ARID1A Downregulation Predicts High PD-L1 Expression and Worse Clinical Outcome in Patients With Gallbladder Cancer.

BACKGROUND: Recent studies have confirmed that AT-rich interactive domain-containing protein 1A (ARID1A) plays a critical role in tumorigenesis, but its role in gallbladder cancer (GBC) remains unclear. METHODS: In total, 224 patients from Zhongshan Hospital were recruited for this retrospective study. The clinicopathological and baseline characteristics of the patients were collected. Bioinformatics analysis was performed to reveal variations in genes and signaling pathways, and ARID1A and PD-L1 expression and the number of PD1+ tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemical staining. RESULTS: ARID1A expression was negatively correlated with overall survival in patients with GBC, and multivariate analysis identified ARID1A as an independent prognostic factor for overall survival. A heatmap and gene set enrichment analysis suggested that cytotoxic T lymphocyte signatures and immune-related signaling pathways were downregulated in ARID1A low tumors. Subsequent immunohistochemical staining confirmed that ARID1A expression was negatively correlated with PD-L1 expression and PD1+ TILs in the tumor microenvironment. The Kaplan-Meier analysis suggested that high ARID1A expression combined with low PD-L1 expression or low PD1+ TIL counts is associated with the best prognosis in patients with GBC. CONCLUSION: ARID1A inactivation can lead to a worse prognosis in patients with GBC, potentially by mediating immune evasion through the PD1/PD-L1 pathway.

The impact of preoperative biliary drainage on postoperative outcomes in patients with malignant obstructive jaundice: a retrospective analysis of 290 consecutive cases at a single medical center.

BACKGROUND: The efficacy of preoperative biliary drainage (PBD) has been debated for several decades, and yet indications for PBD remain controversial. The aim of this study was to compare the postoperative morbidity and mortality in patients with malignant obstructive jaundice undergoing direct surgery versus surgery with PBD. METHODS: All consecutive patients with malignant obstructive jaundice who underwent radical resection between June 2017 and December 2019 at Zhongshan Hospital were analyzed retrospectively. The study population was divided into two groups: PBD group (PG) and direct surgery group (DG). The subgroups were chosen based on the site of obstruction. Perioperative indicators and postoperative complications were compared and analyzed. RESULTS: A total of 290 patients were analyzed. Postoperative complications occurred in 134 patients (46.4%). Patients in the PG group had a lower overall rate of postoperative complications compared with the DG group, with perioperative total bilirubin (TB) identified as an independent risk factor in multivariate analysis (hazard ratio = 1.004; 95% confidence interval 1.001-1.007; P = 0.017). Subgroup analysis showed that PBD reduced the complication rate in patients with proximal obstruction. In the proximal-obstruction subgroup, a preoperative TB level > 162 µmol/L predicted postoperative complications. CONCLUSIONS: PBD may reduce the overall rate of postoperative complications among patients with proximal malignant obstructive jaundice. TRIAL REGISTRATION: ClinicalTrials.gov, 2018ZSLC 24 . Registered May 17, 2018, https://clinicaltrials.gov/ .

Cystic Duct Carcinoma: A New Classification System and the Clinicopathological Features of 62 Patients.

BACKGROUND: Cystic duct carcinoma (CDC) is a rare biliary malignancy with a low incidence and poor prognosis. However, the clinical landscape of the disease has not been clarified and no widely applicable classification system has been developed. METHODS: Sixty-two patients with CDC were included in this retrospective study, and a new classification system was established using imaging data. Blood indices, radiological characteristics, pathological features, surgical procedures, and overall survival data were collected. The efficacy of the new classification in predicting resectability was evaluated using receiver operating characteristic (ROC) curves, and K-means clustering and t-distributed stochastic neighbor embedding were applied to verify the conclusion. RESULTS: The pT stage of patients with type II CDC was significantly worse than that of type I. Patients with type II CDC were more likely to experience distant metastasis and invasion of the nervous system, vascular system, and liver. The resectability of patients with type II CDC was significantly worse than that of patients with type I CDC. Patients with type II CDC had worse prognoses. ROC curve analysis and K-means clustering revealed that the new classification could better categorize patients with CDC than currently available systems. CONCLUSION: Patients with type II CDC have significantly worse clinicopathological outcomes. The new classification system has better accuracy in grouping patients with CDC.

Diversity and intratumoral heterogeneity in human gallbladder cancer progression revealed by single-cell RNA sequencing.

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.

Role of dual-time point 18F-FDG PET/CT imaging in the primary diagnosis and staging of hilar cholangiocarcinoma.

PURPOSE: The aim of this study was to evaluate the role of dual-time point 18F-FDG PET/CT imaging in the primary diagnosis and staging of hilar cholangiocarcinoma (HCCA). METHODS: Dual-time point FDG PET/CT findings, including early phase whole-body scanning and abdominal delayed phased performed 1 and 2 h after radiotracer injection, respectively, were retrospective reviewed in 69 patients conformed HCCA by histology. PET/CT was evaluated based on visual interpretation and the semiquantitative index of SUVmax and tumor-to-normal liver tissue ratio (TNR) for both early and delayed images. RESULTS: For all 69 HCCA patients, the mean SUVmax of the lesion and TNR in delayed phase was significantly higher than that in early phase (6.1 ± 4.7, 2.2 ± 1.7, vs 5.1 ± 3.4, 1.6 ± 1.1; P < 0.001). The sensitivity and accuracy value of detection primary lesions was 69.6% and 70% in early phase vs 76.8% and 76.8% in delay phase, respectively. There was a significant correlation between lesion SUVmax and Ki67 index in both dual-time imaging (r = 0.462, P < 0.001 in early phase vs r = 0.47, P < 0.001 in delay phase). The sensitivity, specificity and accuracy value of metastatic lymph nodes prediction was 50%, 67.3% and 71% in early phase vs 62.5%, 73.3% and 76.8% in delayed phase, respectively. The sensitivity, specificity and accuracy of FDG PET/CT in detecting distant metastasis in our study was 75%, 100% and 97.1%. There was no difference of predicting distant metastasis between early phase and delayed phase. CONCLUSION: Delayed phase in dual-time point 18F-FDG PET/CT scan provides additional usefulness for detection primary tumor and lymph nodes metastases in HCCA, but there was no added benefit of delayed PET/CT imaging in detection of distant metastases in this study. SUVmax in early and delayed phase could be used to assess tumor aggressiveness in pre-treatment HCCA.

Arthroscopic release combined with single-row fixation or double-row suture bridge fixation in patients with traumatic supraspinatus tear and adhesive capsulitis non-responsive to conservative management: A prospective randomized trial.

BACKGROUND: There are few previous studies on traumatic supraspinatus tear with adhesive capsulitis. This study used arthroscopic release with single-row fixation or double-row suture bridge fixation to treat adhesive capsulitis of the shoulder with rotator cuff tears. Further, the clinical efficacy of arthroscopic release with single-row fixation and double-row suture bridge fixation was compared. HYPOTHESES: Arthroscopic release combined with single-row fixation or double-row suture bridge fixation showed good clinical outcomes in patients with traumatic supraspinatus tear with adhesive capsulitis. METHODS: A single-center prospective randomized trial was performed from June 2013 to June 2017. Of the 68 patients with traumatic supraspinatus tear and adhesive capsulitis who underwent arthroscopic release, 34 (22 with tear measuring≤3cm and 12 with tear measuring>3cm) were included in the single-row fixation group and 34 (20 with tear measuring≤3cm and 14 with tear measuring>3cm) were included in the double-row suture bridge fixation group. The visual analogue scale (VAS) score, University of California Los Angeles (UCLA) and American Shoulder and Elbow Surgeons (ASES) shoulder scores, range of motion, time to achieve satisfactory scores, and rotator cuff re-tear rate were compared between the groups. RESULTS: The range of motion, VAS score, UCLA and ASES shoulder scores significantly improved after surgery in both groups. There was a significant difference in the UCLA and ASES shoulder scores, time to achieve satisfactory scores, and rotator cuff re-tear rates in patients with tears measuring>3cm between the groups. CONCLUSIONS: Arthroscopic release combined with single-row fixation or double-row suture bridge fixation showed good clinical outcomes in patients with traumatic supraspinatus tear with adhesive capsulitis. Therefore, the capsule of the shoulder should be thoroughly released to achieve such outcomes. For patients with rotator cuff tears measuring>3cm, double-row suture bridge fixation was superior to single-row fixation and the rotator cuff re-tear rate was low. LEVEL OF EVIDENCE: I; prospective, randomized trial, treatment study.

Prediction Efficacy for Clinical Outcome of Prognostic Nutritional Index in Patients with Resectable Biliary Tract Cancer Depends on Sex and Obstructive Jaundice Status.

BACKGROUND: The Prognostic Nutritional Index (PNI), a marker of nutritional status and systemic inflammation, is a proven prognostic biomarker in some cancers. The predictive value of PNI in biliary tract cancer (BTC) has not been established. OBJECTIVE: The aim of this study was to determine the relationship between the PNI and outcomes of resectable BTC. METHODS: In total, 430 patients with stage I-III resectable BTC [gallbladder cancer (GBC), n = 212; cholangiocarcinoma (CHO), n = 218] who had attended Fudan University Zhongshan Hospital were enrolled. The relationship between the PNI and clinical outcomes was evaluated both in the whole cohort and in selected subgroups. RESULTS: Eligible patients were classified into PNI-low (PNI < 45) and PNI-high (PNI ≥ 45) groups. The PNI-low group had significantly worse overall survival (OS) in both the whole cohort (p = 0.002) and in the GBC subgroup (p = 0.001), but had similar OS as the PNI-high group in the CHO subgroup (p = 0.328). Multivariate analysis revealed that low PNI is an independent risk factor for worse survival in GBC (hazard ratio 1.623, 95% confidence interval 1.063-2.480, p = 0.026). PNI was found to predict clinical outcome in women (p < 0.001) and patients without obstructive jaundice (p = 0.017) with GBC, but was not a prognostic factor in any subgroup with CHO. The estimated area under the time-dependent receiver operating characteristic curve was significantly greater when TNM stage was combined with PNI in women with GBC. CONCLUSIONS: PNI is an independent predictor of OS in GBC, but not in CHO. It has no prognostic value in men with GBC or patients with obstructive jaundice.

3D laparoscopic common bile duct exploration versus 2D in choledocholithiasis patients: a propensity score analysis.

BACKGROUND: This study was designed to investigate whether 3D laparoscopic common bile duct (LCBDE) could improve surgical outcomes in choledocholithiasis patients compared with 2D LCBDE. METHOD: Propensity score-matched analysis was performed to balance the bias in baseline characteristic between two groups. RESULTS: 213 patients underwent 3D LCBDE and 212 patients receiving 2D LCBDE were enrolled in this study. The operation time and blood loss in 3D group were significantly less than that in 2D group. After propensity score matching, a total of 114 paired cases were selected from the two groups. The operation time and blood loss in 3D group remain significantly lower than in 2D group. In the end, the subgroup analysis based on abdominal adhesion level was performed and it was observed that for patients with adhesion level 1 and level 2, 3D surgery could obviously decrease the operation time and intraoperative blood loss. CONCLUSIONS: 3D LCBDE would significantly reduce operation time, blood loss, and conversion rate to laparotomy in choledocholithiasis patients versus 2D LCBDE. For patients with abdominal adhesions level 1 and level 2, 3D LCBDE could provide better surgical outcomes than 2D LCBDE.

High infiltration of mast cells is associated with improved response to adjuvant chemotherapy in gallbladder cancer.

Recent studies have reported that tumor-infiltrating mast cells (TIM) play an important role in tumor regression, but the effect of TIM in gallbladder cancer (GBC) remains unclear. The present study aims to investigate the prognostic value of TIM in GBC patients and its responsiveness to gemcitabine-based adjuvant chemotherapy (ACT). A total of 298 GBC patients from Zhongshan Hospital were recruited for this study. TIM infiltration was measured by immunohistochemical staining. Accumulation of TIM is significantly associated with prolonged overall survival in GBC patients. The benefit from gemcitabine-based ACT was superior among patients with high infiltration of TIM with GBC. Multivariate analysis identified TIM infiltration as an independent prognostic factor for overall survival. A heatmap showed that TIM-activated gene signatures were positively correlated with CD8+ T cells' gene signatures. Gene set enrichment analysis (GSEA) suggested that TIM was related to multiple T cell-related processes and signaling pathways, including the interferon gamma signaling pathway and the leukocyte migration signaling pathway. It was confirmed that CD8+ T cell infiltration was positively correlated with high TIM infiltration in tissue microarray (TMA), suggesting that TIM infiltration was linked to the immune surveillance in GBC. TIM can be used as an independent prognostic factor and a predictor of therapeutic response of gemcitabine-based ACT in GBC patients, which may mediate immune surveillance by recruiting and activating CD8+ T cells in GBC.

Modified staging classification of gallbladder carcinoma on the basis of the 8th edition of the American Joint Commission on Cancer (AJCC) staging system.

PURPOSE: The 8th edition of the American Joint Commission on Cancer (AJCC) Staging System for gallbladder cancer (GBC) has been used in clinical practice, but we have found some deficiencies in this edition. METHODS: Survival analyses were performed to evaluate the application of various editions of the AJCC staging systems using the Surveillance, Epidemiology, and End Results (SEER) database (N = 9616 patients) and Fudan University Zhongshan Hospital (FUZH) database (N = 327 patients). A modified staging system was proposed based on the 8th edition of the AJCC Staging System. RESULTS: Although all N2 diseases were grouped into stage IVB as M1 in the 8th edition, some patients with N2 diseases could undergo R0 resection, and had longer survival than patients with M1 diseases had in both cohorts (p < 0.001 in SEER, p = 0.041 in FUZH). Furthermore, in the SEER database, stage IIIA patients aberrantly had poorer survival than stage IIIB patients had (p < 0.001). Therefore, we proposed a modified staging system by rearranging the substages. N2 disease was subdivided and reappraised according to T stage, and the aberrant survival reversal of stage IIIA and stage IIIB disease was also corrected. Through our modification, the C-index of the 8th AJCC Staging System was elevated from 0.596 [95% confidence interval (CI): 0.585-0.607] to 0.623 (95% CI: 0.612-0.634) for local disease in the SEER cohort. Similar findings were also observed in the FUZH cohort. CONCLUSION: Our modified 8th AJCC Staging System is more suitable for GBC and could be adopted for clinical practice.

Landscape of distant metastasis mode and current chemotherapy efficacy of the advanced biliary tract cancer in the United States, 2010-2016.

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.

Low immune index correlates with favorable prognosis but with reduced benefit from chemotherapy in gallbladder cancer.

Use of immune index is a new potential approach for cancer classification and prediction. To investigate the status and clinical effect of immune index in gallbladder cancer (GBC), 238 GBC patients from Zhongshan Hospital affiliated to Fudan University were involved in the present study, including 113 patients in a training set and 125 patients in a validation set. Five immune cells (macrophages, neutrophils, regulatory T cells, cytotoxic T cells and mast cells) were selected based on a literature review and the immune index for each patient was calculated using the LASSO regression. A low immune index (<1) was defined as immunotype A and a high immune index (≥1) was defined as immunotype B. The 5-year overall survival rate for immunotype A was higher than that for immunotype B in the training set and the validation set (70.0% vs 37.0%, P < 0.001; 68.9% vs 47.5%, P = 0.002; respectively). Moreover, the immune index showed higher prediction efficiency compared with all the single immune cells which we selected. When combined with the immune index, the areas under the curve (AUC) of the TNM staging system in both sets were elevated from 0.677 to 0.787 and from 0.631 to 0.694, respectively. Interestingly, gemcitabine-based chemotherapy only benefits stage II patients of immunotype B and stage III patients of both immunotype A and immunotype B (P = 0.015, P = 0.030, P = 0.011, respectively) but does not work in stage II patients of immunotype A (P = .307). Taken together, the immune index could effectively predict prognosis and the benefits of gemcitabine-based chemotherapy and might improve on the TNM staging system.

Potential therapeutic value of primary tumor resection in ampullary cancer patients with distant metastases at initial diagnosis: a population-based study.

OBJECTIVE: To evaluate the therapeutic value of primary tumor resection (PTR) in metastatic ampullary cancer at the initial presentation. PATIENTS AND METHODS: Patients with metastatic ampullary cancer were identified from Surveillance, Epidemiology and End Results database. Propensity score matching (PSM) was performed to balance the characteristics of our cohort. Kaplan-Meier analyses, log-rank tests and multivariate Cox regression models were employed to evaluate the therapeutic value of PTR. RESULTS: A total of 346 patients with metastatic ampullary cancer were identified from 2004 to 2014 and 90 patients were screened by PSM. PTR was associated with favorable overall survival (OS) and cancer-specific survival (CSS) after PSM (PTR vs no-PTR: 16.0, 95% CI: 9.0-22.0 vs 8.0, 95% CI: 5.0-11.0 for median OS; 22.0, 95% CI: 13.0-33.0 vs 9.0, 95% CI: 5.0-11.0 for median CSS; both log-rank P<0.001). Patients receiving PTR plus chemotherapy showed better survival compared with those receiving only chemotherapy (median OS: 18, 95% CI: 13-27 vs 9.0, 95% CI: 8.0-11.0; median CSS: 23.0, 95% CI: 14.0-36.0 vs 9.0, 95% CI: 8.0-13.0; both log-rank P<0.001). CONCLUSION: PTR might bring a survival benefit to ampullary cancer patients with distant metastasis at the initial presentation and might provide a more favorable prognosis when combined with chemotherapy.

Diagnostic accuracy of imaging modalities in differentiating xanthogranulomatous cholecystitis from gallbladder cancer.

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.

Tumor-infiltrating neutrophils predict prognosis and adjuvant chemotherapeutic benefit in patients with biliary cancer.

Tumor-infiltrating neutrophils (TIN) carry out quite significant but opposite functions in different cancers, and their function in biliary cancer has not been fully characterized. To investigate the prognostic significance of TIN in biliary cancer, a training set (n = 118) and a validation set (n = 127) were involved in this study. TIN were evaluated by immunohistochemical staining of CD66b, and then defined as low (neutrophils <18/high-power field [HPF]) vs high (neutrophils ≥18/HPF). Kaplan-Meier curve, Cox proportional hazards models and receiver operating characteristic curve were used to assess the prognostic significance. TIN was identified as an independent prognostic factor for overall survival in the training set (HR: 4.720; 95% CI: 2.623-8.493; P < .001) which was confirmed in the validation set (HR: 4.993; 95% CI: 2.626-9.492; P < .001). Notably, among patients with stage III and IV disease, those with low TIN could benefit from adjuvant chemotherapy, with a reduced risk of compromised survival compared with those with high TIN (HR: 0.294; 95% CI: 0.099-0.873; P = .047 in the training set; and HR: 0.100; 95% CI: 0.022-0.462; P = .006 in the validation set). In addition, TIN were negatively related to biological pathways as regulation of activated T-cell proliferation and lymphocyte-mediated immunity, and showed a negative correlation with CD8 +  T cells (r = -.324, P < .001). Taken together, our results implicate TIN as an independent marker of prognosis and indicator of patients who would benefit from adjuvant chemotherapy in biliary cancer.

Tumor-infiltrating mast cells predict prognosis and gemcitabine-based adjuvant chemotherapeutic benefit in biliary tract cancer patients.

BACKGROUND: Recent studies have reported TIMs play an important role in tumors progression or regression, but the effect of TIMs in biliary tract cancer remains unclear. The aim of this study is to investigate the prognostic value of tumor infiltrating mast cells (TIMs) and its influence on gemcitabine-based adjuvant chemotherapy (ACT) benefits in biliary tract cancer patients after surgery. METHODS: TIMs were evaluated by immunohistochemical staining of tryptase in 250 patients with resected gallbladder carcinoma (GBC) or extrahepatic bile duct carcinoma (EBDC) from Zhongshan Hospital. The relationships between TIMs and clinicopathological factors and postoperative prognosis were analyzed respectively. RESULTS: High TIMs infiltration was significantly correlated with prolonged overall survival (OS). Furthermore, multivariate analysis indicated TNM stage and TIMs as independent prognostic factors for OS. Patients with high TIMs infiltration appeared to significantly benefit from Gemcitabine-based ACT in the discovery and validation cohorts. Spearman analysis identified that TIMs infiltration were positively correlated with anti-tumor CD8+ T cells. CONCLUSION: TIMs infiltration is an independent favorable prognostic factor in GBC and EBDC patients, which could better stratify patients with different prognosis and predict benefit from gemcitabine-based ACT.

The regulation and function of microRNA-377/RASSF8 signaling axis in gastric cancer.

Gastric cancer is a major cause of cancer-associated mortality worldwide. The aberrant expression of microRNA (miRNA) is involved in tumorigenesis. Ras proteins transfer information from the extracellular environment to internal cellular compartments and are essential in numerous signal transduction pathways. To investigate the regulation, function and clinical significance of the miRNA377/Ras association domain family (RASSF) 8 signaling axis in gastric cancer, reverse transcription-quantitative polymerase chain reaction, immunohistochemistry, cell counting kit-8, western blotting, and Transwell assays were used. The results revealed that expression of RASSF8 was significantly upregulated in normal gastric tissues compared with gastric cancer, which was further confirmed by immunohistochemical analysis, and its expression level was increased in normal gastric cells compared with gastric cancer cell lines. However, the expression of miR-377 was significantly upregulated in gastric cancer compared with normal gastric tissues. In addition, RASSF8 overexpression in BGC-823 gastric cancer cells significantly inhibited the proliferation, apoptosis and invasive abilities of cells. Whereas miR-377 attenuated these effects due to downregulated RASSF8 expression by directly targeting its 3'-untranslated region. Furthermore, in the current study, miR-377 was not able to reverse the effects of RASSF8 overexpression on gastric cancer cells. Collectively, the RASSF8 gene may represent a novel molecular target involved in gastric cancer development and may be useful in targeted therapy of patients with gastric cancer.

Laparoscopic surgery for choledocholithiasis concomitant with calculus of the left intrahepatic duct or abdominal adhesions.

BACKGROUND: Laparoscopic common bile duct exploration (LCBDE) has been widely promoted in recent years as a safe and effective treatment for choledocholithiasis. However, there are no standard guidelines for the treatment of patients who have concomitant hepatolithiasis of the left liver and abdominal adhesions. The aim of the current research was to compare the outcomes of open versus laparoscopic common bile duct exploration with left hepatectomy (OCBDH vs. LCBDH) in patients with choledocholithiasis concomitant with left-sided hepatolithiasis, and to evaluate the safety and feasibility of laparoscopic surgery for choledocholithiasis in patients with abdominal adhesions. METHODS: Between October 2012 and October 2015, a total of 321 consecutive patients with choledocholithiasis underwent surgical treatment. LCBDE was performed in 107 patients, and open common bile duct exploration (OCBDE) was performed in 111 patients. Further, 31 patients and 72 patients underwent LCBDH and OCBDH, respectively. A total of 133 patients who underwent LCBDE or OCBDE had abdominal adhesions, which were classified as mild, moderate, or severe according to an abdominal adhesion scoring system, which was validated in the LCBDE group and OCBDE group. The perioperative results were reviewed and analyzed retrospectively. RESULTS: In the mild adhesion group, blood loss, postoperative recovery in the LCBDE group was lesser than those in the OCBDE group. In the moderate adhesion group, the postoperative recovery was significantly shorter in the LCBDE group than in the OCBDE group. In the severe adhesion group, the operation time and blood loss in the LCBDE group were higher than those in the OCBDE group. The postoperative recovery was significantly better in the LCBDH group than in the OCBDH group. CONCLUSION: LCBDH can obviously improve recovery and shorten the hospitalization period. Further, LCBDE is safe and feasible for patients of choledocholithiasis with mild and moderate abdominal adhesions.

Stathmin decreases cholangiocarcinoma cell line sensitivity to staurosporine-triggered apoptosis via the induction of ERK and Akt signaling.

Cholangiocarcinoma is a rare, but highly fatal malignancy. However, the intrinsic mechanism involved in its tumorigenesis remains obscure. An urgent need remains for a promising target for cholangiocarcinoma biological therapies. Based on comparative proteomical technologies, we found 253 and 231 different spots in gallbladder tumor cell lines and cholangiocarcinoma cell lines, respectively, relative to non-malignant cells. Using Mass Spectrometry (MS) and database searching, we chose seven differentially expressed proteins. High Stathmin expression was found in both cholangiocarcinoma and gallbladder carcinoma cells. Stathmin expression was validated using immunohistochemistry and western blot in cholangiocarcinoma tissue samples and peritumoral tissue. It was further revealed that high Stathmin expression was associated with the repression of staurosporine-induced apoptosis in the cholangiocarcinoma cell. Moreover, we found that Stathmin promoted cancer cell proliferation and inhibited its apoptosis through protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) signaling. Integrin, ß1 appears to serve as a partner of Stathmin induction of ERK and Akt signaling by inhibiting apoptosis in the cholangiocarcinoma cell. Understanding the regulation of anti-apoptosis effect by Stathmin might provide new insight into how to overcome therapeutic resistance in cholangiocarcinoma.