Search tips
Search criteria

Results 1-7 (7)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study) 
We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.
The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.
Between February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p = 0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p = 0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of < 3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p = 0.289) but showed a delayed response.
Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of < 3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.
Trial registration
Trial registration: UMIN000001791.
PMCID: PMC4021539  PMID: 24884643
Peptide vaccine; Peptide cocktail; Colorectal cancer; Phase II study; FOLFOX; Chemotherapy
2.  Simultaneous identification of 36 mutations in KRAS codons 61and 146, BRAF, NRAS, and PIK3CA in a single reaction by multiplex assay kit 
BMC Cancer  2013;13:405.
Retrospective analyses in the West suggest that mutations in KRAS codons 61 and 146, BRAF, NRAS, and PIK3CA are negative predictive factors for cetuximab treatment in colorectal cancer patients. We developed a novel multiplex kit detecting 36 mutations in KRAS codons 61 and 146, BRAF, NRAS, and PIK3CA using Luminex (xMAP) assay in a single reaction.
Tumor samples and clinical data from Asian colorectal cancer patients treated with cetuximab were collected. We investigated KRAS, BRAF, NRAS, and PIK3CA mutations using both the multiplex kit and direct sequencing methods, and evaluated the concordance between the 2 methods. Objective response, progression-free survival (PFS), and overall survival (OS) were also evaluated according to mutational status.
In total, 82 of 83 samples (78 surgically resected specimens and 5 biopsy specimens) were analyzed using both methods. All multiplex assays were performed using 50 ng of template DNA. The concordance rate between the methods was 100%. Overall, 49 (59.8%) patients had all wild-type tumors, 21 (25.6%) had tumors harboring KRAS codon 12 or 13 mutations, and 12 (14.6%) had tumors harboring KRAS codon 61, KRAS codon 146, BRAF, NRAS, or PIK3CA mutations. The response rates in these patient groups were 38.8%, 4.8%, and 0%, respectively. Median PFS in these groups was 6.1 months (95% confidence interval (CI): 3.1–9.2), 2.7 months (1.2–4.2), and 1.6 months (1.5–1.7); median OS was 13.8 months (9.2–18.4), 8.2 months (5.7–10.7), and 6.3 months (1.3–11.3), respectively. Statistically significant differences in both PFS and OS were found between patients with all wild-type tumors and those with KRAS codon 61, KRAS codon 146, BRAF, NRAS, or PIK3CA mutations (PFS: 95% CI, 0.11–0.44; P < 0.0001; OS: 95% CI, 0.15–0.61; P < 0.0001).
Our newly developed multiplex kit is practical and feasible for investigation of a range of sample types. Moreover, mutations in KRAS codon 61, KRAS codon 146, BRAF, NRAS, or PIK3CA detected in Asian patients were not predictive of clinical benefits from cetuximab treatment, similar to the result obtained in European studies.
PMCID: PMC3844320  PMID: 24006859
Luminex assay; KRAS; BRAF; NRAS; PIK3CA; Epidermal growth factor
3.  Radical prostatectomy as radical cure of prostate cancer in a high-risk group: A single-institution experience 
Molecular and Clinical Oncology  2012;1(2):337-342.
This study aimed to evaluate the possibility of performing radical prostatectomy (RP) alone to achieve radical cure of prostate cancer in a high-risk group. Between August 1998 and December 2008, 436 Japanese patients underwent antegrade RP following the exclusion of 139 patients. According to the D’Amico criteria, the low-, intermediate- and high-risk groups comprised 63, 122 and 112 patients, respectively. Twenty-five patients who were classified into the high-risk group based only on T2c stage, were evaluated as a separate intermediate/high-risk group. Results of the multivariate analysis revealed that of the preoperative characteristics only a biopsy Gleason score was a significant predictor in patients with and without PSA failure (P=0.017). After a median follow-up period of 60 months, the PSA failure-free rates in the low-, intermediate-, high- and intermediate/high-risk groups were 96.5, 92.2, 76.8 and 95.0%, respectively. No statistically significant difference was detected in the high- and intermediate/high-risk groups (P=0.064). Thus, patients classified into the high-risk group based on cT2 stage only, are considered to be potentially eligible for radical treatment by surgery alone, and should not be evaluated as high-risk patients.
PMCID: PMC3956272  PMID: 24649172
prostate cancer; radical prostatectomy; D’Amico classification; high-risk group; prostate-specific antigen failure
4.  Impact of treatment with bevacizumab beyond disease progression: a randomized phase II study of docetaxel with or without bevacizumab after platinum-based chemotherapy plus bevacizumab in patients with advanced nonsquamous non–small cell lung cancer (WJOG 5910L) 
BMC Cancer  2012;12:327.
Bevacizumab, a humanized antibody to vascular endothelial growth factor (VEGF), shows clinical activity against human cancer, with its addition to standard chemotherapy having been found to improve outcome in patients with advanced nonsquamous non–small cell lung cancer (NSCLC). However, there have been no evidence-based studies to support the continued use of bevacizumab beyond disease progression in such patients treated with the drug in first-line therapy. We have now designed a randomized phase II trial to examine the clinical benefit and safety of continued bevacizumab treatment in patients with advanced nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet.
WJOG 5910L was designed as a multicenter, open-label, randomized, phase II trial by the West Japan Oncology Group of docetaxel (arm A) versus docetaxel plus bevacizumab (arm B) in patients with recurrent or metatstatic nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. Patients in arm A will receive docetaxel at 60 mg/m2 and those in arm B will receive docetaxel at 60 mg/m2 plus bevacizumab at 15 mg/kg, with each drug administered on day 1 every 21 days until progression or unacceptable toxicity. The primary endpoint of the study is progression-free survival, with secondary endpoints including response rate, overall survival, and safety, for patients treated in either arm.
Trial registration
UMIN (University Hospital Medical Information Network in Japan) 000004715
PMCID: PMC3500214  PMID: 22849580
Bevacizumab; Beyond disease progression; Non-small cell lung cancer
5.  The longitudinal BMI pattern and body composition of patients with anorexia nervosa who require urgent hospitalization: A case control study 
The prevention of serious physical complications in anorexia nervosa (AN) patients is important. The purpose of this study is to clarify which physical and social factors are related to the necessity for urgent hospitalization of anorexia nervosa (AN) patients in a long-term starvation state. We hypothesized that the change of longitudinal BMI, body composition and social background would be useful as an index of the necessity for urgent hospitalization.
AN patients were classified into; urgent hospitalization, due to disturbance of consciousness or difficulty walking(n = 17); planned admission (n = 96); and outpatient treatment only groups (n = 136). The longitudinal BMI pattern and the clinical features of these groups were examined. In the hospitalization groups, comparison was done of body composition variation and the social background, including the educational level and advice from family members.
After adjusting for age and duration of illness, the BMI of the urgent hospitalization group was lower than that of the other groups at one year before hospitalization (P < 0.01) and decreased more rapidly (P < 0.01). Urgent hospitalization was associated with the fat free mass (FFM) (P < 0.01). Between the groups, no considerable difference in social factors was found.
The longitudinal pattern of BMI and FFM may be useful for understanding the severity in AN from the viewpoint of failure of the homeostasis system.
PMCID: PMC3275451  PMID: 22142436
6.  The TAO-Gen Algorithm for Identifying Gene Interaction Networks with Application to SOS Repair in E. coli 
Environmental Health Perspectives  2004;112(16):1614-1621.
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.
PMCID: PMC1247658  PMID: 15598612
gene networks; microarray; Bayesian model selection; SOS repair; toxicogenomics
7.  Gene Interaction Network Suggests Dioxin Induces a Significant Linkage between Aryl Hydrocarbon Receptor and Retinoic Acid Receptor Beta 
Environmental Health Perspectives  2004;112(12):1217-1224.
Gene expression arrays (gene chips) have enabled researchers to roughly quantify the level of mRNA expression for a large number of genes in a single sample. Several methods have been developed for the analysis of gene array data including clustering, outlier detection, and correlation studies. Most of these analyses are aimed at a qualitative identification of what is different between two samples and/or the relationship between two genes. We propose a quantitative, statistically sound methodology for the analysis of gene regulatory networks using gene expression data sets. The method is based on Bayesian networks for direct quantification of gene expression networks. Using the gene expression changes in HPL1A lung airway epithelial cells after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin at levels of 0.1, 1.0, and 10.0 nM for 24 hr, a gene expression network was hypothesized and analyzed. The method clearly demonstrates support for the assumed network and the hypothesis linking the usual dioxin expression changes to the retinoic acid receptor system. Simulation studies demonstrated the method works well, even for small samples.
PMCID: PMC1277115  PMID: 15345368
Bayesian networks; dioxin; gene regulatory networks; Markov chain Monte Carlo; retinoic acid receptor; risk assessment; systems biology; toxicogenomics

Results 1-7 (7)