Published papers

BACKGROUND: Validation of the clinical classification for lung cancer of the 7th edition of the TNM staging system among surgical cases has not been reported previously. METHODS: Data of 489 males and 246 females, with a mean age of 67.6 years, who underwent surgical resection for non-small-cell lung cancer were analyzed retrospectively. RESULTS: The 5-year survival rate of these patients was 72.2% for clinical stage IA (n = 365), 58.4% for IB (n = 158), 51.2% for IIA (n = 77), 49.1% for IIB (n = 42), 36.8% for IIIA (n = 86), 80% for IIIB (n = 5) and 50% for IV (n = 2). The 5-year survival rate of patients was 100% for pathological stage 0 (n = 2), 86.1% for IA (n = 216), 73.8% for IB (n = 173), 46.1% for IIA (n = 97), 47.2% for IIB (n = 69), 33.3% for IIIA (n = 155), 33.3% for IIIB (n = 3) and 30.9% for IV (n = 20). Prognostic factors included female sex and 70 years of age or younger, as well as adenocarcinoma histology. CONCLUSIONS: Deterioration in patient survival was indicated with the exception of stages IIIB and IV, each of which included only a small number of patients. Our study validated the current TNM staging system in surgical cases with regard to both clinical and pathological classifications.

Powerful array-based single-nucleotide polymorphism-typing platforms have recently heralded a new era in which genome-wide studies are conducted with increasing frequency. A genetic polymorphism associated with population pharmacokinetics (PK) is typically analyzed using nonlinear mixed-effect models (NLMM). Applying NLMM to large-scale data, such as those generated by genome-wide studies, raises several issues related to the assumption of random effects as follows: (i) computation time: it takes a long time to compute the marginal likelihood; (ii) convergence of iterative calculation: an adaptive Gauss-Hermite quadrature is generally used to estimate NLMM; however, iterative calculations may not converge in complex models; and (iii) random-effects misspecification leads to slightly inflated type-I error rates. As an alternative effective approach to resolving these issues, in this article, we propose a generalized estimating equation (GEE) approach for analyzing population PK data. In general, GEE analysis does not account for interindividual variability in PK parameters; therefore, the usual GEE estimators cannot be interpreted straightforwardly, and their validities have not been justified. Here, we propose valid inference methods for using GEE even under conditions of interindividual variability and provide theoretical justifications of the proposed GEE estimators for population PK data. In numerical evaluations by simulations, the proposed GEE approach exhibited high computational speed and stability relative to the NLMM approach. Furthermore, the NLMM analysis was sensitive to the misspecification of the random-effects distribution, and the proposed GEE inference is valid for any distributional form. We provided an illustration by using data from a genome-wide pharmacogenomic study of an anticancer drug.

BACKGROUND: In amyotrophic lateral sclerosis (ALS), muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous over the abductor digit minimi (ADM), and this is termed 'split hand'. Previous axonal excitability studies have suggested increased nodal persistent sodium current and reduced potassium current in motor axons in ALS, but the extent of excitability changes in APB and ADM axons in ALS has never been compared. OBJECTIVE: To elucidate the peripheral axonal pathophysiology of split hand. METHODS: In both APB and ADM motor axons of 21 patients with ALS and 17 age-matched normal controls, threshold tracking was used to measure excitability indices such as strength-duration time constant (SDTC; a measure of persistent sodium current) and threshold electrotonus. RESULTS: In normal controls, SDTC was significantly longer for APB than ADM axons, suggesting that axonal excitability is physiologically higher in APB axons. Compared with normal controls, patients with ALS had longer SDTC and greater threshold changes in depolarising threshold electrotonus in both APB and ADM axons. Furthermore, the difference in extent of SDTC prolongation between normal subjects and patients with ALS was greater in APB than ADM axons. CONCLUSIONS: APB axons have physiologically higher excitability than ADM axons, and, in ALS, the hyperexcitability is more prominent in APB axons. Although cortical mechanisms would also be involved, more prominent hyperexcitability of APB axons may contribute to development of split hand, and the altered axonal properties are possibly associated with motor neuronal death in ALS.

We tested the validity of two prognostic indices for stereotactic radiosurgically (SRS)-treated patients with brain metastases (BMs) from five major original cancer categories. The two indices are Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) and our Modified Recursive Partitioning Analysis (RPA). Forty-six hundred and eight BM patients underwent gamma knife SRS during the 1998-2011 period. Primary cancer categories were non-small cell lung cancer (NSCLC, 2827 patients), small cell lung cancer (SCLC, 460), gastro-intestinal cancer (GIC, 582), breast cancer (BC, 547) and renal cell cancer (RCC, 192). There were statistically significant survival differences among patients stratified into four groups based on the DS-GPA systems (p < 0.001) in all five original cancer categories. In the NSCLC category, there were statistically significant mean survival time (MST) differences (p < 0.001) among the four groups without overlapping of 95 % confidence intervals (CIs) between any two pairs of groups with the DS-GPA system. However, among the SCLC, GIC, BC and RCC categories, MST differences between some pairs of groups failed to reach statistical significance with this system. There were, however, statistically significant MST differences (p < 0.001) among the three groups without overlapping of 95 % CIs between any two pairs of groups with the Modified RPA system in all five categories. The DS-GPA system is applicable to our set of patients with NSCLC only. However, the Modified RPA system was shown to be applicable to patients with five primary cancer categories. This index should be considered when designing future clinical trials involving BM patients.

Objective: The Japan Leksell Gamma Knife (JLGK) Society has conducted a prospective multi-institute study (JLGK0901, UNIN000001812) for selected patients in order to prove the effectiveness of stereotactic radiosurgery (SRS) alone using the gamma knife (GK) for 1-10 brain lesions. Herein, we verify the validity of 5 major patient selection criteria for the JLGK0901 trial. Materials and Methods: Between 1998 and 2010, 2246 consecutive cases with 10352 brain metastases treated with GK were analyzed to determine the validity of the following 5 major JLGK0901 criteria; 1) 1-10 brain lesions, 2) less than 10 cm(3) volume of the largest tumor, 3) no more than 15 cm(3) total tumor volume, 4) no cerebrospinal fluid (CSF) dissemination, 5) Karnofsky performance status (KPS) score >/=70. Results: For cases with >10 brain metastases, salvage treatments for new lesions were needed more frequently. The tumor control rate for lesions larger than 10 cm(3) was significantly lower than that of tumors <10 cm(3). Overall, neurological and qualitative survivals (OS, NS, QS) of cases with >15 cm(3) total tumor volume or positive magnetic resonance imaging findings of CSF were significantly poorer. Outcomes in cases with KPS <70 were significantly poorer in terms of OS. Conclusion: Our retrospective results of 2246 GK-treated cases verified the validity of the 5 major JLGK0901 criteria. The inclusion criteria for the JLGK0901 study are appearently good indications for SRS.