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Abstract: Background and aim: PSCA is a tissue specific tumor suppressor or oncogene which has been found to be associated with several human tumors including gallbladder cancer. It is considered to be involved in the cell-proliferation inhibition and/or cell-death induction activity. Therefore, we aimed to investigate the role of PSCA gene polymorphisms in gallbladder cancer risk in North Indian population. Methodology: A total of 405 gallbladder cancer patients and 247 healthy controls were included in the case–control study for risk prediction. We examined the association of two functional SNPs, rs2294008 and rs2978974 in PSCA gene by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. Linkage disequilibrium and haplotype analysis was done with the help of SNPstats software. FDR test was used to correct for multiple comparisons. Results: No significant associations of rs2294008 and rs2978974 genetic variants of the PSCA gene were found with GBC risk at allele, genotype or haplotype levels. Stratifying the subjects on the basis of gallstone also did not show any significant result. However, on gender stratification, we found a significant association of Trs2294008-Grs2978974 haplotype with higher risk of GBC in females (FDR Pcorr=0.021, OR=1.6). In contrary, Trs2294008-A rs2978974 haplotype conferred significant lower risk in males (FDR Pcorr=0.013; OR=0.25). Conclusions: These findings suggest that PSCA genetic variants may have a significant effect on GBC susceptibility in a gender specific manner. [Copyright &y& Elsevier]

Aim: Carcinoma of gallbladder (GBC) is a relatively rare but highly fatal disease. The DNA (cytosine-5-)-methyltransferase 3 beta ( DNMT3B) −579 G>T promoter polymorphism (rs1569686) influences gene function and has been associated with various malignancies. Present population-based case-control study was undertaken to examine the potential association of DNMT3B −579 G>T variation with GBC in North Indian population. Methods: Genotypes and allelic frequencies of the DNMT3B −579 G>T polymorphism were determined for 212 GBC patients and 219 controls using PCR-RFLP. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated for the association of DNMT3B polymorphism with GBC. Analysis of potential transcription factor binding sites was also identified in the region harboring the polymorphism. Results: The DNMT3B −579 G>T polymorphism was found to be non-significantly associated with an overall increased risk of GBC (OR = 1.10 and 1.56 for T/G and G/G genotypes, respectively, P = 0.227). The increased risk was predominant in both male and female cohorts and also non-significantly in GBC patients with gallstone status (OR = 1.44; P = 0.280, OR = 1.06; P = 0.804 and OR = 1.45; P = 0.143, respectively). Conclusion: DNMT3B −579 G>T polymorphism may alter susceptibility to GBC although it may not play a major role in the pathoetiology of this disease in North Indian population. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small, non-coding RNA molecules that function as negative regulators of gene expression. Common genetic variants (single nucleotide polymorphisms, SNPs) in miRNA genes may alter their expression or maturation resulting in varied functional consequences. Present case–control study evaluated the potential association of three SNPs (rs2910164, rs11614913 and rs3746444) in pre-miRNAs with gallbladder cancer (GBC) risk in 230 GBC cases and 230 controls in a North Indian population. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated for the association of individual SNPs and their interactions with GBC. A non-significant increased risk was observed between carriers of variant genotypes of rs2910164, rs11614913 and rs3746444 (ORs=1.3, 1.3 and 1.1, respectively). This increased risk was more profound in GBC patients with gallstones (ORs=1.4, 1.6 and 1.1, respectively). To further evaluate the cumulative effects of the variant allele, we did a combined unfavorable genotype analysis, which showed a borderline statistical significance. In comparison with the low-risk group (0–2 variant alleles), the high-risk group (>2 variant alleles) had a 1.7-fold (95% CI=1.0–2.8) increased risk for GBC (Ptrend=0.056). These findings suggest, for the first time, that common miRNA variants may not contribute to GBC susceptibility in North Indian population. [ABSTRACT FROM AUTHOR]

Background:The majority of patients with gallbladder cancer (GBC) have advanced disease at the time of diagnosis and are unresectable. Longterm survival is usually seen in a subset of patients with early GBC (EGBC)—cancer confined to the mucosa (pT1a) and muscularis (pT1b). Management guidelines of EGBC are not yet defined and are controversial. The purpose of this article is to evaluate the diagnostic aspects and effects of resectional procedures on survival outcome in patients with EGBC.Study Design:EGBC was defined as cancer confined to the mucosa (pT1a) or muscularis (pT1b) according to the TNM classification. Clinicopathological details and survival data of 14 patients who had EGBC were analyzed. There were 9 women and 5 men, with a mean age of 60 years.Results:A definite preoperative diagnosis was possible in only three patients and three patients were diagnosed at surgery; the majority of patients were diagnosed incidentally after cholecystectomy for associated gallstones. Two patients underwent extended cholecystectomy and 12 patients underwent simple cholecystectomy. Two patients had pT1a and 12 had pT1b lesions. Mean (SD) survival was 71.5 (12.2) months and median survival was 42 months. There were five treatment failures with locoregional recurrence and death. All patients with pT1b tumors were treated by simple cholecystectomy. Cumulative 1-, 3-, and 5-year survival was 92%, 68%, and 68% respectively.Conclusions:Simple cholecystectomy is an adequate treatment only for mucosal GBC. Patients with pT1b tumors require extended cholecystectomy. Incidental GBC extending up to the muscularis merits early reoperation for completion of extended cholecystectomy, which offers the only chance of cure. [Copyright &y& Elsevier]

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: To investigate the predictive value of intramuscular adipose tissue content (IMAC) on the outcome of gallbladder cancer (GBC) patients after resection, by then develop and evaluate a nomogram to predict the prognosis of GBC patients., Methods: This research incorporated 123 patients with a pathological diagnosis of GBC. Evaluating the prognosis by the Kaplan-Meier method. Independent predictors of overall survival (OS) were screened using multifactorial Cox regression analysis, and a nomogram was constructed from these. Consistency index and calibration curve were used to identify and calibrate the nomogram. The accuracy of the nomogram was assessed by receiver operating characteristic (ROC) curve and decision curve analysis (DCA) was used to assess the net benefit., Results: Patients with high IMAC showed a worse prognosis. A nomogram was constructed to predict OS based on IMAC. The C-index for the nomogram was 0.804. The calibration curve showed well performance of the nomogram. The area under the ROC curve (AUC) for the nomogram at three and five years was 0.839 and 0.785, respectively. A high net benefit was demonstrated by DCA., Conclusions: IMAC was a valid predictor for GBC patients. A nomogram with good performance is constructed to predict the prognosis of GBC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-123/coif). The authors have no conflicts of interest to declare., (2022 Translational Cancer Research. 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: Coagulation and fibrinolysis activation are frequently observed in cancer patients, and the tumors in these cases are thought to be associated with a higher risk of invasion, metastasis and worse long-term outcome. The specific aim of this study was to develop an effective prognostic nomogram to help make individualized estimates for patients with resected gallbladder cancer (GBC)., Methods: Patients with resected GBC who were diagnosed between 2006 and 2014 at Xinhua Hospital were selected. Model performance was measured by c-index and calibration curve. The results were further validated using bootstrap and a cohort of 38 patients from a branch hospital who underwent surgery from 2006 to 2014., Results: Backward stepwise selection and Lasso were applied respectively to select predictors. T stage, N stage, and preoperative serum fibrinogen were included in the final model. Predictions correlated well with observed 1- and 3-year survival. The c-index for predicting survival was 0.74 (95% confidence interval, 0.70-0.78), which was statistically higher than that of the AJCC 7th system and Nevin system (P=0.04, 0.04, respectively). In the validation cohort, the nomogram performed better than the other two staging systems (c-index: 0.71 vs. 0.67 and 0.67)., Conclusions: The validated nomogram is a practical tool for predicting the overall survival (OS) of postoperative GBC patients. Preoperative serum fibrinogen levels were associated with tumor progression and may be an independent predictor for GBC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jgo-21-357). The authors have no conflicts of interest to declare., (2021 Journal of Gastrointestinal Oncology. 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.)

The clinical outcome of the advanced biliary tract cancer (BTC) is unfavorable, and the mortality rate is high. With local advance and metastasis, the median survival time is less than 1 year. But this patient survived 14 months with no signs of progress under treatment in our hospital. And the patient situation is stable recently. This case report can provide a treatment template for clinicians. This patient was appeared dull pain in the upper abdomen, occasionally poor defaecating. After a series of medical tests, the patient was diagnosed with advanced gallbladder cancer (GBC). This patient received chemotherapy (oxaliplatin 220 mg d1 + capecitabine 1,500 mg bid d1-14; capecitabine 1,500 mg bid d1-14; gemcitabine 1.4 g d1, 8 + capecitabine 1,500 mg bid d1-14) combined with immunotherapy (pembrolizumab 200 mg). The patient is still alive.. And there were no signs of progress. The researches on the treatment of GBC are rare, and only standard first-line treatment, lack of second-line treatment of GBC. This patient of advanced GBC received standard first-line treatment (oxaliplatin 220 mg d1 + capecitabine 1,500 mg bid d1-14; capecitabine 1,500 mg bid d1-14; gemcitabine 1.4 g d1, 8 + capecitabine 1,500 mg bid d1-14) combined with immunotherapy (pembrolizumab 200 mg), the effect is fine and is expected to contribute to the treatment of BTC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2020.04.25). DZ reports grants from National Natural Science Foundation of China (81770212), outside the submitted work; HY reports grants from Key Program of the Changzhou Commission of Health (ZD201709), outside the submitted work; XL reports grants from Program for Young Talents of the Changzhou Commission of Health (QN201902), outside the submitted work. The other authors have no conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)

Background: Patients with biliary tract cancer (BTC) have a dismal prognosis and limited treatment options. Given the potential for immunotherapy in patients with BTC, we studied the expression of programmed death ligand-1 (PD-L1)/programmed death-1 (PD-1) and evaluated for associated genetic alterations in patients with BTC., Methods: By immunohistochemistry (IHC), PD-L1 (SP142 antibody; ≥2+ and/or ≥5% staining on tumor cells considered positive) and PD-1 [NAT105 antibody; ≥1+ staining of tumor infiltrating lymphocytes (TILs) considered positive] expression was studied and next-generation sequencing (NGS) was performed using Caris Life Sciences' sequencing panel of 592 genes. A total of 652 patients with BTC were included in this study: 77 extrahepatic cholangiocarcinoma (ECC), 203 gallbladder cancer (GBC), and 372 intrahepatic cholangiocarcinoma (ICC)., Results: Of the 652 tumors 8.6% were PD-L1 positive with the following distribution: GBC 12.3% (25/203), ICC 7.3% (27/372), and ECC 5.2% (4/77). There was a statistically significant increase in BRAF, BRCA2, RNF43, and TP53 mutations in PD-L1 positive group as compared to PD-L1 negative. Among other biomarkers tested, TOP2A, tumor mutational burden (TMB) high (≥17 mutations per megabase) (10.7%), and microsatellite instability high (MSI-H) (7.1%) were increased in PD-L1 positive tumors versus PD-L1 negative tumors., Conclusions: PD-L1 expression was noted in a small percentage (8.6%) of patients with BTC. This finding suggests potential benefit of immunotherapy in this subset of patients. Furthermore, there was a statistically significant association between PD-L1 expression and certain genomic alterations ( BRAF , BRCA2 , RNF43 , TP53 ) and biomarkers (TOP2A, TMB high, MSI-H), which might direct the use of rational combination strategies and clinical trial development., Competing Interests: Conflicts of Interest: K Mody—Research Support: Agios, Senwha Biosciences, Taiho, ArQule, AstraZeneca, Genentech, Incyte, Tracon Pharmaceuticals, Medimmune, Puma Biotechnology. Consulting: Astra Zeneca, Bayer, Celgene, Eisai, Exelixis, Ipsen, Merrimack, Vicus. M Saul and K Poorman—Employment: Caris Life Sciences. The other authors have no conflicts of interest to declare., (2019 Journal of Gastrointestinal Oncology. 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.

Introduction: Preoperative jaundice is considered a relative contraindication to radical gallbladder cancer (GBC) resection due to poor prognosis and high postoperative morbidity. Recent reports have indicated that aggressive surgery may improve long-term survival for patients with advanced GBC who present with obstructive jaundice. The current systematic review and meta-analysis aimed to compare postoperative outcomes among jaundiced and non-jaundiced patients with resectable GBC., Methods: An electronic search was performed using several Medical Subject Headings terms: cholecyst, gallbladder, tumor, cancer, carcinoma, adenocarcinoma, neoplasia, neoplasm, jaundice, and icterus. Overall survival after surgery was the primary outcome; resectability and postoperative morbidity were the secondary outcomes., Results: Overall survival was shorter among patients who presented with jaundice (Hazard ratio [HR]: 2.21, 95% confidence interval [CI], 1.64-2.97; P < 0.001). Patients with jaundice were less likely to have resectable disease (odds ratio: 0.27, 95% CI, 0.17-0.43; P < 0.001). The jaundice group had higher odds of postoperative morbidity, bile-leak, and posthepatectomy failure versus the non-jaundiced control group., Conclusions: Radical surgery for GBC resection for patients presenting with obstructive jaundice was associated with reduced overall survival and increased postoperative morbidity. Jaundiced patients with advanced GBC should be considered for surgical resection but need careful evaluation and counseling before undertaking extensive surgical resection., (© 2018 Wiley Periodicals, Inc.)

Background: Gallbladder cancer (GBC) and cholangiocarcinoma (CCA) are rare entities with relatively poor prognoses. We compared treatment outcomes of definitive resection with or without neoadjuvant therapy in GBC and CCA patients., Methods: All non-metastatic GBC and CCA patients at a single institution who underwent definitive resection from 1992-2016 were analyzed. We compared overall survival (OS), locoregional failure (LRF) and distant failure (DF) in patients who received neoadjuvant therapy (chemotherapy and/or radiation) versus those who did not receive neoadjuvant treatment. OS was analyzed using the Kaplan-Meier method and log rank tests. Cox proportional hazard models were used to analyze time to recurrence., Results: Out of 128 patients, 90 had GBC and 38 had CCA, 25 patients (27%) among GBC and 8 patients (21%) with CCA were T3, T4 or node positive. Overall, 52 (40%) GBC and 25 (20%) CCA patients received neoadjuvant treatment, chemotherapy alone 60 patients (47%) or radiation with or without chemotherapy 17 patients (13%). Chemotherapy was single agent in 44 patients (34%) and multi-agent in 25 (20%). The median OS for GBC patients was 3.1 years with 2.6 years for no neoadjuvant group and 3.1 years for neoadjuvant group (P=0.6786). Median OS was 2.6 years for CCA patients, 3.6 years for no neoadjuvant therapy versus 2.0 years for neoadjuvant group (P=0.1613). There was a trend towards increased DF in patients with CCA and GBC receiving neoadjuvant therapy: HR 2.74, 95% CI, 0.73-10.3, P=0.14 and 0.92, 95% CI, 0.44-1.93, P=0.82 respectively. The hazard ratio for time to LRF in CCA patients receiving neoadjuvant treatment was 3.17, 95% CI, 0.62-16.31, P=0.16 whereas HR was 0.15, 95% CI, 0.10-1.76, P=0.23 for GBC patients. Among GBC patients, the pattern of first failure was locoregional in 8 (10%) having 3 LRF in neoadjuvant group (2 with chemotherapy, 1 with CRT, 0 with RT alone) as compared to 5 in adjuvant group. Among 28 (35%) patients with DF first, 15 patients received neoadjuvant therapy versus 13 patients in non-neoadjuvant group. In CCA patients, LRF occurred first in 6 patients receiving neoadjuvant treatment (3 with chemotherapy, 1 with CRT, 2 with RT alone) as compared to 2 patients who were treated with non-neoadjuvant CRT. DF was the first site of failure in 9 patients treated with neoadjuvant CRT (8 with chemotherapy, 0 with CRT and 1 with RT alone) as compared to 4 patients without neoadjuvant treatment., Conclusions: In this retrospective data set, a trend towards better survival was seen in adjuvantly treated CCA patients, but not in GBC patients. Recurrence patterns also appear different among the two, which might be attributed to treatment modality used, patient selection or unmeasured factors., Keywords: Gallbladder cancer (GBC); cholangiocarcinoma (CCA); neoadjuvant; resection; chemoradiation; chemotherapy., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Biliary tract cancers (BTC) is a group of malignancies that arise from the epithelial cells of the biliary tree. These cancers are typically classified by anatomic site of origin: intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC). To date, complete surgical resection remains the mainstay of treatment especially for earlier stage disease. Unfortunately, most patients present with advanced or metastatic disease, when systemic chemotherapy is the only treatment option. Due to the paucity of effective treatments, BTCs have a dismal prognosis. There is a tremendous need to better understand the disease biology, discover new therapies, and improve clinical outcomes for this challenging disease. Next-generation sequencing has produced a more accurate and detailed picture of the molecular signatures in BTCs. The three BTC histologic subtypes are, in fact, quite molecularly distinct. IHCC commonly contain FGFR2 fusions and IDH 1 and 2 mutations, whereas EHCC and GBC tend to carry mutations in EGFR, HER2, and MAPK pathway. In light of this emerging knowledge, clinical trials have become more biomarker-driven, which allows capturing of subsets of patients that are most likely to respond to certain therapies. Many new and promising targeted therapeutics are currently in the pipeline. Here we review the genetic landscape of BTCs while focusing on new molecular targets and targeted therapeutics currently being investigated in biomarker-driven clinical trials., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

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.

Genes important to stem cell progression have been involved in the genetics and clinical outcome of cancers. We investigated germ line variants in cancer stem cell (CSC) genes to predict susceptibility and efficacy of chemoradiotherapy treatment in gallbladder cancer (GBC) patients. In this study, we assessed the effect of SNPs in CSC genes (surface markers CD44, ALCAM, EpCAM, CD133) and (molecular markers NANOG, SOX-2, LIN-28A, ALDH1A1, OCT-4) with GBC susceptibility and prognosis. Total 610 GBC patients and 250 controls were genotyped by using PCR-RFLP, ARMS-PCR, and TaqMan allelic discrimination assays. Chemotoxicity graded 2-4 in 200 patients and tumor response was recorded in 140 patients undergoing neoadjuvant chemotherapy (NACT). Differences in genotype and haplotype frequency distributions were calculated by binary logistic regression. Gene-gene interaction model was analyzed by generalized multifactor dimensionality reduction (GMDR). Overall survival was assessed by Kaplan-Meier survival curve and multivariate Cox-proportional methods. ALCAM Ars1157Crs10511244 (P = 0.0035) haplotype was significantly associated with GBC susceptibility. In GMDR analysis, ALCAM rs1157G>A, EpCAM rs1126497T>C emerged as best significant interaction model with GBC susceptibility and ALDH1A1 rs13959T>G with increased risk of grade 3-4 hematological toxicity. SOX-2 rs11915160A>C, OCT-4 rs3130932T>G, and NANOG rs11055786T>C were found best gene-gene interaction model for predicting response to NACT. In both Cox-proportional and recursive partitioning ALCAM rs1157GA+AA genotype showed higher mortality and hazard ratio. ALCAM gene polymorphisms associated with GBC susceptibility and survival while OCT-4, SOX-2, and NANOG variants showed an interactive role with treatment response.

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.

Background: Gallbladder cancer (GBC) is a rare malignancy with a dismal prognosis. Often identified incidentally after laparoscopic cholecystectomy for presumably benign biliary disease, reoperation with partial hepatic resection and periportal lymph node dissection (LND) is frequently performed. The impact of lymph node (LN) clearance for GBC remains unclear., Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients diagnosed with GBC between 1988 and 2009. Survival was calculated using Kaplan-Meier method and compared using log-rank test. Multivariate analysis was performed to identify predictors of survival., Results: A total of 11,815 patients diagnosed with GBC were identified. Cancer-directed surgery was performed in 8,436 (71.3%) patients. Optimal LN clearance (defined as ≥4 LNs) is associated with young age, advanced T-stage, no radiation therapy, and radical surgery (all <0.001). Greater LND improves survival for all stages (P<0.001). After adjusting for confounding factors, multivariable analysis of patients with node-negative disease demonstrated that early stage, greater LND, and radical surgery were strong independent predictors of survival., Conclusions: Extensive lymphadenectomy correlates with longer survival even in node negative patients. Extensive LND should be performed in patients with GBC as many patients in the USA are undertreated.