Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long-term survival and recurrence patterns of ...this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Chicago’s Ann & Robert H. Lurie Children’s Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database. For the institutional cohort, we evaluated clinical and histopathological prognostic factors of overall survival (OS) and progression-free survival (PFS) using the log-rank test, and univariate and multivariate Cox proportional-hazards models. Overall survival rates were compared to those of the SEER cohort. Median follow-up time was 11 years. Ten-year OS and PFS were 50 ± 5% and 29 ± 5%, respectively. Findings were validated in the independent SEER cohort, with 10-year OS rates of 52 ± 3%. GTR and grade II pathology were associated with significantly improved OS. However, GTR was not curative for all children. Ten-year OS for patients treated with a GTR was 61 ± 7% and PFS was 36 ± 6%. Pathological examination confirmed most recurrent tumors to be ependymoma, and 74% occurred at the primary tumor site. Current treatment paradigms are not sufficient to provide long-term cure for children with ependymoma. Our findings highlight the urgent need to develop novel treatment approaches for this devastating disease.
Long-term outcomes related to emergency department revisit, hospital readmission, and all-cause mortality, have not been well characterized across the spectrum of pediatric traumatic brain injury ...(TBI). We evaluated emergency department visit outcomes up to 1 year after pediatric TBI, in comparison to a referent group of trauma patients without TBI. We performed a longitudinal, retrospective study of all pediatric trauma patients who presented to emergency departments and hospitals in California from 2005 to 2014. We compared emergency department visits, dispositions, revisits, readmissions, and mortality in pediatric trauma patients with a TBI diagnosis to those without TBI (Other Trauma patients). We identified 208,222 pediatric patients with an index diagnosis of TBI and 1,314,064 patients with an index diagnosis of Other Trauma. Population growth adjusted TBI visits increased by 5.6% while those for Other Trauma decreased by 40.7%. The majority of patients were discharged from the emergency department on their first visit (93.2% for traumatic brain injury vs. 96.5% for Other Trauma). A greater proportion of TBI patients revisited the emergency department (33.4% vs. 3.0%) or were readmitted to the hospital (0.9% vs. 0.04%) at least once within a year of discharge. The health burden within a year after a pediatric TBI visit is considerable and is greater than that of non-TBI trauma. These data suggest that outpatient strategies to monitor for short-term and longer-term sequelae after pediatric TBI are needed to improve patient outcomes, lessen the burden on families, and more appropriately allocate resources in the healthcare system.
Atypical teratoid rhabdoid tumor (ATRT) of the CNS is a highly malignant neoplasm primarily affecting young children, with a historic median survival ranging from 6 to 11 months. Based on a previous ...pilot series, a prospective multi-institutional trial was conducted for patients with newly diagnosed CNS ATRT.
Treatment was divided into five phases: preirradiation, chemoradiation, consolidation, maintenance, and continuation therapy. Intrathecal chemotherapy was administered, alternating intralumbar and intraventricular routes. Radiation therapy (RT) was prescribed, either focal (54 Gy) or craniospinal (36 Gy, plus primary boost), depending on age and extent of disease at diagnosis.
Between 2004 and 2006, 25 patients were enrolled; 20 were eligible for evaluation. Median age at diagnosis was 26 months (range, 2.4 months to 19.5 years). Gross total resection of the primary tumor was achieved in 11 patients. Fourteen patients had M0 disease at diagnosis, one patient had M2 disease, and five patients had M3 disease. Fifteen patients received radiation therapy: 11 focal and four craniospinal. Significant toxicities, in addition to the expected, included radiation recall (n = 2) and transverse myelitis (n = 1). There was one toxic death. Of the 12 patients who were assessable for chemotherapeutic response (pre-RT), the objective response rate was 58%. The objective response rate observed after RT was 38%. The 2-year progression-free and overall survival rates are 53% +/- 13% and 70% +/- 10%, respectively. Median overall survival has not yet been reached.
This intensive multimodality regimen has resulted in a significant improvement in time to progression and overall survival for patients with this previously poor-prognosis tumor.
Summary
Objective
Seizures are common during and after treatment for a primary brain tumor. Our objective was to describe the incidence and risk factors for seizures in long‐term survivors of ...pediatric brain tumors.
Methods
In a retrospective, longitudinal study, we reviewed all consecutive patients during a 12‐month period who were at least 2 years post initial diagnosis of a brain tumor. Data collection included age at diagnosis, length of follow‐up, extent of initial resection, tumor histology, and treatment modalities. For patients who had experienced seizures at any time, the timing and frequency of seizures, seizure semiology, electroencephalography results, and anticonvulsant use were recorded. Univariate analyses and logistic regression were performed to assess risk factors.
Results
The cohort included 298 patients (140 female). Average duration of follow‐up was 7.6 years. Initial surgical resection was gross‐total in 109 patients, and subtotal for 143. Twenty‐nine patients underwent biopsy alone and 17 had no surgical intervention. Tumor location included posterior fossa (104; 36%), midline (98; 34%), cortical (85; 29%), and other (11; 3%). Most frequent diagnoses were low grade glioma, medulloblastoma, and ependymoma. Other treatments included cranial irradiation (N = 163) and chemotherapy (n = 127). Tumor recurrence occurred in 92 patients (30%). Seventy‐one patients had seizures (24%). Ongoing seizures at the time of most recent follow‐up were present in 42 patients. Risk factors for seizures included tumor location, tumor histology, tumor recurrence, and incomplete resection at time of initial presentation.
Significance
Seizures are a frequent comorbidity in pediatric brain tumor survivors, seen at presentation in 24% of patients and ongoing in 14%. Factors predisposing to seizures include tumor pathology (low/high grade glioma, glioneuronal tumor), cortical location, and subtotal resection. These data may assist in identification and management of patients at highest risk for seizures as well as identification of patients for potential treatment trials with antiepileptogenic agents.
Craniopharyngiomas are neoplasms of the sellar/parasellar region that are classified into adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) subtypes. Surgical resection ...of craniopharyngiomas is challenging, and recurrence is common, frequently leading to profound morbidity. BRAF V600E mutations render PCP susceptible to BRAF/MEK inhibitors, but effective targeted therapies are needed for ACP. We explored the feasibility of targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint pathway in ACP and PCP.
We mapped and quantified PD-L1 and PD-1 expression in ACP and PCP resections using immunohistochemistry, immunofluorescence, and RNA in situ hybridization. We used tissue-based cyclic immunofluorescence to map the spatial distribution of immune cells and characterize cell cycle and signaling pathways in ACP tumor cells which intrinsically express PD-1.
All ACP (15 ± 14% of cells, n = 23, average ± SD) and PCP (35 ± 22% of cells, n = 18) resections expressed PD-L1. In ACP, PD-L1 was predominantly expressed by tumor cells comprising the cyst lining. In PCP, PD-L1 was highly expressed by tumor cells surrounding the stromal fibrovascular cores. ACP also exhibited tumor cell-intrinsic PD-1 expression in whorled epithelial cells with nuclear-localized beta-catenin. These cells exhibited evidence of elevated mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling. Profiling of immune populations in ACP and PCP showed a modest density of CD8+ T cells.
ACP exhibit PD-L1 expression in the tumor cyst lining and intrinsic PD-1 expression in cells proposed to comprise an oncogenic stem-like population. In PCP, proliferative tumor cells express PD-L1 in a continuous band at the stromal-epithelial interface. Targeting PD-L1 and/or PD-1 in both subtypes of craniopharyngioma might therefore be an effective therapeutic strategy.
Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar region of the brain. Patients experience substantial clinical sequelae from both extension of the tumors and ...therapeutic interventions that damage the optic chiasm, the pituitary stalk and the hypothalamic area. Using whole-exome sequencing, we identified mutations in CTNNB1 (β-catenin) in nearly all adamantinomatous craniopharyngiomas examined (11/12, 92%) and recurrent mutations in BRAF (resulting in p.Val600Glu) in all papillary craniopharyngiomas (3/3, 100%). Targeted genotyping revealed BRAF p.Val600Glu in 95% of papillary craniopharyngiomas (36 of 39 tumors) and mutation of CTNNB1 in 96% of adamantinomatous craniopharyngiomas (51 of 53 tumors). The CTNNB1 and BRAF mutations were clonal in each tumor subtype, and we detected no other recurrent mutations or genomic aberrations in either subtype. Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms.
Abstract
Background
Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this ...pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs.
Methods
Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks.
Results
Twenty-three participants (median age, 9.4 y; range, 3.2–21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants.
Conclusion
Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.
Publicly available firearm data are difficult to access. Trauma registry data are excellent at documenting patterns of firearm-related injury. Law enforcement data excel at capturing national ...violence trends to include both circumstances and firearm involvement. The goal of this study was to use publicly available law enforcement data from all 50 states to better define patterns of firearm-related homicides in the young.
All homicides in individuals 25 years or younger in the United States over a 37-year period ending in 2016 were analyzed: infant, 1 year or younger; child, 1 to 9 years old; adolescent, 10 to 19 years old; and young adult, 20 to 25 years old. Primary data files were obtained from the Federal Bureau of Investigation and comprised the database. Data analyzed included homicide type, situation, circumstance, month, firearm type, and demographics. Rates of all homicides and firearm-related homicides per 1 million population and the proportion of firearm-related homicides (out of all homicides) were stratified by year and compared over time using simple linear regression.
A total of 171,113 incidents of firearm-related homicide were analyzed (69% of 246,437 total homicides): 5,313 infants, 2,332 children, 59,777 adolescents, and 103,691 young adults. Most (88%) were male and Black (59%) with a median age of 20 years. Firearm-related homicides peaked during the summer months of June, July, and August (median, 1,156 per year; p = 0.0032). Rates of all homicides (89 to 53 per 1 million population) and firearm-related homicides (56 to 41 per 1 million population) decreased significantly from 1980 to 2016 (β = -1.12, p < 0.0001 and β = -0.57, p = 0.0039, respectively). However, linear regression analysis identified a significant increase in the proportion of firearm-related homicides (out of all homicides) from 63% in 1980 to 76% in 2016 (β = 0.33, p < 0.0001).
For those 25 years or younger, the proportion of firearm-related homicides has steadily and significantly increased over the past 37 years, with 3 of 4 homicides firearm related in the modern era. Despite focused efforts, reductions in the rate of firearm-related homicides still lag behind those for all other methods of homicide by nearly 50%. That is, while the young are less likely to die from homicide, for those unfortunate victims, it is more likely to be due to a firearm. This increasing role of firearms in youth homicides underscores the desperate need to better direct prevention efforts and firearm policy if we hope to further reduce firearm-related deaths in the young.
Epidemiological study, level III.
PDF
