“Myxoid glioneuronal tumor, PDGFRA p.K385‐mutant” is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining ...dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow‐up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports “myxoid glioneuronal tumor, PDGFRA p.K385‐mutant” as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.
Fibroblast growth factors and their receptors (FGFR) have major roles in both human growth and oncogenesis. In adults, therapeutic FGFR inhibitors have been successful against tumors that carry ...somatic FGFR mutations. In pediatric patients, trials testing these anti-tumor FGFR inhibitor therapeutics are underway, with several recent reports suggesting modest positive responses. Herein, we report an unforeseen outcome in a pre-pubescent child with an FGFR1-mutated glioma who was successfully treated with FDA-approved erdafitinib, a pan-FGFR inhibitor approved for treatment of Bladder tumors. While on treatment with erdafitinib, the patient experienced rapid skeletal and long bone overgrowth resulting in kyphoscoliosis, reminiscent of patients with congenital loss-of-function FGFR3 mutations. We utilized normal dermal fibroblast cells established from the patient as a surrogate model to demonstrate that insulin-like growth factor 1 (IGF-1), a factor important for developmental growth of bones and tissues, can activate the PI3K/AKT pathway in erdafitinib-treated cells but not the MAPK/ERK pathway. The IGF-I-activated PI3K/AKT signaling rescued normal fibroblasts from the cytotoxic effects of erdafitinib by promoting cell survival. We, therefore, postulate that IGF-I-activated P13K/AKT signaling likely continues to promote bone elongation in the growing child, but not in adults, treated with therapeutic pan-FGFR inhibitors. Importantly, since activated MAPK signaling counters bone elongation, we further postulate that prolonged blockage of the MAPK pathway with pan-FGFR inhibitors, together with actions of growth-promoting factors including IGF-1, could explain the abnormal skeletal and axial growth suffered by our pre-pubertal patient during systemic therapeutic use of pan-FGFR inhibitors. Further studies to find more targeted, and/or appropriate dosing, of pan-FGFR inhibitor therapeutics for children are essential to avoid unexpected off-target effects as was observed in our young patient.
Cancer cell secretion of TGF-β is a potent mechanism for immune evasion. However, little is known about how central nervous system tumors guard against immune eradication. We sought to determine the ...impact of T-cell TGF-β signaling blockade on progression of medulloblastoma (MB), the most common pediatric brain tumor. Genetic abrogation of T-cell TGF-β signaling mitigated tumor progression in the smoothened A1 (SmoA1) transgenic MB mouse. T regulatory cells were nearly abolished and antitumor immunity was mediated by CD8 cytotoxic T lymphocytes. To define the CD8 T-cell subpopulation responsible, primed CD8 T cells were adoptively transferred into tumor-bearing immunocompromised SmoA1 recipients. This led to generation of CD8 ⁺/killer cell lectin-like receptor G1 high (KLRG1 ʰⁱ)/IL-7R ˡᵒ short-lived effector cells that expressed granzyme B at the tumor. These results identify a cellular immune mechanism whereby TGF-β signaling blockade licenses the T-cell repertoire to kill pediatric brain tumor cells.
Medulloblastoma, a tumor of the cerebellum, is the most common pediatric central nervous system malignancy. These tumors are etiologically linked to mutations in the Sonic hedgehog (Shh) pathway, ...which signals through the primary, non-motile cilium. The growth of these aggressive tumors relies on self-renewal of tumor-propagating cells known as cancer stem cells (CSCs). Previous reports have implicated CD133-expressing cells as CSCs in brain tumors, while those expressing CD15 have been shown to propagate medulloblastoma. Here, we demonstrate that CD133+ and CD15+ cells are distinct medulloblastoma populations. CD15+ cells comprise approximately 0.5-1% of total human medulloblastoma cells, display CSC properties in culture and are detected in the Smoothened A1 transgenic mouse model of medulloblastoma. Additionally, we report on a medulloblastoma patient with enriched CD15+ cells in recurrent vs primary medulloblastoma. We also demonstrate that human medulloblastoma cells critically rely on establishment of primary cilia to drive Shh-mediated cell division. Primary cilia are found in external granule cells of human fetal cerebellum and in 12/14 medulloblastoma samples. Yet, CD15+ medulloblastoma cells lack primary cilia, suggesting that this CSC population signals independently of Shh. These results are important when considering the effects of current and prospective treatment modalities on medulloblastoma CSC populations.
Sacrococcygeal teratoma (SCT) is the most common congenital extragonadal germ cell tumor of infancy. Post-resection recurrence is attributed to tumor spillage, incomplete resection, no coccygectomy, ...and immature or malignant histology. However, in the absence of these risk factors, there are few reports of early aggressive tumor recurrence with intraspinal extension. This report describes a rare early SCT recurrence with intraspinal extension after oncologic resection.
The primary SCT was initially detected at 29-weeks gestation and demonstrated interval growth from 8.5 × 9.5 × 7.7cm on prenatal MRI to 14.1 × 11.1 × 15.6cm on postnatal MRI. The primary SCT was resected on day of life three and noted to be a grade III immature teratoma (<3 % immature elements) with negative margins and no malignant elements. On routine follow-up at 3- and 6-months post-resection, there were no signs of recurrence on physical exam and a downtrending serum AFP level. At approximately eight months post-resection, a palpable mass superior to the surgical scar prompted repeat MRI. A 2.4 × 3.5 × 2.3cm trilobed mass was discovered with invasion into the sacral canal and the patient ultimately underwent resection of this recurrence in collaboration with neurosurgery. Final pathology revealed a mature teratoma with negative margins and no immature or malignant elements. This patient will undergo active surveillance with repeat MRI imaging every three months for the first year after resection.
This rare case highlights the potential utility of imaging in the early post-resection period, as well as the need for additional reports to elucidate factors which may predispose benign SCTs to an early aggressive recurrence.
As the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We ...have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma.
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•Rapid brain tumor modeling with postnatal electroporation and transposon methodology•Modeling methodology allows for extensive interrogation of tumor growth mechanisms•Ras pathway mutations deplete neural stem cells and upregulate Ets factors•Ets signaling block rescues Ras-mediated stem cell loss and prevents tumor formation
Breunig et al. report that increased Ras signaling functions to deplete neural stem cells and expand glial progenitors in gliomagenesis. Inhibition of the upregulated Ets signaling downstream of Ras is sufficient to inhibit glioma formation by attenuating the gliogenesis necessary for tumor propagation.
Glioblastoma (GBM), the most common primary malignant brain tumor, is a highly lethal form of cancer with a very limited set of treatment options. High heterogeneity in the tumor cell population and ...the invasive nature of these cells decrease the likely efficacy of traditional cancer treatments, thus requiring research into novel treatment options. The use of oncolytic viruses as potential therapeutics has been researched for some time. Zika virus (ZIKV) has demonstrated oncotropism and oncolytic effects on GBM stem cells (GSCs). To address the need for safe and effective GBM treatments, we designed an attenuated ZIKV strain (ZOL-1) that does not cause paralytic or neurological diseases in mouse models compared with unmodified ZIKV. Importantly, we found that patient-derived GBM tumors exhibited susceptibility (responders) and non-susceptibility (non-responders) to ZOL-1-mediated tumor cell killing, as evidenced by differential apoptotic cell death and cell viability upon ZOL-1 treatment. The oncolytic effect observed in responder cells was seen both in vitro in neurosphere models and in vivo upon xenograft. Finally, we observed that the use of ZOL-1 as combination therapy with multiple PI3K-AKT inhibitors in non-responder GBM resulted in enhanced chemotherapeutic efficacy. Altogether, this study establishes ZOL-1 as a safe and effective treatment against GBM and provides a foundation to conduct further studies evaluating its potential as an effective adjuvant with other chemotherapies and kinase inhibitors.
We present the case of a child in whom acute hydrocephalus developed secondary to obstruction of the foramen of Monro by a choroid plexus cyst. The patient was seen in the emergency department with ...fevers, acute onset of headaches, and lethargy. Computed tomography demonstrated dilated lateral and third ventricles with a relatively normal-sized fourth ventricle. An external ventricular drain was placed. Despite decompression of the lateral ventricles, follow-up magnetic resonance imaging demonstrated a dilated third ventricle with a possible thin-walled mass extending from the foramen of Monro into the posterior portion of the third ventricle. The patient subsequently underwent endoscopic fenestration of the cyst with endoscopic third ventriculostomy. Although two other cases of symptomatic choroid plexus cysts of the third ventricle have been previously reported in children, our paper highlights the possibility of endoscopic cyst fenestration together with a third ventriculostomy as a treatment option in cases where the cyst extends into the posterior third ventricle. Despite adequate decompression, we were concerned that due to CSF pulsations the remnant cyst wall could result in acute aqueduct obstruction and subsequent hydrocephalus.
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