Munenori Tahara

The novel antioxidant edaravone: from bench to bedside.

Over the last decade, important advances have been made to support the fact that reactive oxygen species (ROS) are generated and play a harmful role during the acute and late stages of cerebral ischemia. Several drugs, such as radical scavengers and antioxidants, have been evaluated in preclinical and clinical studies. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; Radicut, Mitsubishi Tanabe Pharma Corporation) is a novel antioxidant that is currently used in Japan for the treatment of patients in the acute stage of cerebral infarction. Edaravone scavenges ROS and inhibits proinflammatory responses after brain ischemia in animals and humans. In particular, postischemic inflammation, leading to brain edema and infarction due to neuronal damage and endothelial cell death, can be ameliorated by edaravone. In addition to these antistroke effects, edaravone has also been shown to prevent oxidative damage to various extracerebral organs. Therefore, in addition to its usefulness in the treatment of stroke, edaravone is expected to play an integral role in the treatment of many oxidative stress-related diseases.

Perioperative Management of Hepatic Resection Toward Zero Mortality and Morbidity: Analysis of 793 Consecutive Cases in a Single Institution

BACKGROUND The mortality rates associated with hepatectomy are still not zero. Our aim was to define the risk factors for complications and to evaluate our perioperative management. STUDY DESIGN Between 2001 and 2008, 793 consecutive patients (547 men and 246 women; mean age ± SD, 56.1 ± 14.9 years) underwent hepatectomy without gastrointestinal resection and choledocojejunostomy at our center. Of these patients, 354 (44.6%) were positive for the hepatitis B virus surface antigen and/or the hepatitis C virus antibody. We categorized 783 (98.7%) patients as Child-Pugh class A. Major resection (sectionectomy, hemihepatectomy, and extended hemihepatectomy), was performed in 535 patients (67.5%) and re-resection in 81 patients (10.2%). RESULTS The median operative time was 345.5 minutes and median blood loss was 360 mL. The rate of red blood cell transfusion was 6.8%. The morbidity rate was 15.6%. Reoperations were performed in 19 patients (2.4%). The mean postoperative hospital stay was 18.4 ± 10.4 days. The in-hospital mortality rate was 0.1% (1 of 793 patients; caused by hepatic failure). The independent relative risk for morbidity was influenced by an operative time of more than 360 minutes, blood loss of more than 400 mL, and serum albumin levels of less than 3.5 g/dL, as determined using multivariate logistic regression analysis. CONCLUSIONS Shorter operative times and reduced blood loss were obtained by improving the surgical technique and using new surgical devices and intraoperative management, including anesthesia. Additionally, decision making using our algorithm and perioperative management according to CDC guidelines reduced the morbidity and mortality associated with hepatectomy.

Co-expression of mesothelin and CA125 correlates with unfavorable patient outcome in pancreatic ductal adenocarcinoma.

Objectives: Recent studies have shown that the high affinity of mesothelin-CA125 interaction might cause intracavitary tumor metastasis. We examined the clinicopathologic significance and prognostic implication of mesothelin and CA125 expression in pancreatic ductal adenocarcinoma. Methods: Tissue samples from 66 pancreatic ductal adenocarcinomas were immunohistochemically examined. Proportion and intensity of constituent tumor cells with mesothelin and CA125 expression were analyzed and classified as high-level expression, defined as expression by more than 50% of tumor cells and/or moderate to strong staining, or low-level expression otherwise. Results: A high level of mesothelin was correlated with a higher histological grade (P = 0.049) and the level of blood vessel permeation (P = 0.0006), whereas a high level of CA125 expression was correlated with a higher recurrence rate (P = 0.015). The expression of mesothelin was strongly correlated with that of CA125 (P = 0.0041). Co-expression of mesothelin and CA125 were associated with an unfavorable patient outcome (P = 0.0062). Conclusions: This is the first report showing that co-expression of mesothelin and CA125 were in pancreatic ductal adenocarcinoma, and such co-expression is associated with a poor prognosis. Our finding suggests that co-expression of these two factors plays a significant role in the acquisition of aggressive clinical behavior.

Analysis of the risk factors for early death due to disease recurrence or progression within 1 year after hepatectomy in patients with hepatocellular carcinoma

BackgroundLiver resection for hepatocellular carcinoma (HCC) has the highest local controllability among all local treatments and results in a good survival rate. However, the recurrence rates of HCC continue to remain high even after curative hepatectomy Moreover, it has been reported that some patients with HCC have an early death due to recurrence. We analyzed the preoperative risk factors for early cancer death.MethodsBetween 1997 and 2009, 521 consecutive patients who underwent hepatectomy for HCC at our center were assigned to group ED (death due to HCC recurrence or progression within 1 year after hepatectomy) and group NED (alive over 1 year after hepatectomy). Risk factors for early cancer death were analyzed.ResultsGroup ED included 48 patients, and group NED included 473 patients. The cause of death included cancer progression (150; 78.1%), operation-related (1; 0.5%), hepatic failure (15; 7.8%), and other (26; 13.5%). Between the ED and NED groups, there were significant differences in albumin levels, Child-Pugh classifications, anatomical resections, curability, tumor numbers, tumor sizes, macroscopic vascular invasion (portal vein and hepatic vein), alpha-fetoprotein (AFP) levels, AFP-L3 levels, protein induced by vitamin K absence or antagonism factor II (PIVKA-II) levels, differentiation, microscopic portal vein invasion, microscopic hepatic vein invasion, and distant metastasis by univariate analysis. Multivariate analysis identified specific risk factors, such as AFP level > 1,000 ng/ml, tumor number ≥ 4, tumor size ≥ 5 cm, poor differentiation, and portal vein invasion. With respect to the preoperative risk factors such as AFP level, tumor number, and tumor size, 3 (1.1%) of 280 patients with no risk factors, 12 (7.8%) of 153 patients with 1 risk factor, 24 (32.9%) of 73 patients with 2 factors, and 9 (60.0%) of 15 patients with 3 risk factors died within 1 year of hepatectomy (p < 0.0001).ConclusionsHepatectomy should be judiciously selected for patients with AFP level > 1,000 ng/ml, tumor number ≥ 4, and tumor size ≥ 5 cm, because patients with these preoperative risk factors tend to die within 1 year after hepatectomy; these patients might be better treated with other therapy.

Efficacy of preoperative radiotherapy to portal vein tumor thrombus in the main trunk or first branch in patients with hepatocellular carcinoma

BackgroundThe prognosis of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) in the main trunk or the first branch is very poor.MethodsRadiotherapy (RT) to PVTT was followed by hepatectomy within 2 weeks. The dose used was 30–36 Gy, in 10–12 fractions, for 15–20 days. The efficacy of preoperative RT to PVTT in the main trunk or first branch was evaluated by comparing results in patients who underwent hepatectomy (group R; n = 15) with preoperative RT and those without preoperative RT (group N; n = 28).ResultsThe 1-, 3-, and 5-year survival rates in group R were 86.2%, 43.5%, and 34.8%, respectively, while these values in group N were 39.0%, 13.1%, and 13.1%, respectively. The survival curve of group R was significantly better than that of group N (P = 0.0359). In group R, five (83.3%) of six patients whose tumor thrombus was completely necrosed (based on pathological examination) and whose follow-up period was over 2 years survived for more than 2 years. Female sex (P = 0.0066), multiple tumors (P = 0.0369), and absence of preoperative RT (P = 0.0359) were ranked as significant factors for a poor prognosis by univariate analysis. Multivariate analysis revealed absence of preoperative RT and female sex to be significant factors for a poor prognosis.ConclusionPreoperative RT to PVTT in the main trunk or first branch improved the prognosis of patients with HCC with PVTT, and could be a promising new modality in the treatment of these patients.

Preoperative evaluation of hepatic functional reserve by converted ICGR15 calculated from 99mTc‐GSA scintigraphy

Background and Aim:  Conversion of data from technetium 99 m diethylenetriaminepentaacetic acid galactosyl human serum albumin (99mTc‐GSA) scintigraphy to ICGR15 (indocyanin green retention at 15 min) is an easy and convenient method for obtaining parameters to determine the appropriate and safe extent of liver resection. We investigated a conversion method which also accounts for LHL15 (receptor index: uptake ratio of the liver to the liver plus heart at 15 min) and HH15 (blood clearance index: uptake ratio of the heart at 15 min to that at 3 min) characteristics.

Long-Term Results of Hepatectomy for Patients with Alveolar Echinococcosis: A Single-Center Experience

BACKGROUND Hepatectomy is the first-line treatment for alveolar echinococcosis (AE) if complete resection is feasible. However, a strategy for the treatment of patients with AE in whom the tumor cannot be resected completely remains to be defined. STUDY DESIGN Data were retrospectively collected from 188 consecutive patients between 1984 and 2009. Overall survival (OS), progression-free survival (PFS), and risk factors were analyzed in patients classified into 3 groups (group A: complete resection, group B: reduction surgery, and group C: drainage or exploratory laparotomy). RESULTS In group A (n = 119), the 10-, 15-, and 20-year OS was 98.9%. In group B (n = 63), the 10-, 15-, and 20-year OS was 97.1%, 92.8%, and 61.9%. In group C (n = 6), the 10- and 15-year OS was 50.0% and 33.3%. Patients in groups A and B had better prognoses than those in group C (p < 0.001). In group A, the 10-, 15-, and 20-year PFS was 96.5%, 94.4%, and 94.4%. In group B, the 10-, 15-, and 20-year PFS was 87.1%, 71.6%, and 61.4%. In group C, the 10- and 15-year PFS was 50.0% and 33.3%. Patients in group A had better PFS than those in groups B and C (p < 0.001). Curability was the only independent factor for both OS and PFS by multivariate analysis. CONCLUSIONS Although the most effective therapy for AE is complete resection, a better prognosis can be achieved by reduction surgery and/or adjuvant albendazole therapy for patients with AE that cannot be completely resected.

Comparison of the invasiveness between reduced-port laparoscopy-assisted distal gastrectomy and conventional laparoscopy-assisted distal gastrectomy.

It is unknown whether reduced-port gastrectomy has a less invasive nature than conventional laparoscopy-assisted distal gastrectomy (C-LADG). So we compared 30 cases of dual-port laparoscopy-assisted distal gastrectomy (DP-LADG; using an umbilical port plus a right flank 5-mm port) as a reduced-port gastrectomy with 30 cases of C-LADG alternately performed by a single surgeon. No significant differences were observed in blood loss, intraoperative complications, the number of dissected lymph nodes, postoperative complications, the day of first defecation, analgesic agents required, changes in body temperature, heart rate, white blood cell count, serum albumin level, or lymphocyte count between the 2 groups. The amounts of oral intake in the DP-LADG group were significantly higher on postoperative days 9 and 10. We concluded that the amount of oral intake in the DP-LADG group was superior to that in the C-LADG group; however, no other evidence of DP-LADG being less invasive than C-LADG was obtained.

Clinical impacts of mesothelin expression in gastrointestinal carcinomas

Mesothelin, C-ERC/mesothelin is a 40-kDa cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura, peritoneum, and pericardium. Moreover, mesothelin has been shown to be overexpressed in several human cancers, including virtually all mesothelioma and pancreatic cancer, approximately 70% of ovarian cancer and extra bile duct cancer, and 50% of lung adenocarcinomas and gastric cancer. The full-length human mesothelin gene encodes the primary product, a 71-kDa precursor protein. The 71-kDa mesothelin precursor is cleaved into two products, 40-kDa C-terminal fragment that remains membrane-bound via glycosylphosphatidylinositol anchor, and a 31-kDa N-terminal fragment, megakaryocyte potentiating factor, which is secreted into the blood. The biological functions of mesothelin remain largely unknown. However, results of recent studies have suggested that the mesothelin may play a role of cell proliferation and migration. In pancreatic cancer, mesothelin expression was immunohistochemically observed in all cases, but absent in normal pancreas and in chronic pancreatitis. Furthermore, the expression of mesothelin was correlated with an poorer patient outcome in several human cancers. The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy. The present review discusses the expression and function of mesothelin in cancer cells and the utility of mesothelin as a target of cancer therapy.

Postoperative complication rates and invasiveness of laparoscopy-assisted distal gastrectomy and open distal gastrectomy based on the American Society of Anesthesiologists classification system

We investigated potential advantages of laparoscopy‐assisted distal gastrectomy (LADG) in high‐risk gastric cancer patients. We examined the differences among various risk groups by comparing the incidence of postoperative complications and invasiveness of LADG with those of open distal gastrectomy (ODG) based on the American Society of Anesthesiologists (ASA) criteria.