Visual acuity of children treated with chemotherapy for optic pathway gliomas.

BACKGROUND: Chemotherapy is the most common primary treatment modality for pediatric optic pathway gliomas (OPGs). Due to the risk of severe visual impairment, visual acuity (VA) has become a clinical parameter of fundamental importance for children with OPGs. Despite this reality, most studies omit crucial information necessary for analysis of the effect of chemotherapy on VA in patients with cerebral gliomas. The principal goal of this study was to determine the immediate and long-term visual outcome of children treated first with chemotherapy for OPGs. PROCEDURE: Retrospective, non-comparative, case series of children with OPGs treated initially with chemotherapy. VA was measured prior to chemotherapy, directly following chemotherapy, as well as at last follow-up. RESULTS: Seven children (14 eyes) were positive for the neurofibromatosis type-1 (NF1) mutation and 10 children (20 eyes) were without the NF1 mutation (sporadic). Three deaths, all in the sporadic cohort, occurred as a result of their OPG. Median follow-up time of survivors was 10.54 ± 4.36 (SD) years. Both NF1 mutation positive and sporadic cohorts had deterioration in VA over time; however, deterioration was only statistically significant in the sporadic population. The percentage of eyes with vision weaker than 20/200 prior to chemotherapy, directly following chemotherapy and at last follow-up grew from 18% to 24% to 38%, respectively. CONCLUSIONS: In both NF1 mutant and sporadic OPGs, VA deteriorated directly following chemotherapy as well as at long-term follow-up. Despite chemotherapy, eyes with severe functional impairment gradually increased over time.

Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors.

BACKGROUND: The combination of vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus inhibits the growth of neuroblastoma xenografts through pro-apoptotic and anti-angiogenic mechanisms. This phase I study aimed to explore the safety and toxicity of this combination in pediatric patients with advanced solid tumors. PROCEDURE: Patients ≤21 years of age with recurrent/refractory solid tumors (including CNS) were eligible. Sirolimus was administered daily by mouth or nasogastric (NG) tube, with doses adjusted to achieve a target trough concentration of 10-15 ng/ml, with weekly intravenous vinblastine (dose escalated 4-6 mg/m(2)/dose according to 3 + 3 phase I design). RESULTS: Fourteen patients were enrolled (median age 8.7 years; range 2.3-19) of whom 12 were evaluable for toxicity and 11 for response. One patient experienced a dose-limiting toxicity (grade 3 mucositis) at the highest vinblastine dose level. Myelosuppression was the most common toxicity. Dose-adjusted sirolimus trough concentrations were significantly lower in patients receiving drug via NG tube (1.50 ± 0.75 ng/ml/mg vs. 2.25 ± 1.07 ng/ml/mg for oral administration). Correlative biomarker analysis demonstrated a significant reduction in serum concentration of soluble vascular endothelial growth factor receptor (sVEGFR2) at 28 days compared to baseline consistent with inhibition of angiogenesis. One patient had a partial response and three had stable disease for more than 3 months. CONCLUSIONS: The combination of mTOR inhibitor and vinblastine given over an extended continuous schedule is safe, associated with a reduction in circulating angiogenic factor (CAF) VEGFR2 and resulted in clinical responses. Future studies using the intravenously administered mTOR inhibitor temsirolimus are planned.

Multimodal Treatment Including Intracavitary Chemotherapy for Recurrent Pediatric Pleuropulmonary Blastoma.

Pleuropulmonary blastoma (PPB) is a rare pediatric cancer, and although there have been improvements in its treatment approach, recurrences retain a very poor prognosis. Here, we report a case of a 30-month-old female who survived recurrent PPB after undergoing surgery, adjuvant chemotherapy, intrapleural cisplatin infusion, and targeted therapy through whole exome sequencing (WES). Intrapleural cisplatin infusion and target therapy appear to be safe and can be considered in a multimodal approach for the management of recurrent PPB.

Recurrent somatic BRAF insertion (p.V504_R506dup): a tumor marker and a potential therapeutic target in pilocytic astrocytoma.

Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated RAS/RAF/MEK/ERK signaling. In this study, we report the identification of a novel recurrent BRAF insertion (p.V504_R506dup) in five PA cases harboring exclusively this somatic tandem duplication. This recurrent alteration leads to an addition of three amino acids in the kinase domain of BRAF and has functional impact on activating MAPK phosphorylation. Importantly, we show that this mutation confers resistance to RAF inhibitors without changing effectiveness while downstream MEK inhibitors remain effective. Our results further emphasize the importance of BRAF alterations in PA and the need to characterize them in a given tumor as this can affect therapeutic strategies and their potential use as tumor marker in molecular diagnostics.

Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers.

Importance: Little progress in pediatric cancer treatment has been noted in the past decade, urging the development of novel therapeutic strategies for adolescents and children with hard-to-treat cancers. Use of comprehensive molecular profiling in the clinical management of children and adolescents with cancer appears a suitable approach to improve patient care and outcomes, particularly for hard-to-treat cases. Objective: To assess the feasibility of identifying potentially actionable mutations using next-generation sequencing-based assays in a clinically relevant time frame. Design, Setting, and Participants: This diagnostic study reports the results of the TRICEPS study, a prospective genome sequencing study conducted in Québec, Canada. Participants, aged 18 years or younger at diagnosis, with refractory or relapsed childhood and adolescent cancers were enrolled from April 2014 through January 2018. Whole-exome sequencing (WES) of matched tumor normal samples and RNA sequencing of tumor were performed to identify single-nucleotide variants, fusion transcripts, differential gene expression, and copy number alterations. Results reviewed by a team of experts were further annotated, synthesized into a report, and subsequently discussed in a multidisciplinary molecular tumor board. Main Outcomes and Measures: Molecular profiling of pediatric patients with hard-to-treat cancer, identification of actionable and targetable alteration needed for the management of these patients, and proposition of targeted and personalized novel therapeutic strategies. Results: A total of 84 patients with hard-to-treat cancers were included in the analysis. These patients had a mean (range) age of 10.1 (1-21) years and a similar proportion of male (45 [54%]) and female (39 [46%]). Sixty-two patients (74%) had suitable tissues for multimodal molecular profiling (WES and RNA sequencing). The process from DNA or RNA isolation to genomic sequencing and data analysis steps took a median (range) of 24 (4-41) days. Potentially actionable alterations were identified in 54 of 62 patients (87%). Actions were taken in 22 of 54 patients (41%), and 18 (33%) either were on a second or third line of treatment, were in remission, or had stable disease and thus no actions were taken. Conclusions and Relevance: Incorporating genomic sequencing into the management of hard-to-treat childhood and adolescent cancers appeared feasible; molecular profiling may enable the identification of potentially actionable alterations with clinical implications for most patients, including targeted therapy and clinically relevant information of diagnostic, prognostic, and monitoring significance.

Interventions in the operating room for children near end of life: A multidisciplinary approach.

INTRODUCTION: Pediatric surgeons are often involved in the management of severely or terminally ill patients. However, articles addressing their specific roles in the context of palliative care are almost inexistent. We sought to characterize the involvement of pediatric surgeons caring for children near end of life. METHODS: Chart review of children who had a procedure under general anesthesia within 6months of their death over a five-year period at a tertiary children's hospital (excluding traumas and neonatology cases). In addition to demographic and clinical data, we recorded the aim of the procedures performed, the involvement of the palliative care service, and presence of DNAR orders. RESULTS: The analysis included 83 patients (mean age: 8years). Forty-four children had more than one procedure (range 2-10). Pediatric palliative care service was involved in 66 cases (80%). A majority of patients had cancer (50%), and the most frequent cause of death was oncologic progression (46%). Ten patients died of a complication following their intervention. The aim of the procedure was palliative in 48 cases (29 for symptoms control and 19 to facilitate care), diagnostic in 16, and curative in 19. Forty-five procedures were performed urgently and 14 despite DNAR orders. CONCLUSION: Surgeon involvement with children near end of life is not infrequent. The procedures performed are varied and can be categorized according to their aim. Lack of formal palliative care training by surgeons highlights the need for increased collaboration with palliative care services to provide children optimal care when they need it most. LEVEL OF EVIDENCE: IV.