The Effect of Tegafur-Uracil on Survival in T Categories as Defined in the Eighth Edition of the TNM Classification: An Exploratory Analysis of Postoperative Adjuvant Tegafur-Uracil on Survival in Patients with Adenocarcinoma of the Lung.

BACKGROUND: Tegafur-uracil (UFT) improves survival in patients with stage I adenocarcinoma of the lung. We evaluated the effect of UFT on survival in maximum primary tumor diameter (T) categories as defined in the eighth edition of the TNM Classification (TNM8). METHODS: Tumors were subgrouped on the basis of T category (TNM8) as follows: T1a, T ≤1 cm; T1b, 1 < T ≤2 cm; T1c, 2 < T ≤3 cm; T2a, 3 < T ≤4 cm; T2b , 4 < T ≤5 cm; T3, 5 < T ≤7 cm. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazard models. RESULTS: UFT was associated with improved survival. The adjusted HRs were as follows: for T1a, 0.79 (95% CI 0.14-4.50); for T1b, 1.16 (95% CI 0.63-2.12); for T1c, 0.74 (95% CI 0.43-1.27); for T2a, 0.45 (95% CI 0.21-0.96); for T2b, 0.55 (95% CI 0.10-3.07), and for T3, 0.70 (95% CI 0.20-2.50). CONCLUSIONS: The adjuvant chemotherapy with UFT tended to improve survival in patients with adenocarcinoma of the lung of each T category based on TNM8, except T1b.

Development of novel humanized anti-CD20 antibodies based on affinity constant and epitope.

We describe novel humanized anti-CD20 monoclonal antibodies (mAbs) developed for therapeutic use on the basis of their physicochemical properties and cellular cytotoxicity. A distinct correlation between apparent dissociation constants (K(d)) and apoptotic activity for eight murine anti-CD20 mAbs (OUBM1-OUBM8) and previously-developed murine anti-CD20 mAbs enabled us to categorize anti-CD20 mAbs into two groups. Group A mAbs had lower K(d) values and did not induce definite apoptosis, while Group B mAbs had greater K(d) values and did induce definite apoptosis. A murine version mAb of rituximab, 2B8, belongs to Group B. An epitope analysis showed that the epitope of two murine mAbs, OUBM3 and OUBM6, differed from that of 2B8 or 2F2 (ofatumumab). Two mAbs, OUBM3 from Group A and OUBM6 from Group B, were selected and humanized. As expected, the humanized OUBM3 with the lower K(d) did not induce apoptosis, while the humanized OUBM6 (hOUBM6) with the greater K(d) did. Both hOUBM3 and hOUBM6 induced highly-effective, complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity against Burkitt's and follicular lymphomas. Importantly, hOUBM6 exhibited cellular cytotoxicity against diffuse, large B cells that are less effectively depleted by rituximab and also exhibited effective cytotoxicity against tumor cells from human CD20(+) leukemia and lymphoma patients. These results suggest the potential impact of the further development of our anti-CD20 mAbs. Our study shows that the selection of mAbs based on their physicochemical parameters, followed by the biological activity assessment for the selected mAbs, is a rational and efficient approach for pharmaceutical mAb development.

A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung.

BACKGROUND: In a previous phase 3 trial of adjuvant chemotherapy after resection of non-small-cell lung cancer, a combination of uracil and tegafur (often referred to as UFT) taken orally was shown to prolong survival. A subgroup analysis disclosed that most patients who benefited had pathological stage I adenocarcinoma. METHODS: We randomly assigned patients with completely resected pathological stage I adenocarcinoma of the lung to receive either oral uracil-tegafur (250 mg of tegafur per square meter of body-surface area per day) for two years or no treatment. Randomization was performed with stratification according to the pathological tumor category (T1 vs. T2), sex, and age. The primary end point was overall survival. RESULTS: From January 1994 through March 1997, 999 patients were enrolled. Twenty patients were found to be ineligible and were excluded from the analysis after randomization; 491 patients were assigned to receive uracil-tegafur and 488 were assigned to observation. The median duration of follow-up for surviving patients was 73 months. The difference in overall survival between the two groups was statistically significant in favor of the uracil-tegafur group (P=0.04 by a stratified log-rank test). Grade 3 toxic effects occurred in 10 of the 482 patients (2 percent) who actually received uracil-tegafur. CONCLUSIONS: Adjuvant chemotherapy with uracil-tegafur improves survival among patients with completely resected pathological stage I adenocarcinoma of the lung.

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.

Randomized double-blind placebo-controlled trial of bestatin in patients with resected stage I squamous-cell lung carcinoma.

BACKGROUND: Bestatin is a potent aminopeptidase inhibitor that has immunostimulant and antitumor activity. We conducted a prospective randomized, double-blind, placebo-controlled trial to determine whether postoperative adjuvant treatment with bestatin could prolong the survival of patients with completely resected stage I squamous-cell lung carcinoma. METHODS: Patients with confirmed, resected stage I squamous-cell lung carcinoma were randomly assigned to receive either bestatin (30 mg) or placebo daily by mouth for 2 years. We assessed whether bestatin treatment was associated with overall survival and 5-year cancer-free survival and assessed its safety. All statistical tests were two-sided. RESULTS: From July 8, 1992, through March 30, 1995, 402 patients were entered in the study, 202 in the bestatin group and 198 in the placebo group. The median follow-up for surviving patients was 76 months (range = 58-92 months). The 5-year overall survival was 81% in the bestatin group and 74% in the placebo group for a difference of 7% (95% confidence interval [CI] = -1.4% to 15.0%). The 5-year cancer-free survival was 71% in the bestatin group and 62% in the placebo group for a difference of 9% (95% CI = -0.7% to 17.8%). Overall survival (P =.033, log-rank test) and cancer-free survival (P =.017, log-rank test) were statistically significantly different by Kaplan-Meier analysis. Few adverse events were observed in either group. CONCLUSIONS: Survival was statistically significantly better for patients with completely resected stage I squamous-cell lung carcinoma who were treated with bestatin as a postoperative adjuvant therapy than for those who received a placebo. This result requires confirmation in other phase III trials.

Effect of postoperative adjuvant chemotherapy with tegafur-uracil on survival in patients with stage IA non-small cell lung cancer: an exploratory analysis from a meta-analysis of six randomized controlled trials.

BACKGROUND: The Seventh Edition of the Tumor, Node, Metastasis Classification of Malignant Tumors in non-small cell lung cancer (NSCLC) proposes a more detailed classification of primary tumor diameter. Stage IA T1 disease is subdivided into two groups: T1a disease (tumor diameter, < or = 2 cm) and T1b disease (tumor diameter, >2 to < or = 3 cm). Tegafur-uracil (UFT) improves survival in patients with stage I NSCLC. However, whether it is effective in patients with T1 disease (stage IA) remains controversial. METHODS: Data from a 2005 meta-analysis of UFT were reanalyzed to evaluate the effectiveness of UFT according to T1a and T1b tumors as proposed by the new tumor, node, metastasis classification in patients who had T1 tumors with no lymph-node metastasis. RESULTS: Data from 1269 patients were analyzed: 670 (52.8%) had T1a tumors and 599 (47.2%) had T1b tumors. In the surgery-alone group, survival rates at 5 years were 85% in patients with T1a tumors and 82% in those with T1b tumors after surgery alone and 87% in patients with T1a tumors and 88% in those with T1b tumors after surgery followed by adjuvant treatment with UFT. In patients with T1b tumors, the survival rate was significantly higher in the UFT group than in the surgery-alone group (hazard ratio = 0.62; 95% confidence interval, 0.42-0.90; log-rank p = 0.011). The hazard ratio for death in the UFT group when compared with the surgery-alone group was 0.84 for those with T1a disease (95% confidence interval, 0.58-1.23). The results of a test for interaction between treatment response and T1 subgroup were not significant (p = 0.30). CONCLUSIONS: UFT significantly improves survival in patients with stage IA T1b NSCLC compared with surgery alone.

A Digital Filter for the State Estimation of Impulsive Noise Under the Existence of a Background Noise and its Experiment in the Work Environment.

In the actual work environment, a specific objective noise, like machine and industrial noises, shows impulsive fluctuation form. Furthermore, it often occurs that a specific noise is partially or completely contaminated by background noise. In that case, the fluctuation wave form of the specific noise has to be estimated moment by moment in order to evaluate and/or improve the work environment. In this study, a digital filter for estimating an impulsively fluctuating specific noise is proposed. More specifically, after introducing a generalized time series regressive model of the specific noise, a method for estimating the impulsive noise based on an observation contaminated by the background noise is theoretically derived. Furthermore, the proposed method is applied to the actual task of estimating an industrial impact noise.