Hajime Maeta

Role of NAD(P)H Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Cardioprotection of Ischemic Reperfusion Injury by Angiotensin II

Reactive oxygen species (ROS) participate in cardioprotection of ischemic reperfusion (I/R) injury via preconditioning mechanisms. Mitochondrial ROS have been shown to play a key role in this process. Angiotensin II (Ang II) exhibits pharmacological preconditioning; however, the involvement of NAD(P)H oxidase, known as an ROS-generating enzyme responsive to Ang II stimuli, in the preconditioning process remains unclear. We compared the effects of 5-hydroxydecanoate (5-HD; an inhibitor of mitochondrial ATP-sensitive potassium channels), apocynin (an NAD(P)H oxidase inhibitor), and 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol; a membrane permeable radical scavenger) on pharmacological preconditioning by Ang II in rat cardiac I/R injury in vivo. Treatment with a pressor dose of Ang II before a 30-minute coronary occlusion reduced infarct size as determined 24 hours after reperfusion. The protective effects of Ang II were eliminated by pretreatment with 5-HD or apocynin, similar to tempol. Both 5-HD and apocynin suppressed the enhanced cardiac lipid peroxidation and activation of the apoptosis signal-regulating kinase/p38, c-Jun NH2-terminal kinase (JNK) pathways, but not the Raf/MEK/extracellular signal-regulated kinase pathway, elicited by acutely administered Ang II. Apocynin but not 5-HD suppressed Ang II–induced augmentations of the NAD(P)H oxidase complex formation (p47phox, p22phox, and Rac-1) and its activity in the heart. Finally, 5-HD suppressed superoxide production by isolated cardiac mitochondria without any effect on their respiration. These results suggest that the preconditioning effects of Ang II for cardiac I/R injury may be mediated by cardiac mitochondria-derived ROS enhanced through NAD(P)H oxidase via JNK and p38 mitogen-activated protein kinase activation.

Hepatic Resection for Metastatic Tumors From Gastric Cancer

ObjectiveTo assess the surgical results and clinicopathologic features of hepatic metastases from gastric adenocarcinoma to identify patients with a better probability of survival. Summary Background DataMany studies have reported the benefit of hepatic resection for metastatic tumors from colorectal cancer. However, indications for a surgical approach for gastric adenocarcinoma involving the liver have not been clearly defined. MethodsNinety (11%) of 807 patients with primary gastric cancer were diagnosed with synchronous (n = 78) or metachronous (n = 12) hepatic metastases. Of these, 19 underwent 20 resections intended to cure the metastatic lesion in the liver. The clinicopathologic features of the hepatic metastases in, and the surgical results for, the 19 patients were analyzed. ResultsThe actuarial 1-year, 3-year, and 5-year survival rates after hepatic resection were, respectively, 77%, 34%, and 34%, and three patients survived for more than 5 years after surgery. Solitary and metachronous metastases were significant determinants for a favorable prognosis after hepatic resection. Pathologically, a fibrous pseudocapsule between the tumor and surrounding hepatic parenchyma was found in 13 of the 19 patients (68%). The presence of a peritumoral fibrous pseudocapsule and a well-differentiated histologic type of metastatic nodule were significant prognostic factors. Factors associated with the primary lesion were not significant prognostic determinants in patients who underwent curative resection of the primary cancer. ConclusionsSolitary and metachronous metastases from gastric cancer should be treated by a surgical approach and confer a better prognosis. A new prognostic factor, the presence of a pseudocapsule, may be helpful in defining indications for postoperative adjuvant treatment.

COLOR: A Randomized Clinical Trial Comparing Laparoscopic and Open Resection for Colon Cancer

Background: Laparoscopic surgery has proven to be safe and effective. However, the value of laparoscopic resection for malignancy in terms of cancer outcome can only be assessed by large prospective randomized clinical trials with sufficient follow-up. Methods: COLOR (COlon carcinoma Laparoscopic or Open Resection) is a European multicenter randomized trial which has started in September 1997. In 24 hospitals in Sweden, The Netherlands, Germany, France, Italy and Spain, 1,200 patients will be included. The primary end point of the study is cancer-free survival after 3 years. Results: Within <2 years, more than 540 patients have been randomized for right hemicolectomy (45%), left hemicolectomy (10%) and sigmoidectomy (45%). 33 patients (6%) were excluded after randomization. The accrual rate is approximately 25 patients/month. Current survival rates for the whole study group are: stage I: 95%, stage II: 98%, stage III: 93%, stage IV: 64%. For all patients with stage I disease, the mortality was not cancer related. Conclusions: Although laparoscopic surgery appears of value in colorectal malignancy, results of randomized trials have to be awaited to determine the definitive place of laparoscopy in colorectal cancer. Considering the current accrual rate, the COLOR study will be completed in 2002.

Effect of preoperative portal vein embolization on major hepatectomy for advanced-stage hepatocellular carcinomas in injured livers: A preliminary report

With the aim of minimizing postoperative liver dysfunction and promoting increased resectability, we employed portal vein embolization (PVE). In this study, the effect of PVE on major hepatic resection for advanced-stage hepatocellular carcinoma (HCC) in injured livers was evaluated. PVE was performed prior to hepatectomy in 13 patients with stage III and IV HCCs. Following PVE, right trisegmentectomy was performed in 3 patients, extended right lobectomy in 3 and right lobectomy in 7. To evaluate the effect of PVE, the changes in liver functional capacity and estimated remnant liver volume (ERLV), determined by computed tomography, were examined before and after PVE. The operative morbility, mortality, and survival rates after hepatectomy were also assessed. By 2 weeks after PVE, ERLV had increased in all patients, by an average of 28%, and the mean resection rates had decreased from 70.0% to 62.2%. Postoperatively, the 30-day mortality rate was 15.3%, and the 1- and 2-year survival rates were 69% and 46%, respectively. The results of this study indicate that resectability can be increased, and major hepatectomy can be made safer by employing PVE preoperatively, in view of the fact that major hepatectomy was not considered feasible without PVE in these patients.

Intestinal ischemia induces late preconditioning against myocardial infarction: a role for inducible nitric oxide synthase

OBJECTIVE We tested the hypothesis that occlusion of the superior mesenteric artery induces late preconditioning against myocardial infarction and examined the effects of pharmacological modifiers of inducible nitric oxide synthase activity on the late preconditioning in anesthetized rats. METHODS Rats underwent an intestinal ischemia preconditioning protocol (30 min occlusion of the superior mesenteric artery) or were sham-operated. They were subjected to a sustained 30 min of coronary occlusion and 180 min of reperfusion 24 h later. RESULTS In rats receiving no pharmacological intervention, the percentage of myocardial infarct within the area at risk and left ventricle was 72+/-4% and 31+/-2%, respectively, in sham-operated rats, and these were significantly reduced to 44+/-4% and 23+/-2% (P<0.01) 24 h after intestinal ischemia preconditioning. Myeloperoxidase activity was significantly reduced by intestinal ischemia preconditioning. Administration of aminoguanidine (300 mg/kg, s.c.) or S-methylisothiourea sulfate (3 mg/kg, i.v.), both relative inducible NO synthase inhibitors, 60 or 30 min before sustained myocardial ischemia not only abolished the late preconditioning afforded by intestinal ischemia, but also inhibited the ability of intestinal ischemia preconditioning to significantly reduce neutrophil infiltration. A change in inducible NO synthase activity was not observed in normal myocardium 24 h after intestinal ischemia, but 30 min of coronary occlusion significantly increased the inducible NO synthase activity in the preconditioned group, which was abolished by aminoguanidine or S-methylisothiourea sulfate. CONCLUSIONS These data provide pharmacological evidence that induction of inducible nitric oxide synthase, following intestinal ischemia, is associated with increased myocardial tolerance to infarction 24 h later.

Is preoperative portal vein embolization effective in improving prognosis after major hepatic resection in patients with advanced-stage hepatocellular carcinoma?

The impact of the use of preoperative portal vein embolization (PVE) on long‐term survival after surgery was evaluated by retrospective analysis of prognostic factors in patients with advanced‐stage hepatocellular carcinoma (HCC) who had undergone hepatic resection with or without PVE.

Ischemic preconditioning of the murine liver protects through the akt kinase pathway

Hepatic ischemia‐reperfusion (I/R) injury occurs in the settings of transplantation, trauma, and elective liver resection. Ischemic preconditioning has been used as a strategy to reduce inflammation and organ damage from I/R of the liver. However, the mechanisms involved in this process are poorly understood. We examined the role of the phosphatidylinositol 3 (PI3) kinase/Akt‐signaling pathway during hepatic ischemic preconditioning (IPC). Prior to a prolonged warm ischemic insult, BALB/c mice were subjected to a 20‐minute IPC period consisting of 10 minutes of ischemia and 10 minutes of reperfusion. Mice undergoing IPC demonstrated a significantly greater level and earlier activation of Akt in the liver compared with control animals. IPC also resulted in markedly less hepatocellular injury and improved survival compared with control animals. Akt activation associated with hepatic IPC suppressed the activity of several modulators of apoptosis, including Bad, glycogen synthase kinase β, and caspase‐3. In addition, IPC also inhibited the activities of c‐Jun N‐terminal kinase and nuclear factor κB after I/R. Pretreatment of mice with PI3 kinase inhibitors completely abolished Akt phosphorylation and the protective effects seen with IPC. In conclusion, these results indicate that the PI3 kinase/Akt pathway plays an essential role in the protective effects of IPC in hepatic I/R injury. Modulation of this pathway may be a potential strategy in clinical settings of ischemic liver injury to decrease organ damage. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2006;44:573–580.)

Lipopolysaccharide triggers late preconditioning against myocardial infarction via inducible nitric oxide synthase

OBJECTIVE The aim of this study was to investigate the role of inducible nitric oxide synthase (iNOS) as a trigger in lipopolysaccharide (LPS)-induced late preconditioning against myocardial infarction. METHODS Rats were pretreated intraperitoneally with two different doses of LPS (0.5 or 2.5 mg/kg) or normal saline (control) 24 h prior to lethal myocardial ischemia. Subsequently, all rats were subjected to a sustained 30-min coronary occlusion followed by 180-min reperfusion. In the second study, total RNA and protein were extracted from myocardium of the control and LPS-treated rats (after 4, 6 and 24 h of treatment) for reverse transcription-polymerase chain reaction and Western blot analysis. RESULTS In LPS (2.5 mg/kg, but not 0.5 mg/kg)-treated rats receiving no pharmacological intervention, the percentage of myocardial infarct within the area at risk and left ventricle was significantly reduced to 42+/-4 and 24+/-2% (P<0.01) compared with the control group. The cardioprotection was abolished by injection of dexamethasone (4 mg/kg x 2, i.p.) or the selective iNOS inhibitor aminoguanidine (300 mg/kg x 2, s.c.) before LPS treatment. The expression of iNOS mRNA and the iNOS protein significantly increased 4 and 6 h after administration of LPS (2.5 mg/kg), respectively. The increases in iNOS mRNA and protein were eliminated by dexamethasone. But the iNOS mRNA and protein were not detectable 24 h after administration of LPS (2.5 mg/kg). CONCLUSIONS These data provide molecular and pharmacological evidence that LPS-induced late preconditioning against myocardial infarction is triggered by iNOS.

Long-term survival after resection for small cell carcinoma of the esophagus

We describe the rare case of a patient with esophageal small cell carcinoma who was completely cured. A 77-year-old man had small cell carcinoma of the esophagus with extensive lymph node metastases. Treatment comprised a subtotal esophagectomy and extended lymph node dissection. He has survived for more than 7 years with no evidence of recurrent disease. We suggest that radical operations should be considered for future patients if curative resection can be expected.

Measurement of Serum Hyaluronate as a Predictor of Human Liver Failure after Major Hepatectomy

Serum hyaluronate can be used as an index of hepatic sinusoidal endothelial cell function. This study was designed to evaluate its application as a predictor of liver failure after major hepatectomy. Thirty-six patients who underwent right liver lobectomy after percutaneous transhepatic right branch portal vein embolization were divided into two groups based on their postoperative clinical course (groups 1 and 2, with and without postoperative liver failure, n= 6 and n= 30, respectively). We serially measured serum hyaluronate levels using a sandwich binding protein assay system before and after hepatectomy and determined relations with progression of the underlying chronic liver disorder, portal venous pressure, and liver growth of the left lobe after portal embolization. Serum hyaluronate levels were significantly elevated, in line with the degree of severity of the underlying chronic liver disorder, and correlated well with the portal venous pressure and the hypertrophic ratio of the left lobe subsequent to portal embolization. Serum hyaluronate levels in group 1 were significantly higher than those in group 2 before surgery and increased steeply during the early period after hepatectomy. These results suggest that the serum hyaluronate reflects the hepatic functional reserve, and serial measurement of this parameter after hepatectomy can serve as a simple indicator for early detection of posthepatectomy liver failure.