Purpose: Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic a (PIK3CA) gene in several human solid tumors. Although gene amplifications of PIK3CA have been reported in head and neck squamous cell carcinoma (HNSCC), small mutation of the gene has not been evaluated in HNSCC previously. In this study, we examined the mutation frequency of PIK3CA in HNSCC. Experimental Design: More than 75% of the somatic mutations of PIK3CA are clustered in the helical (exon 9) and kinase domains (exon 20). To investigate the possible role of PIK3CA in HNSCC tumorigenesis, exons 1, 4, 5, 6, 7, 9, and 20 of the gene were analyzed by direct genomic DNA sequencing in 38 HNSCC specimens. Results: We identified four missense mutations in the seven exons of PIK3CA from 38 HNSCC specimens (11%). Three of the four mutations (i.e., H1047R, E542K, and E545K) have been previously reported as hotspot mutations.The remaining novel mutation,Y343C, is identified at exon 4 nucleotide 1028 A ! G. Three of the four mutations were shown to be somatic, whereas the fourth mutation (H1047R) was identified in a cell line. Interestingly, three of the four mutations identified were in pharyngeal cancer samples. Conclusions: These data provide evidence that oncogenic properties of PIK3CA contribute to the carcinogenesis of human head and neck cancers, especially in pharyngeal cancer. A specific kinase inhibitor to PIK3CA may potentially be an effective therapeutic reagent against HNSCC or pharyngeal cancer in particular.

Purpose: Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic-a (PIK3CA) gene in various human solid tumors. More than 75% of those somatic mutations are clustered in the helical (exon 9) and kinase domains (exon 20). The three hot-spot mutations, E542K, E545K, and H1047R, have been proven to elevate the lipid kinase activity of PIK3CA and activate the Akt signaling pathway. The mutational status of PIK3CA in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) has not been evaluated previously. Experimental Design: To evaluate a possible role for PIK3CA in the tumorigenesis of IPMN and IPMC, exons 1, 4, 5, 6, 7, 9, 12, 18, and 20 were analyzed in 36 IPMN/IPMC and two mucinous cystadenoma specimens by direct genomic DNA sequencing. Results: We identified four missense mutations in the nine screened exons of PIK3CA from 36 IPMN/IPMC specimens (11%). One of the four mutations, H1047R, has been previously reported as a hot-spot mutation. The remaining three mutations, T324I, W551G, and S1015F, were novel and somatic. Conclusion: This is the first report of PIK3CA mutation in pancreatic cancer. Our data provide evidence that the oncogenic properties of PIK3CA contribute to the tumorigenesis of IPMN/ IPMC.

The Raf/MEK/ERK (MAPK) signal transduction is an important mediator of a number of cellular fates including growth, proliferation and survival. The BRAF gene is activated by onogenic RAS, leading to cooperative effects in cells responding to growth factor signals. Our study was performed to elucidate a possible role of BRAF in the development of IPMN (Intraductal Papillary Mucinous Neoplasm) and IPMC (Intraductal Papillary Mucinous Carcinoma) of the pancreas. Mutations of BRAF and KRAS were evaluated in 36 IPMN/IPMC samples and two mucinous cystadenomas by direct genomic sequencing. Exons 1 for KRAS, and 5, 11, and 15 for BRAF were examined. Totally we identified 17 (47%) KRAS mutations in exon 1, codon 12 and one missense mutation (2.7%) within exon 15 of BRAF. The mutations appear to be somatic since the same alterations were not detected in the corresponding normal tissues. Our data provide evidence that oncogenic properties of BRAF contribute to the tumorigenesis of IPMN/IPMC, but at a lower frequency than KRAS.

Hepatic resection is the only cure for intrahepatic cholangiocellular carcinoma (ICC). The purpose of this study was to clarify the clinicopathologic characteristics and surgical outcome of patients with ICC. We retrospectively studied the records of 67 patients who underwent laparotomy for ICC from January 1995 through December 2005. Univariate and multivariate analyses were conducted for several variables to evaluate their influence on the outcome. Forty-five patients underwent hepatic resection. In 19 patients, the tumors were found to be unresectable at the time of laparotomy. Median 2- and 5-year survival rates in the 45 resected patients were 62% and 35%, respectively. For 36 patients who underwent curative resection, the 2- and 5-year survival were 67% and 41%, respectively; with a median survival of 43 months. The overall 5-year recurrence-free survival was 30%. The 90-day postoperative mortality rate was 4% and morbidity 28%. Multivariate analyses confirmed resection margin, lymph node involvement, blood loss, and blood transfusion to be independent significant variables for overall survival. Predictors of longer recurrence-free survival were lymph node involvement, vascular infiltration, blood loss, and transfusion. Surgical treatment of ICC by curative hepatic resection in patients without nodal invasion provides good long-term results. In contrast, incomplete tumor removal does not provide a survival benefit. An improved quality of preoperative staging was able to increase the resectability rate to acceptable 70%.

BackgroundClinical decision making in abdominal aortic aneurysms (AAA) relies completely on diameter. At this point, improved decision tools remain an unmet medical need. Our goal was to identify changes at the molecular level specifically leading up to AAA rupture.Methods and ResultsAortic wall tissue specimens were collected during open elective (eAAA; n=31) or emergency repair of ruptured AAA (rAAA; n=17), and gene expression was investigated using microarrays. Identified candidate genes were validated with quantitative real‐time polymerase chain reaction in an independent sample set (eAAA: n=46; rAAA: n=18). Two gene sets were identified, 1 set containing 5 genes linked to terminal progression, that is, positively associated with progression of larger AAA, and with rupture (HILPDA,ANGPTL4,LOX,SRPX2,FCGBP), and a second set containing 5 genes exclusively upregulated in rAAA (ADAMTS9,STC1,GFPT2,GAL3ST4,CCL4L1). Genes in both sets essentially associated with processes related to impaired tissue remodeling, such as angiogenesis and adipogenesis. In gene expression experiments we were able to show that upregulated gene expression for identified candidate genes is unique for AAA. Functionally, the selected upregulated factors converge at processes coordinated by the canonical HIF‐1α signaling pathway and are highly expressed in fibroblasts but not inflammatory cells of the aneurysmatic wall. Histological quantification of angiogenesis and exploration of the HIF‐1α network in rAAA versus eAAA shows enhanced microvessel density but also clear activation of the HIF‐1α network in rAAA.ConclusionsOur study shows a specific molecular fingerprint for terminal AAA disease. These changes appear to converge at activation of HIF‐1α signaling in mesenchymal cells. Aspects of this cascade might represent targets for rupture risk assessment.