Hepatitis: Marubashi S

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.

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.

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.

Molmenti EP, Netto GJ, Murray NG, Smith DM, Molmenti H, Crippin JS, Hoover TC, Jung G, Marubashi S, Sanchez EQ, Gogel B, Levy MF, Goldstein RM, Fasola CG, Gonwa TA, Klintmalm GB. · Transplantation Services, Baylor University Medical Center, Dallas, TX 75246, USA. · Liver Transpl. · Pubmed #12037782 links to  free full text

Abstract: We prospectively collected data on 1,429 liver transplant recipients between December 1984 and December 1998. Fifty-five patients (3.8%; 10 men, 45 women; median age, 44.5 +/- 13 [SD] years) with autoimmune hepatitis (AIH) underwent orthotopic liver transplantation (OLT). Transplant recipients with AIH were younger, more likely to be women, and had a greater likelihood of rejection in the first 3, 6, and 12 months. There was no difference in patient survival or graft survival. There were 11 biopsy-proven recurrences (1 man, 10 women) of AIH after OLT. Almost half the episodes occurred within the first year after OLT. No patient required re-OLT because of recurrent disease. AIH has an incidence of 4% and a recurrence rate of 20% in OLT. Transplant recipients are more likely to be young women and have an increased incidence of acute cellular rejection (ACR) during the first post-OLT year. Recurrence should be suspected in those with abnormal liver function test results in the absence of ACR, especially during the first year after OLT. We cannot establish with certainty whether the observed process represents recurrence of the original autoimmune disease, an alloimmune phenomenon, or allograft dysfunction mimicking AIH.