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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., Here, we report on response to Trametinib, a MEK inhibitor in children with NF‐1. Our experience presented in this report demonstrates that Trametinib is an effective therapy for advanced, life‐threatening PNF, and treatment‐refractory PLGG in patients with NF‐1 and is well tolerated in children.

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.

Puberty is initiated by hormonal changes in the adolescent body that trigger physical and behavioral changes to reach adult maturation. As these changes occur, some adolescents experience concerning pubertal symptoms that are associated with dysfunction of the autonomic nervous system (ANS). Vasovagal syncope (VVS) and Postural Orthostatic Tachycardia Syndrome (POTS) are common disorders of the ANS associated with puberty that are related to orthostatic intolerance and share similar symptoms. Compared to young males, young females have decreased orthostatic tolerance and a higher incidence of VVS and POTS. As puberty is linked to changes in specific sex and non-sex hormones, and hormonal therapy sometimes improves orthostatic symptoms in female VVS patients, it is possible that pubertal hormones play a role in the increased susceptibility of young females to autonomic dysfunction. The purpose of this paper is to review the key hormonal changes associated with female puberty, their effects on the ANS, and their potential role in predisposing some adolescent females to cardiovascular autonomic dysfunctions such as VVS and POTS. Increases in pubertal hormones such as estrogen, thyroid hormones, growth hormone, insulin, and insulin-like growth factor-1 promote vasodilatation and decrease blood volume. This may be exacerbated by higher levels of progesterone, which suppresses catecholamine secretion and sympathetic outflow. Abnormal heart rate increases in POTS patients may be exacerbated by pubertal increases in leptin, insulin, and thyroid hormones acting to increase sympathetic nervous system activity and/or catecholamine levels. Given the coincidental timing of female pubertal hormone surges and adolescent onset of VVS and POTS in young women, coupled with the known roles of these hormones in modulating cardiovascular homeostasis, it is likely that female pubertal hormones play a role in predisposing females to VVS and POTS during puberty. Further research is necessary to confirm the effects of female pubertal hormones on autonomic function, and their role in pubertal autonomic disorders such as VVS and POTS, in order to inform the treatment and management of these debilitating disorders.

The objective was to conduct a program evaluation of the Centre for Healthy Weights—Shapedown BC (CHW-SB), a family-centered, multidisciplinary program for obese children, by assessing the change in weight trajectories from program intake to completion. Secondary outcomes included changes in clinical, biochemical and psychological parameters, and in physical activity (PA) levels. The CHW-SB program was evaluated over 10 weeks. Data collection included anthropometric, metabolic, PA and psychological measures. Longitudinal mixed effects regression was performed to evaluate weight change from Phase 1 (before program on waitlist) to Phase 2 (during program). 238 children < 18 years of age were referred to the program of which 119 were eligible for participation. There was a significant decrease in weight trajectory in children following program entry. Participants experienced an average .89% monthly increase before program entry, compared to a .37% monthly decline afterwards, a drop of 1.26% (p < 0.0001, 95%CI 1.08 to 1.44). zBMI (2.26 ± 0.33 to 2.20 ± 0.36, p < 0.001), waist circumference (99 ± 15.7 to 97 ± 16 cm, p < 0.0001) and fasting insulin (137 ± 94.8 to 121 ± 83.4 pmol/L, < 0.001) also decreased in participants who attended the final visit. Significant improvements were seen in all measures of PA, self-concept, and anxiety. CHW-SB, a government-funded program, is the first obesity-treatment program to be evaluated in Canada. While short-term evaluation revealed significant improvements in adiposity, PA, and psychological measures, the lack of full follow-up is a limitation in interpreting the clinical effectiveness of this program, as drop-out may be associated with lack of success in meeting program goals. These data also emphasize the need for ongoing evaluation to assess the long-term implications of this unique program and ultimately optimize utilization of governmental resources.

OBJECTIVE Pleomorphic xanthoastrocytoma (PXA) with anaplasia is a rare histological subtype of central nervous system astrocytoma and generally treated as high grade gliomas. The optimal extent of therapy required is unknown. Here we report on 3 pediatric cases of PXA with anaplasia. We also describe molecular features and methylation profile of PXA with anaplasia compared to age-matched PXA without anaplasia. METHODS Our institutional database was queried for cases of PXA since 1998 and 3 cases with anaplasia were identified and records reviewed. RESULTS 2/3 patients were male and all were aged 12 at diagnosis. All underwent a gross total resection (GTR), where the diagnosis of PXA with anaplasia was made. Immunohistochemistry demonstrated that two cases were BRAF V600E positive and two were CD34 positive. Methylation profiling revealed unique pattern of CpG methylation/unmethylation. All patients underwent 5400cGy radiation to the surgical bed. 2/3 patients received concurrent temozolamide with radiation followed by maintenance chemotherapy with temozolamide and lomustine for 6 cycles as per the Children’s Oncology Group Protocol ACNS0423. These two patients had a continued complete response. The third patient received temozolamide following radiation and subsequently had recurrent disease at the end of treatment and went on to have a re-resection GTR and achieved complete response after 6 cycles of lomustine, vincristine and procarbazine. All are alive with no evidence of disease at more than 2 years post treatment completion (OS=100%,EFS=67%). CONCLUSIONS This rare pediatric tumor is not well understood. The genetic landscape may be informative for optimizing treatment and prognosis.

Delayed diagnosis of CNS tumors in children is well documented, partially due to challenges in recognizing rare diagnoses. Our objective was to describe Canadian family physicians’ attitudes and confidence in diagnosing and managing pediatric CNS tumors. A standardized questionnaire was administered at a Canadian national family physicians’ conference. Items were based on observations from our institutional study of prediagnostic symptomatic interval in pediatric CNS tumors. 449 surveys were completed. 302/443 (68%) physicians practice in cities. 153/447 (34%) report encountering parents that inquire about their children having brain tumors. 261/449 (58%) have not managed a pediatric brain tumor. 153/447 (34%) report they are not confident, 255/447 (57%) somewhat confident and 39/447 (9%) confident in managing a suspected brain tumor in a stable child. 259/447 (58%) would refer directly to a hospital/specialist. The reported median time for suspicion of a brain tumor was 8–14 days for children with vomiting and/or headache and 1 day for children with seizure and/or ataxia. 410/447 (97%) report not knowing any guidelines to help with management. 235/447 (53%) suggested barriers they experience to include 52/235 (22%) wait times for imaging/specialists, 37/235 (16%) geographical location of the child, 27/235 (12%) knowledge, 25/235 (11%) access to imaging/specialist, and 15/235 (6%) patient-related factors or system barriers, and 8/235 (3%) specialist attitudes. 68/235 (29%) identified no barriers in their practice. This study provides insight into family physicians’ perceived challenges and barriers in diagnosing and managing new suspected pediatric CNS tumors. Educational effort and overcoming systemic perceived barriers may increase physicians’ confidence.