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Biomedical subjects

T Hirashima

Publications and source records attributed to T Hirashima.

At least 19 recordsLinked to original sources
PubMed1995

A diabetogenic gene (ODB-1) assigned to the X-chromosome in OLETF rats.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat develops hyperglycemia, hyperinsulinemia and mild obesity, features that closely resemble those in human non-insulin-dependent diabetes mellitus (NIDDM). Here, we report a gene involved in the development of diabetes in OLETF rats. Segregation studies using OLETF and an unrelated strain, F344 showed that no diabetes was observed in F1 progeny and less than 12.5% of the F2 progeny developed diabetes, suggesting that multiple recessive genes are involved in the disease. Interestingly, diabetes was observed in approximately 40% of (OLETF female x LETO male) F1 male rats, whereas less than 4% of males were diabetic in the reverse F1 mating. This suggested that the LETO rat which has been established from the same original colony as the OLETF rat shares some, but not all, diabetogenic genes with the OLETF, and that one of the responsible genes locates on the X-chromosome. Linkage study using (OLETF female x F344 male)F2 progeny has confirmed that one of the diabetogenic loci in the OLETF rats locates on the X-chromosome 14 cM distant from the AR gene (LOD = 2.598) and has been designated as ODB-1.

Animals↗
PubMed1995

Relationship between the pharmacokinetics of irinotecan and diarrhea during combination chemotherapy with cisplatin.

Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 60 mg/m2. The other 13 patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 80 mg/m2 with the granulocyte colony-stimulating factor support (2 micrograms/kg x 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 was 90 mg/m2 in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3-4 diarrhea than those with a lower SN-38 level (P = 0.0003). Stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea (P = 0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin.

Adult↗
PubMed1995

[A report of leiomyosarcoma of the esophagus].

Leiomyosarcoma of the esophagus is an uncommon disease of which only 97 cases including the present case have been reported in Japan. We report a case of the tumor which showed multiple hematogenous metastases after surgery. A 73-year-old male was admitted complaining of dysphagia and vomiting. Esophagography and endoscopy revealed a large protruding lesion in the lower esophagus. CT scanning revealed threefold-sized extramural mass. Boring biopsies failed to yield evidence of malignancy. However, we performed surgical treatment because of the uncommon size for a benign tumor. The excised tumor was 11 x 9 x 5 cm in size and was diagnosed histologically as leiomyosarcoma of the esophagus without any nodular involvement. Metastatic tumor in the right rib was found 14 months after the operation. Radiotherapy failed to decrease tumor size but eliminated pain. Bone metastases appeared successively and the patient died 3 years and 4 months after operation. Chemotherapy had no effect. Autopsy revealed metastases to the ribs, vertebrae, sternum, pelvic kidneys and diaphragm, but no local recurrence. There is a great need for the development of effective anti-cancer drugs for leiomyosarcomas, particularly in cases with extensive metastasis, such as presented here.

Adult↗
PubMed1995

[Gastric cancer in the elderly].

Gastric cancer in the elderly was evaluated with regard to age-related pathomorphological changes. Resected gastric cancer was studied with regard to location, stage, morphology and histology in male young old (65-74 years old) which were 25 cases and 31 lesions, respectively male middle old (75-84 years old); 104 cases and 120 lesions, male very old (85 years-); 96 cases and 110 lesions, female young old; 22 cases and 31 lesions, female middle old; 91 cases and 106 lesions, female very old; 51 cases and 55 lesions. Multiple gastric cancers were more frequent in female older group. In early cancer the frequency of elevated type increased significantly and that of depressed type decreased in very old group. In advanced cancer Borrmann I type was not so common in very old group. Histologically the frequency of signet ring cell cancer decreased and of tubular adenocarcinoma and of papillary adenocarcinoma increased significantly in female very old group. Hepatic metastasis increased significantly in male very old group. Lymph node metastasis and peritoneal metastasis did not show any change in age-related frequency.

Age Factors↗
PubMed1995

Significance of serum neuron-specific enolase as a predictor of relapse of small cell lung cancer.

We conducted a prospective study to evaluate the significance of serum neuron-specific enolase (NSE) as a predictor of relapse of small cell lung cancer (SCLC). Patients entered into the study were drawn from those who had shown a complete or partial response to first-line chemotherapy with a concurrent decline in the NSE level to less than 10 ng/ml. When the serum NSE level increased to more than 15 ng/ml, the patient was restaged on the basis of clinical, radiological, and bronchoscopic examinations. During the period from August 1988 to December 1990, 57 patients with SCLC were enrolled and followed up until May 1992. Of these patients, 45 had clinical relapses, and 14 (31%) of them showed a clear elevation of the serum NSE level prior to the clinical recognition of relapse. Although one false-positive case was noted, this involved only a transient elevation of the NSE level. In patients who showed increased NSE levels, the relapses occurred in more difficult to detect silent sites such as the adrenal gland, liver, and deep lymph nodes. In addition, the percentage of patients demonstrating high NSE levels who were able to benefit from salvage chemotherapy was higher than for those who did not (RHO < 0.05). Our results indicate that serial NSE measurements are useful for the early prediction of SCLC relapse and should help to facilitate early administration of salvage chemotherapy for affected patients.

Adult↗
PubMed1994

OLETF (Otsuka Long-Evans Tokushima Fatty) rat: a new NIDDM rat strain.

The characteristic features of OLETF rats are: (1) late onset of hyperglycemia (after 18 weeks of age); (2) a chronic course of disease; (3) mild obesity; (4) clinical onset of diabetes mellitus (DM) mostly in males; (5) hereditary trait: (a) multiple recessive genes are involved in the induction of DM; (b) rat MHC, RT1 has no diabetogenic effect; (c) control strain, LETO appears to share some of diabetogenic genes with OLETF rats; (d) female OLETF rats also carry diabetogenic genes; and (e) one of the diabetogenic genes, designated as odb-1, is transmitted linked with the X-chromosome of OLETF rats, however testosterone is an important factor involved in developing diabetes; (6) the changes of pancreatic islets can be classified into three stages: (1) an early stage (at less than 9 weeks of age) mild lymphocyte infiltration; (2) a hyperplastic stage (10-40 weeks of age); hyperplastic change and fibrosis in or around islets; (3) a final stage (at more than 40 weeks of age) showing atrophy of islets; (7) diabetic nephropathy; (a) diffuse glomerulosclerosis; (b) nodular lesion (thickening of basement membranes, mesangial proliferation, fibrin cap). These clinical and pathologic features of disease in OLETF rats resemble those of human NIDDM.

Animals↗
PubMed1994

Phase I study of irinotecan and cisplatin with granulocyte colony-stimulating factor support for advanced non-small-cell lung cancer.

PURPOSE: Since leukopenia was one of the dose-limiting toxicities of the combination of irinotecan (CPT-11) and cisplatin in a previous trial, we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-11 dose in combination with a fixed cisplatin dose. PATIENTS AND METHODS: Twenty previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) were treated with CPT-11 on days 1, 8, and 15 in combination with cisplatin 80 mg/m2 intravenously on day 1. In addition, rhG-CSF (2 micrograms/kg/d) was administered on days 4 to 21, except on the days of CPT-11 treatment. The starting dose of CPT-11 was 70 mg/m2, and the CPT-11 dose was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS: Diarrhea was the dose-limiting toxicity at 90 mg/m2. Two of six patients experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CPT-11 dose from 80 to 90 mg/m2 resulted in a marked increase in the plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38). Occurrence of diarrhea was well correlated with the peak plasma concentration (Cmax) of SN-38 (P = .035). There were 10 partial responses (50%) among 20 patients. CONCLUSION: The recommended dose for phase II studies is 80 mg/m2 of CPT-11, and 80 mg/m2 of cisplatin plus rhG-CSF. With the use of rhG-CSF, the CPT-11 dose can be increased 33% above that in the original regimen (60 mg/m2 of CPT-11 and 80 mg/m2 of cisplatin).

Adult↗
PubMed1994

Phase I and pharmacologic study of irinotecan and etoposide with recombinant human granulocyte colony-stimulating factor support for advanced lung cancer.

PURPOSE: We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) support because of the overlapping neutrophil toxicity of both drugs. The aim was to determine the maximum-tolerated dose of CPT-11 combined with a fixed dose of etoposide in patients with advanced lung cancer, as well as the dose-limiting toxicities of this combination. PATIENTS AND METHODS: Twenty-five patients with stage III or IV lung cancer, 15 (60%) with prior chemotherapy, were treated at 4-week intervals using CPT-11 (90-minute intravenous infusion on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3). In addition, rhG-CSF (2 micrograms/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. The starting dose of CPT-11 was 60 mg/m2, and it was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS: The maximum-tolerated dose of CPT-11 was 90 mg/m2, since two of the three patients developed grade 3 to 4 leukopenia or grade 3 to 4 diarrhea during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the dose-limiting toxicities, while thrombocytopenia was only a moderate problem. Elimination of CPT-11 was biphasic, with a mean +/- SD beta half-life of 18.17 +/- 9.09 hours. The mean terminal half-life of 7-ethyl-10-hydroxycamptothecin (SN-38; the major metabolite of CPT-11) was 43.40 +/- 37.84 hours. There was one complete response (5%) and eight partial responses (38%) among 21 assessable patients, for an overall response rate of 43%. The response rates for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) were 58% (seven of 12 patients) and 22% (two of nine patients), respectively. CONCLUSION: The combination of CPT-11 and etoposide with rhG-CSF support seems to be active against lung cancer, especially SCLC, with acceptable toxicity. The recommended dose for phase II studies in previously untreated patients is 80 mg/m2 of CPT-11 (days 1, 8, and 15) and 80 mg/m2 of etoposide (days 1 to 3) plus 2 micrograms/kg of rhG-CSF (days 4 to 21, except when CPT-11 is given). In addition, 70 mg/m2 of CPT-11 appears to be the appropriate dose for previously treated patients receiving this regimen.

Adult↗
PubMed1992

Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain.

A spontaneously diabetic rat with polyuria, polydipsia, and mild obesity was discovered in 1984 in an outbred colony of Long-Evans rats, which had been purchased from Charles River Canada (St. Constant, Quebec, Canada) in 1982. A strain of rats developed from this rat by selective breeding has since been maintained at the Tokushima Research Institute (Otsuka Pharmaceutical, Tokushima, Japan) and named OLETF. The characteristic features of OLETF rats are 1) late onset of hyperglycemia (after 18 wk of age); 2) a chronic course of disease; 3) mild obesity; 4) inheritance by males; 5) hyperplastic foci of pancreatic islets; and 6) renal complication (nodular lesions). Histologically, the changes of pancreatic islets can be classified into three stages: 1) an early stage (6-20 wk of age) of cellular infiltration and degeneration; 2) a hyperplastic stage (20-40 wk of age); and 3) a final stage (at > 40 wk of age). These clinical and pathological features of disease in OLETF rats resemble those of human NIDDM.

Animals↗
PubMed1992

[Prognostic analysis for postoperative complications of abdominal surgery in the elderly].

In order to evaluate the prognostic importance of the conditions before abdominal surgery for patients over 60 years of age. Multivariate analyses of postoperative complications were performed in 634 patients (comprising 525 cases of elective abdominal surgery and 109 cases of emergency abdominal surgery). The Mortality rate was significantly higher (p < 0.01) in the emergency group (11.9%) and relatively low among the elective abdominal surgery group (3.8%). In the emergency group, 13 patients died, and MOF (multiple organ failure) was found to be the direct cause of death in 11 (85%). Although, the majority (75%) of emergency operations were for benign disorders, the remainder (25%) had malignant tumors. It is noteworthy that among 25% of cases, obstructions and perforations due to large bowel cancers were found to be 59% and 19%, respectively. In the elective surgery group, postoperative pulmonary and cardiovascular complications were found in 11.6% and 9.6%, respectively. Death due to cardiovascular problems in rare (5%), however, postoperative pneumonia was the cause of death in 70% of all of postoperative death. Risk factors affecting postoperative pulmonary complications were malnutrition, advanced age, male sex, malignant disease, dementia, cerebrovascular disorders, impaired pulmonary function tests. Surprisingly, the risk factors were identical, except for impaired pulmonary function, for postoperative MRSA pneumonia. In our study, postoperative pulmonary death was not associated with impaired pulmonary function, and it appears to be rather affected by the presence of cerebrovascular disorders and malnutritional state. A poor nutritional states (< 40 according to Onodera's nutritional index) was present in over 50% of patients with cerbrovascular disorders and low ADL.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗
PubMed1992

[Stomal stenosis following gastrectomy in the elderly].

Seven hundred and thirty seven patients over 65 years of age (mean 76 years) undergoing gastrectomies from 1979 to 1991 were reviewed to evaluate the cause of stomal stenosis in the early postoperative period. Fifty seven (7.7%) patients, 24 males (5.6%) and 33 females (10.6%), had overt stomal stenosis or obstruction documented by radiological and endoscopic findings. The incidence of stenosis in females was significantly higher than in males (p < 0.05). Complications developed in 19 (20.0%) of 95 patients after gastroduodenostomy (Billroth-I), 29 (6.2%) of 465 after gastrojejunostomy (Billroth-II and others) and 8 (5.0%) of 159 after esophagojejunostomy (total gastrectomy). The incidence of complications in the first was significantly higher than in the other two (p < 0.01). The cause of stomal stenosis was classified into three groups; (1) transient stenosis due to stomal edema in 21 patients, (2) intestinal obstruction immediately adjacent to the stoma (kinking, invagination and volvulus) in 22, (3) organic stenosis of pathological origin (stomal ulcer, anastomotic leakage and strangulation by the proliferated mesocolon) in 14. The period of recovery from postgastrectomy retention was different in each group. It was 20.7 (mean) +/- 7.7 (SD) days in group (1), 29.7 +/- 12.6 days in group (2) and 62.1 +/- 30.0 days in group (3). These mean periods were significantly different from each other (p < 0.01). Group (1) and most of group (2) responded well to conservative management consisting of decompression by nasogastric suction and parenteral feeding but a reoperation was necessary for only two patients in group (2). Half of group (3) was treated by endoscopic dilatation and one third by reoperation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

[Post operative upper gastrointestinal bleeding in the aged].

A 10-year experience with 2,441 patients over 65 years of age undergoing operations for non-upper gastrointestinal tracts was reviewed to evaluate both the incidence of postoperative upper gastrointestinal bleeding and the clinical risk factors associated with the complication. A total of 18 (0.7%, 7 males and 11 females) patients had overt postoperative upper gastrointestinal bleeding of non-variceal origin documented by endoscopic findings or blood transfusions. Of these, the complication developed in 10 (1.5%) of 646 patients after an operation for biliary or pancreatic disease, 1 (1.5%) of 64 for aneurysmal or obstructive arterial disease, 5 (1.1%) of 43 for colorectal cancer and 2 (0.3%) of 916 for hernia. The incidences of bleeding after an operation for obstructive jaundice (3.8%), for biliary or pancreatic malignancy (4.5%), and of unavoidable diversion colostomy for colorectal anastomosis (3.1%) were significantly higher than for non-jaundice (0.6%), for non-malignancy (1.1%) and of postoperative upper gastrointestinal bleeding in the present study. The origins of bleeding were gastric ulcer in 11, acute gastric mucosal lesion in 4, duodenal ulcer in 1 and other in 2. All cases of bleeding were treated and met success in hemostasis using H2-blockers. Of these, however, 5 patients died of multiple organ failure despite discontinued hemorrhage, prophylactic use of H2-blockers showed a decrease in occurrence of postoperative upper gastrointestinal bleeding in the present study.

Aged↗
PubMed1991

New inbred strain of Long-Evans Tokushima lean rats with IDDM without lymphopenia.

Spontaneously diabetic rats with remarkable polyuria, polyphagia, and polydipsia were discovered in 1983 in an outbred colony of Long-Evans rats purchased from Charles River Canada in 1982. They have since been maintained at the Tokushima Research Institute (Otsuka Pharmaceutical, Tokushima, Japan). A strain of rats (Long-Evans Tokushima Lean [LETL]) with diabetes was bred from these rats. The characteristic features of the disease in LETL rats are 1) sudden onset of polyuria, polyphagia, hyperglycemia, and weight loss; 2) no sex differences in the rate of onset or severity; 3) lymphocyte infiltration into islets followed by destruction of beta-cells and disappearance of lymphocytes at the onset of diabetes; 4) no significant T lymphopenia; 5) lymphocyte infiltration into the salivary glands and lacrimal glands; and 6) at least two recessive genes involved in the pathogenesis of insulitis, one of which is closely linked with RT1u. These characteristics closely resemble those of human insulin-dependent diabetes mellitus (IDDM). Results suggest that the LETL rat is a useful animal model for analysis of genetic and immunologic factors relating to the pathogenesis of human IDDM.

Animals↗
PubMed1990

[Manometric study of vertical banded gastroplasty for morbid obesity].

Morbidly obese patients undergoing vertical banded gastroplasty were studied preoperatively and/or postoperatively to characterize its manometric pattern. The esophageal manometry using station pull through technique involved 14 preoperative patients with a mean age of 28 +/- 7 years who were a obesity index of 220 +/- 32% and 14 postoperative patients with a mean age of 30 +/- 7 years who were a obesity index of 158 +/- 23%. Preoperative lower esophageal sphincter (LES) pressure using gastric base line as O was 16.1 +/- 8.5 cmH2O and a LES length of 3.4 +/- 0.9 cm. Postoperatively, the vertical banded gastroplasty channel had a pressure of 17.7 +/- 7.1 cmH2O and a length of 8.2 +/- 1.7 cm which was higher than gastric base line. No difference was seen between preoperative LES pressure and postoperative channel pressure, however postoperative channel length was significantly (p less than 0.01) larger than preoperative LES length. We concluded that vertical banded gastroplasty for morbid obesity created a longer high pressure zone in accordance with channel which would inhibit reflux of gastric juice.

Adult↗
PubMed1987

Effects of esophageal transection combined with splenectomy on portal hemodynamics.

Portal hemodynamics were studied in 69 patients with cirrhosis and 29 patients with idiopathic portal hypertension to investigate the effects of an operative procedure for varices that consists of transabdominal esophageal mucosal transection, paraesophagogastric devascularization, pyloroplasty, and splenectomy. Portal venous flow measured by the pulsed Doppler flowmeter in 14 patients with cirrhosis and nine patients with idiopathic portal hypertension, who underwent operation 2-5 yr earlier, was significantly reduced compared with that in unoperated 49 patients with cirrhosis and 17 patients with idiopathic portal hypertension who had esophageal varices (410 +/- 158 versus 660 +/- 263 ml/min in cirrhosis; 443 +/- 185 versus 912 +/- 189 ml/min in idiopathic portal hypertension). In nine patients (six cirrhosis, three idiopathic portal hypertension), portal venous flow and portal vein pressure were measured before and after operation. In patients with cirrhosis, portal vein pressure did not change significantly postoperatively even though portal venous flow was reduced. In contrast, portal vein pressure decreased in two patients with idiopathic portal hypertension in whom portal venous flow was reduced. Portal vein pressure was elevated in one patient with idiopathic portal hypertension in whom portal venous flow was increased postoperatively as a result of resection of a large gastro- and splenorenal shunt conducted additionally.

Aged↗
PubMed1985

Lactomer copolymer absorbable staples in gastrointestinal surgery.

We performed a series of experimental studies to determine the clinical feasibility of using lactomer copolymer absorbable staples in gastrointestinal surgery. The stapling properties, reliability of suture and wound healing, and degree of inflammatory response were compared to similar properties of standard metal staples and polyglactin sutures. The absorbable staples were used in partial gastric transection, Billroth II gastrojejunostomy, and to close the ileum and ascending colon as part of an ileocecal resection. There were no deaths or complications in the nine experimental animals. At sacrifice 2 and 4 weeks after operation, the absorbable staples were intact with little or no macroscopic or microscopic evidence of absorption. The mucosal and submucosal layers were completely healed at 2 weeks, but muscular and serosal layers, although in excellent approximation, were incompletely joined. Inflammatory reactions around the lactomer staples and polyglactin sutures were comparable, but greater than that observed around metal staples. The studies suggest that staple techniques using absorbable materials are feasible and safe in gastrointestinal surgery.

Animals↗