Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study

This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk–benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis

Supported by F. Hoffmann–La Roche

LEV NIKOLAEVICH NESTEROV

The annual conference "Actual problems of Epileptology" in Samara

Drug-resistant epilepsy associated with cortical dysplasias

Epilepsy associated with malformations of the cerebral cortex is reported in the literature to account for up to 25% of the total cases of symptomatic epilepsies. It is characterized by the most severe course and often induces drug-resistance in seizures. A group of patients with resistant seizures is singled out among the total number of patients with symptomatic epilepsy caused by cerebral cortical dysgenesis. The most important risk factors for resistance are identified in dysplasias. The prognostically unfavorable clinical features of epilepsy are described. A diagnostic algorithm is proposed to identify risk groups and to prevent drug-resistant forms of epilepsy

Clinico-pharmacological aspects of choice and safety of NSAIDs in patients with cerebrovascular disease against a background of rheumatoid arthritis

The retrospective study evaluated the risk of using non-steroidal antiinflammatory drugs (NSAIDs) for the treatment of back pain in patients with cerebrovascular disease against a background of rheumatoid arthritis. Acute cardio-and cerebrovascular events were reported in 9.7% of subjects treated with NSAIDs. Adverse effects during treatment were associated with diclofenac and nimesulide. Overall risks were low in the group treated with etoricoxib, allowing for all patients to undergo scheduled courses of NSAID therapy, including upon follow-up visits

THE ROLE OF THE THERAPEUTIC DRUG MONITORING WHEN USING ANTIEPILEPTIC DRUGS

Objective. To define therapeutic drug monitoring (TDM) role when using drugs of valproic acid and a levetiraсetam as options of medication with a nonlinear and linear pharmakokinetics.Materials and  methods. Analysed are the results of the therapeutic drug monitoring (TDM) among 80 patients who were using valproic acid during the monotherapy  and levetiracetam during monotherapy  or the combination  of any other antiepileptic drugs (AEDs). We determine  plasma concentration C min (before use next dose  AED). Results.  Аmong  the  group consisting  of 57 patients and taking valproic acid with the individual daily dosages  in the range of 7.5 mg/kg  to 30.7 mg/kg,  C min of valproic acid equaled to the range of 44 to 111 mcg/ml  (therapeutic range is 50-100 mcg/ml).  The  research determined the presence  of significant individual pharmacokinetic features of valproic acid that play a role in achieving clinical effects and appearance of undesired results. 23 patients were taking the daily dosage of levetiracetam starting from 500 to 3000 mg  twice or thrice which equal from 7.5 mg/kg/day  to 36.9 mg/kg/day  individually. TDM confirmed  the linear pharmacokinetics  of levetiracetam, furthermore determining that the method  of determining the daily dosage by the body mass being more effective among the adults. 30 mg/kg can be considered the average effective daily dose of levetiracetam. Conclusion. TDM proved to be a reasonable AEDs treatment not only for patients with the nonlinear pharmacokinetics  but also for those with the linear pharmacokinetics

THE RELATIONSHIP OF THE MORPHOMETRIC CHARACTERISTICS OF RUPTURED CEREBRAL ANEURYSMS TO PATIENTS’ AGE

Objective. To investigate the morphological characteristics of ruptured aneurysms in a group of patients under and over 50 years of age. Material and methods. The investigation enrolled 123 people with ruptured saccular cerebral aneurysms, in whom digital subtraction angiography was carried out in 2011 to 2015. The study took into account the localization of aneurysms, the diameter of the aneurysm dome, the diameter of the aneurysm neck, the axial size of the aneurysmal sac, the distance from the aneurysm neck plane to the aneurysm dome measurement plane, dome-to-neck ratio, axial dimension-to-neck diameter ratio, and aneurysm volume. Results. The diameter of the aneurysm dome (Mann–Whitney U (60; 63)=1384.0; p=0.01), that of the aneurysm neck (U (60; 63) = 1283; p=0.002), aneurysm volume (U (60;63) = 1244.5; p=0.001) were statistically significantly higher in the older age group with a positive correlation with the age of patients. Conclusion. The older age group patients with ruptured cerebral aneurysm had high values of dome and neck diameters and aneurysm volume with a positive correlation between these indicators and the age of patients

A clinical case of SYNGAP1-associated encephalopathy in a girl with epilepsy, intellectual disability, and autism

This paper describes a female patient aged 3 years 6 months with SYNGAP1-associated encephalopathy manifesting with symptomatic epilepsy, intellectual disability, and autism. There were difficulties in  differential diagnosis, since in addition to SYNGAP1 mutation (c2214_2217deltgag), heterozygous BCKDHB gene mutation  (chr6: 80910740G>a, rs3834233) and microduplication of a segment of chromosome 22 were found de novo. The features of the course and  treatment of epilepsy in SYNGAP1 are discussed. A combination of  valproic acid and oxcarbazepine was the most effective treatment for epilepsy

Regularities in the course of epilepsy during various age periods

Objective: to optimize patient management tactics and disease prognosis, by detecting the regularities of the course of epilepsy during various age periods. Patients and methods. The results of following up 1632 patients with epilepsy in the Samara Region were given. Among them, there were 865 (53.0%) men and 767 (47.0%) women. The classification of epilepsy and epileptic syndromes (New Delhi, 1989) was used to establish the diagnosis. Each patient underwent neurological evaluation, electroencephalography (EEG) and video-EEG monitoring, studies of long-latency visual evoked potentials, as well as neuroimaging examinations (brain computed tomography and magnetic resonance imaging (MRI)). Factor and principal component analysis and logistic regression were used to make a mathematical model to predict remission in epilepsy. Results. The specific features of the occurrence and course of epilepsy in various age periods were analyzed. According to the results of mathematical simulation, the age at the onset of late epilepsy can be considered to be 29 years. Remission of epilepsy was more frequently attained and absolute resistance was less frequently observed in the younger age group, except for infants with catastrophic epilepsy and epileptic syndromes. There were fewer remissions and much more patients with relative and absolute resistance and rare seizures in the older age group. Epilepsy in young patients is that of the immature brain and epilepsy of adulthood (late epilepsy) of the involutional brain. Conclusion. Epilepsy runs a benign course in patients who fell ill in adolescence or adulthood and have minimal brain structural changes, as evidenced by MRI. Marked brain morphological changes most frequently determine the drug-resistant course of epilepsy, manifesting in early childhood and at an elderly age