Citations

Abstract Response to stem cell therapy in heart failure is heterogeneous, warranting a better understanding of outcome predictors. This study assessed left ventricular volume, a surrogate of disease severity, on cell therapy benefit. Small to large infarctions were induced in murine hearts to model moderate, advanced, and end-stage ischemic cardiomyopathy. At 1 month postinfarction, cardiomyopathic cohorts with comparable left ventricular enlargement and dysfunction were randomized 1:1 to those that either received sham treatment or epicardial delivery of cardiopoietic stem cells (CP). Progressive dilation and pump failure consistently developed in sham. In comparison, CP treatment produced significant benefit at 1 month post-therapy, albeit with an efficacy impacted by cardiomyopathic stage. Advanced ischemic cardiomyopathy was the most responsive to CP-mediated salvage, exhibiting both structural and functional restitution, with proteome deconvolution substantiating that cell therapy reversed infarction-induced remodeling of functional pathways. Moderate cardiomyopathy was less responsive to CP therapy, improving contractility but without reversing preexistent heart enlargement. In end-stage disease, CP therapy showed the least benefit. This proof-of-concept study thus demonstrates an optimal window, or “Goldilocks principle,” of left ventricular enlargement for maximized stem cell-based cardiac repair. Disease severity grading, prior to cell therapy, should be considered to inform regenerative medicine interventions. Significance statement This article documents that cardiac chamber enlargement postinfarction is a predictor of cardiopoietic stem cell therapy response. Left ventricular size pretherapy could thus serve to guide the selection of ischemic heart failure candidates most suitable to receive a regenerative intervention.

ABSTRACTThe concept of epilepsy syndromes, introduced in 1989, was defined as “clusters of signs and symptoms customarily occurring together”. Definition of epilepsy syndromes based on electro‐clinical features facilitated clinical practice and, whenever possible, clinical research in homogeneous groups of patients with epilepsies. Progress in the fields of neuroimaging and genetics made it rapidly clear that, although crucial, the electro‐clinical description of epilepsy syndromes was not sufficient to allow much needed development of targeted therapies and a better understanding of the underlying pathophysiological mechanisms of seizures. The 2017 ILAE position paper on Classification of the Epilepsies recognized that “as a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking”. The concept of “epilepsy syndromes” evolved, incorporating issues related to aetiologies and comorbidities. A comprehensive update (and revision where necessary) of the EEG diagnostic criteria in the light of the 2017 revised terminology and concepts was deemed necessary. Part 2 covers the neonatal and paediatric syndromes in accordance with the age of onset. [Published with educational EEG plates atwww.epilepticdisorders.com].

AbstractRational. The concept of epilepsy syndromes, introduced in 1989, was defined as “clusters of signs and symptoms customarily occurring together”. Definition of epilepsy syndromes based on electro‐clinical features facilitated clinical practice and, whenever possible, clinical research in homogeneous groups of patients with epilepsies. Progress in the fields of neuroimaging and genetics made it rapidly clear that, although crucial, the electro‐clinical description of epilepsy syndromes was not sufficient to allow much needed development of targeted therapies and a better understanding of the underlying pathophysiological mechanisms of seizures. The 2017 ILAE position paper on Classification of the Epilepsies recognized that “as a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking”. The concept of “epilepsy syndromes” evolved, incorporating issues related to aetiologies and comorbidities. A comprehensive update (and revision where necessary) of the EEG diagnostic criteria in the light of the 2017 revised terminology and concepts was deemed necessary.Methods. The work was commissioned by the Neurophysiology Task Force of the ILAE Committee on the Diagnostic Methods. Diagnostic criteria and recording procedures were developed by group consensus, reached through an “informal”, internal decision‐making process. Each working group member was allocated a number of syndromes, and a standard structured template was used. International literature was extensively reviewed.Results. We developed a simple diagnostic system that is applicable to all epilepsy syndromes which allows the physician (i) to rate the strength of EEG diagnosis (degree of diagnostic certainty) by weighting EEG findings in relation to the available clinical information or the specific clinical question, and ii) to suggest further EEG diagnostics where conclusive diagnostic evidence is lacking. We also propose a system of syndrome‐specific recording protocols that, used with the relevant clinical presentation or specific clinical question, may maximize activation of epileptic discharges and ultimately help with standardization of EEG recording across departments, worldwide. Because recording methodology also depends on available resources, a two‐tier system was developed to embrace clinical EEG services in resource‐limited and industrialized countries. A clinical practice statement for each of the epilepsy syndromes discussed underscores the crucial role of the clinical information with regards to both the optimization of the EEG recording and mainly its meaningful interpretation. Part I covers Genetic (Idiopathic) generalized epilepsies and syndromes, Reflex epilepsies, structural and genetic focal (lobar) syndromes and Progressive Myoclonus Epilepsies [Published with educational EEG plates on www.epilepticdisorders.com].

Objective Excessive inflammation in the central nervous system (CNS) and the periphery can result in neurodegeneration and parkinsonism. Recent evidence suggests that immune responses in Parkinson disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although α‐synuclein pathology is the hallmark of Parkinson disease, it has not been investigated whether pathologic α‐synuclein is a specific trigger for excessive inflammatory responses in Parkinson disease. Methods We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of α‐synuclein by assessing cytokine release upon exposure. Results We show that pathologic α‐synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation‐ dependent, with increasing fibrillation and early onset mutations having the strongest effect on immune activation. We also found that activation of immune cells by extracellular α‐synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of α‐synuclein. Blood extracellular vesicles from Parkinson disease patients induce a stronger activation of monocytes than blood extracellular vesicles from healthy controls. Most importantly, monocytes from Parkinson disease patients are dysregulated and hyperactive in response to stimulation with pathologic α‐synuclein. Furthermore, we demonstrate that α‐synuclein pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model. Interpretation Taken together, our data suggest that α‐synuclein pathology and dysregulation of monocytes in Parkinson disease can act together to induce excessive inflammatory responses to α‐synuclein. ANN NEUROL 2019;86:593–606

Purpose. There are no known effective medical treatments for refractory MPNST. Inactivation of the NF1 tumor suppressor in MPNST results in upregulation of mTOR (mammalian target of rapamycin) signaling and angiogenesis, which contributes to disease progression. We conducted a phase II study for patients (pts) with refractory MPNST combining everolimus (10 mg PO once daily) with bevacizumab (10 mg/kg IV every 2 weeks) to determine the clinical benefit rate (CBR) (complete response, partial response (PR), or stable disease (SD) ≥ 4 months). Patients and Methods. Patients ≥18 years old with chemotherapy refractory sporadic or NF1 MPNST were eligible. Tumor response was assessed after every 2 cycles (the WHO criteria). A two-stage design targeting a 25% CBR was used: if ≥ 1/15 pts in stage 1 responded, enrollment would be expanded by 10 pts, and if ≥ 4/25 patients had clinical benefit, the combination would be considered active. Results. Twenty-five pts, 17 with NF1 and 8 with sporadic MPNST, enrolled. One of 15 pts in stage 1 had clinical benefit. Of 10 additional pts enrolled, 2 had clinical benefit. The median number of completed cycles was 3 (range 1–16). Adverse events were similar to those known for this combination. Conclusion. With a CBR of 12% (3/25), the combination of everolimus and bevacizumab did not reach the study’s target response rate and is not considered active in refractory MPNST.

Abstract Aims Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. Methods and results Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II–III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II–III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II–III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. Conclusion The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II–III loop. This represents a ‘mutation hotspot’ in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

PURPOSE This pilot study examined the ability to operationalize the collection of real-world data to explore the potential use of real-world end points extracted from data from diverse health care data organizations and to assess how these relate to similar end points in clinical trials for immunotherapy-treated advanced non–small-cell lung cancer. PATIENTS AND METHODS Researchers from six organizations followed a common protocol using data from administrative claims and electronic health records to assess real-world end points, including overall survival (rwOS), time to next treatment, time to treatment discontinuation (rwTTD), time to progression, and progression-free survival, among patients with advanced non–small-cell lung cancer treated with programmed death 1/programmed death-ligand 1 inhibitors in real-world settings. Data sets included from 269 to 6,924 patients who were treated between January 2011 and October 2017. Results from contributors were anonymized. RESULTS Correlations between real-world intermediate end points (rwTTD and time to next treatment) and rwOS were moderate to high (range, 0.6 to 0.9). rwTTD was the most consistent end points as treatment detail was available in all data sets. rwOS at 1 year post–programmed death-ligand 1 initiation ranged from 40% to 57%. In addition, rwOS as assessed via electronic health records and claims data fell within the range of median OS values observed in relevant clinical trials. Data sources had been used extensively for research with ongoing data curation to assure accuracy and practical completeness before the initiation of this research. CONCLUSION These findings demonstrate that real-world end points are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision making. Differences observed likely reflect true differences between real-world and protocol-driven practices.

ABSTRACT Here, we show that cells expressing the adherens junction protein nectin-1 capture nectin-4-containing membranes from the surface of adjacent cells in a trans-endocytosis process. We find that internalized nectin-1–nectin-4 complexes follow the endocytic pathway. The nectin-1 cytoplasmic tail controls transfer: its deletion prevents trans-endocytosis, while its exchange with the nectin-4 tail reverses transfer direction. Nectin-1-expressing cells acquire dye-labeled cytoplasmic proteins synchronously with nectin-4, a process most active during cell adhesion. Some cytoplasmic cargo remains functional after transfer, as demonstrated with encapsidated genomes of measles virus (MeV). This virus uses nectin-4, but not nectin-1, as a receptor. Epithelial cells expressing nectin-4, but not those expressing another MeV receptor in its place, can transfer infection to nectin-1-expressing primary neurons. Thus, this newly discovered process can move cytoplasmic cargo, including infectious material, from epithelial cells to neurons. We name the process nectin-elicited cytoplasm transfer (NECT). NECT-related trans-endocytosis processes may be exploited by pathogens to extend tropism. This article has an associated First Person interview with the first author of the paper.

Background Clinical characteristics and outcomes of takotsubo syndrome ( TTS ) patients with malignancy have not been fully elucidated. This study sought to explore differences in clinical characteristics and to investigate short‐ and long‐term outcomes in TTS patients with or without malignancy. Methods and Results TTS patients were enrolled from the International Takotsubo Registry. The TTS cohort was divided into patients with and without malignancy to investigate differences in clinical characteristics and to assess short‐ and long‐term mortality. A subanalysis was performed comparing long‐term mortality between a subset of TTS patients with or without malignancy and acute coronary syndrome (ACS) patients with or without malignancy. Malignancy was observed in 16.6% of 1604 TTS patients. Patients with malignancy were older and more likely to have physical triggers, but less likely to have emotional triggers compared with those without malignancy. Long‐term mortality was higher in patients with malignancy ( P <0.001), while short‐term outcome was comparable ( P =0.17). In a subanalysis, long‐term mortality was comparable between TTS patients with malignancies and ACS patients with malignancies ( P =0.13). Malignancy emerged as an independent predictor of long‐term mortality. Conclusions A substantial number of TTS patients show an association with malignancy. History of malignancy might increase the risk for TTS , and therefore, appropriate screening for malignancy should be considered in these patients. Clinical Trial Registration URL : http://www.clinicaltrial.gov . Unique identifier: NCT 01947621.

AbstractIntroduction:Patients with end‐stage renal disease (ESRD) experience frequent hemodialysis (HD) complications. Intradialytic hypotension (IDH) is a common complication presenting in approximately between 20 and 50% of HD sessions. Available interventions such as volume replacement or vasoactive medications are associated with significant side effects.Intermittent pneumatic compression (IPC) has been proposed as a feasible intervention for the prevention of IDH, treatment of peripheral arterial disease and venous ulcers. These devices apply intermittent pressure to the legs improving arterial blood flow, mobilization of pooled blood with an increase in venous return increasing the effective circulatory volume.Our goal was to identify the published clinical evidence on whether IPC has a circulatory benefit and is it well‐tolerated among patients receiving HD.Methods:We conducted a systematic review to identify studies assessing the efficacy and safety of IPC in patients with ESRD. Our primary outcome was IDH. Secondary outcomes such as HD comfort, ultrafiltration volume, and physical activity were collected. No restrictions where used and we included all observational and interventional studies. Two reviewers performed screening and study quality assessment.Findings:We included seven studies. Out of the seven studies, five addressed IDH, and the rest were included for secondary outcomes such as physical capacity and HD comfort. In one randomized crossover trial comparing exercise against IPC, 21 patients were randomized to 3 different arms (no intervention, cycling, IPC) a decrease in the rates of IDH with IPC was described (43%, 38%, and 24% respectively P = 0.014). The smaller studies corroborated these results. All studies where at high risk of bias.Discussion:IPC might offer significant benefits for patients undergoing HD not limited to prevention of IDH but also improvement of hemodialysis comfort and physical capacity. However, our results should be interpreted in the context of its limitations.