Hidenari Nagai

Therapeutic strategy of advanced hepatocellular carcinoma by using combined intra-arterial chemotherapy.

The majority of primary liver cancer is hepatocellular carcinoma (HCC). HCC has increased in many countries, particularly where hepatitis C virus infection is more common than hepatitis B virus infection. Several non-surgical treatment options, including transcatheter arterial embolization, percutaneous ethanol injection, microwave coagulation, and radiofrequency ablation have been developed and are widely used for unresectable HCC. However, these modalities are not indicated for patients with multifocal disease, invasion or thrombosis of major blood vessels, and poor liver function. The majority of patients with advanced hepatocellular carcinoma (aHCC) do not survive for longer than 6 months from the time of diagnosis. Combined intra-arterial chemotherapy is one of the few remaining options for patients with aHCC. Continuous local arterial infusion of 5-fluorouracil (5-FU) and cisplatin (CDDP) via an infuser pump and implanted reservoir has been shown to prolong the survival of patients with aHCC. When LC patients with aHCC undergo chemotherapy, we should consider the influence of both tumor factors and host immunity. This review focuses on therapeutic strategy of patients with aHCC by using combined intra-arterial chemotherapy and the influence of host immunity on the response to such chemotherapy based on our results. The present article shows some recent patents related to the field.

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 200–800 mg/day for 4 weeks. Blood samples were collected before and after treatment. Results. Eleven patients were treated with sorafenib at 200 mg/day (200 group), 27 patients received sorafenib at 400 mg/day (400 group), and 7 patients were given sorafenib at 800 mg/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.

Disappearance of HCV after cessation of immunosuppression in a patient with ulcerative colitis and renal transplantation

We report a patient, a 45-year-old Japanese woman, who underwent living-related donor renal transplantation in 1986 and 1988, with the second procedure being successful. Ulcerative colitis (UC) was diagnosed in 1987 while she was receiving immunosuppressive therapy after the renal transplantation. She became positive for serum anti-hepatitis C virus (HCV) in November 1990, although her serum aminotransferase levels were normal. In June 2001, she had frequent episodes of melena with abdominal pain, as control of her UC deteriorated. In July 2001, she was admitted to the Department of Surgery at our hospital, and her daily dose of prednisolone was increased from 40 mg to 80 mg. After 2 weeks of high-dose prednisolone therapy, there was a significant increase of serum aminotransferases, and serum HCV-RNA rose above 850 KIU/ml (by reverse transcription-polymerase chain reaction [RT-PCR]). Control of UC was still poor, so cyclosporine A (CyA) was added at a dose that maintained a high serum concentration. The daily dose of prednisolone was tapered and leukapheresis was performed three times weekly. As result, serum aminotransferases decreased to the normal range. However, total colectomy and colostomy were required because the UC could not be controlled by these therapies. Serum aminotransferase levels increased transiently 2 months after the cessation of immunosuppressive therapy (prednisolone, azathioprine [AZP], and CyA). Subsequently, serum aminotransferases rapidly declined below normal, and the serum level of HCV-RNA (by RT-PCR) fell from 480 KIU/ml to less than 0.5 KIU/ml. She was discharged on April 25, 2002. During follow-up as an outpatient, serum HCV-RNA became negative and remained negative for 7 months. To confirm clearance of HCV, liver biopsy was performed, and no HCV-RNA was detected in the liver tissue by RT-PCR. These findings suggested that HCV was cleared by the cessation of immunosuppressive therapy, as a rebound effect.

Characteristics of hepatic insulin‐sensitive nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high‐HIS, mid‐HIS, low‐HIS), as assessed by the hyperinsulinemic‐euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high‐HIS group was identical to that of the non‐NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% ± 5.2% versus 91.0% ± 8.5%, respectively) and was significantly higher than that of the low‐HIS group (66.6% ± 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high‐HIS and low‐HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis‐aconitic acid, were significantly higher in the high‐HIS group compared to the low‐HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% ± 16.1% versus 20.4% ± 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin‐sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634–647)

Diagnosis of hepatic hemangioma by parametric imaging using sonazoid-enhanced US.

BACKGROUND/AIMS Comparison of Parametric Imaging (PI) using Sonazoid-enhanced ultrasonography (US) and microflow imaging (MFI) to determine the possibility of hepatic hemangioma diagnosis using PI. METHODOLOGY Twenty-two hepatic hemangioma nodules (mean±SD diameter: 31.6±19.1mm) undergoing Sonazoid-enhanced US between February 2008 and March 2009. After Sonazoid-enhanced US, COMMUNE ultrasonographic image analysis software was used for analysis of tumor imaging dynamics in the vascular phase using PI and MFI. In PI, 0s was set as the time contrast agent reached the tumor. Imaging within the tumor after 0s was color-coded according to time, and the images were displayed in color. In MFI, 0s was set as the time contrast agent reached the tumor. The path of microbubbles as it flowed through blood vessels was superimposed on the original B-mode images. Three trained physicians used these methods to analyze tumor imaging dynamics. RESULTS All physicians concluded all cases were hepatic hemangioma regardless of method used. However, compared to MFI, PI allowed determination of more detailed blood flow dynamics in high-flow hepatic hemangioma, where blood flow speed was faster than in normal hepatic hemangioma. CONCLUSIONS It is possible to diagnose hepatic hemangioma using PI using sonazoid-enhanced US.

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.

Comparison of the hemodynamics between patients with alcoholic or HCV-related cirrhosis

BACKGROUND/AIMS Hyperdynamic circulation, which is characterized by increased cardiac output (CO), normal or low arterial blood pressure (BP), and decreased systemic vascular resistance (SVR), occurs in patients with liver cirrhosis (LC). However, differences of hemodynamics between patients with alcoholic LC (ALC) and viral LC are not well understood. The aim of the present study was to compare hemodynamics between patients with alcoholic LC and patients with HCV-related LC (CLC). METHODOLOGY Eighteen healthy Japanese volunteers (HV), 10 patients with chronic hepatitis (CH), 46 patients with CLC, and 22 ALC patients with ALC were included in the study. The CLC group was divided into two subgroups (34 non-ascites and 12 ascites patients), as was the ALC group (11 non-ascites and 11 ascites patients). The CO, portal blood flow (PBF), and hepatic congestion index (HCI) were measured by ultrasound. RESULTS The CO of the CLC and the ALC groups was higher than that of the HV group, while the SVR of the CLC and ALC groups was lower than that of the HV group. These changes were more marked in the ALC group. The HCI of the ascitic ALC subgroup was higher than that of the HV group. PBF did not differ among the CLC, ALC and HV groups. CONCLUSIONS Progression of liver diseases such as ALC or CLC leads to a hyperdynamic circulation. The decrease of SVR was more marked in ALC patients than that CLC patients and an increase of the HCI was only found in ALC patients with ascites.

Changes of cytokines in cirrhosis patients with advanced hepatocellular carcinoma treated by intra-arterial chemotherapy.

IntroductionTumor necrosis factor (TNF) induces cancer cell-specific apoptosis by binding to a TNF-related apoptosis-inducing ligand. Binding of the Fas ligand on cytotoxic T lymphocytes to the Fas receptor on hepatocytes is also known to induce apoptosis. The aim of this study was to clarify changes of cytokines in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) receiving intra-arterial combination chemotherapy.MethodsTwenty-one adult Japanese LC patients with aHCC received intra-arterial combination chemotherapy. The serum levels of TNF-alpha, soluble TNF receptor-I (sTNFr-I), soluble Fas ligand (sFas L), and soluble Fas (sFas) were evaluated.ResultsThirteen of the 21 patients (group R) showed an objective response, while the other eight patients (group N) showed no response. The serum level of TNF-alpha was lower after chemotherapy than before chemotherapy in group N, but there was no difference of serum sTNFr-I levels between before and after chemotherapy and there were also no differences between the two groups. The serum sFas levels were higher after chemotherapy than before chemotherapy in group N, while there was no difference among groups.ConclusionsThese results indicate that a high serum TNF-alpha level and a low serum sFas level might be important for successful combined arterial chemotherapy in LC patients with aHCC.

Arrival time parametric imaging of the hemodynamic balance changes between the hepatic artery and the portal vein during deep inspiration, using Sonazoid-enhanced ultrasonography: A case of Budd‑Chiari syndrome

This case report concerns a 40-year-old male who had previously been treated for an esophageal varix rupture, at the age of 30 years. The medical examination at that time revealed occlusion of the inferior vena cava in the proximity of the liver, leading to the diagnosis of the patient with Budd-Chiari syndrome. The progress of the patient was therefore monitored in an outpatient clinic. The patient had no history of drinking or smoking, but had suffered an epileptic seizure in 2004. The patients family history revealed nothing of note. In February 2012, color Doppler ultrasonography (US) revealed a change in the blood flow in the right portal vein branch, from hepatopetal to hepatofugal, during deep inspiration. Arrival time parametric imaging (At-PI), using Sonazoid-enhanced US, was subsequently performed to examine the deep respiration-induced changes observed in the hepatic parenchymal perfusion. US images captured during deep inspiration demonstrated hepatic parenchymal perfusion predominantly in red, indicating that the major blood supply was the hepatic artery. During deep expiration, the portal venous blood flow remained hepatopetal, and hepatic parenchymal perfusion was displayed predominantly in yellow, indicating that the portal vein was the major source of the blood flow. The original diagnostic imaging results were reproduced one month subsequently by an identical procedure. At-PI enabled an investigation into the changes that were induced in the hepatic parenchymal perfusion by a compensatory mechanism involving the hepatic artery. These changes occurred in response to a reduction in the portal venous blood flow, as is observed in the arterialization of hepatic blood flow that is correlated with the progression of chronic hepatitis C. It has been established that the peribiliary capillary plexus is important in the regulation of hepatic arterial blood flow. However, this case demonstrated that the peribiliary capillary plexus also regulates acute changes in portal venous blood flow, in addition to the chronic reduction in blood flow that is observed in patients with chronic hepatitis C.

Influence of bile acids with respect to the time course against cultured rat hepatocytes

The bile acids circulate tightly bound to albumin. There are some reports in which eytotoxic effects of several bile acids for cultured rat hepatocytes are investigated under albumin free condition. We reported that not only primary and secondary bile acids but also taurocholate and ursodeoxycholate inhibited the extraction ofbromosulfophthalein by cultured rat hepatocytes if they were administered overnight with rat hepatocytes under eight times albumin excesses (Am J Physio1267:G458-G464). The aims of this study were to investigate the influences of several bile acids as a cytotoxic agent against cultured rat hepatocytes. METHODS: Hepatocytes were isolated from adult male Spraque-Dawley rats and cuhured with 100 uM of cholate (CA), chenodeoxycholate (CDCA), deoxycholate (DCA), lithocholate (LCA) or taurocholate (TCA) for indicated hours. We examined the releases of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) in the medium, cell viabilities by Tripan blue exclusion test, the protein contents derived from cultured hepatoeytes and intracellular accumulated bile acids contents. RESULT: The bile acids administered for 20 hours under albumin excesses condition induced the releases of LDH and ALT. The cell viability was gradually lowered according to culturing time by only LCA. The protein contents derived from cultured rat hepatocytes were significantly lowered by CDCA, DCA and LCA as compared with control that did not contain any bile acids for 20 hours. Intraeellular accumulated bile acids contents varied by time course, but it seemed that LCA was stored in cultured rat hepatocytes for 20 hours. CONCLUSION: These results may suggest that LCA disturbed to attach rat hepatocytes to the cukure dishes by detergent effects, and other bile acids administered induced leakage of LDH or ALT but not disturb to attach rat hepatocytes to the culture dishes under albumin excesses condition: CIRCULATING AND ASCITIC LEVELS OF SOLUBLE INTERCELLULAR ADHESION MOLECULE-1 IN PATIENTS WITH ALCOHOLIC LIVER CIRRHOSIS: RELATION TO DISEASE ACTIVITY AND ALCOHOL INTAKE. I. Nagy and Y. M~indi, Depts. of Medicine 1 & Microbiology, A. Szent-Gy6rgyi Medical University, Szeged, Hungary