Detection of tumor-derived cell-free DNA in cerebrospinal fluid using a clinically validated targeted sequencing panel for pediatric brain tumors.

PURPOSE: Clinical sequencing of tumor DNA is necessary to render an integrated diagnosis and select therapy for children with primary central nervous system (CNS) tumors, but neurosurgical biopsy is not without risk. In this study, we describe cell-free DNA (cfDNA) in blood and cerebrospinal fluid (CSF) as sources for "liquid biopsy" in pediatric brain tumors. METHODS: CSF samples were collected by lumbar puncture, ventriculostomy, or surgery from pediatric patients with CNS tumors. Following extraction, CSF-derived cfDNA was sequenced using UW-OncoPlex™, a clinically validated next-generation sequencing platform. CSF-derived cfDNA results and paired plasma and tumor samples concordance was also evaluated. RESULTS: Seventeen CSF samples were obtained from 15 pediatric patients with primary CNS tumors. Tumor types included medulloblastoma (n = 7), atypical teratoid/rhabdoid tumor (n = 2), diffuse midline glioma with H3 K27 alteration (n = 4), pilocytic astrocytoma (n = 1), and pleomorphic xanthoastrocytoma (n = 1). CSF-derived cfDNA was detected in 9/17 (53%) of samples, and sufficient for sequencing in 8/10 (80%) of extracted samples. All somatic mutations and copy-number variants were also detected in matched tumor tissue, and tumor-derived cfDNA was absent in plasma samples and controls. Tumor-derived cfDNA alterations were detected in the absence of cytological evidence of malignant cells in as little as 200 µl of CSF. Several clinically relevant alterations, including a KIAA1549::BRAF fusion were detected. CONCLUSIONS: Clinically relevant genomic alterations are detectable using CSF-derived cfDNA across a range of pediatric brain tumors. Next-generation sequencing platforms are capable of producing a high yield of DNA alterations with 100% concordance rate with tissue analysis.

Somatic Versus Germline: A Case Series of Three Children With ATM-Mutated Medulloblastoma.

Somatic versus Germline-A Case Series of Three Children with ATM- mutated Medulloblastoma.

Outcomes of a radiation sparing approach in medulloblastoma by subgroup in young children: an institutional review.

OBJECTIVE: To describe disease outcomes including overall survival and relapse patterns by subgroup in young pediatric patients treated for medulloblastoma with a radiation-sparing approach. METHODS: Retrospective analysis of clinical outcomes includes treatment, relapse, and salvage therapy and late effects in children treated for medulloblastoma with a radiation-sparing approach at British Columbia Children's Hospital (BCCH) between 2000 and 2020. RESULTS: There were 30 patients (median age 2.8 years, 60% male) treated for medulloblastoma with a radiation-sparing approach at BCCH. Subgroups included Sonic Hedgehog (SHH) (n = 14), group 3 (n = 7), group 4 (n = 6), and indeterminate status (n = 3). Three- and 5-year event-free survival (EFS) were 49.0% (30.2-65.4%) and 42.0% (24.2-58.9%) and overall survival (OS) 66.0% (95% CI 46.0-80.1%) and 62.5% (95% CI 42.5 and 77.2%), respectively, with a median follow-up of 9.5 years. Relapse occurred in 12/25 patients following a complete response, of whom six (group 4: n = 4; group 3: n = 1; unknown: n = 1) were successfully salvaged with craniospinal axis (CSA) RT and remain alive at a median follow-up of 7 years. Disease/treatment-related morbidity included endocrinopathies (n = 8), hearing loss n = 16), and neurocognitive abnormalities (n = 9). CONCLUSIONS: This radiation sparing treatment approach for young patients with medulloblastoma resulted in a durable cure in most patients with SHH subgroup medulloblastoma. In those patients with groups 3 and 4 medulloblastoma, relapse rates were high; however, most group 4 patients were salvaged with RT.

Growth hormone after CNS tumor diagnosis: the fundamentals, fears, facts, and future directions.

Growth hormone deficiency (GHD) may occur in pediatric patients with central nervous system (CNS) tumors at initial tumor presentation or later as treatment-related sequelae. While it is well recognized that growth hormone (GH) has beneficial effects on growth and endocrinopathies, there's often hesitancy by clinicians to initiate GH therapy for GHD after CNS tumor diagnosis due to the perceived increased risk of tumor recurrence. The available data is described here and based on this review, there is no evidence of increased risk of tumor recurrence or secondary malignancy in patients treated with GH after CNS tumor diagnosis. Further understanding of tumor biology and presence of downstream GH targets including insulin-like growth factor-1 (IGF-1) and insulin receptor activity is still needed.

Locoregional CAR T cells for children with CNS tumors: Clinical procedure and catheter safety.

Central nervous system (CNS) tumors are the most common solid malignancy in the pediatric population. Based on adoptive cellular therapy's clinical success against childhood leukemia and the preclinical efficacy against pediatric CNS tumors, chimeric antigen receptor (CAR) T cells offer hope of improving outcomes for recurrent tumors and universally fatal diseases such as diffuse intrinsic pontine glioma (DIPG). However, a major obstacle for tumors of the brain and spine is ineffective T cell chemotaxis to disease sites. Locoregional CAR T cell delivery via infusion through an intracranial catheter is currently under study in multiple early phase clinical trials. Here, we describe the Seattle Children's single-institution experience including the multidisciplinary process for the preparation of successful, repetitive intracranial T cell infusion for children and the catheter-related safety of our 307 intracranial CAR T cell doses.

Impact of Time to Diagnosis on Morbidity and Survival in Children With Malignant Central Nervous System Tumors.

OBJECTIVE: The aim was to determine the impact of time to diagnosis (TTD) on morbidity and mortality and to identify factors associated with overall survival (OS) in pediatric patients with malignant central nervous system (CNS) tumors. METHODS: This is a retrospective review of all malignant CNS tumors presenting to 2 tertiary care pediatric hospitals from 2000 to 2019. Cox proportional hazard model analysis outcomes included TTD and OS as well as morbidity; stratified by tumor category, age, relapse, and presence of metastatic disease. RESULTS: There were 197 children with malignant CNS tumors (mean age 8.7 y, 61% male). Tumors included medulloblastoma (N=58, 29.4%), ependymoma (N=27, 13.7%), high-grade glioma (N=42, 21.3%), germ cell tumors (N=47, 23.9%), and other embryonal tumors (N=23, 11.7%). Median TTD from symptom onset was 62 (interquartile range: 26.5 to 237.5 d) and 28% had metastatic disease. Three-year progression free survival was 55% and 3-year OS was 73.1%. Increased OS was associated with increased TTD (parameter estimate 0.12; confidence interval [CI]: 0.019-7.06; P =0.019), high-grade glioma (hazard ratio [HR]: 2.46; CI [1.03-5.86]; P =0.042), other embryonal tumor (HR: 2.84; CI [1.06-7.56]; P =0.037), relapse (HR: 10.14; CI: 4.52-22.70; P <0.001) and metastatic disease (HR: 3.25; CI: 1.51-6.96; P =0.002). Vision change (HR: 0.58; CI: 0.313-1.06; P =0.078), hearing loss (HR: 0.71; CI: 0.35-1.42; P =0.355), and cognitive impairment (HR: 0.73; CI: 0.45-1.19; P =0.205) were not associated with TTD in this model. CONCLUSIONS: Increased median TTD is associated with higher OS in pediatric patients treated for malignant CNS tumors. Tumor biology and treatment modality are more important factors than TTD for predicting morbidity and long-term outcomes in pediatric patients with CNS tumors.

Glomerular Filtration Rate Abnormalities in Children With Type 1 Diabetes.

OBJECTIVES: Type 1 diabetes (T1D) increases the risk of chronic kidney disease (CKD) development. The primary objective of this study was to assess the prevalence of abnormalities in estimated glomerular filtration rate (eGFR) in children with T1D. As a secondary objective, we sought to explore the relationship between clinical characteristics and abnormalities in eGFR. METHODS: This cross-sectional study involved children ≤18 years of age with T1D followed in the diabetes clinic at a pediatric tertiary care centre. Data were collected from health records between 2016 and 2020. Using the Bedside Schwartz, Chronic Kidney Disease in Children Under 25 (CKiD U25) and European Kidney Function Consortium (EKFC) equations, eGFR was categorized as CKD (<60 mL/min/1.73 m2), mildly decreased (60 to <90 mL/min/1.73 m2), normal (90 to <158 mL/min/1.73 m2) and hyperfiltration (≥158 mL/min/1.73 m2). Linear regression analysis was used to describe the relationship between eGFR and clinical characteristics. RESULTS: Of the 420 participants, 225 were male (54%); the median age at diagnosis and duration of T1D were 6.1 and 4.8 years, respectively. The proportion of participants with mildly decreased eGFR was similar regardless of eGFR equation, with 11% to 14% of participants with an eGFR <90 mL/min/1.73 m2. When analyzed as a function of duration of T1D, eGFR was 1.4 mL/min/1.73 m2 lower per year duration of T1D. CONCLUSIONS: A notable proportion of children with T1D demonstrates eGFR abnormalities early in their T1D course. This finding along with evidence of lower eGFR in adolescence is concerning for long-term risk of CKD and warrants systematic serum creatinine monitoring at diagnosis and regular intervals thereafter in children with T1D.

Complete resolution of alopecia totalis following chemotherapy for B-cell acute lymphoblastic leukemia.

Alopecia totalis (AT) is a cosmetically debilitating chronic disease characterized by non-scarring hair loss of the entire scalp. The clinical course of AT is highly unpredictable, and effective durable treatment options are limited. The resolution of alopecia has been reported post-autologous and allogeneic hematopoietic stem cell transplantation; however, no cases of AT remission following chemotherapy alone have been described. Herein, we present a case of complete remission of AT following chemotherapy for B-cell acute lymphoblastic leukemia in a pediatric patient.

Multi-institutional analysis of treatment modalities in basal ganglia and thalamic germinoma.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

Trametinib therapy for children with neurofibromatosis type 1 and life-threatening plexiform neurofibroma or treatment-refractory low-grade glioma.

PURPOSE: To describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib. METHODS: We report on six patients with NF-1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively. RESULTS: Subjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4-28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life-threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1-2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy. CONCLUSION: Trametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF-1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients.

A case series of pediatric survivors of anaplastic pleomorphic xanthoastrocytoma.

BACKGROUND: Anaplastic pleomorphic xanthoastrocytoma (APXA) is a rare subtype of CNS astrocytoma. They are generally treated as high-grade gliomas; however, uncertainty exists regarding the optimal therapy. Here, we report on 3 pediatric cases of APXA. METHODS: Our institutional database was queried for cases of APXA and 3 cases were identified. Surgical samples were processed for methylation profiling and chromosomal microarray analysis. Methylation data were uploaded to the online CNS tumor classifier to determine methylation-based diagnoses to determine copy number variations (CNVs). RESULTS: Two patients were male, 1 female, and all were aged 12 years at diagnosis. All underwent a gross total resection (GTR) and were diagnosed with an APXA. Immunohistochemical analysis demonstrated that 2 cases were BRAF V600E positive. Methylation-based tumor classification supported the APXA diagnosis in all cases. CNV analyses revealed homozygous CKDN2A deletions in all and chromosome 9p loss in 2 cases. All patients received radiation therapy (54 Gy in 30 fractions) with concurrent temozolomide. Two patients received maintenance chemotherapy with temozolomide and lomustine for 6 cycles as per the Children's Oncology Group ACNS0423. The third patient recurred and went on to receive a second GTR and 6 cycles of lomustine, vincristine, and procarbazine. All are alive with no evidence of disease >4 years post-treatment completion (overall survival = 100%, event free survival = 67%). CONCLUSIONS: The natural history and optimal treatment of this rare pediatric tumor are not well understood. This case series supports the use of adjuvant chemoradiotherapy in the treatment of APXA. The genetic landscape may be informative for optimizing treatment and prognosis.

Successful management of symptomatic hydrocephalus using a temporary external ventricular drain with or without endoscopic third ventriculostomy in pediatric patients with germinoma.

OBJECTIVE: The objective of this study was to describe the management of hydrocephalus in a cohort of pediatric patients with germinoma. METHODS: The authors conducted a retrospective chart review of patients with germinoma and symptomatic hydrocephalus treated at the Hospital for Sick Children between 2002 and 2020. Descriptive data included tumor location, CSF diversion procedure (external ventricular drain [EVD], endoscopic third ventriculostomy [ETV], ventriculoperitoneal [VP] shunt) and outcomes. The frontooccipital horn ratio (FOR) method was used to determine the presence of ventriculomegaly. RESULTS: Of 39 patients with germinoma, 22 (73% male) had symptomatic hydrocephalus at diagnosis (11 pineal, 4 suprasellar, and 7 bifocal). Management of hydrocephalus included EVD (n = 5, 22.7%), ETV (n = 5, 22.7%), and combination ETV and EVD (n = 7, 31.8%), whereas 5 patients (22.7%) did not undergo surgical intervention. The median FOR at diagnosis was 0.42 (range 0.38-0.58), which correlated with moderate to severe ventriculomegaly. Carboplatin and etoposide-based chemotherapy induced fast tumor shrinkage, avoiding CSF diversion (n = 5) and resolving hydrocephalus with a transient EVD (n = 5). The median duration until EVD removal was 7 days (range 2-10 days). Two of 12 patients with EVD ultimately required a VP shunt. Kaplan-Meier overall survival was 100% and progression-free survival was 96.4% at a median follow-up of 10.4 years. CONCLUSIONS: Timely initiation of chemotherapy is imperative to rapidly reduce tumor bulk in children with germinoma and limits the need for VP shunt insertions. In children in whom CSF diversion is required, hydrocephalus may be successfully managed with a temporary EVD ± ETV.

Association between in-line filtration and Type I hypersensitivity reactions in pediatric oncology patients receiving intravenous etoposide.

The objective of this study was to describe hypersensitivity reactions with and without the use of in-line filters during intravenous etoposide therapy in pediatric oncology patients. This was a retrospective review of all patients treated in the Division of Oncology/Hematology/Bone Marrow Transplant at British Columbia Children's Hospital with intravenous etoposide between December 1, 2013 and February 1, 2018. Hypersensitivity reactions and anaphylaxis associated with etoposide infusions were compared over time, including 12 months prior to, 27 months during the use of, and for 12 months after the discontinuation of in-line filtration. There were 192 patients (median age 6.0 (IQR 2.8-13.0) years treated with etoposide and 486 etoposide infusions including 137 (28%) before, 261 (54%) during and 88 (18%) after use of in-line filters at our center. Twenty-six of 486 (5%) and 13/486 (3%) of infusions resulted in a type I hypersensitivity reaction and anaphylaxis, respectively. There were 2/137 (1%), 36/261 (14%) and 1/88 (1%) infusion reactions prior to, during and after in-line filter use, respectively. Infusion reactions during the in-line filter period were higher than during the pre-filter (Z = 3.978; p < 0.001) and post-filter (Z = 3.335; p < 0.001) periods of the study. These data suggest that the use of in-line filtration may be associated with increased frequency of hypersensitivity reactions to etoposide in pediatric cancer patients.

Effects of Bisphosphonate Therapy on Bone Mineral Density in Boys with Duchenne Muscular Dystrophy.

The objective of this study was to estimate the comparative effectiveness of bisphosphonate therapy on bone mineral density (BMD) in patients with corticosteroid-treated Duchenne muscular dystrophy (DMD). A retrospective, comparative effectiveness study evaluating changes in BMD and fragility fractures in patients with DMD presenting to British Columbia Children's Hospital from 1989 to 2017 was conducted. Marginal structural generalized estimating equation models weighted by stabilized inverse-probability of treatment weights were used to estimate the comparative effectiveness of therapy on BMD. Of those treated with bisphosphonates (N = 38), 7 (18.4%), 17 (44.7%), and 14 (36.8%) cases were treated with pamidronate, zoledronic acid, or a combination of both, respectively, while 36 cases of DMD were untreated. Mean age of bisphosphonate initiation was 9.2 (SD 2.7) years. Mean fragility fractures declined from 3.5 to 1.0 following bisphosphonate therapy. Compared to the treated group, the untreated group had an additional 0.63-SD decrease (95% confidence interval [CI]: -1.18, -0.08, P = .026) in total BMD and an additional 1.04-SD decrease (95% CI: -1.74, -0.34; P = .004) in the left hip BMD, but the change in lumbar spine BMD (0.15, 95% CI: -0.36, 0.66; P = .57) was not significant. Bisphosphonate therapy may slow the decline in BMD in boys with corticosteroid-treated DMD compared to untreated counterparts. Total number of fragility fractures decreased following bisphosphonate therapy.

High molecular weight adiponectin levels are inversely associated with adiposity in pediatric brain tumor survivors.

While children with brain tumors are surviving at record rates, survivors are at risk of cardiovascular disease and type 2 diabetes mellitus; these conditions may be driven by excess body fat. Adiponectin in an adipokine that is inversely associated with the fat mass, and has been linked to cardiometabolic risk stratification in the general population. However, adiponectin's profile and determinants in SCBT have not been established. We tested the hypothesis that high molecular weight (HMW) adiponectin levels, the more biologically active form of adiponectin, were associated with adiposity in SCBT similarly to non-cancer controls. Seventy-four SCBT (n = 32 female) and 126 controls (n = 59 female) who were 5-17 years old were included. Partial correlations and multivariable regression analyses assessed the relationship between HMW adiponectin and adiposity. HMW adiponectin was inversely associated with total and central adiposity (FM%: ß - 0.21, 95% CI - 0.15, - 0.08; p value < 0.0001; WHR: ß - 0.14, 95% CI - 0.02, - 0.01; p value < 0.0001 ;WHtR: ß - 0.21, 95% CI - 0.05, - 0.03; p value < 0.0001). In conclusion, HMW adiponectin is inversely correlated with adiposity in SCBT. Adiponectin may serve as a biomarker of cardiometabolic risk and response to interventions to prevent and manage obesity and its comorbidities in SCBT.

Clinical Impact and Cost Efficacy of Newborn Screening for Congenital Adrenal Hyperplasia.

OBJECTIVES: To evaluate the clinical impact of a congenital adrenal hyperplasia (CAH) newborn screening program and incremental costs relative to benefits in screened vs unscreened infants. We hypothesized that screening would lead to clinical benefits and would be cost effective. STUDY DESIGN: This was an ambispective cohort study at British Columbia Children's Hospital, including infants diagnosed with CAH from 1988-2008 and 2010-2018. Data were collected retrospectively (unscreened cohort) and prospectively (screened cohort). Outcome measures included hospitalization, medical transport, and resuscitation requirements. The economic analysis was performed using a public payer perspective. RESULTS: Forty unscreened and 17 screened infants were diagnosed with CAH (47% vs 53% male). Median days to positive screen was 6 and age at diagnosis was 5 days (range, 0-30 days) and 6 days (range, 0-13 days) in unscreened and screened populations, respectively. In unscreened newborns, 55% required transport to a tertiary care hospital, 85% required hospitalization, and 35% required a fluid bolus compared with 29%, 29%, and 12% in screened infants, respectively. The cost of care was $33 770 per case in unscreened vs $17 726 in screened newborns. In the screened cohort, the incremental cost-effectiveness ratio was $290 in the best case analysis and $4786 in the base case analysis, per hospital day avoided. CONCLUSIONS: Compared with unscreened newborns, those screened for CAH were less likely to require medical transport and had shorter hospital stays. Screening led to a decrease in hospitalization costs. Although screening did not result in cost savings, it was assessed to be cost effective considering the clinical benefits and incremental cost-effectiveness ratio.