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

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

Background: MicroRNA-messenger RNA (miRNA-mRNA) regulatory networks are essential factors that regulate tumor development and metastasis in various cancers including gallbladder carcinoma (GBC). Here, we identified the miR-195-5p/Fos-like antigen-1 ( FOSL1 ) axis in GBC by bioinformatics analysis and aimed to investigate its role and regulatory mechanism in the development and progression of GBC., Methods: Bioinformatics analysis was used to construct a miRNA-mRNA regulatory network. Real-time quantitative polymerase chain reaction (qRT-PCR), western blot, and dual luciferase reporter assays confirmed that miR-195-5p targets FOSL1 in GBC. Cell Counting Kit-8 (CCK-8), wound healing, transwell, flow cytometry assays, western blotting, and immunofluorescence were used to detect the biological effects of the miR-195-5p / FOSL1 regulatory axis and the Wnt / β-catenin signaling pathway on the proliferation, migration, invasion, and cell cycle of GBC cells. A nude mouse tumorigenesis model was constructed to verify the role of miR-195-5p in vivo ., Results: Bioinformatics analysis and qRT-PCR confirmed that the miR-195-5p / FOSL1 regulatory axis was closely related to GBC cells. Overexpression of miR-195-5p inhibited the proliferation, migration, and invasion of GBC cells, and the cells were blocked in the G0/G1 phase. Dual luciferase reporter gene assays and western blot analysis showed that FOSL1 is targeted by miR-195-5p . The recovery experiment showed that miR-195-5p can inhibit cell proliferation, migration, invasion, and increase of cells in the G0/G1 phase, and the overexpression of FOSL1 could restore this effect by regulating the Wnt/β-catenin signaling pathway. Finally, we confirmed that miR-195-5p inhibited the growth of transplanted tumors in vivo ., Conclusions: The overexpression of miR-195-5p inhibits the proliferation and metastasis of GBC cells by directly targeting FOSL1 and regulating the Wnt/β-catenin signaling pathway., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3685/coif). All authors report that this work was supported by grants from the National Natural Science Foundation of China (Nos. 30671987 and 8180102403), PhD Start-up Fund of Natural Science Foundation of Guangdong Province (No. 2015A030310377) and National Key Clinical Discipline. The authors have no other conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: Gallbladder cancer (GBC) is highly malignant, its early diagnosis is difficult, and the 5-year survival rate is less than 5%. For patients with advanced GBC (GBCa), combined chemotherapy, radiotherapy, targeted therapy, and immunotherapy are needed to improve the overall survival (OS) rate of patients., Methods: Data were collected from 53 patients with GBCa who had volunteered to receive programmed death protein-1 (PD-1)-based treatment at the First Affiliated Hospital of Nanjing Medical University from February 2018 to February 2021. Statistical analysis of the collected data, including Kaplan-Meier method, log-rank test, Cox proportional hazard regression model and other methods., Results: The objective response rates (ORRs) and disease control rates (DCRs) of 53 participants 3 months after receiving immunotherapy were 30.2% and 79.2%, respectively. The ORRs and DCRs of the combined treatment group were higher than those of the camrelizumab group (CG) (P<0.05). The DCRs of the camrelizumab plus apatinib group (CAG) at 3 and 6 months were 90.9% and 45.5% (P=0.003), respectively, while the DCRs at 3 and 6 months of the camrelizumab plus chemotherapy group (CCG) were 85.7% and 71.4% (P=0.450), respectively. After treatment, there were statistically significant differences before and after CA199 for each group (P<0.05). The median progression-free survival (mPFS) of the 53 participants was 7 months, and the median overall survival (mOS) was 12 months. The mPFS and mOS of the CAG and the CCG were greater than those in the CG (6 vs. 3 months, P<0.001, 12 vs. 8 months, P=0.019; 9 vs. 3 months, P<0.001, 13 vs. 8 months, P<0.001, respectively). A total of 16 cases had grade 1 or 2 adverse events, and 3 cases had grade 3 and higher adverse events., Conclusions: For GBCa patients, PD-1 combined with targeted therapy or chemotherapy is more effective than immunotherapy alone. The targeted therapy group has more obvious early effects on the disease control rate, and combined chemotherapy can achieve sustained effects, providing new ideas for the future GBCa application of immune, targeted, and chemotherapy sequential therapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-4747). All authors reported that the project was supported by the National Natural Science Foundation of China (81871259 and 820706752), and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2019-I2M-5-035). Dr. LL serves as an unpaid Associate Editors-in-Chief of Annals of Translational Medicine from Jun 2019 to May 2024. The authors have no other conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: The first-line chemotherapy regimen for advanced gallbladder cancer (GBC) is gemcitabine plus platinum (GP), despite its efficacy is limited. The current investigation is a retrospective study to compare the safety and efficacy between the modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine plus oxaliplatin (GEMOX) as the first-line chemotherapy for unresectable locally advanced or metastatic GBC., Methods: The data of patients with unresectable locally advanced or metastatic GBC, who were treated with mFOLFIRINOX or GEMOX as the first-line therapy between April 2014 and April 2018 at Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, were retrieved. This retrospective study evaluated the clinical characteristics, survival outcomes and adverse events., Results: A total of 44 patients (n=25 in mFOLFIRINOX, n=19 in GEMOX) were included. There were no significant differences between groups in baseline characteristics. The median progression free survival (mPFS) was 5.0 months in the mFOLFIRINOX group and 2.5 months in the GEMOX group [P=0.021; hazard ratio (HR), 0.499; 95% CI, 0.266 to 0.937]. The median overall survival (mOS) was 9.5 months in the mFOLFIRINOX group and 7.0 months in the GEMOX group (P=0.019; HR, 0.471; 95% CI, 0.239 to 0.929). Disease control rate (DCR) was 76.0% in the mFOLFIRINOX group and 47.4% in the GEMOX group (P=0.051). The rate of grade 3-4 adverse events was 48% in the mFOLFIRINOX group and 36.8% in the GEMOX group (P=0.459). The incidence of grade 3-4 neutropenia and diarrhea were more common in the mFOLFIRINOX group, while the incidence of grade 3-4 thrombocytopenia and peripheral neuropathy were more common in the GEMOX group., Conclusions: mFOLFIRINOX might improve the poor prognosis of unresectable locally advanced or metastatic GBC, and the results need to be further verified by prospective clinical studies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/hbsn-20-846). The authors have no conflicts of interest to declare., (2021 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: Increasing evidence suggests that elevated expression of polyA-binding protein-interacting protein 1 (PAIP1) is associated with cancer development and progression. However, how PAIP1 promotes gallbladder cancer (GBC) is still unclear., Methods: Two GBC tissue-derived cell lines, NOZ and GBC-SD cells, were used in this study. Assays of cell proliferation, colony formation, apoptosis, and xenograft tumor model were performed to examine the tumorigenic effects of PAIP1. Immunohistochemical (IHC) staining was used to examine the expression level of PAIP1 in both patient GBC tissues and mouse tumors. Microarray and bioinformatics analysis were used to explore the targets of PAIP1. Quantitative polymerase chain reaction (qPCR) and western blot analysis were used to validate PAIP1-mediated targets., Results: We found that upregulated PAIP1 expression was correlated with GBC. Knockdown of PAIP1 in gallbladder cells alleviated cell proliferation, promoted apoptosis, and inhibited xenograft tumor growth. Gene microarray analysis showed that stable silencing of PAIP1 altered various gene expressions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that PAIP1 regulates cell cycle progression. Finally, we found that the PLK1 kinase, a key regulator of cell cycle, was regulated by PAIP1 at the transcriptional and protein levels. PLK1 level was positively correlated with PAIP1 level in both mouse tumors and GBC tissues. PAIP1 interacted with PLK1, and rescue of PAIP1 could recover PLK1 protein level and inhibit apoptosis., Conclusions: Our data suggest that PAIP1 contributes to GBC progression likely through regulating PLK1 level. Since upregulated PAIP1 expression is positively associated with GBC, PAIP1 may act as a clinical prognostic biomarker of GBC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-2417) The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Gallbladder cancer (GBC) is a highly aggressive biliary epithelial malignancy. The median survival time of GBC patients was less than 1 year. Tumor invasion and metastasis are the major cause of high mortality of GBC patients. However, the molecular mechanisms involved in GBC metastases are still unclear., Methods: We performed 10X genomics single-cell RNA sequencing (scRNA-seq) on GBC liver metastasis tissue to evaluate the characteristics of the GBC liver metastasis microenvironment., Results: In this study, 8 cell types, a total of 7,788 cells, including T cells, B cells, malignant cells, fibroblasts, endothelial cells, macrophages, dendritic cells (DCs), and mast cells were identified. Malignant cells displayed a high degree of intratumor heterogenicity, while neutrophils were found to promote GBC cell proliferation, migration, and invasion. Furthermore, cytotoxic cluster of differentiation (CD8 + ) T cells became exhausted and CD4 + regulatory T cells (Tregs) exhibited immunosuppressive characteristics. Macrophages played an important role in the tumor microenvironment (TME). We identified three distinct macrophage subsets and emergent M2 polarization. We also found that cancer-associated fibroblasts exhibited heterogeneity and may be associated with GBC metastasis., Conclusions: Although preliminary in nature, our study provides a landscape view at the single-cell level. These results offer a unique perspective into understanding the liver metastasis of GBC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-2227). LL serves as an unpaid associate editor-in-chief of Annals of Translational Medicine from June 2019 to May 2024. The other authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) represents an innovative surgical technique used for the treatment of large hepatic lesions at high risk for post-resection liver failure due to a small future liver remnant. The most significant amount of literature concerns the use of ALPPS for the treatment of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCC), and colorectal liver metastases (CRLM). On the opposite, few is known about the role of ALPPS for the treatment of uncommon liver pathologies. The objective of the present study was to evaluate the current literature on this topic. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible articles published up to February 2020 were included using the MEDLINE, Scopus, and Cochrane databases. Among the 486 articles screened, 45 papers met the inclusion criteria, with 136 described cases of ALPPS for rare indications. These 136 cases were reported in 18 different countries. Only in two countries, namely Germany and Brazil, more than ten cases were observed. As for the ALPPS indications, we reported 41 (30.1%) cases of neuroendocrine tumor (NET) metastases, followed by 27 (19.9%) cases of gallbladder cancer (GBC), nine (6.6%) pediatric cases, six (4.4%) gastrointestinal stromal tumors, six (4.4%) adult cases of benign primary liver disease, four (2.9%) adult cases of malignant primary liver disease, and 43 (31.6%) adult cases of malignant secondary liver disease. According to the International ALPPS Registry data, less than 10% of the ALPPS procedures have been performed for the treatment of uncommon liver pathologies. NET and GBC are the unique pathologies with acceptable numerosity. ALPPS for NET appears to be a safe procedure, with satisfactory long-term results. On the opposite, the results observed for the treatment of GBC are poor. However, these data should be considered with caution. The rationale for treating benign pathologies with ALPPS appears to be weak. No definitive response should be given for all the other pathologies. Multicenter studies are needed with the intent to clarify the potentially beneficial effect of ALPPS for their treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/hbsn-20-355). The authors have no conflicts of interest to declare., (2021 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Gallbladder cancer (GBC) is the most aggressive malignancy of the biliary tract with poor prognosis. Several targetable genetic alterations have been identified in GBC; however, responses to targeted therapy are disappointing. We report a case of a 58-year-old Chinese woman with GBC who was detected with a novel ALK genomic rearrangement and received crizotinib after progression from first-line chemotherapy. The patient was diagnosed with stage IV adenocarcinoma of the neck of the gallbladder and received oxaliplatin combined with capecitabine as first-line therapy. After four cycles of this chemotherapy regimen, the patient started to show obstructive jaundice, and progressive disease was evaluated. Biliary drainage surgery was performed to alleviate the symptoms of obstructive jaundice. Upon referral to our department, her archived tissue samples were submitted for next-generation sequencing (Burning Rock Biotech) and immunohistochemistry, which identified the presence of a novel AMBRA1-ALK rearrangement and ALK overexpression, respectively. Oral crizotinib was administered achieving partial response within two cycles of treatment, which lasted for 7 months. AMBRA1-ALK has not been previously reported in any solid tumors and its sensitivity to crizotinib is not well characterized. Moreover, ALK alterations have been rarely reported for GBC. This case suggests that a subset of GBC might be driven by aberrant ALK signaling, which could potentially be explored as a biomarker of therapeutic response to ALK inhibitors in GBC. Moreover, our case report contributes an incremental step in understanding the genetic heterogeneity in GBC and provides clinical evidence of the utility of next-generation sequencing in exploring actionable mutations to expand treatment choices in rare solid tumors including GBC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-1007). AL and XM report that they are employees of Burning Rock Biotech. The other authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: Gallbladder cancer (GBC) is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis. The five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%, and the median survival time is less than a year with standard gemcitabine-based chemotherapy. Survival benefit with second-line treatment is unknown. Thus, there is an urgent need for novel treatment strategies and targeted therapy based on next generation sequencing (NGS) may be of value., Methods: Comprehensive genomic profiling (CGP) was performed with NGS panel on paraffin-embedded tumors from a cohort of 108 Chinese and 107 US GBC patients. Clinical data were collected using an IRB approved protocol from a single-center in US and from China., Results: In Chinese and US GBC cohorts, an average of 6.4 vs. 3.8 genomic alterations (GAs) were identified per patient. The most frequent alterations were TP53 (69.4%), CDKN2A/B (26%), ERBB2 (18.5%), PIK3CA (17%) and CCNE1 (13%) in Chinese cohort, TP53 (57.9%), CDKN2A/B (25%), SMAD4 (17%), ARID1A (14%), PIK3CA (14%) and ERBB2 (13.1%) in US patients. NFE2L2 mutations were present in 6.5% of Chinese patients and not observed in the US cohort. Interestingly, ERBB2 genetic aberrations were significantly associated with better pathological tumor differentiation and tended to co-occurrence with CDKN2A/B mutations in both the Chinese and US GBC cases. Out of the top 9 dysregulated genetic pathways in cancer, Chinese patients harbored more frequent mutations in ERBB genes (30.6% vs. 19.0%, P=0.04). High frequency of PI3K/mTOR pathway variations was observed in both Chinese (37%) and US cohort (33%) (P=0.5). Additionally, both Chinese and US GBC patients exhibited a relatively high tumor mutational burden (TMB) (17.6% and 17.0%, respectively). In the Chinese cohort, a significant association was seen between direct repair gene alterations and TMB ≥10 muts/Mb (P=0.004)., Conclusions: In our study, over 83% Chinese and 68% US GBC patients had actionable alterations that could potentially guide and influence personalized treatment options. The identification of high TMB, ERBB2 , CDKN2A/B , PI3K/mTOR pathway and DNA repair mutations indicated that both Chinese and US GBC patients may benefit from targeted or immune checkpoint inhibitors., Competing Interests: Conflicts of Interest: F Pang, C Zou, S Mu, Y Xing and K Wang are employees of Origimed. The other authors have no conflicts of interest to declare., (2019 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: To study the prognostic significance in gallbladder cancer (GBC) patients of the four N stage methods of log odds of positive lymph nodes (LODDS), lymph node ratio (LNR), and N stage in the 7th and 8 th editions of the American Joint Committee on Cancer (AJCC), and to establish a prognostic model of GBC based on LODDS., Methods: Data of 1,321 patients with GBC who underwent surgical resection of lymph nodes from 2010 to 2014 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. We then randomly divided these data into a training set (n=925) and a validation set (n=396). C-index, Akaike information criterion (AIC), and area under the curve (AUC) were calculated to evaluate the accuracy of LODDS, LNR, and N stage in the 7 th and 8 th editions of the AJCC. Cox multivariate analysis was performed to determine whether LODDS was an independent prognostic factor, and a nomogram model was established. C-index was used to evaluate the accuracy of the nomogram. A receiver operating characteristic (ROC) curve was drawn and the area under the AUC was calculated to evaluate the accuracy of the nomogram in predicting patients' 1-, 3-, and 5-year overall survival (OS)., Results: Univariate analysis showed that the four methods were all correlated with OS. Through C-index, AIC and AUC, We found that LODDS had the best accuracy of the four methods. C-index and AUC analysis revealed that the nomogram based on LODDS had excellent prognostic ability. All the results were verified in the validation set., Conclusions: LODDS is an independent prognostic factor for GBC patients, and it is the best N stage in the SEER database. This new nomogram-containing LODDS system is a great model to predict the prognosis of GBC patients., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Background: The aim of this study was to assess the diagnostic performance of radiological imaging in differentiating xanthogranulomatous cholecystitis (XGC) from gallbladder cancer (GBC)., Methods: A retrospective analysis of the radiological imaging performed in patients who had pathologically confirmed XGC or GBC between December 2004 to April 2016 was performed. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each imaging modality, and combined imaging modalities were calculated., Results: A total of 218 patients (XGC =109, GBC =109) were identified; 19 patients received all of abdominal ultrasound (US), contrast-enhanced ultrasound (CEUS), computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT); 21 received four of these imaging examination types; 45 received three examinations; 58 received two examinations; and 75 received only one examination. The sensitivity and specificity of CEUS was 90% and 93%, respectively, higher than abdominal US (80%, 86%), CT (71%, 92%), MRI (75%, 90%), and PET/CT (55%, 90%) (all values respective). The sensitivity, specificity, NPV, and PPV of the US combined with CEUS were 91%, 90%, 94%, and 85%, respectively. Although the specificity of CEUS + CT and CEUS + MRI were 100% and 92%, respectively, the sensitivity of CEUS + CT and CEUS + MRI were both only 67%., Conclusions: The Abdominal US is not sufficiently accurate to confidently guide clinical practice, and CEUS showed better diagnostic performance than the other imaging modalities in differentiating XGC from GBC. The combination of abdominal CEUS and CT is helpful for differential diagnosis, as it indicates GBC with better specificity and PPV., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Background: Due to absence of large, prospective, randomized, clinical trial data, the potential survival benefit of lymphadenectomy with different number of regional lymph nodes (LNs) remains controversial. We aim to create a predicting model to help estimate individualized potential survival benefit of lymphadenectomy with more regional LNs for patients with resected gallbladder cancer (GBC)., Methods: Patients with resected GBC were selected from the Surveillance, Epidemiology, and End Results database who were diagnosed between 2004 and 2014. Covariates included age, race, sex, grade, histological stage, tumor sizes and receipt of non-primary surgery. Two types of multivariate survival regression models were constructed and compared. The best model performance was tested by the external validation data from our hospital., Results: A total of 1,669 patients met the inclusion criteria for this study. The lognormal survival model showed the best performance and was tested by the external validation data, including 193 patients with resected GBC from our hospital. Nomograms, which based on the accelerated failure time parametric survival model, were built to estimate individualized survival. C-index, was up to 0.754 and 0.710 in internal validation for more and less regional LNs removed, respectively. Both of internal and external calibration curves showed good agreement between predicted and observed outcomes in the 1-, 3-, and 5-year overall survival (OS)., Conclusions: A predicting model can be used as a decision model to predict which patients may obtain benefit from lymphadenectomy with more regional LNs., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: Gallbladder cancer (GBC) is an uncommon but highly fatal malignancy, with limited adjuvant therapy. The present study aims to explore the actionable alterations and precision oncology for GBC patients., Methods: Patients with pathologically confirmed GBC who progressed after first-line systemic treatment were enrolled. Genomic alterations were captured by ultra-deep targeted next-generation sequencing (tNGS). The actionabilities of alterations and the therapeutic regimens were evaluated by a multidisciplinary tumor board (MDTB)., Results: Sixty patients with GBC were enrolled and analyzed. tNGS was successfully achieved in all patients. The median tumor mutation burden for GBC patients was 5.4 (range: 0.8-36.74) mutations/Mb, and the most common mutations were in TP53 (73%), CDKN2A (25%) and PIK3CA (20%). The most frequently copy-number altered genes were CDKN2A deletion (11.7%) and ERBB2 amplification (13.3%). 23% of the patients displayed gene fusion; 17 fusion events were identified, and 14 of the 17 fusion events co-occurred with mutations in driver genes. In total, 46 of the 60 (76%) patients were identified as possessing at least one actionable target to proceed precision oncology., Conclusions: The present study revealed the mutational profile for the clinical practice of precision oncology in GBC patients., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Biliary tract cancer (BTC) is comprised of intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (EHC) and gallbladder cancer (GBC). These tumors arise in the biliary epithelium, share histological characteristics and are associated with grim prognosis even when diagnosed at early stages. Moreover, its relatively low incidence in developed countries has precluded the development of clinical trials addressing specific differences among BTC subgroups in terms of their biology, treatment response and clinical outcomes. In this scenario, the development of effective treatment strategies for patients has been rather modest. To date, the combination of cisplatin plus gemcitabine remains as the standard first line therapy in advanced disease and after progression to this regimen there are limited treatment options. Next generation sequencing (NGS) studies have assessed the distribution of driver genes and potentially actionable genomic alterations among ICC, EHC and GBC. Here, we outline genomic differences among these subsets and describe key milestones in order to develop novel targeted drugs against BTCs. Although the early results of several studies are promising, international collaboration is critical to conduct adequately-powered trials, enrolling patients from high-incidence countries.

The incidence and the mortality of gallbladder cancer (GBC) show significant variation worldwide, with high age-standardized rates in western South America (SA). Due to the lack of effective measures for prevention, the late diagnosis and the small benefit of systemic treatment, GBC has an ominous prognosis and became an important public health problem in this part of the continent, where the most important risk factors are gallstone disease, female gender, age, ethnic groups, and low socioeconomic status. Many genetic abnormalities have been described in series from SA, some of them similar and others unique in comparison to gene alterations in GBC from other regions of the world. Prophylactic cholecystectomy (PC) is one of the strategies to decrease the mortality but its cost-effectiveness is questionable. A way to improve the performance of PC is to identify molecular risk factors that in combination with currently known ones detect patients with very high risk for developing GBC. Also, more research studies are required to better understand the epidemiology and molecular biology in order to improve the prevention and treatment of this lethal disease.

Gallbladder cancer (GBC) is a form of hepatobiliary malignancy that develops from the mucosal lining of the gallbladder. The early development of gallbladder cancer is usually asymptomatic and gallbladder cancer has a high propensity to metastatic dissemination, thus most patients are diagnosed at intermediate to advanced stages for which there is no curative treatment. Consequently, gallbladder cancer is highly lethal. Though the overall global incidence of gallbladder cancer is low, there is marked geographic variation and ethnic communities in Asia as well as Native American populations in both North and South America are affected disproportionately. This article provides a comprehensive overview of the current epidemiology and risk and protective factors associated with gallbladder cancer development. In addition, the current knowledge on environmental and genetic risk associations for gallbladder cancer and the need for additional large-scale genome wide association studies (GWAS) are discussed.

India is a high incidence area for gallbladder cancer (GBC) and contributes to about 10% of the global GBC burden. Within India, the incidence is high in North, North-East, Central and Eastern India, and less common in South and West India. The incidence has been on a steady rise in both genders. The presentation is often with advanced disease and carries dismal prognosis. GBC in India usually affects younger patients in the 5th and 6th decade in contrast to the west. Gallstones are present in 80% of the Indian patients with GBC and its presence increases the vulnerability of the GB to mucosal injury. The incidence of GBC is out of proportion to the prevalence of gallstones in the country. Additional co-factors such as older age, lower socio-economic status, chronic Salmonella typhi (S. typhi) infection, Helicobacter pylori (H. pylori) infection, exposure to pollutants, heavy metals, chemicals, adulterated mustard oil and smoking in patients with gallstones have been identified which promote carcinogenesis. These risk factors act in tandem in an additive manner resulting in higher incidence of GBC as well as hasten the development of GBC. Environmental risk factors such as soil and water contamination by industrial wastes, agricultural effluents and human sewage have been identified as putative risk factors. Combination of a toxic environment, vulnerable GB and a susceptible host play a key role in the pathogenesis of GBC in the country. Large multicentric comprehensive studies are required in India to assess the attributable risk of each of the identified putative risk factors. This will help in formulating cost effective national strategies in preventing GBC related mortality in the country. Meanwhile a high index of suspicion to pick up incidental GBC, and improved access to healthcare facilities to manage GS appropriately will help in reducing GBC related mortality.

Background: The extent of liver resection for gallbladder cancer (GBC) is still debated. We evaluated the post-operative and oncological outcomes of patients with GBC who underwent liver wedge excision., Methods: Patients who underwent an upfront radical cholecystectomy (with a liver wedge excision of 2.5- 3 centimetres) from June 2010 to December 2015 were retrospectively analysed., Results: In total, 558 patients underwent surgery for GBC of which 97 cases of primary GBC who underwent upfront radical cholecystectomy were selected. At a median follow up of 47 months, 57.7% of patients were disease free where as 16.5% were alive with disease. Two (2.1%) patients died in postoperative period, 17 (17.5%) patients died of disease, and 6 (6.2%) died of unrelated causes. Eleven patients had loco-regional recurrence and 22 failed at distant sites. Only one patient recurred in the gall bladder bed. Three-year overall survival (OS) of stage II was 86.1% and of stage III was 59.6%., Conclusions: In our series surgical outcomes of radical cholecystectomy with wedge resection of the liver emphasizes its oncological equivalence compared to formal segment IVb/V excision. Our experience with wedge resection gains significance in the absence of any level I evidence and can prompt a multicentre randomised controlled trial (RCT) in future which may help in standardizing surgery for GBC.

Large differences in terms of incidence and mortality due to gallbladder cancer (GBC) have been reported worldwide. Moreover, it seems that GBC has unique characteristics in South America. We surveyed the literature looking for information about the epidemiology, basic and translational research, and clinical trials performed in South America in order to critically analyze the magnitude of this health problem in the region. Compared to other geographic areas, age-standardized mortality rates (ASMR) for GBC in women are very high, particularly in many western areas of South America. Genetic, as well as dietary and environmental factors likely contribute to the pathogenesis of this disease in the area. Compared to other regions the profile of abnormalities of key genes such as KRAS and TP53 in GBC seems to slightly differ in South America, while the clinical behavior appears to be similar with a median overall survival (OS) of 6.5 to 8 months in advanced GBC. In contrast to Europe and USA, prophylactic cholecystectomy is a common practice in western areas of South America. GBC particularly affects women in South America, and represents a significant public health problem. It appears to have peculiarities that pose an urgent need for additional research aimed to discover risk factors, molecular events associated with its development and new treatment options for this lethal disease.

An analysis of premalignant lesions, risk factors and models of carcinogenesis of gallbladder cancer (GBC) involves the concept of organ specificity. In GBC, the dysplasia-carcinoma sequence and metaplasia-dysplasia-carcinoma sequence are considered to be more important models of carcinogenesis than the adenoma-carcinoma sequence. Cholecystectomy is recommended for gallbladder polyps ≥1.0 cm, and all pre-invasive adenomas and papillary neoplasms ≥1.0 cm are defined as intracholecystic papillary-tubular neoplasms (ICPTNs). Although adenomyomatosis (ADM) and xanthogranulomatous cholecystitis (XGC) are controversial lesions, a knowledge of their clinicopathological features would help clinicians to manage gallbladder lesions associated with ADM or XCG.