Takashi Daimon

Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis

Background:  Low‐dose methotrexate (MTX) therapy is widely used in the treatment of rheumatoid arthritis (RA). Though the difference in response to MTX between patients with RA is large, the factors that contribute to this variability remain unclear.

Arterial Chemoradiotherapy for Locally Advanced Tongue Cancer: Analysis of Retrospective Study of Therapeutic Results in 88 Patients

PURPOSE To retrospectively investigate the therapeutic results of arterial injection therapy by way of the superficial temporal artery for 88 cases of Stage III and IV (M0) tongue cancer and to clarify the factors that affected the therapeutic results. METHODS AND MATERIALS We administered intra-arterial chemoradiotherapy by continuous infusion of carboplatin in 39 patients between January 1993 and July 2002. Systemic concurrent chemotherapy was given to 19 of these patients. We administered intra-arterial chemoradiotherapy with cisplatin with sodium thiosulfate to 49 patients between October 2002 and December 2006. Concurrent systemic chemotherapy was given to 38 of these patients. RESULTS The 3-year local control rate was 72% (T2-T3, 80%; and T4, 48%), and the 3-year survival rate was 57% (Stage III, 67%; Stage IV, 43%). On univariate analysis, age, T stage, N stage, overall stage, systemic chemotherapy, difference in intra-arterial chemotherapy, and performance status had a significant effect on survival. On multivariate analysis, N stage, systemic chemotherapy, difference in intra-arterial chemotherapy, and artery selected had a significant effect on survival. CONCLUSIONS The therapeutic results of intra-arterial chemoradiotherapy using the superficial temporal artery were not inferior to the results of surgery. In particular, the results of arterial injection therapy using cisplatin with sodium thiosulfate were excellent, and we believe it will be a new therapy for advanced tongue cancer.

Bayesian sample size calculations for a non-inferiority test of two proportions in clinical trials

In the process of clinical trials and health-care evaluation, Bayesian approaches have increasingly become the center of attention. In this article, sample size calculations for a non-inferiority test of two independent binomial proportions in a clinical trial are considered in a Bayesian framework. The hybrid Neyman-Pearson-Bayesian (hNPB) probability, the conditionally Bayesian (cB) probability and the unconditionally Bayesian (uB) probability are formulated through a conjugate normal analysis. The sample sizes are calculated based on formulas where normal prior distributions are assumed, and are compared with the Neyman-Pearson (NP) sample size. Our results show that the sample size based on the hNPB probability allows us to critically evaluate the appropriateness of the NP sample size. It is suggested that the sample size calculated based on the cB probability formula is smaller than the NP sample size.

Retrospective Analysis of Severe Neutropenia in Patients Receiving Concomitant Administration of Docetaxel and Clarithromycin

Background: Neutropenia is one of the most important dose-limiting toxicities of docetaxel. Docetaxel is metabolized by cytochrome P450 3A4 (CYP3A4). Clarithromycin, a potent inhibitor of CYP3A4, is occasionally used in combination with docetaxel. The aim of this study was to evaluate whether the risk of severe neutropenia induced by docetaxel was increased by concomitant administration of clarithromycin. Methods: Patients with advanced lung cancer receiving docetaxel were identified from an electronic medical record system and divided into 2 groups: concomitant administration of clarithromycin and no concomitant administration of clarithromycin. The proportion of patients experiencing grade 4 neutropenia between the 2 groups was compared. Potential risk factors associated with grade 4 neutropenia were also examined using univariate and multivariate logistic regression analyses. Results: One hundred and fifty-eight patients were analysed. Grade 4 neutropenia was more frequently detected in the patients receiving clarithromycin than in those not receiving the drug (63.2 vs. 35.3%; p = 0.025). Multivariate analysis showed that co-administration of clarithromycin [odds ratio (OR) 4.98; p = 0.004], pre-treatment absolute neutrophil count (OR 2.62; p = 0.011) and female gender (OR 2.75; p = 0.029) resulted in an increase in the incidence of grade 4 neutropenia. Conclusions: This study shows that concomitant administration of clarithromycin potentiated docetaxel-induced myelosuppression.

Long-term Observation of 64 Patients with Roentgenographically Occult Lung Cancer Treated with External Irradiation and Intraluminal Irradiation Using Low-dose-rate Iridium

OBJECTIVE Therapeutic results of intraluminal irradiation were analyzed in 64 patients with roentgenographically occult lung cancer (ROLC). METHODS The subjects were 64 patients who underwent intraluminal irradiation between 1987 and 2003. Radiotherapy was performed by combining external irradiation with intraluminal irradiation using low-dose-rate iridium (four 370-MBq wires) through a catheter with a spacer. The doses of radiation were 0-70 Gy (median value 46 Gy) by external irradiation and 10-60 Gy (median value 29.3 Gy) by intraluminal irradiation. RESULTS The therapeutic effect was CR in 63 patients and PR in 1 patient, and local recurrence was observed in a PR case and in seven of the 63 patients who showed CR. The 5-year overall and relapse-free survival rates were 56 (95% CI, 43-69%) and 55% (95% CI, 43-68%), respectively. Fatal pulmonary hemorrhage was observed in one case. CONCLUSIONS Considering the facts that ROLC often occurs as multiple cancers and that many patients with ROLC have reduced lung function, radiation therapy by a combination of intraluminal and external irradiation may replace surgery as the first choice for the treatment of this disease.

The Mean Squared Error Optimum Design Criterion for Parameter Estimation in Nonlinear Regression Models

In the context of nonlinear regression models, we propose an optimal experimental design criterion for estimating the parameters that account for the intrinsic and parameter-effects nonlinearity. The optimal design criterion proposed in this article minimizes the determinant of the mean squared error matrix of the parameter estimator that is quadratically approximated using the curvature array. The design criterion reduces to the D-optimal design criterion if there are no intrinsic and parameter-effects nonlinearity in the model, and depends on the scale parameter estimator and on the reparameterization used. Some examples, using a well known nonlinear kinetics model, demonstrate the application of the proposed criterion to nonsequential design of experiments as compared with the D-optimal criterion.

Assessing Nonlinearity in Compartment Models via the Relative Curvature Measure

In pharmacokinetics, compartment models often play an important role in the description of the concentration of the drug in the blood over time after its administration to an individual. Statistical inference in these models can be conducted based on a linear approximation with respect to the parameter related to pharmacokinetic indices, in the same way that the usual nonlinear regression models are dealt with. Therefore, it is necessary to assess the degree of nonlinearity in a compartment model and to evaluate its effect on the linear approximation. The relative curvature measure that enables us to assess the intrinsic and parameter-effects (PE) nonlinearity can be used, but in practice it has not been applied to compartment models in pharmacokinetics. One reason may be that the relative curvature measure cannot be directly applied to blood drug concentration data that exhibit heteroscedasticity. Therefore, the relative curvature measure including the heteroscedastic variance function was utilized to assess the nonlinearity in the compartment models, and in particular, the influences of some of the reparameterizations that are empirically used in fitting the compartment models were examined. Several examples showed that the reparameterized compartment model had less PE nonlinearity than the original compartment model, but that several reparameterizations could increase the PE nonlinearity. In addition, by means of a simulation experiment with heteroscedastic blood drug concentration data, the accuracy, and precision of the relative curvature measure with the heteroscedastic variance function were evaluated and compared with those of the original relative curvature measure. The results showed that the relative curvature measure with the variance function was not affected by heteroscedastic blood drug concentration data and could be utilized for the assessment of the nonlinearity in compartment models.

Relative Curvature Measure for Heteroscedastic or Non Normal Nonlinear Regression

The Bates–Watts relative curvature measure can assess the validity of the linearized approximation in nonlinear regression models. However, it is developed based on an ordinary nonlinear regression in which the observation is assumed to be homoscedastically and normally distributed. In this article, we extend the original Bates–Watts relative curvature measure to one that can be applicable to nonlinear regression with heteroscedastic or non normal data, based on the transformation-both-sides (TBS) approach. In pharmacokinetic models, a diagnostic use of their measures is illustrated. By means of a simulation experiment, the performance of the relative curvature measure for the TBS approach is evaluated.

Identifying patients with peripheral-type early non-small cell lung cancer (T1N0M0) for whom irradiation of the primary focus alone could lead to successful treatment

We investigated the indication of radiotherapy in operable patients with peripheral-type early non-small cell lung cancer (T1N0M0 (TNM staging in 1997)). The subjects comprised 396 patients with non-small cell lung cancer in whom the clinical stage was evaluated as IA. We examined age, gender, Brinkmanns index, histopathological type, the grade of histopathological differentiation, tumour diameter and the level of carcinoembryonic antigen as factors involved in lymph node metastasis. Lymph node metastasis was detected in 79 patients (20%). Factors such as the grade of histopathological differentiation and tumour diameter were involved in lymph node metastasis. In well-differentiated lesions, the probability of metastasis was <10% even when the tumour diameter exceeded 2 cm. However, the probability rapidly increased with tumour size in moderately and poorly differentiated lesions. Among the patients with peripheral-type early non-small cell lung cancer (T1N0M0), the risk of lymph node metastasis was low in those with well-differentiated carcinoma and those with moderately differentiated lesions measuring </=1.5 cm in diameter. The proportion of our patients fitting these criteria was approximately 30%. For these patients, stereotactic body radiotherapy and particle therapy may be indicated.