Very Long-term Survivorship in Pediatric DIPG: Case Report and Review of the Literature.

Diffuse intrinsic pontine gliomas are lethal tumors with a prognosis generally less than 1 year. Few cases of survivors of 5 years or more have been reported. This case report highlights the journey of a 9.5-year survivor who underwent 3 rounds of focal radiotherapy; she experienced 6 years of progression-free survival following the first round but ultimately succumbed to her disease. An autopsy revealed a favorable IDH1 mutation and the absence of H3K27M. This case reiterates the importance of extensive molecular analyses in diffuse intrinsic pontine gliomas and explores the potential benefit of re-irradiation in patients with positive responses and long periods of remission.

Recurrent primary intracranial sarcoma, DICER1-mutant in a pediatric patient with DICER1 syndrome: the importance of molecular testing.

Pediatric intracranial sarcomas are rare, aggressive tumors with a poor prognosis in general. Here we report the case of a child who was initially diagnosed with a primary intracranial sarcoma, DICER1-mutant; subsequent genetic analyses confirmed a pathogenic germline DICER1 mutation. She received multimodal standard treatments consisting of surgery, radiotherapy and chemotherapy. The tumor recurred 2.5 years later within the surgical cavity. Following the gross tumor resection of this new lesion, the same multimodal standard approach was used. From a molecular perspective, evidence of hyperactivation of the MAPK-kinase pathway with a pathogenic KRAS mutation at both diagnosis and recurrence was present. The patient is currently in remission, 18 months post-end of treatment.

Bevacizumab in the Treatment of Refractory Brain Edema in High-grade Glioma.

We report the case of a 14-year-old boy with a steroid-dependent refractory tumor whose longstanding dexamethasone treatment was successfully discontinued after a course of bevacizumab. The use of bevacizumab despite the absence of clear evidence of radionecrosis allowed a significant decrease in the amount of the brain edema.

Stalled developmental programs at the root of pediatric brain tumors.

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.

Trametinib for progressive pediatric low-grade gliomas.

INTRODUCTION: Pediatric pilocytic astrocytomas (PAs) are low grade gliomas and the most common brain tumors in children. They often represent a therapeutic challenge when incompletely resected as they can recur and progress despite the use of several lines of chemotherapeutic agents or even radiation therapy. Genetic alterations leading to activation of the mitogen-activated-protein-kinase pathway are a hallmark of this disease and offer an interesting therapeutic alternative through the use of targeted inhibitors. METHODS: Here, we describe six children with sporadic PA who were treated with trametinib, a MEK inhibitor, following progression under conventional therapies. Retrospective chart review was performed. RESULTS: The median age at diagnosis was 2.3 years (y) old [range 11 months (m)-8.5 y old]. KIAA1549-BRAF fusion was identified in five cases, and hotspot FGFR1/NF1/PTPN11 mutations in one. All patients received at least one previous line of chemotherapy (range 1-4). The median time on treatment was 11 m (range 4-20). Overall, we observed two partial responses and three minor responses as best response; three of these patients are still on therapy. Treatment was discontinued in the patient with progressive disease. The most frequent toxicities were minor to moderately severe skin rash and gastro-intestinal symptoms. Two patients had dose reduction due to skin toxicity. Quality of life was excellent with decreased hospital visits and a close to normal life. CONCLUSION: Trametinib appears to be a suitable option for refractory pediatric low-grade glioma and warrants further investigations in case of progression.

Conservative Management of Large Traumatic Supratentorial Epidural Hematoma in the Pediatric Population.

BACKGROUND/AIMS: Conservative management of traumatic epidural hematomas is being recognized as a safe alternative to surgical treatment in asymptomatic children. There is still debate about the maximal size of epidural hematoma that should be tolerated before deciding for surgery. METHODS: We report - through a retrospective cohort study from a single institution - a series of 16 conservatively managed traumatic epidural hematomas of more than 15 mm thickness. RESULTS: 14 patients (88%) were successfully treated using conservative management. Two patients required surgery. These 2 patients had the only 2 documented high-velocity injury mechanisms. All patients had a Glasgow Outcome Scale of 5/5 on follow-up. CONCLUSION: Conservative management with close observation is a safe alternative even in this population of voluminous hematomas. Injury velocity may be a contributing factor for failure of conservative management in this population.

Survival in pediatric medulloblastoma: a population-based observational study to improve prognostication.

Medulloblastoma is the most common form of brain malignancy of childhood. The mainstay of epidemiological data regarding childhood medulloblastoma is derived from case series, hence population-based studies are warranted to improve the accuracy of survival estimates. To utilize a big-data approach to update survival estimates in a contemporary cohort of children with medulloblastoma. We performed a population-based retrospective observational cohort study utilizing the Surveillance, Epidemiology, and End Results Program database that captures all children, less than 20 years of age, between 1973 and 2012 in 18 geographical regions representing 28% of the US population. We included all participants with a presumed or histologically diagnosis of medulloblastoma. The main outcome of interest is survivors at 1, 5 and 10 years following diagnosis. A cohort of 1735 children with a median (interquartile range) age at diagnosis of 7 (4-11) years, with a diagnosis of medulloblastoma were identified. The incidence and prevalence of pediatric medulloblastoma has remained stable over the past 4 decades. There is a critical time point at 1990 when the overall survival has drastically improved. In the contemporary cohort (1990 onwards), the percentage of participants alive was 86, 70 and 63% at 1, 5 and 10 years, respectively. Multivariate Cox-Regression model demonstrated Radiation (HR 0.37; 95% CI 0.30-0.46, p < 0.001) and Surgery (HR 0.42; 95% CI 0.30-0.58, p < 0.001) independently predict survival. The probability of mortality from a neurological cause is <5% in patients who are alive 8 years following diagnosis. The SEER cohort analysis demonstrates significant improvements in pediatric medulloblastoma survival. In contrast to previous reports, the majority of patients survive in the modern era, and those alive 8 years following initial diagnosis are likely a long-term survivor. The importance of minimizing treatment-related toxicity is increasingly apparent given the likelihood of long-term survival.

Management of skull fractures in children less than 1 year of age.

BACKGROUND: Management of skull fracture (SF) in pediatric patients varies from observation in the emergency department (ED) to floor admission. Since 2010, a protocol for admitting children with SF specifically to the trauma service was implemented at our institution. The purpose of our study was to review the management of children with SF younger than 1 year of age. METHODS: Retrospective chart review of all patients between 0 and 1year of age seen in our ED for a SF was done from 2010 to 2013. RESULTS: A total of 180 patients with a mean age of 4.5months (1day-12months) were identified. Of these, 131 patients (73%) were admitted. Mean length of stay was 1.6days. Admitted patients had more depressed (21 vs. 8%) and diastatic (43 vs. 14%) fractures. Fifty-seven children had intracranial hemorrhages (32%) but only 8 patients required non-emergent surgery for depressed fractures. Admission to the trauma service increased from none to 76% with phone follow-ups increasing from 12% to 91%. CONCLUSIONS: Instituting a protocol allowed a safer management of patients with SF. Moreover, we argue that asymptomatic infants with isolated SF can be safely discharged home after brief observation in the ED.

Association of postoperative furosemide use with a reduced blood transfusion rate in sagittal craniosynostosis surgery.

OBJECT A major challenge in sagittal craniosynostosis surgery is the high transfusion rate (50%-100%) related to blood loss in small pediatric patients. Several approaches have been proposed to prevent packed red blood cell (PRBC) transfusion, including endoscopic surgery, erythropoietin ortranexamic acid administration, and preoperative hemodilution. The authors hypothesized that a significant proportion of postoperative anemia observed in pediatric patients is actually dilutional. Consequently, since 2005, at CHU Sainte-Justine, furosemide has been administered to correct the volemic status and prevent PRBC transfusion. The purpose of this study was to evaluate the impact of postoperative furosemide administration on PRBC transfusion rates. METHODS This was a retrospective study of 96 consecutive patients with sagittal synostosis who underwent surgery at CHU Sainte-Justine between January 2000 and May 2012. The mean age at surgery was 4.9 ± 1.5 months (range 2.8-8.7 months). Patients who had surgery before 2005 constituted the control group. Those who had surgery in 2005 or 2006 were considered part of an implementation phase because furosemide administration was not routine. Patients who had surgery after 2006 were part of the experimental (or furosemide) group. Transfusion rates among the 3 groups were compared. The impact of furosemide administration on transfusion requirement was also measured while accounting for other variables of interest in a multiple logistic regression model. RESULTS The total transfusion rate was significantly reduced in the furosemide group compared with the control group (31.3% vs 62.5%, respectively; p = 0.009), mirroring the decrease in the postoperative transfusion rate between the groups (18.3% vs 50.0%, respectively; p = 0.003). The postoperative transfusion threshold remained similar throughout the study (mean hemoglobin 56.0 g/dl vs 60.9 g/dl for control and furosemide groups, respectively; p = 0.085). The proportion of nontransfused patients with recorded hemoglobin below 70 g/dl did not differ between the control and furosemide groups (41.7% vs 28.6%, respectively; p = 0.489). Surgical procedure, preoperative hemoglobin level, estimated blood loss, and furosemide administration significantly affected the risk of receiving a postoperative PRBC transfusion. When these variables were analyzed in a multiple logistic regression model, furosemide administration remained strongly associated with a reduced risk of being exposed to a blood transfusion (OR 0.196, p = 0.005). There were no complications related to furosemide administration. CONCLUSIONS A significant part of the postoperative anemia observed in patients who underwent sagittal craniosynostosis surgery was due to hypervolemic hemodilution. Correction of the volemic status with furosemide administration significantly reduces postoperative PRBC transfusion requirements in these patients.

Derivation and validation of a clinical decision rule to identify young children with skull fracture following isolated head trauma.

BACKGROUND: There is no clear consensus regarding radiologic evaluation of head trauma in young children without traumatic brain injury. We conducted a study to develop and validate a clinical decision rule to identify skull fracture in young children with head trauma and no immediate need for head tomography. METHODS: We performed a prospective cohort study in 3 tertiary care emergency departments in the province of Quebec. Participants were children less than 2 years old who had a head trauma and were not at high risk of clinically important traumatic brain injury (Glasgow Coma Scale score < 15, altered level of consciousness or palpable skull fracture). The primary outcome was skull fracture. For each participant, the treating physician completed a standardized report form after physical examination and before radiologic evaluation. The decision to order skull radiography was at the physician's discretion. The clinical decision rule was derived using recursive partitioning. RESULTS: A total of 811 patients (49 with skull fracture) were recruited during the derivation phase. The 2 predictors identified through recursive partitioning were parietal or occipital swelling or hematoma and age less than 2 months. The rule had a sensitivity of 94% (95% confidence interval [CI] 83%-99%) and a specificity of 86% (95% CI 84%-89%) in the derivation phase. During the validation phase, 856 participants (44 with skull fracture) were recruited. The rule had a sensitivity of 89% and a specificity of 87% during this phase. INTERPRETATION: The clinical decision rule developed in this study identified about 90% of skull fractures among young children with mild head trauma who had no immediate indication for head tomography. Use of the rule would have reduced the number of radiologic evaluations by about 60%.

Abnormal movements associated with oropharyngeal dysfunction in a child with Chiari I malformation.

BACKGROUND: Chiari I malformations (CM I) are rare hindbrain herniations. Dysphagia and other oropharyngeal dysfunctions may be associated with CM I, but to our knowledge, no clinical presentation similar to ours has ever been reported. The purpose of this communication is to draw attention to a unique and atypical clinical presentation of a child with CM I. CASE PRESENTATION: A 7-year-old boy was evaluated for a two month history of atypical movements which would occur in the evening, and last for an hour after eating. These stereotypical movements with the head and chest bending forward and to the left side, accompanied by a grimace, were associated with sensation of breath locking without cyanosis. Pain and dysphagia were absent. The neurological examination was normal. The possibility of Sandifer syndrome posturing occurring with gastroesophageal reflux disease was considered but neither pain nor back hyperextension were associated with the atypical movements. Neither proton pump inhibitors (PPI) nor prokinetic agents improved his symptoms. Upper endoscopy and esophageal biopsy did not reveal eosinophilic esophagitis nor reflux esophagitis. Ear, throat and nose (ENT) exam was normal. A severe gastroparesis was demonstrated on milk scan study. Two 24 hour oesophageal pH probe studies pointed out severe gastroesophageal reflux (GER). High resolution manometric evaluation of the oesophagus revealed normal sphincter pressures and relaxations with no dysmotility of the esophageal body. Electroencephalography and polysomnography were normal. A brain magnetic resonance imaging (MRI) was performed and revealed a CM I: cerebellar tonsils extending to 12 mm, with syringomyelia (D4-D5). For a long period of time, the child's abnormal movements were considered to be nothing but tics and the CM I a fortuitous finding. Since the child remained symptomatic despite medical treatment, it was decided to proceed with surgery. One year after the onset of his symptoms, he underwent posterior fossa decompression with upper cervical laminectomy and expansion duroplasty. Postoperative MRI confirmed adequate decompression. His atypical posture and dyspnea completely resolved after surgery and he remains asymptomatic two years later. CONCLUSION: Children may have atypical presentations of CM I. Thus, CM I diagnosis should be considered in unexplained atypical oropharyngeal dysfunctions.

Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

Minimal access to deep intracranial lesions using a serial dilatation technique: case-series and review of brain tubular retractor systems.

Surgical access to deep intracranial lesions causing the least amount of iatrogenic trauma to the surrounding brain tissue remains a challenging task. In this article, we evaluate the use of a set of sequential tubes that dilate and provide retraction of the overlying brain tissue acting as a surgical corridor for deep-seated brain lesions resection. In addition, we conducted a comprehensive review of the literature of previously described techniques using variable brain tubular retractor systems. We discuss the adaptation of a system designed for spinal use to intracranial pathologies and evaluate the outcomes for the patients involved in the study. Moreover, the advantages and limitations of the described technique were presented. Between August 2005 and 2011, a total of 30 patients with deep brain lesions were operated on using an incremental increase of tubing size for brain retraction guided by a frameless navigation device. Of these, seven cases were intraventricular, and 23 were intraparenchymal. Gross total resection was achieved in 70 % of cases, and the remaining had planned subtotal resections due to involvement of an eloquent area. In conclusion, the technique of serial dilatation of the brain tissue can be used in conjunction with a microscope or endoscope to provide satisfactory access to deep intracranial pathologies. It appears to minimize the associated retraction injury to the surrounding tissue by gradually dilating the white fiber tracts. This operative approach may be considered as an effective and safe alternative for brain tumor resections in selected cases, especially deep-seated lesions.

Minimally invasive approach for the resection of spinal neoplasm.

STUDY DESIGN: Retrospective Case Series. OBJECTIVE: To determine if extradural, intradural extramedullary, and intramedullary spinal neoplasms can be safely resected through a minimally invasive corridor. SUMMARY OF BACKGROUND DATA: The use of minimally invasive approaches for resection of spinal neoplasms has been described for intradural schwannomas and ependymomas. We demonstrate that this approach can be extended to the resection of a variety of extradural, intradural and intramedullary spinal tumors. METHODS: We undertook a retrospective review of all patients presenting with clinical and radiographic evidence of spinal neoplasm that subsequently underwent a minimally invasive approach for resection of the tumor using the METRx MAST QUADRANT Retractor System (Medtronics, Memphis, TN). Primary endpoints analyzed include completeness of resection, postoperative neurologic status, operative time, blood loss, postoperative pain, length of hospital stay, and operative complications. RESULTS: Two cervical, seven thoracic and 13 lumbar neoplasms were identified in 20 patients operated on between September 2005 and May 2009. Mean intraoperative time was 210 minutes, blood loss 428 mL and average length of hospital stay was 3 days. Four patients required postoperative patient-controlled analgesia for pain control and an average of 5.8 doses of narcotic were given per patient. Two patients developed postoperative complications. Fifteen of 22 tumors (68%) were completely resected, with only one patient requiring repeat operation for residual tumor. All but one patient were improved from preoperative status at 6 months. CONCLUSION: Intramedullary, intradural and extradural spinal neoplasms can be resected through a minimally invasive approach without increased risk for adverse neurologic outcome. This technique may be an appropriate alternative to the open approach for well-circumscribed extramedullary lesions spanning one or two spinal levels. With increasing experience, reduced operative time, blood loss, complications, length of hospital stay, postoperative pain, and spinal instability may be seen.

Moyamoya-like vasculopathy and Seckel syndrome: just a coincidence?

INTRODUCTION: Seckel syndrome (SS) and other microcephalic primordial dwarfisms (MPDs) are a group of autosomal recessive disorders characterized by prenatal and postnatal growth retardation, microcephaly, and distinct facial dysmorphic features. There are an increasing number of reports in the literature linking MPDs with cerebrovascular anomalies, including intracranial aneurysms and moyamoya. CASE REPORT: An 18-year-old female patient with SS and mental retardation was referred for spontaneous subarachnoid hemorrhage. At the age of 3 years, she had suffered multifocal ischemic cerebrovascular accidents following an elective urological procedure. Cardiac, hematologic, and serologic workups were negative, and cerebral angiography was recommended but declined by the parents. Brain MRA and cerebral angiography showed bilateral narrowing of extracranial and intracranial internal carotid arteries (ICAs), obliteration of the right supraclinoid ICA without moya-moya collaterals, and multiple bilateral saccular aneurysms on the hypertrophied posterior cerebral arteries. Considering the patient's previous quality of life and the high risks of either endovascular or surgical treatment, all invasive treatments were withheld at the parents' request and only palliative care was offered. CONCLUSION: It appears that patients with MPD are prone to the development of cerebrovascular anomalies. Therefore, imaging of cerebral vessels should be performed when such patients present with cerebral ischemia or stroke.

Clinical algorithm and resource use in the management of children with minor head trauma.

PURPOSE: There are no clear guidelines for the management of minor head injury, including the use of skull x-rays and computed tomography (CT) scans of the head. This is reflected in clinical practice by a wide variability in imaging study use and by the fact that some patients are discharged home from the emergency room (ER), whereas others are admitted to the hospital with or without a period of observation before admission. To address this issue, we proposed and applied a new protocol for minor head injury at our institution. METHODS: Between January 2004 and December 2005, 417 patients presented to the emergency department at our institution with minor head injury. All of them had fallen from less than 1 m. Every chart was retrospectively evaluated, and pertinent data were extracted. RESULTS: The mean age of the patients was 9.8 months (2 weeks to 32 months). One hundred fifty-three had a skull x-ray, and 13 had a CT scan of the head. Of the 153 patients who had a skull x-ray, only 15 had a skull fracture. Of these 15 patients, 3 also had a CT scan of the head that confirmed the diagnosis of skull fracture. Of the 13 CT scans that were done, only these 3 were positive. Eleven patients were kept in the ER for 6 hours for close observation, and 5 of these were eventually admitted. Overall, 8 patients were admitted to the hospital for observation. Of these 8 patients, 7 had a skull x-ray, from which 5 were positive. Only 2 of the admitted patients had a CT scan, and they were both positive for a skull fracture. One of the CT also demonstrated a subdural hematoma along with subarachnoid hemorrhage. These 2 patients also had a positive skull x-ray. None of the patients that were admitted had headaches or neurologic impairments. The mean age of the patients admitted was 3.8 months (2 weeks to 12 months). The mean hospital stay was 1.2 days (1-3 days). CONCLUSION: Only 10% of the skull x-rays and CT scans were positive for a skull fracture, which led to an admission in half of these patients. The other half was mainly discharged from ER after being observed. Several patients underwent a skull x-ray that we feel was not necessary in the management of their minor head injury. For those who had a head CT scan, only one revealed additional information and none of them had an impact on the final management. Observation in the ER could have been reasonable for most cases.

Genetic polymorphisms of glutathione S-transferases and the risk of adult brain tumors: a meta-analysis.

BACKGROUND: Studies investigating the association between genetic polymorphisms of glutathione S-transferases (GST) and risk of adult brain tumors have reported conflicting results. The rationale of this meta-analysis was to determine whether GST variants increase the susceptibility of adult brain tumors by pooling data. METHODS: Two investigators independently searched the HuGENet database, MEDLINE, EMBASE, conference articles, and manually reviewed bibliographies of retrieved articles. Papers were included if they were observational studies investigating the influence of GSTM1, GSTT1, GSTP1 I105V, or GSTP1 A114V on the development of adult brain cancers. Potential sources of heterogeneity between studies were explored in a meta-regression. RESULTS: We identified eight eligible studies, which included 1,630 cases of glioma, 245 cases of meningioma, and 7,151 controls. Using the random effects model, there was no association between any of the GST variants and the risk of glioma [overall odds ratio (OR), 1.08; 95% confidence interval (95% CI), 0.95-1.22]. Subgroup analyses also showed no relationship between GST variants and histopathologic groups; the overall ORs were 1.13 (95% CI, 0.88-1.43) for high-grade glioma and 1.08 (95% CI, 0.76-1.55) for low-grade glioma. A random effects meta-regression suggested that the use of in-hospital controls produced larger effect estimates in glioma than the use of population controls (overall OR, 1.30; 95% CI, 1.03-1.65). The T1 null genotype was significantly associated with a risk of meningioma (OR, 1.95; 95% CI, 1.02-3.76), but the M1 variant was not. CONCLUSION: This study did not suggest any relationship between GST variants and risks of glioma; the T1 null genotype may influence the susceptibility of meningioma, but larger studies are needed to substantiate this relationship.