Complete response by a combination of 5-fluorouracil and interferon-alpha chemotherapy for lung metastasis of hepatocellular carcinoma after hepatic resection with portal and hepatic vein tumor thrombectomy.

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.

Akt activation protects rat liver from ischemia/reperfusion injury.

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 beta-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 < 0.05) 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. CONCLUSION: Adenoviral gene transfer of myrAkt could inhibit apoptotic cell death and subsequent hepatic I/R injury in the rat, through Bad, not NF-kappaB.

Usefulness of 99mTc-sestamibi scintigraphy in suggesting the therapeutic effect of chemotherapy against gastric cancer.

PURPOSE: Imaging with (99m)Tc-sestamibi ((99m)Tc-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 (99m)Tc-MIBI accumulation in tumors and sensitivity to chemotherapy in gastric cancer patients. EXPERIMENTAL DESIGN: Thirty-six patients with advanced gastric cancer underwent (99m)Tc-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 (99m)Tc-MIBI in tumors and responses to chemotherapy with 5-fluorouracil/cis-diamminedichloroplatinum(II) or epirubicin was examined. RESULTS: Higher accumulation of (9m)Tc-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 (99m)Tc-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 (99m)Tc-MIBI accumulation (15.4%) was much lower than that in patients with low (99m)Tc-MIBI accumulation (54.5%). In contrast, patients with high (99m)Tc-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: (99m)Tc-MIBI scintigraphy is useful to suggest the responses to chemotherapy of patients with advanced gastric cancer.

Cholangitis and liver abscess after percutaneous ablation therapy for liver tumors: incidence and risk factors.

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 <.001; odds ratio = 36.4; 95% CI = 9.67-136.9). 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.

Inactivation of the small GTPase Rac1 protects the liver from ischemia/reperfusion injury in the rat.

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-kappaB (NF-kappaB) in vitro. However, the exact role of Rac in the ROS production and NF-kappaB 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-kappaB activation and messenger RNA expression of tumor necrosis factor-alpha (TNF-alpha) 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-kappaB activation. Immunohistochemical analysis of NF-kappaB (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-kappaB activation after hepatic I/R in vivo, and that inactivation of NF-kappaB in NPCs and suppression of ROS generation in NPCs and hepatocytes possibly account for the protective effect of N17Rac1 in this study.

Resection for hepatocellular carcinoma with duodenal invasion: report of a case.

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.

Myoglobin gene expression attenuates hepatic ischemia reperfusion injury.

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 beta-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.

Results of hepatic resection for hepatocellular carcinoma invading major portal and/or hepatic veins.

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.

Increased expression of collagenase in the liver induces hepatocyte proliferation with cytoplasmic accumulation of beta-catenin in the rat.

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 beta-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.

Significance of serum type IV collagen level of hepatectomized patients with chronic liver damage.

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 of <150, < or = 150 to 300, and > or = 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.

Management of adrenal metastasis from hepatocellular carcinoma.

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.