Qingbao Cheng

Distal Bile Duct Carcinoma: Prognostic Factors After Curative Surgery. A Series of 112 Cases

BackgroundThe identification of independent prognostic indicators in distal bile duct carcinomas (DBDCs) has been limited by the small number of tumors and a lack of molecular prognostic markers. Markers assessed in combination may perform better than those considered individually. We conducted this study to identify prognostic predictors of patients with DBDC with special focus on combination of expression of p53 protein and clinicopathological predictors.MethodsBetween December 1996 and 2002, 112 consecutive patients undergoing pancreaticoduodenectomy in the Eastern Hepatobiliary Surgery Hospital for distal bile duct carcinomas were identified in a prospectively collected database. The survival of patients was comparable with respect to patient characteristics, clinicopathological factors and degree of p53 protein expression followed by a univariate and multivariate analysis.ResultsActual 1, 3, and 5-year survival rates were 85.7, 50.9, and 25.0%, respectively. By Cox proportional hazards survival analysis, the most powerful predictors of survival rate were p53 expression [relative risk (RR) 5.2, 95% CI 4.8–5.6], pancreatic invasion (RR 5.6, 95% CI 4.3–6.9), lymph nodes metastasis (RR 3.9, 95% CI 3.3–4.5), and operative time (RR 1.8, 95% CI 1.5–2.1).ConclusionsOverexpression of p53 in DBDC is strongly associated with significantly reduced survival, independently of clinicopathological prognostic factors. The resection margin status provides little independent prognostic information. Longer operative time may have unfavorable effect on prognosis of patients with DBDC.

Resection with total caudate lobectomy confers survival benefit in hilar cholangiocarcinoma of Bismuth type III and IV

PURPOSE To identify prognostic predictors for overall survival of patients with hilar cholangiocarcinoma of Bismuth type III and IV (HCBT34), and to determine survival benefit and safety of total caudate lobectomy (TCL) in a Chinese centre. METHODS From January 2001 to December 2010, 171 patients with the diagnosis of HCBT34, who underwent a potentially curative resection, were included in this study. Cox proportional hazards regression models were used to determine the association between possible prognostic variables and survival time. Curative resectability rate, morbidity and mortality were investigated also. RESULTS Resection with TCL was significantly associated with more opportunity to achieve curative resection (p < 0.01), did not accompany with more morbidity (p = 0.39) and mortality (p = 0.67). Cox regression analysis demonstrated positive resection margins [Relative Risk (RR) 3.6, 95% CI 3.5-3.7], not well differentiation (RR 2.9, 95% CI 2.7-3.1), higher preoperative serum peak CA19-9 level (RR 1.6, 95% CI 1.5-1.7) and regional lymph nodes involvement (RR 1.5, 95% CI 1.4-1.6) as independent adverse prognostic variables. CONCLUSIONS Resection with TCL offers a long-term survival opportunity for HCBT34, with high curative resectability rates and an acceptable safety profile.

Exploring and exploiting the fundamental role of microRNAs in tumor pathogenesis

miRNAs (miRs) are short RNA molecules that are involved in the posttranscriptional regulation of mRNA. The roles of miRs in tumor pathogenesis have only recently become a focus of research. It is becoming increasingly clear that miRs are important regulators of apoptosis, proliferation, invasion, and metastasis in cancer cells during cancer genesis and progression, furthering our understanding of cancer. In the present review, we summarize and evaluate the recent advances in our understanding of the characteristics of miRs as well as their regulated functions in cancer stem cells (CSCs), the epithelial-mesenchymal transition (EMT), and the tumor microenvironment (TM), describing their roles in tumor pathogenesis and their possible use as new therapeutic targets and biomarkers.

Circulating miR-106a is a Novel Prognostic and Lymph Node Metastasis Indicator for Cholangiocarcinoma

Cholangiocarcinoma (CCA) is a common biliary malignancy. Despite continuing advances, novel indicators are urgently needed to identify patients with a poor prognosis. Several microRNAs (miRNAs) have been reported to be dysregulated in CCA tissues. The purpose of the current study was to explore the potential use of certain miRNAs as serum indicators. A total of 157 individuals, including103 CCA patients, were recruited into this study. We first used qRT-PCR to evaluate 5 CCA-related miRNAs in the serum of 95 individuals to identify significantly deregulated miRNAs. A logistic regression was used to analyse the potential variables influencing lymph node metastasis. Cox proportional hazards regression models were applied to determine the association between possible prognostic variables and overall survival (OS). We observed that decreased serum miR-106a confers a higher likelihood of lymph node metastasis [hazard ratio (HR) 18.3, 95% confidence interval (CI) 5.9–56.4, p < 0.01]. Additionally, lower circulating miR-106a levels (HR 5.1; 95% CI 2.2–11.8; p < 0.01) and non-radical surgery (HR 4.2; 95% CI 2.3–7.7; p < 0.01) were independent predictors for poor prognosis. Together, reduced expression of serum miR-106a is a powerful prognostic indicator for CCA patients. The dismal outcome of these CCA patients might correlate with a higher risk of lymph node metastasis.

Guidance to rational use of pharmaceuticals in gallbladder sarcomatoid carcinoma using patient-derived cancer cells and whole exome sequencing.

Purpose Gallbladder sarcomatoid carcinoma is a rare cancer with no clinical standard treatment. With the rapid development of next generation sequencing, it has been able to provide reasonable treatment options for patients based on genetic variations. However, most cancer drugs are not approval for gallbladder sarcomatoid carcinoma indications. The correlation between drug response and a genetic variation needs to be further elucidated. Experimental Design Three patient-derived cells-JXQ-3D-001, JXQ-3D-002, and JXQ-3D-003, were derived from biopsy samples of one gallbladder sarcomatoid carcinoma patient with progression and have been characterized. In order to study the relationship between drug sensitivity and gene alteration, genetic mutations of three patient-derived cells were discovered by whole exome sequencing, and drug screening has been performed based on the gene alterations and related signaling pathways that are associated with drug targets. Results It has been found that there are differences in biological characteristics such as morphology, cell proliferation, cell migration and colony formation activity among these three patient-derived cells although they are derived from the same patient. Their sensitivities to the chemotherapy drugs-Fluorouracil, Doxorubicin, and Cisplatin are distinct. Moreover, none of common chemotherapy drugs could inhibit the proliferations of all three patient-derived cells. Comprehensive analysis of their whole exome sequencing demonstrated that tumor-associated genes TP53, AKT2, FGFR3, FGF10, SDHA, and PI3KCA were mutated or amplified. Part of these alterations are actionable. By screening a set of compounds that are associated with the genetic alteration, it has been found that GDC-0941 and PF-04691502 for PI3K-AKT-mTOR pathway inhibitors could dramatically decrease the proliferation of three patient-derived cells. Importantly, expression of phosphorylated AKT and phosphorylated S6 were markedly decreased after treatments with PI3K-AKT-mTOR pathway inhibitors GDC-0941 (0.5 μM) and PF-04691502 (0.1 μM) in all three patient-derived cells. These data suggested that inhibition of the PI3K-AKT-mTOR pathway that was activated by PIK3CA amplification in all three patient-derived cells could reduce the cell proliferation. Conclusions A patient-derived cell model combined with whole exome sequencing is a powerful tool to elucidate relationship between drug sensitivities and genetic alternations. In these gallbladder sarcomatoid carcinoma patient-derived cells, it is found that PIK3CA amplification could be used as a biomarker to indicate PI3K-AKT-mTOR pathway activation. Block of the pathway may benefit the gallbladder sarcomatoid carcinoma patient with this alternation in hypothesis. The real efficacy needs to be confirmed in vivo or in a clinical trial.

Lentiviral vector-mediated RNA interference of HBs gene inhibits replication of HBV: Lentiviral vector-mediated RNA interference of HBs gene inhibits replication of HBV

Objective:To construct a lentiviral vector(LV) of RNA interference(RNAi) targeting HBs gene and to observe its effect on the replication of HBV and expression of antigens.Methods: The effective sequence of siRNA targeting HBs gene was confirmed in our previous study.The complementary DNA containing both sense and antisense Oligo DNA of the targeting sequence was designed,synthesized and cloned into the lentivirus vector(pGCLM-GFP).The resulting lentivirus vector containing HBs shRNA was named LVshHBs,and it was confirmed by PCR and sequencing.293T cells were cotransfected with lentivirus vector pGCLM-GFP,pHelper 1.0 and pHelper 2.0.All virus stocks were produced by calcium phosphate-mediated transfection.The titer of virus was tested according to the expression level of GFP.HepG2.2.15 cells were infected with LVshHBs and the supernatant of the cells was subjected to ELISA,Western blotting analysis and HBV DNA quantitative analysis.Results: PCR and DNA sequencing demonstrated that the LVshHBs-producing HBs shRNA was successfully constructed.The titer of concentrated virus was 5×108-2×109 TU /ml.The inhibitory effect was efficient and the corresponding viral transcript and expression of antigens were decreased after infection.The inhibitory effect was observed 4 days after infection and peaked 9 days after the initial treatment with RNAi.Secreted HBsAg was reduced by 70% in cell culture compared with the negative control,which is also confirmed by Western blotting and real-time PCR.After quantification of HBV DNA,the level of DNA relative to the controls was also significantly reduced after RNAi treatment(P0.05).Conclusion: The lentivirus RNAi vector of HBs has been successfully constructed.The lentiviral microRNA-based RNAi targeting HBs can specifically mediate the down-regulation of HBs expression,inhibiting HBV replication and antigen expression.