Citations

Abstract Definitive radiotherapy combined with chemotherapy is associated with enhanced locoregional control and clinical outcomes in non-small cell lung cancer (NSCLC) patients who are not candidates for surgery. However, radiation-induced pneumonitis and esophagitis are common dose-limiting inflammatory conditions that occur in these patients. These events can compromise the effect of the overall treatment and reduce quality of life in these patients. It is not clear what factors contribute to differences in the development of toxicities among patients with same clinical or dosimetric parameters. In this study, we conducted a large scale pathway-based analysis to identify inflammation-related genetic variants associated with radiation-induced pneumonitis or esophagitis. In the initial discovery phase, 11,930 inflammation-related genetic variants were genotyped in 243 stage I-III NSCLC patients who were treated with definitive radiotherapy at MD Anderson Cancer Center. A fast-track validation was performed for the top candidate SNPs in an additional 212 NSCLC cases following the same criteria. A total of 14 SNPs and 12 SNPs were validated for pneumonitis and esophagitis, respectively. Meta-analysis was used to summarize the results from two phases. The most significant SNPs for esophagitis and pneumonitis mapped to chromosome 18p (OR=9.05, 95%CI=2.68-30.59, P-meta=3.90×10−4) and 14q (OR=4.75, 95%CI=2.17-10.41, P-meta =9.61×10−5), respectively. To explore the potential underlying mechanisms, we analyzed radiation sensitivity and eQTL relationships of the identified SNPs and their host genes in 277 ethnically defined human lymphoblastoid cell lines. Among the 24 host genes for the 26 identified SNPs, three genes (DDX58, GZMB, CDC2) showed significant association with radiation responses in these cell lines (P<0.05). Moreover, a significant eQTL relationship was identified between CDC2 expression and the genotype of the identified CDC2 SNP (P=0.022). Interestingly, this CDC2 SNP is predicted to create a new miRNA binding site. Luciferase reporter assays to test the influence of this SNP on miRNA regulation is currently ongoing. Our results provide evidence that inflammation-related genetic variants contribute to the development of radiation-induced pneumonitis and esophagitis. The results also suggest that gene expression changes through altered miRNA binding may be an underlying mechanism for these events. Citation Format: Xia Pu, Liewei Wang, Michelle AT Hildebrandt, Yuanqing Ye, Joe Y. Chang, Charles Lu, Heath D. Skinner, Nifang Niu, Gregory D. Jenkins, Ritsuko Komaki, John D. Minna, Jack A. Roth, Richard M. Weinshilboum, Xifeng Wu. Inflammation-related genetic variants predict radiation-induced toxicity following definitive radiotherapy for non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3626. doi:10.1158/1538-7445.AM2013-3626

BackgroundWe aimed to determine the long‐term outcomes of percutaneous lead extraction and stent placement in patients with pacemaker‐induced superior vena cava (SVC) syndrome.MethodsThe study retrospectively screened patients who underwent lead extraction followed by central vein stent implantation at Mayo Clinic (Rochester, MN, USA), from January 2005 to December 2012, to identify the patients with pacemaker‐induced SVC syndrome. Demographic, clinical, and follow‐up characteristics of those patients were collected from electronic medical records.ResultsSix cases were identified. The mean (standard deviation) age was 56 (15) years (male, 67%). All patients had permanent dual‐chamber pacemakers, with a mean 11‐year history of pacemaker placement. The entire device system was explanted in five patients; one patient had a 21‐year‐old pacemaker lead that could not be removed. Eight stents were implanted in six patients: five patients had one stent, one patient had three. A new pacemaker system was reimplanted through the stented vein in five patients. Technical success was achieved in all patients, without any complication. Symptoms rapidly resolved in all patients after stent deployment. The mean follow‐up duration was 48 months (range, 10–100 months). Three patients remained symptom free. Reintervention with percutaneous balloon venoplasty was successful in three patients with symptom recurrence.ConclusionPercutaneous stent implantation after lead removal followed by reimplantation of leads is a feasible alternative therapy for pacemaker‐induced SVC syndrome, although some cases may require repeat intervention.

Percutaneous Lead Revision for Cardiac PerforationIntroductionCardiac perforation is an infrequent but potentially life‐threatening complication associated with placement of a cardiac implantable electronic device (CIED). The objective of this study was to determine the outcomes of percutaneous lead revision in patients who had lead perforation of the myocardium after CIED placement.Methods and ResultsWe reviewed records of 1,458 patients who underwent CIED lead extraction or repositioning. Of these, 31 (2.1%) had the procedure performed for lead perforation as a complication of CIED placement. Demographic, clinical, and follow‐up characteristics of the patients were analyzed. Mean (SD) patient age was 65 (23) years. Cardiac perforation was detected within 24 hours after implantation in 9 patients, within 1 month in 17, and greater than 1 month in 5. Pericardiocentesis was performed with a pigtail drainage catheter in place before the lead revision in 17 patients (55%) who had pericardial effusion, with or without hemodynamic compromise. All culprit leads were successfully managed with percutaneous lead removal (n = 3 [10%]), new lead placement (n = 12 [38%]), or lead repositioning (n = 16 [52%]). Of the 17 patients with pericardiocentesis before the reoperation, none had tamponade develop; in contrast, 3 of the remaining 14 patients had tamponade develop and required urgent pericardiocentesis. All patients survived without requiring open chest surgery.ConclusionPercutaneous removal or repositioning of the perforating lead is feasible and appears effective. Placement of a prophylactic pericardial drain catheter may reduce the incidence of urgent pericardiocentesis during or after a procedure.

Abstract Genetically modified mice with spontaneous development of mammary carcinoma provide a powerful tool to study the efficacy of tumor vaccines, since they mimic breast cancer development in humans. We used a transgenic murine model expressing polyomavirus middle T oncogene and mucin 1 tumor-associated Ag to determine the preventive effect of a dendritic/tumor fusion cell vaccine. The MMT (a transgenic murine model) mice developed mammary carcinoma between the ages of 65–108 days with 100% penetrance. No spontaneous CTL were detected. However, prophylactic vaccination of MMT mice with dendritic/tumor fusion cells induced polyclonal CTL activity against spontaneous mammary carcinoma cells and rendered 57–61% of the mice free of the disease at the end of experiment (180 days). Furthermore, the level of CTL activity was maintained with multiple vaccinations. The antitumor immunity induced by vaccination with dendritic/tumor fusion cells reacted differently to injected tumor cells and autochthonous tumor. Whereas the injected tumor cells were rejected, the autochthonous tumor evaded the attack and was allowed to grow. Collectively these results indicate that prophylactic vaccination with dendritic/tumor fusion cells confers sufficient antitumor immunity to counter the tumorigenesis of potent oncogenic products. The findings in the present study are highly relevant to cancers in humans.

The microRNAs (miRNAs) are small noncoding RNAs that are potent regulators of gene expression and can regulate several diverse biological functions. This minireview provides an overview of recent studies that have examined the role and involvement of miRNAs in cholangiocarcinomas. These studies provide evidence for deregulated expression of miRNA and are providing new insights into the potential contribution of these in the pathogenesis of cholangiocarcinoma.

Background and Purpose— The prognostic significance of subarachnoid extension of intracerebral hemorrhage was determined in the INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT2) study. Methods— INTERACT2 was an open randomized controlled trial of early intensive compared with guideline-recommended blood pressure lowering in patients with elevated systolic blood pressure within 6 hours of intracerebral hemorrhage. Independent predictors of death or major disability (scores 3–6 on the modified Rankin Scale) at 90 days were analyzed in logistic regression models. Results— Of 2582 participants, 192 (7%) had subarachnoid extension, which was associated with larger hematoma volumes ( P <0.0001) and higher National Institute of Health Stroke Scale score ( P <0.0001). Subarachnoid extension predicted death or major disability at 90 days (71% versus 53%; unadjusted odds ratio, 2.25; 95% confidence interval, 1.63–3.10; P <0.0001). The association remained significant after adjusting for age, region, lipid-lowering therapy, systolic blood pressure, glucose, location of hematoma, intraventricular extension, and randomized treatment (odds ratio, 2.17; 95% confidence interval, 1.50–3.14; P <0.0001), but not after further adjustment for baseline hematoma volume ( P =0.62). Conclusions— Subarachnoid extension of intracerebral hemorrhage is associated with poor prognosis, which is determined by a larger volume of the underlying intraparenchymal hematoma. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00716079.

Abstract To identify the genetic factors that influence overall survival in never smokers who have non–small cell lung carcinoma (NSCLC), we conducted a consistency meta-analysis study using genome-wide association approaches for overall survival in 327 never smoker patients with NSCLC from The University of Texas MD Anderson Cancer Center (Houston, TX) and 293 cases from the Mayo Clinic (Rochester, MN). We then conducted a two-pronged validation of the top 25 variants that included additional validation in 1,256 patients with NSCLC from Taiwan and assessment of expression quantitative trait loci (eQTL) and differential expression of genes surrounding the top loci in 70 tumors and matched normal tissues. A total of 94 loci were significant for overall survival in both MD Anderson and Mayo studies in the consistency meta-analysis phase, with the top 25 variants reaching a P value of 10−6. Two variants of these 25 were also significant in the Taiwanese population: rs6901416 [HR, 1.44; 95% confidence interval (CI), 1.01–2.06] and rs10766739 (HR, 1.23; 95%CI, 1.00–1.51). These loci resulted in a reduction of median survival time of at least eight and five months in three populations, respectively. An additional six variants (rs4237904, rs7976914, rs4970833, rs954785, rs485411, and rs10906104) were validated through eQTL analysis that identified significant correlations with expression levels of six genes (LEMD3, TMBIM, ATXN7L2, SHE, ITIH2, and NUDT5, respectively) in normal lung tissue. These genes were also significantly differentially expressed between the tumor and normal lung tissue. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biologic mechanism for a subset of these observed associations. Cancer Res; 73(13); 4028–38. ©2013 AACR.

The signaling molecule adenosine has been implicated in attenuating acute lung injury (ALI). Adenosine signaling is terminated by its uptake through equilibrative nucleoside transporters (ENTs). We hypothesized that ENT‐dependent adenosine uptake could be targeted to enhance adenosine‐mediated lung protection. To address this hypothesis, we exposed mice to high‐pressure mechanical ventilation to induce ALI. Initial studies demonstrated time‐dependent repression of ENT1 and ENT2 transcript and protein levels during ALI. To examine the contention that ENT repression represents an endogenous adaptive response, we performed functional studies with the ENT inhibitor dipyridamole. Dipyridamole treatment (1 mg/kg; EC 50 =10 μM) was associated with significant increases in ALI survival time (277 vs. 395 min; P <0.05). Subsequent studies in gene‐targeted mice for Ent1 or Ent2 revealed a selective phenotype in Ent2 ‐/‐ mice, including attenuated pulmonary edema and improved gas exchange during ALI in conjunction with elevated adenosine levels in the bronchoalveolar fluid. Furthermore, studies in genetic models for adenosine receptors implicated the A 2B adenosine receptor (Adora2b) in mediating ENT‐dependent lung protection. Notably, dipyridamole‐dependent attenuation of lung inflammation was abolished in mice with alveolar epithelial Adora2b gene deletion. Our newly identified crosstalk pathway between ENT2 and alveolar epithelial Adora2b in lung protection during ALI opens possibilities for combined therapies targeted to this protein set.—Eckle, T., Hughes, K., Ehrentraut, H., Brodsky, K. S., Rosenberger, P., Choi, D.‐S., Ravid, K., Weng, T., Xia, Y., Blackburn, M. R.Eltzschig, H. K., Crosstalk between the equilibrative nucleoside transporter ENT2 and alveolar Adora2b adenosine receptors dampens acute lung injury. FASEB J. 27, 3078–3089 (2013). www.fasebj.org

ABSTRACTProgressive supranuclear palsy is a neurodegenerative disease with progressive brain atrophy over time. It is unknown which specific brain regions decline over time, whether regional volume loss occurs in a linear fashion, and whether regional atrophy correlates with clinical decline over time in progressive supranuclear palsy. Twenty‐eight subjects meeting probable progressive supranuclear palsy criteria were prospectively recruited and completed 96 MRI scans over 2 years. Mixed‐effect models were utilized to determine which regions had significant atrophy over time and whether decline was linear or nonlinear. We assessed 13 regions across the brain, as well as whole‐brain and ventricular volume. Regional trajectories were also correlated with change in clinical measures of executive function and gait and ocular motor impairment. A linear decline was observed in all frontal and temporal regions, the superior parietal lobe, the thalamus, the caudate nuclei, and the midbrain, as well as in the whole brain. Ventricular expansion was also linear. Nonlinear decline was observed for the caudal middle frontal lobe and globus pallidus. Rates of change in the superior frontal lobe, thalamus, and midbrain were beyond those expected in normal aging. Decline in frontal lobe volume and the midbrain area correlated best to decline in clinical measures. In progressive supranuclear palsy, atrophy is occurring in multiple brain regions, particularly in those that have previously been implicated in the disease. Decline is mainly linear but can be nonlinear for some regions. The frontal lobe and midbrain seem to be playing the most significant roles in the progressive worsening of clinical signs in progressive supranuclear palsy. © 2013 Movement Disorder Society