Children with Supratentorial Midline Pilocytic Astrocytomas Exhibit Multiple Progressions and Acquisition of Neurologic Deficits Over Time

Summary Tumor location has been proposed as a prognostic factor for pilocytic astrocytoma (PA), but since resection status varies by CNS location, these two variables are difficult to separate on multivariate analysis. To eliminate resection status as a confounding variable, we analyzed the outcomes of children with subtotally resected PA by brain location. We found that individuals with PA in the supratentorial midline region had an increased likelihood of multiple progression events. These children also exhibited more neurologic deficits over time compared to those with brainstem PA, frequently due to worsening vision and the acquisition of new endocrinopathies or weakness.

Survival rates of children and young adolescents with CNS tumors improved in the Netherlands since 1990: A population-based study

Introduction Survival of children with central nervous system (CNS) tumors varies largely between countries. For the Netherlands, detailed population-based estimation of incidence, survival and mortality of pediatric CNS tumors are lacking but are needed to evaluate progress. Methods All CNS tumors diagnosed in patients <18 years during 1990-2017 were selected from the Netherlands Cancer Registry. Other than pilocytic astrocytomas, non-malignant tumors were included since 2000. Incidence and mortality trends were evaluated by Average Annual Percentage Change (AAPC). Changes over time in Five-year Observed Survival (5-year OS) were evaluated by Poisson regression models adjusted for follow-up time. Results Between 1990 and 2017, 2057 children were diagnosed with a malignant CNS tumor and 885 with a pilocytic astrocytoma. During 2000-17, 695 children were diagnosed with other non-malignant CNS tumors. Incidence rates of malignant tumors remained stable, while pilocytic astrocytomas and other non-malignant tumors increased by 2.0% and 2.4% per year, respectively. 5-year OS rates improved for all groups; however, improvement for malignant tumors was not constant over time. The contribution of malignant tumors located at the optic nerve tumors was 1% in 2000-09. However, shifting from pilocytic astrocytomas, increased to 6% in 2010-17, impacting survival outcomes for malignant tumors. Conclusion Survival rates of CNS tumors improved over time, but was not accompanied by a decreasing mortality rate. The observed temporary survival deterioration for malignant tumors appears to be related to changes in diagnostics and registration practices. Whether differences in treatment regimens contribute to this temporary decline in survival needs to be verified.

Pediatric and Adult Low-Grade Gliomas: Where Do the Differences Lie?

Two thirds of pediatric gliomas are classified as low-grade (LGG), while in adults only around 20% of gliomas are low-grade. However, these tumors do not only differ in their incidence but also in their location, behavior and, subsequently, treatment. Pediatric LGG constitute 65% of pilocytic astrocytomas, while in adults the most commonly found histology is diffuse low-grade glioma (WHO II), which mostly occurs in eloquent regions of the brain, while its pediatric counterpart is frequently found in the infratentorial compartment. The different tumor locations require different skillsets from neurosurgeons. In adult LGG, a common practice is awake surgery, which is rarely performed on children. On the other hand, pediatric neurosurgeons are more commonly confronted with infratentorial tumors causing hydrocephalus, which more often require endoscopic or shunt procedures to restore the cerebrospinal fluid flow. In adult and pediatric LGG surgery, gross total excision is the primary treatment strategy. Only tumor recurrences or progression warrant adjuvant therapy with either chemo- or radiotherapy. In pediatric LGG, MEK inhibitors have shown promising initial results in treating recurrent LGG and several ongoing trials are investigating their role and safety. Moreover, predisposition syndromes, such as neurofibromatosis or tuberous sclerosis complex, can increase the risk of developing LGG in children, while in adults, usually no tumor growth in these syndromes is observed. In this review, we discuss and compare the differences between pediatric and adult LGG, emphasizing that pediatric LGG should not be approached and managed in the same way as adult LCG.

Correlation between Pre- and Post-Surgical Findings for Long-Term Neurocognitive and Behaviour Development Due to Posterior Fossa Pilocytic Astrocytomas: The Trend after 10 Years

Objective: The objective of the present study was to selectively evaluate the long-term impact of posterior fossa pilocytic astrocytomas, which are known to be among the most benign forms of paediatric brain tumours on neurocognitive and behavioural functions. Methods: Children that were operated on for a posterior fossa pilocytic astrocytoma in the Pediatric Neurosurgery Department of the Catholic University Medical School were selected according to the following criteria: (a) age > 5 years (in order to have a complete set of neurocognitive evaluations data), (b) ability to perform a complete set of tests before and after surgery, and (c) children that had a regular follow-up up to 10 years from the surgical treatment. Results: Forty-three percent of the children selected for the present study showed a borderline IQ before surgery, which is a result corresponding to those previously reported in the literature for children affected by posterior fossa pilocytic astrocytomas; praxis and visual perception were the selective functions that were more frequently affected. Language performance tests scores were below average in 40% of the cases but tended to improve in terms of expressive and receptive skills even at the 1-year follow-up; the improvements became significant at the 5-year and 10-year follow-ups. Conclusions: Recognising and measuring the short- and long-term effects of cerebellar tumours in children and their treatment are the first step towards improving their clinical course and quality of life. Early interventions should be offered to all of them, with specific attention bestowed on visual-spatial stimulation, speech and occupational therapies in order to act on praxic and visuo-perceptive skills, as well as on emotion and behaviour tracts of the neurocognitive profile, which more commonly tend to persist in the long term.

Recurrent adult pilocytic astrocytoma presenting with intraventricular and leptomeningeal spread

Background: Infratentorial pilocytic astrocytomas are uncommon tumors in adulthood but are thought to be prognostically similar to their pediatric counterparts with excellent overall survival following gross total resection. However, given the relative rarity of these tumors, no management guidelines exist for recurrent adult pilocytic astrocytomas (APAs). This lack of consensus is especially problematic for inoperable recurrences or those with aggressive features concerning for malignant transformation. Case Description: In 2017, a 26-year-old female presented with headaches, nausea, vomiting, and blurry vision. A brain magnetic resonance imaging (MRI) demonstrated a large, well-circumscribed mass within the fourth ventricle causing obstructive hydrocephalus. She underwent near-total resection through a midline suboccipital transtonsillar approach. Pathology demonstrated a World Health Organization Grade 1 pilocytic astrocytoma. Despite initial improvement in her symptoms, she developed worsening headaches and lethargy 10 months after surgery and repeat MRI demonstrated recurrent tumor within the entire ventricular system and the subarachnoid spaces of the left cerebellopontine angle suggesting leptomeningeal spread. Due to the unresectable nature of the recurrence, the patient declined any further intervention and succumbed to her disease 6 months later. Conclusion: We present the first case of a recurrent APA presenting with intraventricular and leptomeningeal spread. Although thought to be a benign neoplasm, close interval follow-up with serial imaging is of essential, especially in those patients with known residual tumor, to prevent aggressive recurrences such as this.

LGG-13. PILOCYTIC ASTROCYTOMAS WITH NOVEL BRAF FUSIONS DEMONSTRATE MAPK PATHWAY ACTIVATION

Background Pilocytic astrocytomas (PAs) are the most common pediatric low-grade glioma subtype. Oftentimes, PAs demonstrate somatic genetic alterations, the most common being the BRAF-KIAA1549 fusion, which results in constitutive activation of the MAPK pathway. Better understanding of the effects of other RAF fusions is necessary to determine the potential utility of MAPK-targeting therapies. Methods Three patients presented to Children’s Hospital Colorado and were ultimately diagnosed with PAs harboring previously unreported gene fusions identified as FYCO-RAF1, CCTTNNBP2-BRAF, and SLC44A1-BRAF. Utilizing immunohistochemistry, we stained novel samples and controls for ERK and pERK (phosphorylated ERK) to assess the activation of the MAPK pathway. PAs with known BRAF-KIAA1549 fusions (4 samples) and normal brain tissue (5 samples) were used as positive and negative controls, respectively. We additionally performed RNA sequencing to better understand expression changes associated with these fusions, utilizing Metascape and GSEA (Gene Set Enrichment Analysis) for analysis. Results Immunohistochemistry of negative control samples demonstrated less p-ERK than ERK (ratios of 0.6–0.9, mean 0.8). All samples with novel fusions demonstrated statistically significantly higher p-ERK expression compared to negative controls (ratios of 1.3–1.7, mean 1.4). These experimental samples also all fell within the p-ERK to ERK expression range of the positive control samples, which demonstrated the widest range of expression (ratios of 1.1–4.5, mean 2.2). Our molecular analysis further confirmed these results, with GSEA demonstrating positively upregulated MAPK and ERK pathways in 2 positive controls and 1 novel fusion sample. Metascape analysis emphasized overall similar gene expression between these samples, demonstrating many shared genes and functional pathways. Conclusions We identified 3 previously unreported RAF fusions in PA that demonstrate activation of the MAPK pathway, although not as extensively as seen in some positive control samples with BRAF-KIAA1549 fusions. MEK inhibition may be a useful therapeutic strategy in these tumors if targeted therapy is indicated.

LGG-04. MULTIOMIC ANALYSIS OF MAPK PATHWAY ACTIVITY IN PEDIATRIC PILOCYTIC ASTROCYTOMA

Introduction Pilocytic astrocytomas (PA) are the most common pediatric brain tumors. They are characterized by MAPK pathway alterations, leading to its constitutive activation and modulating the balance between cell proliferation and the oncogene-induced senescence (OIS) sustained by senescence-associated secretory phenotype (SASP) factors. This makes PA suitable for MAPK inhibitor (MAPKi) therapies, showing encouraging results in phase 1/2 clinical trials. Little is known about the molecular implications of MAPK downregulation in the proliferating and senescent compartments. Methods DKFZ-BT66 PA cells derived from a primary KIAA:BRAF-fusion positive PA cell line, were used as model system. Gene expression and phospho-proteomic datasets were generated from DKFZ-BT66 cells, in both the proliferative and senescent states, and treated with the MEKi trametinib for different time-spans. A time course analysis based on differentially expressed genes was performed, followed by a single-sample gene set enrichment analysis (ssGSEA). Analysis of the phospho-proteomic data is ongoing. Results Differential gene expression analysis revealed that MEK inhibition leads to the inhibition of the OIS-SASP gene program in senescent DKFZ-BT66. ssGSEA showed that most MAPK-related signatures were downregulated upon MEKi treatment, while pathways related to upstream MAPK activators (including FGFR, NTRK and TGFB pathways) were upregulated, in both proliferating and senescent DKFZ-BT66. Genes regulated by the MAPK pathway and involved in OIS-SASP were identified by analyzing genes differentially regulated between proliferating and senescent DKFZ-BT66, and modulated upon MEKi treatment. Conclusion This data suggests that MAPKi reverses OIS in senescent PA cells, while inducing the activation of MAPK upstream regulators in proliferating and senescent PA cells, identifying putative co-targets that could help prevent growth rebound upon MAPKi withdrawal. Furthermore, the identification of the MAPK-related OIS-SASP genes provide insight about the regulation of OIS-SASP by the MAPK pathway. Validation of this data with the ongoing phospho-proteomic analysis and in primary samples is needed.