Citations

Emerging technologies have greatly expanded our ability to detect, characterize, and treat colorectal cancer. The Coalition of Cancer Cooperative Groups convened a multidisciplinary panel, the Scientific Leadership Council in GI cancer, to discuss and advise on the priorities and opportunities to advance current and future approaches into the clinical arena to impact most rapidly the morbidity and mortality from this disease. The Council's recommendations for research priorities are the result of engagement of community and academic oncologists, patient advocacy groups, and other stakeholders including the pharmaceutical industry and governmental agencies. We detail some key prospects for investigation in the areas of colon cancer detection, prevention, and surgical and medical management. Many are in early or definitive clinical trials, and a focus on rapid accrual is urged. The implementation of biology-directed laboratory investigations, both in association with ongoing clinical trials and as a separate developmental strategy for targeted therapies, is supported as the route to individualized therapy.

Purpose The clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression in glioblastoma multiforme (GBM) and its relationship with other key molecular markers are not clear. We sought to evaluate the clinical significance of GBM subtypes as defined by EGFRvIII status. Patients and Methods The expression of EGFRvIII was assessed by immunohistochemistry in 649 patients with newly diagnosed GBM. These data were then examined in conjunction with the expression of phospho-intermediates (in a subset of these patients) of downstream AKT and Ras pathways and YKL-40 as well as with known clinical risk factors, including the Radiation Therapy Oncology Group's recursive partitioning analysis (RTOG-RPA) class. Results The RTOG-RPA class was highly predictive of survival in EGFRvIII-negative patients but much less predictive in EGFRvIII-positive patients. These findings were seen in both an initial test set (n = 268) and a larger validation set (n = 381). Similarly, activation of the AKT/MAPK pathways and YKL-40 positivity were predictive of poor outcome in EGFRvIII-negative patients but not in EGFRvIII-positive patients. Pair-wise combinations of markers identified EGFRvIII and YKL-40 as prognostically important. In particular, outcome in patients with EGFRvIII-negative/YKL-40–negative tumors was significantly better than the outcome in patients with the other three combinations of these two markers. Conclusion Established prognostic factors in GBM were not predictive of outcome in the EGFRvIII-positive subset, although this requires confirmation in independent data sets. GBMs negative for both EGFRvIII and YKL-40 show less aggressive behavior.

Genetic variants in the gene encoding integrin α2 ( ITGA2) have been reported to be associated with an increased risk for ischemic stroke. The purpose of this study was to investigate the association between haplotype-tagging single-nucleotide polymorphisms (tSNPs) in ITGA2 and risk of ischemic stroke in a collection of North American stroke cases and controls. The study included 484 cases and 263 controls. Thirteen tSNPs were genotyped. Association tests at and across each tSNP were performed, including haplotype association analysis. Secondary analyses considered stroke subtypes on the basis of Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. We observed significant association between tSNP rs3756541 (additive model, odds ratio (OR), 1.49; 95% confidence interval (CI), 1.11 to 2.04; P = 0.009) and disease and a trend toward association at rs2303124 (recessive model, OR, 1.56; 95% CI, 1.05 to 2.33; P = 0.03). These associations remained significant in the haplotype analyses. The associated tSNPs did not distinguish stroke etiology after application of TOAST criteria. Our results suggest that genetic variability within ITGA2 may confer risk for ischemic stroke independent of conventional risk factors. These results provide additional support for a role for platelet receptor genes in the pathogenesis of ischemic stroke of diverse subtypes.

Epimorphin (also known as syntaxin 2) acts as an epithelial morphogen when secreted by stromal cells of the mammary gland, lung, liver, colon, pancreas and other tissues, but the same molecule functions within the cell to mediate membrane fusion. How this molecule, which lacks a signal sequence and contains a transmembrane domain at the C-terminus, translocates across the plasma membrane and is secreted to become a morphogen, and how it initiates morphogenic events is not clear. Here, we show that epimorphin is secreted through a non-classical mechanism, similar to that previously described for secretion of the leaderless protein FGF1, and we identify the key molecular elements responsible for translocation and secretion from the cell. We also show that secreted epimorphin binds to αv-integrin-containing receptors on target epithelial cells, leading to activation of specific downstream signaling pathways and induction of epithelial morphogenesis. These findings provide key insight into how epimorphin functions as an epithelial morphogen.

Background— Little is known about the impact of technological and pharmacological advances on long-term outcome after percutaneous coronary intervention in general clinical practice. Methods and Results— We analyzed in-hospital and long-term outcome of 24 410 percutaneous coronary interventions among 18 575 unique patients who underwent percutaneous coronary intervention at Mayo Clinic over 25 years. The study population was divided into group 1 (n=3708), coronary interventions from 1979 to 1989; group 2 (n=7020), interventions from 1990 to 1996; group 3 (n=10 952), interventions from 1996 to 2003; and group 4 (n=2730), interventions from 2003 to 2004. Despite the fact that patients in groups 3 and 4 were significantly older, sicker, and had greater prevalence of comorbid conditions, heart failure, and previous revascularization than those in groups 1 and 2, procedural success in groups 3 and 4 improved significantly (94%) versus groups 2 (89%) and 1 (78%) ( P <0.001). Significant reduction in in-hospital mortality (groups 4 to 1: 1.8%, 1.7%, 2.6%, 3.0%; P <0.001) and need for emergency bypass surgery (groups 4 to 1: 0.4%, 0.5%, 1.6%, 5%; P <0.001) was noted in groups 3 and 4 compared with groups 1 and 2. Better adherence to currently recommended evidence-based medications for secondary prevention was seen in the recent time periods. After adjustment, significant reduction in follow-up mortality (hazard ratio, 0.81 and 0.74 for groups 3 and 4, respectively); death or myocardial infarction (hazard ratio, 0.80 and 0.75 for groups 3 and 4, respectively); death, myocardial infarction, or revascularization (hazard ratio, 0.76 and 0.58 for groups 3 and 4, respectively) was noted in recent time periods. Conclusions— Despite higher-risk profiles of patients who underwent percutaneous coronary intervention in recent time periods, procedural success as well as in-hospital and long-term outcomes improved significantly over the last 25 years.

OBJECTIVE—To determine the contribution of hepatic insulin resistance to the pathogenesis of impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS—Endogenous glucose production (EGP) and glucose disposal were measured in 31 subjects with IFG and 28 subjects with normal fasting glucose (NFG) after an overnight fast and during a clamp when endogenous secretion was inhibited with somatostatin and insulin infused at rates that approximated portal insulin concentrations present in IFG subjects after an overnight fast (∼80 pmol/l, “preprandial”) or within 30 min of eating (∼300 pmol/l, “prandial”). RESULTS—Despite higher (P &lt; 0.001) insulin and C-peptide concentrations and visceral fat (P &lt; 0.05), fasting EGP and glucose disposal did not differ between IFG and NFG subjects, implying hepatic and extrahepatic insulin resistance. This was confirmed during preprandial insulin infusion when glucose disposal was lower (P &lt; 0.05) and EGP higher (P &lt; 0.05) in IFG than in NFG subjects. Higher EGP was due to increased (P &lt; 0.05) rates of gluconeogenesis in IFG. EGP was comparably suppressed in IFG and NFG groups during prandial insulin infusion, indicating that hepatic insulin resistance was mild. Glucose disposal remained lower (P &lt; 0.01) in IFG than in NFG subjects. CONCLUSIONS—Hepatic and extrahepatic insulin resistance contribute to fasting hyperglycemia in IFG with the former being due at least in part to impaired insulin-induced suppression of gluconeogenesis. However, since hepatic insulin resistance is mild and near-maximal suppression of EGP occurs at portal insulin concentrations typically present in IFG subjects within 30 min of eating, extrahepatic (but not hepatic) insulin resistance coupled with accompanying defects in insulin secretion is the primary cause of postprandial hyperglycemia.