Biomedical subjects

Y Kusunoki

Publications and source records attributed to Y Kusunoki.

At least 73 records · Page 4Linked to original sources

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

A positive correlation between T-cell-receptor mutant frequencies and dicentric chromosome frequencies in lymphocytes from radiotherapy patients.

Dose estimates for the assessment of future risks, following accidental exposure to radiation, for certain diseases such as cancer usually rely on both physical and biological quantitative analyses. A traditional biological method of choice is the measurement of chromosome aberration frequencies in peripheral-blood lymphocytes. However, thorough examination of large sample populations is time and labor intensive. Recently, it became possible to measure mutant frequencies in T lymphocytes; one method is a colony assay at the HPRT gene, and the other is a flow-cytometric assay at the T-cell-receptor (TCR) gene. To test for the possible use of these mutation assays, concurrent measurements were taken on blood samples from women who previously received a full course of radiation therapy for gynecological cancer. The results showed that the frequency of TCR mutants correlated reasonably well with that of dicentric chromosomes, whereas the frequency of HPRT mutants did not. Possible uses of the TCR mutation assay in combination with the conventional chromosome analysis or micronucleus assay after exposure of a relatively large population are discussed.

Chromosome Aberrations↗

PubMed1994

Increased frequency of CD4-8-T cells bearing T-cell receptor alpha beta chains in peripheral blood of atomic bomb survivors exposed to high doses.

A rare T-cell subpopulation, CD4-8- alpha beta T cells, may be differentiated through a pathway (or pathways) different from the pathway(s) of conventional CD4+ or CD8+ T cells. In the present study, the frequencies of CD4-8-T cells in peripheral-blood alpha beta T cells in 409 atomic bomb survivors (160 estimated to have been exposed to 1.5 Gy or more and 249 controls) were determined to investigate late effects of radiation on the composition of human T-cell subpopulations. The frequency of CD4-8- alpha beta T-cell decreased significantly with the subject's age and was higher in females than males. A significant increase in the frequency was found in the survivors exposed to more than 1.5 Gy, suggesting that the previous radiation exposure altered differentiation and development of T cells.

Adult↗

PubMed1994

Immune responses to Epstein-Barr virus in atomic bomb survivors: study of precursor frequency of cytotoxic lymphocytes and titer levels of anti-Epstein-Barr virus-related antibodies.

Precursor frequencies of cytotoxic lymphocytes to autologous Epstein-Barr virus-transformed B cells and serum titers of anti-Epstein-Barr virus-related antibodies were measured in 68 atomic bomb survivors to clarify the immune mechanism controlling Epstein-Barr virus infection. The precursor frequency was negatively correlated with the titer of anti-early antigen IgG, which is probably produced at the stage of viral reactivation. A positive correlation between the precursor frequency and titer of anti-Epstein-Barr virus-associated nuclear antigen antibody was also observed, indicating that the precursor frequency reflects the degree of in vivo destruction by T cells of the virus-infected cells. These results suggest that T-cell memory specific to Epstein-Barr virus keeps the virus under control and that the precursor frequency assay is useful for the evaluation of immune responses to Epstein-Barr virus. However, no significant effect of atomic bomb radiation on the precursor frequency was observed in the present study, probably due to the limited number of participants.

B-Lymphocytes↗

PubMed1994

[A case of pulmonary cryptococcosis diagnosed by percutaneous lung biopsy].

A 53-year-old male was admitted with complaint of bloody sputum. The chest X-ray film revealed a solitary round mass with cavity formation in the left upper lung field. A diagnosis of pulmonary cryptococcosis was made by the percutaneous lung biopsy. As his chest X-ray film did not improve even by administration of antimycotic agents for 6 months, he underwent partial resection of left upper lobe. Thus, the percutaneous lung biopsy was a significant procedure for the definitive diagnosis of this case.

Biopsy, Needle↗

PubMed1993

Frequent occurrence of in vivo clonal expansion of CD4- CD8- T cells bearing T cell receptor alpha beta chains in adult humans.

We have previously reported 2 cases of healthy men showing in vivo monoclonal expansion of mature CD4- CD8- alpha beta T cells. In the present study, an additional 3 adults were found to exhibit such an expansion, among a total 464 adult donors studied. These 5 individuals were otherwise physiologically normal, with no history of severe illness and autoimmune disease at the time of examination. To investigate the mechanisms of the clonal expansion, further characterization of the clonal cells was attempted. No apparent preference for usage of the T cell receptor beta chain variable region was observed in the clonal T cells. These clonal T cells showed lectin-dependent or redirected antibody-dependent cell-mediated cytotoxicities, whereas they could not lyse autologous lymphoblastoid cell lines. Failure of Fas antigen expression was not observed for any of these clones. These results suggest that clonal expansion of CD4- CD8- alpha beta T cells frequently occurs in the periphery without any T cell abnormalities.

Adult↗

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↗

PubMed1993

A positive correlation between the precursor frequency of cytotoxic lymphocytes to autologous Epstein-Barr virus-transformed B cells and antibody titer level against Epstein-Barr virus-associated nuclear antigen in healthy seropositive individuals.

A limiting dilution analysis was established to determine the precursor frequency (PF) of cytotoxic lymphocytes against autologous B cells transformed with the Epstein-Barr virus (EBV). This method was found to detect mainly self-restricted T-cell activity and little non-self-restricted cytotoxicity. The mean PF in 21 healthy EBV-seropositive persons was 1.4 x 10(-3) (range: 0.03 x 10(-3) to 8.7 x 10(-3)) for peripheral blood mononuclear cells, whereas 4 samples of mononuclear cells obtained from umbilical cord blood had PFs below 0.007 x 10(-3). A positive correlation was observed between the PF and serum antibody titers against EBV-associated nuclear antigen among the seropositive persons.

Antibodies, Viral↗

PubMed1993

Enhanced antitumor efficacy of a combination of CPT-11, a new derivative of camptothecin, and cisplatin against human lung tumor xenografts.

The objective of this study was to evaluate the antitumor efficacy of combined use of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and cisplatin (CDDP). The antitumor activities of CPT-11, CDDP and their combination against 3 human lung tumor xenografts were estimated using congenitally athymic BALB/c (nu/nu) mice. The doses were 47 mg/kg for CPT-11 and 6 mg/kg for CDDP on days 1, 5 and 9. In combination therapy, half of the single dosage of each agent was used. The doses were administered intraperitoneally. The antitumor activity and toxicity were evaluated in terms of the tumor volume and body weight change of mice, respectively. The combination therapy resulted in a statistically significant tumor regression compared to the use of only CPT-11 or CDDP in two tumor xenografts out of three. The toxicity of the combination therapy was no higher than that of CPT-11 or CDDP alone. These results suggest that the antitumor activity of the combination of CPT-11 and CDDP is superior to that of CPT-11 or CDDP alone.

Animals↗

PubMed1993

A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. The Japan Lung Cancer Photodynamic Therapy Study Group.

PURPOSE: A phase II study was conducted between June 1989 and February 1992 to evaluate the activity and toxicity of photodynamic therapy (PDT) with photofrin II in centrally located early-stage lung cancer and to determine the complete response (CR) rate as the primary end point. PATIENTS AND METHODS: Patients had histologically proven lung cancer and endoscopically superficial thickening or small protrusions. All lesions were located in subsegmental or larger bronchi. All patients had a performance status (PS) of 0 to 2 and arterial oxygen pressure tension (PaO2) > or = 60 mm Hg. No lymph node or distant metastases were present. All patients received photofrin II (2 mg/kg) intravenously 48 hours before PDT. Tumor lesions were superficially photoradiated by an argon dye laser or an excimer dye laser. RESULTS: Of 54 patients with 64 carcinomas, 51 with 61 carcinomas were eligible for toxicity evaluation and 49 with 59 carcinomas were assessable for response. Of the 59 assessable carcinomas, 50 (84.8%; 95% confidence interval, 73.0% to 92.8%) showed a CR after initial PDT. The median duration of CR was 14.0+ months (range, 2.0+ to 32.4+). The multiple regression model indicates that estimated length of longitudinal tumor extent was the only independent prognostic factor for CR (P = .002). Five carcinomas that had a CR had a local recurrence at 6, 10, 12, 16, and 18 months after initial PDT, respectively. Toxicity assessment (World Health Organization [WHO] grade 2) showed transient elevation of ALT (1.9%), pulmonary toxicity (7.7%), and allergic reaction (7.7%), as well as sunburn (1.9%). CONCLUSION: PDT with photofrin II has an excellent effect on patients with centrally located early-stage lung cancer who have limited tumor invasion extending over a small area (< or = 1 cm).

Aged↗

PubMed1993

Analysis of somatic cell mutations at the glycophorin A locus in atomic bomb survivors: a comparative study of assay methods.

The glycophorin A (GPA) assay for in vivo somatic cell mutations was performed on blood samples from 39 survivors of the atomic bomb at Hiroshima. Parallel analyses were performed at two laboratories using three different GPA assay methods to enumerate cells lacking expression of either the M- or N-allele of GPA. All assay methods yielded significant dose-dependent increases in hemizygous GPA variant cell frequencies (VFs) and smaller increases in homozygous VFs. The slopes of the fitted linear dose-response functions did not differ significantly among assay methods used in the present study, or from slopes obtained in a study reported previously. The version of the assay described most recently (BR6) appears best suited for future studies because the assay has a higher precision than earlier methods. Variant frequencies from different assay methods measuring the same variant cell type agreed with each other better than with the estimated dose, suggesting that the imprecision in the assay is not primarily responsible for VFs that differ from the fitted dose response. Consistent deviations from the dose response were seen for some individuals, suggesting either errors in dose estimates for these individuals or interindividual differences in susceptibility or other exposures. For the study population as a whole, however, discrepancies between assays for M-loss and N-loss variants suggest stochastic factors may have an important effect on individual VFs for A-bomb survivors.

Chromosome Mapping↗

PubMed1993

Study of the titers of anti-Epstein-Barr virus antibodies in the sera of atomic bomb survivors.

Antibody titers to Epstein-Barr virus antigens were determined in the sera of 372 atomic bomb survivors to evaluate the effect of the previous radiation exposure on immune competence against the latent infection of the virus. The proportion of persons with high titers (> or = 1:40) of IgG antibodies to the early antigen was significantly elevated in the exposed survivors. Furthermore, the distribution of IgM titers against the viral capsid antigen was significantly affected by radiation dose with an increased occurrence of titers of 1:5 and 1:10 in the exposed persons, although the dose effect was only marginally suggestive when persons with rheumatoid factor were eliminated from the analysis. These results suggest that reactivation of Epstein-Barr virus in the latent stage occurs more frequently in the survivors, even though this might not be affected by the radiation dose. Otherwise, there was neither an increased trend in the prevalence of high titers (> or = 1:640) of IgG antibodies to the viral capsid antigen among the exposed people nor a correlation between the radiation exposure and distributions of titers of IgA antibodies to the viral capsid antigen or antibodies to the anti-Epstein-Barr virus-associated nuclear antigen.

Adult↗

PubMed1993

[Systemic chemotherapy for brain metastasis from small cell lung cancer].

Small cell lung cancer (SCLC) is rapidly progressive, but is sensitive to chemotherapy. The incidence of brain metastasis is high in patients with this disease. The management of brain metastases is an important problem in SCLC patients, because brain tumors have been regarded as being inaccessible to anti-cancer agents due to the blood-brain-barrier (BBB). Of 15 SCLC patients with brain metastasis at diagnosis who were treated with chemotherapy, 3 achieved a complete response (CR) and 4 had a partial response (PR), giving a response rate of 47%. Of 17 SCLC patients with brain metastasis at relapse, 1 achieved a CR and 6 had a PR by chemotherapy, with a response rate of 30%. The response rate of brain metastasis in SCLC patients treated with chemotherapy was similar to those of primary lesions and other metastatic lesions. SCLC patients with brain metastasis at diagnosis had the same response rate and median survival time as other ED-SCLC patient. The BBB may not be an impending factor in systemic chemotherapy of brain metastasis in SCLC. Systemic chemotherapy may be the treatment of choice for SCLC patients with brain metastasis.

Adult↗

PubMed1992

Detection of large cell component in small cell lung carcinoma by combined cytologic and histologic examinations and its clinical implication.

BACKGROUND: In the classification recently proposed by the Pathology Committee of International Association for the Study of Lung Cancer, small cell lung carcinoma (SCLC) was divided into three subtypes: pure SCLC, mixed small cell/large cell carcinoma (mixed SC/LC), and combined SCLC. METHODS: To examine the clinical utility of this classification, histologic specimens, cytologic specimens obtained by brushing or fine-needle aspiration, and sputum cytologic specimens from 430 patients with SCLC were reviewed. RESULTS: When the subtype of SCLC was determined from the biopsy specimen, cytologic specimen obtained by brushing or fine-needle aspiration, and sputum cytologic specimen, the frequency of mixed SC/LC was 25 of 299 (8.4%), 75 of 400 (18.8%), and 8 of 232 (3.4%), respectively. Whatever the diagnostic method, patients with mixed SC/LC showed a poorer response to treatment and worse prognosis than those with pure SCLC: a median survival of 144 days versus 285 days when classified with the use of biopsy specimens; 160 days versus 275 days with cytologic specimens obtained by brushing or fine-needle aspiration; and 47 days versus 259 days with sputum cytologic specimens, respectively. CONCLUSIONS: These findings showed that mixed SC/LC should be separated from pure SCLC as a distinctive group and that cytologic studies of specimens obtained by brushing or fine-needle aspiration were sensitive and useful procedures for this purpose.

Adult↗

PubMed1992

Evidence for in vivo clonal proliferation of unique population of blood CD4-/CD8- T cells bearing T-cell receptor alpha and beta chains in two normal men.

Rare T lymphocytes bearing CD3 surface antigen and T-cell receptor (TCR) alpha and beta chains, but lacking both CD4 and CD8 antigens, viz, TCR alpha beta+CD4-8- cells, appear at a frequency of 0.1% to 2% in peripheral blood TCR alpha beta+ cells of normal donors. Here we report two unusual cases, found among 100 healthy individuals studied, who showed an abnormally elevated frequency of these T cells, ie, 5% to 10% and 14% to 19%. Southern blot analyses of the TCR alpha beta+CD4-8- clones all showed the identical rearrangement patterns for each individual, demonstrating that these are derivatives of a single T cell. The same rearrangement patterns were also observed for the freshly isolated lymphocytes of TCR alpha beta+CD4-CD8- fraction, which excludes the possible bias in the processes of in vitro cloning. These TCR alpha beta+CD4-8- T cells were found to express other mature T-cell markers such as CD2, CD3, and CD5 antigens, as well as natural killer (NK) cell markers (CD11b, CD16, CD56, and CD57 antigens) for both individuals. Further, although lectin-dependent or redirected antibody-dependent cell-mediated cytotoxicities were observed for both freshly sorted lymphocytes of TCR alpha beta+CD4-8- fraction and in vitro established clones, NK-like activity was not detected.

Antigens, CD↗

PubMed1992

A simple and rapid method for HLA-DQA1 genotyping by polymerase chain reaction-single strand conformation polymorphism and restriction enzyme cleavage analysis.

A simple and rapid method for identification of alleles at the human leucocyte antigen (HLA)-DQA1 locus is described. The polymorphic second exon of the HLA-DQA1 locus was amplified by the polymerase chain reaction (PCR) method. The amplified DNA was analyzed by single-strand conformation polymorphism (SSCP) and restriction enzyme cleavage assay. Using this method, the eight known DQA1 alleles could be distinguished from each other. This paper suggests that the method can be used for quick genotyping of DQA1 alleles, but detecting point mutations at various positions in a fragment as well as new HLA-DQA1 genotypes should also be possible.

Alleles↗

PubMed1992

Frequency of mutant T lymphocytes defective in the expression of the T-cell antigen receptor gene among radiation-exposed people.

The frequency of mutant T lymphocytes defective in T-cell receptor gene (alpha or beta) expression was measured using the 2-color flow cytometric technique. Results for a total of 203 atomic bomb survivors, 78 of whom were proximally exposed (DS86 doses of greater than or equal to 1.5 Gy) and 125 of whom were distally exposed (DS86 dose of less than 0.005 Gy), showed that the mutant frequency was significantly higher in males than in females. No significant dose effects were observed. In contrast, a significant increase of mutant frequency was observed for 6 patients treated with Thorotrast, a contrast medium containing thorium-232 formerly used for radioligands. In addition, thyroid disease patients treated with 131I showed a dose-related increase of mutant frequency. It was suggested that the present T-cell receptor mutation assay has a unique characteristic as a biological dosimeter for measurement of recent exposures to genotoxic agents.

Adult↗