Recent advances on CAR-T signaling pave the way for prolonged persistence and new modalities in clinic.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies. The importance of the receptor costimulatory domain for long-term CAR-T cell engraftment and therapeutic efficacy was demonstrated with second-generation CAR-T cells. Fifth generation CAR-T cells are currently in preclinical trials. At the same time, the processes that orchestrate the activation and differentiation of CAR-T cells into a specific phenotype that predisposes them to long-term persistence are not fully understood. This review highlights ongoing research aimed at elucidating the role of CAR domains and T-cell signaling molecules involved in these processes.

AI-Based Approach to One-Click Chronic Subdural Hematoma Segmentation Using Computed Tomography Images.

This paper presents a computer vision-based approach to chronic subdural hematoma segmentation that can be performed by one click. Chronic subdural hematoma is estimated to occur in 0.002-0.02% of the general population each year and the risk increases with age, with a high frequency of about 0.05-0.06% in people aged 70 years and above. In our research, we developed our own dataset, which includes 53 series of CT scans collected from 21 patients with one or two hematomas. Based on the dataset, we trained two neural network models based on U-Net architecture to automate the manual segmentation process. One of the models performed segmentation based only on the current frame, while the other additionally processed multiple adjacent images to provide context, a technique that is more similar to the behavior of a doctor. We used a 10-fold cross-validation technique to better estimate the developed models' efficiency. We used the Dice metric for segmentation accuracy estimation, which was 0.77. Also, for testing our approach, we used scans from five additional patients who did not form part of the dataset, and created a scenario in which three medical experts carried out a hematoma segmentation before we carried out segmentation using our best model. We developed the OsiriX DICOM Viewer plugin to implement our solution into the segmentation process. We compared the segmentation time, which was more than seven times faster using the one-click approach, and the experts agreed that the segmentation quality was acceptable for clinical usage.

Expression of Cytoskeletal Proteins (GFAP, Vimentin), Proapoptotic Protein (Caspase-3) and Protective Protein (S100) in the Epileptic Focus in Adults and Children with Drug-Resistant Temporal Lobe Epilepsy Associated with Focal Cortical Dysplasia.

The European Commission of the International League Against Epilepsy (ILAE) has identified glial mechanisms of seizures and epileptogenesis as top research priorities. The aim of our study was to conduct a comparative analysis of the expression levels of cytoskeletal proteins (glial fibrillar acidic protein (GFAP) and vimentin), protective protein S100, and proapoptotic caspase-3 protein in patients with drug-resistant epilepsy (DRE) associated with focal cortical dysplasia (FCD). We aimed to investigate how the expression levels of these proteins depend on age (both in children and adults), gender, and disease duration, using immunohistochemistry. Nonparametric statistical methods were employed for data analysis. In the epileptic focus area of the cortex and white matter in patients with FCD-associated temporal lobe DRE, a higher level of expression of these proteins was observed. Age and gender differences were found for vimentin and S100. In the early stages of disease development, there was a compensatory sequential increase in the expression of cytoskeletal and protective proteins. In patients with DRE, depending on the disease duration, patterns of development of neurodegeneration were noted, which is accompanied by apoptosis of gliocytes. These results provide insights into epilepsy mechanisms and may contribute to improving diagnostic and treatment approaches.

Neuroinflammatory Dysfunction of the Blood-Brain Barrier and Basement Membrane Dysplasia Play a Role in the Development of Drug-Resistant Epilepsy.

Drug-resistance epilepsy (DRE) is a key problem in neurology. It is possible that damage to the blood-brain barrier (BBB) may affect resistance in DRE. The aim of this work was to assess the damage and dysfunction in the BBB in the area of epileptic foci in patients with DRE under conditions of neuroinflammation. The changes to the BBB in temporal lobe epilepsy (by immunohistochemistry and transmission electron microscopy), levels of neuroinflammatory proteins, and cytokine levels in the blood (by multiplex analysis) were studied. Increased levels of vascular endothelial growth factor (VEGF) and growth-regulated protein (GRO), and decreased levels of epidermal growth factor (EGF) in plasma, combined with overexpression of the VEGF-A receptor by endotheliocytes were detected. Malformation-like growths of the basement membrane of the capillaries of the brain complicate the delivery of antiepileptic drugs (AEDs). Dysplasia of the basement membrane is the result of inadequate reparative processes in chronic inflammation. In conclusion, it should be noted that damage to the microcirculatory network of the brain should be considered one of the leading factors contributing to DRE.

Neurotrophin-3 (NT-3) as a Potential Biomarker of the Peripheral Nervous System Damage Following Breast Cancer Treatment.

Damage to the peripheral nervous system (PNS) is a common complication of breast cancer (BC) treatment, with 60 to 80% of breast cancer survivors experiencing symptoms of PNS damage. In the current study, the levels of brain-derived neurotrophic factor (BDNF), galectin-3 (Gal-3), and neurotrophin-3 (NT-3) were measured in the blood serum of BC patients by ELISA as potential biomarkers that might indicate the PNS damage. Sixty-seven patients were enrolled in this multi-center trial and compared to the aged-matched healthy female volunteers (control group) (n = 25). Intergroup comparison of biomarker levels (i.e., Gal-3 and BDNF) did not show significant differences in any of the studied subgroups. However, intriguingly, NT-3 levels were significantly higher in BC patients as compared to healthy volunteers, constituting 14.85 [10.3; 18.0] and 5.74 [4.56; 13.7] pg/mL, respectively (p < 0.001). In conclusion, NT-3 might be employed as a potential biomarker in BC patients with clinical manifestations of PNS damage. However, further studies to validate its correlation to the degree of peripheral nervous system lesions are of high value.

Angiogenetic Factors in Chronic Subdural Hematoma Development.

The levels of angiogenic factors were analyzed in eight patients who underwent the embolization of chronic subdural hematoma (CSDH) with non-adhesive liquid embolic agents. Four of these patients had previously undergone surgical treatment for hematoma removal and had recurrences of a similar volume, and four had an increase in hematoma volume due to rebleeding. The levels of vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP 9), angiopoietin-2 (Ang2), transforming growth factor beta 1 (TGF-ß1) and platelet-derived growth factor BB (PDGF-BB) in the arterial and venous blood were analyzed. The most significant results were obtained from the peripheral venous blood samples. The levels of VEGF in the samples of all the patients were close to normal or slightly decreased. There was an increase in the MMP9 levels (the factor that contributes to the disintegration of the vessel wall components) in all the patients. The Ang2 and especially the PDGF TGF-ß1 (the factor that plays an important role in the growth of the vessel wall from the already existing blood vessel tissue) levels were distinctly low in most of the cases and slightly elevated only in a number of patients who had previously been operated on. The results obtained show that there is an imbalance in the angiogenesis factors in patients with rebleeding CSDH. At the same time, the factors determining the formation of the vessel wall were reduced, and the levels of factors contributing to the degradation of extracellular matrix components were significantly increased. Such factors could help us to anticipate the increased risk of hemorrhages. Highlights: The levels of VEGF, MMP 9, Ang2, TGF-ß1 and PDGF-BB in the arterial and venous blood were analyzed. The most significant results were obtained from the peripheral venous blood samples. The results obtained show that there is an imbalance in the angiogenesis factors in patients with rebleeding CSDH. Such a profile of factors could help us to anticipate the increased risk of hemorrhages.

Microstructural Properties of Brain White Matter Tracts in Breast Cancer Survivors: A Diffusion Tensor Imaging Study.

Complex breast cancer (BC) treatment can cause various neurological and psychiatric complications, such as postmastectomy pain syndrome, vestibulocerebellar ataxia, and depression, which can lead to microstructural damage of the white matter tracts of the brain. The purpose of the study is to assess microstructural changes in the white matter tracts of the brain in BC survivors using diffusion tensor imaging (DTI). Single DTI scans were performed on patients (n = 84) after complex BC treatment (i.e., surgery, chemotherapy and/or radiation therapy) and on the control group (n = 40). According to the results, a decrease in the quantitative anisotropy (FDR ≤ 0.05) was revealed in the bilateral corticospinal tracts, cerebellar tracts, corpus callosum, fornix, left superior corticostriatal and left corticopontine parietal in patients after BC treatment in comparison to the control group. A decrease in the quantitative anisotropy (FDR ≤ 0.05) was also revealed in the corpus callosum and right cerebellar tracts in patients after BC treatment with the presence of postmastectomy pain syndrome and vestibulocerebellar ataxia. The use of DTI in patients after BC treatment reveals microstructural properties of the white matter tracts in the brain. The results will allow for the improvement of treatment and rehabilitation approaches in patients receiving treatment for breast cancer.

Breast Cancer Treatment Decreases Serum Levels of TGF-ß1, VEGFR2, and TIMP-2 Compared to Healthy Volunteers: Significance for Therapeutic Outcomes?

Various complications from a breast cancer treatment, in the pathogenesis of which excessive tissue fibrosis plays a leading role, are a common pathology. In this study, the levels of TGF-ß1, VEGFR-2, and TIMP-2 were determined by the immuno-enzyme serum analysis for patients during the long-term period after breast cancer treatment as potential markers of fibrosis. The single-center study enrolled 92 participants, which were divided into two age-matched groups: (1) 67 patients following breast cancer treatment, and (2) 25 healthy female volunteers. The intergroup analysis demonstrated that the patients after breast cancer treatment showed a decrease in the serum levels of TGF-ß1 (U = 666, p < 0.001) and TIMP-2 (U = 637, p < 0.001) as compared to the group of healthy volunteers. The levels of VEGFR-2 in these groups were comparable (U = 1345, p = 0.082). It was also found that the type of treatment, the presence of lymphedema, shoulder joint contracture, and changes in lymphoscintigraphy did not affect the levels of TGF-ß1, VEGFR-2, and TIMP-2 within the group of patients after breast cancer treatment. These results may indicate that these biomarkers do not play a leading role in the maintenance and progression of fibrosis in the long-term period after breast cancer treatment. The reduced levels of TGF-ß1 and TIMP-2 may reflect endothelial dysfunction caused by the antitumor therapy.

Adhesion Molecules ICAM-1 and PECAM-1 as Potential Biomarkers of Central Nervous System Damage in Women Breast Cancer Survivors.

Breast cancer (BC) is the most common tumor in women worldwide with high mortality rates. Surgical methods followed by radio-chemotherapy are used to treat these tumors. Such treatment can lead to various side effects, including neurological complications. The development of a reliable biomarker to predict the onset of CNS complications could improve clinical outcomes. In the current study, ICAM-1 and PECAM-1 serum levels were measured as potential biomarkers in 45 female patients in a long-term follow-up period after breast cancer treatment, and compared to 25 age-matched female healthy volunteers. Serum levels of both biomarkers, ICAM-1 and PECAM-1 were significantly higher in patients after breast cancer treatment and could be associated with cognitive dysfunction, depression, and vestibulocerebellar ataxia. In conclusion, our results provide a first hint that elevated serum levels of ICAM-1 and PECAM-1 could serve as early predictive biomarkers in breast cancer survivors that might help to improve the management of these patients.

Potential Molecular Biomarkers of Central Nervous System Damage in Breast Cancer Survivors.

Damage of the central nervous system (CNS), manifested by cognitive impairment, occurs in 80% of women with breast cancer (BC) as a complication of surgical treatment and radiochemotherapy. In this study, the levels of ICAM-1, PECAM-1, NSE, and anti-NR-2 antibodies which are associated with the damage of the CNS and the endothelium were measured in the blood by ELISA as potential biomarkers that might reflect pathogenetic mechanisms in these patients. A total of 102 patients enrolled in this single-center trial were divided into four groups: (1) 26 patients after breast cancer treatment, (2) 21 patients with chronic brain ischemia (CBI) and asymptomatic carotid stenosis (ICA stenosis) (CBI + ICA stenosis), (3) 35 patients with CBI but without asymptomatic carotid stenosis, and (4) 20 healthy female volunteers (control group). Intergroup analysis demonstrated that in the group of patients following BC treatment there was a significant increase of ICAM-1 (mean difference: −368.56, 95% CI −450.30 to −286.69, p < 0.001) and PECAM-1 (mean difference: −47.75, 95% CI −68.73 to −26.77, p < 0.001) molecules, as compared to the group of healthy volunteers. Additionally, a decrease of anti-NR-2 antibodies (mean difference: 0.89, 95% CI 0.41 to 1.48, p < 0.001) was detected. The intergroup comparison revealed comparable levels of ICAM-1 (mean difference: −33.58, 95% CI −58.10 to 125.26, p = 0.76), PECAM-1 (mean difference: −5.03, 95% CI −29.93 to 19.87, p = 0.95), as well as anti-NR-2 antibodies (mean difference: −0.05, 95% CI −0.26 to 0.16, p = 0.93) in patients after BC treatment and in patients with CBI + ICA stenosis. The NSE level in the group CBI + ICA stenosis was significantly higher than in women following BC treatment (mean difference: −43.64, 95% CI 3.31 to −83.99, p = 0.03). Comparable levels of ICAM-1 were also detected in patients after BC treatment and in the group of CBI (mean difference: −21.28, 95% CI −111.03 to 68.48, p = 0.92). The level of PECAM-1 molecules in patients after BC treatment was also comparable to group of CBI (mean difference: −13.68, 95% CI −35.51 to 8.15, p = 0.35). In conclusion, among other mechanisms, endothelial dysfunction might play a role in the damage of the CNS in breast cancer survivors.

Treatment strategy for multisegmental cervicomedullary ependymoma: illustrative case.

BACKGROUND: Сervicomedullary ependymoma (CME) is a rare tumor of the central nervous system. The CME treatment strategy is insufficiently represented in the literature and is a complex task for neurosurgeons. OBSERVATIONS: The authors describe an infrequent case of a large multisegmental CME that extended from the medulla oblongata to the cervical spinal cord at the level of the sixth cervical vertebra in a 21-year-old female. Neurological disorders presented with headache, dysphagia, hypophonia, and weakness in the limbs. Subtotal removal of the tumor was performed according to intraoperative neurophysiological monitoring (IONM) results. A wait-and-see approach with patient follow-up was chosen. LESSONS: Total tumor removal of the CME is the most important favorable prognostic factor. Subtotal resection can be considered if the borders of the tumor are unclear and the result of IONM is unfavorable. The role of postoperative radiation therapy in the case of subtotal removal of the tumor remains controversial.

C2 spinal nerve tumors in young adults: report of two cases and review of the literature.

C2 spinal nerve schwannomas are rarely encountered, especially in children and young adults. Due to their localization surgical management encompasses a number of distinctive features. We describe two cases of C2 spinal nerve tumors, schwannoma and neurofibroma, in patients aged 13 and 17, respectively. Both patients presented with compressive cervical myelopathy due to large tumors at C1-C2 level with extra-intracanal hourglass extension. Despite prominent tumor size and location of their component ventrally to the spinal cord, our selected surgical approach allowed, in both instances, total tumor removal with minimum surgical trauma and no neurological deficit.

Prognosis of surgical treatment of the tethered cord syndrome in children.

PURPOSE: The aim of this study was to identify the factors relevant to the prognosis of the outcome of the surgical treatment of the tethered cord syndrome (TCS). METHODS: The results of surgical treatment performed on 58 children with TCS were analyzed, with follow-up periods ranging from 6 months to 5 years. The data of preoperative clinical and instrumental examinations, as well as those of intraoperative electrophysiological diagnostics and morphometry, were compared with the dynamics of the TCS clinical presentation. RESULTS: The recovery rate was significantly higher in children with filum terminale abnormality (p = 0.014), as well as grade I tethering (p = 0.0037), and when the spinal cord tracts at the level of intervention were intact (p = 0.018). Complete untethering (p = 0.04) and a low threshold value of amperage in direct stimulation (< 1 mA) (p = 0.016) were identified as factors for a favorable outcome. Worsening of neurological symptoms was more frequent in children operated over the age of 10 (p = 0.03), when the TCS was manifested exclusively through the pelvic dysfunction (p = 0.00004), if the F-wave block is less than 30% (p = 0.0045) and the stimulation threshold during root mapping ranged from 1 to 5 mA (p = 0.01). CONCLUSION: The operation is recommended when structural changes are minimal. In case of severe structural changes, if the spinal cord tracts are intact, the indications for operation are determined by the risk of irreversible structural changes due to the natural course of the disease, although the risks are substantially higher.