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Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. The molecular pathogenesis of HCC involves multiple signaling pathways. This study utilizes systems and bioinformatic approaches to investigate the pathogenesis of HCC.Gene expression microarray data were obtained from 50 patients with chronic hepatitis B and HCC. There were 1649 differentially expressed genes inferred from tumorous and nontumorous datasets. Weighted gene coexpression network analysis (WGCNA) was performed to construct clustered coexpressed gene modules. Statistical analysis was used to study the correlation between gene coexpression networks and demographic features of patients. Functional annotation and pathway inference were explored for each coexpression network. Network analysis identified hub genes of the prognostic gene coexpression network. The hub genes were further validated with a public database.Five distinct gene coexpression networks were identified by WGCNA. A distinct coexpressed gene network was significantly correlated with HCC prognosis. Pathway analysis of this network revealed extensive integration with cell cycle regulation. Ten hub genes of this gene network were inferred from protein-protein interaction network analysis and further validated in an external validation dataset. Survival analysis showed that lower expression of the 10-gene signature had better overall survival and recurrence-free survival.This study identified a crucial gene coexpression network associated with the prognosis of hepatitis B virus-related HCC. The identified hub genes may provide insights for HCC pathogenesis and may be potential prognostic markers or therapeutic targets.

Summary Splenic vein occlusion caused by abdominal lymphadenopathy is rare. We herein present the case of a 80-year-old man with refractory isolated gastric variceal bleeding in the absence of pancreatic or liver disease. Left-sided portal hypertension was confirmed by angiography, and para-aortic lymphadenopathy compressing the splenic vein was identified by serial abdominal computed tomography. Endoscopic sclerosing therapy failed to treat the recurring gastric variceal hemorrhage. Therefore, splenectomy was suggested and the patient was successfully treated. The patient had been variceal bleeding free for 12 months since the surgery. In patients with isolated gastric varices but without advanced liver disease, a variety of diagnostic techniques should be attempted to elucidate the nature of portal hypertension, and left-sided portal hypertension should be suspected. For those cases in which endoscopic treatment failed to treat refractory gastric variceal bleeding, splenectomy can be an effective option.

Summary Hepatocellular carcinoma (HCC) is a leading cause of cancer in the world. The incidence is increasing by age. Radiofrequency ablation (RFA) is widely used for treatment of HCC especially for those in early stage. RFA have some advantages compare to surgery including lower cost, shorter hospital day and lower complication rate. However, there's still some rare but lethal RFA associated adverse events including cardiovascular complication. We hereby reported an elderly patient with HCC in left liver abutting the right atrium. The patient received monopolar RFA for treating HCC and had experienced pericardial effusion during RFA without immediate signs of cardiac tamponade. The HCC was successfully ablated without local recurrence and the pericardial effusion was spontaneously resolved without sequelae.

Summary Background/Aims Most benign gastric ulcers are healed through suppression of gastric acid by a proton pump inhibitor (PPI). Despite prolonged use of a PPI, some gastric ulcers still do not heal. The primary goal of this study is to investigate the relationship between the expression of connexin 32 (Cx32), a major gap junction protein expressed in the gastric mucosa, and the healing response of gastric ulcers. Methods Patients with endoscopically verified gastric ulcer were treated with a standard dose of PPI for 12 weeks. Histological studies were performed to exclude malignancy. In total, 10 patients having endoscopically verified gastric ulcers with delayed healing at the end of the PPI course were included in this study. The control group consisted of 11 patients with gastric ulcers that healed normally. The expression of Cx32 in the gastric mucosa of the ulcer margin was analyzed by immunoblotting. Results Patients with gastric ulcer showing delayed healing had significantly reduced Cx32 expression in the gastric mucosa compared with the patients in whom the ulcers healed normally (i.e., controls). Age, sex, presence of duodenal ulcers, location and size of gastric ulcer, ulcer staging, Helicobacter pylori infection, use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin, smoking, and alcohol consumption were similar in both the control and delayed healing groups. H. pylori infection, use of NSAIDs, smoking, and alcohol consumption all had no significant impacts on the expression of Cx32. Age and expression of Cx32 were not correlated. Conclusion Downregulation of Cx32 in the gastric mucosa of the ulcer margin may predict delayed healing in patients with gastric ulcer following acid-suppression therapy.

Background and aim. The treatment efficacy of peginterferon plus ribavirin for patients with HCV genotype 1 is inferior to that in patients with HCV genotype 2, but the efficacy among patients with mixed HCV genotype 1 + 2 is less clear. We compared the treatment outcome of peginterferon alpha-2b plus ribavirin among naive chronic hepatitis C patients in Taiwan with HCV genotype 1 and 2, and mixed genotype 1 + 2. Material and methods. In this retrospective cohort study, 150 patients were treated with peginterferon alpha-2b once weekly, plus ribavirin, for 24 weeks. The endpoint was sustained virological response after receiving at least one dose of the study medication. Results. There were no differences in clinical characteristics among the 3 groups. There were significant differences in rapid virological response rate between patients with genotype 1 and genotype 2 (64.7 vs. 85.5%, respectively; p < 0.05) and a sustained virological response rate (55.9 vs. 83.6%, respectively; p = 0.001). The rapid virological response rate differed between the genotype 1 and mixed genotype 1 + 2 groups (64.7 vs. 85.2%, respectively; p < 0.05), but the sustained virological response rate was similar (55.9 vs. 74.1%; p = 0.101). Conclusions. Using peginterferon alpha-2b plus ribavirin for 24 weeks to treat patients with HCV genotype 1 + 2 achieved a 74.1% sustained virological response rate; the treatment efficacy was not inferior to patients with HCV genotype 1, but the percentage of liver cirrhosis in mixed genotype 1 + 2 group was higher to 22%, it is worth to be appropriately valued and studied.

MicroRNAs are small RNAs involved in various biological processes and cancer metastasis. miR-196a was associated with aggressive behaviors in several cancers. The role of miR-196a in hepatocellular carcinoma (HCC) metastasis remains unknown. This study aimed to examine the role of miR-196a in HCC progression. Expression of miR-196a was measured in 83 human HCC samples. The HCC patients with high miR-196a expression had younger ages, lower albumin levels, higher frequency with alpha-fetoprotein (AFP) levels &ge, 20 ng/mL, more macrovascular invasion, and non-early stages. Kaplan&ndash, Meier analysis showed that high miR-196a expression was associated with lower recurrence-free survival. Knockdown of miR-196a decreased transwell invasiveness, sphere formation, transendothelial invasion, and Slug, Twist, Oct4, and Sox2 expression, suppressed angiogenesis, and reduced sizes of xenotransplants and number of pulmonary metastasis. Down-regulation of miR-196a decreased Runx2 and osteopontin (OPN) levels. Knockdown of Runx2 in vitro resulted in comparable phenotypes with miR-196a down-regulation. Restoration of Runx2 in miR-196a-knockdown HCC reverted tumor phenotypes. This study showed that high expression of miR-196a is associated with HCC progression in a subset of younger patients. miR-196a mediates HCC progression via upregulation of Runx2, OPN, epithelial&ndash, mesenchymal transition (EMT) regulators, and stemness genes. We proposed that miR-196a can be used as a prognostic marker and a potential therapeutic target.

Summary Ameboma is a rare presentation of intestinal amebiasis, which is caused by infection with Entamoeba histolytica . Amebomas are generally concentric and can be difficult to differentiate from carcinoma in the gastrointestinal tract, which are commonly seen in elderly patients. Radiological studies or colonoscopy can be difficult to provide the diagnosis. We present an elderly man with an ameboma in the ascending colon, which manifested as a submucosal tumor in the radiological or endoscopic studies. His serum antiamebic serology test was positive. He received surgery because of poor response to medical treatment. A full course of antiamebic therapy followed by a luminal agent were given and he had a smooth postoperative course without relapse of amebic infection. Although the elderly population has a higher incidence of colonic malignancy, ameboma should be considered in the differential diagnosis of submucosal tumors in the colon, especially in patients with an insidious onset of disease.

Treatment for hepatitis B virus infection reduces the risk of hepatocellular carcinoma (HCC). However, the long-term protective effects for subgroups of patients with chronic hepatitis B are unclear.We conducted a retrospective nationwide cohort study using data from Taiwan's National Health Insurance Research Database (from January 1, 1997, through December 31, 2010). Cumulative incidences were calculated and multivariable analyses were carried out after adjusting for competing mortality. Propensity scores were used to match 21,595 patients with chronic hepatitis B who received nucleoside analogue therapy for at least 90 days (treated cohort) with 21,595 untreated patients with chronic hepatitis B (controls), who received hepatoprotectants for at least 90 days. Data were collected from the treated cohort for a mean period of 3.46 years and from controls for 5.24 years.The treated cohort had a significantly lower 7-year incidence of HCC (7.32%; 95% confidence interval [CI], 6.77%-7.87%) than controls (22.7%; 95% CI, 22.1%-23.3%; P.001). After adjusting for competing mortality and other confounders, nucleos(t)ide analogue treatment was associated with a reduced risk of HCC, with an adjusted hazard ratio of 0.37 (95% CI, 0.34-0.39; P .001). Sensitivity analyses confirmed the association between nucleos(t)ide analogue treatment and reduced risk of HCC. Age, sex, cirrhosis, and diabetes mellitus modified this association.Based on a retrospective, nationwide study in Taiwan, nucleoside analogue therapy use is associated with reduced risk of HCC in patients with chronic hepatitis B virus infection.

Liver disease may become ameliorated in some patients with chronic hepatitis D virus (HDV) infection. We present here a study based on longitudinal sampling to investigate the viral dynamics in chronic HDV infection. We examined the HDV variants from different time points, especially those before and after the elevation of serum aminotransferase levels. The datasets from each patient were tested for positive selection by using maximum-likelihood methods with heterogeneous selective pressures along the nucleotide sequence. An average of 4.9%, ranging from 3.1 to 6.8%, of the entire delta antigen sites was regulated by a diversifying selection. Most of the positively selected sites were associated with immunogenic domains. Likelihood ratio tests revealed a significant fitness of positive selection over neutrality of the hepatitis delta antigen gene in all patients. We further adapted a neural network method to predict potential cytotoxic T ligand epitopes. Among the HLA-A*0201 cytotoxic T ligand epitopes, three consistent epitopes across all three genotypes were identified: amino acids (aa) 43 to 51, 50 to 58, and 114 to 122. Three patients (60%) had sites evolving under positive selection in the epitope from aa 43 to 51, and four patients (80%) had sites evolving under positive selection in the epitope from aa 114 to 122. The discovery of immunogenic epitopes, especially cytotoxic-T-lymphocyte ligands, associated with chronic HDV infection may be crucial for further development of novel treatments or designs in vaccine for HDV superinfection.

Background: An accurate staging system is required to assess hepatocellular carcinoma (HCC) patients in order to benefit from hepatic resection before surgery. Cancer of the Liver Italian Program (CLIP) score was considered to be better than the Okuda staging system to predict survival. Japan Integrated Staging Score (JIS score) includes tumor, nodes, metastases (TNM) stage and Child–Pugh grade as a new staging system for HCC. The purpose of the present paper was to compare the CLIP, Okuda, TNM and JIS staging systems for HCC patients undergoing surgery. Methods: From 1991 to 1995, 599 patients undergoing hepatic resection for HCC from four medical centers in Taiwan were evaluated. All patients were classified by Okuda, CLIP, TNM and JIS systems. Factors associated survivals were analyzed. Results: There was no statistical difference in survival between CLIP 0 and 1 patients, or among CLIP 2–4 patients. The prognostic validation of the Okuda and CLIP scoring systems in discriminating survival in HCC patients undergoing surgery was not satisfied. The TNM system was successful in predicting survival for HCC patients undergoing surgery. The JIS score could also differentiate survivals for those patients except for JIS 3. By multivariate analysis, age ≥60 years old, serum albumin 5 cm and TNM stage were associated with survival. Conclusion: Both the Okuda and CLIP systems are not superior to TNM staging for HCC patients who undergo surgical resection. Whether JIS score is feasible for those patients with advanced HCC needs further evaluation.

Purpose: The role of transcatheter arterial embolization (TAE) for patients with resectable hepatocellular carcinoma (HCC) is controversial. Analyzing a cohort of nation-wide data can delineate the beneficial effect of TAE for those patients. Methods: From 1991 to 1995, 818 patients who had potentially resectable HCC from four medical centers in Taiwan were enrolled. Among them, 599 underwent curative resection, 157 received TAE and 62 received supportive treatment alone. The survivals among the three groups were compared. Results: The 5-year survival rates for patients who underwent surgery, TAE and supportive treatment were 43.6%, 25.6% and 3.7%, respectively. Surgery offered the best survival for those patients. TAE could also prolong survival as compared with supportive treatment (P=0.0001). However, among patients who were in advanced tumor stage (Cancer and the Liver Italian Program (CLIP) score ≥2), no statistical difference in survival was noted between patients who underwent TAE or supportive treatment. In multivariate analysis, single tumor, serum albumin ≥3.5 g/dl, tumor size less than 5 cm, early-stage tumor (CLIP score=0–1) and aggressive treatment including surgery and TAE were independent factors associated with a better survival. Conclusions: Surgery is superior to TAE for patients with resectable HCC. In patients who refuse surgery, TAE can be considered for selected patients whose tumors are in early stage.

TO THE EDITOR: Invasiveness of Helicobacter pylori is potentially associated with persistence or treatment failure (1). H. pylori is reported to be ubiquitously distributed in the gastric intraepithelial, intercellular, and stromal spaces in patients with dyspepsia or gastric cancer (2). H. pylori may migrate transepithelially, disrupt tight junctions, make its way into intercellular spaces, and taint the lamina propria (2). Such invasiveness has not been described in a chronic gastric ulcer associated with H. pylori. We hereby report a case with a chronic gastric ulcer associated with intercellular invasion of H. pylori.

AIM: To verify whether “defective” mutations existed in hepatitis D virus (HDV). METHODS: Hepatitis delta antigen (HDAg)-coding sequences were amplified using Pfu DNA polymerases with proof-reading activities from sera of five patients with chronic hepatitis D. Multiple colonies were sequenced for each patient. Pfu analyzed a total of 270 HDV clones. Three representative defective HDV clones were constructed in expression plasmids and transfected into a human hepatoma cell line. Cellular proteins were extracted and analyzed by Western blot. RESULTS: Four of five cases (80%) showed defective HDV genomes in their sera. The percentage of defective genomes was 3.7% (10/270). The majority (90%) of the defective mutations were insertions or deletions that resulted in frameshift and abnormal stop translation of the HDAg. The predicted mutated HDAg ranged from 45 amino acids to >214 amino acids in length. Various domains of HDAg associated with viral replication or packaging were affected in different HDV isolates. Western blot analysis showed defected HDAg in predicted positions. CONCLUSION: “Defective” viruses do exist in chronic HDV infected patients, but represented as minor strains. The clinical significance of the “defected” HDV needs further study to evaluate.

Background and Aims: Radiofrequency ablation (RFA) can play an important role in the treatment of primary or metastatic liver tumors. Currently, percutaneous RFA is generally regarded as a safe, effective, and minimally invasive procedure. This study aimed to evaluate the presence and course of pleural effusion after monopolar RFA. Methods: From October 2008 to July 2013, a total of 54 patients (28 male and 26 female, mean age 65.2) treated with monopolar RFA were included in our study. 47 patients were diagnosed with hepatocellular carcinoma, 4 patients with hepatic metastasis, and 3 patients had other diagnoses. There were a total of 115 sessions of treatment and 199 liver tumors to be treated (1.73 ± 1.02 tumors treated per session). The tumor size ranged from 0.8 cm to 5.0 cm (mean 2.31 cm, standard deviation 1.04 cm). Thereafter, a follow-up ultrasound was performed within 24 hours subsequent to ablation to evaluate the presence of pleural effusion. The degree of pleural effusion was assessed by chest X-ray. Results: Fifteen (13.0%) treatment sessions in 14 patients showed right-sided pleural effusion after ablations. One patient had a large amount of effusion, while other patients manifested a minimal to small amount of effusion. There were 5 patients that experienced delayed resolution of pleural effusion; one patient (0.87%) had a minimal amount of pleural effusion even after one month. Overall, there was no pneumothorax, or periprocedural morality. Age, gender, tumor numbers, tumor sizes, and complete ablation of target tumors were similar among groups presenting with or without pleural effusion. Tumor locations associated with S78 segments abutting the diaphragm or right lobe of the liver were not associated with development of pleural effusion. Only the duration of ablation time had a marginal trend toward significance (p = 0.051). Conclusions: The transient appearance of right-sided pleural effusion after percutaneous RFA for hepatic malignancies was not infrequent. However, refractory pleural effusion was rare.