BACKGROUND/AIM: A new gross classification of hepatocellular carcinoma in which Eggel's nodular type is subclassified into type 1 (single nodular type), type 2 (single nodular type with extranodular growth), and type 3 (contiguous multinodular type) has been widely used in Japan. The aim of the study was to determine whether this classification is correlated with patient outcome. METHODS: Sixty-five resected hepatocellular carcinoma nodules (< or = 5 cm) were classified using this new classification. RESULTS: The 65 tumors were classified into 30 type 1 (46%), 20 type 2 (31%), and 15 type 3 (23%) hepatocellular carcinomas. The rate of microscopic vascular invasion significantly increased from type 1 to type 2, and to type 3 tumors (p=0.03). Kaplan-Meier estimates showed that type 1 was significantly associated with lower recurrence rate (type 1 vs. type 2, p=0.01; type 1 vs. type 3, p=0.004; log-rank test), and higher disease-specific survival (type 1 vs. type 2, p=0.02; type 1 vs. type 3, p=0.002). Cox's proportional-hazards model demonstrated that type 1 was an independent factor for low risk of recurrence (p=0.002) and low risk of disease-specific death (p=0.02). CONCLUSION: The gross classification of hepatocellular carcinoma is of clinical value in predicting patient outcome.

Aged↗

PubMed2000

Induction of type 1 plasminogen activator inhibitor in human liver ischemia and reperfusion.

BACKGROUND/AIMS: The detailed role of type 1 plasminogen activator inhibitor (PAI-1) in liver with ischemia reperfusion injury remains unclear. The aim of the present study was to examine this mechanism, focusing on inflammatory cytokines. METHODS: Eighteen patients who underwent partial hepatectomy (PH) for metastatic liver tumors using only Pringle's maneuver were enrolled in the study. Peripheral blood was taken perioperatively and PAI-1, tissue type plasminogen activator (tPA), plasma aspartate aminotransferase (AST) and cytokine levels were measured. Two liver specimens were taken from each patient, one before ischemia and the other after PH, for detection of mRNA of PAI-1, tPA, tumor growth factor (TGF)-beta1, interleukin-1beta and tumor necrosis factor-a. Immunohistochemistry and Western blotting were performed to detect PAI-1 protein in the liver. RESULTS: The average plasma PAI-1 antigen level reached a maximum after the final clamp (121.6+/-5.9 ng/ml). The average PAI-1 level in hepatic veins (140.4+/-6.3 ng/ml) after the last Pringle's maneuver was higher than that in peripheral veins (p<0.0001). A correlation was observed between the ratio of the corrected fluorescent activity of PAI-1 before and after ischemia and TGF-beta1 mRNA levels in the liver after PH (p=0.003). PAI-1 protein could be detected in parenchymal and non-parenchymal cells of the liver obtained after ischemia reperfusion injury. CONCLUSIONS: PAI-1 was produced in human livers after ischemia reperfusion injury provoked by Pringle's maneuver, giving valuable information regarding the degree of warm ischemic damage.

Adult↗

PubMed2000

Chemokine and chemokine receptor expression by liver-derived dendritic cells: MIP-1alpha production is induced by bacterial lipopolysaccharide and interaction with allogeneic T cells.

Dendritic cells (DC) are highly-specialized antigen-presenting cells (APC), that initiate and modulate immune responses. Their specialized migratory and tissue-homing properties are regulated by small molecular weight proteins (chemokines) that govern leukocyte migration and activation. Little is known about the capacity of liver DC to produce or respond to chemokines. Here we examined chemokine and chemokine receptor (CR) gene expression in both immature DC progenitors (DCp) and comparatively mature DC generated from mouse liver. Factors affecting production of the chemokine macrophage inflammatory protein (MIP)-1alpha, and the influence of MIP-1alpha on liver DC migration were also investigated. Dendritic cells were propagated in response to granulocyte-macrophage colony stimulating factor (GM-CSF) +/- interleukin (IL)-4 from bone marrow (BM) cells or liver non-parenchymal cells (NPC) isolated from normal mice, or from mice treated with the hematopoietic growth factor Flt3 ligand (FL). Their phenotype and allostimulatory function were assessed by monoclonal antibody (mAb) staining and flow cytometry, and by the capacity to induce mixed leukocyte reactions, respectively. Specific chemokine and CR gene expression was studied using the RNase protection assay (RPA). Production of MIP-1alpha was determined by enzyme-linked immunoabsorbent assay (ELISA), and the migratory activity of liver DC induced by MIP-1alpha quantitated using microchemotaxis chambers. Like DC generated simultaneously from BM, liver-derived DC expressed mRNA for a variety of CC and CXC chemokines. RANTES (regulated upon activation, normal T cell expressed and secreted) transcripts were the most strongly expressed. Gene transcripts for the receptor CCR1, that binds RANTES and MIP-1alpha were also readily detected, as was CCR2, the receptor for the monocyte chemotactic proteins (MCP)1-4. No major differences in chemokine or CR mRNA expression were detected between immature and more mature liver DC. MIP-1alpha production by liver-derived DC was stimulated by bacterial lipopolysaccharide (LPS), and high levels were also detected in co-cultures of hepatic DC and allogeneic T cells. Chemotactic migration of liver-derived DC was stimulated by MIP-1alpha. Thus, liver-derived DC express mRNA for several CC and CXC chemokines and their receptors that may play key roles in the regulation of hepatic inflammatory responses. Production of MIP-1alpha by liver DC, and their migratory responses to this chemokine, suggest that MIP-1alpha and other chemokines may play significant roles in the regulation of liver DC function and in interactions of liver DC with other leukocytes, under normal and inflammatory conditions.

Animals↗

PubMed2000

Graft hyporeactivity induced by immature donor-derived dendritic cells.

Immature dendritic cells (DCs) are deficient in surface co-stimulatory molecules and have been shown to exhibit a 'tolerogenic' potential. We investigated the allostimulatory activity of immature DCs in one-way mixed leukocyte reactions and their capacity to inhibit anti-donor cytolytic activity in the sponge matrix allograft model. Immature DCs (CD80 and CD86 deficient) were derived from bone marrow cells propagated in GM-CSF and TGF-beta1. Mature DCs (CD80+ and CD86+) were derived from bone marrow cells propagated in GM-CSF and IL-4. Either 2 x 10(6) DBA/2J (DBA, H-2d) immature DCs or 2 x 10(6) mature DCs were injected intravenously into C57BL/6J (B6, H-2b) mice 7 days prior to sponge matrix allograft implantation. On day 12, the sponge was harvested and the graft-infiltrating cells were tested in vitro for cytotoxic T lymphocyte (CTL) activity. Immature dendritic cell (DC) infused significantly and markedly inhibited intra-graft CTL activity compared to mature DCs and syngeneic bone marrow control cells. The administration of immature DCs directly into the sponge allograft failed to induce hyporeactivity. Thus, the only systemic infusion of immature donor DCs was able to recapitulate the donor-specific transfusion effect, and the capacity of donor bone marrow cells to induce donor-specific hyporeactivity in the sponge allograft model.

Animals↗

PubMed2000

Living-related transplantation of left liver plus caudate lobe.

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Adult↗

PubMed2000

Objective evaluation of liver consistency to estimate hepatic fibrosis and functional reserve for hepatectomy.

BACKGROUND: The empiric evaluation of liver consistency is currently used to plan the surgical strategy. The aim of this study was to verify the feasibility of the objective measurement of liver consistency and to check its correlation with liver fibrosis and liver functional reserve. STUDY DESIGN: Fifty-two consecutive patients who underwent hepatic resections in our department were enrolled. The indications for liver resection were hepatocellular carcinoma in 36 patients, metastatic liver tumors in 12 patients, and other conditions in 4 patients. Liver consistency was measured with a new tactile sensor. A fibrosis index was calculated as an expression of the percentage of fibrotic tissue. Liver consistency was compared with the degree of liver fibrosis observed in histologic specimens (fibrosis index) and with liver function parameters. RESULTS: Liver stiffness showed a significant positive correlation with fibrosis index (r = 0.887, p < 0.0001). Liver stiffness also showed significant positive correlation with the indocyanine green test (r = 0.631, p < 0.0001) by a univariate analysis. The indocyanine green test and platelet count were independently and significantly associated with liver stiffness by a multiple regression analysis. In five patients, the liver stiffness values measured intraoperatively differed markedly from those expected from the indocyanine green test values. In these patients, the operative procedures were finally selected based on the liver stiffness measured with the tactile sensor and good clinical outcomes were obtained. CONCLUSIONS: These results show for the first time that liver stiffness can be clinically assessed quantitatively by means of the tactile sensor. The tactile sensor adequately estimates liver stiffness and this estimation is well correlated with liver fibrosis and functional reserve. Liver consistency determined objectively in this manner may be useful for optimizing surgical decision making.

Adult↗

PubMed2000

Splenectomy in patients with hepatocellular carcinoma and hypersplenism.

BACKGROUND: Hypersplenism secondary to portal hypertension is common in hepatocellular carcinoma (HCC), but surgeons still face the unresolved problem of how to manage HCC patients with hypersplenism. STUDY DESIGN: The records of 48 patients with HCC and hypersplenism were retrospectively examined and postoperative changes in platelet counts, serum total bilirubin levels, and dinical staging scores were analyzed to evaluate the clinical value of combined splenectomy and liver resection. Hepatectomy and splenectomy were performed as a two-stage operation in 13 patients and synchronously in 35. RESULTS: Postoperative platelet counts were significantly increased, and serum total bilirubin levels were significantly decreased. Clinical staging scores were also reduced after splenectomy in patients who underwent splenectomy before hepatectomy. CONCLUSIONS: Synchronous or metachronous splenectomy can increase the safety of hepatectomy in selected patients with HCC by reducing both the likelihood of bleeding complications and bilirubin overload.

Aged↗

PubMed2000

Serum endostatin levels in patients with hepatocellular carcinoma.

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Analysis of Variance↗

PubMed2000

Feasibility of CTLA4Ig gene delivery and expression in vivo using retrovirally transduced myeloid dendritic cells that induce alloantigen-specific T cell anergy in vitro.

Dendritic cells (DC) are highly specialised, bone marrow (BM)-derived antigen-presenting cells (APC) that initiate and regulate immune responses. They provide costimulatory signals (in particular, CD40 and the CD28 ligands CD80 and CD86) necessary for naive T cell activation. Functional expression of CD80 and CD86 is blocked by the fusion protein cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4Ig), that promotes tolerance induction in animals. Here, replicating mouse (B10; H2b) myeloid DC progenitors, were retrovirally transduced to express CTLA4Ig using the centrifugal enhancement method. Gene product was detected by immunocyto- or histochemistry. Maximal DC transduction efficiency was 62%. Compared with control, zeomycin-resistance gene (Zeo)-transduced DC, CTLA4Ig-expressing cells showed markedly impaired capacity to stimulate naive allogeneic (C3H; H2k) T cell proliferation and cytotoxic T lymphocyte (CTL) generation. Their ability to induce alloantigen-specific T cell hyporesponsiveness was reversed by exogenous IL-2 in secondary mixed leukocyte reactions (MLR). Following local (s.c.) transfer to allogeneic recipients, the genetically modified DC trafficked to T cell areas of draining lymphoid tissue, where transgene expression was detected. Ex vivo analysis of proliferative and CTL responses revealed donor-specific inhibition of alloimmune reactivity by the CTLA4Ig-transduced DC. This effect was associated with marked inhibition of interferon (IFN)-gamma production, but significant augmentation of IL-4 and IL-10 secretion. Thus, retroviral transduction of DC permits in vivo delivery of CTLA4Ig to the precise microenvironment where antigen (Ag) presentation occurs. Comparatively nonimmunogenic retroviral vectors, that allow permanent transgene expression in DC, and promote localized delivery of the immunosuppressive transgene product, promote immune deviation and Ag-specific T cell hyporesponsiveness.

Abatacept↗