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Chikuma Hamada

Publications and source records attributed to Chikuma Hamada.

At least 19 recordsLinked to original sources
PubMed2007

A method for therapeutic dose selection in a phase II clinical trial using contrast statistics.

This paper proposes a statistical method for determining the therapeutic dose of a test drug in a confirmatory clinical trial based on a phase II clinical trial using 3 or 4 doses of the drug. This method assumes the primary variable has a normal distribution with a common variance, that a test-drug effect is seen when the population means show a response pattern indicating a monotonic increase with dose, and that there is a prior distribution for the population means. Under the proposed method, multiple contrast statistics are determined, such as contrast statistics for linear increase and plateau, and a response pattern is selected based on the maximum contrast statistic. The posterior probability that the selected response pattern is the true one is evaluated, and if this exceeds the cut-off value a therapeutic dose is selected based on the estimated response pattern. To select the appropriate cut-off value, a simulation study was conducted using a loss function for which the loss due to overestimation is greater than the loss due to underestimation. It was found that, as a rule, the appropriate cut-off value to reduce the expected loss for various response patterns is 0.75 for a 3-group trial and 0.70 for a 4-group trial. Using these cut-off values, the proposed method was applied to a previous clinical trial of a leukotriene receptor antagonist in patients with bronchial asthma. The method enabled the selection of what are considered appropriate response patterns and a therapeutic dose. Thus, the proposed method appears reasonable.

Asthma↗
PubMed2006

The confidence interval of allelic odds ratios under the Hardy-Weinberg disequilibrium.

In single nucleotide polymorphism (SNP) data analysis, the allelic odds ratio and its confidence interval (CI) are usually used to evaluate the association between disease and alleles at each SNP. The usual formula for calculating the CI of the allelic odds ratio based on the Hardy-Weinberg equilibrium (HWE) may, however, lead to errors beyond the control assured by the nominal confidence level if HWE is not true. We therefore present a generalized formula for CI that does not assume HWE. CIs calculated by this generalized formula are likely to be wider than those by the usual method if the Hardy-Weinberg disequilibrium (HWD) is toward a relative deficiency of the heterozygotes (fixation index greater than 0), whereas they are likely to be narrower if HWD is toward a relative excess of the heterozygotes (fixation index less than 0). A simulation experiment to examine the influence of the generalization was performed for the case where 2% of SNPs had a fixation index greater than 0. The result revealed that the generalized method slightly decreased the mean number of falsely detected SNPs.

Alleles↗
PubMed2006

Minimization method for balancing continuous prognostic variables between treatment and control groups using Kullback-Leibler divergence.

This paper proposes a method for balancing prognostic variables between treatment and control groups in design of clinical trials. It assumes that some of prognostic variables are continuous and others are categorical and that they are independently distributed. The proposed method uses the Kullback-Leibler divergence (KLD) as the index of difference in distribution between two groups. It sequentially allocates each subject to a group using a biased coin method so as to reduce the estimate of KLD. That is, when first i subjects have been allocated to two groups and the (i+1)th subject is enrolled, the KLD is estimated if the (i+1)th subject was to be allocated to either of the groups, and the subject is then allocated with a certain probability, e.g. 0.80, so as to make the KLD small. Simulation studies based on the hypothetical prognostic variables and on the actual data of hyperlipidemia patients were carried out in order to compare the proposed method with the Pocock-Simon method, which transforms the continuous prognostic variables into categorical variables by dividing the whole scale into several categories. The p values of homogeneity test of means and variances were used to evaluate the achieved balance. The observed p values in the proposed method were better than those in the Pocock-Simon method. In addition to the balance, the precision of parameter estimates assuming analysis of covariance model was examined. The results showed the precision of estimators tended to be more stable in the proposed method than the Pocock-Simon method.

Clinical Trials as Topic↗
PubMed2006

Effective number of subjects and number of raters for inter-rater reliability studies.

A reliability study in which multiple raters evaluate multiple subjects was assumed in order to confirm the inter-rater reliability of rating scales. The two-way ANOVA model defining subjects and raters as random effects was applied, and the combination of the number of subjects and the number of raters that minimizes variance of the intraclass correlation coefficient (ICC) with a fixed total number of ratings (number of subjects x number of raters) was studied. The results revealed that the optimal combination depends on the relative ratio (between-rater variance/error variance), and that large number of raters brings the high precision of estimation of the ICC when the relative ratio was greater. It was concluded that when information concerning the relative ratio is unreliable, the use of identical numbers of raters and subjects minimizes variance when the relative ratio is substantially large and variance is maximized, providing a good study design from the viewpoint of 'maximin'.

Humans↗
PubMed2006

Does perioperative high-dose prednisolone have clinical benefits for generalized myasthenia gravis?

OBJECTIVE: The purpose of this study was to clarify the clinical benefits of perioperative administration of high-dose prednisolone (PSL) combined with extended thymectomy on the long-term outcomes of 116 consecutive patients with generalized myasthenia gravis (MG). METHODS: A retrospective review was conducted on 116 patients diagnosed with generalized MG who received alternate-day oral administration of high-dose PSL (100 mg/alternate days) and had undergone transsternal extended thymectomy. Incidences of postoperative myasthenic crisis, adverse effects of steroid, long-term outcomes, such as complete stable remission (CSR), pharmacologic remission (PR) or improvement (Imp), and disease recurrence after CSR were evaluated. RESULTS: Six patients (5.2%) experienced post-thymectomy myasthenic crisis. Crude cumulative CSR and PR + CSR rates were 44.8 and 62.7%, respectively. Life table analysis showed that 41.8, 52.8 and 63.4% of the patients were in CSR at 3, 5 and 10 years, respectively. Multivariate analysis revealed that age and pretreatment classification according to the Myasthenia Gravis Foundation of America (MGFA) criteria tended to be independent predictors of CSR. There were 6.9% with compressive vertebral fracture, 13.8% with cataract, and 5.2% with steroid-induced diabetes. Life table analysis revealed that recurrence rates after CSR were 36.8 and 46.0% at 3 and 5 years, respectively. Patients with thymoma had a significantly higher rate of recurrence than those without thymoma (p = 0.001). CONCLUSIONS: Alternate-day administration of high-dose prednisolone reduced the risk of post-thymectomy myasthenic crisis. Presence of thymoma was a risk factor for MG recurrence after CSR.

Adult↗
PubMed2006

Identification of prognostic factors associated with early mortality after surgical resection for pancreatic cancer--under-analysis of cumulative survival curve.

BACKGROUND: The cumulative survival curve after surgery for advanced pancreatic cancer is characterized by a steep downward slope in the early postoperative period. The aim of this investigation was to identify the characteristics associated with early mortality in patients undergoing pancreatic resection for pancreatic cancer. METHODS: Thirty-seven patients with extended radical pancreatectomy combined with intraoperative radiation therapy were studied. The cumulative survival curve in this series was depicted using the Kaplan-Meier method. Assuming that there were two distinct survival curves, below and above the breakpoint, each part of the curve was modeled as an exponential distribution. Three parameters, the breakpoint, the high hazard rate below the breakpoint, and the low hazard rate above the breakpoint were estimated by the maximum likelihood method. Prognostic factors associated with early mortality after surgery were evaluated using univariate and multivariate Cox proportional hazards regression analyses. RESULTS: The breakpoint of the survival curve was estimated at 41 months. The short-survival group (SSG) was defined as deceased earlier than 41 months after surgery, and included 31 patients (83.8 %). The long-survival patient group (LSG) consisted of 6 patients who were alive more than 41 months after surgery. Eighteen SSG patients (58.1 %) died of hepatic metastases, whereas no LSG patients died of hepatic metastases. Abdominal pain and/or back pain during clinical course was identified by multivariate analysis as a prognostic factor for patients undergoing pancreatic resection. CONCLUSIONS: The high hazard rate in the early postoperative period was closely linked with death due to liver metastases. The preoperative presence of local pain was a prognostic factor associated with early mortality.

Adenocarcinoma↗
PubMed2005

An individual patient data meta-analysis of adjuvant therapy with carmofur in patients with curatively resected colon cancer.

BACKGROUND: Oral carmofur, either as a single or in combination with other chemotherapeutic agents, has been used as adjuvant chemotherapy for curatively resected colon cancer patients. Past trials and meta-analyses indicate that it is somewhat effective in extending survival of patients with this cancer. The objective of this study was to perform a reappraisal of randomized clinical trials conducted in this regard. METHODS: We designed an individual patient-based meta-analysis of relevant clinical trials to examine the benefit of oral carmofur for curatively resected colon cancer in terms of overall survival (OS) and disease-free survival (DFS). RESULTS: We analyzed individual patient data of three randomized clinical trials, which met the predetermined inclusion criteria. These three trials had a combined total of 2152 patients, carmofur as adjuvant chemotherapy compared with surgery-alone, 5 years follow-up, intention-to-treat-based analytic strategy and similar end points (OS and DFS). In a pooled analysis, 5 year OS rates were 80.4 and 76.4%, and 5 year DFS rates 76.9 and 71.0%, respectively, in carmofur and surgery-alone group. Oral carmofur had significant advantage over surgery-alone in terms of both OS [pooled hazard ratio, 0.82; 95% confidence interval (CI) = 0.68-0.99; P = 0.043] and DFS (pooled hazard ratio, 0.77; 95% CI = 0.65-0.91; P = 0.003). CONCLUSIONS: This individual patient-based meta-analysis demonstrated that oral carmofur significantly improves both OS and DFS in patients with curatively resected colon cancers.

Antineoplastic Agents↗
PubMed2005

Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer.

PURPOSE: Recent clinical trials have shown the efficacy of platinum-based adjuvant chemotherapy for completely resected non-small-cell lung cancer (NSCLC). In Japan, many clinical trials of adjuvant chemotherapy with tegafur-uracil (UFT) have been conducted, and some trials showed positive results while others showed negative results. Thus, we performed a meta-analysis to assess the efficacy of postoperative adjuvant chemotherapy with UFT in NSCLC. METHODS: Among nine trials of postoperative adjuvant UFT-containing chemotherapy, six trials comparing surgery alone with surgery plus UFT were identified. Of six trials, two were three-arm trials including cisplatin-based chemotherapy followed by UFT, and data from that arm were not included in the meta-analysis. RESULTS: Of 2,003 eligible patients, most (98.8%) had squamous cell carcinoma or adenocarcinoma, and most had stage I disease; the tumor classification was T1 in 1,308 (65.3%), T2 in 674 (33.6%), and the nodal status was N0 in 1,923 (96.0%). The two treatment groups did not differ significantly in major prognostic factors. The median duration of follow-up was 6.44 years. The survival rates at 5 and 7 years were significantly higher in the surgery plus UFT group (81.5% and 76.5%, respectively) than in the surgery alone group (77.2% and 69.5%, respectively; P = .011 and .001, respectively). The overall pooled hazard ratio was 0.74, and its 95% CI was 0.61 to 0.88 (P = .001). CONCLUSION: This meta-analysis showed that postoperative adjuvant chemotherapy with UFT was associated with improved 5- and 7-year survival in a Japanese patient population composed primarily of stage I adenocarcinoma patients.

Adenocarcinoma↗
PubMed2005

Postoperative adjuvant therapy for completely resected early-stage non-small cell lung cancer.

Consensus on adjuvant therapy for completely resected non-small cell lung cancer until 2002 was as follows. (1) There was no significant impact of postoperative adjuvant chemotherapy based on meta-analysis and previous clinical trials. (2) Confirmatory studies are necessary in large-scale prospective clinical trials. However, recent mega trials have introduced epoch-making changes for postoperative adjuvant chemotherapy in clinical practice since ASCO 2003. The effectiveness of UFT in N0 patients was confirmed. Patients with completely resected stage I non-small cell lung cancer, especially T2N0 adenocarcinoma, will benefit from adjuvant chemotherapy with UFT. The results of the International Adjuvant Lung Trial (IALT) have confirmed the meta-analysis in 1995. Also, both the JBR10 and Cancer and Leukemia Group B (CALGB) 9633 studies have also confirmed positive IALT results of the benefit for postoperative platinum-based chemotherapy in completely resected non-small cell lung cancer. Adjuvant chemotherapy for pathological stage IB to II, completely resected non-small cell lung cancer is standard care based on clinical trials. UFT showed the strongest evidence for IB in Japan. Platinum doublet chemotherapy with third-generation anticancer agents is also recommended. Adjuvant chemotherapy should be offered as standard care to patients after completely resected early stage non-small cell lung cancer. However, there is no evidence of the feasibility and efficacy for adjuvant chemotherapy with the platinum-based regimen in Japan. Careful management should be necessary in such treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Class of antihypertensive drugs, blood pressure status, and risk of cardiovascular disease in hypertensive patients: a case-control study in Japan.

The purpose of this study was to compare the effect of different classes of antihypertensives on the risk of cardiovascular events in a case-control study of hypertensive patients. The subjects consisted of 171 hypertensive patients who had experienced a cardiovascular event and 537 randomly selected hypertensive controls who were matched to the cases by gender, age, and hospital/clinic. Both cases and controls had been under antihypertensive medication for at least 6 months before the onset of the cardiovascular event (cases) or before the enrollment (controls). A total of 134 physicians across the nation recruited cases and controls, and reported details of the prescription of antihypertensives and clinical and behavioral variables of their patients. Although there was no measurable difference in the risk of cardiovascular events according to the class of antihypertensives, statistically significant increases in the risk of cardiovascular events were observed for non-use of calcium antagonists among patients with angina pectoris and for non-use of the renin-angiotensin system inhibitor (angiotensin-converting enzyme inhibitor and angiotensin II receptor blockers combined) among patients with diabetes mellitus. Higher levels of blood pressure were associated with an increased risk of cardiovascular events. The findings suggest that appropriate control of blood pressure is more important in the treatment of hypertension than the choice of antihypertensives.

Adult↗
PubMed2004

Designing a multistage, SNP-based, genome screen for common diseases.

A genome-wide linkage equilibrium mapping is an emerging strategy to identify risk-modifying genes for common diseases, despite unsettled controversies upon many aspects, including its premises, designs, marker choices and cost benefits. One large-scale attempt in Japan aims to identify disease-associated single nucleotide polymorphisms (SNPs) for five diseases among the Japanese population: Alzheimer's disease, gastric cancer, diabetes, hypertension and asthma. Following an initial screening of c.a. 100,000 SNPs on 940 subjects (five diseases x 188 patients) to select about 2,000 SNPs, we compared which subsequent screening design is more appropriate, and an additional one or two screens to further narrow down any disease-associated SNPs within a fixed total volume of 15,040,000 typings (2,000 SNPs x five diseases x 1,504 subjects, comprising 752 cases and 752 controls). We employed a Monte Carlo simulation to evaluate the probability of identifying truly disease-associated SNPs. The results suggest the single additional stage design (i.e., total two-stage design including the initial screening of 100,000 SNPs) was more practicable for the simple reason that the gain in probability is considered insufficient relative to an associated increase in study complexity in the three-stage design.

Alleles↗
PubMed2004

Creutzfeldt-Jakob disease and cadaveric dura mater grafts in Japan: an updated analysis of incubation time.

The incubation time for 76 patients with cadaveric dura mater-transmitted Creutzfeldt-Jakob disease reported in Japan by November 2001 was analyzed to clarify its distributional feature and the risk factors which affect the earlier onset of the disease. Cluster analysis indicated that cases could be divided into 3 clusters with respect to the incubation time, i.e., short (1.4-6.2 years), medium (7.0-11.9 years) and long (12.9-17.6 years). The incubation time in females was significantly shorter than those in males. Patients who were transplanted dura mater for facial spasms had a significantly shorter incubation time than those who received transplantation for other diseases including meningioma, aneurysm, or acoustic schwannoma. These results suggest that some host factors may have an influence on the incubation time of the disease.

Cadaver↗
PubMed2004

Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials.

PURPOSE: Adjuvant therapy of colorectal cancer with oral fluorinated pyrimidines is attractive because of its ease of administration and good tolerability. The purpose of this meta-analysis is to assess the survival and disease-free survival benefits of treating patients after surgical resection of a primary colorectal tumor with oral fluoropyrimidines for 1 year. PATIENTS AND METHODS: This meta-analysis was performed on individual data from three randomized trials conducted by the Japanese Foundation for Multidisciplinary Treatment for Cancer involving a total of 5,233 patients with stages I to III colorectal cancer. RESULTS: The overall hazard ratio in favor of oral therapy was 0.89 for survival (95% CI, 0.80 to 0.99; P =.04), and 0.85 for disease-free survival (95% CI, 0.77 to 0.93; P <.001). Thus oral therapy reduced the risk of death by 11% and the risk of recurrence or death by 15%. There was no significant heterogeneity between trials, nor did the benefit of oral therapy depend on tumor stage (I, II, or III), tumor site (rectum or colon), patient age, or patient sex. CONCLUSION: Oral fluoropyrimidines improve disease-free survival and survival of patients after resection of early-stage colorectal cancer. These observations support the use of these agents alone after resection of early-stage disease, as well as further testing of oral agents in combination with new drugs that have recently shown antitumor activity in advanced colorectal cancer.

Administration, Oral↗
PubMed2004

Statistical comparison of random allocation methods in cancer clinical trials.

The selection of a trial design is an important issue in the planning of clinical trials. One of the most important considerations in trial design is the method of treatment allocation and appropriate analysis plan corresponding to the design. In this article, we conducted computer simulations using the actual data from 2158 rectal cancer patients enrolled in the surgery-alone group from seven randomized controlled trials in Japan to compare the performance of allocation methods, simple randomization, stratified randomization and minimization in relatively small-scale trials (total number of two groups are 50, 100, 150 or 200 patients). The degree of imbalance in prognostic factors between groups was evaluated by changing the allocation probability of minimization from 1.00 to 0.70 by 0.05. The simulation demonstrated that minimization provides the best performance to ensure balance in the number of patients between groups and prognostic factors. Moreover, to achieve the 1 percentile for the p-value of chi-square test around 0.50 with respect to balance in prognostic factors, the allocation probability of minimization was required to be set to 0.95 for 50, 0.80 for 100, 0.75 for 150 and 0.70 for 200 patients. When the sample size was larger, sufficient balance could be achieved even if reducing allocation probability. The simulation using actual data demonstrated that unadjusted tests for the allocation factors resulted in conservative type I errors when dynamic allocation, such as minimization, was used. In contrast, adjusted tests for allocation factors as covariates improved type I errors closer to the nominal significance level and they provided slightly higher power. In conclusion, both the statistical and clinical validity of minimization was demonstrated in our study.

Aged↗
PubMed2004

Relationship between neutrophil elastase and acute lung injury in humans.

We conducted clinical trials in patients with acute lung injury (ALI) associated with systemic inflammatory response syndrome using a selective neutrophil elastase inhibitor, sivelestat sodium hydrate (Sivelestat), to investigate the involvement of neutrophil elastase in ALI. In the phase III double-blind study (Study 1) in 230 patients, the efficacy of Sivelestat was evaluated with the pulmonary function improvement (PFI) rating as the primary endpoint, and the weaning rate from mechanical ventilator, the discharge rate from intensive care unit (ICU), and the survival rate as secondary endpoints. Afterwards, an unblinded study (Study 2) in 20 patients was conducted using procedures for weaning from mechanical ventilation to reevaluate its efficacy with ventilator-free days (VFD) value, the primary endpoint, and to compare with that of Study 1 subgroup, which met the selection criteria used in Study 2. Sivelestat increased PFI rating, reduced duration of mechanical ventilation, and shortened stay in ICU in Study 1, although there was no significant efficacy on the survival rate. VFD value in Study 2 was comparable to that in the optimal-dose group of Study 1 subgroup, and increase in VFD value correlated with PFI rating and increase in ICU free days. It was concluded that neutrophil elastase may be involved in the pathogenesis of ALI in humans.

Adolescent↗
PubMed2003

Autosynchronized systolic unloading during left ventricular assist with a centrifugal pump.

OBJECTIVES: The purpose of this study was to investigate how the inflow cannulation site of the left ventricular assist system with a centrifugal pump would influence cardiac function on failing heart models. METHODS: In 10 sheep, a left ventricular assist system was instituted by an outflow cannula in the descending aorta, two inflow cannulas in the left atrium and the left ventricle, and connecting those cannulas to a magnetically suspended centrifugal pump. A conductance catheter and a tipped micromanometer for monitoring the pressure-volume loop were also inserted into the left ventricle. Myocardial oxygen consumption was directly measured. Heart failure was induced by injection of microspheres into the left main coronary artery. The assist rate was varied from 0% to 100% at each inflow cannulation site. RESULTS: The pump flow with left ventricular cannulation increased during the systolic phase and decreased during the diastolic phase, whereas it was constant with left atrial cannulation. Ejection fraction with left atrial cannulation decreased as the assist rate increased, whereas that with left ventricular cannulation was maintained up to 75% assist. The external work with left atrial cannulation decreased gradually as the assist rate increased, whereas the external work with left ventricular cannulation did not decrease until the assist rate reached 75%. The myocardial oxygen consumption in both cannulations decreased proportionally as the assist rate increased; they were significantly less with left ventricular cannulation at the 100% assist rate than with left atrial cannulation. CONCLUSION: Left ventricular cannulation during left ventricular assistance maintains ejection fraction and effectively reduces oxygen consumption.

Analysis of Variance↗
PubMed2002

A prospective survey of delayed adverse reactions to iohexol in urography and computed tomography.

We investigated 7505 inpatients who underwent intravenous urography or contrast-enhanced computed tomography to assess risk factors for delayed adverse drug reactions to iohexol, a non-ionic iodinated contrast medium. Focusing on delayed adverse reactions, all adverse events were prospectively investigated for 7 days after injection of iohexol. To explore the relevant risk factors, the relationship between occurrence of adverse reactions to iohexol and 17 different variables was evaluated by logistic regression analysis. To assess the influence of seasonal factors, adverse reactions were separately evaluated during two periods: February to April (the pollinosis period in Japan) and July to September (the non-pollinosis period). The prevalence of delayed adverse events and delayed adverse reactions was 3.5 and 2.8%, respectively, whereas the prevalence of adverse events and adverse reactions was 5.7 and 5.0%, respectively. Multivariate analysis showed that six parameters had a significant influence on delayed adverse reactions to iohexol, including (a) a history of allergy, (b) season, (c) radiographic procedure, (d) age, (e) concomitant surgery or other invasive procedures, and (f) concomitant medication. The prevalence of delayed reactions was lower than in previous large-scale studies. Significant risk factors included a history of allergy and performance of radiography during the pollinosis period, suggesting that allergy was involved in delayed adverse reactions. The type of radiographic procedure also had an influence.

Contrast Media↗