Altered serum cytokines in patients with symptomatic disk herniation and depressive symptoms.

Purpose: An increasing number of studies have indicated the important role of cytokines in the development of depressive disturbances (DD). In medically ill patients, cytokines can provoked sickness behavior, the signs of which resemble DD. This results in alterations in behavior to limit energy expenditure and redirect it to cope with particular diseases. The aim of our study was to investigate the role of pro-inflammatory IL-6, TNF-α, and IL-1ß and anti-inflammatory IL-10 and TGF-ß in DD observed in patients suffering from pain caused by disk herniation (DH) qualified for surgery. Patients and methods: The intensity of DD assessed by using Beck Depression Inventory, pain intensity, and functional impairment were evaluated in 70 patients with DH who were qualified for surgery. Pro-inflammatory serum levels of TNF-α, IL-1, IL-6, anti-inflammatory TGF-ß, and IL-10 were measured. Results: Elevated serum levels of TGF-ß, IL-10, and IL-6 were found in the group with moderate and severe depressive symptoms (SD) compared with the groups with mild (MD) or no depressive symptoms (ND). TGF-ß levels were negatively correlated with pain intensity, as assessed using the Present Pain Intensity scale in SD. Functional impairment measured using the Oswestry Disability Index was the most advanced in SD group. Conclusion: Results of our study can suggest association between depressive disturbances and anti-inflammatory cytokines TGF-ß and IL-10. Functional impairment of SD group is more severe but serum levels of TGF-ß and IL-10, which are involved in the healing processes, are increased.

Stereotactic radiosurgery for Koos grade IV vestibular schwannoma: a systematic review and meta-analysis.

BACKGROUND: Stereotactic radiosurgery (SRS) is a well-established treatment option for Koos stage I-III vestibular schwannomas (VS), often used as the first line of treatment or after subtotal resection. However, the optimal treatment for Koos-IV VS remains unclear. Therefore, our study aimed to evaluate the effectiveness of SRS as a primary treatment for large VS classified as Koos-IV. METHODS: A systematic search was performed on December 28th, 2022, based on PubMed, Web of Science, and Scopus according to the PRISMA statement. The review was updated on September 7th, 2023. The risk of bias was assessed using the NIH Quality Assessment Tool. The R software (ver. 4.3.2) was used for all quantitative analyses and preparation of the forest plots. Publication bias and sensitivity analysis were performed to evaluate the reliability of the obtained results. RESULTS: Among 2941 screened records, ten studies (1398 patients) have been included in quantitative synthesis. The overall tumor control rate was 90.7% (95%CI 86.3-94.4). Kaplan-Meier estimates of tumor control at 2, 6, and 10 years were 96.0% (95% CI 92.9-97.6%), 88.8% (95% CI 86.9-89.8%), and 84.5% (95% CI, 81.2-85.8%), respectively. The overall hearing preservation rate was 56.5% (95%CI 37-75.1). Kaplan-Meier estimates of hearing preservation rate at 2, 6, and 10 years were 77.1% (95% CI 67.9-82.5%), 53.5% (95% CI 44.2-58.5%), and 38.1% (95% CI 23.4-40.7%), respectively. The overall facial nerve preservation rate was 100% (95%CI 99.9-100.0). The overall trigeminal neuropathy rate reached 5.7% (95%CI 2.9-9.2). The overall rate of new-onset hydrocephalus was 5.6% (95%CI 3-9). The overall rates of worsening or new-onset tinnitus and vertigo were 6.8% (95%CI 4.2-10.0) and 9.1% (95%CI 2.1-19.6) respectively. No publication bias was detected according to the used methods. CONCLUSIONS: Our systematic review and meta-analysis demonstrated a high overall tumor control rate, excellent facial nerve preservation, and low incidence of new-onset or worsened tinnitus and vertigo. However, several drawbacks associated with SRS should be noted, such as the presence of post-SRS hydrocephalus risk, mediocre long-term hearing preservation, and the lack of immediate tumor decompression. Nevertheless, the use of SRS may be beneficial in appropriately selected cases of Koos-IV VS. Moreover, further prospective studies directly comparing SRS with surgery are necessary to determine the optimal treatment for large VS and verify our results on a higher level of evidence. Registration and protocol: CRD42023389856.

Metalloproteinase-2 in failed back surgery syndrome caused by epidural fibrosis: can it play a role in persistent pain?

Purpose: Failed Back Surgery Syndrome (FBSS) occurs in 10-40% of patients treated surgically due to disk herniation (DH). There are several factors that can cause a predisposition to FBSS, but the exact pathomechanism has not been elucidated. The aim of this study was to investigate Metalloproteinase-2 (MMP-2) and Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) activities in a homogeneous group of FBSS patients with epidural fibrosis in comparison to its activity in patients with surgically treated DH. Methods: DH, FBSS, and control (CG) groups consisted of 30 subjects. The patients were assessed clinically by the Numerical Rating Scale (NRS), McGill Pain Questionnaire (SF -MPQ), Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI). Serum concentrations of MMP-2 and TIMP-2 were measured by using the immunoenzymatic method. Results: There was a significantly higher MMP-2 expression (medians: 4797.49 vs. 2656.65; p < 0.0001) and TIMP-2 concentration (medians: 166.40 vs. 109.60; p < 0.0001) in the DH compared to the CG. Significantly higher MMP-2 expression (4219.95 vs. 2656.65; p < 0.0001) and TIMP-2 concentration (medians: 150.17 vs. 109.60; p = 0.0003) were also found in the FBSS compared to the CG. The activity of MMP-2, measured as MMP-2/TIMP-2, did not significantly change between the DH, FBSS, and CG. MMP2 expression (p < 0.0001) and TIMP-2 concentration (p < 0.0001) were significantly higher in the DH than FBSS. Conclusion: Results indicate the presence of a contribution of MMP-2 and TIMP-2 in DH and FBSS. Unchanged activity of MMP-2 can indicate an insufficiency in the MMP-2 repair system in both diseases. Lower MMP-2 expression and TIMP-2 concentration in the FBSS group can reflect the chronicity of the process.

Brain stimulation for chronic pain management: a narrative review of analgesic mechanisms and clinical evidence.

Chronic pain constitutes one of the most common chronic complaints that people experience. According to the International Association for the Study of Pain, chronic pain is defined as pain that persists or recurs longer than 3 months. Chronic pain has a significant impact on individuals' well-being and psychosocial health and the economy of healthcare systems as well. Despite the availability of numerous therapeutic modalities, treatment of chronic pain can be challenging. Only about 30% of individuals with non-cancer chronic pain achieve improvement from standard pharmacological treatment. Therefore, numerous therapeutic approaches were proposed as a potential treatment for chronic pain including non-opioid pharmacological agents, nerve blocks, acupuncture, cannabidiol, stem cells, exosomes, and neurostimulation techniques. Although some neurostimulation methods such as spinal cord stimulation were successfully introduced into clinical practice as a therapy for chronic pain, the current evidence for brain stimulation efficacy in the treatment of chronic pain remains unclear. Hence, this narrative literature review aimed to give an up-to-date overview of brain stimulation methods, including deep brain stimulation, motor cortex stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, cranial electrotherapy stimulation, and reduced impedance non-invasive cortical electrostimulation as a potential treatment for chronic pain.

The application of 3D-bioprinted scaffolds for neuronal regeneration after traumatic spinal cord injury - A systematic review of preclinical in vivo studies.

BACKGROUND: The implantation of 3D-bioprinted scaffolds represents a promising therapeutic approach for traumatic Spinal Cord Injury (SCI), currently investigating in preclinical in vivo studies. However, a systematic review of the relevant literature has not been performed to date. Hence, we systematically reviewed the outcomes of the application of 3D-bioprinted implants in the treatment of SCI based on studies conducted on experimental animal models. METHODS: We searched PubMed, Scopus, Web of Science, and Cochrane Library databases. Manuscripts in other designs than in vivo preclinical study and written in other languages than English were excluded. A risk of bias assessment was performed using SYRCLE's tool. The quality of included articles was assessed by ARRIVE guidelines. Extracted data were synthesized only qualitatively because the data were not suitable for conducting the meta-analysis. RESULTS: Overall, eleven animal studies reporting on the transection SCI rat model were included. Six of included studies investigated 3D-bioprinted scaffolds enriched with stem cells, two studies - 3D-bioprinted scaffolds combined with growth factors, and three studies - stand-alone 3D-bioprinted scaffolds. In all included studies the application of 3D-bioprinted scaffolds led to significant improvement in functional scores compared with no treated SCI rats. The functional recovery corresponded with the changes observed at the injury site in histological analyses. Seven studies demonstrated medium, three studies - high, and one study - low risk of bias. Moreover, some of the included studies were conducted in the same scientific center. The overall quality assessment ratio amounted to 0.60, which was considered average quality. CONCLUSION: The results of our systematic review suggest that 3D-bioprinted scaffolds may be a feasible therapeutic approach for the treatment of SCI. Further evidence obtained on other experimental SCI models is necessary before the clinical translation of 3D-bioprinted scaffolds.

Diagnosis and Management of Neuropathic Pain in Spine Diseases.

Neuropathic pain is generally defined as a non-physiological pain experience caused by damage to the nervous system. It can occur spontaneously, as a reaction to a given stimulus, or independently of its action, leading to unusual pain sensations usually referred to as firing, burning or throbbing. In the course of spine disorders, pain symptoms commonly occur. According to available epidemiological studies, a neuropathic component of pain is often present in patients with spinal diseases, with a frequency ranging from 36% to 55% of patients. Distinguishing between chronic nociceptive pain and neuropathic pain very often remains a challenge. Consequently, neuropathic pain is often underdiagnosed in patients with spinal diseases. In reference to current guidelines for the treatment of neuropathic pain, gabapentin, serotonin and norepinephrine reuptake inhibitors and tricyclic antidepressants constitute first-line therapeutic agents. However, long-term pharmacologic treatment often leads to developing tolerance and resistance to used medications. Therefore, in recent years, a plethora of therapeutic methods for neuropathic pain have been developed and investigated to improve clinical outcomes. In this review, we briefly summarized current knowledge about the pathophysiology and diagnosis of neuropathic pain. Moreover, we described the most effective treatment approaches for neuropathic pain and discussed their relevance in the treatment of spinal pain.

Biological and Clinical Aspects of Metastatic Spinal Tumors.

Spine metastases are a common life-threatening complication of advanced-stage malignancies and often result in poor prognosis. Symptomatic spine metastases develop in the course of about 10% of malignant neoplasms. Therefore, it is essential for contemporary medicine to understand metastatic processes in order to find appropriate, targeted therapeutic options. Thanks to continuous research, there appears more and more detailed knowledge about cancer and metastasis, but these transformations are extremely complicated, e.g., due to the complexity of reactions, the variety of places where they occur, or the participation of both tumor cells and host cells in these transitions. The right target points in tumor metastasis mechanisms are still being researched; that will help us in the proper diagnosis as well as in finding the right treatment. In this literature review, we described the current knowledge about the molecular pathways and biomarkers engaged in metastatic processes involving the spine. We also presented a current bone-targeted treatment for spine metastases and the emerging therapies targeting the discussed molecular mechanisms.

Metallic Implants Used in Lumbar Interbody Fusion.

Over the last decade, pedicle fixation systems have evolved and modifications in spinal fusion techniques have been developed to increase fusion rates and improve clinical outcomes after lumbar interbody fusion (LIF). Regarding materials used for screw and rod manufacturing, metals, especially titanium alloys, are the most popular resources. In the case of pedicle screws, that biomaterial can be also doped with hydroxyapatite, CaP, ECM, or tantalum. Other materials used for rod fabrication include cobalt-chromium alloys and nitinol (nickel-titanium alloy). In terms of mechanical properties, the ideal implant used in LIF should have high tensile and fatigue strength, Young's modulus similar to that of the bone, and should be 100% resistant to corrosion to avoid mechanical failures. On the other hand, a comprehensive understanding of cellular and molecular pathways is essential to identify preferable characteristics of implanted biomaterial to obtain fusion and avoid implant loosening. Implanted material elicits a biological response driven by immune cells at the site of insertion. These reactions are subdivided into innate (primary cellular response with no previous exposure) and adaptive (a specific type of reaction induced after earlier exposure to the antigen) and are responsible for wound healing, fusion, and also adverse reactions, i.e., hypersensitivity. The main purposes of this literature review are to summarize the physical and mechanical properties of metal alloys used for spinal instrumentation in LIF which include fatigue strength, Young's modulus, and corrosion resistance. Moreover, we also focused on describing biological response after their implantation into the human body. Our review paper is mainly focused on titanium, cobalt-chromium, nickel-titanium (nitinol), and stainless steel alloys.

Hydroxyapatite Use in Spine Surgery-Molecular and Clinical Aspect.

Hydroxyapatite possesses desirable properties as a scaffold in tissue engineering: it is biocompatible at a site of implantation, and it is degradable to non-toxic products. Moreover, its porosity enables infiltration of cells, nutrients and waste products. The outcome of hydroxyapatite implantation highly depends on the extent of the host immune response. Authors emphasise major roles of the chemical, morphological and physical properties of the surface of biomaterial used. A number of techniques have been applied to transform the theoretical osteoconductive features of HAp into spinal fusion systems-from integration of HAp with autograft to synthetic intervertebral implants. The most popular uses of HAp in spine surgery include implants (ACDF), bone grafts in posterolateral lumbar fusion and transpedicular screws coating. In the past, autologous bone graft has been used as an intervertebral cage in ACDF. Due to the morbidity related to autograft harvesting from the iliac bone, a synthetic cage with osteoconductive material such as hydroxyapatite seems to be a good alternative. Regarding posterolateral lumbar fusion, it requires the graft to induce new bone growth and reinforce fusion between the vertebrae. Hydroxyapatite formulations have shown good results in that field. Moreover, the HAp coating has proven to be an efficient method of increasing screw fixation strength. It can decrease the risk of complications such as screw loosening after pedicle screw fixation in osteoporotic patients. The purpose of this literature review is to describe in vivo reaction to HAp implants and to summarise its current application in spine surgery.

VAS and NRS, Same or Different? Are Visual Analog Scale Values and Numerical Rating Scale Equally Viable Tools for Assessing Patients after Microdiscectomy?

Objectives: To compare the viability of the numerical rating scale (NRS) and the visual analogue scale (VAS) as a pain assessment tools among a large cohort of patients who underwent microdiscectomy. Summary of Background Data. The pain intensity (PI) reduction is a parameter of surgical treatment efficacy. The two most commonly used scales of PI are NRS and VAS. Many studies have shown strong similarities between those two scales, but the direct interchange is difficult. Methods: Patients, who underwent microdiscectomy, were prospectively enrolled into the study and assessed using VAS and NRS for the back (NRS-B) and the leg (NRS-L), Short Form of McGill Pain Questionnaire (SF-MPQ) included Pain Rating Index (PRI) and Oswestry Disability Index (ODI) 1 day before and 1 month and 3 months after the procedure. Results: 131 patients were included in the study. NRS-L, NRS-B, VAS, and ODI were significantly lower (p < 0.001) 1 month after microdiscectomy. NRS-L and NRS-B ratings remained at a similar level while VAS and ODI decreased after 3 months. The rate of decline of PI measured by NRS-L correlated statistically significant (rs = 0.366; p < 0.001) with ODI 1 month after surgery. Before surgery, the most significant correlation was found between ODI and NRS-L (rs = 0.494; p < 0.001), the lowest with NRS-B (rs = 0.319; p < 0.001). 3 months after surgery, there was higher correlations between ODI and VAS (rs = 0.634) than NRS-L (rs = 0.265). PRI correlated significantly (p < 0.001) and more stronger with VAS than with NRS-L and NRS-B in every points of assessment. Conclusion: The results showed that PI measurements by NRS-L/NRS-B and VAS mutually correlate and impair functionality evaluated by ODI (convergent validity) but in different modes (differential validity). NRS and VAS are not parallel scales and assess different aspects of pain. The measurement of NRS-L 1 month after microdiscectomy seems to give quick insight into the effectiveness of the procedure.

New Horizons for Hydroxyapatite Supported by DXA Assessment-A Preliminary Study.

Dual Energy X-ray Absorptiometry (DXA) is a tool that allows the assessment of bone density. It was first presented by Cameron and Sorenson in 1963 and was approved by the Food and Drug Administration. Misplacing the femoral neck box, placing a trochanteric line below the midland and improper placement of boundary lines are the most common errors made during a DXA diagnostic test made by auto analysis. Hydroxyapatite is the most important inorganic component of teeth and bone tissue. It is estimated to constitute up to 70% of human bone weight and up to 50% of its volume. Calcium phosphate comes in many forms; however, studies have shown that only tricalcium phosphate and hydroxyapatite have the characteristics that allow their use as bone-substituted materials. The purpose of this study is aimed at analyzing the results of hip densitometry and hydorxyapatite distribution in order to better assess the structure and mineral density of the femoral neck. However, a detailed analysis of the individual density curves shows some qualitative differences that may be important in assessing bone strength in the area under study. To draw more specific conclusions on the therapy applied for individual patients, we need to determine the correct orientation of the bone from the resulting density and document the trends in the density distribution change. The average results presented with the DXA method are insufficient.

Molecular Mechanisms and Clinical Application of Multipotent Stem Cells for Spinal Cord Injury.

Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well as urinary complications, and a small number of patients experience a complete recovery. Current standard treatment modalities of the SCI aim to prevent secondary injury and provide limited recovery of lost neurological functions. Stem Cell Therapy (SCT) represents an emerging treatment approach using the differentiation, paracrine, and self-renewal capabilities of stem cells to regenerate the injured spinal cord. To date, multipotent stem cells including mesenchymal stem cells (MSCs), neural stem cells (NSCs), and hematopoietic stem cells (HSCs) represent the most investigated types of stem cells for the treatment of SCI in preclinical and clinical studies. The microenvironment of SCI has a significant impact on the survival, proliferation, and differentiation of transplanted stem cells. Therefore, a deep understanding of the pathophysiology of SCI and molecular mechanisms through which stem cells act may help improve the treatment efficacy of SCT and find new therapeutic approaches such as stem-cell-derived exosomes, gene-modified stem cells, scaffolds, and nanomaterials. In this literature review, the pathogenesis of SCI and molecular mechanisms of action of multipotent stem cells including MSCs, NSCs, and HSCs are comprehensively described. Moreover, the clinical efficacy of multipotent stem cells in SCI treatment, an optimal protocol of stem cell administration, and recent therapeutic approaches based on or combined with SCT are also discussed.

IFN-γ Correlations with Pain Assessment, Radiological Findings, and Clinical Intercourse in Patient after Lumbar Microdiscectomy: Preliminary Study.

OBJECTIVES: We investigated the influence of pain decrease after lumbar microdiscectomy on the interferon gamma (IFN-γ) serum level in patients with lumbar disc herniations. The study challenges the mechanism of sciatica pain and the role of IFN-γ in radicular pain development. Material and Methods. We performed clinical and immunoenzymatic assessment in a group of 27 patients with lumbar radicular pain due to disc herniations before and 3 months after surgery. Clinical status was assessed with the use of the Numeric Rating Scale (NRS), the Pain Rating Index and Pain Intensity Index of McGill Pain Questionnaire (SF-MPQ), the Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI). The plasma concentrations of IFN-γ were ascertained by an immunoenzymatic method. RESULTS: We observe significant correlations between the results of the pain in the back region assessment NRS back scale after the surgery with the level of IFN-γ before the procedure (r s = 0.528; p = 0.008) and after the procedure (r s = 0.455; p = 0.025). These are moderate and positive correlations-the decrease in pain is correlated with the lower IFN-γ level. Additionally, there are significant correlations between the results of the PRI scale and the IFN-γ level. The PRI score before surgery correlates positively with IFN-γ after surgery (r s = 0.462; p = 0.023), and the PRI score after surgery correlates positively with IFN before surgery (r s = 0.529; p = 0.005) and after surgery (r s = 0.549; p = 0.003). All correlations are moderate in severity-severe pain before surgery correlates with a higher level of IFN-γ after surgery and also higher IFN-γ before surgery. There were significant differences in the IFN-γ level before (Z = -2.733; p = 0.006) and after (Z = -2.391; p = 0.017) surgery in the groups of patients with and without nerve compression. In the group of patients with nerve compression, the level of IFN-γ before and after surgery was lower. CONCLUSIONS: Less pain ratio after operation correlates with the level of IFN-γ. In the group of patients without significant nerve compression confirmed by MRI scans, the level of IFN-γ before and after surgery was higher than that in the group with nerve root compression.

Clinical and biochemical predictors of late-outcome in patients after ischemic stroke.

OBJECTIVE: The aim of this study is to evaluate neurological scales, as well as biochemical and radiological parameters measured on day 10 after ischemic stroke (IS), according to their value as predictors of the long-term outcome. MATERIAL AND METHODS: 45 patients were assessed according to the Barthel Index (BI) and National Institute of Health Stroke Scale (NIHSS) on day 10, and according to Modified Rankin Scale (mRS) 3 months after the onset of IS. On day 10 of IS, the serum level of C-reactive protein (CRP), albumin, D-dimers (DD), S100BB and Tau proteins was measured and the volume of ischemic focus assessed with the use of Computed Tomography (CT). The patients were divided into groups with good outcome (GO) and mRS 0-2, and with bad outcome (BO) and mRS 3-6. RESULTS: NIHSS and BI scores (p<0.001), the volume of ischemic focus (p<0.01), CRP (p<0.01) and albumin level (p<0.05), but not DD, S100BB and Tau protein levels evaluated on day 10, correlated with mRS after 3 months since IS onset. Patients from the BO group were observed to have lower BI (p=0.001), higher NIHSS (p<0.01) and CRP levels (p<0.05), and bigger volume of ischemic focus (p<0.05) measured on day 10 of IS. In the GO group, there were more patients with atherosclerotic etiology (p=0.02 x2=7.856). Regression analysis showed that only the BI score assessed on day 10 of IS can predict the outcome after 3 months assessed by mRS (OR=1.102, 95%, CI:1.01-1.203; p=0.001). CONCLUSIONS: BI assessed on day 10 has a predictive value for the outcome evaluated by mRS 3 months after the onset of IS.

TLR-4 Signaling vs. Immune Checkpoints, miRNAs Molecules, Cancer Stem Cells, and Wingless-Signaling Interplay in Glioblastoma Multiforme-Future Perspectives.

Toll-like-receptor (TLR) family members were detected in the central nervous system (CNS). TLR occurrence was noticed and widely described in glioblastomamultiforme (GBM) cells. After ligand attachment, TLR-4 reorients domains and dimerizes, activates an intracellular cascade, and promotes further cytoplasmatic signaling. There is evidence pointing at a strong relation between TLR-4 signaling and micro ribonucleic acid (miRNA) expression. The TLR-4/miRNA interplay changes typical signaling and encourages them to be a target for modern immunotherapy. TLR-4 agonists initiate signaling and promote programmed death ligand-1 (PD-1L) expression. Most of those molecules are intensively expressed in the GBM microenvironment, resulting in the autocrine induction of regional immunosuppression. Another potential target for immunotreatment is connected with limited TLR-4 signaling that promotes Wnt/DKK-3/claudine-5 signaling, resulting in a limitation of GBM invasiveness. Interestingly, TLR-4 expression results in bordering proliferative trends in cancer stem cells (CSC) and GBM. All of these potential targets could bring new hope for patients suffering from this incurable disease. Clinical trials concerning TLR-4 signaling inhibition/promotion in many cancers are recruiting patients. There is still a lot to do in the field of GBM immunotherapy.

Recent Trends of microRNA Significance in Pediatric Population Glioblastoma and Current Knowledge of Micro RNA Function in Glioblastoma Multiforme.

Central nervous system tumors are a significant problem for modern medicine because of their location. The explanation of the importance of microRNA (miRNA) in the development of cancerous changes plays an important role in this respect. The first papers describing the presence of miRNA were published in the 1990s. The role of miRNA has been pointed out in many medical conditions such as kidney disease, diabetes, neurodegenerative disorder, arthritis and cancer. There are several miRNAs responsible for invasiveness, apoptosis, resistance to treatment, angiogenesis, proliferation and immunology, and many others. The research conducted in recent years analyzing this group of tumors has shown the important role of miRNA in the course of gliomagenesis. These particles seem to participate in many stages of the development of cancer processes, such as proliferation, angiogenesis, regulation of apoptosis or cell resistance to cytostatics.

Micro RNA Molecules as Modulators of Treatment Resistance, Immune Checkpoints Controllers and Sensitive Biomarkers in Glioblastoma Multiforme.

Based on genome sequencing, it is estimated that over 90% of genes stored in human genetic material are transcribed, but only 3% of them contain the information needed for the production of body proteins. This group also includes micro RNAs representing about 1%-3% of the human genome. Recent studies confirmed the hypothesis that targeting molecules called Immune Checkpoint (IC) open new opportunities to take control over glioblastoma multiforme (GBM). Detection of markers that indicate the presence of the cancer occupies a very important place in modern oncology. This function can be performed by both the cancer cells themselves as well as their components and other substances detected in the patients' bodies. Efforts have been made for many years to find a suitable marker useful in the diagnosis and monitoring of gliomas, including glioblastoma.

Metformin as Potential Therapy for High-Grade Glioma.

Metformin (MET), 1,1-dimethylbiguanide hydrochloride, is a biguanide drug used as the first-line medication in the treatment of type 2 diabetes. The recent years have brought many observations showing metformin in its new role. The drug, commonly used in the therapy of diabetes, may also find application in the therapy of a vast variety of tumors. Its effectiveness has been demonstrated in colon, breast, prostate, pancreatic cancer, leukemia, melanoma, lung and endometrial carcinoma, as well as in gliomas. This is especially important in light of the poor options offered to patients in the case of high-grade gliomas, which include glioblastoma (GBM). A thorough understanding of the mechanism of action of metformin can make it possible to discover new drugs that could be used in neoplasm therapy.

Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) represents a cluster of various vascular disorders with different pathological backgrounds. The advanced vasculature net of cerebral vessels, including small arteries, capillaries, arterioles and venules, is usually affected. Processes of oxidation underlie the pathology of CSVD, promoting the degenerative status of the epithelial layer. There are several classifications of cerebral small vessel diseases; some of them include diseases such as Binswanger's disease, leukoaraiosis, cerebral microbleeds (CMBs) and lacunar strokes. This paper presents the characteristics of CSVD and the impact of the current knowledge of this topic on the diagnosis and treatment of patients.

PD-L1/PD-1 Axis in Glioblastoma Multiforme.

Glioblastoma (GBM) is the most popular primary central nervous system cancer and has an extremely expansive course. Aggressive tumor growth correlates with short median overall survival (OS) oscillating between 14 and 17 months. The survival rate of patients in a three-year follow up oscillates around 10%. The interaction of the proteins programmed death-1 (PD-1) and programmed cell death ligand (PD-L1) creates an immunoregulatory axis promoting invasion of glioblastoma multiforme cells in the brain tissue. The PD-1 pathway maintains immunological homeostasis and protects against autoimmunity. PD-L1 expression on glioblastoma surface promotes PD-1 receptor activation in microglia, resulting in the negative regulation of T cell responses. Glioblastoma multiforme cells induce PD-L1 secretion by activation of various receptors such as toll like receptor (TLR), epidermal growth factor receptor (EGFR), interferon alpha receptor (IFNAR), interferon-gamma receptor (IFNGR). Binding of the PD-1 ligand to the PD-1 receptor activates the protein tyrosine phosphatase SHP-2, which dephosphorylates Zap 70, and this inhibits T cell proliferation and downregulates lymphocyte cytotoxic activity. Relevant studies demonstrated that the expression of PD-L1 in glioma correlates with WHO grading and could be considered as a tumor biomarker. Studies in preclinical GBM mouse models confirmed the safety and efficiency of monoclonal antibodies targeting the PD-1/PD-L1 axis. Satisfactory results such as significant regression of tumor mass and longer animal survival time were observed. Monoclonal antibodies inhibiting PD-1 and PD-L1 are being tested in clinical trials concerning patients with recurrent glioblastoma multiforme.