Hepatitis: Dono K

Marubashi S, Dono K, Miyamoto A, Takeda Y, Nagano H, Umeshita K, Monden M. · Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. · J Hepatobiliary Pancreat Surg. · Pubmed #17013711 No free full text.

Abstract: Hepatitis C virus (HCV) infection is the leading cause of endstage liver disease in Western and Asian countries. However, after liver transplantation, HCV recurs in virtually all patients, and estimated HCV-related graft cirrhosis at 5-year follow-up is 30%. Although immunosuppression accounts for a major part of the accelerated progression of HCV in the transplant population, the best immunosuppression for recipients with HCV that could avoid such complication remains unknown at present. Combination therapy of interferon and ribavirin is thought to be the most effective for the treatment or prophylaxis of HCV infection. However, who should be treated, when treatment should be initiated, and with what agent should patients with HCV infection be treated are still unknown. The current data on HCV recurrence in patients who have received either living- or deceased-donor liver transplantation are controversial, but they are, presumably, similar. Thus, to avoid HCV recurrence in living-donor liver transplantation, we have to take approaches similar to those used for patients receiving deceased-donor liver transplantation. Based on reports from major transplant centers around the world, we consider the best strategy for liver transplantation-related HCV infection is steroid-free immunosuppression and preemptive low-dose interferon and ribavirin combination therapy. Here we describe our experience with living-donor liver transplantion for patients with hepatitis C at Osaka University. There is a need for standardizing the treatment for HCV infection. This can only be achieved through collaborative work between various liver transplant centers worldwide.

Marubashi S, Dono K, Amano K, Hama N, Gotoh K, Takahashi H, Hashimoto K, Miyamoto A, Takeda Y, Nagano H, Umeshita K, Monden M. · Department of Surgery and Clinical Oncology, Osaka University, Graduate School of Medicine, Suita, Japan. · Transplantation. · Pubmed #16177648 No free full text.

Abstract: To examine the benefits of steroid avoidance in adult living donor liver transplantation, we compared the clinical courses of nine recipients receiving basiliximab or daclizumab and 13 historical patients who received steroids. The 1-year patient and graft survival and the incidence of acute cellular rejection were similar in both groups. The side effects of immunosuppression tended to be more frequent in the steroid group. Hepatitis C virus (HCV)-RNA levels measured early after transplantation remained suppressed in the steroid-free group. Steroid avoidance was beneficial in the recipients, as both steroid side effects and recurrence of HCV could be avoided.

Hama N, Yanagisawa Y, Dono K, Kobayashi S, Marubashi S, Nagano H, Umeshita K, Watanabe S, Uchiyama Y, Monden M. · Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. · Liver Transpl. · Pubmed #19399741 No free full text.

Abstract: Acute cellular rejection (ACR) is still a major problem in organ transplantation, and its genetic and molecular mechanisms remain poorly understood. We used DNA microarrays to investigate the gene expression profiles in ACR. We hypothesized that changes of gene expression in grafts could also be detected in peripheral blood leukocytes. We first compared the gene expression profiles in liver isografts (Lewis to Lewis) and allografts (Dark Agouti to Lewis) harvested from rats at days 1, 3, 5, and 7 after transplantation. Hierarchical clustering analysis indicated that gene expression started to change on day 3, and 89 differentially expressed genes were extracted from allografts in comparison with isografts at day 3. Most of the up-regulated genes were associated with graft-infiltrating leukocytes. We then confirmed the similarity of gene expression changes in peripheral leukocytes by quantitative real-time polymerase chain reaction. We also investigated the gene expression changes in other inflammatory and liver dysfunction models. Two interferon-gamma inducible genes, interferon regulatory factor 1 and guanylate nucleotide binding protein 2, were overexpressed in both the peripheral leukocytes and liver graft during ACR. Although further studies are necessary, these 2 genes in peripheral leukocytes could be potentially useful markers for rejection or immunosuppression.

Murakami M, Nagano H, Kobayashi S, Marubashi S, Noda T, Tomimaru T, Takeda Y, Tanemura M, Kitagawa T, Dono K, Umeshita K, Wakasa K, Monden M, Doki Y, Mori M. · Dept. of Surgery, Graduate School of Medicine, Osaka University. · Gan To Kagaku Ryoho. · Pubmed #19106533 No free full text.

Abstract: A 74-year-old male was admitted to Osaka University Hospital for advanced hepatocellular carcinoma in April 2007. CT and MRI scan showed the tumor was located mainly in posterior segment and had portal vein tumor thrombus, and the wall of gall bladder was edematous and thick, but seemed not to be close to the main tumor. We performed an extended posterior segmentectomy, tumor thrombectomy and cholecystectomy. Pathological examination showed that poorly differentiated hepatocellular carcinoma cells, which were same as the main tumor, existed in lamina propria and muscle layer of gall bladder, and invaded the submucosal vessels. So we diagnosed it as gall bladder metastasis from hepatocellular carcinoma.

Marubashi S, Dono K, Miyamoto A, Takeda Y, Nagano H, Umeshita K, Monden M. · Department of Surgery and Clinical Oncology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan. · Arch Surg. · Pubmed #18025333 links to  free full text

Abstract: HYPOTHESIS: Perioperative variables, including portal venous pressure (PVP) and graft size, can predict thrombocytopenia after living donor liver transplant (LDLT). DESIGN: Retrospective analysis. SETTING: University hospital. PATIENTS: Forty-five adult patients with liver cirrhosis who underwent LDLT without splenectomy (n = 38) or with simultaneous splenectomy (n = 7). MAIN OUTCOME MEASURES: Preoperative and postoperative platelet counts and perioperative variables of recipient age, preoperative Model for End-Stage Liver Disease score, donor age, graft volume to standard liver volume ratio, PVP, cold and warm ischemia times, blood loss, and surgical complications. RESULTS: In the 38 recipients who did not undergo splenectomy, there was a strong correlation between PVP at the completion of the transplant and the platelet count (at 14 and 28 days and at 3 months). A high PVP (> or = 25 mm Hg) correlated with posttransplant thrombocytopenia, as did a small graft. Patients undergoing a simultaneous splenectomy had sufficient platelet levels at each measurement, irrespective of the graft volume. CONCLUSIONS: Portal venous pressure and graft size were associated with posttransplant thrombocytopenia. Splenectomy is an option in cases with a high PVP or a small graft, especially for patients receiving postoperative interferon therapy for hepatitis C virus.

Yamamoto T, Nagano H, Imai Y, Fukuda K, Matsumoto H, Kondo M, Ota H, Nakamura M, Wada H, Noda T, Damdinsuren B, Dono K, Umeshita K, Nakamori S, Sakon M, Wakasa K, Monden M. · Department of Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. · Int J Clin Oncol. · Pubmed #17443284 No free full text.

Abstract: We experienced a patient who received successful treatment for multiple hepatocellular carcinoma (HCC) nodules, with tumor thrombi in the major portal branches, with intraarterial 5-fluorouracil perfusion chemotherapy combined with subcutaneous interferon-alpha administration. The patient was a 50-year-old man with hepatitis C virus and HCC. The tumors consisted of a 5-cm main nodule in the right lobe (segment 8) and multiple intrahepatic metastases. The tumor also involved portal vein thrombosis throughout the right portal branch. After two cycles of interferon-alpha/5-fluorouracil combination chemotherapy, tumor markers demonstrated a decreasing tendency. Nine months after the initiation of this therapy, the tumors were limited to the right lobe and were surgically removed by S8 subsegmentectomy, S5 partial hepatectomy, and portal thrombectomy. The serum levels of both alpha-fetoprotein and protein induced by vitamin K absence II fell to normal levels after hepatic resection. Fifty-eight months after the first treatment, he is alive with several recurrent nodules in the liver. In conclusion, the interferon-alpha/5-fluorouracil combination therapy is a useful treatment for HCC in patients who have multiple intrahepatic metastases and portal vein thrombosis. In addition to this therapy, combined modality therapy including, for example, surgical resection, can sometimes have a dramatic therapeutic effect, shown by tumor markers reverting to normal levels.

Arai I, Nagano H, Kondo M, Yamamoto H, Hiraoka N, Sugita Y, Ota H, Yoshioka S, Nakamura M, Wada H, Damdinsuren B, Kato H, Marubashi S, Miyamoto A, Takeda Y, Dono K, Umeshita K, Nakamori S, Wakasa K, Sakon M, Monden M. · Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. · Hepatogastroenterology. · Pubmed #17419254 No free full text.

Abstract: BACKGROUND/AIMS: Extracellular matrix-degrading matrix metalloproteinases (MMPs) are invariably up-regulated in epithelial cancers and are key agonists of angiogenesis, invasion and metastasis. Recent studies have shown high levels of various MMPs, including MT1-MMP, MMP-1, MMP-2 and MMP-9, and their involvement in tumor progression in human hepatocellular carcinoma (HCC). However, the expression and role of MT3-MMP in HCC remains unclear. METHODOLOGY: We examined the immunohistochemical expression of MT3-MMP in surgically resected HCCs (n=58), hepatitis C virus (HCV) and hepatitis B virus (HBV)-related chronic hepatitis (n=34) and cirrhosis (n=24). RESULTS: MT3-MMP expression was observed in all non-cancerous liver tissues. In HCCs, 52% (30/58) of patients showed high MT3-MMP expression while the remaining 48% (28/58) of patients showed low expression. A clinicopathological survey demonstrated a significant correlation between high MT3-MMP expression and capsular invasion of carcinoma (p = 0.034) although there was no correlation between high MT3-MMP expression in HCC and overall survival or disease-free survival. CONCLUSIONS: MT3-MMP was expressed not only in chronic hepatitis and liver cirrhosis, but also in HCC, and high MT3-MMP expression correlated significantly with capsular invasion of carcinoma.

Tang D, Nagano H, Nakamura M, Wada H, Marubashi S, Miyamoto A, Takeda Y, Umeshita K, Dono K, Monden M. · Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. · J Gastrointest Surg. · Pubmed #16843869 No free full text.

Abstract: The clinical features of Allen's type C of combined hepatocellular and cholangiocarcinoma (cHCC-CC) are not well known. In this study, we aim to define the clinicopathologic features of cHCC-CC and to evaluate the preoperative diagnosis and surgical treatment results in comparison with those of hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC). We retrospectively analyzed 13 patients with cHCC-CC, 509 patients with HCC, and 41 patients with CCC treated in our hospital within past two decades. Viral hepatitis B or C backgrounds were more prominent in HCC and cHCC-CC groups than in the CCC group. Elevated serum alpha-fetoprotein (AFP) levels were found in 60.3% of HCC patients and in 46.2% of cHCC-CC patients. Only one patient of cHCC-CC was correctly diagnosed before surgery. The postoperative survival rates between the cHCC-CC and HCC or the CCC group were not significantly different. Both intrahepatic and extrahepatic postoperative recurrences were frequent in cHCC-CC patients, and CCC component recurrences were more frequently seen. In conclusion, the preoperative diagnosis is difficult; liver masses similar to those of HCC, together with moderately elevated serum AFP and CA19-9 levels, are reliable indicators of cHCC-CC. Surgical resection of this tumor yields results intermediate between those of HCC and CCC in character. More cases are needed to further define the characteristics of this tumor.

Kurokawa Y, Honma K, Takemasa I, Nakamori S, Kita-Matsuo H, Motoori M, Nagano H, Dono K, Ochiya T, Monden M, Kato K. · Taisho Laboratory of Functional Genomics, Nara Institute of Science and Technology, Nara 630-0101, Japan. · Int J Oncol. · Pubmed #16391793 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is a common malignancy, but the prognosis remains poor due to the lack of sensitive diagnostic markers. To gain insight into the central molecular features common to all types of HCC, and to identify novel diagnostic markers or therapeutic targets for HCC, we performed a gene expression profiling analysis using a high throughput RT-PCR system. After examining the mRNA expression of 3,072 genes in 204 (119 tumor and 85 non-tumor) liver samples, we identified differential gene expression between the HCV group (n=80), HBV group (n=19) and non-B, non-C group (n=20) with a principal component analysis and a correlation spectrum analysis. After selection of genes differentially expressed between tumor and non-tumor tissues (p<0.01) within each HCC group, a total of 51 differentially expressed genes (23 upregulated and 28 downregulated genes) were found to be common to the three HCC groups. Gene Ontology grouping analysis revealed that genes with functions related to cell proliferation or differentiation and genes encoding extracellular proteins were found to be significantly enriched in these 51 common genes. Using an atelocollagen-based cell transfection array for functional analysis of eight upregulated genes, five (CANX, FAM34A, PVRL2, LAMR1, and GBA) significantly inhibited cellular apoptosis by two independent assays. In conclusion, we identified 51 differentially expressed genes, common to all HCC types. Among these genes, there was a high incidence of anti-apoptotic activity. This combination approach with the advanced statistical methods and the bioinformatical analysis may be useful for finding novel molecular targets for diagnosis and therapy.

Ota H, Nagano H, Sakon M, Eguchi H, Kondo M, Yamamoto T, Nakamura M, Damdinsuren B, Wada H, Marubashi S, Miyamoto A, Dono K, Umeshita K, Nakamori S, Wakasa K, Monden M. · Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka E-2, Suita, Osaka 565-0871, Japan. · Br J Cancer. · Pubmed #16106266 links to  free full text

Abstract: We previously reported the beneficial effects of combination therapy of interferon (IFN)-alpha/5-fluorouracil (FU) for advanced hepatocellular carcinoma (HCC) with tumour thrombi in the major portal branches. This report describes the results of longer follow-up and includes more than double the number of patients relative to the original report, and evaluates the role of IFN-alpha/type 2 interferon receptor (IFNAR2) expression on the response to the combination therapy. The study subjects were 55 patients with advanced HCC and tumour thrombi in the major branches of the portal vein (Vp3 or 4). They were treated with at least two courses of IFN-alpha/5-FU without major complication. In the 55 patients, 24 (43.6%) showed objective response (eight (14.5%) showed complete response, 16 (29.1%) partial response), four (7.3%) showed no response, and 27 (49.1%) showed progressive disease. Immunohistochemically, IFNAR2 expression was detected in nine out of 13 (69.2%) patients. There was significant difference in the time-to-progression survival (P = 0.0002) and the overall survival (P < 0.0001) between IFNAR2-positive and -negative cases. There was a significant correlation between IFNAR2 expression and response to IFN-alpha/5-FU combination therapy in univariate analysis (P = 0.0070). IFN-alpha/5-FU combination therapy is a promising modality for advanced HCC with tumour thrombi in the major portal branches and could significantly depend on IFNAR2 expression.

Damdinsuren B, Nagano H, Kondo M, Yamamoto H, Hiraoka N, Yamamoto T, Marubashi S, Miyamoto A, Umeshita K, Dono K, Nakamori S, Wakasa K, Sakon M, Monden M. · Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan. · Int J Oncol. · Pubmed #15645115 No free full text.

Abstract: Several studies reported that Id (Inhibitor of DNA binding or Differentiation) proteins, helix-loop-helix transcription factors, have important roles in differentiation, cell cycle and angiogenesis in various cells. However, the role of Id proteins in hepatocellular carcinoma (HCC) remains unclear. We examined the immunohistochemical expression of Id1, Id2 and Id3 proteins in 54 surgically resected HCCs with surrounding HCV or HBV-related chronic hepatitis (n=30) and liver cirrhosis (n=24). All non-cancerous livers exhibited immunoreactivity for Id proteins and the expression increased from chronic hepatitis to cirrhosis. In HCCs (n=45), well-differentiated tumors mostly exhibited strong or moderate immunostaining for all Id proteins, while proportion of the samples with weak or no expression increased with tumor dedifferentiation and frequently observed in poorly (66.7, 93.3 and 93.3% respectively for Id1, 2, 3) or undifferentiated (100% for all Ids) HCCs. Clinicopathological survey demonstrated a significant correlation between Id1, 2 and 3 expression and differentiation of carcinoma (p=0.0044, 0.0014 and 0.0014, respectively) although univariate analysis indicated that high expression of Id1 was significant predictive factor for longer disease-free survival of the patients (p=0.047). A similar tendency was also observed with Id2 and Id3. The present study demonstrate high expression of Id1, 2 and 3 in well-differentiated HCC and low expression in advanced dedifferentiated HCC, in contrast to its continuous expression during breast, prostate and colon carcinogenesis. These findings suggested that Id1, 2 and 3 might play a role in the early stages of hepatocarcinogenesis, but not in the development of advanced carcinoma, and might consequently be related to HCC dedifferentiation.

Yamamoto T, Nagano H, Sakon M, Wada H, Eguchi H, Kondo M, Damdinsuren B, Ota H, Nakamura M, Wada H, Marubashi S, Miyamoto A, Dono K, Umeshita K, Nakamori S, Yagita H, Monden M. · Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka, University, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan. · Clin Cancer Res. · Pubmed #15585621 links to  free full text

Abstract: PURPOSE: Our purpose was to explore the contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of IFNalpha and 5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Susceptibility of HCC cell lines to TRAIL and/or 5-FU was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effects of 5-FU, IFNalpha, or both on the expression of TRAIL receptors (R1, R2, R3, and R4) on HCC cells or TRAIL in peripheral blood mononuclear cells (PBMC) were examined by flow cytometry. IFNalpha-induced cytotoxic effects of PBMC on HCC cell lines were examined by (51)Cr release assay. TRAIL expression in peripheral blood mononuclear cells and liver tissue from patients was examined by real-time reverse transcription-PCR or immunohistochemistry. RESULTS: HLE and HepG2 were sensitive to TRAIL, but HuH7, PLC/PRF/5, and HLF were resistant. 5-FU had synergistic effect on TRAIL in HLF and additive effect in four other HCC cell lines. TRAIL receptors on HCC cells were up-regulated by 5-FU, and IFNalpha induced TRAIL on CD4(+) T cells, CD14(+) monocytes, and CD56(+) NK cells. Treatment of effector cells by IFNalpha and target HCC cells by 5-FU enhanced the cytotoxicity of CD14(+) monocytes and CD56(+) NK cells against HCC cells via a TRAIL-mediated pathway. TRAIL mRNA overexpression was noted in PBMC of HCC patients who clinically responded to IFNalpha/5-FU combination therapy, and TRAIL(+) mononuclear cells were found in cancer tissue of a responder. CONCLUSION: Our results suggest that modulation of TRAIL/TRAIL receptor-mediated cytotoxic pathway might partially contribute to the anti-HCC effect of IFNalpha and 5-FU combination therapy.

Kurokawa Y, Matoba R, Takemasa I, Nakamori S, Tsujie M, Nagano H, Dono K, Umeshita K, Sakon M, Ueno N, Kita H, Oba S, Ishii S, Kato K, Monden M. · Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita city, Osaka 565-0871, Japan. · J Hepatol. · Pubmed #14642619 No free full text.

Abstract: BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) usually develops following chronic liver inflammation caused by hepatitis C or B virus. Through expression profiling in a rare type of HCC, for which the causes are unknown, we sought to find key genes responsible for each step of hepatocarcinogenesis in the absence of viral influence. METHODS: We used 68 non-B, non-C liver tissues (20 HCC, 17 non-tumor, 31 normal liver) for expression profiling with PCR-array carrying 3072 genes known to be expressed in liver tissues. To select the differentially expressed genes, we performed random permutation testing. A weighted voting classification algorithm was used to confirm the reliability of gene selection. We then compared these genes with the results of previous expression profiling studies. RESULTS: A total of 220 differentially expressed genes were selected by random permutation tests. The classification accuracies using these genes were 91.8, 92.0 and 100.0% by a leave-one-out cross-validation, an additional PCR-array dataset and a Stanford DNA microarray dataset, respectively. By comparing our results with previous reports on virus-infected HCC, four genes (ALB, A2M, ECHS1 and IGFBP3) were commonly selected in some studies. CONCLUSIONS: The 220 differentially expressed genes selected by PCR-array are potentially responsible for hepatocarcinogenesis in the absence of viral influence.

Iijima S, Kikkawa N, Kurokawa E, Yamamoto H, Kato T, Tsujie M, Ohshima S, Hayashi T, Naoi Y, Hatanaka T, Danno M, Sakon M, Nagano H, Dono K, Nakamori S, Umeshita K, Monden M. · Dept. of Surgery, Gastrointestinal Research Center, Minoh City Hospital. · Gan To Kagaku Ryoho. · Pubmed #14619490 No free full text.

Abstract: The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor. Patient 1 was a 43-year-old male with major portal tumor thrombi. He received combination therapy consisting of continuous arterial infusion (MTX 30 mg/m2, day 1, CDDP/5-FU 6 mg/m2: 250 mg/m2, day 1-14) and subcutaneous injection of IFN-alpha (500 x 10(4) U, 3 times a week, 4 weeks). Patient 2 was a 66-year-old male with major hepatic venous tumor thrombi. He received combination therapy consisting of continuous arterial infusion (5-FU 6 mg/m2: 250 mg/m2, day 1-14) and subcutaneous injection of IFN-alpha (500 x 10(4) U, 3 times a week, 4 weeks). Decrease in tumor was observed in both patients markers and marked regression of tumor was observed in both patients. They are still in complete response. This combination therapy is an effective strategy for advanced HCC.

Eguchi H, Umeshita K, Sakon M, Nagano H, Ito Y, Kishimoto SI, Dono K, Nakamori S, Takeda T, Gotoh M, Wakasa K, Matsuura N, Monden M. · Department of Surgery II, Osaka University Medical School, Suita, Japan. · Dig Dis Sci. · Pubmed #10961718 No free full text.

Abstract: The histologic activity of associated hepatitis was examined in 285 patients who underwent hepatectomy for hepatocellular carcinoma (HCC), to determine if the histologic activity is an independent risk factor for postoperative mortality due to liver failure. The proportion of patients with liver cirrhosis who died due to liver failure (6/180, 3.3%) was not different from that of patients with chronic hepatitis (2/68, 2.9%). However, mortality was higher in patients with liver cirrhosis and active hepatitis (4/46, 8.7%) than in those with cirrhosis and inactive hepatitis (2/134, 1.5%, P < 0.05). Such difference was not observed in the chronic hepatitis group. Multivariate analysis showed that clearance of indocyanine green at 15 min (ICGR15) and activity of hepatitis were two independent risk factors for postoperative mortality due to liver failure. In conclusion, histologic activity of associated hepatitis should be taken into account in hepatic resection of HCC in cirrhotic liver, in addition to the functional reserve of the liver.

Kondo M, Nagano H, Sakon M, Yamamoto H, Morimoto O, Arai I, Miyamoto A, Eguchi H, Dono K, Nakamori S, Umeshita K, Wakasa K, Ohmoto Y, Monden M. · Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Japan. · Int J Oncol. · Pubmed #10853022 No free full text.

Abstract: Interferon-alpha (IFNalpha) plays a crucial role in the antiproliferation and immunoregulatory activity through the specific cell surface receptor, interferon-alpha/beta receptor (IFNalpha/betaR). We examined the immunohistochemical expression of IFNalpha/betaR in 91 hepatocellular carcinoma (HCC), HCV-related chronic hepatitis (n=38) and cirrhosis (n=53), dysplastic nodules (n=5), and normal liver (n=9). The level of IFNalpha/betaR increased in chronic hepatitis and cirrhosis compared with normal liver. All the dysplastic nodules showed moderate or high expression. In HCCs, 26% (24/91) of patients showed high IFNalpha/betaR expression while the remaining 38% (35/91) showed moderate, and 35% (32/91) no or faint expression. Clinicopathological survey demonstrated a significant correlation between IFNalpha/betaR expression and differentiation of carcinoma (P=0.0008) although there was no correlation between IFNalpha/betaR expression in HCC and survival or disease-free survival. Thus, IFNalpha/betaR was expressed not only in chronic hepatitis or liver cirrhosis but in HCC and its expression was significantly correlated with tissue differentiation of carcinoma.

Kondo M, Yamamoto H, Nagano H, Okami J, Ito Y, Shimizu J, Eguchi H, Miyamoto A, Dono K, Umeshita K, Matsuura N, Wakasa K, Nakamori S, Sakon M, Monden M. · Department of Surgery II, Osaka University Medical School, Japan. · Clin Cancer Res. · Pubmed #10632332 links to  free full text

Abstract: Recent studies have shown increased levels of cyclooxygenase-2 (COX-2) in a variety of human malignancies including hepatocellular carcinoma (HCC), but little is known about the prognostic value of COX-2 in HCC or its associated nontumor liver tissue. We examined the expression of COX-2 protein by immunohistochemistry in 53 patients with HCCs whose corresponding nontumor tissues were hepatitis C virus-related chronic hepatitis (n = 21) and cirrhosis (n = 32). Samples of nine histologically normal livers and eight precancerous dysplasias were also analyzed. The level of COX-2 increased from normal liver to chronic hepatitis to cirrhosis. The majority of cirrhotic livers (81%) displayed marked COX-2 expression. In dysplasias, COX-2 expression was mainly moderate or strong (88%). In HCC, 17% of samples displayed a high COX-2 expression, and 37% of samples expressed COX-2 at a moderate level. Concordant results were obtained with reverse transcription-PCR and Western blot analyses. Clinicopathological survey indicated a significant correlation between COX-2 expression and differentiated carcinoma (P = 0.019). Although there was no correlation between COX-2 expression in HCC and prognosis, a striking difference was found between COX-2 expression in nontumor tissue and shorter disease-free survival (P = 0.0132). Moreover, high COX-2 expression in nontumor tissue was significantly correlated with the presence of active inflammation (P < 0.0001). The present findings suggest that COX-2 expression in nontumor tissue may play a positive role in relapse of HCC after surgery.