Pilocytic astrocytoma (PA) is one of the most common central nervous system (CNS) tumors in childhood, accounting for 21-23% of all pediatric CNS tumors. PA is a low grade glioma often characterized by solid and cystic components. Current treatment strategies include surgery, chemotherapy, and/or radiation. Although chemotherapy and radiation are effective against the solid component, they show limited activity on the cystic component. Management of cystic tumor progression often involves surgical intervention and can be problematic. Bevacizumab is a monoclonal antibody that binds vascular endothelial growth factor (VEGF) and prevents formation of new blood vessels. In this case series, we present three patients with PAs and cystic progression, who were treated with bevacizumab from 2012 to 2015. Patient 1 has an optic pathway glioma (OPG) treated with two chemotherapy regimens, multiple surgical procedures for cyst fenestration and placement of an Ommaya reservoir. Patient 2 has a midbrain PA treated with subtotal surgical resection, multiple chemotherapy regimens, and gamma knife radiation. Patient 3 has an OPG treated with two chemotherapy regimens, tumor debulking, and cyst fenestration. All three patients were treated with bevacizumab every two weeks with improvement in the cystic components of their tumors as shown by magnetic resonance imaging. In this case series, we report three patients with significant history of refractory disease in which bevacizumab was well-tolerated and showed substantial improvement in the cystic component of their tumor. We believe bevacizumab is a promising agent for cyst control in patients with pilocytic astrocytoma.
In recent years, drastic improvements in sequencing technologies have led to a better understanding of the specific genetic drivers of cancer. However, one of the greatest barriers to these discoveries is access to primary patient tumor tissue, especially in cancers of the Central Nervous System (CNS). In many cases tissue from surgery is processed and stored in Formalin-Fixed Paraffin-Embedded (FFPE) blocks, which sets limitations on downstream applications. In 2015, our team launched an initiative to collect and efficiently store samples from pediatric CNS tumor patients during surgeries and autopsies. Through extensive collaboration between Neuro-Oncology, Neurosurgery, Pathology, and our Translational Laboratory, we have optimized the collection process to effectively preserve sample integrity and therefore maximize their potential usage. To date, we have collected over 4,509 samples from 293 patients (636 flash-frozen tissue, 1,026 plasma & buffy coat, 748 serum, 996 whole blood, 316 Cerebrospinal Fluid (CSF), and 787 parental blood samples). In addition, we have cultured 31 primary cell lines and collected over 242 dissociated tumor specimens for implantation into patient-derived xenograft (PDX) mouse models. Through our partnership with neurosurgery and pathology, we are permitted to attend surgeries and autopsies to immediately flash-freeze tumor tissue in liquid nitrogen, typically within minutes of the tissue being removed from the body. This immediate flash-freezing process aims to ensure specimen integrity and preserve molecular profiles. From there, the tissue is either stored in our -140oC freezer for future use or sent to partnered consortiums, including the Children’s Brain Tumor Network (CBTN) and Gift from a Child. Since the optimization of the collection process, the focus has now shifted to investigating the efficacy of our storage methods by quantifying DNA/RNA integrity over time. By ensuring the successful preservation of the samples, we can maximize their impact in the pediatric neuro-oncology research field.
INTRODUCTION Horos (LGPL 3.0) is a free, open source medical image viewer that has gained attention in the neurosurgical community because of the familiar OsiriX-based interface and its useful three-dimensional (3D) volumetric rendering capabilities. We present the use of Horos software as a postoperative tool for residual tumor volume analysis in children with high-grade gliomas. METHODS A retrospective study of 11 pediatric patients with histologically confirmed HGG underwent tumor resection (n=8) or biopsy (n=3) as definitive treatment from 6/2011 to 6/2019. Volumetric data and extent of resection were obtained via region of interest-based 3D analysis using Horos image-processing software. Age, initial tumor volume, extent of resection, and postoperative residual volume were assessed as predictors of overall survival or event free survival. TECHNIQUE Region of interest (ROI) segmentation was performed utilizing the “Closed Polygon Tool” to outline the tumor and the “Generate Missing ROIs” function to capture the entirety of the tumor within the MRI series. The “Computer Volume” function was used to render the 3D tumor volumes. The preoperative and postoperative tumor volumes were compared per patient to yield the percent extent of resection and residual volume. RESULTS The Horos software is a highly effective means of volumetric analysis for high-grade gliomas depicted in T1 and T2 MRI series. In our series, eight (73%) patients underwent tumor resection and three (27%) underwent biopsy. Patients who underwent resection were older than biopsy patients [12 (8-18) vs. 9 (8-21) years old]. Age, initial tumor volume, extent of resection, and postoperative residual volume were not significant predictors of overall survival or event free survival. CONCLUSION Horos software provides increased accuracy and confidence in determining post-operative volume and is useful in assessing the impact of residual volume on outcome after maximal safe resection in pediatric patients with high-grade gliomas.
Ependymoma is a heterogeneous disease which is resistant to improvement. Current challenges are the unreliability of histologic classification, the uncertain role of adjuvant chemotherapy, and a lack of clinical trials integrating molecular and clinical diagnostics into risk-guided therapy. Ependymoma can show surprising latency, reoccurring many years after the original diagnosis. In this study, we performed a retrospective analysis of ependymoma cases treated at six centers over a period of 12 years. A total of 73 cases were submitted from six sites; 68 cases were retained for review. Median age at diagnosis was 4.1 years and gender was reported as male (50%) and female (50%). Histologic grade was reported as Grade II (49%) and Grade III (50%)(not reported: 1). Anatomic location reported as supratentorial (27%) and infratentorial (73%). Metastatic disease was reported in 9% of patients. At diagnosis, gross total resection was achieved in 59% of cases. Twenty-eight percent of patients have died, 59% of patients are alive (with and without disease), and 13% of patients are lost to follow-up. Maximal safe surgical resection is currently the best predictor of long-term survival but was achieved in only 60% of cases. Biology-based therapy will be the next step towards improving the prognosis of pediatric ependymoma.
The current consensus is that diagnosis and treatment of ependymoma should be based upon clinical and molecular classification. As we move into this paradigm, it is important all ependymoma cases undergo tumor collection, preservation, and molecular profiling at diagnosis. Our group of 6 sites gathered data on a cohort of 72 ependymoma cases. Sites were asked to report known molecular findings; 60/68 eligible cases (88%) did not include genetic findings. The low number of cases with molecular findings was surprising and since cases were diagnosed from as early as 2004, we asked collaborators to share their current practice in profiling (e.g., how frequently; in what setting were ependymomas sent for testing) to try and better understand current practice at sites. Since the publication of ependymoma molecular data, sites with a neuro-oncology program report sending almost all newly diagnosed ependymomas for molecular testing, whereas current practices at sites without dedicated neuro-oncology were less consistent. Profiling in the setting of relapse was more frequently reported at all centers. The implementation of molecular testing at diagnosis may need support at sites without dedicated neuro-oncology. Lead investigators for upcoming ependymoma clinical trials will need to think carefully about the logistics of profiling at centers where this is not standard practice at diagnosis.
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