Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial.

Intrathecal delivery of autologous culture-expanded adipose tissue-derived mesenchymal stem cells (AD-MSC) could be utilized to treat traumatic spinal cord injury (SCI). This Phase I trial (ClinicalTrials.gov: NCT03308565) included 10 patients with American Spinal Injury Association Impairment Scale (AIS) grade A or B at the time of injury. The study's primary outcome was the safety profile, as captured by the nature and frequency of adverse events. Secondary outcomes included changes in sensory and motor scores, imaging, cerebrospinal fluid markers, and somatosensory evoked potentials. The manufacturing and delivery of the regimen were successful for all patients. The most commonly reported adverse events were headache and musculoskeletal pain, observed in 8 patients. No serious AEs were observed. At final follow-up, seven patients demonstrated improvement in AIS grade from the time of injection. In conclusion, the study met the primary endpoint, demonstrating that AD-MSC harvesting and administration were well-tolerated in patients with traumatic SCI.

Patients of idiopathic normal-pressure hydrocephalus have small dural sac in cervical and upper thoracic levels: A supposed causal association.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder presenting a triad including dementia and ventricular enlargement. The mechanism causing excessive cerebrospinal fluid (CSF) accumulation in the ventricles in iNPH is poorly understood. We hypothesized that the age-related degradation of the spinal shock-absorbing system composed of a spinal dural sac (SDS) and surrounding soft tissue, preventing ventricular enlargement caused by wide CSF pulsation driven by heartbeats, may be involved in the ventricular enlargement observed in iNPH. Methods: Sixty-four patients with iNPH in their seventies who underwent a lumboperitoneal shunt and a control group of 79 people in the same age group who underwent brain check-ups were included in the study. We compared the sizes of the cervical and upper parts of the thoracic SDS using magnetic resonance imaging between the two groups. Results: The anterior-posterior distances of the dural sac at C5 were shorter in patients with iNPH of both sexes than those in the control group (P = 0.0008 in men and P = 0.0047 in women). The number of disc levels with disappeared CSF space surrounding the cervical cord was more in iNPH (P = 0.0176 and P = 0.0003). The midsagittal area of the upper part of the spinal sac, C2-Th4, was smaller in iNPH (P = 0.0057 and P = 0.0290). Conclusion: Narrowing of the cervical dural sac and midsagittal area in the upper part of the SDS in patients with iNPH may reflect the degradation of the shock-absorbing mechanism for CSF pressure pulsations, which may cause iNPH or at least aggravate iNPH by other unknown causes.

Prediction Model for Neurogenic Bladder Recovery One Year After Traumatic Spinal Cord Injury.

INTRODUCTION: Neurogenic bladder is a common complication after spinal cord injury (SCI) that carries substantial burdens on the inflicted individual. The objective of this study is to build a prediction model for neurogenic bladder recovery 1 year after traumatic SCI. METHODS: We queried the National Spinal Cord Injury Model Systems database for patients with traumatic SCI who had neurogenic bladder at the time of injury. The primary outcome of interest was the complete recovery of bladder function at 1 year. Multiple imputations were performed to generate replacement values for missing data, and the final imputed data were used for our analysis. A multivariable odds logistic regression model was developed for complete bladder recovery at 1 year. RESULTS: We identified a total of 2515 patients with abnormal bladder function at baseline who had an annual follow-up. A total of 417 patients (16.6%) recovered bladder function in 1 year. Predictors of complete bladder recovery included the following baseline parameters: sacral sensation, American Spinal Injury Association (ASIA) impairment score, bowel function at baseline, voluntary sphincter contraction, anal sensation, S1 motor scores, and the number of days in the rehabilitation facility. The model performed with a discriminative capacity of 90.5%. CONCLUSIONS: We developed a prediction model for the probability of complete bladder recovery 1 year after SCI. The model performed with a high discriminative capacity. This prediction model demonstrates potential utility in the counseling, research allocation, and management of individuals with SCI.

A review of vascular endothelial growth factor and its potential to improve functional outcomes following spinal cord injury.

Spinal cord injuries (SCI) are traumatic events with limited treatment options. Following injury, the lesion site experiences a drastic change to both its structure and vasculature which reduces its ability for tissue regeneration. Despite the lack of clinical options, researchers are investigating therapies to induce neuronal regeneration. Cell-based therapies have long been assessed in the context of SCI to promote neuronal protection and repair. Vascular endothelial growth factor (VEGF) not only demonstrates this ability, but also demonstrates angiogenic potential to promote blood vessel formation. While there have been numerous animal studies investigating VEGF, further research is still warranted to pinpoint its role following SCI. This review aims to discuss the literature surrounding the role of VEGF following SCI and its potential in promoting functional recovery.

The Role of Alginate Hydrogels as a Potential Treatment Modality for Spinal Cord Injury: A Comprehensive Review of the Literature.

OBJECTIVE: To comprehensively characterize the utilization of alginate hydrogels as an alternative treatment modality for spinal cord injury (SCI). METHODS: An extensive review of the published literature on studies using alginate hydrogels to treat SCI was performed. The review of the literature was performed using electronic databases such as PubMed, EMBASE, and OVID MEDLINE electronic databases. The keywords used were "alginate," "spinal cord injury," "biomaterial," and "hydrogel." RESULTS: In the literature, we identified a total of 555 rat models that were treated with alginate scaffolds for regenerative biomarkers. Alginate hydrogels were found to be efficient and promising substrates for tissue engineering, drug delivery, neural regeneration, and cellbased therapies for SCI repair. With its ability to act as a pro-regenerative and antidegenerative agent, the alginate hydrogel has the potential to improve clinical outcomes. CONCLUSION: The emerging developments of alginate hydrogels as treatment modalities may support current and future tissue regenerative strategies for SCI.

Dural sac shrinkage signs on spinal magnetic resonance imaging indicate overdrainage after lumboperitoneal shunt for idiopathic normal pressure hydrocephalus.

Background: We previously found the usefulness of dural sac shrinkage signs (DSSSs), which are the anterior shift of the spinal cord and dura mater behind the cord, detected by magnetic resonance imaging (MRI) at the thoracic level for the diagnosis of spontaneous intracranial hypotension (IH). This is a retrospective survey on the usefulness of DSSSs for the early detection of iatrogenic IH caused by overdrainage through a lumboperitoneal shunt (LPS) for patients with idiopathic normal pressure hydrocephalus (INPH). Methods: Forty-five INPH patients had an LPS using a pressure programmable valve equipped with an anti-siphon device. Results: Nine patients complained of orthostatic headache after the LPS, indicating IH due to overdrainage, which persisted for more than a week in three patients and 2-7days in six patients. The headache was transient/ nonorthostatic in ten patients and absent in 26 patients. The DSSSs and accompanying enlargement of the venous plexus were observed in all three patients with prolonged orthostatic headaches. Only the anterior shift of the dura mater was observed in 1 (4%) among 25 patients who had short-term orthostatic headache, transient/ nonorthostatic headache, or absent headache, and underwent spinal MRI. A patient with prolonged severe orthostatic headache with both DSSSs eventually developed intracranial subdural effusion and underwent tandem valve surgery, which provided a quick improvement of symptoms. The DSSSs on thoracic MRI also disappeared promptly. Conclusion: DSSSs may serve as objective signs for the diagnosis of IH due to overdrainage through an LPS for INPH.

Dissecting aneurysm of the anterior inferior cerebellar artery in the internal auditory canal presenting with deafness without hemorrhage: A case report and literature review.

Background: Anterior inferior cerebellar artery (AICA) aneurysms in the internal auditory canal (IAC) are rare. We have reported a case of dissecting AICA aneurysm in the IAC presenting initially with the eighth nerve palsy followed by the seventh nerve palsy without hemorrhage. Case Description: A 68-year-old woman presented with a sudden onset of vertigo accompanied by deafness and tinnitus on the right side that was preceded by intermittent right retroauricular pain 2 weeks before. Audiogram showed severe sensorineural hearing loss. Computed tomography and magnetic resonance imaging (MRI) indicated absence of prior subarachnoid hemorrhage. Magnetic resonance angiogram (MRA) suggested a tiny aneurysm at the fundus of the IAC accompanied with thinning of the lateral pontine segment of the AICA. Conservative treatment led to moderate improvement of the symptoms. However, the patient developed the right retroauricular pain again, followed by the right facial paralysis 5 months later but still without signs of hemorrhage on MRI. Digital subtraction angiogram showed dissecting aneurysm in the IAC. The patient was managed with oral steroids and direct intervention was avoided due to a risk of ischemia supposed by large area irrigated by the AICA. Follow-up MRA 18 months after the first presentation showed improvement in the narrowing of the AICA proximal to the aneurysm. The patient was functionally independent despite right-sided hearing loss and slight facial paresis. Conclusion: This report warns physicians that a dissecting AICA aneurysm without subarachnoid hemorrhage may cause eighth and seventh nerve palsy.

Systems neuroimmunology: a review of multiomics methodologies to characterize neuroimmunological interactions in spinal and cranial diseases.

Neuroimmunology plays a critical role in our understanding of the pathophysiological processes that underlie a variety of diseases treated by neurosurgeons, including degenerative disc disease (DDD), glioblastoma (GBM), aneurysmal subarachnoid hemorrhage (aSAH), and others. Compared with traditional methods in neuroimmunology, which study one pathway or gene at a time, emerging multiomics methodologies allow for holistic interrogation of multiple immune-signaling pathways to test hypotheses and the effects of therapeutics at a systems level. In this review, the authors summarize key concepts for gathering and analyzing multiomics data so that neurosurgeons can contribute to the emerging field of systems neuroimmunology. Additionally, they describe 3 use cases, based on original research published by their group and others, that utilize transcriptomic, metabolomic, and proteomic analyses to study immune-signaling pathways in DDD, aSAH, and GBM. Through these use cases, techniques for performing machine learning and network-based analyses to generate new clinical insights from multiomics data are shared. The authors hope that neurosurgeons might use this review as a summary of common tools and principles in systems immunology to better engage in creating the immunotherapies of tomorrow.

Time-to-enrollment in clinical trials investigating neurological recovery in chronic spinal cord injury: observations from a systematic review and ClinicalTrials.gov database.

Currently, large numbers of clinical trials are performed to investigate different forms of experimental therapy for patients suffering from chronic spinal cord injury (SCI). However, for the enrollment process, there are different views on how the time period between injury and interventions should be determined. Herein, we sought to evaluate the impact of time-to-enrollment in chronic SCI clinical trials. A data set comprising 957 clinical studies from clinicalTrials.gov was downloaded and analyzed focusing on the eligibility criteria for post-injury time-to-enrollment. We also aggregated individual patient data from nine clinical trials of regenerative interventions for chronic SCI selected by a systematic literature search from 1990 to 2018. Characteristics of the studies were assessed and compared by dividing into three groups based on time-to-enrollment (group 1 ≤ 12 months, group 2 = 12-23 months and group 3 ≥ 24 months). In ClinicalTrials.gov registry, 445 trials were identified for chronic SCI where 87% (385) were unrestricted in the maximum post-injury time for trial eligibility. From systematic literature search, nine studies and 156 patients (group 1 = 30, group 2 = 55 and group 3 = 71) were included. The range of time-to-enrollment was 0.5 to 321 months in those studies. We also observed various degrees of motor and sensory improvement in between three time-to-enrollment groups. Our results indicate that enrolling wide ranges of time-to-enrollment in a group may present imprecise outcomes. Clinical trial designs should consider appropriate post-injury time frames to evaluate therapeutic benefit.

Characteristics of completed clinical trials for spinal cord injury from 1999 to 2020.

Numerous clinical trials are being conducted in the field of spinal cord injury (SCI). These trials are typically registered on ClinicalTrials.gov. The objective of this study was to identify the characteristics of the completed SCI trials and characterize the potential factors associated with publication. ClinicalTrials.gov database was queried for all the completed trials on patients with SCI. Baseline characteristics of the completed trials were assessed. The publication status of these trials was identified using PubMed or Google Scholar. The secondary and primary outcomes reported in the publication were then compared to the outcomes registered in ClinicalTrial.gov. Multivariable logistic regression analysis was performed to determine the characteristics associated with publication status and time to publication. A total of 457 of 1,061 trials on SCI were completed. Of those, 60% were ultimately published. Trials that had received funding from sources besides the NIH, private industries, or the federal government were more likely to remain unpublished. The median time to publish was three years, with larger trials taking a longer time. The median sample size for completed trials was 30. Assessment of mismatch rates in primary outcomes of published data to registered outcomes was 8.9%. In SCI trials, outcomes registered on ClinicalTrial.gov often matched published results. Additionally, sample size and funding source play a significant role in the publication rate of these trials. Published data represents a reliable source for clinicians, researchers, and patients; efforts to curb publication bias and reporting bias are paramount for implementing evidence-based practices and ensure proper scientific conduct.

Dural sac shrinkage signs on magnetic resonance imaging at the thoracic level in spontaneous intracranial hypotension-its clinical significance.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is secondary to a cerebrospinal fluid leak at the spinal level without obvious causative events. Several signs on brain and cervical spine magnetic resonance (MR) imaging (MRI) have been associated with SIH but can be equivocal or negative. This retrospective study sought to identify characteristic SIH signs on thoracic spinal MRI. METHODS: Cranial and spinal MR images of 27 consecutive patients with classic SIH symptoms, who eventually received epidural autologous blood patches (EBPs), were analyzed. RESULTS: The most prevalent findings on T2-weighted MRI at the thoracic level were anterior shift of the spinal cord (96.3%) and dorsal dura mater (81.5%), probably caused by dural sac shrinkage. These dural sac shrinkage signs (DSSS) were frequently accompanied by cerebrospinal fluid collection in the posterior epidural space (77.8%) and a prominent epidural venous plexus (77.8%). These findings disappeared in all six patients who underwent post-EBP spinal MRI. Dural enhancement and brain sagging were minimum or absent on the cranial MR images of seven patients, although DSSS were obvious in these seven patients. For 23 patients with SIH and 28 healthy volunteers, a diagnostic test using thoracic MRI was performed by 13 experts to validate the usefulness of DSSS. The median sensitivity, specificity, positive-predictive value, negative-predictive value, and accuracy of the DSSS were high (range, 0.913-0.931). CONCLUSIONS: Detection of DSSS on thoracic MRI facilitates an SIH diagnosis without the use of invasive imaging modalities. The DSSS were positive even in patients in whom classic cranial MRI signs for SIH were equivocal or minimal.

Clinical characteristics and management differences for grade II and III spinal meningiomas.

PURPOSE: The majority of spinal meningiomas are grade I tumors, as defined by World Health Organization (WHO) classification making atypical (grade II) or anaplastic (grade III) tumors extremely rare lesions to encounter in clinical practice. Here, we present our institutional experience of management of grade II and III spinal meningiomas. METHODS: Following IRB approval, we queried all available institutional electronic medical records for patients undergoing surgical resection of pathology-proven spinal meningiomas, with further review of patients with grade II and III. Variables of interest included age, sex, histological type, tumor size, symptoms at baseline, treatment characteristics, symptom resolution at the last follow-up, recurrence, NF-2 status, concurrent intracranial meningioma, and mortality. Kaplan Meier curves were constructed to study time to progression/recurrence. RESULTS: A total of 188 patients undergoing surgical resection of spinal meningioma between 1988 and 2018 were identified. Among those, 172 (91.5%) patients had grade I meningioma and 16 (8.5%) patients had high grade meningiomas [grade II (15) and III (1)]. Over a median (IQR) follow-up of 8.0 years (5.1-13.0), mortality and recurrence rates were 18.8% (n = 3) and 47.1% (n = 8), respectively. In univariate analysis, adjuvant radiotherapy and thoracic segment involvement were associated with lower rates of recurrence while male sex was associated with a higher rate of recurrence. CONCLUSIONS: Results showed variations in clinical outcomes for patients with high grade spinal meningiomas, especially the recurrence. Adjuvant radiotherapy and thoracic segment involvement was associated with lower rates of recurrence while recurrence ocurred at a higher rate in males.

Early and sustained improvements in motor function in rats after infusion of allogeneic umbilical cord-derived mesenchymal stem cells following spinal cord injury.

STUDY DESIGN: Animal study. OBJECTIVES: Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have recently been shown to hold great therapeutic potential for spinal cord injury (SCI). However, majority of the studies have been done using human cells transplanted into the rat with immunosuppression; this may not represent the outcomes that occur in humans. Herein, we present the therapeutic effect of using rat UC-MSCs (rUC-MSC) without immunosuppression in a rat model of SCI. SETTING: Mayo Clinic, Rochester, MN, USA. METHODS: Twelve female rats were randomly divided into two groups, control, and rUC-MSC group, and then subjected to a T9 moderate contusion SCI. Next, 2 × 106 rUC-MSCs or ringer-lactate solution were injected through the tail vein at 7 days post injury. Rats were assessed for 14 weeks by an open-field Basso, Beattie, and Bresnahan (BBB) motor score as well as postmortem quantification of axonal sparing/regeneration, cavity volume, and glial scar. RESULTS: Animals treated with rUC-MSCs were found to have early and sustained motor improvement (BBB score of 14.6 ± 1.9 compared to 10.1 ± 1.7 in the control group) at 14 weeks post injury (mean difference: 4.55, 95% CI: 2.04 to 7.06; p value < 0.001). Total cavity volume in the injury epicenter was significantly reduced in the rUC-MSC group; control: 33.0% ± 2.1, rUC-MSC: 25.3% ± 3.8 (mean difference: -7.7% (95% CI: -12.3 to -2.98); p value < 0.05). In addition, spinal cords from rats treated with rUC-MSCs were found to have a significantly greater number of myelinated axons, decreased astrogliosis, and reduced glial scar formation compared to control rats. CONCLUSIONS: Our study indicates that intravenous injection of allogenic UC-MSCs without immunosuppression exert beneficial effects in subacute SCI and thus could be a useful therapy to improve the functional capacity among patients with SCI.

The first 3-D volumetric analysis of mesencephalothalamic giant perivascular spaces showing steady and slow growth over 17 years.

BACKGROUND: Giant perivascular spaces (PVSs) are very rare condition in the brain and can be associated with neurological symptoms. It often enlarges and causes obstructive hydrocephalus which requires surgical intervention. However, the growth velocity has never been investigated. CASE DESCRIPTION: Here, we report a woman in her early eighties with giant PVSs eventually followed up 17 years. She presented with dizziness and mild headache for a week and her neurological examination showed no abnormality. Her brain magnetic resonance imaging (MRI) showed a multiple cystic lesion, 28 mm in maximum diameter as a whole, in the left mesencephalothalamic region. There were no solid part, rim enhancement, or perilesional intensity change suggesting edema or gliosis. Smaller PVSs were also seen in bilateral-hippocampi, basal ganglia, white matter, and left frontal operculum. Retrospectively, five MRI studies over 17 years were analyzed using a 3-D volumetric software and found a very slow growth of the lesion, from 6.54 ml to 9.83 ml indicating gain of 0.1752 ml (2.68%) per year. CONCLUSION: This is the first report verifying a gradual enlargement of giant PVSs in a natural course. The prospective 3-D volumetric analysis on PVSs may elucidate the true nature of these lesions.

Use of regenerative treatments in treatment of lumbar Degenerative Disc Disease: A systematic review.

Low back pain due to lumbar Degenerative Disc Disease (DDD) is one of the most common causes of disability and morbidity, particularly among older adults. Current research efforts in lumbar DDD management are shifting towards identifying and correcting the pathology in intervertebral discs without any external manipulation. Herein, we present a systematic review of current literature regarding regenerative treatments for lumbar DDD. An electronic search of databases including PubMed, Ovid/MEDLINE, Cochrane and Scopus was conducted for articles in all available years. Studies that investigated treatment for discogenic pain in lumbar DDD, including any type of stem cell or bone marrow concentrate as the treatment agent and studies that report both baseline and follow-up pain and Oswestry Disability Index (ODI) scores were included in the review. Changes in pain and ODI scores were calculated for 3-month, 6-month and 12-month periods. Six studies with a total of 93 patients were evaluated. Mean (SD) age of the pooled sample was 40.0(8.1) and 39.5% (32/81) of patients were female. Pain improvement was reported in 38.8% of patients at 3-month, 40.8% at 6-month and 44.1% at 12-month follow-up. Average improvement in ODI score for 3-month, 6-month and 12-month follow-ups was calculated to be 24.0, 26.5 and 25.7, respectively. Regenerative treatments are being increasingly employed across all spectrums of medicine. Review of six single arm studies revealed a potential positive impact in the preliminary results. However, these promising 'preliminary' results should not be interpreted as the definite treatment and should be validated with further prospective studies.

Precision of preoperative diagnosis in patients with brain tumor - A prospective study based on "top three list" of differential diagnosis for 1061 patients.

BACKGROUND: Accurate diagnosis of brain tumor is crucial for adequate surgical strategy. Our institution follows a comprehensive preoperative evaluation based on clinical and imaging information. METHODS: To assess the precision of preoperative diagnosis, we compared the "top three list" of differential diagnosis (the first, second, and third diagnoses according to the WHO 2007 classification including grading) of 1061 brain tumors, prospectively and consecutively registered in preoperative case conferences from 2010 to the end of 2017, with postoperative pathology reports. RESULTS: The correct diagnosis rate (sensitivity) of the first diagnosis was 75.8% in total. The sensitivity of the first diagnosis was high (84-94%) in hypothalamic-pituitary and extra-axial tumors, 67-75% in intra-axial tumors, and relatively low (29-42%) in intraventricular and pineal region tumors. Among major three intra-axial tumors, the sensitivity was highest in brain metastasis: 83.8% followed by malignant lymphoma: 81.4% and glioblastoma multiforme: 73.1%. Sensitivity was generally low (≦60%) in other gliomas. These sensitivities generally improved when the second and third diagnoses were included; 86.3% in total. Positive predictive value (PPV) was 76.9% in total. All the three preoperative diagnoses were incorrect in 3.4% (36/1061) of cases even when broader brain tumor classification was applied. CONCLUSION: Our institutional experience on precision of preoperative diagnosis appeared around 75% of sensitivity and PPV for brain tumor. Sensitivity improved by 10% when the second and third diagnoses were included. Neurosurgeons should be aware of these features of precision in preoperative differential diagnosis of a brain tumor for better surgical strategy and to adequately inform the patients.

Improved 3-year survival rates for glioblastoma multiforme are associated with trends in treatment: analysis of the national cancer database from 2004 to 2013.

PURPOSE: Glioblastoma multiforme (GBM) is a common and aggressive malignancy associated with poor prognosis. Characteristics and treatment of long-term survivors are of particular interest in efforts to improve outcomes. Therefore, the objective of this study was to examine trends and prognostic factors for 3-year survival from a national database. METHODS: The National Cancer Database (NCDB) was queried for patients diagnosed with cranial GBM from 2004 to 2013 and with 3-year follow-up. Trends in 3-year and overall survival, patient characteristics, tumor properties, and treatment modalities were examined. Multivariable logistic regression was utilized to investigate the association of these factors with 3-year survival. Predictor importance analysis was conducted using a metric defined as Wald χ2 penalized by degrees of freedom. RESULTS: A total of 88,919 GBM patients with 3-year follow-up were identified. Overall, 8757 (9.8%) patients survived ≥ 3 years. Three-year survival significantly improved from 8.0 to 10.5% (p < 0.001) from 2004 to 2013. Trimodal treatment administration also significantly increased from 38.7 to 55.9% (p < 0.001). During this span, patients increasingly presented as older (p = 0.040), without private insurance (p < 0.001), and with a higher comorbidity index (p < 0.001). On multivariable regression, factors such as trimodal treatment (p < 0.001), younger age (p < 0.001), and MGMT methylation (p < 0.001) were significantly associated with increased odds of 3-year survival. Predictor importance analysis indicated that MGMT methylation, age, and treatment modality were the most significant relative determinants of 3-year survival. CONCLUSION: These findings illustrate an improved 3-year survival rate for GBM patients from 2004 to 2013 with a concurrent increase in trimodal treatment administration despite more adverse patient presenting characteristics.

Lumbar intervertebral disc mRNA sequencing identifies the regulatory pathway in patients with disc herniation and spondylolisthesis.

Lumbar degenerative disc disease (DDD) is a multifaceted progressive condition and often accompanied by disc herniation (DH) and/or degenerative spondylolisthesis (DS). Given the high prevalence of the disease (up to 20% according to some estimates) and the high costs associated with its care, there is a need to explore novel therapies such as regenerative medicine. Exploring these novel therapies first warrants investigation of molecular pathways underlying these disorders. Here, we show results from next generation RNA sequencing (RNA-seq) on mRNA isolated from 10 human nucleus pulposus (NP) samples of lumbar degenerated discs (DH and DS; n = 5 for each tissue) and other musculoskeletal tissues (Bone, cartilage, growth plate, and muscle; n = 7 for each tissue). Pathway and network analyses based on gene ontology (GO) terms were used to identify the biological functions of differentially expressed mRNAs. A total of 701 genes were found to be significantly upregulated in lumbar NP tissue compared to other musculoskeletal tissues. These differentially expressed mRNAs were primarily involved in DNA damage, immunity and G1/S transition of mitotic cell cycle. Interestingly, DH-specific signaling genes showed major network in chemotactic (e.g., CXCL10, CXCL11, IL1RL2 and IL6) and matrix-degrading pathway (e.g., MMP16, ADAMTSL1, 5, 8, 12, and 15), while DS-specific signaling genes were found to be those involved in cell adhesion (e.g., CDH1, EPHA1 and EFNA2) and inflammatory cytokines (e.g., CD19, CXCL5, CCL24, 25 and XCL2). Our findings provide new leads for therapeutic drug discovery that would permit optimization of medical or pharmacological intervention for cases of lumbar DDD.

CELLTOP Clinical Trial: First Report From a Phase 1 Trial of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells in the Treatment of Paralysis Due to Traumatic Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating condition with limited pharmacological treatment options to restore function. Regenerative approaches have recently attracted interest as an adjuvant to current standard of care. Adipose tissue-derived (AD) mesenchymal stem cells (MSCs) represent a readily accessible cell source with high proliferative capacity. The CELLTOP study, an ongoing multidisciplinary phase 1 clinical trial conducted at Mayo Clinic (ClinicalTrials.gov Identifier: NCT03308565), is investigating the safety and efficacy of intrathecal autologous AD-MSCs in patients with blunt, traumatic SCI. In this initial report, we describe the outcome of the first treated patient, a 53-year-old survivor of a surfing accident who sustained a high cervical American Spinal Injury Association Impairment Scale grade A SCI with subsequent neurologic improvement that plateaued within 6 months following injury. Although he improved to an American Spinal Injury Association grade C impairement classification, the individual continued to be wheelchair bound and severely debilitated. After study enrollment, an adipose tissue biopsy was performed and MSCs were isolated, expanded, and cryopreserved. Per protocol, the patient received an intrathecal injection of 100 million autologous AD-MSCs infused after a standard lumbar puncture at the L3-4 level 11 months after the injury. The patient tolerated the procedure well and did not experience any severe adverse events. Clinical signs of efficacy were observed at 3, 6, 12, and 18 months following the injection in both motor and sensory scores based on International Standards for Neurological Classification of Spinal Cord Injury. Thus, in this treated individual with SCI, intrathecal administration of AD-MSCs was feasible and safe and suggested meaningful signs of improved, rather than stabilized, neurologic status warranting further clinical evaluation.