Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial.

BACKGROUND: Over 70% of the patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage and lose the opportunity for radical surgery. Combination therapy of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death protein-1 (PD-1) antibodies has achieved a high tumor response rate in both the first-line and second-line treatment of advanced HCC. However, few studies have prospectively evaluated whether TKIs plus anti-PD-1 antibodies could convert unresectable intermediate-advanced HCC into resectable disease. METHODS: This single-arm, phase II study enrolled systemic therapy-naïve adult patients with unresectable Barcelona Clinic Liver Cancer stage B or C HCC. Patients received oral lenvatinib one time per day plus intravenous anti-PD-1 agents every 3 weeks (one cycle). Tumor response and resectability were evaluated before the fourth cycle, then every two cycles. The primary endpoint was conversion success rate by investigator assessment. Secondary endpoints included objective response rate (ORR) by independent imaging review (IIR) assessment per modified RECIST (mRECIST) and Response Evaluation Criteria in Solid Tumors, V.1.1 (RECIST 1.1), progression-free survival (PFS) and 12-month recurrence-free survival (RFS) rate by IIR per mRECIST, R0 resection rate, overall survival (OS), and safety. Biomarkers were assessed as exploratory objectives. RESULTS: Of the 56 eligible patients enrolled, 53 (94.6%) had macrovascular invasion, and 16 (28.6%) had extrahepatic metastasis. The median follow-up was 23.5 months. The primary endpoint showed a conversion success rate of 55.4% (31/56). ORR was 53.6% per mRECIST and 44.6% per RECIST 1.1. Median PFS was 8.9 months, and median OS was 23.9 months. Among the 31 successful conversion patients, 21 underwent surgery with an R0 resection rate of 85.7%, a pathological complete response rate of 38.1%, and a 12-month RFS rate of 47.6%. Grade ≥3 treatment-related adverse events were observed in 42.9% of patients. Tumor immune microenvironment analysis of pretreatment samples displayed significant enrichment of CD8+ T cells (p=0.03) in responders versus non-responders. CONCLUSION: Lenvatinib plus anti-PD-1 antibodies demonstrate promising efficacy and tolerable safety as conversion therapy in unresectable HCC. Pre-existing CD8+ cells are identified as a promising biomarker for response to this regimen. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR1900023914.

Elevated Transient Receptor Potential Melastatin 8 (TRPM8) Expression Is Correlated with Poor Prognosis in Pancreatic Cancer.

BACKGROUND The transient receptor potential melastatin 8 (TRPM8) was found to be expressed abnormally in a variety of tumors and is associated with unfavorable prognosis in human cancers. However, its clinical significance in pancreatic cancer (PC) is mostly unknown. MATERIAL AND METHODS qRT-PCR was performed to measure the expression of TRPM8 in 110 pairs of PC tissues and the adjacent non-cancerous tissues. The association of TRPM8 expression with the clinical characters of PC patients was analyzed using the chi-square test. Furthermore, the prognostic value of TRPM8 was determined with Kaplan-Meier survival curve and Cox regression analysis. RESULTS We found that the expression level of TRPM8 was significantly elevated in PC tissues compared to the non-cancerous controls (P<0.001). In addition, a close relationship was observed between elevated TRPM8 expression with large tumor size (P=0.001), advanced TNM (P=0.013), and distant metastasis (P=0.034). Survival analysis suggested that patients with high TRPM8 expression has worse OS (P=0.001) and DFS (P<0.001) than those with low TRPM8 expression. Moreover, TRPM8 was confirmed as a valuable prognostic biomarker for OS (HR=1.913; 95% CI: 1.020-3.589; P=0.043) or DFS (HR=2.374; 95% CI: 1.269-4.443; P=0.007) of PC patients. CONCLUSIONS This study shows that TRPM8 expression is significantly up-regulated in PC and it might be a useful prognostic factor for patients with PC.

Usefulness of three-dimensional visualization technology in minimally invasive treatment for infected necrotizing pancreatitis.

AIM: To explore the value of three-dimensional (3D) visualization technology in the minimally invasive treatment for infected necrotizing pancreatitis (INP). METHODS: Clinical data of 18 patients with INP, who were admitted to the PLA General Hospital in 2017, were retrospectively analyzed. Two-dimensional images of computed tomography were converted into 3D images based on 3D visualization technology. The size, number, shape and position of lesions and their relationship with major abdominal vasculature were well displayed. Also, percutaneous catheter drainage (PCD) number and puncture paths were designed through virtual surgery (percutaneous nephroscopic necrosectomy) based on the principle of maximum removal of infected necrosis conveniently. RESULTS: Abdominal 3D visualization images of all the patients were well reconstructed, and the optimal PCD puncture paths were well designed. Infected necrosis was conveniently removed in abundance using a nephroscope during the following surgery, and the median operation time was 102 (102 ± 20.7) min. Only 1 patient underwent endoscopic necrosectomy because of residual necrosis. CONCLUSION: The 3D visualization technology could optimize the PCD puncture paths, improving the drainage effect in patients with INP. Moreover, it significantly increased the efficiency of necrosectomy through the rigid nephroscope. As a result, it decreased operation times and improved the prognosis.

Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial.

OBJECTIVE: There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need. DESIGN AND RESULTS: A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively. CONCLUSIONS: This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. TRIAL REGISTRATION: NCT01770431; Post-results.

Identfication of key miRNAs in pancreatitis using bioinformatics analysis of microarray data.

Pancreatitis is a type of inflammation in the pancreas, which frequently occurs due to alcohol and gallstones. The present study aimed to identify pancreatitis­associated microRNAs (miRNAs) by analyzing the microarray of GSE24279. GSE24279 was downloaded from the Gene Expression Omnibus, composed of a collective of 27 pancreatitis and 22 normal control samples. The differentially expressed miRNAs (DE­miRNAs) in pancreatitis samples were screened using the Limma package in Bioconductor. Subsequently, target genes of the DE­miRNAs were predicted using the miRecords and miRWalk databases. Their potential functions were analyzed by functional and pathway enrichment analysis using the Database for Annotation, Visualization and Integrated Discovery online tool. Finally, pancreatitis­associated genes among the target genes identified were searched using the Comparative Toxicogenomics Database, and a regulatory network of pancreatitis­associated genes and their target miRNAs were constructed using Cytoscape software. A total 14 upregulated and 39 downregulated miRNAs were identified in pancreatitis samples compared with control samples and 290 target genes of DE­miRNAs were determined. Cyclin D1 (CCND1), v­akt murine thymoma viral oncogene homolog 2 (AKT2), cyclin­dependent kinase 6 (CDK6) and SMAD family member 2 (SMAD2) were involved in the pathway of pancreatic cancer. Among the target genes, 279 genes were pancreatitis­associated genes, which in turn were targeted by 37 miRNAs in the regulatory network. Hsa­miR­15a, hsa­miR­16, hsa­miR­155, hsa­miR­375 and hsa­miR­429 in particular may be involved in pancreatitis by targeting genes in the regulatory network, including hsa­miR­15a→CCND1, hsa­miR­16→CCND1, hsa­miR­155→CCND1/SMAD2, hsa­miR­375→AKT2/CDK6 and hsa­miR­429→CCND1. The above miRNAs and their targets may contribute to the pathogenesis of pancreatitis; therefore, they may be potential therapeutic targets.

Perioperative and long-term outcomes of liver resection for hepatitis B virus-related hepatocellular carcinoma without versus with hepatic inflow occlusion: study protocol for a prospective randomized controlled trial.

BACKGROUND: The high prevalence of hepatitis B virus (HBV) imposes a huge burden of hepatocellular carcinoma (HCC) in Asia. Surgical resection remains an important therapeutic strategy for HCC. Hepatic inflow occlusion, known as the Pringle maneuver, is the most commonly used method of reducing blood loss during liver parenchymal transection. A major issue with this maneuver is ischemia-reperfusion injury to the remnant liver, and the hemodynamic disturbance it induces in the tumor-bearing liver raises an oncological concern. Given the technical advances in living donor liver transplantation, vascular occlusion in liver resection can be avoided in experienced hands. The aim of this study is to compare the perioperative and long-term outcomes of liver resection for HBV-related HCC without versus with hepatic inflow occlusion. METHODS/DESIGN: This study will include eligible patients with HBV-related HCC elected for liver resection. Fifty-seven patients will be enrolled in each randomization arm to detect a 20 % difference in the serum level of total bilirubin on postoperative day 5 (80 % power and α = 0.05). The secondary endpoints include procedural parameters, perioperative liver function and inflammatory response, postoperative morbidity and mortality, and long-term outcomes. Patients will be followed for up to 5 years. Data will be statistically analyzed on an intention-to-treat basis. DISCUSSION: This prospective randomized controlled trial is designed to compare the perioperative and long-term outcomes of liver resection for HBV-related HCC without versus with vascular occlusion. The clinical implications of these outcomes may change current surgical practice and fill the oncological gaps therein. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02563158 . Registered on 28 September 2015.

Loss of GATA5 expression due to gene promoter methylation induces growth and colony formation of hepatocellular carcinoma cells.

GATA5 is a transcription factor that is capable of suppressing the development of various types of human cancer. The present study investigated the expression of GATA5 and GATA4, and examined their roles in the proliferation and colony formation ability of hepatocellular carcinoma (HCC) tissues and cells. The GATA4 and GATA5 expression levels and gene promoter methylation of HCC tissue samples from 38 patients and HCC cell lines were analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and methylation-specific PCR (MSP), respectively. The effects of GATA4 and GATA5 overexpression on the proliferation and colony forming ability of HCC cells were also assessed using cell viability and colony formation assays. A luciferase reporter assay was utilized to investigate the transcriptional interaction of GATA4 and GATA5 with canonical Wnt signaling. The results indicated that the expression levels of GATA4 and GATA5 were lost or reduced following methylation of gene promoters in HCC tissues and cell lines. Treatment with a demethylating agent, 5-aza-2'-deoxycytidine (5-AZA), restored GATA4 and GATA5 expression in HCC cell lines. Furthermore, methylation of the GATA5 promoter was observed to be associated with the age of patients exhibiting HCC. Restoration of GATA4 and GATA5 expression inhibited colony formation and induced apoptosis of HCC cells in vitro. The present study concluded that the expression levels of GATA4 and GATA5 were reduced in HCC tissues and cell lines. Treatment with 5-AZA restored GATA4 and GATA5 expression in HCC cell lines, suppressing tumor cell growth and colony formation, as well as inducing apoptosis.

Ultrasound-guided radiofrequency ablation of the segmental Glissonian pedicle: A new technique for anatomic liver resection.

BACKGROUND: Anatomic liver resection is widely accepted as the optimal surgical treatment for hepatocellular carcinoma (HCC); however, the complexity of conventional operative methods limits their use. To explore the possibility of using modern techniques to achieve a simpler approach, we have evaluated ultrasound-guided segmental radiofrequency ablation (RFA) of the Glissonian pedicle before liver resection in a porcine model and in HCC patients. METHODS: This study had 2 stages. First, we piloted anatomic liver resection using ultrasound-guided RFA of the segmental Glissonian pedicle in 6 Bama miniature pigs. Having found this technique safe and effective, we selected 21 HCC patients to treat with the same approach. RESULTS: The pigs had no postoperative mortality or morbidity. Demarcation areas were apparent in all targeted segments. The mean length of segmental portal, arterial, and biliary tract branches ablated was 1.7, 1.4, and 1.6 cm, respectively. Human HCC operations consisted of 8 subsegmentectomies, 8 segmentectomies, and 5 multisegmentectomies. The procedure was feasible in all patients, with no mortality, morbidity, or need for blood transfusions. A demarcation area was apparent in all patients within 157 seconds of RF application for each target feeding vessel. The mean number of target feeding vessels was 2 (range, 1-7). CONCLUSION: Our study demonstrates that ultrasound-guided RFA ablation of the segmental Glissonian pedicle is expedient, safe, and effective, and is suitable for resection of any hepatic segments or subsegments, from segments 2 to 8.

Risk factors of delayed gastric emptying following pancreaticoduodenectomy.

BACKGROUND: This study aims to explore the morbidity and risk factors of delayed gastric emptying (DGE) following pancreaticoduodenectomy. METHODS: Between 1 January 2013 and 31 December 2013, data from 196 consecutive patients who underwent pancreaticoduodenectomy in the Chinese PLA General Hospital were recorded retrospectively. A total of 17 factors were examined with univariate analysis, and multivariate logistic regression analysis was used to estimate relative risks. RESULTS: DGE occurred in 71 patients (36.2%). The incidence rates of grade A, grade B and grade C DGE were 22.4% (44/196), 6.1% (12/196) and 7.7% (15/196), respectively. There were three post-operative deaths for the entire series, with an overall mortality rate of 1.5%. Braun enteroenterostomy, clinically relevant post-operative pancreatic fistula (CR-POPF) and intra-abdominal collection correlated with DGE rates significantly in univariate analysis, whereas CR-POPF and intra-abdominal collection were independent risk factors in multivariate logistic regression analysis. Body mass index ≥25 kg/m(2) , CR-POPF and intra-abdominal collection correlated with clinically relevant DGE rates significantly and were independent risk factors in univariate analysis and multivariate regression. CONCLUSION: Only post-operative complications instead of operative methods were associated with DGE. Early diagnosis and timely treatment for pancreatic fistula and intra-abdominal collection were helpful to decrease morbidity and promote recovery of DGE.

[Percutaneous nephroscopic necrosectomy for post-operatively resident infection of severe acute pancreatitis].

OBJECTIVE: To investigate the method and effect of percutaneous nephroscopic necrosectomy (PNN) for post-operatively resident infection of severe acute pancreatitis (SAP). METHODS: Data of the 15 SAP patients with post-operatively resident infection treated by PNN from June 2008 to December 2014 in Chinese People's Liberation Army General Hospital were reviewed. Twelve of the patients underwent the laparotomy within 1 week, 1 in 3(rd) week, 1 in 4(th) week and the other one on the 127(th) day. All of the referrals firstly received (multi-)percutaneous catheter drainage (PCD), and then PNN operation according to the disease, followed by continuous irrigation-drainage. RESULTS: Eleven patients were healed after received only one PNN operation, 2 patients for twice, 1 for three times and 1 for four times. The average post-operative time of hospital stay was 66.2 days (10-223 days). The complications after operation contained colon fistula (n = 1), abdominal hemorrhage (n = 1), pancreatic pseudocyst (n = 1), severe pulmonary infection (n = 1). Three patients eventually died. CONCLUSIONS: Percutaneous nephroscopic necrosectomy is a minimally invasive approach which could prevent the complicated re-laparotomy operation, result in less complication. It is an ideal method for treating SAP patients with post-operatively resident infection.

A New Segmental Hepatectomy Approach Using Ultrasound-Guided Portal Branch Infusion of a Thermosensitive Gel in Pigs.

BACKGROUND: The aim of this study was to evaluate the safety, feasibility, and efficacy of a new segmental hepatectomy (SH) approach using intraoperative ultrasound (IOUS) guided infusion of a reversible thermosensitive gel into the portal vein branch in pigs; MATERIALS AND METHODS: Poloxamer 407 aqueous solution (20%, W/V) was mixed with indocyanine green (P407-ICG) in this study to make it green, and it remained liquid at room temperature and turned into a firm gel upon reaching body temperature. In experiment I, six pigs were used to detect the outcome of infusing the mixture into the biliary tract, liver parenchyma, and hepatic vein for a safety study. In experiment II, another 12 pigs were randomly segmented into two groups [SH group and partial hepatectomy (PH) group] to investigate the feasibility and efficacy of the new approach using IOUS-guided infusion of the mixture into the portal branch; RESULTS: No thermosensitive gel-induced abnormal changes were observed in the safety study. In the SH group, IOUS-guided infusion of the P407-ICG solution was effective in occluding the portal blood temporarily and demarcating the target liver segment to achieve precise SH. The blood loss in the SH group was significantly less than that of the PH group; CONCLUSIONS: SH assisted by IOUS-guided infusion of the reversible thermosensitive gel into the feeding portal vein branches is feasible, safe, simple, and effective.

MicroRNA­506 participates in pancreatic cancer pathogenesis by targeting PIM3.

MicroRNA (miRNA) is a type of short non-coding RNA that suppresses the expression of protein coding genes by partial complementary binding to the 3'­untranslated regions (UTRs) of mRNAs. miRNA expression alterations are involved in the initiation, progression and metastasis of human cancer and it has been suggested that miRNAs function as tumor suppressors as well as oncogenes in cancer development. PIM-3 is a member of the proto-oncogene PIM family, the aberrant expression of which exists in human pancreatic cancer tissues. There are reports indicating that overexpression of PIM3 is associated with the promotion of pancreatic cancer cell proliferation. The aim of the present study was to identify micro (mi)RNAs that regulate the expression of the oncogene PIM3 in PC. It was confirmed that the expression of PIM3 was regulated by miRNAs through an AGO2 knockout experiment. Subsequently, a dual luciferase assay system was constructed and used to screen 13 selected miRNAs that may target the PIM3 3'UTR directly. The results indicated that miR­15a/b, miR­16, miR­33a/b, miR­124, miR­195 and miR­506 repressed the luciferase activity by targeting the PIM3 3'UTR. However, only the expression of miR­506 was negatively correlated with PIM3 expression in PC tissues (r=­0.38, P=0.017). Furthermore, a biological functional study indicated that miR­506 functioned as a tumor suppressor by repressing PC cell proliferation, which was partially reversed by PIM3 overexpression. To the best of our knowledge, the present study was the first to reveal the tumor suppressor function of miR­506 in PC, which has the potential to be employed in the diagnosis and treatment of PC.

Risk scoring system and predictor for clinically relevant pancreatic fistula after pancreaticoduodenectomy.

AIM: To establish a scoring system to predict clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD). METHODS: The clinical records of 921 consecutive patients who underwent PD between 2008 and 2013 were reviewed retrospectively. Postoperative pancreatic fistula (POPF) was defined and classified by the international study group of pancreatic fistula (ISGPF). We used a logistic regression model to determine the independent risk factors of CR-POPF and developed a scoring system based on the regression coefficient of the logistic regression model. The optimal cut-off value to divide the risk strata was determined by the Youden index. The patients were divided into two groups (low risk and high risk). The independent sample t test was used to detect differences in the means of drain amylase on postoperative day (POD) 1, 2 and 3. The optimal cut-off level of the drain amylase to distinguish CR-POPF from non-clinical POPF in the two risk strata groups was determined using the receiver operating characteristic (ROC) curves. RESULTS: Grade A POPF occurred in 106 (11.5%) patients, grade B occurred in 57 (6.2%) patients, and grade C occurred in 32 (3.5%) patients. A predictive scoring system for CR-POPF (0-6 points) was constructed using the following four factors: 1 point for each body mass index ≥ 28 [odds ratio (OR) = 3.86; 95% confidence interval (CI): 1.92-7.75, P = 0.00], soft gland texture (OR = 4.50; 95%CI, 2.53-7.98, P = 0.00), and the difference between the blood loss and transfusion in operation ≥ 800 mL (OR = 3.45; 95%CI, 1.92-7.75, P = 0.00); and from 0 points for a 5 mm or greater duct diameter to 3 points for a less than 2 mm duct (OR = 8.97; 95%CI: 3.70-21.77, P = 0.00). The ROC curve showed that the area under the curve of this score was 0.812. A score of 3 points was suggested to be the best cut-off value (Youden index = 0.485). In the low risk group, a drain amylase level ≥ 3600 U/L on POD3 could distinguish CR-POPF from non-clinical POPF (the sensitivity and specificity were 75% and 85%, respectively). In the high risk group, the best cut-off was a drain amylase level of 1600 (the sensitivity and specificity were 77 and 63%, respectively). CONCLUSION: A 6-point scoring system accurately predicted the occurrence of CR-POPF. In addition, a drain amylase level on POD3 might be a predictor of this complication.

Identification of MicroRNAs and target genes involvement in hepatocellular carcinoma with microarray data.

The aim of the study is to identify the differentially expressed microRNAs (miRNAs) between hepatocellular carcinoma (HCC) samples and controls and provide new diagnostic potential miRNAs for HCC. The miRNAs expression profile data GSE20077 included 7 HCC samples, 1 HeLa sample and 3 controls. Differentially expressed miRNAs (DE-miRNAs) were identified by t-test and wilcox test. The miRNA with significantly differential expression was chosen for further analysis. Target genes for this miRNA were selected using TargetScan and miRbase database. STRING software was applied to construct the target genes interaction network and topology analysis was carried out to identify the hub gene in the network. And we identified the mechanism for affecting miRNA function. A total of 54 differentially expressed miRNAs were identified, in which there were 13 miRNAs published to be related to HCC. The differentially expressed hsa-miR-106b was chosen for further analysis and PTPRT (Receptor-type tyrosine-protein phosphatase T) was its potential target gene. The target genes interaction network was constructed among 33 genes, in which PTPRT was the hub gene. We got the conclusion that the differentially expressed hsa-miR-106b may play an important role in the development of HCC by regulating the expression of its potential target gene PT-PRT.

Increased expression of pleiotrophin is a prognostic marker for patients with gastric cancer.

UNLABELLED: BACKGROUND/AIMs: Pleiotrophin (PTN) have been demonstrated to play an important role in the development of human gastric cancer. However, the prognostic value remains unclear. The aim of this study was to investigate whether expression of PTN has prognostic relevance in human gastric cancer. METHODOLOGY: Immunohistochemistry was used to investigate the expression of PTN proteins in 178 patients with gastric cancer. The level of PTN mRNA in gastric cancer tissues and paratumor tissues were evaluated in 52 paired cases by quantitative real-time polymerase chainreaction(qRT-PCR). Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. RESULTS: The expression level of PTN in gastric cancer tissues was significantly higher (P<0.001) than those in paratumor tissues according to the immunohistochemistry analysis, which was confirmed by qRT-PCR analysis. Additionally, the overexpression of PTN was significantly associated with the tumor site (P=0.001), Lauren's classification (P<0.001),histologic differentiation(P=0.014),depth of invasion(P<0.001), TNM stage (P=0.003),and lymph node metastasis (P=0.002). Moreover, the Cox proportional- hazards regression analysis revealed that the increased expression of PTN was an independent prognostic factor for poor recurrence-free survival(RFS) and overall survival(OS)(both P<0.001). CONCLUSIONS: These findings indicated that the expression of PTN is significantly correlated with prognosis in gastric cancer patients, suggesting that the expression of PTN may be used as an independent prognostic marker.

Double stranded RNA-dependent protein kinase promotes the tumorigenic phenotype in HepG2 hepatocellular carcinoma cells by activating STAT3.

Previously known as a first-response protein upon viral infection and other stress signals, double-stranded RNA-dependent protein kinase (PKR, also termed EIF2AK2) has been found to be differentially expressed in multiple types of tumor, including hepatocellular carcinoma, suggesting that PKR may be involved in tumor initiation and development. However, whether and how PKR promotes or suppresses the development of hepatocellular carcinoma remains controversial. In the present study, PKR expression was investigated using qPCR and western blot analysis, which revealed that PKR expression was upregulated in liver tumor tissues, when compared to that of adjacent normal tissues, which were obtained from four primary liver cancer patients. Furthermore, in vitro cellular assays revealed that PKR exerts a key role in maintaining the proliferation and migration of HepG2 human hepatocellular carcinoma cells. Mouse models with xenograft transplantations also confirmed a tumorigenic role of PKR in HepG2 cells. Furthermore, a transcription factor, signal transducer and activator of transcription 3 (STAT3), was revealed to mediate the tumor-promoting function of PKR in HepG2 cells, as shown by in vitro cellular proliferation and migration assays. In conclusion, the results suggested a tumorigenic role of PKR in liver cancer and a detailed mechanism involving an oncogenic transcription factor, STAT3, is described. Therefore, PKR may present a potential novel therapeutic target for the treatment of liver cancer.

Post-pancreaticoduodenectomy hemorrhage: risk factors, managements and outcomes.

BACKGROUND: Post-pancreaticoduodenectomy (PD) hemorrhage (PPH) is an uncommon but serious complication. This retrospective study analyzed the risk factors, managements and outcomes of the patients with PPH. METHODS: A total of 840 patients with PD between 2000 and 2010 were retrospectively analyzed. Among them, 73 patients had PPH: 19 patients had early PPH and 54 had late PPH. The assessment included the preoperative history of disease, pancreatic status and surgical techniques. Other postoperative complications were also evaluated. RESULTS: The incidence of PPH was 8.7% (73/840). There were no independent risk factors for early PPH. Male gender (OR=4.40, P=0.02), diameter of pancreatic duct (OR=0.64, P=0.01), end-to-side invagination pancreaticojejunostomy (OR=5.65, P=0.01), pancreatic fistula (OR=2.33, P=0.04) and intra-abdominal abscess (OR=12.19, P<0.01) were the independent risk factors for late PPH. Four patients with early PPH received conservative treatment and 12 were treated surgically. As for patients with late PPH, the success rate of medical therapy was 27.8% (15/54). Initial endoscopy was operated in 12 patients (22.2%), initial angiography in 19 (35.2%), and relaparotomy in 15 (27.8%). Eventually, PPH resulted in 19 deaths. The main causes of death were multiple organ failure, hemorrhagic shock, sepsis and uncontrolled rebleeding. CONCLUSIONS: Careful and ongoing observation of hemorrhagic signs, especially within the first 24 hours after PD or within the course of pancreatic fistula or intra-abdominal abscess, is recommended for patients with PD and a prompt management is necessary. Although endoscopy and angiography are the standard procedures for the management of PPH, surgical approach is still irreplaceable. Aggressive prevention of hemorrhagic shock and re-hemorrhage is the key to treat PPH.