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Kato Y.,University of Colorado at Denver | Kato Y.,Tokyo Medical University | Peled N.,University of Colorado at Denver | Wynes M.W.,University of Colorado at Denver | And 9 more authors.
Journal of Thoracic Oncology | Year: 2010

Background: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict better outcome to EGFR tyrosine kinase inhibitors. The most common mutations are exon 19 deletions (most frequently E746-A750) and L858R point mutation in exon 21. Here, we evaluated the accuracy of novel EGFR mutation-specific antibodies in a Japanese cohort with NSCLC and compared with direct DNA sequencing and clinical outcome. Materials and Methods: Immunohistochemistry (IHC) using antibodies specific for the E746-A750 and L858R mutations in EGFR was performed on tissue microarrays of tumors from 70 gefitinib treated NSCLC patients. Extracted DNA was sequenced for mutational analysis of EGFR exons 18 to 21. Results: DNA sequencing showed EGFR mutations in 41 patients (58.6%) and exon 19 deletions in 18 patients (25.7%), 11 of 18 (61%) had a deletion in the range of E746-A750 and 12 (17.1%) had exon 21 mutations (L858R). IHC showed, for the E746-A750 and L858R mutations, sensitivity (81.8 and 75%), specificity (100 and 96.6%), positive predictive value (100 and 81.8%), and negative predictive value (96.7 and 94.9%). Analysis for objective response rates and survival were not correlated to IHC staining, although the combined staining showed nonsignificant trends toward better overall survival for patients with EGFR mutations. Conclusions: The mutation-specific IHC antibodies have high sensitivity and specificity for predefined EFGR mutations and may be suitable for screening for these predefined mutations. However, negative IHC results require further mutation analyses before excluding EGFR-targeted therapy. Copyright © 2010 by the International Association for the Study of Lung Cancer. Source


Lin Y.,Aichi Medical University | Ueda J.,Aichi Medical University | Yagyu K.,Aichi Medical University | Ishii H.,Cancer Institute Hospital | And 6 more authors.
BMC Cancer | Year: 2013

Background: It is clear that genetic variations in the fat mass and obesity-associated (FTO) gene affect body mass index and the risk of obesity. Given the mounting evidence showing a positive association between obesity and pancreatic cancer, this study aimed to investigate the relation between variants in the FTO gene, obesity and pancreatic cancer risk.Methods: We conducted a hospital-based case-control study in Japan to investigate whether genetic variations in the FTO gene were associated with pancreatic cancer risk. We genotyped rs9939609 in the FTO gene of 360 cases and 400 control subjects. An unconditional logistic model was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between rs9939609 and pancreatic cancer risk.Results: The minor allele frequency of rs9939609 was 0.18 among control subjects. BMI was not associated with pancreatic cancer risk. Compared with individuals with the common homozygous TT genotype, those with the heterozygous TA genotype and the minor homozygous AA genotype had a 48% (OR=1.48; 95%CI: 1.07-2.04), and 66% increased risk (OR=1.66; 95%CI: 0.70-3.90), respectively, of pancreatic cancer after adjustment for sex, age, body mass index, cigarette smoking and history of diabetes. The per-allele OR was 1.41 (95%CI: 1.07-1.85). There were no significant interactions between TA/AA genotypes and body mass index.Conclusions: Our findings indicate that rs9939609 in the FTO gene is associated with pancreatic cancer risk in Japanese subjects, possibly through a mechanism that is independent of obesity. Further investigation and replication of our results is required in other independent samples. © 2013 Lin et al.; licensee BioMed Central Ltd. Source


Wada H.,Kanagawa Cancer Center Hospital | Shiozawa M.,Kanagawa Cancer Center Hospital | Katayama K.,Kanagawa Cancer Center | Okamoto N.,Kanagawa Cancer Center | And 4 more authors.
Journal of Gastroenterology | Year: 2015

Background: In this study we examined whether histopathological findings, specifically lymphatic vessel invasion identified by an anti-human podoplanin antibody, and several other factors are associated with lymph node metastasis in T1 colorectal cancer. Methods: We searched PubMed and Cochrane Library, and also handsearched relevant journals, for reports written in English and published between 1998 and 2012, utilizing combination headings, such as ‘colorectal cancer,’ ‘lymph node metastasis,’ and ‘risk factors.’ For the report to be included in our study, the following criteria had to be met: (1) data on the frequency of lymph node metastasis in T1 colorectal cancer in relation to histopathological factors were reported; (2) patients had undergone bowel resection and had histologically diagnosed T1 colorectal cancer; (3) lymphatic vessel invasion was identified by immunohistochemistry with an anti-human podoplanin antibody rather than by hematoxylin and eosin staining; (4) univariate and multivariate analyses were conducted. Studies investigating molecular markers were excluded. The independent predictive factors were confirmed in at least one study included in the meta-analysis in the present systematic review. Microsoft Excel 2013 for Windows was used for the statistical analysis. Results: Initially, 369 publications were identified in the database searches and handsearches, of which five ultimately met all of the inclusion criteria and selected for this systematic review. The meta-analysis revealed that only two factors were significantly associated with T1 colorectal cancer lymph node metastasis: (1) lymphatic vessel invasion identified by an anti-human podoplanin antibody [Mantel–Haenszel odds ratio (OR) 5.19; (95 % confidence interval (CI) 3.31–8.15; P = 0.01]; (2) tumor budding (OR 7.45; 95 % CI 4.27–13.02; P = 0.0077). Conclusion: Our meta-analysis revealed that lymphatic vessel invasion identified by an anti-human podoplanin antibody and tumor budding were significantly associated with T1 colorectal cancer lymph node metastasis. © 2015, Springer Japan. Source


Okusaka T.,National Cancer Center Hospital | Furuse J.,National Cancer Center Hospital East | Furuse J.,Kyorin University | Funakoshi A.,National Kyushu Cancer Center | And 10 more authors.
Cancer Science | Year: 2011

Erlotinib combined with gemcitabine has not been evaluated in Japanese patients with unresectable pancreatic cancer. This two-step phase II study assessed the safety and pharmacokinetics of erlotinib 100mg/day (oral) plus gemcitabine 1000mg/m2 (i.v. days 1, 8, 15) in a 28-day cycle in the first step, and efficacy and safety in the second step. The primary end-point was safety. One hundred and seven patients were enrolled (first step, n=6; second step, n=101). The most common adverse event was RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) in 93.4% of patients. One treatment-related death occurred. While interstitial lung disease-like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%), all patients recovered or improved. The median overall survival, the 1-year survival rate and median progression-free survival were 9.23months, 33.0% and 3.48months, respectively. The overall response and disease control rates were 20.3% and 50.0%, respectively. In Japanese patients with unresectable pancreatic cancer, erlotinib plus gemcitabine had acceptable toxicity and efficacy that was not inferior to that seen in Western patients. (Cancer Sci 2011; 102: 425-431) © 2010 Japanese Cancer Association. Source


Kindler H.L.,University of Chicago | Ioka T.,Japan National Cardiovascular Center Research Institute | Richel D.J.,University of Amsterdam | Bennouna J.,Center Rene Gauducheau | And 13 more authors.
The Lancet Oncology | Year: 2011

Background: Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. Methods: In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m2 intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. Findings: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). Interpretation: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. Funding: Pfizer. © 2011 Elsevier Ltd. Source

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