Pleomorphic Xanthoastrocytoma Research Articles

Clinical Relevance of BRAF V600E Mutation Status in Brain Tumors with a Focus on a Novel Management Algorithm.

The possible application of BRAF-targeted therapy in brain tumors is growing continuously. We have analyzed clinical strategies that address BRAF activation in primary brain tumors and verified current recommendations regarding screening for BRAF mutations. There is preliminary evidence for a range of positive responses in certain brain tumor types harboring the BRAF V600E mutation. National Comprehensive Cancer Network Guidelines for central nervous system cancers recommend screening for the BRAF V600E mutation in pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma. We suggest additional testing in glioblastomas WHO grade IV below the age of 30 years, especially those with epithelioid features, papillary craniopharyngiomas, and pediatric low-grade astrocytomas. BRAF-targeted therapy should be limited to the setting of a clinical trial. If the patient harboring a V600E mutation does not qualify for a trial, multimodality treatment is recommended. Dual inhibition of both RAF and MEK is expected to provide more potent and durable effects than anti-BRAF monotherapy. First-generation RAF inhibitors should be avoided. Gain-of-function mutations of EGFR and KIAA fusions may compromise BRAF-targeted therapy. BRAF alterations that result in MAPK pathway activation are common events in several types of brain tumors. BRAF V600E mutation emerges as a promising molecular target. The proposed algorithm was designed to help oncologists to provide the best therapeutic options for brain tumor patients.

Exploring DNA Methylation for Prognosis and Analyzing the Tumor Microenvironment in Pleomorphic Xanthoastrocytoma.

Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that affects children and young adults. Molecular prognostic markers of PXAs remain poorly established. Similar to gangliogliomas, PXAs show prominent immune cell infiltrate, but its composition also remains unknown. In this study, we correlated DNA methylation and BRAF status with clinical outcome and explored the tumor microenvironment. We performed DNA methylation in 21 tumor samples from 18 subjects with a histological diagnosis of PXA. MethylCIBERSORT was used to deconvolute the PXA microenvironment by analyzing the associated immune cell-types. Median age at diagnosis was 16 years (range 7-32). At median follow-up of 30 months, 3-year and 5-year overall survival was 73% and 71%, respectively. Overall survival ranged from 1 to 139 months. Eleven out of 18 subjects (61%) showed disease progression. Progression-free survival ranged from 1 to 89 months. Trisomy 7 and CDKN2A/B (p16) homozygous deletion did not show any association with overall survival (p = 0.67 and p = 0.74, respectively). Decreased overall survival was observed for subjects with tumors lacking the BRAF V600E mutation (p = 0.02). PXAs had significantly increased CD8 T-cell epigenetic signatures compared with previously profiled gangliogliomas (p = 0.0019). The characterization of immune cell-types in PXAs may have implications for future development of immunotherapy.

Association between adjuvant radiation therapy and overall survival in Pleomorphic Xanthoastrocytoma

BackgroundPleomorphic Xanthoastrocytoma (PXA) is a low-grade central nervous system (CNS) tumor with a generally favorable prognosis. However, due to its rarity, optimal adjuvant treatment guidelines have not been established by large scale studies. In this study, we investigated the effect of adjuvant radiation therapy (RT) on overall survival (OS) in adult patients with PXA to help address this unanswered question. MethodsThe National Cancer Database (NCDB) was used to identify adult patients (age ≥ 18 years old) diagnosed with histologically confirmed grade II PXA (2004–2016). Patient demographics, tumor characteristics, and treatment information were collected. Kaplan-Meier curves were generated to study OS, and factors that affected OS were identified using a multivariate Cox proportional hazards (CPH) model. ResultsA total of 546 patients were identified. The average age of patients at diagnosis was 36.6 years old, and overall median survival was 128.6 months. RT was used to treat 179 (33.3 %) patients. Those who received RT had a shorter median OS (33.3 months) compared to those who did not (>128.6 months, p < 0.001). Our multivariate model demonstrated receiving RT was independently associated with a significantly higher risk of death (hazard ratio [HR] = 4.28, 95 % confidence interval [CI] = 1.77−10.38, p = .0013). Patients ≥65 years of age also demonstrated significantly higher risk of death (HR = 2.20, CI = 1.54−4.16, p = .006) and had a decreased median OS (26.0 months). ConclusionIn adults with PXA, treatment with RT is independently associated with a significantly higher risk of mortality. The routine use of this modality in treating PXA warrants further study.

Uveitis Induced by Biological Agents Used in Cancer Therapy

ABSTRACT Purpose: To report cases of uveitis induced by biological therapy given for cancer. Methods: Retrospective review of medical charts of patients. Results: Included were six patients aged 14–81 years. Three were treated with vemurafenib and one each with nivolumab, ipilimumab, and osimertinib. The oncological diagnoses were metastatic thyroid carcinoma, pleomorphic xanthoastrocytoma, metastatic melanoma, adenocarcinoma of the lung, and metastatic breast cancer. Ocular manifestations appeared 4–82 weeks after the biological treatment was initiated. The most common ocular presentation was anterior uveitis. Onset was sudden in all cases. The median duration of uveitis was 70 weeks. Treatment included topical or systemic corticosteroids; one patient received a single intravitreal steroid injection in one eye. Conclusions: Uveitis may rarely be induced by treatment with biological agents for cancer. Both oncologists and ophthalmologists should be aware of this potential side effect. Early detection and management can prevent permanent complications and save the patient’s vision.

Clinical impact of combined epigenetic and molecular analysis of pediatric low-grade gliomas.

Both genetic and methylation analysis have been shown to provide insight into the diagnosis and prognosis of many brain tumors. However, the implication of methylation profiling and its interaction with genetic alterations in pediatric low-grade gliomas (PLGGs) are unclear. We performed a comprehensive analysis of PLGG with long-term clinical follow-up. In total 152 PLGGs were analyzed from a range of pathological subtypes, including 40 gangliogliomas. Complete molecular analysis was compared with genome-wide methylation data and outcome in all patients. For further analysis of specific PLGG groups, including BRAF p.V600E mutant gliomas, we compiled an additional cohort of clinically and genetically defined tumors from 3 large centers. Unsupervised hierarchical clustering revealed 5 novel subgroups of PLGG. These were dominated by nonneoplastic factors such as tumor location and lymphocytic infiltration. Midline PLGG clustered together while deep hemispheric lesions differed from lesions in the periphery. Mutations were distributed throughout these location-driven clusters of PLGG. A novel methylation cluster suggesting high lymphocyte infiltration was confirmed pathologically and exhibited worse progression-free survival compared with PLGG harboring similar molecular alterations (P = 0.008; multivariate analysis: P = 0.035). Although the current methylation classifier revealed low confidence in 44% of cases and failed to add information in most PLGG, it was helpful in reclassifying rare cases. The addition of histopathological and molecular information to specific methylation subgroups such as pleomorphic xanthoastrocytoma-like tumors could stratify these tumors into low and high risk (P = 0.0014). The PLGG methylome is affected by multiple nonneoplastic factors. Combined molecular and pathological analysis is key to provide additional information when methylation classification is used for PLGG in the clinical setting.

The efficacy of DNA mismatch repair enzyme immunohistochemistry as a screening test for hypermutated gliomas

A subset of gliomas has DNA repair defects that lead to hypermutated genomes. While such tumors are resistant to alkylating chemotherapies, they may also express more mutant neoantigens on their cell surfaces, and thus be more responsive to immunotherapies. A fast, inexpensive method of screening for hypermutated gliomas would therefore be of great clinical value. Since immunohistochemistry (IHC) for the DNA mismatch repair (MMR) proteins Msh2, Msh6, Mlh1, and Pms2 is already used to screen for hypermutated colorectal cancers, we sought to determine whether that panel might have similar utility in gliomas. MMR IHC was scored in 100 WHO grade I-IV gliomas (from 96 patients) with known tumor mutation burden (TMB), while blinded to TMB data. Cases included 70 grade IV GBMs, 13 grade III astrocytomas, 4 grade II astrocytomas (3 diffuse astrocytomas and 1 pleomorphic xanthoastrocytoma), 1 grade I pilocytic astrocytoma, 2 grade III oligodendrogliomas, 7 grade II oligodendrogliomas, and 3 grade I glioneuronal tumors. Eight of 100 tumors showed loss of one or more MMR proteins by IHC, and all 8 were hypermutated. Among the remaining 92 gliomas with intact MMR IHC, only one was hypermutated; that tumor had an inactivating mutation in another DNA repair gene, ATM. Overall accuracy, sensitivity, and specificity for DNA MMR IHC compared to the gold standard of TMB were 99, 89, and 100%, respectively. The strongest correlates with hypermutation were prior TMZ treatment, MGMT promoter methylation, and IDH1 mutation. Among the 8 MMR-deficient hypermutated gliomas, 4 (50%) contained both MMR-lost and MMR-retained tumor cells. Together, these data suggest that MMR IHC could be a viable front-line screening test for gliomas in which immunotherapy is being considered. They also suggest that not all cells in a hypermutated glioma may actually be MMR-deficient, a finding that might need to be considered when treating such tumors with immunotherapies.

Malignant transformation of pleomorphic xanthoastrocytoma and differential diagnosis: case report

BackgroundPleomorphic xanthoastrocytoma (PXA) is a rare astrocytic glioma, characterized by large pleomorphic and frequently multinucleated cells, spindle and lipidized cells, a dense pericellular reticulin network, and numerous eosinophilic granular bodies according to the grade II glial tumor standards of the World Health Organization’s (WHO) 2016 guidelines. PXA rarely transforms into anaplastic PXA or glioblastoma (GBM) and anaplastic PXA, classified as WHO grade III, has a more aggressive clinical behavior with poorer prognosis than PXA.Case presentationHere we describe an unusual case of PXA in a 19-year-old woman, first admitted with headache and a mass in the left temporal lobe in 2005 that was removed. Twelve years later, she returned with left temporal headache, diplopia and tinnitus. A local tumor recurrence was found, and a second resection was performed. The specimen showed highly malignant findings, such as necrosis, microvascular proliferation, and multiple mitoses. The integrated diagnosis was made as high grade glioma, probably derived from PXA. Immunohistochemical (IHC) stains were positive for oligo2, and approximately 21% positive for Ki-67, while negative for CD34, IDH1 R132H. INI1 and ATRX were retained. As the histological classification was glioblastoma, the patient received GBM-appropriate chemotherapy and radiation therapy and outpatient follow-ups have demonstrated no obvious symptoms for 1 year after surgery. Additional molecular analyses found BRAF V600E mutations in both resections, supporting the idea that the recurrent tumor had derived from PXA.ConclusionsThis case highlights the complexities of differential diagnosis based on the World Health Organization’s 2016 guidelines. More integrated criteria to differentiate anaplastic PXA from GBM and epithelioid GBM, combined with genetic screening results, might be needed.

Molecular Features and Prognostic Factors of Pleomorphic Xanthoastrocytoma: A Collaborative Investigation of the Tohoku Brain Tumor Study Group.

Pleomorphic xanthoastrocytoma (PXA) is a rare glial tumor, however, its histological differentiation from high-grade gliomas is often difficult. Molecular characteristics may contribute to a better diagnostic discrimination. Prognostic factors of PXA are also important but few relevant reports have been published. This study investigated the molecular features and prognostic factors of PXAs. Seven university hospitals participated in this study by providing retrospective clinical data and tumor samples of PXA cases between 1993 and 2014. Tumor samples were analyzed for immunohistochemical (IHC) neuronal and glial markers along with Ki67. The status of the BRAF and TERT promoter (TERTp) mutation was also evaluated using the same samples, followed by feature extraction of PXA and survival analyses. In all, 19 primary cases (17 PXA and 2 anaplastic PXA) were included. IHC examination revealed the stable staining of nestin and the close association of synaptophysin to NFP. Of the PXA cases, 57% had the BRAF mutation and only 7% had the TERTp mutation. On univariate analysis, age (≥60 years), preoperative Karnofsky performance status (KPS) (≤80%), and marked peritumoral edema were significantly associated with progression-free survival (PFS). No independent factor was indicated by the multivariate analysis. In conclusion, PXA was characterized by positive nestin staining and a few TERTp mutations. The neuronal differential marker and BRAF status may help in diagnosis. Patient age, preoperative KPS, and marked perifocal edema were associated with PFS. The present study is limited because of small number of cases and its retrospective nature. Further clinical study is needed.

Surgical treatment of low-grade brain tumors associated with epilepsy.

To explore the strategy of surgical treatment of low-grade brain tumors associated with epilepsy. Clinical data of 158 patients with low-grade brain tumors were collected from January 2011 to December 2017 in Guangdong Sanjiu brain hospital. All patients received Preoperative evaluation. Lesion site: 18 cases were located in multiple cerebral lobes, 10 cases were in the functional zones, 130 cases were in the non-functional zones (including 74 cases were in the medial of temporal lobe). The surgical strategy included subtotal resection, gross-total resection and enlarged resection. Postoperative effects were evaluated by Engel classification. A total of 158 patients underwent surgical treatment, among these patients, only 1 patient underwent intracranial electrode implantation. Surgical methods: 34 cases of subtotal resection, 3 cases of gross-total resection, 119 cases of enlarged resection (including Anterior temporal lobectomy in 74 cases) and 2 case of Selective hippocampal amygdalectomy. The final pathology suggested that there are 74 cases of ganglionglioma, 25 cases of dysembryoplastic neuroepithelial tumors, 9 cases of pilocytic astrocytoma, 16 cases of oligodendroglioma, 10 cases of pleomorphic xanthoastrocytoma, 4 case of diffuse astrocytoma, 9 cases of unclassified astrocytoma, 11 case of oligoastrocytoma. The follow-up time was between 1 and 7 years, with an average of 3.44±1.77 years. Postoperative recovery: 147 patients had an Engel Class I outcome, 10 patients were in Engel Class II, 1 patient was in Class IV. The strategy of surgical treatment of low-grade brain tumors associated with epilepsy should pay more attention to the preoperative assessment of the epileptogenic zone. The tumor is not exactly the same as the epileptogenic zone, and the strategy of surgical treatment depends on the tumor feature as well as whether it was located in temporal lobe or involved in functional areas.

Using methylation profiling to diagnose systemic metastases of pleomorphic xanthoastrocytoma.

Using methylation profiling to diagnose systemic metastases of pleomorphic xanthoastrocytoma.

Successful Targeting of an ATG7-RAF1 Gene Fusion in Anaplastic Pleomorphic Xanthoastrocytoma With Leptomeningeal Dissemination.

Successful Targeting of an ATG7-RAF1 Gene Fusion in Anaplastic Pleomorphic Xanthoastrocytoma With Leptomeningeal Dissemination.

Using personalized medicine in gliomas: a genomic approach to diagnosis and overcoming treatment resistance in a case with pleomorphic xanthoastrocytoma

IntroductionA patient who was initially considered to have a glioblastoma (GBM) had molecular analysis, showing that it was a pleomorphic xanthoastrocytoma (PXA). Up to 78% of PXA tumors have BRAF V600E mutations. Primary brain tumors with BRAF mutations can have a good response to BRAF MEK inhibitors (BRAF MEKi), and there may be a synergistic response when combined with autophagy inhibitors.Presentation of the caseA 20-year-old man found to have a large brain mass with midline shift underwent resection. He was diagnosed with “GBM” and treated with radiation and temozolomide with subsequent disease recurrence. Review of histology showed malignant PXA with BRAF V600E mutation. Treatment with Dabrafenib and Trametinib was started, and tumor size increased in size after 14 months of treatment. Given studies showing that resistance to BRAF inhibition can be overcome by autophagy inhibition, chloroquine was added. Patient has been on “triple” therapy for 15 months and has radiographically Stable Disease. At MCC, 3% of patients with gliomas have BRAF mutations who could potentially benefit from this combination therapy.ConclusionThis is the first report of a PXA patient receiving therapy with BRAF MEKi and an autophagy inhibitor with prolonged stable disease. This patient highlights the importance of a molecular interrogation in gliomas to provide an integrated diagnosis and effective treatment. This may be useful in up to 3% of glioma patients with BRAF mutations. Molecular testing in neuro-oncology is providing new avenues of diagnosis and treatment, and detailed molecular interrogation should be considered routine.

Ki67 labeling in CNS tumours

A study of Ki67 Labeling Index (LI) by immunohistochemistry was carried out in 47 CNS neoplasms. Astrocytic and oligodendroglial tumours were the most common group with glioblastoma, NOS and diffuse astrocytoma, NOS Grade II predominating. Ki67 LI of diffuse astrocytomas varied from 0.72 to 13.9% with a mean of 4.36%. In glioblastomas the Ki67 LIs varied from 5.96 to 22.4% with a mean of 12.3% which was comparable with various studies. 1 pleomorphic xanthoastrocytoma was reclassified as anaplastic type based on a high LI of 21.66%. All histological variants of ependymomas showed uniformly low Ki67 LIs. Grade I meningiomas show ed a mean Ki67 LI of 2.22% for benign, 5.85% for atypical Grade II and 30% in the anaplastic Grade III meningioma. Choroid plexus carcinoma and Non Hodgkins lymphomas showed very Ki67 LIs from 60 to 91%. The findings correlated well with WHO CNS tumour grade and helped to identify histologically defined lower grade tumours with potential for recurrence and progression. Keywords: CNS neoplasms, Gliomas, Proliferation markers, Ki67.

INNV-30. RESPONSE WITH COMBINED DABRAFENIB AND TRAMETINIB AFTER BRAF INHIBITOR FAILURE IN BRAF-MUTATED GLIOBLASTOMA: A CASE REPORT

Abstract Glioblastoma (GBM) carries a poor prognosis despite aggressive multimodality therapy. Oncogenic BRAF mutations are present in &lt; 2% of GBM, along with other glioma types (ganglioglioma, pleomorphic xanthoastrocytoma). Although oral inhibitors of the oncogenic BRAFv600 kinase have demonstrated some efficacy in GBM, several mechanisms mediating resistance to BRAF inhibitors through MAPK reactivation have been described. BRAF inhibitor monotherapy is also associated with an increased risk for hyperproliferative skin lesions. We present a case of a 44-year-old man who initially presented with headaches and seizures and was diagnosed with a left temporal, MGMT unmethylated, BRAF V600E mutant GBM. He underwent gross total resection followed by radiation therapy with concurrent temozolomide, followed by 9 cycles of adjuvant temozolomide. He presented with progression of disease (POD) and subsequently failed treatment with carboplatin after two cycles (first recurrence). He had a repeat resection, and was enrolled in a clinical trial of autologous dendritic cell vaccine and presented with POD after 10 months on this treatment (second recurrence). He was started on another clinical trial of BRAF inhibitor, achieving partial response but developed POD after 7 months on this therapy (third recurrence). He was started on BRAF inhibitor dabrafenib and MEK inhibitor trametinib (D+T), achieving complete response. At the time of this report, 8 months after initiating treatment, the patient remains clinically stable with MRI showing CR. To our knowledge, this is the first report of clinical and radiographic response to combined D+T after BRAF inhibitor failure in BRAF-mutated glioblastoma. Several ongoing trials (NCT01677741, NCT01748149, NCT02124772, NCT02684058, NCT02285439), will elucidate the precise role of these drugs as single agent and in combination in pediatric and adult brain tumors.

INNV-40. TARGETED NEXT GENERATION SEQUENCING OF PEDIATRIC HIGH-GRADE GLIOMA AND ITS THERAPEUTIC IMPLICATIONS, MD ANDERSON EXPERIENCE

Abstract INTRODUCTION The new understanding of molecular pathways in cancer is paving the way towards personalized cancer medicine, especially in refractory disease. High-grade gliomas (HGG) are common pediatric brain tumors that tend to recur, with no available standard therapy upon recurrence. HGG are challenging tumors with illusive biology and poor outcome. We report here the molecular testing of 27 pediatric HGG patients. MATERIALS AND METHODS An analysis of pediatric patients with HGG treated at UT MD Anderson Cancer Center (MDACC) who underwent molecular genetic profiling using next generation sequencing with different genomic panels (AmpliSeq™Cancer Hotspot and Oncomine Panels – by Thermo Fisher Scientific). RESULTS 27 patients with HGG (median age 14 years, range 3–18 years old) underwent genomic profiling. Primary diagnoses were glioblastoma multiforme (n=22), anaplastic astrocytoma (n = 2), gliosarcoma (n= 1), anaplastic pleomorphic xanthoastrocytoma (n= 1) and anaplastic oligoastrocytoma (n= 1). There are 46 genes common to the panels used. The most common mutation was in TP53 (73%). Other mutations included PIK3CA (19%), IDH1 (11.5%), 7.7% for ATM, EGFR and PTEN, and 3.8% for BRAF, FGFR1 and FGFR2. 24 out of 27 patients were tested at initial diagnosis and 3 upon relapse/progression. Patients at initial diagnosis received standard of care therapy of radiation and temozolomide. Only 5 patients received targeted therapy upon progression/recurrence. Some challenges of genomically-matched therapy included lack of clinical trials accepting pediatric patients, unavailability of a liquid form of a drug, and insurance disapproval for off-label use. CONCLUSION The next generation of therapy for childhood cancers will be based upon in-depth molecular phenotyping that may facilitate the development of rational risk-adapted and target-based therapies. This cohort, though limited by sample size, highlights the opportunity to perform molecular testing and identification of alterations in actionable genes.

RARE-31. TREATMENT OUTCOME OF CHILDREN WITH PLEOMORPHIC XANTHOASTROCYTOMA: RETROSPECTIVE ANALYSIS – A SINGLE INSTITUTION EXPERIENCE

Abstract BACKGROUND Pleomorphic xanthoastrocytoma (PXA) and anaplastic pleomorphic xanthoastrocytoma (APXA) are two types of rare astrocytomas in pediatrics. There is limited literature reporting their outcomes. METHODS A retrospective analysis of pediatric patients with diagnosis of PXA and APXA treated at Nicklaus Children’s Hospital was conducted using descriptive measures. RESULTS A chart review of patients with brain tumors from 2001 to 2019 revealed that 13 patients (median age 6 years, range 2–17 years) were diagnosed with non-metastatic PXA (n=12) and APXA (n=1). Six patients (46%) were male. Clinical presentation included seizures (n=8), headaches (n=2) cranial nerve palsies (n=2). Diagnostic imaging showed tumor in the temporal lobe (n=5), parietal lobe (n=2), temporoparietal lobe (n=2), frontal lobe (n=1), occipital lobe (n=1), others (n=2). BRAF V600E mutation were identified in three of five analyzed tumors including PXA (n=4) and APXA (n=1). Surgical intervention consisted of gross total resection (n=8) and near/subtotal resection (n=5). Ten patients (76%) required a second surgery (median 2; range 1–4) due to local recurrence. The median time to recurrence was 3 years (range 6 months - 7 years). Three patients (23%) had malignant transformation of PXA, which occurred three to eight years from the initial surgery; one of them also had extensive spinal metastasis. Focal radiation was given to six patients (46%) due to multiple recurrence (n=2), malignant transformation (n=3), APXA (n=1). At a median follow up of 8 years (range 3 to 20 years), eight patients remain alive, three patients had lost to follow up, two patients died from progressive disease. Long-term sequelae varied as follows; seizures (n=5), motor weakness (n=4), cranial nerve palsies (n=2), and learning disability (n=1). CONCLUSION PXA is associated with high local recurrence rate and uncommonly malignant transformation to APXA in pediatrics, which requires close follow-up due to unpredictable biological behavior of these tumors.

GENE-30. PRELIMINARY STUDY ON WHOLE-EXOME SEQUENCING TECHNOLOGY IN THE GENETIC ANALYSIS OF PEDIATRIC PATIENTS WITH GLIOMAS

Abstract OBJECTIVE To analyze the genes related to the signaling pathways in pediatric gliomas and drug-related genes with whole-exome sequencing technology. METHODS The tumor tissues and matched blood samples of 17 enrolled patients were detected with whole-exome sequencing technology. There were 3 cases of diffuse midline gliomas, 2 cases of childhood glioblastomas, 3 cases of disffuse astrocytoma, 1 case of pleomorphic xanthoastrocytoma, 1 case of ganglioglioma, 6 cases of anaplastic ependymoma and 1 case of ependymoma in this study. All the enrolled patients who were no more than 14 years old received surgery in the Department of Neurosurgery, Guangdong Sanjiu Brain Hospital. The diagnosis was confirmed by pathological examination and the sample acquisition was approved by hospital ethics committee. RESULTS With the use of whole-exome sequencing technology, a total of 31 related genetic mutations were detected in 15 cases, while no genetic mutation was detected in the other 2 cases. The genes related to the signaling pathways in pediatric gliomas included ATRX, ASL1, BCOR, EP300, FGFR1, H3F3A, IGF1R, MED12, PIK3R1, PRKDC, RB1, SETD2, SMARCA4, SOX2, TGFBR2, and the drug-related genes included AKT1, BCL2, BRAF, BRCA2, CCND1, CCND2, CDK6, EGFR, FGF3, KRAS, MET, PDGFRA, PIK3CA, PTEN, TP53, TSC1. One patient only had genes related to the signaling pathways, and 14 patients had drug-related genes. CONCLUSION Applying whole-exome sequencing technology in the genetic analysis of pediatric patients with gliomas has remarkable guiding significance for revealing the mechanism of disease, searching for therapeutic targets and adopting individualized treatment, which can bring potential benefits to pediatric patients. However, more samples and further data analysis and verification are needed in future study.

Secondary INI1-deficient rhabdoid tumors of the central nervous system: analysis of four cases and literature review

Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly malignant neoplasms of the central nervous system that predominantly occur in infants, and are characterized by the presence of rhabdoid cells and inactivation of INI1 or (extremely rarely) BRG1. The vast majority of AT/RT are recognized as primary tumors; however, rare AT/RT or INI1-deficient RT arising from other primary tumors have been reported. To better characterize secondary RT, we performed a histological and molecular analysis of four RT arising from pleomorphic xanthoastrocytoma (PXA), anaplastic PXA, low-grade astrocytoma, or ependymoma. Histologically, although conventional AT/RT are usually not largely composed of rhabdoid cells, three secondary RT were composed mainly of rhabdoid cells, two of which arising from (anaplastic) PXA exhibited marked nuclear pleomorphism reminiscent of that in the precursor lesions. Regarding INI1 alterations, although mutations including small indels are frequent in conventional AT/RT, only in one secondary RT had a mutation. Moreover, together with previously reported cases, biallelic INI1 inactivation in secondary RT was mostly due to biallelic focal and/or broad deletions. Although conventional AT/RT have stable chromosomal profiles, i.e., the frequency of copy number changes involving chromosomes other than chromosome 22 is remarkably low, our array comparative genomic hybridization analysis revealed numerous copy number changes in the secondary RT. In conclusion, secondary RT of the central nervous system are clinicopathologically and molecularly different from conventional pediatric AT/RT, and a nosological issue is whether these secondary RT should be called secondary "AT/RT" as most of the reported cases were.

Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity.

BRAF V600E is a common oncogenic driver in a variety of primary brain tumors. Dual inhibitor therapy using dabrafenib (a selective oral inhibitor of several mutated forms of BRAF kinase) and trametinib (a reversible inhibitor of MEK1 and MEK2) has been used successfully for treatment of metastatic melanoma, anaplastic thyroid cancer, and other tumor types, but has been reported in only a few patients with primary brain tumors and none with pleomorphic xanthoastrocytoma. Here, the authors report on the substantial clinical response and reduction in cutaneous toxicity in a case series of BRAF V600E primary brain cancers treated with dual BRAF/MEK inhibitor therapy. The authors treated 4 BRAF V600E patients, each with a different type of primary brain tumor (pilocytic astrocytoma, papillary craniopharyngioma, ganglioglioma, and pleomorphic xanthoastrocytoma) with the combination of dabrafenib and trametinib. The patients with pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and papillary craniopharyngioma experienced near-complete radiographic and complete clinical responses after 8 weeks of therapy. A substantial partial response (by RANO [Response Assessment in Neuro-Oncology] criteria) was observed in the patient with ganglioglioma. The patient with craniopharyngioma developed dramatic, diffuse verrucal keratosis within 2 weeks of starting dabrafenib. This completely resolved within 2 weeks of adding trametinib. Dual BRAF/MEK inhibitor therapy represents an exciting treatment option for patients with BRAF V600E primary brain tumors. In addition to greater efficacy than single-agent dabrafenib, this combination has the potential to mitigate cutaneous toxicity, one of the most common and concerning BRAF inhibitor-related adverse events.

Xantoastrocitoma pleomórfico espinal: Reporte de caso y revisión de la literatura

El Xantoastrocitoma Pleomórfico Espinal (XAPE) es una neoplasia primaria infrecuente del sistema nervioso central, descrita por primer vez en 1979. De estirpe astrocítica y aunque clasificada como grado II por la OMS, pueden existir variantes anaplásicas o malignas. Con localización usualmente temporal, pocos casos espinales se han descrito a la fecha, debido probablemente a un subdiagnóstico o un subregistro. El pronóstico es generalmente bueno y depende en gran medida del tipo histológico y extensión de la resección quirurgica. Describimos el caso de un hombre de 30 años de edad con dorsalgia y paresia del miembro inferior izquierdo. Se encontró en imágenes de resonancia magnética una lesión aparentemente intradural, extraaxial en los segmentos T8-T9 que se llevó a resección. Se confirmó por histopatología la presencia de un XAPE primario. En la presente publicación realizamos una revisión de la literatura disponible.