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A 75-year-old female was admitted to our hospital and diagnosed with hepatocellular carcinoma (HCC). Computed tomography (CT) revealed a liver tumor with tumor thrombi in the portal trunk and main hepatic vein, as well as small lung metastases. The patient had good liver function with no sign of hepatitis B or C infection. She underwent right trisectionectomy of the liver with tumor thrombectomy. Intrahepatic recurrence and progression of lung metastases were observed 4 months later. Intrahepatic recurrent tumors were treated with transcatheter arterial chemoembolization (TACE), and lung metastases were treated with systemic combination chemotherapy of 5-fluorouracil (5FU) and interferon-alpha (IFN-alpha). Computed tomography showed no viable lesions in the liver and lung 6 months after these treatments. The patient has been disease free for 18 months. Prognosis is poor for patients with hepatocellular carcinoma with portal vein tumor thrombus (PVVT) or extrahepatic metastasis. This systemic combination chemotherapy with 5-fluorouracil and interferon-alpha might be effective for patients with good liver function when intrahepatic lesions are well controlled by multidisciplinary treatments, including hepatic resection with tumor thrombectomy.

Background Apoptosis as well as necrosis may play an important role in hepatic ischemia/reperfusion (I/R) injury. Akt, a serine-threonine protein kinase, is known to promote cell survival. We investigated whether gene transfer of constitutively active or dominant negative Akt could affect hepatic I/R injury. Materials and methods Hepatic I/R injury was induced in rats by Pringle’s maneuver for 20 min followed by reperfusion. Adenoviruses encoding a constitutively active form of Akt (myrAkt), a dominant negative form of Akt (dnAkt), or β-galactosidase (LacZ) were injected through the tail vein 72 h before hepatic I/R. Results Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining demonstrated a significant increase in the positive cells 240 min after reperfusion. Immunoblotting with phospho-Akt antibody showed phosphorylation of Akt from 90 to 180 min after reperfusion. The expression of myrAkt reduced the number of TUNEL-positive cells and hepatic necrosis around the central veins in the liver after reperfusion. This expression also significantly inhibited the increase in serum alanine aminotransferase (297 ± 131 IU/L, P c after reperfusion. No difference in nuclear translocation of nuclear factor (NF)-κB, p65 was seen among the three groups of rats, however. Conclusion Adenoviral gene transfer of myrAkt could inhibit apoptotic cell death and subsequent hepatic I/R injury in the rat, through Bad, not NF-κB.

Purpose: Imaging with 99mTc-sestamibi (99mTc-MIBI) has been used to assess 170-kDa P-glycoprotein (P-gp) expression and predict chemotherapy responses in several types of malignancy, such as breast and lung cancers. The purpose of this study was to evaluate the relationship between 99mTc-MIBI accumulation in tumors and sensitivity to chemotherapy in gastric cancer patients. Experimental Design: Thirty-six patients with advanced gastric cancer underwent 99mTc-MIBI scintigraphy before chemotherapy. Patients also underwent endoscopic biopsy, and the expression of P-gp or multidrug resistance-associated protein was analyzed by immunohistochemical staining. The relationship between the accumulation of 99mTc-MIBI in tumors and responses to chemotherapy with 5-fluorouracil/cis-diamminedichloroplatinum(II) or epirubicin was examined. Results: Higher accumulation of 9mTc-MIBI in tumors was observed in 25 and 23 of 36 gastric cancer patients at the early (30 min) and delayed (120 min) images, respectively. Accelerated accumulation of 99mTc-MIBI negatively correlates with increased expression of P-gp, but not of multidrug resistance-associated protein, as determined by immunohistochemistry in gastric cancer tissues. The response rate to 5-fluorouracil/cis-diamminedichloroplatinum(II) chemotherapy in patients with high 99mTc-MIBI accumulation (15.4%) was much lower than that in patients with low 99mTc-MIBI accumulation (54.5%). In contrast, patients with high 99mTc-MIBI accumulation show a higher response rate (41.7%) to chemotherapy with epirubicin, which is known to be a substrate of P-gp transporter. Conclusions: 99mTc-MIBI scintigraphy is useful to suggest the responses to chemotherapy of patients with advanced gastric cancer.

症例は80歳の男性で, 心窩部痛, 右季肋部痛および黄疸を主訴に近医受診し, 肝S5に径5cm大の腫瘍を指摘され当科紹介となった. HBsAg (-), HBcAb (-), HCVAb (-). 胃前庭部後壁にも腫瘍性病変を認め, 血清AFP, PIVKA-II, CEA値はいずれも異常高値であった. 術前診断は3型胃癌の肝転移とし, 胃亜全摘術, 肝右葉切除術を施行した. 胃病変はT1 (sm, IIa+IIc), 肝腫瘍は白色調で硬く被膜を有さず, 右肝管1次分枝内に腫瘍栓を伴っていた. 胃肝両病変ともに充実性配列主体の低分化腺癌 (hepatoid-adenocarcinoma) の像を呈し, 類似の免疫組織染色パターンであることから, 胃低分化腺癌の肝転移と診断した. AFP, PIVKA-II産生T1胃癌の報告は少なく, 胆管腫瘍栓を伴う転移性肝癌も非常にまれである. 胃癌の幼若化現象, 癌胎児性抗原産生の面から興味深い症例であると考えられる.

PURPOSE To determine the risk factors of cholangitis and liver abscess occurring after percutaneous ablation therapy for liver tumors. MATERIALS AND METHODS Between October 1995 and September 2002, 358 patients with 455 liver tumors underwent a total of 683 ablation procedures, such as percutaneous ethanol injection (PEI), percutaneous microwave coagulation (PMC), and radiofrequency (RF) ablation therapy. With a retrospective review of medical records, the rates and outcomes of cholangitis and/or liver abscess occurring after ablation therapy were evaluated. The relationship between cholangitis and/or liver abscess and multiple variables (age, disease, Child-Pugh class, size of nodules, multiplicity of nodules, history of transcatheter arterial embolization, presence of bilioenteric anastomosis, and lack of prophylactic antibiotics administration) were statistically analyzed. RESULTS Cholangitis and/or liver abscess occurred in 10 sessions (1.5%) in 10 patients: six sessions after PEI, three sessions after PMC, and one session after RF ablation. Both cholangitis and liver abscess were noted in seven sessions, cholangitis was noted in two, and liver abscess was noted in one. Six patients recovered, but two developed recurrent cholangitis and liver abscess, one developed lung abscess complicated with liver abscess, and one died of septic shock associated with cholangitis. On stepwise regression analysis, bilioenteric anastomosis was the sole significant predictor of cholangitis and/or liver abscess formation ( P CONCLUSION Bilioenteric anastomosis strongly correlated with the development of cholangitis and/or liver abscess after percutaneous ablation therapy. Close posttreatment attention should be paid to this subgroup of patients.

Background. Cellular functions are maintained by a continuous supply of ATP, which is supplied efficiently by mitochondrial oxidative phosphorylation. Since myoglobin, found in cardiac myocytes and red skeletal muscle, but not in the liver, facilitates oxygen diffusion under low oxygen conditions and enhances oxidative phosphorylation, this study seeks to enhance hepatic ATP levels and attenuate ischemia-reperfusion injury in rodent livers by adenovirus-mediated myoglobin expression. Material and methods. After infecting Hep3B and rodent livers with adenovirus carrying CMV promoter sequences linked to the human myoglobin gene (AdCMVMyo), reverse transcriptase-PCR and immunodetection for myoglobin, and cellular and hepatic ATP levels were examined. The effect of myoglobin was evaluated in a hepatic ischemia-reperfusion model in the rat. Results. Myoglobin expression was confirmed in Hep3B and rat livers after AdCMVMyo infection. The ATP levels in Hep3B cells and C57BL/6 mice livers 72 h after AdCMVMyo transfection were significantly higher than control levels and those after adenovirus-mediated β-galactosidase transfection. Finally, expression of myoglobin attenuated ischemia-reperfusion injury in the rat liver. Conclusion. These results indicate that myoglobin gene transfer to the liver enhanced ATP levels both in vitro and in vivo and might be a novel strategy to reduce ischemia-reperfusion injury.

Nonsurgical therapy for patients with advanced hepatocellular carcinoma (HCC) has yielded poor long-term survival. This study evaluates the effects of surgical treatments for patients with HCC invading major portal and/or hepatic veins. The surgical results of 112 patients with HCC invading major portal and/or hepatic veins who underwent hepatic resection between 1985 and 2001 were studied to evaluate the feasibility of hepatic resection as a local treatment.

Purpose: Although the adrenal gland is a common site of extrahepatic metastasis from hepatocellular carcinoma (HCC), there are no definitive guidelines for the treatment of adrenal metastasis. This study examines the effectiveness of various treatments for this disease. Methods: We retrospectively analyzed 20 patients treated for adrenal metastasis of HCC by adrenalectomy (n = 13), transarterial chemoembolization (TACE), or percutaneous ethanol injection therapy (PEIT) (n = 7). Results: There were no significant differences in cumulative survival rates between patients given adrenalectomy and those given TACE or PEIT, either after completing treatment for primary HCC or after the first treatment for adrenal metastasis. Six of seven patients with tumor thrombi in the inferior vena cava (IVC) from adrenal metastasis underwent adrenalectomy combined with intracaval thrombectomy, five of whom survived for more than 1 year after surgery, and two of whom are still alive without any recurrence more than 3 years after surgery. PEIT showed good results for small adrenal metastasis. Conclusion: These findings suggest that therapeutic modalities should be chosen according to the clinical features of each individual, including the size of the metastatic tumor, whether there is invasion into the IVC, the function of the remaining liver, and the existence of intra- and/or nonadrenal extrahepatic lesions. Furthermore, intracaval tumor thrombectomy could be indicated for patients with IVC thrombus if they are suitable candidates for surgery.

The aim of this study was to target Kupffer cells (KCs) selectively and efficiently by the intraportal injection of fusigenic cationic liposomes with hemagglutinating virus of Japan components (HVJ cationic liposomes). Phosphorothioate FITC-oligodeoxynucleotides (FITC-ODNs) encapsulated in either HVJ cationic liposomes, HVJ anionic liposomes or conventional cationic liposomes without HVJ were transferred to the rat. FITC-ODNs in HVJ cationic liposomes administered via portal vein were selectively transfected to KCs for up to 24 h with no apparent cytotoxicity at higher transfection efficiency than FITC-ODNs in conventional cationic liposomes without HVJ administered via portal vein or tail vein. On the other hand, FITC-ODNs in HVJ anionic liposomes were observed mainly in hepatocytes, not KCs. This new method will be useful for the modulation of KCs activity in both basic research and clinical applications.

固有肝動脈瘤に対して, 術前3次元画像診断を施行し治療方針および術式決定に有用であった1例を経験した. 症例は65歳の男性. 肝嚢胞の経過観察中に腹部CT検査にて固有肝動脈瘤を偶然発見された. 血管造影を施行したが, 動脈瘤と左右肝動脈の分岐形態が明確に描出されず, 3次元CT検査および3次元CT内視鏡画像(cruising eye view)により血管分岐形態, さらには動脈瘤内部の形態が容易に把握でき, 安全に固有肝動脈瘤切除および動脈再建を施行しえた. 本症例のような腹腔内臓器動脈瘤症例では, 3次元CT検査が術前診断のみならず術式決定にも有用であり, 積極的に施行されるべきであると考える.

The case of a 74-year-old female patient who underwent a right hepatic lobectomy for hepatocellular carcinoma (HCC) which developed in primary biliary cirrhosis (PBC) is reported herein. During a follow-up examination for Parkinson's disease, an elevation of hepatobiliary tract-related enzymes and alpha-fetoprotein was uncovered. Diagnostic imagings showed a hypervascular, solitary, and encapsulated tumor measuring about 7 cm in diameter located mainly in the posterior segment. Positive antimitochondrial and antinuclear antibodies and a preoperative liver biopsy strongly suggested well differentiated HCC developed in PBC (Scheuer's classification stage II). Since the natural prognosis of PBC estimated by the Mayo risk score was fairly good and the liver function indicated sufficient tolerance for major hepatic resection, and preoperative computed tomography (CT) volumetry showed the atrophy of the right hepatic lobe, a right hepatic lobectomy was performed. A pathological examination revealed well encapsulated, moderately differentiated HCC with, in part, well-differentiated HCC in the tumor and stage II PBC in the noncancerous region. CT volumetry performed at postoperative day 14 showed a 146% enlargement of the remnant liver. An early detection of HCC and PBC by strict screening would prevent a limitation of surgical therapy due to a deteriorated liver function.

We report a patient with cholangiocellular carcinoma with tumor thrombi in the main portal trunk who has survived for 9.5 years after hepatic resection. A 57-year-old woman underwent an extended left lobectomy, and resection of the caudate lobe plus the main portal trunk for a liver tumor that had a portal tumor thrombus in the main portal trunk. The portal vein was reconstructed with an autologous vein graft obtained from the external iliac vein. Histological examination of the resected specimen revealed moderately differentiated tubular adenocarcinoma compatible with cholangiocellular carcinoma. Factors contributing to the patient's long-term survival are discussed. Aggressive surgical resection can be effective even for such an advanced case of cholangiocellular carcinoma.

This study investigated whether prostaglandin E1 (PGE1) could reduce hepatic injury to the liver graft caused by harvesting and 24-h preservation in University of Wisconsin (UW) solution in a canine model. The PGE1-treated group was intravenously administered 0.5 microgram/kg per minute of PGE1 for 30 min before harvesting, as well as a concentration of 1 mg/l PGE1 in the washout and UW solutions. In both the PGE1-treated and the control group, all recipients survived for 1 week or more after transplantation. Arterial ketone body ratio (AKBR) remained over 1.0 in the early postoperative period. The PGE1 group showed significant reductions in guanase, GOT, and LDH during the early postoperative period compared to the untreated control group. Histological examination disclosed partial mitochondrial swelling, hepatocyte vacuolation, and necrosis in the control group, while such abnormalities were rarely seen in the PGE1 group. These results suggest that PGE1 can effectively reduce hepatic injury to liver grafts preserved in UW solution prior to transplantation.

The size of segmental liver grafts assessed by preoperative computed tomography (CT) volumetry was evaluated in relation to surgical outcome in 14 living related partial liver transplantations (LRLTs). The aim was to show that graft size can be accurately assessed before operation and to estimate the lower safety limit of graft size in assessing subsequent graft function and survival. The relationship between calculated CT volume and weight of the liver was linear in the recipient (r = 0.97) and donor (r = 0.98). The mean (s.e.m.) modified liver weight ratio (MLWR; ratio of graft weight to recipient's expected liver weight based on body-weight) was 0.59(0.07) (range 0.27–1.09). Surgical complications related to an oversized graft and primary graft failure caused by a small-for-size graft were not observed. The lowest MLWR of any survivor was 0.27. These results suggest that a partial liver graft reduced to about 30 per cent of the recipient's expected liver weight can tolerate LRLT well.

This study was designed to investigate the influence of intracellular ionized calcium ([Ca2+]i) on the induction of c-fos, c-jun, c-myc, and hsp70 genes after oxidant stress induced by xanthine/xanthine oxidase (X/XOD) treatment or after heat shock using primary cultures of rat proximal tubule epithelium (PTE). X/XOD (500 microM/25 mU/mL) induced all of these genes; ionomycin also resulted in similar kinetics of induction of all genes. The expression of both c-fos following X/XOD treatment and hsp70 following heat shock was markedly decreased through chelation of [Ca2+]i by Quin 2/AM. The c-fos expression following X/XOD treatment was partly reduced by a protein kinase C inhibitor, staurosporine (ST), and markedly inhibited by another protein kinase inhibitor, 2-aminopurine (2AP), while both ST and 2AP markedly reduced hsp70 expression. The ADP-ribosylation transferase inhibitor 3-aminobenzamide had no effect on either c-fos or hsp70 expression. These results suggest that cell injuries leading to increased [Ca2+]i in PTE result in induction of c-fos, c-jun, c-myc, and hsp70; and that the activation of c-fos and hsp70 genes may be regulated by [Ca2+]i and [Ca2+]i-dependent protein kinases.

1. The difference in the extent of liver ischaemia between a hepatic vascular exclusion model and an inflow occlusion model were investigated by determining Indocyanine Green retention and hepatic mitochondrial redox state during 2 h of ischaemia in 10 mongrel dogs. The splanchnic venous bed and/or the infra-hepatic inferior vena cava were decompressed by pump-driven veno-venous bypass. 2. The Indocyanine Green retention test revealed that there was no hepatic blood flow in the hepatic vascular exclusion model during ischaemia (96.8 ± 0.73% retention of the dye after 20 min), whereas hepatic blood perfusion was still present significantly in the inflow occlusion model (78.1 ± 1.19% retention of the dye after 20 min) (P 3. The mitochondrial redox potential of the liver in the dogs with hepatic vascular exclusion decreased immediately after the induction of ischaemia and remained fixed at extremely low levels. By contrast, in the dogs with inflow occlusion the redox potential decreased gradually after induction and was maintained significantly higher than that in dogs with hepatic vascular exclusion during 2 h of ischaemia (P 4. It is concluded that the extent of liver ischaemia in the hepatic vascular exclusion model with pump-driven shunt is significantly different from that in the inflow occlusion model with shunt.

Porcine livers were preserved for 72 h using continuous hypothermic perfusion with UW solution and fluorocarbon emulsion (FC-43). They were then recirculated with human blood for 2 h at 37 degrees C for the evaluation of their viability. During hypothermic perfusion and recirculation, the main metabolites of the perfusate and adenine nucleotide concentrations were measured in order to examine the energy metabolism of the livers. This study revealed that hypothermically perfused livers, which mainly utilize endogenous fatty acids as an energy substrate during this time were adequately preserved for 72 h. In terms of energy metabolism, it is suggested that when using the method of continuous hypothermic perfusion with UW solution and FC-43, the administration of adequate amounts of certain fatty acids might prolong the preservation period.

In order to confirm a complete ischemia model, 1-hour warm hepatic ischemia by hepatic vascular exclusion (HVE) was studied in dogs, in comparison with that by inflow occlusion (IOC) only. The splanchnic venous bed and/or infrahepatic inferior vena cava were decompressed by a centripetal pump-driven venovenous bypass. Indocyanine green retention test revealed no hepatic blood flow in the HVE model during ischemia, while hepatic blood perfusion was still present in the IOC model. All 5 of the IOC dogs survived more than 7 days after revascularization, while 4 of the 5 HVE dogs died within 9 h. After the induction of hepatic ischemia, lactate increased in both HVE and IOC dogs. After revascularization, transaminases and guanase were elevated, the arterial ketone body ratio (acetoacetate/3-hydroxybutyrate) decreased and the serum lactate accumulated more in HVE dogs than in IOC dogs. The hepatic redox state of IOC dogs was significantly decreased by additional clamping of the inferior vena cava. It is concluded that the HVE model with a pump-driven active bypass provides complete and stable hepatic ischemia, resulting in greater deterioration of hepatic cellular functions; hence it is more suitable as a model of complete hepatic ischemia than the IOC one.

We performed 22 canine orthotopic partial liver transplantations (PLTs) with three different revascularization methods; portal vein arterialization (PVA group, n = 11), hepatic arterial shunt (HAS group, n = 5), and conventional portal vein reperfusion (control group, n = 6). Our purpose was to evaluate the feasibility of PVA as a revascularization technique in PLT assessing the changes in arterial ketone body ratio (KBR) as an index of hepatic energy status. After the first anastomosis (left hepatic vein), the ischemic partial liver graft was revascularized with arterial blood flow shunted from the external iliac artery to the hepatic side of the portal vein (PVA group) or the proper hepatic artery (HAS group). Both anhepatic period and ischemia time were significantly shortened in groups PVA and HAS as compared with those in control. In the PVA group, 10 out of 11 recipients survived for at least 5 days (14.2 +/- 3.8 days, mean +/- SEM), while 3 out of 5 (5.2 +/- 1.0) survived in the HAS group and 4 out of 6 (6.2 +/- 1.3) in the controls. Although portal blood flow during PVA was only about 25% of the total hepatic blood flow at preclamping, the KBR was rapidly restored after PVA and showed almost the same values at preclamping. The KBR values during the arterialization time and initial velocity of KBR recovery in the PVA group were significantly higher than those in the HAS and control groups. These results suggest that PVA presents an attractive option in PLT.

Apoptosis as well as necrosis may play an important role in hepatic ischemia/reperfusion (I/R) injury. Akt, a serine-threonine protein kinase, is known to promote cell survival. We investigated whether gene transfer of constitutively active or dominant negative Akt could affect hepatic I/R injury.Hepatic I/R injury was induced in rats by Pringle's maneuver for 20 min followed by reperfusion. Adenoviruses encoding a constitutively active form of Akt (myrAkt), a dominant negative form of Akt (dnAkt), or beta-galactosidase (LacZ) were injected through the tail vein 72 h before hepatic I/R.Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining demonstrated a significant increase in the positive cells 240 min after reperfusion. Immunoblotting with phospho-Akt antibody showed phosphorylation of Akt from 90 to 180 min after reperfusion. The expression of myrAkt reduced the number of TUNEL-positive cells and hepatic necrosis around the central veins in the liver after reperfusion. This expression also significantly inhibited the increase in serum alanine aminotransferase (297 +/- 131 IU/L, P0.05) 120 min after I/R, compared with increases in uninfected (1761 +/- 671 IU/L), LacZ adenovirus (1528 +/- 671 IU/L)-, and dnAkt adenovirus (1342 +/- 485 IU/L)-infected rats. MyrAkt expression phosphorylated Bad and inhibited the release of cytochrome-c after reperfusion. No difference in nuclear translocation of nuclear factor (NF)-kappaB, p65 was seen among the three groups of rats, however.Adenoviral gene transfer of myrAkt could inhibit apoptotic cell death and subsequent hepatic I/R injury in the rat, through Bad, not NF-kappaB.

Background In ischemia/reperfusion (I/R) injury, a massive generation of reactive oxygen species (ROS) after reperfusion is a critical factor. Rac, a member of the Rho GTPase superfamily, plays important roles in the production of ROS and activation of nuclear factor-κB (NF-κB) in vitro. However, the exact role of Rac in the ROS production and NF-κB activation in vivo after I/R is still obscure. Methods We blocked Rac1 activity in the rat liver using adenovirus encoding a dominant negative rac1 mutant (Ad5N17Rac1) and examined whether inactivation of Rac1 could prevent ROS generation in the hepatic I/R injury. Seventy-two hours after the adenoviral infection, hepatic I/R was induced by Pringle's maneuver for 20 minutes, followed by reperfusion in the rats. Results Ad5N17Rac1 infection significantly attenuated ROS production after reperfusion and suppressed the hepatic injury. Furthermore, N17Rac1 suppressed NF-κB activation and messenger RNA expression of tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthetase (iNOS). Ad5LacZ, a control adenovirus, had no effect on the induced hepatic I/R injury, nor did it affect NF-κB activation. Immunohistochemical analysis of NF-κB (p65) revealed that translocation of p65 to the nucleus after reperfusion was blocked in many of non-parenchymal cells (NPCs) and in hepatocytes in the Ad5N17Rac1-infected liver. Conclusion We conclude that Rac1 is required in ROS generation and NF-κB activation after hepatic I/R in vivo, and that inactivation of NF-κB in NPCs and suppression of ROS generation in NPCs and hepatocytes possibly account for the protective effect of N17Rac1 in this study.

A 73-year-old man was admitted to our hospital on emergency for severe anemia. Upper gastrointestinal endoscopic study revealed a hemorrhagic ulcer in the duodenal bulb. He underwent endoscopic hemostasis. Abdominal ultrasonography and computed tomography showed a huge mass in segment 4 of the liver, growing into the extrahepatic space with direct invasion to the duodenal bulb. Extended left lobectomy and partial gastroduodenectomy was performed, because the endoscopic management of hemostasis was incomplete. He was discharged on the 30th postoperative day. Histopathologically, the tumor cells were moderately differentiated hepatocellular carcinoma with direct invasion to the duodenal mucosa. This report demonstrated the first case with a hepatocellular carcinoma with duodenal invasion, for which hepatic resection was performed successfully.

Background/Aims : Since the hepatic extracellular matrix is remodeled in liver regeneration, we investigated whether increased collagenase activity in the liver can induce hepatocyte proliferation in vivo. Methods : To increase hepatic collagenase activity, human matrix metalloproteinase-1 was delivered to the rat liver by the recombinant adenoviral vector Ad5MMP-1. Results : Hepatic delivery of Ad5MMP-1 increased the 5-bromo-2-deoxyuridine labeling index and mitotic index in hepatocytes, causing an increase in the dry liver weight; control adenovirus, Ad5LacZ, had minimal effect. Hepatocyte proliferation started approximately 48 h after infection with Ad5MMP-1 and ended after about 2 weeks. The increase in the dry liver weight also returned to baseline after 2 weeks. Transient liver injury by Ad5MMP-1, reflected by increased aspartate and alanine aminotransferase levels, peaked around 1 week, and was associated with hepatocyte apoptosis. Collagenase-induced hepatocyte proliferation was accompanied by cytoplasmic accumulation of β-catenin and a transient decrease in E-cadherin expression. Conclusions : Modification of the hepatic extracellular matrix by collagenase induces transient hepatocyte proliferation in vivo, suggesting that the condition of the hepatic extracellular matrix per se plays a pivotal role in regulating hepatocyte proliferation.

Type IV collagen, one of the serum markers for hepatic fibrosis, was measured perioperatively in patients with and without chronic liver damage to investigate whether this parameter changes in response to acute stress to the liver and can predict the surgical risk of hepatic resection. The serum type IV collagen level was significantly elevated in patients with liver cirrhosis. There were significant correlations between serum type IV collagen levels and the indocyanine green clearance test and cholinesterase activity, although the correlation coefficients were not high. The size of the resected hepatic mass was not the primary factor to influence the postoperative serum type IV collagen level. In patients with liver cirrhosis, the postoperative serum type IV collagen level increased significantly compared to that in patients with normal liver or chronic hepatitis. Postoperative liver failure occurred in 0%, 11.6%, and 44.4% of patients with preoperative serum type IV collagen levels of150,or = 150 to 300, andor = 300 ng/ml, respectively. In those with postoperative liver failure, the serum type IV collagen levels were significantly higher both pre- and postoperatively compared to those in patients with uneventful courses. Several preoperative liver function tests indicated that type IV collagen is an independent risk factor for postoperative liver failure. Thus perioperative measurement of the serum type IV collagen levels seemed to be useful for predicting the risk of hepatic resection in patients with chronic liver damage.

Background. Proliferative cholangitis (PC) associated with hepatolithiasis results in stricture of the main bile ducts and is a major cause of residual and/or recurrent stones after repeated treatment for hepatolithiasis. The transcription factor E2F controls the expression of several genes involved in cell proliferation. The aim of this study was to inhibit PC using cytostatic gene therapy by transferring fusigenic anionic liposome–hemagglutinating virus of Japan (HVJ–anionic liposome) complexes containing a synthetic double-stranded oligodeoxynucleotide with high affinity for E2F (E2F decoy). Materials and methods. PC was induced by introducing a fine nylon thread into the bile duct in a rat model. HVJ–anionic liposomes containing the E2F decoy were administered directly into the biliary tract. HVJ–anionic liposomes containing a missense oligodeoxynucleotide (scramble decoy) were also given as a control. The count of peribiliary glands in the bile duct, 5′-bromodeoxyuridine (BrdU) labeling index, and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) in the bile duct were compared among untransfected, scramble decoy-transfected, and E2F decoy-transfected rats. Results. E2F decoy-transfected bile ducts showed inhibition of the papillary proliferation of the biliary epithelium and peribiliary gland hyperplasia. BrdU incorporation and PCNA expression in the bile ducts were inhibited in E2F decoy-transfected rats. Conclusion. Our cytostatic gene therapy approach using direct E2F decoy transfer into the biliary tract suppressed PC in a rat model and may offer an effective therapeutic option for reducing recurrence following treatment for hepatolithiasis.

A combination of an in situ pedicle resection of the liver and a hepatic vein reconstruction using a cranially transpositioned segment of the IVC after implantation of an ePTFE graft at the missing IVC was useful in treating a patient who suffered from a huge liver tumor involving all of the hepatic venous confluence and the IVC. Although early tumor recurrence remains an unresolved problem for such patients, a surgical approach is feasible. This technique can be justified as a therapeutic modality, not only because it improves quality of life, but also because it provides patients with an opportunity for additional treatment.

Background. The aim of this study was to evaluate the clinicopathologic characteristics of patients with hepatocellular carcinoma (HCC) and bile duct thrombi (BDT). Patients. Seventeen patients with HCC and BDT among 671 patients with HCC who underwent hepatic resection were enrolled in this study. Results. There were no significant differences in the survival rates between patients with and those without BDT, although the rate of stage IV or portal vein invasion was significantly higher in patients with HCC and BDT than in those with HCC but without BDT. In 9 of 17 patients with BDT, preoperative jaundice was observed. Five of the 17 patients underwent a bile duct resection combined with hepatic resection, and 12 patients underwent hepatic resection with removal of the BDT without bile duct resection. None of the patients had histopathologic evidence of direct tumor invasion into the bile duct wall or of any tumor recurrence related to the BDT. There were no significant differences in the survival rates between patients who underwent bile duct resection and those who did not. Conclusion. Hepatic resection and the removal of BDT without bile duct resection were sufficient surgical interventions to treat patients with HCC and BDT. (Surgery 2000;127:779-83.)

Intracaval tumor thrombus is one of the characteristic features of advanced hepatocellular carcinoma. To formulate an appropriate operative strategy for removing intracaval tumor thrombi, it is of great importance to accurately diagnose the location, any invasion into the wall of the vena cava, and the extent of intracaval tumor spread. Intravascular ultrasonographic imaging is a novel technology that enables the precise catheter-based assessment of the dimensions and morphology of the vascular structure and any lesions. We have applied this technology to the diagnosis of intracaval tumor thrombi originating from adrenal metastasis secondary to hepatocellular carcinomas. This modality was thus found to be useful in determining the best operative procedure for removing tumor thrombi in the inferior vena cava.

Background/Aims: The ability to transfer foreign genes into the biliary tract would be useful for the treatment of biliary tract diseases, including cancer, cystic fibrosis and other genetic diseases. To introduce a foreign gene precisely into the rat biliary epithelial cells, we developed a new technique, inserting a polyethylene catheter into the common bile duct through the papilla of Vater by use of a fusigenic cationic liposome with hemagglutinating virus of Japan (HVJ-cationic liposome). Methods: Transfection efficiency was estimated with the use of FITC-oligonucleotides (FITC-ODNs) and cDNA of β-galactosidase (pCAG-lacZ). Results: FITC-ODNs encapsulated in HVJ-cationic liposome were effectively transfected into cell nuclei of human cholangiocellular carcinoma in vitro after a 30-min incubation as compared with the simple application of naked FITC-ODNs. After in vivo injection of FITC-ODNs using the HVJ-cationic liposome method through the papilla of Vater, fluorescence accumulation was observed only in the epithelial cells of the biliary tract, but not in the parenchymal cells of the liver. β-galactosidase expression was observed in the biliary epithelial cells 3 days after the transfection of pCAG-lacZ and was also detected at 14 days, but not at 28 days, without obvious cytotoxicity. Conclusions: HVJ-cationic liposome-mediated gene transfer to the biliary tract via the papilla of Vater is a minimally-invasive and an effective gene-delivery method for site-specific targeting to the epithelial cells of the biliary tract, which could be applied to the treatment of human biliary tract diseases.

We report on a 65-year-old man who received asynchronous bilateral adrenalectomy for adrenal metastasis of hepatocellular carcinoma. Fifteen months after curative resection of right hepatic lobe for hepatocellular carcinoma, a metastatic lesion of the left adrenal gland was detected and left adrenalectomy was performed. Ten months after the second operation, a metastatic lesion in the right adrenal gland, associated with tumor thrombus in the inferior vena cava, was revealed. Transcatheter arterial embolization of the arteries feeding the metastatic tumor was performed, but its effects were incomplete. As there was the tumor thrombus in the inferior vena cava and no other intrahepatic recurrence or extrahepatic metastasis was found, resection of the right adrenal gland with tumor thrombus, without the employment of veno-venous bypass, was performed, followed by postoperative hormonal supplementation. Changes in the patient's alpha-fetoprotein level were clinically useful for the detection of the metastatic lesions and the evaluation of therapeutic effects. Metastasis to adrenal gland from hepatocellular carcinoma should be actively managed, and the appropriate surgical treatment selected, if intrahepatic recurrence and/or other extrahepatic metastasis are controlled. To achieve higher curability and better outcome in patients with bilateral adrenal metastasis of hepatocellular carcinoma, bilateral total adrenalectomy is indicated, accompanied by effective postoperative hormonal supplementation.

Although extrinsic denervation is inevitable after intestinal transplantation and leads to poor intestinal function, little is known about the occurrence of extrinsic reinnervation. In this study, extrinsic sympathetic reinnervation was investigated morphologically following syngeneic intestinal transplantation performed on male Lewis strain rats. At 1, 3, 6, 9, 15, and 27 weeks after transplantation, the graft mesenteric arteries and their branches in the intestinal wall were histochemically examined by a glyoxylic acid method demonstrating perivascular sympathetic nerve fibers. At 3 weeks after transplantation, extrinsic sympathetic reinnervation was recognized in the graft mesenteric arteries, where it traversed the arterial anastomosis and extended along the course of the mesenteric arteries from proximal to distal. The degree of reinnervation in the mesenteric arteries was similar to the results obtained in the simple denervation model. The transplanted intestinal tract itself was sympathetically denervated for at least 9 weeks after transplantation, and reinnervation was not recognized until 15 weeks after transplantation. Reinnervation extended into the intestinal wall in every preparation, and the enteric nerves began to be reinnervated at 27 weeks after transplantation, but the density was still at a low level and complete extrinsic reinnervation of the graft would seem to require a much longer time to reestablish itself.

Role of cytosolic Ca 2+ and protein kinases in the induction of the hsp70 gene. The role of cytosolic Ca 2+ ([Ca 2+ ] i ) and protein kinases in the hsp70 induction following heat shock was investigated in cultured rat proximal tubular epithelial (PTE) cells. Changes in [Ca 2+ ] i were measured by digital imaging fluorescence microscopy using fura 2. Steady state levels of hsp70 mRNA were examined by either Northern or dot blot analyses. [Ca 2+ ] i increased within 10 minutes and continued to increase following heat shock. The increases in [Ca 2+ ] i were reduced in nominally Ca 2+ -free media with or without EGTA. [Ca 2+ ] i also increased within 0.5 minutes following ionomycin, but then declined to normal levels by 1.0 to 1.5 minutes. Heat shock induced hsp70 mRNA within 15 minutes, which continued to increase up to three hours. Ionomycin also induced hsp70 mRNA, which peaked at 30 minutes, and gradually decreased thereafter. The hsp70 induction following heat shock was attenuated when extracellular Ca 2+ was reduced. Chelation of [Ca 2+ ] i by quin-2 also reduced the hsp70 induction. Inhibitors of protein kinases, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), calphostin C, genistein, and 2-aminopurine, also had inhibitory effects on the hsp70 induction. In contrast, a calmodulin inhibitor, chlorpromazine, had little effect. These results suggest that heat shock increases [Ca 2+ ] i in rat PTE cells and that [Ca 2+ ] i and protein kinases are involved in the hsp70 induction following heat shock.

Arterial ketone body ratio (AKBR) was measured serially in 49 pediatric orthotopic liver transplantations. The AKBR pattern correlated with hepatic synthetic function, as well as with short-term graft and patient survival. A rapid recovery pattern of AKBR to above 1.0 within 40 hr after reperfusion was associated with 94% graft and patient survival. Pediatric liver grafts were found to have better tolerance to low energy levels when compared with previously published data for adult OLT. The salvage rate of pediatric grafts exhibiting a slow recovery pattern (AKBR 0.7-1.0) was 71%. No recovery pattern (AKBR0.7) was seen in all 6 cases of primary nonfunction, and in 3 of 4 cases of early hepatic artery thrombosis (HAT). All these grafts were lost; however, 56% of the children in this group survived retransplantation. Unlike the PNF grafts, the no recovery pattern after HAT was characterized by gradual improvement of the synthetic function, despite the low energy state.

The influence of combined replenishment of L-3,5,3'-triiodothyronine (T3) and vasopressin (antidiuretic hormone [ADH]) on both hepatic metabolism and systemic hemodynamics was assessed in brain-dead dogs. Arterial ketone body ratio (AKBR) was measured as a parameter of hepatic metabolism, which reflects the redox state (free nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide) of liver mitochondria. Mean arterial blood pressure (MAP) was significantly decreased from 110.4 +/- 3.8 to 44.4 +/- 1.7 mmHg, at 1 hr after completion of brain death (P less than 0.01). In the control group AKBR was maintained thereafter at near control value of 1.0 with a significant decrease in serum lactate concentration in spite of marked hypotension. T3 infusion at a rate of 1 microgram/kg/hr elevated the AKBR but did not elevate MAP. Vasopressin infusion at a rate of 0.1 U/kg/hr sustained AKBR and elevated MAP significantly at 1 hr after administration but tended to decrease thereafter. Combined administration of T3 and ADH elevated the AKBR to about 2.0, and MAP was restored to near-normal level. Other parameters such as glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactic dehydrogenase, reflecting liver cell injury and serum creatinine, and blood urea nitrogen as renal function, were maintained within normal range. These results indicate that combined T3 and vasopressin administration has a beneficial synergistic effect on both hepatic energy metabolism and systemic hemodynamics without any detrimental influence to other conventional parameters. Therefore, it is suggested that this combined administration may contribute to the management of potential multiorgan donors.

The effects of organ preservation on mitochondrial oxidative phosphorylation activity, adenylate hepatic energy charge, cytochrome content, and redox state of NAD+/NADH couple in rat liver transplantation were compared between a nonpreservation group and a preservation group with grafts preserved for 12 hr in Euro-Collin's solution. At 3 hr after transplantation, the energy charge in the preservation group decreased to 0.60 +/- 0.02 from the control value of 0.86 +/- 0.01, accompanied by a reduction of intramitochondrial redox state of NAD+/NADH couple. In contrast, in the nonpreservation group, the decrease in energy charge was minimally decreased to 0.79 +/- 0.04 due to the compensatory enhancement of mitochondrial oxidative phosphorylation activity. These results suggest that an enhanced mitochondrial ATP synthesis and a reduced intramitochondrial redox state are important factors affecting survival following rat liver transplantation.

Porcine livers preserved for 72 hr using continuous hypothermic perfusion (CHP) were studied in order to compare the effects of CHP on energy metabolism with those of simple cold storage (SCS). The livers of the CHP group were perfused in situ for 72 hr at 7 degrees C with University of Wisconsin (UW) solution and FC-43 as an oxygen carrier, while those of the S1 group were stored ex situ for 48 hr at 4 degrees C in UW solution, and those of the S2 group for 72 hr. They were then recirculated with human blood at 37 degrees C for 2 hr for the evaluation of their viability. At the end of preservation, significantly higher levels of total adenine nucleotides (TAN) and energy charge (EC) were observed in the CHP group compared with the S1 and S2 groups. At 2 hr recirculation, the level of TAN was significantly higher in the CHP group than in the S1 and S2 groups. The EC level was also higher in the CHP group than in the S2 group. During recirculation, the ketone body ratio (acetoacetate/beta-hydroxybutyrate) was higher in the CHP group than in the S2 group. The values in the CHP group were above 1.0 after 45 min recirculation. There were no significant differences in the pyruvate/lactate ratio and lactate level between the CHP and S1 groups. However, these values were significantly different from those in the S2 group. The present findings demonstrate that CHP using UW solution and the oxygen carrier was better able to preserve the energy metabolism of the porcine liver for 72 hr than 48-hr SCS in UW solution.

Arterial ketone body ratio (AKBR [acetoacetate/beta-hydroxybutyrate]) was measured in nineteen patients under medical supportive therapy for fulminant hepatic failure (FHF), in order to evaluate its predictive value relative to liver transplantation. Of the 19 patients 8 (42%) were salvaged and 11 (58%) died. Seven of 8 survivors showed an increased AKBR over 0.6 at 24-hr after admission, and all of them showed AKBR over 0.8 at 48-hr with subsequent maintenance of the value over 1.0. By contrast, all 11 nonsurvivors demonstrated sustained suppression of AKBR below 0.4 from 24 to 72 hr after admission. AKBR values at 24 and 48 hr showed statistically significant differences between survivors and nonsurvivors. Neither the grade of portal systemic encephalopathy (PSE) nor other conventional laboratory parameters--such as AST, bilirubin, ammonia, prothrombin time, hepaplastin test, fibrinogen, and platelet count--could discriminate between survivors and nonsurvivors by univariate analysis. These results indicate that AKBR can accurately predict the prognosis of FHF at the initial 24-48 hr after admission, and that it can play an important role in setting the indication of FHF for liver transplantation.

The transcription factor NF-KB has anti-apoptotic properties and may confer chemo-resistance to cancer cells, NF-KB is constitutively activated in bladder cancer, breast cancer, and melanoma, in which cancer cell lines, inhibition of NF-KB induces cell death in bepatocellular carcinoma (HCC), constitutive activation of NF-KB was tbund more frequently in tumor tissue compared with non-tumor tissue. Our AIM is to clarify the role of NF-KB in camptothecin-induced apoptosis of HCC. METHODS: Studies were performed in 3 hepatoma cell lines, Hep3B, HepG2 and Huh7. Camptothecin-induced apoptosis was evaluated wath DNA [addering assay" and DNA fragmentation ELISA. Western blot analysis for NF-KB (p65) and IKB were performed with nuclear extracts and whole lysates, respectively, to examine the activation of NF-KB by, camptothecin. To block NF-KB activation, adenov~rus expressing IKB super-repressor (Ad5IgBsf) was intected with ceils 12 hours befm'e the treatment of camptothecin We examined whether camptothecin (0.5-2 t~M)-iuduced apoptosis was enhanced under transt~ction of Ad5IKBsr (50-200 MOI) by" DNA fragmentation ELISA. RESULTS DNA laddering was clearly shown alter 1-2 p.M of camptnthecin treatment in all 3 HCC cells. DNA fragmentation ELISA demonstrated that the rate of apoptotic cell death in Hep3B was 20% lower than that of HepG2, indicating that Hep3B is resistant to camptothecininduced apoptosis. The pretreatment of cyclobeximide (to block the protein symthesis) with Hep3B did not enhance camptothecin-induced apoptosis. NF-KB was constitutively activated in Hep3B and camptothecni enhanced the translocation of NF-KB to the nucleus from 30 to 120min after camptothecin. After 12 hours of AdSIKBsr infection, we confirmed the expression of IKB super-repressor in Hep3B However, inactivation of NF-KB by Ad5lKBsr did not sensitize Hep3B to camptothecin-induced apoptosis in Hep3B in Conchision, HCC chemo-resistance to camptothecin is through NF-,~rB-independent pathway.

• In situ hypothermic hepatic perfusion was performed in dogs to explore whether the time limit of hepatic vascular exclusion could be prolonged. During hepatic vascular exclusion, hepatic hypothermic perfusion was performed via portal vein using various perfusates under active bypass from the portal vein and infrahepatic inferior vena cava area to the superior vena cava system. Dogs receiving hepatic hypothermic perfusion for 1 hour died when given Ringer's solution but survived more than 7 days when given Euro-Collins' and University of Wisconsin solutions. Although dogs tolerated 2 hours of hepatic hypothermic perfusion when give University of Wisconsin solution, all dogs died by 2 hours of hepatic hypothermic perfusion when given Euro-Collins' solution. The hepatic energy charge and arterial ketone body ratio of dogs that died were significantly lower than for those that survived. This suggests that the regimen of hepatic hypothermic perfusion with University of Wisconsin solution is able to maintain the energy metabolism of the liver under hepatic vascular exclusion for prolonged periods, hence, its possible clinical application. ( Arch Surg . 1992;127:427-431)

Concerning Cr-Mo steels used actually for motor shafts, etc. by Japanese National Railways, we examined their mechanical properties with the same test material, especially tensile strengths, strains, contractions and rotational bending fatigue strengths.As a result of our experiments, in which we compared the effects of the difference of forging ratio and heat treatment conditions, or those of standard specimens and sectional parts of large size materials given on statical tension and fatigue strengths, we found various differences in data.About the standard specimens, we could not find any difference in influences of heat treatment conditions on statical tension data. But the fatigue strengths of materials oil-or water-tempered were larger than those of materials air-tempered.Also, the effects of the difference in forging ratio did not appear in the statical tension experiments, but appeared a little in the rotational bending fatigue tests.On the other hand, about the sectional parts of large size specimens (840°C HWQ-680°C OT or AT), we found fairly large differences, namely in yielding p't σs, tensile strength σB, and fatigue strength σwb; data of outer layer parts were larger than those of inner parts.The tensile strength was in a range of 78-92kg/mm2, and the fatigue strength was about 37-41kg/mm2.

When containing small holes of faults which are the source of fatigue fracture, or when their inner fatigue limits are lower than outer ones, materials are often cracked from inner parts.In this report, by an illustration of large size rotational bending fatigue test, the author relates the mechanism of fatigue fracture started from inner parts.