Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy.

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.

ApoA-I binding protein (AIBP) regulates transient receptor potential vanilloid 1 (TRPV1) activity in rat dorsal root ganglion neurons by selective disruption of toll-like receptor 4 (TLR4)-lipid rafts.

Toll-like receptor 4 (TLR4) and the transient receptor potential vanilloid subtype 1 (TRPV1) are both upregulated and play key roles in the induction and expression of paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Using Apolipoprotein A-I binding protein, non-specific cholesterol depletion, TLR4 mis-sense rats and a TLR4 inhibitor, we demonstrate that co-localization of TRPV1 with TLR4 to cholesterol-rich lipid membrane rafts in nociceptors is essential for its normal activation as well as for its exaggerated activation that underlies the development and expression of CIPN. The findings suggest that TLR4-lipid rafts may have an essential role in numerous neuroinflammatory and neuropathic pain conditions. This mechanism is also generalized to female rats for the first time.

Spinal laser interstitial thermal therapy and radiotherapy for thoracic metastatic epidural spinal cord compression.

PURPOSE: Spinal laser interstitial thermal therapy (sLITT) is a less invasive alternative to surgery for metastatic epidural spinal cord compression. Here, we analyze outcomes of patients treated with sLITT either in conjunction with radiotherapy or as a standalone salvage therapy. METHODS: We included patients with thoracic vertebral metastatic cord compression treated with sLITT. Outcomes included freedom from local failure (FFLF) and overall survival (OS). Factors associated with FFLF were identified with univariable and multivariable analyses via a Cox proportional hazards model. RESULTS: Between 2013-2022, 129 patients received sLITT to 144 vertebral segments; 69% were radiotherapy naïve, 81% were radioresistant histologies, and 74% were centered in the vertebral body. Median age was 61 years. Pre-sLITT Bilsky score was 3 in 28%, 2 in 33%, and 1c in 37%. Radiotherapy was delivered in conjunction with sLITT for 80% of cases, including 68% that received stereotactic radiotherapy, at a median of 5 days after sLITT. Median follow-up was 9.1 months. One-year FFLF and OS was 80% and 78%, respectively. On multivariable analysis, variables independently associated with adverse FFLF included paraspinal/foraminal disease location (p = 0.001), and post-sLITT imaging Bilsky score of 2 (p = 0.073) or 3 (p = 0.011). Prior radiotherapy, technique of radiotherapy, and time between radiotherapy and sLITT were not associated with FFLF. CONCLUSION: sLITT with radiotherapy is an effective minimally invasive treatment approach for thoracic metastatic epidural spinal cord compression. Early treatment response may serve as a prognostic imaging biomarker.

RNA profiling of human dorsal root ganglia reveals sex differences in mechanisms promoting neuropathic pain.

Neuropathic pain is a leading cause of high-impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the dorsal root ganglia is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human dorsal root ganglia from these patients, allowing comprehensive identification of molecular changes in these samples by contrasting them with non-pain-associated dorsal root ganglia. We sequenced 70 human dorsal root ganglia, and among these 50 met inclusion criteria for sufficient neuronal mRNA signal for downstream analysis. Our expression analysis revealed profound sex differences in differentially expressed genes including increase of IL1B, TNF, CXCL14 and OSM in male and CCL1, CCL21, PENK and TLR3 in female dorsal root ganglia associated with neuropathic pain. Coexpression modules revealed enrichment in members of JUN-FOS signalling in males and centromere protein coding genes in females. Neuro-immune signalling pathways revealed distinct cytokine signalling pathways associated with neuropathic pain in males (OSM, LIF, SOCS1) and females (CCL1, CCL19, CCL21). We validated cellular expression profiles of a subset of these findings using RNAscope in situ hybridization. Our findings give direct support for sex differences in underlying mechanisms of neuropathic pain in patient populations.

Nociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain.

Nociceptors, sensory neurons in the DRG that detect damaging or potentially damaging stimuli, are key drivers of neuropathic pain. Injury to these neurons causes activation of translation regulation signaling, including the mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase interacting kinase (MNK) eukaryotic initiation factor (eIF) 4E pathways. This is a mechanism driving changes in excitability of nociceptors that is critical for the generation of chronic pain states; however, the mRNAs that are translated to lead to this plasticity have not been elucidated. To address this gap in knowledge, we used translating ribosome affinity purification in male and female mice to comprehensively characterize mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain (CIPN) caused by paclitaxel treatment. This unbiased method creates a new resource for the field, confirms many findings in the CIPN literature and also find extensive evidence for new target mechanisms that may cause CIPN. We provide evidence that an underlying mechanism of CIPN is sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling. This demonstrates a novel translation regulation signaling circuit wherein MNK1-eIF4E activity drives mTORC1 via control of RagA translation. CIPN and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We identify a novel translational circuit for the genesis of neuropathic pain caused by chemotherapy with important implications for therapeutics.SIGNIFICANCE STATEMENT Neuropathic pain affects up to 10% of the population, but its underlying mechanisms are incompletely understood, leading to poor treatment outcomes. We used translating ribosome affinity purification technology to create a comprehensive translational profile of DRG nociceptors in naive mice and at the peak of neuropathic pain induced by paclitaxel treatment. We reveal new insight into how mechanistic target of rapamycin complex 1 is activated in neuropathic pain pointing to a key role of MNK1-eIF4E-mediated translation of a complex of mRNAs that control mechanistic target of rapamycin complex 1 signaling at the surface of the lysosome. We validate this finding using genetic and pharmacological techniques. Our work strongly suggests that MNK1-eIF4E signaling drives CIPN and that a drug in human clinical trials, eFT508, may be a new therapeutic for neuropathic pain.

Electrophysiological and transcriptomic correlates of neuropathic pain in human dorsal root ganglion neurons.

Neuropathic pain encompasses a diverse array of clinical entities affecting 7-10% of the population, which is challenging to adequately treat. Several promising therapeutics derived from molecular discoveries in animal models of neuropathic pain have failed to translate following unsuccessful clinical trials suggesting the possibility of important cellular-level and molecular differences between animals and humans. Establishing the extent of potential differences between laboratory animals and humans, through direct study of human tissues and/or cells, is likely important in facilitating translation of preclinical discoveries to meaningful treatments. Patch-clamp electrophysiology and RNA-sequencing was performed on dorsal root ganglia taken from patients with variable presence of radicular/neuropathic pain. Findings establish that spontaneous action potential generation in dorsal root ganglion neurons is associated with radicular/neuropathic pain and radiographic nerve root compression. Transcriptome analysis suggests presence of sex-specific differences and reveals gene modules and signalling pathways in immune response and neuronal plasticity related to radicular/neuropathic pain that may suggest therapeutic avenues and that has the potential to predict neuropathic pain in future cohorts.

DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage-gated sodium channel 1.7 (Nav1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Nav1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Nav1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP), and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch-clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II (a selective Nav1.7 channel blocker)-sensitive sodium currents. Bath-applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN, while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain also showed electrophysiological and immunofluorescence results indicating an increased expression of Nav1.7 associated with spontaneous activity. Nav1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Nav1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain.SIGNIFICANCE STATEMENT This work demonstrates that the expression and function of the voltage-gated sodium channel Nav1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of-function mutations in human Nav1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Nav1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact, indicating an important novel therapeutic avenue for neuropathic pain as a class.

Pediatric thoracic outlet syndrome: a systematic review and meta-analysis.

OBJECTIVE: Thoracic outlet syndrome (TOS) is a complex disorder affecting the neurovascular structures of the upper extremity as they traverse from the neck and thorax to the upper extremity. This systematic review and meta-analysis focuses on pediatric TOS, offering insights into its clinical presentation, etiology, treatment modalities, and outcomes in contrast to those reported in adult TOS. METHODS: A comprehensive search for pediatric TOS in the PubMed database using PRISMA guidelines identified 6 relevant studies published between 2008 and 2022. In total, 227 pediatric TOS cases in 216 patients were analyzed. Data categories explored for TOS in pediatric patients included study design, number of patients included, mean age and sex of patients, TOS type, laterality, bony abnormalities, time to surgery, symptoms, treatment modalities, initial surgical technique, surgical complications, percent lost to follow-up, mean follow-up period, and treatment outcome. RESULTS: The results from the 6 studies of 216 patients show a distinct pattern in pediatric TOS, with a 1.84:1 female-to-male ratio, a mean age of 15.49 years, and a lower prevalence of neurogenic TOS (75%, 95% CI 0.41-0.93; I2 = 86%, p < 0.01) compared with the prevailing literature on adults (87.5%-99%). Venous and arterial TOS accounted for a higher proportion of cases in pediatric patients than in adults, challenging the traditional adult-oriented perspective. Right-sided presentations were more common, reflecting right-arm dominance in most individuals. Additionally, bony abnormalities were more common in adults (30%) than in children (10.65%). Treatments involved mixed methods, predominantly using combinations of muscle resection (95.26%), neurolysis (78.02%), and bone resection (72.41%). Patients had high rates of symptom improvement (89%, 95% CI 0.67-0.97; I2 = 85%, p < 0.01) following surgery, with improvement of symptoms ranging from slight to complete relief. Complications were infrequent (5.66%), and most patients reported positive outcomes. The limitations of this analysis include subjective diagnostic and reporting criteria for TOS given its broad range of presentations. CONCLUSIONS: This systematic review and meta-analysis brings to light the distinctive characteristics of pediatric TOS and underscores the importance of recognizing these differences to ensure accurate diagnosis and effective treatment in this patient population. Further research is needed to understand the predictive value of conservative treatments, especially in pediatric TOS cases.

Surgical decompression in spinal Paget's disease: illustrative case.

BACKGROUND: Paget's disease of bone (PDB) is a common bone metabolic pathology in older adults, characterized by mixed osteolytic, osteoblastic, and quiescent periods. Surgical guidelines for PDB involving the spine are not well-defined and are reserved for cases refractory to medical treatments, typically bisphosphonates like zoledronic acid. This case study describes a 52-year-old male with PDB who presented with rapidly progressing myelopathy symptoms refractory to standard medical treatment, warranting surgical decompression. OBSERVATIONS: Surgical decompression and fusion, involving laminectomy with partial facetectomies, placement of pedicle screw instrumentation, and posterolateral arthrodesis spanning beyond the pathological segment, was performed. Follow-up visits indicated progressive improvement in symptoms and mobility, and imaging showed stable postsurgical changes with increased sclerosis in the affected vertebrae on a 2-year postsurgical course. LESSONS: This case underscores that PDB of the spine can transition from asymptomatic to significant impairment and demonstrates that surgical intervention can provide effective symptomatic relief in myelopathy secondary to PDB. The case contributes to the growing evidence of the effectiveness of surgical decompression in PDB involving the spine. https://thejns.org/doi/10.3171/CASE24203.

Chronic shoulder pain due to spinal accessory nerve palsies present opportunities for improved care integration.

Aim: Chronic shoulder pain due to iatrogenic spinal accessory nerve (SAN) injury continues to be under-recognized, resulting in delayed time-to-diagnosis and poorer outcomes. Solutions are needed to improve the management of this condition, which can be challenging as care needs to be coordinated across pain management, neurophysiology, rehabilitation and reconstructive surgery.Cases: We present a series of six patients with shoulder pain refractory to conservative pain treatments to highlight how SAN injuries continued to be missed and treatment delayed, even at advanced care centers. The time to diagnosis of SAN palsy took an average of 21 months and treatment was inconsistent for all patients.Discussion: None of the six cases had initial suspicion of SAN palsy and only one patient received targeted SAN injury care. SAN treatment should be started as early as possible so that patients can be referred for prompt surgical evaluation if they fail conservative management. Integrated care pathways may be a solution for formalizing multidisciplinary team involvement and improving SAN injury outcomes.Conclusion: Systemic processes, such as integrated care pathways, are needed to optimize early recognition and targeted treatment of SAN injury and may be beneficial for other underdiagnosed and undertreated neuropathic pain conditions.

Neck dissection surgeries, which are done to treat various head and neck cancers, can often lead to shoulder pain. This pain commonly involves damage to a nerve called the spinal accessory nerve (SAN). Even though this nerve injury has been well-described by experts, many patients continue to experience delays in getting a correct diagnosis and treatment for this pain.This study describes six cases from a large cancer center where patients developed chronic shoulder pain after neck dissection. These patients waited an average of 21 months to reach a correct diagnosis of SAN injury. The pain and symptoms were often mistaken for other conditions. In one case, a patient received delayed treatment from a coordinated team of medical specialists, leading to improvements in her pain and shoulder function.The delay in diagnosing SAN injuries is likely due to two main challenges: a lack of awareness among providers and a tendency for healthcare to focus on specific areas rather than a team-based approach. Early diagnosis is crucial to prevent and minimize long-term pain and muscle loss.To improve patient care, this study suggests using an integrated care pathway approach and gives an example of how providers can adopt this approach. This method involves coordinating various medical specialists to ensure prompt diagnosis and treatment. By improving how SAN injuries are managed, patients can receive better care and avoid chronic pain and disability.

Hybrid open-endovascular onyx embolization of spinal type IVb perimedullary spinal arteriovenous fistula through direct posterior spinal vein access: A case report.

Background: Spinal arteriovenous fistulas (SAVFs) are direct communication between arteries and veins without intervening abnormal vessel nidus, which often results in venous congestion and spinal cord dysfunction. Ventrally located SAVF can be challenging to treat through traditional open or endovascular approaches. Case Description: We describe a hybrid (open/endovascular) procedure in a 72-year-old male with a Takai Type IVb SAVF presenting with paraparesis and sphincter dysfunction. Imaging revealed a conus medullaris SAVF in which the main fistulous connection was located ventrally. The conventional endovascular approach was deemed risky, and open surgery failed in the first attempt. The SAVF was resolved using a hybrid approach: under direct visualization, an engorged dorsal vein was punctured with an Angiocath, and a fluoroscopy-guided microcatheter was advanced through it to reach and embolize the ventral perimedullary fistulous connection. After surgery, his progressive neurological decline stabilized, radiographic spinal cord edema improved, and follow-up angiography confirmed obliteration of the fistula. Neurological function remained at the preoperative baseline. Conclusion: This approach may be a treatment for selected cases of type IVb SAVF. Easily accessible feeding vessels are coagulated and cut; the inaccessible ones can be embolized endovascularly during the same procedure.

Quantification of MRI Artifacts in Carbon Fiber Reinforced Polyetheretherketone Thoracolumbar Pedicle Screw Constructs prior to Spinal Stereotactic Radiosurgery.

PURPOSE: Carbon fiber reinforced polyetheretherketone (CFRP) is a nonmetallic material that is a subject of growing interest in the field of spinal instrumentation manufacturing. The radiolucency and low magnetic susceptibility of CFRP has potential to create less interference with diagnostic imaging compared with titanium implants. However, an objective comparison of the image artifact produced by titanium and CFRP implants has not been described. Spinal oncology, particularly after resection of spinal tumors and at the time of spinal stereotactic radiosurgery planning, relies heavily on imaging interpretation for evaluating resection, adjuvant treatment planning, and surveillance. We present a study comparing measurements of postoperative magnetic resonance imaging artifacts between titanium and CFRP pedicle screw constructs in the setting of separation surgery for metastatic disease. METHODS AND MATERIALS: The diameter of the signal drop around the screws (pedicle screw artifact) and the diameter of the spinal canal free from artifacts (canal visualization) were measured in consecutive patients who had spinal instrumentation followed by spinal stereotactic radiosurgery in the June 2019 to May 2022 timeframe. The spinal cord presented a shift at the screw level in sagittal images which was also measured (Sagittal Distortion, SagD). RESULTS: Fifty patients, corresponding to 356 screws and 183 vertebral levels, were evaluated overall. CFRP produced less artifacts in all the 3 parameters compared with titanium: mean pedicle screw artifact (CFRP = 5.8 mm, Ti = 13.2 mm), canal visualization (CFRP = 19.2 mm, Ti = 15.5 mm), and SagD (CFRP = .5 mm, Ti = 1.9 mm), all P < .001. In practice, these findings translate into better-quality magnetic resonance imaging. CONCLUSIONS: The initial perceived advantages are easier evaluation of postoperative imaging, facilitating radiation treatment planning, recurrence detection, and avoidance in repeating a suboptimal computed tomography myelogram. Further clinical studies analyzing long-term outcomes of patients treated with CFRP implants are necessary.

Utility of 3D-Printed Models in the Surgical Planning for Primary Spine Tumors: A Survey of International Spinal Oncology Experts.

STUDY DESIGN: Survey study. OBJECTIVES: The purpose of this study was to characterize the utility of 3D printed patient specific anatomic models for the planning of complex primary spine tumor surgeries. METHODS: A survey of individual members of an international study group of spinal oncology surgeons was performed. Participants were provided a clinical vignette, pathologic diagnosis, and pre-operative imaging for three primary spinal oncology cases. Study participants provided a free text surgical plan for resection and were then presented an associated 3D printed model for each case and asked to re-evaluate their surgical plan. RESULTS: Ten spinal oncology surgeons participated in the study, representing nine institutions across five countries. Four of the surgeons (40%) made significant changes to their surgical plan after reviewing the 3D models, including sacrifice of an additional nerve root to obtain negative margins, sparing an SI joint that was originally planned for inclusion in the en bloc resection, adjusting the location of osteotomy cuts, changes to the number of surgical stages and/or staging order, and preservation of neurology that was originally planned for sacrifice. The overall impression of the 3D models was positive, with 90% of the participants stating they found the 3D model useful in developing a surgical plan. CONCLUSIONS: Surgical planning for resection of primary spinal column tumors is challenging and time intensive. 3D printed patient specific surgical models may be an additional tool that can augment surgical planning and execution by improving the chance of accomplishing surgical resection goals and minimizing morbidity.

Definitive single fraction spine stereotactic radiosurgery for metastatic sarcoma: Simultaneous integrated boost is associated with high tumor control and low vertebral fracture risk.

INTRODUCTION: Sarcoma spinal metastases (SSM) are particularly difficult to manage given their poor response rates to chemotherapy and inherent radioresistance. We evaluated outcomes in a cohort of patients with SSM uniformly treated using single-fraction simultaneous-integrated-boost (SIB) spine stereotactic radiosurgery (SSRS). MATERIALS AND METHODS: A retrospective review was conducted at a single tertiary institution treated with SSRS for SSM between April 2007-April 2023. 16-24 Gy was delivered to the GTV and 16 Gy uniformly to the CTV. Kaplan-Meier analysis was conducted to assess time to progression of disease (PD) with proportionate hazards modelling used to determine hazard ratios (HR) and respective 95 % confidence intervals (CI). RESULTS: 70 patients with 100 lesions underwent SSRS for SSM. Median follow-up was 19.3 months (IQR 7.7-27.8). Median age was 55 years (IQR42-63). Median GTV and CTVs were 14.5 cm3 (IQR 5-32) and 52.7 cm3 (IQR 29.5-87.5) respectively. Median GTV prescription dose and biologically equivalent dose (BED) [α/ß = 10] was 24 Gy and 81.6 Gy respectively. 85 lesions received 24 Gy to the GTV. 27 % of patients had Bilsky 1b or greater disease. 16 of 100 lesions recurred representing a crude local failure rate of 16 % with a median time to failure of 10.4 months (IQR 5.7-18) in cases which failed locally. 1-year actuarial local control (LC) was 89 %. Median overall survival (OS) was 15.3 months (IQR 7.7-25) from SSRS. Every 1 Gy increase in GTV absolute minimum dose (DMin) across the range (5.8-25 Gy) was associated with a reduced risk of local failure (HR = 0.871 [95 % CI 0.782-0.97], p = 0.009). 9 % of patients developed vertebral compression fractures at a median of 13 months post SSRS (IQR 7-25). CONCLUSION: This study represents one of the most homogenously treated and the largest cohorts of patients with SSM treated with single-fraction SSRS. Despite inherent radioresistance, SSRS confers durable and high rates of local control in SSM without unexpected long-term toxicity rates.

Outcomes and Pattern of Care for Spinal Myxopapillary Ependymoma in the Modern Era-A Population-Based Observational Study.

(1) Background: Myxopapillary ependymoma (MPE) is a rare tumor of the spine, typically slow-growing and low-grade. Optimal management strategies remain unclear due to limited evidence given the low incidence of the disease. (2) Methods: We analyzed data from 1197 patients with spinal MPE from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2020). Patient demographics, treatment modalities, and survival outcomes were examined using statistical analyses. (3) Results: Most patients were White (89.9%) with a median age at diagnosis of 42 years. Surgical resection was performed in 95% of cases. The estimated 10-year overall survival was 91.4%. Younger age (hazard ratio (HR) = 1.09, p < 0.001) and receipt of surgery (HR = 0.43, p = 0.007) were associated with improved survival. Surprisingly, male sex was associated with worse survival (HR = 1.86, p = 0.008) and a younger age at diagnosis compared to females. (4) Conclusions: This study, the largest of its kind, underscores the importance of surgical resection in managing spinal MPE. The unexpected association between male sex and worse survival warrants further investigation into potential sex-specific pathophysiological factors influencing prognosis. Despite limitations, our findings contribute valuable insights for guiding clinical management strategies for spinal MPE.

Ulnar fascicle to brachialis branch of musculocutaneous nerve for restoration of elbow flexion associated with spinal cord tumor and radiation-induced lower motor neuron disease.

Transfer of the ulnar fascicle to the biceps branch of the musculocutaneous nerve, or Oberlin transfer, has been widely used for the treatment of elbow flexion weakness in the setting of upper trunk brachial plexus palsy. The authors present a modified application of this technique for restoration of functional elbow flexion in a 30-year-old woman with a history of recurrent upper cervical spinal cord pilocytic astrocytoma, complex spinal deformity, and radiation-induced lower motor neuron disease. The video can be found here: https://stream.cadmore.media/r10.3171/2022.10.FOCVID2299.

MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain.

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in preclinical models and in patients suffering from this largely untreated disease. While many intracellular signaling mechanisms have been examined in preclinical models that drive this spontaneous activity (SA), none of these have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we show that inhibition of mitogen activated protein kinase interacting kinase (MNK) with eFT508 (25 nM) reverses SA in human sensory neurons associated with painful dermatomes. MNK inhibition in spontaneously active nociceptors decreased action potential amplitude and produced alterations in the magnitude of afterhyperpolarizing currents suggesting modification of Na+ and K+ channel activity downstream of MNK inhibition. The effects of MNK inhibition on SA took minutes to emerge and were reversible over time with eFT508 washout. MNK inhibition with eFT508 led to a profound loss of eIF4E Serine 209 phosphorylation, a specific target of the kinase, within 2 min of drug treatment, consistent with the rapid action of the drug on SA in electrophysiology experiments. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.

Advances in the management of spinal metastases: what the radiologist needs to know.

Spine is the most frequently involved site of osseous metastases. With improved disease-specific survival in patients with Stage IV cancer, durability of local disease control has become an important goal for treatment of spinal metastases. Herein, we review the multidisciplinary management of spine metastases, including conventional external beam radiation therapy, spine stereotactic radiosurgery, and minimally invasive and open surgical treatment options. We also present a simplified framework for management of spinal metastases used at The University of Texas MD Anderson Cancer Center, focusing on the important decision points where the radiologist can contribute.

Risk factors for sacral fracture following en bloc chordoma resection.

OBJECTIVE: The purpose of this study was to analyze risk factors for sacral fracture following noninstrumented partial sacral amputation for en bloc chordoma resection. METHODS: A multicenter retrospective chart review identified patients who underwent noninstrumented partial sacral amputation for en bloc chordoma resection with pre- and postoperative imaging. Hounsfield units (HU) were measured in the S1 level. Sacral amputation level nomenclature was based on the highest sacral level with bone removed (e.g., S1 foramen amputation at the S1-2 vestigial disc is an S2 sacral amputation). Variables collected included basic demographics, patient comorbidities, surgical approach, preoperative radiographic details, neoadjuvant and adjuvant radiation therapy, and postoperative sacral fracture data. RESULTS: A total of 101 patients (60 men, 41 women) were included; they had an average age of 69 years, BMI of 29 kg/m2, and follow-up of 60 months. The sacral amputation level was S1 (2%), S2 (37%), S3 (44%), S4 (9%), and S5 (9%). Patients had a posterior-only approach (77%) or a combined anterior-posterior approach (23%), with 10 patients (10%) having partial sacroiliac (SI) joint resection. Twenty-seven patients (27%) suffered a postoperative sacral fracture, all occurring between 1 and 7 months after the index surgery. Multivariable logistic regression analysis demonstrated S1 or S2 sacral amputation level (p = 0.001), combined anterior-posterior approach (p = 0.0064), and low superior S1 HU (p = 0.027) to be independent predictors of sacral fracture. The fracture rate for patients with superior S1 HU < 225, 225-300, and > 300 was 38%, 15%, and 9%, respectively. An optimal superior S1 HU cutoff of 300 was found to maximize sensitivity (89%) and specificity (42%) in predicting postamputation sacral fracture. In addition, the fracture rate for patients who underwent partial SI joint resection was 100%. CONCLUSIONS: Patients with S1 or S2 partial sacral amputations, a combined anterior-posterior surgical approach, low superior S1 HU, and partial SI joint resection are at higher risk for postoperative sacral fracture following en bloc chordoma resection and should be considered for spinopelvic instrumentation at the index procedure.

Syrinx regression after correction of iatrogenic kyphotic deformity: illustrative case.

BACKGROUND: Syringomyelia has a long-established association with pediatric scoliosis, but few data exist on the relationship of syringomyelia to pediatric kyphotic deformities. OBSERVATIONS: This report reviewed a unique case of rapid and sustained regression of syringomyelia in a 13-year-old girl after surgical correction of iatrogenic kyphotic deformity. LESSONS: In cases of syringomyelia associated with acquired spinal deformity, treatment of deformity to resolve an associated subarachnoid block should be considered because it may obviate the need for direct treatment of syrinx.