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Background: The clinical benefits and efficacies of adjuvant therapies for gallbladder cancer (GBC) have not been verified due to insufficient clinical evidence. Methods: Patients with resected nonmetastatic stage II–IV GBC were selected from the Surveillance, Epidemiology, and End Results database and distributed into nonchemotherapy and chemoradiotherapy (NCRT), chemotherapy (CT), and chemoradiotherapy (CRT) groups. Generalized propensity score and inverse probability of treatment weighting (IPTW) were used to reduce the imbalances between groups. Results: A total of 2,689 patients were enrolled, among whom 1,193 (44.4%) were classified as stage II, 1,371 (51.0%) as stage III, and 125 (4.6%) as stage IV GBC. A total of 1,703, 444, and 542 patients were placed in the NCRT, CT, and CRT groups, respectively. After the IPTW, there were no significant differences in overall survival (OS) between the 3 treatment groups (p > 0.05) in stage II GBC patients. In patients with stage III–IV GBC, the CT group exhibited a superior OS compared to the NCRT group (p < 0.001). In addition, the CRT group exhibited a superior OS compared to the CT (p < 0.001) and NCRT (p < 0.001) groups. For patients with stage III–IV tumors, a nomogram was constructed to predict the survival benefits of adjuvant therapies. Conclusion: Patients with stage II GBC may not benefit from adjuvant therapy, while patients with stage III–IV GBC were shown to benefit from chemotherapy and chemoradiotherapy. Furthermore, chemoradiotherapy exhibited a superior OS. Nevertheless, the results need to be explained in the context of retrospective studies. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer (GC) is a malignant disease characterized with highly cellular heterogeneity and poor prognosis. Determining the intratumoral heterogeneity and microenvironment (TME) can provide novel therapeutic strategies for GC. Methods: We performed the single‐cell RNA sequencing on the primary and lymph node metastatic gallbladder tumors and the adjacent normal tissues of five patients. The transcriptomic atlas and ligand–receptor‐based intercellular communication networks of the single cells were characterized. Results: The transcriptomic landscape of 24,887 single cells was obtained and characterized as 10 cellular clusters, including epithelial, neuroendocrine tumor cells, T&NK cells, B cells, RGS5+ fibroblasts, POSTN+ fibroblasts, PDGFRA+ fibroblasts, endothelial, myeloid cells, and mast cells. Different types of GC harbored distinct epithelial tumor subpopulations, and squamous cell carcinoma could be differentiated from adenocarcinoma cells. Abundant immune cells infiltrated into adenocarcinoma and squamous cell carcinoma, rather than neuroendocrine neoplasms, which showed significant enrichment of stromal cells. CD4+/FOXP3+ T‐reg and CD4+/CXCL13+ T helper cells with higher exhausting biomarkers, as well as a dynamic lineage transition of tumor‐associated macrophages from CCL20hi/CD163lo, CCL20lo/CD163hi to APOE+, were identified in GC tissues, suggesting the immunosuppressive and tumor‐promoting status of immune cells in TME. Two distinct endothelial cells (KDR+ and ACKR1+), which were involved in angiogenesis and lymphangiogenesis, showed remarkable ligand–receptor interactions with primary GC cells and macrophages in gallbladder tumors. Conclusions: This study reveals a widespread reprogramming across multiple cell populations in GC progression, dissects the cellular heterogeneity and interactions in gallbladder TME, and provides potential therapeutic targets for GC. [ABSTRACT FROM AUTHOR]

Background: The distant metastasis (DM) mode and treatment efficacies in the advanced biliary tract cancer (BTC) were obscure, and a credible evaluation is urgently needed. Method: A total of 6348 advanced BTC patients (ICC, intrahepatic cholangiocarcinoma, n = 1762; PHCC, perihilar cholangiocarcinoma, n = 1103; GBC, gallbladder cancer, n = 2580; DCC, distal cholangiocarcinoma, n = 538; AVC, carcinoma of Vater ampulla, n = 365) were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) process was carried out for less bias. Result: The proportion of M1 patients in each subtype at first diagnosis was 26.4% (ICC), 37.2% (PHCC), 41. 0% (GBC), 24.5% (DCC), and 12.7% (AVC), and the constitution of DM sites in different subtypes varied apparently. Moreover, the survival of metastasis sites was different (P <.05 in all the subtypes) where the multi‐metastasis and distant lymph node (dLN) only always indicated the worst and best prognosis, respectively. Chemotherapy presented the most significant survival impact with the lowest hazard ratio by multivariate cox model and still provided a survival improvement after PSM (all P <.001) in all subtypes. However, the median months manifested different between patients with and without chemotherapy among the subtypes (ICC, from 5 to 9; PHCC, from 6 to 10; AVC, from 4 to 9; GBC, from 6 to 7; DCC from 6 to 8). Conclusion: We provided a landscape about the detailed DM mode of the advanced BTC in a large population, found the survival differences among DM sites, and revealed the different chemotherapy efficacies in the BTC subtypes. [ABSTRACT FROM AUTHOR]

Gallbladder carcinoma (GBC) is a highly lethal malignancy of the gastrointestinal tract. Despite extensive research, the underlying molecular mechanism of GBC remains largely unclear. Deleted in malignant brain tumors 1 (DMBT1) is low-expression during cancer progression and as a potential tumor-suppressor gene in various types of cancer. However, its role in Gallbladder cancer remains poorly understood. Here, we found that DMBT1 was significantly low-expression and deletion of copy number in GBC tissues by qRT-PCR and Western blot. Overexpression of DMBT1 impaired survival, promoted apoptosis in GBC cells in vitro, and inhibited tumor progression in vivo. Further study of underlying mechanisms demonstrated that DMBT1 combined with PTEN which could stabilize PTEN protein, resulting in inhibiting the activation of PI3K/AKT signaling pathway. Our study revealed a new sight of DMBT1 as a tumor-suppressor gene on the PI3K/AKT pathway in GBC, which may be a potential therapeutic target for improving treatment. Down-regulation of DMBT1 suppresses progression of gallbladder carcinoma through PI3K/AKT signaling pathway activation by targeting PTEN. [ABSTRACT FROM AUTHOR]

Abstract: CD133+ tumor cells are responsible for the initiation, propagation and recurrence of tumors, which raises the question of how to effectively target CD133+ tumor cells. Arsenic trioxide (As2O3) has considerable efficacy in treating solid tumors with induction of apoptosis. Here, we found that purified CD133+ gallbladder carcinoma cells are highly resistant to conventional chemotherapy. However, As2O3 effectively induces CD133+ gallbladder carcinoma cells apoptosis. Treatment with As2O3 reduces CD133 expression at transcriptional levels. Furthermore, the ectopic expression of CD133 attenuated the apoptotic effect of As2O3 on cells through activation of AKT signaling pathways. Collectively, As2O3 effectively targets CD133 in gallbladder carcinoma, providing a new mechanism of As2O3-induced cell apoptosis and a better understanding of drug resistance in gallbladder carcinoma. [Copyright &y& Elsevier]

B Introduction: b The 8 SP th sp edition of the AJCC staging system for gallbladder cancer (GBC) has been used in clinical practice, but we have found some deficiencies in the new edition. In our modified edition, N2 disease obtained a significant subdivision and reappraisal according to T stage, and the aberrant survival reversal of stage IIIA and stage IIIB was also corrected. [Extracted from the article]