Xiangji Luo

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.

Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation

Aim:To determine the efficacy and toxicities of sorafenib in the treatment of patients with multiple recurrences of hepatocellular carcinoma (HCC) after liver transplantation in a Chinese population.Methods:Twenty patients with multiple recurrences of HCC after liver transplantation were retrospectively studied. They received either transarterial chemoembolization (TACE) or TACE combined with sorafenib.Results:The median survival times (MST) after multiple recurrences was 14 months (TACE+sorafenib group) and 6 months (TACE only group). The difference was significant in MST between the two groups (P=0.005). The TACE + sorafenib group had more stable disease (SD) patients than the TACE group. The most frequent adverse events of sorafenib were hand–foot skin reaction and diarrhea. In the univariate analysis, preoperative bilirubin and CHILD grade are found to be significantly associated with tumor-free survival time, the survival time after multiple recurrences and overall survival time. TACE+sorafenib group showed a better outcome than single TACE treatment group. In the multivariate COX regression modeling, the preoperative high CHILD grade was found to be a risk factor of tumor-free survival time. In addition, the preoperative high bilirubin grade was also found to be a risk factor of survival time after recurrence and overall survival time. Furthermore, survival time after recurrence and overall survival time were also associated with therapeutic schedule, which was indicated by the GROUP.Conclusion:Treatment with TACE and sorafenib is worthy of further study and may have more extensive application prospects.

Inhibitory effect of Survivin promoter-regulated oncolytic adenovirus carrying P53 gene against gallbladder cancer

Gene therapy has become an important strategy for treatment of malignancies, but problems remains concerning the low gene transferring efficiency, poor transgene expression and limited targeting specific tumors, which have greatly hampered the clinical application of tumor gene therapy. Gallbladder cancer is characterized by rapid progress, poor prognosis, and aberrantly high expression of Survivin. In the present study, we used a human tumor‐specific Survivin promoter‐regulated oncolytic adenovirus vector carrying P53 gene, whose anti‐cancer effect has been widely confirmed, to construct a wide spectrum, specific, safe, effective gene‐viral therapy system, AdSurp‐P53. Examining expression of enhanced green fluorecent protein (EGFP), E1A and the target gene P53 in the oncolytic adenovirus system validated that Survivin promoter‐regulated oncolytic adenovirus had high proliferation activity and high P53 expression in Survivin‐positive gallbladder cancer cells. Our in vitro cytotoxicity experiment demonstrated that AdSurp‐P53 possessed a stronger cytotoxic effect against gallbladder cancer cells and hepatic cancer cells. The survival rate of EH‐GB1 cells was lower than 40% after infection of AdSurp‐P53 at multiplicity of infection (MOI) = 1 pfu/cell, while the rate was higher than 90% after infection of Ad‐P53 at the same MOI, demonstrating that AdSurp‐P53 has a potent cytotoxicity against EH‐GB1 cells. The tumor growth was greatly inhibited in nude mice bearing EH‐GB1 xenografts when the total dose of AdSurp‐P53 was 1 × 109 pfu, and terminal dUTP nick end‐labeling (TUNEL) revealed that the apoptotic rate of cancer cells was (33.4 ± 8.4)%. This oncolytic adenovirus system overcomes the long‐standing shortcomings of gene therapy: poor transgene expression and targeting of only specific tumors, with its therapeutic effect better than the traditional Ad‐P53 therapy regimen already on market; our system might be used for patients with advanced gallbladder cancer and other cancers, who are not sensitive to chemotherapy, radiotherapy, or who lost their chance for surgical treatment.

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.

Establishment and validation of a prognostic nomogram for patients with resectable perihilar cholangiocarcinoma

As the conventional staging systems have poor prognosis prediction ability for patients with perihilar cholangiocarcinoma (pCCA), we established and validated an effective prognostic nomogram for pCCA patients based on their personal and tumor characteristics. A total of 235 patients who received curative intent resections at the Eastern Hepatobiliary Surgery Hospital from 2000 to 2009 were recruited as the primary training cohort. Age, preoperative CA19-9 levels, portal vein involvement, hepatic artery invasion, lymph node metastases, and surgical treatment outcomes (R0 or R1/2) were independent prognostic factors for pCCA patients in the primary cohort as suggested by the multivariate analyses and these were included in the established nomogram. The calibration curve showed good agreement between overall survival probability of pCCA patients for the nomogram predictions and the actual observations and the concordance index (C-index) was 0.68 (95% CI, 0.61-0.71). The C-index values and time-dependent ROC tests suggested that the nomogram is superior to the conventional staging systems including the Bismuth-Corlette, Gazzaniga, Memorial Sloan Kettering Cancer Center (MSKCC), American Joint Committee on Cancer (AJCC) TNM 7th edition, and Mayo Clinic. The nomogram also performed better than the traditional staging system in the internal cohort with 93 pCCA patients from the same institution and an external validation cohort including 84 pCCA patients from another institution in predicting the overall survival of the pCCA patients as suggested by the C-index values and the time-dependent ROC tests. In summary, the proposed nomogram has superior predictive accuracy of prognosis for resectable pCCA patients.

Effectiveness and safety of sorafenib in the treatment of unresectable and advanced intrahepatic cholangiocarcinoma: a pilot study

Patients with unresectable and advanced intrahepatic cholangiocarcinoma (ICC) usually have short survival due to a lack of effective treatment. This multicenter, single arm, open labeled, prospective study was conducted to evaluate the effectiveness and safety of sorafenib combined with best supportive care (BSC) in these patients. We enrolled 44 patients with unresectable and advanced ICC who were treated with sorafenib (400 mg, twice daily) and BSC. The primary endpoint was disease control rate (DCR) at week 12, and the secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), duration of therapy (DOT), and adverse events (AEs). Our results showed that the DCR was 15.9%, the median TTP was 5.6 months, and the median PFS and OS were 3.2 and 5.7 months (95% confidence interval [CI]: 2.4-4.1 months; 3.7-8.5 months), respectively. The median DOT was 1.8 months (95% CI: 1.9-3.9 months). AEs of grades 1 and 2 events occurred in 75% of patients, and AE of grade 4 (severe) was observed in 1 patient. Therefore, sorafenib in combination with BSC had an acceptable DCR and safety profile in patients with unresectable and advanced ICC.

Midkine promotes hepatocellular carcinoma metastasis by elevating anoikis resistance of circulating tumor cells

Midkine is overexpressed in hepatocellular carcinoma (HCC) and plays a role in tumor progression, but less is known about its role in resistance of circulating tumor cells (CTCs) to anoikis which leading to recurrence and metastasis. The aim of the present study was to analyze whether midkine was associated with HCC progression with anoikis resistance. We found that cultured HCC cells were more resistant to anoikis, which paralleled midkine expression, and midkine treatment significantly inhibited anoikis in a dose-dependent manner. Furthermore, in in vitro and in vivo assays, knockdown of midkine resulted in significant sensitivity to anoikis, decreased cell survival and significantly decreased tumor occurrence rate. Patients with midkine-elevated HCC had higher CTC counts and less apoptotic CTCs, as well as significantly higher recurrence rate and shorter recurrence-free interval. To understand the molecular mechanism underlying the midkine with HCC progression, we performed in vitro and in vivo studies. We found that midkine plays an important role in enhancement of HCC cell resistance to anoikis, thereby promoting subsequent metastasis. Activation of PI3K/Akt/NF-κB/TrkB signaling by midkine-activated anaplastic lymphomakinase (ALK) is responsible for anoikis resistance.

Risk factors of intra-abdominal bacterial infection after liver transplantation in patients with hepatocellular carcinoma

OBJECTIVE To explore the risk factors of intra-abdominal bacterial infection (IAI) after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). METHODS A series of 82 HCC patients who received LT surgeries in our department between March 2004 and April 2010 was recruited in this study. Then we collected and analyzed the clinical data retrospectively. Statistical analysis system (SPSS) software was adopted to perform statistical analysis. Chi-square test, t-test and Wilcoxon rank sum test were used to analyze the clinical data and compute the significance of the incidences of early-stage IAI after LT for HCC patients. Binary logistic regression was performed to screen out the risk factors, and multiple logistic regression analyses were performed to compute the independent risk factors. RESULTS A series of 13 patients (13/82, 15.9%) had postoperative IAI. The independent risk factors of postoperative intra-abdominal bacterial infections after LT for HCC patients were preoperative anemia [Hemoglobin (HGB) <90 g/L] and postoperative abdominal hemorrhage (72 hours >400 mL), with the odds ratios at 8.121 (95% CI, 1.417 to 46.550, P=0.019) and 5.911 (95% CI, 1.112 to 31.432, P=0.037). CONCLUSIONS Postoperative IAI after LT in patients with HCC was a common complication. Preoperative moderate to severe anemia, as well as postoperative intra-abdominal hemorrhage more than 400 mL within the first 72 hours might independently indicate high risk of IAI for these patients.

Early control of short hepatic portal veins in isolated or combined hepatic caudate lobectomy

BACKGROUND Caudate lobectomy has long been considered technically difficult. This study aimed to elaborate the significance of early control of short hepatic portal veins (SHPVs) in isolated hepatic caudate lobectomy or in hepatic caudate lobectomy combined with major partial hepatectomy, and to describe the anatomical characteristics of SHPVs. METHODS The data of 117 patients who underwent either isolated or combined caudate lobectomy by the same team of surgeons from 2005 to 2009 were retrospectively analyzed. From 2005 to 2007 (group A, n=55), we carried out early control of short hepatic veins (SHVs) only; from 2008 to 2009 (group B, n=62), we carried out early control of both SHVs and SHPVs. The two groups were compared to evaluate which surgical procedure was better. A detailed anatomical study was then carried out on the last 25 consecutive patients in group B to study the number and distribution of SHPVs during surgery. RESULTS Patients in group B had less intra-operative blood loss, less impairment of liver function, shorter postoperative hospital stay, fewer postoperative complications and required less blood transfusion (P<0.05). The number of SHPVs in the 25 patients was 183, with 7.3+/-2.7 per patient. The diameters of SHPVs were 1 to 4 mm. On average, 3.4 SHPVs/patient came from the left portal vein, 2.2 from the bifurcation, 1.4 from the right portal vein, and 0.3 from the main portal vein. On average, 3.3 SHPVs/patient supplied segment I of the liver, 0.4 for segment II, 2.1 for segment IV, 1.4 for segment V and 0.1 for segment VI. CONCLUSION Early control of SHPVs in isolated or combined hepatic caudate lobectomy may be a useful method to decrease surgical risk and improve postoperative recovery.