Citations

Abstract BACKGROUND Aggressive LDL cholesterol (LDL-C)-lowering strategies are recommended for primary and secondary prevention of cardiovascular events. A newly derived equation for LDL-C estimation was recently published that addressed limitations in the commonly used Friedewald LDL-C calculation method. The novel method was reported to classify patients with superior concordance to measured LDL-C compared to the Friedewald method, particularly in patients with LDL-C <70 mg/dL. METHODS We evaluated the performance of the novel method within an independent cohort of 23 055 patients with LDL-C measured by the gold standard β-quantification reference method. RESULTS Overall Friedewald underestimated and the novel method overestimated measured LDL-C. Both estimations significantly deviated from the reference method when LDL-C was <70 mg/dL. Overall, the Friedewald and novel calculations correctly classified 77% and 78% of patients, respectively. The largest discrepancy in classification was observed in individuals with measured LDL-C <70 mg/dL. For this group the novel calculation would reclassify 8.7% of patients as >70 mg/dL compared to the Friedewald equation. CONCLUSIONS We compared both novel and Friedewald estimated LDL-C against the LDL-C reference method; in contrast, the prior study relied on validation of a subset of samples by β-quantification to allow the use of the vertical autoprofile method for LDL-C measurement. We conclude that the novel method has some benefits but it is unclear whether improvements over the Friedewald calculation are substantive enough to justify making the change in routine clinical practice and to improve patient outcomes.

Abstract Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.

BackgroundOptimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS‐C) are uncertain.ObjectiveThe objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS‐C symptoms.MethodsUsing pooled 12‐week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed.ResultsCorrelations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48–0.54, 0.32–0.39, and 0.61–0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS‐C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%–76% and 71%–82% of weeks with agreement, respectively).ConclusionsAR bridges IBS‐C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.

Abstract This report describes results from our analysis of the activity and biodistribution of a novel pan-ERBB inhibitor, NT113, when used in treating mice with intracranial glioblastoma (GBM) xenografts. Approaches used in this investigation include: bioluminescence imaging (BLI) for monitoring intracranial tumor growth and response to therapy; determination of survival benefit from treatment; analysis of tumor IHC reactivity for indication of treatment effect on proliferation and apoptotic response; Western blot analysis for determination of effects of treatment on ERBB and ERBB signaling mediator activation; and high-performance liquid chromatography for determination of NT113 concentration in tissue extracts from animals receiving oral administration of inhibitor. Our results show that NT113 is active against GBM xenografts in which wild-type EGFR or EGFRvIII is highly expressed. In experiments including lapatinib and/or erlotinib, NT113 treatment was associated with the most substantial improvement in survival, as well as the most substantial tumor growth inhibition, as indicated by BLI and IHC results. Western blot analysis results indicated that NT113 has inhibitory activity, both in vivo and in vitro, on ERBB family member phosphorylation, as well as on the phosphorylation of downstream signaling mediator Akt. Results from the analysis of animal tissues revealed significantly higher NT113 normal brain-to-plasma and intracranial tumor-to-plasma ratios for NT113, relative to erlotinib, indicating superior NT113 partitioning to intracranial tissue compartments. These data provide a strong rationale for the clinical investigation of NT113, a novel ERBB inhibitor, in treating patients with GBM. Mol Cancer Ther; 13(12); 2919–29. ©2014 AACR.

BackgroundPast research has explored patients' expectations about the informed consent process. However, it is currently unknown if the complexity of the surgical procedure influences the type of anesthesia‐related risks that patients wish disclosed. This study explored fears of anesthesia‐related complications and whether these changed based on severity of surgery classification.MethodsPatients presenting to our pre‐operative evaluation clinic from February 2013 to May 2013 were asked to participate in a survey‐based study meant to evaluate their perception of five possible anesthetic risks (peripheral nerve injury, death, nausea and vomiting, heart attack and stroke) when confronted with differing levels of surgical severity.ResultsOne thousand surveys were administered, and 894 were returned for an overall response rate of 89%. Fear of death was the greatest concern as compared to the other risk factors independent of the severity of surgery. The level of fear for all risk factors, with the exception of stroke and heart attack, were dependent on the severity of surgery. Fear of death decreased as the severity of surgery decreased (major 46%, moderate 38%, minor 25%). For major surgery, the fear of perioperative death differed significantly with age (P < 0.001); specifically, with increasing age came a lessened fear of death.ConclusionAwareness by anesthesia providers of those fears that patients report may allow for a more personalized approach to providing information that may better allay anxiety. Further, these results may better tailor the informed consent process to one that meets particular patient concerns.

SummaryBackgroundEstimation of the prevalence of oesophageal narrowing and its clinical relevance in patients with oesophageal eosinophilia is probably underestimated by endoscopy.AimsTo determine the sensitivity and specificity of oesophagogastroduodenoscopy (EGD) for oesophageal narrowing when compared to a structured oesophagram.MethodsWe conducted a retrospective chart review at Mayo Clinic, Rochester of adult patients with eosinophilic oesophageal infiltration of >15 eosinophils/hpf with symptomatic dysphagia, who underwent a structured barium oesophagram. The sensitivity and specificity of EGD were evaluated against the gold standard of oesophagram. Demographic and multiple clinical factors were evaluated as potential predictors of oesophageal narrowing.ResultsOf the 58 patients identified, 34 (58.6%) had a narrowed oesophageal diameter (<21 mm). EGD had poor sensitivity (14.7%, 95% CI 5.0–31.1%) for detection of a narrowed oesophagus and only modest specificity (79.2%, 95% CI 57.8–92.9%). Even at a cut‐off diameter of EDmax ≤ 15 mm, EGD had a sensitivity of only 25.0% (95% CI 5.5–57.2%) for narrowed oesophagus. A history of >5 food impaction episodes, endoscopic rings, and female sex were the best predictors of oesophageal narrowing. 86% (6/7) patients with persistent dysphagia despite remission of histological eosinophilia responded to oesophageal dilation all of whom had radiological oesophageal narrowing and 71% of whom had no perceived oesophageal narrowing at EGD.ConclusionsSymptomatic oesophageal narrowing identified by barium oesophagography is common and under‐recognised at endoscopy in patients with oesophageal eosinophilia.

Objective (1) To characterize long‐term dizziness following observation, microsurgery, and stereotactic radiosurgery (SRS) for small to medium‐sized vestibular schwannoma (VS) using a validated self‐assessment inventory; and (2) to identify clinical variables associated with long‐term dizziness handicap. Study Design Cross‐sectional observational study. Setting Two independent tertiary academic referral centers: one located in the United States and one in Norway. Subjects and Methods All patients with sporadic VS of less than 3 cm who underwent primary microsurgery, SRS, or observation between 1998 and 2008 were identified. Subjects were surveyed via a postal questionnaire using the Dizziness Handicap Inventory (DHI) and a VS symptom questionnaire. Results The overall survey response rate was 79%. A total of 538 respondents (mean age, 64 years; 56% female) were analyzed, and the mean time interval between treatment and survey was 7.7 years. Pretreatment variables associated with greater dizziness handicap included female sex, older age, larger tumor size, preexisting diagnosis of headache or migraine, and symptoms of dizziness predating treatment. Significant posttreatment features strongly associated with poor long‐term DHI scores included frequency and severity of ongoing headache. On multivariable analysis, treatment modality did not influence long‐term dizziness handicap. Conclusion At a mean of approximately 8 years following treatment, over half of patients with VS reported ongoing dizziness. The authors have identified several baseline features that may help predict the risk of lasting dizziness. Treatment modality does not appear to influence long‐term DHI score. We found a strong association between posttreatment headache and poor dizziness handicap. Future study is needed to further define this relationship.

Abstract Background An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. Methods Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web‐platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. Results The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). Conclusions The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.