An advantage of this new model is the ability to switch off transgene expression. Doxycycline withdrawal in Fra-1tetON mutant mice led to decreased cholestasis and regression of liver fibrosis. Such “transgene addiction” demonstrates the requirement for Fra-1 to maintain the cholestasis phenotype and provides a rationale for experimentally addressing the functional relevance of Fra-1 in clinical cholestasis and liver fibrosis, identifying

Fra-1′s transcriptional targets, and examining its role in regression of selleck chemicals llc fibrosis and elimination of fibrogenic myofibroblasts. Through a careful analysis of Fra-1 knockout and Fra-1 hepatocyte-specific and general overexpressing mice, combined with chromatin and transcriptional analysis, relevant Fra-1-regulated genes were identified. These included induction of the fibrogenic gene, osteopontin (opn), and inhibition of the antifibrotic gene, cxcl9, in hepatocytes. Interestingly, overexpression of Fra-1 only in hepatocytes is not sufficient to induce cholestasis and liver fibrosis, suggesting that Fra-1 overexpression

HM781-36B cell line in other cells, such as cholangiocytes or myofibroblasts, is required for cholestasis and fibrosis. Further studies are required to identify the origin and fate of the fibrogenic myofibroblasts in this reversible model of cholestatic liver injury and fibrosis.[9] Cholestasis and hepatotoxicity are counteracted by protective

mechanisms, including modulating transport and detoxification of bile acids and xenobiotics. For example, glutathione S-transferases (GSTs) catalyze the conjugation of toxic compounds with reduced glutathione, thus facilitating their biliary secretion. In additional experiments, the overexpressing Fra-1 mutant mice were protected from 3,5-diethoxycarbonyl-1,4-dihydrocollidine- this website and acetaminophen (APAP)-induced liver injury. The proposed mechanism is that GSTP1 (glutathione S-transferase pi 1) is up-regulated by the AP-1 transcription factor, cJun/Fra-1, thus increasing the detoxification of APAP. This effect is unique to Fra-1, because Fra-1-deficient mice had increased sensitivity to APAP hepatotoxicity, whereas Fra-2-overexpressing mice were not protected. Further elucidation of the genetic and cellular targets of Fra-1 that produce hepatoprotection in some situations, but increased hepatic injury in others, should provide new insights into the complex role of AP-1 in liver disease and the potential role of inhibitors of the signaling pathway in the treatment of specific liver diseases. David A. Brenner, M.D. “
“CD81 is a required receptor for Hepatitis C virus (HCV) infection of human hepatocytes in vitro. We generated several high affinity anti-human CD81 monoclonal antibodies (mAb) that demonstrated potent, specific and cross-genotype inhibition of HCV entry.

4,5,23 Certain morphological features have been used to predict particular types of pancreatic cysts. A cystic lesion with accompanying parenchymal changes, in the absence of intracystic septation or mural nodule, suggests a pseudocyst.24 The finding of multiple microcysts (< 3 mm) within a cystic lesion is suggestive of SCA.32 Occasionally, there might be a honeycomb-like area that is solid due to aggregation of small cysts in a part of the lesion.

A macrocystic-type serous cystic neoplasm might see more present with multiple lobules (Fig. 1), as in IPMN, making it difficult to differentiate between the two. If a communication between the cyst and the main pancreatic duct can be identified, that strongly suggests IPMN. On EUS, MCN usually appears as a cyst with septations of variable thickness, a visible wall, and peripheral calcifications in up to 15% of cases.33 More data have recently emerged on the role of EUS for the differentiation between benign and malignant pancreatic cysts. The clinicopathological features suggestive of malignant mucinous

cystic tumors of the pancreas that have been cited to date are shown in Table 2.6–9,28,34,35 A cyst diameter PXD101 order of greater than 3 cm was shown in a few studies to be associated with malignancy. The diameter of the main pancreatic duct that was shown to be associated with malignancy ranged widely from 5 to 15 mm, possibly

because the measurement might also include main pancreatic duct IPMN in some cases, but not in others. However, the size of the cystic lesion and main pancreatic duct diameter was not different between benign and malignant IPMN in one click here study.33 If patients were to be managed by cyst size alone, approximately 20% would have received inappropriate treatment. Therefore, some authors recommended that the size of pancreatic cystic lesions alone should not be used a sole basis for determining management.36,37 Furthermore, a study reported considerable variation in size estimates of pancreatic cysts by the different imaging modalities of CT, MRI/MRCP, and EUS, which clinicians should take into account when making management decisions, and follow up of pancreatic cysts should be with the same imaging modality, if possible.38 Thus, further studies using standardized criteria for measurements of pancreatic cystic lesions are needed to resolve this issue. Apart from cyst size, many studies have reported the index of malignancy based on the presence and size of nodules within the cysts (Fig. 2). Baba et al.

A greater proportion of participants in the lifestyle intervention group (11/18, 61%) had 3 or more points’ reduction in overall NAS from baseline than participants in the control group (2/10, 20%) (P = 0.04). Selleckchem Alvelestat Similarly, at the end of the study period, a higher proportion of participants in the lifestyle intervention group had NAS of 2 or less and no longer met minimal histological criteria for NASH as compared with the control group (67% versus 20%, P = 0.02). Overall, 13 of 18 (72%) participants in the lifestyle intervention

group versus 3 of 10 (30%) participants in the control group had achieved the study end point (P = 0.03). The three subjects in the control group who achieved the study histological end point had a variable degree of weight change (−6.0%, +0.9%, and +9.8%). Two had diabetes (one was taking metformin, and none were taking thiazolidinediones). Two participants were obese (one class I and one class II obesity), and two fulfilled criteria for the metabolic syndrome. One participant who lost 6% of body weight had normalization of transaminases. Participants who achieved study weight loss goal (≥7%) had significant improvements in steatosis, parenchymal inflammation, ballooning injury, and overall NAS in comparison with those who did not achieve study weight loss goal (Table 4; all P < 0.05). There was no improvement in fibrosis score in those who lost at least 7% compared with DNA Synthesis inhibitor those

who lost less than 7% of body weight check details (P = 0.10). There was a significantly greater reduction in ALT levels in the lifestyle group in comparison with the control group. The mean reduction in ALT levels (SD) over the 48-week period were 42.4 (39.9) U/L (from 84 to 42 U/L) in the lifestyle group and 16.5 (36.6) (from 86 to 69 U/L) in the control group (P = 0.01) (Table 2; Fig. 3) Normalization of ALT occurred in 12 of 20 (60%) of the participants in the lifestyle group and 3 of 10 (30%) in the control group (P = 0.12). AST levels decreased in both groups over the study period (20.2 [22.8] U/L in the lifestyle group and 18.0 [44.3] U/L in the control group). There was

no statistical difference in AST reduction between the two groups (P = 0.11). Percent weight reduction from baseline correlated significantly with improved liver chemistry (ALT values) (r = 0.496, P = 0.005), improvements in the degree of hepatic steatosis (r = 0.616, P < 0.001), and overall NASH disease activity (r = 0.497, P = 0.007) (Fig. 4). There were no adverse events related to the weight loss interventions. Two participants had abdominal pain after liver biopsy, but none had internal bleeding or perforation of visceral organ. A major problem in the management of NASH is the lack of effective therapy.5 Weight reduction through diet and exercise has been promoted as initial therapy for NASH; however, there is very little evidence to support the effectiveness of this approach.

Although autophagy

has been reported to paradoxically promote cell survival and death during tumor development and in cancer therapy,27 our results demonstrate that HDAC6 functions as a tumor suppressor by activating autophagic cell death in liver cancer. Earlier studies on the mechanism underlying the regulation of autophagy in cancer cells showed that autophagy is regulated by multiple diverse signaling pathways, such as the class II PI3K, the protein kinase mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK), and the p38 pathways.26 In this regard, we noted with interest a report that the activation of JNK can mediate Beclin 1 expression, which see more is known to play a key role in the autophagic cell death of cancer cells.21 Concordantly, Beclin 1 expression was found to be induced

in mouse xenograft tumor tissues injected with HDAC6-overexpressing Hep3B cells (Fig. 6F). It was also found that sustained expression of HDAC6 induced Beclin 1 expression, whereas its resilencing suppressed Beclin 1 induction and autophagy, as determined by reduced LC3B-II conversion in Hep3B_HDAC6 Clone #1 and Clone #2 cells (Fig. 7A,B). AT9283 mouse Thus, we postulated that HDAC6 could activate the JNK pathway and mediate Beclin 1-dependent autophagy in liver cancer cells. To clarify this hypothesis, we focused on the relationships between JNK pathway activation and Beclin 1 expression in HDAC6-induced autophagy, and demonstrated that during HDAC6-induced autophagy the JNK pathway is activated in liver cancer cell lines, and that this induced Beclin 1 expression. On the other hand, the JNK-specific inhibitor SP600125 and HDAC6 knockdown inhibited Beclin 1 induction and autophagy activation (Fig. 8). Moreover, we observed that c-Jun was also involved

in the regulation of Beclin 1 in response to HDAC6-induced autophagy. These results suggest a novel mechanism for the regulation of Beclin 1 expression in HDAC6-induced autophagy in liver cancer. Although it is not clear whether HDAC6 directly activates JNK/c-Jun signaling, it is obvious that selleck HDAC6 causes autophagic cell death by way of JNK-mediated Beclin 1 expression in liver cancer cells. Taken together, the present study shows that HDAC6 expression is suppressed or lost in HCC, and that the ectopic expression of HDAC6 inhibits in vitro and in vivo tumor growth by promoting autophagic cell death and by activating a JNK-mediated Beclin 1 pathway. Future detailed analyses of the molecular mechanisms governing HDAC6 inactivation should illustrate how HDAC6 influences the balance of autophagic signals. Here, we propose for the first time that HDAC6 functions as a tumor suppressor by activating caspase-independent autophagic cell death during hepatocarcinogenesis, and thus, our findings might support the clinical potential of HDAC6 for the treatment of liver cancer.

Overall, 51% of

InC3 participants were IL28B CC positive, and in the subpopulation studied 52% (139/267) were CC positive. Among 137 with SI, 56% were IL28B CC compared to 46% of asymptomatic patients in models adjusting for age and sex (Adjusted odds ratio [AOR] 0.7, 95% CI: 0.4, 1.1). 64% of patients with jaundice were IL28B CC genotype compared to 42% of those without jaundice (AOR 0.3, 95% CI:0.1, 0.9).69% of patients with elevated ALT were IL28B CC positive compared to 43% of those without elevated ALT (AOR 0.3, 95% CI: 0.2,0.6). Conclusions: IL28B CC genotype is associated selleck chemicals with elevated ALT and jaundice during acute HCV infection among patients with seroconversion illness. The association between symptoms of acute HCV and clearance reported in many studies may be related to IL28B status. Disclosures: Barbara H. McGovern – Employment: AbbVie Jason Grebely – Advisory Committees or Review Panels: Merck, Merck, Merck, Merck; Grant/Research Support: Merck, Merck, Merck, Merck Arthur Y. Kim – Consulting: Abbvie Pharmaceuticals, Gilead Pharmaceuticals; Grant/Research Support: Bristol-Myers Squibb Maria Prins – Speaking and Teaching: msd, roche Gregory J. Dore Sirolimus ic50 – Board Membership: Bristol-Myers Squibb, Roche, Gilead, Merck, Janssen, Abbvie; Grant/Research Support: Janssen, Bristol-Myers Squibb, Vertex, Roche, Gilead, Merck, Abbvie; Speaking

and Teaching: Roche, Merck, Janssen The following people have nothing to disclose: Kimberly Page, Jennifer Evans, Meghan D. Morris, Andrea Cox, Thomas M. Rice,

Rachel Sacks-Davis, Margaret Hellard, Julie Bruneau, Naglaa Shoukry, Lisa Maher, Andrew R. Lloyd Background and aims: NK cells display anti-fibrotic activity via killing of activated hepatic stellate cells (HSC). NK cell function is regulated by cross-talk with other immunocompetent cells as well as soluble factors. Recently, we demonstrated that regulatory T cells in hepatitis C produce high amounts of IL-8 and induce up-regulation of profibrogenic learn more markers in human primary HSC (Langhans et al., J Hepatology 2013). Here, we analyzed in vitro whether stimulation of human primary HSC with profibrogenic cytokines results in altered activation of NK cells. Methods: Human primary HSC (ScienCell Research Laboratories) were pre-cultured in vitro in the absence or presence of recombinant IL-8 or IL-10 (0–100 ng/ml each). HSC were co-cultured with purified peripheral NK cells from healthy donors at 1:1 ratio. After 24 hours activation of NK cells was determined by flow cytometric analysis of NK cell degranula-tion (CD107a expression). Results: Compared to untreated HSC, CD107a expression of CD56brightCD16negative NK cells was significantly reduced in co-cultures using IL-8 pre-treated HSC (p>0,005). Reduced NK cell degranulation was dose dependent.

Cookson, Shannon Lauriski Background: Over 2500 HCV genotype (GT) 1-infected patients have been treated with ombitasvir/ABT-450/r and dasabuvir (3D) ± ribavirin (RBV) in 2 Phase 2 (M13-386 and AVIATOR) and 6 Phase 3 (SAPPHIRE-I, SAPPHIRE-II, PEARL-II, PEARL-III, PEARL-IV, and TURQUOISE-II) clinical trials. Seventy-four patients experienced virologic failure (VF) in these studies, and were evaluated for the presence

of resistance-associated variants (RAVs) at baseline and at the Ponatinib mouse time of VF. Methods: Baseline polymorphisms and treatment-emergent variants in HCV NS3, NS5A and NS5B from patients who experienced VF were analyzed by population sequencing. The number and percentage of subjects with baseline RAVs was compared between subjects experiencing VF and subjects who achieved sustained virologic response (SVR) by chi-square test. Results: Baseline sequencing was conducted on a subset

of samples comprising over 700 GT1a and 1b-infected patients. Baseline RAVs in either GT1a or 1b in NS3 were rare (<1%); baseline RAVs in NS5A were observed in 12.5% of GT1a and 7.5% of the GT1b samples; baseline RAVs in NS5B were observed in 5.2% of GT1a and 28.6% of the GT1b samples; no subject had baseline Alvelestat RAVs in all 3 targets. The presence of baseline RAVs had no impact on treatment outcome. Among patients receiving the 3D ± RBV regimens in the Phase 2/3 clinical trials, 67 GT1a-infected patients experienced

VF including 18 patients who experienced on-treatment breakthrough and 49 who relapsed; and 7 GT1b-infected patients experienced VF including 2 patients who experienced on-treatment breakthrough and 5 who relapsed. At the time of VF, the predominant RAVs in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The predominant RAVs in GT1b were Y56H+D168V in NS3, Y93H in NS5A, and S556G in NS5B. Among patients see more who experienced VF, 39 GT1a- and 4 GT1b-infected patients had RAVs in all 3 targets; 15 GT1a- and 1 GT1b-infected patient had RAVs in any 2 targets; 4 GT1a-infected patients had RAVs in only 1 target; while 9 GT1a- and 2 GT1b-infected patients had no RAVs in any target. Long-term studies to monitor persistence of these variants are ongoing. Conclusions: In the 3D ± RBV regimens, the virologic failure rate was very low (3.0%). Of the 74 patients who experienced VF, 43 had RAVs in all 3 targets, while 11 had no RAVs in any target.

The researchers performed a thorough evaluation of the integration events from 38 mice that were serially transplanted. The data obtained by ligation-mediated polymerase chain reaction and 454 Life Sciences pyrosequencing of repopulated livers implies a polyclonal distribution, not clonal dominance, of LV-transduced hepatocytes. The researchers also noted

that approximately 4% of the integration events were located next to genes with a potential cancer risk; these clonal events could provide a rich source of data for future investigations. It would also be interesting to examine the integration profile and clonality in Fah(−/−) mice that are repopulated with LV-transduced human hepatocytes to determine whether HIF activation any species differences are observed. Overall, this study nicely complements a growing body of work that indicates that gene therapy in adult animals with LV is not genotoxic, even in disease models. Furthermore, these data suggest that the liver is a safe target organ for gene therapy, because treatment with the latest-generation LV has a low risk of inducing tumor formation through insertional

mutagenesis. Although each disease and therapeutic vector is different and every treatment option will need to be independently evaluated for safety and efficacy, it appears that hepatic gene therapy is, once more, a promising possibility. “
“Ribavirin, a synthetic nucleoside analogue, is used in Selleck Barasertib combination with pegylated interferon-α (IFN-α) as the standard of care for the treatment of patients with chronic hepatitis C. The combination of ribavirin significantly improves the sustained virologic response of IFN-α therapy, but the exact mechanism remains enigmatic.1 Although ribavirin monotherapy appears to have only limited clinical efficacy,1, 2in vitro studies have shown that ribavirin by itself has a remarkable broad antiviral activity, equivalent

to IFNs, against a spectrum of RNA and DNA viruses.3 Now, an exciting new study by Thomas et al. in HEPATOLOGY4 shows that ribavirin treatment induces the expression of particular IFN-stimulated genes selleck kinase inhibitor (ISGs), including IRF7 and IRF9, thereby potentiating the antiviral action of IFN-α in hepatitis C virus (HCV) cell culture models. Because the transcription factors IRF7 and IRF9 are known to be critical for antiviral defenses, including against HCV, the authors conclude that antiviral action of ribavirin alone1, 2 and in particular in combination with IFN-α4 acts via the induction of ISGs. This study supports earlier clinical evidence by the same group that patients receiving ribavirin in addition to IFN-α had a more rapid and higher elevation of the IFN-induced cytokine, IFN-inducible protein 10/chemokine (C-X-C motif) ligand 10.

Stomach tissue was stained with haematoxylin and eosin (HE) and measured for mucosal thickness and carcinogenesis. Serum gastrin concentrations

were analyzed using ELISA. The expression of B-cell lymphoma/leukemia 2 gene (Bcl-2), and proliferating cell nuclear antigen (Ki-67) were examined with immunohistochemical (IHC) staining. Results: No gastric cancer was found in group G. The incidence of gastric cancer was higher in group MG (45.28%) than in group M (25%) (P=0.044). After 48 weeks, group G had significantly thickened mucosa compared with group A (P<0.05). Gastric cancer formed in animals that had higher serum gastrin concentrations than that in no carcinogenic animals both in group M and group MG(P<0.05).In malignant tissue, Bcl-2, and Ki-67 levels were ABT-199 supplier significantly higher in group MG than in group M (P<0.05). Conclusion: Gastrin had synergistic effects on the development of gastric cancer induced by MNNG. Gastrin may act by promote cell proliferation, http://www.selleckchem.com/products/LDE225(NVP-LDE225).html and to inhibit apoptosis. Key Word(s): 1. gastrin; 2. gastric cancer; 3. MNNG; 4. hypergastrinemia; Presenting Author: TING LI Additional Authors: FANG WANG, BIN ZHANG, HONG LI, QIONG WU, LI YANG, YONGZHAN NIE, KAICHUN WU, YONGQUAN SHI, DAIMING FAN Corresponding Author: LI YANG, YONGQUAN SHI Affiliations: Xijing Hospital of Digestive Diseases; Department of Gastroenterology Objective: Multidrug resistance (MDR) is the major reason

for the failure of gastric see more cancer chemotherapy. Cytological basis of MDR was intricate, involving multiple processes including dysregulation of microRNAs (miRNAs). Members of miR-17-92 cluster including miR-19a/b were considered as oncomiRs influencing multiple malignant phenotypes of gastric cancer.

However, the role of miR-19a/b in MDR of gastric cancer and its underlying mechanism remains unclear. Methods: Expressions of miR-19a/b were examined in multidrug-resistant gastric cancer cell lines by quantitative Real Time-PCR. miR-19a/b mimics and inhibitor were used to establish gain-of or loss-of-function models in SGC7901 or its MDR variants. The influence of miR-19a/b on the sensitivity of gastric cancer cells to anticancer drugs were investigated by MTT and colony forming assay. The effects of miR-19a/b on drug efflux were determined by fluorescence intensity assay of intracellular adriamycin (ADR). The effects of miR-19a/b on drug induced apoptosis were evaluated by Fluorescence activated cell sorting assay. PTEN, AKT and the proteins related to drug efflux and cell apoptosis were examined by qRT-PCR and western blot. Results: miR-19a/b was found to be upregulated in MDR variants SGC7901/ADR and SGC7901/VCR compared with their parental cells SGC7901. Overexpression of miR-19a/b decreased the sensitivity of gastric cancer cells to anticancer drugs and vice versa. miR-19a/b upregulation accelerated the efflux of ADR in gastric cancer cells by increasing mdr1 and P-gp levels.

Discoveries in migraine pathophysiology have given us better understanding of the complex processes involved, although there remain many unknown factors in migraine treatment. Additional, unrecognized therapeutic

targets may exist throughout the neuronal connections of the brainstem, cortex, and cerebral vasculature. Ergots interact with a broader spectrum of receptors than triptans. This lack of receptor specificity explains potential ergot side effects, but may also account for efficacy. The role of ergots in headache should be revisited, especially in view of newer ergot formulations with improved Saracatinib tolerability and side effect profiles, such as orally inhaled dihydroergotamine. Redefining where in the headache treatment spectrum ergots belong and deciding when they may be the optimal choice of treatment is necessary. “
“Objective.— The study aimed to evaluate the effects of salivary stimulation therapy on the salivary flow, quality of saliva, and symptoms in patients with burning mouth syndrome (BMS). Background.— BMS

is a chronic disorder characterized by a burning selleck screening library sensation. Some reports have proposed a role for saliva in the pathogenesis of BMS. Methods.— Twenty-six BMS patients underwent treatment with salivary mechanical stimulation. Resting and stimulated saliva were collected before and after therapy. Salivary levels of total protein, brain-derived neurotrophic factor, interleukin-10, tumor necrosis factor-α, interleukin-6, and nerve growth factor were assessed before and 90 days after therapy by enzyme-linked immunosorbent assay. Results.— A significant reduction in the burning sensation and number of burning sites as well as an improvement of taste disturbances and xerostomia were selleck compound observed after therapy. The salivary flow was not significantly modified. However, the therapy resulted in a significant decrease in salivary levels of total protein and

an increase of tumor necrosis factor-α. Conclusion.— Salivary mechanical stimulation therapy is effective in reducing clinical symptoms of BMS. “
“Objective.— To describe the syndrome of migraine with binocular blindness. Background.— Rarely do migraine patients complain of losing vision in both eyes during an attack of headache. There are no large clinic-based studies looking at the prevalence of binocular blindness in migraine sufferers and no information about patient demographics, neuroimaging, and laboratory testing. Methods.— Over a 14-month time period, 383 new patients with a diagnosis of migraine were seen at the Geisinger Headache Center. All patients were asked if they ever experienced an episode of complete bilateral blindness along with their headaches. Those with a positive history had coagulopathy testing as well as brain magnetic resonance imaging and magnetic resonance angiography of the intracranial circulation. Results.— A total of 6 patients or only 1.6% of the new migraine patients had episodes of binocular blindness with their headaches.

17 HCV-RNA was determined using the COBAS TaqMan HCV test (Roche Diagnostics, Basel, Switzerland). The serum samples stored at −80°C before IFN therapy were used. The linear dynamic range of the assay was 1.2-7.8 log IU/mL, and the undetectable samples were defined IDH inhibitor review as negative. A sustained virological response (SVR) was defined as clearance of HCV-RNA using the COBAS TaqMan HCV test 6 months after

the cessation of IFN therapy. Status of liver was mainly determined on the basis of peritoneoscopy and/or liver biopsy. Liver biopsy specimens were obtained using a modified Vim Silverman needle with an internal diameter of 2 mm (Tohoku University style; Kakinuma Factory, Tokyo, Japan), fixed in 10% formalin, and stained with hematoxylin and eosin, Masson’s trichrome, silver impregnation, and periodic acid-Schiff after diastase digestion. The size of specimens for examination was more than six portal areas.18 The observation BTK inhibitor ic50 starting point was 6 months after the termination of IFN therapy. After that, patients were

followed up at least twice a year in our hospital. Physical examination and biochemical tests were conducted at each examination together with a regular checkup. In addition, annual examinations during follow-up were undertaken. When a patient had complaints during follow-up, the physician click here in charge performed additional examinations based on symptoms.

Four hundred eighteen patients were lost to follow-up. The final date of follow-up in 418 patients with loss of follow-up was regarded as the last consulting day. In addition, 881 patients were retreated with IFN. The final date of follow-up in 881 patients re-treated with IFN were regarded as the time of the initiation of IFN retreatment. Thus, 418 patients with loss of follow-up and 881 patients retreated with IFN were counted censored data in statistical analysis.19 The mean follow-up period was 6.8 (SD 4.3) years in 418 patients with loss of follow-up and 7.5 (SD 4.8) years in 881 patients retreated with IFN. Censored patients were counted in the analysis. Clinical differences among three groups of patients with HCC with malignancies other than HCC without events were evaluated using the Kruskal-Wallis test. The cumulative development rates of malignancies were calculated using the Kaplan-Meier technique, and differences in the curves were tested using the log-rank test.20,21 Independent risk factors associated with malignancies were studied using the stepwise Cox regression analysis.