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Abstract Background Gallbladder cancer (GBC) is a highly aggressive malignancy, with limited survival profiles after curative surgeries. This study aimed to develop a practical model for predicting the postoperative overall survival (OS) in GBC patients. Methods Patients from three hospitals were included. Two centers (N = 102 and 100) were adopted for model development and internal validation, and the third center (N = 85) was used for external testing. Univariate and stepwise multivariate Cox regression were used for feature selection. A nomogram for 1-, 3-, and 5-year postoperative survival rates was constructed accordingly. Performance assessment included Harrell's concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves. Kaplan-Meier curves were utilized to evaluate the risk stratification results of the nomogram. Decision curves were used to reflect the net benefit. Results Eight factors, TNM stage, age-adjusted Charlson Comorbidity Index (aCCI), body mass index (BMI), R0 resection, blood platelet count, and serum levels of albumin, CA125, CA199 were incorporated in the nomogram. The time-dependent C-index consistently exceeded 0.70 from 6 months to 5 years, and time-dependent ROC revealed an area under the curve (AUC) of over 75% for 1-, 3-, and 5-year survival. The calibration curves, Kaplan-Meier curves and decision curves also indicated good prognostic performance and clinical benefit, surpassing traditional indicators TNM staging and CA199 levels. The reliability of results was further proved in the independent external testing set. Conclusions The novel nomogram exhibited good prognostic efficacy and robust generalizability in GBC patients, which might be a promising tool for aiding clinical decision-making.

Background: Gallbladder cancer (GBC) is a highly aggressive malignancy, with limited survival profiles after curative surgeries. This study aimed to develop a practical model for predicting the postoperative overall survival (OS) in GBC patients. Methods: Patients from three hospitals were included. Two centers (N = 102 and 100) were adopted for model development and internal validation, and the third center (N = 85) was used for external testing. Univariate and stepwise multivariate Cox regression were used for feature selection. A nomogram for 1-, 3-, and 5-year postoperative survival rates was constructed accordingly. Performance assessment included Harrell's concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves. Kaplan-Meier curves were utilized to evaluate the risk stratification results of the nomogram. Decision curves were used to reflect the net benefit. Results: Eight factors, TNM stage, age-adjusted Charlson Comorbidity Index (aCCI), body mass index (BMI), R0 resection, blood platelet count, and serum levels of albumin, CA125, CA199 were incorporated in the nomogram. The time-dependent C-index consistently exceeded 0.70 from 6 months to 5 years, and time-dependent ROC revealed an area under the curve (AUC) of over 75% for 1-, 3-, and 5-year survival. The calibration curves, Kaplan-Meier curves and decision curves also indicated good prognostic performance and clinical benefit, surpassing traditional indicators TNM staging and CA199 levels. The reliability of results was further proved in the independent external testing set. Conclusions: The novel nomogram exhibited good prognostic efficacy and robust generalizability in GBC patients, which might be a promising tool for aiding clinical decision-making. Highlights: • A representative surgical cohort of GBC was retrospectively established. • Clinical variables related to surgical management were comprehensively collected and analyzed. • The study introduced the independent prognostic significance of aCCI and CA125 in GBC. • A novel multi-factor nomogram was developed with satisfactory prognostic performance, as confirmed by internal and external validations. [ABSTRACT FROM AUTHOR]

Xanthogranulomatous cholecystitis (XGC) is a rare type of cholecystitis that, despite being benign poses diagnostic challenges due to its low prevalence and need for consensus on diagnostic criteria. Consequently, distinguishing XGC from gallbladder cancer (GBC) is challenging, leading to clinical misdiagnoses. This article presents a case where a patient initially diagnosed with GBC was later found to have XGC. [ABSTRACT FROM AUTHOR]

BackgroundThe incidence of gall bladder cancer (GBC), one of the most prevalent bile duct malignancies, differs with ethnicity and geographic location. To treat unresected GBC in the Chinese setting, this study aimed to assess the financial effectiveness of a combination of modified gemcitabine and oxaliplatin.MethodsData from a randomized controlled study in which individuals with metastatic GBC were treated with oxaliplatin and gemcitabine demonstrated improved survival. A Markov model is built to calculate the incremental cost–benefit ratio (ICER) from the viewpoint of Chinese society on the basis of clinical symptoms and disease development. One-way certainty and probability sensitivity analyses are used to describe the uncertainty in the model.ResultsCompared with those of fluorouracil (FU) and folinic acid, the utility value of modified oxaliplatin combined with gemcitabine increased by 0.22QALY throughout the course of the 10-year simulation (FA). In a Chinese healthcare setting, the cost-effectiveness ratio (ICER) is $52765.59/QALY, with a 0% chance of cost–benefit at the WTP (willing-to-pay) level of $37697.00/QALY. The ICERs predicted by sensitivity analysis were not significantly affected by cost variations related to the management of Grade 3–4 AEs, the diagnostics used, or hospitalization expenditures.ConclusionIn a Chinese healthcare context, modified gemcitabine coupled with oxaliplatin (mGEMOX) is not a cost-effective treatment option for unresectable GBC.

Abstract Gallbladder cancer (GBC) is a rare but very aggressive most common digestive tract cancer with a high mortality rate due to delayed diagnosis at the advanced stage. Moreover, GBC progression shows asymptomatic characteristics making it impossible to detect at an early stage. In these circumstances, conventional therapy like surgery, chemotherapy, and radiotherapy becomes refractive. However, few studies reported some molecular markers like KRAS (Kirsten Rat Sarcoma) mutation, upregulation of HER2/neu, EGFR (Epidermal Growth Factor Receptor), and microRNAs in GBC. However, the absence of some specific early diagnostic and prognostic markers is the biggest hurdle for the therapy of GBC to date. The present study has been designed to identify some specific molecular markers for precise diagnosis, and prognosis, for successful treatment of the GBC. By In Silico a network-centric analysis of two microarray datasets; (GSE202479) and (GSE13222) from the Gene Expression Omnibus (GEO) database, shows 50 differentially expressed genes (DEGs) associated with GBC. Further network analysis revealed that 12 genes are highly interconnected based on the highest MCODE (Molecular Complex Detection) value, among all three genes; TRIP13 (Thyroid Receptor Interacting Protein), NEK2 (Never in Mitosis gene-A related Kinase 2), and TPX2 (Targeting Protein for Xklp2) having highest network interaction with transcription factors and miRNA suggesting critically associated with GBC. Further survival analysis data corroborate the association of these genes; TRIP13, NEK2, and TPX2 with GBC. Thus, TRIP13, NEK2, and TPX2 genes are significantly correlated with a greater risk of mortality, transforming them from mere biomarkers of the GBC for early detections and may emerge as prognostic markers for treatment.

This article provides an overview of the role of imaging in the diagnosis, staging, and treatment of biliary tract cancer (BTC), which includes cancers of the biliary tree and gallbladder. The incidence of BTC varies by region. Imaging techniques such as ultrasound, CT, and MRI are commonly used for detection and staging of BTC. The article also mentions emerging approaches like radiomics and artificial intelligence that can provide valuable information for diagnosis and prognosis. The document is a list of references related to hepatic and biliary regeneration, cholangiocarcinoma, and gallbladder cancer. [Extracted from the article]

The progression of gallbladder inflammatory lesions to invasive cancer remains poorly understood, necessitating research on biomarkers involved in this transition. This study aims to identify and validate proteins associated with this progression, offering insights into potential diagnostic biomarkers for gallbladder cancer (GBC). Label-free liquid chromatography assisted tandem mass spectrometry (LC-MS/MS) proteomics was performed on samples from 10 cases each of GBC and inflammatory lesions, with technical duplicates. Validation was conducted through the enzyme-linked immunosorbent assay (ELISA) using 80 samples (40 GBC and 40 inflammatory lesions). Bioinformatics tools analyzed protein-protein interaction (PPI) networks and pathways. Statistical correlations with clinicopathological variables were assessed. Prognostic evaluation utilized Kaplan–Meier survival analysis and Cox regression analyses. mRNA expressions were studied using real time-polymerase chain reaction (RT-PCR). Out of 5,714 proteins analyzed, 621 were differentially expressed. Three upregulated (the S100 calcium-binding protein P [S100P], polymeric immunoglobulin receptor [PIGR], and complement C1q-binding protein [C1QBP]) and two downregulated (transgelin [TAGLN] and calponin 1 [CNN1]) proteins showed significant expression. Pathway analysis implicated involvement of proteoglycans in cancer and glycosaminoglycan metabolism. Significant correlations were observed between protein concentrations and clinicopathological variables. Prognostic factors such as tumor size, lymph node metastasis, and preoperative bilirubin levels were associated with overall survival. Protein-based assays demonstrated higher resolution compared to mRNA analysis, suggesting their utility in GBC risk stratification. S100P, PIGR, C1QBP, TAGLN, and CNN1 emerge as potential protein-based biomarkers involved in the progression from gallbladder inflammatory lesions to invasive cancer. These findings hold promise for improved diagnostic and prognostic strategies in GBC management.

Gallbladder cancer (GBC) is one of the quiet prevalent and aggressive biliary tract malignant neoplasms distinguished by significant cellular heterogeneity, metastatic activity, and a poor prognosis, with varied frequency worldwide. Most cases are detected incidentally while routine screening imaging or pathological investigation of cholecystectomy tissues and usually present with advanced disease. The surgical resection is usually done in the initial clinical stage having limited spread. Despite the surgical therapy, the death rate is significant. Furthermore, the molecular mechanisms affecting the clinical course of inflammatory gallbladder to carcinogenesis remain poorly understood. There is an impending need for developing diagnostic biomarkers and targeted approaches for GBC. The newer molecular platform, such as next-generation sequencing (NGS), such as RNA-sequencing (RNAseq), single-cell sequencing, and microarray technology, has revolutionized the field of genomics, opened a new perspective in defining genetic and epigenetic characteristics identifying molecules as possible therapeutic targets. Therefore, in this review, we would analyze transcriptomic and epigenomics profiles of GBC using already published high-throughput sequencing-based studies published between 2010 and 2023. The review would also analyze the possible impact of the technological advancement on the patient management strategy and overall survival. This may also help identify target genes and pathways linked to GBC, which may help establish molecular biomarkers, for early GBC diagnosis, personalized therapy, and management. [ABSTRACT FROM AUTHOR]

Introduction: Systemic inflammatory markers have been validated as prognostic factors for patients with biliary tract cancer (BTC). The aim of this study was to evaluate specific immunologic prognostic markers and immune responses by analyzing preoperative plasma samples from a large prospectively collected biobank. Methods: Expression of 92 proteins representing adaptive and innate immune responses was investigated in plasma from 102 patients undergoing resection for BTC 2009-2017 (perihilar cholangiocarcinoma n=46, intrahepatic cholangiocarcinoma n=27, gallbladder cancer n=29), by means of a highthroughput multiplexed immunoassay. Association with overall survival was analyzed by Cox regression, with internal validation and calibration. Tumor tissue bulk and single-cell gene expression of identified markers and receptors/ligands was analyzed in external cohorts. Results: Three preoperative plasma markers were independently associated with survival: TRAIL, TIE2 and CSF1, with hazard ratios (95% confidence intervals) 0.30 (0.16-0.56), 2.78 (1.20-6.48) and 4.02 (1.40-11.59) respectively. The discrimination of a preoperative prognostic model with the three plasma markers was assessed with concordance-index 0.70, while the concordanceindex of a postoperative model with histopathological staging was 0.66. Accounting for subgroup differences, prognostic factors were assessed for each type of BTC. TRAIL and CSF1 were prognostic factors in intrahepatic cholangiocarcinoma. In independent cohorts, TRAIL-receptor expression was higher in tumor tissue and seen in malignant cells, with TRAIL and CSF1 expressed by intra- and peritumoral immune cells. Intratumoral TRAIL-activity was decreased compared to peritumoral immune cells, while CSF1-activity was increased. The highest CSF1 activity was seen in intratumoral macrophages, while the highest TRAIL-activity was seen in peritumoral T-cells. Discussion: In conclusion, three preoperative immunological plasma markers were prognostic for survival after surgery for BTC, providing good discrimination, even compared to postoperative pathology. TRAIL and CSF1, prognostic factors in intrahepatic cholangiocarcinoma, showed marked differences in expression and activity between intra- and peritumoral immune cells. [ABSTRACT FROM AUTHOR]

Abstract Background Gallbladder cancer (GBC) is the most prevalent and invasive biliary tract malignancy. As a GTPase-activating protein, Neurofibromin 1 (NF1) is a tumor suppressor that negatively regulates the RAS signaling pathway, and its abnormality leads to neurofibromatosis type 1 (NF-1) disease. However, the role of NF1 playing in GBC and the underlying molecular mechanism has not been defined yet. Methods A combination of NOZ and EH-GB1 cell lines as well as nude mice, were utilized in this study. mRNA expression and protein levels of NF1 and YAP1 were evaluated by quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC). In vitro and in vivo assays were performed to explore the biological effects of NF1 in NOZ and EH-GB1 cells via siRNA or lv-shRNA mediated knockdown. Direct interaction between NF1 and YAP1 was detected by confocal microscopy and co-immunoprecipitation (Co-IP), and further confirmed by GST pull-down assay and isothermal titration calorimetry assay (ITC). The stability of proteins was measured by western blot (WB) in the presence of cycloheximide. Results This study showed that a higher level of NF1 and YAP1 was found in GBC samples than in normal tissues and associated with worse prognoses. The NF1 knockdown impaired the proliferation and migration of NOZ in vivo and in vitro by downregulating YAP1 expression. Moreover, NF1 co-localized with YAP1 in NOZ and EH-GB1 cells, and the WW domains of YAP1 specifically recognized the PPQY motif of NF1. The structural modeling also indicated the hydrophobic interactions between YAP1 and NF1. On the other hand, YAP1 knockdown also impaired the proliferation of NOZ in vitro, phenocopying the effects of NF1 knockdown. Overexpression of YAP1 can partially rescue the impaired proliferation in NF1 stably knockdown cells. In mechanism, NF1 interacted with YAP1 and increased the stability of YAP1 by preventing ubiquitination. Conclusions Our findings discovered a novel oncogenic function of NF1 by directly interacting with YAP1 protein and stabilizing YAP1 to protect it from proteasome degradation in NOZ cells. NF1 may serve as a potential therapeutic target in GBC.

Chronic inflammation in the gallbladder leading to persistent epithelium damage promotes invasive cancer. The study aimed to assess the prognostic value of PDL1 and CA19-9 markers in cancer/inflammatory lesions of the gallbladder. A total of 29 cases (19 cancer and 10 inflammatory) were included. The PDL1 protein concentration level and mRNA expression were assessed in the tissues’ lysates by ELISA and real-time PCR, respectively. PDL1 and CA19-9 concentration levels were compared and statistically related with clinico-pathological variables. The PDL1 protein level and its relative mRNA expression were correlated. Kaplan–Meir survival and Cox regression analyses were conducted for predicting prognosis. This study investigated the PDL1 and CA19-9 marker expression in both cancer and inflammatory cases of the gallbladder (p = 0.48 and p = 0.17 respectively). PDL1 protein expression was significantly associated with the hormonal profile of the cases (p = 0.04) at an optimum cut-off value of 13 pg/mL, while the CA19-9 marker expression was correlated with the status of liver metastasis (p = 0.0043) and size of the tumor (p = 0.004). A low PDL1 concentration was found when compared to the CA19-9 level among cancer cases (p = 0.12) and proportional in the inflammatory lesions (p = 0.63). A significant positive correlation was found between the PDL1 protein and its relative mRNA expressions in the inflammatory lesions (p = 0.029) when compared to cancer cases (p = 0.069). Our results showed that a protein-based assay for PDL1 expression would be more sensitive compared to RNA based assays for GBC risk stratifications. Overall survival was predicted with CA19-9 and PDL1 levels (p = 0.0074, p = 0.23, respectively). PDL1 and CA19-9 may act as a probable predictor of a poor prognosis in gallbladder cancer (GBC) cases.

Abstract Background The present study aims to evaluate the survival status of patients with gallbladder cancer (GBC) and explore the prognostic factors for the improvement and preventions. Methods The study consists of 176 patients with clinically diagnosed gallbladder cancer; the study was conducted between 2019 and 2021 registered at Kamala Nehru Memorial Cancer Hospital, Prayagraj, India. The survival rates were analyzed by the Kaplan-Meier method; survival rate difference was analyzed by log-rank test, prognosis factors; and hazard ratio for mortality outcomes was estimated using Cox regression method. Results The overall median survival time of patients was 5 months with the 1-year, 2-year, and 3-year survival rates of 24.4%, 8.5%, and 4.5%, respectively. The 3-year survival for patients with jaundice was 2.9%, liver infiltration (4.2%), gallstones (0.8%), and with advanced tumor grade (1.4%). Elderly GBC patients had lower survival rates (3.8%), while the 3-year overall survival for patients residing in urban areas dropped to zero. No patients in the tumor stage (T3/T4) and with distance metastasis stage survived in 3 years, while only 1.1% of patients with advanced nodal stage survived. On receiving surgery and radiation therapy, the 3-year survival rate increased to 19.5% and 35%, respectively. The results of multivariate analysis showed that urban region (HR = 1.568, p = 0.040), gallstone or not (1.571, p = 0.049), N stage (HR = 1.468, p = 0.029), and M stage (HR = 2.289, p < 0.0001) were independent risk factors for prognosis, while surgery or not (HR = 0.573, p = 0.030) was the protective factor for the prognosis of GBC. Conclusion The overall survival of GBC in the Gangetic belt is poor. The geographical region of patients, gallstones, and N and M stage was the risk factors for prognosis, while surgery or not was the protective factor for the prognosis of GBC.

Abstract Background Biliary tract cancers (BTCs) are a series of heterogeneous malignancies that are broadly grouped based on the anatomical site where they arise into subtypes including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Methods and Results The present study provides an overview of the epidemiology of the various BTCs based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2018. Distinct differences in both incidence and mortality rates were observed for these BTCs as a function of age, sex, ethnicity, and calendar year. In 2018, BTCs emerged as the fifth most prevalent form of alimentary tract cancer in the USA. While the incidence and mortality of ICC appear to be increasing, the incidence rates of GBC, ECC, and AVC have remained stable, as have the corresponding mortality rates. The most common and deadliest BTCs in 2018 were ICC and GBC among males and females, respectively. The ethnic groups exhibiting the highest incidence rates of these different BTCs were American Indians and Alaska Natives for GBC, and Asian and Pacific Islanders for ICC, ECC, and AVC. The incidence of all of these forms of BTC rose with age. There were some variations in BTCs in terms of staging, locoregional surgical treatments, adjuvant therapies, and prognostic outcomes from 2000 to 2018. Conclusions The epidemiological characteristics, staging, locoregional surgical treatments, adjuvant therapies, and prognostic outcomes were distinct for each of these BTCs.

Background: Gallbladder cancer (GBC) is the most prevalent and invasive biliary tract malignancy. As a GTPase-activating protein, Neurofibromin 1 (NF1) is a tumor suppressor that negatively regulates the RAS signaling pathway, and its abnormality leads to neurofibromatosis type 1 (NF-1) disease. However, the role of NF1 playing in GBC and the underlying molecular mechanism has not been defined yet. Methods: A combination of NOZ and EH-GB1 cell lines as well as nude mice, were utilized in this study. mRNA expression and protein levels of NF1 and YAP1 were evaluated by quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC). In vitro and in vivo assays were performed to explore the biological effects of NF1 in NOZ and EH-GB1 cells via siRNA or lv-shRNA mediated knockdown. Direct interaction between NF1 and YAP1 was detected by confocal microscopy and co-immunoprecipitation (Co-IP), and further confirmed by GST pull-down assay and isothermal titration calorimetry assay (ITC). The stability of proteins was measured by western blot (WB) in the presence of cycloheximide. Results: This study showed that a higher level of NF1 and YAP1 was found in GBC samples than in normal tissues and associated with worse prognoses. The NF1 knockdown impaired the proliferation and migration of NOZ in vivo and in vitro by downregulating YAP1 expression. Moreover, NF1 co-localized with YAP1 in NOZ and EH-GB1 cells, and the WW domains of YAP1 specifically recognized the PPQY motif of NF1. The structural modeling also indicated the hydrophobic interactions between YAP1 and NF1. On the other hand, YAP1 knockdown also impaired the proliferation of NOZ in vitro, phenocopying the effects of NF1 knockdown. Overexpression of YAP1 can partially rescue the impaired proliferation in NF1 stably knockdown cells. In mechanism, NF1 interacted with YAP1 and increased the stability of YAP1 by preventing ubiquitination. Conclusions: Our findings discovered a novel oncogenic function of NF1 by directly interacting with YAP1 protein and stabilizing YAP1 to protect it from proteasome degradation in NOZ cells. NF1 may serve as a potential therapeutic target in GBC. [ABSTRACT FROM AUTHOR]

Objectives: It is significant to develop effective prognostic strategies and techniques for improving the survival rate of gallbladder carcinoma (GBC). We aim to develop the prediction model from multi-clinical indicators combined artificial intelligence (AI) algorithm for the prognosis of GBC. Methods: A total of 122 patients with GBC from January 2015 to December 2019 were collected in this study. Based on the analysis of correlation, relative risk, receiver operator characteristic curve, and importance by AI algorithm analysis between clinical factors and recurrence and survival, the two multi-index classifiers (MIC1 and MIC2) were obtained. The two classifiers combined eight AI algorithms to model the recurrence and survival. The two models with the highest area under the curve (AUC) were selected to test the performance of prognosis prediction in the testing dataset. Results: The MIC1 has ten indicators, and the MIC2 has nine indicators. The combination of the MIC1 classifier and the "avNNet" model can predict recurrence with an AUC of 0.944. The MIC2 classifier and "glmet" model combination can predict survival with an AUC of 0.882. The Kaplan-Meier analysis shows that MIC1 and MIC2 indicators can effectively predict the median survival of DFS and OS, and there is no statistically significant difference in the prediction results of the indicators (MIC1: x² = 6.849, P = 0.653; MIC2: x² = 9.14, P = 0.519). Conclusions: The MIC1 and MIC2 combined with avNNet and mda models have high sensitivity and specificity in predicting the prognosis of GBC. [ABSTRACT FROM AUTHOR]

IntroductionSystemic inflammatory markers have been validated as prognostic factors for patients with biliary tract cancer (BTC). The aim of this study was to evaluate specific immunologic prognostic markers and immune responses by analyzing preoperative plasma samples from a large prospectively collected biobank.MethodsExpression of 92 proteins representing adaptive and innate immune responses was investigated in plasma from 102 patients undergoing resection for BTC 2009-2017 (perihilar cholangiocarcinoma n=46, intrahepatic cholangiocarcinoma n=27, gallbladder cancer n=29), by means of a high-throughput multiplexed immunoassay. Association with overall survival was analyzed by Cox regression, with internal validation and calibration. Tumor tissue bulk and single-cell gene expression of identified markers and receptors/ligands was analyzed in external cohorts.ResultsThree preoperative plasma markers were independently associated with survival: TRAIL, TIE2 and CSF1, with hazard ratios (95% confidence intervals) 0.30 (0.16-0.56), 2.78 (1.20-6.48) and 4.02 (1.40-11.59) respectively. The discrimination of a preoperative prognostic model with the three plasma markers was assessed with concordance-index 0.70, while the concordance-index of a postoperative model with histopathological staging was 0.66. Accounting for subgroup differences, prognostic factors were assessed for each type of BTC. TRAIL and CSF1 were prognostic factors in intrahepatic cholangiocarcinoma. In independent cohorts, TRAIL-receptor expression was higher in tumor tissue and seen in malignant cells, with TRAIL and CSF1 expressed by intra- and peritumoral immune cells. Intratumoral TRAIL-activity was decreased compared to peritumoral immune cells, while CSF1-activity was increased. The highest CSF1 activity was seen in intratumoral macrophages, while the highest TRAIL-activity was seen in peritumoral T-cells.DiscussionIn conclusion, three preoperative immunological plasma markers were prognostic for survival after surgery for BTC, providing good discrimination, even compared to postoperative pathology. TRAIL and CSF1, prognostic factors in intrahepatic cholangiocarcinoma, showed marked differences in expression and activity between intra- and peritumoral immune cells.

Chronic inflammation in the gallbladder leading to persistent epithelium damage promotes invasive cancer. The study aimed to assess the prognostic value of PDL1 and CA19-9 markers in cancer/inflammatory lesions of the gallbladder. A total of 29 cases (19 cancer and 10 inflammatory) were included. The PDL1 protein concentration level and mRNA expression were assessed in the tissues' lysates by ELISA and real-time PCR, respectively. PDL1 and CA19-9 concentration levels were compared and statistically related with clinico-pathological variables. The PDL1 protein level and its relative mRNA expression were correlated. Kaplan–Meir survival and Cox regression analyses were conducted for predicting prognosis. This study investigated the PDL1 and CA19-9 marker expression in both cancer and inflammatory cases of the gallbladder (p = 0.48 and p = 0.17 respectively). PDL1 protein expression was significantly associated with the hormonal profile of the cases (p = 0.04) at an optimum cut-off value of 13 pg/mL, while the CA19-9 marker expression was correlated with the status of liver metastasis (p = 0.0043) and size of the tumor (p = 0.004). A low PDL1 concentration was found when compared to the CA19-9 level among cancer cases (p = 0.12) and proportional in the inflammatory lesions (p = 0.63). A significant positive correlation was found between the PDL1 protein and its relative mRNA expressions in the inflammatory lesions (p = 0.029) when compared to cancer cases (p = 0.069). Our results showed that a protein-based assay for PDL1 expression would be more sensitive compared to RNA based assays for GBC risk stratifications. Overall survival was predicted with CA19-9 and PDL1 levels (p = 0.0074, p = 0.23, respectively). PDL1 and CA19-9 may act as a probable predictor of a poor prognosis in gallbladder cancer (GBC) cases. [ABSTRACT FROM AUTHOR]

Gallbladder carcinoma (GBC) is a relatively rare disease of old age with adenocarcinoma being the most prevalent subtype. It is extremely rare in childhood and adolescence, and only a few cases have been reported to date. A 15-year-old boy presented in the outpatient department referred from the periphery with dull progressive right upper quadrant abdominal pain, associated with jaundice, abdominal distension, anorexia and significant weight loss for the past three months. The patient's medical history was inconclusive. Laboratory evaluations revealed obstructive jaundice. Imaging showed an infiltrative mass at the porta hepatis which upon biopsy demonstrated a moderately differentiated gallbladder adenocarcinoma. Percutaneous transhepatic biliary drainage (PTBD) was done for symptom relief. Chemotherapy with a combination of gemcitabine and carboplatin was opted with palliative intent. After three cycles the patient still showed no response, so the chemotherapy was stopped and only symptomatic treatment was continued. Urgent provision of medical care upon the development of symptoms, early sonographic diagnosis and timely cholecystectomy along with adjuvant chemotherapy are crucial in significantly prolonging survival and reducing patient suffering. Gene panel testing and chemosensitivity assay further optimize treatment and help in better understanding of disease., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Sabih et al.)

Background: Biliary tract cancers (BTCs) are a series of heterogeneous malignancies that are broadly grouped based on the anatomical site where they arise into subtypes including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Methods and Results: The present study provides an overview of the epidemiology of the various BTCs based on data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2018. Distinct differences in both incidence and mortality rates were observed for these BTCs as a function of age, sex, ethnicity, and calendar year. In 2018, BTCs emerged as the fifth most prevalent form of alimentary tract cancer in the USA. While the incidence and mortality of ICC appear to be increasing, the incidence rates of GBC, ECC, and AVC have remained stable, as have the corresponding mortality rates. The most common and deadliest BTCs in 2018 were ICC and GBC among males and females, respectively. The ethnic groups exhibiting the highest incidence rates of these different BTCs were American Indians and Alaska Natives for GBC, and Asian and Pacific Islanders for ICC, ECC, and AVC. The incidence of all of these forms of BTC rose with age. There were some variations in BTCs in terms of staging, locoregional surgical treatments, adjuvant therapies, and prognostic outcomes from 2000 to 2018. Conclusions: The epidemiological characteristics, staging, locoregional surgical treatments, adjuvant therapies, and prognostic outcomes were distinct for each of these BTCs. [ABSTRACT FROM AUTHOR]

Background: The present study aims to evaluate the survival status of patients with gallbladder cancer (GBC) and explore the prognostic factors for the improvement and preventions. Methods: The study consists of 176 patients with clinically diagnosed gallbladder cancer; the study was conducted between 2019 and 2021 registered at Kamala Nehru Memorial Cancer Hospital, Prayagraj, India. The survival rates were analyzed by the Kaplan-Meier method; survival rate difference was analyzed by log-rank test, prognosis factors; and hazard ratio for mortality outcomes was estimated using Cox regression method. Results: The overall median survival time of patients was 5 months with the 1-year, 2-year, and 3-year survival rates of 24.4%, 8.5%, and 4.5%, respectively. The 3-year survival for patients with jaundice was 2.9%, liver infiltration (4.2%), gallstones (0.8%), and with advanced tumor grade (1.4%). Elderly GBC patients had lower survival rates (3.8%), while the 3-year overall survival for patients residing in urban areas dropped to zero. No patients in the tumor stage (T3/T4) and with distance metastasis stage survived in 3 years, while only 1.1% of patients with advanced nodal stage survived. On receiving surgery and radiation therapy, the 3-year survival rate increased to 19.5% and 35%, respectively. The results of multivariate analysis showed that urban region (HR = 1.568, p = 0.040), gallstone or not (1.571, p = 0.049), N stage (HR = 1.468, p = 0.029), and M stage (HR = 2.289, p < 0.0001) were independent risk factors for prognosis, while surgery or not (HR = 0.573, p = 0.030) was the protective factor for the prognosis of GBC. Conclusion: The overall survival of GBC in the Gangetic belt is poor. The geographical region of patients, gallstones, and N and M stage was the risk factors for prognosis, while surgery or not was the protective factor for the prognosis of GBC. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) is the sixth most common gastrointestinal tract cancer with a very low overall survival and poor prognosis. Profiling of cancer-derived extracellular vesicles (EVs) is an emerging strategy for identification of candidate biomarkers for the detection and prognosis of the disease. The aim of the study was to analyse the protein content from GBC cell line- derived EVs with emphasis on proteins which could be used as candidate biomarkers for the detection of GBC. NOZ and OCUG-1 cell lines were cultured and EVs were isolated from conditioned media. LC-MS/MS analysis of total EV proteins led to the identification of a total of 268 proteins in both the cell lines. Of these, 110 proteins were identified with ≥2 unique peptides with ≥2 PSMs in at least two experimental and technical replicate runs. STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) database was used to perform bioinformatics analysis of 110 proteins which showed 'cell adhesion molecule binding', 'integrin binding', 'cadherin binding' among the top molecular functions and 'focal adhesion' to be among the top pathways associated with the EV proteins. A total of 42 proteins including haptoglobin (HP), pyruvate kinase (PKM), annexin A2 (ANXA2), thrombospondin 1 (THBS1), were reported to be differentially abundant in GBC tissue. Of these, 16 proteins were reported to be differentially abundant in plasma and plasma-derived EVs. We infer these proteins to be highly important to be considered as potential circulatory biomarkers for the detection of GBC. To check the validity of this hypothesis, one of the proteins, haptoglobin (HP) as a representative case, was analysed in plasma by quantitative Enzyme linked immunosorbent assay (ELISA) and we observed its increased levels in GBC in comparison to controls (p value= 0.0063). Receiver operating character (ROC) curve analysis for GBC vs controls showed an Area under the ROC Curve (AUC) of 0.8264 for HP with 22% sensitivity against 100% specificity. We propose that HP along with other candidate proteins may be further explored for their clinical application. [ABSTRACT FROM AUTHOR]

BackgroundThe feasibility and safety of robotic extended cholecystectomy (REC) are still uncertain. This study was performed to compare the short- and long-term outcomes of REC with those of open extended cholecystectomy (OEC) for T1a–T3 gallbladder cancer.MethodsFrom January 2015 to April 2022, 28 patients underwent REC in our center. To minimize any confounding factors, a 1:2 propensity score-matching analysis was conducted based on the patients’ demographics, liver function indicators, T stage, and symptoms. The data regarding demographics, perioperative outcomes, and long-term oncologic outcomes were reviewed.ResultsThe visual analogue scale score was significantly lower in the REC than OEC group immediately postoperatively (3.68 ± 2.09 vs. 4.73 ± 1.85, P = 0.008), on postoperative day 1 (2.96 ± 1.75 vs. 3.69 ± 1.41, P = 0.023), and on postoperative day 2 (2.36 ± 1.55 vs. 2.92 ± 1.21, P = 0.031). In addition, the REC group exhibited a shorter time to first ambulation (P = 0.043), a shorter time to drainage tube removal (P = 0.038), and a shorter postoperative stay (P = 0.037), but hospital costs were significantly higher in the REC group (P

Gallbladder cancer (GBC) is the sixth most common gastrointestinal tract cancer with a very low overall survival and poor prognosis. Profiling of cancer-derived extracellular vesicles (EVs) is an emerging strategy for identification of candidate biomarkers for the detection and prognosis of the disease. The aim of the study was to analyse the protein content from GBC cell line- derived EVs with emphasis on proteins which could be used as candidate biomarkers for the detection of GBC. NOZ and OCUG-1 cell lines were cultured and EVs were isolated from conditioned media. LC-MS/MS analysis of total EV proteins led to the identification of a total of 268 proteins in both the cell lines. Of these, 110 proteins were identified with ≥2 unique peptides with ≥2 PSMs in at least two experimental and technical replicate runs. STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) database was used to perform bioinformatics analysis of 110 proteins which showed ‘cell adhesion molecule binding’, ‘integrin binding’, ‘cadherin binding’ among the top molecular functions and ‘focal adhesion’ to be among the top pathways associated with the EV proteins. A total of 42 proteins including haptoglobin (HP), pyruvate kinase (PKM), annexin A2 (ANXA2), thrombospondin 1 (THBS1), were reported to be differentially abundant in GBC tissue. Of these, 16 proteins were reported to be differentially abundant in plasma and plasma-derived EVs. We infer these proteins to be highly important to be considered as potential circulatory biomarkers for the detection of GBC. To check the validity of this hypothesis, one of the proteins, haptoglobin (HP) as a representative case, was analysed in plasma by quantitative Enzyme- linked immunosorbent assay (ELISA) and we observed its increased levels in GBC in comparison to controls (p value= 0.0063). Receiver operating characteristic (ROC) curve analysis for GBC vs controls showed an Area under the ROC Curve (AUC) of 0.8264 for HP with 22% sensitivity against 100% specificity. We propose that HP along with other candidate proteins may be further explored for their clinical application.

Gallbladder cancer (GBC) is one of the lethal cancers with an extremely poor prognosis. In the recent 20 years, research on GBC has developed rapidly. Here we aim to perform a systematical bibliometric analysis on the current foci and status of GBC research. This study analyzes trends in GBC research and compares contributions from different countries and regions, institutions, and authors. All publications in GBC research from 2001 to 2021 in the Web of Science Core Collection (WoSCC) database were collected. Microsoft Excel 2010 and GraphPad Prism 9 were used to analyze publication data and publication trends. VOSviewer 1.6.17 was adapted to generate a visual network of keywords in surgical training research. A total of 3,323 publications were included. China was the most productive country, with the highest number of publications (n = 900, 27.08%). Shanghai Jiaotong University and Roa JC were the most productive institution and authors, contributing 215 and 89 publications, respectively. Keywords were classified into five clusters, each representing a key topic. The main clusters of GBC are related to surgery therapy, mechanism research-related study, and non-surgery therapy, while migration is the current hotspot of GBC research. The scientific progression of GBC research over the past two decades was comprehensively analyzed by this bibliometric study. Finding deeper mechanisms in the migration of GBC cells, new biomarkers, and highly effective nomograms will be the major problems and directions in the future. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer (GBC) represents a wide geographical diversity as well as heterogeneity in clinical and genomic landscape. There seems to be little progress in the development of diagnostic biomarkers, targeted therapies or individualized approaches to GBC management. In this study, we investigated the whole transcriptome profile of GBC patients using RNA sequencing and identified key genes and pathways associated with gallbladder cancer using bioinformatics. Methodology: A total of 10 cases of GBC were collected and sequenced. The raw reads of the gallbladder sample was compared with the gallbladder normal control (SRA Database ID: ERX288537: HPA RNA-seq normal tissues gallbladder). Using Gene ontology analysis the differentially expressed genes were categorized into the biological pathway, cellular component, and molecular function. Pathway enrichment analyses, protein-protein interaction, transcription factor and miRNA interaction that regulate the expression of hub genes were conducted using bioinformatics tool. Results: A total of 954 differentially expressed mRNA transcripts were identified, including overexpression of REG4, TMEM238, S100A2, LYPD2, and KRT17, as well as underexpressed genes like CCKAR, IGSF10, CHRM2, CRISP3, and FGF19. Enrichment analysis showed the metabolic pathways to be the top five cancer pathways in gallbladder carcinogenesis besides PI3k-Akt signalling pathway, cAMP signalling pathway, miRNAs in cancer, and cell adhesion profile of GBC. Conclusions: CCKAR, CDKN2A and LRRK2 were found to be most involved genes in its progression and development through different regulatory pathways. Further, most of the genes were significantly involved in PI3k-Akt, Wnt and hedgehog signaling pathways which have a key role in gallbladder cancer development. [ABSTRACT FROM AUTHOR]

Aims: To investigate the clinical efficacy and prognostic factors of primary gallbladder cancer (GBC) treated by radical surgery. Methods: The clinical and pathological data of 168 patients with primary gallbladder cancer admitted and treated in the Third Affiliated Hospital of Soochow University from January 1st, 2010 to December 31st, 2018 were analyzed retrospectively. Kaplan Meier method was used to draw the survival curve and evaluate the survival rate. Chi-square test was used for univariate analysis and binary logistic regression was used for multivariate analysis. Results: 94 cases showed symptoms of abdominal pain and abdominal distension. 7 cases showed symptoms of fatigue and weight loss. Jaundice occurred in 10 patients. Fever occurred in 6 patients. 51 patients had no symptoms at all. The median survival time of 168 patients was 35.0 (1.0 ~ 142.0) months. The overall 1-, 2- and 3-year cumulative survival rates were 69.6%, 55.4% and 48.8% respectively. The univariate analysis indicated that preoperative bilirubin, tumor size, tumor location, pathological type, degree of differentiation, liver invasion, nerve invasion, vascular invasion, surgical margin, filtration depth and N staging were significant factors influencing prognosis of patients with primary GBC (P<0.05). The results of multivariate analysis demonstrated that degree of differentiation, nerve invasion, filtration depth and N staging were independent risk factors for prognosis of patients with primary GBC (P<0.05). Conclusion: Patients with risk factors of gallbladder cancer should be more active in early cholecystectomy to avoid the malignant transformation of benign diseases. Degree of differentiation, nerve invasion, filtration depth and N staging were important factors for poor prognosis of patients with primary GBC. For T4 staging patients, preoperative evaluation should be more comprehensive, and patients and surgeons should be more prudent in adopting appropriate clinical treatment. The primary purpose should be prolonging the survival time and improving the quality of life. [ABSTRACT FROM AUTHOR]

AimsTo investigate the clinical efficacy and prognostic factors of primary gallbladder cancer (GBC) treated by radical surgery.MethodsThe clinical and pathological data of 168 patients with primary gallbladder cancer admitted and treated in the Third Affiliated Hospital of Soochow University from January 1st, 2010 to December 31st, 2018 were analyzed retrospectively. Kaplan Meier method was used to draw the survival curve and evaluate the survival rate. Chi-square test was used for univariate analysis and binary logistic regression was used for multivariate analysis.Results94 cases showed symptoms of abdominal pain and abdominal distension. 7 cases showed symptoms of fatigue and weight loss. Jaundice occurred in 10 patients. Fever occurred in 6 patients. 51 patients had no symptoms at all. The median survival time of 168 patients was 35.0 (1.0 ~ 142.0) months. The overall 1-, 2- and 3-year cumulative survival rates were 69.6%, 55.4% and 48.8% respectively. The univariate analysis indicated that preoperative bilirubin, tumor size, tumor location, pathological type, degree of differentiation, liver invasion, nerve invasion, vascular invasion, surgical margin, filtration depth and N staging were significant factors influencing prognosis of patients with primary GBC (P

Background: Gallbladder cancer (GBC) was once considered a contraindication for laparoscopic surgery, but it is becoming more common to use laparoscopic surgery for GBC treatment. The aim of this study was to analyze the long- and short-term outcomes of patients with more advanced T-staged GBC treated with curative intent as defined by the National Comprehensive Cancer Network (NCCN) after laparoscopic resection (LR) versus open resection (OR)., Methods: A multicenter database was used to select consecutive GBC patients treated with curative-intent resection as defined by the NCCN between 2016 and 2020. The patients were divided into the LR group and the OR group. Propensity score matching (PSM) was used to eliminate selection bias. The endpoints were overall survival (OS), progression-free survival (PFS), and short-term outcomes. Risk factors that were independently associated with OS and PFS were identified., Results: Of 626 GBC patients treated with curative-intent resection, after PSM, 51 patients were in the LR group and 153 patients were in the OR group. The LR group had more patients who were suitable to receive adjuvant chemotherapy (AC), a longer operation time, more harvested lymph nodes, and a lower overall morbidity rate. The rates of OS and PFS were not significantly different between the two groups. AC was independently associated with better OS and PFS., Conclusions: The overall morbidity of GBC patients after LR was lower, but the long-term outcomes between LR and OR were not significantly different. The GBC patients treated with LR were more likely to receive AC, and the use of AC after curative-intent resection of GBC helped achieve better long-term survival outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-518/coif). W.Y.L. serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

ObjectivesThe primary laparoscopic approach (PLA) for T1b/T2 gallbladder cancer (GBC) remains contradicted. We aimed to compare the perioperative and long-term outcomes after PLA versus open approach (OA) for T1b/T2 GBC.MethodsPatients with resected T1b/T2 GBC were selected from our hospital between January 2011 and August 2018. Overall survival (OS), disease-free survival (DFS), and several secondary outcomes were used to evaluate safety and effectiveness. Subgroup analyses were performed to identify significant risk factors for OS/DFS in GBC patients undergoing PLA/OA.ResultsA total of 114 patients who underwent OA (n = 61) or PLA (n = 53) were included in the study. The percent of PLA cases was increased over time from 40.0% in 2011 to 70.0% in 2018 (p < 0.05). There was no significant difference in OS [hazard ratio (HR), 1.572; 95% confidence interval (CI), 0.866–2.855; p = 0.13] and DFS (HR, 1.225; 95% CI, 0.677–2.218; p = 0.49). No significance was found for intraoperative drainage placement (p = 0.253), intraoperative blood loss (p = 0.497), operation time (p = 0.105), postoperative hospitalization (p = 0.797), positive LNs (p = 0.494), total harvested LNs (p = 0.067), and recurrence rates (P = 0.334). Subgroup analyses demonstrated no significance of conversion rates after PLA (all p > 0.05). Patients undergoing PLA with good/poor OS would have similar recurrence rates (p = 0.402). Positive LNs (p = 0.032) and tumor differentiation (p = 0.048) were identified as risk factors for OS after PLA, while positive LNs (p = 0.005) was identified for OS after OA. Moreover, age (p = 0.013), gallbladder stone (p = 0.008), tumor size (p = 0.028), and positive LNs (p = 0.044) were potential risk factors for DFS after OA.ConclusionsPLA for T1b/T2 GBC was comparable to OA in terms of perioperative and long-term outcomes. Less positive LNs and well-differentiated tumors were independent predictors for better OS after PLA, and less positive LNs were also identified for better OS after OA. Additionally, younger age, without gallbladder stone, smaller tumor size, and less positive LNs were potential risk factors for better DFS after OA.

Objectives: The primary laparoscopic approach (PLA) for T1b/T2 gallbladder cancer (GBC) remains contradicted. We aimed to compare the perioperative and long-term outcomes after PLA versus open approach (OA) for T1b/T2 GBC. Methods: Patients with resected T1b/T2 GBC were selected from our hospital between January 2011 and August 2018. Overall survival (OS), disease-free survival (DFS), and several secondary outcomes were used to evaluate safety and effectiveness. Subgroup analyses were performed to identify significant risk factors for OS/DFS in GBC patients undergoing PLA/OA. Results: A total of 114 patients who underwent OA (n = 61) or PLA (n = 53) were included in the study. The percent of PLA cases was increased over time from 40.0% in 2011 to 70.0% in 2018 (p < 0.05). There was no significant difference in OS [hazard ratio (HR), 1.572; 95% confidence interval (CI), 0.866–2.855; p = 0.13] and DFS (HR, 1.225; 95% CI, 0.677–2.218; p = 0.49). No significance was found for intraoperative drainage placement (p = 0.253), intraoperative blood loss (p = 0.497), operation time (p = 0.105), postoperative hospitalization (p = 0.797), positive LNs (p = 0.494), total harvested LNs (p = 0.067), and recurrence rates (P = 0.334). Subgroup analyses demonstrated no significance of conversion rates after PLA (all p > 0.05). Patients undergoing PLA with good/poor OS would have similar recurrence rates (p = 0.402). Positive LNs (p = 0.032) and tumor differentiation (p = 0.048) were identified as risk factors for OS after PLA, while positive LNs (p = 0.005) was identified for OS after OA. Moreover, age (p = 0.013), gallbladder stone (p = 0.008), tumor size (p = 0.028), and positive LNs (p = 0.044) were potential risk factors for DFS after OA. Conclusions: PLA for T1b/T2 GBC was comparable to OA in terms of perioperative and long-term outcomes. Less positive LNs and well-differentiated tumors were independent predictors for better OS after PLA, and less positive LNs were also identified for better OS after OA. Additionally, younger age, without gallbladder stone, smaller tumor size, and less positive LNs were potential risk factors for better DFS after OA. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer (GBC) is a rare malignancy of the digestive tract, characterized by a remarkably poor prognosis. Currently, there is a controversy on the relationship between type 2 diabetes (T2D) and GBC. Additionally, no definitive conclusions were established regarding the causal relationships between alcohol intake frequency (AIF), age at menarche (AAM) and GBC. The objective of this study was to elucidate the causal association between T2D, AIF, AAM, and GBC., Methods: Single-nucleotide polymorphisms (SNPs) associated with exposures and outcomes were sourced from the Integrative Epidemiology Unit (IEU) Open Genome-Wide Association Study (GWAS) database. Specifically, the data of GBC comprised 907 East Asians (pathological results of all cases were registered into Biobank Japan) and 425,707 SNPs; T2D comprised 655,666 Europeans with 5,030,727 SNPs; AIF comprised 462,346 Europeans and 9,851,867 SNPs; AAM comprised 243,944 Europeans and 9,851,867 SNPs. The measurement of exposure traits is collected uniformly from the UK Biobank (UKB) database and presented in the form of standard deviation (SD) or the logarithmic form of the odds ratio (logOR). We employed a two-sample Mendelian randomization (MR) analysis to discern the causalities between T2D, AIF, AAM, and GBC. Sensitivity analyses were conducted to identify and address potential heterogeneity, horizontal pleiotropy, and outliers., Results: Our findings indicated that T2D reduced GBC risk [odds ratio (OR) =0.044; 95% confidence interval (CI): 0.004-0.55; P=0.015, inverse variance-weighted (IVW)]. However, no causal relationship was observed between AIF (OR =0.158; 95% CI: 5.33E-05 to 466.84; P=0.65, IVW), AAM (OR =0.19; 95% CI: 0.0003-140.34; P=0.62, IVW), and GBC. Sensitivity analysis revealed no evidence of horizontal pleiotropy, heterogeneity, or outliers, suggesting the robustness and reliability of our conclusions., Conclusions: T2D emerged as a potentially protective factor against GBC, whereas neither AIF nor AAM demonstrated a causal relationship with GBC risk. Regulation of glucose metabolism may be one of the methods for preventing GBC., Competing Interests: Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-358/coif). The authors have no conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: Concerns over the security of laparoscopic radical operation for gallbladder cancer (GBC) persist. This systematic review and meta-analysis attempted to compare the safety and efficacy of laparoscopic surgery (LS) versus open surgery (OS) in the treatment of GBC., Methods: The PubMed, EMBASE, and Web of Science were searched from inception to July 18, 2022. Literature search, quality assessment, and data extraction were completed independently and in duplicate. Effect-size estimates expressed as weighted mean difference (WMD) or odds ratio (OR) with 95% confidence interval (CI) were derived under the random-effects model., Results: A total of 27 independent studies including 2,868 participants were meta-analyzed. Significance was noted for intraoperative blood loss (WMD: -117.194, 95% CI: -170.188 to 64.201, P<0.001), harvested lymph nodes (WMD: -1.023, 95% CI: -1.776 to -0.269, P=0.008), postoperative hospital stay (WMD: -3.555, 95% CI: -4.509 to -2.601, P<0.001), postoperative morbidity (OR: 0.596, 95% CI: 0.407 to 0.871, P=0.008), overall survival rate at 2-year (OR: 1.524, 95% CI: 1.143 to 2.031, P=0.004), T2 survival at 1-year (OR: 1.799, 95% CI: 1.777 to 2.749, P<0.01) and 2-year (OR: 2.026, 95% CI: 1.392 to 2.949, P<0.001), as well as T3 survival at 1-year (OR: 2.669, 95% CI: 1.564 to 4.555, P<0.001) and 2-year (OR: 2.300, 95% CI: 1.308 to 4.046, P=0.004). Subgroup analyses revealed that ethnicity, incidental GBC, sample size, and follow-up period were possible sources of heterogeneity. There was a low probability of publication bias for all outcomes except postoperative morbidity., Conclusions: Our findings indicated that LS statistically had better 2-year survival rates, less intraoperative bleeding, shorter hospitalization times, and lower rates of complications than OS. However, the superiority and even the safety of LS still remain an open question due to the impact of incidental GBC, unaccounted heterogeneity, publication bias, lymph node dissection, and port-site metastasis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-597/coif). The authors have no conflicts of interest to declare., (2024 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Gallbladder cancer (GBC) stands out as one of the most widespread malignancies impacting the biliary tract globally. Despite increasing interest, to the best of our knowledge, no meta-analysis has been undertaken to amalgamate the existing data concerning the prognostic significance of micro-RNAs (miRNAs) in GBC in comparison to studies on miRNAs in other cancers. Hence, this systematic review and meta-analysis aimed at determining the prognostic significance of miRNAs in GBC patients. Comprehensive literature searches were conducted across PubMed, Cochrane Library, Ovid, Scopus, and Science Direct databases. Studies that evaluated the association between miRNAs and overall survival in GBC patients were included. Random-effect meta-analysis was employed to pool hazard ratios (HRs) and their 95% confidence intervals (CIs) across studies. A total of 15 studies, encompassing 16 miRs, were included for our analysis. The pooled analysis revealed that a high expression of miR-204, miR-7-2-3p, miR-29c-3p, miR-125b, miR-20a, miR-139-5p, miR-141, miR-92b-3p, miR-335, and miR-372 was significantly associated with poor prognosis and increased risk (HR>1 and the upper bound of the 95% CI>1). Additionally, these miRNAs were associated with the overall survival (HR = 1.56, 95% CI = 0.91-2.20, I 2 = 91.82%). Significant heterogeneity was observed and could be attributed to the limited number of studies available on the GBC and significant reliance on quantitative real-time PCR for the detection of miRNAs. In conclusion, specific miRNAs exhibit prognostic significance in GBC, with potential implications for patient stratification and targeted therapeutic interventions. However, due to the heterogeneity among studies, these findings should be interpreted cautiously and validated in larger cohorts., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Saxena et al.)

Background: Gallbladder cancer (GBC) is different from other biliary tract cancers in terms of molecular phenotype and microenvironment. Specific treatments for GBC need to be urgently explored. This study preliminarily investigated the clinical value of hepatic artery infusion chemotherapy (HAIC) combined with bevacizumab plus a programmed death receptor-1 (PD-1) inhibitor for treatment of GBC with hepatic oligometastasis., Methods: We retrospectively collected data on GBC patients with hepatic oligometastasis, who received this combination therapy. The clinical data, conversion rate, treatment response, adverse events (AEs), and short-term survival were summarized. The responses of primary gallbladder lesions and hepatic metastasis, and their effect on prognosis, were investigated., Results: A total of 27 patients were included in the analysis. No grade 4 AEs were observed. The overall objective response rate (ORR) was 55.6% and the disease control rate (DCR) was 85.2%. Median overall survival (OS) time was 15.0 months and the 1-year survival rate was 64.0%. Median progression-free survival (PFS) time was 7.0 months and the 1-year PFS rate was 16.2%. Six patients (22.2%) were successfully converted to resection. Compared with primary gallbladder lesions, it appeared more difficult for patients with hepatic metastasis to achieve remission (ORR: 40.7% vs. 77.8%; P=0.012), but its response appeared to be closely related to the prognosis [median OS: 16.0 months in the complete response (CR) or partial response (PR) group vs. 11.0 months in the stable disease (SD) or progressive disease (PD) group, P=0.070; median PFS: 12.0 months in the CR or PR group vs. 6.5 months in the SD or PD group, P<0.001]. Preoperative CA19-9 of >1,900 U/mL and >5 cm metastatic lesions were associated with an unsatisfactory response, whereas a significant decrease of 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake may be a marker of tumor remission., Conclusions: The combination of HAIC, a PD-1 inhibitor, and bevacizumab shows potential for advanced GBC with hepatic oligometastasis. The therapeutic response of hepatic metastasis had a greater influence on prognosis than that of primary gallbladder lesions., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-816/coif). The authors have no conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: Gallbladder cancer (GBC) has a peculiar geographical distinction, with a high prevalence seen in North India and Chile. There are various aetiopathogenetic mechanisms of GBC causation; one of them is a series of pathogenic mutations, which is responsible for the malignant transformation of gallbladder epithelium. Therefore, the present study aimed to find out cancer-specific hot spot mutations in five major cancer-related genes KRAS exon1 &2, NRAS exon1, IDH2 exon, PIK3CA exon 20, IDH2 exon 4 and EGFR exon 20 in North Indian GBC patients and their association with clinicopathological variables. Material and methods: This study included 34 histopathologically confirmed GBC cases. The clinical material consisted of formalin-fixed paraffin-embedded (FFPE) blocks of the patients. DNA isolation was done from FFPE tissue. DNA sequencing was performed by the capillary electrophoresis method. The chi-square (X2) test was used to test for a statistically significant relationship between two categorical study variables. Results: The overall incidence of somatic mutations in KRAS exon 1&2, NRAS exon1, IDH2 exon4, PIK3CA exon20, and EGFR exon 20 in Indian GBC patients was found in 8/34 (23.5%), 3/34 (8.8%), 4/34 (11.7%), 7/34 (20.6%), 7/34 (20.6%), respectively. KRAS exon 1 and two mutations were found to be significantly associated with advanced stage GBC patients. Conclusion: KRAS, PIK3CA, and EGFR were found to be the most frequently mutated genes among the five tested in this study. [ABSTRACT FROM AUTHOR]

Despite of the high lethality of gallbladder cancer (GBC), little is known regarding molecular regulation of the tumor immunosuppressive microenvironment. Here, we determined tumor expression levels of YKL-40 and the molecular mechanisms by which YKL-40 regulates escape of anti-tumor immune surveillance. We found that elevated expression levels of YKL-40 in plasma and tissue were correlated with tumor size, stage IV and lymph node metastasis. Single cell transcriptome analysis revealed that YKL-40 was predominantly derived from M2-like subtype of infiltrating macrophages. Blockade of M2–like macrophage differentiation of THP-1 cells with YKL-40 shRNA resulted in reprogramming to M1-like macrophages and restricting tumor development. YKL-40 induced tumor cell expression and secretion of growth differentiation factor 15 (GDF15), thus coordinating to promote PD-L1 expression mediated by PI3K, AKT and/or Erk activation. Interestingly, extracellular GDF15 inhibited intracellular expression of GDF15 that suppressed PD-L1 expression. Thus, YKL-40 disrupted the balance of pro- and anti-PD-L1 regulation to enhance expression of PD-L1 and inhibition of T cell cytotoxicity, leading to tumor immune evasion. The data suggest that YKL-40 and GDF15 could serve as diagnostic biomarkers and immunotherapeutic targets for GBC. • Increased YKL-40 in plasma were correlated with tissue expression of YKL-40 and GBC progression. • Blockade of YKL-40 in M2-like macrophages resulted in M1-like macrophage reprogramming. • YKL-40 promoted GDF15 secretion, which in turn inhibited intracellular GDF15 function that suppressed PD-L1 expression. • YKL-40 and GDF15 induced PD-L1 expression and abrogated cytotoxicity of infiltrating CD8+ T lymphocytes. [ABSTRACT FROM AUTHOR]

• The serum surface-enhanced Raman spectra from gallbladder cancer and healthy people are different. • The Gaussian radial basis function- support vector machine algorithm has the best classification results. • Surface enhanced Raman spectroscopy for serum analysis has great potential for screening gallbladder cancer. Gallbladder cancer (GBC) is a rare but frequently fatal biliary tract malignancy that is typically discovered when it is already advanced. In this study, we investigated a novel technique for the quick and non-invasive diagnosis of GBC based on serum surface-enhanced Raman spectroscopy (SERS). SERS spectra of serum from 41 patients with GBC and 72 normal subjects were recorded. Principal component analysis-linear discriminant analysis (PCA-LDA), and PCA-support vector machine (PCA-SVM), Linear SVM and Gaussian radial basis function-SVM (RBF-SVM) algorithms were used to establish the classification models, respectively. When the Linear SVM was used, the overall diagnostic accuracy for classifying the two groups could achieve 97.1%, and when RBF-SVM was used, the diagnostic sensitivity of GBC was 100%. The results demonstrated that SERS combination with a machine learning algorithm is a promising candidate to be one of the diagnostic tools for GBC in the future. [ABSTRACT FROM AUTHOR]

Genes important to stem cell progression have been involved in the genetics and clinical outcome of cancers. We investigated germ line variants in cancer stem cell (CSC) genes to predict susceptibility and efficacy of chemoradiotherapy treatment in gallbladder cancer (GBC) patients. In this study, we assessed the effect of SNPs in CSC genes (surface markers CD44, ALCAM, EpCAM, CD133) and (molecular markers NANOG, SOX-2, LIN-28A, ALDH1A1, OCT-4) with GBC susceptibility and prognosis. Total 610 GBC patients and 250 controls were genotyped by using PCR-RFLP, ARMS-PCR, and TaqMan allelic discrimination assays. Chemotoxicity graded 2-4 in 200 patients and tumor response was recorded in 140 patients undergoing neoadjuvant chemotherapy (NACT). Differences in genotype and haplotype frequency distributions were calculated by binary logistic regression. Gene-gene interaction model was analyzed by generalized multifactor dimensionality reduction (GMDR). Overall survival was assessed by Kaplan-Meier survival curve and multivariate Cox-proportional methods. ALCAM AC ( P = 0.0035) haplotype was significantly associated with GBC susceptibility. In GMDR analysis, ALCAM rs1157G>A, EpCAM rs1126497T>C emerged as best significant interaction model with GBC susceptibility and ALDH1A1 rs13959T>G with increased risk of grade 3-4 hematological toxicity. SOX-2 rs11915160A>C, OCT-4 rs3130932T>G, and NANOG rs11055786T>C were found best gene-gene interaction model for predicting response to NACT. In both Cox-proportional and recursive partitioning ALCAM rs1157GA+AA genotype showed higher mortality and hazard ratio. ALCAM gene polymorphisms associated with GBC susceptibility and survival while OCT-4, SOX-2, and NANOG variants showed an interactive role with treatment response. [ABSTRACT FROM AUTHOR]

Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene-gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) involves interplay of sex steroids, including estrogen and progesterone. Since CYP17 is a key enzyme involved in estrogen and testosterone hormone biosynthesis as well as in xenobiotic metabolism, it may be a potential candidate gene in the carcinogenesis of the gallbladder. Hence, the present study aimed to investigate the association of CYP17 (rs2486758, and rs743572) polymorphisms with GBC susceptibility. The present study included a total of 414 histologically confirmed GBC and 230 healthy controls. The CYP17 (rs2486758 and rs743572) polymorphisms were genotyped by TaqMan-Allele discrimination assays. Statistical analysis was performed by using SPSS ver. 16. Overall, both the CYP17 SNPs did not indicate any association with GBC risk at genotype, haplotype, or at the genotypic interaction levels. However, in the case-only analysis, CYP rs743572 showed association with increased risk of GBC in tobacco users at hetero genotype and dominant models, as compared to non-user GBC patients. The TC-AG genotypic combination was also associated with increased GBC susceptibility in tobacco users. CYP17 rs743572 is associated with increased risk of GBC in tobacco users in the North Indian population. However, the study requires confirmation in other populations. [ABSTRACT FROM AUTHOR]

Purpose: Gallbladder cancer (GBC), the most common gastrointestinal and biliary tract malignancy, often coincides with gallstone disease (GSD). The genetic variants of adrenergic receptor (ADR) have been previously reported to be associated with hypomotility disorder of cardiovascular system and GSD. Since GSD may function as GBC precursor, the present study aimed to investigate the association of common functional genetic variants of ADRA2A C-1291G, ADRβ3 T190C or Trp64Arg, and ADRβ1 C1165G or Arg389Gly with GBC and GSD susceptibility. Methods: The present study included a total of 400 histologically confirmed GBC, 230 GSD, and 268 healthy controls. The ADRA2A C-1291G, ADRβ3 T190C, and ADRβ1 C1165G polymorphisms were determined by PCR-RFLP. Statistical analysis was performed by using SPSS version 16. Results: ADRβ3 T190C polymorphism was significantly associated with increased risk of GBC (CT: Pcorr = 0.015, OR 2.87; CC: Pcorr = 0.038, OR 10.33; C allele: Pcorr = 0.014, OR 2.7; CT + CC: Pcorr = 0.017, OR 3.05). These associations existed even after gallstone and gender stratification. Similarly, ADRβ3 T190C polymorphism was also associated with GSD risk, though limited only to female GSD patients. In contrary, ADRA2A C-1291G conferred a marginally increased risk only in GSD patients. ADRβ1 C1165G polymorphism was not associated with GBC and GSD susceptibility when compared to controls. Conclusion: ADRβ3 T190C polymorphism is significantly associated with GBC and GSD susceptibility. The ADRβ3 T190C may be involved in the pathophysiology of GBC by both gallstone-dependent pathway and by some other independent mechanisms. [ABSTRACT FROM AUTHOR]

Highlights: [•] Quantitative proteomic analysis of gallbladder cancer. [•] LC–MS/MS analysis using Fourier transform high resolution mass spectrometry. [•] 2575 proteins identified including several upregulated lysosomal proteins. [•] Prosaposin and transgelin validated as candidate markers using tissue microarrays. [Copyright &y& Elsevier]

CD44 is an important marker for cancer stem cells. Germline variants in CD44 gene have been associated with susceptibility to breast and nasopharyngeal carcinomas but no study in gallbladder cancer (GBC) has been done yet. The present study included 405 GBC patients and 200 healthy controls from North India. Tagger SNPs for CD44 were selected from the GIH population data. Genotyping was carried out by PCR-RFLP and Taqman probes. Statistical analysis was done by SPSS. Bonferroni correction was applied in subgroup analysis. Logistic regression analysis showed no individual association of CD44 polymorphisms with GBC risk. However, [CCAT] haplotype was associated with overall reduced risk of GBC [ P = 0.04, odds ratios (OR) = 0.47]. Gender stratification revealed that [CCAT] and [TAGT] haplotypes were significantly associated with decreased risk in female GBC patients [ P = 0.022, OR = 0.38; P = 0.011, OR = 0.17, respectively]. The CAAT haplotype was marginally associated with low GBC risk in patients with co-existing gallstones [ P = 0.026, OR = 0.53]. The cancer risk was not further modified with tobacco usage or age of onset. In silico analysis showed change in transcriptional regulation of selected SNPs. This study reports an important role of CD44 haplotypes with reduced risk of GBC. [ABSTRACT FROM AUTHOR]