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Biomedical subjects

T Ohtsu

Publications and source records attributed to T Ohtsu.

At least 37 records · Page 2Linked to original sources
PubMed1998

Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma. The IDEC-C2B8 Study Group.

BACKGROUND: In clinical trials in the USA, IDEC-C2B8 (a mouse-human chimeric anti-CD20 monoclonal antibody) has demonstrated high response rates with only mild toxic effects in relapsed B-cell lymphoma at a dose of four weekly 375 mg/m2 infusions. The aim of the present trial was to determine whether or not this dose is practically applicable to Japanese patients with relapsed B-cell lymphoma with respect to safety, pharmacokinetics and efficacy. PATIENTS AND METHODS: Patients with relapsed CD20+ B-cell lymphoma received intravenous infusions of IDEC-C2B8 once a week for four weeks. A total of 12 patients (four at 250 mg/m2 and eight at 375 mg/m2) were enrolled. RESULTS: All 11 eligible patients treated with either dose level tolerated IDEC-C2B8 well. Commonly observed adverse drug reactions were grades 1 or 2 non-hematologic toxicities during the infusion, consisting mostly of flu-like symptoms and skin reactions. All of the observed hematologic toxicities were of grade 3 or less, and transient. A rapid and sustained B-cell decrease in peripheral blood was observed, but no infectious episodes were encountered. Human anti-mouse and anti-chimeric antibodies were not detected. Of the 11 eligible patients (eight with follicular, two with diffuse large-cell and one with mantle cell lymphoma), two showed a complete response and five showed a partial response, and all of the seven responders had lymphoma with follicular histology. A pharmacokinetic analysis showed that the elimination half-life (T1/2) of IDEC-C2B8 was 445 +/- 361 hours, and that the serum antibody levels increased in parallel with the course of infusions, and in most patients was still measurable at three months. CONCLUSIONS: The dose of four weekly 375 mg/m2 infusions of IDEC-C2B8 is safe and effective in Japanese patients with relapsed B-cell lymphoma. Further studies evaluating IDEC-C2B8 are warranted.

Adult↗
PubMed1998

A phase I trial of docetaxel and 5-day continuous infusion of 5-fluorouracil in patients with advanced or recurrent breast cancer.

To determine the maximum-tolerated doses (MTDs), the dose-limiting toxicities (DLTs) and the recommended doses for further trials of docetaxel in combination with a 5-day continuous infusion of 5-fluorouracil (5-FU) in advanced or recurrent breast cancer patients who had been treated previously with at least one chemotherapeutic regimen, patients were treated with docetaxel as a 1-h infusion on day 1 followed by 5-FU as a continuous infusion on days 1 through 5 every 3-4 weeks. Three or six patients were assessed at the following escalating dose levels of docetaxel/5-FU per day: 40/150, 40/300, 50/300, 50/500 and 60/500 mg m(-2). Nineteen patients entered this trial, of whom 18 could be assessed for adverse event and therapeutic efficacy. The DLTs were neutropenia and diarrhoea. The MTDs were 60 mg m(-2) of docetaxel on day 1 and 500 mg m(-2) per day of 5-day continuous infusion of 5-FU. One of 18 patients achieved a complete response and eight achieved partial response (over all response rate: 50%). The recommended doses of docetaxel and 5-day continuous infusion of 5-FU for a phase II trial are 50 mg m(-2) and 500 mg m(-2) per day every 3 or 4 weeks.

Adult↗
PubMed1998

Acute myelogenous leukemia with monosomy 7, inv(3) (q21q26), involving activated EVI 1 gene occurring after a complete remission of lymphoblastic lymphoma: a case report.

A 42-year-old female with a mediastinal tumor and massive pleural effusion ws admitted to our hospital in June 1993. Biopsy revealed lymphoblastic lymphoma. She had no evidence of distant metastasis except pleural effusion. Bone marrow examination revealed a normal karyotype (46, XY). The patient had been progression-free for more than 1 year after achieving complete remission by induction, consolidation and maintenance therapy according to the standard chemotherapy and involved-field radiation for lymphoblastic lymphoma. From May 1996 progressive leukopenia and thrombocytopenia developed. The diagnosis of refractory anemia with excess of blasts (RAEB) was made. Subsequently, in November 1996, she developed acute myelogenous leukemia (AML), M4 type by FAB classification. The karyotype of MDS and AML clones involved inversion (3) (q21q26) and monosomy 7. The EVI 1 gene was examined and was proved to be rearranged and activated. This may be the first case among the therapy-related cases of MDS/AML reported whose karyotypes were followed and in which the mRNA expression of EVI 1 gene involved was directly proved in the leukemogenesis process of chemotherapy-induced secondary MDS and AML.

Chromosome Inversion↗
PubMed1998

Determination of cytosol c-erbB-2 protein in breast cancer by sandwich enzyme immunoassay.

We determined cytosol c-erbB-2 protein levels using a sandwich enzyme immunoassay in benign breast disease and primary and recurrent breast cancer and analyzed the relationship between c-erbB-2 protein levels and clinicopathological factors. Overexpression of c-erbB-2 protein, the cut-off value being set at 18 ng/mg protein, was observed in 26 of the 139 cases of stages I-IIIB breast cancer (18.7%), four of the 12 cases of stage IV breast cancer (33.3%) and seven of the 13 recurrent breast cancer cases (53.8%). The levels of c-erbB-2 protein were significantly different between the stages. Overexpression of c-erbB-2 protein in stages I-IIIB breast cancer was associated with histological grade and serum CEA level, but not with other clinicopathological factors. In addition, there was an inverse correlation in the group of stages I-III plus IV breast cancer between c-erbB-2 protein expression and estrogen receptor status. Overexpression of c-erbB-2 protein can be easily determined in the cytosol fraction together with hormonal receptor by this method. The prognostic importance will be evaluated in ongoing adjuvant trials for operable breast cancer patients.

Breast Diseases↗
PubMed1998

Successful treatment by radiation and hormone therapy of isolated local recurrence of breast cancer 24 years after mastectomy accompanied by immune thrombocytopenia: a case report.

We report a case of isolated local recurrence of breast cancer, which was accompanied by idiopathic thrombocytopenic purpura (ITP) and benign monoclonal gammopathy that presented 24 years after the patient underwent mastectomy. A 72-year-old female patient with a chest wall tumor was referred to our hospital in November 1994. Twenty-four years previously she had surgically treated breast cancer, of which the pathology was scirrhous carcinoma. Needle biopsy of the tumor revealed tubular carcinoma, which is compatible with local recurrence of breast cancer. She had no evidence of regional lymph node involvement or distant metastasis. Hematological and serological examination revealed a low platelet count accompanied by M-proteinemia (IgG, kappa-type) and a mild increase in platelet-associated IgG. She was initially treated with extensive-field chest wall radiation (60 Gy), followed by systemic administration of tamoxifen. Complete local control of isolated local recurrence (LR) was achieved after radiation therapy (RT) and the patient has been progression-free for more than 2 years. Platelet count recovered gradually to a normal level after achievement of complete remission induced by radiation and tamoxifen. This may be the first case suggestive of a paraneoplastic syndrome of immune thrombocytopenia accompanied by local recurrence of breast cancer.

Adenocarcinoma↗
PubMed1998

Successful treatment with nedaplatin in patients with ovarian cancer that recurred after platinum-containing chemotherapy: report of two cases.

We report the successful treatment with nedaplatin of two cases of ovarian cancer that recurred after platinum-containing chemotherapy. A 52-year-old woman presented in June 1994 with massive accumulation of ascitic fluid. Pathological diagnosis of the specimen obtained at surgery in July 1994 was serous papillary adenocarcinoma of the ovary. In September 1995, approximately seven months after the completion of six cycles of CAP chemotherapy (cyclophosphamide, adriamycin and cisplatinum), she was referred to our hospital because of massive accumulation of ascitic fluid. The carbohydrate antigen 125 (CA-125) value was 485 U/ml. Cytologic study of her ascitic fluid was positive for adenocarcinoma cells. She did not respond to intravenous irinotecan and two cycles of intraperitoneal cisplatin. Nedaplatin 100 mg/m2 was administered. Complete response was achieved in September 1996 and continued for four months with a total of seven cycles of nedaplatin. The second case was a 60-year-old woman who was admitted to our hospital in December 1994 because of ascitic fluid. Diagnosis of ovarian cancer was based on an elevated level of CA-125 (1380 U/ml). Treatment with CAP and CC (cyclophosphamide and carboplatin) maintained a partial response for seven months. In August 1996, her disease progressed, although she was receiving CC therapy. Nedaplatin 100 mg/m2 was administered. Partial response was achieved again in November 1996 and continued for four months, with a total of five cycles of nedaplatin. In the light of our experience, treatment with nedaplatin in a patient with recurrent ovarian cancer might be worthwhile as palliative chemotherapy.

Adenocarcinoma, Papillary↗
PubMed1998

Unexpected hepatotoxicities in patients with non-Hodgkin's lymphoma treated with irinotecan (CPT-11) and etoposide.

BACKGROUND: Irinotecan (CPT-11) is a topoisomerase I inhibitor that has been confirmed to be active against a broad spectrum of neoplasms including non-Hodgkin's lymphoma (NHL). Because the combination of topoisomerase I and II inhibitors seemed to be an attractive therapeutic strategy owing to their complementary functions, we conducted a combination phase I study of CPT-11 and etoposide, a topoisomerase II inhibitor, in relapsed or refractory non-Hodgkin's lymphoma (NHL). METHODS: The starting doses of CPT-11 and etoposide were 30 mg/m2/day (days 1-3 and 8-10) and 40 mg/m2 (days 1-3), respectively. RESULTS: All three patients who received the starting dose developed dose-limiting toxicities including one case of grade 4 neutropenia lasting for > 7 days, one of grade 3 serum transaminase elevation and one of grade 3 hyperbilirubinemia. All three patients presented hepatotoxicity > or = grade 2. The starting dose level was judged to be the maximum tolerated dose (MTD) and further dose escalation of this combination was halted. The patient who developed grade 3 hyperbilirubinemia presented a second peak of plasma SN-38, an active metabolite of CPT-11, on the concentration-time curve for day 3, suggesting the possibility of the enterohepatic circulation of SN-38 and of a drug-to-drug interaction. No durable objective response was observed in the three patients treated at the starting dose. CONCLUSIONS: We conclude that etoposide is not recommended for combination with CPT-11 in NHL patients because of unexpected frequent hepatotoxicities.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

[Gastric lymphoma--a case report].

A 24-year-old male patient with a history of gastric ulcer was referred to our hospital in September 1995. His chief complaints were epigastralgia and weight loss of 3 kg during a short period. The upper G.I endoscopy performed on 9/22/1995 revealed multiple ulcers with a histological diagnosis of atypical lymphoid cell proliferation. Follow-up endoscopy, one month later, showed an appearance of superficial gastric lymphoma, and histology of the biopsy specimen revealed MALT lymphoma associated with H. pylori. Despite an eradication therapy for H. pylori, which consisted of lansoprazole, teprenone and amoxicillin, the progression of the ulcerative lesions was observed on the endoscopy two weeks after initiation of the treatment. However, the subsequent endoscopy, one month later, disclosed a regression both macroscopically and histologically. The lymphoma disappeared completely on the follow-up endoscopy in April 1996 with no lymphoma cells in histology. No recurrences of the lymphoma have been observed up to now.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1997

Patients in phase I trials of anti-cancer agents in Japan: motivation, comprehension and expectations.

We attempted to characterize the motivation, comprehension and expectations of patients who had given informed consent to participate in phase I trials of anti-cancer agents at the National Cancer Center of Japan. Thirty-three patients were given a simple multiple-choice questionnaire and asked to return it at a later date. The completed survey was returned by 32 patients. The patients were surveyed before they had received any investigational phase I agents. Nineteen per cent of patients were motivated to participate in the phase I trials by the possibility of therapeutic benefit, 9% because participation seemed a better choice than no treatment and only 6% for altruistic reasons. Most patients comprehended the major features of a phase I trial, namely its investigational nature, the unknown effects of the agent investigated and the unclear benefit to the patients themselves. Fifty-nine per cent of the patients anticipated that they might suffer severe or life-threatening side-effects if they participated in the phase I trial, and 43% were able to indicate accurately the purpose of the phase I trial as a dose determination study. Although only a minority of the patients indicated that their motivation to participate was possible treatment benefit to themselves, when answering questions regarding expectations, more than half indicated that there might be personal benefits of varying degrees by participation.

Antineoplastic Agents↗
PubMed1996

A case of extragonadal germ cell tumor with elevated postchemotherapy HCG successfully treated by resection of a solitary metastasis and chronic oral etoposide.

We report a 39 year-old man with disseminated extragonadal germ cell tumor (GCT), whose serum level of human chorionic gonadotropin (HCG) increased again after platinum-based combination chemotherapy, high-dose chemotherapy with autologous bone marrow rescue and radical adjunctive surgery. The increase in the HCG level was progressive in spite of multiple chemotherapy, and after a while, a coin lesion in the right lung was identified by chest roentgenography. The pulmonary lesion was refractory to additional chemotherapy. After a systemic survey to confirm that the lesion was solitary, video-assisted thoracoscopic wedge resection of the right lower lobe was performed. Because the resected tumor included viable tumor cells and the serum HCG level remained slightly high one month after the operation, oral low-dose etoposide was begun. In a short time, the level of the serum tumor marker decreased and remained normal during the subsequent 7 months of therapy and thereafter. The patient remains in complete remission 13 months after completion of the final therapy and 3 years after the initial diagnosis. Even if the level of a serum tumor marker is high, salvage resection can be a promising therapeutic option for operable tumors that are refractory to chemotherapy. The usefulness of chronic oral etoposide for patients with GCT should be examined by further clinical trials.

Administration, Oral↗
PubMed1996

Recurrent breast cancer treated successfully with mitomycin-C and vinblastine after failure of both doxorubicin-containing regimen and paclitaxel--a case report.

Cross-resistance is one of the chief obstacles in salvage therapy for refractory breast cancer. Although paclitaxel is one of the most promising drugs, it shows a response rate of 30% at most for patients with breast cancer resistant to doxorubicin, and no effective treatments for tumors refractory to both agents have been reported. We describe a 38-year-old woman with recurrent breast cancer, who was treated successfully with mitomycin-C and vinblastine after doxorubicin-based chemotherapy and paclitaxel failed. The combinations of mitomycin-C and microtubule inhibitors including vinca alkaloids and taxanes may have a potential application to refractory breast cancer.

Adenocarcinoma, Scirrhous↗
PubMed1996

[Tumor markers in lymphoproliferative disorders].

The tumor markers detected in patients' peripheral blood with lymphoproliferative disorders, especially malignant lymphomas were reviewed and classified as follows: I) Biochemical marker and reactive protein, II) Cytokine and soluble cytokine receptor, III) Soluble form of tumor-surface marker, IV) Circulating tumor and V) Others. They were reported to be useful to predict the prognosis, to monitor the effects of the treatment, to detect minimum residual disease and to diagnose early relapse. At present clinical practice, non-specific tumor markers such as LDH, ESR, CRP and beta 2-MG are generally used. In the future when the convenient methods of biological assays including molecular biology-technique are developed, it will be possible to detect the specific tumor markers in clinical setting.

Biomarkers, Tumor↗
PubMed1995

Pharmacological correlation between total drug concentration and lactones of CPT-11 and SN-38 in patients treated with CPT-11.

The pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were examined to establish the pharmacokinetic variability of the active lactones of CPT-11 and SN-38 in comparison with that of the total (lactone and carboxylates) plasma CPT-11 and SN-38. Twelve patients with malignancies were entered in the study. All received 100 mg/m2 of CPT-11 by intravenous drip infusion over 90 min. Blood was sampled at 10 time points in heparin-containing syringes. Analysis by high-performance liquid chromatography showed that the ratio of CPT-11 lactone to total CPT-11 concentration was highest (66%) just after the end of infusion and gradually decreased to 30% at 24 h. Almost 70% of SN-38 lactone was detected after the end of infusion and this decreased to 50% within 24 h. The standard errors of percent lactone of CPT-11 of SN-38 to total drug concentration at each sampling point were less than 12%. The area under the concentration-time curve (AUC) of total CPT-11 and that of total SN-38 were significantly correlated with the AUCs of the lactone CPT-11 and those of lactone SN-38, respectively. We conclude that, for practical purposes, monitoring of total CPT-11 and SN-38 has essentially the same clinical significance as monitoring of lactone CPT-11 and SN-38.

Adult↗
PubMed1995

A limited sampling model for estimating pharmacokinetics of CPT-11 and its metabolite SN-38.

The objective of this study was to develop a limited sampling model (LSM) to estimate the area under the curve (AUC) of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and that of 7-ethyl-10-hydroxycamptothecin (SN-38) as predictive pharmacokinetic variables for leukopenia and episodes of diarrhea induced by CPT-11 administration. The model was developed with a training set consisting of pharmacokinetic studies in 36 patients who received a 90-min i.v. infusion of CPT-11 at a dose of 100 mg/m2. A multiple regression analysis of CPT-11 or SN-38 concentrations observed at each time point in the training set was used to predict the AUC of CPT-11 or SN-38. The final sampling models using only two time points were: AUCCPT-11 = 3.7891*C2.5 + 14.0479*C13.5 + 1.5463 AUCSN-38 = 0.5319*C2.5 + 19.1468*C13.5 + 72.7349 where C2.5 and C13.5 are the plasma concentration of CPT-11 (micrograms/ml) or SN-38 (ng/ml) at 2.5 and 13.5 h after the initiation of CPT-11 infusion, respectively. The models were validated prospectively on a separate test data set of 12 patients receiving the same dose of CPT-11 investigated in a previous study. Validation of the final LSM on the test data set gave values of root mean square error (RMSE) of 12.72% and 5.97% for the AUC of CPT-11 and that of SN-38, respectively. The model can be used to monitor the AUCs of both CPT-11 and SN-38 for the early prediction of toxicities and to establish a pharmacokinetically based dose modification strategy for safe administration of CPT-11.

Adult↗
PubMed1995

The confusion associated with breast cancer chemotherapy in Japan: the first year's experience at the Division of Oncology and Hematology, National Cancer Center Hospital East.

The current status of breast cancer chemotherapy in Japan was examined and compared with internationally accepted standard therapy, by reviewing the previous treatment of patients with advanced or metastatic breast cancer who had been referred to the National Cancer Center Hospital East. Forty patients were referred mainly from middle-sized or large hospitals between July 1992 and June 1993. The most commonly used regimen for adjuvant therapy was a combination of long-term and oral low-dose fluoropyrimidine compounds (LDFU), which is rarely used in Western countries, and tamoxifen. Some patients had received perioperative intravenous mitomycin C. The adjuvant polychemotherapy most commonly used internationally has been given to only a few patients. The first-line treatment for advanced or metastatic disease in the previous hospitals varied, but myelosuppressive chemotherapy including anthracyclines was given to half of the patients. Oral LDFU was also used for some patients alone or in combination as the first-line chemotherapy. Local therapy for metastasis to soft tissue was performed in 9 patients. Oral LDFU therapy that is frequently used for cancer treatment in Japan should be evaluated in a well designed controlled trial.

Adult↗
PubMed1995

Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion.

The present study was conducted to compare the pharmacokinetics and pharmacodynamics (PD) of paclitaxel between Phase I trials of 3- and 24-h infusions and to determine the most informative pharmacokinetic parameter to describe the PD. Twenty-seven patients were treated in a Phase I study of paclitaxel by a 3-h infusion at one of six doses: 105, 135, 180, 210, 240, and 270 mg/m2. Pharmacokinetic data were obtained from all patients. Paclitaxel concentrations were measured in the plasma and urine using HPLC. The pharmacokinetics and PD were compared with those of a Phase I trial of paclitaxel by a 24-h schedule previously performed. The maximum tolerated dose of paclitaxel by a 3-h infusion was determined to be 240 mg/m2. The major toxicities were granulocytopenia, neuromuscular toxicities, and hypotension. Apparent differences in pharmacodynamic relationships for the change in granulocytes with dose, peak concentration, and areas under the concentration versus time curve were observed between the 3- and 24-h schedules. However, the relationship between the duration of plasma concentration above 0.05 microM and the change in granulocytes could be fitted to the same sigmoid maximum effect model in either schedule (P < 0.01). There were no clear relationships between peripheral neuropathy or hypotension and any pharmacokinetic parameters. The pharmacokinetics and PD of paclitaxel were schedule dependent. The duration of plasma concentration above 0.05 microM could be a common pharmacokinetic parameter predicting granulocytopenia for both schedules.

Agranulocytosis↗
PubMed1994

Therapeutic response and potential pitfalls in phase I clinical trials of anticancer agents conducted in Japan.

The published reports of phase I clinical trials of anticancer agents conducted in Japan from 1981 to 1991 were reviewed. A total of 56 clinical studies that evaluated 38 different agents were reviewed. An average of five agents were studied each year. A total of 2200 patients had been recruited into the 56 clinical trials conducted during this period. A total of 91 patients (4.1%) responded to the treatment, with 23 showing a complete response (1.1%) and 48, a partial response (2.2%). In all, 62% of the responses were observed when patients were treated with doses ranging from 76% to 125% of the recommended doses for phase II studies. The response rates obtained for hematological malignancies were higher than those reported for other malignancies. The past status of phase I clinical trials in Japan can be summarized as follows. (1) A median of seven institutes participated in a single trial. The number of institutes participating correlated with the number of patients enrolled. However, too many institutes participated in a single phase I clinical trial in some studies. (2) The median duration of study for the clinical trials was 14 months. The duration of study was too long in some studies, considering the small number of patients enrolled. In conclusion, the methodology of phase I clinical trials of anticancer agents conducted in Japan should be improved in an efficient and scientific manner, especially for the testing of imported agents.

Antineoplastic Agents↗