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Background Appropriate drug distribution is needed for effective treatment of brain metastases and leptomeningeal carcinomatosis. Lack of proper drug bioavailability in the CNS contributes to the poor outcome in these patients. EnClear Therapies has developed a device delivering intrathecal therapeutics utilizing the active control of CSF flow through an external pump. Herein, we look at intrathecal drug delivery of methotrexate with EnClear’s system and its impact of drug concentration in sheep and non-human primates. METHODS The EnClear device utilizes two implantable catheters (intracranial in the ventricular system and lumbar thecal sac) and an extracorporeal pump that controls the speed and direction of CSF flow. Software monitors the output from sensor arrays for pressure, respiration, and heart rate. Gadolinium and MRI were used to determine the CSF flow characteristics. Administration of Methotrexate via the EnClear system was compared to current two standards of delivery, intracerebroventricular or lumbar intrathecal administration. Methotrexate levels were measured with Liquid Chromatography/Mass Spectrometry in CSF, blood, and multiple CNS and peripheral tissues. RESULTS There was a two-fold increase in methotrexate levels in multiple regions of the brain including deeper brain structures including the striatum using the EnClear's system, compared to traditional lumbar intrathecal and intracerebroventricular delivery. Higher peak levels of methotrexate were reached in the CSF with the use of EnClear’s system, with simultaneous reduction in the peripheral nerves and systemic tissues – a potential source of toxicity. Conclusions In large animal studies, the EnClear device has for the first time, demonstrated increased brain parenchymal drug levels via intrathecal delivery. In addition to the drug parenchyma, drug delivery with this novel device has shown improved distribution throughout CNS and leptomeninges as compared to traditional intrathecal drug delivery and decreased peripheral distribution.

Background The US opioid epidemic continues to afflict patients and the healthcare system. Surgery remains a risk factor for opioid misuse, and treatment of low back pain in orthopedics and neurosurgery is one of the largest introductions of opioids into the community. The objective of the study is to understand how opioid prescribing practices for spinal surgery have evolved in two academic hospital in the last 18 years. Methods Data were obtained from the Research Patient Data Registry for Brigham and Women's and Massachusetts General Hospital from January 2000 to December 2018. Patients included had a primary diagnosis of degenerative diseases, trauma, spinal infection, spinal deformities, or spinal pain symptoms/syndromes; were aged > 18 years; and had an opioid prescription. Covariates included demographics, diagnoses, comorbidities, procedures, opioid type, number of prescriptions, route of administration, doses and length of prescription. Results A total of 38,250 patients with spine-related diagnoses received an opioid prescription. The median age was 63 years (18-107), 50% male and 86% white. A total of 32,304 patients (84.4%) received at least one opioid prescription during their hospitalization. The sum of opioid prescriptions filled (inpatient and outpatient) were 889,868 between 2000 and 2018 (55.2% oral, 41.7% intravenous). Oxycodone was the most prescribed. The dose of ≥ 50 morphine milligram equivalents MME/day was reduced from 65.0% in 2000 to 17.3% in 2018, and doses ≥ 90 MME/day dropped from 26.9% in 2000 to 6.4% in 2018. However, the duration of prescription has increased from 4.1% having an opioid prescription for >7 days in 2000, to 21.7% in 2018. Conclusions Opioid prescription rates for spinal surgery patients have increased since 2000, declined temporarily in 2016, but are rising again. Physicians are prescribing fewer MMEs per day but have increased longitudinal dosing, which still leaves patients at risk for misuse and opioid use disorder. Key messages Between 2000 and 2016 there was an increase of 140 times the number of opioid prescriptions for spine patients. More interventions and non-pharmacological solutions are needed to reduce this public health epidemic.

INTRODUCTION Most high grade gliomas (HGG) are located supratentorially, while less than 1% arise infratentorially. Growing evidence suggests that infratentorial HGGs (iHGG) represent a collection of distinct molecular entities and that further elucidation of their molecular features can help guide management. We perform here a clinical and molecular analysis of our institutional iHGG case series. METHODS We retrospectively reviewed iHGG patients treated surgically at Brigham and Women’s Hospital (1992-2020), and evaluated their history of prior malignancies, tumor location, treatment, molecular profile, tumor recurrence, and survival. iHGG were identified by review of pathology records, using WHO Histologic Grading Criteria as grade III-IV gliomas located infratentorially. Molecular analysis data was obtained from pathology records. RESULTS Among 37 iHGGs, 16 (43%) were glioblastomas, 11 (30%) were anaplastic astrocytomas, 2 (5%) were diffuse midline gliomas, 2 (5%) were infiltrating gliomas, 2 (5%) were anaplastic ependymomas, 1 (3%) was an anaplastic oligodendroglioma, and 3 (8%) were HGG not otherwise specific. Sixteen (43%) patients were female, median age was 49 years. Fifteen patients had history prior malignancy, 11 of which received radiation and 8 chemotherapy. Surgical resection of iHGG included gross total resection in 4 (11%) and subtotal in 33 (89%). Twenty-one patients (57%) received adjuvant radiation and 19 (51%) chemotherapy. At follow-up, 13 (35%) patients demonstrated symptomatic deterioration, 15 (41%) were stable, and 7 (19%) were improved. Seven patients (19%) experienced recurrence at a mean time of 19 months, and one-year survival was 35%. Molecular analysis revealed 7/15 (47%) tumors were MGMT promoter methylated, IDH was mutated in 3/24 (13%), EGFR was amplified in 3/10 (30%), CDKN2A/B homozygous deletion in 4/7 (57%), TP53 was mutated in 14/15 (93%), and H3K27M was present in 4/10 (40%). CONCLUSIONS iHGGs demonstrate substantial distinction from their supratentorial counterparts. Herein we examined their clinical course, molecular features, management, and outcomes.

Introduction The Centers for Disease Control and Prevention (CDC) reports that there were 2.87 million cases of traumatic brain injury (TBI) in the United States in 2014, 69 million worldwide. Some studies suggest a connection between TBI and increased risk of dementia, but it remains unclear whether the risk increases with age and TBI severity. Given our aging population, it is essential to better characterize the link between TBI and dementia. Methods We conducted a retrospective cohort study of two major academic medical centers for years 2000-2015. We identified all patients with TBI, aged 45 and older. Variables included age, TBI severity, pre-existing dementia, dementia diagnosed after TBI, years to dementia, and follow-up time. TBI severity was determined by head/neck AIS score, using ICD-PIC software. Mild TBI was defined as AIS 0-2, and Moderate/Severe as AIS 3-6. Analysis was done in R.v.3.0.1 software. Results Overall, there were 14,199 patients with TBI, of which 9,938 (70%) were mild and 4,261 (30%) were moderate/severe. Mean age was 70.5 (±14.0). There were 1,422 cases (10%) of pre-existing dementia, and 850 (6%) cases of dementia diagnosed after TBI. The mean follow-up time was 1,129 (±1,474) days. The 75-84 age group had the highest incidence of TBI (28%). When compared by age group and TBI severity, the proportion of moderate/severe TBI increased with increasing age. The proportion of pre-existing dementia increased with age, as expected. Notably, there is increased incidence of dementia after TBI in patients aged 65 and older (7-10%, p < 0.001). There was no observed effect of TBI severity on the risk of dementia after TBI. Conclusions Our results indicate that TBI is a risk factor for the development of dementia, especially in patients aged 65 and older. Given the global public health burden of these two diseases it is critical to develop effective TBI primary prevention strategies. Key messages TBI is a risk factor for the development of dementia. Need for public health measures to mitigate the risk of TBI in the patient population 65 and older.

BACKGROUND: Although survival statistics for glioblastoma patients are well-defined on population-scale, individualizing survival prognostication remains challenging. Furthermore, treatment efficacy proven on group-level does not directly apply to the same extent in each individual patient. This study compares a variety of statistical and machine learning algorithms in their ability to predict the individual survival benefit of adjuvant chemo- and radiotherapy. The best performing model was used to develop an online survival calculator. METHODS: Patients operated for a histopathologically confirmed glioblastoma were extracted from the Surveillance Epidemiology and End Results database (2005–2015) and split into a training and hold-out test set with an 80/20 ratio. Fifteen statistical and machine learning algorithms were trained based on 13 demographic, socioeconomic, clinical, and radiographic features to predict overall survival, one-year survival status, and subject-level ten-year survival curves. The resultant models were compared based on discriminatory performance and calibration, as well as interpretability, predictive applicability, and computational efficiency. FINDINGS: In total, 20,821 patients met our inclusion criteria. The accelerated failure time (AFT) model demonstrated superior performance in terms of discrimination (concordance index 0.70), calibration, interpretability, predictive applicability, and computational efficiency compared to cox-proportional hazards regression and a variety of competitive machine learning models. The AFT model was, therefore, deployed through a free, publicly-available software. INTERPRETATION: This study provides a framework for the development of outcome prediction tools in cancer patients, as well as an online calculator for the prediction of survival and treatment benefit in glioblastoma patients. Model deployment of survival calculators requires a multidimensional assessment rather than a single metric comparison. Future research efforts should improve the interpretability, predictive applicability, and computational efficiency of existing machine learning algorithms, increase the granularity of population-based registries, and externally validate the proposed prediction tool.

Operation Just Cause was until recently the largest American combat operation since Vietnam, and remains the largest nighttime parachute operation since World War II. All 252 casualties were airlifted to San Antonio, Texas, for medical treatment. Greater than 80% sustained orthopedic injuries. Sixteen patients were admitted for injuries to the back or neck. Three of the four patients with significant fractures or fracture-dislocations were paraplegic. Two of the three patients with gunshot wounds to the back required extensive reconstruction for wound management. In addition to the 252 casualties, there were 23 fatalities, among whom 7 suffered major injuries to the spine. Spine injuries represented the most significant source of long-term morbidity among those soldiers wounded in combat in Panama, and were common among the fatalities. Noteworthy in these cases was the high percentage of severe neurologic injuries in patients with significant fractures (75%), particularly fractures associated with gunshot wounds. Also of interest were the cases of major soft tissue injury associated with high-velocity gunshot wounds (66%) and the extensive soft tissue surgery needed to treat these injuries. Language: en