Biomedical subjects

Y Maehara

Publications and source records attributed to Y Maehara.

At least 91 records · Page 5Linked to original sources

PubMed1999

Genetic analysis with calcium-induced calcium release test in Japanese malignant hyperthermia susceptible (MHS) families.

Some genetic studies have shown a linkage between malignant hyperthermia susceptibility (MHS) and chromosome 19q or the skeletal muscle ryanodine receptor (RYR1) gene. Some types of MHS seem to be caused by an abnormality of calcium-induced calcium release (CICR). We analyzed the linkage of RYR1 gene polymorphisms in Japanese MHS families and investigated the correlation between genetic evidence of RYR1 gene mutations and an accelerated rate of CICR. We studied 63 subjects who were referred to our institute for investigation of MHS. CICR rates were measured by the skinned fiber method in 23 subjects. DNA samples were collected from 63 individuals belonging to 22 unrelated families. Restriction fragment length polymorphism (RFLP) analyses on the RYR1 locus and hypervariable microsatellite analysis were performed. We found one family with a linkage between acceleration of the CICR mechanism and a group of RFLPs. In CICR tests, ten of the 11 patients who had presented with fulminant MH showed accelerated rates of CICR. Analysis for the mutation C1840T, which was performed in 63 samples, did not demonstrate an alteration in any of the patients. Although we found heterozygotes in RFLP studies, we did not recognize a specific relationship between the acceleration of CICR and the RFLPs. We suggest a linkage between the acceleration of CICR and an abnormal human RYR1 gene in MHS. These results also suggest that heterogeneity exists for MH. We conclude that genetic tests cannot replace CICR tests or caffeine-halothane contracture tests with muscle biopsy as a diagnosing test for MH in the near future.

Calcium↗

PubMed1999

Prediction of the chemosensitivity of lung cancer by 99mTc-hexakis-2-methoxyisobutyl isonitrile SPECT.

UNLABELLED: 99mTc-hexakis-2-methoxyisobutyl isonitrile (MIBI) has been reported to accumulate in various tumors and to be a transport substrate for P-glycoprotein (Pgp). The aim of this study was to evaluate the usefulness of 99mTc-MIBI SPECT for in vivo assessment of lung cancer chemosensitivity. Also examined was the relationship between 99mTc-MIBI uptake and Pgp expression. METHODS: Ten lung cancer patients who had undergone surgery were examined. Before surgery, 99mTc-MIBI SPECT was performed 15 and 120 min after injection, and the early uptake (L/Ne), delayed uptake (L/Nd) and washout rate (L/Nwr) of 99mTc-MIBI were calculated by the count ratio of lesion to contralateral normal lung tissue. The results were then compared with chemosensitivity determined by the succinate dehydrogenase inhibition test using six antitumor drugs (doxorubicin, mitomycin C [MMC], vindesine, etoposide [VP-16], cyclophosphamide and cisplatin). Pgp expression was determined by immunohistochemical staining. RESULTS: Sensitivity to MMC correlated significantly with L/Ne (P < 0.01) and L/Nwr (P < 0.05). Sensitivity to VP-16 correlated weakly and insignificantly with L/Nwr. L/Nd showed no correlation with sensitivity to any drug. Neither L/Ne, L/Nd nor L/Nwr was significantly different between the Pgp-positive group (n = 2) and the Pgp-negative group (n = 8). CONCLUSION: The results suggest that 99mTc-MIBI SPECT, a noninvasive in vivo examination, can predict the chemosensitivity of lung cancer to MMC and VP-16 independently of Pgp expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

MST-16, a novel bis-dioxopiperazine anticancer agent, ameliorates doxorubicin-induced acute toxicity while maintaining antitumor efficacy.

MST-16 [4,4-1,2-(ethanediyl)bis(1-isobutoxycarbonyl-oxy-methyl-2,6-pipera zinedione)], recently approved as an oral anticancer drug for clinical use in Japan, was evaluated as a chemotherapeutic agent in combination with doxorubicin (DOX) in vitro and in vivo. Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and murine Colon 26 and human KATO III adenocarcinoma cells were used. The combination index derived from these cytotoxic values indicated a synergistic interaction between DOX and MST-16 or its active metabolite, ICRF-154 (1,1'-ethylenedi-3,5-dioxopiperazine). A maximal tolerated dose of DOX administered to female BALB/c mice bearing a solid Colon 26 tumor resulted in severe body weight loss and diarrhea, but a limited tumor growth delay (1.8 days). However, when combined with an oral dose of MST-16, DOX-induced body weight loss and diarrhea were significantly ameliorated, and an additive tumor growth delay (8.7 days) was obtained. The LD50 of DOX administered i.p. to control female BALB/c mice increased more than 1.5-fold when combined with MST-16. Thus, MST-16 ameliorates DOX-induced acute toxicity while maintaining antitumor efficacy. These results indicate that MST-16 may be effective chemotherapy for cancer patients when combined with DOX.

Animals↗

PubMed1998

Long-term survival of patients with stage IV gastric carcinoma.

BACKGROUND: Survival of patients with Stage IV (based on general rules established by the Japanese Research Society for Gastric Cancer) gastric carcinoma often is unfavorable. Among patients with a poor prognosis, a few do survive > 5 years. The authors examined pathologic and biologic features of tumors of long term survivors. METHODS: The authors analyzed data from 442 patients with Stage IV gastric carcinoma, including 20 surviving for > 5 years after gastrectomy (Group A) and 422 who died of gastric carcinoma within 5 years (Group B). Mutant p53 was immunohistochemically stained using the monoclonal antibody PAb1801. Proliferative activity was estimated by argyrophilic nuclear organizer region (AgNOR) staining and proliferating cell nuclear antigen (PCNA) staining. RESULTS: Group A had smaller and more localized tumors than Group B (P < 0.05 and P < 0.01, respectively). Lymphatic or venous invasion and peritoneal dissemination were less frequent in Group A than in Group B (P < 0.01). Abnormalities of p53 expression were found in 3 of the 14 tumors in Group A (21%), a value significantly lower than the 58 of 118 tumors in Group B (49%; P < 0.05). AgNOR count and percentage of PCNA labeling were not significantly different between Groups A and B. A multivariate analysis showed that lymph node dissection, liver metastasis, gastric resection, venous invasion, and tumor size were independent prognostic factors. CONCLUSIONS: Even in patients with Stage IV gastric carcinoma, radical gastrectomy and extensive lymph node dissection can lead to long term survival. The authors believe that combination analysis of pathologic features and p53 overexpression predict length of survival for patients with Stage IV gastric carcinoma.

Adult↗

PubMed1998

Interrelation between tumor-associated cell surface glycoprotein and host immune response in gastric carcinoma patients.

BACKGROUND: Expression of changes in cell surface glycoprotein may correlate with the malignant potential and development of gastric carcinoma. Immunologic defense mechanisms of the host against the tumor can be effective in preventing the development of gastric carcinoma. The authors studied the effects of immunologic defense of the host against the tumor, using infiltration of S-100 protein positive dendritic cells (DC) as a marker. In cases with or without changes in the surface glycoprotein of tumor cells, determinations were made by binding of Helix pomatia agglutinin (HPA). METHODS: Paraffin blocks of 123 gastric carcinoma specimens were prepared for immunohistochemical staining with the antibody against HPA and S-100 protein. Clinicopathologic factors and patient prognosis were examined for each indicator. RESULTS: Patients with HPA positive tumors had a more aggressive character in several important prognostic aspects and poorer 5-year survival rates compared with patients with HPA negative tumors. The degree of infiltration of DC had no particular correlation with pathologic factors, and there was no significant difference between the prognosis of patients with slight and marked DC infiltration. In the HPA negative patients there was no significant difference in the 5-year survival rates between patients with slight and marked DC infiltration; however, in the HPA positive patients the 5-year survival rates of patients with marked infiltration of DC were higher. Further investigation showed that patients with marked DC infiltration had better 5-year survival rates than patients with slight DC infiltration, especially in patients with HPA positive and histologically advanced disease. CONCLUSIONS: Patients with a higher immunologic defense against cancer cells, as indicated by marked infiltration of DC, had a better prognosis in cases of gastric carcinomas of highly malignant potential, as indicated by a positive HPA.

Adult↗

PubMed1998

A microsatellite instability analysis in neuroblastoma based on a high resolution fluorescent microsatellite analysis.

It has recently been reported that mismatch repair enzymes, which are one type of DNA repair enzymes, are the causative genes for a major group of hereditary non-polyposis colon cancers (HNPCC). Abnormalities in the mismatch repair system can be monitored by observing instability at the microsatellite loci (MSI) in cancer cells. MSI has been reported not only in tumors associated with hereditary non-polyposis colorectal cancer but also in sporadic forms of various tumors. No correlation between pediatric malignant tumors and the mismatch repair system has yet been reported. In the present study, we examined the frequency of MSI in 21 neuroblastomas, which are the most common solid tumors in childhood, using a high resolution fluorescent microsatellite analysis. MSI on five microsatellite loci was detected in none of the 21 samples. Other mechanisms independent of mismatch repair deficiency may thus play a role in both tumorigenesis and the development of neuroblastoma.

Child↗

PubMed1998

MST-16, a novel derivative of bis(2,6-dioxopiperazine), synergistically enhances the antitumor effects of anthracyclines.

MST-16, a derivative of bis(2,6-dioxopiperazine), is a newly developed anticancer agent that is potentially effective in combination with anthracyclines. It has a structural similarity to ICRF-187. The effects of MST-16 and its active form, ICRF-154, on the cytotoxic activities of six anthracyclines were investigated both in vitro and in vivo. Adriamycin (ADM), therarubicin (THP) and ME2303 (ME) showed synergistic cytotoxicity against colon 26 cells, when combined with MST-16. Epirubicin (EPI) and menogaril (TUT-7) and daunomycin (DM) all had a combination index of less than 1.0 only in the lower fraction affected range and, so there were probably no synergistic interactions between these drugs and MST-16. In colon 26 tumor-bearing mice, a significant delay in tumor growth was noted in the mice treated with ADM (7.5 mg/kg) and MST-16 (750 mg/kg) compared with mice given either drug alone. Similarly, tumor growth in mice treated with THP (10 mg/kg) or ME (10 mg/kg) with MST-16 (750 mg/kg) was significantly delayed. To elucidate the mechanism of synergy between these anthracyclines and MST-16, the concentration of anthracyclines in the treated cells was measured by flow cytometry. No increased intracellular accumulation of ADM. THP or ME was evident even when combined with MST-16. Cell cycle analysis revealed that MST-16 enhanced the accumulation of cells in G2M induced by ADM, THP and ME 1.6, 1.4, and 1.5 times, respectively. We thus conclude that the administration of ADM, THP and ME combined with MST-16 is synergistic and that the mechanism may not include an increase in the intracellular drug uptake but rather an increase in G2M accumulation.

Animals↗

PubMed1998

Laparoscopic repair of a perforated duodenal ulcer in two patients.

The laparoscopic repair of a perforated duodenal ulcer was effectively done in two patients both of whom were poor risks for surgery. One was a 39-year-old woman with a history of bronchial asthma since she was 20 years of age, while the other was a 76-year-old man with hepatocellular carcinoma, lung cancer, and diabetes mellitus. The postoperative course of these patients was uneventful. Based on these findings, the laparoscopic repair of a perforated duodenal ulcer should thus be considered as a first choice of treatment for a perforated duodenal ulcer, even in poor-risk patients.

Adult↗

PubMed1998

Early experience of endoscopic extirpation of benign breast tumors via an extra-mammary incision.

The early results of 6 patients with a benign breast mass who underwent an endoscopic extirpation via an extra-mammary incision were presented. Under general anesthesia in either a lateral or supine position, a 12-mm and two 5-mm incisions in the infra-mammary line in 2 patients and in the mid-axillary line in the remaining 4 patients were made. The tumors were then endoscopically extirpated. Preoperative aspiration needle cytology revealed six fibroadenomas in 5 patients and one intraductal papilloma in the other patient. All patients were single females with a mean age of 22.5 years. The maximal size of the masses was 5 cm on average. The average operation time was 3 hours 20 minutes. Regarding postoperative complications, subcutaneous emphysema extending to the neck due to CO2 gas inflation and a burn in the skin were seen in 1 patient each; however, no further treatment was required in these cases. The postoperative hospital stay was 1.7 days on average, and all patients were extremely satisfied with the cosmetic results of the procedure. The cosmetic results are drastically improved by the application of endoscopic removal via extra-mammary approaches, which are newly introduced, for benign breast tumors.

Adolescent↗

PubMed1998

Spinal R-phenyl-isopropyl adenosine inhibits spinal dorsal horn neurons responding to noxious heat stimulation in the absence and presence of sensitization.

The effects of spinally administered R(-)N6-(2-phenylisopropyl) adenosine (R-PIA) on spinal dorsal horn neurons were investigated in anesthetized rats. Extracellular, single-unit recordings were measured during noxious heating of receptive fields on the hind paw. Three series of experiments were carried out to characterize the effects of R-PIA on spinal dorsal horn neuronal activity. In the first set of experiments, R-PIA dose-dependently suppressed noxiously evoked activity of spinal dorsal horn neurons. In the second set of experiments, R-PIA suppressed noxiously evoked activity in neurons sensitized by the topical application of mustard oil to a region of skin adjacent to their receptive fields. In the third set of experiments, R-PIA prevented mustard oil induced sensitization of dorsal horn neurons. In all cases, the adenosine receptor antagonist theophylline reversed the action of R-PIA. The results of these investigations indicate the involvement of spinal adenosine receptors in spinal pathways of central sensitization and in the modulation of somatically induced noxious pain.

Adenosine↗

PubMed1998

Induction of apoptosis in human tumour xenografts after oral administration of uracil and tegafur to nude mice bearing tumours.

Various types of anti-neoplastic agents induce apoptosis in vitro, but less is known of the role of this mode of cell death in tumours treated in vivo. We examined the induction of apoptosis by oral anti-neoplastic agents, tegafur and uracil (UFT, a combined preparation of 1 mol tegafur and 4 mol uracil), and the relationship of effects on tumour growth. Seven different human gastrointestinal tumour xenografts were transplanted into nude mice, including two colon adenocarcinomas (KM20C and Col-1), three gastric carcinomas (SC-6, St-40 and 4-1ST) and two pancreatic carcinomas (PAN-4 and PAN-12), followed by oral administration of UFT (24 mg kg(-1) day(-1)) for 9 days. The percentage of apoptotic cells in each tumour was scored in histological sections, chronologically, using a molecular biological-histochemical system and growth inhibition was examined in each tumour. A significant growth inhibition by UFT was observed for all tumours, except PAN-12. In KM20C and SC-6, growth inhibition rates were 61.7% and 60.6% respectively. Quantitative assay for apoptosis showed a remarkable induction of apoptosis in KM20C (4.2%) and SC-6 (3.5%), which were relatively sensitive to UFT. In addition, KM20C and SC-6 showed a higher incidence of spontaneous apoptosis. In five other tumours, which responded to a lesser extent than KM20C and SC-6, UFT altered little the changes in apoptosis (less than 2%) and spontaneous apoptosis was relatively low. Thus, tumours with a higher apoptosis induced by UFT had a higher response to UFT. Apoptosis observed in tumours might serve as a predictor of a preferable response to UFT.

Animals↗

PubMed1998

Treatment of advanced gastric cancer with 5-fluorouracil and cisplatin in combination with dipyridamole.

We investigated the efficacy of combination chemo-therapy using 5-fluorouracil (5-FU), cisplatin (CDDP), and dipyridamole (DP), which is based on the concept of double biochemical modulation. Twenty-eight patients with advanced gastric cancer were treated with the simultaneous continuous intravenous (i.v.) infusion of 5-FU (800 mg/m2/day) and DP (4 mg/kg/day), and i.v. infusion of CDDP (20 mg/m2/day) for 5 days. The cycles were repeated every 4 weeks. Twelve patients (43%) had a partial response (PR), while stable disease (NC) occurred in 13 patients (46%), and progression (PD) in 3 patients (11%). An improved performance status was observed in 20 patients (71%). The carcinoembryonic antigen (CEA) level was markedly decreased in 75% of the CEA-positive patients. Toxicity was acceptable. The mean steady state plasma concentration of total DP was 6.40.5 microM, which thus seemed adequate to potentiate the cytotoxicity of 5-FU. The treatment regimen described herein thus appears to be effective, safe and well tolerated by patients with advanced gastric cancer.

Adult↗

PubMed1998

Gastric carcinoma with pyloric stenosis.

BACKGROUND: The surgical outcome of gastric carcinomas with pyloric stenosis and their prognostic factors are sparsely documented. METHODS: A clinicopathologic study of gastric carcinoma with pyloric stenosis (PS group, n = 122) was done and findings were compared with the cases involving the antrum (A group, n = 695). Independent prognostic factors for survival of the patients with PS were determined by Cox's proportional hazard model. RESULTS: There were no differences in age and gender between the two groups. The PS group was characterized by an infiltrating growth pattern and undifferentiated adenocarcinoma. The incidence of serosal invasion, direct invasion into neighboring organs, peritoneal dissemination, lymph node metastasis, and liver metastasis of the PS group was higher than those of the A group (p < 0.01). The resection rate and 5-year survival of the PS group were 78% and 22%, respectively; these values were significantly lower than 98% and 58% of the A group (p < 0.01). Multivariate analyses showed that operative curability, resection of the stomach, liver metastasis, serosal invasion, and histologic type were the independent prognostic factors of the PS group. CONCLUSIONS: In cases of gastric carcinoma with pyloric stenosis, efforts should be made to do a curative operation, but for other patients with poor prognostic factors, intensive surgery and adjuvant therapy should be considered.

Aged↗

PubMed1998

[A new microsatellite instability analysis using fluorescent primers and laser scanning].

To demonstrate the instability of microsatellite sequences, which have been linked to DNA mismatch repair deficiency and indicate a high risk of carcinogenesis, polymerase chain reaction (PCR) and electrophoretic analysis have been used. However, the electrophoretic profiles of PCR-amplified microsatellite sequences are often too complicated, and the conventional method using autoradiography has critical problems in detection characteristics and migration accuracy. First, we made use of fluorescence-labeled PCR and laser scanning to detect bands quantitatively. Second, we characterized Taq polymerase-dependent modification of the amplified microsatellite sequences and optimized the electrophoretic profiles by enzymatic modification with T4 DNA polymerase. Third, we developed a dual fluorescence co-electrophoresis system, in which both samples derived from cancer and normal tissues are electrophoresed in the same lane, in order to minimize migration errors. Furthermore, we classified all of the observed patterns of microsatellite alteration and set up new criteria for assessing microsatellite instability. Using the system developed here and the criteria we proposed, a precise judgment can be made and rates of positivity in various human malignancies may be corrected.

DNA-Directed DNA Polymerase↗

PubMed1998

Transaxillary approach for the endoscopic extirpation of benign breast tumors.

Cosmetic factors in the treatment of breast disease have long been neglected despite the fact that patients are highly concerned about the length and extent of the incision. Recent developments in both endoscopy and endoscopic devices have now made it possible to reach breast mass(es) from small incisions in the axilla. We describe the successful extirpation of a giant fibroadenoma of the breast in a 20-year-old woman, using a 3-mm or 10-mm endoscope and a 3-mm or 5-mm endoscopic device with a transaxillary approach. A scar-free breast with an excellent cosmetic result was achieved by use of this technique and these devices. Benign tumors (both single large tumors and multiple masses) are therefore considered to be ideal candidates for this type of minimally invasive endoscopic surgery.

Adult↗

PubMed1998

Tumor angiogenesis and micrometastasis in bone marrow of patients with early gastric cancer.

In a subset of patients with early gastric cancer, there were recurrences of the disease after a curative resection had been done. Direct evidence of tumor seeding in distant organs at the time of surgery for gastric cancer is not available. An immunocytochemical assay for epithelial cytokeratin protein may fill this gap because it is a feature of epithelial cells that would not normally be present in bone marrow. From 1994-1997, the bone marrow of 45 patients with early gastric cancer was examined for tumor cells, using immunocytochemical techniques and an antibody reacting with cytokeratin, a component of the intracytoplasmic network of intermediate filaments. Intratumoral microvessels were stained with anti-CD31 monoclonal antibody. Clinicopathological characteristics were determined for subjects with cytokeratin-positive cells in the bone marrow. Of these 45 patients, 9 (20.0%) had cytokeratin-positive cells in the bone marrow at the time of primary surgery. These positive findings were not related to tumor advance-related factors of lymph node metastasis and distinct lymphatic and vascular invasion. Microvessel density in the primary tumor exceeded 2-fold in cytokeratin-positive cells, compared with findings in negative cells (P < 0.05). Tumor cells in bone marrow are indicative of the general disseminative metastasis in patients with early gastric cancer, and the metastatic potential was closely related to angiogenesis in the primary tumor.

Aged↗

PubMed1997

Precise assessment of microsatellite instability using high resolution fluorescent microsatellite analysis.

The instability of microsatellite sequences dispersed in the genome has been linked to a deficiency in cellular mismatch repair. This phenotype has been frequently observed in various human neoplasms and is regarded as a major factor in tumorigenesis. To demonstrate alterations in microsatellite sequences, polymerase chain reaction (PCR) and electrophoretic analysis are techniques often used. However, the electrophoretic profiles of PCR-amplified microsatellite sequences have not been well characterized. Moreover, the conventional method using autoradiography has critical problems in detection characteristics and migration accuracy. We made use of fluorescence-labeled PCR and laser scanning with linear detection characteristics, so as to detect bands quantitatively. Next, we characterized Taq polymerase-dependent modification of the amplified microsatellite sequences, using artificially synthesized microsatellite alleles and we optimized the electrophoretic profiles by enzymatic modification with T4 DNA polymerase. We developed a dual fluorescence co-electrophoresis system, in which both samples derived from cancer and normal tissues are electrophoresed in the same lane, in order to minimize migration errors. These improvements remarkably facilitate precise and objective assessments of microsatellite instability. Analyzing many positive cases in cell lines and tissue specimens, we classified all the patterns of microsatellite alteration and set up new criteria for assessing microsatellite instability.

Adenocarcinoma↗

PubMed1997

Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis.

The mta1 gene is a recently identified novel candidate metastasis-associated gene. The deduced amino acid sequence contains an src homology-3 domain binding motif, a zinc finger motif and possible phosphorylation sites, suggesting that this gene is involved in signal transduction or regulation of gene expression. The purpose of our study was to examine the mRNA expression levels of the MTA1, the human homologue of the rat mta1 gene in colorectal and gastric carcinomas and thus to evaluate the relevance of the expression of this gene to human carcinoma progression. The expression of MTA1 mRNA in 36 colorectal and 34 gastric carcinoma samples was compared with that in corresponding normal mucosa tissues by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) and the results were compared with clinico-pathologic data. A relative overexpression of MTA1 mRNA (tumor/normal ratio > or = 2) was observed in 14 of 36 (38.9%) colorectal carcinomas and 13 of 34 (38.2%) gastric carcinomas. Clinico-pathologic correlations demonstrated that in colorectal carcinomas, tumors overexpressing MTA1 mRNA exhibited a significantly deeper wall invasion and a higher rate of metastasis to lymph nodes, and tended to be at an advanced Dukes' stage with frequent lymphatic involvement. In gastric carcinomas, the tumors overexpressing MTA1 mRNA showed significantly higher rates of serosal invasion and lymph node metastasis and tended to have a higher rate of vascular involvement. Our data suggest that overexpression of the MTA1 gene correlates with tumor invasion and the presence of metastases and that a high expression of MTA1 mRNA may be a potential indicator for assessing the malignant potential of colorectal and gastric carcinomas.

Aged↗