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Katsuaki Ogushi,1,* Makoto Chuma,1,* Haruki Uojima,2 Hisashi Hidaka,2 Kazushi Numata,1 Satoshi Kobayashi,3 Shunji Hirose,4 Nobuhiro Hattori,5 Tomoaki Fujikawa,6 Takahide Nakazawa,2 Naohisa Wada,2 Shuitirou Iwasaki,2 Taito Fukushima,3 Yusuke Sano,3 Makoto Ueno,3 Kuniyuki Kawano,3 Kota Tsuruya,4 Masako Shomura,4 Tsunamasa Watanabe,5 Kotaro Matsunaga,5 Yosuke Kunishi,7 Yusuke Saigusa,8 Kuniyasu Irie,9 Shogo Iwabuchi,6 Makoto Kako,10 Manabu Morimoto,3 Tatehiro Kagawa,4 Katsuaki Tanaka,11 Shin Maeda9 1Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan; 2Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan; 3Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan; 4Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; 6Department of Gastroenterology, Shonan Fujisawa General Hospital, Fujisawa, Japan; 7Department of Gastroenterology, Kanagawa Prefectural Ashigarakami Hospital, Kanagawa, Japan; 8Department of Biostatistics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; 9Department of Gastroenterology, Yokohama City University Hospital, Yokohama, Japan; 10Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Japan; 11Gastroenterology Division, Hadano Red Cross Hospital, Hadano, Japan*These authors contributed equally to this workCorrespondence: Makoto Chuma Gastroenterological CenterYokohama City University Medical Center, 4-57 Urafune-Cho, Minami-Ku, Yokohama, Kanagawa 2320024, JapanTel +81 45 261 5656Fax +81 45 253 9955Email chuma@yokohama-cu.ac.jpPurpose: 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.Keywords: lenvatinib, tyrosine kinase inhibitor, hepatocellular carcinoma, Child-Pugh, adverse events, overall survival

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.

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.

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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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-naive, 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.

The patient was a 45-year-old man who had Down syndrome and hepatitis B virus (HBV) with a high virus load and the presence of hepatitis B e antigen. He had received lamivudine (100mg/day: per os) as nucleoside/ nucleotide analogues (NAs) from April 2005 to December 2012. Although the initial response of HBV DNA was favorable, a high level of viral breakthrough without hepatitis reactivation occurred after 16 -months of lamivudine administration. In December 2012, the therapy with lamivudine was substituted with adefovir dipi‐ voxil (ADV) and entecavir hydrate (ETV) after informed consent was obtained. Serum HBV DNA gradually decreased over 7 -months of this drug substitution; however, there was a gradual increase in the serum alkali‐ phosfatase (ALP) level without increase in the other hepatobiliary enzymes and nephrotoxicity. Since he was suspected as having drug-induced liver damage and nephropathy caused by NAs, ADV and ETV were adminis‐ tered every other day for 3 months, resulting in no improvement. The laboratory data was obtained in December 2013 as follows; peak 3 dominant in the ALP isoenzyme analysis, low levels of serum carcium, phosphorus and urinary acid, excessive urinary excretion of amino acid and increased level of serum creatinine. Thus, we sug‐ gested that he suffered from acquired Fanconi’s syndrome induced by ADV. Administration of ADV was then discontinued after 12 months of drug substitution and only ETV was prescribed. Six months after ADV discon‐ tinuation, some of the indicative markers of renal dysfunction, including Fanconi’s syndrome, were normalized and recovered to the same levels before the combined use of ADV and ETV. The patient had been treated with sodium valproate and carbamazepine for the unstable mental state and epilepsy before the lamivudine adminis‐ tration; however, the negative synergic action among these drugs and NAs was not evaluated sufficiently. Here, we report the earlier onset of Fanconi’s syndrome triggered by ADV, which is usually diagnosed after long-term ADV administration. We suggest that the adequate evaluation of renal function, including proximal tubular damage before administration of ADV and close observation from the early period during treatment with ADV, is required.

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.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.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.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.

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.

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.

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 >6months, 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 32.4Gy (30.3–35.4) and 34.4Gy (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 30Gy/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.

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

This study aimed to assess the imaging appearances of focal liver reactions following stereotactic body radiotherapy (SBRT) for small hepatocellular carcinoma (HCC) and to examine relationships between imaging appearance and baseline liver function. We retrospectively studied 50 lesions in 47 patients treated with SBRT (30- 40 Gy in 5 fractions) for HCC, who were followed up for more than 6 months. After SBRT, all patients underwent regular follow-ups with blood tests and dynamic CT scans. At a median follow-up of 18.1 months (range 6.2-43.7 months), all lesions but one were controlled. 3 density patterns describing focal normal liver reactions around HCC tumours were identified in pre-contrast, arterial and portal-venous phase scans: iso/iso/ iso in 4 patients (Type A), low/iso/iso in 8 patients (Type B) and low/iso (or high)/high in 38 patients (Type C). Imaging changes in the normal liver surrounding the treated HCC began at a median of 3 months after SBRT, peaked at a median of 6 months and disappeared 9 months later. Liver function, as assessed by the Child-Pugh classification, was the only factor that differed significantly between reactions to treatment showing ''non-enhanced'' (Type A and B) and ''enhanced'' (Type C) appearances in CT. Hence, liver tissue with preserved function is more likely to be well enhanced in the delayed phase of a dynamic contrast-enhanced CT scan. The CT appearances of normal liver seen in reaction to the treatment of an HCC by SBRT were therefore related to background liver function and should not be misread as recurrence of HCC.

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.

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

部分的脾動脈塞栓術（PSE）を行った肝硬変症43例の脾静脈および門脈血流量を超音波ドプラ法で測定し，門脈と脾静脈血流量の差からPSEによる消化管からの血流量変化率を算出し血清アルブミン値の変化と比較検討した．（門脈―脾静脈）血流量変化率はPSEによるアルブミン上昇率と正相関を示した．PSEによるアルブミンの変化は肝予備能や側副血行路および静脈瘤，術後のインターフェロン治療にも影響を受けるが，消化管からの血流と考えられる（門脈―脾静脈）血流量の上昇はアルブミンの上昇に強く関連していると考えられた．PSEによる脾静脈血流量の低下は，門脈への消化管からの血流増加に繋がり肝でのアルブミン合成に好影響を与える可能性が示唆された．

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.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.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.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.

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

B型慢性肝炎100例 (HBe抗原陽性58例, HBe抗原陰性42例) に対し, 遺伝子組替え型インターフェロンーα2a, 1回900万単位をはじめの2週間は連日, つぎの22週間は週3回, 合計24週間投与した. HBe抗原陽性例のe抗原陰性化率は治療終了時44% (23/52), 終了後24週で52% (27/52) であった. 治療中血中HBVDNA量は低下し2例で消失したが, IFN終了後は全例で陽性となった. 血清ALTの正常化は治療終了時46% (24/52), 終了後24週48% (25/52) にみられた.HBe抗原陰性例のALT正常化率は, IFN投与終了時, 終了後24週でそれぞれ62% (24/39), 59% (23/39) であった. 血中HBVDNAの陰性化は投与終了時9例 (23%) にみられたが, 2例を除きいずれも治療終了後に再出現した.IFN 24週投与はB型慢性肝炎の有効な治療法と考えられる.

Sixty-eight consecutive patients with chronic hepatitis B received 702 million units of recombinant interferon-alpha 2a. Of the 24 patients negative for hepatitis B e antigen (HBeAg) in serum, the normalization of serum transaminase occurred in 14 (58%) at the completion of interferon therapy and in 13 (54%) at 12 months thereafter; it was normalized in 17 (39%) and 13 (30%), respectively, of the 44 HBeAg-positive patients. Of the HBeAg-negative patients, hepatitis B virus DNA was cleared from serum in six (25%) at the completion and in one (4%) at 12 months thereafter, in contrast to only one (2%, p < 0.05) and none of the HBeAg-positive patients, respectively. The 1896th nucleotide of G (G1896) for codon 28 for tryptophan or A (A1896) for the stop codon 28 in the precore region was determined by restriction fragment length polymorphism. The ten HBeAg-negative patients with A1896 only in the precore region had lower pretreatment levels of viral markers, which decreased more rapidly and extensively after interferon than in the 14 HBeAg-negative patients with a mixture of G1896 and A1896 or in the 44 HBeAg-positive patients. These results indicate that patients with HBeAg-negative chronic hepatitis B may respond better to interferon than HBeAg-positive patients, and that the precore mutant with the stop codon 28 may be sensitive to interferon.

16歳の若年女性でtoxic epidermal necrolysis (TEN) 治療中に, 高度な急性肝内胆汁うっ滞を発症. 種々内科的治療に抵抗性にて, 難治性慢性肝内胆汁うっ滞へ移行し, 約3年の短期間に続発性胆汁性肝硬変症に進展し, 死亡した極めて稀な例を経験した. 本症例はSherlockらの提唱するthe disappearing intrahepatic bile ductsの範躊にはいるが, 臨床的にprimary biliary cirrhosis (PBC), Alagille病, Byler病などは否定的であった. アセトアミノフェンの服用歴とLST陽性やTEN様の皮疹, ステロイドの中止後胆汁うっ滞の悪化を認めたことより, 薬剤アレルギーが病態の背景にあり, 肝内胆管の潜在的なhypoplasiaやprimary screlosing cholangitis (PSC) の存在が病態の増悪因子となった可能性が示唆された, 残された治療選択は肝移植のみと考えられたが, 高度な胆汁うっ滞を主とした病態においては, 経過中にその適応および時期の適切な判断を下すことは難しく, 類似症例の参考となると考えられ報告した.

大量飲酒歴のためにアルコール性肝障害として観察されていた原発性胆汁性肝硬変 (PBC) の一男性例を経験した.症例は69歳, 男性. 約6年前, 健康診断にて肝障害を指摘され, 推定積算飲酒量1.5tの飲酒歴からアルコール性肝障害として観察されていた. その後, 約2年の禁酒にもかかわらずγGTPの低下が乏しいため精査を行ったところ, PBCの診断を得た. 経過中, 抗核抗体およびIgGは高力価陽性, HLAクラスIIはDR4を呈すも抗ミトコンドリア抗体 (AMA) は陰性ないし低力価にとどまり, IgMも正常範囲にあった. しかし肝組織像ではPBCに一致する所見を示し, western blot法によるM2抗体の検索ではPDH-E2およびBCKD-E2が検出された. AMA測定の普及により無症候性PBCの診断は比較的容易になった. しかし本症例のように, γGTP高値でも男性かつ大量の飲酒歴を有し, かつAMA, IgMなども定型的でないところから, PBCの病態が想定しにくい症例も存在し, 興味深い一例と考え報告した.

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.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.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).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.

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.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 bowels25 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.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.SBRT for HCC was safe and provided equivalent outcomes when administered either in 35 or 40 Gy/5 fractions.

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 × (causal viruses, 1 point for type A or type B in acute hepatitis B virus [HBV] infection, 2 points for others) + 0.056 × (total bilirubin, mg/dl) −0.014 × (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.

Background: A daily injection of glycyrrhizin (Stronger Neo-Minophagen C (SNMC) containing 40 mg glycyrrhizin in a 20 mL ampoule) lowers alanine aminotransferase (ALT) levels in patients with chronic viral hepatitis. Methods: The therapeutic effects of intermittent administration of SNMC three times a week for 12 weeks were evaluated and compared between two doses (40 and 100 mL) in a randomized clinical trial. Results: Overall, the therapeutic response was better in the 53 patients allocated 100 mL than the 59 who were allocated to have 40 mL SNMC (P = 0.0243). At the completion of SNMC treatment, ALT levels decreased more extensively in the patients on 100 mL than those on 40 mL SNMC (−29 vs−50% in comparison with the baseline value, P = 0.0002). Minor side-effects occurred in both the patients on 100 mL (20%) and those on 40 mL (12%), but they did not require any therapies. Conclusions: Intermittent SNMC would be efficient in suppressing ALT levels in patients with chronic viral hepatitis in a dose-dependent manner. Taken along with infrequent and very mild side-effects, long-term intermittent SNMC would benefit patients with chronic hepatitis by maintaining their quality of life with easier compliance. © 2002 Blackwell Publishing Asia Pty Ltd

A 56-year-old female HB carrier developed fulminant hepatic failure with propagation of precore mutant hepatitis B virus following two sessions of intensive chemotherapy for non-Hodgkin's lymphoma. She was treated with interferon and cyclosporin A for the suppression of viral replication and enhanced host immune responses. She recovered from liver failure with histological evidence of marked regenerative activity.