A high-dose pharmacokinetic study of a new IgG4 monoclonal antibody temelimab/GNbAC1 antagonist of an endogenous retroviral protein pHERV-W Env

PURPOSE : Temelimab/GNbAC1 is a humanized immunoglobulin G4 monoclonal antibody antagonist of the human endogenous retrovirus W envelope protein, which is associated with multiple sclerosis (MS) pathophysiology and possibly with other autoimmune disorders. Human endogenous retrovirus W envelope protein is expressed in the central nervous system of patients with MS, and sufficient amount of temelimab must reach the target. The safety of very high dosages of temelimab should be tested to support further clinical trials in MS. METHODS : This randomized, placebo-controlled, dose-escalation study evaluated the safety and pharmacokinetic profile of temelimab in 24 healthy volunteers after a single intravenous infusion at doses of 36, 60, 85, and 110 mg/kg administered sequentially. FINDINGS : Temelimab was well tolerated, with no particular adverse drug reactions at any dose. The maximal dose of 110 mg/kg could be administered, and no antidrug antibodies were induced. After administration of 36–110 mg/kg, mean temelimab Cmax increased from 859 to 2450 μg/mL, and AUC values increased from 319,900 to 1,030,000 μg·h/mL. There was an approximate dose-proportional increase in exposure, similar to observations at lower doses. IMPLICATIONS : The favorable data in terms of safety and pharmacokinetic variables support temelimab use at high doses in future MS trials to optimally neutralize the temelimab target in the central nervous system. ClinicalTrials.gov identifier: NCT03574428.GeNeuro SAhttps://www.journals.elsevier.com/clinical-therapeutics2020-09-01hj2020Pharmacolog

Consensus conference on core radiological parameters to describe lumbar stenosis - an initiative for structured reporting

Purpose: To define radiological criteria and parameters as a minimum standard in a structured radiological report for patients with lumbar spinal stenosis (LSS) and to identify criteria and parameters for research purposes. Material and methods: All available radiological criteria and parameters for LSS were identified using systematic literature reviews and a Delphi survey. We invited to the consensus meeting, and provided data, to 15 internationally renowned experts from different countries. During the meeting, these experts reached consensus in a structured and systematic discussion about a core list of radiological criteria and parameters for standard reporting. Results: We identified a total of 27 radiological criteria and parameters for LSS. During the meeting, the experts identified five of these as core items for a structured report. For central stenosis, these were "compromise of the central zone” and "relation between fluid and cauda equina”. For lateral stenosis, the group agreed that "nerve root compression in the lateral recess” was a core item. For foraminal stenosis, we included "nerve root impingement” and "compromise of the foraminal zone”. Conclusion: As a minimum standard, five radiological criteria should be used in a structured radiological report in LSS. Other parameters are well suited for research. Key Points : • The five most important radiological criteria for standard clinical reporting were selected • The five most important quantitative radiological parameters for research purposes were selected • These core criteria could help standardize the communication between health care provider

A new therapeutic approach for type 1 diabetes : rationale for GNbAC1, an anti‐HERV‐W‐Env monoclonal antibody

We describe a newly identified therapeutic target for type 1 diabetes (T1D): an envelope protein of endogenous retroviral origin, human endogenous retrovirus W envelope (HERV‐W‐Env). HERV‐W‐Env was found to be detected in the blood of ~60% of patients with T1D and is expressed in acinar pancreatic cells of 75% of patients with T1D at post mortem examination. Preclinical experiments showed that this protein displays direct cytotoxicity on human β‐islet cells. In vivo HERV‐W‐Env impairs the insulin and glucose metabolism in transgenic mice expressing HERV‐W‐Env. GNbAC1, an IgG4 monoclonal antibody, has been developed to specifically target HERV‐W‐Env and to neutralize the effect of HERV‐W‐Env in vitro and in vivo. GNbAC1 is currently in clinical development for multiple sclerosis and > 300 subjects have been administered with GNbAC1 so far. GNbAC1 is now being tested in T1D in the RAINBOW‐T1D study, which is a randomized placebo‐controlled study with the objective of showing the safety and pharmacodynamic response of GNbAC1 in patients who have had T1D with a maximum of 4 years' duration. GNbAC1 is being tested vs placebo at the dose of 6 mg/kg in 60 patients during six repeated administrations for 6 months; a 6‐month open‐label extension will follow. The primary endpoint is to assess safety, and secondary endpoints are the pharmacodynamic responses to GNbAC1. GNbAC1 targeting HERV‐W‐Env is currently in clinical development in T1D, with the first safety and pharmacodynamic study. If the study results are positive, this may open the door to the development of an innovative non‐immunomodulatory disease‐modifying treatment for T1D.The RAINBOW-T1D study is financed by GeNeuro Australia Pty Ltd, a subsidiary of GeNeuro SA, Switzerland.http://wileyonlinelibrary.com/journal/dom2019-09-01hj2018Pharmacolog

Multimodal intraoperative monitoring (MIOM) during 409 lumbosacral surgical procedures in 409 patients

A prospective study on 409 patients who received multimodel intraoperative monitoring (MIOM) during lumbosacral surgical procedures between March 2000 and December 2005 was carried out. The objective of this study was to determine the sensitivity and specificity of MIOM techniques used to monitor conus medullaris, cauda equina and nerve root function during lumbosacral decompression surgery. MIOM has increasingly become important to monitor ascending and descending pathways, giving immediate feedback information regarding any neurological deficit during the decompression and stabilisation procedure in the lumbosacral region. Intraoperative spinal- and cortical-evoked potentials, combined with continuous EMG- and motor-evoked potentials of the muscles, were evaluated and compared with postoperative clinical neurological changes. A total of 409 consecutive patients with lumbosacral spinal stenosis with or without instability were monitored by MIOM during the entire surgical procedure. A total of 388 patients presented true-negative findings while two patients presented false negative and 1 patient false-positive findings. Eighteen patients presented true-positive findings where neurological deficit after the operation was intraoperatively predicted. Of the 18 true-positive findings, 12 patients recovered completely; however, 6 patients recovered only partially. The sensitivity of MIOM applied during decompression and fusion surgery of the lumbosacral region was calculated as 90%, and the specificity was calculated as 99.7%. On the basis of the results of this study, MIOM is an effective method of monitoring the conus medullaris, cauda equina and nerve root function during surgery at the lumbosacral junctions and might reduce postoperative surgical-related complications and therefore improve the long-term results

Theoretical investigation of the adsorption of methanol on the (110) surface of g-alumina

The adsorption of MeOH on the (110) surface of g-alumina was studied using both ab initio and d. functional theory quantum chem. methods. A [Al3O9H10]+ cluster model comprising one tetrahedral and 2 octahedral Al cations were used to describe the surface and the mechanism of adsorption of MeOH. This has allowed one to rationalize the stable structures of adsorbate and the mode of bonding. The IR frequency shifts between the gas phase and the adsorbed species were also calcd. and they exhibit good agreement with expt. [on SciFinder (R)

Validation of a surgical invasiveness index in patients with lumbar spinal disorders registered in the Spine Tango registry

Introduction: Being able to quantify the invasiveness of a surgical procedure is important to weigh up its associated risks, since invasiveness governs the blood loss, operative time and likelihood of complications. Mirza et al. (Spine (Phila Pa 1976) 33:2651–2661, 2008) published an invasiveness index for spinal surgery. We evaluated the validity of a modified version of the Mirza invasiveness index (mMII), adapted for use with registry data. Methods: A cross-sectional analysis was performed with data acquired from the Spine Tango registry including 21,634 patients. The mMII was calculated as the sum of six possible interventions on each vertebral level: decompression, fusion and stabilization either on anterior or posterior structures. The association between the mMII and blood loss, operative time and complications was evaluated using multiple regression, adjusting for possible confounders. Results: The mean (± SD) mMII was 3.9 ± 5.0 (range 0–40). A 1-point increase in the mMII was associated with an additional blood loss of 12.8% (95% CI 12.6–13.0; p < 0.001) and an increase of operative time of 10.4 min (95% CI 10.20–10.53; p < 0.001). The R$^{2}$ for the blood loss model was of 43% and for operative time, 47%. The mean mMII was significantly (p < 0.001) higher in patients with surgical complications (4.5 ± 5.6) and general medical complications (6.5 ± 7.0) compared to those without (3.8 ± 4.9). Our results were comparable to those reported in the original publication of Mirza et al. Conclusion: The mMII appeared to be a valid measure of surgical invasiveness in our study population. It can be used in predictor models and to adjust for surgical case-mix when comparing outcomes in different studies or different hospitals/surgeons in a registry

Clinical outcome in lumbar decompression surgery for spinal canal stenosis in the aged population: a prospective swiss multicenter cohort study

STUDY DESIGN This is a prospective, multicenter cohort study including 8 medical centers in the metropolitan area of the Canton Zurich, Switzerland. OBJECTIVES To examine whether outcome and quality of life might improve after decompression surgery for degenerative lumbar spinal stenosis (DLSS) even in patients older than 80 years and to compare data with a younger patient population from our own patient collective. SUMMARY AND BACKGROUND DATA Lumbar decompression surgery without fusion has been shown to improve quality of life in lumbar spinal canal stenosis. In the population older than 80 years, treatment recommendations for DLSS show conflicting results. METHODS Eight centers in the metropolitan area of Zurich, Switzerland agreed on the classification of DLSS, surgical principles, and follow-up protocols. Patients were followed from baseline, at 6 months, and 12 months. Baseline characteristics were analyzed with 5 different questionnaires "Spinal Stenosis Measure, Feeling Thermometer, Numeric Rating Scale, 5D-3L, and Roland and Morris Disability Questionnaire." In addition, our study population was compared with a younger control group. Furthermore, we calculated the minimal clinically important differences. RESULTS Thirty-seven patients with an average age of 82.5 ± 2.5 years reached the 12-month follow-up. Spinal Stenosis Measure scores, the Feeling Thermometer, the Numeric Rating Scale, and the Roland and Morris Disability Questionnaire showed significant improvements at the 6-month and 12-month follow-ups (P < 0.001). One EQ-5D-3Lsubgroup "anxiety/depression" showed no significant improvement (P = 0.109) at 12-month follow-up. The minimal clinically important difference for the "Symptom Severity scale" in the Spinal Stenosis Measure was achieved with improvement of 70% in the older patient population. CONCLUSION Patients 80 years or older can expect a clinically meaningful improvement after lumbar decompression for symptomatic DLSS. Our patient population showed significant positive development in quality of life in the short- and long-term follow-ups. LEVEL OF EVIDENCE 3