Citations

Abstract Background: The EML4-ALK fusion gene is more frequently found in younger, never smoking patients with lung cancer. Meanwhile, never smokers exposed to secondhand tobacco smoke (SHS) during childhood are diagnosed at a younger age compared with never smoking patients with lung cancer who are not exposed. We, therefore, hypothesized that SHS, which can induce DNA damage, is associated with the EML4-ALK fusion gene. Methods: We compared the frequency of the EML4-ALK fusion gene among 197 never smoker patients with lung cancer with and without a history of exposure to SHS during childhood at Mayo Clinic. Results: The EML4-ALK fusion gene was detected in 33% of cases from never smokers with a history of SHS exposure during childhood, whereas 47% of never smoking lung cancer cases without a history of childhood SHS exposure tested positive for the fusion gene. Conclusions: The EML4-ALK fusion gene is not enriched in tumors from individuals exposed to SHS during childhood. Impact: These data suggest that childhood exposure to SHS is not a significant etiologic cause of the EML4-ALK fusion gene in lung cancer. Cancer Epidemiol Biomarkers Prev; 23(7); 1432–4. ©2014 AACR.

Background— Coronary collateral flow is an alternative source of myocardial perfusion in patients with totally occluded coronary arteries. Clinical evaluation of collateral flow has been limited by the need of invasive measurements. We investigated whether noninvasive coronary computed tomographic angiography can evaluate the angiographic extent of coronary collateral flow. Methods and Results— We enrolled 325 coronary computed tomographic angiography cases with angiographically confirmed chronic total occlusion (median age, 63 years; men 83%). Transluminal attenuation gradient (TAG), which reflects the kinetics of contrast media in coronary artery, of an entire artery as well as of a distal vessel was assessed to evaluate the flow in entire vessel and distal vessel. TAGs were validated against visually assessed angiographic collateral connection and Rentrop grading. TAG of an entire artery increased consistently according to the angiographic extent of collateral flow ( P <0.001). Well-developed collaterals, defined by highest collateral connection and Rentrop grades (n=103), could be predicted by TAG of an entire artery (cutoff, ≥−7.6 Hounsfield units/10 mm; c -statistics, 0.72; sensitivity, 65%; specificity, 73%; positive predictive value, 52%; negative predictive value, 82%). TAG of a distal vessel could discriminate the antegrade (n=143) and retrograde (n=182) flows in distal artery (cutoff, 0.0 Hounsfield unit/10 mm; c -statistics, 0.88; sensitivity, 78%; specificity, 85%; positive predictive value, 87%; negative predictive value, 75%). Conclusions— TAG, an intracoronary attenuation-based analysis of coronary computed tomographic angiography, moderately reflected the functional extent and direction of collateral flow.

Abstract Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote KrasG12D-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in KrasG12D mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer–promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1–STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials. Significance: Our study points to the existence of an oncogenic NFATc1–STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1–STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies. Cancer Discov; 4(6); 688–701. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 621

SummaryObjectiveTo better understand the relationship between efficacy and perampanel dose, integrated actual (last) dose data from three phase III trials and an extension study (blinded Conversion Period; open‐label Maintenance Period) were analyzed.MethodsSeizure frequency data were analyzed in patients who were randomized to and completed the 13‐week Maintenance Period of the phase III studies on perampanel 8 mg, and who received an actual (last) dose of 12 mg during (1) the extension 16‐week blinded Conversion Period or (2) weeks 1–13 of the extension Maintenance Period. Due to a treatment‐by‐region interaction (p = 0.042), analyses excluded patients from the Latin America region (n = 162/1,480; 10.9% of the treated cohort).ResultsOf 372 patients randomized to 8 mg in the phase III studies, 273 completed the Maintenance Period at 8 mg and 267 entered the extension study. In patients who then had an actual (last) dose of 12 mg during the extension blinded Conversion Period (n = 217), median percent change in seizure frequency per 28 days improved from −32.4% (8 mg, phase III Maintenance Period) to −44.2% (12 mg, extension blinded Conversion Period); 50% responder rates increased slightly from 37.3% to 42.9%. In patients who completed the phase III studies on 8 mg and had an actual (last) dose of 12 mg during weeks 1–13 of the extension Maintenance Period (n = 181), median percent change in seizure frequency per 28 days improved from −34.1% (phase III Maintenance Period) to −46.0% (weeks 1–13 extension Maintenance Period); 50% responder rates were 39.2% and 46.4%. Seizure control remained substantially unchanged in patients who completed the phase III studies at 12 mg and continued on that dose during the extension.SignificanceIncreasing perampanel dose from 8 to 12 mg can produce additional benefits in seizure control in at least some patients who tolerate the higher dose.

Leptin is a circulating hormone secreted by adipose and a few other tissues. The leptin receptor consists of a single transmembrane-spanning polypeptide that is present as a long physiologically important form as well as in several short isoforms. Recent studies have suggested that the anterior pituitary may have a role in the regulatory effects of leptin in animal models. To test this possibility in human pituitaries, we examined the expression of leptin and OB-R in normal and neoplastic pituitaries, and the possible functions of leptin in the pituitary were also analyzed. Leptin was present in 20–25% of anterior pituitary cells and was expressed in most normal anterior pituitary cells, including ACTH (70% of ACTH cells), GH (21%), FSH (33%), LH (29%), TSH (32%), and folliculo-stellate cells (64%), but was colocalized with very few PRL cells (3%), as detected by double labeling immunohistochemistry with two different antileptin antibodies. In addition, leptin expression was detected by RT-PCR in some pituitary tumors, including ACTH (three of four), GH (one of four), null cells (two of four), and gonadotroph (one of four) tumors as well as in normal pituitary. Immunohistochemical staining showed greater immunoreactivity for leptin in normal pituitaries compared to adenomas. Treatment of an immortalized cultured anterior pituitary cell line, HP75, with leptin stimulated pancreastatin secretion in vitro. Leptin also inhibited cell growth in the human HP75 and in the rat pituitary GH3 cell lines. Both long (OB-Rb) and common (OB-Ra) forms of the leptin receptor messenger ribonucleic acid and leptin receptor protein were expressed in normal and neoplastic anterior pituitary cells. These findings show for the first time that leptin is expressed by most human anterior pituitary cell types and that there is decreased leptin protein immunoreactivity in pituitary adenomas compared to that in normal pituitary tissues. We also show that OB-Rb is widely expressed by normal and neoplastic anterior pituitary cells, implicating an autocrine/paracrine loop in the production and regulation of leptin in the pituitary.

AbstractWe examined the specific cell types in normal human pituitaries that expressed PRL receptor (PRL-R) messenger ribonucleic acid (mRNA) by combined in situ hybridization and immunohistochemistry. The distribution of PRL-R mRNA in 28 pituitary adenomas was examined by in situ hybridization and reverse transcription-PCR in 12 cases of adenomas. In another set of experiments, 34 PRL adenomas from men, women, and bromocriptine-treated patients were analyzed for PRL-R by in situ hybridization.In the normal pituitary, PRL- and LH-producing cells had significantly more mean grain counts per cell and higher percentages of cells positive for PRL-R than GH and TSH cells. PRL-R mRNA was present in all groups of adenomas by in situ hybridization and reverse transcription-PCR. PRL adenomas had a significantly higher density of labeling compared to other adenoma types. Although there was no difference in the levels of PRL-R mRNA in PRL adenomas from men and premenopausal and postmenopausal women, patients treated with bromocriptine before pituitary surgery had significantly lower levels of PRL-R compared to all other groups. These results indicate that in the normal pituitary, PRL and LH cells have the highest level of PRL-R mRNA, whereas PRL adenomas have significantly higher levels of PRL-R mRNA than other types of adenomas, and bromocriptine treatment decreases the levels of PRL-R mRNA in PRL adenomas.