Mie Shinohara

Long-term follow-up of chronic hepatitis C patients treated with oral lactoferrin for 12 months.

BACKGROUND/AIMS: Bovine lactoferrin (bLF) has been shown to prevent the infection of cultured hepatocytes by hepatitis C virus (HCV). The present study attempted to clarify the effects of long-term administration of bLF on serum parameters, including immunomodulatory cytokines, in patients with chronic hepatitis C (CHC). METHODS: Sixty-three CHC patients were randomly assigned into 2 groups. At an oral dose of 600 mg/day, bLF was administered for 12 months to 36 patients (bLF group), while no bLF was given to the remaining 27 patients (control group. Serum levels of alanine aminotransferase, HCV-RNA, IL-10, and IL-18 were evaluated, as well as CD4-positive T cell subsets in the peripheral blood. RESULTS: The serum IL-18 level was increased by bLF administration, but not in the control group. After 3 months of bLF treatment, it was significantly higher than before bLF administration, but it decreased gradually thereafter. The percentage of interferon (IFN)-gamma+ and IL-4- (Th1) cells in the peripheral blood increased along with the serum IL-18 level, although the change was not statistically significant. The other parameters did not change significantly during the study period in both groups. CONCLUSIONS: These results suggest that oral administration of bLF to CHC patients for up to 3 months can produce a Th1-cytokine dominant environment in the peripheral blood that favors the eradication of HCV by IFN therapy.

Sorafenib Prevents Escape from Host Immunity in Liver Cirrhosis Patients with Advanced Hepatocellular Carcinoma

Purpose. It has been reported that Th2 cytokines downregulate antitumor immunity, while activation of type T cells promotes antitumor immunity. The aim of this paper was to evaluate host immunity in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) receiving sorafenib therapy. Methods. Forty-five adult Japanese LC patients received sorafenib for aHCC between 2009 and 2011 at our hospital. Sorafenib was administered at a dose of 200–800u2009mg/day for 4 weeks. Blood samples were collected before and after treatment. Results. Eleven patients were treated with sorafenib at 200u2009mg/day (200 group), 27 patients received sorafenib at 400u2009mg/day (400 group), and 7 patients were given sorafenib at 800u2009mg/day (800 group). There was no significant change in the percentage of Th1 cells after treatment in any group. However, the percentages of Th2 cells and regulatory T cells were significantly decreased after treatment in the 400 group and 800 group compared with before treatment, although there was no significant change after treatment in the 200 group. Conclusions. These results indicate that treatment with sorafenib might induce Th1 dominance and prevent the escape of tumor cells from the host immune system in LC patients with aHCC.

Hepatotoxicity of intra-arterial combination chemotherapy in patients with liver cirrhosis and advanced hepatocellular carcinoma

PurposeWe have previously reported that 24-h intra-arterial combination chemotherapy (IACC) prolongs the survival of patients with advanced hepatocellular carcinoma (aHCC). However, it has also been reported that 5-fluorouracil (5-FU) exacerbates liver damage in patients with liver cirrhosis (LC). The aim of this study was to clarify the hepatotoxicity of IACC in LC patients with aHCC.MethodsTwenty-one adult Japanese patients (20 men and 1 woman) with aHCC and LC underwent IACC between 2004 and 2007 at our hospital. These patients showed multiple partial responses or stable disease, except for five patients who showed no response and three patients with tumors more than 30xa0mm in diameter. All patients had inoperable disease on the basis of computed tomography (CT) findings. IACC (leucovorin at 12xa0mg/h, cisplatin at 10xa0mg/h, and 5-FU at 250xa0mg/22xa0h) was delivered via the proper hepatic artery every 5xa0days for 4xa0weeks.ResultsTwelve patients were in Child-Pugh class A (group A), and nine were in class B (group B). The Child-Pugh score was significantly increased after chemotherapy compared with before chemotherapy in both groups. Serum albumin was significantly decreased after chemotherapy, and the number of patients with ascites also increased after chemotherapy. Serum type IV collagen and N-terminal propeptide of type III procollagen were significantly increased after chemotherapy, although there was no significant change in serum aminotransferases.ConclusionsIACC might cause hepatotoxicity that induces fibrosis without releasing aminotransferases.

Visualization of segmental arterialization with arrival time parametric imaging using Sonazoid-enhanced ultrasonography in portal vein thrombosis: A case report

A 55-year-old male was admitted in mid-April 2011 with a fever of >39°C and pain in the lower right abdomen. A medical examination revealed sepsis originating from colonic diverticulitis. Abdominal B-mode ultrasonography (US) performed on admission detected thrombi in the superior mesenteric vein and in the right branch of the hepatic portal vein. Arrival time parametric imaging (At-PI) using Sonazoid-enhanced US showed arterialization of the entire right lobe of the liver. The treatment for the sepsis and portal thrombi that had been started upon admission dissolved the thrombi by day 22, with the exception of one thrombus in the P8 branch of the portal vein. At-PI performed on the same day confirmed arterialization in segment 8, but portal vein dominance was restored elsewhere. When the blood inflow from the hepatic portal vein was reduced, the hepatic arterial blood flow was increased to compensate for the reduction in the total blood supply. The At-PI functions used in the Sonazoid-enhanced US were simple yet effective in visualizing the changes in the hepatic hemodynamics caused by the portal thrombus.

Effects of mutation number in interferon sensitivity determining region on peripheral blood CD4(+) T cell subsets (Th1, Th2) in chronic hepatitis C patients with hepatitis C virus genotype 1b and high viral load

Background/aimThe number of amino acid (AA) mutations in the interferon sensitivity determining region (ISDR) of NS5A is reported to affect the response to interferon (IFN) therapy in patients with chronic hepatitis C (CHC). The aim of this study was to clarify whether host immunity is influenced by the number of AA mutations in the ISDR.Patients and methodsSubjects included 44 patients with CHC infected with genotype 1b and high viral load. The number of AA mutations in the ISDR was retrospectively determined using stored serum samples taken immediately before starting therapy. All patients received IFN-alpha 2b or pegylated-IFN (PEG-IFN)-alpha 2b and ribavirin. When serum hepatitis C virus-ribonucleic acid (HCV-RNA) was negative at 4 or 12xa0weeks after starting therapy, the patient was defined as having rapid viral response (RVR) or early viral response (EVR), respectively. CD4+ T cell (Th1 or Th2) in peripheral blood (PB) before and until day 56 of treatment was analyzed.ResultsRates of RVR and EVR were 0 (0/21) and 14% (3/21), respectively, in patients with one or fewer AA mutations in the ISDR (ISDR0-1), and 30 (7/23), and 74% (17/23), respectively, with two or more AA mutations in the ISDR (ISDRxa0>xa02). Although the percentage of PB Th1 cells did not differ between the two groups during the study period, the percentage of PB Th2 cells was significantly lower in the ISDR0-1 group than in the ISDRxa0>xa02 group at baseline and on daysxa03, 7, 14, and 28 of treatment.ConclusionThe number of AA mutations in the ISDR influenced PB Th2 cells before and until day 28, and was associated with higher RVR and EVR rates.

Changes of cytokines in patients with liver cirrhosis and advanced hepatocellular carcinoma treated by sorafenib

PurposeRecently, the oral multikinase inhibitor sorafenib has been used to treat advanced hepatocellular carcinoma (aHCC). Tumor necrosis factor (TNF) induces apoptosis of tumor cells by binding to TNF-related apoptosis-inducing ligand, while binding of the Fas ligand on cytotoxic T lymphocytes to the Fas receptor on hepatocytes also causes apoptosis. The aim of this study was to retrospectively evaluate changes of cytokines in patients with liver cirrhosis (LC) and aHCC receiving sorafenib therapy.MethodsFifty-seven adult Japanese LC patients received sorafenib for aHCC (200–800xa0mg/day for 4xa0weeks) between 2009 and 2012 at our hospital. Blood samples were collected in the early morning before and after treatment, and the serum levels of soluble TNF-alpha (sTNF-alpha), soluble TNF receptor (sTNF-R), soluble Fas ligand (sFas L), and soluble Fas (sFas) were evaluated.ResultsTen patients were treated with sorafenib at 200xa0mg/day (200xa0mg group), 37 patients were given 400xa0mg/day (400xa0mg group), and 10 patients received 800xa0mg/day (800xa0mg group). The serum level of sTNF-alpha was significantly increased after treatment compared with before treatment in the 400 and 800xa0mg groups. The serum level of sTNF-R also showed a significant increase after treatment in the 400xa0mg group, although there was no significant difference of sTNF-R between before and after treatment in the 200 and 800xa0mg groups. sFas showed a significant decrease after treatment compared with before treatment in the 400 and 800xa0mg groups, although the serum level of sFas L never exceeded 0.15xa0ng/ml.ConclusionsThese findings suggest that treatment with sorafenib at doses ≥400xa0mg/day might promote TNF-related or Fas-related apoptosis by increasing the circulating level of TNF-alpha or decreasing that of sFas.

Ultrasonography of intrahepatic bile duct adenoma with renal cell carcinoma: correlation with pathology

Intrahepatic bile duct adenoma (BDA) is a relatively rare benign tumor. Most cases are incidentally discovered during surgery or autopsy. We report here the co-existence of renal cell carcinoma and BDA mimicking metastasis in a 30-year-old female. An isoechoic nodule with a hypoechoic rim sized 10xa0×xa09xa0mm was observed by ultrasonography in S2 of the liver. On contrast-enhanced ultrasonography (CEUS), the mass was enhanced in the early vascular phase and a defect with a clear border appeared in the post-vascular phase. We present the ultrasonography findings of BDA, including those yielded by CEUS using Sonazoid, along with the gross and microscopic pathological correlation.

Hepatic arterialization can predict the development of collateral veins in patients with HCV-related liver disease

PurposeArrival time parametric imaging (At-PI) using contrast-enhanced ultrasonography (CEUS) is a procedure for evaluating liver disease progression in chronic hepatitis C infection (CHC). We investigated At-PI diagnostic efficacy in predicting development of collateral veins.MethodsIn total, 171 CHC patients underwent CEUS and upper gastrointestinal (UGI) endoscopy before liver biopsy. Conventional US was performed before CEUS to identify paraumbilical veins (PV) or splenorenal shunts (SRS). After intravenous perflubutane, contrast dynamics of liver segments 5–6 and the right kidney were saved as raw data. At-PI image ratio of red (ROR) pixels to the entire liver was analyzed. Receiver operating characteristic (ROC) curves were generated to investigate the utility of At-PI for collateral vein identification.ResultsConventional US revealed PV in two patients and SRS in five patients; UGI endoscopy detected esophageal varices (EV) in eight patients. Diagnostic capability of At-PI for detecting PV, SRS, and EV was satisfactory, and high for PV and SRS [PV; area under the ROC curve (AUROC) 0.929, cutoff value 77.9%, SRS; AUROC 0.970, cutoff value 82.0%, EV; AUROC 0.883, cutoff value 66.9%].ConclusionsEvaluation of hepatic arterialization by At-PI was useful for predicting collateral vein development in CHC patients.SommarioScopoL’imaging parametrico con calcolo del tempo di arrivo (At-PI) mediante l’uso dell’ecografia con mezzo di contrasto ( CEUS) è una procedura che può valutare la progressione della malattia cronica di fegato in corso di epatite HCV relata (CHC). Gli Autori hanno indagato l’efficacia diagnostica di At-PI nel predire lo sviluppo di circoli collaterali.MetodiIn totale 171 pazienti sono stati sottoposti a CEUS e ad endoscopia del tratto digestivo superiore (UGI) prima della biopsia epatica. Un’ecografia convenzionale è stata eseguita prima della CEUS per identificare pervietà della v. ombelicale (PV) o di shunt spleno-renale spontaneo (SRS). Dopo iniezione e.v. di perflubutano sono stati salvati i dati grezzi della dinamica del m.d.c. raccolti dai segmenti 5 e 6. E’ stato inoltre analizzato il rapporto dell’immagine At-pi con i pixel rossi (ROR) dell’intero fegato. Sono state ottenute delle curve ROC per valutare l’utilità della At-PI nell’identificare circoli collaterali.RisultatiL’ecografia di base ha identificato PV in due pazienti e SRS in cinque pazienti; UGI ha diagnosticato varici esofagee in otto pazienti. La capacità diagnostica di At-PI per identificare PV, SRS e varici esofagee è stata soddisfacente ed elevata per PV ed SRS (PV : area sotto la curva ROC (AUROC) = 0,929 con valore di cut-off = 77,9%; SRS : AUROC = 0,970 con cut-off = 82;0% ; varici esofagee : AUROC = 0,883 con cut-off = 66,9 ).ConclusioniLa valutazione dell’arterializzazione epatica mediante At-PI è stata utile nel predire circoli collaterali spontanei nei pazienti con malattia cronica di fegato HCV relata.