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Background It is unclear whether hepatocyte function and/or portal hypertension improves if a sustained virologic response (SVR) is achieved with direct-acting antivirals in patients with decompensated hepatitis C-related cirrhosis. Methods We examined the safety and efficacy of a 12-week course of sofosbuvir/velpatasvir (SOF/VEL) in 20 patients with decompensated hepatitis C-related cirrhosis. We also investigated changes in the hepatocyte receptor index (LHL15) and blood clearance index (HH15) by Tc-99 m-galactosyl human serum albumin scintigraphy, liver stiffness measurement (LSM) by transient elastography, and hepatic venous pressure gradient (HVPG) in patients who achieved an SVR at 24 weeks after treatment (SVR24). Results One patient discontinued treatment because of rectal variceal hemorrhage, and 19 patients completed treatment. SVR24 was achieved in 17 patients (89%). Median LHL15 increased from 0.72 pre-treatment to 0.82 after SVR24 (p = 0.012), and median HH15 decreased from 0.82 pre-treatment to 0.76 after SVR24 (p = 0.010). The percentage of patients with LSM ≥ 20 kPa was 90% before treatment and remained at 90% after SVR24. However, the percentage with severe portal hypertension (defined as HVPG ≥ 12 mmHg) decreased from 92% pre-treatment to 58% after SVR24 (p = 0.046). Patients with a decreased HVPG from pre-treatment to after SVR24 had a smaller pre-treatment spleen volume than those with an increased HVPG (median, 252 vs. 537 mL, p = 0.028). Conclusion Achieving SVR24 with SOF/VEL treatment in patients with decompensated hepatitis C-related cirrhosis can be expected to improve hepatocyte function and portal hypertension on short-term follow-up.

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

研究グループは、C型肝炎ウイルスの感染がある初期の肝がん患者に対して、がんの治療後に経口治療薬(DAA)治療によりC型肝炎ウイルスを排除することで、肝がんの進行リスクを低下させることを初めて明らかにしました。さらに、肝がんの治療頻度、死亡リスクも低下させることを明らかにしました。本研究成果により、DAA治療が肝がん治療後の患者にも有益性が高いことが示されました。C型肝炎ウイルス感染症は肝がんの原因となる感染症で、DAA治療はC型肝炎ウイルスに直接作用して増殖を抑える飲み薬です。肝がんになったことのない患者にDAA治療を行うと、肝がんが発生しにくくなることが明らかとなっていますが、肝がん根治後の患者にもがんを抑える効果があるかどうかははっきりしていませんでした。今回、本研究グループは、初発で初期の肝がんを根治した患者165例を対象とし、がんの治療後にDAA治療でC型肝炎ウイルス感染症を治すことにより、肝がんの再発リスク、がんの進行リスク、がんの治療頻度、肝臓病による死亡リスクがどのように変化するか調査しました。その結果、DAA治療をした患者としなかった患者では、再発リスクはすでにいくつもの研究で報告されているのと同じく差が見られませんでした。しかし、がんの進行リスクは、DAA治療をした患者で72%も低下しました。さらに、肝臓病による死亡リスクは88%も低下し、治療頻度も1年で59%も低下しました。, Hepatocellular carcinoma (HCC) has high recurrence rates. HCC sometimes progresses from early-stage HCC (Barcelona Clinic Liver Cancer [BCLC] stage 0/A) to advanced-stage HCC after repeated recurrences and treatments. HCC progression deteriorates quality of life and prognosis. However, ......

A direct-acting antiviral (DAA)-induced sustained virological response (SVR) reduces the risk of mortality. However, the risk factors associated with liver-related and non-liver-related mortality following a SVR after DAA treatment are unclear. We assessed the incidence and risk factors of liver-related and non-liver-related mortality in 1,180 patients who achieved a SVR after DAA treatment. During the follow-up period after DAA treatment (median duration, 1,099 [range: 84-2,345] days), 53 (4.5%) patients died: 15 due to liver-related mortality, 25 due to non-liver-related mortality, and 13 due to unknown causes. The all-cause, liver-related, and non-liver-related mortality rates were 14.9, 4.2, and 7.0/1,000 person-years, respectively. In a multivariate analysis, the development of hepatocellular carcinoma (HCC) after DAA treatment (p = 0.009; hazard ratio [HR], 31.484), an estimated glomerular filtration rate (eGFR) at baseline ≤ 61.68 mL/min/1.73 m

Background and Aim We assessed direct‐acting antiviral (DAA) treatment for patients with hepatitis C virus (HCV) and a history of injection drug use (IDU) in Japan. Method This retrospective observational study was based on clinical records. Overall, 804 DAA‐naïve HCV‐infected patients were enrolled, treated with a 12‐week regimen of DAAs, and had available information about a history of IDU. Anti‐HCV efficacy was defined as a sustained viral response 12 weeks post‐treatment (SVR12) only in patients who were assessed after 12 weeks [modified intention‐to‐treat (ITT) analyses]. We compared the antiviral effect between patients with (past‐IDU) and without a history of IDU (non‐IDU). We also evaluated the characteristics of each group, including the overall dropout rate and economic background. Results Overall, 78 (9.7%) patients had a history of IDU. Compared to the non‐IDU group at baseline, the past‐IDU group consisted of predominantly male and younger patients infected with HCV genotype 2. Overall, 3% (3/78) and 16% (116/726) of the patients had cirrhosis in the past‐IDU and non‐IDU group, respectively. There was a significantly higher rate of welfare recipients in the past‐IDU group. SVR rate was 97% (59/61) in the past‐IDU group and 99% (689/699) in the non‐IDU group. The cumulative rate of dropout from an aftercare program was high in the past‐IDU group (P, The cumulative dropout rates from the aftercare program of antihepatitis C therapy were significantly higher in the past‐IDU group compared to those in the non‐IDU group (P

Various positron emission tomography (PET) probes have been developed to assess in vivo activities in humans of drug transporters, which aid in the prediction of pharmacokinetic properties of drugs and the impact of drug-drug interactions. We developed a new PET probe, sodium (3R, 5R)-3, 5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8- ((1-[11C]-(E)-2-methyl-but-2-enoyl) oxy) -1, 2, 6, 7, 8, 8a-hexahydronaphthalen-1-yl) heptanoate ([11C]DPV), and demonstrated its usefulness for the quantitative investigation of Oatps (gene symbol SLCO) and Mrp2 (gene symbol ABCC2) in rats. To further analyze the species differences and verify the pharmacokinetic parameters in humans, serial PET scanning of the abdominal region with [11C]DPV was performed in six healthy volunteers with and without an OATP1Bs and MRP2 inhibitor, rifampicin (600 mg, oral), in a crossover fashion. After intravenous injection, [11C]DPV rapidly distributed to the liver and kidney followed by secretion into the bile and urine. Rifampicin significantly reduced the liver distribution of [11C]DPV 3-fold, resulting in a 7.5-fold reduced amount of excretion into the bile and the delayed elimination of [11C]DPV from the blood circulation. The hepatic uptake clearance (CLuptake, liver) and canalicular efflux clearance (CLint, bile) of [11C]DPV (544 ± 204 and 10.2 ± 3.5 µl/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 µl/min per gram liver, respectively) (Shingaki et al., 2013). Furthermore, rifampicin treatment significantly reduced CLuptake, liver and CLint, bile by 58% and 44%, respectively. These results suggest that PET imaging with [11C]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.

Background The efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR). Material and methods A total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy. The patients were treated with 100 mg asunaprevir twice daily plus 60 mg daclatasvir once daily for 24 weeks. The primary endpoint was SVR 24 weeks after completing treatment. In addition, we evaluated the improvement of liver function and development of HCC for 1 year from the end of treatment (EOT). Results The SVR24 rate was 96% (47/49) in the cirrhotic group and 96% (91/95) in the non-cirrhotic group (p = 0.69). During treatment, grade III/IV adverse events occurred more frequently in cir-rhotic patients (10/49; 20.4%) than in non-cirrhotic patients (10/96; 10.4%) (p = 0.099). After EOT, alanine aminotransferase and AFP levels were significantly decreased in cirrhotic patients with SVR. In addition, serum levels of albumin and platelet counts were significantly increased. On the other hand, the rates of HCC recurrence (43%) and development (7.4%) were higher in cirrhotic patients than in the non-cirrhotic patients (12.5% and 1.1%, respectively). Conclusion RAS-oriented asunaprevir/daclatasvir therapy has a strong anti-HCV effect in patients with HCV genotype 1b. However, careful management is necessary in patients with cirrhosis.

Background and Aim It is unclear whether polymorphism in the inosine triphosphatase (ITPA) gene correlates with the reduction in hemoglobin (Hb) concentrations during sofosbuvir (SOF) and ribavirin (RBV) therapy. We investigated the effects of the ITPA polymorphism in Japanese patients with chronic hepatitis C virus genotype 2 infection treated with SOF/RBV therapy. Methods In 106 patients treated with SOF/RBV therapy, we assessed the effects of the ITPA polymorphism (rs1127354) on anemia, RBV dose reduction, and sustained virological response (SVR). Results Of the 106 patients, 80 had the CC genotype, whereas 26 had a non-CC genotype in ITPA. Patients with the CC genotype had significantly larger reductions in Hb concentrations than those with a non-CC genotype throughout the treatment course. RBV dose reduction was required in 18/106 (17.0%) patients, with a significantly higher frequency in patients with the CC genotype than in those with a non-CC genotype (p = 0.010). In multivariate analysis, age ≥ 65 years (p = 0.011) and the ITPA CC genotype (p

A 77-year-old man with chronic hepatitis C underwent transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) for early-stage hepatocellular carcinoma (HCC) in segment 8 of the liver. Necrosis was confirmed radiologically. After 19 months, recurrent HCC in segment 6 was treated with TACE and RFA. There was no recurrence. Direct-acting antiviral (DAA) therapy 24 months after the initial procedure led to a sustained virologic response. AFP-L3 markedly increased 11 months after DAA therapy, and MRI 6 months after that showed a solitary lymph node near the common bile duct. Because no intrahepatic recurrence or other lymph nodes were seen, the solitary node was excised. Histopathology showed metastatic HCC. There has been no subsequent recurrence over 13 months of follow-up.

Simeprevir (SMV) is a potent, macrocyclic hepatitis C virus (HCV) non-structural 3/4 A protease inhibitor. This prospective study compared the efficacy and safety of SMV in combination with peginterferon α2a + ribavirin (P2aR) and with peginterferon α2b + ribavirin (P2bR) in Japanese patients with HCV genotype 1b infection. Methods Hepatitis C virus genotype 1b patients were randomly assigned to receive SMV (100 mg QD) with P2aR for 12 weeks, then P2aR alone for 12 or 36 weeks; or SMV (100 mg QD) with P2bR for 12 weeks, then P2bR alone for 12 or 36 weeks. The primary endpoint was a sustained virologic response 24 weeks after completing treatment (SVR24). Results In total, 151 patients were randomly assigned to the P2aR (n = 76) or P2bR group (n = 75). Six patients dropped out. Sustained virologic response 24 weeks after completing treatment was achieved in 55 (75.3%) of 73 P2aR patients and 55 (76.4%) of 72 P2bR patients. There was no difference in the rate of SVR24 between the two groups (P = 0.88). No differences in the proportion of patients who became HCV RNA-negative were detected between the P2aR and P2bR groups. The two groups had comparable numbers of adverse events, which led to the discontinuation of treatment in 9.6% and 8.3% of participants in the P2aR and P2bR groups, respectively. Conclusion Peginterferon α2a or α2b in combination with SMV + ribavirin therapy showed identical antiviral effects in patients with chronic hepatitis C. Also, the incidence of adverse events was identical for both regimens.

Tc-99m-galactosyl human serum albumin (GSA) scintigraphy is used to assess the hepatic functional reserve, and allows for visual assessment of the residual hepatocyte distribution on single-photon emission computed tomography/computed tomography (SPECT/CT) images. The association between heterogeneous liver uptake of Tc-99m-GSA and liver fibrosis remains to be studied in detail. We analyzed this association. Fifty-one patients with chronic hepatobiliary disease undergoing a Tc-99m-GSA scintigraphy were included in this study. The receptor (LHL15) and blood clearance (HH15) indexes (the uptake ratios of the liver and heart) were obtained from dynamic planar images. The liver uptake count maximum-to-mean ratio (LUC Max/Mean) was calculated from single-photon emission computed tomography/computed tomography (SPECT/CT) images as an indicator of the Tc-99m-GSA liver uptake heterogeneity. We assessed the relationship between these quantified values and liver fibrosis. There were 30 Child-Pugh classification grade A patients, 16 grade B patients, and 5 grade C patients. Among the 30 patients whose liver histopathology was evaluable, those with advanced liver fibrosis (F2-4) had a lower LHL15 than those with mild liver fibrosis (F0-1) (median, 0.90 vs. 0.92, P = .04), and a higher LUC Max/Mean (median, 1.80 vs. 1.70, P = .02). The multivariate analysis identified platelets (P = .04) and the LUC Max/Mean (P = .04) as contributing factors of advanced liver fibrosis. These findings suggest that Tc-99m-GSA SPECT/CT can be used not only to assess the hepatic functional reserve, but also to evaluate a degree of liver fibrosis.

【概要】C型慢性肝炎に対するDAA治療後の肝病理組織所見の検討は、これまで十分になされていませんでした。本研究ではDAA治療によってウイルス排除に成功し、かつ血液検査で異常が見られなかった51症例に対し肝生検を行い、炎症、線維化、鉄沈着、脂肪化などの項目について調べました。その結果、ほとんどの症例で肝組織の改善が見られました。また、同時に約2割程度の症例に有意な炎症が残存していることがわかりました。DAAによってC型肝炎ウイルスを排除することにより、血液検査のみならず肝生検結果の改善も見られたことから、治療によって将来的には肝硬変や肝臓がんへの進展が予防できることが期待されます。一方、炎症が残存していた症例の少なくとも一部は脂肪肝炎が原因であったことから、治療後もアルコール多飲や肥満などを避けて生活習慣に注意する必要があると考えられます。, Background: Interferon-free, direct-acting antiviral (DAA) treatments can result in a sustained virologic response (SVR) in nearly 100% of patients with chronic hepatitis C virus (HCV) infection. / Aims: To evaluate histological improvement after achieving an SVR to DAA treatments in patients with chronic hepatitis C. / Methods: Among 691 patients with chronic hepatitis C who achieved an SVR to DAAs, 51 underwent liver biopsy 41 ± 20 weeks after the end of treatment despite normal transaminase levels. In 20 patients, liver biopsy specimens obtained a median of 1.2 years before the start of treatment were available....

Background Hepatocellular carcinoma (HCC) develops in some patients who achieve sustained virological response (SVR) against hepatitis C virus (HCV) infection via anti-HCV therapy. To examine the pathogenesis of HCC development after HCV eradication, histopathological changes and clinical markers were evaluated in SVR patients. Methods Of 654 SVR patients treated with interferon (IFN)-based therapies, 34 patients who had undergone liver biopsy before initiating IFN therapy and after SVR achievement were enrolled: 11 patients with HCC and 23 patients without HCC (male/female, 9/2 and 8/15, respectively: age, 58 ± 5 and 54 ± 11 years, respectively). We compared the clinical and histopathological factors between the two groups. Immunohistochemistry for Cytoglobin (CYGB) and α smooth muscle actin (α-SMA) was also performed. Results At baseline, prior to initiating the IFN-based therapy, there were significant differences between the SVR-non-HCC and SVR-HCC groups in the male gender, HBc antibody positivity, prothrombin activity, and histological inflammatory grade. Histopathological evaluation, using the new Inuyama classification system, revealed an improvement in the inflammatory grade, from 2.1 ± 0.6 to 1.0 ± 0.6 (p < 0.0001), whereas the fibrosis stage remained unchanged, from 2.3 ± 0.9 to 2.0 ± 1.2 (p = 0.2749), during the 97 ± 72-month observation period in the SVR-HCC group. Both the grade and stage scores were significantly improved in the SVR-non-HCC group. The area of collagen deposition, evaluated using Sirius red staining, showed a marked decrease, from 18.6 ± 7.6% to 7.7 ± 4.6%, in the SVR-non-HCC group, with no change in the SVR-HCC group. CYGB- and α-SMA-positive hepatic stellate cells (HSCs), indicative of the HSC activated phenotype, remained in the fibrotic tissue of livers among patients in the SVR-HCC group. Conclusion Stagnation of fibrosis regression is associated with a high risk for HCC after SVR. HSC activation may inhibit improvement in fibrosis after SVR and potentially contribute to hepatocarcinogenesis.

Supplemental material, Supplementary Tables for Short-term histological evaluations after achieving a sustained virologic response to direct-acting antiviral treatment for chronic hepatitis C by Masaru Enomoto, Yoshihiro Ikura, Akihiro Tamori, Ritsuzo Kozuka, Hiroyuki Motoyama, Etsushi Kawamura, Atsushi Hagihara, Hideki Fujii, Sawako Uchida-Kobayashi, Hiroyasu Morikawa, Yoshiki Murakami and Norifumi Kawada in United European Gastroenterology Journal

Supplemental material, Supplementary Figures for Short-term histological evaluations after achieving a sustained virologic response to direct-acting antiviral treatment for chronic hepatitis C by Masaru Enomoto, Yoshihiro Ikura, Akihiro Tamori, Ritsuzo Kozuka, Hiroyuki Motoyama, Etsushi Kawamura, Atsushi Hagihara, Hideki Fujii, Sawako Uchida-Kobayashi, Hiroyasu Morikawa, Yoshiki Murakami and Norifumi Kawada in United European Gastroenterology Journal

Aim. Anemia is the most common adverse event in patients with chronic hepatitis C virus (HCV) treated with telaprevir (TVR) combined triple therapy. We examined the effects of drug dose adjustment on anemia and a sustained viral response (SVR) during combination therapy. Material and methods. This study enrolled 62 patients treated with TVR (2,250 mg) for 12 weeks plus pegylated interferon-alpha-2b and ribavirin for 24 weeks. The patients were assigned randomly to the TVR-standard or -reduced groups before treatment. At the occurrence of anemia (hemoglobin < 12 g/dL), the TVR-reduced group received 1500 mg TVR plus the standard dose of ribavirin, whereas the TVR-standard group received the standard TVR dose (2,250 mg) and a reduced dose of ribavirin (200 mg lower than prescribed originally). The safety and SVR at 24 weeks were compared between the TVR-standard (n = 28) and TVR-reduced (n = 25) groups. Results. No differences in the proportion of patients who became HCV RNA-negative were detected between the TVRstandard and -reduced groups (72 and 72% at week 4, 79 and 84% at the end of treatment, and 76 and 80% at SVR24, respectively). Two groups had comparable numbers of adverse events, which led to the discontinuation of TVR in 14 patients of TVR-standard group and in 14 of TVR-reduced group. A lower incidence of renal impairment was observed in the TVR-reduced group (6%) than the TVR-standard group (11%, not statistically significant). Conclusions. TVR dose adjustment could prevent anemia progression without weakening the anti-viral effect during triple therapy in HCV-patients.

We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, p < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.

Background and Aim 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) may detect primary lesions (PLs) and extrahepatic metastases (EHMs) only in advanced hepatocellular carcinoma (HCC) patients. We investigated the requirement of PET and the optimal timing of PET scanning for accurate staging and treatment planning. Methods We conducted a retrospective investigation of 64 HCC patients who underwent PET (median age, 74 years; male/female, 41/23; etiology, 46 hepatitis C virus/4 hepatitis B virus/4 alcoholic/10 others). To determine the best timing for PET examinations, we analyzed PET result-based recommended treatment changes and characteristics of patients with FDG-avid PLs or EHMs. Results FDG-avid PLs were detected by PET in 22 patients (34%): 18 with hypervascular PL, 11 with serum α-fetoprotein levels ≥ 200 ng/mL, and 11 beyond Milan criteria. EHMs were detected in 21 patients (33%: lymph nodes, 8; lung, 5; abdominal wall, 4; bone, 3; other organs, 4 [including overlapping]). Recommended treatments changed for 16 patients (25%) because of Barcelona Clinic Liver Cancer stage increases based on PET scanning. In multivariate analyses, serum α-fetoprotein levels ≥ 200 ng/mL and beyond Milan criteria were independent factors for FDG-avid PLs and a maximum standardized uptake value (SUVmax) of PLs of ≥ 4.0 was an independent factor for FDG-avid EHMs (P = 0.002, 0.008, and 0.045, respectively). Conclusions PET allows detection of HCC spread in patients with elevated serum α-fetoprotein levels or those beyond Milan criteria and detects EHMs in patients with PLs with high SUVmax values. Optimally timed PET scans can complement conventional imaging for accurate staging and treatment strategy determination.

Background and Aim To elucidate the clinical characteristics of hepatitis B virus reactivation (HBV-R), we performed a prospective long-term study of patients with hematologic malignancy, including both hepatitis B virus (HBV) carriers and those with resolved HBV infection. Methods Twenty-one patients with hematopoietic stem-cell transplants (HSCT) and 36 patients given rituximab-based chemotherapy were enrolled. Entecavir was administered prophylactically to eight patients with HBV surface antigen (HBsAg). HBV-DNA was measured every month in 49 patients with resolved HBV infection, and preemptive therapy was given to eight patients with HBV-R. Results HBV-R developed in five (26%) of 19 patients with HSCT and three (10%) of 30 patients given rituximab-based chemotherapy. HBV-R occurred a median of 3 months (range: 2–10) after the end of rituximab-based chemotherapy and 22 months (range: 9–36) after HSCT. HBV-R did not develop in patients with an antibodies against HBsAg (anti-HBs) titer exceeding 200 mIU/mL at baseline. Mutations in the “a” determinant region with amino acid replacement were detected in four of the eight patients with HBV-R. Preemptive therapy prevented severe hepatitis related to HBV-R. Entecavir treatment was stopped in four patients with HBV-R. Since the withdrawal of entecavir, HBV-DNA has not been detected in two patients persistently positive for anti-HBs. No patient had fatal hepatitis. Conclusions Proper management of patients with HBsAg or resolved HBV infection prevented fatal hepatitis related to HBV-R in patients who received immunosuppressive or cytotoxic therapy. Entecavir could be safely discontinued in patients with HBV-R who had acquired anti-HBs.

Cytoglobin (CYGB) is ubiquitously expressed in the cytoplasm of fibroblastic cells in many organs, including hepatic stellate cells. As yet, there is no specific marker with which to distinguish stellate cells from myofibroblasts in the human liver. To investigate whether CYGB can be utilized to distinguish hepatic stellate cells from myofibroblasts in normal and fibrotic human liver, human liver tissues damaged by infection with hepatitis C virus (HCV) and at different stages of fibrosis were obtained by liver biopsy. Immunohistochemistry was performed on histological sections of liver tissues using antibodies against CYGB, cellular retinol-binding protein-1 (CRBP-1), α-smooth muscle actin (α-SMA), thymocyte differentiation antigen 1 (Thy-1), and fibulin-2 (FBLN2). CYGB- and CRBP-1-positive cells were counted around fibrotic portal tracts in histological sections of the samples. The expression of several of the proteins listed above was examined in cultured mouse stellate cells. Quiescent stellate cells, but not portal myofibroblasts, expressed both CYGB and CRBP-1 in normal livers. In fibrotic and cirrhotic livers, stellate cells expressed both CYGB and α-SMA, whereas myofibroblasts around the portal vein expressed α-SMA, Thy-1, and FBLN2, but not CYGB. Development of the fibrotic stage was positively correlated with increases in Sirius red-stained, α-SMA-positive, and Thy-1-positive areas, whereas the number of CYGB- and CRBP-1-positive cells decreased with fibrosis development. Primary cultured mouse stellate cells expressed cytoplasmic CYGB at day 1, whereas they began to express α-SMA at the cellular margins at day 4. Thy-1 was undetectable throughout the culture period. In human liver tissues, quiescent stellate cells are CYGB positive. When activated, they also become α-SMA positive; however, they are negative for Thy-1 and FBLN2. Thus, CYGB is a useful marker with which to distinguish stellate cells from portal myofibroblasts in the damaged human liver.

Background and Aim It is not yet clear which factors are associated with the outcome of 72-week treatment with pegylated-interferon and ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Methods In 66 patients with HCV genotype 1 who had a late viral response (LVR) to 72-week treatment of pegylated-interferon and RBV, we examined the factors that determined the outcome, including single nucleotide polymorphisms of interleukin-28B and inosine triphosphatase (ITPA) genes. Results Thirty seven of 66 (56%) patients with LVR achieved a sustained viral response (SVR). The mean age of these 37 SVR patients was 55, compared with 61 in 29 relapsed patients (P = 0.009). Twenty six of 54 (48%) patients with the CC genotype and 11 of 12 (92%) with the CA/AA genotype of ITPA rs1127354 achieved SVR (P = 0.006). The SVR rates were 79%, 40%, 60%, and 33% in patients with undetectable HCV RNA on weeks 16, 20, 24, and 28 or later, respectively (P = 0.014). Finally, serum RBV concentration at week 44 of treatment was significantly higher in the SVR group (2651 ng/mL) than in the relapse group (1989 ng/mL, P = 0.002). In contrast, the rate of the interleukin-28B genotype was not different between the groups. Multiple regression analysis showed that age

SummaryAim Delayed gastric emptying, including gastroparesis, is a common complication in diabetes mellitus. The association between delayed gastric emptying and overall diabetic complications remains to be studied in detail. We analysed this association. Methods We performed gastric emptying scintigraphy of 99mTc-diethylenetriaminepentaacetic acid in 34 patients with diabetes to measure the gastric emptying half-times (T1/2) of the whole stomach (WS), proximal stomach (PS) and distal stomach (DS). We assessed T1/2, diabetic-related factors and complications. Results The prevalence of autonomic neuropathy was higher in the group with delayed T1/2 of the WS than in the normal group. Analysis of intima-media thickness (IMT) and ankle brachial pressure index (ABI), which are risk indicators for vascular disorder, showed that IMT of the carotid bulb was greater in the group with delayed T1/2 of the WS than in the normal group (2·41 mm [1·50–2·81] versus 1·40 mm [0·81–2·08], P = 0·015). T1/2 of the WS correlated positively with IMT of the carotid bulb (r = 0·391, P = 0·027) and negatively with ABI (r = −0·389, P = 0·028). These correlations were mainly attributed to PS and were the same in patients without autonomic neuropathy. In seven of nine patients who received scintigraphy again after diabetic treatment, glycosylated haemoglobin (HbA1c) levels decreased and T1/2 of the WS shortened compared with before treatment. Conclusion Vascular disorder, among other cofactors such as autonomic neuropathy, could be involved in the pathophysiology of delayed gastric emptying. Medium- to long-term glycaemic control was associated with gastric emptying.

Aim The association between sarcopenia and nutritional status is thought to be an important problem in patients with cirrhosis. In this study, we investigated whether nutritional factors were related to sarcopenia in patients with liver cirrhosis. Methods The subjects were 50 patients with cirrhosis aged 41 years or older. In this study, the subjects were interviewed about their dietary habits, and their daily physical activity was surveyed using a pedometer. The skeletal muscle mass index (SMI) was calculated using the appendicular skeletal muscle mass (ASM) measured by bioelectric impedance analysis. The handgrip strength was measured using a hand dynamometer. Sarcopenia was defined by SMI and handgrip strength. The patients with cirrhosis were categorized as normal group or sarcopenia group, and the two groups were compared. Univariate and multivariate logistic regression modeling were used to identify the relevance for sarcopenia in patients with cirrhosis. Results Height (odds ratio (OR), 5.336; 95% confidence interval [CI], 1.063-26.784; P = 0.042), energy intake per ideal bodyweight (IBW) (OR, 5.882; 95% CI, 1.063-32.554; P = 0.042) and number of steps (OR, 4.767; 95% CI, 1.066-21.321; P = 0.041) were independent relevant factors for sarcopenia. Moreover, a significantly greater number of the patients in the sarcopenia group had low values for both parameters' energy intake per IBW and number of steps. Conclusion Our results suggest that walking 5000 or more steps per day and maintaining a total energy intake of 30 kcal/IBW may serve as a reference for lifestyle guidelines for compensated cirrhotic patients.

It is unclear whether polymorphism in the inosine triphosphatase (ITPA) gene correlates to the reduction in hemoglobin (Hb) concentrations during sofosbuvir (SOF) and ribavirin (RBV) therapy. This study investigated the effects of the ITPA polymorphism on Japanese patients with chronic hepatitis C virus genotype 2 infection treated with SOF/RBV therapy.In 106 patients treated with SOF/RBV therapy, this study assessed the effects of the ITPA polymorphism (rs1127354) on anemia, RBV dose reduction, and sustained virological response.Of the 106 patients, 80 had the CC genotype, whereas 26 had a non-CC genotype in ITPA. Patients with the CC genotype had significantly larger reductions in Hb concentrations than those with a non-CC genotype throughout the treatment course. RBV dose reduction was required in 18/106 (17.0%) patients, with a significantly higher frequency in patients with the CC genotype than in those with a non-CC genotype (P = 0.010). In multivariate analysis, age ≥ 65 years (P = 0.011) and the ITPA CC genotype (P 0.0001) were factors significantly associated with anemia throughout the treatment course. Sustained virological response was achieved in 99.0% of all patients: 98.7% of patients with the CC genotype and 100% of patients with a non-CC genotype.Inosine triphosphatase polymorphism appeared to correlate with anemia incidence and RBV dose reduction during SOF/RBV therapy, but not the clinical outcome. Careful monitoring of Hb concentrations and prompt adjustment of RBV doses are required for successful treatment, particularly in patients harboring the ITPA CC genotype or age ≥ 65 years.

Simeprevir (SMV) is a potent, macrocyclic hepatitis C virus (HCV) non-structural 3/4 A protease inhibitor. This prospective study compared the efficacy and safety of SMV in combination with peginterferon α2a + ribavirin (P2aR) and with peginterferon α2b + ribavirin (P2bR) in Japanese patients with HCV genotype 1b infection.Hepatitis C virus genotype 1b patients were randomly assigned to receive SMV (100 mg QD) with P2aR for 12 weeks, then P2aR alone for 12 or 36 weeks; or SMV (100 mg QD) with P2bR for 12 weeks, then P2bR alone for 12 or 36 weeks. The primary endpoint was a sustained virologic response 24 weeks after completing treatment (SVR24).In total, 151 patients were randomly assigned to the P2aR (n = 76) or P2bR group (n = 75). Six patients dropped out. Sustained virologic response 24 weeks after completing treatment was achieved in 55 (75.3%) of 73 P2aR patients and 55 (76.4%) of 72 P2bR patients. There was no difference in the rate of SVR24 between the two groups (P = 0.88). No differences in the proportion of patients who became HCV RNA-negative were detected between the P2aR and P2bR groups. The two groups had comparable numbers of adverse events, which led to the discontinuation of treatment in 9.6% and 8.3% of participants in the P2aR and P2bR groups, respectively.Peginterferon α2a or α2b in combination with SMV + ribavirin therapy showed identical antiviral effects in patients with chronic hepatitis C. Also, the incidence of adverse events was identical for both regimens.

Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are liver originated malignant tumors. Of the two, ICC has the worse prognosis because it has no reliable diagnostic markers and its carcinogenic mechanism is not fully understood. The aim of this study was to integrate metabolomics and transcriptomics datasets to identify variances if any in the carcinogenic mechanism of ICC and HCC. Ten ICC and 6 HCC who were resected surgically, were enrolled. miRNA and mRNA expression analysis were performed by microarray on ICC and HCC and their corresponding non-tumor tissues (ICC_NT and HCC_NT). Compound analysis was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Principle component analysis (PCA) revealed that among the four sample groups (ICC, ICC_NT, HCC and HCC_NT) there were 14 compounds, 62 mRNAs and 17 miRNAs with two distinct patterns: tumor and non-tumor and ICC and non-ICC. We accurately (84.38%) distinguished ICC by the distinct pattern of its compounds. Pathway analysis using transcriptome and metabolome showed that several pathways varied between tumor and non-tumor samples. Based on the results of the PCA, we believe that ICC and HCC have different carcinogenic mechanism therefore knowing the specific profile of genes and compounds can be useful in diagnosing ICC.

Because of the chronic shortage of liver donors, hepatologists are required to prolong the liver transplant waiting period by preserving the hepatic reserve of scheduled recipients. This study examined the effectiveness of oral branched-chain amino acids (BCAAs), using outcome markers indicating pretransplant hepatic reserve. Fifty-six consecutive eligible patients with Child class A cirrhosis without major complications were randomly assigned to receive oral BCAA granules (12.45 g/day) for least 1 year or no BCAAs. Differences between groups in the Model for End-Stage Liver Disease (MELD) score, Child-Turcotte-Pugh (CTP) score, asialoscintigraphic clearance index (CI), and complications were examined. Of 50 remaining patients, 27 received BCAAs, and 23 received no BCAAs (mean duration, 3.2 years). The mean annual changes in the MELD score, CTP score, and asialoscintigraphic CI were smaller in the BCAA group than in the control group (-0.06 +/- 0.23 versus 0.10 +/- 0.40, P = 0.024, 0.06 +/- 0.30 versus 0.30 +/- 0.48, P = 0.037, and 0.00 +/- 0.02 versus 0.02 +/- 0.04, P = 0.040, respectively). The mean annual changes in the serum total bilirubin and the serum albumin in the BCAA group were better preserved than those in the control group (-0.07 +/- 0.20 versus 0.12 +/- 0.18 mg/dL, P < 0.001, and 0.07 +/- 0.13 versus -0.02 +/- 0.19 g/dL, P = 0.005, respectively); other laboratory variables were not significant. The incidence of overall major cirrhotic complications was lower in the BCAA group than in the control group [14.8% (4 of 27 patients) versus 30.4% (7 of 23 patients) at 3 years, P = 0.043]; only ascites was significant individually. In conclusion, early interventional oral BCAAs might prolong the liver transplant waiting period by preserving hepatic reserve in cirrhosis.

In bone scintigraphy, abnormal RI accumulation in ossified thyroid cartilage is often noted. However, because similar accumulation is also seen in tumor-involved cartilage, distinction between these two lesions is sometimes difficult. We examined the differences in RI accumulation by ossification of the thyroid cartilage and cartilage invasion with anterior, posterior, and oblique views of bone scintigraphy in this study.This study included 120 patients (104 men, 16 women; mean age 67.8 +/- 9.6 years; range 48-90 years) with laryngeal or lower pharyngeal carcinoma. The patients had exhibited abnormal accumulation of RI on thyroid cartilage on bone scintigraphy between February 1999 and March 2007. We evaluated accumulation of thyroid cartilage in the anterior, posterior, and oblique views on bone scintigraphy. The presence/absence of tumor invasion of the thyroid cartilage was checked by comparing the findings of enhanced computed tomography and magnetic resonance imaging (MRI) as well as evaluating operative records. RI accumulation in thyroid cartilage was divided into four types (diffuse accumulation, intense diffuse accumulation, slight inhomogeneous accumulation, and intense inhomogeneous accumulation).Tumor invasion of thyroid cartilage was noted in 2 of the 42 patients with diffuse accumulation, 1 of the 18 patients with intense diffuse accumulation, 1 of the 38 patients with slight inhomogeneous accumulation, and 17 of 22 patients with intense inhomogeneous accumulation. Because the degree of tumor invasion was highest in cases in which bone scintigraphy revealed intense inhomogeneous accumulation of RI in the thyroid cartilage, we judged this pattern of RI accumulation to be an indicator of tumor invasion. When diagnosis was based on this criterion, positive predictive value, negative predictive value, and accuracy were 77%, 96%, and 93%, respectively (P0.0001, Chi-square test).The findings of this study suggest that ossification of thyroid cartilage can be distinguished from tumor-involved thyroid cartilage on the basis of the pattern of abnormal RI accumulation in the thyroid cartilage in patients with head/neck cancer.

Single-photon emission computed tomography (SPECT) using gallium (Ga) has been frequently used for diagnosing head and neck tumors in patients. Although the usefulness of Ga-SPECT is well known, the degree of the increase in diagnostic ability with Ga-SPECT for head and neck tumors has not been reported. We compared the ability of the planar images of Ga scintigraphy, SPECT images of Ga scintigraphy, and CT images to diagnose head and neck primary tumors and neck metastases.The subjects of this study were 167 patients with malignant head/neck lesions. For Ga scintigraphy, Ga-67-citrate (74 MBq) was injected via a cubital vein. Planar and SPECT images were taken 72 h after the Ga-67-citrate injection. The rate of detection of the primary lesions was compared first between SPECT and planar images then between SPECT and CT images. The rate of detection for each stage of disease according to the TNM classification was also analyzed.The rate of detection of primary lesions was 50% with planar imaging and 69% with SPECT. And similarly, regarding the rate of detection of lymph node metastases, there was a significant difference between planar imaging and SPECT. The rate of detection of primary lesions was 70% for both CT and SPECT. At T stage, the rates of detection of primary lesions with each imaging technique were 11% with planar imaging and 39% with SPECT, and 22% with CT for stage T1.This study revealed the marked superiority of SPECT images over planar images in terms of the ability to detect primary tumors and tumor metastasis to cervical lymph nodes. Furthermore, the primary T1 tumor detection rate of SPECT images was higher than that of CT images. On the basis of these results, the concomitant use of SPECT is highly recommended when Ga scintigraphy is performed to check for malignant head/neck tumors.

We report a 67-year-old woman with systemic lupus erythematosus and systemic disseminated tuberculosis affecting the femoral trochanteric bursae, a site rarely affected by tuberculosis. For quantification of the inflammation with gallium-67 scintigraphy, we calculated the radioisotope count ratio in the most inflamed areas, the right lateral thorax and bursa of the right greater trochanter. Systemic scanning with this modality allowed evaluation of the extent of lesions and simple quantitative determination of the severity of inflammation, yielding information useful for the follow-up of the patient during the course of tuberculosis treatment.

The extrapancreatic bile duct lesions in autoimmune pancreatitis are termed sclerosing cholangitis (SC with AIP), which is known to complicate AIP somewhat more frequently than other extrapancreatic lesions. In cases of SC with AIP, differentiation from primary SC, pancreatic cancer, and bile duct cancer is often difficult. In our patient, pancreatic cancer had to be ruled out at admission, given the findings of obstructive jaundice, pancreatic duct stenosis, and swelling of the pancreas. Fluorine-18-fluorodeoxyglucose positron emission tomography was useful in checking for the presence of extrapancreatic lesions, including SC, and was also useful in the evaluation of the response to steroid therapy for following the course of AIP.

Summary Background Atrophic and inflammatory changes in the gastric mucosa are commonly observed in Japanese patients with functional dyspepsia. However, detailed data regarding the correlation between the severity of these changes and the symptoms of functional dyspepsia are not available. Aim To evaluate grading scales of gastric atrophy and inflammation, severity of clinical symptoms, and gastric emptying in patients with functional dyspepsia. Methods Ninety-three patients with dyspepsia were enrolled. The severity of gastric atrophy was graded through serological and histological examination, and gastric inflammation was evaluated histologically. Clinical symptoms were evaluated on the Gastrointestinal Symptoms Rating Scale, including subscales for abdominal pain, acid reflux, diarrhoea, indigestion and constipation. Gastric emptying half-time was measured using a radioisotope technique. Results Helicobacter pylori infection and gastric inflammation influenced neither clinical symptoms nor gastric emptying time. However, a correlation was observed between gastric atrophy as graded by serological examination and indigestion (R = 0.31, P = 0.01). Histological examination also showed a correlation between gastric atrophy and abdominal pain and indigestion (R = 0.31, P = 0.04 and R = 0.35, P = 0.02 respectively). Conclusion Gastric atrophy associated with H. pylori infection may be partly responsible for the clinical symptoms experienced by patients with functional dyspepsia.

Small cell carcinoma (SmC) of the esophagus is rare, and is sometimes impossible to detect by macroscopic inspection using an endoscope or histological examination of biopsied specimens. A 73-year-old man received F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate the response to radiofrequency thermal ablation therapy for lung cancer. FDG-PET showed abnormal accumulation in the posterior mediastinum. Endoscopy disclosed ulcerous lesions with marginal elevation in the middle segment of the esophagus, but the biopsy specimen taken concurrently was not malignant histologically. FDG-PET, performed two months later, revealed abnormal accumulation in the suspect area, and the extent of accumulation was wider than previously. Histological examination of the specimen biopsied during the endoscopy led to a diagnosis of SmC. FDG-PET thus proved useful in the early detection of SmC.