Neuroepithelial Tumors Research Articles

PATH-12. A new powerful tool to simultaneously deliver DNA methylation profile and driver fusions detection based on Nanopore Sequencing

Abstract The fast advances in molecular biology have led to the discovery of new genetic and epigenetic driver events that play a key role in the pathogenesis of central nervous system (CNS) tumors. These data showed the importance of molecular biology, and in particular methylation profiling and fusion detection, to complete the histological examination. Exploring all these complex genomic and epigenomic alterations with the technologies implemented in the routine diagnosis requires massive laboratory equipment. In addition, it could take weeks before getting data that could be important to adapt the diagnosis, prognosis, and to ultimately guide the treatment’s choice. We describe the innovative potential of a nanopore sequencing device to obtain fast and multiple information to characterize CNS tumors. Adaptive-sampling is a software-controlled enrichment unique method that allows simultaneous methylation profiling, copy number landscape assessment, and fusion gene detection. Thereby, this technology brings comprehensive molecular information that could be very important for CNS tumor classification in a very short delay (below one week) and with a relative low cost compared to the combined other molecular analysis needed to get the same information. We report ten cases of diverse CNS tumors with already known oncogenic structural variants such as YAP1-MAMLD1 fused ependymoma, CNS neuroblastoma with FOXR2 activation, CNS high-grade neuroepithelial tumor with BCOR and MEN1 alteration, and atypical teratoid rhabdoid tumors (ATRT). For these tumors, using adaptive sampling with the nanopore sequencing, we were able to detect fusion genes as driver events, while obtaining at the same time the methylation profile to corroborate the tumor classification. Our results with this combined approach, never described before, demonstrate its feasibility as a new extremely powerful tool and show remarkable perspectives for this technology to bring a fast and comprehensive tumor molecular characterization.

ETMR-01. Management of CNS tumor with BCOR internal tandem duplication with multimodalities therapy: Surgery, Intensive Chemotherapy, and Radiation

The 2021WHO CNS tumor classification includes CNS tumors with internal tandem duplications in the BCL6 corepressor (BCOR) gene as a new entity of CNS embryonal tumors labelled high-grade neuroepithelial tumors with BCOR alterations (HGNET-BCOR) are characterized by genetic aberrations in the BCOR gene located at Xp11.4, leading to increased expression of BCOR mRNA and distinct DNA methylation profiles. currently no agreement on the optimal strategy to manage these rare tumors, which mostly occur in young children These tumors are usually treated as high grade glioma HGG with upfront radiation therapy with poor outcome. We report 2.5 years old boy presenting with headache and vomiting. MRI showed a well-defined left cerebellar mass, hyperintense in T2 and hypointense in T1, with restricted diffusion and no spinal CSF seeding metastases. He underwent gross surgical resection of the tumor initial pathological diagnosis was epithelioid high grade malignant neoplasm. Brain tumor methylation classifier analysis of resected tumor tissue confirmed a CNS tumor with BCOR internal tandem duplication (WHO grade 4). The patient was treated per COG ACNS0334 (3 induction cycles of vincristine, cyclophosphamide, cisplatin, etoposide, HDMTX, followed by consolidation with 3 cycles of carboplatin and thiotepa with autologous hematopoietic stem cell rescue). MRI brain before the start of chemotherapy showed a small recurrent mass within the surgical cavity. post-induction MRI detected stable-sized residual lesion in the surgical cavity; however, post-consolidation MRI showed complete resolution of the residual mass. The patient subsequently received craniospinal irradiation (36 Gy [CSI]) with a boost to the tumor bed up to 54 GY. By the time of writing this report our patient is still in complete remission. Our case showed that this aggressive brain tumor may respond well to intensive multimodalities therapy Further case studies and international prospective trials are needed to optimize the clinical management of these rare tumors.

PATH-15. Molecular and clinical landscape of CNS tumors arising among adolescents and young adults (AYA) at Memorial Sloan Kettering Cancer Center (MSKCC): a single-institutional experience

Abstract BACKGROUND: The management of CNS tumors arising among AYA represents an unmet challenge. Treatment may be split between pediatric and adult centers, often with conflicting approaches. Biology also appears to be distinct compared to younger/older age groups but has yet to be fully characterized. Such features would have important implications for prognostication and informing vulnerabilities for targeted therapies.METHODS: To establish the clinical and molecular landscape of these tumors, we analyzed all cases in patients aged 15-39 years old who were treated at MSKCC between 2018-2021. RESULTS: 302 patients with accompanying MSK-IMPACT targeted sequencing, copy number analysis, Archer fusion panel, and clinical data were found. 239/302 cases (79%) were gliomas, with the remaining consisting mainly of neuro-epithelial tumors (n=15; 5%), meningiomas (9; 3%), ependymomas (10; 3%), and embryonal tumors (7; 2%). Among gliomas, 163/239 (68%) had IDH1/2 mutations, which were significantly more enriched for TP53 (121/163; 74%) and ATRX (90/163; 55%) co-mutations compared to IDH-wild type (IDH-WT) (q<0.0001). In comparison, IDH-WT gliomas (n=76) were enriched for alterations in BRAF (16/76 with SNV, 9/76 fusion; q<0.0001), H3F3A (14/76; q<0.0001), PTEN (10/76; q=0.038), and CDKN2A (16/76; q=0.038). Among 113 patients with high-grade gliomas (WHO grade 3/4), those with IDH-WT tumors (n=34) had a poorer prognosis that those with IDH-mutant tumors (n=79) (1 and 5-year OS of 68% and 28% vs. 97% and 76%, respectively) (p<0.0001). Further, a lower frequency of alterations in TERT (26/113; 23%), EGFR (6/113; 5%), and PDGFRA (4/113; 4%) were observed compared to previous studies for adult-only cohorts (~50-70%, 40%, and 10%, respectively). CONCLUSIONS: IDH-mutant gliomas were the most common tumor type seen in this AYA cohort. However, some alterations characteristic of adult high-grade gliomas (TERT, EGFR, PDGFRA) were not as frequently observed. Additional identification of molecular features that predict response to conventional and targeted therapies is underway.

LINC-03. A single center retrospective analysis of current therapy and outcome of central nervous system tumors in children of Beijing

OBJECTIVE: To explore the clinical characteristics, therapy and outcome in children with central nervous system (CNS) tumors in Beijing, China. METHODS: Clinical data of 1003 patients with newly diagnosed CNS tumors under the age of 15 years admitted to Beijing Shijitan Hospital between January 2017 and December 2021 were retrospectively analyzed. The diagnoses were confirmed by pathology and/or molecular tests. RESULTS: 34 patients were lost to follow up. Medulloblastoma (n=472), ependymoma (n=79), ETMR (n=59) and pinealoblastoma (n=19) were treated according to HIT-2000/2017, 5-year progression-free survival (PFS) and overall survival (OS) were 76.4 ± 2.3%/ 84.8 ±1.9% in MB, 88.8±3.7% /89.5±3.8% in ependymoma, 49.9±7.6%/59.6±10.7% in ETMR, and 3y-PFS/OS of 11.1±10.5%, 90.0±9.5% in pinealoblastoma. The detailed histology of 59 cases of embryonal tumors included 40 cases of CNS embryonal tumor, 9 neuroblastoma, 7 ETMR, and 3 rare tumors (Intracranial mesenchymal tumor with FET-CREB fusion, CNS high-grade neuroepithelial tumor with BCOR alteration, and Melanotic neuroectodermal tumor of infancy). Among 19 cases of pinealoblastoma, two contain DICER1 mutations. Atypical teratoid/rhabdoid tumors (n=36) were treated by EU-RHAB-Protocol with 3y-PFS/OS of 42.2 ± 9.4 % and 62.8 ± 9.5 %. For low-grade gliomas (n=153, 114 cases of OPG and 39 other non-STR/NTR or progressive cases) under SIOP-LGG 2004, 5y-PFS/OS rates were 77.6±5.2% and 92.4±3.2%; Comparatively, among 63 cases of high-grade gliomas, 19 cases survived with median survival of 52 months, 44 cases died. Choroid plexus cancers (n=13) were treated according to CPT-SIOP-2009 with 5y-PFS /OS of 68.4 ± 13.1 % and 64.8±14.3 %. Among 109 germ cell tumors, 5y-PFS/OS were 93.8±2.8% and 95.5±2.2%, respectively. CONCLUSION: The prognosis of CNS tumors are related to pathology, molecular type and individualized therapy. By international multicenter cooperation and adopting advanced protocols, the survival rates of pediatric CNS tumors can be significantly improved.

PATH-13. Methylation analysis in the diagnosis of pediatric CNS tumors; a single center experience

Abstract BACKGROUND: Tumors of Central Nervous System (CNS) comprise major cause of cancer-related morbidity and mortality during childhood. Recent advances in genome and epigenome research allow for molecular classification of CNS tumors, treatment stratification and therapeutic target identification. In many countries, including Greece, this integrated diagnosis is not possible, yet, in a routine setting due to financial and infrastructural reasons. DESIGN/METHODS: We analyzed the results from the methylation profiling performed on tumor samples from newly diagnosed and selected retrospective patients followed in our unit. Analyses were performed through the PTT2.0 and MNP2.0 Studies, as part of a collaboration project between ACCC (Athens Cancer Comprehensive Center) and DKFZ (German Cancer Research Center). RESULTS: Methylation arrays from 50 patients (mean age: 8years, range: 0-17years) have been analyzed. High calibrated score (>0.9) was achieved in 38 patients (76%) and in 33 (86%) of these, the histological diagnosis matched the methylation class. The remaining 5 cases, diagnosed by the local pathologist as ganglioneuroma, primitive neuroectodermal tumor, anaplastic astrocytoma, pineoblastoma and oligodendroglioma, were classified according to the methylation profiling as dermatofibrosarcoma protuberans, medulloblastoma group 3, high-grade glioma H3.3G34mutant, high-grade neuroepithelial tumor with BCOR alteration and glioneuronal tumor, respectively. Only four cases had no match in the classifier, while seven cases received low score (0.5-0.8). In 6 out of the 7 cases with low score, the diagnosis was confirmed with the use either of the copy-number profile inferred from the methylation array or by additional testing for gene fusions and mutations. In 25 medulloblastomas, methylation profiling provided molecular classification, according to the 2021 WHO Classification. CONCLUSIONS: Our experience on the first 50 cases suggests that methylation array needs to be considered as an integral part of the diagnostic process of pediatric patients with CNS tumors and highlights the importance of international collaboration programs in pediatric neuro-oncology.

PATH-01. Infant-Type Hemispheric Glioma: New Molecular Alterations and Precision-Medicine Treatment

BACKGROUND: Infant-type hemispheric glioma, harboring alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET, is a new subtype of Pediatric-type diffuse high-grade gliomas in the 2021 WHO classification of CNS tumors. It has important clinical therapeutic value with specialized therapeutic drugs. Here, we presented 3 cases of infant-type hemispheric glioma. Patient1 with EML4-ALK fusion which often appeared in lung cancer, the other 2 patients have new molecular alterations which has not been reported before (Patient2 has both NTRK1-TP53/TP53-NTRK1 fusions and p53 protein showed characteristic cytoplasm positive; Patient3 presented a brand-new ALK-QKI fusion combined with ALK mutation and focal SMARCB1 deletion. All these 3 cases received corresponding targeted therapy and have a good recovery and normal neurologic function till now.METHOD: Immunohistochemistry, fluorescent in situ hybridization and whole-transcriptome sequencing. RESULTS: Case 18 months, male, right semiovale center occupation. Histopathology: High-grade neuroepithelial neoplasm. IHC: GFAP(only few cells+), Olig2(-), S100(+), CD56(+), Syn(-), NSE(focal+), NeuN(-), CD34(-), INI-1(+), Ki67(10%+). Characteristic Molecular Information: EML4-ALK fusion. Follow-up: 15 months, alive. Case 2: 3 years, female, insular lobe occupation.Histopathology: Gliosarcoma. IHC: GFAP(partly+), Olig2(partly+), Vimentin(+), P53(cytoplasm+), pan-TRK(+), Ki67(25%+). Reticular fiber staining showed biphasic tissue pattern with reticulin-rich sarcomatous and reticulin-free gliomatous elements. Characteristic Molecular Information: NTRK1-TP53 and TP53-NRTK1 fusion. Follow-up: 27 months, alive. Case 3: 3 years, male, left parietal occipital lobe occupation. Histopathology: GBM and AT/RT. IHC: GFAP(partly+), Olig2(partly+), INI-1(partly-), BRG1(+), SYN(-), CD34(-), BRAF(-), S100(-), CK(-), H3K27M(-), IDH1(-), P53(40%+), ATRX(+), pan-TRK(-), ALK(+), Ki67(30%+). Characteristic Molecular Information: ALK mutation, ALK-QKI fusion, RAD51C mutation and focal SMARCB1(INI-1) deletion. Follow-up: 14 months, alive. CONCLUSION: Infant-type hemispheric glioma is a special kind of glioma, which is particularly suitable for precision-medicine treatment approaches. Their overall survival is good compared with other three pHGG subtype.

A paediatric dysembryoplastic neuroepithelial tumour (DNET) with deregulated stem cell markers: a case report

BackgroundDysembryoplastic neuroepithelial tumours (DNETs) are rare, with only a few reported lethal cases. Currently, there are focused efforts by neuro-oncology professionals to reveal the molecular characterisations of individual central nervous system tumours (CNSTs). Here, we report the status of cancer stem cell (CSC) genes associated with resilience and drug resistance in a paediatric DNET, since the deregulations and variations of CSC genes may prove critical to these tumours’ molecular characterisations.Case DescriptionImmunofluorescence, clonogenic assay and whole exome sequencing (WES) were applied to the patient’s tissue and its corresponding cell line. The case is for of a 6-year-old boy with intractable epilepsy and unremarkable physical and neurological examinations. Following magnetic resonance imaging (MRI) and histopathological tests, the patient was diagnosed with DNET. The child underwent a right posterior temporoparietooccipital neuronavigation-assisted craniotomy. Several CSC markers were upregulated in situ, including the metastasis-related protein, anterior gradient 2 (AGR2; 67%), and the Wnt-signalling-related protein, frizzled class receptor 9 (FZD9; 79%). The cell line possessed a similar DNA profile as the original tissue, stained positive for the tumorigenic marker [BMI1 proto-oncogene (BMI)] and CSC markers, and displayed drug resistance. Variants identified in the tissue DNA, which are listed in the catalogue of somatic mutations in cancer (COSMIC) database for genes previously known to be necessary for the development of the embryonic brain, included variants in the cell division cycle 27 (CDC27) gene.Conclusionswe report the in situ and in vitro presence of CSCs in a paediatric DNET.

Transcriptomic profiling of nonneoplastic cortical tissues reveals epileptogenic mechanisms in dysembryoplastic neuroepithelial tumors.

Low-grade dysembryoplastic neuroepithelial tumors (DNTs) are a frequent cause of drug-refractory epilepsy. Molecular mechanisms underlying seizure generation in these tumors are poorly understood. This study was conducted to identify altered genes in nonneoplastic epileptogenic cortical tissues (ECTs) resected from DNT patients during electrocorticography (ECoG)-guided surgery. RNA sequencing (RNAseq) was used to determine the differentially expressed genes (DEGs) in these high-spiking ECTs compared to non-epileptic controls. A total of 477 DEGs (180 upregulated; 297 downregulated) were observed in the ECTs compared to non-epileptic controls. Gene ontology analysis revealed enrichment of genes belonging to the following Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways: (i) glutamatergic synapse; (ii) nitrogen metabolism; (iii) transcriptional misregulation in cancer; and (iv) protein digestion and absorption. The glutamatergic synapse pathway was enriched by DEGs such as GRM4, SLC1A6, GRIN2C, GRM2, GRM5, GRIN3A, and GRIN2B. Enhanced glutamatergic activity was observed in the pyramidal neurons of ECTs, which could be attributed to altered synaptic transmission in these tissues compared to non-epileptic controls. Besides glutamatergic synapse, altered expression of other genes such as GABRB1 (synapse formation), SLIT2 (axonal growth), and PROKR2 (neuron migration) could be linked to epileptogenesis in ECTs. Also, upregulation of GABRA6 gene in ECTs could underlie benzodiazepine resistance in these patients. Neural cell-type-specific gene set enrichment analysis (GSEA) revealed transcriptome of ECTs to be predominantly contributed by microglia and neurons. This study provides first comprehensive gene expression profiling of nonneoplastic ECTs of DNT patients and identifies genes/pathways potentially linked to epileptogenesis.

Thirteen-year long-term follow-up in a rare case of anaplastic astroblastoma: What makes the difference?

Background: Astroblastomas are uncommon neuroepithelial tumors of the central nervous system with a distinct, yet, controversial radiological, histological, and molecular profile. Debatable differences between low- and high-grade astroblastoma have been reported in the medical literature; indeed, despite the increasing relevance of molecular genetic profiling in the realm of astroblastoma, its application is still in its early stages. As a result, the diagnostic criteria for astroblastoma remain undecided with yet no real consensus on the most ideal management.Case Description: This report describes a case of astroblastoma diagnosed 13 years ago in a young woman who despite six episodes of recurrence, transformation, and progression was able to retain a perfomace status of 0 by World Health Organization standard, throughout.Conclusion: This report discusses the clinical, radiological, histological features, and management of this rare tumor with an extraordinarily long survival, with an aim to strengthen the literature on management options. To the best of our knowledge, this is the longest surviving case of anaplastic astroblastoma reported in the available medical literature.

Stereotactic radiosurgery of recurrent malignant gliomas

High-grade gliomas (HGG) are the most aggressive primary neuroepithelial tumors. In this group of patients, high mortality rates persist, and the median survival rate fluctuates around 24.5 months. In order to clarify the issue of choosing adequate doses of the necessary stereotactic radiosurgery (SRS), as well as to elucidate the factors affecting the effectiveness of radiosurgical treatment, we have undertaken this study. The N.V. Sklifosovsky Clinical and Research Institute for Emergency Medicine uses SRS on the gamma knife device, which is a successful combination of surgical and radio-oncological treatment technologies. All patients underwent SRS procedure with a relapse of HGG. The prescribed dose was in the range of 10–24 Gy. In all cases, before SRS, in addition to MRI in T1 mode with contrast enhancement, PET-CT with amino acids (11C-methionine, 18F-fluoroethylthyrosine) was also performed. The median overall survival for the entire HGG group from the date of surgical treatment was recorded at the level of 23,66 months, the median overall survival after SRS was 13,51 months, relapse-free survival after SRS for the entire HGG group was noted at the level of 7,1 months. Radiation toxicity was observed in 16,33 % of cases. SRS is a promising method of choice in a case of small local and distant relapses of HGG, allowing for a fairly long period of time to control the progression of the disease while maintaining a high quality of patients’ life. Meanwhile, the minimum of pronounced toxic effects of SRS makes it possible to use it repeatedly, up to a significant volume of tumor relapse.

Central nervous system high-grade neuroepithelial tumor with BCOR alteration: case report

Central nervous system high-grade neuroepithelial tumor with BCOR alteration: case report

Uncommon Glioneuronal Tumors: A Radiologic and Pathologic Synopsis.

Glioneuronal tumors are characterized exclusively by neurocytic elements (neuronal tumors) or a combination of neuronal and glial features (mixed neuronal-glial tumors). Most of these tumors occur in young patients and are related to epilepsy. While ganglioglioma, dysembryoplastic neuroepithelial tumor, and desmoplastic infantile tumor are common glioneuronal tumors, anaplastic ganglioglioma, papillary glioneuronal tumor, rosette-forming glioneuronal tumor, gangliocytoma, and central neurocytoma are less frequent. Advances in immunohistochemical and molecular diagnostics have improved the characterization of these tumors and favored the description of variants and new subtypes, some not yet classified by the World Health Organization. Not infrequently, the histologic findings of biopsies of glioneuronal tumors simulate low-grade glial neoplasms; however, some imaging findings favor the correct diagnosis, making neuroimaging essential for proper management. Therefore, the aim of this review was to present key imaging, histopathology, immunohistochemistry, and molecular findings of glioneuronal tumors and their variants.

Bilateral oligodendroglial hamartomas: A rare cause of drug-resistant epilepsy in a pediatric patient.

Intractable or drug-resistant seizures in pediatric patients are often secondary to cortical malformations, hamartomas, or mass lesions. Various subtypes of intracerebral hamartomas, associated with seizure disorders, have been described. In this report, we describe a subtype of intracerebral hamartoma associated with intractable epilepsy in a 10-year-old patient. Initial MR imaging demonstrated a mildly expansile, T2/FLAIR hyperintense, T1 isointense, nonenhancing lesion with blurring of the gray-white junction in the left amygdala. Surgical resection was performed, and pathology confirmed oligodendroglial hamartoma. Patient’s seizures recurred after a two-year interval with imaging demonstrating a similar lesion in the right amygdala which in retrospect was also seen on multiple imaging studies. This case report demonstrates the importance of recognizing oligodendroglial hamartomas as a cause of intractable seizures given the imaging findings, distinguishing it from ganglioglioma, dysembryoplastic neuroepithelial tumor, and oligodendroglioma, and the importance of closely looking/searching for contralateral lesions, which has important therapeutic and prognostic implications.

Glioneuronal and neuronal tumors: A review with special reference to the new types in the WHO CNS5 classification.

Glioneuronal and neuronal tumors (GNTs) are slow-growing lower-grade neuroepithelial tumors with mature neuronal and, less consistently, glial differentiation. Their identification has relied solely on histological proof of neuronal differentiation, which was considered to represent the well-differentiated nature of GNTs. However, after discovering the genetic alterations in GNTs, particularly those in the MAP-kinase pathway, it became evident that histological diagnoses are not always concurrent with genetic alterations and vice versa. Furthermore, since several inhibitors mediating the MAP-kinase pathway are available, at least for clinical trials, molecular-based classification is now warranted. Thus, the upcoming WHO Classification of Central Nervous System Tumors, 5th edition (WHO5CNS) applied DNA methylation profiling to segregate low-grade neuroepithelial tumors. This review gives an overview of the pathological features of GNTs with particular reference to the newly listed tumor types in WHO5CNS. The knowledge and awareness of each tumor type are essential to make a correct diagnosis and avoid unnecessary radical resection and chemoradiotherapy, as GNTs are relatively indolent and have a prolonged clinical course. In addition, being distinctive in location, age group, and histology, the integration of clinicopathological information will help identify relevant tumor types of GNTs without genetic testing, even in resource-limited settings.

Pediatric-type diffuse low grade gliomas: Histomolecular profile and practical approach to their integrated diagnosis according to the WHO CNS5 classification.

Low-grade gliomas are the most common primary central nervous system (CNS) neoplasms in the pediatric age group. The majority of these tumors are circumscribed, while diffuse low-grade gliomas are relatively rare. The pediatric type diffuse low-grade gliomas (pDLGG) have a distinctly different biological behavior, molecular profile, and clinical outcome as compared to their adult counterpart. In the 5th edition of World Health Organization (WHO) CNS classification, pDLGGs are subclassified into four distinct histomolecular entities, namely, (i) diffuse astrocytoma, MYB- or MYBL1-altered, (ii) angiocentric glioma, (iii) polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and (iv) diffuse low-grade glioma, MAPK pathway-altered. Although the molecular profile, to a great extent, aligns with the morphological features, it is not specific. Many of the molecular alterations described in pDLGG have therapeutic implications with the availability of newer targeted therapies. A wide range of testing platforms are available for routine assessment of these molecular alterations in clinical laboratories, though WHO does not recommend any particular method.

Thoracic low grade glial neoplasm with concurrent H3 K27M and PTPN11 mutations

We present the case of a 41-year-old man who developed worsening mid-thoracic back pain and imaging revealed a well-circumscribed intramedullary tumor in the thoracic spinal cord. Subtotal resection was performed, and histopathological analysis showed a cytologically bland, minimally proliferative glial neoplasm. Sequencing revealed H3 K27M and an activating PTPN11 mutation. Serial imaging revealed slow tumor regrowth over a three year period which prompted a second resection. The recurrent tumor displayed a similar low grade-appearing histology and harbored the same H3 K27M and PTPN11 mutations as the primary. While the prognostic importance of isolated H3 K27M in spinal gliomas is well-known, the combination of these two mutations in spinal low grade glioma has not been previously reported. Importantly, PTPN11 is a component of the MAPK signaling pathway. Thus, as building evidence shows that low grade-appearing gliomas harboring H3 K27M mutations along with BRAF or FGFR1 mutations have a relatively more favorable course compared to isolated H3 K27M-mutant midline gliomas, the present case provides new evidence for the prognostic importance of activating mutations in other components of the MAPK signaling pathway. This case further highlights the importance of clinico-radio-pathologic correlation when incorporating evolving genetic data into the integrated diagnosis of rare neuroepithelial tumors.

Integrated Analysis of Transcriptome Data Revealed AURKA and KIF20A as Critical Genes in Medulloblastoma Progression.

Medulloblastoma is the neuroepithelial tumor with the highest degree of malignancy in the central nervous system, accounting for about 8% to 10% of children’s brain tumors. It has a high degree of malignancy and is easily transmitted through cerebrospinal fluid, with a relatively poor prognosis. Although medulloblastoma has been widely studied and treated, its molecular mechanism remains unclear. To determine which gene plays a crucial role in medulloblastoma development and progression, we analyzed three microarray datasets from Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to detect and evaluate differentially expressed genes. Protein interaction network was established, and the hub genes were determined in cytoHubba through various assessment methods, while the target genes were screened out using survival analysis. Ultimately, human medulloblastoma samples were utilized to confirm target gene expression. In conclusion, This study found that aurora kinase A (AURKA) and kinesin family member 20A (KIF20A) may be involved in the initiation and development of medulloblastoma, have a close association with prognosis, and may become a potential therapeutic target and prognostic marker of MED.

Stereo-electroencephalography evidence of an eccentrically located seizure-onset zone around a polymorphous low-grade neuroepithelial tumor of the young: illustrative case.

BACKGROUNDPolymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a newly identified low-grade brain tumor with frequent epileptic presentation. Despite the facilitated use of invasive electroencephalography owing to the growing availability of stereo-electroencephalography (SEEG), intracranial features of tumor-related seizures are still scarcely described. This report provides the first description of SEEG-recorded seizures in PLNTY to provide an insight into its surgical strategy.OBSERVATIONSSpontaneous clinical seizures were recorded with SEEG in a young adult patient with drug-resistant epilepsy associated with a PLNTY in the left lateral temporal cortex. The seizure onset was characterized by low-voltage fast activity (LVFA) and showed eccentric localization with respect to the tumor: LVFA was localized in the anterior portion of the tumor and spread toward the adjacent polar cortex. The language risks associated with the resection of the posterior temporal cortex could thus be minimized.LESSONSPLNTY can show a focal and eccentric seizure-onset zone around the tumor. The present findings serve to improve the functional and seizure outcomes using the staged invasive approach in PLNTY.

Nuclear respiratory factor 1 transcriptomic signatures as prognostic indicators of recurring aggressive mesenchymal glioblastoma and resistance to therapy in White American females.

The mechanisms contributing to recurrence of glioblastoma (GBM), an aggressive neuroepithelial brain tumor, remain unknown. We have recently shown that nuclear respiratory factor 1 (NRF1) is an oncogenic transcription factor and its transcriptional activity is associated with the progression and prognosis of GBM. Herein, we extend our efforts to (1) identify influential NRF1-driven gene and microRNA (miRNA) expression for the aggressiveness of mesenchymal GBM; and (2) understand the molecular basis for its poor response to therapy. Clinical data and RNA-Seq from four independent GBM cohorts were analyzed by Bayesian Network Inference with Java Objects (BANJO) and Markov chain Monte Carlo (MCMC)-based gene order to identify molecular drivers of mesenchymal GBM as well as prognostic indicators of poor response to radiation and chemotherapy. We are the first to report sex-specific NRF1 motif enriched gene signatures showing increased susceptibility to GBM. Risk estimates for GBM were increased by greater than 100-fold with the joint effect of NRF1-driven gene signatures-CDK4, DUSP6, MSH2, NRF1, and PARK7 in female GBM patients and CDK4, CASP2, H6PD, and NRF1 in male GBM patients. NRF1-driven causal Bayesian network genes were predictive of poor survival and resistance to chemoradiation in IDH1 wild-type mesenchymal GBM patients. NRF1-regulatable miRNAs were also associated with poor response to chemoradiation therapy in female IDH1 wild-type mesenchymal GBM. Stable overexpression of NRF1 reprogramed human astrocytes into neural stem cell-like cells expressing SOX2 and nestin. These cells differentiated into neurons and form tumorospheroids. In summary, our novel discovery shows that NRF1-driven causal genes and miRNAs involved in cancer cell stemness and mesenchymal features contribute to cancer aggressiveness and recurrence of aggressive therapy-resistant glioblastoma.

Retrograde Trans-Synaptic Degeneration from an Occipital Lobe Tumor

A 29-year-old woman underwent resection of a left occipital lobe dysembryoplastic neuroepithelial tumor 12 years prior to evaluation. Visual acuity was 20/20 in each eye with normal ophthalmoscopic examination. Automated perimetry demonstrated a right homonymous hemianopsia. Magnetic resonance imaging showed a resection cavity within the left occipital lobe. Ganglion cell complex analysis demonstrated a left homonymous hemi-macular thinning. Although once thought to not be possible in adults, lesions posterior to the lateral geniculate nucleus can result in retinal changes from the loss of trophic signals incited by neuronal injury to connecting neurons, leading to retinal ganglion cell death (Magnified version of Figure 1 is available online at www.aaojournal.org).