Management of chordoma and chondrosarcoma with definitive dose-escalated single-fraction spine stereotactic radiosurgery.

PURPOSE: The management of chordoma or chondrosarcoma involving the spine is often challenging due to adjacent critical structures and tumor radioresistance. Spine stereotactic radiosurgery (SSRS) has radiobiologic advantages compared with conventional radiotherapy, though there is limited evidence on SSRS in this population. We sought to characterize the long-term local control (LC) of patients treated with SSRS. METHODS: We retrospectively reviewed patients with chordoma or chondrosarcoma treated with dose-escalated SSRS, defined as 24 Gy in 1 fraction to the gross tumor volume. Overall survival (OS) was calculated by Kaplan-Meier functions. Competing risk analysis using the cause-specific hazard function estimated LC time. RESULTS: Fifteen patients, including 12 with chordoma and 3 with chondrosarcoma, with 22 lesions were included. SSRS intent was definitive, single-modality in 95% of cases (N = 21) and post-operative in 1 case (5%). After a median censored follow-up time of 5 years (IQR 4 to 8 years), median LC time was not reached (IQR 8 years to not reached), with LC rates of 100%, 100%, and 90% at 1 year, 2 years, and 5 years. The median OS was 8 years (IQR 3 years to not reached). Late grade 3 toxicity occurred after 23% of treatments (N = 5, fracture), all of which were managed successfully with stabilization. CONCLUSION: Definitive dose-escalated SSRS to 24 Gy in 1 fraction appears to be a safe and effective treatment for achieving durable local control in chordoma or chondrosarcoma involving the spine, and may hold particular importance as a low-morbidity alternative to surgery in selected cases.

Systemic considerations for the surgical treatment of spinal metastatic disease: a scoping literature review.

Systemic assessment is a pillar in the neurological, oncological, mechanical, and systemic (NOMS) decision-making framework for the treatment of patients with spinal metastatic disease. Despite this importance, emerging evidence relating systemic considerations to clinical outcomes following surgery for spinal metastatic disease has not been comprehensively summarised. We aimed to conduct a scoping literature review of this broad topic. We searched MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, and CINAHL databases from Jan 1, 2000, to July 31, 2021. 61 articles were included, accounting for a total of 22 335 patients. Preoperative systemic variables negatively associated with postoperative clinical outcomes included demographics (eg, older age [>60 years], Black race, male sex, low or elevated body-mass index, and smoking status), medical comorbidities (eg, cardiac, pulmonary, hepatic, renal, endocrine, vascular, and rheumatological), biochemical abnormalities (eg, hypoalbuminaemia, atypical blood cell counts, and elevated C-reactive protein concentration), low muscle mass, generalised motor weakness (American Spinal Cord Injury Association Impairment Scale grade and Frankel grade) and poor ambulation, reduced performance status, and systemic disease burden. This is the first comprehensive scoping review to broadly summarise emerging evidence relevant to the systemic assessment component of the widely used NOMS framework for spinal metastatic disease decision making. Medical, surgical, and radiation oncologists can consider these findings when prognosticating spinal metastatic disease-related surgical outcomes on the basis of patients' systemic condition. These factors might inform a shared decision-making approach with patients and their families.

Single-center outcomes for percutaneous pedicle screw fixation in metastatic spinal lesions: can spontaneous facet fusion occur?

OBJECTIVE: Survival of cancer patients continues to improve with systemic treatment advancements, leading to an increase in cancer-related complications such as pathological spinal fractures. In this study, the authors aimed to evaluate the outcome of percutaneous stabilization with cement augmentation of the pedicle screws in the management of patients with metastatic cancer to the spine. METHODS: The authors reviewed a retrospective case series of 74 patients with symptomatic pathological spine fractures treated with cement-augmented pedicle screws implanted with a percutaneous technique. The mean imaging follow-up was 11.3 months. Data on demographics, clinical outcomes, and complications were collected. Cement extravasation, spinal hardware integrity, and fusion rates were assessed on CT scans. RESULTS: Among 50 patients with follow-up imaging, 23 patients (46%) showed facet joint fusion. The length of segmental stabilization was not a significant predictor of the occurrence of fusion. Pre- or postoperative radiation therapy, postoperative chemotherapy, and the location of spinal lesions did not have a statistically significant effect on the occurrence of fusion. Patients older than 60 years of age were more likely to have fusion across facet joints compared with younger patients. There was a significant difference in the mean visual analog scale pain score, with 6.28 preoperatively and 3.41 postoperatively, regardless of fusion status (p < 0.001). Cement extravasation was seen in 51% of the cohort, but in all instances, patients remained asymptomatic. Most importantly, the incidence of hardware failure was low (4%). CONCLUSIONS: Percutaneous fixation with cement-augmented pedicle screws in patients with pathological spine fractures provides an improvement in mechanical back pain, with a low incidence of failure, and in some patients, spontaneous facet fusion was observed. Further research is necessary with regard to both short-term benefits and long-term outcomes.

Feasibility of achieving planned surgical margins in primary spine tumor: a PTRON study.

OBJECTIVE: Oncological resection of primary spine tumors is associated with lower recurrence rates. However, even in the most experienced hands, the execution of a meticulously drafted plan sometimes fails. The objectives of this study were to determine how successful surgical teams are at achieving planned surgical margins and how successful surgeons are in intraoperatively assessing tumor margins. The secondary objective was to identify factors associated with successful execution of planned resection. METHODS: The Primary Tumor Research and Outcomes Network (PTRON) is a multicenter international prospective registry for the management of primary tumors of the spine. Using this registry, the authors compared 1) the planned surgical margin and 2) the intraoperative assessment of the margin by the surgeon with the postoperative assessment of the margin by the pathologist. Univariate analysis was used to assess whether factors such as histology, size, location, previous radiotherapy, and revision surgery were associated with successful execution of the planned margins. RESULTS: Three hundred patients were included. The surgical plan was successfully achieved in 224 (74.7%) patients. The surgeon correctly assessed the intraoperative margins, as reported in the final assessment by the pathologist, in 239 (79.7%) patients. On univariate analysis, no factor had a statistically significant influence on successful achievement of planned margins. CONCLUSIONS: In high-volume cancer centers around the world, planned surgical margins can be achieved in approximately 75% of cases. The morbidity of the proposed intervention must be balanced with the expected success rate in order to optimize patient management and surgical decision-making.

Free Vascularized Fibula Flap Reconstruction of Total and Near-total Destabilizing Resections of the Sacrum.

BACKGROUND: Vascularized bone grafts (VBGs) are associated with improved union and fewer instrumentation complications in the mobile spine. It is not known if VBGs are similarly efficacious after sacrectomy. METHODS: We conducted a retrospective chart review of all patients who underwent total sacrectomy and immediate reconstruction with VBG between 2005 and 2019. Patient and surgical characteristics in addition to union and functional outcomes were analyzed. RESULTS: We identified 10 patients (6 women and 4 men) with a mean age of 42 years (range, 12-71 years). All patients received iliolumbar instrumentation as well as a free fibula flap as a VBG. There were no complications at the fibula flap donor site or specifically related to the VBG. Bony union was achieved in 7 (88%) of 8 patients with an average union time of 6.3 months (range, 2-10 months). Surgical complications occurred in 5 patients, 4 patients required reoperation for wound dehiscence, and 1 patient required conversion to a 4-rod construct and bone grafting for instrumentation loosening and partial nonunion. Instrumentation failure developed in 1 patient, but no surgical intervention was required. One patient was able to walk independently without any limitation, 5 patients required a walker, 2 were wheelchair-bound except for short (<15 ft) distances, and 2 were lost to follow-up. CONCLUSIONS: The free vascularized fibula flap is a safe and effective option for supplementing spinal reconstruction after destabilizing sacrectomy.

Spine stereotactic radiosurgery for metastases from hepatobiliary malignancies: patient selection using PRISM scoring.

OBJECTIVE: Dose escalation via stereotactic radiation therapy techniques has been necessary for hepatobiliary malignancies in the primary and oligometastatic setting, but such dose escalation is challenging for spine metastases due to spinal cord proximity. Here, we investigate the role of spine stereotactic radiosurgery (SSRS) in the management of such metastases. METHODS: We retrospectively reviewed patients treated with SSRS to spinal metastases from hepatobiliary malignancies between 2004 and 2017 at our Institution. We used the Kaplan-Meier method to calculate overall survival (OS) and local control (LC) and Cox regression analysis to identify factors associated with disease-related outcomes. RESULTS: We identified 28 patients treated to 43 spinal metastases with SSRS for either HCC or cholangiocarcinoma. The 1-year LC and OS were 85% and 23%, respectively. The median time to death was 6.2 months, while median time to local failure was not reached. Tumor volume > 60 cc (SHR 6.65, p = 0.03) and Bilsky ≥ 1c (SHR 4.73, p = 0.05) predicted for poorer LC, while BED10 > 81 Gy trended towards better local control (SHR 4.35, p = 0.08). Child-Pugh Class (HR 3.02, p = 0.003), higher PRISM Group (HR 3.49, p = 0.001), and systemic disease progression (HR 3.65, p = 0.001) were associated with worse mortality based on univariate modeling in patients treated with SSRS; on multivariate analysis, PRISM Group (HR 2.28, p = 0.03) and systemic disease progression (HR 2.67, p = 0.03) remained significant. Four patients (10%) developed compression deformity and one patient (2%) developed radiation neuritis. CONCLUSION: SSRS provides durable local control in patients with metastatic hepatobiliary malignancies, with higher BED necessary to ensure excellent LC. PRISM scoring is a promising prognostic tool to aid SSRS patient selection.

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.

Patient satisfaction with treatment outcomes after surgery and/or radiotherapy for spinal metastases.

BACKGROUND: Patient satisfaction is infrequently investigated despite its importance in assessing efficacy and patient comprehension. The purpose of this study was to investigate patient satisfaction with treatment outcomes after surgery and/or radiotherapy for spinal metastases and to evaluate how health-related quality of life (HRQOL) is related to patient satisfaction. METHODS: Patients with spinal metastases treated with surgery and/or radiotherapy were enrolled in a prospective, international, observational study. Demographic, histologic, treatment, and HRQOL data were collected. HRQOL was evaluated with the Numeric Rating Scale pain score, the 3-level version of the EuroQol 5-Dimension (EQ-5D-3L) instrument, and the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ2.0). Patient satisfaction was derived from the SOSGOQ2.0 at 6, 12, and 26 weeks after treatment. Patients were classified as satisfied, neutral, or dissatisfied. RESULTS: Twelve weeks after treatment, 183 of the surgically treated patients (84%) were satisfied, and only 11 (5%) were dissatisfied; in contrast, 101 of the patients treated with radiotherapy alone (77%) were satisfied, and only 7 (5%) were dissatisfied. Significant improvements in pain, physical function, mental health, social function, leg function, and EQ-5D were associated with satisfaction after surgery. Satisfaction after radiotherapy was associated with significant improvements in pain, mental health, and overall SOSGOQ2.0 scores. Dissatisfaction after treatment was associated with lower baseline values for leg strength and lower social functioning scores for surgically treated patients and with lower social functioning scores and being single for patients treated with radiotherapy. CONCLUSIONS: High levels of satisfaction with treatment outcomes are observed after surgery and/or radiotherapy for spinal metastases. Posttreatment satisfaction is associated with significant improvements in pain and different dimensions of HRQOL.

Association of neurologic deficits with surgical outcomes and health-related quality of life after treatment for metastatic epidural spinal cord compression.

BACKGROUND: A critical knowledge gap exists regarding the impact of neurologic deficits on surgical outcomes and health-related quality of life (HRQOL) for patients surgically treated for metastatic epidural spinal cord compression (MESCC). METHODS: This prospective, multicenter and international study analyzed the impact of the neurologic status on functional status, HRQOL, and postoperative survival. The collected data included the patient demographics, overall survival, American Spinal Injury Association (ASIA) impairment scale, Spinal Instability Neoplastic Score, treatment details and complications and HRQOL measures, including version 2 of the 36-Item Short Form Health Survey (SF-36v2) and version 2.0 of the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ2.0). RESULTS: A total of 239 patients surgically treated for spinal metastases were included. Six weeks after treatment, 99 of the 108 patients with a preoperative ASIA grade of E remained stable, 8 deteriorated to ASIA D, and 1 deteriorated to ASIA A. Of 55 patients with ASIA D, 27 improved to ASIA E, 27 remained stable and 1 deteriorated to ASIA C. Of 11 patients with ASIA A to C, 2 improved to ASIA E, 4 improved to ASIA D, and 5 remained stable. At the 6- and 12-week follow-up, better ASIA scores were associated with better scores on multiple SF-36v2 and SOSGOQ items. Postoperatively, patients with ASIA grades of A to D were more likely to have urinary tract infections and wound complications. Patients with a baseline ASIA grade of E or D survived significantly longer. CONCLUSIONS: Patients with neurologic deficits due to MESCC have worse HRQOL and decreased overall survival. Nevertheless, surgery can result in stabilization or improvement of neurologic function which may translate into better HRQOL. Postoperative care and follow-up are challenging for patients with neurologic deficits because they experience more complications.

Survival, local control, and health-related quality of life in patients with oligometastatic and polymetastatic spinal tumors: A multicenter, international study.

BACKGROUND: The treatment of oligometastatic (≤5 metastases) spinal disease has trended toward ablative therapies, yet to the authors' knowledge little is known regarding the prognosis of patients presenting with oligometastatic spinal disease and the value of this approach. The objective of the current study was to compare the survival and clinical outcomes of patients with cancer with oligometastatic spinal disease with those of patients with polymetastatic (>5 metastases) disease. METHODS: The current study was an international, multicenter, prospective study. Patients who were admitted to a participating spine center with a diagnosis of spinal metastases and who underwent surgical intervention and/or radiotherapy between August 2013 and May 2017 were included. Data collected included demographics, overall survival, local control, and treatment information including surgical, radiotherapy, and systemic therapy details. Health-related quality of life (HRQOL) measures included the EuroQOL 5 dimensions 3-level questionnaire (EQ-5D-3L), the 36-Item Short Form Health Survey (SF-36v2), and the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ). RESULTS: Of the 393 patients included in the current study, 215 presented with oligometastatic disease and 178 presented with polymetastatic disease. A significant survival advantage of 90.1% versus 77.3% at 3 months and 77.0% versus 65.1% at 6 months from the time of treatment was found for patients presenting with oligometastatic disease compared with those with polymetastatic disease. It is important to note that both groups experienced significant improvements in multiple HRQOL measures at 6 months after treatment, with no differences in these outcome measures noted between the 2 groups. CONCLUSIONS: The treatment of oligometastatic disease appears to offer a significant survival advantage compared with polymetastatic disease, regardless of treatment choice. HRQOL measures were found to improve in both groups, demonstrating a palliative benefit for all treated patients.

Predictive factors of survival in a surgical series of metastatic epidural spinal cord compression and complete external validation of 8 multivariate models of survival in a prospective North American multicenter study.

BACKGROUND: This study was designed to identify preoperative predictors of survival in surgically treated patients with metastatic epidural spinal cord compression (MESCC), to examine how these predictors are related to 8 prognostic models, and to perform the first full external validation of these models in accordance with the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement. METHODS: One hundred forty-two surgically treated patients with MESCC were enrolled in a prospective, multicenter North American cohort study and were followed for 12 months or until death. Cox regression was used. Noncollinear predictors with < 10% missing data, with ≥ 10 events per stratum, and with P < .05 in a univariate analysis were tested through a backward stepwise selection. For the original and revised Tokuhashi prognostic scoring systems (PSSs), Tomita PSS, modified Bauer PSS, van der Linden PSS, Bartels model, Oswestry Spinal Risk Index, and Bollen PSS, this study examined calibration graphically, discrimination with Harrell c-statistics, and survival stratified by risk groups with the Kaplan-Meier method and log-rank test. RESULTS: The following were significant in the univariate analysis: type of primary tumor, sex, organ metastasis, body mass index, preoperative radiotherapy to MESCC, physical component (PC) of the 36-Item Short Form Health Survey, version 2 (SF-36v2), and EuroQol 5-Dimension (EQ-5D) Questionnaire. Breast, prostate and thyroid primary tumor (HR: 2.9; P =.0005), presence of organ metastasis (hazard ratio (HR): 2.0; P = .005) and SF-36v2 PC (HR: 0.95; P < .0001) were associated with survival in multivariable analysis. Predicted prognoses poorly matched observed values on calibration plots; Bartels model calibration slope was 0.45. Bollen PSS (0.61; 95% CI: 0.58-0.64) and Bartels model (0.68; 95% CI: 0.65-0.71) had the lowest and highest c-statistics, respectively. CONCLUSIONS: The primary tumor type (breast, prostate, or thyroid), an absence of organ metastasis, and a lower degree of physical disability are preoperative predictors of longer survival for surgical MESCC patients. These results are in keeping with current models. This full external validation of 8 prognostic PSSs or model of survival in surgical MESCC patients has revealed that calibration is poor, especially for long-term survivors, whereas discrimination is possibly helpful.

Psychometric evaluation and adaptation of the Spine Oncology Study Group Outcomes Questionnaire to evaluate health-related quality of life in patients with spinal metastases.

BACKGROUND: The Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ) was developed as the first spine oncology-specific health-related quality of life (HRQOL) measure. This study evaluated the psychometric properties and clinical validity of the SOSGOQ in a diverse cohort of patients with spinal metastases. METHODS: An international, multicenter, prospective observational cohort study including patients with spinal metastases who underwent surgery and/or radiotherapy was conducted by the AOSpine Knowledge Forum Tumor. Demographic, tumor, and treatment data were collected. HRQOL was evaluated using the SOSGOQ and Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) at baseline and fixed follow-up times. Construct validity was assessed using multitrait scaling analyses, confirmatory factor analyses, and correlation with the SF-36 and NRS pain score. Test-retest reliability was assessed in a subgroup of patients between 12 weeks after treatment and the retest 4 to 9 days later. RESULTS: A total of 238 patients were enrolled at 9 centers across North America; 153 of these patients had HRQOL data available at 12 weeks after treatment. Multitrait scaling analyses and confirmatory factor analyses resulted in a refined version of the SOSGOQ with 4 domains and 4 single items. The revised SOSGOQ (SOSGOQ2.0) demonstrated strong correlations with SF-36 and the ability to discriminate between clinically distinct patient groups. Reliability of the SOSGOQ2.0 was demonstrated to be good, with an intraclass correlation coefficient ranging from 0.58 to 0.92 for the different domains. CONCLUSIONS: The SOSGOQ2.0 is a reliable and valid measure with which to evaluate HRQOL in patients with spinal metastases. It is recommended to use the SOSGOQ2.0 together with a generic HRQOL outcome measure to comprehensively assess HRQOL and increase sensitivity and specificity. Cancer 2018;124:1828-38. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Laser interstitial thermal therapy of the spine: technical aspects.

Spinal laser interstitial thermal therapy has been developed as a minimally invasive modality to treat epidural spinal tumors percutaneously. The safe and effective use of this technology requires meticulous preoperative trajectory planning and an intraoperative workflow incorporating navigation and MR thermography. Instrumented stabilization can be performed during the same operation if needed. Operative considerations and technical aspects are reviewed. The video can be found here: https://youtu.be/P--frsag6gU .

An integrated multidisciplinary algorithm for the management of spinal metastases: an International Spine Oncology Consortium report.

Spinal metastases are becoming increasingly common because patients with metastatic disease are living longer. The close proximity of the spinal cord to the vertebral column limits many conventional therapeutic options that can otherwise be used to treat cancer. In response to this problem, an innovative multidisciplinary approach has been developed for the management of spinal metastases, leveraging the capabilities of image-guided stereotactic radiosurgery, separation surgery, vertebroplasty, and minimally invasive local ablative approaches. In this Review, we discuss the variables that should be considered during the management of these patients and review the role of each discipline and their respective management options to provide optimal care. This work is synthesised into a practical algorithm to aid clinicians in the management of patients with spinal metastasis.

The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4.

Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1(+) neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS-RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1(+) neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy. Significance statement: In this original work, it is shown for the first time that paclitaxel activates peripheral sensory and spinal neurons directly and sensitizes these cells to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated capsaicin responses via Toll-like receptor 4 (TLR4) in multiple species. A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1-coexpressing HEK293 cells, and in both rat and mouse spinal cord slices. Moreover, this is the first study to show that this interaction plays an important role in the generation of behavioral hypersensitivity in paclitaxel-related neuropathy. The key translational implications are that TLR4 and TRPV1 antagonists may be useful in the prevention and treatment of chemotherapy-induced peripheral neuropathy in humans.

Can the spinal instability neoplastic score prior to spinal radiosurgery predict compression fractures following stereotactic spinal radiosurgery for metastatic spinal tumor?: a post hoc analysis of prospective phase II single-institution trials.

The aim of this study was to determine the predictability of vertebral compression fracture (VCF) development applying the spinal instability neoplastic score (SINS) prior to delivery of stereotactic spinal radiosurgery (SSRS) for spinal metastases. From two prospective cohorts of SSRS for spinal metastases, we selected patients with a low degree of cord compression or cauda equine from C3 to S1 and analyzed 79 patients enrolled according to binary SINS criteria. The primary endpoint was the development of a de novo VCF or progression of an existing fracture after SSRS. We identified 32 fractures (40.5%): 19 de novo and 13 progressive. The mean time to fracture after SSRT was 3.3 months (range, 0.4-34.1 months). In 41 patients with low SINS (0-6), 7 patients (17.1%) developed a fracture after SSRS. In 38 patients with high SINS (7-12), 25 (65.8%) developed a fracture. Among the 32 fractures, 15 were symptomatic. Patients with high SINS were more likely to experience symptomatic fractures (31.6%) than were patients with lower SINS (7.4%). On univariate and multivariate analysis, 24-month fracture-free rates were 78.7 and 33.7% in low and high SINS group, respectively and high SINS was found to be a significant risk factor for VCFs and symptomatic fractures (respectively, HR 5.6, p = 0.04; HR 5.3, p = 0.01). SINS is a useful tool for predicting the development of VCF after SSRS for spinal metastases. Prophylactic cement augmentation should not be considered for patients with lower SINS, since the risk of fracture is low.

Percutaneous surgery for treatment of epidural spinal cord compression and spinal instability: technical note.

OBJECTIVE An emerging paradigm for treating patients with epidural spinal cord compression (ESCC) caused by metastatic tumors is surgical decompression and stabilization, followed by stereotactic radiosurgery. In the setting of rapid progressive disease, interruption or delay in return to systemic treatment can lead to a negative impact in overall survival. To overcome this limitation, the authors introduce the use of spinal laser interstitial thermotherapy (sLITT) in association with percutaneous spinal stabilization to facilitate a rapid return to oncological treatment. METHODS The authors retrospectively reviewed a consecutive series of patients with ESCC and spinal instability who were considered to be poor surgical candidates and instead were treated with sLITT and percutaneous spinal stabilization. Demographic data, Spine Instability Neoplastic Scale score, degree of epidural compression before and after the procedure, length of hospital stay, and time to return to oncological treatment were analyzed. RESULTS Eight patients were treated with thermal ablation and percutaneous spinal stabilization. The primary tumors included melanoma (n = 3), lung (n = 3), thyroid (n = 1), and renal cell carcinoma (n = 1). The median Karnofsky Performance Scale score before and after the procedure was 60, and the median hospital stay was 5 days (range 3-18 days). The median Spine Instability Neoplastic Scale score was 13 (range 12-16). The mean modified postoperative ESCC score (2.75 ± 0.37) was significantly lower than the preoperative score (4.5 ± 0.27) (Mann-Whitney test, p = 0.0044). The median time to return to oncological treatment was 5 days (range 3-10 days). CONCLUSIONS The authors present the first cohort of sLITT associated with a percutaneous spinal stabilization for the treatment of ESCC and spinal instability. This minimally invasive technique can allow a faster recovery without prejudice of adjuvant systemic treatment, with adequate local control and spinal stabilization.

Surgical treatment of sacral chordoma: prognostic variables for local recurrence and overall survival.

PURPOSE: Sacral chordomas (SC) are rare, locally invasive, malignant neoplasms. Despite surgical resection and adjuvant therapies, local recurrence (LR) is common and overall survival (OS) is poor. The objective of this study was to identify prognostic factors that have an impact on the local recurrence-free survival (LRFS) and OS of patients with SC. METHODS: Utilizing the AOSpine Knowledge Forum Tumor multicenter ambispective database, surgically treated SC cases were identified. Cox regression modeling was used to assess the effect of several clinically relevant variables on OS and LRFS. RESULTS: A total of 167 patients with surgically treated SC were identified. The male/female ratio was 98/69 with a mean age of 57 ± 15 years at the time of surgery. The LR was 35% (n = 57), death occurred in 30% of patients (n = 50) during the study period. The median OS was 6 years post-surgery and LRFS was 4 years. In the univariate analysis, previous tumor surgery at the same site (P = 0.002), intralesional resection (P < 0.001), and larger tumor volume (P = 0.030) were significantly associated with LR. Increasing age (P < 0.001) and a preoperative motor deficit of C or D (P = 0.003) were significantly associated with poor OS, and nerve root sacrifice showed a trend towards significance (P = 0.088). In the multivariate models, previous surgery and intralesional resection were significantly related to LR, while increasing age and motor deficit of C or D were associated with poor OS. CONCLUSIONS: This study identified two predictive variables for LRFS (previous tumor surgery and type of surgical resection) and two for OS (age and impaired motor function) in surgically treated SC patients. Our results indicate that en bloc resection reduces LR but does not influence OS. However, this was likely due to short follow-up (3.2 years).

Aneurysmal bone cysts of the spine: treatment options and considerations.

Aneurysmal bone cysts (ABCs) are benign bone lesions with annual incidences ranging from 1.4 to 3.2 cases per million people. Approximately, 10-30% of ABCs are found in the spine. Such lesions are traditionally treated with curettage or other intralesional techniques. Because ABCs can be locally aggressive, intralesional resection can be incomplete and result in recurrence. This has led to increased use of novel techniques, including selective arterial embolization (SAE). This study aims to: (1) compare outcomes based on extent of surgical resection, and (2) compare the efficacy of SAE versus surgical resection. Clinical data pertaining to 71 cases of spinal ABCs were ambispectively collected from nine institutions in Europe, North America, and Australia. Twenty-two spinal ABCs were treated with surgery, 32 received preoperative embolization and surgery, and 17 were treated with SAE. Most tumors were classified as Enneking stage 2 (n = 29, 41%) and stage 3 (n = 29, 41%). Local recurrence and survival were investigated and a significant difference was not observed between treatment groups. However, all three local recurrences occurred following surgical resection. Surgical resection was further categorized based on Enneking appropriateness. Recurrences only occurred following intralesional Enneking inappropriate (EI) resections (P = 0.10), a classification that characterized 47% of all surgical resections. Furthermore, 56% of intralesional resections were EI, compared to only 10% of en bloc resections (P = 0.01). Although SAE treatment did not result in any local recurrences, 35% involved more than five embolization procedures. Spinal ABCs can be effectively treated with intralesional resection, en bloc resection, or SAE. Preoperative embolization should be considered before intralesional resection to limit intraoperative bleeding. Treatment plans must be guided by lesion characteristics and clinical presentation.