Resolving medulloblastoma cellular architecture by single-cell genomics.

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.

Novel predictive scoring system for morbid hypothalamic obesity in patients with pediatric craniopharyngioma.

PURPOSE: To identify the independent risk factors for developing morbid hypothalamic obesity, to propose a predictive scoring system for morbid hypothalamic obesity, and to propose an algorithm for management in order to minimize the risk of developing morbid hypothalamic obesity in patients with pediatric craniopharyngioma. METHODS: A retrospective analysis of all pediatric craniopharyngioma patients diagnosed and treated at Boston Children's Hospital (BCH) between 1985 and 2017. Analysis of the data was conducted using IBM SPSS Statistics. RESULTS: We identified 105 patients, 90 (47 males and 43 females) fulfilled the inclusion criteria. The median age of patients at time of diagnosis was 8.4 years. The median follow-up was 10.6 years. Morbid hypothalamic obesity was evident in 28 (31.1%) patients at the last follow-up visit. Age of patients at time of diagnosis > 10 years (P = 0.023), preoperative body mass index (BMI) > 95th percentile (P = 0.006), and preoperative papilledema (P < 0.001) were the independent risk factors for developing morbid hypothalamic obesity. CONCLUSION: We developed a unique predictive scoring system in order to differentiate between patients with and without high risk for developing morbid hypothalamic obesity.

Analysis of 2141 pediatric craniopharyngioma admissions in the USA utilizing the Kids' Inpatient Database (KID): predictors of discharge disposition.

OBJECTIVES: To recognize the national trends in management of pediatric craniopharyngioma and to address the significant predictors of discharge disposition. METHODS: We utilized the Kids' Inpatient Database (KID), a pediatric inpatient sample generated by the Healthcare Cost and Utilization Project (HCUP) triennially from 1997 to 2016. RESULTS: KID contains 2141 pediatric craniopharyngioma admissions. Patient demographics had no effect on discharge disposition. Based on the multivariable logistic regression analysis, we confirmed a significantly higher non-routine discharge rate among patients with hydrocephalus (P = 0.01). Patients who developed diabetes insipidus were at higher risk for non-routine discharge (P = 0.02). Admission of patients to a freestanding children's hospital increased the likelihood of routine discharge (P = 0.001). CONCLUSION: Hydrocephalus, diabetes insipidus, and admission to a freestanding children's hospital are significant independent predictors of discharge disposition.

Sixty years single institutional experience with pediatric craniopharyngioma: between the past and the future.

PURPOSE: To demonstrate the paradigm shift in management strategies of pediatric craniopharyngioma at our institution over the past six decades. METHODS: Retrospective analysis of all pediatric patients with craniopharyngioma treated at Boston Children's Hospital between 1960 and 2017. RESULTS: One hundred seventy-eight patients with craniopharyngioma were treated between 1960 and 2017; 135 (70 males and 65 females) fulfilled the inclusion criteria. Forty-five patients were treated in the old era (1960-1984) and 90 patients were treated in the new era (1985-2017). Gross total resection (GTR) was achieved in 4% and 43% of patients in old and new eras respectively. Sub-total resection (STR) and radiotherapy (XRT) were performed in 27% and 28% of patients in old and new eras respectively. STR without XRT was performed in 20% and 29% of patients in old and new era respectively. Cyst drainage and adjuvant radiotherapy were performed in 49% of patients in the old era while no patients in the new era underwent such conservative management. Aggressive surgical resection was associated with a higher risk of worsening visual outcomes (20% vs 16%), panhypopituitarism and diabetes insipidus (86% vs 53%), psycho-social impairment (42% vs 26%), and new-onset obesity (33% vs 22%). The mortality rate was higher in the old era in comparison with that of the new one (9% vs 2%). CONCLUSION: There was a paradigm shift in management strategies of pediatric craniopharyngioma over the past six decades which in turn affected the long-term outcomes and quality of life of patients.

Correction to: Iatrogenic obstructive hydrocephalus resulting from Gelfoam accumulation within the cerebral aqueduct: a case report.

The original version of this article unfortunately contained an error. The authors apologize to have miss looked a typo of author name "Joseph Diver". The correct name is "Joseph Driver".

Iatrogenic obstructive hydrocephalus resulting from Gelfoam accumulation within the cerebral aqueduct: a case report.

The authors present the case of a previously healthy 12-year-old male with intractable seizures localized to a right frontal area of encephalomalacia and porencephalic cyst who underwent resection of the seizure focus. The surgical resection cavity extended into the right lateral ventricle, and due to encountered hemorrhage, Gelfoam was used for optimal hemostasis. The patient did well following the procedure, but presented 5 months later with headaches and emesis and was discovered to have obstructive hydrocephalus on imaging studies. Endoscopic third ventriculostomy (ETV) was performed, where Gelfoam was encountered in the third ventricle, obstructing the cerebral aqueduct. After the completion of the ETV, the patient did well and continues to be asymptomatic 1 year following the procedure.

Rethinking childhood ependymoma: a retrospective, multi-center analysis reveals poor long-term overall survival.

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.

Brain tumors and epileptic spasms: Natural history and outcomes.

While brain tumors are a frequent cause of seizures, they rarely cause epileptic spasms (ES). The objective of this study was to investigate features of tumor-associated ES. We conducted a retrospective review of patients with ES and a brain tumor. Demographics; pathologic, radiologic, and EEG data; treatment response; and long-term outcome were collected. Twenty four patients were identified; 11 met inclusion criteria. Epileptic spasm (ES) onset occurred prior to tumor diagnosis in seven patients (63%), and after tumor resection in 4 patients (36%). Spasms and ictal EEG often had focal features (45%). Gross total tumor resection resulted in ES freedom in 3/7 patients. There was poor response to first-line therapy (ACTH/vigabatrin; 1/5 with ES freedom). Low grade tumors predominated (8/11) with dual pathology (associated cortical malformation) in 2 patients. All tumors involved cortex; half involved subcortical regions and/or brainstem. Ten patients developed other seizure types; eight experienced refractory epilepsy, and nine had a Modified Rankin Scale of >3. In summary, EEG in tumor-associated ES often has focal features of either the semiology or EEG. Complete tumor resection yielded ES freedom in only a subset of patients. Most patients developed refractory epilepsy and adverse developmental outcomes.

Long-term visual outcomes of optic pathway gliomas in pediatric patients without neurofibromatosis type 1.

Sporadic optic pathway gliomas (OPGs) have been reported to cause more vision loss than OPGs associated with neurofibromatosis type-1, but long-term visual outcome data are limited. The purpose of this study was to report the visual outcomes of a cohort of pediatric patients with sporadic OPGs. This was a retrospective, cohort study at a tertiary care pediatric hospital and cancer institute. The study included all patients with sporadic OPGs evaluated from 1990 to 2014. The primary outcome was visual acuity at final follow-up. Secondary outcomes were risk factors for a poor visual outcome and the rate of progression. There were 59 pediatric patients included in the study. Median age at presentation was 2.5 years old and median follow-up was 5.2 years. In the worse eye at final follow-up, 16 patients (27 %) were 20/30 or better, 9 patients (15 %) were between 20/40 and 20/80, and 34 patients (58 %) were 20/100 or worse. In the better eye at final follow-up, 33 patients (56 %) were 20/30 or better, 11 patients (19 %) were between 20/40 and 20/80, and 15 patients (25 %) were 20/100 or worse. Risk factors for a poor visual outcome included younger age at presentation, optic nerve pallor, and tumor extent. Of the 54 patients (92 %) who received treatment, 40 (74 %) experienced disease progression during or after treatment. A majority of pediatric patients with sporadic OPGs had significant long-term visual impairment. In spite of treatment, tumor progression is common. Serial ophthalmic examinations with quantitative vision measurements are essential in the management of sporadic OPGs.

Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation.

Disseminated glioneuronal tumors of childhood are rare. We present a retrospective IRB-approved review of the clinical course and frequency of BRAF mutations in disseminated glioneuronal tumors at two institutions. Defining features of our cohort include diffuse leptomeningeal-spread, often with a discrete spinal cord nodule and oligodendroglioma-like histologic features. Patients were identified through a pathology database search of all cases with disseminated low-grade neoplasms with an oligodendroglioma-like component. De-identified clinical information was collected by chart review and all imaging was reviewed. We retrieved the results of targeted genomic analyses for alterations in BRAF. Ten patients (aged 2-14 years) were identified from the Dana-Farber/Boston Children's Hospital and the Royal Children's Hospital, Melbourne pathology databases. Nine patients received chemotherapy. Eight patients are alive, although three have had episodes of progressive disease. We identified genomic alterations affecting the MAPK pathway in six patients. One patient had a germline RAF1 mutation and a clinical diagnosis of cardio-facio-cutaneous syndrome. BRAF duplications were identified in four and BRAF V600E mutation was identified in one. These data support the presence of targetable genomic alterations in this disease.

Myxopapillary ependymomas in children: imaging, treatment and outcomes.

Myxopapillary ependymomas (MPEs) are rare spinal tumors in children. The natural history and clinical course of pediatric MPEs are largely unknown and the indication for adjuvant therapy remains to be clarified. We performed an IRB-approved, retrospective review of children with MPEs treated at the Dana-Farber/Boston Children's Cancer and Blood Disorder Center between 1982 and 2013. Eighteen children (age range 8-21 years, median age 14 years) met inclusion criteria. We reviewed the histopathology, magnetic resonance imaging, tumor location and stage, surgical management, adjuvant therapy, and clinical outcomes. The median follow-up duration was 9.4 years (range 1-30 years). Children most commonly presented with pain, scoliosis, and urinary symptoms. All primary tumors were located in the lower thoracic or lumbar spine. Nine children (50%) had leptomeningeal tumor seeding at presentation, most commonly located within the distal thecal sac. A gross-total resection was achieved in nine children (50%). Three children were treated with irradiation following initial surgery. No child received adjuvant chemotherapy at diagnosis. The 10-year event-free survival (EFS) was 26% ± 14.8. Children with disseminated disease trended towards inferior EFS compared to those with localized disease (10-year EFS 12.7% ± 12 vs. 57 ± 25%, p value 0.07). The 10-year overall survival was 100%. The efficacy of adjuvant irradiation could not be assessed due to the small sample size. Although children with MPEs frequently present with disseminated tumor and/or develop recurrent or progressive disease, their overall survival is excellent. Treatment should aim to minimize both tumor- and therapy-related morbidity.

Central Versus Extraventricular Neurocytoma in Children: A Clinicopathologic Comparison and Review of the Literature.

BACKGROUND: Central neurocytomas (CN) are rare pediatric CNS tumors most often with a benign clinical course. Occasionally, these tumors occur outside the ventricles and are called extraventricular neurocytomas (EVN). We present a retrospective institutional analysis of children with neurocytoma with prolonged follow-up. PROCEDURE: Twelve patients were diagnosed with neurocytoma at our institution between 1993 and 2004. RESULTS: Six patients were male and the median age at diagnosis was 12 years (1.5 to 16 y). Seven patients had CN and 5 had EVN. Presenting symptoms included headaches (67%), vomiting (50%), nausea (33%), seizures (33%), and mental status changes (25%). Obstructive hydrocephalus was present at diagnosis in 42% of the cases. Younger age and seizures were more common in patients with EVN. Gross total resection (GTR) was achieved in 42% (5/12) of the patients. Patients with GTR received no adjuvant therapy upfront; 1 patient subsequently had recurrence with leptomeningeal disease. Patients with subtotal resection received additional treatment: 1 underwent reoperation (GTR), 2 patients received focal radiation, 2 patients received adjuvant chemotherapy, and 2 patients received craniospinal irradiation followed by chemotherapy. The 20-year overall survival for this cohort was 83% with event free survival of 56%. Overall survival for CNs was 100%, versus 40% for EVN. Event free survival for CNs was 57% and 53% for the EVNs. An MIB-1 fraction >2% was associated with worse prognosis. CONCLUSIONS: Neurocytomas are rare brain tumors in children usually cured with GTR. Adjuvant focal radiation therapy and/or chemotherapy may improve disease control in cases with subtotal resection, but case-by-case analysis should be done. EVNs might be associated with worse outcome due to a higher proliferative index.

Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1.

Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog (MYB) on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.

Risk of seizures in children with tectal gliomas.

The objective of this study was to determine the prevalence of seizures in children with tectal gliomas and to determine if there are common clinical, electroencephalography (EEG), or radiologic findings that predict risk of seizures in these patients. We conducted a retrospective review of all patients with tectal gliomas over a 22-year period at a single institution. Data extraction included sex, age at presentation of tectal glioma and age of presentation with seizures, magnetic resonance imaging (MRI) findings, seizure frequency and semiology, and EEG findings. We identified 79 patients, 66 of whom had adequate imaging and clinical data for further analysis. Eight patients (12.1%) had a history of seizures. Three patients had a clear symptomatic cause of seizures. Three patients were diagnosed with a tectal glioma as an incidental finding after a first seizure. One patient had a history of febrile convulsions. One patient had a generalized seizure 5 years after presenting with macrocephaly. Although the risk of seizure in children with known tectal glioma was relatively high, we did not identify specific clinical, radiologic, EEG, or MRI features that are predictive of increased risk. Thus, in children with tectal gliomas who have seizures, alternative causes for the seizures must be sought.

Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.

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.

Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database.

BACKGROUND: Children with pediatric low-grade gliomas (PLGG) are known to have excellent 10-year survival rates; however the outcomes of adult survivors of PLGG are unknown. We identified patients diagnosed with PLGG diagnosed between 1973 and 2008 through the Surveillance Epidemiology and End Results (SEER) database to examine outcomes of adult survivors of PLGG. PROCEDURE: Four thousand and forty patients with either WHO grade I or II PLGG were identified and outcome data retrieved. Two analyses were performed to assess survival and risk of death from tumor. Competing risks analysis was conducted and cumulative incidence curves of death due to disease were generated. Cox proportional hazards regression was performed, with adjustment for non-disease death. Kaplan-Meier curves for overall cancer specific survival (OS) were also generated. RESULTS: The 20-year OS was 87% ± 0.8% and the 20-year cumulative incidence of death due to glioma was 12% ± 0.8%. The incidence of death after transition to adulthood (age greater than 22 years) was slightly lower, with 20-year cumulative incidence of disease death of 7% ± 1.8%. Year of diagnosis, age of diagnosis, histology, WHO grade, primary site, radiation, and degree of initial resection were prognostic in univariate analysis, while the administration of radiation was the greatest risk of death in multivariate analysis of OS (hazard ratio = 3.9). CONCLUSIONS: PLGGs are associated with an excellent long-term survival, with a low likelihood of PLGG related death in adult survivors. Treatment strategies for pediatric tumors should therefore aim for disease control during childhood and adolescence with an emphasis on minimizing long-term treatment induced toxicities.

Predictors of neoplastic disease in children with isolated pituitary stalk thickening.

BACKGROUND: The significance of pituitary stalk thickening (PST) on magnetic resonance imaging (MRI) is often unclear. We evaluated presenting symptoms, MRI findings, clinical course, and outcome predictors of patients with PST. PROCEDURE: We used a computerized search of the medical record from 1995 to 2008 to identify patients with PST without pituitary mass on MRI. Baseline and follow-up MRIs were reviewed in a blinded fashion. Relevant clinical data were abstracted. RESULTS: 69 patients with reported PST and adequate imaging for review were identified; 42 met study criteria. Median age at first abnormal MRI was 13.6 years (range: 0.8-19.7); 43% were male. Median follow-up was 3.4 years (range 0-12.8). Patients with diabetes insipidus (DI) were significantly more likely to have a neoplastic process than those without (P = 0.0008). Of 16 patients with DI, 8 (50%) had a neoplastic process, including germ cell tumor (n = 4), Langerhans cell histiocytosis (n = 3), and lymphoma (n = 1). Among patients with DI, 7 (44%) also developed anterior pituitary hormone dysfunction (APD), either at presentation or on pre-biopsy follow-up, including 6/8 patients with stalk neoplasm and only 1/8 patients with non-neoplastic PST (P = 0.04). Twenty-six patients presented without DI; none was found to have neoplasm of the stalk except one patient with craniopharyngioma. Progression of PST on follow-up imaging was significantly associated with a subsequent neoplastic diagnosis (P = 0.04). CONCLUSION: Patients with PST without DI are unlikely to have a neoplastic process. Among patients with DI, APD or progressive stalk increase over time are predictive of neoplasia.

ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma.

PURPOSE: Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established. EXPERIMENTAL DESIGN: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations. RESULTS: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib. CONCLUSIONS: These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. See related commentary by Mack and Bertrand, p. 2567.

Sleep dysfunction in long term survivors of craniopharyngioma.

Craniopharyngiomas are slow growing tumors of the sellar and parasellar region and may also involve the hypothalamus. Treatment involves maximal surgical excision or subtotal resection followed by focal radiation therapy. Late effects of treatment include endocrinopathies, cognitive deficits, behavioral changes, obesity and sleep dysfunction. We conducted a retrospective review of all patients with craniopharyngioma more than 2 years off treatment and who were evaluated in the neuro-oncology survivorship clinic between 2003 and 2007. Clinical data, extent of resection, treatment modalities, endocrine status, patient symptom report and sleep study results were collected to evaluate the presence of patient reported daytime sleepiness and sleep disturbance and to determine possible risk factors. 28 patients were identified (25 %) female. 19/28 self-reported daytime fatigue or sleep disturbance; this included 4/6 patients with gross total resection and 15/22 with subtotal resection. 16/22 patients treated with cranial irradiation reported sleep-related abnormalities, compared to 3/6 patients who did not receive radiation. All but one patient had pituitary dysfunction requiring hormonal replacement. Patients with more than ≥2 sleep related complaints had a higher BMI (44.6 vs. 32.6, p = 0.0192). 8 patients underwent formal sleep evaluation. 3 patients had documented central or obstructive sleep apnea. The mean arousal index was 11.0/h (normal <5). Two patients were treated with melatonin for sleep disturbance and 2 were treated with stimulants for excessive daytime sleepiness. A majority of patients with craniopharyngioma have self-reported daytime fatigue and/or sleep dysfunction after treatment. Extent of resection did not increase the likelihood of patient-reported daytime sleepiness and/sleep dysfunction; however, patients who received radiation more frequently reported daytime sleepiness and/or sleep dysfunction. Patients with a higher BMI were more likely to experience sleep disturbance. Formal sleep evaluations should be considered in all patients with craniopharyngioma.

Liquid biopsy detection of genomic alterations in pediatric brain tumors from cell-free DNA in peripheral blood, CSF, and urine.

BACKGROUND: The ability to identify genetic alterations in cancers is essential for precision medicine; however, surgical approaches to obtain brain tumor tissue are invasive. Profiling circulating tumor DNA (ctDNA) in liquid biopsies has emerged as a promising approach to avoid invasive procedures. Here, we systematically evaluated the feasibility of profiling pediatric brain tumors using ctDNA obtained from plasma, cerebrospinal fluid (CSF), and urine. METHODS: We prospectively collected 564 specimens (257 blood, 240 urine, and 67 CSF samples) from 258 patients across all histopathologies. We performed ultra-low-pass whole-genome sequencing (ULP-WGS) to assess copy number variations and estimate tumor fraction and developed a pediatric CNS tumor hybrid capture panel for deep sequencing of specific mutations and fusions. RESULTS: ULP-WGS detected copy number alterations in 9/46 (20%) CSF, 3/230 (1.3%) plasma, and 0/153 urine samples. Sequencing detected alterations in 3/10 (30%) CSF, 2/74 (2.7%) plasma, and 0/2 urine samples. The only positive results were in high-grade tumors. However, most samples had insufficient somatic mutations (median 1, range 0-39) discoverable by the sequencing panel to provide sufficient power to detect tumor fractions of greater than 0.1%. CONCLUSIONS: Children with brain tumors harbor very low levels of ctDNA in blood, CSF, and urine, with CSF having the most DNA detectable. Molecular profiling is feasible in a small subset of high-grade tumors. The level of clonal aberrations per genome is low in most of the tumors, posing a challenge for detection using whole-genome or even targeted sequencing methods. Substantial challenges therefore remain to genetically characterize pediatric brain tumors from liquid biopsies.