ABSTRACT
Introduction: S1-L5 transdiscal screw fixation is a direct stabilization technique used for surgical treatment of high-grade (III-IV) L5-S1 spondylolisthesis. It has not been used for nonspondylolisthetic cases or in combination with an interbody cage (IC). This study aimed to develop a novel, direct S1-L5 sacrolumbar interbody fusion (SLIF) technique, a combination of IC and sacrolumbar transdiscal screw. Methods: SLIF was tested in cadaveric, clinical, and finite element analysis settings. Three cadaveric lumbar spines were used to test the SLIF procedure before clinical application. Eight patients underwent the SLIF procedure. Clinical outcomes were evaluated by visual analog score for leg and back pain, short form 36, Oswestry disability index, and neurological examination. CT scans of the lumbar spine were used to assess the hardware placement and subsequent fusion. Finite element analysis was performed on a healthy human CT-based L5-S1 model. Intact segment, unilateral facetectomy and discectomy, SLIF, and transforaminal lumbar interbody fusion (TLIF) procedures were compared in terms of the range of motion (ROM), von Mises stress on hardware, and shear-induced directional deformity. Additionally, the same set of tests were conducted in an osteoporotic model. Results: Excellent hardware placement was feasible in three cadavers and eight patients. Preoperative neurological deficits improved in all patients. Statistically significant improvements were obtained on all self-reported questionnaire scores. All patients developed solid, Bridwell grade I fusions. Biomechanical testing revealed similar outcomes for TLIF and SLIF regarding the ROM. However, the screw's von Mises stress and shear-induced directional deformity were low for SLIF of healthy and osteoporotic bone. Conclusions: SLIF is a feasible, safe, and effective L5-S1 fusion option suitable for all clinical scenarios. It provides several biomechanical advantages, yielding excellent clinical outcomes.
ABSTRACT
BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. METHODS: The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1 min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. RESULTS: Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. CONCLUSIONS: The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. TRIAL REGISTRATION: NCT04539964; August 31, 2020.
ABSTRACT
Cervical degenerative disc diseases such as myelopathy and radiculopathy often require conventional treatments like artificial cervical disc replacement or anterior cervical discectomy and fusion (ACDF). When designing a medical device, like the stand-alone cage, there are many design inputs to consider. However, the precise biomechanics of the force between the vertebrae and implanted devices under certain conditions require further investigation. In this study, a new method was developed to evaluate the pressure between the vertebrae and implanted devices by embedding a sensor array into a 3D-printed C2-C3 cervical spine. The 3D-printed cervical spine model was subjected to a range of axial loads while under flexion, extension, bending and compression conditions. Cables were used for the application of a preload and a robotic arm was used to recreate the natural spine motions (flexion, extension, and bending). To verify and predict the total pressure between the vertebrae and the implanted devices, a 3D finite element (FE) numerical mathematical model was developed. A preload was represented by applying 22 N of force on each of the anterior tubercles for the C2 vertebra. The results of this study suggest that the sensor is useful in identifying static pressure. The pressure with the robot arm was verified from the FE results under all conditions. This study indicates that the sensor array has promising potential to reduce the trial and error with implants for various surgical procedures, including multi-level artificial cervical disk replacement and ACDF, which may help clinicians to reduce pain, suffering, and costly follow-up procedures.
Subject(s)
Intervertebral Disc Degeneration , Spinal Fusion , Humans , Spinal Fusion/methods , Cervical Vertebrae/surgery , Intervertebral Disc Degeneration/surgery , Diskectomy/methods , Biomechanical Phenomena , Range of Motion, Articular , Printing, Three-DimensionalABSTRACT
The study aimed to investigate the impact of posterior element and ligament removal on the maximum von Mises stress, and maximum shear stress of the eight-layer annulus for treating stenosis at the L3-L4 and L4-L5 levels in the lumbar spine. Previous studies have indicated that laminectomy alone can result in segmental instability unless fusion is performed. However, no direct correlations have been established regarding the impact of posterior and ligament removal. To address this gap, four models were developed: Model 1 represented the intact L2-L5 model, while model 2 involved a unilateral laminotomy involving the removal of a section of the L4 inferior lamina and 50% of the ligament flavum between L4 and L5. Model 3 consisted of a complete laminectomy, which included the removal of the spinous process and lamina of L4, as well as the relevant connecting ligaments between L3-L4 and L4-L5 (ligament flavum, interspinous ligament, supraspinous ligament). In the fourth model, a complete laminectomy with 50% facetectomy was conducted. This involved the same removals as in model 3, along with a 50% removal of the inferior/superior facets of L4 and a 50% removal of the facet capsular ligaments between L3-L4 and L4-L5. The results indicated a significant change in the range of motion (ROM) at the L3-L4 and L4-L5 levels during flexion and torque situations, but no significant change during extension and bending simulation. The ROM increased by 10% from model 1 and 2 to model 3, and by 20% to model 4 during flexion simulation. The maximum shear stress and maximum von-Mises stress of the annulus and nucleus at the L3-L4 levels exhibited the greatest increase during flexion. In all eight layers of the annulus, there was an observed increase in both the maximum shear stress and maximum von-Mises stress from model 1&2 to model 3 and model 4, with the highest rate of increase noted in layers 7&8. These findings suggest that graded posterior element and ligament removal have a notable impact on stress distribution and range of motion in the lumbar spine, particularly during flexion.
ABSTRACT
BACKGROUND: Genomic profiling cannot solely predict the complexity of how tumor cells behave in their in vivo microenvironment and their susceptibility to therapies. The aim of the study was to establish a functional drug prediction model utilizing patient-derived GBM tumor samples for in vitro testing of drug efficacy followed by in vivo validation to overcome the disadvantages of a strict pharmacogenomics approach. METHODS: High-throughput in vitro pharmacologic testing of patient-derived GBM tumors cultured as 3D organoids offered a cost-effective, clinically and phenotypically relevant model, inclusive of tumor plasticity and stroma. RNAseq analysis supplemented this 128-compound screening to predict more efficacious and patient-specific drug combinations with additional tumor stemness evaluated using flow cytometry. In vivo PDX mouse models rapidly validated (50 days) and determined mutational influence alongside of drug efficacy. We present a representative GBM case of three tumors resected at initial presentation, at first recurrence without any treatment, and at a second recurrence following radiation and chemotherapy, all from the same patient. RESULTS: Molecular and in vitro screening helped identify effective drug targets against several pathways as well as synergistic drug combinations of cobimetinib and vemurafenib for this patient, supported in part by in vivo tumor growth assessment. Each tumor iteration showed significantly varying stemness and drug resistance. CONCLUSIONS: Our integrative model utilizing molecular, in vitro, and in vivo approaches provides direct evidence of a patient's tumor response drifting with treatment and time, as demonstrated by dynamic changes in their tumor profile, which may affect how one would address that drift pharmacologically.
ABSTRACT
The cervical spine poses many complex challenges that require complex solutions. Anterior cervical discectomy and fusion (ACDF) has been one such technique often employed to address such issues. In order to address the problems with ACDF and assess the modifications that have been made to the technique over time, finite element analyses (FEA) have proven to be an effective tool. The variations of cervical spine FEA models that have been produced over the past couple of decades, particularly more recent representations of more complex geometries, have not yet been identified and characterized in any literature. Our objective was to present material property models and cervical spine models for various simulation purposes. The outlining and refinement of the FEA process will yield more reliable outcomes and provide a stable basis for the modeling protocols of the cervical spine.
ABSTRACT
Adaptive plasticity of Breast Cancer stem cells (BCSCs) is strongly correlated with cancer progression and resistance, leading to a poor prognosis. In this study, we report the expression profile of several pioneer transcription factors of the Oct3/4 network associated with tumor initiation and metastasis. In the triple negative breast cancer cell line (MDA-MB-231) stably transfected with human Oct3/4-GFP, differentially expressed genes (DEGs) were identified using qPCR and microarray, and the resistance to paclitaxel was assessed using an MTS assay. The tumor-seeding potential in immunocompromised (NOD-SCID) mice and DEGs in the tumors were also assessed along with the intra-tumor (CD44+/CD24-) expression using flow cytometry. Unlike 2-D cultures, the Oct3/4-GFP expression was homogenous and stable in 3-D mammospheres developed from BCSCs. A total of 25 DEGs including Gata6, FoxA2, Sall4, Zic2, H2afJ, Stc1 and Bmi1 were identified in Oct3/4 activated cells coupled with a significantly increased resistance to paclitaxel. In mice, the higher Oct3/4 expression in tumors correlated with enhanced tumorigenic potential and aggressive growth, with metastatic lesions showing a >5-fold upregulation of DEGs compared to orthotopic tumors and variability in different tissues with the highest modulation in the brain. Serially re-implanting tumors in mice as a model of recurrence and metastasis highlighted the sustained upregulation of Sall4, c-Myc, Mmp1, Mmp9 and Dkk1 genes in metastatic lesions with a 2-fold higher expression of stem cell markers (CD44+/CD24-). Thus, Oct3/4 transcriptome may drive the differentiation and maintenance of BCSCs, promoting their tumorigenic potential, metastasis and resistance to drugs such as paclitaxel with tissue-specific heterogeneity.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Mice , Humans , Animals , Female , Breast Neoplasms/metabolism , Up-Regulation , Mice, SCID , Mice, Inbred NOD , Triple Negative Breast Neoplasms/pathology , Paclitaxel/pharmacology , Paclitaxel/metabolism , Neoplastic Stem Cells/metabolism , Cell Line, TumorABSTRACT
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.
Subject(s)
COVID-19 , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Respiratory Distress Syndrome , Male , Female , Humans , Adult , Middle Aged , Aged , COVID-19/therapy , COVID-19/etiology , Feasibility Studies , Mesenchymal Stem Cell Transplantation/adverse effects , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapyABSTRACT
PURPOSE: Various factors have been examined in relation to cage subsidence risk, including cage material, cage geometry, bone mineral density, device type, surgical level, bone graft, and patient age. The present study aims to compare and synthesize the literature of both clinical and biomechanical studies to evaluate and present the factors associated with cage subsidence. METHODS: A comprehensive search of the literature from January 2003 to December 2021 was conducted using the PubMed and ScienceDirect databases by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Following the screening for inclusion and exclusion criteria, a total of 49 clinical studies were included. Correlations between clinical and biomechanical studies are also discussed. RESULTS: Patients treated with the cage and plate combination had a lower subsidence rate than patients with the stand-alone cage. Overall, Polyetheretherketone material was shown to have a lower subsidence rate than titanium and other materials. The subsidence rate was also higher when the surgery was performed at levels C5-C7 than at levels C2-C5. No significant correlation was found between age and cage subsidence clinically. CONCLUSIONS: Cage subsidence increases the stress on the anterior fixation system and may cause biomechanical instability. Severe cage subsidence decreases the Cobb angle and intervertebral height, which may cause destabilization of the implant system, such as screw/plate loosening or breakage of the screw/plate. Various factors have been shown to influence the risk of cage subsidence. Examining clinical research alongside biomechanical studies offers a more comprehensive understanding of the subject.
Subject(s)
Diskectomy , Polyethylene Glycols , Humans , Diskectomy/adverse effects , Ketones , Bone Plates , Bone ScrewsABSTRACT
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 (nâ =â 44) mOS was 11.64 months (80% one-sided CI 8.62, 15.02) and OS-12 was 46%. A subgroup (nâ =â 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.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/pathology , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Receptors, Interleukin-4/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Tumor MicroenvironmentABSTRACT
Over the past few decades, there has been a growing popularity in utilizing finite element analysis to study the spine. However, most current studies tend to use one specimen for their models. This research aimed to validate multiple finite element models by comparing them with data from in vivo experiments and other existing finite element studies. Additionally, this study sought to analyze the data based on the gender and age of the specimens. For this study, eight lumbar spine (L2-L5) finite element models were developed. These models were then subjected to finite element analysis to simulate the six fundamental motions. CT scans were obtained from a total of eight individuals, four males and four females, ranging in age from forty-four (44) to seventy-three (73) years old. The CT scans were preprocessed and used to construct finite element models that accurately emulated the motions of flexion, extension, lateral bending, and axial rotation. Preloads and moments were applied to the models to replicate physiological loading conditions. This study focused on analyzing various parameters such as vertebral rotation, facet forces, and intradiscal pressure in all loading directions. The obtained data were then compared with the results of other finite element analyses and in vivo experimental measurements found in the existing literature to ensure their validity. This study successfully validated the intervertebral rotation, intradiscal pressure, and facet force results by comparing them with previous research findings. Notably, this study concluded that gender did not have a significant impact on the results. However, the results did highlight the importance of age as a critical variable when modeling the lumbar spine.
ABSTRACT
The role of Aß 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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Brain Injuries , Cognitive Dysfunction , Subarachnoid Hemorrhage , Female , Male , Mice , Animals , Microglia/metabolism , Toll-Like Receptor 4/metabolism , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/metabolism , Clodronic Acid/metabolism , Liposomes/metabolism , Mice, Inbred C57BL , Neurons/metabolism , Brain Injuries/etiology , Disease Models, Animal , Cognitive Dysfunction/etiologyABSTRACT
STUDY DESIGN: This study compares four cervical endplate removal procedures, validated by finite element models. PURPOSE: To characterize the effect of biomechanical strength and increased contact area on the maximum von Mises stress, migration, and subsidence between the cancellous bone, endplate, and implanted cage. OVERVIEW OF LITERATURE: Anterior cervical discectomy and fusion (ACDF) has been widely used for treating patients with degenerative spondylosis. However, no direct correlations have been drawn that incorporate the impact of the contact area between the cage and the vertebra/endplate. METHODS: Model 1 (M1) was an intact C2C6 model with a 0.5 mm endplate. In model 2 (M2), a cage was implanted after removal of the C4-C5 and C5-C6 discs with preservation of the osseous endplate. In model 3 (M3), 1 mm of the osseous endplate was removed at the upper endplate. Model 4 (M4) resembles M3, except that 3 mm of the osseous endplate was removed. RESULTS: The range of motion (ROM) at C2C6 in the M2-M4 models was reduced by at least 9º compared to the M1 model. The von Mises stress results in the C2C3 and C3C4 interbody discs were significantly smaller in the M1 model and slightly increased in the M2-M3 and M3-M4 models. Migration and subsidence decreased from the M2-M3 model, whereas further endplate removal increased the migration and subsidence as shown in the transition from M3 to M4. CONCLUSIONS: The M3 model had the least subsidence and migration. The ROM was higher in the M3 model than the M2 and M4 models. Endplate preparation created small stress differences in the healthy intervertebral discs above the ACDF site. A 1 mm embedding depth created the best balance of mechanical strength and contact area, resulting in the most favorable stability of the construct.
ABSTRACT
BACKGROUND: The limitations of anterior cervical discectomy and fusion (ACDF) are related to mechanical failure of the construct after recurring subsidence and migration. In the present study, we evaluated the effect of the maximum rotation of variable angle screws on the range of motion (ROM), cage migration, and subsidence. METHODS: Five finite element models were developed from a C2-C7 cervical spine model. The first model was an intact C2-C7 spine model, and the second model was an altered C2-C7 model with C4-C6 cage insertion and a 2-level static plate. The other three models were altered C2-C7 models with the same C4-C6 cage insertion and a 2-level dynamic plate. RESULTS: The ROM of C4-C6 in the static plate model was reduced by â¼14° from the intact model but only reduced by â¼9° in the dynamic plate models. The maximum migration and subsidence at the cage-endplate interface in the dynamic plate models were lower than those in the static plate model for all moments. The von Mises stress of the C3-C4 and C6-C7 discs in the dynamic plate models was lower than that in the static plate model. CONCLUSIONS: Our results indicate that dynamic plating has promising potential (greater ROM and lower von Mises stress of discs) for stabilization in multilevel anterior cervical discectomy and fusion than static plating, although both dynamic and static plates showed lower ROM than the intact model. A lower screw rotational angle resulted in superior biomechanical performance (lower incidence of migration and subsidence) compared with a higher rotational angle in multilevel applications, regardless of loading.
Subject(s)
Diskectomy , Spinal Fusion , Biomechanical Phenomena , Cervical Vertebrae/diagnostic imaging , Cervical Vertebrae/surgery , Diskectomy/methods , Finite Element Analysis , Humans , Range of Motion, Articular , Spinal Fusion/methodsABSTRACT
Glioblastoma multiforme (GBM) is a lethal brain tumor characterized by developmental hierarchical phenotypic heterogeneity, therapy resistance and recurrent growth. Neural stem cells (NSCs) from human central nervous system (CNS), and glioblastoma stem cells from patient-derived GBM (pdGSC) samples and cultured in both 2D well-plate and 3D monoclonal neurosphere culture system (pdMNCS). The pdMNCS model shows promise to establish a relevant 3D-tumor environment that maintains GBM cells in the stem cell phase within suspended neurospheres. Utilizing the pdMNCS, we examined GBM cell-lines for a wide spectrum of developmental cancer stem cell markers, including the early blastocyst inner-cell mass (ICM)-specific Nanog, Oct3/4,B, and CD133. We observed that MNCS epigenotype is recapitulated using gliomasphere-derived cells. CD133, the marker of GSC is robustly expressed in 3D-gliomaspheres and localized within the plasma membrane compartment. Conversely, gliomasphere cultures grown in conventional 2D culture quickly lost CD133 expression, indicating its variable expression is dependent on cell-culture conditions. Critically, this experiment demonstrates incomplete differentiation of cytoskeleton microtubules and intermediate filaments (IFs) of patient derived cells, similar to commercially available GBM cell lines. Subsequently, in order to determine whether Oct3/4 it was necessary for CD133 expression and cancer stemness, we transfected 2D and 3D culture with siRNA against Oct3/4 and found a significant reduction in gliomasphere formation. These results suggest that expression of Oct3/4,Aand CD133 suppress differentiation of GSCs.
ABSTRACT
INTRODUCTION: Hydrocephalus is a neurological disorder caused by excessive accumulation of the cerebrospinal fluid (CSF) in the ventricles of the brain. It can be treated by diverting the extra fluid to different parts of the body using a device called a shunt. This paper reviews different shunt devices that are used for this purpose. AREAS COVERED: Shunts have high failure rates either due to infection or mechanical failure, therefore there is still ongoing work to address these two main handicaps. They require additional devices for performance assessment. Here, the paper also reviews different approaches for assessing shunt limitations. Moreover, future prospects are also discussed. EXPERT OPINION: This study shows that shunt devices still remain an important treatment option for hydrocephalus. However, further efforts are required to design more advanced shunts, to eliminate high failure rates in clinical use. Sophisticated sensor systems that can accurately detect and regulate changes in CSF drainage to optimize drainage for individual needs. Moreover, shunt infection problem is still present despite recent improvements such as antibiotic impregnated catheters.
Subject(s)
Cerebrospinal Fluid Shunts , Hydrocephalus , Anti-Bacterial Agents/therapeutic use , Catheters , Humans , Hydrocephalus/drug therapy , Hydrocephalus/surgery , Prostheses and ImplantsABSTRACT
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.
Subject(s)
Prostheses and Implants , Spinal Fusion/instrumentation , Spinal Neoplasms/surgery , Benzophenones , Biomechanical Phenomena , Carbon Fiber , Humans , PolymersABSTRACT
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 (R2 = 0.66, P < 0.0001) and centrally determined reads (R2 = 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.