Biomedical subjects

Hideaki Shimada

Publications and source records attributed to Hideaki Shimada.

86 records · Page 5Linked to original sources

PubMed2002

Tandem repeat polymorphism of the CYP2E1 gene: an association study with esophageal cancer and lung cancer.

BACKGROUND: Cytochrome P-450 (CYP) enzymes have been shown to play important roles in chemical carcinogenesis. Reports have indicated that polymorphism in CYP1A1, CYP1A2, CYP2A6, CYP2E1, and CYP2D6 are associated with an altered risk of developing cancers of the lung, bladder, liver, and colon. CYP2E1 plays an important role in alcohol metabolism and participates in the metabolic activation of various carcinogens, such as N-nitrosodimethylamine. Recently, we found repeated sequences that consist of four alleles (A1, A2, A3, and A4) and six genotypes (A1/A2, A2/A2, A2/A3, A2/A4, A3/A4 and A4/A4) of the CYP2E1 gene. In the present study, we investigated whether these polymorphisms are associated with lung cancer and esophageal cancer. METHODS: DNA was isolated from blood samples of 192 healthy control subjects, 85 patients with lung cancer, and 82 patients with esophageal cancer in Japanese males. DNA samples were amplified by polymerase chain reaction in the 5'-flanking region of the CYP2E1 gene and in exon 12 in the ALDH2 gene. The tandem repeat polymorphisms were examined using DNA fragment analysis. Missense mutations in exon 12 of the ALDH2 gene were examined using fluorescence-based single strand conformational change polymorphism analysis. Written informed consent was obtained from all the subjects. RESULTS: In the CYP2E1 gene 5'-flanking region polymorphism, patients with esophageal cancer showed significantly higher frequency of the A4/A4 genotype compared with the control subjects (p = 0.02), but no difference was found in patients with lung cancer. The frequencies of the mutant ALDH2*2 allele were significantly higher in patients with esophageal cancer (27.7%) than in healthy control subjects (7.3%; p< 0.0001; habitual alcohol drinkers). CONCLUSIONS: The distribution of genotypes and allele frequencies of the tandem repeats of the 5'-flanking region of the CYP2E1 gene was significantly different in patients with esophageal cancer.

5' Flanking Region↗

PubMed2002

Decrease in growth factor receptors after treatment with serine protease inhibitor ONO-3403.

FOY-305 is a synthetic serine protease inhibitor and ONO-3403 is a derivative with a higher protease-inhibitory activity. The growth-suppressive effects of ONO-3403 were more prominent in Ha-ras-transformed NIH3T3 (ras-NIH) cells than in non-transformed NIH3T3 cells. After treatment of ras-NIH cells with ONO-3403 at 100-200 microg/ml, the percentage of cells found in G(1) phase decreased and, concomitantly, that in S phase increased. Molecular events caused by ONO-3403 were investigated by Western blot analysis using anti-phosphotyrosine antibody. The results showed a marked decrease in the tyrosine phosphorylation level of a 180-kDa protein after treatment with ONO-3403. This 180-kDa phosphotyrosine-containing molecule which was tentatively designated pY-p180 might be platelet-derived growth factor (PDGF) receptor since addition of PDGF to serum-starved NIH3T3 cells induced a marked tyrosine phosphorylation of the same size within 5 min. This was further confirmed by immunoprecipitation of cell extract with anti-PDGF-receptor antibody followed by Western blot analysis using anti-phosphotyrosine antibody. Treatment of T.Tn human esophageal carcinoma cells with ONO-3403 caused also decrease in pY-p180, which appeared to be epidermal growth factor receptor. Thus, ONO-3403 may induce growth suppression by down-regulation of cell surface growth factor receptors.

3T3 Cells↗

PubMed2002

[Gene therapy for esophageal cancer].

Esophageal cancer is a highly malignant disease in which progression is observed in most patients even at the first medical examination. Neoadjuvant cytoreduction treatments are frequently used for the purpose of tumor down-staging, increasing the resection rate, and possibly improving survival. Although combination therapy with radiation and anticancer agents is available, no satisfactory treatment regimen has yet been established due to the development of resistance. Based on the concepts of genetic alteration in carcinogenesis, cancer gene therapy has been developing rapidly. We previously reported the growth inhibitory effect of adenovirus-mediated wild-type p53 gene transfer into esophageal squamous carcinoma cell lines. After extensive preclinical study of p53 gene therapy in vitro and in vivo, we are conducting a phase I/II clinical trial. The target of this trial is patients with unresectable esophageal cancer resistant to chemoradiotherapy. As of December 1, 2001, 8 candidates had been admitted to our hospital. After extensive examination, 4 patients were enrolled in this trial. After giving informed consent, the first patient received injections of Ad5 CMV-p53 on December 19, 2000. No serious adverse events have occurred so far in these patients, and the trial has been conducted safely.

Adenoviridae↗

PubMed2001

Cadmium exposure decreases androgen-dependent metabolism of acetohexamide in liver microsomes of male rats through its testicular toxicity.

Administration of cadmium (Cd) at a dose of 1.23 mg/kg (2.0 mg/kg as CdCl(2)) markedly decreased the activity of an enzyme (acetohexamide reductase) catalysing the ketone-reduction of acetohexamide, an oral antidiabetic drug, in liver microsomes of male rats. However, the decreased enzyme activity was increased by repeated treatment with testosterone propionate (TP). When male rats were castrated and TP was given to the castrated ones, a similar decrease and increase, as described above, were observed in the microsomal enzyme activity. Cd exposure to male rats induced haemorrhage and atrophy of the testes and significantly diminished serum testosterone levels. There was no possibility that Cd accumulated in liver microsomes of male rats causing direct inhibition of the microsomal enzyme activity. We conclude that Cd exposure decreases androgen-dependent metabolism of acetohexamide in liver microsomes of male rats through its testicular toxicity. Cd exposure had no effect on acetohexamide reductase activity in liver cytosol of male rats.

Acetohexamide↗

PubMedDate not supplied

Strain- and sex-related differences of carbonyl reductase activities in kidney microsomes and cytosol of rats.

This study was designed to elucidate strain- and sex-related differences of carbonyl reductase activity in rat kidney by using the oral antidiabetic drug acetohexamide as substrate. The frequency distribution of carbonyl reductase activities in kidney microsomes of male Fischer 344 (Fischer), Sprague-Dawley, Wistar and Wistar-Imamichi (Wistar-IM) rats exhibited a marked strain-related difference. Furthermore, the enzyme activities in kidney microsomes of Fischer, Sprague-Dawley and Wistar rats were male-specific, resulting insignificant sex-related differences in these strains. There was no sex-related difference of carbonyl reductase activity in kidney microsomes of the Wistar-IM strain, which lacked its activity in both sexes. On the other hand, although carbonyl reductase activities were fully detectable in kidney cytosols from all the strains of male and female rats, no strain- or sex-related difference was observed among the cytosolic enzyme activities. These results provide new information for understanding the influence of internal factors on the renal metabolism of ketone-containing xenobiotics.

Acetohexamide↗

PubMedDate not supplied

Increased serum midkine concentration as a possible tumor marker in patients with superficial esophageal cancer.

Midkine, a heparin-binding growth factor, is expressed in numerous cancer tissues and is reportedly elevated in patients with various neoplasms. The aim of this study was to evaluate the clinicopathological significance of serum midkine concentration (S-MK) in patients with superficial esophageal squamous cell carcinoma (SCC). Pretreatment S-MK was measured by enzyme-linked immunosorbent assay in 135 healthy controls, 16 patients with benign esophageal disease, and 60 patients with primary superficial esophageal squamous cell cancer (SESCC). All patients with SESCC underwent curative resection. The disease was staged according to TNM/UICC guidelines. Serum concentrations of carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC-Ag), and cytokeratin 19 fragment (CYFRA21-1) were also evaluated in the same populations. S-MK in patients with SESCC (388+/-411 pg/ml) was significantly higher than in benign esophageal disease or healthy controls (183+/-73 and 154+/-76 pg/ml, respectively). Using the mean + 2 standard deviations of healthy control S-MK (300 pg/ml) as the cut-off level, 50% of patients with esophageal SESCC were deemed positive. This S-MK positivity rate for detecting SESCC was significantly higher than for other tumor markers. Thus, S-MK may be useful as a tumor marker to detect SESCC.

Adult↗

PubMedDate not supplied

Complete recovery from fulminant hepatic failure with severe coma by living donor liver transplantation.

In Japan, living donor liver transplantation has been established as a therapeutic strategy for the rescue of terminal liver disease, including fulminant hepatic failure that shows no signs of recovery. We performed living donor liver transplantation for a subacute type fulminant hepatic failure patient, who had developed a hepatic coma of grade V (no right reflex, no response to pain stimuli). The electroencephalogram indicated almost flat waves. However, cranial computed tomography revealed that brain edema was not severe in this case. The recipient did not have hepatitis virus and had not taken medication that had been determined to cause hepatitis. The recipient was a 12-year-old boy, 165.5 cm in height and 45.5 kg in weight. The donor was his mother, who was 42 years old; her blood type, type B, was identical to that of the boy. The mother's right hepatic lobe was transplanted to her son (the recipient). The post-transplantation condition of recipient was quite excellent. He recovered consciousness 3 days after liver transplantation, and rapidly attained normal hepatic function. The donor was discharged on the 20th postoperative day without any problems. The recipient was discharged on the 79th postoperative day without any neurological deficits. This case suggests that deep coma without electroencephalogram waves may not be a contraindication for living donor liver transplantation in fulminant hepatic failure patients, if the brain edema is not severe.

Adult↗

PubMedDate not supplied

Evaluation of D3/D4 lymph node dissection for patients with grossly N2 positive advanced gastric cancer.

BACKGROUND/AIMS: Extended lymphadenectomy (D2) with complete resection of gastric cancer has been generally accepted as a standard treatment modality in Japan. However, the clinical evaluation of the superextended lymphadenectomy (D3/D4) for advanced type of gastric cancer has not been established. METHODOLOGY: Eight hundred and twenty primary gastric cancer patients underwent gastric resection in our institute (1987-1997). Of those patients, 436 patients with more than t2 depth of cancer invasion underwent curative gastrectomy either with D2 (337 cases) or D3/D4 (99 cases). D3/D4 was performed for the cases in which metastasis was recognized in N2 lymph nodes with gross inspection at the time of operation. RESULTS: There was no statistically significant survival advantage to the D3/D4 when comparing between the D2 and D3/D4 groups. However, the relative risk of death due to postoperative relapse in the D3/D4 showed a significantly lower hazard ratio than in the D2, in the Cox proportional-hazard model (0.67; 95% CI: 0.47-0.94). Patients receiving D3/D4 lymphadenectomy showed a better 5-year survival rate in stage IIIb than those with D2 (18.4% vs. 48.9%, p = 0.039). No statistically significant differences were found between the two groups as regards postoperative morbidity and mortality. CONCLUSIONS: D3/D4 lymphadenectomy might be of therapeutic value for limited patients with advanced gastric cancer.

Female↗

PubMedDate not supplied

Effect of the anastomosis-site after Billroth I gastrectomy on the motility of the remnant stomach.

BACKGROUND/AIMS: Gastric emptying, in healthy individuals, is a highly regulated process, and plasma cholecystokinin plays a major role in its feedback regulation. However, the hormonal regulation of postprandial gastric emptying of the remnant stomach after distal gastrectomy with Billroth I reconstruction procedure has not been well described. The aim of this study is to characterize the gastroduodenal motility and gastric emptying of the two anastomosis-methods after Billroth I gastrectomy, while assessing the effect of cholecystokinin on the motility of the remnant stomach. METHODOLOGY: Two types of anastomosis (end-to-end, side (posterior wall)-to-end) after Billroth I gastrectomy were measured with strain gauge force transducers, and evaluated as to gastroduodenal motility, gastric emptying, gastrointestinal hormones (cholecystokinin, gastrin), and blood glucose associated with food administration. RESULTS: Remnant stomachs with side-to-end anastomosis showed superior motility as compared to those with end-to-end anastomosis. Plasma cholecystokinin was higher in the end-to-end anastomosis group. No differences as to gastric emptying, levels of plasma gastrin, or blood glucose were observed between the two groups. CONCLUSIONS: Plasma cholecystokinin may explain the difference in motility index between the two groups.

Animals↗

PubMedDate not supplied

Efficacy and toxicities of concurrent chemoradiation for elderly patients with esophageal cancer.

BACKGROUND: To evaluate the efficacy and toxicity of concurrent chemoradiation in patients with esophageal cancer aged 75 and older. PATIENTS AND METHODS: Twenty-two elderly patients were treated with concurrent chemoradiation. Seventeen received a combination of cisplatin/carboplatin and 5-fluorouracil, 5 received daily 5-fluorouracil. Total doses of radiotherapy ranged from 50 to 65 Gy. RESULTS: Nineteen out of 22 patients completed the planned chemoradiation. Five in 8 patients (63%) with T1-2 lesion and 1 in 14 patients (7o%) with T3-4 lesion achieved complete response (p=0.011). Only 2 patients experienced grade 3 toxicities. Grade 2 or worse hematological toxicities were less frequently observed in patients who received local-field radiotherapy (p=0.006). There was no isolated lymph node recurrence. The median survival time was 9 months. CONCLUSION: This study showed the potential for chemoradiation in elderly patients. A planning target volume of radiotherapy should include only clinically involved lesions in this setting.

Aged↗

PubMedDate not supplied

Inhibitory remnant stomach motility by duodenal distention after B-I gastrectomy.

BACKGROUND/AIMS: Although control of gastric motility is a highly regulated process, B-I gastrectomy causes accelerated gastric emptying. We found few reports so far concerned with the mechanical effect of balloon distention of the duodenum on the remnant stomach in B-I dogs. METHODOLOGY: Four weeks after conventional distal gastrectomy with B-I reconstruction procedure, a balloon was inserted into the duodenum, and strain gauge force transducers (SGTs) were sutured onto the wall of the gastric remnant and duodenal serosa in beagles. After a two-week postoperative recovery period, gastro-duodenal motility was measured with SGTs prior to distention, during distention, and after evacuation of the balloon. The motility index (MI) was calculated every 30 minutes. RESULTS: Upon duodenal distention with 4 mL of water, motility of gastric remnant was significantly inhibited, however, no reduction in duodenal MI was observed. The response was maintained for as long as duodenal distension continued. Ninety minutes after evacuation of the balloon, MI returned to predistension levels. Increased plasma levels of cholecystokinin (CCK) were observed upon distention of the duodenal balloon. CONCLUSIONS: Motility of the remnant stomach in B-I dogs was inhibited by duodenal distension. Increased levels of plasma CCK during distention might play a role in this feedback mechanism.

Animals↗

PubMedDate not supplied

Generation of antitumor immunity against large colon tumors by repeated runs of electrochemotherapy.

BACKGROUND/AIMS: Electrochemotherapy, which uses two parallel electrodes for delivery of electric pulses, may be useful for treatment of tumor nodules. However, in clinical fields, tumors that are larger than the distance between the two electrodes are frequently observed, and it would be difficult in such cases to deliver electric pulses to the tumor. This study was done to define how host antitumor immunity is generated by repeated electrochemotherapy treatments, and whether it is associated with regression of even large tumor nodules. METHODOLOGY: Balb/c mice and Balb/c nude mice were inoculated subcutaneously with colon 26. Electrochemotherapy using bleomycin and electroporation (CUY21) was administered as a treatment for tumor nodules that were larger than the distance between the electrodes. RESULTS: In Balb/c mice, growth of large tumors at the start of treatment is not inhibited by a single electrochemotherapy treatment. However, complete tumor regression was obtained through repeated electrochemotherapy treatments. No tumor cure was observed among Balb/c nude mice under the same therapeutic conditions. Inflammatory cells were accumulated in the tumor tissue seven days after the third electrochemotherapy treatment. CONCLUSIONS: Repeated electrochemotherapy is a promising treatment, even for large tumors, such as are usually encountered in clinical practice, by generating T-cell dependent, antitumor immunity.

Animals↗

PubMedDate not supplied

Evaluation of Ki-67 and p53 expression in primary and repeated liver metastases of GISTs.

There has been little research evaluating changes related to tumor cell proliferation between primary and metastatic tumors of gastrointestinal tumors in the same case. We herein report the case of a 50-year-old woman with a gastric gastrointestinal stromal tumor (GIST), who developed metastatic liver tumors three times in the 7 years after proximal gastrectomy for GIST. The primary and all the metastatic liver tumors, except the second, showed fascicular/storiform architecture and the short spindle cell type. The diffuse epithelioid cell proliferation was observed in the second metastatic liver tumor. Although the immunostaining pattern with respect to GIST differentiation markers had been preserved in the primary tumor as well as in all of the metastatic tumors, the latter showed weaker positivity of both Ki-67 and p53 than the primary GIST. The primary tumor showed diffuse positive p53, and the highest value of Ki-67 labeling index (LI) among them. The metastatic liver tumors showed focal, negative or sporadic positive appearances of p53, however, Ki-67 LI were scattering among them. Immunohistochemical assessment of Ki-67 LI and p53 might be useful for evaluating changes related to tumor cell proliferation between primary and metastatic tumors of GISTs.

Biomarkers, Tumor↗

PubMedDate not supplied

High en bloc resection rate achieved by endoscopic mucosal resection with IT knife for early gastric cancer.

BACKGROUND/AIMS: Circumferential endoscopic mucosal resection (EMR) around lesions performed by an insulation-tipped diathermic knife (IT knife) increases en bloc resection rates, suggesting the possibility of expanding indications for EMR. METHODOLOGY: Clinical outcome of EMR performed by IT knife under general anesthesia was evaluated for 26 patients with 29 early gastric cancer. RESULTS: Successful en bloc resection rates obtained by the IT knife were 100, 87.5, 90.0 and 100% for lesions < or =10 mm in size, 11-20 mm, 21-30 mm, and > or =31 mm, respectively. They were significantly higher with the IT knife than those obtained by the conventional method (IT knife method: 93.1% vs. conventional method: 28.5%, p<0.0001). Two lesions were lateral margin positive, and in three cases invasion of lesions was observed as deep as the submucosa. Distal, total, and proximal gastrectomy with D2 lymphadenectomy, respectively, was provided in 3 cases; however, no lymph node involvement was found in any of the resected specimens. Bleeding and perforation were observed in 3 cases, respectively, however, no additional surgical treatment was required for these patients. CONCLUSIONS: EMR by means of the IT knife under general anesthesia can be performed safely and adequately. It is a useful treatment modality for early gastric cancer.

Aged↗