This paper discusses the analysis of randomized clinical trials where the primary endpoint is a recurrent event observed during a time period which can vary among patients. In particular it describes a method of estimating robust confidence limits for clinically relevant parameters. As an illustrative example, a clinical trial of a macrophage colony stimulating factor (M-CSF) for patients with acute myeloblastic leukaemia (AML) is introduced where the endpoint is the incidence and duration of febrile neutropenia. The causal effects in the framework of Rubin's deterministic model are defined as estimands. A non-parametric method based on the permutation test, using an accelerated search procedure proposed by Garthwaite, is compared with other standard methods by simulation and by application to the AML trial data.

Computer Simulation↗

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Multidisciplinary treatment of head and neck cancer using BCG, OK-432, and GE-132 as biologic response modifiers.

Since 1979, we have performed multidisciplinary treatment using intensive immunotherapy with biologic response modifiers (BRM) in combination with surgical treatment of oral cancer. Chemotherapy and radiotherapy were also included as part of the therapy. A historic control study was performed. Adjuvant therapy was administered by standardized methods, and the distribution of patients at various stages was similar between groups. The immunotherapy group showed a shorter treatment period, lower rates of recurrence, metastases, and side effects, greater histologic effects at the end of the first treatment, and a higher survival rate than the nonimmunotherapy group. Immunologically, immunotherapy tended to promote positive immune reactions and inhibit negative immune reactions.

Antineoplastic Agents↗

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The continual reassessment method and its applications: a Bayesian methodology for phase I cancer clinical trials.

We discuss the continual reassessment method (CRM) and its extension with practical applications in phase I and I/II cancer clinical trials. The CRM has been proposed as an alternative design of a traditional cohort design and its essential features are the sequential (continual) selection of a dose level for the next patients based on the dose-toxicity relationship and the updating of the relationship based on patients' response data using Bayesian calculation. The original CRM has been criticized because it often tends to allocate too toxic doses to many patients and our proposal for overcoming this practical problem is to monitor a posterior density function of the occurrence of the dose limiting toxicity (DLT) at each dose level. A simulation study shows that strategies based on our proposal allocate a smaller number of patients to doses higher than the maximum tolerated dose (MTD) compared with the original method while the mean squared error of the probability of the DLT occurrence at the MTD is not inflated. We present a couple of extensions of the CRM with real prospective applications: (i) monitoring efficacy and toxicity simultaneously in a combination phase I/II trial; (ii) combining the idea of pharmacokinetically guided dose escalation (PKGDE) and utilization of animal toxicity data in determining the prior distribution. A stopping rule based on the idea of separation among the DLT density functions is discussed in the first example and a strategy for determining the model parameter of the dose-toxicity relationship is suggested in the second example.

Animals↗

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Combined intensive chemotherapy and radical surgery for incurable gastric cancer.

BACKGROUND: To improve the poor prognosis of patients with advanced incurable gastric cancer, intensive chemotherapy combined with radical surgery was used. PATIENTS AND METHODS: Thirty patients with incurable gastric cancer were treated with a combination of 5-fluorouracil (370 mg/m2) and leucovorin (30 mg/person), given intravenously for five consecutive days, followed by cisplatinum (70 mg/m2) and etoposide (70 mg/m2) on days 6 and 20, delivered through a catheter placed either in the aorta with its tip at the level of the ninth thoracic vertebra or in the celiac artery. This treatment (FLEP therapy) was repeated twice every 5 weeks. Radical or palliative surgery followed chemotherapy. RESULTS: The overall response rate to the chemotherapy was 50.0% (15 of 30 patients, 95% confidence limit 0.305-0.671). Nineteen patients (15 with a partial response, three showing no change, and one with progressive disease) underwent surgery. Of these, nine underwent curative surgery and 10 palliative surgery. The median survival time was 6.5 months overall, 12.7 months for responders, and 4.7 months for nonresponders. Long-term survivors were exclusively found among patients with distant lymph node metastasis treated by curative surgery (55.6% at 5 years). CONCLUSIONS: Favorable results of this small phase II study justify a phase III trial.

Adenocarcinoma↗

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Pilot study of prescription-event monitoring in Japan comparing troglitazone with alternative oral hypoglycemics.

OBJECTIVE: To examine adverse events reported in a pilot study of the prescription-event monitoring in Japan (J-PEM) scheme, comparing troglitazone with other oral hypoglycemics. METHODS: We used a cohort study with a concurrent control in which information was gathered from both doctors and pharmacists. Crude event rates were calculated and compared between troglitazone (T) and alternative oral hypoglycemics (control drugs, C) using the likelihood ratio test. When the difference was statistically significant, possible confounding mechanisms were examined using Poisson regression analysis. RESULTS: Of 3,115 patient codes registered, pharmacists were sent 2,078 questionnaires and returned 1,814 (87%), while doctors were sent 1,858 questionnaires and returned 671 (36%). The difference in crude rates was statistically significant in 11 events (seven where T > C and four where C > T) reported by pharmacists and ten events (three where T > C and seven where C > T) reported by doctors. Among those, in two events, "weight increased" (T > C) and "abnormal hepatic function" (T > C), significant differences were observed in data from both doctors and pharmacists. Regression analysis revealed that the difference in crude rates for "nausea" (T > C) was possibly due to an uneven distribution of genders and that for "weight increased" (T >C) was possibly due to an uneven distribution of compliance. Patients with hepatic function abnormalities associated with troglitazone could be divided into two subtypes: one with a slight increase in serum lactate dehydrogenase concentration only and the other with elevated serum alanine aminotransferase. CONCLUSIONS: Comparison of the event rates between troglitazone and control drugs, followed by regression analysis, revealed several features of adverse events associated with drugs, including possible confounding mechanisms. Troglitazone-induced hepatic function abnormalities may be divided into two subtypes.

Adolescent↗

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Novel mutations, no detectable mRNA and familial genetic analysis of the Wiskott-Aldrich syndrome protein gene in six Japanese patients with Wiskott-Aldrich syndrome.

The Wiskott-Aldrich syndrome (WAS) is a primary X-linked immunodeficiency disease caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene. The present molecular studies of six Japanese WAS patients identified five different mutations of WASP, including two novel mutations (45delG, 395insGGAGAT), the latter appearing to have occurred de novo. Familial carriers were detected by polymerase chain reaction-single strand conformational polymorphism analysis, restriction enzyme digestion and direct sequencing of PCR products. Neither mRNA nor the protein product were detectable in any of the patients, while various amounts of WASP protein were expressed in carriers, normal controls, haematopoietic cell lines of all lineages and in one patient after receiving allogeneic bone marrow transplantation. Conclusion Genetic and protein analysis is useful in the definite diagnosis and follow up of Wiskott-Aldrich syndrome patients and in carrier detection, especially of atypical or sporadic patients.

Bone Marrow Transplantation↗

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Mitogenic activities of heteroglycan and heteroglycan-protein fractions from culture medium of Lentinus edodes mycelia.

The water soluble material (LEM) was prepared from the solid culture medium in which Lentinus edodes mycelia were growing actively. An alcohol insoluble material was prepared from LEM and subjected to Sepharose 6B gel filtration. The void fraction (LAP1) was composed mainly of xylose-rich heteroglycan and protein. From LAP1, a heteroglycan fraction (LAF1) was prepared by DEAE-Sepharose CL-6B column chromatography. LAP1 and LAF1 enhanced the incorporation of [3H]thymidine into mouse splenic cells (SPs). At each of the optimum doses, the rate of the incorporation was about 10 times as high with LAF1 as with LAP1. Such mitogenic responses were not induced in nylon-column effluent SPs and thymocytes. sIg-expressed cells were responsive to LAF1, but not to LAP1. Moreover, with each fraction, the incorporation was enhanced more in plastic adherent splenic cells (ADs) than in SPs. The flow cytometric assay revealed that the number of Mac-1+ cells is about 13 times as many in ADs as in SPs and that the number of Ly-5+ or Thy-1.2+ cells is considerably reduced in ADs compared with that in SPs. Thus, the present studies suggest that LAP1 and LAF1 act as mitogens predominantly for mouse splenic macrophages and/or monocytes.

Animals↗

PubMedDate not supplied

Productions of interferon-gamma and nitrite are induced in mouse splenic cells by a heteroglycan-protein fraction from culture medium of Lentinus edodes mycelia.

A xylose-rich heteroglycan-protein fraction (LAP1) was prepared from a solid culture medium in which Lentinus edodes mycelia were growing actively. Mouse splenic cells (SPs) were incubated with [3H]TdR in the presence of LAP1. The incubated SPs were fractionated into plastic adherent splenic cells (ADs), nylon-column effluent splenic cells (NEs) and sIg-expressed splenic cells (SIs), which are rich in Mac-1+, Thy-1.2+ and Ly-5+ cells, respectively. The incorporation of [3H]TdR in response to LAP1 was enhanced in each of the fractionated cell populations. Northern or dot blot hybridization showed that productions of IFN-gamma and its receptor mRNAs are induced predominantly in NEs. In another experiment, SPs were fractionated into ADs, NEs and SIs. Then, NE-AD, SI-AD and NE-SI mixtures were prepared and incubated in the same manner. A significant incorporation of [3H]TdR was shown only in the NE-AD mixture. The enzyme-linked immunosorbent assay showed that IFN-gamma production in response to LAP1 is induced in SPs or in the NE-AD mixture, but not in NEs alone. The level of the production was about 5 times higher in the mixture than in SPs after a 72 h incubation. Moreover, LAP1 was capable of inducing NO2- production in SPs. Thus, the present studies imply that this heteroglycan-protein fraction stimulates productions of IFN-gamma and nitrite in mouse splenic cells, augmenting antitumor immune response(s).

Animals↗