3-jigen G1(M) no bekutorujo to sono tokuchozuke ni tsuite

制度:新 ; 文部省報告番号:乙1830号 ; 学位の種類:博士(理学) ; 授与年月日:2003-10-16 ; 早大学位記番号:新3651早稲田大

The TAO-Gen Algorithm for Identifying Gene Interaction Networks with Application to SOS Repair in E. coli

One major unresolved issue in the analysis of gene expression data is the identification and quantification of gene regulatory networks. Several methods have been proposed for identifying gene regulatory networks, but these methods predominantly focus on the use of multiple pairwise comparisons to identify the network structure. In this article, we describe a method for analyzing gene expression data to determine a regulatory structure consistent with an observed set of expression profiles. Unlike other methods this method goes beyond pairwise evaluations by using likelihood-based statistical methods to obtain the network that is most consistent with the complete data set. The proposed algorithm performs accurately for moderate-sized networks with most errors being minor additions of linkages. However, the analysis also indicates that sample sizes may need to be increased to uniquely identify even moderate-sized networks. The method is used to evaluate interactions between genes in the SOS signaling pathway in Escherichia coli using gene expression data where each gene in the network is over-expressed using plasmids inserts

Tegafur-Uracil Plus Gemcitabine Combination Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer Previously Treated with Platinum

BackgroundAn open-label, single-arm prospective study was conducted to evaluate the efficacy and toxicity of the combination of gemcitabine and tegafur-uracil (UFT) in patients with advanced nonsmall-cell lung cancer (NSCLC) after the failure of previous platinum-containing regimens.Patients and MethodsPatients with advanced NSCLC received 200 mg/m2 of UFT twice daily from day 1 through 14 plus 900 mg/m2 of gemcitabine per day via intravenous injection on days 8 and 15. This regimen was repeated every 3 or 4 weeks.ResultsA total of 40 patients were enrolled. Eleven patients (28%; 95% confidence interval [CI], 15–44%) achieved a partial response. The median progression-free survival, median overall survival, and 1-year survival rate were 4.0 months (95% CI, 3.3–6.7 months), 12.6 months (95% CI, 7.0–22.3 months), and 51% (95% CI, 33–66%), respectively. The most common grade 3 or 4 toxicity was neutropenia (38%; 95% CI, 23–54%) and the rate of grade 3 or 4 nonhematologic toxicity remained at less than 5%. A multivariate Cox model showed that adenocarcinoma, nonsmoking history, and good performance status predicted better survival.ConclusionsCombination chemotherapy with UFT and gemcitabine showed a promising effectiveness and acceptable toxicity for patients with platinum-resistant NSCLC

S-1 Plus Cisplatin with Concurrent Radiotherapy for Locally Advanced Non-small Cell Lung Cancer: A Multi-Institutional Phase II Trial (West Japan Thoracic Oncology Group 3706)

Purpose:To evaluate the combination chemotherapy using oral antimetabolite S-1 plus cisplatin (SP) with concurrent thoracic radiotherapy (RT) followed by the consolidation SP for locally advanced non-small cell lung cancer.Patients and Methods:Patients with stage III non-small cell lung cancer, 20 to 74 years of age, and Eastern Cooperative Oncology Group performance status 0 to 1 were eligible. The concurrent phase consisted of full dose S-1 (orally at 40 mg/m2/dose twice daily, on days 1–14) and cisplatin (60 mg/m2 on day 1) repeated every 4 weeks for two cycles with RT delivered beginning on day 1 (60 Gy/30 fractions over 6 weeks). After SP-RT, patients received an additional two cycles of SP as the consolidation phase.Results:Fifty-five patients were registered between November 2006 and December 2007. Of the 50 patients for efficacy analysis, the median age was 64 years; male/female 40/10; Eastern Cooperative Oncology Group performance status 0/1, 21/29; clinical stage IIIA/IIIB 18/32; and adenocarcinoma/others 20/30. There were 42 clinical responses including one complete response with an objective response rate of 84% (95% confidence interval [CI], 71–93%). The 1- and 2-year overall survival rates were 88% (95% CI, 75–94%) and 70% (95% CI, 55–81%), respectively. The median progression-free survival was 20 months. Of the 54 patients for safety analysis, common toxicities in the concurrent phase included grade 3/4 neutropenia (26%), thrombocytopenia (9%), and grade 3 esophagitis (9%) and febrile neutropenia (9%). In one patient, grade 3 pneumonitis was observed in the consolidation phase. There were two treatment-related deaths caused by infection in the concurrent phase.Conclusions:SP-RT showed a promising efficacy against locally advanced NCSLC with acceptable toxicity

Duration of adjuvant chemotherapy for stage III colon cancer

BACKGROUND Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. METHODS We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. RESULTS After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). CONCLUSIONS Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.

Randomised phase II trial of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab as first-line treatment for colorectal liver metastasis (ATOM trial)

BackgroundChemotherapy with biologics followed by liver surgery improves the resection rate and survival of patients with colorectal liver metastasis (CRLM). However, no prospective study has compared the outcomes of chemotherapy with bevacizumab (BEV) versus cetuximab (CET).MethodsThe ATOM study is the first randomised trial comparing BEV and CET for initially unresectable CRLM. Patients were randomly assigned in a 1:1 ratio to receive mFOLFOX6 plus either BEV or CET. The primary endpoint was progression-free survival (PFS).ResultsBetween May 2013 and April 2016, 122 patients were enrolled. Median PFS was 11.5 months (95% CI 9.2–13.3 months) in the BEV group and 14.8 months (95% CI 9.7–17.3 months) in the CET group (hazard ratio 0.803; P = 0.33). Patients with a smaller-number but larger-sized metastases did better in the CET group. In the BEV and CET groups, the response rates were 68.4% and 84.7% and the resection rates were 56.1% and 49.2%, respectively.ConclusionAlthough CET achieved a better response rate than BEV for patients with a small number of large liver metastases, both biologics had similar efficacy regarding liver resection and acceptable safety profiles. To achieve optimal PFS, biologics should be selected in accordance with patient conditions.Trial registrationThis trial is registered at ClinicalTrials.gov (number NCT01836653), and UMIN Clinical Trials Registry (UMIN-CTR number UMIN000010209)

A phase I/II clinical trial for the hybrid of intracavitary and interstitial brachytherapy for locally advanced cervical cancer

BackgroundThis paper describes about a study protocol of phase I/II multicenter prospective clinical trial evaluating the feasibility and efficacy of the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced uterine cervical cancer patients.Methods and designPatients with histologically confirmed FIGO stage IB2, IIA2, IIB, and IIIB uterine cervical carcinoma width of which is larger than 5 cm assessed by MRI will be entered to this clinical trial. Protocol therapy is 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP (40 mg/m2), followed by 24 Gy in 4 fractions of HBT and central shield EBRT up to 50-50.4 Gy in 25-28 fractions. Tumor width is assessed again within one week before the first HBT and if the tumor width is larger than 4 cm, patients proceed to the secondary registration. In phase I section, feasibility of this will be investigated. If less than 10 % out of 20 patients experienced greater than grade 3 acute non-hematologic adverse effects, the study proceeds to phase II part. In phase II part a total of 55 patients will be accrued and the efficacy of the HBT will be investigated comparing with historical control data. If the lower margin of 90 % confidence interval of the 2-year pelvic progression-free survival of the HBT trial is higher than 64 %, the HBT is considered to be more effective than conventional ICBT.DiscussionThe aim of this study is to demonstrate the feasibility and efficacy of the HBT for locally advanced cervical cancer. This trial will clarify the indication, feasibility, and efficacy of this new technique

Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study

Background: Glutathione plays crucial roles in the detoxification and antioxidant systems of cells and has been used to treat acute poisoning and chronic liver diseases by intravenous injection. This is a first study examining the therapeutic effects of oral administration of glutathione in patients with nonalcoholic fatty liver disease (NAFLD). Methods: The study was an open label, single arm, multicenter, pilot trial. Thirty-four NAFLD patients diagnosed using ultrasonography were prospectively evaluated. All patients first underwent intervention to improve their lifestyle habits (diet and exercise) for 3 months, followed by treatment with glutathione (300 mg/day) for 4 months. We evaluated their clinical parameters before and after glutathione treatment. We also quantified liver fat and fibrosis using vibration-controlled transient elastography. The primary outcome of the study was the change in alanine aminotransferase (ALT) levels. Results: Twenty-nine patients finished the protocol. ALT levels significantly decreased following treatment with glutathione for 4 months. In addition, triglycerides, non-esterified fatty acids, and ferritin levels also decreased with glutathione treatment. Following dichotomization of ALT responders based on a median 12.9% decrease from baseline, we found that ALT responders were younger in age and did not have severe diabetes compared with ALT non-responders. The controlled attenuation parameter also decreased in ALT responders. Conclusions: This pilot study demonstrates the potential therapeutic effects of oral administration of glutathione in practical dose for patients with NAFLD. Large-scale clinical trials are needed to verify its efficacy. Trial registration: UMIN000011118 (date of registration: July 4, 2013)

A Multicenter Phase II Trial of Docetaxel, Cisplatin, and Cetuximab (TPEx) Followed by Cetuximab and Concurrent Radiotherapy for Patients With Local Advanced Squamous Cell Carcinoma of the Head and Neck (CSPOR HN01: ECRIPS Study)

Background: Induction chemotherapy (IC) is a treatment option for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). However, treatment with docetaxel, cisplatin, and 5-FU (TPF) followed by cisplatin and radiotherapy is controversial because of toxicity concerns. The aim of this phase II study was to assess the feasibility of docetaxel, cisplatin, and cetuximab (TPEx) followed by cetuximab and concurrent radiotherapy for LA SCCHN.Patients and Methods: We enrolled patients with histological evidence of squamous cell carcinoma of the oropharynx, hypopharynx, or larynx without distant metastases. IC comprised cisplatin (75 mg/m2) and docetaxel (75 mg/m2) on day 1, repeated every 3 weeks for up to three courses. Cetuximab was initiated at 400 mg/m2, followed by 250 mg/m2 doses weekly until the end of radiotherapy. Radiotherapy (70 Gy/35 fr/7 w) was initiated after the last docetaxel administration. The primary endpoint was the rate of treatment completion.Results: We enrolled 54 patients (median age, 58 years) between August 2013 and October 2015. Our patients were 49 males and 5 females with hypopharyngeal (n = 28), oropharyngeal (n = 19), or laryngeal (n = 7) cancers, and 48 of them had stage IV disease. The overall response rate was 72.2% with a median follow-up of 36.1 months and a 3-year overall survival of 90.7%. The treatment completion rate was 76%; 50 patients (93%) received ≥2 courses of IC, and 41 (76%) completed radiotherapy. The frequencies of grade ≥3 febrile neutropenia or allergy/infusion reactions were 39% and 11%, respectively. There was one treatment-related death.Conclusions: IC with TPEx followed by cetuximab with concurrent radiotherapy showed acceptable compliance for the treatment of LA SCCHN. However, high frequency of febrile neutropenia remains a challenge and further improvement in the management of TPEx is necessary.Trial Registration: UMIN00000992

Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With EGFR Mutations

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients’ reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients