Integrative transcriptomic and genomic analyses unveil the IFI16 variants and expression as MASLD progression markers.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a broad and continuous spectrum of liver diseases ranging from fatty liver to steatohepatitis. The intricate interactions of genetic, epigenetic, and environmental factors in the development and progression of MASLD remain elusive. Here, we aimed to achieve an integrative understanding of the genomic and transcriptomic alterations throughout the progression of MASLD. APPROACH AND RESULTS: RNA-Seq profiling (n = 146) and whole-exome sequencing (n = 132) of MASLD liver tissue samples identified 3 transcriptomic subtypes (G1-G3) of MASLD, which were characterized by stepwise pathological and molecular progression of the disease. Macrophage-driven inflammatory activities were identified as a key feature for differentiating these subtypes. This subtype-discriminating macrophage interplay was significantly associated with both the expression and genetic variation of the dsDNA sensor IFI16 (rs6940, A>T, T779S), establishing it as a fundamental molecular factor in MASLD progression. The in vitro dsDNA-IFI16 binding experiments and structural modeling revealed that the IFI16 variant exhibited increased stability and stronger dsDNA binding affinity compared to the wild-type. Further downstream investigation suggested that the IFI16 variant exacerbated DNA sensing-mediated inflammatory signals through mitochondrial dysfunction-related signaling of the IFI16-PYCARD-CASP1 pathway. CONCLUSIONS: This study unveils a comprehensive understanding of MASLD progression through transcriptomic classification, highlighting the crucial roles of IFI16 variants. Targeting the IFI16-PYCARD-CASP1 pathway may pave the way for the development of novel diagnostics and therapeutics for MASLD.

Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The phase III STAH trial.

BACKGROUND & AIMS: Sorafenib is first-line standard of care for patients with advanced hepatocellular carcinoma (HCC), yet it confers limited survival benefit. Therefore, we aimed to compare clinical outcomes of sorafenib combined with concurrent conventional transarterial chemoembolization (cTACE) vs. sorafenib alone in patients with advanced HCC. METHODS: In this investigator-initiated, multicenter, phase III trial, patients were randomized to receive sorafenib alone (Arm S, n = 169) or in combination with cTACE on demand (Arm C, n = 170). Sorafenib was started within 3 days and cTACE within 7-21 days of randomization. The primary endpoint was overall survival (OS). RESULTS: For Arms C and S, the median OS was 12.8 vs. 10.8 months (hazard ratio [HR] 0.91; 90% CI 0.69-1.21; p = 0.290); median time to progression, 5.3 vs. 3.5 months (HR 0.67; 90% CI 0.53-0.85; p = 0.003); median progression-free survival, 5.2 vs. 3.6 months (HR 0.73; 90% CI 0.59-0.91; p = 0.01); and tumor response rate, 60.6% vs. 47.3% (p = 0.005). For Arms C and S, serious (grade ≥3) adverse events occurred in 33.3% vs. 19.8% (p = 0.006) of patients and included increased alanine aminotransferase levels (20.3% vs. 3.6%), hyperbilirubinemia (11.8% vs. 3.0%), ascites (11.8% vs. 4.2%), thrombocytopenia (7.2% vs. 1.2%), anorexia (7.2% vs. 1.2%), and hand-foot skin reaction (10.5% vs. 11.4%). A post hoc subgroup analysis compared OS in Arm C patients (46.4%) receiving ≥2 cTACE sessions to Arm S patients (18.6 vs. 10.8 months; HR 0.58; 95% CI 0.40-0.82; p = 0.006). CONCLUSION: Compared with sorafenib alone, sorafenib combined with cTACE did not improve OS in patients with advanced HCC. However, sorafenib combined with cTACE significantly improved time to progression, progression-free survival, and tumor response rate. Sorafenib alone remains the first-line standard of care for patients with advanced HCC. LAY SUMMARY: For patients with advanced hepatocellular carcinoma requiring sorafenib therapy, co-administration with conventional transarterial chemoembolization did not improve overall survival compared to sorafenib alone. Therefore, sorafenib alone remains the first-line standard of care for patients with advanced hepatocellular carcinoma. Clinical Trial Number: NCT01829035.

Tumor-to-muscle ratio of 8F-FDG PET for predicting histologic features and recurrence of HCC.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) recurrence is observed in up to 70-80% of patients despite a curative treatment. Microvascular invasion (MVI) and poor differentiation are strong risk factors for recurrence, but these cannot be known preoperatively. The aim of this study was to investigate the correlation of 18F-FDG PET with MVI and differentiation, and predictive role of tumor-to-background ratio of PET for recurrence in HCC. METHODOLOGY: Fifty-four patients had 18F-FDG PET/CT study before surgical resection as a first treatment of HCC between December 2008 and December 2012. We analyzed the predictive role of metabolic parameters of PET for recurrence of HCC. Maximal standardized uptake value, tumor-to-nontumor ratio, tumor-to-muscle ratio (TMR) and tumor-to-blood ratio were tested as metabolic index of 18F-FDG PET. RESULTS: Twenty-seven patients had increased uptake in preoperative PET and 14 (51.9%) of them experienced the recurrence. Increased uptake in PET and TMR were associated with MVI (p = 0.04, p = 0.005) and histologic differentiation (p = 0.018, p = 0.002). MVI was the only predictive factor for re- currence in multivariate analysis although TMR ≥ 6.36 showed a favorable result despite no statistical significance (p = 0.061). CONCLUSIONS: Increased 18F-FDG uptake of HCC, especially high TMR might be correlated with MVI and poor differentiation, and tends to have a risk for recurrence in HCC.

Identification of signature gene set as highly accurate determination of metabolic dysfunction-associated steatotic liver disease progression.

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by fat accumulation in the liver. MASLD encompasses both steatosis and MASH. Since MASH can lead to cirrhosis and liver cancer, steatosis and MASH must be distinguished during patient treatment. Here, we investigate the genomes, epigenomes, and transcriptomes of MASLD patients to identify signature gene set for more accurate tracking of MASLD progression. METHODS: Biopsy-tissue and blood samples from patients with 134 MASLD, comprising 60 steatosis and 74 MASH patients were performed omics analysis. SVM learning algorithm were used to calculate most predictive features. Linear regression was applied to find signature gene set that distinguish the stage of MASLD and to validate their application into independent cohort of MASLD. RESULTS: After performing WGS, WES, WGBS, and total RNA-seq on 134 biopsy samples from confirmed MASLD patients, we provided 1,955 MASLD-associated features, out of 3,176 somatic variant callings, 58 DMRs, and 1,393 DEGs that track MASLD progression. Then, we used a SVM learning algorithm to analyze the data and select the most predictive features. Using linear regression, we identified a signature gene set capable of differentiating the various stages of MASLD and verified it in different independent cohorts of MASLD and a liver cancer cohort. CONCLUSION: We identified a signature gene set (i.e., CAPG, HYAL3, WIPI1, TREM2, SPP1, and RNASE6) with strong potential as a panel of diagnostic genes of MASLD-associated disease.

Serological and molecular characteristics of the first Korean case of Echinococcus multilocularis.

In December 2011, we reported an autochthonous case of Echinococcus multilocularis infection in a 42-year-old woman in Korea. The diagnosis was based on histopathological findings of the surgically resected liver cyst. In the present study, we evaluated the serological and molecular characteristics of this Korean E. multilocularis case. The patient's serum strongly reacted with affinity-purified native Em18 and recombinant Em18 antigens (specific for E. multilocularis) but negative for recombinant antigen B8/1 (reactive for Echinococcus granulosus). In immunoaffinity chromatography, the serum also strongly reacted with E. multilocularis and only weakly positive for E. granulosus. We determined the whole nucleotide sequence of cox1 (1,608 bp) using the paraffin-embedded cystic tissue which was compared with E. multilocularis isolates from China, Japan, Kazakhstan, Austria, France, and Slovakia. The Korean case showed 99.8-99.9% similarity with isolates from Asia (the highest similarity with an isolate from Sichuan, China), whereas the similarity with European isolates ranged from 99.5 to 99.6%.

A case report of advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy and sorafenib combination therapy followed by metastasectomy of lung and muscle metastases.

Currently, various tyrosine kinase inhibitors and immune checkpoint inhibitors have been suggested in the treatment guidelines for advanced hepatocellular carcinoma (HCC). However, sorafenib was the only systemic drug approved 10 years ago. In 2010, a woman diagnosed with HCC rupture and multiple lung metastases visited our hospital. At the time of visiting our hospital, she had undergone transarterial chemoembolization at another hospital to control bleeding due to HCC rupture. We treated her with hepatic arterial infusion chemotherapy and sorafenib combination therapy to increase the control of intrahepatic tumors in consideration of the modest efficacy of sorafenib. The intrahepatic tumor was almost controlled. Metastasectomy was performed to control lung oligometastasis. Subsequently, additional muscle metastasis was confirmed, and metastasectomy was performed. Although this is a very rare case, it shows that a multidisciplinary approach can improve the prognosis of patients with HCC.

Selective and efficient retardation of cancers expressing cytoskeleton-associated protein 2 by targeted RNA replacement.

Human cytoskeleton-associated protein 2 (hCKAP2) is upregulated and highly expressed in various human malignances. hCKAP2 has microtubule-stabilizing characteristics and potentially regulates the dynamics and assembly of the mitotic spindle and chromosome segregation, indicating that hCKAP2 plays important functions during mitosis. In this study, we evaluated hCKAP2 as a plausible anticancer target through development and validation of a targeted cancer gene therapy strategy based on targeting and replacement of hCKAP2 RNA using a trans-splicing ribozyme. This targeted RNA replacement triggered transgene activity via accurate trans-splicing reaction selectively in human cancer cells expressing the hCKAP2 RNA and simultaneously reduced the expression level of the RNA in the cells. Adenoviral vector encoding the hCKAP2-specific trans-splicing ribozyme selectively induced cytotoxicity in tumor cells expressing hCKAP2. Moreover, intratumoral injection of the virus produced selective and efficient regression of tumor that had been subcutaneously inoculated with hCKAP2-positive colon cancer cells in mice with minimal liver toxicity. Furthermore, orthotopically multifocal hCKAP2-positive hepatocarcinoma established in mice were efficiently regressed by systemic delivery of adenoviral vector encoding the specific ribozyme under the control of a liver-selective phosphoenolpyruvate carboxykinase promoter with least hepatotoxicity. The results indicate that hCKAP2 RNA is a promising target for anticancer approach based on trans-splicing ribozyme-mediated RNA replacement.

Recurrent hepatic alveolar echinococcosis: report of the first case in Korea with unproven infection route.

Human alveolar echinococcosis (AE), a hepatic disorder that resembles liver cancer, is a highly aggressive and lethal zoonotic infection caused by the larval stage of the fox tapeworm, Echinococcus multilocularis. E. multilocularis is widely distributed in the northern hemisphere; the disease-endemic area stretches from north America through Europe to central and east Asia, including northern parts of Japan, but it has not been reported in Korea. Herein, we represent a first case of AE in Korea. A 41-year-old woman was found to have a large liver mass on routine medical examination. The excised mass showed multinodular, necrotic, and spongiform appearance with small irregular pseudocystic spaces. Microscopically, the mass was composed of chronic granulomatous inflammation with extensive coagulation necrosis and parasite-like structure, which was revealed as parasitic vesicles and laminated layer delineated by periodic acid-Schiff (PAS) stain. Clinical and histologic features were consistent with AE. After 8 years, a new liver mass and multiple metastatic pulmonary nodules were found and the recurred mass showed similar histologic features to the initial mass. She had never visited endemic areas of AE, and thus the exact infection route is unclear.

[Treatment efficacy of clevudine, entecavir and lamivudine in treatment-naive patients with HBeAg-positive chronic hepatitis B].

BACKGROUND/AIMS: clevudine is a potent antiviral agent that has demonstrated efficacy in patients with chronic hepatitis B. This study compared the efficacy of clevudine (C), entecavir (E) and lamivudine (L) in treatment-naive patient with HBeAg-positive chronic hepatitis B. METHODS: a total of 146 treatment-naive patients with HBeAg-positive chronic hepatitis B received clevudine, entecavir or lamivudine. C group (n=39) received 30 mg of clevudine, E group (n=39) received 0.5 mg of entecavir and L group (n=68) received 100 mg of lamivudine once a day for more than 48 weeks. The efficacy analysis estimated the mean changes of the HBV DNA levels as a virologic response, the normalization of the ALT levels (less than 35 IU/L) as a biochemical response and loss of HBeAg or seroconversion as a serologic response. The serum HBV DNA level was quantified by hybrid capture and real-time PCR assay. RESULTS: before the administration of clevudine, entecavir and lamivudine, the mean HBV DNA and ALT levels and the gender and age were well balanced among the three groups (p>0.05). For the virologic response at 48 weeks, the mean changes of the HBV DNA levels from baseline of the C, E and L groups were -3.8+/-2.2, -4.5+/-1.9 and -2.5+/-2.1 log copies/mL. C and E group showed superior antiviral activity compared to that of L group (p<0.0001), but no significant differences in antiviral response were noted between C and E groups. For the biochemical response at 48 weeks, the normalization of the ALT levels (less than 35 IU/L) among the C, E and L groups was 82%, 74% and 71%, respectively (p=0.46). The rates of undetectable serum HBV DNA (less than 300 copies/mL) of the C, E and L groups were 39%, 69% and 27%, respectively (p<0.0001). For the serologic response at 48 weeks, the loss of HBeAg was 13%, 31% and 24% and the seroconversion was 10%, 23% and 17%, respectively. There was no difference of efficacy among the three groups regarding ALT normalization or serologic response (p>0.05). Viral breakthrough in C group was noted at 24 weeks (5%) and 48 weeks (21%), but no biochemical breakthrough was noted. The elevation of the serum CK level was noted in only 1 patient of group C at 48 weeks (2.56%) after therapy. For the patients without or with liver cirrhosis (LC), C and E group showed superior antiviral activity compared to that of the L group, but the antiviral activity was more effective in non- LC group than LC group (p<0.0001 vs p=0.036). CONCLUSIONS: clevudine therapy compared with lamivudine for 48 weeks showed significantly potent antiviral efficacy in treatment-naive patients with HBeAg-positive chronic hepatitis B, and especially in the non-LC patients. However, the antiviral efficacy of clevudine was similar to that of entecavir even though taking into account relatively short follow up period and retrospective study.

[Clinical features of gas-forming liver abscesses: comparison between diabetic and nondiabetic patients].

BACKGROUND/AIMS: Patients with diabetes mellitus (DM) are more likely to have a pyogenic liver abscess with gas formation, which is associated with higher morbidity and mortality. The morbidity and mortality in pyogenic liver abscess are also higher in DM patients than in non-DM patients. This study evaluated the morbidity, mortality, and clinical features in patients with gas-forming liver abscesses associated with DM. METHODS: Among 379 cases of pyogenic liver abscess excluding malignancy from January 2001 through December 2009, 25 patients treated for pyogenic-gas-forming liver abscesses were reviewed retrospectively. We compared the morbidity, mortality, and clinical findings in patients with pyogenic-gas-forming liver abscesses between DM and non-DM patients. RESULTS: Gas formation was present in 25 (6.6%) of 379 cases with pyogenic liver abscess. DM was combined with gas-forming liver abscesses in 19 cases (76%). The most common organism responsible for the gas formation was Klebsiella pneumoniae (82%). Complications were present in 23 cases (92%) of gas-forming liver abscesses, with pulmonary complications (especially pleural effusion) being the most common (n=14, 61%). Four patients (16%) died of sepsis. CONCLUSIONS: Gas-forming liver abscesses are not uncommon in cases of pyogenic liver abscesses and are associated with high morbidity and mortality rates. The clinical manifestations and complications do not differ significantly between DM and non-DM patients.

Long-term outcomes of endoscopic submucosal dissection in gastric neoplastic lesions at a single institution in South Korea.

OBJECTIVE. Although endoscopic treatment for early gastric cancer (EGC) is an accepted therapy in South Korea and Japan, long-term outcomes remain unknown. We evaluated the clinical outcome of endoscopic submucosal dissection (ESD) for gastric dysplasia and EGC. MATERIAL AND METHODS. A total of 402 patients with gastric dysplasia and EGC were treated with ESD at a single hospital from January 2004 to December 2007. The patients underwent ESD and then received periodic endoscopic follow-up and metastatic surveys for 9-49 months (median 30 months). Resectability (en bloc or piecemeal resection), curability (complete or incomplete), local recurrence, and disease-free survival rates were estimated. RESULTS. There were 107 patients with low-grade dysplasia (LGD), 97 with high-grade dysplasia (HGD) and 198 with EGC. In EGC patients, en bloc resection was achieved in 89.7% (177/198), the complete resection rate was 87.9% (174/198), and the local recurrence rate was 5.1% (10/198). Tumor size >20 mm was significantly associated with local recurrence (odds ratio 6.45; 95% CI 1.20-20.11; p=0.001). There were significant correlations between the incidences of a piecemeal or incomplete resection and that of local recurrence (odds ratio 5.23; 95% CI 1.02-18.34; p=0.001; and odds ratio 6.99; 95% CI 1.22-21.65; p=0.002, respectively). The 3-year cancer-free survival rate was 94.9%. CONCLUSIONS. Curative treatment with successful en bloc resection can reduce the local recurrence of gastric neoplastic lesions after ESD. Clinical outcome may be excellent, although longer follow-up studies are warranted.

Risk factors for immediate and delayed bleeding associated with endoscopic submucosal dissection of gastric neoplastic lesions.

OBJECTIVE. Endoscopic submucosal dissection (ESD) of gastric neoplasia has been reported to have a higher bleeding rate than conventional endoscopic mucosal resection (EMR). The aim of this study was to identify the risk factors for bleeding associated with ESD. MATERIAL AND METHODS. The records of consecutive patients who underwent ESD for gastric adenoma/early gastric cancer were reviewed. Potential risk factors included patient age, lesion size, gross findings, location, and histology of the tumor. The primary end-point was the incidence of immediate or delayed bleeding related to ESD. RESULTS. A total of 144 patients were studied; bleeding occurred in 32 cases (22.2%) with immediate bleeding in 29 cases. Delayed bleeding (3 cases) occurred at day 2 (2 patients) and at day 7 in 1 patient. In all cases of immediate bleeding, immediate hemostatic therapy was successful. The histology of tumor was the only factor that was statistically significantly associated with bleeding (adjusted hazard ratio 6.770, 95% confidence interval 1.830-25.048, p=0.004). CONCLUSIONS. The only factor that correlated with an increased risk of bleeding with ESD was the presence of gastric malignancy. We found no factor that would, prospectively, be amenable to prevention of bleeding.

Diagnostic role and correlation with staging systems of PIVKA-II compared with AFP.

BACKGROUND/AIMS: Alpha-fetoprotein (AFP) and protein-induced by vitamin K absence or antagonist (PIVKA-II) are representative markers of hepatocellular carcinoma (HCC). The aim of this study was to evaluate the usefulness of PIVKA-II when compared with AFP for detecting HCC. Furthermore, we evaluated the correlation between PIVKA-II and HCC staging. METHODOLOGY: One hundred patients with liver cirrhosis (LC) and 227 with HCC were analyzed between January 2004 and March 2006. To compare the diagnostic value of PIVKA-II and AFP, Receiver operating characteristic curve was constructed. RESULTS: The area under the curve indicated a better accuracy for PIVKA-II than AFP in diagnosis of HCC (0.829 vs. 0.712). The positive rates of PIVKA-II in patients with tumor size larger than 5 cm, 3-5 cm, and less than 3 cm were higher than that of AFP (96%, 83%, 74% vs. 65%, 57%, 48%, respectively). In addition, there seems to be correlation between PIVKA-II and staging systems, Tumor Node Metastasis, Cancer of the Liver Italian Program score and Japan Integrated Staging score (p<0.05). CONCLUSIONS: The results of this study show that a PIVKA-II is a useful marker for detecting HCC, especially in small HCC and may have correlations with known staging systems.

[Predictive significance of serum IL-6, VEGF, and CRP in gastric adenoma and mucosal carcinoma before endoscopic submucosal dissection].

BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) is commonly used for radical resection of gastric adenoma and mucosal cancer, but there is about 30% of discrepancy rate between the histology of the endoscopic biopsy and that of the resected specimen obtained from the same lesion by ESD. The aim of this study was to clarify the clinical significance of IL-6, VEGF, CRP before ESD. METHODS: We investigated the correlation between serum IL-6, VEGF, CRP level and discrepancy rate of gastric neoplastic lesions (10 low-grade dysplasias, 18 high-grade dysplasias, and 25 early gastic cancers). RESULTS: Serum levels of IL-6 in gastric adenoma and mucosal cancer patients were significantly higher than in healthy controls (p<0.05). Especially, serum IL-6 level of high-grade dysplasia patient was significantly higher than low-grade dysplasia and mucosal cancer patients, and the positive rate, sensitivity, and negative predictive value of serum IL-6 levels were higher in high-grade dysplasia patient compared to low-grade dysplasia patient and mucosal cancer patient. Serum levels of VEGF in patients with gastric adenoma and mucosal cancer were significantly higher than healthy controls (p<0.01). Serum levels of CRP in patients with mucosal cancer were significantly higher than in the controls (p<0.05), and the positive rate, sensitivity, and positive predictive value of serum CRP levels were higher in high-grade dysplasia and mucosal cancer patients compared to low-grade dysplasia patient. CONCLUSIONS: Serum levels of IL-6, VEGF, and CRP in patients with gastric neoplastic lesions were significantly higher than healthy controls, especially, serum IL-6 level of high grade dysplasia patient was significantly higher than low-grade dysplasia and mucosal cancer patients.

Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial.

BACKGROUND: JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer. METHODS: Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10.9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial (standard 3x3 design; two to six patients for each dose with 12-18 estimated total patients). Patients received one of four doses of intratumoral JX-594 (10(8) plaque-forming units [pfu], 3x10(8) pfu, 10(9) pfu, or 3x10(9) pfu) every 3 weeks at Dong-A University Hospital (Busan, South Korea). Patients were monitored after treatment for at least 48 h in hospital and for at least 4 weeks as out-patients. Adverse event-monitoring according to the National Cancer Institute Common Toxicity Criteria (version 3) and standard laboratory toxicity grading for haematology, liver and renal function, coagulation studies, serum chemistry, and urinalysis were done. The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment. Data were also collected on pharmacokinetics, pharmacodynamics, and efficacy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00629759. FINDINGS: Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated (5.6 previous treatments, SD 2.8, range 2.0-12.0) and had large tumours (7.0 cm diameter, SD 2.7, range 1.8-10.9). Patients received a mean of 3.4 (SD 2.2, range 1.0-8.0) cycles of JX-594. All patients were evaluable for toxicity. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose; the MTD was therefore 1x10(9) pfu. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses; non-evaluable patients had contraindications to contrast medium (n=2) or no post-treatment scans (n=2). According to Response Evaluation Criteria in Solid Tumors (RECIST), three patients had partial response, six had stable disease, and one had progressive disease. INTERPRETATION: Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway.

Gene transfer using liposome-complexed adenovirus seems to overcome limitations due to coxsackievirus and adenovirus receptor-deficiency of cancer cells, both in vitro and in vivo.

Use of adenoviruses as vehicle for gene therapy requires that target cells express appropriate receptors such as coxsakievirus and adenovirus receptor (CAR). We show here that CAR-deficiency in cancer cells, that limits adenoviral gene delivery, can be overcome by using adenovirus complexed with the liposome, Ad-PEGPE [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly-ethylene glycol)-2000]. We first confirmed that CT-26 mouse colon cancer cells are deficient in CAR by RT-PCR, and then showed that CT-26 cells infected with Ad-GFP/PEGPE exhibited highly enhanced expression of green fluorescent protein (GFP), compared with those infected with Ad-GFP. GFP expression depends on the dose of liposome and adenovirus. Luciferase expression in livers treated with Ad-luc/PEGPE was about 1,000-fold less than those infected with Ad-luc. In a liver metastasis mouse tumor model developed by intrasplenic injection of CT-26 cells, luciferase expression following i.v. injection of Ad-luc/PEGPE was significantly higher in tumors than in adjacent non-neoplastic liver. Following systemic administration of Ad-GFP/PEGPE, GFP expression increased in tumors more than in adjacent liver while the reverse was true following administration of Ad-GFP. In the latter case, GFP expression was higher in liver than in tumors. This study demonstrates that systemic delivery of PEGPE-adenovirus complex is an effective tool of adenoviral delivery as it overcomes limitation due to CAR deficiency of target cells while reducing hepatic uptake and enhancing adenoviral gene expression in tumors.

[Clinical outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C].

BACKGROUND/AIMS: The purpose of this study is to elucidate the efficacy and safety of combined peginterferon and ribavirin therapy in Korean patients with chronic HCV infection. METHODS: We retrospectively analyzed the clinical records of 84 patients. Thirty five patients with genotype 1 HCV infection were treated with peginterferon alpha-2a 180 microg/week and ribavirin 1,000-1,200 mg/day for 48 weeks, and 49 patients with genotype non-1 were treated with peginterferon alpha-2a 180 microg/week and ribavirin 800 mg/day for 24 weeks. RESULTS: An early virologic response was seen in 87.0% of patients with genotype 1 HCV. An end of treatment response (ETR) was seen in 82.6% and 97.6% of patients with genotype 1 and genotype non-1, respectively. An overall sustained virologic response (SVR) was seen in 53 patients (82.8%) of the 64 patients: in 16 (69.6%) of 23 patients with genotype 1 and in 37 (90.2%) of 41 patients with genotype non-1. An end of treatment biochemical response was seen in 58 patients (90.6%) [genotype 1, 20 patients (87.0%); genotype non-1, 38 patients (92.7%)], and a sustained biochemical response was achieved in 49 patients (76.6%) [genotype 1, 14 patients (60.9%); genotype non-1, 35 patients (85.4%)]. Independent factors affecting an SVR were HCV genotype and the baseline HCV RNA level. CONCLUSIONS: This study shows that a combination therapy of peginterferon and ribavirin is highly effective for chronic HCV infection, producing a high SVR and ETR.

Mushroom Poisoning by Macrolepiota neomastoidea.

There are currently over 5,000-known species of mushrooms worldwide. Only 20-25% of mushrooms have been named, and 3% of these are poisonous. More than 95% of mushroom poisoning cases occur due to difficulties associated with the identification of mushroom species. Most of the fatal mushroom poisoning cases recorded to date have been related to the Amanita species. Until now, a case of fatal poisoning caused by Macrolepiota neomastoidea (M. neomastoidea) has not been reported in Asia. A 57-year-old male patient was admitted to the emergency room with nausea, vomiting, diarrhea, and abdominal pain. He reported ingesting wild mushrooms with his mother and sister about 2 days ago. His mother and sister were treated with only supportive care, but he was admitted to the intensive care unit and underwent liver transplantation due to acute liver failure. We are reporting a case of fatal M. neomastoidea intoxication from wild mushrooms, a rare case of mushroom poisoning.

[Endoscopic submucosal dissection for early gastric cancer and gastric adenoma].

BACKGROUND/AIMS: Endoscopic Submucosal Dissection (ESD) is a new endoscopic mucosal resection (EMR) technique which enables en bloc resection even in large and depressed lesions. The aims of this study were to assess the therapeutic efficacy and the safety of ESD in gastric adenoma and in early gastric cancer (EGC). METHODS: We analyzed 101 lesions in 101 patients. ESD with insulated-tipped (IT) knife were performed in 52 adenomas and 49 EGCs from January 2003 to December 2005 in Dong-A University Hospital. RESULTS: The mean size of the lesion was 2.58 cm (0.7-4.5 cm). En bloc resection rate was 90.1% which was influenced by size (p0.05). Complete resection rate was 83.2% even in large or in malignant tumors (p0.05). Bleeding after ESD occurred in 41.6%. Tumor recurrence rate was 2.0%. CONCLUSIONS: ESD with IT knife is effective for the treatment of EGC and gastric adenoma even in large or in malignant lesions without definite increased risk of complications.

[Prognostic factors for survival in patients with hepatocellular carcinoma after radiofrequency ablation].

BACKGROUND/AIMS: Currently there is no consensus on which staging system is the best in predicting the survival of patients with hepatocellular carcinoma (HCC). The aim of this study was to identify independent factors to predict survival and to compare 4 available prognostic staging systems in patients with early HCC after radiofrequency ablation. METHODS: We retrospectively studied 100 Korean patients with early HCC. Prognostic factors for survival were analysed by univariate and multivariate analysis using the Kaplan-Meier method and Cox proportional hazard regression models. Okuda, Cancer of the Liver Italian Program (CLIP), TNM and Japanese integrated staging score (JIS score) were evaluated before the treatments. RESULTS: Overall survival rates of 12, 24 and 36 months were 89%, 76%, and 64% respectively and the mean survival duration was 45 months. Multivariable analysis showed that albumin, total bilirubin and size of tumor were independent prognostic factors. Multivariate analysis showed that TNM and JIS score staging systems were significant staging systems for the prediction of prognosis. CONCLUSIONS: Both TNM and JIS score are more effective than the Okuda and CLIP staging systems in stratifying patients into different risk groups with early HCC. However, JIS score gives better prediction of prognosis in patients with HCC after radiofrequency ablation.