Citations

Abstract Background: Glioblastomas (GBMs) are aggressive primary brain tumors with high levels of genomic heterogeneity impacting prognosis and treatment response. A recurrent in-frame deletion within the extracellular domain of the epidermal growth factor receptor (EGFR variant III, or vIII) is found in a substantial fraction of GBMs. Methods: The Radiation Therapy Oncology Group (RTOG) 0525 trial of temozolomide dosing in newly-diagnosed GBM enrolled 1174 patients. Of these, 494 eligible GBMs were analyzed for EGFRvIII expression by RT-PCR. The Kaplan-Meier method was used to compare the progression free survival (PFS) and overall survival (OS) of GBMs expressing EGFRvIII with those not expressing EGFRvIII. Results: 142 of 494 tested GBMs (29%) had expressed EGFRvIII. There were no significant differences in PFS or OS between patients whose tumors did (494) or did not (631) undergo EGFRvIII expression analysis. EGFRvIII expression was significantly associated with age (p=0.005), Karnofsky performance status (p=0.02), and RTOG recursive partitioning analysis (RPA) class (p=0.005). EGFRvIII expression analyzed in the entire study population did not reveal an association with PFS or OS. In a univariate subgroup analysis of patients treated on the standard-of-care arm of RTOG-0525, EGFRvIII expression was was significantly associated with worse PFS (HR=1.43, 95% CI: [1.05, 1.96], p=0.025), and worse OS (HR 1.45, 95% CI:[1.03, 2.05], p=0.032). However, in multivariate models, when adjusted for RPA class and MGMT methylation status, EGFRvIII was not an independent predictor of either PFS or OS. Conclusion: For GBMs treated with standard-of-care therapy in RTOG-0525, EGFRvIII expression was associated with worse PFS and OS. However, well-established stratification metrics such as age, KPS, and RPA override this prognostic association, suggesting that trials of therapeutic modalities directed against EGFRvIII should utilize these standard prognostic variables when survival is being analyzed or compared. Project Support: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough Corporation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A110. Citation Format: Daniel P. Cahill, Asha George, Mark R. Gilbert, Arnab Chakravarti, Roger Stupp, Monika Hegi, Paul Brown, Kurt A. Jaeckle, Benjamin Corn, Erik P. Sulman, Luis Souhami, Maria Werner-Wasik, Bethany M. Anderson, Minesh Mehta, Kenneth D. Aldape. EGFRvIII expression is associated with shorter progression-free and overall survival in glioblastoma patients treated with standard-of-care temozolomide and radiation: A report from the RTOG-0525 trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A110.

Endothelial progenitor cells (EPCs) participate in renal repair, but their number and function may be impaired by exposure to cardiovascular risk factors. The number of circulating EPCs is decreased in essential and renovascular hypertensive patients, but the effects of hypertension on EPC function are incompletely understood. We hypothesized that EPC function was preserved under well-controlled conditions in treated hypertensive patients. Patients with atherosclerotic renal artery stenosis (ARAS; n=22) or essential hypertension (n=24) were studied during controlled sodium intake and antihypertensive regimen. Late-outgrowth EPCs were isolated from the inferior vena cava (IVC) and renal vein blood of ARAS and essential hypertension patients and a peripheral vein of matched normotensive controls (n=18). The angiogenic function of EPCs was assessed in vitro, and multidetector computed tomography was used to measure single-kidney hemodynamics and function in ARAS and essential hypertension patients. Inflammatory biomarkers and EPC homing signal levels and renal release were calculated. Inferior vena cava and renal vein–obtained EPC function were similar in ARAS and essential hypertension patients and comparable to that in normal controls (tube length, 171.86±16.846, 191.09±14.222, 174.925±19.774 μm, respectively). Function of renal vein–obtained EPCs directly correlated with stenotic kidney glomerular filtration rate, EPC homing factors, and anti-inflammatory mediator levels in ARAS patients. Therefore, EPC function was relatively preserved in ARAS patients, although it directly correlated with renal function. Adequate EPC function supports the feasibility of using autologous EPCs as a therapeutic option in essential and renovascular hypertensive patients. Homing signals and inflammatory mediators may potentially regulate EPC angiogenic function.

AbstractAlthough coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult‐onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw‐opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult‐onset primary dystonia.

Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. Results A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue. Conclusion This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.

Morbidity and mortality attributable to hypertension are higher in black essential hypertensive (EH) compared with white EH patients, possibly related to differential effects on vascular injury and repair. Although circulating endothelial progenitor cells (EPCs) preserve endothelial integrity, inflammatory endothelial cells (IECs) detach from sites of injury and represent markers of vascular damage. We hypothesized that blood levels of IECs and inflammatory markers would be higher in black EH compared with white EH patients. Inferior vena cava and renal vein levels of CD34+/KDR+ (EPC) and VAP-1+ (IEC) cells were measured by fluorescence-activated cell sorting in white EH and black EH patients under fixed sodium intake and blockade of the renin–angiotensin system, and compared with systemic levels in normotensive control subjects (n=19 each). Renal vein and inferior vena cava levels of inflammatory cytokines and EPC homing factors were measured by Luminex. Blood pressure, serum creatinine, lipids, and antihypertensive medications did not differ between white and black EH patients, and EPC levels were decreased in both. Circulating IEC levels were elevated in black EH patients, and inversely correlated with EPC levels ( R 2 =0.58; P =0.0001). Systemic levels of inflammatory cytokines and EPC homing factors were higher in black EH compared with white EH patients, and correlated directly with IECs. Renal vein inflammatory cytokines, EPCs, and IECs did not differ from their circulating levels. Most IECs expressed endothelial markers, fewer expressed progenitor cell markers, but none showed lymphocyte or phagocytic cell markers. Thus, increased release of cytokines and IECs in black EH patients may impair EPC reparative capacity and aggravate vascular damage, and accelerate hypertension-related complications.

The objective of this study was to identify the relationship between lambda waves (LWs) and other occipital waveforms, in a retrospective analysis of electroencephalograms (EEGs) of clinic and hospitalized patients at a single center. The LWs were correlated with α rhythm, photic driving, and positive occipital sharp transients of sleep (POSTS). A computer-generated cursor quantified amplitude and duration of POSTS and LWs (3 waveforms and both hemispheres). Fisher exact test was used for significance ( P ≤ .05). A total of 116 patients were evaluated. Of 111 patients, with interpretable results, 74 (66.67%) had visual scanning during EEG, with 37 (50.0%) having LWs. The LWs (17.69 µV) were consistently smaller than POSTS (31.40 µV) despite similar morphology. Patients with an α rhythm of >8.5 Hz were strongly correlated with the presence of LWs ( P < .0001), and those with LWs were strongly predictive of normal EEG ( P = .001). Of the 37 patients, 27 (73.0%) with LWs had photic driving ( P = .0496). No correlation was found between LWs and POSTS ( P = .45). The presence of LWs and a low normal posterior dominant rhythm (PDR) suggests intact electrocerebral health. LWs and the photic driving response suggest similar generators but stimulus-specific networks. POSTS differ from LWs despite similar morphology, suggesting different network activation of occipital generators. LWs have clinical significance in excluding encephalopathy. Occipital generators are differentiated by state and stimulus-dependent network activation and not by location and morphology.

OBJECTIVE Stroke symptoms among individuals reporting no physician diagnosis of stroke are associated with an increased risk of future stroke. Few studies have assessed whether individuals with diabetes or prediabetes, but no physician diagnosis of stroke, have an increased prevalence of stroke symptoms. RESEARCH DESIGN AND METHODS This study included 25,696 individuals aged ≥45 years from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who reported no history of stroke or transient ischemic attack at baseline (2003–2007). Glucose measurements, medication use, and self-reported physician diagnosis were used to categorize participants into diabetes, prediabetes, or normal glycemia groups. The presence of six stroke symptoms was assessed using a validated questionnaire. RESULTS The prevalence of any stroke symptom was higher among participants with diabetes (22.7%) compared with those with prediabetes (15.6%) or normal glycemia (14.9%). In multivariable models, diabetes was associated with any stroke symptom (prevalence odds ratio [POR] 1.28 [95% CI 1.18–1.39]) and two or more stroke symptoms (1.26 [1.12–1.43]) compared with normal glycemia. In analyses of individual stroke symptoms, diabetes was associated with numbness (1.15 [1.03–1.29]), vision loss (1.52 [1.31–1.76]), half-vision loss (1.54 [1.30–1.84]), and lost ability to understand people (1.34 [1.12–1.61]) after multivariable adjustment. No association was present between prediabetes and stroke symptoms. CONCLUSIONS In this population-based study, almost one in four individuals with diabetes reported stroke symptoms, which suggests that screening for stroke symptoms in diabetes may be warranted.

Recently published evidence-based guidelines of the Society for Vascular Surgery (SVS) and the American Venous Forum (AVF) include recommendations for evaluation, classification, outcome assessment and therapy of patients with varicose veins and more advanced chronic venous insufficiency (CVI). The need for such guidelines has been evident since imaging techniques and minimally invasive technologies have progressed by leaps and bounds and radiofrequency ablation, laser and sclerotherapy have largely replaced classical open surgery of saphenous stripping. This report reviews the most important guidelines recommended by the SVS/AVF Venous Guideline Committee. It is obvious, however, that some of the technology that is recommended in North America is either not available or not affordable in some parts of the world for patients with varicose veins and CVI. The readers are urged therefore to also consult the guidelines of their national societies, recent publications of the National Institute for Clinical Excellence and the Venous Forum of the Royal Society of Medicine. Venous specialists should also keep in mind that scientific evidence should always be combined with the physician's clinical experience and the patient's preference when the best treatment is selected for an individual patient.