Citations

Abstract Purpose: The interaction of programmed death-1 ligand (PD-L1) with its receptor (PD-1) on T cells inactivates antitumor immune responses. PD-L1 expression has been associated with poor outcomes in renal cell carcinoma (RCC) but has not been investigated in advanced RCC patients receiving VEGF-targeted therapy. Experimental Design: Formalin-fixed paraffin-embedded specimens were collected at baseline from patients in the COMPARZ trial. Tumor cell PD-L1 expression by IHC was evaluated using H-score (HS). Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages. Intratumor CD8-positive T cells were quantified morphometrically. Associations between biomarkers and survival were investigated using the log-rank test. Results: HS data were available from 453 of 1,110 patients. Sixty-four percent of patients had negative PD-L1 expression (HS = 0). Patients with HS > 55 (n = 59, 13%) had significantly shorter overall survival (OS) than those with HS ≤ 55 in both pazopanib and sunitinib arms (median 15.1 vs. 35.6 and 15.3 vs. 27.8 months, respectively, P = 0.03). In both arms, median OS was shortest in patients with HS > 55 and intratumor CD8-positive T-cell counts > 300 (9.6 and 11.9 months with pazopanib and sunitinib, respectively). Median OS in patients with HS ≤ 55 and CD8-positive T-cell counts ≤ 300 was 36.8 and 28.0 months with pazopanib and sunitinib, respectively. Progression-free survival results were similar to OS results. Conclusions: Increased tumor cell PD-L1, or PD-L1 plus tumor CD8-positive T-cell counts, were associated with shorter survival in patients with metastatic RCC receiving VEGF-targeted agents. These findings may have implications for future design of randomized clinical trials in advanced RCC. Clin Cancer Res; 21(5); 1071–7. ©2014 AACR.

Background Migraine is an incompletely understood, debilitating disorder that lacks a universally effective treatment. Magnesium participates in a variety of biochemical processes related to migraine pathophysiology, and a deficiency could contribute to migraine development. Methods A review of the literature from 1990 to the present on magnesium and migraine was conducted. Review The authors identified 16 studies aimed at magnesium status assessment in migraine, and four intervention trials assessing the efficacy of oral magnesium supplementation, independent of other therapies, in the prevention of migraine. Conclusion The strength of evidence supporting oral magnesium supplementation is limited at this time. With such limited evidence, a more advantageous alternative to magnesium supplementation, in patients willing to make lifestyle changes, may be to focus on increasing dietary magnesium intake.

There is no standard of care for catheter size or post-procedure supine time in cerebral angiography. Catheter sizes range from 4-Fr to 6-Fr with supine times ranging from two to over six hours. The objective of our study was to establish the efficacy, safety, and cost savings of two-hour supine time after 4-Fr elective cerebral angiography. A prospective, single arm study was performed on 107 patients undergoing elective cerebral angiography. All cerebral angiograms were performed with a 4-Fr sheath-based system without closure devices. Ten minutes of manual compression was applied to the femoral access site, with further compression held as clinically indicated. Patients were then monitored in a nursing unit for two hours supine and subsequently mobilized. Nursing discretion was allowed for earlier mobilization. Patients were called the next day to assess delayed hematoma and bleeding. Estimates of cost savings and productivity increases are provided. All patients ambulated in two hours or less. There were no strokes or vessel dissections. Five patients (4.7%) experienced a palpable hematoma, three patients (2.8%) experienced bleeding immediately following the procedure requiring further compression, and one patient (0.9%) experienced minor groin oozing at home. No patient required transfusion, thrombin injection, or endovascular/surgical management of a groin complication. A two-hour post-procedure supine time resulted in cost savings of $952 per angiogram and a total of $101,864. 4-Fr sheath based cerebral angiography with two-hour post-procedure supine time is safe and effective, and allows for a considerable increase in patient satisfaction, cost savings and productivity.

OBJECT Despite a promising outlook, existing intraspinal microstimulation (ISMS) techniques for restoring functional motor control after spinal cord injury are not yet suitable for use outside a controlled laboratory environment. Thus, successful application of ISMS therapy in humans will require the use of versatile chronic neurostimulation systems. The objective of this study was to establish proof of principle for wireless control of ISMS to evoke controlled motor function in a rodent model of complete spinal cord injury. METHODS The lumbar spinal cord in each of 17 fully anesthetized Sprague-Dawley rats was stimulated via ISMS electrodes to evoke hindlimb function. Nine subjects underwent complete surgical transection of the spinal cord at the T-4 level 7 days before stimulation. Targeting for both groups (spinalized and control) was performed under visual inspection via dorsal spinal cord landmarks such as the dorsal root entry zone and the dorsal median fissure. Teflon-insulated stimulating platinum-iridium microwire electrodes (50 μm in diameter, with a 30- to 60-μm exposed tip) were implanted within the ventral gray matter to an approximate depth of 1.8 mm. Electrode implantation was performed using a free-hand delivery technique (n = 12) or a Kopf spinal frame system (n = 5) to compare the efficacy of these 2 commonly used targeting techniques. Stimulation was controlled remotely using a wireless neurostimulation control system. Hindlimb movements evoked by stimulation were tracked via kinematic markers placed on the hips, knees, ankles, and paws. Postmortem fixation and staining of the spinal cord tissue were conducted to determine the final positions of the stimulating electrodes within the spinal cord tissue. RESULTS The results show that wireless ISMS was capable of evoking controlled and sustained activation of ankle, knee, and hip muscles in 90% of the spinalized rats (n = 9) and 100% of the healthy control rats (n = 8). No functional differences between movements evoked by either of the 2 targeting techniques were revealed. However, frame-based targeting required fewer electrode penetrations to evoke target movements. CONCLUSIONS Clinical restoration of functional movement via ISMS remains a distant goal. However, the technology presented herein represents the first step toward restoring functional independence for individuals with chronic spinal cord injury.

Objectives/HypothesisFibrous dysplasia is a condition of nonmalignant osseous change and may occur in a monostotic or polyostotic pattern, the latter potentially being associated with McCune‐Albright syndrome. Symptoms are highly variable and dependent upon lesion location and size.Study DesignRetrospective review.MethodsConsecutive subjects with fibrous dysplasia of the temporal bone were evaluated between 2000 and 2013 at two tertiary academic referral centers. Main outcome measures included disease presentation, diagnostic evaluation, management strategy, and outcome.ResultsSixty‐six patients with fibrous dysplasia of the skull were found to have involvement of the temporal bone. The mean age at diagnosis was 25 years, 39 (59%) were female, and the mean duration of follow‐up was 48 months. Six (11%) patients had monostotic disease, with the remaining 60 (89%) patients having the polyostotic form; 16 (24%) patients had McCune‐Albright syndrome. The most common presenting complaint was headache (59%), followed by hearing loss (29%). The most common exam finding was cosmetic deformity (50%). Cholesteatoma (3%) and spontaneous cerebrospinal fluid fistula (1.5%) were found in a small percentage. No patients had evidence of motor cranial neuropathy by history or physical examination.ConclusionsThe clinical presentation of fibrous dysplasia involving the temporal bone is variable. A growing number of patients are diagnosed incidentally through imaging, and since most patients experience a benign course, the majority can be followed clinically without need for intervention.Level of Evidence4. Laryngoscope, 125:1438–1443, 2015

Background— The goal of this study was to identify genetic determinants of plasma N-terminal proatrial natriuretic peptide (NT-proANP) in the general community by performing a large-scale genetic association study and to assess its functional significance in in vitro cell studies and on disease susceptibility. Methods and Results— Genotyping was performed across 16 000 genes in 893 randomly selected individuals, with replication in 891 subjects from the community. Plasma NT-proANP 1–98 concentrations were determined using a radioimmunoassay. Thirty-three genome-wide significant single-nucleotide polymorphisms were identified in the MTHFR-CLCN6-NPPA-NPPB locus and were all replicated. To assess the significance, in vitro functional genomic studies and clinical outcomes for carriers of a single-nucleotide polymorphism rs5063 (V32M) located in NPPA that represented the most significant variation in this genetic locus were assessed. The rs5063 variant allozyme in transfected HEK293 cells was decreased to 55±8% of wild-type protein ( P =0.01) as assessed by quantitative western blots. Carriers of rs5063 had lower NT-proANP levels (1427 versus 2291 pmol/L; P <0.001) and higher diastolic blood pressures (75 versus 73 mm Hg; P =0.009) and were at an increased risk of stroke when compared with wild-type subjects independent of age, sex, diabetes mellitus, hypertension, atrial fibrillation, and cholesterol levels (hazard ratio, 1.6; P =0.004). Conclusions— This is the first large-scale genetic association study of circulating NT-proANP levels performed with replication and functional assessment that identified genetic variants in the MTHFR-CLCN6-NPPA-NPPB cluster to be significantly associated with NT-proANP levels. The clinical significance of this variation is related to lower NT-proANP levels, higher blood pressures, and an increased risk of stroke in the general community.

Abstract BACKGROUND Although cardiac troponin is associated with outcomes in atrial fibrillation (AF), the complementary prognostic information provided by cardiac troponin I (cTnI) and cTnT is unknown. This study investigated the distribution, determinants, and prognostic value of cTnI and cTnT concentrations in patients with AF. METHODS Samples were collected. At the time of randomization, we analyzed cTnI and cTnT concentrations of 14806 AF patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial using high-sensitivity assays. Correlations (Spearman), determinants (multivariable linear regression), and outcomes (adjusted Cox models and c-statistics) were investigated. RESULTS Concentrations of cTnI and cTnT were correlated (r = 0.70) and measurable in most participants [cTnI 98.5% (median 5.4 ng/L, ≥99th percentile in 9.2%) and cTnT 93.5% (median 10.9 ng/L, ≥99th percentile in 34.4%)]. Renal impairment was the most important factor affecting the concentrations of both troponins. cTnI increase was more associated with heart failure, vascular disease, and persistent/permanent AF, and cTnT with age, male sex, and diabetes. Over a median 1.9 years of follow-up, patients with both troponins above the median had significantly higher risk for stroke/systemic embolism [hazard ratio (HR) 1.72 (95% CI 1.31–2.27)], cardiac death [3.14 (2.35–4.20)], and myocardial infarction [2.99 (1.78–5.03)] than those with both troponins below median (all P &lt; 0.005). Intermediate risks were observed when only 1 troponin was above the median. When combined with clinical information, each marker provided similar prognostication and had comparable c-index. CONCLUSIONS cTnI and cTnT concentrations are moderately correlated and measurable in plasma of most AF patients. The risk of stroke and cardiovascular events is highest when both troponins are above median concentrations. Each troponin provides comparable prognostic information when combined with clinical risk factors. ClinicalTrials.gov/NCT00412984

Arrhythmogenic Substrate of Ventricular Arrhythmias at the AMCIntroductionCatheter ablation of ventricular arrhythmia (VA) at the fibrous aortic mitral continuity (AMC) has been described, yet the nature of the arrhythmogenic substrate remains unknown.MethodsProcedural records of 528 consecutive patients undergoing ablation of VA at Mayo Clinic, Rochester, MN, were reviewed. The electrocardiographic and electrophysiologic characteristics of patients with successful ablation at the AMC were analyzed to characterize the underlying arrhythmogenic substrate.ResultsOf the 21 patients (mean age 53.2 ± 13.4 years, 47.6% male) who underwent ablation of VA at the AMC with acute success, prepotentials (PPs) were found at the ablation sites preceding the ventricular electrogram (VEGM) during arrhythmias in 13 (61.9%) patients and during sinus rhythm in 7 (53.8%) patients. VAs with PPs were associated with a significantly higher burden of premature ventricular complexes (PVCs; 26.1 ± 10.9% vs. 14.9 ± 10.1%, P = 0.03), shorter VEGM to QRS intervals (9.0 ± 28.5 milliseconds vs. 33.1 ± 8.8 milliseconds, P = 0.03), lower pace map scores (8.7 ± 1.6 vs. 11.4 ± 0.8, P = 0.001), and a trend toward shorter V‐H intervals during VA (32.1 ± 38.6 milliseconds vs. 76.3 ± 11.1 milliseconds, P = 0.06) as compared to those without PP. A strong and positive correlation was found between V‐H interval and QRS duration during arrhythmia in those with PPs (B = 2.11, R2 = 0.97, t = 13.7, P < 0.001) but not in those without PPs.ConclusionLocal EGM characteristics and relative activation time of the His bundle suggest the possibility of conduction tissue as the origin for VA arising from the fibrous AMC. Specific identification and targeting of PPs when ablating VAs at this location may improve procedural success.