Atlantic Health System

About: Atlantic Health System is a healthcare organization based out in Morristown, New Jersey, United States. It is known for research contribution in the topics: Catheter ablation & Antiarrhythmic agent. The organization has 277 authors who have published 299 publications receiving 6594 citations.

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572

Abstract: Background Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. Methods Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. Results The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. Conclusions The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Endothelin-Converting Enzymes and Related Metalloproteases in Alzheimer's Disease

Abstract: The efficient clearance of amyloid-β (Aβ) is essential to modulate levels of the peptide in the brain and to prevent it from accumulating in senile plaques, a hallmark of Alzheimer's disease (AD) pathology.We and others have shown that failure in Aβ catabolism can produce elevations in Aβ concentration similar to those observed in familial forms of AD. Based on the available evidence, it remains plausible that in late-onset AD, disturbances in the activity of Aβ degrading enzymes could induce Aβ accumulation, and that this increase could result in AD pathology. The following review presents a historical perspective of the parallel discovery of three vasopeptidases (neprilysin and endothelin-converting enzymes-1 and -2) as important Aβ degrading enzymes. The recognition of the role of these vasopeptidases in Aβ degradation, beyond bringing to light a possible explanation of how cardiovascular risk factors may influence AD risk, highlights a possible risk of the use of inhibitors of these enzymes for other clinical indications such as hypertension. We will discuss in detail the experiments conducted to assess the impact of vasopeptidase deficiency (through pharmacological inhibition or genetic mutation) on Aβ accumulation, as well as the cooperative effect of multiple Aβ degrading enzymes to regulate the concentration of the peptide at multiple sites, both intracellular and extracellular, throughout the brain.

Long-term rhythm control of drug-refractory atrial fibrillation with "hybrid therapy" incorporating dual-site right atrial pacing, antiarrhythmic drugs, and right atrial ablation.

Abstract: We evaluated the long-term efficacy, safety, and applicability of a "hybrid" therapy strategy for rhythm control in atrial fibrillation (AF), incorporating dual-site right atrial pacing, antiarrhythmic drugs, and right atrial ablation. One hundred thirteen patients (paroxysmal AF [n = 70], persistent/permanent AF [n = 43]) with refractory symptomatic AF were treated with this strategy and followed for 1 to 81 months (mean 30 +/- 23). All-cause mortality, AF recurrences, and progression to permanent AF were monitored and recorded by implanted device data logs. There was no procedural mortality. Rhythm control was achieved in 90% of all patients at 3 and 5 years, with comparable efficacy in subpopulations with paroxysmal (98%), persistent, or permanent AF (87%, p >2). Overall survival was 84% at 3 years and 80% at 5 years, and was higher in patients with paroxysmal AF than in patients with persistent or permanent AF (86% vs 67% at 4 years, p <0.001). Patients with persistent or permanent AF had a greater need for cardioversion (p <0.004) and right atrial ablation (p <0.04) than patients with paroxysmal AF to achieve comparable rhythm control. A hybrid therapy strategy can provide safe and effective long-term rhythm control in patients with drug-refractory AF, and can be implemented in subpopulations presenting with paroxysmal, persistent, or permanent AF.

Pediatric early warning score at time of emergency department disposition is associated with level of care.

Abstract: ObjectiveThe objective of this study was to determine the association between the Pediatric Early Warning Score (PEWS) at time of emergency department (ED) disposition and level of care.MethodsWe conducted a prospective observational study with a convenience sample of patients aged 0 to 21 years in

Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis.

Abstract: Background Dysembryoplastic neuroepithelial tumors (DNETs) are uncommon neural tumors presenting most often in children and young adults and associated with intractable seizures. Rare midline neoplasms with similar histological features to those found in DNETs have been described near the septum pellucidum and termed "DNET-like neoplasms of the septum pellucidum." Due to their rarity, these tumors have been described in just a few reports and their genetic alterations sought only in small series. Methods We collected 20 of these tumors for a comprehensive study of their clinical, radiological, and pathological features. RNA sequencing or targeted DNA sequencing was undertaken on 18 tumors, and genome-wide DNA methylation profiling was possible with 11 tumors. Published cases (n = 22) were also reviewed for comparative purposes. Results The commonest presenting symptoms and signs were related to raised intracranial pressure; 40% of cases required cerebrospinal fluid diversion. Epilepsy was seen in approximately one third of cases. All patients had an indolent disease course, despite metastasis within the neuraxis in a few cases. Radiologically, the septum verum/septal nuclei were involved in all cases and are the proposed site of origin for septal DNET (sDNET). Septal DNET showed a high frequency (~80%) of mutations of platelet derived growth factor receptor A (PDGFRA), and alterations in fibroblast growth factor receptor 1 (FGFR1) and neurofibromatosis type 1 (NF1) were also identified. In a genomic DNA methylation analysis alongside other neural tumors, sDNETs formed a separate molecular group. Conclusions Genetic alterations that are different from those of cerebral DNETs and a distinct methylome profile support the proposal that sDNET is a distinct disease entity.