Long-term results of microvascular decompression with video endoscopy in the treatment of patients with atypical trigeminal neuralgia

Background: The incidence of atypical trigeminal neuralgia (aNTN) varies from 1 to 7 per 100,000 population per year. The main cause of its development is compression of the trigeminal nerve (TN) root by a vein and/or artery in the cerebellar cistern. To date, the final tactics of treatment for patients with aNTN has not been specified. The effectiveness of conservative methods of therapy does not exceed 50%. The aim of this study was to evaluate the results of microvascular decompression using video endoscopy in the treatment of patients with atypical trigeminal neuralgia. Methods: In the period from 2014 to 2021, 34 patients with aNTN were operated on, of which 18 (53%) patients had neuropathic pain (more than 4 points on the DN4 scale), and 15 (44%) patients had transformation of classical trigeminal neuralgia into atypical neuralgia. The conservative therapy (carbamazepine, gabapentin, pregabalin), administered to all the patients in the preoperative period, was not accompanied by a significant relief of pain syndrome. The maximum intensity of pain upon admission to the hospital was, according to the visual analog scale (VAS), 10 points, according to the BNI (Barrow Neurological Institute) Pain Intensity Scale V (severe, persistent pain). All the patients underwent microvascular decompression of the trigeminal nerve root with the use of Teflon; in 12 (35%) patients, in addition to microscopy, video endoscopy was used. The average follow-up period after the surgery was 3.41.7 years (from 1 to 5 years). Results: In all (100%) patients, the pain was completely eliminated (BNI I) after the surgery. A total five-year excellent and good outcome of the disease on the J. Miller and BNI scale (I -II) was noted in 80% (n=27) of patients with aNTN. The risk of pain recurrence after microvascular decompression was 14% (n=3) in the first three years, and 34% (n=4) after 5 years. The use of video endoscopy made it possible to identify the blood vessels compressing the root of the trigeminal nerve with a minimal displacement of the cerebellum and cranial nerves when visualizing the neurovascular conflict. Conclusion: The microvascular decompression method with video endoscopy is effective in the treatment of patients with aNTN

Safety and efficacy of convalescent plasma for COVID-19: the preliminary results of a clinical trial

Background. The lack of effective etiotropic therapy for COVID-19 has prompted researchers around the globe to seekr various methods of SARS-CoV-2 elimination, including the use of convalescent plasma. Aim. The aim of this work was to study the safety and efficacy of the convalescence plasma treatment of severe COVID-19 using the plasma containing specific antibodies to the receptor binding domain (RBD) of SARS-CoV-2 S protein in a titer of at least 1:1000. Methods. A single-center, randomized, prospective clinical study was performed at the FRCC FMBA of Russia with the participation of 86 patients who were stratified in two groups. The first group included 20 critically ill patients who were on mechanical ventilation the second group included 66 patients with moderate to severe COVID-19 and with spontaneous respiration. The patients in the second group were randomized into two cohorts in a ratio of 2:1. In the first cohort (46 patients), pathogen-reduced convalescent plasma was transfused (twice, 320 ml each), in the second cohort (20 patients) a similar amount of non-immune freshly frozen plasma was transfused to the patients. Results. The use of plasma of convalescents in patients with severe COVID-19 being on mechanical ventilation does not affect the disease outcome in these patients. The mortality rate in this group was 60%, which corresponds to the average mortality of COVID patients on mechanical ventilation in our hospital. In the second group, clinical improvement was detected in 75% and 51%, for convalescent and non-immune plasma, respectively. Of the 46 people who received convalescent plasma, three patients (6.5%) were transferred to mechanical ventilation, two of them died. In the group receiving non-immune plasma, the need for mechanical ventilation also arose in three patients (15%), of which two died. The hospital mortality in the group of convalescent plasma was 4.3%, which is significantly lower than the average COVID-19 hospital mortality at our Center (6.73%) and more than two times lower than the hospital mortality in the control group (n=150), matched by age and by the disease severity. Conclusions. Thus, we demonstrated a relative safety of convalescent plasma transfusion and the effectiveness of such therapy for COVID-19 at least in terms of the survival of hospitalized patients with severe respiratory failure without mechanical ventilation. In the absence of bioengineered neutralizing antibodies and effective etiotropic therapy, the use of hyperimmune convalescent plasma is the simplest and most effective method of specific etiopathogenetic therapy of severe forms of COVID-19

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care

Recent Developments in Glioblastoma Therapy: Oncolytic Viruses and Emerging Future Strategies

Glioblastoma is the most aggressive form of malignant brain tumor. Standard treatment protocols and traditional immunotherapy are poorly effective as they do not significantly increase the long-term survival of glioblastoma patients. Oncolytic viruses (OVs) may be an effective alternative approach. Combining OVs with some modern treatment options may also provide significant benefits for glioblastoma patients. Here we review virotherapy for glioblastomas and describe several OVs and their combination with other therapies. The personalized use of OVs and their combination with other treatment options would become a significant area of research aiming to develop the most effective treatment regimens for glioblastomas

New Experimental Model of Brain Tumors in Brains of Adult Immunocompetent Rats

Aims: Xenograft models, namely heterotransplantation of human cancer cells or tumor biopsies into immunodeficient rodents are the major preclinical approach for the development of novel cancer therapeutics. However, in these models the animals must be used only after the severe systemic immune suppression in order to ensure graft survival. Thus, additional new human brain tumor models without immune suppression of the recipient rodent may be required. Place and Duration of Study: Laboratory of Immunochemistry, V.P. Serbsky National Research Centre for Social and Forensic Psychiatry and Department of Nanobiotechnology, N.I. Pirogov Russian State Medical University and Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics between June 2009 and July 2010. Methodology: Brain tumor modeling was performed by intracerebral stereotactic implantation of cells to the healthy adult rats without any artificial immunodepression. Cells were implanted to the striatum region of ketamine-anesthetized rats at specific coordinates according to Swanson's rat brain atlas. Tumor growth was monitored weekly via registration of neurological signs and in vivo Bruker MRI system. Results: On the 21st day after implantation of C6 glioma, U251 or 293_CHI3L1 cells severe neurological deficit appeared in rats. Huge intracerebral tumors were found in each animal under investigation while no tumor growth was observed for at least 8 weeks in rats injected with empty vector-transfected 293 cells. Tumors contained the dense superficial cell layer and prominent lobules with central newly ingrowing blood vessels. Histological assay revealed displacement of median cerebral structures and hydrocephalus in contralateral hemisphere. All tumors were surrounded by numerous GFAP-positive reactive astrocytes. Conclusion: Positive results with transplantation of 293_CHI3L1 cells into adult rat brains without any immunosupression show the validity of this animal model. In all experiments such implantations provoked malignant tumor formation while there were no visible tumors in control rats. We believe this to be the first animal model of human brain tumor that displays the possibility to study various biologic features of and host therapeutic response to brain tumor in an immunocompetent host

Downregulation of Gap Junctions in Astrocytes by Monoclonal Antibodies against the Second Extracellular Loop of Connexin-43

Downregulation of gap junctions by monoclonal antibodies against the second extracellular loop of connexin-43 (E2Cx43) was studied in a passaged culture of astrocytes. The results of confocal laser scanning microscopy demonstrated that, after two hours of coincubation of cells loaded with Calcein AM and Dil according to Goldberg et al. and unlabelled cells, the cytoplasmic dye Calcein AM was actively transferred to unlabelled cells through newly formed gap junctions. This transfer could be almost completely blocked by addition of 60 μg/ml of anti-E2Cx43 antibodies. Flow cytometric analysis showed that, in experiments carried out according to Goldberg et al., with approximately 2% of labeled cells added to unlabelled ones, about 2.5% of the total cell population took up Calcein AM through gap junctions, thus forming a cell pool characterized by low-intensity green fluorescence. In the presence of antibodies, the proportion of these cells was no more than 0.6%, which indicates an at least fourfold suppression of the gap junction function by E2Cx43 antibodies. The data obtained were reproduced in several independent series. Thus, we obtained monoclonal antibodies capable of modulating the gap junction function in cultures of Cx43-positive cells

Functional Profiling of In Vitro Reactivated Memory B Cells Following Natural SARS-CoV-2 Infection and Gam-COVID-Vac Vaccination

Both SARS-CoV-2 infection and vaccination have previously been demonstrated to elicit robust, yet somewhat limited immunity against the evolving variants of SARS-CoV-2. Nevertheless, reports performing side-by-side comparison of immune responses following infection vs. vaccination have been relatively scarce. The aim of this study was to compare B-cell response to adenovirus-vectored vaccination in SARS-CoV-2-naive individuals with that observed in the COVID-19 convalescent patients six months after the first encounter with the viral antigens. We set out to use a single analytical platform and performed comprehensive analysis of serum levels of receptor binding domain (RBD)-specific and virus-neutralizing antibodies, frequencies of RBD-binding circulating memory B cells (MBCs), MBC-derived antibody-secreting cells, as well as RBD-specific and virus-neutralizing activity of MBC-derived antibodies after Gam-COVID-Vac (Sputnik V) vaccination and/or natural SARS-CoV-2 infection. Overall, natural immunity was superior to Gam-COVID-Vac vaccination. The levels of neutralizing MBC-derived antibodies in the convalescent patients turned out to be significantly higher than those found following vaccination. Our results suggest that after six months, SARS-CoV-2-specific MBC immunity is more robust in COVID-19 convalescent patients than in Gam-COVID-Vac recipients. Collectively, our data unambiguously indicate that natural immunity outperforms Gam-COVID-Vac-induced immunity six months following recovery/vaccination, which should inform healthcare and vaccination decisions

Functional Profiling of In Vitro Reactivated Memory B Cells Following Natural SARS-CoV-2 Infection and Gam-COVID-Vac Vaccination

Both SARS-CoV-2 infection and vaccination have previously been demonstrated to elicit robust, yet somewhat limited immunity against the evolving variants of SARS-CoV-2. Nevertheless, reports performing side-by-side comparison of immune responses following infection vs. vaccination have been relatively scarce. The aim of this study was to compare B-cell response to adenovirus-vectored vaccination in SARS-CoV-2-naive individuals with that observed in the COVID-19 convalescent patients six months after the first encounter with the viral antigens. We set out to use a single analytical platform and performed comprehensive analysis of serum levels of receptor binding domain (RBD)-specific and virus-neutralizing antibodies, frequencies of RBD-binding circulating memory B cells (MBCs), MBC-derived antibody-secreting cells, as well as RBD-specific and virus-neutralizing activity of MBC-derived antibodies after Gam-COVID-Vac (Sputnik V) vaccination and/or natural SARS-CoV-2 infection. Overall, natural immunity was superior to Gam-COVID-Vac vaccination. The levels of neutralizing MBC-derived antibodies in the convalescent patients turned out to be significantly higher than those found following vaccination. Our results suggest that after six months, SARS-CoV-2-specific MBC immunity is more robust in COVID-19 convalescent patients than in Gam-COVID-Vac recipients. Collectively, our data unambiguously indicate that natural immunity outperforms Gam-COVID-Vac-induced immunity six months following recovery/vaccination, which should inform healthcare and vaccination decisions

Oncolytic therapy with recombinant vaccinia viruses targeting the interleukin-15 pathway elicits a synergistic response

We developed recombinant variants of oncolytic vaccinia virus LIVP strain expressing interleukin-15 (IL-15) or its receptor subunit alpha (IL-15Rα) to stimulate IL-15-dependent immune cells. We evaluated their oncolytic activity either alone or in combination with each other in vitro and in vivo using the murine CT26 colon carcinoma and 4T1 breast carcinoma models. We demonstrated that the admixture of these recombinant variants could promote the generation of the IL-15/IL-15Rα complex. In vitro studies indicated that 4T1 breast cancer cells were more susceptible to the developed recombinant viruses. In vivo studies showed significant survival benefits and tumor regression in 4T1 breast cancer syngeneic mice that received a combination of LIVP-IL15-RFP with LIVP-IL15Ra-RFP. Histological analysis showed recruited lymphocytes at the tumor region, while no harmful effects to the liver or spleen of the animals were detected. Evaluating tumor-infiltrated lymphocytes represented profound activation of cytotoxic T cells and macrophages in mice receiving combination therapy. Thus, our experiments showed superior oncolytic effectiveness of simultaneous injection of LIVP-IL15-RFP and LIVP-IL15Ra-RFP in breast cancer-bearing mice. The combined therapy by these recombinant variants represents a potent and versatile approach for developing new immunotherapies for breast cancer

SARS-CoV-2 Establishes a Productive Infection in Hepatoma and Glioblastoma Multiforme Cell Lines

Severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and rapidly caused a pandemic that led to the death of >6 million people due to hypercoagulation and cytokine storm. In addition, SARS-CoV-2 triggers a wide array of pathologies, including liver dysfunction and neurological disorders. It remains unclear if these events are due to direct infection of the respective tissues or result from systemic inflammation. Here, we explored the possible infection of hepatic and CNS cell lines by SARS-CoV-2. We show that even moderate expression levels of the angiotensin-converting enzyme 2 (ACE2) are sufficient for productive infection. SARS-CoV-2 infects hepatoma Huh7.5 and HepG2 cells but not non-transformed liver progenitor or hepatocyte/cholangiocyte-like HepaRG cells. However, exposure to the virus causes partial dedifferentiation of HepaRG cells. SARS-CoV-2 can also establish efficient replication in some low-passage, high-grade glioblastoma cell lines. In contrast, embryonal primary astrocytes or neuroblastoma cells did not support replication of the virus. Glioblastoma cell permissiveness is associated with defects in interferon production. Overall, these results suggest that liver dysfunction during COVID-19 is not due to infection of these tissues by SARS-CoV-2. Furthermore, tumors may potentially serve as reservoirs for the virus during infection