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Biomedical subjects

T Hirashima

Publications and source records attributed to T Hirashima.

At least 37 records · Page 2Linked to original sources
PubMed1996

A diabetogenic gene, ODB2, identified on chromosome 14 of the OLETF rat and its synergistic action with ODB1.

Genetic analysis of diabetogenic genes involved in developing spontaneous diabetes of NIDDM type in the OLETF rat was performed in (OLETF female X B N male)F2 and (OLETF female X BN male)F1 female X OLETF male backcross male offspring. In the F2 and/or backcross offspring, a high frequency of diabetes was found to be associated with a coat color gene, H (hooded). Since it is know that H gene is located on chromosome 14. an attempt was made to examine the linkage association of the gene responsible for elevating plasma glucose with various microsatellite markers of chromosome 14 in male F2 and/or backcross offspring. The results show that a high linkage exists with a microsatellite marker, D14Mit4 (LOD > 2). The gene was designated Odb2. It was also found that both genes, Odb1 which was previously found on chromosome X, and homozygous Odh2 are required to cause elevated plasma glucose in OGTT.

Animals↗
PubMed1996

Point mutations of the topoisomerase IIalpha gene in patients with small cell lung cancer treated with etoposide.

Reverse transcription-PCR-single-strand conformation polymorphism analysis was performed to detect topoisomerase IIalpha mutations using total RNA from 19 bronchial biopsy specimens obtained from 13 patients with small cell lung cancer. An abnormally migrating single-strand conformation polymorphism band was observed in one tumor sample from a patient treated with etoposide-containing chemotherapy. DNA sequence analysis of this tumor showed two transversions at codons 486 (G to A) and 494 (A to G), resulting in two missense mutations (Arg to Lys and Glu to Gly, respectively). The codon 486 mutation was identical to that previously found in two cell lines selected for amsacrine resistance. These results demonstrate that mutations of topoisomerase IIalpha occur in patients with small cell lung cancer. The significance of these mutations in the development of resistance to etoposide needs further investigation.

Aged↗
PubMed1996

Relationships between diet control and the development of spontaneous type II diabetes and diabetic nephropathy in OLETF rats.

The effect of a 30% restricted diet on the development of diabetes and diabetic nephropathy was examined using the Otsuka Long Evans Tokushima Fatty (OLETF) rat which develops non-insulin-dependent diabetes mellitus (NIDDM) spontaneously after 25-30 weeks of age. The first experimental group that received 30% restricted feeding from six to 80 weeks old, showed complete suppression of spontaneous diabetes up to 40 weeks of age and showed milder histopathological change of pancreatic islets, that those of the control group. The second group which received 30% restricted feeding during 30-80 weeks, showed a gradual decrease in clinical diabetes with age, even though they had already developed diabetes at 25 weeks. In both groups, levels of urinary protein content appeared to decrease, compared with that in control rats, although a gradual increase of urinary protein was observed with age. Histopathologically, glomerular damages were slight to mild in both groups. However, no improvement in nephrotic complication was observed for the group which received a 30% restricted feeding after 70 weeks of age. These results clearly show that the balanced-control diet, given at a 30% restricted feeding level and at an early phase, is effective in the prevention or improvement of NIDDM and nephrotic complications. Diet therapy after 70 weeks of age, however, had little or no effect.

Age Factors↗
PubMed1996

Randomised trial for the prevention of delayed emesis in patients receiving high-dose cisplatin.

Despite recent advances in control of acute emesis following cisplatin-based chemotherapy regimens, delayed emesis remains a significant cause of treatment-related morbidity and factors associated with delayed emesis have not yet been evaluated. A prospective randomised trial was conducted to compare the efficacy and toxicity of granisetron, dexamethasone plus prochlorperazine with granisetron alone in controlling cisplatin-induced delayed emesis and to identify the important factors that influence its occurrence and severity. Seventy cisplatin-naive patients with inoperable solid tumors participated in the trial. Patients who received 80 mg m-2 or 100 mg m-2 of cisplatin were randomly assigned to receive either granisetron 40 micrograms kg-1 intravenously (i.v.) on day 1, dexamethasone 20 mg i.v. on days 2 and 3 and prochlorperazine 5 mg orally thrice daily on days 1-5 or granisetron 40 micrograms kg-1 i.v. on day 1 alone. There was no difference in their acute antiemetic efficacy. A combination regimen was more effective than granisetron alone in preventing delayed symptoms, with superior rates of complete plus major responses of 77% vs 51% (P = 0.0460). Treatment arm was the only determinant factor for the occurrence of delayed emesis (P = 0.0101).

5-Hydroxytryptophan↗
PubMed1996

[Trial of home infusion therapy for near-terminal stage patients with lung cancer].

To improve the quality of life in patients with malignant diseases at the near-terminal stage, we established a system for home infusion therapy (HIT) in Osaka Prefectural Habikino Hospital in 1994. Thirty-three patients were taken care of at home using the HIT system from January, 1995 to May, 1996. Their average age was 70 years old. The duration of HIT varied from 1 to 105 days (mean:25.5 days). Twenty-four cases received parenteral nutrition. The others received agents for brain edema (4 cases), morphine hydrochloride (2 cases), and anti-fungal agents (3 case). Additionally, 63% of these patients required home oxygen therapy (HOT) with HIT. Questionnaires to their families revealed that they were afraid of the progress of the disease in patients and their physical burden became heavier after the start of HIT. However, they were quite satisfied with the results of HIT.

Adolescent↗
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

[Risk factors of operative death and prognosis following operations for esophageal cancer in the elderly].

Risk factors of operative death and prognosis in the elderly following operations for esophageal cancer were evaluated by multivariate analyses. Data were obtained from 45 operations over a 14-year period in patients of a mean age of 72.6 +/- 6.3 years. Using a multiple logistic model analysis, it was determined that the significant risk factor of death within 50 postoperative days was postoperative pulmonary complication. No other factors were significant as risk factors with regard to survival. Cox's proportional hazards model analysis was used to assess the prognostic factors of long-term survival following operations. Independent predictors were the stage of cancer and age. We conclude that two points are essential to improve the survival rate of elderly patients with esophageal cancer; first, postoperative special attention in order to prevent pulmonary complications and secondly, performing operations at as early a stage of cancer as possible.

Aged↗
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↗
PubMed1994

[Changes in surgical treatment of peptic ulcer in the elderly by H2-blockers].

It has common knowledge that the advent of H2-blockers has radically changed the treatment of peptic ulcer. We reviewed 26,667 endoscopic examinations, 5,800 consecutive autopsies and 134 consecutive patients operated for peptic ulcer over an 18-year period to evaluate the effects of H2-blockers on the treatment of peptic ulcer in the elderly (> or = 60 years of age). The number of operations for peptic ulcer in the elderly markedly declined after H2-blocker therapy was introduced. This is mainly due to decreased operative indications for gastric bleeding as a result of conservative treatment. However, the incidence of perforating ulcers has hardly changed even after the introduction of H2-blockers. More than 90% of these cases were non-diagnosed or non-treated ulcers and 50% of them were NSAID- or steroid-treated, which is characteristic in the elderly. We conclude that patients to be treated by anti-inflammatory drugs should be screened by endoscopy, and should be given anti-ulcer drugs prophylactically if necessary.

Aged↗
PubMed1994

[Prognostic factors influencing survival after operations for gastric cancer in the elderly].

The prognostic factors influencing survival after operations for gastric cancer in the elderly were evaluated by Cox's proportional hazards model analysis. Data were obtained from 511 operations over a 10-year period, in patients with a mean age of 75.6 +/- 7.9 years. The significant prognostic factors of survival out of 47 examined risk factors were, in order of standardized coefficient values, (1) stage of cancer, (2) %IBW, (3) peritoneal dissemination (P-factor), (4) multiple non-gastric cancers, (5) postoperative hepatic injury and (6) postoperative cardiac complication. No other factors, including preoperative associated diseases and postoperative pulmonary complication (the major risk factor of operative death), were significant risk factors of survival. We conclude that by giving special postoperative attention to prevent hepatic injury and cardiac complication, the length of survival of elderly patients with gastric cancer will improve.

Aged↗
PubMed1993

Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer.

We have conducted a Phase I trial to determine the maximum tolerated dose of CPT-11 together with a fixed dose of cisplatin in patients with advanced lung cancer, and the dose-limiting toxicities of this combination. Fourteen previously untreated patients with stage IIIB or IV disease were treated with CPT-11 (90-min intravenous infusion on days 1, 8, and 15) plus cisplatin (60 mg m-2, intravenously on day 1). The starting dose of CPT-11 was 60 mg m-2, and diarrhea was the dose-limiting toxicity at the 90 mg m-2 dose level. All three patients (all four cycles) given 90 mg m-2 of CPT-11 experienced grade 3 diarrhea. Hematologic toxicity was relatively mild. Elimination of CPT-11 was biphasic with a mean (+/- s.d.) beta half-life of 11.36 +/- 7.26 h. The mean terminal half-life of the major metabolite (7-ethyl-10-hydroxycamptothecin; SN-38) was 22.13 +/- 13.28 (s.d.) h, and modest escalation of the CPT-11 dose from 80 mg m-2 to 90 mg m-2 resulted in a statistically significant apparent increase in the plasma concentrations of SN-38. There were one complete response (7%) and five partial responses (36%) among the 14 patients for an overall response rate of 43%. The recommended dose for Phase II studies is 80 mg m-2 of CPT-11 and 60 mg m-2 of cisplatin.

Adult↗