High-grade gliomas (HGGs) are malignant tumors and typically include glioblastoma multiforme and anaplastic astrocytoma subtypes. Brainstem gliomas and ependymomas are separate entities with respect to clinical presentation, treatment, prognosis, and outcome in comparison with supratentorial HGGs. In children, these tumors account for 3% to 7% of newly diagnosed brain tumors and 20% of all diagnoses of pediatric supratentorial brain tumors. These neoplasms are highly proliferative and mitotically active and of glial origin. This article reviews clinical, diagnostic, and pathologic features of HGG and current treatments and potential future therapies specific to pediatric patients with HGGs.

The treatment of children with low-grade glioma has evolved over the last several decades, beginning initially with focal radiotherapy, which has now been largely replaced by systemic treatment with conventional chemotherapy agents or more recently molecularly targeted therapeutics. A consensus standard of care is not well defined, leaving clinicians and parents to choose from an increasing number of options, often without complete information concerning the associated risks and benefits. Issues critical to this topic include timing of interventions (when to treat), preservation of neurological function (goals of treatment), choice of initial therapy strategy (conventional cytotoxic chemotherapy vs molecularly targeted therapy), duration of treatment (how long, and what clinical or imaging endpoints to consider), and perhaps most important, risk reduction relative to anticipated benefit. The groups from the University of California, San Francisco and Dana Farber Cancer Institute, moderated by Michael Prados, herein debate the merits of cytotoxic chemotherapy and targeted therapeutics as initial treatment strategies in pediatric low-grade glioma, a topic discussed daily in Tumor Boards across the United States and abroad. Prospective, randomized, phase 3 trials comparing the 2 strategies, conducted within homogenous disease settings, with consistently evaluated functional and imaging endpoints, are not available to guide the risks/benefit discussion. As is often the case in rare biologically diverse diseases, in a vulnerable population, therapy decisions are frequently based on incomplete data, physician experience, bias to some degree, and patient/family preference.

To evaluate the role of chemotherapy and radiation therapy in the treatment of pure germinomas of the central nervous system (CNS). We reviewed a historical cohort of 79 patients between the ages of 3-35 years who received definitive treatment for newly diagnosed, pure CNS germinoma between 1985 and 2010 at the University of California, San Francisco (UCSF). Median age at diagnosis was 15 years (interquartile range, IQR 12-20 years) and 61 (77.2 %) patients were male. Median follow-up for the cohort was 111.1 months (IQR 45.7-185.1 months). Five-year PFS rate was 86.4 % (95 % CI 76.1-92.4) and 5 year OS rate was 93.0 % (95 % CI 84.1-97.1). Median PFS was 104.6 months (IQR 41.4-170.1 months). Fourteen patients progressed and 8 died of their disease. Patients who received focal irradiation (XRT) and chemotherapy had a significantly higher rate of progression compared to those who received whole brain irradiation (WBI) or whole ventricle irradiation (WVI). Three of 8 patients had a PR to chemotherapy and received focal XRT progressed whereas only 1 of 9 patients who had a CR to chemotherapy who went on to receive focal XRT progressed. Elevation of hCGβ > 50 mIU/ml was not significantly associated with disease progression (HR 5.64, 95 % CI 0.97-32.7, p = 0.054). Patients treated with WBI or WVI with or without chemotherapy achieve better disease control compared to patients treated with focal XRT + chemotherapy.

Purpose

To assess, in a retrospective cohort study, rates and predictors of first and recurrent stroke in patients treated with cranial irradiation (CRT) and/or cervical irradiation at ≤18 years of age.

Methods and materials

We performed chart abstraction (n=383) and phone interviews (n=104) to measure first and recurrent stroke in 383 patients who received CRT and/or cervical radiation at a single institution between 1980 and 2009. Stroke was defined as a physician diagnosis and symptoms consistent with stroke. Incidence of first stroke was number of first strokes per person-years of observation after radiation. We used survival analysis techniques to determine cumulative incidence of first and recurrent stroke.

Results

Among 325 subjects with sufficient follow-up data, we identified 19 first strokes (13 ischemic, 4 hemorrhagic, 2 unknown subtype) occurring at a median age of 24 years (interquartile range 17-33 years) in patients treated with CRT. Imaging was reviewed when available (n=13), and the stroke was confirmed in 12. Overall rate of first stroke was 625 (95% confidence interval [CI] 378-977) per 100,000 person-years. The cumulative incidence of first stroke was 2% (95% CI 0.01%-5.3%) at 5 years and 4% (95% CI 2.0%-8.4%) at 10 years after irradiation. With each 100-cGy increase in the radiation dose, the stroke hazard increased by 5% (hazard ratio 1.05; 95% CI 1.01-1.09; P=.02). We identified 6 recurrent strokes; 5 had available imaging that confirmed the stroke. Median time to recurrence was 15 months (interquartile range 6 months-3.2 years) after first stroke. The cumulative incidence of recurrent stroke was 38% (95% CI 17%-69%) at 5 years and 59% (95% CI 27%-92%) at 10 years after first stroke.

Conclusion

Cranial irradiation puts childhood cancer survivors at high risk of both first and recurrent stroke. Stroke prevention strategies for these survivors are needed.

PURPOSE: To assess, in a retrospective cohort study, rates and predictors of first and recurrent stroke in patients treated with cranial irradiation (CRT) and/or cervical irradiation at ≤18 years of age. METHODS AND MATERIALS: We performed chart abstraction (n=383) and phone interviews (n=104) to measure first and recurrent stroke in 383 patients who received CRT and/or cervical radiation at a single institution between 1980 and 2009. Stroke was defined as a physician diagnosis and symptoms consistent with stroke. Incidence of first stroke was number of first strokes per person-years of observation after radiation. We used survival analysis techniques to determine cumulative incidence of first and recurrent stroke. RESULTS: Among 325 subjects with sufficient follow-up data, we identified 19 first strokes (13 ischemic, 4 hemorrhagic, 2 unknown subtype) occurring at a median age of 24 years (interquartile range 17-33 years) in patients treated with CRT. Imaging was reviewed when available (n=13), and the stroke was confirmed in 12. Overall rate of first stroke was 625 (95% confidence interval [CI] 378-977) per 100,000 person-years. The cumulative incidence of first stroke was 2% (95% CI 0.01%-5.3%) at 5 years and 4% (95% CI 2.0%-8.4%) at 10 years after irradiation. With each 100-cGy increase in the radiation dose, the stroke hazard increased by 5% (hazard ratio 1.05; 95% CI 1.01-1.09; P=.02). We identified 6 recurrent strokes; 5 had available imaging that confirmed the stroke. Median time to recurrence was 15 months (interquartile range 6 months-3.2 years) after first stroke. The cumulative incidence of recurrent stroke was 38% (95% CI 17%-69%) at 5 years and 59% (95% CI 27%-92%) at 10 years after first stroke. CONCLUSION: Cranial irradiation puts childhood cancer survivors at high risk of both first and recurrent stroke. Stroke prevention strategies for these survivors are needed.

To report long-term results for children with low-grade hypothalamic/chiasmatic gliomas treated on a phase II chemotherapy protocol. Between 1984 and 1992, 33 children with hypothalamic/chiasmatic LGGs received TPDCV chemotherapy on a phase II prospective trial. Median age was 3.0 years (range 0.3–16.2). Twelve patients (36%) underwent STRs, 14 (42%) biopsy only, and seven (21%) no surgery. Twenty patients (61%) had pathologic JPAs, nine (27%) grade II gliomas, and four (12%) no surgical sampling. Median f/u for surviving patients was 15.2 years (range 5.3–20.7); 20 of the 23 surviving patients had 14 or more years of follow-up. Fifteen-year PFS and OS were 23.4 and 71.2%, respectively. Twenty-five patients progressed, of whom 13 are NED, two are AWD, and 10 have died. All children who died were diagnosed and first treated at age three or younger. Age at diagnosis was significantly associated with relapse and survival (P = 0.004 for PFS and P = 0.037 for OS). No PFS or OS benefit was seen with STR versus biopsy/no sampling (P = 0.58 for PFS, P = 0.59 for OS). For patients with JPAs and WHO grade II tumors, the 15-year PFS was 18.8 and 22.2% (P = 0.95) and 15-year OS was 73.7 and 55.6% (P = 0.17), respectively. Upfront TPDCV for children with hypothalamic/chiasmatic LGGs resulted in 15-year OS of 71.2% and 15-year PFS of 23.4%. No survival benefit is demonstrated for greater extent of resection. Age is a significant prognostic factor for progression and survival.

Abstract Introduction: Pediatric low-grade gliomas (PLGG) constitute the most common group of central nervous system tumors in children. Although they exhibit rare malignant transformation and relatively slow growth, PLGGs pose great morbidity. Viewed as a chronic disease, ideal therapy for PLGG should carry limited side effects that can be best achieved through selective, personalized therapy. Despite the known heterogeneity of PLGGs and characterized driver mutations that together offer the perfect, timely platform for personalized approaches to therapy, most children are still treated with standard chemotherapy protocols in a “one treatment fits all” approach. Recent genomic studies have defined recurrent, diverse alterations driving WHO grade 1 and 2 PLGGs. Activation of mitogen protein kinase (MAPK) and phosphatidylinositol-3′ kinase (PI3K) in PLGGs suggests the potential efficacy of agents that target these key growth regulatory pathways. BRAF, a kinase within the MAPK pathway, is activated by missense mutation (V600E) in ∼20% of grade 2-4 pediatric gliomas or KIAA1549-BRAF fusion in ∼60% of pilocytic astrocytomas. In addition to RAS/MEK/MAPK/ERK, the PI3K/AKT/mTOR signaling cascade is activated in ∼half of PLGGs. We hypothesize that knowledge of individual tumor BRAF genotype can guide selection of PI3K/MAPK inhibitors as single agents and in combinations, to maximize efficacy of therapy and overcome innate and acquired resistance to targeted agents. Methods: We used human glioma cell lines containing BRAFV600E (AM38, DBT-RG, BT40), or wild-type BRAF (BRAFWT; SF188, SF9427, SF9402) and isogenic systems of KIAA1549:BRAF-expressing NIH3T3 cells and BRAFV600E-expressing murine brain tumors. Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAFV600E), and AZD6244 (MEK). Cell cycle distribution and apoptosis were assessed using flow cytometry; proliferation was determined using an ATP-based assay (CellTiter-Glo). In vivo activity of these inhibitors was assessed in the BT40 PLGG xenograft mouse model. Results: In BRAFV600E cells, combination of PLX4720+everolimus and PLX4720+AZD6244 exhibited significantly greater effects on cell viability, apoptosis, and cell cycle than respective single agents. In BRAFWT cells, everolimus+AZD6244 was superior compared to respective monotherapies. Similar results were found using isogenic murine cells. In KIAA1549:BRAF fusion cells, MEK inhibition reduced cell viability and S-phase content, effects that were modestly augmented by mTOR inhibition. In vivo experiments in the PLGG xenograft model BT40 showed the greatest survival advantage in mice treated with combination of AZD6244+PLX4720 or AZD6244+everolimus compared with respective monotherapies (p<0.01). Conclusions: For BRAFV600E tumors, combination of everolimus+MEK or PLX4720+MEK inhibitors is equally efficacious and superior to single agents, and the choice between these two might be dictated by clinical tolerability. For BRAFWT PLGGs, combination of everolimus+MEK inhibitor is superior to single agent therapies. Optimal treatment of KIAA1549:BRAF-expressing PLGGs is still under investigation as single agent MEK inhibition is extremely efficacious but mTOR inhibition may contribute to greater overall anti-neoplastic effects. Citation Format: Aleksandra K. Olow, Sabine Mueller, Xiaodong Yang, Rintaro Hashizume, William Weiss, Adam C. Resnick, Angela J. Sievert, Mitchel S. Berger, Nalin Gupta, David C. James, Daphne A. Haas-Kogan. Targeting PI3K in personalized treatment of BRAF-mutated pediatric low-grade gliomas. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B42.

Background

Pineal parenchymal tumors (PPTs) are rare neoplasms of the central nervous system, and data concerning clinical outcomes are limited. The purpose of this study was to define the clinical behavior of PPT according to current histopathologic criteria and identify prognostic factors to guide therapeutic decisions.

Methods

Seventy-five patients treated for PPT at a single institution between 1992 and 2015 were retrospectively identified. Forty-five resection specimens were available and re-reviewed. Freedom from progression (FFP) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using log-rank tests.

Results

Median follow-up was 4.1 years. All patients initially underwent surgery; 78% of patients with PPT of intermediate differentiation (PPTID) and all patients with pineoblastoma received adjuvant therapy. Pathologic re-review refined classification in 27% of cases, with the majority of these being adult patients with pineal tumors originally classified as pineoblastomas that more accurately resembled PPTID based on the 2007 WHO classification.

Classification

Our histologic review also identified that PPTIDs can be classified into small-cell and large-cell morphologic subtypes, which have distinct clinical outcomes. Tumor grade, extent of resection, and neuraxis spread were prognostic for FFP. PPTID subtype, extent of resection, and neuraxis spread were prognostic for OS. Genetic analysis of a pineoblastoma case identified somatic mutations of DICER1, ARID1A, and KDM5C genes.

Conclusions

PPTIDs can be classified into 1 of 2 novel morphologic subtypes that are associated with distinct clinical outcomes. Tumor grade, neuraxis spread, and extent of resection also influence outcome for patients with PPT.

Rates and characteristics of intracerebral cavernous malformations after cranial radiation therapy remain poorly understood. Herein we report on intracerebral cavernous malformations detected on follow-up imaging in pediatric cancer patients who received cranial radiation therapy at age ≤18 years from 1980 to 2009. Through chart reviews (n = 362) and phone interviews (n = 104) of a retrospective cohort, we identified 10 patients with intracerebral cavernous malformations. The median latency time for detection of intracerebral cavernous malformations after cranial radiation therapy was 12 years (range 1-24 years) at a median age of 21.4 years (interquartile range = 15-28). The cumulative incidence was 3% (95% confidence interval 1%-8%) at 10 years post cranial radiation therapy and 14% (95% confidence interval 7%-26%) at 15 years. Three patients underwent surgical resection. Two surgical specimens were pathologically similar to sporadically occurring intracerebral cavernous malformations; one was consistent with capillary telangiectasia. Intracerebral cavernous malformations are common after cranial radiation therapy and can show a spectrum of histologic features.

The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitors erlotinib and osimertinib were tested separately in combination with the JAK2 inhibitor AZD1480. Combination therapy induced apoptosis of glioblastoma tumors in both flank and in patient-derived orthotopic xenograft models, providing a preclinical rationale to test analogous combinations in patients. SIGNIFICANCE: These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.