Citations

Abstract Purpose: Esophageal cancer is an aggressive malignancy and often resistant to therapy. Overexpression of EGFR has been associated with poor prognosis of patients with esophageal cancer. However, clinical trials using EGFR inhibitors have not provided benefit for patients with esophageal cancer. Failure of EGFR inhibition may be due to crosstalk with other oncogenic pathways. Experimental Design: In this study, expression of YAP1 and EGFR were examined in EAC-resistant tumor tissues versus sensitive tissues by IHC. Western blot analysis, immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis, and in vitro and in vivo functional assays were performed to elucidate the YAP1-mediated EGFR expression and transcription and the relationship with chemoresistance in esophageal cancer. Results: We demonstrate that Hippo pathway coactivator YAP1 can induce EGFR expression and transcription in multiple cell systems. Both YAP1 and EGFR are overexpressed in resistant esophageal cancer tissues compared with sensitive esophageal cancer tissues. Furthermore, we found that YAP1 increases EGFR expression at the level of transcription requiring an intact TEAD-binding site in the EGFR promoter. Most importantly, exogenous induction of YAP1 induces resistance to 5-fluorouracil and docetaxcel, whereas knockdown of YAP1 sensitizes esophageal cancer cells to these cytotoxics. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics. Conclusions: Our data provide evidence that YAP1 upregulation of EGFR plays an important role in conferring therapy resistance in esophageal cancer cells. Targeting YAP1-EGFR axis may be more efficacious than targeting EGFR alone in esophageal cancer. Clin Cancer Res; 21(11); 2580–90. ©2015 AACR.

Objective Atrial fibrillation (AF) often progresses from paroxysmal or persistent to more sustained forms, but the rate and predictors of AF progression in clinical practice are not well described. Methods Using the Outcomes Registry for Better Informed Treatment of AF, we analysed the incidence and predictors of progression and tested the discrimination and calibration of the HATCH (hypertension, age, TIA/stroke, chronic obstructive pulmonary disease, heart failure) and CHA2DS2VASc scores for identifying AF progression. Results Among 6235 patients with paroxysmal or persistent AF at baseline, 1479 progressed, during follow-up (median 18 (IQR 12–24) months). These patients were older and had more comorbidities than patients who did not progress (CHADS2 2.3±1.3 vs 2.1±1.3, p<0.0001). At baseline, patients with AF progression were more often on a rate control as opposed to a rhythm control strategy (66 vs 56%, p<0.0001) and had higher heart rate (72(64–80) vs 68(60–76) bpm, p<0.0001). The strongest predictors of AF progression were AF on the baseline ECG (OR 2.30, 95% CI 1.95 to 2.73, p<0.0001) and increasing age (OR 1.16, 95% CI1.09 to 1.24, p<0.0001, per 10 increase), while patients with lower heart rate (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001, per 10 decrease ≤80) were less likely to progress. There was no significant interaction between rhythm on baseline ECG and heart rate (p=0.71). The HATCH and CHA2DS2VASc scores had modest discriminatory power for AF progression (C-indices 0.55 (95% CI 0.53 to 0.58) and 0.55 (95% CI 0.52 to 0.57)). Conclusions Within 1.5 years, almost a quarter of the patients with paroxysmal or persistent AF progress to a more sustained form. Progression is strongly associated with heart rate, and age.

Background— The appropriate indication for coronary computed tomographic angiography (CTA) as a part of preoperative evaluation has not been defined yet. We investigated the value of coronary CTA in patients undergoing noncardiac surgery. Methods and Results— We included 844 patients (median age, 67 years; male sex, 62%) who underwent coronary CTA for screening of coronary artery disease before noncardiac surgery. Clinically determined revised cardiac risk index were compared with the extent and severity of coronary artery disease assessed by coronary CTA. Perioperative major cardiac event (PMCE), defined as cardiac death, myocardial infarction, or pulmonary edema within postoperative 30 days, developed in 25 patients (3.0%). Significant coronary CTA finding was defined as >3 any lesions with ≥1 (diameter stenosis ≥70%) stenosis based on the relationship between the severity of coronary artery disease and PMCE risk. The risk of PMCE was 14.0% in patients with significant CTA findings, whereas 2.2% of patients without significant CTA findings regardless of revised cardiac risk index score. The predictive performance of revised cardiac risk index could be improved significantly after addition of significant coronary CTA findings (c-statistics=0.631 versus 0.757; net reclassification improvement=0.923; integrated discrimination improvement=0.051). On the basis of revised cardiac risk index and coronary CTA, the risk of PMCE could be estimated with sensitivity, specificity, positive predictive value, and negative predictive value of 76%, 73%, 8%, and 99%, respectively. Conclusions— Addition of coronary CTA to clinical risk improved perioperative risk stratification. Absence of significant coronary CTA findings conferred low PMCE risk with high specificity and negative predictive value regardless of clinical risk. Coronary CTA may improve perioperative risk stratification in patients undergoing noncardiac surgery.

Abstract The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

Background Probe‐based confocal laser endomicroscopy (pCLE) provides microscopic imaging during an endoscopic procedure. Its introduction as a standard modality in gastroenterology has brought significant progress in management strategies, affecting many aspects of clinical care and requiring standardisation of practice and training. Objective This study aimed to provide guidance on the standardisation of its practice and training in Barrett's oesophagus, biliary strictures, colorectal lesions and inflammatory bowel diseases. Methods Initial statements were developed by five group leaders, based on the available clinical evidence. These statements were then voted and edited by the 26 participants, using a modified Delphi approach. After two rounds of votes, statements were validated if the threshold of agreement was higher than 75%. Results Twenty‐six experts participated and, among a total of 77 statements, 61 were adopted (79%) and 16 were rejected (21%). The adoption of each statement was justified by the grade of evidence. Conclusion pCLE should be used to enhance the diagnostic arsenal in the evaluation of these indications, by providing microscopic information which improves the diagnostic performance of the physician. In order actually to implement this technology in the clinical routine, and to ensure good practice, standardised initial and continuing institutional training programmes should be established.

Significance We have identified a lethal subtype of gastric cancer (GC) that is characterized by high levels of clonal heterogeneity and TP53 (tumor protein P53) mutation. We have also uncovered key novel mutations in the targetable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair and identified BRCA2 (breast cancer 2, early onset) mutations as new genetic markers to predict better survival for GC. Our study represents a novel approach for GC personalized medicine and identified novel clinical actionable therapies for GC therapy.

AbstractIntroductionAnalyzing hospital naloxone use may assist in identification of areas for quality and safety improvement. Our primary objective is to quantitate the incidence of hospital naloxone use and to assess certain patient populations at risk.MethodsDuring the years 2008 to 2011, each clinical scenario where naloxone was administered on an in‐patient care ward was reviewed. The events were assessed to separate situations where naloxone rescue was effective in reversing opioid‐induced intoxication vs. others. Further analysis was conducted to stratify patient populations at greatest risk.ResultsNaloxone was administered for well‐defined opioid‐induced respiratory depression and oversedation 61% of the time, the remainder used for patient deterioration of other etiology. Surgical populations are at risk with an incidence of 3.8/1,000 hospitalized patients, and this is the greatest within 24 hours of surgery. General surgical patients represent the highest surgical patient risk at 5.5/1,000. Medical patients represent lower risk at 2.0/1,000. Patients with patient‐controlled analgesia and epidural opioid infusion are high risk at 12.1 and 13.1/1,000 patients, respectively. Many quality and safety interventions were gradually implemented in response to this data and are summarized. These include nursing and provider education, electronic medical record modification, and more stringent patient monitoring practices.ConclusionExamination of naloxone use can assist in the identification and stratification of patients at risk for opioid‐induced respiratory depression and oversedation and can serve as a driver for improvements in hospital patient safety. This information can also guide other institutions interested in similar improvements.