Gallbladder and biliary tract cancer (GBTC) presents a worldwide health challenge with a poor prognosis. Previous studies indicated an escalating burden and potential health inequalities, necessitating an updated investigation.

This study utilized data from the Global Burden of Disease (GBD) study, covering 204 countries from 1990 to 2021. Joinpoint regression evaluated temporal trends in age-standardized incidence rates (ASIR) and age-standardized disability-adjusted life years rates (ASDR) for GBTC. The Bayesian age-period-cohort (BAPC) model projected disease burden up to 2050. Inequality analysis assessed disparities by genders across countries, and decomposition analysis determined the contributions of demographic and epidemiological factors.

From 1990 to 2021, the incident cases of GBTC increased from 107,797 to 216,768, while Disability-Adjusted Life Years (DALYs) rose from 2,326,089 years to 3,732,121. Joinpoint regression analysis revealed a global decrease in ASIR (AAPC = -0.39, 95% CI: -0.49 to -0.28) and ASDR (AAPC = -0.97, 95% CI: -1.07 to -0.88). Gender disparities were notable, with a polar reversal observed: females exhibited consistently higher ASDR levels across three decades, although both ASDR and ASIR showed continuous decreases. In contrast, males experienced a decreased ASDR but increased ASIR, with both metrics eventually surpassing those of females. The projection model also suggested diverging ASIR trends between genders. Cross-country inequality analysis revealed persistent disparities, where higher SDI countries continue to bear a greater burden, and global improvement in health equity for males remains insufficient. Decomposition analysis indicated that population growth and ageing were primary drivers of disease burden increase, whereas epidemiological changes contributed to a reduction, particularly in higher SDI quintiles.

Despite improvements, GBTC burden is still greater in high SDI regions compared to lower SDI areas, contrary to expectations. Unexpected polar reversal of gender differences warrants further attention.

This study evaluates the effectiveness of machine learning (ML) models that incorporate clinical and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG)-positron emission tomography (PET)-radiomic features for predicting outcomes in gallbladder cancer patients.

The study analyzed 52 gallbladder cancer patients who underwent pre-treatment [18F]-FDG-PET/CT scans between January 2011 and December 2021. Twenty-seven patients were assigned to the training cohort between January 2011 and January 2018, and the data randomly split into training (70%) and validation (30%) sets. The independent test cohort consisted of 25 patients between February 2018 and December 2021. Eight clinical features (T stage, N stage, M stage, Union for International Cancer Control [UICC] stage, histology, tumor size, carcinoembryonic antigen level, and carbohydrate antigen 19-9 level) and 49 radiomic features were used to forecast progression-free survival (PFS). Three feature selection methods were applied including the univariate statistical feature selection test method, least absolute shrinkage and selection operator Cox regression method and recursive feature elimination method, and two ML algorithms (Cox proportional hazard and random survival forest [RSF]) were employed. Predictive performance was assessed using the concordance index (C-index).

Two clinical variables (UICC stage, N stage) and three radiomic features (total lesion glycolysis, grey-level size-zone matrix_grey level non-uniformity and grey-level run-length matrix_run-length non-uniformity) were identified by the statistical feature selection method as significant for PFS prediction. The RSF model incorporating these features demonstrated strong predictive performance, with C-indices above 0.80 in both training and testing sets (training 0.81, testing 0.89). This model almost closely matched the actual and predicted progression timelines with a low mean absolute error of 1.435, a median absolute error of 0.082, and a root mean square error of 2.359.

This study highlights the potential of using ML approaches with clinical and pre-treatment [18F]-FDG-PET radiomic data for predicting the prognosis of gallbladder cancer.

The platelet-to-high-density lipoprotein cholesterol ratio(PHR), a novel marker of inflammatory response and metabolic dysregulation, has been linked to various chronic conditions.This study aimed to evaluate the association between PHR and the prevalence of gallstones.

This cross-sectional study analyzed data collected from the United States National Health and Nutrition Examination Survey(NHANES)between 2017 and 2023. Multivariate logistic regression, generalized additive models, and subgroup analyses were employed to assess the relationship between PHR and gallstone prevalence.

A total of 13,163 participants were included, of whom 1,441(10.95%) self-reported a history of gallstones. After adjusting for potential confounders, a positive association was observed between the natural log-transformed PHR(LN[PHR])and gallstone prevalence(OR = 1.27, 95%CI: 1.09-1.49). This positive correlation became more pronounced with increasing PHR levels(P-trend = 0.01). Smooth curve fitting analysis indicated a linear relationship between PHR and gallstone prevalence. Subgroup analyses revealed that the association was strongest in participants aged 20-39 years, women, and individuals of other racial/ethnic groups.

Elevated PHR levels are significantly associated with a higher risk of gallstones. While our observational data suggest plausibility for PHR-gallstone, these findings should be interpreted as hypothesis-generating rather than definitive clinical evidence. Future mechanistic studies should elucidate whether this association reflects causal pathways or epiphenomenal relationships.

Gallbladder cancer (GBC) is an aggressive malignancy, with gallstone disease (GSD) recognized as the primary risk factor. Although the precise mechanism linking GSD to GBC remains unclear, evidence suggests that gallstone characteristics play a significant role. This study investigates the physicochemical characteristics of gallstones critical for GBC development. We analyzed 40 gallstone samples from 30 GSD and 10 GBC with GSD (GBCGS) patients using advanced spectroscopic and imaging techniques such as fourier transform infrared (FTIR), powder X-ray diffraction (PXRD), nuclear magnetic resonance (NMR), and scanning electron microscopy energy-dispersive X-ray (SEM-EDX)). Subsequently, elemental analysis of 10 gallstones each from GBCGS and GSD was conducted via inductively coupled plasma-mass spectrometry (ICP-MS). Gallstones from the GSD group were identified as cholesterol (70%), mixed (13.3%), pigment (6.7%), and calcium carbonate (10%), while the GBCGS group included only cholesterol (70%) and mixed (30%) types. Cholesterol was the dominant organic component in most gallstones, with the cholesterol and mixed types exhibiting highly crystalline phases characterized by a stacked plate-like microstructure, particularly prominent in the GBCGS group. Additionally, the GBCGS group revealed significantly higher concentrations of carcinogenic elements such as arsenic, chromium, mercury, iron, and lead (p < 0.05), suggesting their accumulation in the gallbladder and gallstones. Consequently, our findings highlight that the physicochemical properties of cholesterol-rich gallstones and exposure to carcinogenic elements play a key role in the pathogenesis of GBC in Assam. These results emphasize the need for further research into cholesterol dysregulation and its link to elemental toxicity.

Gallbladder and biliary tract diseases pose a significant global health burden, yet comprehensive analyses of their long-term epidemiological trends and future projections remain limited. This study aims to examine the temporal and spatial patterns of these diseases globally from 1990 to 2021, analyze healthcare workforce distribution relative to disease burden, and project the disease burden to 2035.

Using data from the Global Burden of Disease Study 2021, we analyzed incidence, prevalence, disability-adjusted life years (DALYs), and mortality for gallbladder and biliary tract diseases. We employed the Estimated Annual Percentage Change (EAPC) to assess trends, decomposition analysis to identify drivers of change, health inequality analysis to evaluate distributional disparities, and the Bayesian Age-Period-Cohort (BAPC) model for projections to 2035. Additionally, we examined correlations between healthcare workforce density and disease burden across countries.

The global age-standardized incidence rate decreased by 12.84% from 1990 to 865.4 per 100,000 population in 2021, while the absolute number of cases increased by 60.11%. Age-standardized prevalence decreased by 13.31%, DALYs by 20.98%, and mortality by 28%. Decomposition analysis revealed that population aging contributed 95.37% and population growth 73.96% to the increase in global deaths, while epidemiological improvements offset 69.33% of this increase. High SDI regions had significantly higher disease burden, with Western Europe showing the highest prevalence (4,009.85 per 100,000). Our healthcare workforce analysis revealed substantial disparities; high-burden Honduras had only 48.3 health workers per 10,000 population (8.4 physicians), while Austria had 385.5 (45.6 physicians), despite similar disease prevalence. Health inequality increased between 1990 and 2021, with the concentration index for mortality rising from 0.24 to 0.31. By 2035, despite decreasing age-standardized rates, the absolute number of cases is projected to increase by 20.3%, DALYs by 26.1%, and deaths by 36.9%, primarily driven by demographic changes.

The increasing absolute burden of gallbladder and biliary diseases despite improvements in age-standardized rates necessitates targeted interventions. Health systems should implement enhanced screening programs for high-risk populations, expand surgical workforce capacity in underserved regions, develop region-specific clinical guidelines for early intervention, and adopt policies addressing modifiable risk factors such as obesity and diet. Strategic healthcare workforce planning is crucial, as our analysis revealed significant imbalances in both the density and composition of healthcare personnel relative to disease burden.

Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis, often diagnosed at advanced stages. TEA domain transcription factor 4 (TEAD4) has been implicated in mediating the progression of various cancers, but its function and underlying mechanism in gallbladder cancer remain unclear. This study assessed the expression levels of TEAD4 and TMPRSS4 using reverse transcription quantitative polymerase chain reaction and western blotting. The functional role of TEAD4 in the progression of gallbladder cancer was investigated through CCK-8, EdU assays, Transwell, wound-healing assays, western blotting, immunohistochemistry, and hematoxylin and eosin (H&E) staining in cellular and animal models. The potential regulatory mechanism was explored by chromatin immunoprecipitation and dual-luciferase reporter assays. Results revealed that TEAD4 expression was significantly elevated in GBC tissues and cell lines. TEAD4 knockdown suppressed cell viability, decreased the percentage of EdU-positive cells, reduced invasive capacity, and increased wound closure width in GBC-SD and NOZ cells. Conversely, overexpression of TEAD4 produced opposite effects. Mechanistically, TEAD4 was predicted and confirmed to bind with the promoter region of TMPRSS4, as validated by the Chip-PCR and dual luciferase results. The mitigatory role of sh-TEAD4 on cell growth, invasion, and mobility of GBC was reversed by overexpression TMPRSS4 overexpression. In vivo, silencing of TEAD4 declined the tumor size and weight, the expression of TEAD4 and TMPRSS4, the ki-67 level, and the numbers of liver metastasis foci. In conclusion, the knockdown of TEAD4 suppressed the growth and metastasis of GBC via TMPRSS4.

The objective of this study was to compare the diagnostic efficacy and safety of ultrasound-guided percutaneous transhepatic gallbladder biopsy (PTGB) with endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in the assessment of gallbladder tumors. We conducted a retrospective, single-center study involving 101 patients diagnosed with gallbladder cancer who underwent either PTGB or EUS-FNA between January 2019 and December 2022. The study cohort was divided into two groups: 52 patients underwent PTGB, and 49 underwent EUS-FNA. Clinical data, diagnostic outcomes, patient demographics, and complications were systematically documented. The sensitivity, accuracy, and incidence of complications were evaluated for both groups. The sensitivity and accuracy rates were 94.23% and 94.23% for PTGB compared to 97.82% and 97.96% for EUS-FNA, with no significant difference between the two techniques. However, EUS-FNA was associated with significantly lower rate of adverse reactions (2.04%) compared to PTGB (15.38%). Both PTGB and EUS-FNA exhibited high diagnostic efficacy for gallbladder tumors. However, EUS-FNA demonstrated a significantly lower incidence of complications, making it a compelling alternative to PTGB, especially when percutaneous biopsy is unsuccessful or not feasible. High-quality prospective, multicenter trials are recommended to further validate these findings and to refine biopsy guidelines for gallbladder tumors.

Patients undergoing cholecystectomy for a presumed benign disease may present with histopathology report revealing carcinoma in the gallbladder specimen, in which case it is referred to as incidental gallbladder cancer (IGBC). This review highlights the approach to evaluation and management of these patients.

Available literature from various sources has been reviewed and presented in a narrative format.

Early referral to a tertiary centre for appropriate staging and definitive management is paramount. Once distant metastasis is ruled out, re-resection is indicated in patients with pathological T-stage ≥T1b with the aim to attain R0 resection, and perform complete staging lymphadenectomy, and has been shown to confer survival benefit. Feasibility and safety of minimally invasive approaches have been demonstrated in recent years. Role of peri-operative chemo(radio)-therapy in IGBC remains uncertain and prospective trials are warranted.

IGBC is being increasingly diagnosed as the number of cholecystectomies for presumed benign diseases is steadily increasing globally. Overall prognosis depends on the stage and is especially poor in those with residual disease at re-operation.

Gallbladder cancer (GBC) is associated with a poor prognosis. Recurrence patterns and their effect on survival remain ill-defined. This study aimed to analyze recurrence patterns and develop a machine learning (ML) model to predict survival after recurrence (SAR) of GBC.

Patients who underwent curative-intent resection of GBC between 1999 and 2022 were identified using an international database. An Extreme Gradient Boosting ML model to predict SAR was developed and validated.

Among 348 patients, 110 (31.6%) developed disease recurrence during follow-up. The most common recurrence site was local (29.1%), followed by multiple site (26.4%), liver (21.8%), peritoneal (18.2%), and lung (0.05%). The median SAR was the longest in patients with lung recurrence (36.0 months), followed by those with local recurrence (15.7 months). In contrast, patients with peritoneal (8.9 months), liver (8.5 months), or multiple-site (6.4 months) recurrence had a considerably shorter SAR. Patients with multiple-site recurrence had a worse SAR than individuals with single-site recurrence (6.4 vs 11.10 months, respectively; P =.014). The model demonstrated good performance in the evaluation and bootstrapping cohorts (area under the receiver operating characteristic curve: 71.4 and 71.0, respectively). The most influential variables were American Society of Anesthesiologists classification, local recurrence, receipt of adjuvant chemotherapy, American Joint Committee on Cancer T and N categories, and developing early disease recurrence (<12 months). To enable clinical applicability, an easy-to-use calculator was made available (https://catalano-giovanni.shinyapps.io/SARGB).

Except for lung recurrence, SAR for GBC was poor. A subset of patients with less aggressive disease biology may have favorable SAR. ML-based SAR prediction may help individuate candidates for curative re-resection when feasible.

Gallstones are a common disease of the digestive system, and its complications pose serious risks to human health and impose a significant economic burden on society. Inadequate dietary potassium intake may be associated with the development of gallstones, however, there is a lack of current epidemiological research on this topic.

The purpose of this research was a preliminarily exploration of the relationship between dietary potassium intake and the prevalence of gallstones, providing direction for the next step of quantitativeanalysis on the association between dietary potassium intake and the prevalence of gallstones.

Data from the National Health and Nutrition Examination Survey (NHANES) spanning 2017 to 2020 were used for a cross-sectional analysis. The presence of gallstones was assessed based on the NHANES questionnaire data for the corresponding time frame. To investigate the link between dietary potassium consumption and the likelihood of developing gallstones, multiple logistic regression models were used. Subgroup analyses were conducted based on variables such as age, gender, poverty-to-income ratio (PIR), body mass index (BMI), hypertension, diabetes, dietary supplement use, and physical activity. An analysis of linear associations was carried out using smoothing curves.

The study comprised 6,223 participants aged 20 years and older, excluding pregnant individuals. Among these participants, 671 were diagnosed with gallstones. In the final adjusted model, with a 95% confidence interval (CI) of 0.70 to 0.93, it was determined that dietary potassium intake and gallstone incidence were negatively correlated (OR = 0.81, p = 0.003). Individuals in the highest tertile of dietary potassium intake experienced a 31% lower risk of developing gallstones compare to those in the lowest tertile (OR = 0.69, 95% CI: 0.51-0.94, p = 0.017). In Model 1, the prevalence of gallstones exhibited an inverse relationship with dietary potassium intake. This negative association persisted even after stratifying by variables such as age, gender, PIR, BMI, hypertension, diabetes, dietary supplement use, and physical activity. Sensitivity analyses demonstrated the stability of this relationship.

Our research revealed that increased dietary potassium intake is associated with a lower prevalence of gallstones. Nevertheless, additional prospective studies are required to confirm a precise dietary potassium intake level and the long-term effects of potassium metabolism on gallstone formation.

Cholesterol crystallization is integral to the pathology of diseases such as atherosclerosis and gallstones, yet the relevant mechanisms of crystal growth have remained elusive. Here, we use a variety of in situ techniques to examine cholesterol monohydrate crystallization over multiple length scales. In this study, we first identified a biomimetic solvent to generate triclinic monohydrate crystals, while avoiding the formation of nonphysiological solvates and enabling crystallization at rates where the dynamics of surface growth could be captured in real time. Using a binary mixture of water and isopropanol, with the latter serving as a surrogate for lipids in physiological environments, we show that cholesterol monohydrate crystals grow classically by the nucleation and spreading of crystal layers. Time-resolved imaging confirms that layers are generated by dislocations and monomers incorporate into advancing steps after diffusion along the crystal surface and not directly from the solution. In situ atomic force microscopy (AFM) and microfluidics measurements concertedly reveal abundant macrosteps, which engender a self-inhibition mechanism that reduces the rate of crystal growth. This finding stands in contrast to numerous other systems, in which classical mechanisms lead to unhindered growth by spreading of single layers.

Oxidative stress is a significant contributor to the progression of gallstones. However, the combined or independent effects of dietary and lifestyle pro-antioxidants and antioxidants on gallstone formation remain unclear. Our study aims to investigate the potential link between the oxidative balance score (OBS) and the occurrence of gallstones.

This study utilized data from the National Health and Nutrition Examination Survey (NHANES), conducted in the United States between 2017 and March 2020, identifying 750 gallstone cases among the 7,489 participants. Gallstone status was self-reported. The data in this study were analyzed using a range of statistical techniques, such as Multivariable logistic regression, restricted cubic spline curves (RCS), mediation effects analysis, subgroup analyses and sensitivity analysis.

Using fully adjusted multivariable logistic regression analysis, we identified a significant negative correlation between OBS and the occurrence of gallstones, with an odds ratio (OR) of 0.97 and a 95% confidence interval (CI) of 0.96 to 0.99. Furthermore, participants in the highest quartile of OBS exhibited a 41% reduced risk of gallstones compared to those in the lowest quartile, with an OR of 0.59 (95% CI: 0.45, 0.79) relative to the reference population. Additionally, a linear inverse association between OBS and gallstones was observed. Mediation analysis indicated that diabetes and cardiovascular diseases (CVD) mediated 3.5 and 4% of the association between OBS and gallstones, respectively.

This research suggests that lower OBS levels are associated with a higher susceptibility to gallstone formation, potentially offering a new perspective on clinical strategies for the management and prevention of gallstones.

Lymph node metastasis (LNM) is among the most important predictors of poor prognosis after surgery for gallbladder cancer (GBC). Traditionally, staging has been based on the raw count of LNM, with a high risk of understaging patients who undergo inadequate lymph node dissection (LND). The log odds of metastatic lymph nodes (LODDS) may represent an alternative staging approach to stratify patients more accurately after resection of GBC.

In this cross-sectional study, patients who underwent curative-intent surgery with LND for GBC were identified from an international database. Two predictive models were built and compared, each integrating a different lymph nodes status indicator [i.e., American Joint Committee on Cancer (AJCC) and LODDS].

Among 199 patients, the median number of lymph nodes examined was 5 [interquartile range (IQR): 3.0, 8.0]; most patients had T1 (n = 26, 13.1%) or T2 (n = 97, 48.7%) disease, and a subset had LNM (n = 87, 44.0%). Multivariable Cox analysis demonstrated LODDS was an independent predictor of overall survival [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.5-2.3; p < 0.001]. The LODDS model demonstrated better performance compared with a traditional model that utilized the AJCC N category [concordance (C) index: 0.814 versus 0.763; p < 0.001]. Patients classified as high- versus low-risk based on LODDS had much worse overall survival (OS) (4.9% versus 83.7%, respectively; p < 0.001). The LODDS model performance remained high even among patients with inadequate LND (< 6 LN) (C index: 0.87). An online calculator was developed ( https://catalano-giovanni.shinyapps.io/LoddsGBC/ ).

A novel prognostic model based on LODDS may overcome the inherent limitations of the current AJCC staging system, reducing understaging among patients with fewer than six total lymph nodes evaluated.

Gallbladder neuroendocrine carcinomas (GB-NECs) are a rare subtype of malignant gallbladder cancer (GBC). The genetic and molecular characteristics of GB-NECs are rarely reported. This study aims to assess the frequency of microsatellite instability (MSI) in GB-NECs and characterize their clinicopathologic and molecular features in comparison with gallbladder adenocarcinomas (GB-ADCs). Data from six patients with primary GB-NECs and 13 with GB-ADCs were collected and reevaluated. MSI assay, immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2), comprehensive genomic profiling (CGP) via next-generation sequencing (NGS), and evaluation of tumor mutation burden (TMB) were conducted on these samples. The six GB-NEC cases were all female, with a mean age of 62.0±9.2 years. Of these, two cases were diagnosed as large cell neuroendocrine carcinomas (LCNECs), while the remaining four were small cell neuroendocrine carcinomas (SCNECs). Microsatellite states observed in both GB-NECs and GB-ADCs were consistently microsatellite stable (MSS). Notably, TP53 (100%, 6/6) and RB1 (100%, 6/6) exhibited the highest mutation frequency in GB-NECs, followed by SMAD4 (50%, 3/6), GNAS (50%, 3/6), and RICTOR (33%, 2/6), with RB1, GNAS, and RICTOR specifically present in GB-NECs. Immunohistochemical (IHC) assays of p53 and Rb in the six GB-NECs were highly consistent with genetic mutations detected by targeted NGS. Moreover, no statistical difference was observed in TMB between GB-NECs and GB-ADCs (p=0.864). Although overall survival in GB-NEC patients tended to be worse than in GB-ADC patients, this difference did not reach statistical significance (p=0.119). This study has identified the microsatellite states and molecular mutation features of GB-NECs, suggesting that co-mutations in TP53 and RB1 may signify a neuroendocrine inclination in GB-NECs. The IHC assay provides an effective complement to targeted NGS for determining the functional status of p53 and Rb in clinical practice.

Gallbladder cancer has historically been characterized with a poor prognosis. This study aims to describe the global patterns and temporal trends in gallbladder cancer survival using data from cancer registries.

We conducted a systematic review by searching six databases-PubMed, Web of Science, EMBASE, SEER, CNKI, and Wanfang-for using of registry-based data published before January 1, 2024. Survival data were carefully extracted and analyzed from the final set of included studies.

Among the 55 studies included, more than 320,000 people, suggest that survival improvements for gallbladder cancer have stagnated over the past three decades. No significant improvements in 5-year relative survival rates were observed worldwide. After age standardization, the highest 5-year relative survival rate is 30.6 % (Changzhou, China, 2011-2013 and Korea, 2013-2019), while the lowest is 6.0 % (Austria, 1990). The 5-year relative survival rate for gallbladder cancer was generally higher in Asian populations than in other regions. Survival rates were more favorable in younger individuals, with no differences in survival observed between the sexes.

Over the past 30 years, the prognosis of patients with gallbladder cancer has not improved significantly worldwide. There is an urgent need for new treatments for gallbladder cancer as well as simple and effective screening methods to improve the survival rate of gallbladder cancer.

We aimed to develop a preoperative clinical radiomics survival prediction model based on the radiomics features via deep learning to provide a reference basis for preoperative assessment and treatment decisions for patients with gallbladder carcinoma (GBC).

A total of 168 GBC patients who underwent preoperative upper abdominal enhanced CT from one high-volume medical center between January 2011 to December 2020 were retrospectively analyzed. The region of interest (ROI) was manually outlined by two physicians using 3D Slicer software to establish a nnU-Net model. The DeepSurv survival prediction model was developed by combining radiomics features and preoperative clinical variables.

A total of 1502 radiomics features were extracted from the ROI results based on the nnU-Net model and manual segmentation, and 13 radiomics features were obtained through the 4-step dimensionality reduction methods, respectively. The C-index and AUC of 1-, 2-, and 3-year survival prediction for the nnU-Net based clinical radiomics DeepSurv model was higher than clinical and nnU-Net based radiomics DeepSurv models in the training and testing sets, and close to manual based clinical radiomics DeepSurv model. Delong-test was performed on the AUC of 1-, 2-, and 3-year survival prediction for the two preoperative clinical radiomics DeepSurv prediction models in the testing set, and the results showed that the two models had the same prediction efficiency (all P > 0.05).

By using the DeepSurv model via nnU-Net segmentation, postoperative survival outcomes for individual gallbladder carcinoma patients could be assessed and stratified, which can provide references for preoperative diagnosis and treatment decisions.

Selective internal radiation therapy (SIRT) is a promising option for liver-only unresectable intrahepatic cholangiocarcinoma (iCCA). The Real-SIRTCCA study retrospectively assessed the benefit of adding SIRT to chemotherapy in this setting within the French nationwide observational cohort ACABi-GERCOR-PRONOBIL.

Inclusion criteria were advanced iCCA with limited or no extrahepatic disease, treated with first-line gemcitabine plus platinum chemotherapy +/- concurrent SIRT. All patients treated with chemotherapy and concurrent SIRT were included. To ensure groups' similarity, a rigorous selection was applied to the chemo-only group, with exclusion of patients with liver involvement >50% and extrahepatic metastases. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), objective response rate (ORR) and tumor resection rate. Propensity score and inverse probability of treatment weighting (IPTW) propensity approaches were used to address confounding factors between groups.

Between July 2007 and December 2023, 277 patients met the Real-SIRTCCA inclusion criteria, with 88 in the chemo-SIRT group and 189 in chemo-only group. Chemo-SIRT was associated with longer PFS (median = 10.8 vs. 5.5 months, hazard ratio [HR] 0.54, 95% CI 0.41-0.71, p <0.0001), a trend for longer OS (median = 22.5 vs. 15.1 months, HR 0.76, 95% CI 0.57-1.01), higher ORR (58.3% vs. 28.5%, odds ratio [OR] 3.51, 95% CI 2.03-6.09, p <0.0001), and resection rate (18.7% vs. 8.8%, p = 0.0279) compared to chemo-alone. After IPTW, the superiority of chemo-SIRT was confirmed with better PFS (HR 0.55, 95% CI 0.45-0.66, p <0,0001), OS (HR 0.70, 95% CI 0.58-0.85, p = 0.0004), ORR (OR 3.17, 95% CI 2.18-4.49, p <0.0001) and resection rate (OR 2.94, 95% CI 1.71-5.03, p <0.0001).

Adding SIRT to first-line chemotherapy significantly improved survival outcomes, ORR, and secondary tumor resection rates in locally advanced iCCA. Prospective randomized data are needed to confirm these results.

Herein, we report the results of the Real-SIRTCCA study, comparing the efficacy of the gemcitabine-platinum systemic first-line chemotherapy with or without selective internal radiation therapy (SIRT) in 277 patients with locally advanced intrahepatic cholangiocarcinoma within the cohort ACABi-PRONOBIL. An improvement of progression-free survival, overall survival, tumor response and secondary surgical resection rate was observed in favor of chemo-SIRT, before adjustment and after inverse probability of treatment weighting propensity score analyses. Even though prospective randomized data would be needed to confirm these findings, we believe that this study constitutes new evidence of the potential benefit of combining SIRT with chemotherapy. The safety and efficacy of this strategy whether as a bridge to intent-to-cure strategies or in a palliative setting, should encourage its adoption in a larger panel of clinical centers, or at very least, prompt clinicians to refer their patients to centers where SIRT is performed.

NCT04935853.

Background & objectives Gallbladder cancer (GBC) is a highly aggressive malignancy with a poor prognosis, often due to late-stage diagnosis. Existing diagnostic methods are invasive and not always feasible in resource-limited settings. Circulating free DNA (cfDNA) has emerged as a potential non-invasive biomarker for malignancies, including GBC. This study aimed to evaluate the diagnostic accuracy of cfDNA levels in distinguishing GBC patients from healthy controls, considering its potential for early detection and personalised treatment. Methods This case-control study included 42 newly diagnosed GBC affected individuals and 15 age- and sex-matched healthy controls. Plasma cfDNA was extracted using a bead-based protocol and quantified through quantitative PCR (qPCR) targeting the β-globin gene. Diagnostic thresholds were identified using Receiver Operating Characteristics (ROC) and precision-recall curve analyses, assessing sensitivity, specificity, and predictive values. Results cfDNA levels were significantly elevated in GBC patients compared to controls (P<0.05), with a mean cfDNA level of 721 ng/ml. Four diagnostic offering distinct clinical thresholds were identified: 75.5 ng/ml, 130 ng/ml, 188 ng/ml, and 372.92 ng/ml. The ROC curve demonstrated an area under the curve (AUC) of 0.94, indicating high diagnostic accuracy. cfDNA achieved high sensitivity (97.6% at 75.5 ng/ml) and 100 per cent specificity at 188 ng/ml. Interpretation & conclusion cfDNA serves as a reliable, non-invasive biomarker for GBC diagnosis, providing high diagnostic accuracy and utility in early detection and disease monitoring. These findings highlight cfDNA's potential as both a standalone diagnostic tool and a complementary marker to traditional tumour markers, enhancing diagnostic precision and aiding in personalised medicine. Its integration into diagnostic protocols can be particularly valuable in resource-limited settings.

The trend of gallstones occurring in younger populations has become a noteworthy public health issue. This study aims to investigate the association between complete blood cell count (CBC)-derived inflammatory indicators and gallstones in adults under 60 years of age in the United States.

This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. Associations between CBC-derived inflammatory biomarkers and gallstones were assessed using multivariable logistic regression models, with results presented as odds ratio (OR) and 95% confidence interval (CI). Restricted cubic splines (RCS) were employed to examine potential non-linear relationships. Subgroup analyses were also conducted to explore differences across population subgroups.

This study comprised 4,977 participants, among whom 398 were diagnosed with gallstones. After adjusting for confounding variables, the highest quartile of systemic inflammation response index (SIRI) [OR (95%CI): 1.65(1.12,2.43)], systemic immune-inflammation index (SII) [OR (95%CI): 1.53(1.05,2.25)], monocyte-to-lymphocyte ratio (MLR) [OR (95%CI): 1.66(1.16,2.37)], and pan immune inflammatory value (PIV) [OR (95%CI): 1.82(1.23,2.71)] were associated with a significantly increased risk of gallstones compared to the lowest quartiles. RCS plots indicated a nonlinear relationship between several inflammatory biomarkers and gallstones.

Our study found that SIRI, SII, MLR, and PIV can serve as clinical indicators for predicting the risk of gallstones in adults under 60 years of age in the United States.

The novel diagnostic term Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) requires at least one cardiovascular risk factor for diagnosis. While the relationship between gallstones and Non-Alcoholic Fatty Liver Disease (NAFLD) has been debated, the association between MASLD and gallstones remains unclear. This cross-sectional study aimed to explore this relationship using National Health and Nutrition Examination Survey (NHANES) data from 2017 to 2020. Participants were stratified into two groups based on MASLD diagnosis, and propensity score matching (PSM) was employed to reduce biases. Of 15,560 participants, 7922 met the inclusion criteria, with 2697 (34.0%) diagnosed with MASLD. Gallstone prevalence was higher in the MASLD group (14.2%) compared to the non-MASLD group (8.5%). After PSM, 4536 participants were analyzed, revealing a significant association between MASLD and gallstones (OR = 1.30, 95% CI 1.09-1.56, P = 0.003). This association remained robust across crude and adjusted analyses, with subgroup and sensitivity analyses further supporting the findings. In conclusion, MASLD is significantly associated with an increased risk of gallstones in the US population. These findings highlight the need to consider this relationship in clinical strategies for prevention and management of gallstone disease.

Gallbladder cancers (GBC) are insidious, malignant, and associated with poor prognosis, with a 5-year survival rate of 5%. Long-term survival in advanced GBC is rare. Here, we report a case of a 45-year-old female who presented with intermittent right upper quadrant pain for 1 month. A gallbladder mass and two liver masses were identified on a computed tomography (CT) scan of the abdomen and pelvis with intravenous contrast, which was highly suspicious for GBC. The patient underwent extended radical surgery, and a low to moderately differentiated gallbladder adenocarcinoma was diagnosed through pathology. Postoperatively, the patient received chemotherapy with gemcitabine and cisplatin but only tolerated one cycle. The patient has been disease-free for over 7 years, representing an unusually long survival.

Ulcerative colitis can present with extra-intestinal manifestations, including interstitial lung disease and primary sclerosing cholangitis. When pulmonary symptoms precede gastrointestinal, diagnosis can be challenging. Consideration of Ulcerative colitis in patients with unexplained lung and hepatic pathology is crucial, as a failure of timely intervention can lead to multiorgan complications.

To investigate the utility of combining clinical and contrasted-enhanced tomography (CECT) parameters for the preoperative evaluation of perineural invasion (PNI) in gallbladder carcinoma (GBC).

A total of 134 patients with GBC (male/female, 52/82; age, 64.4 ± 9.7 years) were divided into PNI-positive (n = 63) and PNI-negative groups (n = 71). Clinical characteristics (demographic information, liver function indicators and tumor markers) and CECT parameters (tumor type, tumor size, gallbladder stone, invasion of gallbladder neck/cystic duct, clinical T stage and N stage) were collected and compared between two groups. Binary logistic regression analysis, receiver operating characteristic curves analyses and Delong test were used in further statistical analyses in clinical T3-4 stage (cT3-4) GBC patients. Overall survival (OS) rates after surgery were compared between PNI-negative group and PNI-positive group of cT3-4 GBC patients.

The majority of GBC patients with PNI were classified as cT3-4 (61/63, 96.8%), while only 3.2% (2/63) of PNI-positive cases were identified at cT1-2. Among cT3-4 GBC, OS was significantly lower in the PNI-positive group than the PNI-negative group after surgery (HR,1.661; 95% CI, 1.044-2.643; P = 0.032). Gender and gallbladder neck/cystic duct invasion were independent predictive factors for cT3-4 GBC patients with PNI. A combination of gender and gallbladder neck/cystic duct invasion showed the best diagnostic performance than that of individual parameters (all P < 0.05).

Preoperative T staging using CECT enables the initial assessment of PNI status in GBC patients. A combination of gender and gallbladder neck/cystic duct invasion may effectively predict PNI in GBC, particularly in cT3-4 GBC.

Carcinoma of the gall bladder (CAGB) has a poor prognosis. Molecular analysis of bile could classify indicators of CAGB. Bile samples (n = 87; training cohort) were screened for proteomics and metabolomics signatures of cancer detection. In bile, CAGB showed distinct proteomic (217 upregulated, 258 downregulated) and metabolomic phenotypes (111 upregulated, 505 downregulated, p < 0.05, fold change > 1.5, false discovery rate <0.01) linked to significantly increased inflammation (coagulation, arachidonic acid, bile acid) and alternate energy pathways (pentose-phosphate pathway, amino acids, lipid metabolism); and decreased glycolysis, cholesterol metabolism, PPAR, RAS, and RAP1 signaling, oxidative phosphorylation, and others compared to gallstone or healthy controls (p < 0.05). Bile proteins/metabolites signatures showed significant correlation (r 2  > 0.5, p < 0.05) with clinical parameters. Metabolite/protein signature-based probability of detection for CAGB (cancer) was >90% (p < 0.05), with area under the receiver operating characteristic curve >0.94. Validation of the top four metabolites-toluene, 5,6-DHET, creatine, and phenylacetaldehyde-in separate cohorts (n = 80; bile [T1] and paired plasma [T2]) showed accuracy (99%) and sensitivity/specificity (>98%) for CAGB detection. Tissue validation showed bile 5,6-DHET positively correlated with tissue PCNA (proliferation), and caspase-3 linked to cancer development (r 2 >0.5, p < 0.05). In conclusion, the bile molecular landscape provides critical molecular understanding and outlines metabolomic indicator panels for early CAGB detection.

Gallbladder cancer (GBC) is an aggressive and lethal malignancy with a poor prognosis. Long noncoding RNAs (lncRNAs) and natural products have emerged as key orchestrators of cancer pathogenesis through widespread dysregulation across GBC transcriptomes. Functional studies have revealed that lncRNAs interact with oncoproteins and tumor suppressors to control proliferation, invasion, metastasis, angiogenesis, stemness, and drug resistance. Curcumin, baicalein, oleanolic acid, shikonin, oxymatrine, arctigenin, liensinine, fangchinoline, and dioscin are a few examples of natural compounds that have demonstrated promising anticancer activities against GBC through the regulation of important signaling pathways. The lncRNAs, i.e., SNHG6, Linc00261, GALM, OIP5-AS1, FOXD2-AS1, MINCR, DGCR5, MEG3, GATA6-AS, TUG1, and DILC, are key players in regulating the aforementioned processes. For example, the lncRNAs FOXD2-AS1, DILC, and HOTAIR activate oncogenes such as DNMT1, Wnt/β-catenin, BMI1, and c-Myc, whereas MEG3 and GATA6-AS suppress the tumor proteins NF-κB, EZH2, and miR-421. Clinically, specific lncRNAs can serve as diagnostic or prognostic biomarkers based on overexpression correlating with advanced TNM stage, metastasis, chemoresistance, and poor survival. Therapeutically, targeting aberrant lncRNAs with siRNA or antisense oligos disrupts their oncogenic signaling and inhibits GBC progression. Overall, dysfunctional lncRNA regulatory circuits offer multiple avenues for precision medicine approaches to improve early GBC detection and overcome this deadly cancer. They have the potential to serve as novel biomarkers as they are detectable in bodily fluids and tissues. These findings enhance gallbladder treatments, mitigating resistance to chemo- and radiotherapy.

The global burden of gallbladder and biliary tract cancer (GBTC) has been on the rise, making it a major public health concern. We aim to comprehensively analyze sex disparities in the temporal trends of GBTC incidence, mortality, and disability-adjusted life years (DALYs) regionally and globally from 2010 to 2019.

Age-standardized rates of GBTC incidence, death, and DALYs were analyzed utilizing the Global Burden of Disease study 2019.

From 2010 to 2019, the estimated annual percent change (APC) of the age-standardized incidence rates (ASIRs) and age-standardized disability-adjusted life years (ASDALYs) due to GBTC globally decreased in both sexes (males, APC: -0.80%; APC: -1.00%) and (females, APC: -0.89%; APC: -0.96%). At the same time, age-standardized death rates (ASDRs) decreased only in males (APC: -0.82%) and remained stable in females. By regions, ASIRs and ASDR increased in both sexes only in Southeast Asia (SEA) but decreased in the other regions. All regions had decreased ASDALYs except for an increase in ASDALYs for females only in the SEA region (APC: 0.41%), and males have a stable trend.

Our study reveals substantial geographic variance in the burden of GBTC, specifically in the SEA region. Therefore, localized interventional methodologies must be undertaken to effectively address this global burden from GBTC.

Gallbladder cancer is a major health concern in China, and awareness of the associated incidence and mortality rates is particularly important given the aging population.

To determine trends in gallbladder cancer incidence and mortality rates over 12 years and quantitatively analyze the influence of demographic factors on these rates in China.

We performed a retrospective study of 98,860 Chinese citizens using the Chinese Cancer Registry, a national database. Gallbladder cancer incidence and mortality data pertaining to patients treated between 2005 and 2017 were collected. Joinpoint regression models were used to estimate the annual percentage change (APC) and average APC (AAPC). We used age-period-cohort analyses and decomposition methods to investigate differing trends in incidence and mortality.

The age-standardized gallbladder cancer incidence and mortality rates in China trended downward between 2005 and 2017, with AAPCs of -2.023% and -1.603%, respectively. Coefficients of age effect for incidence rate increased with age up to 70 years and peaked at 70-79 years, while coefficients of age effect for the mortality rate showed a consistent increase with age. Both coefficients of period for incidence and mortality rates increased in more recent periods; in terms of the cohort effect, coefficients of cohort for rates generally decreased in later birth years but showed a partial rise between 1982 and 1996. The crude incidence rates of gallbladder cancer according to demographic and non-demographic factors were 626.09% and -526.09% respectively (366.23% and -266.23% among men, and 6068.93% and -5968.93% among women, respectively). The rates were 543.01% and -443.01%, respectively, in urban areas and were 68.22% and 31.78%, respectively, in rural areas. The mortality rates according to demographic and non-demographic factors were -495.93% and 595.93%, respectively (-1763.10% and -1863.10% for men and -270.56% and -370.56% for women, respectively). These rates were -930.33% and 1030.33%, respectively, in urban areas and were 101.48% and -1.48%, respectively, in rural areas.

The overall standardized gallbladder cancer incidence and mortality rates in China are trending downward, but not sufficiently so. Proper living and eating habits should be encouraged while exploring the establishment of long-term, standardized gallbladder cancer screening programs.

Metabolic Visceral Fat Score (METS-VF) recently introduced is posited to be a superior metric for assessing visceral adipose tissues (VAT) compared to traditional obesity indexes. This study aims to elucidate the correlation between METS-VF and the incidence of gallstones.

In this cross-sectional study, the data from the National Health and Nutrition Examination Survey (NHANES) during the period from 2013 to 2020 were analyzed. And the correlation between METS-VF and the incidence of gallstones was explored through multivariate logistic regression analysis, receiver operating characteristic (ROC) curve, subgroup analysis and restricted cubic spline (RCS) regression.

This study included 5,975 participants, of whom 645 (10.8%) were gallstone formers. As the quartile range of METS-VF increased, a notable rise in the prevalence of gallstones was observed (3.2% vs. 7.4% vs. 12.1% vs. 20.6%, p < 0.001). Logistic regression analyses indicated a significant positive correlation between METS-VF and the risk of gallstones (OR = 3.075, 95% CI: 2.158, 4.381). Subgroup analyses further revealed a stronger correlation between gallstones and METS-VF in subjects over 50 years old. RCS regression identified a non-linear positive correlation, with an inflection point at 6.698. Finally, the area under the ROC curve (AUC) of METS-VF was significantly larger (AUC = 0.705, 95%: 0.685, 0.725) than those of traditional obesity indexes and other VAT surrogate markers.

This study is the first to reveal a significant positive correlation between the prevalence of gallstones and METS-VF, with METS-VF outperforming other VAT surrogate markers in the diagnosis of gallstones.

This study aims to evaluate the feasibility and efficacy of chemotherapy combined with irreversible electroporation (IRE) in patients with locally advanced gallbladder carcinoma (GBC) presenting as gallbladder masses.

Patients with unresectable GBC masses of size greater than 2 cm and less than 6 cm without evidence of distant metastases and with no contraindication to general anaesthesia will be enrolled in the study. They will be randomized using computer generated table into two arms with 1:1 allocation ratio to include 15 patients in each group. Group I will be the chemotherapy alone arm and Group II will be the combined image-guided irreversible electroporation of the tumour and chemotherapy arm. The primary outcome assessed shall be the clinical benefit rate (complete response, CR; partial response, PR and stable disease, SD) based on the mRECIST criteria and overall survival. The secondary outcome shall be feasibility and safety of the procedure and quality of life pre and post procedure. The quality of life will be assessed by a questionnaire as given by EORTC-Quality of Life Group before starting therapy and 4 weeks after completion of therapy.

The combined local and systemic effects of irreversible electroporation and systemic chemotherapy respectively may improve the outcomes in inoperable cases of gallbladder carcinoma.

Clinical Trials Registry - India ( https://ctri.nic.in/Clinicaltrials/advancesearchmain.php ). Identifier: CTRI/2021/05/033803. Primary Register of the International Clinical Trials Registry Platform (WHO ICTRP) ( http://www.who.int/ictrp/search/en/ ).

The differentiation between reactive atypical changes and dysplasia/carcinoma in the daily cases of cholecystectomies is a routine histopathological challenge. Up to our knowledge, no immunohistochemical marker can definitely differentiate between these two changes. Many promising markers have been proposed to be helpful tools in this situation. One of them is B-cell lymphoma-2 (BCL-2) immunohistochemical stain. Therefore, this study aims to evaluate its usefulness as a marker that might be helpful in such challenging cases.

From the archive of the histopathology laboratories of Qassim University Medical City and King Fahad Specialist Hospital in Qassim, five dysplastic/neoplastic gallbladder cases were collected (in the shape of formalin-fixed, paraffin-embedded blocks) as well as five cholecystitis with reactive atypical changes cases. Two slides from each block were prepared: One was stained with H&E and the other was stained immunohistochemically with BCL-2. The slides were evaluated by two histopathologist consultants in the same sitting using multiheaded microscope to confirm the original diagnosis and to evaluate the BCL-2 staining.

Five dysplastic/carcinoma cases and five cholecystitis with reactive atypia were collected. The original diagnoses were confirmed by two pathologists. They also confirmed that all the BCL-2 stained slides (with the exception of one reactive case) were negative for BCL-2 immunohistochemical stain.

BCL-2 immunohistochemical stain is not a promising marker in the differentiation between reactive epithelium and dysplasia/carcinoma in the gallbladder.

Gallbladder cancer (GBC) is a common gastrointestinal malignancy noted for its aggressive characteristics and poor prognosis, which is mostly caused by delayed detection. However, the scarcity of information regarding somatic mutations in Indian patients with GBC has hampered the development of efficient therapeutic options. In the present study, the authors attempted to bridge this gap by revealing the mutational profile of GBC.

To evaluate the somatic mutation profile, whole exome sequencing (WES) was performed on 66 tumor and matched blood samples from individuals with GBC. Somatic variant calling was performed using GATK pipeline. Variants were annotated at pathogenic and oncogenic levels, using ANNOVAR, VEP tools and the OncoKB database. Mutational signature analysis, oncogenic pathway analysis and cancer driver genes identification were performed at the functional level by using the maftools package.

Our findings focused on the eight most altered genes with pathogenic and oncogenic mutations: TP53, SMAD4, ERBB3, KRAS, ARID1A, PIK3CA, RB1, and AXIN1. Genes with pathogenic single nucleotide variations (SNVs) were enriched in oncogenic signaling pathways, particularly RTK-RAS, WNT, and TP53 pathways. Furthermore, our research related certain mutational signatures, such as cosmic 1, cosmic 6, and cosmic 18, 29, to known characteristics including patient age and tobacco smoking, providing important insights into disease etiology.

Given the scarcity of exome-based sequencing studies focusing on the Indian population, this study represents a significant step forward in providing a framework for additional in-depth mutational analysis. Genes with substantial oncogenic and pathogenic mutations are promising candidates for developing targeted mutation panels, particularly for GBC detection.

Inflammatory responses and lipid metabolism make vital impacts on the development of gallstones. This study investigated the relationship between gallstone disease (GSD) and the neutrophil-to-high-density lipoprotein cholesterol ratio (NHR) in American patients with gallstones.

The data analyzed were sourced from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) and comprised of participants with complete data on GSD and NHR. The relationship between NHR and GSD was evaluated with weighted multivariable logistic regression analysis. Additionally, subset analyses, interaction tests, smoothed curve fitting, and threshold effect analyses were conducted.

Among the 7894 participants analyzed in this study, the prevalence of GSD was 10.98%, and the average NHR value was 3.41 ± 0.06. The fully adjusted multivariable logistic regression results demonstrated an obvious positive association between NHR and the likelihood of GSD (OR = 1.09, 95% CI: 1.01, 1.16; P = 0.0197). Consistency of this association was confirmed through subset analyses and interaction tests across various subgroups, including those categorized by smoking status and asthma. Furthermore, smoothed curve fitting and threshold effect analyses revealed a nonlinear relationship with a threshold of 2.86.

NHR shows a positive relationship to an increased likelihood of GSD among Americans. It can act as an easy and cost-effective tool for the early detection and management of individuals at risk for GSD.

Gallbladder cancer is often associated with poor prognosis, especially when patients experience early recurrence after surgery. Machine learning may improve prediction accuracy by analysing complex non-linear relationships. The aim of this study was to develop and evaluate a machine learning model to predict early recurrence risk after resection of gallbladder cancer.

In this cross-sectional study, patients who underwent resection of gallbladder cancer with curative intent between 2001 and 2022 were identified using an international database. Patients were assigned randomly to a development and an evaluation cohort. Four machine learning models were trained to predict early recurrence (within 12 months) and compared using the area under the receiver operating curve (AUC).

Among 374 patients, 56 (15.0%) experienced early recurrence; most patients had T1 (51, 13.6%) or T2 (180, 48.1%) disease, and a subset had lymph node metastasis (120, 32.1%). In multivariable Cox analysis, resection margins (HR 2.34, 95% c.i. 1.55 to 3.80; P < 0.001), and greater AJCC T (HR 2.14, 1.41 to 3.25; P < 0.001) and N (HR 1.59, 1.05 to 2.42; P = 0.029) categories were independent predictors of early recurrence. The random forest model demonstrated the highest discrimination in the evaluation cohort (AUC 76.4, 95% c.i. 66.3 to 86.5), compared with XGBoost (AUC 74.4, 53.4 to 85.3), support vector machine (AUC 67.2, 54.4 to 80.0), and logistic regression (AUC 73.1, 60.6 to 85.7), as well as good accuracy after bootstrapping validation (AUC 75.3, 75.0 to 75.6). Patients classified as being at high versus low risk of early recurrence had much worse overall survival (36.1 versus 63.8% respectively; P < 0.001). An easy-to-use calculator was made available (https://catalano-giovanni.shinyapps.io/GallbladderER).

Machine learning-based prediction of early recurrence after resection of gallbladder cancer may help stratify patients, as well as help inform postoperative adjuvant therapy and surveillance strategies.

Gallbladder cancer (GBC) presents as an aggressive malignancy with poor patient outcome. Like other epithelial cancers, the mechanisms of GBC cancer progression remain vague and efforts in finding targeted therapies fall below expectations. This study combined proteomic analysis of formalin-fixed paraffin-embedded (FFPE) GBC samples, functional and molecular characterization of potential oncogenes and identification of potential therapeutic strategies for GBC. We identified Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) as one of the significantly most upregulated proteins in GBC. CEACAM6 overexpression has been observed in other cancer entities but the molecular function remains unclear. Our functional analyses in vitro and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer progression and metastasis by decreasing cell adhesion and promoting migration and invasion of GBC cells. Conversely, CEACAM6 knockdown abolished GBC aggressiveness by increasing cell adhesion while reducing cell migration, cell proliferation, and colony formation. BirA-BioID followed by mass-spectrometry revealed Integrin Beta-1 (ITGB1) and Protein Kinase C Delta (PRKCD) as direct molecular and functional partners of CEACAM6 supporting GBC cell migration. ERK and AKT signaling and their downstream target genes were regulated by CEACAM6 and thus the treatment with AKT inhibitor capivasertib or ERK inhibitor ulixertinib mitigated the CEACAM6-induced migration. These findings demonstrate that CEACAM6 is crucially involved in gallbladder cancer progression by promoting migration and inhibiting cell adhesion through ERK and AKT signaling providing specific options for treatment of CEACAM6-positive cancers.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, and is often undetected until advanced stages, making curative surgery unfeasible for many patients. Curative surgery remains the only option for long-term survival. Accurate postsurgical prognosis is crucial for effective treatment planning. tumor-node-metastasis staging, which focuses on tumor infiltration, lymph node metastasis, and distant metastasis, limits the accuracy of prognosis. Nomograms offer a more comprehensive and personalized approach by visually analyzing a broader range of prognostic factors, enhancing the precision of treatment planning for patients with GBC.

To identify risk factors and develop a predictive model for GBC prognosis.

A retrospective study analyzed the clinical and pathological data of 93 patients who underwent radical surgery for GBC at Peking University People's Hospital from January 2015 to December 2020. Kaplan-Meier analysis was used to calculate the 1-, 2- and 3-year survival rates. The log-rank test was used to evaluate factors impacting prognosis, with survival curves plotted for significant variables. Single-factor analysis revealed statistically significant differences, and multivariate Cox regression identified independent prognostic factors. A nomogram was developed and validated with receiver operating characteristic curves and calibration curves.

Among 93 patients who underwent radical surgery for GBC, 30 patients survived, accounting for 32.26% of the sample, with a median survival time of 38 months. The 1-year, 2-year, and 3-year survival rates were 83.87%, 68.82%, and 53.57%, respectively. Univariate analysis revealed that carbohydrate antigen 19-9 expression, T stage, lymph node metastasis, histological differentiation, surgical margins, and invasion of the liver, extrahepatic bile duct, nerves, and vessels (P ≤ 0.001) significantly impacted patient prognosis after curative surgery. Multivariate Cox regression identified lymph node metastasis (P = 0.03), histological differentiation (P < 0.05), nerve invasion (P = 0.036), and extrahepatic bile duct invasion (P = 0.014) as independent risk factors. A nomogram model with a concordance index of 0.838 was developed. Internal validation confirmed the model's consistency in predicting the 1-year, 2-year, and 3-year survival rates.

Lymph node metastasis, tumor differentiation, extrahepatic bile duct invasion, and perineural invasion are independent risk factors. A nomogram based on these factors can be used to personalize and improve treatment strategies.