The Neurosurgeon's Dilemma-Do Antiplatelet/Anticoagulant Medications Increase the Risk of Catheter-Associated Hemorrhage in External Ventricular Drain Placement?

OBJECTIVE: External ventricular drain (EVD) placement is a common neurosurgical procedure that can be performed at bedside. A frequent complication following EVD placement is catheter-associated hemorrhage (CAH). The hemorrhage itself is rarely clinically significant but may be complicated in patients taking anticoagulant or antiplatelet (AC/AP) medications. METHODS: A total of 757 patients were who underwent EVD placement at bedside were included as part of a retrospective study at a large academic medical center. Demographic factors, use of AC/AP therapies, and several other clinical variables were recorded and assessed in univariate and multivariate regression analysis for association with CAH and mortality. RESULTS: One hundred (13.2%) patients experienced CAH within 24 hours of the procedure. After univariate analysis, in 2 tandem-run multivariate regression analyses after stepwise variable selection, use of 2 or more AC/AP agents (odds ratio [OR] = 2.362, P = 0.020) and dual antiplatelet therapy with aspirin and clopidogrel (OR = 3.72, P = 0.009) were significantly associated with CAH. Use of noncoated catheters was a protective factor against CAH compared to use of antibiotic-coated catheters (OR = 0.55, P = 0.019). Multivariate analysis showed age, multiagent therapy, and thrombocytopenia were significantly associated with increased mortality. CONCLUSIONS: There was increased risk of CAH after EVD placement in patients taking more than one AC/AP agent regardless of presenting pathology. In particular, use of aspirin and clopidogrel combined was associated with significantly higher odds of CAH, although it was not associated with higher mortality. In addition, there appears to be an association between use of antibiotic-coated catheters and CAH across univariate and multivariate analysis.

Focused Ultrasound Central Lateral Thalamotomy for the Treatment of Refractory Neuropathic Pain: Phase I Trial.

BACKGROUND AND OBJECTIVES: Magnetic resonance-guided focused ultrasound (MRgFUS) central lateral thalamotomy (CLT) has not yet been validated for treating refractory neuropathic pain (NP). Our aim was to assess the safety and potential efficacy of MRgFUS CLT for refractory NP. METHODS: In this prospective, nonrandomized, single-arm, investigator-initiated phase I trial, patients with NP for more than 6 months related to phantom limb pain, spinal cord injury, or radiculopathy/radicular injury and who had undergone at least one previous failed intervention were eligible. The main outcomes were safety profile and pain as assessed using the brief pain inventory, the pain disability index, and the numeric rating scale. Medication use and the functional connectivity of the default mode network (DMN) were also assessed. RESULTS: Ten patients were enrolled, with nine achieving successful ablation. There were no serious adverse events and 12 mild/moderate severity events. The mean age was 50.9 years (SD: 12.7), and the mean symptom duration was 12.3 years (SD: 9.7). Among eight patients with a 1-year follow-up, the brief pain inventory decreased from 7.6 (SD: 1.1) to 3.8 (SD: 2.8), with a mean percent decrease of 46.3 (SD: 40.6) (paired t -test, P = .017). The mean pain disability index decreased from 43.0 (SD: 7.5) to 25.8 (SD: 16.8), with a mean percent decrease of 39.3 (SD: 41.6) ( P = .034). Numeric rating scale scores decreased from a mean of 7.2 (SD: 1.8) to 4.0 (SD: 2.8), with a mean percent decrease of 42.8 (SD: 37.8) ( P = .024). Patients with predominantly intermittent pain or with allodynia responded better than patients with continuous pain or without allodynia, respectively. Some patients decreased medication use. Resting-state functional connectivity changes were noted, from disruption of the DMN at baseline to reactivation of connectivity between DMN nodes at 3 months. CONCLUSION: MRgFUS CLT is feasible and safe for refractory NP and has potential utility in reducing symptoms as measured by validated pain scales.

In Vitro Effect of Low-Level Lasers on Total Bilirubin Concentration in Human Blood Plasma Using 375 and 650 nm Lasers.

Background: The current research extends previous laboratory investigations by investigating the effects of low-level laser irradiation (LLLI) on human blood plasma. Total bilirubin is of special importance because of its potential biostimulatory and modulatory actions. Objective: This study aims to analyze changes in total bilirubin content as a consequence of LLLI on human blood plasma. This study aims to determine how changes in exposure duration and laser wavelength affect these adjustments. Methodology: Plasma was isolated from a healthy adult donor's whole blood using the anticoagulant ethylenediaminetetraacetic acid (EDTA). Plasma samples were exposed to LLLI at 375 and 650 nm for 5, 10, 15, 20, and 25 min. Total bilirubin concentrations were measured both before and after irradiation using spectrophotometric analysis. The difference between 375 and 630 nm lasers was also investigated. Results: Five, 10, 15, 20, and 25 min of exposure to LLLI at 375 and 650 nm wavelengths resulted in statistically significant differences in total bilirubin content (p ˂ 0.05, p ˂ 0.001, p ˂ 0.0001). There was no statistically significant difference in total bilirubin concentration between the 375 and 630 nm lasers. Conclusions: Human blood plasma total bilirubin levels were considerably lower following LLLI at 375 and 630 nm than controls. Multiple exposures provide the same results. These findings demonstrate the role of biostimulation by laser irradiation in blood plasma applications and suggest that low-level laser treatment may control total bilirubin levels, particularly at 375 and 630 nm.

Variability in the Arterial Supply of Intracranial Meningiomas: An Anatomic Study.

BACKGROUND AND OBJECTIVES: Intracranial meningiomas are a diverse group of tumors, which vary by grade, genetic composition, location, and vasculature. Expanding the understanding of the supply of skull base (SBMs) and non-skull base meningiomas (NSBMs) will serve to further inform resection strategies. We sought to delineate the vascular supply of a series of intracranial meningiomas by tumor location. METHODS: A retrospective study of intracranial meningiomas that were studied using preoperative digital subtraction angiograms before surgical resection at a tertiary referral center was performed. Patient, tumor, radiologic, and treatment data were collected, and regression models were developed. RESULTS: One hundred sixty-five patients met inclusion criteria. The mean age was 57.1 years (SD: 12.6). The mean tumor diameter was 4.9 cm (SD: 1.5). One hundred twenty-six were World Health Organization Grade I, 37 Grade II, and 2 Grade III. Arterial feeders were tabulated by Al-Mefty's anatomic designations. SBMs were more likely to derive arterial supply from the anterior circulation, whereas NSBMs were supplied by external carotid branches. NSBMs were larger (5.61 cm vs 4.45 cm, P = <.001), were more often presented with seizure (20% vs 8%, P = .03), were higher grade ( P = <.001) had more frequent peritumoral brain edema (84.6% vs 66%, P = .04), and had more bilateral feeders (47.7% vs 28%, P = .01) compared with SBMs. More arterial feeders were significantly associated with lower tumor grade ( P = .023, OR = 0.59). Higher tumor grade (Grade II/III) was associated with fewer arterial feeders ( P = .017, RR = 0.74). CONCLUSION: Meningioma location is associated with specific vascular supply patterns, grade, and patient outcomes. This information suggests that grade I tumors, especially larger tumors, are more likely to have diverse vascular supply patterns, including internal carotid branches. This study may inform preoperative embolization and surgical considerations, particularly for large skull base tumors.

Technical Optimization of Decompressive Craniectomy for Possible Conversion to Hinge Craniotomy in Traumatic Brain Injury.

Hinge craniotomy for the management of elevated intracranial pressure (ICP) in traumatic brain injury remains a technique not widely adopted. The hinged bone flap decreases the allowable intracranial volume expansion, which can lead to persistent post-operative elevated ICP and the need for salvage craniectomy. Herein, we describe the technical nuances in performing a decompressive craniectomy that, when optimized, allows for stronger consideration for hinge craniotomy as a definitive technique. To conclude, hinge craniotomy is a reasonable option in the setting of traumatic brain injury. Trauma neurosurgeons can consider the technical steps to optimize a decompressive craniectomy and perform hinge craniotomy when allowable.

Surgical Decompression of Traumatic Cervical Spinal Cord Injury: A Pilot Study Comparing Real-Time Intraoperative Ultrasound After Laminectomy With Postoperative MRI and CT Myelography.

BACKGROUND: Decompression of the injured spinal cord confers neuroprotection. Compared with timing of surgery, verification of surgical decompression is understudied. OBJECTIVE: To compare the judgment of cervical spinal cord decompression using real-time intraoperative ultrasound (IOUS) following laminectomy with postoperative MRI and CT myelography. METHODS: Fifty-one patients were retrospectively reviewed. Completeness of decompression was evaluated by real-time IOUS and compared with postoperative MRI (47 cases) and CT myelography (4 cases). RESULTS: Five cases (9.8%) underwent additional laminectomy after initial IOUS evaluation to yield a final judgment of adequate decompression using IOUS in all 51 cases (100%). Postoperative MRI/CT myelography showed adequate decompression in 43 cases (84.31%). Six cases had insufficient bony decompression, of which 3 (50%) had cerebrospinal fluid effacement at >1 level. Two cases had severe circumferential intradural swelling despite adequate bony decompression. Between groups with and without adequate decompression on postoperative MRI/CT myelography, there were significant differences for American Spinal Injury Association motor score, American Spinal Injury Association Impairment Scale grade, AO Spine injury morphology, and intramedullary lesion length (IMLL). Multivariate analysis using stepwise variable selection and logistic regression showed that preoperative IMLL was the most significant predictor of inadequate decompression on postoperative imaging (P = .024). CONCLUSION: Patients with severe clinical injury and large IMLL were more likely to have inadequate decompression on postoperative MRI/CT myelography. IOUS can serve as a supplement to postoperative MRI/CT myelography for the assessment of spinal cord decompression. However, further investigation, additional surgeon experience, and anticipation of prolonged swelling after surgery are required.

Research Fever-An Ever More Prominent Trend in the Residency Match.

This Viewpoint discusses the rising trend in research output among matched US MD seniors in the National Resident Matching Program Main Residency Match from 2009 to 2020.

Proposal of a Management Algorithm to Predict the Need for Expansion Duraplasty in American Spinal Injury Association Impairment Scale Grades A-C Traumatic Cervical Spinal Cord Injury Patients.

Expansion duraplasty to reopen effaced subarachnoid space and improve spinal cord perfusion, autoregulation, and spinal pressure reactivity index (sPRX) has been advocated in patients with traumatic cervical spinal cord injury (tCSCI). We designed this study to identify candidates for expansion duraplasty, based on the absence of cerebrospinal fluid (CSF) interface around the spinal cord on magnetic resonance imaging (MRI), in the setting of otherwise adequate bony decompression. Over a 61-month period, 104 consecutive American Spinal Injury Association Impairment Scale (AIS) grades A-C patients with tCSCI had post-operative MRI to assess the adequacy of surgical decompression. Their mean age was 53.4 years, and 89% were male. Sixty-one patients had falls, 31 motor vehicle collisions, 11 sport injuries, and one an assault. The AIS grade was A in 56, B in 18, and C in 30 patients. Fifty-four patients had fracture dislocations; there was no evidence of skeletal injury in 50 patients. Mean intramedullary lesion length (IMLL) was 46.9 (standard deviation = 19.4) mm. Median time from injury to decompression was 17 h (interquartile range 15.2 h). After surgery, 94 patients had adequate decompression as judged by the presence of CSF anterior and posterior to the spinal cord, whereas 10 patients had effacement of the subarachnoid space at the injury epicenter. In two patients whose decompression was not definitive and post-operative MRI indicated inadequate decompression, expansion duraplasty was performed. Candidates for expansion duraplasty (i.e., those with inadequate decompression) were significantly younger (p < 0.0001), were AIS grade A (p < 0.0016), had either sport injuries (six patients) or motor vehicle collisions (three patients) (p < 0.0001), had fracture dislocation (p = 0.00016), and had longer IMLL (p = 0.0097). In regression models, patients with sport injuries and inadequate decompression were suitable candidates for expansion duraplasty (p = 0.03). Further, 9.6% of patients failed bony decompression alone and either did (2) or would have (8) benefited from expansion duraplasty.

Effectiveness of BBIBP-CorV vaccine against severe outcomes of COVID-19 in Abu Dhabi, United Arab Emirates.

The effectiveness of the inactivated BBIBP-CorV vaccine against severe COVID-19 outcomes (hospitalization, critical care admission and death due to COVID-19) and its long-term effectiveness have not been well characterized among the general population. We conducted a retrospective cohort study using electronic health records of 3,147,869 adults, of which 1,099,886 vaccinated individuals were matched, in a 1:1 ratio to 1,099,886 unvaccinated persons. A Cox-proportional hazard model with time varying coefficients was used to assess the vaccine effectiveness adjusting for age, sex, comorbidity, ethnicity, and the calendar month of entry into the study. Our analysis showed that the effectiveness was 79.6% (95% CI, 77.7 to 81.3) against hospitalization, 86% (95% CI, 82.2 to 89.0) against critical care admission, and 84.1% (95% CI, 70.8 to 91.3) against death due to COVID-19. The effectiveness against these severe outcomes declined over time indicating the need for booster doses to increase protection against severe COVID-19 outcomes.

Anti-breast cancer synthetic peptides derived from the Anabas testudineus skin mucus fractions.

Previous study has shown the antimicrobial activities of mucus protein extracted from Anabas testudineus. In this study, we are interested in characterizing the anticancer activity of the A. testudineus antimicrobial peptides (AMPs). The mucus was extracted, fractioned, and subjected to antibacterial activity testing to confirm the fish's AMPs production. The cytotoxic activity of each fraction was also identified. Fraction 2 (F2), which shows toxicity against MCF7 and MDA-MB-231 were sent for peptide sequencing to identify the bioactive peptide. The two peptides were then synthetically produced and subjected to cytotoxic assay to prove their efficacy against cancer cell lines. The IC50 for AtMP1 against MCF7 and MDA-MB-231 were 8.25 ± 0.14 µg/ml and 9.35 ± 0.25 µg/ml respectively, while for AtMP2 it is 5.89 ± 0.14 µg/ml and 6.97 ± 0.24 µg/ml respectively. AtMP1 and AtMP2 treatment for 48 h induced breast cancer cell cycle arrest and apoptosis by upregulating the p53, which lead to upregulate pro-apoptotic BAX gene and downregulate the anti-apoptotic BCL-2 gene, consequently, trigger the activation of the caspase-3. This interaction was supported by docking analysis (QuickDBD, HPEPDOCK, and ZDOCK) and immunoprecipitation. This study provided new prospects in the development of highly effective and selective cancer therapeutics based on antimicrobial peptides.

Localized blood-brain barrier opening in infiltrating gliomas with MRI-guided acoustic emissions-controlled focused ultrasound.

Pharmacological treatment of gliomas and other brain-infiltrating tumors remains challenging due to limited delivery of most therapeutics across the blood-brain barrier (BBB). Transcranial MRI-guided focused ultrasound (FUS), an emerging technology for noninvasive brain treatments, enables transient opening of the BBB through acoustic activation of circulating microbubbles. Here, we evaluate the safety and utility of transcranial microbubble-enhanced FUS (MB-FUS) for spatially targeted BBB opening in patients with infiltrating gliomas. In this Phase 0 clinical trial (NCT03322813), we conducted comparative and quantitative analyses of FUS exposures (sonications) and their effects on gliomas using MRI, histopathology, microbubble acoustic emissions (harmonic dose [HD]), and fluorescence-guided surgery metrics. Contrast-enhanced MRI and histopathology indicated safe and reproducible BBB opening in all patients. These observations occurred using a power cycling closed feedback loop controller, with the power varying by nearly an order of magnitude on average. This range underscores the need for monitoring and titrating the exposure on a patient-by-patient basis. We found a positive correlation between microbubble acoustic emissions (HD) and MR-evident BBB opening (P = 0.07) and associated interstitial changes (P < 0.01), demonstrating the unique capability to titrate the MB-FUS effects in gliomas. Importantly, we identified a 2.2-fold increase of fluorescein accumulation in MB-FUS-treated compared to untreated nonenhancing tumor tissues (P < 0.01) while accounting for vascular density. Collectively, this study demonstrates the capabilities of MB-FUS for safe, localized, controlled BBB opening and highlights the potential of this technology to improve the surgical and pharmacologic treatment of brain tumors.

Efficacy of Early (≤ 24 Hours), Late (25-72 Hours), and Delayed (>72 Hours) Surgery with Magnetic Resonance Imaging-Confirmed Decompression in American Spinal Injury Association Impairment Scale Grades C and D Acute Traumatic Central Cord Syndrome Caused by Spinal Stenosis.

The therapeutic significance of timing of decompression in acute traumatic central cord syndrome (ATCCS) caused by spinal stenosis remains unsettled. We retrospectively examined a homogenous cohort of patients with ATCCS and magnetic resonance imaging (MRI) evidence of post-treatment spinal cord decompression to determine whether timing of decompression played a significant role in American Spinal Injury Association (ASIA) motor score (AMS) 6 months following trauma. We used the t test, analysis of variance, Pearson correlation coefficient, and multiple regression for statistical analysis. During a 19-year period, 101 patients with ATCCS, admission ASIA Impairment Scale (AIS) grades C and D, and an admission AMS of ≤95 were surgically decompressed. Twenty-four of 101 patients had an AIS grade C injury. Eighty-two patients were males, the mean age of patients was 57.9 years, and 69 patients had had a fall. AMS at admission was 68.3 (standard deviation [SD] 23.4); upper extremities (UE) 28.6 (SD 14.7), and lower extremities (LE) 41.0 (SD 12.7). AMS at the latest follow-up was 93.1 (SD 12.8), UE 45.4 (SD 7.6), and LE 47.9 (SD 6.6). Mean number of stenotic segments was 2.8, mean canal compromise was 38.6% (SD 8.7%), and mean intramedullary lesion length (IMLL) was 23 mm (SD 11). Thirty-six of 101 patients had decompression within 24 h, 38 patients had decompression between 25 and 72 h, and 27 patients had decompression >72 h after injury. Demographics, etiology, AMS, AIS grade, morphometry, lesion length, surgical technique, steroid protocol, and follow-up AMS were not statistically different between groups treated at different times. We analyzed the effect size of timing of decompression categorically and in a continuous fashion. There was no significant effect of the timing of decompression on follow-up AMS. Only AMS at admission determined AMS at follow-up (coefficient = 0.31; 95% confidence interval [CI]:0.21; p = 0.001). We conclude that timing of decompression in ATCCS caused by spinal stenosis has little bearing on ultimate AMS at follow-up.

Technical Comparison of Treatment Efficiency of Magnetic Resonance-Guided Focused Ultrasound Thalamotomy and Pallidotomy in Skull Density Ratio-Matched Patient Cohorts.

OBJECTIVE: MR-guided focused ultrasound (MRgFUS) is increasingly being used to treat patients with essential tremor (ET) and Parkinson's disease (PD) with thalamotomy and pallidotomy, respectively. Pallidotomy is performed off-center within the cranium compared to thalamotomy and may present challenges to therapeutic lesioning due to this location. However, the impact of target location on treatment efficiency and ability to create therapeutic lesions has not been studied. This study aimed to compare the physical efficiency of MRgFUS thalamotomy and pallidotomy. METHODS: Treatment characteristics were compared between patients treated with thalamotomy (n = 20) or pallidotomy (n = 20), matched by skull density ratios (SDR). Aspects of treatment efficiency were compared between these groups. Demographic and comparative statistics were conducted to assess these differences. Acoustic field simulations were performed to compare and validate the simulated temperature profile for VIM and GPi ablation. RESULTS: Lower SDR values were associated with greater energy requirement for thalamotomy (R2 = 0.197, p = 0.049) and pallidotomy (R2 = 0.342, p = 0.007). The impact of low SDR on efficiency reduction was greater for pallidotomy, approaching significance (p = 0.061). A nearly two-fold increase in energy was needed to reach 50°C in pallidotomy (10.9kJ) than in thalamotomy (5.7kJ), (p = 0.002). Despite lower energy requirement, the maximum average temperature reached was higher in thalamotomy (56.7°C) than in pallidotomy (55.0°C), (p = 0.017). Mean incident angle of acoustic beams was lesser in thalamotomy (12.7°) than in pallidotomy (18.6°), (p < 0.001). For all patients, a lesser mean incident angle correlated with a higher maximum average temperature reached (R2 = 0.124, p = 0.026), and less energy needed to reach 50°C (R2=0.134, p = 0.020). Greater skull thickness was associated with a higher maximum energy for a single sonication for thalamotomy (R2 = 0.206, p = 0.045) and pallidotomy (R2 = 0.403, p = 0.003). An acoustic and temperature field simulation validated similar findings for thalamotomy and pallidotomy in a single patient. CONCLUSION: The centrally located VIM offers a more efficient location for therapeutic lesioning compared to GPi pallidotomy in SDR matched cohort of patients. The impact on therapeutic lesioning with lower SDR may be greater for pallidotomy patients. As newer off-center targets are investigated, these findings can inform patient selection and treatment requirements for lesion production.

Surgical resection of granular cell tumor of the sellar region: three indications.

PURPOSE: This case series evaluates the surgical management of granular cell tumor (GCT) of the sellar region. This rare entity presents a unique diagnostic and surgical challenge. METHODS: Institutional neuropathology databases at Brigham and Women's Hospital and Massachusetts General Hospital were searched for cases with a tissue diagnosis of GCT, and with a location in the sellar region. Patient, treatment, tumor, and follow-up data were extracted. RESULTS: Three patients had a diagnosis of GCT of the sellar region occurring over an 18-year period. All three patients were followed postoperatively at our multidisciplinary pituitary center (median follow-up = 30 months; range 12-30 months). Hormonal disturbances, an incidental lesion requiring diagnosis, and neurological symptoms were indications for surgery in these patients. Two patients underwent a craniotomy and one underwent endoscopic transsphenoidal surgery. All three patients were free of tumor recurrence at last follow-up. In one case tested, positive thyroid transcription factor-1 (TTF-1) immunohistochemistry was observed. CONCLUSION: GCT is generally a benign tumor of the sellar region. Surgical resection is the standard treatment, more recently with transsphenoidal surgery when indicated. Surgical resection results in optimal outcome for patients.

Predicting Readmission and Reoperation for Benign Cranial Nerve Neoplasms: A Nationwide Analysis.

OBJECTIVE: Readmission and reoperation are risks in the resection of benign cranial nerve tumors (BCNTs). This report analyzes the impact of patient-level and surgical factors on these adverse outcomes. METHODS: This retrospective cohort review comprised patients with a diagnosis of BCNT enrolled in the American College of Surgeons National Surgical Quality Improvement Program registry from 2011 to 2015. Multivariate logistic regression was used to determine the impact of select medical and operative factors on the primary outcomes of readmission and reoperation within 30 days, adjusted for relevant covariates. RESULTS: We identified 996 patients who underwent resection of a BCNT. The most frequent major complications were readmission (11%), reoperation (8%), surgical site infections (2.6%), and venous thromboembolism (1.5%). The most frequent indications for readmission were management of infection (2.5%), cerebrospinal fluid leak (2.3%), and hydrocephalus (0.5%). Repair of cranial and meningeal defects (3.0%), correction of lagophthalmos (1.2%), and repair of middle ear defects (1.0%) were the most common indications for reoperation. Logistic regression revealed that extremes of age were associated with readmission, whereas preoperative steroid usage, long operative time, and postoperative length of stay >3 days were associated with reoperation (P < 0.05). Obesity trended toward an association with readmission and reoperation. CONCLUSIONS: Extremes of age were associated with readmission; preoperative steroid use, long operative time, and postoperative length of stay >3 days were associated with reoperation. Surgeons should consider these factors when assessing risk of postoperative complications for BCNTs.

Geographic proximity to specialized pediatric neurosurgical care in the contiguous United States.

OBJECTIVE Absent from an analysis of supply is consideration of the geographic distribution of pediatric neurosurgeons. Several patient socioeconomic metrics are known to be associated with outcome in pediatric neurosurgical diseases, such as hydrocephalus. The purpose of this study was to determine current geographic proximity to pediatric neurosurgical care using professional society databases. This study also sought to establish how socioeconomic factors are related to distance to care, using federal government-collected data. METHODS A list of currently practicing American Board of Pediatric Neurological Surgery (ABPNS)-certified neurosurgeons was compiled (ABPNS group). A separate list of practicing members of the Joint Pediatric Section (JPS) of the American Association of Neurological Surgeons/Congress of Neurological Surgeons was prepared (JPS group). Current primary practice locations were collected from each professional society database for each ABPNS or JPS neurosurgeon and were charted using ArcGIS mapping software (ESRI, version 10.3) on a United States Census Bureau map. The straight distance from the centroid of each zip code tabulation area (ZCTA) to the nearest neurosurgeon was determined by group type of neurosurgeon (ABPNS vs ABPNS + JPS). ZCTA-level data on demographic and socioeconomic factors were acquired from the American Community Survey, including data in children and young adults (0-18 or 0-24 years old) and the general population. These data were compared by distance to care and by groups of neurosurgeons (Pearson's chi-square analysis; the threshold of significance was set at 0.05). RESULTS Three hundred fifty-five practicing neurosurgeons providing pediatric care were located, of whom 215 surgeons were certified by the ABPNS and 140 were JPS members only. The analysis showed that 1 pediatric neurosurgeon is in practice for every 289,799 persons up to the age of 24 years. The average distance between a ZCTA and the nearest pediatric neurosurgeon is 63.3 miles (SE 0.3, range 0.0-499.7 miles). Geographic analysis showed that 27.1% of children live farther than 60 miles from an ABPNS-certified neurosurgeon and 19.7% from either an ABPNS-certified neurosurgeon or a JPS member. ZCTAs with children who live farther than 60 miles from a neurosurgeon providing pediatric care had a marginally higher rate of uninsured children, a higher percentage of families with children living below the federal poverty level, and a higher proportion of persons living in rural areas compared with ZCTAs with children who live within 60 miles of care (p < 0.005 for each finding). CONCLUSIONS The results of this study indicate that there is considerable variation in proximity to pediatric neurosurgical subspecialty care by geographic region. In addition, there is a relationship between distance to neurosurgical care and socioeconomic indicators. Optimization of access to pediatric neurosurgical care may involve strategies to overcome long geographic distances, particularly in rural and underserved areas. Such areas may have disproportionately lower socioeconomic levels, which may further limit access to care and affect outcomes. Both the total number of pediatric neurosurgeons per pediatric population and their geographic distribution could be important in determining appropriate subspecialty supply factors (e.g., the number of accredited pediatric neurosurgical fellowship training programs), as well as being important drivers of neurosurgical patient outcomes.

Presentation, Treatment, and Long-Term Outcome of Intrasellar Chordoma: A Pooled Analysis of Institutional, SEER (Surveillance Epidemiology and End Results), and Published Data.

BACKGROUND: Chordoma that occurs primarily in the sella turcica is rare and presents unique treatment challenges. OBJECTIVE: The purpose of this study was to determine common features, treatment approaches, and survival characteristics of intrasellar chordoma. METHODS: Institutional databases, the SEER (Surveillance Epidemiology and End Results) database, and PubMed/EMBASE were queried for chordoma with a primarily intrasellar component. The SEER database was also queried for adult skull base chordoma. Patient-level data were extracted where available. Kaplan-Meier survival analyses were conducted. RESULTS: Among 80 cases, the mean age at presentation was 55.6 (standard deviation, 15.9), with a female predominance (1.16:1.00). Patients experienced symptoms for a mean duration of 19.0 months, including cranial nerve deficits, hypopituitarism, and hyperprolactinemia. Among patients receiving treatment, 77.5% underwent surgery. In addition, less than half of the patients (n = 34, 47.3%) received adjuvant radiation therapy. The 5-year overall survival (OS) of intrasellar chordoma was 60.0% (standard error [SE], 6.9). Patients aged 40 years and younger had a 5-year OS of 80.8% (SE, 12.2), compared with patients older than 40 years, who had an OS of 55.4% (SE, 7.7) (Mantel-Cox, P = 0.044). Males experienced a lower 5-year OS (44.0; SE, 9.7) than did females (76.8; SE, 8.5), (Mantel-Cox, P = 0.003). Median OS was greater in patients with skull base chordoma than in patients with intrasellar chordoma (Mantel-Cox, P = 0.046). CONCLUSIONS: Intrasellar chordoma presents frequently with visual disturbances and hyperprolactinemia and has a slightly higher incidence in females. Young age predicts a better prognosis. Intrasellar chordoma has a lower overall survival than has skull base chordoma.

Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma.

Background: Combined immunotherapy approaches are promising cancer treatments. We evaluated anti-programmed cell death protein 1 (PD-1) treatment combined with gene-mediated cytotoxic immunotherapy (GMCI) performed by intratumoral injection of a prodrug metabolizing nonreplicating adenovirus (AdV-tk), providing in situ chemotherapy and immune stimulation. Methods: The effects of GMCI on PD ligand 1 (PD-L1) expression in glioblastoma were investigated in vitro and in vivo. The efficacy of the combination was investigated in 2 syngeneic mouse glioblastoma models (GL261 and CT-2A). Immune infiltrates were analyzed by flow cytometry. Results: GMCI upregulated PD-L1 expression in vitro and in vivo. Both GMCI and anti-PD-1 increased intratumoral T-cell infiltration. A higher percentage of long-term survivors was observed in mice treated with combined GMCI/anti-PD-1 relative to single treatments. Long-term survivors were protected from tumor rechallenge, demonstrating durable memory antitumor immunity. GMCI led to elevated interferon gamma positive T cells and a lower proportion of exhausted double positive PD1+TIM+CD8+ T cells. GMCI also increased PD-L1 levels on tumor cells and infiltrating macrophages/microglia. Our data suggest that anti-PD-1 treatment improves the effectiveness of GMCI by overcoming interferon-induced PD-L1-mediated inhibitory signals, and GMCI improves anti-PD-1 efficacy by increasing tumor-infiltrating T-cell activation. Conclusions: Our data show that the GMCI/anti-PD-1 combination is well tolerated and effective in glioblastoma mouse models. These results support evaluation of this combination in glioblastoma patients.