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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.
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Encefalocele , Humanos , Estudios Retrospectivos , Encefalocele/epidemiología , Femenino , Masculino , Adulto Joven , Recién Nacido , Adulto , Adolescente , Resultado del Tratamiento , Determinantes Sociales de la SaludRESUMEN
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.
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Malformación de Arnold-Chiari , Siringomielia , Estados Unidos , Niño , Humanos , Femenino , Adolescente , Masculino , Malformación de Arnold-Chiari/cirugía , Malformación de Arnold-Chiari/complicaciones , Siringomielia/complicaciones , Readmisión del Paciente , Complicaciones Posoperatorias/etiología , Descompresión Quirúrgica/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
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.
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Neoplasias Encefálicas , Enfermedades de los Nervios Craneales , Mucocele , Enfermedades de los Senos Paranasales , Niño , Enfermedades de los Nervios Craneales/etiología , Humanos , Masculino , Mucocele/complicaciones , Mucocele/diagnóstico por imagen , Mucocele/cirugía , Enfermedades de los Senos Paranasales/complicaciones , Enfermedades de los Senos Paranasales/diagnóstico por imagen , Enfermedades de los Senos Paranasales/cirugía , Seno Esfenoidal/diagnóstico por imagen , Seno Esfenoidal/cirugía , Tomografía Computarizada por Rayos XRESUMEN
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.
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Traumatismos Craneocerebrales , Heridas por Arma de Fuego , Adolescente , Niño , Estudios de Cohortes , Traumatismos Craneocerebrales/complicaciones , Humanos , Estudios Retrospectivos , Centros Traumatológicos , Heridas por Arma de Fuego/complicaciones , Heridas por Arma de Fuego/cirugíaRESUMEN
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.
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Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Receptores ErbB/genética , Femenino , Estudios de Seguimiento , Amplificación de Genes , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Variantes Farmacogenómicas , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
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.
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Hidrocefalia/cirugía , Meningomielocele/cirugía , Complicaciones Posoperatorias/cirugía , Insuficiencia del Tratamiento , Femenino , Humanos , Hidrocefalia/complicaciones , Recién Nacido , Masculino , Meningomielocele/complicaciones , Neuroendoscopía/métodos , Tercer Ventrículo/cirugía , Resultado del Tratamiento , Derivación Ventriculoperitoneal/métodos , Ventriculostomía/métodosRESUMEN
Objective To establish a maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of Cetuximab after osmotic disruption of the blood-brain barrier (BBB) with mannitol, and examine safety of the procedure in patients with recurrent malignant glioma. Methods A total of 15 patients with recurrent malignant glioma were included in the current study. The starting dose of Cetuximab was 100 mg/m(2) and dose escalation was done to 250 mg/m(2). All patients were observed for 28 days post-infusion for any side effects. Results There was no dose-limiting toxicity from a single dose of SIACI of Cetuximab up to 250 mg/m(2) after osmotic BBB disruption with mannitol. A tolerable rash was seen in 2 patients, anaphylaxis in 1 patient, isolated seizure in 1 patient, and seizure and cerebral edema in 1 patient. Discussion SIACI of mannitol followed by Cetuximab (up to 250 mg/m(2)) for recurrent malignant glioma is safe and well tolerated. A Phase I/II trial is currently underway to determine the efficacy of SIACI of cetuximab in patients with high-grade glioma.
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Antineoplásicos Inmunológicos/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Cetuximab/administración & dosificación , Diuréticos Osmóticos/uso terapéutico , Glioma/tratamiento farmacológico , Manitol/uso terapéutico , Adulto , Anciano , Antineoplásicos Inmunológicos/efectos adversos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Cetuximab/efectos adversos , Quimioterapia Combinada , Femenino , Glioma/diagnóstico por imagen , Glioma/metabolismo , Humanos , Infusiones Intraarteriales , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Resultado del TratamientoRESUMEN
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.
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Armas de Fuego , Heridas por Arma de Fuego , Niño , Humanos , Masculino , Femenino , Adolescente , Heridas por Arma de Fuego/epidemiología , Estudios de Cohortes , Estudios Retrospectivos , IncidenciaRESUMEN
Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic data set that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor 5-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB.
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Diterpenos , Compuestos Epoxi , Meduloblastoma , Fenantrenos , Proteínas Proto-Oncogénicas c-myc , Ensayos Antitumor por Modelo de Xenoinjerto , Fenantrenos/farmacología , Diterpenos/farmacología , Compuestos Epoxi/farmacología , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Meduloblastoma/patología , Meduloblastoma/metabolismo , Animales , Humanos , Ratones , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Línea Celular Tumoral , Profármacos/farmacología , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , OrganofosfatosRESUMEN
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.
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Traumatismos de la Médula Espinal , Heridas por Arma de Fuego , Humanos , Masculino , Niño , Femenino , Heridas por Arma de Fuego/diagnóstico por imagen , Heridas por Arma de Fuego/cirugía , Columna Vertebral , Traumatismos de la Médula Espinal/diagnóstico por imagen , Traumatismos de la Médula Espinal/etiología , Traumatismos de la Médula Espinal/cirugía , Estudios Retrospectivos , Progresión de la EnfermedadRESUMEN
Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, whose manifestations include mental retardation and renal Fanconi syndrome. OCRL has been implicated in membrane trafficking, but disease mechanisms remain unclear. We show that OCRL visits late-stage, endocytic clathrin-coated pits and binds the Rab5 effector APPL1 on peripheral early endosomes. The interaction with APPL1, which is mediated by the ASH-RhoGAP-like domains of OCRL and is abolished by disease mutations, provides a link to protein networks implicated in the reabsorptive function of the kidney and in the trafficking and signaling of growth factor receptors in the brain. Crystallographic studies reveal a role of the ASH-RhoGAP-like domains in positioning the phosphatase domain at the membrane interface and a clathrin box protruding from the RhoGAP-like domain. Our results support a role of OCRL in the early endocytic pathway, consistent with the predominant localization of its preferred substrates, PI(4,5)P(2) and PI(3,4,5)P(3), at the cell surface.
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Endocitosis/fisiología , Endosomas/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Secuencia de Aminoácidos , Animales , Células COS , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular , Chlorocebus aethiops , Vesículas Cubiertas por Clatrina/metabolismo , Cristalografía por Rayos X , Endosomas/enzimología , Glutatión Transferasa/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Riñón/citología , Modelos Biológicos , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosfatidilinositoles/metabolismo , Monoéster Fosfórico Hidrolasas/química , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/aislamiento & purificación , Fosforilación , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/metabolismo , Homología de Secuencia de Aminoácido , Factores de TiempoRESUMEN
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.
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Neoplasias Cerebelosas , Meduloblastoma , Humanos , Proteínas Hedgehog/metabolismo , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Meduloblastoma/metabolismo , Transducción de Señal/genética , Neoplasias Cerebelosas/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
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.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Cerebelosas/genética , Niño , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/genética , Meduloblastoma/patología , Recurrencia Local de Neoplasia , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Transducción de Señal , Proteína con Dedos de Zinc GLI1/metabolismoRESUMEN
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.
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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.
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Quiste Coloide/cirugía , Adolescente , Adulto , Anciano , Niño , Quiste Coloide/complicaciones , Quiste Coloide/patología , Femenino , Humanos , Hidrocefalia/epidemiología , Hidrocefalia/etiología , Masculino , Persona de Mediana Edad , Neuroendoscopía/efectos adversos , Neuroendoscopía/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
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).
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Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/administración & dosificación , Bevacizumab/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Cetuximab/administración & dosificación , Cetuximab/uso terapéutico , Glioma Pontino Intrínseco Difuso/tratamiento farmacológico , Adolescente , Antineoplásicos Inmunológicos/efectos adversos , Bevacizumab/efectos adversos , Neoplasias del Tronco Encefálico/diagnóstico por imagen , Cetuximab/efectos adversos , Niño , Preescolar , Glioma Pontino Intrínseco Difuso/diagnóstico por imagen , Sistemas de Liberación de Medicamentos , Femenino , Glioblastoma/tratamiento farmacológico , Humanos , Inyecciones Intraarteriales , Imagen por Resonancia Magnética , Masculino , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
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.
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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.
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Benzoatos/farmacología , Caseína Quinasa Ialfa/genética , Meduloblastoma/tratamiento farmacológico , Receptor Smoothened/genética , Anilidas/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Xenoinjertos , Humanos , Meduloblastoma/genética , Meduloblastoma/patología , Ratones , Proteína Proto-Oncogénica N-Myc/genética , Metástasis de la Neoplasia , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Receptor Smoothened/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Proteína con Dedos de Zinc GLI1/genéticaRESUMEN
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.