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Introduction: Minimally invasive oncological resections have become increasingly widespread in the surgical management of cancers. However, the role of minimally invasive surgery (MIS) for gallbladder cancer (GBC) remains unclear. We aim to perform a systematic review and network meta-analysis of existing literature to evaluate the safety and feasibility of laparoscopic and robotic surgery in the management of GBC compared to open surgery (OS) by comparing outcomes., Methods: A literature search of the PubMed/MEDLINE (2000 to December 2021) and EMBASE (2000 to December 2021) databases was conducted. The primary outcome studied was overall survival, and secondary outcomes studied were postoperative morbidity, severe complications, incidence of bile leak, length of hospital stay, operation time, R0 resection rate, local recurrence and lymph node yield., Results: Thirty-two full-text articles met the eligibility criteria and were included in the final analysis with a total of 5883 patients undergoing either OS or MIS (laparoscopic or robotic) for GBC. 1- and 2-stage meta-analyses did not reveal any significant differences between OS, laparoscopic and robotic surgery in terms of overall survival, R0 resection, lymph node harvest, local recurrence and post-operative complications. Patients who underwent OS had significantly longer hospitalization stay and intra-operative blood loss compared to those who underwent laparoscopic or robotic surgery. Network meta-analysis did not reveal any significant differences between post-operative and survival outcomes of laparoscopic vs robotic surgery groups., Conclusion: This network meta-analysis suggests that both laparoscopic and robotic surgery are safe and effective approaches in the surgical management of GBC, with post-operative and survival outcomes comparable to OS. An MIS approach may also lead to shorter hospitalization stay, less intraoperative blood loss and post-operative complications compared to OS. There was no obvious benefit of either MIS approach (laparoscopic versus robotic) over the other., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Gallbladder cancer (GBC) is a highly aggressive malignant tumor with a poor prognosis. Despite being first described two centuries ago, there are no targeted therapies available beyond conventional cytotoxic therapy. Epidemiological studies have shown that the incidence of gallbladder cancer is higher in females than males. This suggests that the gallbladder may be a female sex hormone-responsive organ, and these hormones might be involved in the pathogenesis of gallbladder cancer. Therefore, we aimed to analyze the expression of ERα and PR in GBC and correlate their expression with clinicopathological variables and overall survival., Patients and Methods: A total of 235 histopathologically diagnosed GBC cases were included in this hospital-based cross-sectional study. Clinicopathological data were collected, and the expression of ERα and PR was evaluated by immunohistochemistry., Results: The mean age of this study population was 55.47 ± 8.45 with range 28-87 years. Females were predominated over male with a male-to-female ratio of 1:3.5. Positive nuclear expression of the ERα and PR was found in 13 (5.5%) and eight (3.4%) cases, respectively. Apart from nuclear staining, cytoplasmic expression of ERα and PR was found in three (1.2%) and 31 (13.2%) cases, respectively. Higher percentage of positive nuclear expression of ER was found in < 50 years age (p value = 0.04), parity > 4 (p value = 0.02), advanced pT stage (T3) (p value = 0.01), lymphovascular invasion (p value = 0.02), and liver invasion (p value = 0.04) which were statistically significant. Higher percentage of PR expression was also observed in < 50 years age (p value = 0.01), and tumor associated with gallstone (p value = 0.04). There was no significant correlation between cytoplasmic expression of ER, PR, and clinicopathological variables. In multivariate analysis, there was no significant correlation between ER or PR positive expression and overall survival., Conclusion: Although nuclear expression of ERα was significantly associated with progressive disease factors but the positive expression was found in very small percentage of GBC cases. So anti-hormone therapy might be an option in patient with ER α positive gallbladder carcinoma., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Gallbladder cancers (GBCs) occur a decade earlier in India in comparison to the global occurrence, limiting the applicability of existing literature on age adjusted outcomes., Methods: Patients who underwent surgery between 01.01.2010 and 31.12.2020 for GBC were analyzed. Patients were divided into three age groups: group 1(≤40 years), group 2(41-60 years), group 3(>60 years) and their outcomes were compared., Results: Total of 6190 patients were treated for suspected or diagnosed GBC with a median age of 57 years. Curative resection was performed in 749 (67.9%) patients, of whom 114 (16.2%), 471 (62.9%), and 164 (21.9%) patients were in groups 1, 2, and 3, respectively. 5-year disease-free survival (DFS) [46.8% vs. 58.5%, p = 0.031] and overall survival (OS)[53.5% vs. 66.6%, p = 0.05] of group 3 were significantly lower than group 1. Patient age (HR 1.021), AJCC stage (HR 6.413), pathologic residual disease in the gallbladder fossa (HR 2.44), and extranodal tumor deposits (HR 1.762) were identified as independent predictors of poor OS., Conclusions: Gallbladder cancers in the Indian population show poorer outcomes with advancing age. Higher proportion of males in the elderly group with a more advanced stage at presentation are plausible reasons for poorer outcomes., Competing Interests: Conflict of interest The authors of the present study declare no conflicts of interest., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: Systemic inflammation and nutrition are vital for tumor progression. This study aimed to identify prognostic inflammation nutrition markers and develop a predictive nomogram for gallbladder cancer (GBC)., Methods: A total of 123 patients with GBC who underwent surgical resection at the First Affiliated Hospital of Soochow University and Suzhou Kowloon Hospital were included in our study. The final prognostic variables were identified using univariate and multivariate analyses. A nomogram model was then established, and the consistency index (C-index), calibration curves, and Kaplan-Meier analysis were performed to evaluate the accuracy and discrimination of the nomogram. The area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) suggested that our nomogram had better predictive ability and clinical feasibility than a published model., Results: The cox regression analysis showed that carcinoembryonic antigen (CEA) > 4.580, albumin-bilirubin (ALBI) > -2.091, geriatric nutritional risk index (GNRI) < 90.83, T3-T4, and N2 are independent prognostic factors. A predictive nomogram was constructed with a C-index of 0.793. In the calibration curves, the nomogram-predicted 1-, 3-, and 5-year survival matched well with the actual survival. Kaplan-Meier analysis showed that the high-risk group had worse survival than the low-risk group (P < 0.001). Finally, our nomogram achieved better 1-, 3- and 5-year AUCs than an established model (0.871, 0.844, and 0.781 vs. 0.753, 0.750, and 0.693). DCA also confirmed that our model outperformed the established model., Conclusions: In conclusion, our study revealed that CEA > 4.580, GNRI < 90.83, ALBI > -2.091, T3-T4 stage, and N2 were related to clinical outcomes of patients with GBC after surgical resection. The constructed nomogram has superior predictive ability and clinical practicality., (© 2024. The Author(s).)

Background: The association between marital status and gallbladder cancer (GBC) remains uncertain. This study aimed to verify the relationship between marital status and GBC and construct a prognostic nomogram to predict the impact of marital status on GBC patients., Method: GBC patients were divided into married and unmarried groups using data from the Surveillance, Epidemiology, and End Results (SEER) database. We employed competing risk analyses, propensity score matching (PSM), and Kaplan-Meier survival analyses. The relationship between marital status and GBC was then verified, and the predicted nomogram was constructed., Results: A total of 3913 GBC patients were obtained from the SEER database, and an additional 76 GBC patients from Hangzhou Traditional Chinese Medicine Hospital were selected as the external validation group. The competing risk analysis revealed a significant disparity in the 5-year cumulative incidence of cancer-specific death (CSD) between the two cohorts (59.1% vs. 65.2%, p = 0.003). Furthermore, the multivariate competing hazards regression analysis identified a significant association (HR, 1.17; 95% CI, 1.04-1.31; p = 0.007) between marital status and CSD. To assess the 1-, 3-, and 5-year risks of CSD, a comprehensive competing event nomogram was constructed using factors derived from the multivariate analysis. The area under the receiver operating characteristic curve (AUC) values for the 1-, 3-, and 5-year training cohorts were 0.806, 0.785, and 0.776, respectively. In the internal validation cohort, these values were 0.798, 0.790, and 0.790, while the external validation cohort exhibited AUC values of 0.748, 0.835, and 0.883 for the corresponding time intervals. Furthermore, calibration curves demonstrated a commendable level of concordance between the observed and predicted probabilities of CSD., Conclusion: Marriage was a protective factor for GBC patients after taking competing risk into consideration. The proposed nomogram demonstrated exceptional predictive power., (© 2024. The Author(s).)

Purpose: Intrahepatic cholangiocarcinoma (IHC) is a heterogeneous tumor. The hidden-genome classifier, a supervised machine learning-based algorithm, was used to quantify tumor heterogeneity and improve classification., Experimental Design: A retrospective review of 1,370 patients with IHC, extrahepatic cholangiocarcinoma (EHC), gallbladder cancer (GBC), hepatocellular carcinoma (HCC), or biphenotypic tumors was conducted. A hidden-genome model classified 527 IHC based on genetic similarity to EHC/GBC or HCC. Genetic, histologic, and clinical data were correlated., Results: In this study, 410 IHC (78%) had >50% genetic homology with EHC/GBC; 122 (23%) had >90% homology ("biliary class"), characterized by alterations of KRAS, SMAD4, and CDKN2A loss; 117 IHC (22%) had >50% genetic homology with HCC; and 30 (5.7%) had >90% homology ("HCC class"), characterized by TERT alterations. Patients with biliary- versus non-biliary-class IHC had median overall survival (OS) of 1 year (95% CI, 0.77, 1.5) versus 1.8 years (95% CI, 1.6, 2.0) for unresectable disease and 2.4 years (95% CI, 2.1, NR) versus 5.1 years (95% CI, 4.8, 6.9) for resectable disease. Large-duct IHC (n = 28) was more common in the biliary class (n = 27); the HCC class was composed mostly of small-duct IHC (64%, P = 0.02). The hidden genomic classifier predicted OS independent of FGFR2 and IDH1 alterations. By contrast, the histology subtype did not predict OS., Conclusions: IHC genetics form a spectrum with worse OS for tumors genetically aligned with EHC/GBC. The classifier proved superior to histologic subtypes for predicting OS independent of FGFR2 and IDH1 alterations. These results may explain the differential treatment responses seen in IHC and may direct therapy by helping stratify patients in future clinical trials., (©2024 American Association for Cancer Research.)

Importance: There is limited evidence with regard to the benefit of adjuvant chemotherapy chemoradiotherapy in resected gallbladder cancers (GBCs)., Objective: To establish a baseline survival rate for operated GBCs in patients receiving either gemcitabine plus cisplatin (GC) or capecitabine and capecitabine concurrent with chemoradiation (CCRT)., Design, Setting, and Participants: The GECCOR-GB study was a multicenter, open-label, randomized phase 2 noncomparator "pick the winner" design trial of adjuvant GC and CCRT in patients with resected histologically confirmed adenocarcinoma or adenosquamous carcinoma of the gallbladder, (stage II/III) with no local residual tumor (R0) or microscopic residual tumor (R1). The study was carried out in 3 tertiary cancer institutions in India. Patients 18 years or older with adequate end-organ functions, and Eastern Cooperative Oncology Group Performance Status of 1 or lower between May 2019 and February 2022 were enrolled. The cutoff date for data analysis was February 28, 2023., Interventions: Patients were randomized 1:1 to receive either GC every 3 weeks (maximum of 6 cycles) or CCRT comprising capecitabine with concurrent chemoradiation (capecitabine concurrent with radiotherapy) sandwiched between capecitabine chemotherapy., Main Outcomes and Measures: The primary outcome was disease-free survival (DFS) at 1 year in randomized patients. This study was conducted as 2 parallel, single-stage phase 2 clinical trials. Within each treatment arm, a 1-year DFS rate of less than 59% was considered as insufficient activity, whereas a 1-year DFS rate of 77% or higher would be considered as sufficient activity., Results: With a median follow-up of 23 months, 90 patients were randomized, 45 in each arm. Overall, there were 31 women (69%) and 14 men (31%) in the GC arm with a mean (range) age of 56 (33-72) years and 34 women (76%) and 11 men (24%) in the CCRT group with a mean (range) age of 55 (26-69) years. In the GC and CCRT arms, 1-year DFS and estimated 2-year DFS was 88.9% (95% CI, 79.5-98.3) and 74.8% (95% CI, 60.4-89.2), and 77.8% (95% CI, 65.4-90.2) and 74.8% (95% CI, 59.9-86.3), respectively. Completion rates for planned treatment was 82% in the GC arm and 62% in the CCRT arm., Conclusions and Relevance: In this randomized clinical trial, GC and CCRT crossed the prespecified trial end points of 1-year DFS in patients with resected stage II/III GBCs. The results set a baseline for a larger phase 3 trial evaluating both regimens in operated GBCs., Trial Registration: ClinicalTrials.gov Identifier: CTRI/2019/05/019323I.

Background: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer., Methods: Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching., Results: Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p = 0.004)., Conclusion: Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers., (© 2024. The Author(s).)

Background & Aims: Accumulating data has shown the rising incidence and poor prognosis of early-onset gastrointestinal cancers, but few data exist on biliary tract cancers (BTC). We aimed to analyse the clinico-pathological, molecular, therapeutic characteristics and prognosis of patients with early onset BTC (EOBTC, age ≤50 years at diagnosis), versus olders., Methods: We analysed patients diagnosed with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder adenocarcinoma between 1 January 2003 and 30 June 2021. Baseline characteristics and treatment were described in each group and compared. Progression-free survival, overall survival and disease-free survival were estimated in each group using the Kaplan-Meier method., Results: Overall, 1256 patients were included, 188 (15%) with EOBTC. Patients with EOBTC demonstrated fewer comorbidities (63.5% vs. 84.5%, p < .0001), higher tumour stage (cT3-4: 50.0% vs. 32.3%, p = .0162), bilobar liver involvement (47.8% vs. 32.1%, p = .0002), and metastatic disease (67.6% vs. 57.5%, p = .0097) compared to older. Patients with EOBTC received second-line therapy more frequently (89.5% vs. 81.0% non-EOBTC, p = .0224). For unresectable patients with BTC, median overall survival was 17.0 vs. 16.2 months (p = .0876), and median progression-free survival was 5.8 vs. 6.0 months (p = .8293), in EOBTC vs. older. In advanced stages, fewer actionable alterations were found in EOBTC (e.g., IDH1 mutations [7.8% vs. 16.6%]; FGFR2-fusion [11.7% vs. 8.9%]; p = .029)., Conclusions: Patients with EOBTC have a more advanced disease at diagnosis, are treated more heavily at an advanced stage but show similar survival. A distinctive molecular profile enriched for FGRF2 fusions was found., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

The platelet to lymphocyte ratio (PLR) is the marker of host inflammation and it is a potential significant prognostic indicator in various different tumors. The serum carbohydrate antigen 19-9 (CA19-9) is a tumor-associated antigen and it is associated with poor prognosis of gallbladder cancer (GBC). We aimed to analyze the prognostic value of the combination of preoperative PLR and CA19-9 in patients with GBC. A total of 287 GBC patients who underwent curative surgery in our institution was included. To analyze the relationship between PLR and CA19-9 and clinicopathological features. A receiver operating characteristic (ROC) curve was used to identify the optimal cutoff value for PLR and CA19-9. The Kaplan-Meier method was used to estimate the overall survival (OS). Meanwhile, the univariate and multivariate Cox regression models were used to assess the risk factors for OS. The cutoff values of 146.82 and 36.32U/ml defined as high PLR and high CA19-9, respectively. Furthermore, survival analysis showed that patients with PLR > 146.82 and CA19-9 > 36.32 U/ml had a worse prognosis than patients with PLR ≤ 146.82 and CA19-9 ≤ 36.32 U/ml, respectively. The multivariate analysis demonstrated that PLR (hazard ratio (HR) = 1.863, 95% CI: 1.366-2.542, P < 0.001) and CA19-9 (HR = 1.412, 95% CI: 1.021-1.952, P = 0.037) were independent prognostic factors in the GBC patients. When we combined these two parameters, the area under the ROC curve increased from 0.624 (PLR) and 0.661 (CA19-9) to 0.711. In addition, the 1-, 3-, and 5-year OS of group A (patients with PLR ≤ 146.82 and CA19-9 ≤ 36.32 U/ml), group B (patients with either of PLR > 146.82 or CA19-9 > 36.32 U/ml) and group C (patients with PLR > 146.82 and CA19-9 > 36.32 U/ml) were 83.6%, 58.6%, 22.5%, 52.4%, 19.5%, 11.5%, and 42.3%, 11.9%, 0%, respectively. The preoperative PLR and serum CA19-9 are associated with prognosis of patients with GBC. The combination of PLR and CA19-9 may serve as a significant prognostic biomarker for GBC patients superior to either PLR or CA19-9 alone., (© 2024. Italian Society of Surgery (SIC).)

Background: Gallbladder mixed neuroendocrine-non-neuroendocrine neoplasm generally consists of a gallbladder neuroendocrine tumor and a non-neuroendocrine component. The World Health Organization (WHO) in 2019 established a guideline requiring each component, both neuroendocrine and non-neuroendocrine, to account for a minimum of 30% of the tumor mass., Methods: Patients after surgery resection and diagnosed at microscopy evaluation with pure gallbladder neuroendocrine carcinoma (GBNEC), gallbladder mixed adeno-neuroendocrine carcinoma (GBMANEC, GBNEC≥30%), and gallbladder carcinoma mixed with a small fraction of GBNEC (GBNEC <30%) between 2010 and 2022 at West China Hospital of Sichuan University were collated for the analyses. Demographic features, surgical variables, and tumor characteristics were evaluated for association with patients' overall and recurrence-free survival (OS and RFS)., Results: The study included 26 GBNEC, 11 GBMANEC, 4 gallbladder squamous-cell carcinoma (GBSCC), and 7 gallbladder adenocarcinoma (GBADC) mixed with a small fraction of GBNEC. All patients had stage III or higher tumors (AJCC 8th edition). The majority of included patients (79.17%) underwent curative surgical resection (R0), with only ten patients having tumoral resection margins. In the analysis comparing patients with GBNEC percentage (GBNEC≥30% vs. GBNEC<30%), the basic demographics and tumor characteristics of most patients were comparable. The prognosis of these patients was also comparable, with a median OS of 23.65 months versus 20.40 months (P=0.13) and a median RFS of 17.1 months versus 12.3 months (P=0.24). However, patients with GBADC or GBSCC mixed with GBNEC <30% had a statistically significant decreased OS and RFS (both P<0.0001)) compared with GBNEC and GBMANEC. Patients with GBNEC who exhibited advanced tumor stages and lymphovascular invasion had a higher risk of experiencing worse overall survival (OS) and recurrence-free survival (RFS). However, a 30% GBNEC component was not identified as an independent risk factor., Conclusion: Patients with GBNEC were frequently diagnosed at advanced stages and their prognosis is poor. The 30% percentage of the GBNEC component is not related to the patient's survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hu, Wang, Ma, Hu, Gu, Liu, Lv, Yang, Dai, Zou, Jin and Li.)

Background: Gallbladder cancer (GBC) is an aggressive malignancy that is usually diagnosed at a late stage. Prior data showed increasing incidence of GBC in the US. However, little is known about race/ethnic-specific incidence and mortality trends of GBC per stage at diagnosis. Therefore, we aimed to conduct a time-trend analysis of GBC incidence and mortality rates categorized by race/ethnicity and stage-at-diagnosis., Methods: Age-adjusted GBC incidence and mortality rates were calculated using SEER*Stat software from the United States Cancer Statistics database (covers ~98% of US population between 2001 and 2020) and NCHS (covers ~100% of the US population between 2000 and 2020) databases, respectively. Race/Ethnic groups were Non-Hispanic-White (NHW), Non-Hispanic-Black (NHB), Hispanic, Non-Hispanic-Asian/Pacific-Islander (NHAPI), and Non-Hispanic-American-Indian/Alaska-Native (NHAIAN). Stage-at-diagnoses were all stages, early, regional, and distant stages. Joinpoint regression was used to generate time-trends [annual percentage change (APC) and average APC (AAPC)] with parametric estimations and a two-sided t-test (p-value cut-off 0.05)., Results: 76,873 patients were diagnosed with GBC with decreasing incidence rates in all races/ethnicities except NHB who experienced an increasing trend between 2001 and 2014 (APC = 2.08, p < 0.01) and plateauing afterward (APC = -1.21, p = 0.31); (AAPC = 1.03, p = 0.03). Among early-stage tumors (9927 patients), incidence rates were decreasing only in Hispanic (AAPC = -4.24, p = 0.006) while stable in other races/ethnicities (NHW: AAPC = -2.61, p = 0.39; NHB: AAPC = -1.73, p = 0.36). For regional-stage tumors (29,690 patients), GBC incidence rates were decreasing only in NHW (AAPC = -1.61, p < 0.001) while stable in other races/ethnicities (NHB: AAPC = 0.73, p = 0.34; Hispanic: AAPC = -1.58, p = 0.24; NHAPI: AAPC = -1.22, p = 0.07). For distant-stage tumors (31,735 patients), incidence rates were increasing in NHB (AAPC = 2.72, p < 0.001), decreasing in Hispanic (AAPC = -0.64, p = 0.04), and stable in NHW (AAPC = 0.07, p = 0.84) and NHAPI (AAPC = 0.79, p = 0.13). There were 43,411 deaths attributed to GBC with decreasing mortality rates in all races/ethnicities except NHB who experienced a stable trend (AAPC = 0.25, p = 0.25)., Conclusion: Nationwide data over the last two decades show that NHB patients experienced increasing GBC incidence between 2001 and 2014 followed by stabilization of the rates. This increase was driven by late-stage tumors and occurred in the first decade. NHB also experienced non-improving GBC mortality, compared to other race and ethnic groups who had decreasing mortality. This can be due to lack of timely-access to healthcare leading to delayed diagnosis and worse outcomes. Future studies are warranted to investigate contributions to the revealed racial and ethnic disparities, especially in NHB, to improve early detection., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Biliary spillage (BS) is a common complication following initial cholecystectomy for gall bladder cancer (GBC). Few studies have explored the importance of BS as a long-term prognostic factor. We perform a meta-analysis of the association between BS and survival in GBC., Methods: A systematic literature search was performed in February 2023. Studies evaluating the incidence of BS and its association with long-term outcomes in patients undergoing initial laparoscopic or open cholecystectomy for either incidental or resectable GBC were included. Overall survival (OS), disease-free survival (DFS), and rate of peritoneal carcinomatosis (RPC) were the primary end points. Forest plot analyses were used to calculate the pooled hazard ratios (HRs) of OS, DFS, and RPC. Metaregression was used to evaluate study-level association between BS and perioperative risk factors., Results: Of 181 published articles, 11 met inclusion criteria with a sample size of 1116 patients. The rate of BS ranged between 9% and 67%. On pooled analysis, BS was associated with worse OS (HR = 1.68, 95% confidence interval [CI] = 1.32-2.14), DFS (pooled HR= 2.19, 95% CI = 1.30-3.68), and higher RPC (odds ratio = 9.37, 95% CI = 3.49-25.2). The rate of BS was not associated with higher T stage, lymph node metastasis, higher grade, positive margin status, reresection, or conversion rates., Conclusions: Our meta-analysis shows that BS is a predictor of higher peritoneal recurrence and poor survival in GBC. BS was not associated with tumor characteristics or conversion rates. Further research is needed to identify other potential risk factors for BS and investigate the ideal treatment schedule to improve survival., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This study aims to investigate the clinical and pathological characteristics, treatment approaches, and prognosis of gallbladder neuroendocrine carcinoma (GB-NEC)., Methods: Retrospective analysis was conducted on the clinical data of 37 patients with GB-NEC admitted to Shanxi Cancer Hospital from January 2010 to June 2023. The study included an examination of their general information, treatment regimens, and overall prognosis., Results: Twelve cases, either due to distant metastasis or other reasons, did not undergo surgical treatment and received palliative chemotherapy (Group 1). Two cases underwent simple cholecystectomy (Group 2); four patients underwent palliative tumor resection surgery (Group 3), and nineteen patients underwent radical resection surgery (Group 4). Among the 37 GB-NEC patients, the average pre-surgery CA19-9 level was 113.29 ± 138.45 U/mL, and the median overall survival time was 19 months (range 7.89-30.11 months). Of these, 28 cases (75.7%) received systemic treatment, 25 cases (67.6%) underwent surgical intervention, and 16 cases (64.0%) received postoperative adjuvant treatment, including combined radiochemotherapy or chemotherapy alone. The median overall survival time was 4 months (0.61-7.40 months) for Group 1 (n = 12), 8 months for Group 2 (n = 2), 21 months (14.67-43.33 months) for Group 3 (n = 4), and 19 months (range 7.89-30.11 months) for Group 4 (n = 19). A significant difference in median overall survival time was observed between Group 1 and Group 4 (P = 0.004)., Conclusion: Surgery remains the primary treatment for GB-NEC, with radical resection potentially offering greater benefits to patient survival compared to other therapeutic options. Postoperative adjuvant therapy has the potential to extend patient survival, although the overall prognosis remains challenging., (© 2024. The Author(s).)

Background: Gallbladder cancer (GBC) is the most common biliary tract malignancy and has a poor prognosis. The clinical significance of focal vs diffuse GBC remains unclear., Methods: A retrospective review was conducted on all patients with non-metastatic GBC at a quaternary care center. Pathology was reviewed, and gallbladder cancer pattern was defined based on the extent of mucosal involvement; "diffuse" if the tumor was multicentric or "focal" if the tumor was only in a single location. Patients undergoing liver resection and portal lymphadenectomy were considered to have definitive surgery. The primary outcome was overall survival and assessed by Kaplan-Meier curves., Results: 63 patients met study criteria with 32 (50.7%) having diffuse cancer. No difference was observed in utilization of definitive surgery between the groups (14 [43.8%] with focal and 12 [38.7%] with diffuse, P = .88). Lymphovascular invasion ( P = .04) and higher nodal stage ( P = .04) were more common with diffuse GBC. Median overall survival was significantly improved in those with focal cancer (5.1 vs 1.2 years, P = .02). Although not statistically significant, this difference in overall survival persisted in patients who underwent definitive surgery (4.3 vs 2.4 years, P = .70)., Discussion: Patients with diffuse involvement of the gallbladder mucosa likely represent a subset with aggressive biology and worse overall survival compared to focal disease. These findings may aid surgeons in subsequent surgical and medical decision-making for patients with GBC., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rationale and Objectives: An accurate prognostic model is essential for the development of treatment strategies for gallbladder cancer (GBC). This study proposes an integrated model using clinical features, radiomics, and deep learning based on contrast-enhanced computed tomography (CT) images for survival prediction in patients with GBC after surgical resection., Methods: A total of 167 patients with GBC who underwent surgical resection at two medical institutions were retrospectively enrolled. After obtaining the pre-treatment CT images, the tumor lesions were manually segmented, and handcrafted radiomics features were extracted. A clinical prognostic signature and radiomics signature were built using machine learning algorithms based on the optimal clinical features or handcrafted radiomics features, respectively. Subsequently, a DenseNet121 model was employed for transfer learning on the radiomics image data and as the basis for the deep learning signature. Finally, we used logistic regression on the three signatures to obtain the unified multimodal model for comprehensive interpretation and analysis., Results: The integrated model performed better than the other models, exhibiting the highest area under the curve (AUC) of 0.870 in the test set, and the highest concordance index (C-index) of 0.736 in predicting patient survival rates. A Kaplan-Meier analysis demonstrated that patients in high-risk group had a lower survival probability compared to those in low-risk group (log-rank p < 0.05)., Conclusion: The nomogram is useful for predicting the survival of patients with GBC after surgical resection, helping in the identification of high-risk patients with poor prognosis and ultimately facilitating individualized management of patients with GBC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic value of carbohydrate antigen 19-9 (CA19-9) is known to be affected by elevated bilirubin levels in patients with gallbladder carcinoma (GBC). The clinical significance of changes in the ratio of CA19-9 levels to total bilirubin (TB) levels in patients with GBC after curative-intent resection remains unknown. The aim of this study was to determine the prognostic value of changes in preoperative and postoperative CA19-9/TB ratio in these patients., Methods: Prospectively collected data on consecutive patients who underwent curative-intent resection for GBC between January 2015 and December 2020 stored in a multicenter database from 10 hospitals were analyzed in this retrospective cohort study. Based on the adjusted CA19-9 defined as the ratio of CA19-9 to TB, and using 2×10 3  U/µmol as the upper normal value, patients were divided into a normal group (with normal preoperative and postoperative adjusted CA19-9), a normalization group (with abnormal preoperative but normal postoperative adjusted CA19-9), and a non-normalization group (with abnormal postoperative adjusted CA19-9). The primary outcomes were overall survival (OS) and recurrence-free survival (RFS). The log-rank test was used to compare OS and RFS among the groups. The Cox regression model was used to determine factors independently associated with OS and RFS., Results: The normal group ( n =179 patients) and the normalization group ( n =73 patients) had better OS and RFS than the non-normalization group ( n =65 patients) (the 3-year OS rates 72.0%, 58.4% and 24.2%, respectively; the RFS rates 54.5%, 25.5% and 11.8%, respectively; both P <0.001). There were no significant differences between the normal and the normalization groups in OS and RFS (OS, P =0.255; RFS, P =0.130). Cox regression analysis confirmed that the non-normalization group was independently associated with worse OS and RFS. Subgroup analysis revealed that the non-normalization group of patients who received adjuvant therapy had significantly improved OS and RFS as compared to those who did not receive adjuvant therapy (OS, P =0.025; RFS, P =0.003)., Conclusions: Patients with GBC who underwent curative-intent surgical resection with postoperative abnormal levels of adjusted CA19-9 (the CA19-9/TB ratio) were associated with poorer long-term survival outcomes. Adjuvant therapy after surgery improved the long-term outcomes of these patients., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Management of early-stage gallbladder cancer is becoming more important as the rate of early detection is increasing. Although there have been many studies about the clinical implication of the invasion depth or peritoneal/hepatic location of gallbladder cancers, there is no study on the clinical implication of the geometric location of cancer along the longitudinal length of the gallbladder., Methods: The location of gallbladder cancer was defined as the geometric center of the primary site of a tumour, which lies on the longitudinal diameter of the surgical specimens. We compared the oncologic outcomes following surgery between gallbladder cancers located on the fundal end and those located on the cystic ductal end. We also analysed patients with stage 1 gallbladder cancer who recurred after surgery., Results: A total of 575 patients with gallbladder cancer were included in this study. Patients with gallbladder cancer on the cystic ductal end had significantly lower rates of recurrence-free survival (P = 0.016) and overall survival (P = 0.023) compared to those with gallbladder cancer on the fundal end. Among 90 patients with stage 1 gallbladder cancer, three patients had a recurrence, all of whom had cystic ductal end gallbladder cancer and showed cystic duct invasion or concomitant xanthogranulomatous cholecystitis in permanent pathology., Conclusions: Gallbladder cancers on the cystic ductal end had worse postoperative oncologic outcomes compared with those on the fundal end., (© 2024 Royal Australasian College of Surgeons.)

Introduction: Neuroendocrine neoplasms (NENs) are classified as neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed neuroendocrine and nonneuroendocrine neoplasms (MiNENs) according to World Health Organization classification. We present our experience of NENs of the gallbladder (GB) from a high-volume cancer hospital., Materials and Methods: The present study is a retrospective analysis of all patients with GB NENs who presented between January 2015 and June 2023. The patient details and treatment received with follow-up were noted. The primary endpoint was overall survival (OS)., Results: A total of 147 patients were included in the study. The median age was 52 (27-81) years. There was a female predominance (70.7%). NEC was the most common subtype (84.4%) followed by MiNEN (12.9%) and NET (2.7%). The most common stage at presentation was metastatic (70.7%) followed by locally advanced (21.8%), and early disease (7.5%). The median follow-up was 9.92 (1.77-76.06) months. Median OS was 6.14 (3.93-8.35) months. Median OS in patients who received multimodality treatment was 20.20 (17.99-22.41) months versus 4.00 (2.91-5.10) months in those who did not receive it., Conclusion: GB NENs are rare, but aggressive tumors with NEC being the most common type. Multimodality treatment yields favorable outcomes. However, the development of better systemic therapy is needed to help improve survival further., (© 2024 Wiley Periodicals LLC.)

Introduction: Locally advanced, inoperable, or metastatic gallbladder cancers (GBC) are treated with either gemcitabine-platinum combinations or gemcitabine alone based on physician discretion. However, the combination of gemcitabine, cisplatin, and nab-paclitaxel (GCNP) has shown increased response rates and prolonged survival in a phase II trial of biliary tract patients., Materials and Methods: Consecutive series of patients diagnosed with locally advanced (liver infiltration > 5 cm, large nodes at porta, abutting duodenum), inoperable, and metastatic biliary tract patients between January 2018 and August 2022 were evaluated for first-line chemotherapy GCNP, in the multidisciplinary joint clinic (MDJC). The primary endpoint was ORR, and the major secondary endpoint was event-free survival (EFS)., Results: A total of 142 patients received GCNP during the specified time period. The median age of the cohort was 52 years (range: 21-79), the majority were females (61.3%), and the majority were GB (81.7%). Response rates were available in 137 patients. Complete response, partial response, and stable disease were seen in 9 (6.3%), 87 (61.3%), and 24 (16.9%), respectively, for an ORR of 67.6% and a clinical benefit rate of 84.5%. The median EFS was 9.92 (95% CI, 7.69-12.14) months. Of the 52 patients in whom GCNP was given with NACT intent for locally advanced GBC, 17 patients underwent surgery (34%)., Conclusion: Our study indicates that GCNP leads to improved response rates, increased chances of resectability, and possibly better survival in patients with GBC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The effect of neoadjuvant chemotherapy (NACT) in gallbladder cancer (GBC) patients remains controversial. The aim of this study was to assess the impact of NACT on overall survival (OS) and cancer specific survival (CSS) in patients with localized or locoregionally advanced GBC, and to explore possible protective predictors for prognosis., Methods: Data for patients with localized or locoregionally advanced GBC (i.e., categories cTx-cT4, cN0-2, and cM0) from 2004 to 2020 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients in the NACT and non-NACT groups were propensity score matched (PSM) 1:3, and the Kaplan-Meier method and log-rank test were performed to analyze the impact of NACT on OS and CSS. Univariable and multivariable Cox regression models were applied to identify the possible prognostic factors. Subgroup analysis was conducted to identify patients who would benefit from NACT., Results: Of the 2676 cases included, 78 NACT and 234 non-NACT patients remained after PSM. In localized or locoregionally advanced GBC patients, the median OS of the NACT and non-NACT was 31 and 16 months (log-rank P < 0.01), and the median CSS of NACT and non-NACT was 32 and 17 months (log-rank P < 0.01), respectively. Longer median OS (31 vs 17 months, log-rank P < 0.01) and CSS (32 vs 20 months, log-rank P < 0.01) was associated with NACT compared with surgery alone. Multivariable Cox regression analysis showed that NACT, stage, and surgery type were prognostic factors for OS and CSS in GBC patients. Subgroup analysis revealed that the survival hazard ratios (HRs) of NACT vs non-NACT for localized or locoregionally advanced GBC patients were significant in most subgroups., Conclusions: NACT may provide therapeutic benefits for localized or locoregionally advanced GBC patients, especially for those with advanced stage, node-positive, poorly differentiated or undifferentiated disease. NACT combined with radical surgery was associated with a survival advantage. Therefore, NACT combined with surgery may provide a better treatment option for resectable GBC patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The prognosis of non-metastatic gallbladder adenocarcinoma (NM-GBA) patients is affected by the status of metastatic lymph nodes. The purpose of this study was to explore the prognostic value of the log odds of positive lymph nodes (LODDS) and develop a novel nomogram to predict the overall survival in NM-GBA patients. A total of 1035 patients confirmed to have NM-GBA were selected from the Surveillance, Epidemiology, and End Results (SEER) database and further divided into training and validation cohorts. The discrimination and calibration of the nomogram were evaluated using the concordance index (C-index), the area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and calibration plots. The net benefits and clinical utility of the nomogram were quantified and compared with those of the 8th edition American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) staging system using decision curve analysis (DCA), net reclassification index (NRI), and integrated discrimination improvement (IDI). The risk stratifications of the nomogram and the TNM-staging system were compared. LODDS showed the highest accuracy in predicting OS for NM-GBA. The C-index (0.730 for the training cohort and 0.746 for the validation cohort) and the time-dependent AUC (> 0.7) indicated the satisfactory discriminative ability of the nomogram. The calibration plots showed a high degree of consistency. The DCA, NRI, and IDI indicated that the nomogram performed significantly better than the TNM-staging (P < 0.05). A novel LODDS-included nomogram was developed and validated to assist clinicians in evaluating the prognosis of NM-GBA patients., (© 2022. The Author(s).)

Background: The survival outcomes and optimal extent of surgery of T2 gallbladder cancers remain controversial. We aimed to investigate the difference in overall/disease-free survival rates and assess the prognosis of T2 gallbladder cancers., Methods: We retrospectively reviewed electronic medical records of 147 patients who underwent surgical resection for pathologically confirmed T2 gallbladder cancer between January 2003 and December 2012. Patients were categorized into two groups according to the tumor location (T2a vs. T2b) and three groups according to surgery method (simple cholecystectomy, cholecystectomy with lymph node dissection, and extended cholecystectomy). We compared the overall and disease-free survival rates according to T2 subgroups and surgery methods. Cox proportional hazard analysis was performed to evaluate prognostic factors for the overall survival of T2 gallbladder cancer., Results: Of all patients, 40 (27.2%) and 107 (72.8%) were diagnosed with T2a and T2b gallbladder cancers, respectively. The 5-year overall and disease-free survival rates were 75.0% vs. 73.8% (p = 0.653) and 72.5% vs. 70.1% (p = 0.479) in T2a and T2b gallbladder cancers, respectively. There was no difference in the survival rate among T2a gallbladder cancer according to the surgery method. However, in T2b gallbladder cancer, extended cholecystectomy showed a better overall survival than simple cholecystectomy and cholecystectomy with lymph node dissection groups (p = 0.043 and p = 0.003, respectively)., Conclusions: There is no difference in overall and disease-free survival rates according to the location of T2 gallbladder cancers. Extended cholecystectomy increases overall survival rate, especially in T2b gallbladder cancers., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Preoperative diagnosis for suspected gallbladder cancers is challenging, with a risk of overtreating benign disease, for example, xanthogranulomatous cholecystitis, with radical cholecystectomies. We retrospectively evaluated the surgeon's intraoperative assessment alone, and with the addition of intraoperative frozen sections, for suspected gallbladder cancers from a tertiary hepatobiliary multidisciplinary team (MDT)., Methods: MDT patients with complex gallbladder disease were included. Collated data included demographics, MDT discussion, operative details, and patient outcomes., Results: A total of 454 patients with complex gallbladder disease were reviewed, 48 (10.6%) were offered radical surgery for suspected cancer. Twenty-five underwent frozen section that led to radical surgery in 6 (25%). All frozen sections were congruent with final histopathology but doubled the operating time (p < 0.0001). Both the surgeon's subjective and additional frozen section's objective assessment, allowed for de-escalation of unnecessary radical surgery, comparing favourably to a 13.0% cancer diagnosis among radical surgery historically., Conclusions: The MDT process was highly sensitive in identifying gallbladder cancers but lacked specificity. The surgeon's intraoperative assessment is paramount in suspected cancers, and deescalated unnecessary radical surgery. Intraoperative frozen section was a safe and viable adjunct at a cost of resources and operative time., (© 2021 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background and Objective: Gallbladder cancer (GBC) is an aggressive malignancy where curative resection is possible in few and survival is poor. There are limited data on outcomes in patients with de novo GBC from endemic regions undergoing surgery for curative intent. We report survival outcomes in this group of patients from a region with high incidence of disease., Methods: We reviewed the records of all GBC patients (2014-2018) and included those who underwent radical cholecystectomy (RC) for de novo GBC. Univariable and multivariable analyses were performed to identify factors influencing recurrence and survival., Results: A total of 649 patients with GBC were evaluated for surgery and curative intent surgery was attempted in 246 (38%) patients. Of these 246 patients, RC was performed in 115 patients, with histologically confirmed de novo GBC. Locally advanced disease (≥stage IIIB) was present in 52 (45.2%) patients. Median time to recurrence and overall survival (OS) were 31 and 36 months, respectively. Lymph node positivity (p = 0.005) and grade significantly influenced OS on multivariable analysis., Conclusion: Satisfactory survival outcomes are possible after RC for de novo GBC. Extended resections performed in high volume centers combined with appropriate adjuvant treatment can offer significant survival benefits, with acceptable morbidity and mortality rates., (© 2021 Wiley Periodicals LLC.)

Importance: Gallbladder cancer is uncommon but highly fatal. Surgery remains the only potentially curative treatment for localized or locoregionally advanced gallbladder cancer. The rate of use of neoadjuvant and adjuvant chemotherapy in resectable gallbladder cancer is unknown., Objective: To assess factors associated with the use of neoadjuvant and adjuvant chemotherapy in patients with resectable gallbladder cancer and survival outcomes., Design, Setting, and Participants: The National Cancer Database was used to identify 6391 adults who underwent definitive surgical resection for gallbladder cancers between January 1, 2004, and January 1, 2016. Data analysis was performed from January 15 to February 15, 2020. Patients with localized or locoregionally advanced gallbladder cancers (ie, categories cTx-cT4, cN0-2, and cM0) were categorized as receiving neoadjuvant chemotherapy, adjuvant chemotherapy, or surgery alone. Categorical variables were compared using the χ2 test, with 1:3 nearest-neighbor propensity score matching based on neoadjuvant chemotherapy. Survival outcomes between groups were compared using Kaplan-Meier and Cox proportional hazards regression analyses., Main Outcomes and Measures: The use and survival outcomes of adjuvant and neoadjuvant chemotherapy., Results: Of 6391 patients who underwent definitive surgery for gallbladder cancer, 4559 were women (71.3%); median age was 68 (IQR, 59-77) years. A total of 3145 patients (49.2%) received adjuvant chemotherapy, 3145 patients (49.2%) underwent surgery without chemotherapy, and 101 patients (1.6%) received neoadjuvant chemotherapy. Neoadjuvant chemotherapy use was associated with treatment at an academic facility (61 patients [60%] vs 38 patients [38%] treated in a nonacademic facility; P < .001) and in those with private insurance (65 patients [65%] vs 11 patients [11%] with Medicaid insurance; P < .001). Surgery alone was frequently used in older patients (median age, 72 [IQR, 63-81] years vs 59 [IQR, 52-66] years in patients with neoadjuvant chemotherapy; P < .001), those with Medicare insurance (1925 patients [57%] vs 1438 patients [43%] with adjuvant chemotherapy; P < .001), and patients with a higher comorbidity index score (326 patients [62%] vs 197 patients [38%] with adjuvant chemotherapy; P < .001). Adjuvant or neoadjuvant chemotherapy was used more frequently than surgery in patients with node-positive cancer (1482 [67.2%] vs 53 [65.4%] vs 912 [49.7%]). On propensity score matching analysis, adjuvant chemotherapy was associated with longer survival than surgery alone (22 vs 18 months, hazard ratio [HR], 0.78; 95% CI, 0.63-0.96); survival with neoadjuvant chemotherapy was not statistically significant compared with surgery alone and adjuvant chemotherapy groups (27 months, HR, 0.78; 95% CI, 0.58-1.04). However, in patients with node-positive gallbladder cancer, neoadjuvant therapy was associated with longer median overall survival (30 months [95% CI, 24-36 months] vs 14 months [95% CI, 11-17] in patients with surgery alone; P = .002)., Conclusions and Relevance: In this cohort study, use of adjuvant and neoadjuvant chemotherapy was low in patients with surgically resected gallbladder cancers. Chemotherapy was used more frequently than surgery in lymph node-positive disease compared with lymph node-negative disease. Adjuvant chemotherapy was associated with a survival advantage in resectable gallbladder cancer, and neoadjuvant chemotherapy was associated with increased survival in node-positive gallbladder cancers. These findings suggest that adjuvant chemotherapy and neoadjuvant chemotherapy should be considered in treatment of gallbladder cancer.

Gallbladder carcinoma is an uncommon malignancy with an overall 5-year survival of less than 5%. Gallbladder carcinoma has been strongly linked with cholelithiasis and chronic inflammation. Case reports and series have described cholecystitis with acute (neutrophilic) inflammation in association with gallbladder carcinoma, although a clear relationship to patient outcome has not been established. Our series included 8 cases of gallbladder carcinoma with high tumor-associated neutrophils (>25 per high power field) that were associated with shorter patient survival (Cox regression coefficient 6.2, p = 0.004) than age- and stage-matched controls. High tumor-associated neutrophils were not associated with gallbladder rupture/perforation or increased bacterial load measured by 16S PCR. Neutrophilic inflammation with gallbladder carcinoma correlates to shorter survival, independent of patient age and stage of carcinoma. The findings suggest that the degree of neutrophilic inflammation may have prognostic significance in specimens from patients with gallbladder carcinoma after cholecystectomy. Further studies with larger case numbers are needed to confirm and generalize these findings., (Copyright © 2021. Published by Elsevier Inc.)

Gall bladder cancer (GBC) is a rare and one of the most aggressive types of malignancies, often associated with a poor prognosis and survival. It is a highly metastatic cancer and is often not diagnosed at the initial stages, which contributes to a poor survival rate of patients. The poor diagnosis and chemoresistance associated with the disease limit the scope of the currently available surgical and nonsurgical treatment modalities. Thus, there is a need to explore novel therapeutic targets and biomarkers that will help relieve the severity of the disease and lead to advanced therapeutic strategies. Accumulating evidence has correlated the atypical expression of various noncoding RNAs (ncRNAs), including circular RNAs (circRNAs), long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and small nucleolar RNAs (snoRNA) with the increased cell proliferation, epithelial-mesenchymal transition (EMT), invasion, migration, metastasis, chemoresistance, and decreased apoptosis in GBC. Numerous reports have indicated that the dysregulated expression of ncRNAs is associated with poor prognosis and lower disease-free and overall survival in GBC patients. These reports suggest that ncRNAs might be considered novel diagnostic and prognostic markers for the management of GBC. The present review recapitulates the association of various ncRNAs in the initiation and progression of GBC and the development of novel therapeutic strategies by exploring their functional and regulatory role.

Yes-associated protein (YAP) and TEA domain-containing sequence-specific transcription factors 4 (TEAD4) are essential components of the Hippo pathway. Abnormal regulation of the Hippo pathway contributes to the progression and metastasis of many cancer types. However, their clinicopathologic and prognostic significances have not been studied in gallbladder cancers. Here, we systematically evaluated the YAP and TEAD4 immunolabelings and their association with clinicopathologic characteristics and survival outcomes using 212 specimens of surgically resected gallbladder cancers. High YAP and TEAD4 immunolabelings were identified in 70 (33%) cases and were associated with infiltrative growth pattern, poor differentiation, perineural invasion, and advanced pT classification and AJCC stage. High YAP immunolabeling was significantly associated with high TEAD4 immunolabeling (p < 0.001). High immunolabeling levels of YAP or TEAD4 alone and the combined YAP high TEAD4 high group were significantly associated with poor survival in both univariate (p < 0.001) and multivariate analyses (HR = 2.358; 95% CI, 1.369-4.061; p = 0.002). Therefore, the YAP and TEAD4 immunolabelings are associated with aggressive behavior of gallbladder cancers and may be useful as a prognostic indicator in patients with surgically resected gallbladder cancer., (© 2021 Scandinavian Societies for Medical Microbiology and Pathology.)

Gallbladder cancer (GBC), the most common malignancy in the biliary tract, is highly lethal malignant due to seldomly specific symptoms in the early stage of GBC. This study aimed to identify exosome-derived miRNAs mediated competing endogenous RNAs (ceRNA) participant in GBC tumorigenesis. A total of 159 differentially expressed miRNAs (DEMs) was identified as exosome-derived miRNAs, contains 34 upregulated exo-DEMs and 125 downregulated exo-DEMs based on the expression profiles in GBC clinical samples downloaded from the Gene Expression Omnibus database with the R package. Among them, 2 up-regulated exo-DEMs, hsa-miR-125a-3p and hsa-miR-4647, and 5 down-regulated exo-DEMs, including hsa-miR-29c-5p, hsa-miR-145a-5p, hsa-miR-192-5p, hsa-miR-194-5p, and hsa-miR-338-3p, were associated with the survival of GBC patients. Results of the gene set enrichment analysis showed that the cell cycle-related pathways were activated in GBC tumor tissues, mainly including cell cycle, M phase, and cell cycle checkpoints. Furthermore, the dysregulated ceRNA network was constructed based on the lncRNA-miRNA-mRNA interactions using miRDB, TargetScan, miRTarBase, miRcode, and starBase v2.0., consisting of 27 lncRNAs, 6 prognostic exo-DEMs, and 176 mRNAs. Together with prognostic exo-DEMs, the STEAP3-AS1/hsa-miR-192-5p/MAD2L1 axis was identified, suggesting lncRNA STEAP3-AS1, might as a sponge of exosome-derived hsa-miR-192-5p, modulates cell cycle progression via affecting MAD2L1 expression in GBC tumorigenesis. In addition, the biological functions of genes in the ceRNA network were also annotated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Our study promotes exploration of the molecular mechanisms associated with tumorigenesis and provide potential targets for GBC diagnosis and treatment., (© 2021. The Author(s).)

Background: It remains unclear whether lymph node dissection is necessary for patients with N0 gallbladder carcinoma (GBC). The objective of this study was to evaluate the effect of lymphadenectomy on the prognosis for N0 GBC patients. The secondary objective was to establish a prognostic model of survival for N0 GBC patients being founded on the large samples., Methods: Patient data were obtained from the database named SEER (Surveillance, Epidemiology, and End Results database) between 2010 and 2014. Analyses of Kaplan-Meier survival and multivariate Cox regression were performed in subgroups based on regional lymph nodes removal (LNR) to calculate the excess risk of cause-specific death. A prognosis nomogram was constructed build on the results of a multivariate analysis to predict the specific survival time (CSS) rates of N0 GBC patients., Result: A total of 1406 N0 GBC patients were included in this research. The majority of N0 GBC patients undergoing cancer-directed surgery did not undergo LNR (64.5%). The results showed that LNR can improve the survival of N0 GBC patients, including those at the T1a and T1b stages, and a wider range of lymph node dissection (LNR2) compared to LNR1 was more conducive to the prognosis. Furthermore, multivariate regression analysis showed that LNR was an independent favorable prognostic factor of N0 GBC. Finally, a nomogram was constructed to accurately predict the prognosis of N0 gallbladder cancer patients., Conclusion: This study demonstrated a significant survival benefit for extended lymph nodes removed in N0 GBC patients. These results recommend that an extended lymph node dissection strategy is needed for N0 GBC patients., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background and Aims: Biliary tract cancer (BTC) is rare and has limited treatment options. We aimed to examine aspirin use on cancer-specific survival in various BTC subtypes, including gallbladder cancer, ampulla of Vater cancer, and cholangiocarcinoma., Approach and Results: Nationwide prospective cohort of newly diagnosed BTC between 2007 and 2015 were included and followed until December 31, 2017. Three nationwide databases, namely the Cancer Registration, National Health Insurance, and Death Certification System, were used for computerized data linkage. Aspirin use was defined as one or more prescriptions, and the maximum defined daily dose was used to evaluate the dose-response relationship. Cox's proportional hazards models were applied for estimating HRs and 95% CIs. Analyses accounted for competing risk of cardiovascular deaths, and landmark analyses to avoid immortal time bias were performed. In total, 2,519 of patients with BTC were exposed to aspirin after their diagnosis (15.7%). After a mean follow-up of 1.59 years, the 5-year survival rate was 27.4%. The multivariate-adjusted HR for postdiagnosis aspirin users, as compared with nonusers, was 0.55 (95% CI: 0.51 to 0.58) for BTC-specific death. Adjusted HRs for BTC-specific death were 0.53 (95% CI: 0.48 to 0.59) and 0.42 (95% CI: 0.31 to 0.58) for ≤ 1 and > 1 maximum defined daily dose, respectively, and showed a dose-response trend (P < 0.001; nonusers as a reference). Cancer-specific mortality was lower with postdiagnosis aspirin use in patients with all major BTC subtypes., Conclusions: The nationwide study revealed that postdiagnosis aspirin use was associated with improved BTC-specific mortality of various subtypes. The findings suggest that additional randomized trials are required to investigate aspirin's efficacy in BTC., (© 2021 by the American Association for the Study of Liver Diseases.)

Background: Few population-based studies have examined incidence and mortality of cancers of the biliary tract, including intrahepatic bile duct, extrahepatic bile duct, ampulla of Vater, and overlapping or other lesions of the biliary tract in one study., Methods: To further the understanding of recent rates of biliary tract cancers, we used population-based data, to examine incidence and mortality during 2013 to 2017. We examined how rates varied by sex, age, race/ethnicity, U.S. census region, and stage at diagnosis., Results: Intrahepatic bile duct was the most common biliary tract cancer, with an incidence rate of 1.49 per 100,000 persons. Cancer incidence rates per 100,000 persons were 0.96 for extrahepatic bile duct, 0.45 for ampulla of Vater, and 0.24 for overlapping or other lesions of the biliary tract. Cancer death rates per 100,000 persons were 1.66 for intrahepatic bile duct and 0.45 for other biliary tract. Intrahepatic bile duct incidence and death rates were higher among males than females, higher among Hispanic and Asian and Pacific Islander persons compared with non-Hispanic Whites, and higher in the Northeast and in urban counties., Conclusions: This report provides national estimates of these rare biliary tract cancers., Impact: Key interventions targeted to high-risk populations may help reduce incidence and mortality of cancers of the biliary tract by improving primary prevention through strategies to reduce tobacco and alcohol use, control overweight and obesity, and promote hepatitis B vaccination and use of syringe service programs meant to curb the transmission of infectious diseases such as viral hepatitis., (©2021 American Association for Cancer Research.)

Purpose: Data related to the role of epigenetic modifications in gallbladder carcinoma (GBC) is limited. We intended to assess the role of crucial epigenetic modifiers pertaining to histone modification and DNA-methylation system in gallbladder carcinogenesis., Methods: The expression of EZH2, H3K27me3, and DNA methyltransferases (DNMTs) was analyzed by immunohistochemistry in cases of GBC (n = 39), gallbladder dysplasia (GBD, n = 12), and benign mucosa (BM, n = 16). A semi-quantitative scoring system was used for assessing the immunohistochemical expression., Results: The expression of EZH2 was significantly higher in cases of GBC than GBD (p value 0.001). The cases of BM were negative. Its expression was also higher in poorly differentiated tumors and positively correlated with the proliferative activity (MIB-1 labeling index) (p value 0.03 and 0.01, respectively). There was no significant difference in the expression levels of H3K27me3, DNMT-1, and DNMT-3B among GBC, GBD, and BM cases. Although GBC cases with strong EZH2 expression showed a shorter overall survival, the difference was not statistically significant., Conclusion: This study highlights the crucial role of the key epigenetic regulators EZH2 in the pathobiology and evolution of gallbladder carcinogenesis. Given the reversibility of epigenetic alterations, EZH2 may be a novel therapeutic target for gallbladder carcinogenesis., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Programmed death-1 (PD1) expression has not been reported in gallbladder adenocarcinoma. In this study we examined PD1 expression in gallbladder cancer to explore the correlation between PD1 expression and the clinicopathologic parameters. We found that 98% (46/47) cases expressed programmed death-ligand 1 (PD-L1) with 85% cases being PD-L1 3+. PD1+ tumor-infiltrating lymphocytes (TILs) were present in 78.7% cases (37/47). The tumor size was significantly smaller and the stromal CD3+ TILs were significantly higher in tumors with PD1+ TILs than those with PD1- TILs. In the tumors with size of <3 cm, stromal CD3+ TILs >115/HPF or stromal CD8+ TILs >45/HPF were associated with much better survival than those with stromal CD3+ TILs ≤115/HPF or stromal CD8+ TILs ≤45/HPF. In tumors with the size of 3 cm or larger, PD1+ TILs or stromal CD8+ TILs >45/HPF carried a significantly poorer survival than PD1- tumors or stromal CD8+ TILs <=45/HPF. No correlation was identified between PD1 expression and lymphovascular invasion, distant metastasis, pathologic tumor stage or prognostic stage. Multivariate survival analysis showed that tumor TNM stage and age were independent prognostic factors in gallbladder adenocarcinomas. We conclude that gallbladder adenocarcinomas may have high PD-L1 expression and PD1+ TILs. Smaller tumor size and greater amount of stromal CD3+ T cells were found in tumors with PD1+ TILs. In small tumors (<3 cm), high stromal CD3+ TILs or high stromal CD8+ TILs were associated with better survival. However, in large tumors (≥3 cm), PD1+ TILs or high stromal CD8+ TILs carried a poorer survival. Our study implied that immune-based therapy including PD1/PD-L1 checkpoint blockade might be useful in gallbladder adenocarcinomas., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cancer-associated fibroblasts (CAFs) with different gene profiles from normal fibroblasts (NFs) have been implicated in tumor progression. Angiopoietin-like protein 4 (ANGPTL4) has been shown to regulate tumor angiogenesis and metastasis, and predict poor prognosis. However, the ANGPTL4 expression in CAFs, especially in gallbladder CAFs (GCAFs) and its relationship with patient prognosis is unclear., Methods: Affymetrix gene profile chip analysis in vitro was performed to detect the different gene expression profiles between GCAFs and NFs. RT-qPCR, immunohistochemistry, and western blotting were performed to investigate the different expression levels of ANGPTL4 in GCAFs/NFs in vitro and in an in vivo nude mouse model of xenograft tumors. Finally, the ANGPTL4 expression was investigated in the stroma of different lesion tissues of the human gallbladder by immunohistochemistry, especially the expression in GCAFs in vivo by co-immunofluorescence, and their prognostic significance in patients with gallbladder cancer (GBC) was assessed., Results: ANGPTL4 was upregulated in both GCAFs in vitro and in the xenograft stroma of nude mice in vivo, and its expression was also significantly upregulated in human GBC stroma co-localized with the interstitial markers fibroblast secreted protein-1 and α-smooth muscle actin. In addition, the elevated ANGPTL4 expression in GCAFs was correlated with tumor differentiation, liver metastasis, venous invasion and Nevin staging, and GBC patients with an elevated ANGPTL4 expression in GACFs were found to have a lower survival rate., Conclusions: Increased ANGPTL4 expression in GCAFs correlates with poor patient prognosis, which indicates a potential therapeutic target for human GBCs., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Invasive gallbladder carcinoma (GBC) is preceded by two main types of precursor lesions: intracholecystic papillary-tubular neoplasms (ICPNs) and biliary intraepithelial neoplasias (BilINs). Invasive GBCs with an ICPN component have more favorable prognoses than those without an ICPN component. Some BilINs show a relatively exophytic papillary pattern but do not meet the ICPN criteria; at our institution, we call these papillary neoplasias. To clarify the clinical significance of papillary neoplasia, we herein examined 80 invasive GBCs and classified them into three groups based on the type of preinvasive lesions: those with ICPN (ICPN group, n = 35), those with papillary neoplasia (pap-neoplasia group, n = 13), and those without ICPN/papillary neoplasia (group without ICPN/pap-neoplasia, n = 32). We then compared the prognostic differences and characterized the tumors of each group by determining the immunohistochemical expressions of various biomarkers. The overall survival periods of the ICPN and pap-neoplasia groups were significantly longer than that of the group without ICPN/pap-neoplasia (P < 0.0001, P = 0.0036, respectively). Multivariate analysis revealed that lacking ICPN/papillary neoplasia was independently associated with poor prognosis (P = 0.0007), as were poor differentiation (P = 0.0395), presence of preoperative symptoms (P = 0.0488), and advanced stage (P = 0.0234). Invasive components of the ICPN and pap-neoplasia groups were characterized by higher expressions of p16 and p53 compared with those of the group without ICPN/pap-neoplasia. The prognoses of the invasive GBCs with either papillary neoplasia or ICPN were thus more favorable than those of the invasive GBCs without ICPN/pap-neoplasia. Invasive GBCs with exophytic papillary preinvasive lesions (ICPN and papillary neoplasia) may be biologically different from those without such lesions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Growing evidence indicates that systemic immune inflammation index (SII) can predict the prognosis of various solid tumors. The objective of this study aimed to investigate the efficacy of SII in predicting the prognosis of gallbladder carcinoma (GBC) patients after radical surgery., Methods: A consecutive series of 93 patients with GBC who underwent radical resection were enrolled in the retrospective study. The cutoff value for the SII was calculated using the time-dependent receiver operating characteristic (ROC) curve analysis by overall survival (OS) prediction. The associations between the SII and the clinicopathologic characteristics were analyzed using Pearson's χ 2 test and Fisher's exact test. Survival curves were calculated using the Kaplan-Meier method. Univariate analysis was performed to evaluate the prognostic relevance of preoperative parameters. The multivariate Cox regression proportional hazard model was used to assess variables significant on univariate analysis., Results: The Kaplan-Meier survival analysis and the multivariate analysis of patients with GBC who received radical resection showed SII independently predicted OS. The univariate analysis showed that the TNM stage, SII, CA19-9, ALP, prealbumin, NLR, MLR, lymph node metastasis, and histopathological type were all associated with overall survival. In time-dependent ROC analysis, the area of the SII-CA19-9 under the ROC curve (AUC) was higher than that of the preoperative SII or CA19-9 levels for the prediction of OS., Conclusion: Our results demonstrate that high SII was a predictor of poor long-term outcomes among patients with GBC undergoing curative surgery. SII-CA19-9 classification may be more effective in predicting the postoperative prognosis of GBC patients., (© 2021 Wiley Periodicals LLC.)

Purpose: The study was done to evaluate the role of adjuvant therapy in curatively resected Stage II and III gallbladder carcinoma (GBC)., Materials and Methods: This was a retrospective analysis of patients of GBC registered between 2008 and 2017 in outpatient department of a tertiary cancer hospital in India. Patients who had any of the following adjuvant treatment after radical surgery: (a) external beam radiotherapy (RT) alone, (b) chemotherapy (CT) alone, and (c) RT with CT (CRT) were considered for the study., Results: A total of fifty patients could meet the selection criteria. It was seen that seven patients were treated with RT, 20 with CT, and 23 with CRT. Median follow-up for patients who were alive was 26.7 months. Nineteen patients had locoregional failure while eight had distant failure. Patients treated with CRT had a significantly better mean overall survival compared to those treated with RT or CT (44.0 months, 12.5 months, and 15.1 months, respectively; P = 0.003). Similarly, mean disease-free survival was superior in CRT arm compared to RT and CT arms (43.6 months, 9.6 months, and 12.4 months, respectively; P = 0.002)., Conclusions: Adjuvant CRT had better survival outcome compared to patients treated with either RT or CT with Stage II and III disease after curative cholecystectomy., Competing Interests: None

Treatment options for gallbladder carcinoma (GBC) are limited and GBC prognosis remains poor. There is no well-accepted targeted therapy to date, so effective biomarkers of GBC are urgently needed. Here we investigated the expression and correlations of fibroblast growth factor receptors (FGFR1-4) and 18 fibroblast growth factors (FGFs) in two independent patient cohorts and evaluated their prognostic significance. Consequently, we demonstrated that both FGF19 and FGFR4 were unfavorable prognostic biomarkers, and their co-expression was a more sensitive predictor. By analyzing the correlations between all 18 FGFs and FGFR4, we showed that FGF19 expression was significantly associated with FGFR4 and promoted GBC progression via stimulating FGFR4. With experiments using GBC cells, GPBAR1 -/- mice models, and human subjects, we demonstrated that elevated bile acids (BAs) could increase the transcription and expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promoted GBC progression by stimulating FGFR4 and downstream ERK in an autocrine manner with bile as a potential carrier. Patients with GBC had significantly higher FGF19 in serum and bile, compared to patients with cholelithiasis. BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line. In conclusion, upregulation of BAs elevated co-expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Golgi phosphoprotein 3 (GOLPH3) has been demonstrated to promote tumor progression in various gastrointestinal malignancies. However, its effects in gallbladder carcinoma (GBC) remain unknown. In the present study, the expression levels of GOLPH3 and nucleotide‑binding domain leucine‑rich repeat and pyrin domain containing receptor 3 (NLRP3) in human GBC tissues were detected by immunohistochemistry, and the clinical data and survival of these patients were analyzed. Next, whether GOLPH3 could affect tumor proliferation via regulation of the NLRP3 inflammasome was investigated in vitro . The results demonstrated that GOLPH3 could promote GBC cell proliferation, and that it regulated protein expression levels of NLRP3, as well as Caspase‑1 P10. Conversely, knockdown of NLRP3 reversed the effects of GOLPH3 overexpression on GBC cell proliferation. GOLPH3 and NLRP3 expression levels were found to be upregulated in GBC tissues and their expression was positively correlated. The expression of GOLPH3 and NLRP3 was associated with the expression of the proliferative marker Ki‑67 in tissues, and associated with poor survival, tumor stage, degree of differentiation, depth of invasion, carbohydrate antigen 19‑9 and C‑reactive protein levels in patients with GBC. In summary, these results indicate that GOLPH3 promotes GBC cell proliferation via a NLRP3/Caspase‑1 pathway. GOLPH3 and NLRP3 participate in the process of human GBC growth and may serve as a potential therapeutic targets.

Introduction: Recent trends in the incidence and mortality of biliary tract cancers are unknown. We estimated the trends in biliary tract cancers-related incidence and mortality stratified by anatomical site, age, sex, and race/ethnicity in the US adults., Methods: We performed a population-based trend analysis using the US national incidence (2009-2017) and mortality records (2009-2018). We identified age-standardized incidence and mortality from intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer using appropriate ICD-10 code. Temporal mortality was calculated by joinpoint trend analysis with estimates of annual percentage change (APC) described as each trend segment., Results: The incidence rates of ICC increased linearly (APC 8.9%, 95% confidence interval [CI] 7.8%-10.0%) while gallbladder cancer-related incidence rates remained stable early and decreased significantly later in the study (APC -2.8%, 95% CI -5.5% to -0.0% [2014-2017]). Age-standardized mortality from biliary tract cancers steadily increased with an annual increase of 2.0% (95% CI 1.6%-2.3%). Although there was a linear increase in the ICC-related mortality (APC 3.5%, 95% CI 3.1%-3.8%), extrahepatic cholangiocarcinoma-related mortality tended to remain stable earlier and increased later (APC 7.0%, 95% CI 4.6%-9.5% [2013-2018]). By contrast, gallbladder cancer-related mortality steadily decreased over 10 years (APC -1.6%, 95% CI -2.1% to -1.1%). Significant differences in mortality and changes in trends over time were observed in non-Hispanic blacks, Hispanics, and non-Hispanic Asians., Discussion: In this analysis of nationally representative data, changing mortality trends in various biliary tract cancers was noted with a disproportionately higher burden of fatality in minorities., (Copyright © 2021 by The American College of Gastroenterology.)

Published data on survival of T2 gallbladder carcinoma (GBC) from different countries show a wide range of 5-year survival rates from 30-> 70%. Recently, studies have demonstrated substantial variation between countries in terms of their approach to sampling gallbladders, and furthermore, that pathologists from different continents apply highly variable criteria in determining stage of invasion in this organ. These findings raised the question of whether these variations in pathologic evaluation could account for the vastly different survival rates of T2 GBC reported in the literature. In this study, survival of 316 GBCs from three countries (Chile n = 137, South Korea n = 105, USA n = 74), all adequately sampled (with a minimum of five tumor sections examined) and histopathologically verified as pT2 (after consensus examination by expert pathologists from three continents), was analyzed. Chilean patients had a significantly worse prognosis based on 5-year all-cause mortality (HR: 1.89, 95% CI: 1.27-2.83, p = 0.002) and disease-specific mortality (HR: 2.41, 95% CI: 1.51-3.84, p < 0.001), compared to their South Korean counterparts, even when controlled for age and sex. Comparing the USA to South Korea, the survival differences in all-cause mortality (HR: 1.75, 95% CI: 1.12-2.75, p = 0.015) and disease-specific mortality (HR: 1.94, 95% CI: 1.14-3.31, p = 0.015) were also pronounced. The 3-year disease-specific survival rates in South Korea, the USA, and Chile were 75%, 65%, and 55%, respectively, the 5-year disease-specific survival rates were 60%, 50%, and 50%, respectively, and the overall 5-year survival rates were 55%, 45%, and 35%, respectively. In conclusion, the survival of true T2 GBC in properly classified cases is neither as good nor as bad as previously documented in the literature and shows notable geographic differences even in well-sampled cases with consensus histopathologic criteria. Future studies should focus on other potential reasons including biologic, etiopathogenetic, management-related, populational, or healthcare practice-related factors that may influence the survival differences of T2 GBC in different regions.

Background & Aims: Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterise GBC and explore molecular subtypes associated with patient survival., Methods: We profiled the mutational landscape of GBC tumours (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n = 45), we interrogated the matched transcriptomes, DNA methylomes, and somatic copy number alterations. We explored molecular subtypes identified through clustering tumours by genes whose expression was associated with survival in 47 tumours and validated subtypes on 34 publicly available GBC cases., Results: Exome analysis revealed TP53 was the most mutated gene. The overall mutation rate was low (median 0.82 Mut/Mb). APOBEC-mediated mutational signatures were more common in tumours with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in ≥50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95-gene signature that stratified all GBC patients into 3 subtypes that suggested an association with overall survival post-resection. The 2 poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive micro-environments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, whereas the good-survival subtype showed the opposite features., Conclusion: These data suggest that the tumour micro-environment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles., Lay Summary: Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumours to see if there were differences between tumours in genetic information such as DNA and RNA. We found evidence of aflatoxin exposure in these tumours, and immune cells surrounding the tumours were associated with survival., Competing Interests: Conflict of interest The authors have no relevant affiliation or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Please refer to the accompanying ICMJE disclosure forms for further details., (Published by Elsevier B.V.)

Background: Gallbladder neuroendocrine carcinoma (GB-NEC) is rare and there are few reports at present. We sought to review the current knowledge of GB-NEC and provide recommendations for clinical management., Methods: A systemic literature research was conducted in the websites of Pubmed, Medline, Web of Science, CNKI, Wanfang Data using the keywords including gallbladder combined with neuroendocrine carcinoma or neuroendocrine tumor or neuroendocrine neoplasm. Two reviewers independently screened the articles by reading the title, abstract and full-text., Results: In computed tomography (CT) and magnetic resonance imaging (MRI) examination, a well-defined margin, gallbladder replacing type with larger hepatic and lymphatic metastases could be helpful for differential diagnosis of GB-NEC and gallbladder adenocarcinoma (GB-ADC). Older age, unmarried status, large tumor size (>5 cm), positive margins, and distant Surveillance, Epidemiology and End result (SEER) stage are independently associated with poor survival. Surgical resection remains as the preferred and primary treatment. The potential survival benefit of lymphadenectomy for patients remains controversial. Platinum-based postoperative adjuvant chemotherapy may improve the survival. The efficacy of other treatments including immunotherapy, targeted therapy and somatostatin analogue needs further investigation., Conclusion: Typical imaging features could be helpful for preoperative diagnosis. Age, margin status, tumor size, marital status, histopathologic subtype and SEER stage may be independent predictors for the survival. Remarkable advances regarding the treatment for GB-NEC have been achieved in recent years. Further studies are needed to investigate the survival benefit of lymphadenectomy for patients with GB-NEC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Gallbladder carcinoma (GBC) commonly occurs in gastrointestinal malignancy and has the fifth highest mortality rate among gastrointestinal malignancy. Recently, miR-188-5p, a small noncoding RNA, has been implicated in various types of cancer such as nasopharyngeal carcinoma, oral squamous cell carcinoma, liver cancer, and prostate cancer. However, the effect of miR-188-5p on GBC remains unclear. Here, we demonstrated that miR-188-5p was downregulated in GBC tissues, and downregulation of miR-188-5p correlated with larger tumor size, lymph node metastasis, and extensive metastasis. In addition, the overall survival time of patients with higher miR-188-5p expression was significantly longer than that of patients with low-miR-188-5p expression. Moreover, downregulation of miR-188-5p promoted the proliferation, migration, and invasion of GBC cells, while its overexpression inhibited cell invasion and induced cell apoptosis, and arrested GBC growth in vivo. Importantly, miR-188-5p-dependent tumorigenesis was correlated with Wnt/β-catenin signaling and p-38/JNK signaling. In conclusion, miR-188-5p plays a direct role in GBC tumorigenesis. Our study suggests that miR-188-5p could serve as a novel diagnosis marker and therapeutic target in GBC., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Background/aim: Inflammation-based prognostic scores are proven prognostic biomarkers in various cancers. This study aimed to identify a useful prognostic score for patients with biliary tract cancer (BTC) after surgical resection., Patients and Methods: This retrospective study recruited 115 patients with BTC during 2010-2020. The relationship between clinicopathological variables, including various prognostic scores and overall survival (OS), was investigated using univariate and multivariate analyses., Results: BTC included 58 cholangiocarcinoma, 29 gallbladder carcinoma, 16 ampullary carcinoma, and 12 perihilar cholangiocarcinoma cases. A significant difference was detected in OS of patients with a Japanese modified Glasgow prognostic score (JmGPS) 0 (n=62) and JmGPS 1 or 2 (high JmGPS) (n=53). In the multivariate analysis, tumour differentiation (p=0.014) and a high JmGPS (p=0.047) were independent prognostic factors., Conclusion: The high JmGPS was an independent prognostic predictor after surgical resection and was superior to other prognostic scores., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

BACKGROUND Gallbladder adenocarcinoma (GBAC) is globally acknowledged as one of the most common malignancies among all gastrointestinal cancers. Despite prognosis of GBAC patients remains poor, patients with early-stage disease can be observed with long-term survival. MATERIAL AND METHODS In this study, 2556 patients with pathological GBAC between 2010 and 2015 were derived from the Surveillance, Epidemiology, and End Results (SEER) database. The prognostic nomograms containing all independent prognostic factors for predicting overall survival (OS) and cancer-specific survival (CSS) were constructed to achieve superior prognostic discriminatory ability. RESULTS Based on the AJCC 7th TNM staging system, we found the TNM substaging was not accurate enough to predict the survival and stratify the risk. Based on the results of univariate and multivariate analyses, a more precise prognostic nomogram was constructed containing all significant independent prognostic factors (age, grade, TNM stage, bone metastasis, and chemotherapy) for OS, while age, grade, TNM stage, bone metastasis and radiotherapy significant independent prognostic factors for CSS. The C-index of the constructed nomogram for predicting OS and CSS was 0.740 and 0.737 higher than that of TNM staging alone (0.667 for OS and 0.689 for CSS), respectively. In addition, the calibration curves and decision curve analysis further showed its robust power in survival prediction. CONCLUSIONS The constructed nomograms showed better discrimination abilities to predict OS and CSS rates at 1, 3, and 5 years. In the future, these constructed models for this disease will assist in risk stratification to guide GBAC treatment.

Purpose: There are only a few reports on the treatment-based survival of gallbladder cancer (GBC). The primary objective of this study was to examine the change in treatment modality and the related trends in the survival of GBC., Methods: This study includes all cases of primary GBC diagnosed in the province of Ontario, Canada, from January 2007 to December 2015 with known disease stage. Treatment modalities were classified as no treatment, radiation or chemotherapy, and surgical resection. We examined the association between surgical resection and demographics and tumor characteristics and estimated the trends in survival based on treatment modality., Results: In total, 564 patients with GBC were identified, of which 374 (66.3%) were female. Although there were no significant trends in treatment modalities over the study period (p = 0.276), survival rates improved for all treatment modalities over time. There was a 35% increase in 5-year survival for the surgical resection group from 2007 to 2015. For patients with stage I-II disease, the 5-year survival rate increased 40% over time. The highest 5-year survival was observed for the surgical resection group in patients with stage I-II disease (0.533 (95% CI, 0.514-0.552)) while the average 5-year survival rate for all patients over the study period was 0.247 (95% CI, 0.228-0.266)., Conclusions: Most cases of GBC continue to be diagnosed in the late stage. Five-year survival for the surgical resection group has markedly improved over time, specifically for patients with stage I-II disease which increased from 30% in 2007 to 70% in 2015.