Treatment of intramedullary spinal cord tumors: a modified Delphi technique of the North American Spine Society Section of Spine Oncology.

OBJECTIVE: Intramedullary spinal cord tumors (IMSCTs) are rare tumors with heterogeneous presentations and natural histories that complicate their management. Standardized guidelines are lacking on when to surgically intervene and the appropriate aggressiveness of resection, especially given the risk of new neurological deficits following resection of infiltrative tumors. Here, the authors present the results of a modified Delphi method using input from surgeons experienced with IMSCT removal to construct a framework for the operative management of IMSCTs based on the clinical, radiographic, and tumor-specific characteristics. METHODS: A modified Delphi technique was conducted using a group of 14 neurosurgeons experienced in IMSCT resection. Three rounds of written correspondence, surveys, and videoconferencing were carried out. Participants were queried about clinical and radiographic criteria used to determine operative candidacy and guide decision-making. Members then completed a final survey indicating their choice of observation or surgery, choice of resection strategy, and decision to perform duraplasty, in response to a set of patient- and tumor-specific characteristics. Consensus was defined as ≥ 80% agreement, while responses with 70%-79% agreement were defined as agreement. RESULTS: Thirty-six total characteristics were assessed. There was consensus favoring surgical intervention for patients with new-onset myelopathy (86% agreement), chronic myelopathy (86%), or progression from mild to disabling numbness (86%), but disagreement for patients with mild numbness or chronic paraplegia. Age was not a determinant of operative candidacy except among frail patients, who were deemed more suitable for observation (93%). Well-circumscribed (93%) or posteriorly located tumors reaching the surface (86%) were consensus surgical lesions, and participants agreed that the presence of syringomyelia (71%) and peritumoral T2 signal change (79%) were favorable indications for surgery. There was consensus that complete loss of transcranial motor evoked potentials with a 50% decrease in the D-wave amplitude should halt further resection (93%). Preoperative symptoms seldom influenced choice of resection strategy, while a distinct cleavage plane (100%) or visible tumor-cord margins (100%) strongly favored gross-total resection. CONCLUSIONS: The authors present a modified Delphi technique highlighting areas of consensus and agreement regarding surgical management of IMSCTs. Although not intended as a substitute for individual clinical decision-making, the results can help guide care of these patients. Additionally, areas of controversy meriting further investigation are highlighted.

Virus-like particle-based delivery of Cas9/guide RNA ribonucleoprotein efficiently edits the brachyury gene and inhibits chordoma growth in vivo.

PURPOSE: Chordoma is a rare and aggressive bone cancer driven by the developmental transcription factor brachyury. Efforts to target brachyury are hampered by the absence of ligand-accessible small-molecule binding pockets. Genome editing with CRISPR systems provides an unprecedented opportunity to modulate undruggable transcription factor targets. However, delivery of CRISPR remains a bottleneck for in vivo therapy development. The aim was to investigate the in vivo therapeutic efficiency of Cas9/guide RNA (gRNA) ribonucleoprotein (RNP) delivery through a novel virus-like particle (VLP) by fusing an aptamer-binding protein to the lentiviral nucleocapsid protein. METHODS: The p24 based ELISA and transmission electron microscopy were used to determine the characterization of engineered VLP-packaged Cas9/gRNA RNP. The deletion efficiency of brachyury gene in chordoma cells and tissues was measured by genome cleavage detection assay. RT-PCR, Western blot, immunofluorescence staining, and IHC were employed to test the function of brachyury deletion. Cell growth and tumor volume were measured to evaluate the therapeutic efficiency of brachyury deletion by VLP-packaged Cas9/gRNA RNP. RESULTS: Our "all-in-one" VLP-based Cas9/gRNA RNP system allows for transient expression of Cas9 in chordoma cells, but maintains efficient editing capacity leading to approximately 85% knockdown of brachyury with subsequent inhibition of chordoma cell proliferation and tumor progression. In addition, this VLP-packaged brachyury-targeting Cas9 RNP avoids systemic toxicities in vivo. CONCLUSION: Our preclinical studies demonstrate the potential of VLP-based Cas9/gRNA RNP gene therapy for the treatment of brachyury-dependent chordoma.

FGFR1/MAPK-directed brachyury activation drives PD-L1-mediated immune evasion to promote lung cancer progression.

Immune checkpoint inhibitors provide promising benefits for patients with cancer. However, efficacy has been encumbered by high resistance rates. It is critical to understand the basic mechanisms of tumor-mediated resistance to this treatment modality. Previous studies have found that the transcription factor brachyury is highly expressed in lung cancer. Here, we show that brachyury activation induces the upregulation of PD-L1 leading to inactivation of T cell proliferation in vitro and inhibited infiltration of CD8+ and CD3+ T cells into tumor in an immunocompetent mouse model. We further demonstrate that FGFR1/MAPK activation regulates brachyury and PD-L1 expressions and promotes immunosuppression. Blocking FGFR1/MAPK suppresses brachyury and PD-L1 expressions, revives immune activity, and reverses the resistance to anti-PD-1 treatment to produce a durable therapeutic response. We also find that lung cancer patients with high activation of the FGFR1-MAPK-brachyury-PD-L1 signature and low expression of CD8A, CD3D, or PDCD1 have worse survival outcomes. These findings elucidate a novel mechanism of immune escape from immune checkpoint therapy and provide an opportunity to enhance its therapeutic efficacy in the treatment of a subset of FGFR1/MAPK/brachyury/PD-L1-driven lung cancer.

Attitudes and trends in the use of radiolucent spinal implants: A survey of the North American Spine Society section of spinal oncology.

Background: In spinal oncology, titanium implants pose several challenges including artifact on advanced imaging and therapeutic radiation perturbation. To mitigate these effects, there has been increased interest in radiolucent carbon fiber (CF) and CF-reinforced polyetheretherketone (CFR-PEEK) implants as an alternative for spinal reconstruction. This study surveyed the members of the North American Spine Society (NASS) section of Spinal Oncology to query their perspectives regarding the clinical utility, current practice patterns, and recommended future directions of radiolucent spinal implants. Methods: In February 2021, an anonymous survey was administered to the physicians of the NASS section of Spinal Oncology. Participation in the survey was optional. The survey contained 38 items including demographic questions as well as multiple-choice, yes/no questions, Likert rating scales, and short free-text responses pertaining to the "clinical concept", "efficacy", "problems/complications", "practice pattern", and "future directions" of radiolucent spinal implants. Results: Fifteen responses were received (71.4% response rate). Six of the participants (40%) were neurosurgeons, eight (53.3%) were orthopedic surgeons, and one was a spinal radiation oncologist. Overall, there were mixed opinions among the specialists. While several believed that radiolucent spinal implants provide substantial benefits for the detection of disease recurrence and radiation therapy options, others remained less convinced. Ongoing concerns included high costs, low availability, limited cervical and percutaneous options, and suboptimal screw and rod designs. As such, participants estimated that they currently utilize these implants for 27.3% of anterior and 14.7% of all posterior reconstructions after tumor resection. Conclusion: A survey of the NASS section of Spinal Oncology found a lack of consensus with regards to the imaging and radiation benefits, and several ongoing concerns about currently available options. Therefore, routine utilization of these implants for anterior and posterior spinal reconstructions remains low. Future investigations are warranted to practically validate these devices' theoretical risks and benefits.

National trends in the surgical management of metastatic lung cancer to the spine using the national inpatient sample database from 2005 to 2014.

Optimal management of metastatic lung cancer to the spine (MLCS) incorporates a multidisciplinary approach. With improvements in lung cancer screening andnonsurgical treatment, the role for surgerymay be affected. The objective of this study is to assess trends in the surgical management of MLCS using the National Inpatient Sample (NIS) database. The NIS was queried for patients with MLCS who underwent surgery from 2005 to 2014. The frequencies of spinal decompression alone, spinal stabilization with or without (+/-) decompression, and vertebral augmentation were calculated. Statistical analysis was performed to analyze the effect of patient characteristics on outcomes. The most common procedure performed was vertebral augmentation (10719, 44.3%), followed by spinal stabilization +/- decompression (8634, 35.7%) and then decompression alone (4824, 20.0%). The total number of surgeries remained stable, while the rate of spinal stabilizations increased throughout the study period (p < 0.001). Invasive procedures such as stabilization and decompression were associated with greater costs, length of stay,complications and mortality. Increasingcomorbidity was associated with increased odds of complication, especially in patients undergoing more invasive procedures. In patients with lowpre-operative comorbidity, the type of procedure did not influence the odds of complication. Graded increases in length of stay, cost and mortality were seen with increasing complication rate.The rate of spinal stabilizations increased, which may be due to either increased early detection of disease facilitating use of outpatient vertebral augmentation procedures and/or the recognition that surgical decompression and stabilization are necessary for optimal outcome in the setting of MLCS with neurological deficit.

Current trends in incidence, characteristics, and surgical management of metastatic breast cancer to the spine: A National Inpatient Sample analysis from 2005 to 2014.

Management of metastatic breast cancer to the spine (MBCS) incorporates a multimodal approach. Improvement in screening and nonsurgical therapies may alter the trends in surgical management of MBCS. The objective of this study is to assess trends in surgical management of MBCS and short-term outcomes based on the National Inpatient Sample (NIS) database. The NIS database was queried for patients with MBCS who underwent surgery from 2005 to 2014. The weighted frequencies of spinal decompression alone, spinal stabilization +/- decompression, and vertebral augmentation were calculated. Multivariate analysis was performed to analyze the effect of patient characteristics on outcomes stratified by procedure. The most common procedure performed was vertebral augmentation (11,114, 53.4%), followed by stabilization +/- decompression (6,906, 33.2%) and then decompression alone (3,312, 13.4%). The total population-adjusted rate of surgical management for MBCS remained stable, while the rate of spinal stabilization increased (P < 0.001) and vertebral augmentation decreased (p < 0.003). The risk of complication increased with spinal stabilization and decompression compared to vertebral augmentation procedures in those with fewer comorbidities. This relative increase in risk abated in patients with higher numbers of pre-operative comorbidities. Any single complication was associated with increases in length of stay, cost, and mortality. The rate of in-hospital interventions remained stable over the study period. Stratified by procedure, the rate of stabilizations increased with a concomitant decrease in vertebral augmentations, which suggests that patients who require hospitalization for MBCS are becoming more likely to represent advanced cases that are not amenable to palliative vertebral augmentation procedures.

Usefulness of the measurement of neurite outgrowth of primary sensory neurons to study cancer-related painful complications.

Abnormal outgrowth of sensory nerves is one of the important contributors to pain associated with cancer and its treatments. Primary neuronal cultures derived from dorsal root ganglia (DRG) have been widely used to study pain-associated signal transduction and electrical activity of sensory nerves. However, there are only a few studies using primary DRG neuronal culture to investigate neurite outgrowth alterations due to underlying cancer-related factors and chemotherapeutic agents. In this study, primary DRG sensory neurons derived from mouse, non-human primate, and human were established in serum and growth factor-free conditions. A bovine serum albumin gradient centrifugation method improved the separation of sensory neurons from satellite cells. The purified DRG neurons were able to maintain their heterogeneous subpopulations, and displayed an increase in neurite growth when exposed to cancer-derived conditioned medium, while they showed a reduction in neurite length when treated with a neurotoxic chemotherapeutic agent. Additionally, a semi-automated quantification method was developed to measure neurite length in an accurate and time-efficient manner. Finally, these exogenous factors altered the gene expression patterns of murine primary sensory neurons, which are related to nerve growth, and neuro-inflammatory pain and nociceptor development. Together, the primary DRG neuronal culture in combination with a semi-automated quantification method can be a useful tool for further understanding the impact of exogenous factors on the growth of sensory nerve fibers and gene expression changes in sensory neurons.

Changes in the Operative Corridor in Oblique Lumbar Interbody Fusion Between Preoperative Magnetic Resonance Imaging and Intraoperative Cone-Beam Computed Tomography Using Morphometric Analysis.

Background The oblique lumbar interbody fusion or anterior-to-psoas (OLIF/ATP) technique relies on a corridor anterior to the psoas and posterior to the vasculature for lumbar interbody fusion. This is evaluated preoperatively with CT and/or MRI. To date, there have been no studies examining how intraoperative, lateral decubitus positioning may change the dimensions of this corridor when compared to preoperative imaging. Objective Our objective was to evaluate changes in the intraoperative corridor in the supine and lateral positions utilizing preoperative and intraoperative imaging. Methods We performed a retrospective analysis among patients who have undergone an OLIF/ATP approach at two tertiary care centers from 2016 to 2018 by measuring the distance between the left lateral border of the aorta or iliac vessels and anteromedial border of the psoas muscle from L1-L2 through L4-5 disc spaces. We compared this corridor between supine, preoperative MRI axial and intraoperative CT acquired in the right lateral decubitus position. Results Thirty-three patients, 15 of whom were female, were included in our study. The average age of the patients was 65.4 years and the average BMI was 31 kg/m2. The results revealed a statistically significant increase (p<.05) in the intraoperative corridor from supine to lateral decubitus positioning at all levels. However, age, BMI, and gender had no statistically significant impact on the preoperative versus intraoperative corridor. Conclusion This is the first study to provide objective evidence that lateral decubitus positioning increases the intraoperative corridor for OLIF/ATP. Our study demonstrates that lateral decubitus positioning provides a more favorable corridor for the OLIF/ATP technique from L1-L5 disc levels.

Cannabinoids in the Treatment of Back Pain.

Marijuana is increasingly utilized for the treatment of multiple medical problems, including back pain, in the United States. Although there is strong preclinical evidence supporting the promise of cannabinoids in the treatment of back pain, there is a paucity of clinical data supporting their use in clinical practice. Opioids are an important medication for the treatment of acute and chronic back pain, but utilization of opioid-based regimens have likely contributed to the growing opioid epidemic. The significant risk of morbidity, mortality, and dependence secondary to opioid medications have increased the interest in nonopioid medications, including cannabinoid-based pain regimens, in treating back pain. This review will provide an overview on the pharmacology, drug delivery methods, clinical evidence, and safety considerations critical to understanding the potential role of cannabinoids in the treatment of back pain.

Will immunotherapy change the role of spine radiosurgery in high-grade epidural disease? A case report and a call for an update of current treatment algorithms.

Epidural disease closer than 3 mm from the spinal cord is sometimes regarded as a contraindication to spine radiosurgery (SRS) or stereotactic body radiotherapy (SBRT). Current guidelines on the management of high-grade epidural disease recommend surgical decompression followed by conventionally fractionated external-beam radiotherapy (EBRT) or post-operative SBRT [1, 2]. For patients with high-grade epidural disease who are medically inoperable, conventional EBRT is typically recommended, even though clinical response rates are lower and durability is limited[3]. A few expert centers use decompressive SRS in a single fraction for high-grade epidural disease[4, 5], but this technique has not been incorporated into treatment algorithms such as the neurologic, oncologic, mechanical, and systemic (NOMS) decision framework [1, 2]. Here we present a case where five-fraction SBRT followed by immunotherapy resulted in a complete radiographic and clinical response for a patient with epidural disease that was compressing the thecal sac. We compare the radiographic response in this patient to data in a prior publication that quantified the improvement in thecal sac patency after decompressive SRS, and we suggest that current treatment algorithms need to be updated in the era of immunotherapy.

Far Lateral Tubular Decompression: A Case Series Studying One and Two Year Outcomes with Predictors of Failure.

Introduction The optimal surgical treatment of isolated lumbar foraminal stenosis has not been defined. Minimally invasive decompression of the foramen from a far lateral tubular decompression (FLTD) approach has been shown to not only have minimal morbidity but also highly variable success rates at short-term follow-up. It is important to quantify improvement and define the demographic and radiographic parameters that predict failure in this promising, minimally invasive surgical technique. This study investigates pain and disability score improvement following FLTD at 12 and 24 months and investigates associations with failure. Methods All patients who underwent lumbar FLTD by a single surgeon at a single institution from September 2015 to January 2018 were included in this prospective case series. Visual analog scale (VAS) for back pain and leg pain and Oswestry Disability Index (ODI) were collected preoperatively and at the 12- and 24- month follow-ups. Outcomes between visits were fitted to a linear mixed-effects model. The univariate analysis investigated demographic, radiographic, and operative associations with subsequent open revision. Results A total of 42 patients were included in this study. Back pain (VAS 5.84 to 3.32, p<0.001), leg pain (VAS 7.33 to 2.71, p<0.001), and ODI (48.97 to 28.50, p<0.001) demonstrated significant improvements at the 12-month follow-up. Back pain (VAS 3.71, p=0.004), leg pain (VAS 3.04, p<0.001), and ODI (30.63, p<0.001) improvements were maintained at 24-month follow-up. Four patients (9.5%) required subsequent open revision. Subsequent open revision was associated with prior spine surgery (RR=2.85 (2.07-3.63), p=0.045) and scoliosis ≥10° (RR=6.33 (4.87-7.80), p=0.013). Conclusion Back pain, leg pain, and ODI showed significant improvement postoperatively. Improvement is maintained at two years. Prior spine surgery and scoliosis ≥ 10° may be relative contraindications to FLTD.

Unilateral Laminotomy with Bilateral Decompression: A Case Series Studying One- and Two-Year Outcomes with Predictors of Minimal Clinical Improvement.

OBJECTIVE: To assess factors that may predict failure to improve at 12 and 24 months after unilateral laminotomy with bilateral decompression (ULBD) for the management of lumbar spinal stenosis. METHODS: A database of 255 patients who underwent microdecompression surgery by a single orthopedic spine surgeon between 2014 and 2018 was queried. Patients who underwent primary single-level ULBD of the lumbar spine were included. Visual analog scale (VAS) for back pain and leg pain and Oswestry Disability Index (ODI) results were collected preoperatively and at 12 and 24 months postoperatively. Demographic, radiographic, and operative factors were assessed for associations with failure to improve. Clinically important improvement was defined as reaching or surpassing the previously established minimum clinically important difference for ODI (12.8) and not requiring revision. RESULTS: A total of 68 patients were included. Compared with preoperative values for back pain, leg pain, and ODI (7.32, 7.53, and 51.22, respectively), there were significant improvements on follow-up at 12 months (2.89, 2.23, and 22.40, respectively; P < 0.001) and 24 months (2.80, 2.11, 20.32, respectively; P < 0.001). Based on the defined criteria, 50 patients showed clinically important improvement after ULBD. Of the 18 patients who failed to improve, 12 required revision. Independent predictors of failure to improve included female sex (adjusted odds ratio, 5.06; 95% confidence interval, 1.49-21.12; P = 0.014) and current smoker status (adjusted odds ratio, 5.39; 95% confidence interval, 1.39-23.97; P = 0.018). CONCLUSIONS: ULBD for the management of lumbar spinal stenosis leads to clinically important improvement that is maintained over a 24-month follow-up period. Female sex and tobacco smoking are associated with poorer outcomes.

A review of Big Data analytics and potential for implementation in the delivery of global neurosurgery.

Global access to neurosurgical care is still a work in progress, with many patients in low-income countries not able to access potentially lifesaving neurosurgical procedures. "Big Data" is an increasingly popular data collection and analytical technique predicated on collecting large amounts of data across multiple data sources and types for future analysis. The potential applications of Big Data to global outreach neurosurgery are myriad: from assessing the overall burden of neurosurgical disease to planning cost-effective improvements in access to neurosurgical care, and collecting data on conditions which are rare in developed countries. Although some global neurosurgical outreach programs have intelligently implemented Big Data principles in their global neurosurgery initiatives already, there is still significant progress that remains to be made. Big Data has the potential to drive the efficient improvement of access to neurosurgical care across low- and medium-income countries.

Cerebral Abscess in Young Adult with Hypoplastic Left Heart Syndrome.

BACKGROUND: Cerebral abscesses are rare, potentially life-threatening entities that result from local spread or hematogenous dissemination to the brain. Prompt diagnosis and initiation of treatment is key in lowering morbidity and preventing mortality associated with cerebral abscesses. Congenital heart diseases with right-to-left intracardiac shunts can be complicated by brain abscesses via paradoxical embolism of infected microthrombi. Hypoplastic left heart syndrome (HLHS) is a rare congenital heart disease characterized by an underdeveloped left heart that uses intracardiac shunting to achieve adequate systemic circulation. We present the first reported case of a cerebral abscess in a patient with HLHS. The pathophysiology of HLHS and how it predisposes patients to development of cerebral abscesses is discussed. CASE DESCRIPTION: A 25-year-old male was transferred to our institution complaining of headache, nausea, and vomiting. The patient was not an intravenous (IV) drug user, and serologic testing was negative for human immunodeficiency virus. Magnetic resonance imaging revealed a 2.6-cm left occipital abscess, which was surgically resected without complication, and the patient was treated with IV antibiotics. CONCLUSION: HLHS is a rare congenital cardiac malformation. The long-term outcome of patients with this condition continues to improve as treatment paradigms evolve. As such, patients with HLHS are living longer, and their potential to develop cerebral abscesses secondary to their unique systemic circulation is increasing with improved life expectancy. Surgeons and physicians should maintain a high index of suspicion for cerebral abscess in the setting of HLHS.

Amplified hearing device use in acute care settings for patients with hearing loss: A feasibility study.

The objective of this study was to assess the feasibility of using amplified hearing devices (AHD) in acute care settings for patients with hearing loss. Secondary objectives include patient and nurse satisfaction, and nursing perceived productivity. Twenty-five adult hard of hearing patients and 15 nurses were evaluated. Patients with a perceived hearing handicap were identified through the Hearing Handicap for the Elderly Screening Version. Patient and staff nurse surveys were used to assess for satisfaction with using the AHD. Nurses were surveyed to evaluate whether they felt the AHD made patient communication more efficient and effective. Twenty-four patients expressed satisfaction with the AHD and would use it in future hospitalizations. Nurses also reported satisfaction, perceived improvement of patient communication and decreased time spent communicating with patients. Results demonstrate the feasibility of using an AHD in acute care inpatient settings where elderly hard of hearing patients are common.

Fungal Contamination of Methylprednisolone Causing Recurrent Lumbosacral Intradural Abscess.

Fungal meningitis transmitted through injections of methylprednisolone contaminated with Exserohilum rostratum affected 753 persons and caused 61 deaths in the United States in 2012. We report a case of infection recurrence after 24-months with the unique manifestation of an intradural fungal abscess. Fungal disease should remain on the differential diagnosis list for previously exposed patients.

Regulation of brachyury by fibroblast growth factor receptor 1 in lung cancer.

Recent evidence suggests that T-box transcription factor brachyury plays an important role in lung cancer development and progression. However, the mechanisms underlying brachyury-driven cellular processes remain unclear. Here we found that fibroblast growth factor receptor 1/mitogen-activated protein kinase (FGFR1/MAPK) signaling regulated brachyury in lung cancer. Analysis of FGFR1-4 and brachyury expression in human lung tumor tissue and cell lines found that only expression of FGFR1 was positively correlated with brachyury expression. Specific knockdown of FGFR1 by siRNA suppressed brachyury expression and epithelial-mesenchymal transition (EMT) (upregulation of E-cadherin and ß-catenin and downregulation of Snail and fibronectin), whereas forced overexpression of FGFR1 induced brachyury expression and promoted EMT in lung cancer cells. Activation of fibroblast growth factor (FGF)/FGFR1 signaling promoted phosphorylated MAPK extracellular signal-regulated kinase (ERK) 1/2 translocation from cytoplasm to nucleus, upregulated brachyury expression, and increased cell growth and invasion. In addition, human lung cancer cells with higher brachyury expression were more sensitive to inhibitors targeting FGFR1/MAPK pathway. These findings suggest that FGFR1/MAPK may be important for brachyury activation in lung cancer, and this pathway may be an appealing therapeutic target for a subset of brachyury-driven lung cancer.

Pneumocephalus leading to the diagnosis of cerebrospinal fluid leak and esophageal perforation after cervical spine surgery.

Pneumocephalus is a collection of air within in the intracranial cavity, most commonly seen following traumatic injury or cranial surgeries. Esophageal injury and cerebrospinal fluid (CSF) leak are rare complications that may occur following anterior cervical discectomy and fusion (ACDF). We present a novel case of pneumocephalus arising from unrestricted leakage of CSF via coincident esophageal injury and durotomy in a patient who underwent an ACDF after trauma. A 21-year-old man presented to an outside hospital with C5/C6 subluxation, complete spinal cord injury, and quadriplegia from a motor vehicle accident. He underwent an ACDF, during which a CSF leak was observed. He was then transferred to our institution for rehabilitation and tracheostomy placement 1 week after the ACDF surgery. Following the tracheostomy, the patient developed intractable fevers and nonspecific symptoms. A CT scan demonstrated frontal pneumocephalus without mass effect. Air was found in the retropharyngeal space. There were no accumulations of CSF in the neck. Extravasation of contrast around instrumentation at C5/C6 on a cine esophagogram demonstrated an esophageal perforation at that level. Pneumocephalus may form when large volumes of CSF escape from the intracranial space and air is drawn into the space by the negative pressure. In this unusual case, the esophageal perforation promoted the formation of the pneumocephalus. Treatment included closure of both defects, disrupting the suspected communication between the intracranial space and the esophagus.

Liposome-Protamine-DNA Nanoparticle-Mediated Delivery of Short Hairpin RNA Targeting Brachyury Inhibits Chordoma Cell Growth.

Recent evidence suggests that brachyury is a crucial molecular driver in the initiation and propagation of chordoma. However, no small molecules have been used to specifically target brachyury. Short hairpin RNA (shRNA) has therapeutic promise for the genetic treatment of cancer, but the usage of shRNA therapeutics is limited by obstacles related to effective delivery into the nuclei of target cancer cells due to their inherent sensitivity to nucleases and large polyanionic characteristics. To overcome instability and low transfection efficiency, liposome-protamine-DNA (LPD) nanoparticles were synthesized and investigated as a non-viral carrier of shRNA targeting brachyury in chordoma cells. The size, zeta potential, affinity and transfection efficiency of LPD-shRNA complexes were characterized, and their biological functions in chordoma cells were evaluated. The transfection efficiency of LPD-shRNA was significant higher than naked shRNA. LPD delivered brachyury shRNA into chordoma cells and inhibited brachyury expression, induced apoptosis, upregulated the epithelial biomarker, E-cadherin, downregulated the mesenchymal biomarker, Snail and Slug, and suppressed cell growth. These data indicate that LPD might be a promising non-viral carrier for shRNA in gene targeted therapy of chordoma.