Anaplastic Pleomorphic Xanthoastrocytoma Research Articles

Ganglioglioma with anaplastic/high-grade transformation: Histopathologic, molecular, and epigenetic characterization of 3 cases.

Ganglioglioma (GG) with anaplasia (anaplastic ganglioglioma) is a rare and controversial diagnosis. When present, anaplasia involves the glial component of the tumor, either at presentation or at recurrence. To date, most published cases lack molecular characterization. We describe the histologic and molecular features of 3 patients presenting with BRAF p. V600E-mutant GG (CNS WHO grade 1) with high-grade glial transformation at recurrence. The tumors occurred in pediatric patients (age 9-16 years) with time to recurrence from 20 months to 7 years. At presentation, each tumor was low-grade, with a BRAFV600E-positive ganglion cell component and a glial component resembling pleomorphic xanthoastrocytoma (PXA) or fibrillary astrocytoma. At recurrence, tumors resembled anaplastic PXA or high-grade astrocytomas without neuronal differentiation. CDKN2A homozygous deletion (HD) was absent in all primary tumors. At recurrence, 2 cases acquired CDKN2A HD; the third case showed loss of p16 and MTAP immunoexpression, but no CDKN2A/B HD or mutation was identified. By DNA methylation profiling, all primary and recurrent tumors either grouped or definitely matched to different methylation classes. Our findings indicate that malignant progression of the glial component can occur in GG and suggest that CDKN2A/B inactivation plays a significant role in this process.

Response Rate and Molecular Correlates to Encorafenib and Binimetinib in BRAF-V600E Mutant High-Grade Glioma.

Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.

PATH-53. ANAPLASTIC PLEOMORPHIC XANTHROASTROCYTOMA WITH BEND5-NTRK2 FUSION IN A YOUNG ADULT WITH A HISTORY OF CRANIAL RADIATION FOR CHILDHOOD RHABDOMYOSARCOMA

Abstract INTRODUCTION: Pleomorphic xanthoastrocytoma (PXA) is a rare subset of circumscribed astrocytic glioma. While PXA typically has a favorable prognosis, anaplastic (WHO Grade III) PXA (aPXA) has a poorer prognosis. Molecular analysis of PXA often reveals BRAF mutations or CDKN2A/B homozygous deletions. NTRK fusions have been identified in a few cases of pediatric gliomas including PXA. BEND-5 gene alterations have been rarely reported in CNS tumors such as glioblastoma but have not been previously reported in PXA. Case Presentation The patient is a 24-year-old female with history of nasopharyngeal embryonal rhabdomyosarcoma treated with chemotherapy and radiation at age 3. She was tested for Li-Fraumeni Syndrome and was reportedly negative. One year ago, she presented with visual changes and was found to have an occipital aPXA. She underwent a gross total resection but declined further treatment with radiation. Next-generation sequencing (NGS) identified a BEND5-NTRK2 fusion, and she began treatment with Larotrectinib. Serial MRI scans have shown no evidence of disease recurrence. Discussion Pediatric patients are at increased risk for glioma after radiation which is age- and dose/volume-dependent. Radiation-induced gliomas are typically higher grade, present in atypical sites, and have a poor prognosis. Development of PXA following radiation is rare but has been reported. Our patient was diagnosed with aPXA almost 20 years after initial treatment for rhabdomyosarcoma. Her aPXA exhibited a BEND5-NTRK2 fusion and lacked classical BRAF alterations and CDKN2A/B deletions that are present in de novo cases. A Neuro-Onc Panel did not identify her fusion or include testing for BEND5 alterations. However, an expanded RNA Exome Fusion Panel NGS identified a unique fusion, which opened her up to targeted treatment with an NTRK inhibitor. Our patient is now 1 year from resection without disease progression on larotrectinib. This case highlights the importance of expanded NGS testing, particularly in rare tumors.

P07.03.A COMPLETE LONG-LASTING RESPONSE TO MULTIMODAL THIRD LINE TREATMENT WITH NEUROSURGICAL RESECTION, CARMUSTINE WAFER IMPLANTATION AND DABRAFENIB PLUS TRAMETINIB IN A BRAFV600E MUTATED HIGH-GRADE GLIOMA

Abstract BACKGROUND BRAF mutations are drivers of oncogenesis in a variety of tumors and they can be successfully targeted with small molecule inhibitors. In primary central nervous system tumors, BRAFV600E mutations are most frequently found in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma and epithelioid glioblastoma. Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that was approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harboring BRAFV600E mutation. MATERIAL AND METHODS In February 2016, a 21-year-old female was admitted to our Unit for seizures. A brain magnetic resonance imaging (MRI) revealed a frontal contrast enhanced lesion. Neurosurgical resection was performed. The histological analysis diagnosed anaplastic pleomorphic xanthoastrocytoma (PXA) WHO grade III. A volumetric modulated radiotherapy course was delivered for a total dose of 59,4 Gy in 33 fractions with concomitant and adjuvant temozolomide therapy (Stupp protocol). In October 2017, a brain MRI showed relapsing disease. Six courses of chemotherapy with procarbazine, lomustine and vincristine (PCV) were administered, and then neurosurgical partial removal and carmustine wafer implantation were performed. The histological analysis confirmed BRAF V600E mutated anaplastic PXA. RESULTS In April 2019 the 24-year-old female patient with BRAF mutated anaplastic PXA started her third-line therapy with dabrafenib. The well-known tumor residue was less evident on the subsequent MRIs performed every three/four months. Given the literature data of the most effectiveness and the best control of the side effects, in August 2020 the patient was put on combined treatment with dabrafenib plus trametinib. Since December 2021 the residual tumor has not been longer visible. Last MRI evaluation, performed on January 26th 2023, showed no recurrence of the disease, four years after BRAF inhibitor treatment beginning. CONCLUSION Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E-mutant glioma, with high overall response and manageable toxicity. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients in third-line therapy, showing complete response and for such a long time. The emergence of optimized sequencing strategies and targeted agents, including multimodal treatment and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG and to improve patient outcomes.

Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion

Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson’s r = 0.794–0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4–9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient’s tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient’s resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.

Abstract 5498: SHP2 inhibition enhances antitumor effect of mirdametinib in a pediatric brain tumor model bearing CDC42SE2BRAF fusion by rewiring the proteome and phosphoproteome landscape

Abstract Pediatric gliomas are the most common type of pediatric brain tumors representing wide range of molecularly and clinically heterogenous subtypes. The hyperactivity of mitogen-activated protein kinases (MAPK) pathway has been identified in the majority of pediatric glioma suggesting its therapeutic potential. However, pharmacologic targeting single MAPK pathway’s component is limited due to the development of drug resistance and differential response associated with tumor molecular landscape. Therefore, effective combination strategy in the framework of precision medicine is needed. Here we report combination benefit and molecular underpinning therapeutic response of brain penetrant MEK inhibitor (mirdametinib) and SHP2 inhibitor (SHP099) in a pediatric patient derived xenograft (PDX) and xenoline developed at our institution. Our model was derived from a pediatric patient who was diagnosed with rare high-grade subtype of glioma, anaplastic pleomorphic xanthoastrocytoma, and did not respond to MEK inhibitor, trametinib. Integrative multi-omics revealed molecular fidelity between our model and its patient tumor counterpart including the presence of 7q35 fusion, CDC52SE2-BRAF, CDKN2A/B loss, and MAPK pathway hyperactivation. In vitro studies using our xenoline IU-X128 demonstrated synergy between SHP099 and mirdametinib to curtail cell proliferation (p&amp;lt;0.05). Moreover, this combination was well tolerated in our PDX, IU-RHT128, and potentiated anti-tumor effect of the single agent within clinically achievable doses. Reverse Phase Proteome Array (RPPA) identified MAPK reactivation via Mushasi RNA binding protein-PI3K-AKT crosstalk as a potential innate resistance mechanism to single agent MEK inhibitor in the PDX tumor. Further, tandem mass tags (TMT)-LC-MS/MS profiling on tumor treated with single agent SHP099 or mirdametinib and their combination revealed that combination therapy does not only revert certain proteome and phosphoproteome reprogramming from single agent treatment but also created a novel landscape which can be associated with anti-tumor effect. In this case, kinase network reprograming leading to MAPK reactivation was identified in mirdametinib treated tumor which was attenuated in the combination treatment. In summary, our results demonstrated that combination SHP099 and mirdametinib is superior to single agent alone in the pediatric A-PXA brain tumor model with proteome and phosphoproteome reprogramming of multiple networks as potential molecular mechanisms underlying therapeutic benefit of combination therapy. Ultimately, clinical translation of this finding will potentially benefit patient of this malignant rare pediatric glioma subset which currently does not have standard therapy. Citation Format: Nur P. Damayanti, Anthony Alfonso, Josue D. Ordaz, Erika Dobrota, M. Reza Saadatzadeh, Pankita Pandya, Barbara J. Bailey, Khadijeh Bijangi-Vishehsaraei, Harlan E. Shannon, Kathy Coy, Melissa Trowbridge, Anthony L. Sinn, Rosa Gallager, Julia Wulfkuhle, Emanuel Petricoin, Amber Mosley, Mark S. Marshall, Alex Lion, Michael J. Fergusson, Karl Balsara, Karen E. Pollok. SHP2 inhibition enhances antitumor effect of mirdametinib in a pediatric brain tumor model bearing CDC42SE2BRAF fusion by rewiring the proteome and phosphoproteome landscape. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5498.

Anaplastic Pleomorphic Xanthoastrocytoma, WHO Grade 3, Located on the Hippocampal Region: A Case Report

Anaplastic pleomorphic xanthoastrocytoma (APXA) is a rare and aggressive brain tumor that requires a multidisciplinary approach for proper diagnosis and treatment. This case report presents the case of a 15-year-old male patient diagnosed with APXA in the left temporal region. The patient underwent a combination of imaging studies, including MRI, followed by a biopsy of the tumor tissue and surgery. The patient was then closely monitored for recurrence and progression of the tumor, and further received six cycles of chemotherapy and radiation therapy. This report aims to provide detailed information about the diagnostic process for APXA, which can be challenging due to its similarity to other tumors, such as pilocytic astrocytoma. Additionally, the report highlights the varying treatment options and outcomes for patients with APXA, as well as the importance of close monitoring for the recurrence and progression of the tumor. More research is needed to fully understand the best treatment options for APXA and to improve outcomes for patients diagnosed with this rare and aggressive brain tumor.

A pediatric case of anaplastic pleomorphic xanthoastrocytoma (Grade 3)

Pleomorphic xanthoastrocytoma (PXA) is a glial tumor which accounts for less than 1% of astrocytomas. PXA most commonly occurs in the temporal lobe in the outer cortex of brain and usually seen in young adults and children. As per 2020 WHO classification of CNS tumors, PXA with a mitotic activity ≥5 mitoses/10 HPF is defined as anaplastic pleomorphic xanthoastrocytoma (APXA), WHO grade 3. Here we present a rare case of Anaplastic Pleomorphic Xanthoastrocytoma developing in a female child of 11 years of age.A 11 years old female child presented with symptoms of continuous headache, giddiness, fever and vomiting since last 15 days. Computed Tomography of her brain revealed a soft tissue density mass lesion in right temporal lobe involving the insular cortex and capsuloganglionic region. The radiological differential diagnosis was a neoplastic lesion, most likely glioma. The patient underwent surgery for removal of temporal lobe tumor and the resected tumor bits were sent for histopathological assessment. Microscopically, many multinucleated lipidized giant cells were seen having eccentrically pushed nuclei, conspicuous nucleoli and abundant eosinophilic granular cytoplasm. A second population of few spindled cells with less amount of cytoplasm was also noted in the intervening parenchyma. Immunohistochemical workup showed the tumor to be positive for GFAP, S-100, Synaptophysin, p53 and CD-68. The tumor was negative for CD34. Ki-67 index was 15-20%. A final diagnosis of Anaplastic Pleomorphic Xanthoastrocytoma (grade 3) was made.APXA is a rare astrocytic tumor and has relatively more aggressive radiological and histomorphological features than pleomorphic xanthoastrocytomas and therefore it needs to be identified and treated separately.

CBMS-4 CHROMOSOMAL INSTABILITY IN GLIOMA USING SPECTRAL KARYOTYPING METHOD

Abstract Introduction Chromosomal instability, the cell condition in which chromosome mis-segregation occur at a high frequency during cell division, has been considered to be involved in the molecular mechanisms that give rise to the complex genetic background of glioma. However, most of this phenomenon has been based on researches using cell line, and there have been few studies of chromosomal instability in clinical specimens of gliomas. Methods Primary cell culture was obtained from 11 glioma specimens (eight Glioblastoma (GBM), one Anaplastic PXA (aPXA), one Astrocytoma, and one Ependymoma), which was removed at our hospital, and chromosomes of up to five cells per case were analyzed by the SKY method. Chromosome instability was quantified by two parameters, one was AS (Aneuploidy score), which means the number of gain or loss of whole of the chromosome, and the other was SS: Structural abnormality score, which means the number of chromosome structural abnormality per cell. In addition, the phenotypes, which were characteristic of chromosomal instability were observed individually. Results Each quantitative value was as follows: GBM; AS:2.30±0.51 /SS:1.64±0.38, aPXA; AS :1.40±1.33 / SS:8.20±0.99, Astrocytoma and Ependymoma; AS:0.00 /SS:0.00, suggesting that chromosomal instability was associated with GBM and aPXA. Chromosome 7 amplification was most frequent in GBM (57%), and Mosaic loss of chromosome Y was also observed in 60% of males. Some characteristic karyotypes which suggest the phenomenon of Chromothripsis or Double minute were also observed. The karyotype concordance rate in the cases with p53 mutation was 60%, and that with p53 wild type was 100%, indicating that the p53 mutation increased the genotype heterogeneity in the same specimen. Discussion In clinical specimens of gliomas, aneuploidy and structural abnormalities were identified in GBM and aPXA, suggesting that chromosomal instability contributes to their cellular phenotype and malignancy.

CTNI-60. PRELIMINARY RESULTS OF BINIMETINIB AND ENCORAFENIB IN ADULTS WITH RECURRENT BRAF V600E-MUTATED HIGH-GRADE GLIOMA

Abstract BACKGROUND Although &amp;lt; 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are being identified more frequently as genetic testing increases in gliomas. Given the treatment-refractory nature HGG, RAF-targeted therapy is of special interest. The combination of encorafenib (BRAF inhibitor) with binimetinib (MEK inhibitor) was evaluated in adults with recurrent BRAFV600-mutated HGG. METHODS In this phase 2, open-label, Adult Brain Tumor Consortium trial(NCT03973918) encorafenib (450mg daily) and binimetinib (45mg twice daily) were administered continuously until disease progression, unacceptable toxicity, or death. Eligible patients had a histologically-confirmed HGG with BRAF-V600E mutation identified by PCR or next generation sequencing, and had progressed after radiation and any number of prior medical therapies. The primary endpoint was radiographic response rate by RANO criteria. Plasma was collected at baseline, on-study, and at progression for correlatives. RESULTS Five patients enrolled between January 2020 and November 2021. All patients had at least one prior recurrence (range 1-4) and received radiation one or more times. Median age was 27 years(range 22-77). Histopathologic diagnosis was glioblastoma(n = 2), anaplastic PXA(aPXA; n = 2), and anaplastic ganglioglioma(aGG; n = 1). Patients received treatment for 2-28months; currently 2/5 patients remain on treatment (8 and 30 months). Radiographic response rate was 60%(3/5): CR in two (glioblastoma, treated 10months; glioblastoma, 8months treatment ongoing), PR in one (aPXA, 28months treatment ongoing), SD in one (aGG, treated 3months), and PD in one (aPXA, treated 2months). Likely attributable adverse events (CTCAE grade ≥ 3) included cilioretinal artery occlusion (came off study) and asymptomatic elevated CPK. Analysis of paired plasma samples and correlation with response is ongoing. CONCLUSIONS Encorafenib and binimetinib demonstrate promising tumor responses in patients with recurrent BRAFV600E-mutated HGG with sustained responses in all GBM and 50% of aPXA in this small series, warranting careful consideration in this rare tumor subgroup. This Phase 2 study has closed due to enrollment issues

BRAF/MEK Dual Inhibitors Therapy in Progressive and Anaplastic Pleomorphic Xanthoastrocytoma: Case Series and Literature Review.

Recurrent and anaplastic pleomorphic xanthoastrocytoma (r&aPXA) is a rare primary brain tumor that is challenging to treat. Two-thirds of PXA tumors harbor a BRAF gene mutation. BRAF inhibitors have been shown to improve tumor control. However, resistance to BRAF inhibition develops in most cases. Concurrent therapy with MEK inhibitors may improve tumor control and patient survival. In this study, we identified 5 patients diagnosed with BRAF-mutated PXA who received BRAF and MEK inhibitors over a 10-year interval at our institution. Patient records were evaluated, including treatments, adverse effects (AEs), outcomes, pathology, next-generation sequencing, and MRI. The median age was 22 years (range, 14-66 years), 60% male, and 60% anaplastic PXA. Median overall survival was 72 months (range, 19-112 months); 1 patient died of tumor-related hemorrhage while off therapy, and the other 4 experienced long-term disease control (21, 72, 98, and 112 months, respectively). Dual BRAF/MEK inhibitors were well tolerated, with only grade 1-2 AEs, including rash, neutropenia, fatigue, abdominal discomfort, and diarrhea. No grade 3-5 AEs were detected. A literature review was also performed of patients diagnosed with BRAF-mutated PXA and treated with BRAF and/or MEK inhibitors through August 2021, with a total of 32 cases identified. The median age was 29 years (range, 8-57 years) and the median PFS and OS were 8.5 months (range, 2-35 months) and 35 months (range, 10-80 months), respectively. The most common AEs were grade 1-2 fatigue and skin rash. Results of this case series and literature review indicate that dual-drug therapy with BRAF and MEK inhibitors for r&aPXA with BRAF V600E mutation may delay tumor progression without unexpected AEs.

The role of angiogenic factors eNOS / VEGF in the treatment of anaplastic glioma

Introduction: Anaplastic gliomas (AG) account for 6–15 % of all primary brain tumors. These include: anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic oligoastrocytoma (AOA), and rarer forms — anaplastic pleomorphic xanthoastrocytoma and anaplastic ganglioma. According to the data on these factors, endothelial nitric oxide synthase (eNOS) is promising in terms of the prognostic value of the course of the tumor process. It was reported that a number of vascular VEGF factors interact with eNOS, contributing to the formation of an intra-tumor vascular network, which can create conditions for uneven prolonged hypoxia, leading to the emergence of more stable tumor cells. Its role in the development of a higher anaplasia level has not been studied in isolation, which determines the relevance of this study. The prognostic role of changes in endothelial nitric oxide synthase (eNOS) in the continued growth and malignant transformation of anaplastic gliomas was studied. Results: Histological samples of brain tumors of 22 patients at the University Clinic in Nizhny Novgorod from 2017 to 2019 were examined and verified for the presence of high-grade III glioma, according to the data of the World Health Organization. The average age of the patients was 50.7 years. The material was obtained as a result of surgical removal of recurrent tumors after chemo and radiotherapy. Discussion: The microenvironment of anaplastic glioma plays an essential role in its pathogenesis. More importantly, angiogenesis, which causes the supply of glioma cells with oxygen, growth factors, nutrients, and hormones, is a significant process of tumor dissemination and growth. The degree of microvascular proliferation and angiogenesis was associated with poor survival rate, transition from a lower grade to a high grade, and relapse. In high-grade glioma, such as anaplastic glioma, neoangiogenesis is an important physiological process that provides adequate blood supply for the proliferation, survival, and invasion of glioma cells. Conclusion: The high mortality rate in gliomas underscores the urgent need for effective treatment. The glioma pathogenesis is complex and can be caused by various mechanisms, as evidenced by abnormal activation of tumor angiogenesis and mutation of isocitrate dehydrogenase. VEGF acts as a regulator of angiogenesis and is widely recognized as a critical factor in glioma development and progression. Our results suggest that VEGF and eNOS inhibition may be an effective way to control and/or block endothelial barrier damage and prevent tumor progression.

5-ALA fluorescence-guided resection of a recurrent anaplastic pleomorphic xanthoastrocytoma: illustrative case.

BACKGROUND5-aminolevulinic acid (5-ALA)–induced fluorescence of neoplastic tissue is known to occur in a number of high-grade gliomas. This fluorescence helps surgeons maximize safe resection by distinguishing previously indiscernible neoplastic tissue from brain parenchyma. Still, the effectiveness of 5-ALA has not been fully explored for all central nervous system tumors. Consequently, the full spectrum of tumors that would benefit from fluorescence-guided surgery using 5-ALA is unknown.OBSERVATIONSThis report describes successfully utilizing 5-ALA to achieve complete resection of a recurrent anaplastic pleomorphic xanthoastrocytoma (APXA).LESSONSAPXA tumor cells accumulate sufficient amounts of 5-ALA and its fluorescent metabolite to produce visible intraoperative fluorescence. However, further investigation is needed to determine if 5-ALA fluorescent labeling routinely occurs in patients with APXAs.

A clinicopathologic study of malignancy in VCP-associated multisystem proteinopathy

BackgroundValosin containing protein (VCP) is an important protein with many vital functions mostly related to the ubiquitin–proteasome system that provides protein quality control. VCP-associated inclusion body myopathy with Paget disease of bone and frontotemporal dementia, also termed VCP disease and multisystem proteinopathy (MSP 1), is an autosomal dominant disorder caused by monoallelic variants in the VCP gene on human chromosome 9. VCP has also been strongly involved in cancer, with over-activity of VCP found in several cancers such as prostate, pancreatic, endometrial, esophageal cancers and osteosarcoma. Since MSP1 is caused by gain of function variants in the VCP gene, we hypothesized our patients would show increased risk for developing malignancies. We describe cases of 3 rare malignancies and 4 common cancers from a retrospective dataset.ResultsUpon surveying 106 families with confirmed VCP variants, we found a higher rate of rare tumors including malignant peripheral nerve sheath tumor, anaplastic pleomorphic xanthoastrocytoma and thymoma. Some of these subjects developed cancer before displaying other classic VCP disease manifestations. We also present cases of common cancers; however, we did not find an increased rate compared to the general population. This could be related to the early mortality associated with this disease, since most patients die in their 50–60 s due to respiratory failure or cardiomyopathy which is earlier than the age at which most cancers appear.ConclusionThis is the first study that expands the phenotype of VCP disease to potentially include rare cancers and highlights the importance of further investigation of the role of VCP in cancer development. The results of this study in VCP disease patients suggest that patients may be at an increased risk for rare tumors. A larger study will determine if patients with VCP disease develop cancer at a higher rate than the general population. If that is the case, they should be followed up more frequently and screened for recurrence and metastasis of their cancer.

Summary of virtual tumor board platforms and implementation in neuro-oncology.

e13604 Background: Virtual tumor board [VTB] platforms are an important aspect of cancer management. They enable easier access to a multidisciplinary team of experts. VTBs are an emerging resource across various cancer care networks in the United States. Methods: We performed a systematic search of all VTBs incorporating a platform designed for this specific role. We reviewed Xcures, Genomet, Oncolens, Navify Tumor Board, Medical University of South Carolina [MUSC] Virtual Tumor Board, Virtual Tumor Board Tahoe Forest Cancer Center, UC Davis Health Care Center VTB and MassiveBio. Summary data examined include year of launch, demographics, characteristics of cases, average response time, advantages, and how they handle protected health information. Results: 30% of all VTBs examined launched in 2017. All had a HIPAA compliant online environment. Xcures records were reviewed where the median age of female patients was 57yrs and the median age of male patients was 55 years. The data showed that 44% (4.4 out of every 10 patients) with a confirmed treatment chose VTB integrated option. 76% of patients in Xcures registry consist primary CNS tumors. With at least 556 patients in tumor registry which included 46% Glioblastoma cases [96% primary;, 4% secondary], 13% Diffuse midline glioma with H3K27M-mutant cases, 5% Diffuse intrinsic pontine glioma cases, 3% Astrocytoma and Diffuse Astrocytoma cases, 3% Anaplastic astrocytoma cases; Glioma and Diffuse Glioma, 1% Anaplastic Oligodendroglioma cases and &lt; 1% Gliosarcoma, Oligodendroglioma, Pilocytic astrocytoma, Anaplastic pleomorphic Xanthoastrocytoma, Fibrillary astrocytoma, Oligoastrocytoma and Pleomorphic Xanthoastrocytoma cases. In the MUSC VTB, 9 neuro-oncology cases were reviewed. They meet weekly, and average response time was within 24hrs of case review.Patient demographics were not recorded. Genomet Virtual Board de-identifies all patient information; this is a virtual platform primarily focused on neuro-oncology cases. Cases involved a median of 5 specialist most commonly neuro-oncologists, neurosurgeons, radiation oncologists, molecular pathologists and neuroradiologists. Participants had an average of 23 cases reviewed. Case review revealed an age range from 6 months to 84 years [mean age 44.5 years] with 69.6% males and 30.4% females, 43.5% glioblastoma, 8.7% adenocarcinoma, 8.7% infra-tentorial tumor, &lt; 5% each: pineoblastoma, melanoma, hemangioblastoma and pilocytic astrocytoma. Average response time observed in all cases was ≤24 hours. Detailed metrics for number/percentages of brain tumor cases were not available for most other platforms at time of submission. This will be updated at presentation. Conclusions: VTBs have allowed for quicker expert analysis of cases. This has resulted in an accelerated number of cases reviewed with a shortened communication time. More studies are needed to gain additional insight into user engagement

Anaplastic Pleomorphic Xanthoastrocytoma with Extracranial Bone Metastasis: A Case Report and Literature Review (P15-9.004)

Anaplastic Pleomorphic Xanthoastrocytoma with Extracranial Bone Metastasis: A Case Report and Literature Review (P15-9.004)

Anaplastic pleomorphic xanthoastrocytoma - single-center analysis of 42 patients

To study neuroimaging, morphological features of tumors, as well as factors affecting treatment and prognosis. A retrospective study enrolled 42 patients operated on at the Burdenko Neurosurgery Center between 2003 and 2020. MR characteristics of anaplastic pleomorphic xanthoastrocytoma were analyzed. All patients underwent resection of tumor (total resection in 83.3% of cases). Redo surgeries were performed in 1/3 of patients. Mutational status of BRAF V600E was assessed in all patients. Adjuvant radio- and chemotherapy was performed in more than 80% of cases. Tyrosine kinase inhibitors were administered in 19% of cases. The follow-up period was 152 months (median 34 months). We found no pathognomonic MR signs of this disease. Indeed, anaplastic pleomorphic xanthoastrocytoma have the same signal characteristics as other malignant gliomas. The BRAF V600E mutation status was positive in 54.8% of cases. None patient had IDH-1 mutation. Mean Ki-67 index was 12.5%. The overall survival was 79 months (range 4-152). Seven (17%) patients are alive for more than 90 months. Only Ki-67 index and BRAF mutation significantly influenced the treatment prognosis and overall survival regardless the use of tyrosine kinase inhibitors. Such well-known factors for malignant glioma as patient age, total resection and adjuvant therapy did not significantly affect overall survival. Perhaps, searching for new molecular genetic features will reveal additional significant factors of prognosis in patients with anaplastic pleomorphic xanthoastrocytoma.

Anaplastic pleomorphic xanthoastrocytoma versus pleomorphic xanthoastrocytoma: The uncharted entities with significant prognostic implication – Report of two cases

Pleomorphic xanthoastrocytoma (PXA), WHO grade II, is a rare entity accounting for <1% of all astrocytic tumors. It affects children and young adults and is commonly found in the temporal lobe. Anaplastic PXA (APXA) has a similar location and clinical manifestation as that of PXA but has a significantly worse prognosis than the latter. WHO 2016 defined PXA as having >5/10 HPF mitosis and with or without necrosis as APXA (grade III). Herein, we present two such cases with unusual locations and ages: (1) APXA inside lateral ventricle, in a 10-year-old female child and (2) PXA in a 39-year adult male. Histologically, both cases revealed a tumor comprised a highly pleomorphic heterogeneous population of cells, eosinophilic granular bodies, and psammoma bodies, however, necrosis and increased mitosis (>5/10 HPF) were appreciated only in the first case. Immunohistochemistry is supported by strongly positive glial fibrillary acidic protein, vimentin, and synaptophysin. This study analyzed all the characteristics of both these entities with their unusual presentations to prevent future misdiagnoses.

Clinical-pathological study of 28 glial and mixed neuronal-glial tumors diagnosed within the first year of life.

Our purpose was to investigate the incidence of gliomas and neuronal-glial tumors, their outcome, and H3.3K27M, BRAFV600E, and IDH status in children within 1 year of age affected by CNS tumor. We collected 28 consecutive gliomas and mixed tumors. Immunohistochemistry and/or molecular analyses were performed on formalin-fixed/paraffin-embedded specimens. 24 (86%) tumors were supratentorial. 15 (54%) tumors were astrocytomas (5 glioblastomas, 1 anaplastic astrocytoma, 1 pilocytic astrocytoma, 3 pilomixoid astrocytomas, 2 subependymal giant cell astrocytomas, 3 astrocytomas not otherwise specified (NOS)), 4 (14%) were anaplastic ependymomas, and 9 (32%) were mixed tumors (5 gangliogliomas, 2 gangliocytomas, 2 desmoplastic infantile gangliogliomas (DIGs)). Alive patients were: 4 (67%) affected by high-grade astrocytoma (mean follow-up 64 months), 4 (67%) affected by low-grade astrocytoma (mean follow-up 83 months), 2 (67%) affected by astrocytoma NOS (mean follow-up 60 months), 1 (25%) affected by anaplastic ependymoma (follow-up 12 months), and 9 (100%) affected by mixed tumors (mean follow-up 74 months). H3.3K27M and IDH were not-mutated in any tumor (100%). BRAFV600E mutation was documented in 6 (21%) tumors (4 gangliogliomas, 1 gangliocytoma, and 1 astrocytoma NOS resulted as anaplastic pleomorphic xanthoastrocytoma 8 years later). Gliomas and mixed tumors diagnosed within 1 year of age are morphologically heterogeneous. Moreover, analogously to those affecting older children, they are IDH1-2 and H3.3K27M (when located outside midline) not-mutated while BRAFV600E mutation is typical of gangliogliomas/gangliocytomas and pleomorphic xanthoastrocytomas. High-grade astrocytomas have a more favorable prognosis compared with the same lesions occurring later in life while ependymomas have a poorer outcome.

Anaplastic pleomorphic xanthoastrocytoma with epithelioid morphology misdiagnosed and treated as melanoma.

Anaplastic pleomorphic xanthoastrocytoma with epithelioid morphology misdiagnosed and treated as melanoma.