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T Shinkai

Publications and source records attributed to T Shinkai.

At least 91 records · Page 5Linked to original sources
PubMed1993

[Phase II clinical trials in patients with lung cancer].

The goal of phase II clinical trials is to determine whether a new drug has activity against particular cancers. This trial, therefore, is the most important study in the process of development of investigational new agents and frequently may give misleading results. The design of phase II clinical trials of new anticancer agents in lung cancer has been reviewed based on the Guidelines for the Clinical Evaluation of Antineoplastic Agents notified by the Ministry of Health and Welfare in Japan. These guidelines present general approaches to clinical trials and should be adhered to in the development of investigational drugs in humans, although they are not directly mandated by law or regulations. We considered the policies of these guidelines and instituted them based on the actual circumstances in Japan, in order to develop a scientific and rational approach for clinical phase II trials. In addition, we introduced new active agents having a novel mechanism of action that show clinical activity in the treatment of lung cancer, such as irinotecan (CPT-11), a topoisomerase I inhibitor, and paclitaxel (taxol) and taxotere, targeting the microtubules.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Cytogenetic effects of CPT-11 and its active metabolite, SN-38 on human lymphocytes.

CPT-11, a new camptothecin analogue, has been demonstrated to be a promising antineoplastic agent. Late side effects of carcinogenicity and teratogenicity have been unclear from clinical phase I and II trials. In order to elucidate the carcinogenicity and teratogenicity of CPT-11, we have examined the cytogenetic changes in human peripheral blood lymphocytes induced by CPT-11 and its active metabolite, SM-38. We have also analyzed the correlation between chromosomal damage and acute clinical side effects. When peripheral blood lymphocytes obtained from a healthy donor were exposed to CPT-11, SN-38, cisplatin and mitomycin C, a significant dose-dependent increase of sister chromatid exchange (SCE) was obtained. The SCE frequency per cell cultured with 0.244 nM SN-38 was similar to that cultured with 100 nM CPT-11, 300-500 times the concentration of SN-38. A transient increase in SCE frequency was also observed in the peripheral blood lymphocytes of 11 cancer patients receiving 100 mg/m2 of CPT-11 intravenously, compared with pretreatment values (P = 0.0001). In addition, a significant correlation was observed between the frequency of SCE on day 3 and the degree of decrease in platelet count (P = 0.012). In conclusion, SN-38 might possibly have a high risk of mutagenicity and carcinogenicity; and measurement of SCE values in peripheral blood lymphocytes appears to have a potential application in the clinical prediction of chemotherapy-induced side effects.

Antineoplastic Agents, Phytogenic↗
PubMed1992

A prognostic-factor risk index in advanced non-small-cell lung cancer treated with cisplatin-containing combination chemotherapy.

Prognostic factors for response and survival were retrospectively evaluated in 192 previously untreated patients with advanced non-small-cell lung cancer (NSCLC) who had received either vindesine plus cisplatin or mitomycin plus vindesine plus cisplatin as initial treatment. Univariate analysis demonstrated that squamous-cell histology, early stage, and a small number of metastatic sites were favorable prognostic factors for response to chemotherapy. Multivariate analysis using Cox's proportional hazard model indicated that the number of metastatic sites was the only significant pretreatment factor for response (P = 0.0005). Multivariate regression analysis revealed that the number of metastatic sites (P = 0.0002), sex (P = 0.0009), serum albumen levels (P = 0.0018), performance status (P = 0.0026) and lactic dehydrogenase values (P = 0.0026) contributed independently to survival. On the basis of these five prognostic factors, a prognostic index for survival was used to define three prognostic groupings (good, intermediate, and poor) for survival (median survival, 16.5 vs 9.4 vs 4.6 months; P = 0.0001). This particular regression model should aid in the design and analysis of new treatment strategies and may be useful for indirect comparisons of different studies carried out in similar patient populations.

Adenocarcinoma↗
PubMed1992

Identification of the phenotypic modulation of rabbit arterial smooth muscle cells in primary culture by flow cytometry.

In atherosclerotic lesions, smooth muscle cells (SMC) change from a contractile to a synthetic phenotype. The in vivo and in vitro phenotypic transformations of SMC have been confirmed by transmission electron microscopy (TEM), but the relationship between this change and the cell cycle is still unknown. We demonstrated the structural modulation of rabbit arterial SMC in primary culture by TEM and immunocytochemistry and simultaneously studied changes in two-dimensional histograms of the relative DNA and RNA contents by flow cytometry. During the first day of primary culture, the cells exhibited the contractile phenotype and were composed of a population in the G0 phase characterized by low contents of DNA and RNA. On the second day of culture, some of the cells (18.2%) had started but not completed the transition into the synthetic phenotype and a cell population in the G1A phase with an RNA content above the G0 level appeared in almost the same proportion. This cell population could be categorized as an "intermediate" type. Moreover, after 3 days when about three-quarters of the cells had undergone structural transition, the same proportion of cells had entered into the cycling phase, while some cells still remained in the G0 and G1A phases. Thus, cell cycle analysis by flow cytometry corresponded well with the observations obtained by TEM and immunocytochemistry. These results show that flow cytometry can rapidly and relatively conveniently monitor the process of phenotypic modulation in SMC and is a useful method for the analysis of such transitions.

Animals↗
PubMed1992

Chemotherapy-induced anemia in patients with primary lung cancer.

To elucidate the factors which influence the value of hemoglobin, the nadir value of hemoglobin, frequency of blood transfusion and prognostic value of blood transfusion in patients with primary lung cancer during intensive chemotherapy, the hematological features of 124 patients entered into a randomized phase III study containing cisplatin were retrospectively analyzed. There was no difference in the percent nadir hemoglobin value of the first course of chemotherapy (% of pretreatment value) in any of the subgroups with respect to sex, body weight loss, performance status, age, stage, number of metastatic sites or treatment arms. The only predictive indicator for the nadir hemoglobin value in the first course of chemotherapy was the pretreatment value of hemoglobin. The equation for the regression line was y = 1.07 + 0.73x (R2 = 0.663, p < 0.001). The lowest nadir hemoglobin value (% of pretreatment value) during all chemotherapy courses was significantly lower in the subgroups older than 60 years and those with body weight loss. There was an inverse correlation between the accumulated dose of cisplatin and the lowest nadir hemoglobin value (p < 0.05). The frequency of blood transfusion in patients with more than two metastatic sites was significantly higher than in those with one or no metastatic sites (p < 0.05). Survival of patients who had required blood transfusion after chemotherapy was significantly shorter than that of patients who had not (p < 0.05).

Adult↗
PubMed1991

Phase I study and pharmacological analysis of cis-diammine(glycolato)platinum (254-S; NSC 375101D) administered by 5-day continuous intravenous infusion.

A phase I study of cis-diammine(glycolato)platinum (254-S; NSC 375101D) was conducted in 15 patients with refractory or relapsing malignancy by 5-day continuous i.v. infusion. Three to 5 patients per dose were given 50, 75, 87.5, or 100 mg/m2/120 h (10-20 mg/m2 daily for 5 days). Toxicity evaluation and pharmacokinetic analysis were performed in 15 and 14 patients, respectively. Thrombocytopenia and neutropenia were the dose-limiting toxicities at the maximum tolerated dose of 87.5 mg/m2/120 h (17.5 mg/m2/day); however, nonhematological toxicities including renal toxicity, nausea and vomiting, and peripheral neuropathy were mild and well tolerated. The nadir of platelets and neutrophils was observed 4 and 5 weeks, respectively, after the initiation of drug infusion. Plasma and urine samples were obtained during and after infusion for quantification by atomic absorption spectrophotometry of total and free platinum levels derived from 254-S. The maximum level of total platinum was obtained after 120 h of infusion, whereas the steady state concentration of free platinum in the patients given 75 mg/m2 or more was over 0.1 microgram/ml. Free platinum levels declined monophasically, with half-lives of 0.65-2.56 h/100 mg/m2 dose. The mean area under the concentration versus time curve (AUC) in the patients treated with 75 mg/m2 was 1069 micrograms/ml, which was similar to that obtained in the patients receiving 100 mg/m2 of 254-S by i.v. drip infusion over 30 min. There was a direct correlation between the dose administered and the AUC of platinum (R = 0.757, P = 0.002) or the steady state plasma concentration of free platinum (R = 0.763, P = 0.002). The percentage of platinum excreted in urine 144 h after the initiation of infusion ranged from 73.1 to 100% for each dose level. No significant relationship was established between creatinine clearance in patients before treatment and the AUC or steady state concentration of free platinum. The plasma platinum AUC showed a linear correlation with the percentage of change in leukocytes [formula: see text] (R = 0.736, P = 0.003). In conclusion, the recommended phase II dose for a continuous infusion of 254-S is 75.5 mg/m2/120 h every 6 hours.

Adult↗
PubMed1991

Growth hormone-releasing factor (GRF) suppresses the in vitro proliferation of mammotrophs from the adult rat.

In order to examine the hypothalamic control of acidophilic proliferation, anterior pituitary cells from adult female rats were cultured with or without rat growth hormone-releasing factor fragment 1-29 (GRF-29). Changes in the numbers of mammotrophs and somatotrophs during culture were measured by immunocytochemical staining. The addition of GRF suppressed the increase in the number of mammotrophs even at the very low concentration of 10(-12) M. The number of somatotrophs increased in the medium containing GRF. The increase in mammotroph number was blocked by cytosine arabinoside, a mitotic inhibitor. GRF had no effect on the in vitro proliferation of fibroblasts. These results indicate the important role of hypothalamic GRF in the differential growth and secretion of the acidophils in vivo.

Animals↗
PubMed1991

Altered cellular responses to serum mitogens, including platelet-derived growth factor, in cultured smooth muscle cells derived from arteries of patients with moyamoya disease.

Progressive stenosis or occlusion of bilateral internal carotid arteries by fibrocellular intimal thickening results in cerebral ischemia in moyamoya disease. The etiology is unknown. We examined cultured arterial smooth muscle cells (SMC) from scalp arteries of five patients with moyamoya disease. In this study we investigated the responsiveness of the cells in culture to serum mitogens including platelet-derived growth factor (PDGF), a major mitogen of SMC, and compared the response to that of cells derived from age-matched control patients. SMC from patients with moyamoya disease proliferated less rapidly in a medium with 15% serum than did control SMC and responded poorly to the addition of PDGF to 5% serum. PDGF alone did not stimulate SMC in a quiescent state to initiate DNA synthesis in moyamoya disease, without serum factors other than bovine serum albumin, though it significantly stimulated the controls. Simultaneous additions of epidermal growth factor, insulin-like growth factor-I, and PDGF stimulated initiation of DNA synthesis in cells from moyamoya disease, but not as much as PDGF alone did in the controls. Although direct correlations with the pathogenesis of the disease remain to be clarified, the results indicate altered interrelations between serum factors and the cellular responses in vessels of moyamoya disease.

Adolescent↗
PubMed1991

Prediction of the antitumor activity of new platinum analogs based on their ex vivo pharmacodynamics as determined by bioassay.

We report the predictive model for the clinical response of new platinum analogs against lung cancer by a bioassay using human lung-cancer cell lines including small-cell (SCLC) and non-small-cell lung cancer (NSCLC). Exponentially growing cells of six different SCLC and six NSCLC lines were exposed to different concentrations of the three platinum compounds, cisplatin, carboplatin, and 254-S in a double-agar colony-forming cell assay. The concentrations inhibiting 50% of colony formation (IC50 value) for cisplatin, carboplatin and 254-S in SCLC cell lines were significantly lower than those in NSCLC cell lines. A total of 15 patients entered the pharmacological study. In all, 80 mg/m2 cisplatin, 450 mg/m2 carboplatin, and 100 mg/m2 254-S were each given to five patients by intravenous drip infusion. Bioassay as well as chemical assay was achieved by clonogenic techniques using NCI-H-69 (SCLC cell line) and PC-9 (NSCLC cell line) as target cells. Biological comparison of antitumor activity was performed on the basis of the antitumor activity of patients' plasma using the antitumor index (ATI), which was defined as the area under the percentage of colony suppression versus time curve obtained by bioassay and calculated by the trapezoidal rule. When NCI-H-69 and PC-9 were used as target cells for bioassay, colony-inhibitory activity was revealed by the ATIs. The ATIs obtained by bioassay showed better correlation than the AUCs obtained by chemical assay with the clinical response for cisplatin and carboplatin against SCLC and NSCLC, according to the following equation: [Reported Response (%)] = 11.5668 + 0.0014 x [ATI] (r = 0.97). The response rates for 254-S against SCLC and NSCLC were predicted by this formula to be 40%-65% and 14%-16%, respectively. 254-S is prospectively suspected of having the same, if not more, activity then carboplatin against SCLC and of having almost the same activity as cisplatin against NSCLC.

Antineoplastic Agents↗
PubMed1991

Y/6 chromosome translocation in a male with triple primary cancers involving the breast.

Cytogenic studies were performed in a 72-year-old male patient with triple primary cancers including breast, skin and lung. Left breast cancer was diagnosed at the age of 46 and he received mastectomy and thoracic irradiation. Squamous cell carcinoma and Bowen's disease were diagnosed from two separated parts of a skin lesion at the age of 70. Small-cell lung cancer was diagnosed 1 year later, and he received chemotherapy and radiotherapy. Chromosome analysis was carried out on both peripheral lymphocyte and skin fibroblast cultures at the age of 72. Out of 30 fibroblast cells karyotyped at the second passage, 7 cells (23%) consistently showed a reciprocal translocation t(Y;6)(q12;p21). The same translocation was found in one of 200 cells from lymphocyte cultures. The findings suggest that the translocation t(Y;6) might be inherent in nature, and that the patient was a mosaic of 46,XY/46,X,t(Y;6)(q12;p21). These results highlight the constitutional chromosomal abnormality as one of the possible high-risk factors for multiple primary cancers.

Breast Neoplasms↗
PubMed1991

A randomised clinical trial of vindesine plus cisplatin versus mitomycin plus vindesine and cisplatin in advanced non-small cell lung cancer.

This trial was carried out to evaluate the therapeutic benefit of the addition of mitomycin to vindesine plus cisplatin (80 mg/m2) in 126 previously untreated non-small cell lung cancer (NSCLC) patients. 124 patients were evaluable for toxicity and survival and 122 for response. No patient achieved complete response. The partial response rate (PR) in the vindesine plus cisplatin (VP) and mitomycin plus vindesine and cisplatin (MVP) groups were 23% (14/62) vs. 35% (21/60) (P = 0.13) with a median duration of response of 23 vs. 37 weeks (P = 0.071), respectively. Time to progression (TTP) and survival time (ST) were similar for both treatment arms [median TTP; 14 vs. 21 weeks (P = 0.10), median ST; 9.1 vs. 10.5 months (P = 0.94), respectively]. No difference in the frequency of side-effects was observed except that WHO grade 3 and 4 leukopenia was higher in the MVP group. In multivariate analysis, the significant predictors of survival were serum albumin, sex, performance status, lactate dehydrogenase and stage. In conclusion, the addition of mitomycin to the VP regimen appears to have limited value in advanced NSCLC.

Adult↗
PubMed1991

Late toxicities and complications in three-year survivors of small cell lung cancer.

123 patients with small cell lung cancer (SCLC) presented to the National Cancer Center Hospital (Tokyo) between 1978 and 1986. 22 of 71 patients with limited stage disease (LD) and none of 52 patients with extensive disease (ED) survived for 3 years. 15 of the 22 three year survivors had significant late complications. All patients received chemotherapy and either thoracic irradiation, resection or both. No prophylactic cranial irradiation was given. 4 patients developed cardiac failure, 2 with a dilated cardiomyopathy, despite the fact that no patient received over 420 mg/m2 of doxorubicin. 12 patients of the 17 who received thoracic irradiation developed radiation pneumonitis and 3 required hospitalisation for severe haemoptysis (2) or cavity formation (1). 1 patient who received nimustine developed a fatal myelodysplastic syndrome and 2 additional patients developed second primary tumours in the oesophagus (1) and stomach (1). Mild peripheral neuropathy (WHO grade 1) was persistent in 3 patients and asymptomatic azotemia (WHO grade 1) in 7. Despite advances in the treatment of SCLC there are very few asymptomatic long-term survivors.

Adult↗
PubMed1991

A retrospective analysis of patients receiving surgery after chemotherapy for small cell lung cancer.

From 1984 to 1989, 20 of 142 patients with small cell carcinoma of the lung received surgery after intensive chemotherapy alone or chemotherapy combined with thoracic irradiation. All patients giving informed consent and having an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 were included in the present retrospective study. Ages ranged from 37-74 (median 58) years. All patients received 1-10 cycles of chemotherapy intravenously every three or four weeks (PVP: 80 mg cisplatin/m2, 100 mg etoposide/m2 x 3; CAV: 800 mg cyclophosphamide/m2, 50 mg doxorubicin/m2, 1.4 mg vincristine/m2, and other combinations) and were evaluated for surgery 1-27 months after the initial systemic chemotherapy. Clinically, two, three, eleven and for patients were diagnosed as having stages I, II, III and IV disease, respectively at the beginning of treatment. At the time of reevaluation after chemotherapy or chemotherapy plus chest radiotherapy there were one (5%) complete responder, 17 (85%) partial responders, and two (10%) with stable disease. Twenty patients underwent thoracotomy consisting of nine lobectomies and 11 pneumonectomies. Eighteen of the 20 had resectable lesions. According to postoperative pathological findings, there were six, one, seven and two patients with stages I, II, III and IV disease, respectively. In two patients no tumor was demonstrated pathologically. Small cell carcinoma was detected in 15 specimens and three had non-small cell carcinoma. Two of the 20 patients survived for more than five years. The median survival of the 20 patients was 22 months. It would appear that resection is applicable in only a selected subset of patients with small cell carcinoma of the lung.

Adult↗
PubMed1991

Analysis of three-year survivors among patients with advanced inoperable non-small cell lung cancer.

Among 238 patients with advanced inoperable non-small cell lung cancer (NSCLC), we evaluated the characteristics of three-year survivors and analyzed them to determine whether or not there were any specific pretreatment prognostic factors which could make it possible to discriminate this group the rest. All patients received chemotherapy according to the protocol for phase II or III trials at the National Cancer Center, Japan, between 1980 and 1987. Eighteen (8%) patients survived for over three years. Five of the 18 responded to initial therapy, seven received thoracic irradiation and five surgical resection after chemotherapy. No patient achieved a complete response by chemotherapy. Among five disease-free survivors, two received surgery after completion of chemotherapy. Their clinical stage was IIIA. Three patients received radiation therapy, but they could not be evaluated. Although some radiologically detectable shadows remained, these patients survived for more than three years with no active lesion, indicating the difficulty in diagnosing a complete response to treatment. Thirteen patients survived for more than three years with disease. Some unknown biological factors might influence survival in this group. Pulmonary fibrosis, as treatment toxicity, was observed in six of the 18. The pretreatment prognostic factors that discriminated three-year survivors from the rest were Eastern Cooperative Oncology Group performance status (PS) (P = 0.0015), clinical T factor (P = 0.0093), and serum LDH (P = 0.0317) by means of univariate analysis, and PS (P = 0.0134) and clinical T factor (P = 0.0117) by means of multivariate analysis with a logistic regression procedure.

Adult↗
PubMed1991

The frequency and management of infectious episodes and sepsis in small cell lung cancer patients receiving intensive chemotherapy with granulocyte-colony stimulating factor.

The relation between degree of myelosuppression and episodes of infection was analyzed in 36 patients (92 treatment courses) with small cell lung cancer (SCLC) treated with intensive chemotherapy. The two regimens used were cisplatin (CDDP) + adriamycin (ADR) + cyclophosphamide (CPA) + etoposide (VP-16) + granulocyte-colony stimulating factor (G-CSF) and CDDP + teniposide (VM-26) + G-CSF, and they induced grade 3 or 4 leukopenia in 88% of treatment courses and febrile episodes in 60%. In the febrile courses, the mean nadirs of leukocyte and neutrophils (820 +/- 581/mm3, 101 +/- 267/mm3) were significantly longer (P less than 0.01) and the mean durations of grade 3 and 4 leukopenia and neutropenia significantly longer (P less than 0.001) than those of the non-febrile courses. It was noted, however, that febrile episodes appeared frequently in courses having the nadir of leukocytes below 1,000/mm3 (80%) or the nadir of neutrophils below 100/mm3 (74%). The administration of antibiotics was required for about 7 days to patients with febrile episodes. Sepsis was experienced in five courses, in which the neutrophils were all zero. All the patients, however, could be managed by an administration of antibiotics immediately after a febrile episode appeared, without delaying the subsequent chemotherapy except for one patient, who had had a performance status (PS) of 3 prior to chemotherapy.

Adult↗
PubMed1991

[The relation between myelotoxicity and performance status or aging in chemotherapy of non-small cell lung cancer].

One hundred eighty six patients of non-small cell lung cancer treated with cisplatin-based chemotherapy were analyzed. Significant incidence of anemia was observed in PS 2-3 patients as compared to PS 0-1 cases. Incidence of thrombocytopenia was significant in cases 70 or more years old as compared those less than 50 years old. No correlation was detected between myelotoxicity and aging.

Aged↗
PubMed1990

Heterogenous amplification of myc family oncogenes in small cell lung carcinoma.

One hundred forty-two foci of small cell lung carcinoma (SCLC) from 47 patients were examined for amplification of myc family oncogenes (c-myc, N-myc, and L-myc), by dot blot hybridization using formalin-fixed and paraffin-embedded materials which were resected surgically or obtained at autopsy. Some selected patients were also examined by in situ hybridization. Amplification of myc family genes was detected in 11 patients (23.4%) (c-myc in one, N-myc in five, and L-myc in five). Two of the 11 patients (one with N-myc and one with L-myc) had heterogenously amplified clones. In the patient with N-myc amplification, amplification was detected in metastatic tumors in the pancreas, lung, and pleura, but not in the liver and lymph node metastases. In the primary tumor, areas with and without N-myc amplification were seen. In the patient with L-myc amplification, although amplification was not detected in the surgically resected primary lesion, mediastinal lymph node metastatic lesions obtained at autopsy showed L-myc gene amplification. These two cases, together with previously reported evidence, suggest that myc gene amplification plays an important role in malignant progression, rather than development, of SCLC. In Stage III and IV groups, patients with over ten-fold myc gene amplification were suggested to survive for a shorter time than patients without such amplification (P = 0.06).

Aged↗