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Alzheimer's disease (AD) is the most common neurodegenerative disease that is responsible for about one-third of dementia cases worldwide. It is believed that AD is initiated with the deposition of Ab plaques in the brain. Genetic studies have shown that a high number of AD risk genes are expressed by microglia, the resident macrophages of brain. Common mode of action by microglia cells is neuroinflammation and phagocytosis. Moreover, it has been discovered that inflammatory marker levels are increased in AD patients. Recent studies advocate that neuroinflammation plays a major role in AD progression. Microglia have different activation profiles depending on the region of brain and stimuli. In different activation, profile microglia can generate either pro-inflammatory or anti-inflammatory responses. Microglia defend brain cells from pathogens and respond to injuries; also, microglia can lead to neuronal death along the way. In this review, we will bring the different roles played by microglia and microglia-related genes in the progression of AD., (© 2022 Wiley Periodicals LLC.)

The role of Aβ plaques and neurofibrillary tangles in Alzheimer's disease (AD) pathogenesis have recently come into question due to failure of many pharmaceutical agents targeting these deposits and detection of these misfolded proteins in normal human brains. Therefore, we investigated correlations between microglial activation and toll like receptor 4 (TLR4) and Lck/Yes novel tyrosine (LYN) kinase signaling in an AD mouse model. In this study, we used 5-6-month-old 5XFAD and wild type (WT) male and female mice. Immunohistochemistry (IHC) and flow cytometry (FC) were performed on their brains. Cognitive performance was assessed with the Barnes-Maze. IHC showed more Ab aggregation in microglia of female 5XFAD mice compared to their male counterparts. Increased co-localization of microglial TLR4 and LYN was also observed in AD more than WT and females more than males. IHC also suggests microglial phagocytosis of neurons in AD mice, which is supported by FC data. Our FC data also support the involvement of disease associated microglia (DAMs) in this process based on cytokine secretion. Cognitive assessment by the Barnes maze showed 5XFAD females performed worse than males. In this study, we investigated the relationship between microglial TLR4 and LYN kinase in 5XFAD male and females. Our data reveals a correlation between microglial TLR4 and LYN co-localization and AD pathogenesis, more in females than males. Targeting microglial TLR4 and Lyn in DAMs may offer new therapeutic opportunities in the treatment of AD., (© 2022 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Background: MDNA55 is an interleukin 4 receptor (IL4R)-targeting toxin in development for recurrent GBM, a universally fatal disease. IL4R is overexpressed in GBM as well as cells of the tumor microenvironment. High expression of IL4R is associated with poor clinical outcomes., Methods: MDNA55-05 is an open-label, single-arm phase IIb study of MDNA55 in recurrent GBM (rGBM) patients with an aggressive form of GBM (de novo GBM, IDH wild-type, and nonresectable at recurrence) on their 1st or 2nd recurrence. MDNA55 was administered intratumorally as a single dose treatment (dose range of 18 to 240 ug) using convection-enhanced delivery (CED) with up to 4 stereo-tactically placed catheters. It was co-infused with a contrast agent (Gd-DTPA, Magnevist®) to assess distribution in and around the tumor margins. The flow rate of each catheter did not exceed 10μL/min to ensure that the infusion duration did not exceed 48 h. The primary endpoint was mOS, with secondary endpoints determining the effects of IL4R status on mOS and PFS., Results: MDNA55 showed an acceptable safety profile at doses up to 240 μg. In all evaluable patients (n = 44) mOS was 11.64 months (80% one-sided CI 8.62, 15.02) and OS-12 was 46%. A subgroup (n = 32) consisting of IL4R High and IL4R Low patients treated with high-dose MDNA55 (>180 ug) showed the best benefit with mOS of 15 months, OS-12 of 55%. Based on mRANO criteria, tumor control was observed in 81% (26/32), including those patients who exhibited pseudo-progression (15/26)., Conclusions: MDNA55 demonstrated tumor control and promising survival and may benefit rGBM patients when treated at high-dose irrespective of IL4R expression level.Trial Registration: Clinicaltrials.gov NCT02858895., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Treatment options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) are desperately needed. Allogeneic human umbilical cord derived mesenchymal stromal cells (hCT-MSCs) have potential therapeutic benefits in these critically ill patients, but feasibility and safety data are lacking., Materials and Methods: In this phase I multisite study, 10 patients with COVID-19-related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg, maximum dose 100 million cells). The primary endpoint assessed safety., Results: Ten patients (7 females, 3 males; median age 62 years (range 39-79)) were enrolled at 2 sites and received a total of 30 doses of study product. The average cell dose was 0.93 cells/kg (range 0.56-1.45 cells/kg and total dose range 55-117 million cells) with 5/30 (17%) of doses lower than intended dose. Average cell viability was 85% (range 63%-99%) with all but one meeting the >70% release criteria. There were no infusion-related reactions or study-related adverse events, 28 non-serious adverse events in 3 unique patients, and 2 serious adverse events in 2 unique patients, which were expected and unrelated to the study product. Five patients died: 3 by day 28 and 5 by day 90 of the study (median 27 days, range 7-76 days). All deaths were determined to be unrelated to the hCT-MSCs., Conclusion: We were able to collect relevant safety outcomes for the use of hCT-MSCs in patients with COVID-19-related ARDS. Future studies to explore their safety and efficacy are warranted., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Toll-like receptor 4 (TLR4) activation causes excessive production of proinflammatory mediators and an increased expression of costimulatory molecules that leads to neuroinflammation after subarachnoid hemorrhage (SAH). Although TLR4-mediated inflammatory pathways have long been studied in neuroinflammation, the specific glia implicated in initiation and propagation of neuroinflammation in SAH have not been well elucidated. In this study, we investigated the involvement of glial TLR4 including microglia and astrocytes in brain damage and poor neurological outcome., Methods: In this study, global TLR4 knockout, cell-specific TLR4 knockout, and floxxed control male and female mice were used. The mice were injected with 60 μl autologous blood near the mesencephalon to induce SAH; animals were euthanized on postoperative day 7 for immunohistochemistry of glia and apoptotic cells. Microglial morphology was evaluated by using immunofluorescence density quantification to determine correlations between morphology and neuroinflammation. Microglial depletion was accomplished with the intracerebroventricular administration of clodronate liposomes. Cognitive function was assessed with Barnes maze., Results: On postoperative day 7 after SAH induction, neuronal apoptosis was markedly reduced in the clodronate liposome group compared with phosphate-buffered saline control liposomes, and cognitive performance in the clodronate group was improved, as well. Differences in microglial activation, assessed by morphometric analysis, and neuronal apoptosis were significantly greater in wildtype knockouts compared with cell-specific and global TLR4 knockouts. The mice lacking TLR4 on astrocytes and neurons showed no differences compared with wildtype mice on any end points., Conclusions: Our data suggest that microglial depletion with the intracerebroventricular administration of clodronate can improve the cognitive function in an SAH mouse model, and TLR4 is critical for microglial activation and neuronal injury. Only microglial TLR4 is necessary for brain damage and poor cognitive outcome rather than astrocyte or neuronal TLR4. Thus, microglial TLR4 could be a potent therapeutic target to treat SAH-associated neuronal injury and protect against cognitive dysfunction., (© 2022. The Author(s).)

The management of spine tumors is multimodal and personalized to each individual patient. Patients often require radiation therapy after surgical fixation. Although titanium implants are used most commonly, they produce significant artifact, leading to decreased confidence in target-volume coverage and normal tissue sparing. Carbon-based materials have been found to have minimal effects on dose perturbation in postoperative radiation therapy and have shown biostability and biocompatibility that are comparable to titanium implants. Using the PubMed and Web of Sciences databases, we conducted a systematic review of carbon-based screw and rod fixation systems in the treatment of spinal tumors. We reviewed clinical studies regarding safety of spine fixation with carbon fiber-reinforced (CFR) implants and biomechanical studies, as well as radiation and dosimetric studies. The radiolucency of CFR-polyether ether ketone implants has the potential to benefit patients with spine tumor. Clinical studies have shown no increase in complications with implementation of CFR-polyether ether ketone implants, and these devices seem to have sufficient stiffness and pullout strength. However, further trials are necessary to determine if there is a clinically significant impact on local tumor control., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM)., Patients and Methods: A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied., Results: A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, P < 0.0001; HR = 0.3) and mRANO ( P < 0.0001; HR = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, P = 0.47; central, P = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements ( P = 0.017), but not central measurements ( P = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local ( R 2 = 0.66, P < 0.0001) and centrally determined reads ( R 2 = 0.57, P = 0.0007)., Conclusions: No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients., (©2021 American Association for Cancer Research.)

Introduction: Osteochondromas are benign bone tumors which occur as solitary lesions or as part of the syndrome multiple hereditary exostoses. While most osteochondromas occur in the appendicular skeleton, they can also occur in the spine. Most lesions are asymptomatic however some may encroach on the spinal cord or the nerve roots causing neurological symptoms. While most patients with osteochondromas undergo laminectomy without fusion, laminectomy with fusion is indicated in appropriately selected cases of spinal decompression., Case Presentation: We present a case of a 32-year-old male with history of multiple hereditary exostoses who presented with symptoms of bilateral upper extremity numbness and complaints of gait imbalance and multiple falls. He reported rapid progression of his symptoms during the 10 days before presentation. Computed tomography of the cervical spine revealed a lobulated bony tumor along the inner margin of the cervical 4 lamina. He underwent cervical 3 and 4 laminectomies, partial cervical 2 and 5 laminectomies and cervical 3-5 mass screw placement. Pathology was consistent with osteochondroma. The patient's symptoms had markedly improved at follow-up., Conclusion: According to our literature review, osteochondromas most commonly occur at cervical 2 and cervical 5. We present a case of an osteochondroma at a less common level, cervical 4. While most osteochondromas are addressed with laminectomy without arthrodesis, the decision of whether arthrodesis is necessary should be considered in all patients with osteochondroma as with any cervical decompression.

Study Design: A retrospective data review., Objective: To evaluate the efficacy of CyberKnife (CK) stereotactic radiosurgery (SRS) for thyroid spinal metastasis (SMs)., Summary of Background Data: Thyroid carcinoma is an infrequent cause of SM. The absolute efficacy of SRS generally and CK in particular remains poorly characterized for thyroid SM. The current study is the first to specifically evaluate the efficacy of CK SRS for thyroid SMs., Methods: A retrospective review of patients at our institution between 2003 and 2013 was done. Details about tumor location, radiographic findings before and after CK SRS, tumor recurrence, prescription isodose level, total and maximum dose, number of fractions, and gross tumor volume coverage were similarly collected. For comparison with other studies, the biologically effective dose and the equivalent total dose in 2 Gy fractions were calculated. Each patient was assessed for survival and local disease control from the time of the first CK session and survival analysis was carried out using the Kaplan-Meier method. Risk factors for local failure were assessed using multivariate logistic regression., Results: A total of 12 patients with 32 spinal metastases from thyroid carcinoma that were treated with CK SRS were identified. Survival for 1, 2, and 3 years was 55%, 44%, and 33%, and local control was 67%, 56%, and 34% respectively. The study found that the single strongest factor associated with local control was prior radiotherapy (β-coefficient -27.72, P = 0.01). No complications occurred in the immediate or late follow-up period., Conclusion: This was the first study to specifically investigate the efficacy of CK for treatment of thyroid SMs. Our findings suggest that CK can be safely used to treat spinal SMs from thyroid cancer and is associated with a high rate of local control., Level of Evidence: 4.

Multiple myeloma (MM) represents approximately 15% of haematological malignancies and most of the patients present with bone involvement. Focal or diffuse spinal osteolysis may result in significant morbidity by causing painful progressive vertebral compression fractures (VCFs) and deformities. Advances in the systemic treatment of myeloma have achieved high response rates and prolonged the survival significantly. Early diagnosis and management of skeletal events contribute to improving the prognosis and quality of life of MM patients. The management of patients with significant pain due to VCFs in the acute phase is not standardised. While some patients are successfully treated conservatively, and pain relief is achieved within a few weeks, a large percentage has disabling pain and morbidity and hence they are considered for surgical intervention. Balloon kyphoplasty and percutaneous vertebroplasty are minimally invasive procedures which have been shown to relieve pain and restore function. Despite increasing positive evidence for the use of these procedures, the indications, timing, efficacy, safety and their role in the treatment algorithm of myeloma spinal disease are yet to be elucidated. This paper reports an update of the consensus statement from the International Myeloma Working Group on the role of cement augmentation in myeloma patients with VCFs.

Objectives: Although treatment of superior sulcus tumors with induction chemoradiotherapy (CRT) followed by surgery employed in the Intergroup INT-0160 trial is widely adopted as a standard of care, there may be significant associated morbidity and mortality. We describe our experience using standard and alternative induction regimens to assess survival rates and treatment toxicity in these patients., Materials and Methods: Electronic medical records of all patients who underwent multimodality treatment including resection of lung cancer invading the superior pulmonary sulcus between 1994 and 2016 were retrospectively reviewed. Multivariable Cox Proportional Hazards model was constructed., Results: Of 102 consecutive patients, 53 (52%) underwent induction CRT, 34 (33%) underwent induction chemotherapy only (Ch) followed by adjuvant radiotherapy, and 15 (15%) underwent no induction therapy followed by adjuvant therapy. There were 2 postoperative deaths (1.9%). To date, 42 patients are alive with a median follow-up 72.5 months. Overall 5-year survival rate was 45.4%. Survival was significantly influenced by age, FEV 1 , positive resection margins, surgical complications, but not the induction regimen. CRT resulted in higher complete pathological response rate than Ch: 38% vs. 3% (p < 0.001). CRT was associated with higher post-operative re-intubation rate: 13% vs. 0% (p = 0.03)., Conclusions: Our single-institutional experience indicated that while induction CRT produced greater complete pathological response than Ch, it also increased the risk of post-operative complications. With careful patient selection, induction Ch followed by adjuvant radiotherapy may provide comparable survival outcomes to induction CRT. Since induction Ch is associated with lower risk of complications, it may be a particularly desirable choice for patients with impaired performance status., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Patients with metastatic spinal disease are affected by disabling pain. The treatment of spinal metastases is focused on pain reduction and improvement in quality of life. Until recently, many patients with metastatic spinal disease did not qualify as surgical candidates due to the risks of surgery and length of recovery period. However, recent advances in minimally invasive surgery such as kyphoplasty and vertebroplasty allow patients to safely undergo surgery for pain relief with a short recovery period. The studies reviewed here suggest that vertebral augmentation is successful in reducing pain and disability scores in patients with painful metastases and multiple myeloma and are a safe modality to provide lasting pain relief. As the use of kyphoplasty and vertebroplasty for treatment of vertebral metastases is becoming more common, new combinations of cement augmentation with other techniques such as percutaneous pedicle screws and radiofrequency ablation are being explored. The implementation of kyphoplasty and vertebroplasty, in conjunction with other minimally invasive surgical techniques as well as nonsurgical modalities, may lead to the best palliative management of cancer patients with spinal metastases and help them ultimately achieve a better quality of life., Competing Interests: The authors have declared that no competing interests exist.

Tumor related fractures of the spine frequently dictate surgical management. The most critical factors influencing the need and type of surgery are degree of epidural cord compression, radiosensitivity of the tumor, presence of spinal instability and patient medical status/ estimated survivorship. There is a wide spectrum of therapeutic options: major en bloc resections in primary or oligometastatic disease; decompression and fusion in non-radiosensitive tumors with cord compression followed by adjuvant radiation therapy (RT); kyphoplasty/ vertebroplasty for stable compression fractures or minimally invasive corpectomy for more unstable fractures and RT- only for radiosensitive tumors not causing overt instability. Radiation therapy has always been essential component of the treatment algorithm although it has been displaced from principal treatment modality in the last 2 decades. However, the advent of more targeted and efficient forms of RT (radiosurgery) may be a new treatment paradigm for more radioresistant tumors and may obviate the need for major operations.

Background: Aquaporin-4 (aqp-4) is a member of water channel family proteins primarily expressed in the central nervous system. Physiologically it is the main channel providing water transport into the nervous system water compartments and across the blood-brain barrier. Several studies demonstrated its compensatory role in severe hydrocephalus. However, its role is not clear during the initial stages of hydrocephalus., Objective: This study was designed to investigate aqp-4 expression in less severe forms of hydrocephalus and to determine its role in disease progression., Methods: Twenty-five male Wistar-Hannover rats, were distributed into experimental (n = 20) and control (n = 5) groups. Hydrocephalus was induced in the experimental group by injection of 5 μl 25% kaolin suspension into the cisterna magna. Control animals received an injection of 5 μl normal saline. Eight weeks later, the animals were killed by the perfusion-fixation method. Immunohistochemical and Western blot analysis were performed., Results: Ventricular dilatations were noted in all experimental animals. Both groups demonstrated positive immunoreactive signals to aqp-4. Immunohistochemically there were no changes in aqp-4 pattern and expression intensity between experimental and control animals. Similarly, Western blot analysis revealed mean aqp-4 values in experimental and control groups as 0.3436 and 0.3917, respectively, and the difference did not reach statistical significance (p > 0.05)., Conclusion: Our results indicate that aqp-4 is not up-regulated during the initial stages of hydrocephalus. This implies that aqp-4 may not play a significant role in hydrocephalus compensation until severe ventricular dilatation occurs.

Object: Aquaporins (aqp) are protein channels providing water transport across cell membranes. The main member of this family expressed in the CNS is aqp-4. The pattern and amount of expression of this channel suggest a dominant role in bulk water movement into the nervous tissue. It has also been shown to play a role in several water balance disorders in the CNS. In this study, the authors investigated the possible role of aqp-4 in syringomyelia., Methods: Twenty-five male Wistar-Hannover rats were divided into experimental (20 rats) and control (5 rats) groups. Syringomyelia was induced in the experimental group by kaolin injection into the cisterna magna. Eight weeks later, the animals were killed, and their spinal cords were removed. Central canal dilations were noted in all experimental animals. Immunohistochemistry and Western blot analysis were performed to evaluate aqp-4 expression., Results: Both groups demonstrated positive immunoreactive signals to aqp-4. Western blot analysis revealed a slight decrease in the mean aqp-4 value in the experimental group; however, the difference did not reach statistical significance (p > 0.05). Immunohistochemical analysis showed a similar pattern and intensity of aqp-4 staining in both groups., Conclusions: The results of this study indicate that aqp-4 most likely does not play a major role in chronic syringomyelia. Its slight downregulation during the initial stage of syrinx formation is possibly a compensatory mechanism. This effect is not present during the late stage of syringomyelia, and aqp-4 is most likely not involved in the pathophysiology of syrinx cavity formation.

Purpose of Review: To review the current status of vertebral augmentation procedures (VAPs) in the management of symptomatic vertebral compression fractures (VCFs) in cancer patients., Recent Findings: The natural history of VCFs in the cancer setting is presumably different from the one seen with osteoporotic fractures. Factors contributing to the poor outcome with conservative treatment in cancer patients include continued bone loss due to tumor invasion, poor nutritional status, immobilization, prolonged steroid use, gonadal ablation, chemotherapy and radiotherapy. VAPs have been shown by retrospective and prospective randomized studies to be effective in treating symptomatic VCFs. Advantages of VAPs include immediate pain relief, avoiding delays in chemoradiation, outpatient care in the majority of cases, biopsy, vertebral height restoration, and potential antitumor effect of bone cement. Results from the prospective randomized Cancer Fracture Evaluation (CAFÉ) trial show superiority of balloon kyphoplasty (BKP) over conservative management in cancer patients with VCFs with similar rate of adverse events between treatment arms. Additionally, the field is still evolving with advances such as combination with radiosurgery and spinal radiofrequency ablation (RFA), use of kyphoplasty without a balloon and highly viscous cement to prevent leakage., Summary: VAPs are well tolerated and effective methods to provide palliative care for cancer patients with VCFs and should be offered to symptomatic patients.