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Clevudine therapy with vaccine inhibits progression of chronic hepatitis and delays onset of hepatocellular carcinoma in chronic woodchuck hepatitis virus infection

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ANTIVIRAL THERAPY 2004年第6期9卷 H4-H5页

作者： Korba, B Cote, P Menne, S Toshkov, I Tennant, BC Gerin, JL Georgetown Univ Med Ctr Div Mol Virol & Immunol Rockville MD USA Cornell Univ New York State Coll Vet Med Dept Clin Sci Ithaca NY 14853 USA

We examined a rational approach to therapy of chronic hepatitis B virus (HBV) infection that utilized the reduction of viral load combined with appropriately timed immune modulation/stimulation. In a placebo-controlled study, chronic woodchuck hepatitis virus (WHV) carrier woodchucks received clevudine (L-FMAU), previously shown to have especially potent and sustained antiviral activity in woodchucks, for 32 weeks followed by WHV surface antigen (WHsAg) alum-adjuvanted vaccine at 32, 36, 40 and 48 weeks. Clevudine induced significant reductions in viraemia, surface antigenaemia, hepatic WHV nucleic acids, and hepatic core and surface antigens. Viral replication markers remained markedly suppressed in 75% of the clevudine-treated woodchucks following drug withdrawal, but remained at high levels in the vaccine monotherapy and placebo groups. Combination drug and vaccine therapy had benefits based on sustained reduction of viraemia, antigenaemia, and hepatic WHV DNA and RNA; inhibition of progression of chronic hepatitis; reduced frequency of chronic liver injury; and delayed onset of hepatocellular carcinoma (HCC). Combination therapy contributed to prevention of HCC in up to 38% of treated carriers, although the growth rate of established HCC was not affected. This study demonstrates enhanced benefits of combination chemo-immunotherapy against viral load and disease progression in chronic hepadnaviral infection, and provides a platform for further development of such treatment regimens.

关键词： Hepatitis B Vaccines Hepatitis B Virus Woodchuck Hepatitis B Chronic 肝炎疫苗乙型肝炎病毒旱獭肝炎慢性 progressions Hepatitis B virus Surface Antigens Vaccines Vaccine Therapy Hepatitis B Vaccines Hepatocellular Cancer liver injury Clevudine Marmota monax Viral Load Hepatitis B Chronic Hepatitis Woodchuck Hepatitis B Virus human-centered computing

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Enhanced anti-rotavirus action of human cystatin C by site-specific glycosylation in yeast

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BIOCONJUGATE CHEMISTRY 2004年第6期15卷 1289-1296页

作者： Nakamura, S Hata, J Kawamukai, M Matsuda, H Ogawa, M Nakamura, K Jing, H Kitts, DD Nakai, S Shimane Univ Dept Life & Environm Sci Shimane Shimane 6908504 Japan Shimane Univ Dept Life Sci & Biotechnol Shimane Shimane 6908504 Japan Univ British Columbia Vancouver BC V6T 1Z4 Canada

The cDNA encoding human cystatin C (HCC) was subjected to site-specific substitution of alanine for serine at the position 37, to obtain the Asn(35)-Lys(36)-Ser(37) sequence that is a signal for asparagine-linked (N-linked) glycosylation of protein in eukaryotes, and was transformed into Pichia pastoris X33. As a result, 1.2 mg/L oligomannosyl HCC with a carbohydrate chain of Man(10)GlcNAc(2) was produced by the Pichia transformant. The oligomannosyl HCC was more stable at the low ionic strength condition of 50 mM potassium phosphate buffer, pH 7.0, than the wild-type. In addition, the oligomannosylation substantially improved the molecular stability of cystatin against an aspartic proteinase, cathepsin D, in which the susceptibility decreased to less than 50% of nonglycosylated one. The anti-rotavirus activity of HCC was substantially enhanced by the site-directed glycosylation using the yeast expression system. A MA-104 cell line was used as a host cell for human rotavirus type-2 Wa strain in this study, to which both the wild-type and oligomannosyl. HCCs did not show cytotoxicity at a concentration of 100,mug/mL. More than 80% viability of the host cell infected with 1.0 x 10(5) PFU/mL of rotavirus was conserved under the condition coexisting with 75 mug/mL of the oligomannosyl HCC, which was 15.2% higher than that of wild-type HCC. Thus, the in vitro antirotavirus assay indicated that the supplement of a proper amount of the oligomannosyl HCC could be used as an anti-rotavirus agent.

关键词： Host Cell Rotavirus Yeast Alanine Molecular stability human-centered computing site-specific Cystatins Cystatin C Glycosylation

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Multimodality tumor control and living donor transplantation for unresectable hepatocellular carcinoma

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TRANSPLANTATION PROCEEDINGS 2004年第8期36卷 2287-2288页

作者： Chui, AKK Rao, ARN Island, ER Chan, HLY Leung, TWT Lau, WY Chinese Univ Hong Kong Dept Surg Prince Wales Hosp Shatin Hong Kong Peoples R China Chinese Univ Hong Kong Dept Med & Therapeut Prince Wales Hosp Shatin Hong Kong Peoples R China Chinese Univ Hong Kong Dept Oncol Prince Wales Hosp Shatin Hong Kong Peoples R China

Liver transplantation (LT) is an acceptable mode of -treatment for selected patients with unresectable hepatocellular carcinoma (HCC). However, due to the scarcity of cadaveric donor organs, it is considered desirable for patients to opt for living donor liver transplantation (LDLT) or, for those not being transplanted soon, to have some form of tumor control therapy. Such an approach in our program is analyzed and reported. At our institution, 42 LTs were performed between October 1999 and April 2003. Of these, 18 recipients (15 men, 3 women) had 27 HCC. The average number and size of HCC was 1.59 (1 to 4) and 2.31 (0.2 to 6.5) cm, respectively. Thirteen (72%) patients were transplanted primarily for the HCC, whereas five (28%) others were incidental HCC cases. Seven patients (5 LRLT, 2 cadaveric LT) were transplanted soon after listing, and thus did not require tumor control therapy. Six patients waited for 11 (6 to 19) months before LT. Three patients underwent microwave coagulation therapy, and one had additional alcohol injections. One patient received the novel PIAF (cisplatin, interferon, adriamycin, and 5-FU) chemotherapy regimen followed by selective internal irradiation (SIR) treatment. One patient received conformal radiation therapy and another received SIR treatment before LT. Besides 2 postoperative deaths, the remaining 16 patients have been well, with a mean follow-up of 20.4 (3.6 to 41.2) months. In conclusion, for patients with unresectable HCC, in areas with poor cadaveric donor rate, living donation should be the first option. If a suitable live donor is not available, aggressive multimodality therapy is recommended while waiting for cadaveric LT.

关键词： Lymphotoxin livin g unresectable control 淋巴毒素 Level Trigger Organ Donors Combined Modality Therapy Conformal Radiotherapy Lymphotoxin-alpha BIRC7 protein, human human-centered computing Living Donors Patients

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Lymphoblastoid alpha-interferon in the prevention of hepatocellular carcinoma (HCC) in high-risk HbsAg-positive resected cirrhotic HCC cases: A 14-year follow-up

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CANCER INVESTIGATION 2003年第3期21卷 394-399页

作者： Oon, CJ Chen, WN Singapore Gen Hosp Dept Clin Res Singapore 0316 Singapore Singapore Gen Hosp Hepatitis & Liver Canc Res Unit Singapore 0316 Singapore

Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. It is also a common long-term complication of chronic hepatitis B or C infections, with cirrhosis as a risk factor for premalignant development. Natural lymphoblastoid alpha-interferon (alphaN1-IFN) has been widely used in treating chronic HBV and HCV carriers. To investigate its long-term beneficial effect in reducing the development of HCC, 20 hepatitis B surface antigen (HBsAg) positive resected cirrhotic HCC patients who have undergone chemotherapy followed by long-term treatment of 3MU alphaN1-IFN daily for 10 days every 3 months were analyzed in a 14 year follow-up. Results indicated that these patients survived and remained free of HCC. In contrast, 10 other patients receiving chemotherapy alone after resection eventually had HCC recur. Similar recurrence of HCC was seen in patients who had either reduced dosage of alphaN1-IFN or stopped interferon therapy or received 30MU dose at 6-month intervals. Our findings indicate the therapeutic potential and long-term safety of alphaN1-IFN in suppressing the development of HCC in high-risk patients.

关键词： N1 Excision development aspects Risk Primary carcinoma of the liver cells 危险 Cause of Death N1 Stage Finding Hepatocellular Cancer Interferon-alpha human-centered computing

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Multimodality management of hepatocellular carcinoma larger than 10 cm

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JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 2003年第5期197卷 730-738页

作者： Mok, KT Wang, BW Lo, GH Liang, HL Liu, SI Chou, NH Tsai, CC Chen, IS Yeh, MH Chen, YC Vet Gen Hosp Dept Surg Div Gen Surg Kaohsiung 813 Taiwan Vet Gen Hosp Div Gastroenterol Dept Internal Med Kaohsiung 813 Taiwan Vet Gen Hosp Dept Radiol Kaohsiung 813 Taiwan Natl Yang Ming Univ Sch Med Taipei 112 Taiwan

BACKGROUND: Hepatic resection for huge hepatocellular carcinoma (HCC) is challenging. The role of multimodality nonsurgical therapy for HCC larger than 10 cm is unclear. STUDY DESIGN: We retrospectively investigated 131 HCC patients with main tumors larger than 10 cm in diameter seen between October 1990 and October 2001. Fifty-six patients (group A) underwent hepatectomy and 75 patients (group B) underwent nonsurgical multidisciplinary therapy including hepatic arterial infusion, transcatheter arterial embolization, and percutaneous acetic acid injection. RESULTS: Patients in group B were older, had lower serum albumin levels, and there were more patients with liver cirrhosis and great vessel invasion. Median survivals of group A and B patients were 17 months and 7 months, respectively (p < 0.001). But the 1-, 3-, 5-year survival rates in group B using 38 patients undergoing 3 or more sessions of nonsurgical treatment were not significantly worse than those for group A using 53 patients with followup (57.1%, 19.0%, 16.3% versus 60.7%, 24.5%, 24.5%, respectively). Group A patients had 37.7% and 71.7% recurrence rates at 6 and 12 months, respectively, after operation, and they had a significantly higher frequency of overall extrahepatic recurrence compared with group B patients (43.4% versus 18.7%, p = 0.005). In group B, only 3 of 35 patients younger than 60 years had tumor. shrinkage after nonsurgical treatment modalities in comparison to 17 of 40 patients in the elderly group (p = 0.003). Younger patients had a significantly higher prevalence of hepatitis B surface antigen positivity (85.7% versus 47.5%) and infiltrating tumor growth pattern (74.3% versus 45.0%) compared with older patients. CONCLUSIONS: Our study suggests that the advantage of hepatic resection in patients with huge HCC is marginal. An effective adjuvant therapy is needed to improve outcomes after hepatic resection. The experience in using nonsurgical treatment shows that the result is poor in yo

关键词： Antineoplastic Combined Chemotherapy Protocols Carcinoma Hepatocellular 癌肝细胞化学栓塞治疗性肝切除术肝肿瘤 Antineoplastic Combined Chemotherapy Protocols Patients Carcinoma multimodality Hepatocellular Cancer human-centered computing Hepatic Organ System

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Underestimation of nodules while staging hepatocellular carcinoma prior to neoadjuvant treatment on waiting list for transplantation

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TRANSPLANTATION PROCEEDINGS 2003年第4期35卷 1423-1424页

作者： Stippel, DL Kasper, HU Schleimer, K Benz, C Hölscher, AH Beckurts, KTE Univ Cologne Dept Visceral & Vasc Surg Inst Pathol D-50931 Cologne Germany Univ Cologne Dept Internal Med D-50931 Cologne Germany

Neoadjuvant therapy of hepatocellular carcinoma (HCC) has increasing importance for patients awaiting liver transplantation, as waiting time increases. The therapeutic options (ethanol injection, radiofrequency ablation, chemoembolization) are only effective locally. Therefore, occult carcinomas can overcome the efficacy of these therapies. To evaluate the impact of occult nodules, we analyzed the staging results and histology from 21 HCC patients. The average pretransplant waiting time was 5.2 +/- 3.2 months. The staging before transplantation was reliable concerning the maximum diameter of the HCC. The number of HCC nodules increased from 30 at the time of clinical staging to 59 in histology, hence from 1.4 +/- 1.5 to 2.8 +/- 1.9 per patient. Patients with pT1/2 HCCs experienced an even larger increase (from 1.3 to 3.2 nodules) than patients suffering of pT3/4 HCCs (2.6 to 3.4 nodules). All occult HCCs were less than 2 cm in diameter and showed no prognostically negative histological features such as vascular invasion. The 3-year survival of the patients with small HCCs was 86% compared to 34% for those with advanced cancer. The survival of patients with small HCCs was similar to the survival of patients receiving a transplant for a nonmalignant indication. Only after neoadjuvant therapy with radiofrequency ablation or ethanol injection but not with chemoembolization, was significant necrosis of HCC observed. Considering the current average waiting time, repetitive staging and treatment of new nodules seems justified to achieve a low dropout rate during the waiting time.

关键词： With staging waiting time survival aspects transplantation therapeutic aspects Waiting time Patients Parapsychology Occultism Staging radiofrequency ablation chemoembolization Waiting Lists human-centered computing Neoadjuvant Therapy Transplantation

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Polymorphisms in XRCC1 and glutathione S-transferase genes and hepatitis B-related hepatocellular carcinoma

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JOURNAL OF THE NATIONAL CANCER INSTITUTE 2003年第19期95卷 1485-1488页

作者： Yu, MW Yang, SY Pan, IJ Lin, CL Liu, CJ Liaw, YF Lin, SM Chen, PJ Lee, SD Chen, CJ Natl Taiwan Univ Coll Publ Hlth Grad Inst Epidemiol Taipei 100 Taiwan Taipei Municipal Jen Ai Hosp Dept Internal Med Div Gastroenterol Taipei Taiwan Natl Taiwan Univ Hosp Hepatitis Res Ctr Taipei Taiwan Natl Yang Ming Univ Vet Gen Hosp Dept Med Taipei 112 Taiwan Natl Yang Ming Univ Sch Med Taipei 112 Taiwan Chang Gung Univ Chang Gung Mem Hosp Liver Res Unit Taoyuan Taiwan

Chronic infection with hepatitis B virus (HBV) causes DNA damage. An arginine (Arg)-to-glutamine (Gln) polymorphism at codon 399 in the XRCC1 gene is putatively associated with DNA damage. In a case-control study of 577 HBV surface antigen carriers with hepatocellular carcinoma (HCC) and 389 HBV carrier control subjects, we investigated the association between this polymorphism and the risk of HCC and assessed whether this association varied with glutathione S-transferase (GST) status;GSTs are involved in carcinogen metabolism. All statistical tests were two-sided. The XRCC1 Gln allele was associated with a dose-dependent increased risk of early-onset HCC (<50 years) but not with the risk of late-onset HCC (P-trend =.01). The GSTT1-null genotype alone did not affect risk, but the GSTM1-null genotype was associated with a decreased risk for early-onset HCC. Various combinations of GSTM1 and GSTT1 genotypes differentially modified the association of XRCC1 with HCC (P-interaction =.005);e.g., for individuals with the GSTTI-null/ GSTM1-present genotype, the risk of HCC was greater for those with the Gln/Gln genotype (odds ratio = 8.07, 95% confidence interval = 1.67 to 38.93) than for those with the Arg/Arg genotype. Thus, GST status appears to affect the risk of HCC associated with this XRCC1 polymorphism.

关键词： Carcinoma Hepatocellular DNA Repair DNA-Binding Proteins Glutathione Transferase 癌肝细胞 DNA修复 DNA结合蛋白质类肝炎乙型肝肿瘤 Association (Psychology) DNA-Binding Proteins Carcinogen Metabolism DNA XRCC1 gene DNA Repair Hepatitis B Virus-Related Hepatocellular Carcinoma Hepatitis B virus Genotype Glutathione Transferase human-centered computing Carcinoma

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Is the incidence of intrahepatic multicentric recurrence of hepatocellular carcinoma more frequent in "the carcinogenic stage" than in liver cirrhosis?

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JOURNAL OF GASTROENTEROLOGY 2003年第9期38卷 918-920页

作者： Izumi, N Musashino Red Cross Hosp Dept Gastroenterol & Hepatol Musashino Tokyo 1808610 Japan

Hpeatocellular carcinoma (HCC) develops with hepatitis B or C virus infection as the basis in the majority of cases. The proportion of HCC cases positive for markers for both types of hepatitis virus reaches levels of... 详细信息

关键词： Liver Cirrhosis Hepatitis Viruses Incidence Hepatocellular Cancer Relapse Virus Diseases human-centered computing Hepatitis B

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Can we expand the indications for liver transplantation among hepatocellular carcinoma patients with increased tumor size?

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TRANSPLANTATION PROCEEDINGS 2003年第5期35卷 1818-1820页

作者： Fernández, JA Robles, R Marin, C Sánchez-Bueno, F Ramirez, P Pons, JA Garre, MC Pérez, D Parrilla, A Navalón, JC Parrilla, P Hosp Virgen Arrixaca Serv Cirugia 1 Liver Transplant Unit Dept Surg Murcia 30120 Spain Hosp Virgen Arrixaca Liver Transplant Unit Dept Biostat Murcia 30120 Spain Hosp Virgen Arrixaca Liver Transplant Unit Dept Digest Dis Murcia 30120 Spain Hosp Virgen Arrixaca Liver Transplant Unit Dept Radiol Murcia 30120 Spain

Introduction: Due to the scarcity of donors and the fact that size is the main prognostic factor, Milan criteria have been used since 1996 to select hepatocellular carcinoma (HCC) patients for liver transplantation. In 2001 UCSF criteria showed that including layer tumors did not reduce the survival results. The objective of this paper was to evaluate whether HCC tumor sizes exceeding the Milan criteria adversely influence survival rates. Patients and methods: Between May 1988 and July 2001, 53 patients were transplanted due to HCC and cirrhosis. The etiology of cirrhosis was HCV in 23 cases and HBV in 6. In 11 cases the HCC were incidental by discovered namely, a mean/ diameter of 1.8 cm (versus 2.6 cm in nonincidental HCC). Sixty-two percent of tumors met the Milan criteria, and 68% the USCF criteria. Results. The actuarial survival was 79% at 1 year and 62% at 5 years. The survival of patients with incidental HCC was 82% at 1 year and 82% at 5 years, which is better than the survival of those with nonincidental HCC (78% at 1 year and 57% at 5 years, P < .05). According to Milan criteria, the survival patients with early tumors was 82% at 1 year and 68% at 5 years, and for advanced tumors (NS), 75% and 54%, respectively. Comparison of early versus advanced tumors according to UCSF criteria showed survivals of 84% versus 64% at I year (P < .05) and 67% versus 48% at 5 years (P < .05), respectively. Conclusion. Increasing the HCC size among LT according to the California criteria did not reduce survival rates compared with the Milan criteria.

关键词： criteria survival aspects SIZES Neoplasms 肿瘤 tumor size Cancer Survival Liver Transplantation Tumours Neoplasms human-centered computing

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Liver transplantation for hilar cholangiocarcinoma:: Spanish experience

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TRANSPLANTATION PROCEEDINGS 2003年第5期35卷 1821-1822页

作者： Robles, R Figueras, J Turrión, VS Margarit, C Moya, A Varo, E Calleja, J Valdivieso, A Garcia-Valdelcasas, JC López, P Gómez, M de Vicente, E Loinaz, C Santoyo, J Casanova, D Bernardos, A Fernández, JA Marín, C Ramírez, P Bueno, FS Jaurrieta, E Parrilla, P Virgen Arrixaca Univ Hosp Murcia Spain Bellvitge Univ Hosp Barcelona Spain Puerta Hierro Clin Madrid Spain Valle Hebron Univ Hosp Barcelona Spain La Fe Univ Hosp Valenica Spain Santiago Clin Hosp Santiago De Compostela Spain Hosp Gen Gregorio Maranon Madrid Spain Cruces Hosp Bilbao Spain Clin Hosp Barcelona Spain Reina Sofia Univ Hosp Cordoba Spain Juan Canalejo Univ Hosp A Corunna Spain Ramon y Cajal Univ Hosp Madrid Spain Doce Octubre Univ Hosp Madrid Spain Carlos Haya Univ Hosp Malaga Spain Marques de Valdecilla Univ Hosp Santander Spain Virgen Rocio Univ Hosp Seville Spain

Introduction. Palliative treatment for nondisseminated irresectable hilar cholangiocarcinoma (HCC) carries a 0% 5-year survival rate. The role of orthotopic liver transplantation (OLT) in these patients is controversial because the survival rate is lower than that for other indications for transplantation and the lack of available donor organs. The aim of this paper was to review the Spanish experience in OLT for HCC and identify prognostic factors for survival. Methods. We retrospectively reviewed 36 patients undergoing OLT for HCC over 13 years. Results. The actuarial survival rate at 1, 3, and 5 years was 82%, 53%, and 30%, respectively. The main cause of death was tumor recurrence (53%). In the univariate analysis, the factors for a poor prognosis were vascular invasion (P < .001) namely 0% survival at 3 years when present versus 63% and 35% at 3 and 5 years, respectively, when it was not;and stages III to IVA (P < .05), namely 15% survival at 5 years versus 47% for stages I to II. Lymph node and perineural invasion also reduce survival. In the multivariate analysis, the factors for poor prognosis included vascular invasion (P < .01) and stages III to IVA (P < .01). Conclusions. OLT for nondisseminated irresectable HCC has higher survival rates at 3 and 5 years than palliative treatments, especially with initial stage tumors, which means that more information is needed to better select cholangiocarcinoma patients for transplantation.

关键词： survival aspects experience prognostic Spanish Language Factor analysis Transplantation Prognostic Survival Rate Cause of Death Optical Line Terminal poor prognosis Terminal Care experience Spanish human-centered computing Perineural Invasion Recurrent Neoplasm

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