Analysis of efficacy of lenvatinib treatment in highly advanced hepatocellular carcinoma with tumor thrombus in the main trunk of the portal vein or tumor with more than 50% liver occupation: A multicenter analysis.

AIMS: To assess the safety, efficacy, and prognostic impact of clinical factors associated with lenvatinib treatment in highly advanced hepatocellular carcinoma (HCC) with tumor thrombus in the main portal vein trunk (VP4) or tumor with more than 50% liver occupation (tm50%LO). METHODS: A total of 61 highly advanced HCC patients (41 patients with tm50%LO and 20 patients with VP4) who were treated with lenvatinib at multicenter were enrolled and retrospectively analyzed for treatment outcomes according to their clinical status, including tumor morphology. RESULTS: The most frequent grade ≥3 adverse event in tm50%LO HCC was elevated aspartate aminotransferase (17.1%). Objective response rates were 37.5% and 0% in tm50%LO HCC patients with Child-Pugh grade (CP)-A and CP-B, respectively, and 26.7% and 0% in VP4 HCC patients with CP-A and CP-B, respectively. Estimated median progression-free survival and overall survival were 132 days and 229 days, and 101 days and 201 days in patients with tm50%LO and VP4, respectively. In multivariate analysis, modified albumin-bilirubin grade (hazard ratio 0.372, 95% CI 0.157-0.887; p = 0.0241) and tumor morphology (hazard ratio 0.322, 95% CI 0.116-0.889; p = 0.0287) were independently associated with progression-free survival in patients with tm50%LO HCC. In VP4 HCC, median progression-free survival was worse in CP-B (57 days) than in CP-A patients (137 days, p = 0.0462). CONCLUSIONS: Lenvatinib treatment offers a benefit in highly advanced HCC (tm50%LO or VP4) patients with good liver function or nodular-type tumor. The various characteristics identified in this study might be useful as indicators of lenvatinib treatment in highly advanced HCC with tm50%LO or VP4, which are considered very refractory cancers.

Safety and Efficacy of Lenvatinib Treatment in Child-Pugh A and B Patients with Unresectable Hepatocellular Carcinoma in Clinical Practice: A Multicenter Analysis.

PURPOSE: To assess the safety, efficacy and prognostic impact of clinical factors related to lenvatinib treatment in Child-Pugh class A (CP-A) and class B (CP-B) patients with unresectable hepatocellular carcinoma (u-HCC). METHODS: Patients with u-HCC who were treated with lenvatinib at multiple centers in Japan were retrospectively analyzed for treatment outcomes according to their respective CP status. Radiological objective response (OR) was assessed using modified response evaluation criteria in solid tumors (mRECIST) guidelines. RESULTS: Baseline demographic parameters were comparable between 126 (69.6%) patients with CP-A disease and 55 patients (30.4%) with CP-B disease. Frequency of lenvatinib-related adverse events, including decreased appetite (P=0.034), diarrhea (P=0.040), elevated serum bilirubin (P=0.016) and vomiting (P=0.009), were higher in CP-B than in CP-A patients. Relative dose intensity (RDI) was significantly higher in CP-A (0.69) than CP-B patients (0.50, P <0.001). Furthermore, OR rate (44.0%) was markedly higher in CP-A5 patients as compared to CP-A6 (25.5%), CP-B7 (22.2%), and CP-B8 patients (5.3%), respectively (P=0.002). In multivariable analysis, performance status (0 vs 1, 2, P=0.026), CP class (A vs B, P=0.045) and RDI (≥0.7 vs <0.7, P=0.034) were identified as factors associated with response to lenvatinib treatment. Overall survival (OS) at 12 months was significantly different between CP-A (66.3%) and CP-B patients (30.0%, P=0.002), and between CP 5-7 (59.2%) and CP 8 patients (34.8%, P=0.003). In multivariable analysis, CP class (A vs B, P=0.007) and Barcelona clinic liver cancer (BCLC) stage (B vs C, P=0.002) were associated with OS following lenvatinib treatment. CONCLUSION: Lenvatinib treatment offers significant benefits in patients with good liver function in real-world practice. The various characteristics identified in this study might be helpful as clinical predictors of response to lenvatinib and survival in clinical practice. Further studies are required to address eligibility for lenvatinib treatment in CP 7 patients.

Influence of NOS3 rs2070744 genotypes on hepatocellular carcinoma patients treated with lenvatinib.

We investigated whether or not nitric oxide synthase 3 (NOS3) rs2070744 genotypes can affect the response for lenvatinib treatment in patients with hepatocellular carcinoma (HCC). We evaluated the relation of the NOS3 rs2070744 genotypes to the tumor response, progression-free survival (PFS), and overall survival (OS) as the response for lenvatinib. We also examined the association between fibroblast growth factor receptor (FGFR) gene polymorphisms, a potential feature of lenvatinib, and the response. There were no significant differences between the studies for either PFS or OS, even though patients with the TT genotype had a longer mean PFS (hazard ratio [HR] 0.60; p = 0.069) and mean OS (HR 0.46; p = 0.075) than those with the TC/CC genotypes. However, patients with a single-nucleotide polymorphism (SNP) combination pattern of the NOS3 rs2070744 TC/CC and FGFR4 rs351855 CT/TT genotypes had a significantly shorter mean PFS (HR 2.56; p = 0.006) and mean OS (HR 3.36; p = 0.013) than those with the other genotypes. The NOS3 rs2070744 genotypes did not influence the clinical response. However, the SNP combination pattern of the NOS3 rs2070744 and FGFR4 rs351855 genotypes may be helpful as treatment effect predictors and prognostic factors for HCC patients treated with lenvatinib.

Skeletal Muscle Mass Influences Tolerability and Prognosis in Hepatocellular Carcinoma Patients Treated with Lenvatinib.

BACKGROUND: Low skeletal muscle mass is significantly associated with severe adverse events (AEs) from chemotherapy, and low tolerability leads to decreased survival. We aimed to investigate whether body skeletal muscle mass is correlated with tolerability and prognosis in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. METHODS: This multicenter, retrospective study was conducted at five locations in Japan. We included 100 patients with HCC treated with lenvatinib. Skeletal muscle mass was measured by computed tomography and normalized for height in m2 as skeletal muscle index (SMI). The assessment criteria for low SMI were taken from the sarcopenia criteria of the Japan Society of Hepatology. We investigated the influence of low SMI on drug withdrawal due to severe AEs in the first 2 months and on time to treatment failure (TTF) and overall survival (OS). RESULTS: The numbers of high- and low-SMI patients were 41 and 59, respectively. Those with severe AEs leading to withdraw in the high- and low-SMI groups were 7 and 23, respectively. The low-SMI group had a higher withdrawal rate than the high-SMI group (p = 0.042). The median TTF in the low- and high-SMI groups was 139 and 230 days, respectively. The median OS in the low- and high-SMI groups was 264 and 353 days, respectively. Patients in the low-SMI group experienced significantly worse OS and TTF than those in the high-SMI group (log-rank test for trend: TTF, p = 0.010; OS, p = 0.021). CONCLUSION: Decreased skeletal muscle mass is associated with the occurrence of severe AEs and worse TTF and OS. Skeletal muscle mass can be used as a predictive marker for tolerability and prognosis to lenvatinib in patients with HCC.

The First Case of TEMPI Syndrome in Japan.

TEMPI syndrome, a disease entity comprising telangiectasia, erythrocytosis with high erythropoietin, monoclonal gammopathy, perinephric fluid collection, and intrapulmonary shunting, was first described by Sykes et al. in 2011. To our knowledge, only 15 cases have been reported worldwide, none of which were in Japan. We herein report a 47-year-old man who had intractable ascites for 2 and a half years and was referred to our department for a peritoneovenous shunt. In addition to ascites, he had telangiectasia, high erythropoietin, monoclonal gammopathy, and perinephric fluid collection. Thus, this is the first case of TEMPI syndrome in Japan.

Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment.

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.

Efficacy of ledipasvir/sofosbuvir with or without ribavirin for 12 weeks in genotype 1b HCV patients previously treated with a nonstructural protein 5A inhibitor-containing regimen.

AIM: The therapeutic benefit of adding ribavirin (RBV) to 12 weeks of ledipasvir/sofosbuvir (LDV/SOF) for patients who experienced failure of a previous nonstructural protein (NS) 5A inhibitor-containing regimen is unclear. METHODS: A total of 29 genotype 1b HCV patients who had failed prior daclatasvir (DCV) plus asunaprevir (ASV) treatment were retreated for 12 weeks of LDV/SOF, with or without RBV. Antiviral efficacy and predictive factors associating with a sustained virological response at 24 weeks (SVR24) were evaluated retrospectively. RESULTS: SVR24 was achieved in 67% (10/15) of patients who received LDV/SOF with, and 64% (9/14) without, RBV. The SVR24 rates were 80% in patients with, and 58% without, mild fibrosis (FIB-4 < 3.25). The SVR24 rate was lower with unfavorable IL28B rs8099917 SNP genotypes; specifically, the TT, TG and GG had SVR24 rates of 78%, 50% and 40%. The SVR24 rate was lower with a poor response to prior DCV plus ASV, where relapse, viral breakthrough and no response had SVR24 rates 71%, 58% and 0%. The SVR24 rate was lower with the number of NS5A resistance-associated substitutions (RAS), where 2, 3, 4 and 5 RAS had SVR24 rates of 78%, 67%, 50% and 0%. A patient with an NS5A-P32 deletion, which shows resistance to next-generation NS5A inhibitors, was retreated with LDV/SOF with RBV and achieved SVR24. CONCLUSIONS: The addition of RBV to 12 weeks of LDV/SOF has little therapeutic benefit when retreating patients in whom a prior NS5A inhibitor-containing regimen had failed.

Relationship of hepatitis B virus infection to the recurrence of hepatocellular carcinoma after direct acting antivirals.

Recently, two conflicting articles about recurrence of hepatocellular carcinoma (HCC) after direct acting antivirals (DAA) against hepatitis C virus (HCV) were published. We investigated the relationship between DAA and HCC recurrence. Eligible patients were (1) history of HCC and treated curatively with interventions, and (2) interferon-free DAA therapy was initiated after eradication of HCC. We analyzed contributing factor for HCC recurrence. Ten out of 23 participants (43%) encountered recurrence of HCC. Age, sex, diabetes mellitus, fibrosis score, chemistry, and alpha-fetoprotein did not differ between patients with recurrence and patients without recurrence. The patients with recurrence had significantly higher values of antibody to hepatitis B core antigen (anti-HBc) than the patients without recurrence, 6.06±3.75 vs. 0.91±2.43 (p=0.0019). The relative risk of HCC recurrence comparing anti-HBc positive to negative was 5.2 (95% confidence interval 1.40 to 19.32). Odds ratio was 22.0 (95% confidence interval 2.5 to 191.1). We conclude that anti-HBc positivity was a strong contributing factor for HCC recurrence after DAA therapy.

Phase 2 study of stereotactic body radiotherapy and optional transarterial chemoembolization for solitary hepatocellular carcinoma not amenable to resection and radiofrequency ablation.

BACKGROUND: Curative treatment options for patients with early stage hepatocellular carcinoma (HCC) include resection, liver transplantation, and percutaneous ablation therapy. However, even patients with solitary HCC are not always amenable to these treatments. The authors prospectively investigated the clinical outcomes of patients who received stereotactic body radiotherapy (SBRT) for solitary HCC. METHODS: A phase 2 study involving SBRT and optional transarterial chemoembolization (TACE) was conducted in patients with Child-Pugh grade A or B and underlying, solitary HCC (greatest tumor dimension, ≤4 cm) who were unsuitable candidates for resection and radiofrequency ablation. The prescription dose was 35 to 40 grays in 5 fractions. The primary endpoint was 3-year local tumor control. RESULTS: From 2007 to 2012, 101 patients were enrolled, and 90 were evaluable with a median follow-up of 41.7 months (range, 6.8-96.2 months). Thirty-two patients were treatment-naïve, 20 were treated for newly diagnosed intrahepatic failure, and 38 were treated for residual or recurrent HCC as salvage therapy. Thirty-two patients did not receive TACE, 48 received insufficient TACE, and 10 attained full lipiodol accumulation. The 3-year local control rate was 96.3%, the 3-year liver-related cause-specific survival rate was 72.5%, and the overall survival rate was 66.7%. Grade 3 laboratory abnormalities were observed in 6 patients, and 8 patients had Child-Pugh scores that worsened by 2 points. CONCLUSIONS: SBRT achieved high local control and overall survival with feasible toxicities for patients with solitary HCC, despite rather stringent conditions. SBRT can be effective against solitary HCC in treatment-naive, intrahepatic failure, residual disease, and recurrent settings, taking advantage of its distinctive characteristics. Cancer 2016;122:2041-9. © 2016 American Cancer Society.

Long-term evaluation of partial splenic embolization followed by interferon therapy in patients with hepatitis C virus (HCV) cirrhosis and thrombocytopenia.

OBJECTIVE: Patients with hepatitis C virus (HCV) cirrhosis and thrombocytopenia are often excluded from receiving interferon therapy because the treatment results in severe platelet depletion. Surgical splenectomy or partial splenic embolization (PSE) is a promising procedure for increasing the platelet count before interferon therapy. We performed PSE and evaluated the long-term clinical course in HCV cirrhotic patients. METHODS: Patients with HCV cirrhosis and thrombocytopenia were included (n=108) in this study. The straight-coiled PSE procedure (Takatsuka method) was performed. The platelet count, hemodynamic changes, rate of a sustained virological response (SVR) and prevalence of hepatocellular carcinoma (HCC) were evaluated. RESULTS: PSE resulted in a significant increase in the platelet count (before PSE: 7.9±2.3×10(4)/µL, two weeks after PSE: 16.7±6.6×10(4)/µL (p<0.001). Therefore, all participants were started on regular-dose interferon therapy. The SVR rate was 24% for serotype 1 and 62% for serotype 2. In the biochemical responders (BR) with SVR, the overall survival rate was 94.6% over five years and 89.3% over 10 years. In the non-responders (NR), the overall survival rate was 78.7% over five years and 62.2% over 10 years. The overall survival rate of the patients with SVR+BR was significantly higher than that observed in the patients with NR (p=0.0082). There were no differences in the prevalence of HCC between the patients with SVR+BR and NR. CONCLUSION: PSE enabled the induction of regular-dose interferon therapy in patients with HCV cirrhosis and thrombocytopenia. Although the prevalence of HCC did not differ between the SVR+BR and NR patients, there was a significant survival benefit in the patients with SVR+BR.

Threshold doses for focal liver reaction after stereotactic ablative body radiation therapy for small hepatocellular carcinoma depend on liver function: evaluation on magnetic resonance imaging with Gd-EOB-DTPA.

PURPOSE: Focal liver reaction (FLR) appears on radiographic images after stereotactic ablative body radiation therapy (SABR) in patients with hepatocellular carcinoma (HCC) and chronic liver disease. We investigated the threshold dose (TD) of FLR and possible factors affecting the TD on gadoxetate acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI). METHODS AND MATERIALS: In 50 patients who were treated with SABR for small HCC and followed up by MRI for >6 months, FLR, seen as a hypointense area, was evaluated on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. The follow-up MRI with the largest extent of FLR was fused to the planning computed tomography (CT) image, and patients with good image fusion concordance were eligible. After delineating the border of the FLR manually, a dose-volume histogram was used to identify the TD for the FLR. Clinical and volumetric factors were analyzed for correlation with the TD. RESULTS: A total of 45 patients were eligible for analysis with a median image fusion concordance of 84.9% (range, 71.6-95.4%). The median duration between SABR and subsequent hepatobiliary phase MRI with the largest extent of FLR was 3 months (range, 1-6 months). The median TD for FLR was 28.0 Gy (range, 22.3-36.4 Gy). On univariate analysis, pre-treatment Child-Pugh (CP) score and platelet count were significantly correlated with the TD. On multiple linear regression analysis, CP score was the only parameter that predicted TD. Median TDs were 30.5 Gy (range, 26.2.3-36.4 Gy) and 25.2 Gy (range, 22.3-27.5 Gy) for patients with CP-A and CP-B disease, respectively. CONCLUSION: The TD was significantly correlated with baseline liver function. We propose 30 Gy for CP-A disease and 25 Gy for CP-B disease in 5 fractions as TDs for FLR after SABR for patients with HCC and chronic liver disease. Use of these TDs will help to predict potential loss of liver tissue after SABR.

Stereotactic body radiotherapy for small hepatocellular carcinoma: a retrospective outcome analysis in 185 patients.

BACKGROUND: Since 2005, we have treated hepatocellular carcinoma (HCC) with stereotactic body radiotherapy (SBRT) uniformly at two dose levels, according to baseline liver function and normal liver dose. We retrospectively examined the outcomes for these patients. MATERIAL AND METHODS: Between 2005 and 2012, 221 HCC patients were treated with SBRT. Eligibility criteria for SBRT included a single (either solitary or recurrent) HCC lesion; unfeasible, difficult or refusal to undergo other surgery or percutaneous ablative therapies; Child-Pugh Classification (CPC) A or B; tumors ≤ 5 cm; dose to the bowels < 25 Gy/5 fractions; curative intent. Patients followed up ≥ 6 months were eligible. The prescribed dose depended on liver function and liver dose: 40 Gy for CPC-A and 35 Gy for CPC-B, in 5 fractions, requiring a 5-Gy dose reduction if the proportion of the liver receiving ≥ 20 Gy exceeded 20%. Treatment outcomes and safety were analyzed. RESULTS: A total of 185 patients (n = 48 in the 35-Gy group; n = 137 in the 40-Gy group) were eligible, with a median follow-up duration of 24 months (range 3-80). The three-year local control and overall survival rates were 91% and 70%, respectively. There were no significant differences in outcomes between dose levels: the three-year local control and overall survival rates in the 35-Gy and 40-Gy groups were 91% and 89% (log-rank p = 0.99) and 66% and 72% (p = 0.54), respectively. Acute toxicities ≥ grade 3 were observed in 24 (13.0%) patients, and 19 (10.3%) patients had worsening of CPC score by two points. All but three (1.6%) patients promptly recovered to grade 1-2. Grade 5 liver failure occurred in two patients in the 35-Gy group. CONCLUSION: SBRT for HCC was safe and provided equivalent outcomes when administered either in 35 or 40 Gy/5 fractions.

Tumor response on CT following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinoma with cirrhosis.

OBJECTIVE: The purpose of this study is to evaluate the CT appearances of tumor responses following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinomas (HCCs) and to assess the relationship between tumor responses and local control. MATERIALS AND METHODS: Among 277 HCC tumors treated with stereotactic ablative body radiotherapy (35 or 40 Gy per five fractions), we selected enhanced lesions on arterial phase CT performed before stereotactic ablative body radiotherapy. Radiographic findings after stereotactic ablative body radiotherapy were evaluated during a 2-year follow-up period with the modified Response Evaluation Criteria in Solid Tumors. Local control and survival rates were calculated with the Kaplan-Meier method. RESULTS: Forty-two tumors with a median size of 2.1 cm (range, 1.0-3.8 cm) were selected with a median follow-up of 23.3 months (range, 9-56 months). Local recurrence was observed in two tumors after achieving a complete response (CR). The 2-year local control rate was 97%, and the overall survival rate was 81%. CR increased from 10 (24%) to 28 (67%) to 30 (71%) tumors at 3, 6, and 12 months after stereotactic ablative body radiotherapy. Overall CR at maximum follow-up was 39 tumors (93%), yet three enhanced tumors persisted for more than 2 years. The median time to achieve CR was 5.9 months (range, 1.2-34.2 months). CONCLUSION: The CR rate in hypervascular HCCs after hypofractionated stereotactic ablative body radiotherapy increased during the 2-year follow-up period. Cautious and continuous observation until tumor regrowth is considered relevant to evaluate a true effect of this treatment. Further studies for the optimal evaluation of treatment outcome after stereotactic ablative body radiotherapy are warranted.

Dose volume histogram analysis of focal liver reaction in follow-up multiphasic CT following stereotactic body radiotherapy for small hepatocellular carcinoma.

PURPOSE: To investigate threshold dose (TD) of focal liver reaction (FLR) following stereotactic body radiotherapy (SBRT) for patients with hepatocellular carcinoma (HCC) and liver cirrhosis. MATERIALS AND METHODS: In consecutive 50 patients receiving SBRT for small HCC, 38 patients receiving SBRT and follow up >6 months, FLR on follow-up CT had been previously studied. Patients with good concordance between FLR and highly irradiated area were eligible. Dose volume histogram (DVH) was used to identify TDs for FLR. Clinical factors were analyzed for correlation with TDs. RESULTS: Of 24 eligible patients, 23 had Child-Pugh score A and 1 scored B. Presence of FLR peaked at a median of 6 (range; 3-12) months. The median and 95% confidential intervals of TDs of pre-contrast and portal-venous phase CT were 32.4 Gy (30.3-35.4) and 34.4 Gy (31.9-36.0), respectively. Each median coefficient representing the concordance was 74.9% (range; 55.8-98.0%) and 80.5% (range; 70.8-92.4%), respectively. No clinical factors significantly correlated with the TDs. CONCLUSION: We proposed 30 Gy/5 fractions as TD of FLRs following SBRT for patients with HCC and liver cirrhosis. This TD will enable us to predict injured liver volume and to avoid complication beforehand from toxicity. Further pathological and clinical studies, in addition to more practical and precise data of DVH, are needed to clarify the significance of FLRs.

Possible role of early transabdominal ultrasound in patients undergoing cytapheresis for active ulcerative colitis.

BACKGROUND: Cytaphresis (CAP) is an effective modality in the treatment of active ulcerative colitis (UC), but the time lag before a notable clinical response on scheduled therapy frequently causes a significant delay in the modification of treatment. We previously reported that the clinical response after CAP was predicted by early application of transabdominal ultrasound (TAUS), but the predictability of long-term outcome after CAP still remains uncertain. METHODS PATIENTS: Twenty-six patients with active UC who received CAP were followed for 1 year. In addition to CAP they received pharmaceutical regimens, such as corticosteroid, 5-aminosalicylic acid, and immunomodulator, as indicated clinically. The mean UC-DAI score was 9.7 before CAP, and 3.2 at 1 year after CAP. Prognostic factor: Total colonic wall thickness was measured by TAUS at 2 to 3 weeks after the initiation of the treatment, and decrement from baseline was calculated. Early ultrasonographic response (EUR) was defined as a decrement statistically. UC-DAI score of 2 or less at 1 year was defined as sustained clinical remission. Score of 6 or more was defined as clinical relapse. RESULTS: EUR was defined as a decrement in wall thickness by at least 2.5 mm from the baseline. EUR was noted in 11 patients, and the remaining 15 did not attain EUR. OUTCOME MEASURES: In the UC-DAI score measured at 1 year after initiation of treatment 90.9% of patients with EUR, whereas 40.0% with non-EUR (p<0.05) showed sustained clinical remission. Regarding relapse, within 1 year 9.1% of patients with EUR relapsed whereas 46.7% with non-EUR (p<0.05) relapsed. CONCLUSION: Early application of TAUS may predict the long-term clinical outcome after CAP in patients with active UC.

Two week induction of interferon-beta followed by pegylated interferon alpha-2b and ribavirin for chronic infection with hepatitis C.

OBJECTIVES: To elucidate the efficacy of interferon (IFN)-beta induction therapy followed by pegylated IFN alpha and ribavirin for chronic infection with hepatitis C virus (HCV). METHODS: Patients chronically infected with HCV genotype 1, high titer were enrolled. Twice daily bolus injections of 3 million units IFN-beta were administered for 14 days. Thereafter, weekly injection of pegylated IFN alpha 2b and daily intake of ribavirin were followed. Therapy duration was adjusted according to the response to the therapy. When time to an undetectable HCV-RNA was 1, 2, 4, 8, and 12 weeks, total duration of therapy was 12, 24, 36, 48 and 60 weeks, respectively. Patients who failed to achieve an undetectable HCV-RNA within 12 weeks discontinued therapy on 12 week. RESULTS: Among the 101 patients treated, 56 (55.4%) achieved sustained virological response (SVR). SVR rate for each treatment duration was 10/10 for 12 weeks, 12/14 for 24 weeks, 18/19 for 36 weeks, 15/26 for 48 weeks, 1/4 for 60 weeks and 0/28 for patients who discontinued therapy at 12 weeks. Mean time to an undetectable HCV-RNA was 35.5 +/- 2.7 days. Mean therapy duration was 27.3 +/- 1.4 weeks. Using a cut off value of 21.5 fmol/L of HCV core-antigen in the first week, SVR could be predicted by sensitivity of 0.91 and specificity of 0.78. CONCLUSION: IFN-beta induction therapy resulted in acceptable SVR rates despite short therapy duration. Steep reduction of HCV by IFN-beta enables us to predict SVR in the first week of therapy.

Partial splenic embolization reverses insulin resistance in patients with liver cirrhosis.

BACKGROUND: It is well known that patients with liver cirrhosis often develop insulin resistance and diabetes mellitus. Recently, we encountered a liver cirrhosis patient in whom partial splenic embolization (PSE) improved insulin sensitivity. Therefore, we conducted further investigation about PSE and insulin resistance. METHODS: Thirty-seven consecutive patients with liver cirrhosis underwent PSE. Hemodynamic changes, blood counts, and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed before and 2 weeks after PSE. RESULTS: PSE resulted in decreased splenic venous flow and increased intestinal venous flow to the liver. Platelet counts before and after PSE were 7.7+/-0.5 x 10(4) /microL, 15.0+/-1.4 x 10(4) /microL, respectively (p<0.01). HOMA-IR before and after PSE were 6.5+/-2.1, 3.3+/-0.6, respectively (p<0.05). HCV core antigen before and after PSE were 6,340+/-1,296 fmol/L, 4,112+/-873 fmol/L, respectively (p<0.05). Conclusion PSE significantly reverses insulin resistance in patients with liver cirrhosis. The increase in intestinal venous flow to the liver and reduced HCV viral load were thought to be mechanisms of improvement in insulin sensitivity after PSE.

Detection, using a novel method, of a high prevalence of cryoglobulinemia in persistent hepatitis C virus infection.

To elucidate precisely the prevalence and significance of cryoglobulinemia in hepatitis C, we examined the prevalence of serum cryoglobulin (CG) among 232 consecutive hepatitis C virus carriers (23 asymptomatic carriers, 164 with chronic hepatitis, 45 with cirrhosis), 30 consecutive hepatitis B virus carriers and 100 age- and sex-matched healthy volunteers. We used a gel-diffusion procedure that detects CG with greater sensitivity and specificity than the conventional precipitation method. Among the 232 patients, 166 were tested for the presence or absence of CG by the precipitation method also, which showed 60 (36.1%) patients to be positive for CG. On the other hand, 164 of the 232 patients (70.7%) were positive for CG using the diffusion method. 5 (16.7%) of the 30 HBV carriers and 2 (2%) of the healthy volunteers also were positive for CG using the gel-diffusion procedure. CG was detected more frequently among the patients with chronic hepatitis or cirrhosis than the asymptomatic carriers. In spite of the high prevalence of CG positivity, only one patient had symptoms related to cryoglobulinemia. Positivity for CG was not related to viral serogroup, viral load or the presence of antinuclear antibody, but it was related closely to CH50: 58 of 63 (92.1%) patients with lower levels of CH50 were positive for serum CG. In conclusion, cryoglobulinemia is a very common feature of chronic hepatitis C.

Accurate prediction of fulminant hepatic failure in severe acute viral hepatitis: multicenter study.

BACKGROUND: We have attempted to predict the development of fulminant hepatic failure at the stage of severe acute hepatitis before the onset of coma. This prediction is valuable because it may be used to block the development of fulminant hepatic failure with appropriate medical treatment. METHODS: To establish a discrimination formula, we retrospectively compared 13 clinical and laboratory variables in 36 patients with acute viral hepatitis and prothrombin levels of 40% or less of the control value who later developed fulminant hepatic failure with these variables in 12 patients who recovered spontaneously. A prospective study of 58 patients who developed fulminant hepatic failure and 18 who spontaneously recovered confirmed the validity of this formula. RESULTS: In the retrospective study,we established the following discrimination equation: Z = -0.89 + 1.74 x (causal viruses, 1 point for type A or type B in acute hepatitis B virus [HBV] infection, 2 points for others) + 0.056 x (total bilirubin, mg/dl)-0.014 x (cholinesterase, U/ml). A positive Z value indicates that fulminant hepatic failure will develop. In the prospective study, the specificity, sensitivity, predictive accuracy, and positive and negative predictive values were 0.833, 0.983, 0.947, 0.950, and 0.938, respectively. CONCLUSIONS: The present study indicated that fulminant hepatic failure can be predicted, by a simple discrimination equation, at the stage of severe acute hepatitis.