk groups, with the high-risk group having a median survival of only 14.5 months (P<0.001). Conclusions: The nomogram developed in this study innovatively integrates multidimensional indicators reflecting patients' physiological reserve (ASA classification), nutritional/immune status (Alb), and tumor biological behavior (ultrasonographic echogenicity, N stage). Notably, the discovery of "hyperechoic" appearance as an independent adverse prognostic imaging marker holds significant clinical implication. This model demonstrates high accuracy and strong practicality, effectively identifying high-risk postoperative populations and guiding individualized adjuvant therapy and follow-up strategies.
Background:Noninvasive liver disease assessment (NILDA) tools, such as the fibrosis-4 (FIB-4) index, are widely used to identify patients with metabolic dysfunction-associated steatotic liver disease (MASLD) at risk of advanced fibrosis (≥ F3). However, their predictive accuracy for fibrosis staging and long-term outcomes remains limited. This study aimed to develop and validate FibroX, an explainable machine learning-based model for improving the detection of advanced fibrosis and the prediction of long-term clinical outcomes in adults with MASLD. Methods:FibroX was developed using data from adults with MASLD (N=1,487) in the National Health and Nutrition Examination Survey (NHANES) 2017-2020. Fibrosis stage was determined using a two-step approach-initial NILDA screening followed by vibration-controlled transient elastography (TE)-in accordance with 2024 American Association for the Study of Liver Diseases guidance. The model was built using extreme gradient boosting (XGBoost), optimized at a 95% specificity threshold, and internally validated using 5-fold cross-validation. External validation was performed in two independent cohorts: 337 biopsy-confirmed MASLD patients and 4,276 participants from NHANES III with up to 30 years of mortality follow-up. Model interpretability was evaluated using SHapley Additive Explanations (SHAP). Results:In NHANES 2017-2020, FibroX demonstrated superior discrimination for advanced fibrosis compared with FIB-4 [area under the receiver operating characteristic curve (AUROC) 0.97 vs. 0.62; P<0.001]. In biopsy-confirmed MASLD patients, FibroX also outperformed FIB-4 (AUROC 0.84 vs. 0.82; P<0.001). In NHANES III, FibroX predicted all-cause mortality (C-statistic 0.80) and remained independently associated with cardiovascular mortality after adjustment for established risk factors [adjusted hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.01-1.47]. SHAP analysis identified platelet count, age, hemoglobin A1c, aspartate aminotransferase (AST), and estimated glomerular filtration rate (eGFR) as the most influential predictors. Conclusions:FibroX is a transparent and accurate machine learning model that improves detection of advanced fibrosis and prediction of long-term cardiovascular mortality compared with FIB-4. These findings support the use of explainable machine learning-based noninvasive tools for risk stratification and outcome prediction in patients with MASLD.
Background: Circulating tumor cells (CTCs) are pivotal in determining postoperative prognosis in periampullary carcinoma. However, the influence of preoperative biliary drainage (PBD) on CTC levels after pancreaticoduodenectomy (PD) remains unclear. Therefore, we explored the correlation of PBD with post-PD CTC changes in patients with resectable periampullary carcinoma and obstructive jaundice. Methods: We conducted a retrospective analysis of 125 patients with periampullary malignancies who underwent PD at Beijing Friendship Hospital, Capital Medical University, between June 2017 and October 2024. Participants were stratified into PBD and non-PBD (control) groups. Propensity score matching (PSM) was employed to balance baseline characteristics, followed by binary multivariate logistic regression. Multiple linear regression was further utilized to identify factors influencing postoperative CTC levels. Results: Serial CTC analysis demonstrated a significantly higher rate of postoperative CTC reduction in the PBD group compared to the control group (64.3% vs. 27.3%, P<0.001), along with a greater proportion of patients converting from CTC-positive to CTC-negative status (35.7% vs. 0%, P<0.001). Subgroup analysis revealed that antegrade drainage was superior to retrograde drainage in reducing postoperative bilirubin levels (P<0.05). Binary logistic regression confirmed PBD as an independent protective factor against postoperative CTC increase (P<0.01). Conclusions: PBD was significantly associated with postoperative positive-to-negative CTC conversion and lower postoperative CTC levels. These findings support the role of PBD as an independent protective factor against CTC elevation following surgery.
Background: The ratio of monocyte to apolipoprotein A1 (MAR) has emerged as a potential diagnostic marker for various chronic conditions, yet its utility in hepatocellular carcinoma (HCC) remains unexplored. This retrospective study aimed to evaluate the MAR's predictive capacity in HCC diagnosis and differentiation from hepatitis B virus (HBV) infection. Methods: A total of 1,350 participants were enrolled, including 270 HCC patients, 540 HBV patients, and 540 healthy controls. Hematological parameters including monocyte counts and apolipoprotein A1 levels were retrospectively collected from electronic medical records. Receiver operating characteristic (ROC) curve analysis was performed to determine optimal cut-off values and area under the curve (AUC). Multivariate logistic regression was used to identify independent predictor of HCC. Correlation analysis was conducted to explore associations between MAR and other clinical parameters. Results: MAR level was the highest in the HCC, followed by HBV group, and the lowest in the healthy controls (P<0.001). ROC analysis revealed MAR's discriminative capacity (AUC =0.829 for HCC vs. controls; AUC =0.762 for HCC vs. HBV). Multivariate analysis identified MAR as an independent HCC predictor [odds ratio (OR) =6.001, P<0.001]. Significant correlations emerged between MAR and lymphocytes (r=-0.075, P<0.05), carcinoembryonic antigen (r=0.171, P<0.001), and albumin (r=-0.445, P<0.001). Conclusions: MAR is a potential new indicator for differential diagnosis of HCC and HBV, and also an independent risk factor for HCC. The biomarker's dual reflection of inflammatory and metabolic pathways offers unique diagnostic value, warranting prospective validation.
Background: Microsatellite instability (MSI) is an important molecular subtype of colorectal cancer (CRC). However, the molecular characteristics of MSI in Chinese patients with CRC remain unclear. The aim of this study was to investigate the molecular characteristics of MSI in Chinese patients with CRC. Methods: A total of 14,239 individuals with CRC were analyzed using tumor tissue and plasma samples for single nucleotide variations (SNVs), insertion-deletions (Indels), copy number variations (CNVs), fusion, MSI, tumor mutational burden (TMB), Epstein-Barr virus (EBV), and homologous recombination deficiency (HRD) using next-generation sequencing (NGS). Results: The incidence rate of MSI was found to be 7.15%, and patients with microsatellite instability-high (MSI-H) tumors showed variations in age at diagnosis, tumor location, and sample type. TMB was significantly higher in patients with MSI-H tumors than in those with microsatellite stable tumors (MSS) (92.28 vs. 12.07 mutations/Mb, P<0.05), while HRD scores were lower (4.53 vs. 13.5, P<0.05). Additionally, EBV positivity was observed in 0.4% of all patients with CRC, but no patients with positive EBV were detected among those with MSI-H tumors. With regard to genetic mutations, ERBB2, PIK3CA, and BRAF were found to have significantly higher frequencies among patients with MSI-H tumors, whereas APC (51.26% vs. 70.76%, P<0.05), TP53 (27.76% vs. 69.54%, P<0.05), and NRAS (1.86% vs. 3.98%, P<0.05) had higher positive rates among those with MSS tumors. Due to limited germline and epigenetic data, MSI-H tumors could not be classified as Lynch-associated or sporadic. Conclusions: Overall, MSI-H and MSS CRCs in the Chinese population demonstrate distinct molecular landscapes in terms of TMB, HRD, EBV status, and driver gene alterations, underscoring the molecular heterogeneity of MSI-H CRC and the need for future studies integrating germline and epigenetic data to refine subtype classification.
Background:Familial adenomatous polyposis (FAP) is an inherited predisposition to colorectal cancer and characterized by profuse colorectal adenomas starting from the second decade of life. Regional (left vs. right) differences in the colonic microbiologic and immunologic microenvironment may impact adenoma evolution but are poorly understood. We aimed to characterize regional molecular, microbial, DNA damage, and immune differences in pediatric FAP polyps to test the hypothesis that polyps in pediatric FAP exhibit distinct regional and molecular features that contribute to differential growth and genomic instability. Methods:Colonic polyps and adjacent non-polyp mucosa were harvested from pediatric FAP patients undergoing colonoscopy. Tandem mass tag-based proteomic and phosphoproteomic profiling was performed and were followed by functional assays including colony formation, spheroid growth, and patient-derived organoid culture. γH2AX staining was used to quantify induction of DNA double-strand breaks (DSBs) in HCT116 colon cancer cells cultured in Fusobacterium nucleatum conditioned media (FnCM). Immunohistochemistry and immunofluorescence were used to assess ATR, CDK4, γH2AX, and oxidative damage (8-OxoG). Immune profiling was performed by flow cytometry, focusing on CD103+ tissue-resident memory T cells (TRMs). Results:Right-sided polyps exhibited increased ATR and CDK4 expression compared with left-sided lesions and adjacent mucosa. FnCM exposure induced a marked increase in γH2AX staining in HCT116 cells, consistent with our in vivo findings of elevated DSB burden in proximal versus distal FAP polyps. Biofilm enrichment and higher microbial staining were observed in right-sided lesions, whereas distal polyps were enriched with CD103+ TRM populations. Pharmacologic inhibition of ATR or CDK4 significantly suppressed both colony formation and spheroid growth. Organoids derived from proximal colon polyps exhibited accelerated growth and crypt budding, with higher expression of stemness markers (CD44, CD133, Lgr5, BMI-1) compared with distal polyps. Conclusions:Integrated proteomic, phosphoproteomic, and immune-microbiome profiling reveals regional heterogeneity of adenomas in pediatric FAP. Right compared to left sided polyps harbor greater DNA damage, elevated ATR/CDK4 kinase activity, reduced immune surveillance, and increased stem-like growth. These findings identify ATR and CDK4 as potential therapeutic targets and suggest that regional microenvironmental differences can impact chemoprevention strategies in pediatric FAP.
Background:In clinical practice, bilirubin levels are recognized as a crucial biochemical indicator closely associated with hepatobiliary function and the severity of biliary obstruction, and there is growing interest in exploring the potential correlation between varying preoperative bilirubin levels and clinical outcomes in patients with obstructive jaundice. Obstructive jaundice, characterized by impaired bile excretion and subsequent bilirubin accumulation, poses significant challenges to clinical treatment due to its heterogeneous etiologies and variable patient responses to intervention, highlighting the need for personalized therapeutic strategies based on key prognostic factors. This study conducted a single-center retrospective analysis to systematically investigate differences in patient clinical outcomes across different preoperative bilirubin levels. The aim of this study is to clarify the association between preoperative bilirubin stratification and postoperative recovery, complication rates, and long-term prognosis, thereby providing evidence-based support for establishing more rational, targeted, and individualized treatment strategies for patients with obstructive jaundice. Methods:Based on the level of bilirubin elevation before biliary drainage, patients were stratified into mild jaundice group (bilirubin <250 μmol/L) and severe jaundice group (bilirubin ≥250 μmol/L). Perioperative and prognostic outcomes were compared between the two groups. Categorical data were analyzed using the Chi-squared test, and continuous data that followed a normal distribution were analyzed using independent sample t-tests. Non-normally distributed data were analyzed using the Mann-Whitney U test. Survival analyses of overall survival (OS) and progression-free survival (PFS) was performed using the GraphPad Prism 9 software. P≤0.05 was considered statistically significant. Results:A total of 78 patients (55%) were included in the mild jaundice group and 63 patients (45%) in the severe jaundice group. There was a significant difference in the preferred drainage methods (P<0.001). Regarding surgical and postoperative complications, the proportion of vascular invasion was significantly higher in the severe jaundice group (50.8%) than in the mild jaundice group (33.3%) (P=0.04). However, no impact of vascular invasion on OS and PFS was found in subsequent studies. The OS rate was higher in the mild jaundice group than in the severe jaundice group (P=0.02), but multivariate Cox proportional hazards regression analysis failed to identify this difference as statistically significant. In contrast, patients with biliary tract or pancreatic tumors had significantly worse PFS than those with intestinal tumors (P=0.02), a finding that was confirmed by multivariate Cox proportional hazards regression analysis (P=0.044). Other indicators showed no significant differences (P>0.05). Conclusions:Patients with mild jaundice may have a better OS rate than those with severe jaundice; however, additional studies are required to validate this finding. Different preoperative biliary drainage (PBD) methods did not affect patients' short- or long-term outcomes, biliary tract and pancreatic tumors may be associated with more rapid relapse and progression.
Background: Gut microbiota plays a pivotal role in human homeostasis and health. This study adopted network pharmacology to clarify the metabolic transformation of gut microbiota metabolites and their molecular mechanisms in hepatocellular carcinoma (HCC) pathogenesis, aiming to unravel the complex crosstalk between gut microbiota, metabolites, and key genes. Methods: Gut microbiota metabolites and their associated genes were retrieved from the gutMGene database. Metabolite target genes were predicted using the SEA and STP databases, while HCC-related genes were compiled from GeneCards, OMIM, and CTD. Intersection analysis identified key genes mediating metabolite-regulated HCC progression. Core genes were screened via a protein-protein interaction (PPI) network, and comprehensive Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were further performed. A "microbiota-substrate-metabolite-target" network was constructed, and metabolites were evaluated for drug-likeness and toxicity to identify therapeutic candidates. Results: A total of 52 key genes involved in the gut microbiota-HCC interaction were screened, with IL6, TNF, and TP53 as hub genes. The Microbial Substrate Metabolite Target (M-S-M-T) network showed these hubs regulate HCC via 8 metabolites, 5 substrates, and 20 microorganisms. GO enrichment analysis indicated these key genes were mainly enriched in bacterial molecule response, membrane rafts, and DNAbinding transcription factor binding. KEGG enrichment analysis showed they were primarily associated with PI3K-Akt, MAPK, and Toll-like receptor signaling pathways. Three metabolites exhibited HCC therapeutic potential. Conclusions: Gut microbiota metabolites may exert regulatory effects on HCC mainly by targeting core genes. Targeting these genes in the regulatory network may offer a novel multidimensional therapeutic approach for HCC, and the identified metabolites could act as potential therapeutic candidates for HCC.
Background: Accurate and efficient detection of internal openings (IO) of anal fistulas (AF) in endorectal ultrasound (ERUS) images is crucial for diagnosis and treatment planning. This study aimed to develop an artificial intelligence (AI) system to automatically identify these anatomical landmarks in real time, thereby improving diagnostic efficiency. Methods: An AI system based on the YOLOv11 architecture (YOLOv11n model) was constructed. The model was trained and evaluated using a dataset consisting of 238 ERUS cases from The Fifth People's Hospital of Chengdu. The system's performance was assessed using conventional object detection metrics, including precision, recall, and mean average precision (mAP) at various intersection-over-union (IoU) thresholds. Results: The proposed YOLOv11n model demonstrated excellent performance in detecting IO of AF. The results showed precision of 0.925, recall of 1.0, mAP of 0.99 at an IoU threshold of 0.5, and mAP of 0.602 across IoU thresholds from 0.50 to 0.95. These findings highlight the model's robustness, reliability, and accuracy in rapidly analyzing ERUS images. Conclusions: Utilizing the YOLOv11 architecture, this AI system enables real-time, precise identification of IO of AF in ERUS images, significantly enhancing diagnostic efficiency. The system's outstanding performance offers potential for standardized training for radiologists and colorectal surgeons, effectively integrating AI advancements with clinical educational needs.
Background:Pancreaticoduodenectomy (PD), as a challenging surgical procedure, is associated with considerable morbidity and mortality rates. Currently, the impact of preoperative biliary drainage (PBD) on the surgical risk of PD remains controversial. Therefore, we conducted a retrospective cohort study to analyze factors influencing the surgical risk of PD and to evaluate the role of biliary drainage therein. Methods:A retrospective analysis was performed on the clinical data of 354 patients with periampullary malignancies who underwent PD at Beijing Friendship Hospital, Capital Medical University, between June 2017 and October 2022. Through comprehensive scoring based on surgical approach, operative time, and intraoperative blood loss, we derived surgical risk scores and stratified patients into high-risk and low-risk groups. Variables including patient history, preoperative procedures, and laboratory and imaging findings were included in least absolute shrinkage and selection operator (LASSO) regression to identify variables at the optimal lambda value. These variables were then incorporated into binary multivariate logistic regression to analyze factors influencing the surgical risk of PD. Furthermore, we analyzed influencing factors specifically in patients who underwent PBD to identify risk factors affecting surgical risk in this subgroup. Results:A total of 354 patients were included in this study, with 195 cases stratified into the low-risk group and 159 cases assigned to the high-risk group. Among all 354 enrolled patients, 184 did not undergo PBD, while 170 underwent PBD. Analysis revealed that the biliary drainage group had a higher surgical risk compared to the non-drainage group [odds ratio (OR): 1.615; 95% confidence interval (CI): 1.020-2.556, P=0.04]. Further analysis of the impact of different biliary drainage methods on surgical difficulty showed that, among patients who underwent PBD, retrograde drainage was a risk factor for surgical risk (OR: 2.032; 95% CI: 1.016-4.064, P=0.045). Conclusions:PBD was identified as an independent risk factor for elevated surgical risk in PD. Among patients undergoing biliary drainage, retrograde drainage, compared to antegrade drainage, is an independent risk factor for surgical risk.
The KRAS G12D mutation, defined by substitution of glycine with aspartic acid at codon 12 within the GTP-binding region of the KRAS gene, occurs with particularly high prevalence in digestive system malignancies, especially pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). Oncogenic KRAS variants drive persistent activation of downstream signaling cascades, including the MAPK and PI3K pathways, thereby circumventing upstream regulation and fueling tumor initiation, progression, and therapeutic resistance. Because of its high intrinsic affinity for GTP/GDP and the lack of a readily accessible binding pocket, KRAS was long considered a difficult therapeutic target. The emergence of MRTX1133, a highly selective, noncovalent inhibitor that specifically binds the Switch II pocket of KRAS G12D, represents a major advance in precision oncology. By engaging this unique pocket, MRTX1133 effectively blocks effector interactions and potently suppresses MAPK and PI3K signaling. Preclinical investigations have revealed that MRTX1133 elicits strong antitumor responses in KRAS G12D mutant PDAC and CRC models, including pronounced tumor regression, enhanced apoptosis, and inhibition of metastatic features. Nonetheless, as observed with other targeted agents, resistance can arise through feedback activation of receptor tyrosine kinases, reactivation of parallel signaling pathways, metabolic reprogramming, and tumor microenvironmental influences. These findings underscore the importance of combination therapeutic approaches in overcoming resistance. This review summarizes current evidence on the mechanisms of action, resistance pathways, and potential combination strategies of MRTX1133 in digestive system cancers, and discusses its translational relevance and clinical implications for KRAS G12D mutant malignancies.
Background:Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of United States (USA) cancer death. Overweight and obesity developing into a growing global medical and socio-economic problem, affecting approximately 42% of adults in the USA population. The aim of our analysis was to evaluate the influence of overweight and obesity on complications and clinical outcome in patients with stage IV PDAC. Methods:We retrospectively reviewed electronic health records of patients diagnosed with stage IV PDAC (n=162) who followed with the University of Kentucky from January 2017-October 2024. Comparisons were based on the body mass index (BMI): low BMI (BMI <25 kg/m2) vs. high BMI (BMI ≥25 kg/m2). Associations between groups were analysed by Chi Square method, t-tests, and if needed, Fischer exact test. Results:Smoking status showed significant higher current and former smokers in the high BMI group (P=0.005). No significant difference was seen for lab parameter. Hypertension was the most frequent comorbidity (n=101). Type 2 diabetes was significantly more prevalent in the high BMI group (55.8% vs. 38.2%; P=0.03). FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) therapy was more frequent in the high BMI group (44.2% vs. 34.2%). No significant differences were observed between the groups in terms of chemotherapy lines or complications, including thrombosis, infection, endoscopic interventions and gastrointestinal (GI) bleeding. No difference for mortality was observed. Conclusions:Our data clearly show that neither higher nor lower BMI is a contraindication for systemic chemotherapy of stage IV PDAC. Complications and mortality were not different between the groups. However, hospice referrals were more frequent in patients with low BMI, which may be from cognitive biases due to the more cachectic appearing phenotype.
Background:Video capsule endoscopy (VCE) is a noninvasive modality in the assessment among patients with very early onset inflammatory bowel disease (VEOIBD). Little is known about the application of VCE in this rare disorder. The aim of this study is to evaluate the features of patients with VEOIBD undergoing VCE. Methods:We retrospectively reviewed 37 VEOIBD patients who underwent VCE from five tertiary centers. Clinical data, including endoscopic findings and treatment were retrieved from medical records. Next generation sequencing was performed to confirm the monogenic defects. Results:During a decade, a total of 37 VEOIBD patients were retrospectively included from 5 specialist centers. The total number of VCE procedures performed was 58. The VCE was performed at an average age of 7.8±3.2 years. Twelve patients had undergone follow-up VCE. Next-generation sequencing confirmed the known monogenic inflammatory bowel disease (IBD) in 18 patients. Multiple ulcers, erosions and pseudo-polyps have been identified among patients with TNFAIP3, XIAP and PIK3CD mutations. No adverse effect including capsule retention or endoscopic delivery procedures related adverse effects were reported. Eighteen patients (48.6%) achieved clinical remission. Conclusions:This multicenter study showed the features of small bowel lesions among VEOIBD by VCE. Safety of VCE in VEOIBD patients have also been demonstrated.
Background:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic syndrome characterized by increased fat storage in hepatocytes. In the hepatocytes, autophagy protects against cytotoxic stress and harmful cellular conditions. In the hepatic stellate cells (HSCs), autophagy exerts pro-fibrotic properties and promotes the release of pro-inflammatory metabolites. We investigated the modulation of autophagy as a therapeutic approach for MASLD. Methods:Murine liver tissue and human hepatic cells were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot. Real time fluorescence was performed to monitor the autophagy maturation process. Accumulation of fat was detected by Oil Red O staining. Collagen fibers were detected by picrosirius staining under polarized light. Results:The loss of leptin in obese mice affected by metabolic dysfunction-associated steatohepatitis (MASH) promoted the over-expression of Becn1, Map1lc3b, Sqstm1, Uvrag and Prkaa1_2 and the accumulation of their proteins. The oleic acid caused an accumulation of fat, followed by the reduction of the autophagy proteins and the increase of the P-AMPK-α in LEP-/- HepG2 cells and the maturation of autophagosome vesicles in LEP-/- Hep3B cells. Oleic acid increased the accumulation of fat in human HSCs and the COL1A1 transcript level, but not the collagen I fibers. BECN1 and MAP1LC3B were up-regulated. Instead, all the autophagy proteins were downregulated, but not P-AMPK-α. Instead, the treatment with caffeine prompted neither the transactivation nor the autophagy. Conclusions:Leptin loss contributes to the autophagy process in obese mice. The administration of oleic acid in LEP-/- cells prompted autophagy not only in hepatocyte-like cells but also in human HSCs.
Background:Esophageal variceal bleeding (EVB) is a common gastrointestinal (GI) emergency associated with a high risk of morbidity and mortality. Esophageal varices are a result of portal hypertension, commonly caused by cirrhosis. When these varices rupture, they cause rapid exsanguination if not intervened on quickly. Hospital admissions during the weekend are associated with worse outcomes in many categories of emergent GI pathology, including upper GI hemorrhage. However, the relationship between weekend admission and hospital outcomes for EVB patients remains controversial. Our study aims to investigate this potential disparity further using a large nationwide sample. Methods:The National Inpatient Sample (NIS) [2008-2020] was used, patients over 18 with a primary EVB diagnosis using ICD-9/10 codes were selected. Patients were grouped by weekend or weekday admission. Baseline characteristics (age, gender, race, insurance, comorbidities) were compared. Outcomes included mortality, shock, acute myocardial infarction (AMI), acute kidney injury (AKI), composite outcome, length of stay (LOS), hospital charges, endoscopy/TIPS performance, and procedure timeliness. Weighted logistic regression calculated odds ratios (ORs), adjusted for age, gender, race, hospital characteristics, region, and Charlson Comorbidity Index (CCI). Results:Of 322,155 EVB patients, 82,293 were weekend admissions, and 239,862 were weekday admissions. Baseline characteristics [age (P=0.07), gender (P=0.71), race (P>0.05), insurance (P>0.05)) were similar. Patients admitted on weekends had lower rates of anemia but higher smoking (P=0.005), alcohol use disorder (P=0.002), more medically complex (CCI 5.30 vs. 5.25, P=0.03). The two groups had similar rates of mortality (P=0.14), AMI (P=0.18), and AKI (P=0.14). Weekends had higher odds of shock (OR 1.14, CI 1.08-1.21, P<0.001) and composite outcome (OR 1.08, CI 1.04-1.13, P<0.001). Weekends had lower odds of receiving an endoscopic intervention on hospital day 0 [OR 0.90, 95% confidence interval (CI) 0.86-0.94, P<0.001) or TIPS before day four (OR 0.778, 95% CI 0.65-0.94, P=0.009). The following outcomes of mortality (OR 0.962, 95% CI: 0.867-1.068, P=0.47), AMI (OR 1.214, 95% CI: 0.983-1.499, P=0.07), AKI (OR 1.03, 95% CI: 0.975-1.089, P=0.29), composite (OR 1.034, 95% CI: 0.982-1.089, P=0.20), endoscopy (OR 1.015, 95% CI: 0.960-1.073, P=0.60), and total charges (OR 1,102, 95% CI: -89,717 to 2,295.41, P=0.07) between the two groups. Conclusions:The increased risk of shock in these patients, but no difference in hospital mortality, could be explained by the lower odds of having an endoscopy done on the day of admission and TIPS before day four, compared to patients admitted on weekdays. Thus, more research is needed to determine how the weekend effect can be mitigated in admitted EVB patients.
Background:Steatotic liver disease (SLD) is prevalent among women with breast cancer, but the influence of hormonotherapy on its severity and progression remains uncertain. This study evaluated the prevalence, severity, and predictors of SLD in relation to hormone therapy. Methods:In this cross-sectional study, women with breast cancer were stratified by endocrine therapy exposure and evaluated with liver transient elastography and ultrasound. A subset of patients exposed to hormone therapy was prospectively followed for approximately 24 months to assess changes in liver stiffness over time. Results:Among 171 women [mean age 58±10 years; median follow-up 53 months (range, 1-315 months)], comorbidities included diabetes (26.9%), hypertension (53.2%), dyslipidemia (31.0%), and obesity (70.2%). Patients were divided into four groups: no hormone therapy (n=55, 32.2%), tamoxifen only (n=72, 42.1%), anastrozole only (n=16, 9.4%), and both drugs (n=28, 16.4%). SLD was present in 57.9% of participants, with no significant differences in steatosis prevalence (P=0.09) or liver stiffness (P=0.20) across groups. Liver stiffness ≥8 kPa occurred in 12.3%, and stiffness ≥12 kPa in 5.8%. Diabetes was independently associated with steatosis, and metabolic syndrome with advanced fibrosis, regardless of hormone therapy duration. Among 35 patients in the prospective sub-cohort, no significant changes in liver stiffness were detected after 24 months of continuous endocrine therapy. Conclusions:Over half of the participants had SLD, with advanced fibrosis in ~10%. Metabolic factors were independently associated with SLD development and progression, regardless of hormone therapy exposure. Patients in continuous use of endocrine therapy had no dynamic changes in liver stiffness after 24 months of follow-up.
Background:Polypoid lesions of the gallbladder (PLGs) are common lesions that can be classified as either nonneoplastic or neoplastic polyps. Surgical resection is recommended for neoplastic polyps, and accurate preoperative identification of neoplastic polyps is needed to guide appropriate management. However, accurately distinguishing neoplastic polyps remains challenging. Therefore, the aim of this study is to establish a preoperative prediction model for neoplastic polyps on the basis of a convolutional neural network (CNN) model using ultrasound images and evaluate its reliability. Methods:This was a multicentre retrospective study. All included cases were divided into a training set, an internal test set, and an external test set. A CNN model was established using the Inception-V3 model, and the ultrasound images from the training set were input into the CNN for feature processing. The internal and external test set images were subsequently used to assess the predictive performance of the CNN model, which was then compared with the diagnostic performance of three sonographers with different levels of experience and an ultrasound feature-based nomogram model. Results:A total of 380 cases (921 images in total) were retrospectively collected, with 194 cases in the training set (547 images in total), 83 cases in the internal test set (234 images in total), and 103 cases in the external test set (140 images in total). The areas under the curves (AUCs) of the CNN model were 0.896 and 0.852 in the internal and external test sets, respectively. In addition, the CNN model outperformed the three sonographers with varying levels of experience (AUC =0.687, 0.703, and 0.803, respectively), but was comparable to the nomogram model (AUC =0.880) in terms of diagnostic efficacy. Conclusions:The CNN model, which is based on ultrasound images, has demonstrated relatively good predictive performance in preoperatively identifying neoplastic polyps and is highly important for assisting in the selection of treatment methods for PLG patients.
