Bioconjugation of gold-polymer core-shell nanoparticles with bovine serum amine oxidase for biomedical applications.

Core-shell gold nanoparticles [AuNPs], stabilized with a hydrophilic polymer, poly(3-dimethylammonium-1-propyne hydrochloride) [PDMPAHCl], have been used for the immobilization of bovine serum amine oxidase [BSAO]. The functionalized surface of the hybrid nanoparticles is pH responsive, due to the presence of aminic groups that carry out a double role: on one hand they act as ligands for the gold nanoparticle surface, allowing the colloidal stabilization and, on the other hand, they give a hydrophilic characteristic to the whole colloidal suspension. The core-shell nanoparticles [Au@PDMPAHCl] have been characterized by using UV-vis and X-ray photoelectron spectroscopy, DLS, ζ-potential measurements and by FE-TEM microscopy. BSAO enzyme can be loaded by non-covalent immobilization onto Au@PDMPAHCl nanoparticles up to 70% in weight, depending on the pH values of the environmental medium. Activity tests on Au@PDMPAHCl-BSAO bioconjugates confirm an enzymatic activity up to 40%, with respect to the free enzyme activity. Moreover, our results show that loading and enzymatic activity are rather interrelated characteristics and that, under appropriate polymer concentration and pH conditions, a satisfactory compromise can be reached. These results, as a whole, indicate that Au@PDMPAHCl-BSAO bioconjugate systems are promising for future biomedical applications.

Successful combined liver/kidney transplantation from a donor with Pompe disease.

Pompe disease results from inherited deficiency of the enzyme acid alpha-glucosidase resulting in lysosomal accumulation of glycogen primarily in skeletal muscle. Reported is the first case in which a donor with late onset Pompe disease (LOPD) was successfully used for deceased donor liver and kidney transplantation. This case demonstrates co-operative transplant surgery and genetic medicine evaluation and risk estimation for donors with inherited metabolic disorders some of which may be suitable for donation of selected organs for transplantation.

Cost-effectiveness of combination peginterferon alpha-2a and ribavirin compared with interferon alpha-2b and ribavirin in patients with chronic hepatitis C.

BACKGROUND: Sustained virological response (SVR) is the primary objective in the treatment of chronic hepatitis C (CHC). Results from a recent clinical trial of patients with previously untreated CHC demonstrate that the combination of peginterferon alpha-2a and ribavirin produces a greater SVR than interferon alpha-2b and ribavirin combination therapy. However, the cost-effectiveness of peginterferon alpha-2a plus ribavirin in the U.S. setting has not been investigated. METHODS: A Markov model was developed to investigate cost-effectiveness in patients with CHC using genotype to guide treatment duration. SVR and disease progression parameters were derived from the clinical trials and epidemiologic studies. The impact of treatment on life expectancy and costs were projected for a lifetime. Patients who had an SVR were assumed to remain virus-free for the rest of their lives. In genotype 1 patients, the SVRs were 46% for peginterferon alpha-2a plus ribavirin and 36% for interferon alpha-2b plus ribavirin. In genotype 2/3 patients, the SVRs were 76% for peginterferon alpha-2a plus ribavirin and 61% for interferon alpha-2b plus ribavirin. Quality of life and costs were based on estimates from the literature. All costs were based on published U.S. medical care costs and were adjusted to 2003 U.S. dollars. Costs and benefits beyond the first year were discounted at 3%. RESULTS: In genotype 1, peginterferon alpha-2a plus ribavirin increases quality-adjusted life expectancy (QALY) by 0.70 yr compared to interferon alpha-2b plus ribavirin, producing a cost-effectiveness ratio of $2,600 per QALY gained. In genotype 2/3 patients, peginterferon alpha-2a plus ribavirin increases QALY by 1.05 yr in comparison to interferon alpha-2b plus ribavirin. Peginterferon alpha-2a combination therapy in patients with HCV genotype 2 or 3 is dominant (more effective and cost saving) compared to interferon alpha-2b plus ribavirin. Results weighted by genotype prevalence (75% genotype 1; 25% genotype 2 or 3) also show that peginterferon alpha-2a plus ribavirin is dominant. Peginterferon alpha-2a and ribavirin remained cost-effective (below $16,500 per QALY gained) under sensitivity analyses on key clinical and cost parameters. CONCLUSION: Peginterferon alpha-2a in combination with ribavirin with duration of therapy based on genotype, is cost-effective compared with conventional interferon alpha-2b in combination with ribavirin when given to treatment-naïve adults with CHC.

Albumin dialysis in cirrhosis with superimposed acute liver injury: possible impact of albumin dialysis on hospitalization costs.

Albumin dialysis using the Molecular Adsorbents Recirculating System (MARS) has been found to be beneficial in the treatment of cirrhotic patients with acute decompensation to improve survival as well as reduce associated complications. The present study attempts to analyze the costs involved, and compare it to the benefit as a result of the MARS therapy, thus evaluating its cost-effectiveness. Using the results of a study by Kim et al. describing the effects of complications on the cost of hospitalization in alcoholic liver disease patients, the expenditure incurred in a group of 11 patients treated with standard medical therapy (five survivors) and a group of 12 patients treated with MARS in addition (11 survivors) (Heemann et al., Hepatology 2002) were analyzed. MARS resulted in a reduction of in-hospital deaths, as well as liver disease-related complications. Both these factors led to a substantial reduction of costs in the MARS group, which was enough to counterbalance the extra costs associated with extra-corporeal therapy. In the control group, the total hospitalization cost per survivor were calculated to be at $35,904. In the MARS group, the overall expenditure per survivor including standard medical therapy plus additional MARS liver support therapy were $32,036--a saving of nearly $4000 compared to the control group. Therefore, it appears that the benefits of MARS therapy are enough to justify the cost of treatment and safe hospital costs, at least in the described population. However, further studies are needed to confirm these results.

Serum aminotransferase levels and platelet counts as predictors of degree of fibrosis in chronic hepatitis C virus infection.

OBJECTIVE: In patients with chronic hepatitis C virus (HCV) infection, liver fibrosis stage is a prognostic factor for therapy outcome. So far, a liver biopsy is necessary to determine disease stage accurately. We sought to develop a simple, noninvasive method of accurately predicting the degree of liver fibrosis in chronic HCV infection. METHODS: We retrospectively studied 211 consecutive patients with chronic HCV, who received a liver biopsy at the Liver Center of the University of California, San Diego. A total of 58 of these patients had a positive history of alcohol abuse, and we analyzed them separately in a sensitivity analysis. AST/ALT ratio and platelet counts were determined in all patients. Fibrosis was staged using the METAVIR score. RESULTS: Both AST/ALT ratio and platelet counts correlated significantly with the disease stage (r = 0.190, p = 0.006, and r = -0.543, p < 0.00, respectively). In a sensitivity analysis, there was no correlation between AST/ALT ratio and disease stage for patients with a history of alcohol abuse. For patients without history of alcohol abuse, the correlation between disease stage, AST/ALT ratio, and platelet counts was r = 0.297, p < 0.00, and r = 0.560, p < 0.00, respectively. In these patients, AST/ALT ratio > or =1 in combination with a platelet count of <150,000/mm3 can identify patients with severe fibrosis or cirrhosis (stages 3 and 4) with a positive predictive value of 93.1%. Sensitivity, specificity, and negative predictive value were 41.2%, 99.1%, and 85.0%, respectively. In patients with ALT/AST ratio of <1 or platelet counts of >150,000/mm3, these laboratory parameters cannot predict liver fibrosis stage. CONCLUSION: AST/ALT ratio in combination with platelet counts may obviate a liver biopsy for fibrosis staging in some patients with chronic HCV infection.

Integral role of interventional radiology in the development of a pediatric liver transplantation program.

The aim of this study was to examine the role of interventional radiology (IR) in the pretransplant evaluation of potential living-related liver transplantation (LRLT) donors and in the post-transplant management of pediatric liver transplant recipients. Medical records and procedural reports were reviewed of 12 potential donors and five recipients for left lateral segment liver transplants. Procedures performed by the IR Division, clinical indications, and complications were tabulated. Retrospective calculation of radiation exposure to the skin and gonads of the donors and recipients were made. Three-dimensional ultrasound (3D US) was used in all 12 potential donors to screen for the donor with the most appropriately sized left lateral segment. The four optimal donor candidates underwent contrast angiography in order to measure the diameter and screen for variant arterial supply to the left lateral segment. Pretransplantation, one recipient underwent mesenteric angiography with indirect portography to confirm thrombosis of the portal vein and to prove patency of the splenomesenteric venous confluence. Three children underwent LRLT and two children received split livers from cadaveric donors. Thirty-two IR procedures were performed after transplantation (Tx) in the four transplant survivors (one child died following Tx). These IR procedures included: ultrasound-guided percutaneous liver biopsy to evaluate the pathologic cause of liver dysfunction (seven); placement of nasal jejunal feeding tubes (three) or a peripherally inserted central catheter (four) for nutritional and pharmacologic support; large-volume diagnostic and therapeutic paracentesis (two) and thoracentesis (one); percutaneous catheter drainage of symptomatic large pleural effusions (two), large-volume chylous ascites (one) (with later drain removal [one]), and a large biloma (one); percutaneous biliary drain placement (three), biliary drain replacement (two), and balloon cholangioplasty (four) to relieve obstructive jaundice from biliary enteric anatomic strictures; and mesenteric arteriography (one) for suspected thrombosis of the hepatic artery. No complications occurred. Mean skin and gonadal radiation doses were 193 mGy and 27 mGy, respectively, for donors, and 164 mGy and 60 mGy, respectively, for recipients. Even in a program such as this, with a limited series of pediatric liver Txs, it is apparent that IR plays an integral role in optimizing the clinical outcome and use of resources. Specific benefits included: selection of optimal donors; accurate mapping of the donor and occasionally recipient hepatic vasculature; and, most importantly, providing relatively safe minimally invasive procedures for nutritional support and diagnosis and management of untoward events after Tx. When possible, ultrasound guidance should be used to avoid excessive cumulative fluoroscopic exposure to recipients.

Value of three-dimensional US for optimizing guidance for ablating focal liver tumors.

PURPOSE: To determine if three-dimensional ultrasound (3D US), by nature of its ability to simultaneously evaluate structures in three orthogonal planes and to study relationships of devices to tumor(s) and surrounding anatomic structures from any desired orientation, adds significant additional information to real-time 2D US used for placement of devices for ablation of focal liver tumors. MATERIALS AND METHODS: Sixteen patients underwent focal ablation of 23 liver tumors during two intraoperative cryoablation (CA) procedures, three intraoperative radiofrequency ablation (RFA) procedures, 11 percutaneous ethanol injections (PEI) procedures, and six percutaneous RFA procedures. After satisfactory placement of the ablative device(s) with 2D US guidance, 3D US was used to reevaluate adequacy to device position. Information added by 3D US and resultant alterations in device deployment were tabulated. RESULTS: 3D US added information in 20 of 22 (91%) procedures and caused the operator to readjust the number or position of ablative devices in 10 of 22 (45%) of procedures. Specifically, 3D US improved visualization and confident localization of devices in 13 of 22 (59%) procedures, detected unacceptable device placement in 10 of 22 (45%), and determined that 2D US had incorrectly predicted device orientation to a tumor in three of 22 (14%). CONCLUSIONS: Compared to conventional 2D US, 3D US provides additional relationship information for improved placement and optimal distribution of ablative agents for treatment of focal liver malignancy.

Adjunctive 3D US for achieving portal vein access during transjugular intrahepatic portosystemic shunt procedures.

PURPOSE: To evaluate the usefulness of information provided by three-dimensional ultrasound (3D US) and to determine whether 3D US decreased the number of passes required to obtain portal vein (PV) access during creation of transjugular intrahepatic portosystemic shunts (TIPS). MATERIALS AND METHODS: Intermittent 3D US volume acquisitions were obtained during creation of TIPS in 20 patients. Useful information provided by 3D US was tabulated. The number of passes required to achieve PV access was recorded and results were compared retrospectively to 25 patients who underwent TIPS without 3D US. RESULTS: 3D US documented that the operator's opinion of which hepatic vein had been selected was incorrect in nine patients (45%), detected unfavorable PV anatomy that required modification of equipment or technique in seven patients (35%), permitted estimation of the trajectory required to access the targeted PV in all patients (100%), assisted in selecting the optimal point along the hepatic vein for origination of the needle pass in 11 patients (55%), allowed avoidance of a large hepatocellular carcinoma in one patient (5%), and confirmed that access into the main PV was intrahepatic in four patients (20%). The mean number of needle passes decreased from 10.4 in the historic control group to 4.6 in the 3D US group (P = .0001). CONCLUSION: 3D US provided imaging information that detected technical errors and altered anatomy, and provided positional and directional information to significantly improve needle pass efficiency.

Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens.

During a 6-and-a-half month period, we identified 10 human immunodeficiency virus (HIV)-infected men who were receiving antiretroviral regimens, including nucleoside analogues, and who developed unexplained reproducible hyperlactatemia in association with either abdominal symptoms or an unaccounted-for elevated alanine aminotransferase level, or both. After careful consideration of the possible etiologies, antiretrovirals were discontinued; lactate levels normalized in all patients. The estimated incidence of this phenomenon in our clinic was 20.9 cases per 1000 person-years of nucleoside analogue treatment. These observations extend the spectrum of the nucleoside analogue-induced lactic acidosis/hepatic steatosis syndrome by the identification of a subtle and perhaps earlier form, which has characteristic symptoms and laboratory abnormalities, and a favorable prognosis on discontinuation of antiretroviral therapy.

Adjunctive 3D US for achieving portal vein access during transjugular intrahepatic portosystemic shunt procedures.

PURPOSE: To evaluate the usefulness of information provided by three-dimensional ultrasound (3D US) and to determine whether 3D US decreased the number of passes required to obtain portal vein (PV) access during creation of transjugular intrahepatic portosystemic shunts (TIPS). MATERIALS AND METHODS: Intermittent 3D US volume acquisitions were obtained during creation of TIPS in 20 patients. Useful information provided by 3D US was tabulated. The number of passes required to achieve PV access was recorded and results were compared retrospectively to 25 patients who underwent TIPS without 3D US. RESULTS: 3D US documented that the operator's opinion of which hepatic vein had been selected was incorrect in nine patients (45%), detected unfavorable PV anatomy that required modification of equipment or technique in seven patients (35%), permitted estimation of the trajectory required to access the targeted PV in all patients (100%), assisted in selecting the optimal point along the hepatic vein for origination of the needle pass in 11 patients (55%), allowed avoidance of a large hepatocellular carcinoma in one patient (5%), and confirmed that access into the main PV was intrahepatic in four patients (20%). The mean number of needle passes decreased from 10.4 in the historic control group to 4.6 in the 3D US group (P = .0001). CONCLUSION: 3D US provided imaging information that detected technical errors and altered anatomy, and provided positional and directional information to significantly improve needle pass efficiency.

c-Myb modulates transcription of the alpha-smooth muscle actin gene in activated hepatic stellate cells.

Expression of alpha-smooth muscle actin (alpha-SMA) defines the phenotype of activated (myofibroblastic) hepatic stellate cells. These cells, but not quiescent stellate cells, have a high level of alpha-SMA and c-Myb expression, as well as increased c-Myb-binding activities to the proximal alpha-SMA E box. Therefore, we analyzed the role of c-Myb in alpha-SMA transcription and stellate cell activation. Activated primary rat stellate cells displayed a high expression of the -724 and -271 alpha-SMA/luciferase (LUC) chimeric genes, which contain c-Myb binding sites (-223/-216 bp). Alpha-SMA/LUC minigenes with mutation (-219/-217 bp), truncation (-224 bp), or deletion (-191 bp) of the c-Myb binding site were not efficiently transcribed. Transfection of wild-type c-Myb into quiescent stellate cells, which do not express endogenous c-Myb, induced a approximately 10-fold stimulation of -724 alpha-SMA/LUC expression. Conversely, expression of either a dominant-negative c-Myb basic domain mutant (Cys(43) --> Asp) or a c-Myb antisense RNA blocked transcription from the -724 alpha-SMA/LUC or -271 alpha-SMA/LUC in activated cells. Moreover, transfection of c-myb antisense, but not sense, RNA inhibited both expression of the endogenous alpha-SMA gene and stellate cell activation, whereas transfection of c-myb stimulated alpha-SMA expression in quiescent stellate cells. These findings suggest that c-Myb modulates the activation of stellate cells and that integrity of the redox sensor Cys(43) in c-Myb is required for this effect.

Liver transplantation for chronic viral liver disease.

Liver transplantation (LTx) for chronic viral liver disease has evolved rapidly during the last two decades. The major problem in cases of LTx for viral hepatitis is the extremely high rate of recurrent viral infection in the liver allograft. While recurrent hepatitis C virus (HCV) infection typically causes a mild hepatitis and has a slow progression, hepatitis B virus (HBV) infection of the liver allograft has been reported to result in cirrhosis in as short a period of time as 1 year. The risk of graft infection is greatest for patients with actively replicating virus. The high rate of disease recurrence, and the accelerated course of both HBV and HCV related liver disease post LTx, is a consequence of the high viral loads experienced by the allograft and the life-long immunosuppression required to prevent allograft rejection. Thus, efforts to clear virus prior to LTx, in order to prevent disease recurrence, are extremely important. In cases where this is not possible, the use of treatments directed at controlling or inhibiting recurrent disease in the allograft are essential. Hepatitis B immunoglobulin (HBIg) is an example of the latter, while the recent introduction of nucleoside analogues, molecules targeted at essential steps in viral replication such as lamivudine and famciclovir, are example of the former. The use of these two agents is likely to markedly change current approaches to transplantation for viral hepatitis.

Aureobasidium pneumonia in a post liver transplant recipient: a case report.

This is the first report of Aureobasidium (A.) pullulans as an opportunistic pulmonary infection in a liver transplant recipient. A 46-year-old caucasian man had an orthotopic liver transplant in 1988. His liver disease was primary sclerosing cholangitis. He required 2 subsequent liver re-transplants for primary graft non-function and acute rejection. The patient had been living in the California desert for two months prior to admission and presented with ventilator-dependent acute respiratory failure and hemodialysis-dependent acute renal failure. Imaging studies revealed severe bilateral infiltrates. His initial bronchoalveolar lavage (BAL) and brushings grew A. pullulans. Pancultures, including sputum and throat cultures, were negative for bacterial or other fungal organisms. The patient responded to pulmonary support and aggressive systemic antifungal agents while being maintained on cyclosporine and prednisone for immunosuppression. He was discharged to a skilled nursing facility 37 days after hospitalisation. Delay in discharge was primarily due to severe malnutrition and renal impairment. Opportunistic fungal infections continue to be a major problem in immunosuppressed patients including liver transplant recipients. Here we report a pulmonary infection with Coccidioides (C.) immitis and superinfection with A. pullulans. Opportunistic infections such as A. pullulans can be treated successfully with systemic fluconazole when amphotericin B is not well tolerated.

Lamivudine treatment of advanced and decompensated liver disease due to hepatitis B.

The purpose of this study was to evaluate the effectiveness and safety of lamivudine treatment in patients with advanced and end-stage liver disease caused by hepatitis B. Nine cases of advanced or end-stage liver disease due to hepatitis B infection were treated with lamivudine. Four received liver transplants while receiving lamivudine. Moreover, each of these four has been maintained on lamivudine therapy post-transplantation while receiving immunosuppression. No cases of HBV reactivation have been seen. More importantly, the allograft liver tissue has been HBc and HBs antigen negative as well as HBV-DNA negative by PCR. This report suggests that: 1) lamivudine can be given safely to liver transplant candidates; 2) lamivudine suppresses HBV replication, so much so that HBV-DNA becomes undetectable in the serum; 3) despite powerful immunosuppression associated with transplantation, HBV reactivation does not occur under lamivudine therapy; and 4) the observations should cause transplant physicians, surgeons and third-party payers to reconsider their positions relative to transplantation of individuals with HBV-associated cirrhosis.

A comparison of the prevalence of autoantibodies in individuals with chronic hepatitis C and those with autoimmune hepatitis: the role of interferon in the development of autoimmune diseases.

BACKGROUND AND OBJECTIVES: Viral hepatitis due to hepatitis C virus results in chronic liver disease in more than 70% of individuals infected with the virus. Hepatitis C virus is also thought to be the cause of autoimmune chronic hepatitis, type II. The only treatment for chronic hepatitis C is interferon (IFN). IFN is both an antiviral agent and an up regulator of the cellular immune system. The latter effect is non-specific. Thus, IFN diffusely activates the cellular immune system and can initiate new autoimmune diseases in patients treated with it. To determine the prevalence of autoantibodies in patients with chronic hepatitis C and in patients with autoimmune hepatitis and to determine the incidence of new onset autoimmune disease in IFN-treated subjects with chronic hepatitis C, the records of 323 unselected patients with chronic hepatitis were reviewed. MATERIAL AND METHODS: A total of 203 patients with a mean age of 45.7 +/- 0.8, ranging 18-81 with either HCV disease or autoimmune hepatitis, were identified and studied. One hundred sixty-two patients with chronic hepatitis C defined by elevations of serum alanine aminotransferase (ALT) for at least 6 months, the presence of detectable anti-HCV (HCV; second generation enzyme immunoassay [EIA2], a positive recombinant immunoblot assay [RIBA], the presence of HCV-RNA by PCR in serum and an abnormal biopsy consistent with chronic hepatitis C) were identified. Each was also negative for HbsAg, HbeAg and anti-Delta. Forty-one patients with a putative autoimmune chronic hepatitis (AIH) diagnosed on the basis of serologic positivity for classical autoantibodies (ANA and anti-smooth muscle antibodies), tissue typing (B8, Dr3 positive), characteristic liver biopsy findings and the absence of anti-HCV and HCV-RNA in serum were identified. The records of both of these groups of patients were reviewed for the following antibodies: anti-nuclear antibodies (ANA), antimitochondrial antibodies (AMA), anti-liver-kidney microsomal antibody (LKM), anti-smooth muscle antibodies (SMA), anti-microsomal antibodies (MSA). RESULTS: The rate of ANA positivity was 63% in both groups; the rate of SMA positivity was 65% in patients with HCV infection (group I) and 63% in patients with AIH (group II). AMA was positive in 4% of the subjects in group I and 50% of the subjects in group II; anti-LKM antibodies were absent in all 91 HCV cases and were present in 4% of the cases in group II; MSA positivity was present in 17% of group I and 10% of group II. Eighty-one of the one hundred sixty-two patients (50%) with chronic hepatitis C received IFN treatment at a dose of 5 MU SQ daily for 6 months. Thirty-two of these eighty-one patients (42 females and 39 males with a mean age of 45.0 +/- 1.3, ranging from 18 to 81 yr.) had at least two autoantibodies detectable prior to the IFN therapy (subgroup 1) and 49 had one or no identifiable autoantibodies (subgroup 2) present prior to IFN therapy. No significant differences in the interferon response rate defined by HCV-RNA negativity and normalization of serum ALT levels at the end of therapy was noted between those with autoantibodies and those without autoantibodies. Fifteen of the interferon-treated patients developed a clinical manifestation of a new onset autoimmune disease during the course of their interferon treatment. Six of the fifteen patients belonged to subgroup 1 (n = 32) and the remaining 9 patients to subgroup 2 (n = 49) (p > 0.05). None were managed by discontinuing the interferon. Most required some form of specific treatment.(ABSTRACT TRUNCATED)

Conventional care of fulminant hepatic failure: medical and surgical aspects.

Fulminant hepatic failure (FHF) is a clinical syndrome with a poor outcome. Survival rates are between 10% and 40% depending on the etiology of hepatic necrosis. Multiple supportive modalities have been tried to improve patient outcome. However, orthotopic liver transplantation has been shown to be the most effective therapy at improving survival. Management of these patients requires invasive monitoring, mechanical ventilation, and infection prophylaxis, all of which are conducted most efficiently in specialized units. The goal is to allow the native liver to regenerate and to prevent the development of complications while maintaining the patient in a condition suitable for orthotopic liver transplantation. Therapeutic plasma exchange improves survival in patients with sufficient residual capacity for regeneration. It is effective in restoring hemostasis, improving neurological function, and prolonging biochemical stability of patients awaiting liver transplantation. Hepatoprotective and hepatotrophic substances are still in the experimental stage. Auxiliary liver grafting and artificial liver support devices have proved to be an adjunct or a bridge to transplantation; however, they are not yet widely available.

A preliminary experience with GM-CSF plus interferon in patients with HBV and HCV resistant to interferon therapy.

An open label trial of GM-CSF plus high-dose interferon (IFN) alpha 2b was performed in eight patients with chronic hepatitis B infection and 16 patients with chronic hepatitis C, who either failed to clear virus with 6 months of daily high-dose IFN (5 MU daily) therapy (n = 22) or were considered untreatable because of advanced disease and leukopenia (n = 2). The dose of GM-CSF used was 500 micrograms subcutaneously twice weekly. The dose of IFN used was 5 MU daily. Both agents were administered for 4 months. Five of the eight hepatitis B patients and five of the 16 hepatitis C virus patients responded to combined therapy having previously failed IFN therapy alone. The hepatitis B virus responders had low entry ALT, AST, and gamma GPT levels as compared to the non-responders. No such differences for responders and non-responders were seen with the hepatitis C virus patients. These data suggest that the combination of GM-CSF and IFN may be more effective at achieving viral clearance than IFN alone.

Interferon-alpha 2b improves short-term survival in patients transplanted for chronic liver failure caused by hepatitis B.

Liver transplantation for cirrhosis caused by hepatitis B virus (HBV) has a poor prognosis. This is primarily a consequence of the near universal reinfection of the allograft, subsequent accelerated hepatic disease while receiving immunosuppression, and a reduced long-term survival. Because interferon-alpha has been shown to have an antiviral effect on HBV, a study was initiated in 1986 to assess the effect of interferon-alpha therapy on the course of liver transplantation in HBV-positive recipients. Twenty-eight patients with decompensated endstage liver disease caused by HBV were treated with 5, 2.5 or 1.25 million units (MU) of human recombinant interferon-alpha 2b (r-IFN-alpha 2b) daily for a minimum of 14 days prior to transplantation and continuing for 42 days post-transplantation. HBV antigens, HBV antibodies, HBV DNA and serum transaminase levels were measured throughout the treatment and post-treatment period. HBV DNA was eliminated in 10 of 19 patients, who survived 3 months or more post-transplantation, and was associated with a significant flare of hepatitis as detected by symptoms and transaminase levels (P < 0.05). Patients who cleared HBV DNA had lower HBV DNA levels (P < 0.05) at entry compared with those who did not. While four of 10 patients with hepatitis B e antigen (HBeAg) converted to hepatitis B e antibody (HBeAb), no surviving patient cleared hepatitis B surface antigen (HBsAg) on a long-term basis. Nonetheless, post-transplant survival was significantly better (P < 0.0001, median follow-up 42 months) in the IFN-alpha treated patients as compared with historical controls, and was similar to that of patients transplanted for all causes of parenchymal liver disease other than HBV cancer. Hence IFN-alpha therapy in the perioperative liver transplantation period improves short-term survival but does not prevent HBV infection of the allograft.

The medical management of hepatocellular carcinoma (HCC) in Japan: a review with implications for HCC seen in the west.

The problem and approaches to the treatment of hepatocellular carcinoma as seen in Japan are reported. Current Japanese methods for the detection of hepatocellular carcinoma and the methods used to treat hepatocellular carcinoma are described. Included in the latter discussion is a description of the untoward effects of each treatment. Finally an alogorithm for the treatment of hepatocellular carcinoma is presented based upon the Japanese experience.