Accuracy of [(18)Fluorine]-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography-Computed Tomography Response Assessment Following (Chemo) radiotherapy for Locally Advanced Laryngeal/Hypopharyngeal Carcinoma

Introduction: The accuracy of response assessment positron emission tomography (PET)-computed tomography (CT) following radiotherapy with or without chemotherapy for laryngeal/hypopharyngeal squamous cell carcinoma is uncertain. Methods: In all, 35 patients with laryngeal or hypopharyngeal squamous cell carcinoma who were treated between 2009 and 2014 with (chemo)radiotherapy were identified. The accuracy of response assessment PET-CT was made by correlation with clinical follow-up and pathological findings. Results: Of the 35 patients, 20 (57%) had an overall complete metabolic response. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for response assessment [18Fluorine]-fluoro-2-deoxy-d-glucose (FDG) PET-CT for primary and nodal sites, respectively, were 100%, 73%, 46%, and 100% and 83%, 95%, 83%, and 95%. Conclusions: Response assessment FDG PET-CT following (chemo)radiotherapy for laryngeal and hypopharyngeal carcinomas has a high NPV for both primary site and lymph nodes and can be used to guide treatment decisions. The PPV of residual FDG uptake at the primary tumour site is limited and requires examination and biopsy confirmation

Programmed Death-Ligand 1 Expression in Lung Cancer and Paired Brain Metastases-a Single-Center Study in 190 Patients.

Expression of programmed death-ligand 1 (PD-L1) is the only routinely used tissue biomarker for predicting response to programmed cell death protein 1/PD-L1 inhibitors. It is to date unclear whether PD-L1 expression is preserved in brain metastases (BMs). In this single-center, retrospective study, we evaluated PD-L1 expression using the SP263 assay in consecutively resected BMs of lung carcinomas and paired primary tumors, diagnosed from 2000 to 2015, with correlation to clinicopathological and molecular tumor and patient characteristics. PD-L1 tumor proportional score (TPS) could be evaluated on whole tissue slides in 191 BMs and 84 paired primary lung carcinomas. PD-L1 TPS was less than 1% in 113 of 191 (59.2%), 1% to 49% in 34 of 191 (17.8%), and greater than or equal to 50% in 44 of 191 (23.0%) BMs. TPS was concordant between BMs and paired primary lung carcinomas in most cases, with discordance regarding the clinically relevant cutoffs at 1% and 50% in 18 of 84 patients (21.4%). Four of 18 discordant cases had no shared mutations between the primary lung carcinoma and BM. Intratumoral heterogeneity, as assessed using tissue microarray cores, was only significant at the primary site (p <sub>Wilcoxon signed rank</sub> = 0.002) with higher PD-L1 TPS at the infiltration front (mean = 40.4%, interquartile range: 0%-90%). Neither TPS greater than or equal to 1% nor TPS greater than or equal to 50% nor discordance between the primary lung carcinoma and BMs had prognostic significance regarding overall survival or BM-specific overall survival. PD-L1 expression was mostly concordant between primary lung carcinoma and its BM and between resections of BM and stereotactic biopsies, mirrored by tissue microarray cores. Differences in PD-L1 TPS existed primarily in cases with TPS greater than 10%, for which also human assessment tends to be most error prone

Diagnosis, management, and outcomes of patients with syncope and bundle branch block

Although patients with syncope and bundle branch block (BBB) are at high risk of developing atrio-ventricular block, syncope may be due to other aetiologies. We performed a prospective, observational study of the clinical outcomes of patients with syncope and BBB following a systematic diagnostic approach. Patients with ≥1 syncope in the last 6 months, with QRS duration ≥120 ms, were prospectively studied following a three-phase diagnostic strategy: Phase I, initial evaluation; Phase II, electrophysiological study (EPS); and Phase III, insertion of an implantable loop recorder (ILR). Overall, 323 patients (left ventricular ejection fraction 56 ± 12%) were studied. The aetiological diagnosis was established in 267 (82.7%) patients (102 at initial evaluation, 113 upon EPS, and 52 upon ILR) with the following aetiologies: bradyarrhythmia (202), carotid sinus syndrome (20), ventricular tachycardia (18), neurally mediated (9), orthostatic hypotension (4), drug-induced (3), secondary to cardiopulmonary disease (2), supraventricular tachycardia (1), bradycardia-tachycardia (1), and non-arrhythmic (7). A pacemaker was implanted in 220 (68.1%), an implantable cardioverter defibrillator in 19 (5.8%), and radiofrequency catheter ablation was performed in 3 patients. Twenty patients (6%) had died at an average follow-up of 19.2 ± 8.2 months. In patients with syncope, BBB, and mean left ventricular ejection fraction of 56 ± 12%, a systematic diagnostic approach achieves a high rate of aetiological diagnosis and allows to select specific treatment

LNCS

Static program analyzers are increasingly effective in checking correctness properties of programs and reporting any errors found, often in the form of error traces. However, developers still spend a significant amount of time on debugging. This involves processing long error traces in an effort to localize a bug to a relatively small part of the program and to identify its cause. In this paper, we present a technique for automated fault localization that, given a program and an error trace, efficiently narrows down the cause of the error to a few statements. These statements are then ranked in terms of their suspiciousness. Our technique relies only on the semantics of the given program and does not require any test cases or user guidance. In experiments on a set of C benchmarks, we show that our technique is effective in quickly isolating the cause of error while out-performing other state-of-the-art fault-localization techniques

The M235T Polymorphism in the AGT Gene and CHD Risk: Evidence of a Hardy-Weinberg Equilibrium Violation and Publication Bias in a Meta-Analysis

BACKGROUND: The M235T polymorphism in the AGT gene has been related to an increased risk of hypertension. This finding may also suggest an increased risk of coronary heart disease (CHD). METHODOLOGY/PRINCIPAL FINDINGS: A case-cohort study was conducted in 1,732 unrelated middle-age women (210 CHD cases and 1,522 controls) from a prospective cohort of 15,236 initially healthy Dutch women. We applied a Cox proportional hazards model to study the association of the polymorphism with acute myocardial infarction (AMI) (n = 71) and CHD. In the case-cohort study, no increased risk for CHD was found under the additive genetic model (hazard ratio [HR] = 1.20; 95% confidence interval [CI], 0.86 to 1.68; P = 0.28). This result was not changed by adjustment (HR = 1.17; 95% CI, 0.83 to 1.64; P = 0.38) nor by using dominant, recessive and pairwise genetic models. Analyses for AMI risk under the additive genetic model also did not show any statistically significant association (crude HR = 1.14; 95% CI, 0.93 to 1.39; P = 0.20). To evaluate the association, a comprehensive systematic review and meta-analysis were undertaken of all studies published up to February 2007 (searched through PubMed/MEDLINE, Web of Science and EMBASE). The meta-analysis (38 studies with 13284 cases and 18722 controls) showed a per-allele odds ratio (OR) of 1.08 (95% CI, 1.01 to 1.15; P = 0.02). Moderate to large levels of heterogeneity were identified between studies. Hardy-Weinberg equilibrium (HWE) violation and the mean age of cases were statistically significant sources of the observed variation. In a stratum of non-HWE violation studies, there was no effect. An asymmetric funnel plot, the Egger's test (P = 0.066), and the Begg-Mazumdar test (P = 0.074) were all suggestive of the presence of publication bias. CONCLUSIONS/SIGNIFICANCE: The pooled OR of the present meta-analysis, including our own data, presented evidence that there is an increase in the risk of CHD conferred by the M235T variant of the AGT gene. However, the relevance of this weakly positive overall association remains uncertain because it may be due to various residual biases, including HWE-violation and publication biases

Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition.

Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes, depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive cell-based prosenescence screen with detailed validation assays. We characterize the screen using a focused tool compound kinase inhibitor library. We identify a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses show that all of the compounds that induce tetraploid senescence inhibit Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint, and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed in only a small population of oncogenic RAS-induced senescence, and provides additional justification for AURKB as a cancer therapeutic target.This work was supported by the University of Cambridge, Cancer Research UK, Hutchison Whampoa; Cancer Research UK grants A6691 and A9892 (M.N., N.K., C.J.T., D.C.B., C.J.C., L.S.G, and M.S.); a fellowship from the Uehara Memorial Foundation (M.S.).This is the author accepted manuscript. The final version is available from the American Society for Cell Biology via http://dx.doi.org/10.1091/mbc.E15-01-000

Dental caries and fluorosis in low- and high-fluoride areas in Turkey

Objective: The aim of this study was to investigate the caries prevalence of children living in either low- or high-fluoride areas and to relate caries experience to the severity of dental fluorosis. Method and materials: A total of 278 12- to 14-year-old schoolchildren, 149 in a low-fluoride area (LFA) and 129 in a high-fluoride area (HFA), were included in the study. The naturally occurring fluoride concentrations in the drinking water were 0.30 to 0.40 ppm in the LFA, 1.42 to 1.54 ppm in the HFA1, and 1.55 to 1.66 ppm in the HFA2. Dental caries was recorded with the World Health Organization criteria, and dental fluorosis was measured using the Tooth Surface Index of Fluorosis. Results: The percentages of children who had an average TSIF greater than or equal to 1 were 0%, 29%, and 77% in the LFA, HFA1, and HFA2, respectively. The mean decayed, missing, and filled permanent teeth (DMFT) and decayed, missing, and filled permanent surfaces (DMFS) were 0.84 +/- 0.98 and 1.58 +/- 2.24 in LFA, 1.30 +/- 1.46 and 1.78 +/- 2.52 in HFA1, and 1.26 +/- 1.42 and 1.97 +/- 2.60 in HFA2, respectively. There was no significant difference in caries prevalence among children living in low- and high-fluoride areas when evaluated with an analysis of covariance model, including the frequency of toothbrushing. Toothbrushing frequency had a significant effect on the decayed teeth, decayed surfaces, DMFT, and DMFS. In high-fluoride areas, there was no relationship between caries prevalence and severity of fluorosis. Conclusion: Increasing water fluoride levels were associated with higher prevalence and severity of dental fluorosis and had no influence on caries experience in children with poor oral hygiene

Dental caries and fluorosis in low- and high-fluoride areas in Turkey

WOS: 000183454700005PubMed ID: 12795354Objective: The aim of this study was to investigate the caries prevalence of children living in either low- or high-fluoride areas and to relate caries experience to the severity of dental fluorosis. Method and materials: A total of 278 12- to 14-year-old schoolchildren, 149 in a low-fluoride area (LFA) and 129 in a high-fluoride area (HFA), were included in the study. The naturally occurring fluoride concentrations in the drinking water were 0.30 to 0.40 ppm in the LFA, 1.42 to 1.54 ppm in the HFA1, and 1.55 to 1.66 ppm in the HFA2. Dental caries was recorded with the World Health Organization criteria, and dental fluorosis was measured using the Tooth Surface Index of Fluorosis. Results: The percentages of children who had an average TSIF greater than or equal to 1 were 0%, 29%, and 77% in the LFA, HFA1, and HFA2, respectively. The mean decayed, missing, and filled permanent teeth (DMFT) and decayed, missing, and filled permanent surfaces (DMFS) were 0.84 +/- 0.98 and 1.58 +/- 2.24 in LFA, 1.30 +/- 1.46 and 1.78 +/- 2.52 in HFA1, and 1.26 +/- 1.42 and 1.97 +/- 2.60 in HFA2, respectively. There was no significant difference in caries prevalence among children living in low- and high-fluoride areas when evaluated with an analysis of covariance model, including the frequency of toothbrushing. Toothbrushing frequency had a significant effect on the decayed teeth, decayed surfaces, DMFT, and DMFS. In high-fluoride areas, there was no relationship between caries prevalence and severity of fluorosis. Conclusion: Increasing water fluoride levels were associated with higher prevalence and severity of dental fluorosis and had no influence on caries experience in children with poor oral hygiene