The impact of stem cells in neuro-oncology: applications, evidence, limitations and challenges

Background: Stem cells (SCs) represent a recent and attractive therapeutic option for neuro-oncology, as well as for treating degenerative, ischemic and traumatic pathologies of the central nervous system. This is mainly because of their homing capacity, which makes them capable of reaching the inaccessible SC niches of the tumor, therefore, acting as living drugs. The target of the study is a comprehensive overview of the SC-based therapies in neuro-oncology, also highlighting the current translational challenges of this type of approach. Methods: An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites, restricting it to the most pertinent keywords regarding the systematization of the SCs and their therapeutic use for malignant brain tumors. A large part of the search was dedicated to clinical trials. Only preclinical and clinical data belonging to the last 5 years were shortlisted. A further sorting was implemented based on the best match and relevance. Results: The results consisted in 96 relevant articles and 31 trials. Systematization involves a distinction between human embryonic, fetal and adult, but also totipo-tent, pluripotent or multipotent SCs. Mesenchymal and neuronal SCs were the most studied for neuro-oncological illnesses. 30% and 50% of the trials were phase I and II, respectively. Conclusion: Mesenchymal and neuronal SCs are ideal candidates for SCs-based therapy of malignant brain tumors. The spectrum of their possible applications is vast and is mainly based on the homing capacity toward the tumor microenvironment. Availability, delivery route, oncogenicity and ethical issues are the main translational challenges concerning the use of SCs in neuro-oncology. (www.actabiomedica.it)

Innovative therapies for malignant brain tumors: the road to a tailored cure

Background: Immune tolerance, immune escape, neoangiogenesis, phenotypic changes, and glioma stem cells are all responsible for the resistance of malignant brain tumors to current therapies and persistent recurrence. The present study provides a panoramic view of innovative therapies for malignant brain tumors, especially glioblastoma, aimed at achieving a tailored approach. Methods: PubMed/Medline and ClinicalTri-als.gov were the main sources of an extensive literature review in which “Regenerative Medicine,” “Cell-Based Therapy,” “Chemotherapy,” “Vaccine,” “Cell Engineering,” “Immunotherapy, Active,” “Immunotherapy, Adoptive,” “Stem Cells,” “Gene Therapy,” “Target Therapy,” “Brain Cancer,” “Glioblastoma,” and “Malignant Brain Tumor” were the search terms. Only articles in English published in the last 5 years were included. A further selection was made according to the quality of the studies and level of evidence. Results: Cell-based and targeted therapies represent the newest frontiers of brain cancer treatment. Active and adoptive im-munotherapies, stem cell therapies, and gene therapies represent a tremendous evolution in recent years due to many preclinical and clinical studies. Clinical trials have validated the effectiveness of antibody-based immunotherapies, including an in-depth study of bevacizumab, in combination with standard of care. Pre-clinical data highlights the role of vaccines, stem cells, and gene therapies to prevent recurrence. Conclusion: Monoclonal antibodies strengthen the first-line therapy for high grade gliomas. Vaccines, engineered cells, stem cells, and gene and targeted therapies are good candidates for second-line treatment of both newly diagnosed and recurrent gliomas. Further data are necessary to validate this tailored approach at the bedside. (www.actabiomedica.it)

Advanced pharmacological therapies for neurofibromatosis type 1-related tumors

Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor-predisposition disorder that is caused by a heterozygous loss of function variant in the NF1 gene, which encodes a protein called neurofi-bromin. The absence of neurofibromin causes increased activity in the Rat sarcoma protein (RAS) signalling pathway, which results in an increased growth and cell proliferation. As a result, both oncological and non-oncological comorbidities contribute to a high morbidity and mortality in these patients. Optic pathways gliomas, plexiform neurofibromas and malignant peripheral nerve sheath tumor (MPNST) are the most fre-quent NF1-associated tumors. The treatment of these complications is often challenging, since surgery may not be feasible due to the location, size, and infiltrative nature of these tumors, and standard chemotherapy or radiotherapy are burdened by significant toxicity and risk for secondary malignancies. For these reasons, following the novel discoveries of the pathophysiological mechanisms that lead to cell proliferation and tumori-genesis in NF1 patients, emerging drugs targeting specific signalling pathways (i.e. the MEK/ERK cascade), have been developed with promising results. (www.actabiomedica.it)

Photometry of comet 9P/Tempel 1 during the 2004/2005 approach and the Deep Impact module impact

The results of the 9P/Tempel 1 CARA (Cometary Archive for Amateur Astronomers) observing campaign is presented. The main goal was to perform an extended survey of the comet as a support to the Deep Impact (DI) Mission. CCD R, I and narrowband aperture photometries were used to monitor the $Af\rho$ quantity. The observed behaviour showed a peak of 310 cm 83 days before perihelion, but we argue that it could be distorted by the phase effect, too. The phase effect is roughly estimated around 0.0275 mag/degree, but we had no chance for direct determination because of the very similar geometry of the observed apparitions. The log-slope of $Af\rho$ was around -0.5 between about 180--100 days before the impact but evolved near the steady-state like 0 value by the impact time. The DI module impact caused an about 60%{} increase in the value of $Af\rho$ and a cloud feature in the coma profile which was observed just after the event. The expansion of the ejecta cloud was consistent with a fountain model with initial projected velocity of 0.2 km/s and $\beta$=0.73. Referring to a 25~000 km radius area centered on the nucleus, the total cross section of the ejected dust was 8.2/$A$ km$^2$ 0.06 days after the impact, and 1.2/$A$ km$^2$ 1.93 days after the impact ($A$ is the dust albedo). 5 days after the event no signs of the impact were detected nor deviations from the expected activity referring both to the average pre-impact behaviour and to the previous apparitions ones.Comment: 25 pages (including cover pages), 9 figures, 1 table, accepted by Icarus DI Special Issu

Dust Environment Model of the Interstellar Comet 2I/Borisov

2I/Borisov is the first interstellar comet discovered on 2019 August 30, and it soon showed a coma and a dust tail. This study reports the results of images obtained at the Telescopio Nazionale Galileo telescope, on La Palma - Canary Islands, in 2019 November and December. The images have been obtained with the R filter in order to apply our dust tail model. The model has been applied to the comet 67P/Churyumov-Gerasimenko and compared to the Rosetta dust measurements showing a very good agreement. It has been applied to the comet 2I/Borisov, using almost the same parameters, obtaining a dust environment similar to that of 67P/Churyumov-Gerasimenko, suggesting that the activity may be very similar. The dust tail analysis provided a dust-loss rate Qd ≍ 35 kg s-1 in 2019 November and Qd ≍ 30 kg s-1 in 2019 December

Bickerstaff Brainstem Encephalitis and overlapping Guillain-Barre syndrome in children: Report of two cases and review of the literature

Bickerstaff Brainstem Encephalitis (BBE) is a rare autoimmune encephalitis, characterized by acute ophthalmoplegia, ataxia and altered state of consciousness. Together with Guillan-Barre Syndrome (GBS) and Miller-Fisher Syndrome, it forms a spectrum of post-infectious demyelinating diseases. Overlapping forms between BBE and GBS (BBE/GBS) are described in patients with lower limbs weakness and typical signs of BBE, suggesting a combined involvement of Central and Peripheral Nervous System (PNS), but only few reported cases are focused on pediatric population. We reviewed all cases of pediatric BBE in the literature, to determine if any patient showed features suggestive for BBE/GBS. Data analysis focused on the diagnostic tests performed (e.g. anti-GQ1b antibodies), neuroimaging and nerve conduction studies (NCS). Further attention was given to the therapeutic management and to patients' outcome. We additionally present two previously unreported pediatric cases. Our review retrieved 19 cases of BBE/GBS, only 2 of which were originally and correctly diagnosed by the authors. The prevalence was higher in male subjects (ratio 3:1) and median age at diagnosis was 8 years. Anti-GQ1b were positive in 46% of the patients, while NCS were altered in 64%. Only 25% of the patients that underwent brain MRI showed abnormal findings. The incidence of BBE/GBS has been underrated in the past, mostly due to an underestimation of the PNS involvement. We therefore suggest to investigate all patients with a clinical picture suggestive of BBE/GBS through electroencephalogram, NCS, brain and spine MRI in order to promptly achieve the correct diagnosis. (C) 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved

Biotin-Thiamine Responsive Encephalopathy: Report of an Egyptian Family with a Novel SLC19A3 Mutation and Review of the Literature

Biotin-thiamine responsive basal ganglia disease (BTRBGD) is an autosomal recessive neurometabolic disorder with poor genotype-phenotype correlation, caused by mutations in the SLC19A3 gene on chromosome 2q36.6. The disease is characterized by three stages: stage 1 is a sub-acute encephalopathy often triggered by febrile illness; stage 2 is an acute encephalopathy with seizures, loss of motor function, developmental regression, dystonia, external ophthalmoplegia, dysphagia, and dysarthria; stage 3 is represented by chronic or slowly progressive encephalopathy. Clinical and biochemical findings, as well as the magnetic resonance imaging (MRI) pattern, resemble those of Leigh's syndrome, so that BTRBGD can be misdiagnosed as a mitochondrial encephalopathy. Here we report the clinical and radiological phenotypes of two siblings diagnosed with BTRBGD in which a novel SLC19A3 mutation (NM_025243.3: c.548C > T; p.Ala183Val) was found by whole exome sequencing (WES) of the family members