Evaluating the potential role of determinants of health on encephalocele patient outcomes - a combined retrospective study and systematic review.

INTRODUCTION: To evaluate the outcomes and demographics of encephalocele patients who were born and received treatment in our neonatal ICU and conduct a PRISMA literature review. METHODS: An Institutional Review Board (IRB)-approved retrospective cohort study was undertaken to investigate the results of treating encephalocele patients at Jackson Memorial Hospital (JMH) from 1998 to 2022. The study focused on assessing outcomes and the impact of maternal socioeconomic factors, such as religion, age, and education, along with the timing of diagnosis, in connection with a systematic review. RESULTS: A total of 20 encephalocele patients were identified (13 females and 7 males), with 15 having available medical records for review. Most of these cases involved occipital encephaloceles (73.3%). Maternal ages at the time of delivery ranged from 15 to 42 years, with a mean age of 27.3 years. The average gestational age at birth was 37 weeks. Ten cases had a prenatal diagnosis documented, occurring between 12 and 24.5 weeks of gestation. Three of the surviving patients had records of prenatal counseling that included discussions about termination. No infections were reported. Among the 15 cases, 11 patients (73.3%) were alive at the last follow-up, with a mean age at follow-up of 4.12 years, ranging from 6 weeks to 15 years post-birth. Hydrocephalus was noted in 26.7%. Only 1 mother had completed high school. Most mothers were either on Medicaid (9 patients) or uninsured (3 patients), with only 3 having commercial insurance. Religious affiliations varied among the mothers, with 14 out of 15 identifying with a particular religion. The systematic review identified 22 articles from various countries, with 11 articles meeting the inclusion criteria for qualitative analysis. These articles revealed potential maternal risk factors for encephaloceles, including low-nutrient diets, inadequate folic acid intake, young maternal age, advanced maternal age, low socioeconomic status, and limited educational attainment. CONCLUSIONS: In the twenty-first century, there is a positive trend in the survival rates of children born with encephalocele. However, maternal factors such as low socioeconomic status and limited educational attainment remain prominent, affecting their ability to access timely prenatal care and impacting follow-up medical care for these children.

Prognostic and Diagnostic Utility of Serum Biomarkers in Pediatric Traumatic Brain Injury.

Traumatic brain injury (TBI) remains a major cause of morbidity and death among the pediatric population. Timely diagnosis, however, remains a complex task because of the lack of standardized methods that permit its accurate identification. The aim of this study was to determine whether serum levels of brain injury biomarkers can be used as a diagnostic and prognostic tool in this pathology. This prospective, observational study collected and analyzed the serum concentration of neuronal injury biomarkers at enrollment, 24h and 48h post-injury, in 34 children ages 0-18 with pTBI and 19 healthy controls (HC). Biomarkers included glial fibrillary acidic protein (GFAP), neurofilament protein L (NfL), ubiquitin-C-terminal hydrolase (UCH-L1), S-100B, tau and tau phosphorylated at threonine 181 (p-tau181). Subjects were stratified by admission Glasgow Coma Scale score into two categories: a combined mild/moderate (GCS 9-15) and severe (GCS 3-8). Glasgow Outcome Scale-Extended (GOS-E) Peds was dichotomized into favorable (≤4) and unfavorable (≥5) and outcomes. Data were analyzed utilizing Prism 9 and R statistical software. The findings were as follows: 15 patients were stratified as severe TBI and 19 as mild/moderate per GCS. All biomarkers measured at enrollment were elevated compared with HC. Serum levels for all biomarkers were significantly higher in the severe TBI group compared with HC at 0, 24, and 48h. The GFAP, tau S100B, and p-tau181 had the ability to differentiate TBI severity in the mild/moderate group when measured at 0h post-injury. Tau serum levels were increased in the mild/moderate group at 24h. In addition, NfL and p-tau181 showed increased serum levels at 48h in the aforementioned GCS category. Individual biomarker performance on predicting unfavorable outcomes was measured at 0, 24, and 48h across different GOS-E Peds time points, which was significant for p-tau181 at 0h at all time points, UCH-L1 at 0h at 6-9 months and 12 months, GFAP at 48h at 12 months, NfL at 0h at 12 months, tau at 0h at 12 months and S100B at 0h at 12 months. We concluded that TBI leads to increased serum neuronal injury biomarkers during the first 0-48h post-injury. A biomarker panel measuring these proteins could aid in the early diagnosis of mild to moderate pTBI and may predict neurological outcomes across the injury spectrum.

Using intent to get ahead of pediatric cranial firearm injuries.

OBJECTIVE: Pediatric firearm injuries (PFI) are a public health crisis. Little is known about how injury intent may influence the outcome of pediatric cranial firearm injuries (PCFI). The current study sought to compare demographics and outcomes of PCFI based on intent of injury. METHODS: The Nationwide Readmission Database (2010-2014) was queried to identify patients <18 years old with PCFI. Demographics and outcomes were compared by injury intent (assault, self-inflicted, unintentional), and results were weighted for national estimates to create a population-based cohort study. RESULTS: There were 1,365 cases of PCFI identified for an incidence of 11% of all PFI. The majority of patients were male (83 %), >13 years (81 %), and had an injury severity score >15 (79 %). Overall PCFI mortality was 43 %, compared to 6 % for all PFI. Assault was the most common intent (51 %), followed by self-inflicted (25 %), and unintentional (24 %). Assault was more likely to occur in patients from low-income households (61 % vs. 31 % self-inflicted vs. 42 % unintentional), p < 0.001. Unintentional injuries occurred in those <13 years old (40 % vs. 12 % assault vs. 16 % self-inflicted) and more often resulted in facial fracture (19 % vs. 11 % vs. 13 %), all p < 0.001. Readmission rate within the year was 21 %. The majority (56 %) of readmissions were unplanned, and the rate was highest for assault (77 % vs. <1 % self-inflicted vs. 44 % unintentional, p < 0.001). CONCLUSIONS: PCFI are associated with significant morbidity and mortality. Demographics and outcomes vary by intent of injury; knowledge of these patterns can direct future interventions to reduce injuries and impact outcomes.

Treating Delinquent and Feebleminded Juveniles at the Beloit Industrial School for Girls in Early Twentieth-Century Kansas.

This study explores the troubling and unintended consequences of public health efforts to address the problem of juvenile delinquency and feeblemindedness. Health care professionals, superintendents, and other authority figures equated undesirable juvenile behaviors such as keeping "bad company" or "falling in with the wrong crowd," truancy, and petty theft with poor breeding, low intelligence, and inheritable criminal tendencies. This article interrogates historical documentation culled from the Kansas State Historical Society (KSHS) and focuses on a few specific cases to reveal the ways a patriarchal political and medical state system both protected and alienated young woman accused of a myriad of behavior issues including delinquency, incorrigibility, and feeblemindedness. I highlight the lives of juvenile women sentenced to the Beloit Industrial School for Girls not simply to better understand an isolated period in United States history but also reproduction. The broader implications of the narratives of girls housed at the Beloit Industrial School for Girls throughout the first half of the twentieth century in Kansas reveal troubling and unintended consequences of public health efforts to fix the problems of delinquency, contagion, and the generational inheritance of undesirable characteristics.

Assessment of neuromonitoring use and postoperative readmission rates in pediatric Chiari I malformation with syrinx.

INTRODUCTION: While operative intervention for Chiari malformation type I (CMI) with syringomyelia is well established, there is limited data on outcomes of intraoperative neuromonitoring (IONM). This study sought to explore differences in procedural characteristics and their effects on postoperative readmission rates. METHODS: The Nationwide Readmission Database was queried from 2010 to 2014 for patients ≤ 18 years of age with CMI and syringomyelia who underwent cranial decompression or spinal decompression. Demographics, hospital characteristics, and outcomes were analyzed. RESULTS: Over the 5-year period, 2789 patients were identified that underwent operative treatment for CMI with syringomyelia. Mean age was 10 ± 4 years with 55% female. During their index hospitalization 14% of the patients had IONM. Patients receiving IONM had no significant difference in Charleston Comorbidity Index ≥ 1 (16% vs. 15% without, p = 0.774). IONM was more often used in those with private insurance (63% vs. 58% without, p = 0.0004) and less likely in those with Medicaid (29% vs. 37% without, p = 0.004). Patients receiving IONM were more likely to have a postoperative complication (23% vs 17%, p = 0.004) and were more likely to have hospital lengths of stay > 7 days (9% vs. 5% without, p = 0.005). Readmission rates for CMI were 9% within 30 days and 15% within the year. The majority (89%) of readmissions were unplanned. 25% of readmissions were for infection and 27% of readmissions underwent a CMI reoperation. The 30-day readmission rate was higher for those with IONM (12% vs. 8% without, p = 0.010). Median cost for hospitalization was significantly higher for patients with IONM ($26,663 ($16,933-34,397)) vs. those without ($14,577 ($11,538-18,392)), p < 0.001. CONCLUSION: The use of intraoperative neuromonitoring for operative repair of CMI is associated with higher postoperative complications and readmissions. In addition, there are disparities in its use and increased cost to the healthcare system. Further studies are needed to elucidate the factors underlying this association.

Clinical course of pediatric gunshot wounds involving the spine and spinal cord: the Miami experience.

OBJECTIVE: Civilian gunshot wounds (GSWs) involving the skeletal spine and spinal cord in pediatric patients are fortunately rare. Nevertheless, their presentation mandates judicious evaluation, and their clinical outcomes remain poorly defined. Thus, the authors aimed to characterize the clinical course of this traumatic presentation in the pediatric population based on their institutional experience. METHODS: A retrospective review of a level I trauma center database was performed for the period 2011-2021. Clinical data were included for patients aged ≤ 18 years who had presented with radiographic and clinical evidence of a GSW to the spine and had at least one documented follow-up at least 6 months after injury. The primary outcomes of the study were the categorization of gunshot injuries and the results of neurological and functional examinations. RESULTS: A total of 13 patients satisfied the study selection criteria. The mean patient age was 15.7 ± 1.6 years, and all presentations were assault in nature. Most of the patients were male (n = 12, 92%) in gender, Black in race (n = 11, 85%), and from zip codes with a median household income below the local county average (n = 10, 77%). All patients presented with a minimum Glasgow Coma Scale score of 14. Examination at presentation revealed American Spinal Injury Association Impairment Scale (AIS) grade A in 3 cases (23%), grade B in 2 (15%), grade C in 1 (8%), grade D in 2 (15%), and grade E in 5 (38%). Gunshot injury involved all regions of the spine, most commonly the cervical and thoracic spine (n = 6 for each, 46%). In terms of skeletal injury, the most common injuries were to the facet (n = 10, 77%) and the pedicle (n = 8, 62%), with evidence of intracanal injury in 9 patients (69%). Neurosurgical intervention was pursued in 1 patient (8%). Overall, 7 patients (54%) experienced a complication during admission, and the median length of hospitalization was 12 days (range 1-88 days) without any mortality events. Within 90 days from discharge, 2 patients (15%) were readmitted to the hospital for further care. The mean follow-up was 28.9 months (range 6-74 months), by which only 1 patient (8%) had an improved AIS examination; all other patients remained at their initial AIS grade. CONCLUSIONS: Pediatric GSWs involving the spine are typically nonfatal presentations, and their long-term functional outlook appears contingent on clinical examination findings at initial presentation. Although neurosurgical intervention is not necessary in most cases, judicious evaluation of radiographic and clinical examinations by a neurosurgical team is strongly recommended to optimize recovery.

A Druggable UHRF1/DNMT1/GLI Complex Regulates Sonic Hedgehog-Dependent Tumor Growth.

Dysregulation of Sonic hedgehog (SHH) signaling drives the growth of distinct cancer subtypes, including medulloblastoma (MB). Such cancers have been treated in the clinic with a number of clinically relevant SHH inhibitors, the majority of which target the upstream SHH regulator, Smoothened (SMO). Despite considerable efficacy, many of these patients develop resistance to these drugs, primarily due to mutations in SMO. Therefore, it is essential to identify druggable, signaling components downstream of SMO to target in SMO inhibitor resistant cancers. We utilized an integrated functional genomics approach to identify epigenetic regulators of SHH signaling and identified a novel complex of Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), DNA methyltransferase 1 (DNMT1), and GLI proteins. We show that this complex is distinct from previously described UHRF1/DNMT1 complexes, suggesting that it works in concert to regulate GLI activity in SHH driven tumors. Importantly, we show that UHRF1/DNMT1/GLI complex stability is targeted by a repurposed FDA-approved therapy, with a subsequent reduction in the growth of SHH-dependent MB ex vivo and in vivo. IMPLICATIONS: This work describes a novel, druggable UHRF1/DNMT1/GLI complex that regulates SHH-dependent tumor growth, and highlights an FDA-approved drug capable of disrupting this complex to attenuate tumor growth.

Noncanonical activation of GLI signaling in SOX2+ cells drives medulloblastoma relapse.

SRY (sex determining region Y)-box 2 (SOX2)-labeled cells play key roles in chemoresistance and tumor relapse; thus, it is critical to elucidate the mechanisms propagating them. Single-cell transcriptomic analyses of the most common malignant pediatric brain tumor, medulloblastoma (MB), revealed the existence of astrocytic Sox2+ cells expressing sonic hedgehog (SHH) signaling biomarkers. Treatment with vismodegib, an SHH inhibitor that acts on Smoothened (Smo), led to increases in astrocyte-like Sox2+ cells. Using SOX2-enriched MB cultures, we observed that SOX2+ cells required SHH signaling to propagate, and unlike in the proliferative tumor bulk, the SHH pathway was activated in these cells downstream of Smo in an MYC-dependent manner. Functionally different GLI inhibitors depleted vismodegib-resistant SOX2+ cells from MB tissues, reduced their ability to further engraft in vivo, and increased symptom-free survival. Our results emphasize the promise of therapies targeting GLI to deplete SOX2+ cells and provide stable tumor remission.

Clinical complications of surviving gunshot wounds to the head in children and adolescents: the Miami experience.

BACKGROUND: Gunshot wounds (GSWs) to the head in the pediatric population are both rare and devastating, with the clinical course of pediatric survivors poorly understood. Correspondingly, the aim of this study was to summarize the clinical complications clinicians can expect of survivors of GSW to the head in children and adolescents in hospital and after discharge. METHODS: A retrospective review of our Level 1 trauma center database between 2011 and 2021 was performed. Clinical data was extracted for those patients aged ≤ 18 years old who survived initial hospitalization with at least one documented follow-up. Categorical data were then compared using Chi-squared test. RESULTS: A total of 19 pediatric survivors of GSW to the head satisfied all selection criteria with an average age was 15.3 years. The majority of cases were isolated head injuries (63%), with an average Glasgow Coma Score (GCS) of 11.9. Bullet trajectory was intraparenchymal in 11 (58%) cases and extraparenchymal in 8 (42%) cases, with 15 (79%) patients treated by surgical intervention. A total of 13 (68%) patients experienced a complication during their hospitalization, with the most common being sympathetic hypertension and endocrinologic salt wasting, each occurring in 5 (26%) patients. With respect to complication categories, the intraparenchymal patients experienced statistically more complications than extraparenchymal patients that were infectious (54% vs 0%, P = 0.01) and sympathetic (45% vs 0%, P = 0.03) in nature. However, with respect to overall neurologic (P = 0.24), endocrinologic (P = 0.24), and traumatic (P = 0.24) complications, their incidences were statistically comparable. All patients were successfully discharged on average post-injury day 22 with an average GCS of 14.0. Mean follow-up for the cohort was 42.6 months, with an average GCS of 14.3. A total of 6 (32%) patients experienced a complication relatable to their initial GSW injury after discharge. The most common individual complication was new-onset seizures in 3 (16%) patients. CONCLUSIONS: Survivors of pediatric GSW to the head can experience multi-systemic complications during both initial hospitalization and afterwards, and bullet trajectory involving the parenchyma may be associated with specific complications more than others. Dedicated inpatient management and outpatient follow-up involving surveillance for complications across all systems, not just neurological, are recommended to ensure patients receive the best care possible.

Large sphenoid mucocele presenting with cranial neuropathies in a 10-year-old boy: case report and literature review.

INTRODUCTION: Mucoceles in the sphenoid sinus are rare, making up 1-3% of all paranasal sinus mucoceles. Sphenoid sinus mucoceles among pediatric patients are uncommon and have a range of presentations due to their proximity to other structures, in rare cases causing oculomotor and visual disturbances through expansion and mass effect. CASE REPORT: We present a case of a large expansile sphenoid sinus mucocele causing cranial nerve III and VI palsies in a 10-year-old boy. Endoscopic resection of the mucocele was performed for diagnosis and decompression, leading to immediate relief of the patient's symptoms and improvement in cranial nerve function. Post-operative imaging showed complete resolution of the mucocele. CONCLUSION: Our case report and review of the current literature emphasizes that prompt diagnosis and intervention can lead to a good clinical outcome and prevention of permanent cranial neuropathy.

Intraarterial delivery of bevacizumab and cetuximab utilizing blood-brain barrier disruption in children with high-grade glioma and diffuse intrinsic pontine glioma: results of a phase I trial.

OBJECTIVE: Delivery of drugs intraarterially to brain tumors has been demonstrated in adults. In this study, the authors initiated a phase I trial of superselective intraarterial cerebral infusion (SIACI) of bevacizumab and cetuximab in pediatric patients with refractory high-grade glioma (diffuse intrinsic pontine glioma [DIPG] and glioblastoma) to determine the safety and efficacy in this population. METHODS: SIACI was used to deliver mannitol (12.5 ml of 20% mannitol) to disrupt the blood-brain barrier (BBB), followed by bevacizumab (15 mg/kg) and cetuximab (200 mg/m2) to target VEGF and EGFR, respectively. Patients with brainstem tumors had a balloon inflated in the distal basilar artery during mannitol infusion. RESULTS: Thirteen patients were treated (10 with DIPG and 3 with high-grade glioma). Toxicities included grade I epistaxis (2 patients) and grade I rash (2 patients). There were no dose-limiting toxicities. Of the 10 symptomatic patients, 6 exhibited subjective improvement; 92% showed decreased enhancement on day 1 posttreatment MRI. Of 10 patients who underwent MRI at 1 month, 5 had progressive disease and 5 had stable disease on FLAIR, whereas contrast-enhanced scans demonstrated progressive disease in 4 patients, stable disease in 2, partial response in 2, and complete response in 1. The mean overall survival for the 10 DIPG patients was 519 days (17.3 months), with a mean posttreatment survival of 214.8 days (7.2 months). CONCLUSIONS: SIACI of bevacizumab and cetuximab was well tolerated in all 13 children. The authors' results demonstrate safety of this method and warrant further study to determine efficacy. As molecular targets are clarified, novel means of bypassing the BBB, such as intraarterial therapy and convection-enhanced delivery, become more critical. Clinical trial registration no.: NCT01884740 (clinicaltrials.gov).

Intracranial arachnoid cysts in an infant: A technical note on the innovative use of navigation and flexible endoscopy for cyst fenestration.

BACKGROUND: Intracranial arachnoid cysts (ACs) are a cerebral spinal fluid (CSF) collection within the meninges. They typically arise during embryologic development. Some are stable overtime with little consequence, but large or growing cysts may require surgical intervention. The optimal surgical technique is debated and may be more technically challenging in the infant age group. CASE DESCRIPTION: Our unique case report details a 10-month-old (6 months corrected age) infant who presented with a drastic increase in head circumference and was found to have midline shift and three cysts - one large and two smaller ones. He was treated with an innovative surgical approach combining stereotactic introduction of a catheter to facilitate subsequent flexible endoscopy allowing three separate cysts to be treated through one small surgical incision with no complications and a stable examination on 2-year follow-up. CONCLUSION: Symptomatic ACs in the infant population that require treatment can be addressed with open surgery to fenestrate the cyst, endoscopic cyst fenestration, or cystoperitoneal shunting. Typically, surgeons must choose between a rigid endoscope which allows stereotactic navigation or a flexible endoscope which allows multiple trajectories but precludes navigation. Our case demonstrates that combining stereotactic ventricular placement before flexible endoscopy provides the benefit of both approaches and allows for successful endoscopic treatment in a young patient with durable results.

Colloid cysts of the third ventricle in children.

OBJECTIVE: The rarity of colloid cysts in children makes it difficult to characterize this entity and offer meaningful advice on treatment. Infrequent case reports exist, but to date there has been no age-specific assessment. The purpose of this study was to define any differences between children and adults who are evaluated and treated for colloid cysts of the third ventricle. METHODS: Patients with colloid cysts were reviewed and stratified by age. Individuals ≤ 18 years of age were defined as pediatric patients and those > 18 years of age as adults. Clinical and radiographic data, treatment, and postoperative outcomes were compared between both groups. Bivariate analysis was conducted using the Fisher exact test for categorical variables and Mann-Whitney U-test for continuous variables. RESULTS: Of 132 endoscopic resections (121 primary, 10 secondary, and 1 tertiary) of a colloid cyst, 9 (6.8%) were performed in pediatric patients (mean age 14.1 years, range 9-18 years) and 123 (93.2%) were performed in adult patients (mean age 43.8 years, range 19-73 years). Cases were found incidentally more commonly in pediatric than adult patients (66.7% vs 37.4%, p > 0.05), and pediatric patients had lower rates of hydrocephalus than adult patients (11.1% vs 63.4%, p < 0.05). Acute decompensation at presentation was found in 8 adults (6.5%) but no children. Complete cyst removal (88.9% vs 90.2%, p > 0.05) and length of stay (1.6 days vs 2.9 days, p > 0.05) were not significantly different between the groups. Postoperative complications (6.5% in adults, 0% in children) and recurrence (2.4% in adults, 0% in children) were rare in both groups, and there were no treatment-related deaths. The mean postoperative radiological follow-up was longer in pediatric patients (45 months, range 4-89 months) than adults (44.1 months, range 1-171 months). CONCLUSIONS: While differences exist between children and adults regarding colloid cyst presentation, these are in keeping with the predicted evolution of a slow-growing lesion. Consistent with this observation, children had lower rates of hydrocephalus and a smaller mean maximal cyst diameter. Contrary to the published literature, however, sudden deterioration was not observed in pediatric patients but occurred in adult patients. In this limited pediatric sample size, the authors have not recorded any postoperative complications or recurrences to date. These encouraging results with endoscopic removal may positively impact future decisions related to children given their protracted life expectancy and projected rates of progression.

Myelomeningocele-associated hydrocephalus: nationwide analysis and systematic review.

OBJECTIVE: Myelomeningocele (MMC), the most severe form of spina bifida, is characterized by protrusion of the meninges and spinal cord through a defect in the vertebral arches. The management and prevention of MMC-associated hydrocephalus has evolved since its initial introduction with regard to treatment of MMC defect, MMC-associated hydrocephalus treatment modality, and timing of hydrocephalus treatment. METHODS: The Nationwide Inpatient Sample (NIS) database from the years 1998-2014 was reviewed and neonates with spina bifida and hydrocephalus status were identified. Timing of hydrocephalus treatment, delayed treatment (DT) versus simultaneous MMC repair with hydrocephalus treatment (ST), and treatment modality (ETV vs ventriculoperitoneal shunt [VPS]) were analyzed. Yearly trends were assessed with univariable logarithmic regression. Multivariable logistic regression identified correlates of inpatient shunt failure. A PRISMA systematic literature review was conducted that analyzed data from studies that investigated 1) MMC closure technique and hydrocephalus rate, 2) hydrocephalus treatment modality, and 3) timing of hydrocephalus treatment. RESULTS: A weighted total of 10,627 inpatient MMC repairs were documented in the NIS, 8233 (77.5%) of which had documented hydrocephalus: 5876 (71.4%) were treated with VPS, 331 (4.0%) were treated with ETV, and 2026 (24.6%) remained untreated on initial inpatient stay. Treatment modality rates were stable over time; however, hydrocephalic patients in later years were less likely to receive hydrocephalus treatment during initial inpatient stay (odds ratio [OR] 0.974, p = 0.0331). The inpatient hydrocephalus treatment failure rate was higher for patients who received ETV treatment (17.5% ETV failure rate vs 7.9% VPS failure rate; p = 0.0028). Delayed hydrocephalus treatment was more prevalent in the later time period (77.9% vs 69.5%, p = 0.0287). Predictors of inpatient shunt failure included length of stay, shunt infection, jaundice, and delayed treatment. A longer time between operations increased the likelihood of inpatient shunt failure (OR 1.10, p < 0.0001). However, a meta-analysis of hydrocephalus timing studies revealed no difference between ST and DT with respect to shunt failure or infection rates. CONCLUSIONS: From 1998 to 2014, hydrocephalus treatment has become more delayed and the number of hydrocephalic MMC patients not treated on initial inpatient stay has increased. Meta-analysis demonstrated that shunt malfunction and infection rates do not differ between delayed and simultaneous hydrocephalus treatment.

Increased sensitivity to traumatic axonal injury on postconcussion diffusion tensor imaging scans in National Football League players by using premorbid baseline scans.

OBJECTIVE: Statistical challenges exist when using diffusion tensor imaging (DTI) to assess traumatic axonal injury (TAI) in individual concussed athletes. The authors examined active professional American football players over a 6-year time period to study potential TAI after concussion and assess optimal methods to analyze DTI at the individual level. METHODS: Active American professional football players recruited prospectively were assessed with DTI, conventional MRI, and standard clinical workup. Subjects underwent an optional preseason baseline scan and were asked to undergo a scan within 5 days of concussion during gameplay. DTI from 25 age- and sex-matched controls were obtained. Both semiautomated region-of-interest analysis and fully automated tract-based spatial statistics (TBSS) were used to examine DTI at individual and group levels. Statistical differences were assessed comparing individual DTI data to baseline imaging versus a normative database. Group-level comparisons were also performed to determine if longer exposure to professional-level play or prior concussion cause white matter microstructural integrity changes. RESULTS: Forty-nine active professional football players were recruited into the study. Of the 49 players, 7 were assessed at baseline during the preseason and after acute concussion. An additional 18 players were assessed after acute concussion only. An additional 24 players had only preseason baseline assessments. The results suggest DTI is more sensitive to suspected TAI than conventional MRI, given that 4 players demonstrated decreased fractional anisotropy (FA) in multiple tracts despite normal conventional MRI. Furthermore, the data suggest individual assessment of DTI data using baseline premorbid imaging is more sensitive than typical methods of comparing data to a normative control group. Among all subjects with baseline data, 1 reduced FA tract (± 2.5 standard deviations) was found using the typical normative database reference versus 10 statistically significant (p < 0.05) reduced FA tracts when referencing internal control baseline data. All group-level comparisons were statistically insignificant (p > 0.05). CONCLUSIONS: Baseline premorbid DTI data for individual DTI analysis provides increased statistical sensitivity. Specificity using baseline imaging also increases because numerous potential etiologies for reduced FA may exist prior to a concussion. These data suggest that there is a high potential for false-positive and false-negative assessment of DTI data using typical methods of comparing an individual to normative groups given the variability of FA values in the normal population.

Long-term outcomes of lumbar microdiscectomy in the pediatric population: a large single-institution case series.

OBJECTIVE: Few studies describe long-term functional outcomes of pediatric patients who have undergone lumbar microdiscectomy (LMD) because of the rarity of pediatric disc herniation and the short follow-up periods. The authors analyzed risk factors, clinical presentation, complications, and functional outcomes of a single-institution series of LMD patients over a 19-year period. METHODS: A retrospective case series was conducted of pediatric LMD patients at a large pediatric academic hospital from 1998 to 2017. The authors examined premorbid risk factors, clinical presentation, physical examination findings, type and duration of conservative management, indications for surgical intervention, complications, and postoperative outcomes. RESULTS: Over the 19-year study period, 199 patients underwent LMD at the authors' institution. The mean age at presentation was 16.0 years (range 12-18 years), and 55.8% were female. Of these patients, 70.9% participated in competitive sports, and among those who did not play sports, 65.0% had a body mass index greater than 25 kg/m2. Prior to surgery, conservative management had failed in 98.0% of the patients. Only 3 patients (1.5%) presented with cauda equina syndrome requiring emergent microdiscectomy. Complications included 4 cases of postoperative CSF leak (2.0%), 1 case of a noted intraoperative CSF leak, and 3 cases of wound infection (1.5%). At the first postoperative follow-up appointment, minimal or no pain was reported by 93.3% of patients. The mean time to return to sports was 9.8 weeks. During a mean follow-up duration of 8.2 years, 72.9% of patients did not present again after routine postoperative appointments. The total risk of reoperation was a rate of 7.5% (3.5% of patients underwent reoperation for the same level; 4.5% underwent adjacent-level decompression, and one patient [0.5%] ultimately underwent a fusion). CONCLUSIONS: Microdiscectomy is a safe and effective treatment for long-term relief of pain and return to daily activities among pediatric patients with symptomatic lumbar disc disease in whom conservative management has failed.

Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies.

The high selectivity of the human blood-brain barrier (BBB) restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic organ-on-a-chip BBB model lined by induced pluripotent stem cell-derived human brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins and functional efflux pumps, and it displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB.

EGFR amplification and classical subtype are associated with a poor response to bevacizumab in recurrent glioblastoma.

PURPOSE: The highly vascular malignant brain tumor glioblastoma (GBM) appears to be an ideal target for anti-angiogenic therapy; however, clinical trials to date suggest the VEGF antibody bevacizumab affects only progression-free survival. Here we analyze a group of patients with GBM who received bevacizumab treatment at recurrence and are stratified according to tumor molecular and genomic profile (TCGA classification), with the goal of identifying molecular predictors of the response to bevacizumab. METHODS: We performed a retrospective review of patients with a diagnosis of glioblastoma who were treated with bevacizumab in the recurrent setting at our hospital, from 2006 to 2014. Treatment was discontinued by the treating neuro-oncologists, based on clinical and radiographic criteria. Pre- and post-treatment imaging and genomic subtype were available on 80 patients. We analyzed time on bevacizumab and time to progression. EGFR gene amplification was determined by FISH. RESULTS: Patients with classical tumors had a significantly shorter time on bevacizumab than mesenchymal, and proneural patients (2.7 vs. 5.1 vs. 6.4 and 6.0 months respectively, p = 0.011). Classical subtype and EGFR gene amplification were significantly associated with a shorter time to progression both in univariate (p < 0.001 and p = 0.007, respectively) and multivariate analysis (both p = 0.010). CONCLUSION: EGFR gene amplification and classical subtype by TCGA analysis are associated with significantly shorter time to progression for patients with recurrent GBM when treated with bevacizumab. These findings can have a significant impact on decision-making and should be further validated prospectively.

A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma.

PURPOSE: Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup medulloblastoma driven by TRP53 mutations is essentially lethal. Casein kinase 1α (CK1α) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a second-generation CK1α activator against TRP53-mutant, MYCN-amplified medulloblastoma. EXPERIMENTAL DESIGN: The ability of this CK1α activator to block SHH signaling was determined in vitro using GLI reporter cells, granular precursor primary cultures, and PATCHED1 (PTCH1)-mutant sphere cultures. While in vivo efficacy was tested using 2 different medulloblastoma mouse models: PTCH1 and ND2:SMOA1. Finally, the clinical relevance of CK1α activators was demonstrated using a TRP53-mutant, MYCN-amplified patient-derived xenograft. RESULTS: SSTC3 inhibited SHH activity in vitro, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH medulloblastoma. SSTC3 accumulated in the brain, inhibited growth of SHH medulloblastoma tumors, and blocked metastases in a genetically engineered vismodegib-resistant mouse model of SHH medulloblastoma. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derived TRP53-mutant, MYCN-amplified, SHH subgroup medulloblastoma xenografts, increasing overall survival. CONCLUSIONS: Using a newly described small-molecule, SSTC3, we show that CK1a activators could address a significant unmet clinical need for patients with SMO inhibitor-resistant medulloblastoma, including those harboring mutations in TRP53.