Imatinib facilitates gemcitabine sensitivity by targeting epigenetically activated PDGFC signaling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.

Renin-angiotensin system inhibitors improve the survival of cholangiocarcinoma: a propensity score-matched cohort study.

BACKGROUND: Hypertension is a risk factor for cholangiocarcinoma (CCA). The effect of anti-hypertensive drugs on the prognosis of CCA is not clear. METHODS: This is a retrospective study of 102 patients (56.9% males, median age 66 years) diagnosed with CCA and hypertension concurrently and received radical surgery (R0), with a median follow-up of 36.7 months. Kaplan-Meier analysis, Cox regressions, and propensity score (PS) matching were applied for statistical analysis. RESULTS: Results of multivariable cox analysis showed that renin-angiotensin system inhibitors (RASis) usage was a protective factor for progression-free survival (PFS) (hazard ratio [HR] = 0.55, 95% confidence interval [95% CI]: 0.32-0.96) and overall survival (OS) (HR = 0.40, 95% CI: 0.20-0.79), respectively. Calcium channel blockers, diuretics, and ß-blockers didn't show significant associations. The association of RASis usage and PFS and OS was derived by PS matching, with a cohort of 28 RASis users and 56 RASis non-users. The median PFS and OS of RASis users (PFS, 17.6 months (9.2-34.4); OS, 24.8 months (16.5-42.3)) were longer than RASis non-users (PFS, 10.5 months (4.1-24.1); OS, 14.6 months (10.6-28.4)). The 1 year, 2 years, and 3 years' survival rates of RASis users (89.1%, 77.0%, and 65.5%) were higher than RASis non-users (70.9%, 54.0%, and 40.0%). CONCLUSIONS: RASis usage improves the survival of patients with CCA and hypertension concurrently.

The presence of microvascular invasion guides treatment strategy in recurrent HBV-related HCC.

OBJECTIVES: We used the status of microvascular invasion (MVI) at primary resection to help treatment selection for hepatitis B virus-positive (HBV+) recurrent hepatocellular carcinoma (rHCC) patients in Barcelona Clinic Liver Cancer (BCLC) stage B-C. METHODS: From 2009 to 2017, we enrolled 221 consecutive HBV+ rHCC patients at BCLC stage B-C who underwent re-resection (RR), radiofrequency ablation (RFA), or transarterial chemoembolization (TACE). Post recurrence survival (PRS) and overall survival (OS) were compared between RR/RFA and TACE according to MVI status. A one-to-one propensity score matching analysis was performed. RESULTS: For MVI(-) patients, the median PRS was 62.3 months for the RR/RFA group and 21.1 months for the TACE group (p = 0.039). The corresponding OS was 71.4 months and 26.6 months, respectively (p = 0.010). For MVI(+) patients, the median PRS in the RR/RFA group and TACE group was 14.7 months and 10.1 months (p = 0.115). The corresponding OS was 23.4 months and 16.4 months, respectively (p = 0.067). After matching, the dominance of RR/RFA over TACE remained in MVI(-) patients for both PRS (62.3 months vs 15.3 months, p = 0.019) and OS (98.1 months vs 33.4 months, p = 0.046). No significant difference was found in MVI(+) patients for either PRS (14.7 months vs 11.8 months, p = 0.593) or OS (23.4 months vs 28.1 months, p = 0.662). CONCLUSIONS: MVI status definitely helps select treatment options in HBV+ rHCC patients. For MVI(-) patients, RR/RFA provided better survival than TACE while for MVI(+) patients, TACE shared similar survival outcomes. KEY POINTS: • This study aimed at the determination of the optimal treatment options (ablation /resection vs TACE) in case of recurrent HBV-related HCC. • It showed that MVI status, established at primary resection of HCC, was a powerful marker for selecting the best treatment option in these patients. • In MVI(-) patients, RR/RFA achieved a better survival than TACE. In MVI(+) patients, TACE shared similar survival.

Regulation of the extrinsic apoptotic pathway by microRNA-21 in alcoholic liver injury.

IL-6/Stat3 is associated with the regulation of transcription of key cellular regulatory genes (microRNAs) during different types of liver injury. This study evaluated the role of IL-6/Stat3 in regulating miRNA and miR-21 in alcoholic liver disease. By microarray, we identified that ethanol feeding significantly up-regulated 0.8% of known microRNAs in mouse liver compared with controls, including miR-21. Similarly, the treatment of normal human hepatocytes (N-Heps) and hepatic stellate cells (HSCs) with ethanol and IL-6 significantly increased miR-21 expression. Overexpression of miR-21 decreased ethanol-induced apoptosis in both N-Heps and HSCs. The expression level of miR-21 was significantly increased after Stat3 activation in N-Heps and HSCs, in support of the concept that the 5'-promoter region of miR-21 is regulated by Stat3. Using real time PCR, we confirmed that miR-21 activation is associated with ethanol-linked Stat3 binding of the miR-21 promoter. A combination of bioinformatics, PCR array, dual-luciferase reporter assay, and Western blot analysis revealed that Fas ligand (TNF superfamily, member 6) (FASLG) and death receptor 5 (DR5) are the direct targets of miR-21. Furthermore, inhibition of miR-21 by specific Vivo-Morpholino and knock-out of IL-6 in ethanol-treated mice also increased the expression of DR5 and FASLG in vivo during alcoholic liver injury. The identification of miR-21 as an important regulator of hepatic cell survival, transformation, and remodeling in vitro, as well as its upstream modulators and downstream targets, will provide insight into the involvement of altered miRNA expression in contributing to alcoholic liver disease progression and testing novel therapeutic approaches for human alcoholic liver diseases.

Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and microRNA let7a in mice.

BACKGROUND & AIMS: Proliferating cholangiocytes secrete and respond to neuroendocrine hormones, including secretin. We investigated whether secretin secreted by S cells and cholangiocytes stimulates biliary proliferation in mice. METHODS: Cholestasis was induced in secretin knockout (Sct(-/-)) and wild-type (control) mice by bile duct ligation (BDL). At days 3 and 7 after BDL, control and Sct(-/-) mice received tail-vein injections of morpholinos against microRNA 125b or let7a. One week later, liver tissues and cholangiocytes were collected. Immunohistochemical, immunoblot, luciferase reporter, and real-time polymerase chain reaction assays were performed. Intrahepatic bile duct mass (IBDM) and proliferation were measured. Secretin secretion was measured in conditioned media from cholangiocytes and S cells and in serum and bile. RESULTS: Secretin secretion was increased in supernatants from cholangiocytes and S cells and in serum and bile after BDL in control mice. BDL Sct(-/-) mice had lower IBDM, reduced proliferation, and reduced production of vascular endothelial growth factor (VEGF) A and nerve growth factor (NGF) compared with BDL control. BDL and control mice given morpholinos against microRNA 125b or let7a had increased IBDM. Livers of mice given morpholinos against microRNA 125b had increased expression of VEGFA, and those treated with morpholinos against microRNA let7a had increased expression of NGF. Secretin regulated VEGF and NGF expression that negatively correlated with microRNA 125b and let7a levels in liver tissue. CONCLUSIONS: After liver injury, secretin produced by cholangiocytes and S cells reduces microRNA 125b and let7a levels, resulting in up-regulation of VEGF and NGF. Modulation of cholangiocyte expression of secretin could be a therapeutic approach for biliary diseases.

DNA methylation profiling identifies EYA4 gene as a prognostic molecular marker in hepatocellular carcinoma.

BACKGROUND: DNA hypermethylation plays important roles in carcinogenesis by silencing key genes. This study aims to identify pivotal genes in hepatocellular carcinoma (HCC) by DNA methylation microarray and to assess their prognostic values. MATERIALS AND METHODS: DNA methylation microarray was performed in 45 pairs of HCC and adjacent nontumorous tissues and six normal liver tissues to identify hypermethylated genes in HCC. Potential prognosis-related genes were selected among hypermethylated genes by analyzing influences of methylation levels on disease-free survival (DFS) and overall survival (OS) in 45 patients. Their prognostic values were validated in 154 patients with HCC (including the initial 45 patients) to determine the independent prognostic gene. RESULTS: Altogether, 54 CpG islands in 44 genes were hypermethylated in HCC compared with liver tissues. Among them, methylation levels of ERG and HOXA11 were inversely associated with DFS (both P < 0.050), and methylation levels of EYA4 were inversely related to DFS and OS (both P < 0.050). EYA4 expression was inversely related to tumor size (P < 0.050). Lower EYA4 expression and larger tumor size were independent predictors of both shorter DFS and OS, and higher Barcelona Clinic Liver Cancer (BCLC) staging was an independent predictor of shorter OS (all P < 0.050). CONCLUSIONS: EYA4 functions as a prognostic molecular marker in HCC. Its aberrant hypermethylation and subsequent down-regulation may promote tumor progression.

Effects of target tree management on understory regeneration in Pinus massoniana plantations.

To clarify the effects of target tree management on natural forest regeneration, with Pinus massoniana plantations in the low mountainous regions of eastern Sichuan with target tree densities of 100, 150 and 200 trees·hm-2 as test object, we analyzed the effects of management densities on canopy structure, plant diversity, and soil physicochemical properties on understory regeneration. The results showed that the regeneration index increased with management density, which increased 0.08-0.10 in the managed plantations compared with unmanaged sites. When the density of the target trees was 150 trees·hm-2, an increase of 9 regeneration tree species and an increase of 800 trees·hm-2 in quantity were observed. The dominance of herbaceous species was not prominent, but canopy structure was improved, and the regeneration ability of understory plants was enhanced. The impact of habitat factors on the regeneration index ranked as soil total porosity (0.591) > leaf area index (-0.536) > Shannon index (-0.085) > available P (0.053) > total N (-0.007) > Pielou index (-0.005). Target tree management facilitated understory regeneration in the P. massoniana plantations by improving soil pore conditions, reducing leaf area index, and decreasing herbaceous plant diversity index. A management density of 150 trees·hm-2 was more sui-table for target tree management in P. massoniana plantations.

Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events.

The secretion of dopamine and serotonin is increased in cholangiocarcinoma, which has growth-promoting effects. Monoamine oxidase A (MAOA), the degradation enzyme of serotonin and dopamine, is suppressed in cholangiocarcinoma via an unknown mechanism. The aims of this study were to (i) correlate MAOA immunoreactivity with pathophysiological parameters of cholangiocarcinoma, (ii) determine the mechanism by which MAOA expression is suppressed and (iii) evaluate the consequences of restored MAOA expression in cholangiocarcinoma. MAOA expression was assessed in cholangiocarcinoma and nonmalignant controls. The control of MAOA expression by promoter hypermethylation was evaluated and the contribution of interleukin-6 (IL-6) signaling to the suppression of MAOA expression was determined. The effects of MAOA overexpression on cholangiocarcinoma growth and invasion were also assessed. MAOA expression is correlated with differentiation, invasion and survival in cholangiocarcinoma. The MAOA promoter was hypermethylated immediately upstream of the start codon in cholangiocarcinoma samples and cell lines but not in nonmalignant counterparts. IL-6 signaling also decreased MAOA expression via a mechanism independent of hypermethylation, involving the regulation of the balance between SP-1 transcriptional activity and its inhibitor, R1 repressor. Inhibition of both IL-6 signaling and DNA methylation restored MAOA levels to those observed in cholangiocytes. Forced MAOA overexpression inhibited cholangiocarcinoma growth and invasion. MAOA expression is suppressed by the coordinated control of promoter hypermethylation and IL-6 signaling. MAOA may be a useful prognostic marker in the management of cholangiocarcinoma, and therapies designed to increase MAOA expression might prove beneficial in the treatment of cholangiocarcinoma.

Comparison between robotic-assisted and laparoscopic left hemi-hepatectomy.

OBJECTIVE: To compare the safety and short-term outcomes between robotic-assisted and laparoscopic left hemi-hepatectomies in a single academic medical center. METHODS: A cohort of 52 patients, who underwent robotic-assisted or laparoscopic left hemi-hepatectomies between April 2015 and January 2020 in Department of Pancreatobiliary Surgery, the First Affiliated Hospital of Sun Yat-Sen University was recruited into the study. Their clinicopathological features and short-term outcomes were analyzed retrospectively. RESULTS: There were 25 robotic-assisted and 27 laparoscopic cases, with a median age of 55 years (34-77 years). There was one conversion to open in laparoscopic group. There were no significant differences in clinicopathological features between two groups, except robotic group had higher body mass index (23.9 vs. 22.0 kg/m2, p = 0.047). Robotic-assisted and laparoscopic groups had similar operative time (300 vs. 310 min, p = 0.515), length of hospital stay (8 vs. 8 days, p = 0.981) and complication rates (4.0% vs. 14.8%, p = 0.395), but the former had less blood loss (100 vs. 200 ml, p < 0.001) and lower incidence of blood transfusion (0% vs. 22.2%, p = 0.023) in comparison with laparoscopic group. R0 resection was achieved for all patients with malignancies. There was no perioperative mortality in both groups. The cost of robotic group was higher than laparoscopic group (105,870 vs. 64,191 RMB yuan, p = 0.02). CONCLUSION: The robotic-assisted and laparoscopic approaches had similar safety and short-term outcomes in left hemi-hepatectomy, and the former can reduce operative blood loss and blood transfusion. However, the costs were higher in robotic group.

Foxp3+ regulatory T cells and the formation of portal vein tumour thrombus in patients with hepatocellular carcinoma.

BACKGROUND: Most patients with hepatocellular carcinoma (HCC) have advanced-stage disease at diagnosis. The prognosis for patients with HCC is very poor, especially for those with portal vein tumour thrombi (PVTT). The purpose of our study was to observe the prognostic value of PVTT and tumour-infiltrating regulatory T cells (Tregs) and the correlation between them. METHODS: We examined 76 HCC specimens by immunohistochemistry for CD4+, CD8+ T cells and Foxp3+ Tregs. The survival of patients was prospectively followed up. Patients with HCC were grouped according to the formation of PVTT or Treg infiltration status. We performed a Kaplan-Meier survival analysis to observe the difference in prognosis between the groups. We analyzed the correlation of Treg expression with clinical and pathologic features. RESULTS: Survival analysis revealed that both the disease-free survival rate and total survival rate after hepatic resection were significantly lower in patients in the PVTT group than those in the non-PVTT group (p=0.026 and p=0.022, respectively). Likewise, both the disease-free survival rate and the total survival rate were significantly lower in patients in the high Treg group than those in the low Treg group (p=0.012 and p=0.023, respectively). We found that intratumoural Tregs were associated with PVTT formation (p=0.001) and that patients with high Treg infiltration had a higher percentage of PVTT formation. CONCLUSION: Patients with PVTT formation or high intratumoural Treg infiltration tended to have a poor prognosis. Intratumoural Treg was associated with formation of PVTT in patients with HCC.

[Combination with vascular resection and reconstruction in resection of hilar cholangiocarcinoma].

OBJECTIVE: To investigate the value of vascular resection and reconstruction in resection of hilar cholangiocarcinoma. METHODS: The clinical data of 17 patients with hilar cholangiocarcinoma received resection in combination with vascular resection and reconstruction from January 2000 to September 2009 was retrospectively analyzed. Among the 17 patients, 6 underwent portal vein segmental resection and end-to-end anastomosis, 3 underwent portal vein wedge resection, 1 underwent hepatic artery ligature, 2 underwent hepatic artery segmental resection and end-to-end anastomosis, 1 underwent portal vein arterialization, 1 underwent portal vein wedge resection and hepatic artery ligature simultaneously, 2 underwent portal vein segmental resection and hepatic artery segmental resection and end-to-end anastomosis simultaneously, 1 underwent portal vein segmental resection and right hepatic artery and gastroduodenal artery end-to-end anastomosis simultaneously. RESULTS: Four patients died and the mortality was 4/17. Three patients died of renal dysfunction followed with multiple organ dysfunction and 1 patient died of sepsis shock. Among the 13 survive patients, 6 had a smooth postoperative recover and 7 developed complications: 3 had bile leakage, 1 had respiratory failure, 1 had cholangitis due to obstruction of U tube, 1 had abdominal infection and thrombosis in portal vein system and 1 had portal vein stenosis and liver abscess. Follow-up investigation showed that the median survival time was 18 months and four patients still alive. CONCLUSIONS: Combination of vascular resection and reconstruction in the resection of hilar cholangiocarcinoma may help to improve the resection rate but still have a high postoperative risk. The complications of renal dysfunction should be alert during the postoperative observation. The procedure of hepatic arterial reconstruction may help to reduce postoperative morbidity.

Mechanisms and influence of octreotide-induced regulation of somatostatin receptor 2 on hepatocellular carcinoma.

BACKGROUND: Somatostatin receptors (SSTRs) belong to the family of G protein-coupled receptors. Exposure of G protein-coupled receptors to their agonists induces a rapid decrease in their initial response. The goal of this study is to investigate alteration in SSTR2 by the treatment of SSTR agonist octreotide (OCT) in hepatocellular carcinoma (HCC) and the resulting consequence. METHODS: Morphology, proliferation and cell cycle of the human HCC cell line (Bel7402) were evaluated. Effect of OCT on HCC growth and development was assessed in vivo. SSTR2 expression was measured by RT-PCR and detected by immunohistochemistry. RESULTS: Short-term OCT treatment on Bel7402 cells barely changed cell proliferation and morphology, and no apoptosis was induced. The SSTR2 protein level was markedly decreased on Bel7402 cells after exposure to OCT. However, the weight of the HCC xenograft was significantly lower in the OCT treatment group as compared with the control group. In the rat hepatocarcinogenesis model, the mortality and incidence of HCC in the OCT treatment group were remarkably less than those in the control group. Long-term OCT treatment led to increased levels of both SSTR2 mRNA and protein in hepatocytes and HCC cells. CONCLUSION: Short-term OCT treatment could lead to SSTR2 desensitization, resulting in a reduced inhibitory effect on HCC by OCT. However, long-term OCT treatment effectively inhibited the development and growth of HCC probably via resensitization and upregulation of SSTR2.

[Determination of the postoperative effect on intestinal structure and myoelectric motility in rabbits: modified uncut jejunal loop versus Roux-en-Y biliodigestive anastomosis].

OBJECTIVE: To evaluate influences on intestinal structure and myoelectric motility between modified uncut jejunal loop and Roux-en-Y procedures for biliodigestive anastomosis. METHODS: Fifteen rabbits were randomized in modified uncut jejunal loop group, Roux-en-Y group and control group. Traced fasting slow-wave frequency (SWF) before biliodigestive diversion and 25 d postoperative (POD25) during laparotomy. Before the second laparotomy on POD21, the fasting SWF, percentage of abroad migrating myoelectric complex (MMC%), the postprandial spike potential frequency (SPF) and percentage of abroad propagation (SP%) were recorded in vivo. Compared myoelectric recordings according to parameters above. On POD90, harvested the stitched ligation of ascending loop and part of descending loop in uncut group, and biliary limb in R-Y animals, which assessed under HE, c-kit labeling immunohistochemical staining and transmission electron microscope(TEM). RESULTS: On POD25, SWF declined mildly in uncut group (8.4%) and markedly in R-Y group (23.8%) respectively. The difference was significant (P<0.05). Before laparotomy on POD21 when abdomen closed, between uncut and control animals, there were statistical difference in fasting SWF and postprandial SPF (P<0.05), while no significance in MMC% and SP% (P>0.05). Moreover, differences of each parameters between R-Y group and control or uncut group were markedly statistical (P<0.01). Abroad myoelectric propagation through the ligated segment can be observed in uncut animals. Meanwhile, ectopic pacemaker was detected locating in the proximal segment of the Roux limb and triggering retrograde propagation in R-Y animals. On POD90, no recanalization were observed In uncut animals. Furthermore, occluded lumen with mild atrophic mucosa under microscope and c-kit labeling cells located in the inner circular muscle layer were observed, which proven to be Interstitial cells of Cajal (ICCs) by TEM. In R-Y animals, lumen of the Roux limb dilated. There's no significant difference in c-kit labeling area between R-Y and uncut animals by image analysis system. Reductions of processes and intercellular gap junction in ICCs, and loose interconnections between ICCs and SMCS or nerve endings were observed in R-Y animals. CONCLUSIONS: Impaired gastrointestinal motility after the Roux-en-Y procedure may due to the aberrant interstitial cells of Cajal. Modified uncut technique reveals a reliable and effective alternative for biliodigestive reconstruction.

Bile leakage after hepatectomy for hepatolithiasis: risk factors and management.

BACKGROUND: Bile leakage remains a major postoperative complication after liver resection. Bile leakage after hepatectomy for liver neoplasms has been well studied. However, the risk factors and management of this complication after liver resection for intrahepatic lithiasis has not been investigated. METHODS: From January 1992 to June 2004, 312 consecutive patients with intrahepatic lithiasis underwent hepatic resections Sun Yet-san University. Perioperative risk factors pertaining to the development of bile leakage were identified using univariate and multivariate analysis. The management and outcome of these patients with bile leakage were evaluated. RESULTS: Bile leakage developed in 23 (7.4%) of 312 patients. The multivariate logistic regression analysis identified that left hepatectomy (P=.024, odds ratio [OR]=3.695, 95% confidence interval [CI]: 1.185 to 11.517) and the period greater than 1 month between operative time and the latest acute cholangitis attack (P=.02, OR=4.144, 95% CI: 1.248 to 13.757) were the independent risk factors for development of bile leakage after hepatectomy for hepatolithiasis. The septic complications were higher in the patients with bile leakage than in those without bile leakage (ie, wound infection: 56.5% vs 13.5%, P=.001; subphrenic abscess: 21.7% vs 4.8%, P=.01; septicemia: 8.7% vs 0.7%, P=.029). Percutaneous drainage or combined endoscopic naso-biliary drainage was the first choice of treatment for bile leakage; 20 (87.0%) of 23 patients were treated by this method. One patient underwent re-operation for diffuse peritonitis due to withdrawal of T tube inadvertently at postoperative day 1. Two patients with bile leakage were re-operated due to uncontrollable hemobilia at postoperative day 5 and 12, respectively. CONCLUSIONS: Patients who underwent hepatectomy at the period less than 1 month after the latest attack of acute cholangitis carry high risk for the development of bile leakage. Preoperative cholangiography to identify the aberrant hepatic duct for high risk patients and avoidance of hepatectomy at the acute phase of cholangitis are of critical importance to prevent bile leakage after hepatectomy. Percutaneous drainage is the primary and effective treatment for bile leakage.

Hepaticojejunostomy for hepatolithiasis: a critical appraisal.

AIM: To evaluate the long-term outcome and surgical indications of hepaticojejunostomy (HJ) for the treatment of hepatolithiasis. METHODS: Three hundred and fourteen elective cases with hepatolithiasis but without biliary stricture or cystic dilatation treated in the past 10 years were reviewed retrospectively. The patients were divided into HJ group and T tube drainage group according to biliary drainage procedure. Furthermore, four subgroups were subdivided by hepatectomy as a balance factor, group A(1): hepatectomy+HJ; group A(2): choledochoctomy+HJ; group B(1): hepatectomy + choledochoctomy T tube drainage; group B(2): choledochoctomy + T tube drainage. The stone residual rate, surgical efficacy and long-term outcome were compared among different procedures. RESULTS: There was no surgical mortality among all patients. The total hospital mortality was 1.6%. The overall stone residual rate after surgical clearance was 25.9%. There was no statistical difference between HJ group and T tube drainage group in terms of stone residual rate after surgical clearance, however, after postoperative choledochoscopic lithotripsy, the total stone residual rate of T tube drainage group was significantly lower than that of HJ group (0.5% vs 16.7%, P < 0.01). Hepatectomy + choledochoctomy tube drainage achieved the optimal therapeutic effect, only 8.2% patients suffered from an attack of cholangitis postoperatively, which was significantly lower than that of hepatectomy + HJ (8.2% vs 22.0%, P = 0.034). The major reason for postoperative cholangitis was stone residual in the HJ group (16/23, 70.0%), and stone recurrence in the T tube drainage group (34/35, 97.1%). The operative times were significantly prolonged in those undergoing HJ, and the operative morbidity of HJ was higher than those of T tube drainage. CONCLUSION: The treatment result of HJ for hepatolithiasis is not satisfactory in this retrospective study due to high rate of stone residual and postoperative cholangitis. HJ could not drain residual stone effectively. HJ may hinder post-operative choledochoscopic lithotripsy, which is the optimal management for postoperative residual stone. The indications of HJ for hepatolithiasis should be strictly selected.

[Surgical resection versus percutaneous thermal ablation for early-stage hepatocellular carcinoma: a randomized clinical trial].

OBJECTIVE: To compare the clinical results of surgical resection (SR) and percutaneous thermal ablation (PTA) for early-stage hepatocellular carcinoma (HCC) (single tumor nodule

[Experience of surgical resection of 103 hilar cholangiocarcinoma].

OBJECTIVE: To summarize the experience of surgical resection of 103 hilar cholangiocarcinoma. METHODS: One hundred and three consecutive cases of hilar cholangiocarcinoma who underwent surgical resection at our hospital over the past ten years were reviewed retrospectively. The clinical data and long-term outcome were analyzed. RESULTS: Out of 103 cases, 43 patients underwent radical resection (41.7%), and 60 patients underwent palliative resection. There were 34 patients developed postoperative complications and 8 patients died in hospital. For the radical resection group, the median survival time was 29.9 months and 1-year, 3-year, 5-year survival rate was 69.6%, 42.0%, 20.9%, respectively, which was significant greater than 34.1%, 10.2%, 0 of the palliative resection group (P < 0.05). Over the past five years, 42 cases underwent pre-operative drainage of bile and the rate of combined liver resection reached 53.8%. The tumor radical resection rate has increased to 45.7%, the median survival time have reached 24.7 months (P < 0.05). CONCLUSIONS: Improvement of pre-operative management, intraoperative pathology for resection margin, and combined liver resection may help in increasing the radical resection rate. Radical resection can improve postoperative survival, and produce a satisfactory outcome for patient with hepatic hilar cholangiocarcinoma.

EYA4 gene functions as a prognostic marker and inhibits the growth of intrahepatic cholangiocarcinoma.

BACKGROUND: The molecular prognostic markers and carcinogenesis of intrahepatic cholangiocarcinoma (ICC) have not been well documented. The purpose of this study was to investigate the prognostic value of the eyes absent homolog 4 (EYA4) gene in ICC and its biological effects on ICC growth in vitro and in vivo. METHODS: One hundred twelve patients with ICC who underwent hepatectomy were enrolled in the study. EYA4 mRNA and EYA4 protein levels in ICC and adjacent non-tumoral tissues were evaluated using real-time quantitative polymerase chain reaction and immunohistochemical staining, respectively. EYA4 protein levels in ICC cells were determined using western blot analysis. The associations between EYA4 expression and clinicopathologic features of ICC were analyzed. To identify independent prognostic factors, univariate and multivariate analyses were performed. The biological effects of EYA4 on ICC cells were evaluated by establishing stable EYA4-overexpressing transfectants in vitro, and EYA4's effects on tumor growth were evaluated by intra-tumoral injection of EYA4-expressing plasmids in a NOD/SCID murine model of xenograft tumors. RESULTS: ICC tissues had significantly lower EYA4 mRNA and protein levels compared with adjacent non-tumoral tissues (both P < 0.001). Univariate and multivariate analyses showed that EYA4 protein level, tumor number, adjacent organ invasion, lymph node metastasis, and tumor differentiation were independent prognostic factors for disease-free survival and overall survival (all P < 0.05). In vitro, EYA4 overexpression inhibited tumor cell growth, foci formation, and cell invasiveness. In vivo, intra-tumoral injection of EYA4-expressing plasmids significantly inhibited ICC growth in the murine xenograft model compared with the control group (P < 0.05). CONCLUSION: EYA4 gene functioned as a molecular prognostic marker in ICC, and its overexpression inhibited tumor growth in vitro and in vivo.

EYA4 functions as tumor suppressor gene and prognostic marker in pancreatic ductal adenocarcinoma through ß-catenin/ID2 pathway.

Eye absent homolog 4 (EYA4) was initially found as key gene in controlling eye development in Drosophila. We recently found that EYA4 was an independent prognostic factor in hepatocellular carcinoma. Its biological functions in malignancies remained unknown. The present study aimed at investigating its biological functions, molecular mechanisms and prognostic values in pancreatic ductal adenocarcinoma (PDAC). Overexpression of EYA4 in PDAC cells inhibited proliferation and invasion in vitro and tumor growth in vivo. Depletion of EYA4 in PDAC cells enhanced proliferation and invasion in vitro and tumor growth in vivo. Mechanistically, armed with the serine/threonine-specific protein phosphatase activity, EYA4 dephosphorylated ß-catenin at Ser675, blocked ß-catenin nuclear translocation and inhibited ID2 transactivation. Consistently, EYA4 expression inversely correlated with the levels of p-Ser675-ß-catenin and ID2 in tissues. EYA4 expression in PDAC tissues was significantly reduced as compared with adjacent non-tumoral tissues. EYA4 expression was an independent prognostic factor in PDAC, with a lower EYA4 level in association with shorter long-term survival and disease-free time. We showed that EYA4 functioned as tumor suppressor gene in PDAC via repressing ß-catenin/ID2 activation, and was an independent prognostic factor in PDAC.

Systemic chemo-immunotherapy for advanced-stage hepatocellular carcinoma.

AIM: To evaluate the therapeutic efficacy of systemic chemo-immunotherapy for advanced hepatocellular carcinoma (HCC). METHODS: Twenty-six patients with advanced HCC were treated by using systemic chemo-immunotherapy (PIAF regimen), which consisted of cisplatin (20 mg/m2) intravenously daily for 4 consecutive day, doxorubicin (40 mg/m2) intravenously on day 1, 5-fluorouracil (400 mg/m2) intravenously daily for 4 consecutive day, and human recombinant alpha-interferon-2a (5 MU/m2) subcutaneous injection daily for 4 consecutive day. The treatment was repeated every 3 wk, with a maximum of six cycles. RESULTS: A total of 90 cycles of PIAF treatment were administered, with a mean number of 3.9 cycles per patient. Eight patients received six cycles of treatment (group A), and the remaining 18 were subjected to two to five cycles (group B). There were 0 complete responses, 4 partial responses, 9 static diseases and 13 progressive diseases, with a disease control rate of 50% (13/26). The 1-year survival rate was 24.3%, with a median survival time of 6.0 mo. Group A had a remarkably better survival as compared with group B, the 1- and 2-year survival rates were 62.5% vs 6.1% and 32.3% vs 0%, and a median survival time was 12.5 mo vs 5.0 mo (P = 0.001). CONCLUSION: Systemic chemo-immunotherapy using PIAF regimen represented an effective treatment and could improve the survival rate and prolong the survival time in selected patients with advanced HCC.