Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma.

Sonic hedgehog subgroup of medulloblastoma (SHH-MB) is characterized by aberrant activation of the SHH signaling pathway. An inhibition of the positive SHH regulator Smoothened (SMO) has demonstrated promising clinical efficacy. Yet, primary and acquired resistance to SMO inhibitors limit their efficacy. An understanding of underlying molecular mechanisms of resistance to therapy is warranted to bridge this unmet need. Here, we make use of genome-wide CRISPR-Cas9 knockout screens in murine SMB21 and human DAOY cells, in order to unravel genetic dependencies and drug-related genetic interactors that could serve as alternative therapeutic targets for SHH-MB. Our screens reinforce SMB21 cells as a faithful model system for SHH-MB, as opposed to DAOY cells, and identify members of the epigenetic machinery including DNA methyltransferase 1 (DNMT1) as druggable targets in SHH-dependent tumors. We show that Dnmt1 plays a crucial role in normal murine cerebellar development and is required for SHH-MB growth in vivo. Additionally, DNMT1 pharmacological inhibition alone and in combination with SMO inhibition effectively inhibits tumor growth in murine and human SHH-MB cell models and prolongs survival of SHH-MB mouse models by inhibiting SHH signaling output downstream of SMO. In conclusion, our data highlight the potential of inhibiting epigenetic regulators as a novel therapeutic avenue in SMO-inhibitor sensitive as well as resistant SHH-MBs.

Role of surgery in the treatment of pediatric low-grade glioma with various degrees of brain stem involvement.

OBJECTIVE: Posterior fossa pediatric low-grade glioma involving the brainstem and cerebellar peduncles (BS-pLGG) are a subgroup with higher risks at surgery. We retrospectively analyzed the role of surgery in the interdisciplinary armamentarium of treatment options in our institutional series of BS-pLGG with various degrees of brainstem involvement. MATERIAL AND METHODS: We analyzed data of 52 children with BS-pLGG after surgical intervention for clinical/molecular characteristics, neurological outcome, factors influencing recurrence/progression pattern, and tumor volumetric analysis of exclusively surgically treated patients to calculate tumor growth velocity (TGV). Tumors were stratified according to primary tumor origin in four groups: (1) cerebellar peduncle, (2) 4th ventricle, (3) pons, (4) medulla oblongata. RESULTS: The mean FU was 6.44 years. Overall survival was 98%. The mean PFS was 34.07 months. Two patients had biopsies only. Fifty-two percent of patients underwent remission or remained in stable disease (SD) after initial surgery. Patients with progression underwent further 23 resections, 15 chemotherapies, 4 targeted treatments, and 2 proton radiations. TGV decreased after the 2nd surgery compared to TGV after the 1st surgery (p < 0.05). The resection rates were significantly higher in Groups 1 and 2 and lowest in medulla oblongata tumors (Group 4) (p < 0.05). More extended resections were achieved in tumors with KIAA1549::BRAF fusion (p = 0.021), which mostly occurred in favorable locations (Groups 1 and 2). Thirty-one patients showed postoperatively new neurological deficits. A total of 27/31 improved within 12 months. At the end of FU, 6% had moderate deficits, 52% had mild deficits not affecting activities, and 36% had none. Fifty percent of patients were free of disease or showed remission, 38% were in SD, and 10% showed progression. CONCLUSION: The first surgical intervention in BS-pLGG can control disease alone in overall 50% of cases, with rates differing greatly according to location (Groups 1 > 2 > 3 > 4), with acceptable low morbidity. The second look surgery is warranted except in medullary tumors. With multimodality treatments almost 90% of patients can obtain remission or stable disease after > 5 years of follow-up. An integrated multimodal and multidisciplinary approach aiming at minimal safe residual disease, combining surgery, chemo-, targeted therapy, and, as an exception, radiation therapy, is mandatory.

Dissecting the Natural Patterns of Progression and Senescence in Pediatric Low-Grade Glioma: From Cellular Mechanisms to Clinical Implications.

Pediatric low-grade gliomas (PLGGs) comprise a heterogeneous set of low-grade glial and glioneuronal tumors, collectively representing the most frequent CNS tumors of childhood and adolescence. Despite excellent overall survival rates, the chronic nature of the disease bears a high risk of long-term disease- and therapy-related morbidity in affected patients. Recent in-depth molecular profiling and studies of the genetic landscape of PLGGs led to the discovery of the paramount role of frequent upregulation of RAS/MAPK and mTOR signaling in tumorigenesis and progression of these tumors. Beyond, the subsequent unveiling of RAS/MAPK-driven oncogene-induced senescence in these tumors may shape the understanding of the molecular mechanisms determining the versatile progression patterns of PLGGs, potentially providing a promising target for novel therapies. Recent in vitro and in vivo studies moreover indicate a strong dependence of PLGG formation and growth on the tumor microenvironment. In this work, we provide an overview of the current understanding of the multilayered cellular mechanisms and clinical factors determining the natural progression patterns and the characteristic biological behavior of these tumors, aiming to provide a foundation for advanced stratification for the management of these tumors within a multimodal treatment approach.

A multi-institutional series of a novel, recurrent TRIM24::MET fusion-driven infant-type hemispheric glioma reveals significant clinico-pathological heterogeneity.

Within the past decade, incremental integration of molecular characteristics into the classification of central nervous system neoplasms increasingly facilitated precise diagnosis and advanced stratification, beyond potentially providing the foundation for advanced targeted therapies. We report a series of three cases of infant-type hemispheric glioma (IHG) involving three infants diagnosed with neuroepithelial tumors of the cerebral hemispheres harboring a novel, recurrent TRIM24::MET fusion. Histopathology showed glial tumors with either low-grade or high-grade characteristics, while molecular characterization found an additional homozygous CDKN2A/B deletion in two cases. Two patients showed leptomeningeal dissemination, while multiple supra- and infratentorial tumor manifestations were found in one case. Following subtotal resection (two cases) and biopsy (one case), treatment intensity of adjuvant chemotherapy regimens did not reflect in the progression patterns within the reported cases. Two patients showed progression after first-line treatment, of which one patient died not responding to tyrosine kinase inhibitor cabozantinib. As the detection of a recurrent TRIM24::MET fusion expands the spectrum of renowned driving fusion genes in IHG, this comparative illustration may indicate a distinct clinico-pathological heterogeneity of tumors bearing this driver alteration. Upfront clinical trials of IHG promoting further characterization and the implementation of individualized therapies involving receptor tyrosine kinase inhibition are required.

Age, preoperative tumor volume and widening of the internal acoustic meatus are independent factors associated with poor preoperative hearing in vestibular schwannoma patients - results of a single-center retrospective analysis.

Preoperative hearing function shows wide variations among patients diagnosed with vestibular schwannoma. Besides the preoperative tumor size there are other factors that influence the preoperative hearing function that are frequently discussed. A comprehensive analysis of a large cohort of vestibular schwannomas has the potential to describe new insights and influence the preoperative management. We analyzed clinical factors, imaging data and the expression of the proliferation marker MIB1 as potential influencing factors on the preoperative hearing function in a retrospective cohort of 523 primary sporadic vestibular schwannomas. The results of the preoperative audiometry were quantified using the Gardner-Robertson Score. Uni- and multivariate analyses were performed. Serviceable hearing (Gardner-Robertson class 1 or 2) was documented in 391 patients (74.8%). Factors associated with non-serviceable hearing (Gardner-Robertson class 3-5) were patients of older age (p < 0.0001), larger preoperative tumor volume (p = 0.0013) and widening of the internal acoustic meatus compared to the healthy side (p = 0.0353). Gender and differences in the expression of the proliferation marker MIB1 had no influence on preoperative hearing. In the multivariate nominal logistic regression older age (OR 27.60 (CI 9.17-87.18), p < 0.0001), larger preoperative tumor volume (OR 20.20 (CI 3.43-128.58), p = 0.0011) and widening of the internal acoustic canal (OR 7.86 (CI 1.77-35.46), p = 0.0079) remained independent factors associated with non-serviceable hearing. Widening of the internal acoustic canal is an independent factor for non-serviceable preoperative hearing in vestibular schwannoma patients together with older age and larger preoperative tumor volume.

Meningioma: International Consortium on Meningiomas (ICOM) consensus review on scientific advances & treatment paradigms for clinicians, researchers, and patients.

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and the rising availability of neuroimaging. While most exhibit non-malignant behaviour, a subset of meningiomas are biologically aggressive and lead to significant neurological morbidity and mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) working group. There also remains clinical equipoise on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas (ICOM) including field-leading experts, have prepared a comprehensive consensus narrative review directed towards clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality of life studies, and management strategies for unique meningioma patient populations. In each section we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

Targeting TGFß-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome.

Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS. CD19-directed CAR (CAR19) T cell transfer in B cell lymphoma-bearing mice caused microglia activation and neurocognitive deficits. The TGFß-activated kinase-1 (TAK1)-NF-κB-p38 MAPK pathway was activated in microglia after CAR19 T cell transfer. Pharmacological TAK1 inhibition or genetic Tak1 deletion in microglia using Cx3cr1CreER:Tak1fl/fl mice resulted in reduced microglia activation and improved neurocognitive activity. TAK1 inhibition allowed for potent CAR19-induced antilymphoma effects. Individuals with ICANS exhibited microglia activation in vivo when studied by translocator protein positron emission tomography, and imaging mass cytometry revealed a shift from resting to activated microglia. In summary, we prove a role for microglia in ICANS pathophysiology, identify the TAK1-NF-κB-p38 MAPK axis as a pathogenic signaling pathway and provide a rationale to test TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy.

Comparative analysis of intraoperative and imaging features of invasive growth in pituitary adenomas.

BACKGROUND: Most pituitary adenomas (PAs), also termed pituitary neuroendocrine tumors, are benign in nature and can be treated effectively by surgical resection, medical treatment, and in special cases by radiotherapy. However, invasive growth can be an important feature of a more aggressive behavior and adverse prognosis. The extension of PAs into the cavernous sinus can be categorized according to the Knosp criteria on magnetic resonance imaging (MRI). Comparative analyses of MRI features and intraoperative findings of invasive growth regarding different clinical factors are still scarce. MATERIALS AND METHODS: We performed a retrospective single-center analysis of 764 PAs that were surgically treated between October 2004 and April 2018. Invasive growth was assessed according to the surgical reports and preoperative MRI (Knosp criteria). Clinical data, such as patient age at diagnosis and gender, histopathological adenoma type, and extent of resection, were collected. RESULTS: Invasive features on MRI were seen in 24.4% (Knosp grades 3A-4, 186/764) of the cases. Intraoperatively, invasion was present in 42.4% (324/764). Complete resection was achieved in 80.0% of adenomas and subtotal resection, in 20.1%. By multivariate analysis, invasion according to intraoperative findings was associated with the sparsely granulated corticotroph (SGCA, P = .0026) and sparsely granulated somatotroph (SGSA, P = .0103) adenoma type as well as age (P = .0287). Radiographic invasion according to Knosp grades 3A-4 correlated with age (P = .0098), SGCAs (P = .0005), SGSAs (P = .0351), and gonadotroph adenomas (P = .0478). Both criteria of invasion correlated with subtotal resection (P = .0001, respectively). CONCLUSIONS: Both intraoperative and radiographic signs of invasive growth are high-risk lesions for incomplete extent of resection and occur more frequently in older patients. A particularly high prevalence of invasion can be found in the SGCA and SGSA types. Cavernous sinus invasion is also more common in gonadotroph adenomas. Usage of the Knosp classification is a valuable preoperative estimation tool.

Prognostic utility and characteristics of MIB-1 labeling index as a proliferative activity marker in childhood low-grade glioma: a retrospective observational study.

PURPOSE: The prognostic utility of MIB-1 labeling index (LI) in pediatric low-grade glioma (PLGG) has not yet conclusively been described. We assess the correlation of MIB-1 LI and tumor growth velocity (TGV), aiming to contribute to the understanding of clinical implications and the predictive value of MIB-1 LI as an indicator of proliferative activity and progression-free survival (PFS) in PLGG. METHODS: MIB-1 LI of a cohort of 172 nonependymal PLGGs were comprehensively characterized. Correlation to TGV, assessed by sequential MRI-based three-dimensional volumetry, and PFS was analyzed. RESULTS: Mean MIB-1 LI accounted for 2.7% (range: < 1-10) and showed a significant decrease to 1.5% at secondary surgery (p = .0013). A significant difference of MIB-1 LI in different histopathological types and a correlation to tumor volume at diagnosis could be shown. Linear regression analysis showed a correlation between MIB-1 LI and preoperative TGV (R2 = .55, p < .0001), while correlation to TGV remarkably decreased after incomplete resection (R2 = .08, p = .013). Log-rank test showed no association of MIB-1 LI and 5-year PFS after incomplete (MIB-1 LI > 1 vs ≤ 1%: 48 vs 46%, p = .73) and gross-total resection (MIB-1 LI > 1 vs ≤ 1%: 89 vs 95%, p = .75). CONCLUSION: These data confirm a correlation of MIB-1 LI and radiologically detectable TGV in PLGG for the first time. Compared with preoperative TGV, a crucially decreasing correlation of MIB-1 LI and TGV after surgery may result in limited prognostic capability of MIB-1 LI in PLGG.

BCOR::CREBBP fusion in malignant neuroepithelial tumor of CNS expands the spectrum of methylation class CNS tumor with BCOR/BCOR(L1)-fusion.

Methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" was recently defined based on methylation profiling and tSNE analysis of a series of 21 neuroepithelial tumors with predominant presence of a BCOR fusion and/or characteristic CNV breakpoints at chromosome 22q12.31 and chromosome Xp11.4. Clear diagnostic criteria are still missing for this tumor type, specially that BCOR/BCOR(L1)-fusion is not a consistent finding in these tumors despite being frequent and that none of the Heidelberger classifier versions is able to clearly identify these cases, in particular tumors with alternative fusions other than those involving BCOR, BCORL1, EP300 and CREBBP. In this study, we introduce a BCOR::CREBBP fusion in an adult patient with a right temporomediobasal tumor, for the first time in association with methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" in addition to 35 cases of CNS neuroepithelial tumors with molecular and histopathological characteristics compatible with "CNS tumor with BCOR/BCOR(L1)-fusion" based on a comprehensive literature review and data mining in the repository of 23 published studies on neuroepithelial brain Tumors including 7207 samples of 6761 patients. Based on our index case and the 35 cases found in the literature, we suggest the archetypical histological and molecular features of "CNS tumor with BCOR/BCOR(L1)-fusion". We also present four adult diffuse glioma cases including GBM, IDH-Wildtype and Astrocytoma, IDH-Mutant with CREBBP fusions and describe the necessity of complementary molecular analysis in "CNS tumor with BCOR/BCOR(L1)-alterations for securing a final diagnosis.

Case report: Solitary mass of the sciatic nerve confirmed as a primary extranodal manifestation of diffuse large B-cell lymphoma in a geriatric patient.

Background: Neoplastic lesions affecting peripheral nerves are rare in the general population and, most often, are benign peripheral nerve sheath tumors. However, a minority of lesions represent high-grade malignancies associated with a poor prognosis, such as malignant peripheral nerve sheath tumors (MPNSTs). Very rarely, these tumors represent peripheral non-nerve sheath tumors (PNNSTs), such as hematological neoplasms that impair nerve function. These can be hard to distinguish from MPNSTs and other lesions arising from the nerve itself. In the present case report, we describe a rare case of direct infiltration of nerves by tumor cells of a hematological neoplasm. Methods: We report the case of a 90-year-old woman with acute onset of right-sided foot palsy, sensory loss, and pain, caused by an extensive solitary mass of the sciatic nerve in the thigh. We present and discuss the clinical presentation, multimodal diagnostic procedures, and treatment. Results: MRI of the right thigh and the caudal pelvis revealed a contrast-enhancing lesion infiltrating the sciatic nerve. Additionally performed staging imaging was non-revealing. After multidisciplinary discussion in the neuro-oncology tumor board, a MPNST was suspected and the patient underwent radical tumor resection. However, final histopathology revealed a diffuse large B-cell lymphoma (DLBCL). The patient received adjuvant palliative local radiotherapy which led to acceptable symptom control. Conclusion: Rare PNNSTs, including extranodal manifestations of DLBCL can have similar clinical and radiological diagnostical features as PNSTs. Comprehensive diagnostic workup of contrast-enhancing lesions affecting peripheral nerves including MRI and metabolic imaging are recommended. Discussion in interdisciplinary tumor boards facilitates finding individual treatment approaches.

Neuroanatomical location of brain metastases from solid tumours based on pathology: An analysis of 511 patients with a comparison to the provided clinical history.

Brain metastases are a frequent occurrence in neuropathology practices. The literature on their neuroanatomical location is frequently derived from radiological analyses. This work examines brain metastases through the lens of pathology specimens. All brain surgical pathology reports for cases accessioned 2011-2020 were retrieved from a laboratory. Specimens were classified by neuroanatomical location, diagnosis and diagnostic category with a hierarchical free text string-matching algorithm (HFTSMA) and also subsequently audited. All reports classified as probable metastasis were reviewed by a pathologist. The provided history was compared to the final categorization by a pathologist. The cohort had 4,625 cases. The HFTSMA identified 854 cases (including metastases from a definite primary, metastases from primary not known and improperly classified cases). 514/854 cases had one definite primary site per algorithm and on report review 538/854 cases were confirmed as such. The 538 cases originated from 511 patients. Primaries from breast, gynecologic tract, and gastrointestinal tract not otherwise specified were most frequently found in the cerebellum. Kidney metastases were most frequently found in the occipital lobe. Lung, metastatic melanoma and colorectal primaries were most commonly found in the frontal lobe. The provided clinical history predicted the primary in 206 cases (40.3%), was discordant in 17 cases (3.3%) and non-contributory in 280 cases (54.8%). The observed distribution of the metastatic tumours in the brain is dependent on the primary site. In the majority (54.8%) of cases, the provided clinical history was non-contributory; this suggests surgeon-pathologist communication may have the potential for optimization.

Potential of pre-operative MRI features in glioblastoma to predict for molecular stem cell subtype and patient overall survival.

AIM OF THE STUDY: A molecular signature based on 10 mRNA abundances that characterizes the mesenchymal-to-proneural phenotype of glioblastoma stem(like) cells (GSCs) enriched in primary culture has been previously established. As this phenotype has been proposed to be prognostic for disease outcome the present study aims to identify features of the preoperative MR imaging that may predict the GSC phenotype of individual tumors. MATERIAL/METHODS: Molecular mesenchymal-to-proneural mRNA signatures and intrinsic radioresistance (SF4, survival fraction at 4 Gy) of primary GSC-enriched cultures were associated with survival data and pre-operative MR imaging of the corresponding glioblastoma patients of a prospective cohort (n = 24). The analyzed imaging parameters comprised linear vectors derived from tumor volume, necrotic volume and edema as contoured manually. RESULTS: A necrosis/tumor vector ratio and to a weaker extent the product of this ratio and the edema vector were identified to correlate with the mesenchymal-to-proneural mRNA signature and the SF4 of the patient-derived GSC cultures. Importantly, both parameter combinations were predictive for overall survival of the whole patient cohort. Moreover, the combination of necrosis/tumor vector ratio and edema vector differed significantly between uni- and multifocally recurring tumors. CONCLUSION: Features of the preoperative MR images may reflect the molecular signature of the GSC population and might be used in the future as a prognostic factor and for treatment stratification especially in the MGMT promotor-unmethylated sub-cohort of glioblastoma patients.

Differences in intraoperative sampling during meningioma surgery regarding CNS invasion - Results of a survey on behalf of the EANS skull base section.

Introduction: and Research Question: Invasive growth of meningiomas into CNS tissue is rare but of prognostic significance. While it has entered the WHO classification as a stand-alone criterion for atypia, its true prognostic impact remains controversial. Retrospective analyses, on which the current evidence is based, show conflicting results. Discordant findings might be explained by different intraoperative sampling methodologies. Material and methods: To assess the applied sampling methods in the light of the novel prognostic impact of CNS invasion, an anonymous survey was designed and distributed via the EANS website and newsletter. The survey was open from June 5th until July 15th, 2022. Results: After exclusion of 13 incomplete responses, 142 (91.6%) datasets were used for statistical analysis. Only 47.2% of participants' institutions utilize a standardized sampling method, and 54.9% pursue a complete sampling of the area of contact between the meningioma surface and CNS tissue. Most respondents (77.5%) did not change their sampling practice after introduction of the new grading criteria to the WHO classification of 2016. Intraoperative suspicion of CNS invasion changes the sampling for half of the participants (49.3%). Additional sampling of suspicious areas of interest is reported in 53.5%. Dural attachment and adjacent bone are more readily sampled separately if tumor invasion is suspected (72.5% and 74.6%, respectively), compared to meningioma tissue with signs of CNS invasion (59.9%). Discussion and conclusions: Intraoperative sampling methods during meningioma resection vary among neurosurgical departments. There is need for a structured sampling to optimize the diagnostic yield of CNS invasion.

Surgical management of syringomyelia associated with spinal arachnoid web: strategies and outcomes.

Spinal arachnoid web (SAW) is a rare disease entity characterized as band-like arachnoid tissue that can cause spinal cord compression and syringomyelia. This study aimed to analyze the surgical management of the spinal arachnoid web in patients with syringomyelia, focusing on surgical strategies and outcomes. A total of 135 patients with syringomyelia underwent surgery at our department between November 2003 and December 2022. All patients underwent magnetic resonance imaging (MRI), with a special syringomyelia protocol (including TrueFISP and CINE), and electrophysiology. Among these patients, we searched for patients with SAW with syringomyelia following careful analysis of neuroradiological data and surgical reports. The criteria for SAW were as follows: displacement of the spinal cord, disturbed but preserved CSF flow, and intraoperative arachnoid web. Patients were evaluated for initial symptoms, surgical strategies, and complications by reviewing surgical reports, patient documents, neuroradiological data, and follow-up data. Of the 135 patients, 3 (2.22%) fulfilled the SAW criteria. The mean patient age was 51.67 ± 8.33 years. Two patients were male, and one was female. The affected levels were T2/3, T6, and T8. Excision of the arachnoid web was performed in all cases. No significant change in intraoperative monitoring was noted. Postoperatively, none of the patients presented new neurological symptoms. The MRI 3 months after surgery revealed that the syringomyelia improved in all cases, and caliber variation of the spinal cord could not be detected anymore. All clinical symptoms improved. In summary, SAW can be safely treated by surgery. Even though syringomyelia usually improves on MRI and symptoms also improve, residual symptoms might be observed. We advocate for clear criteria for the diagnosis of SAW and a standardized diagnostic (MRI including TrueFISP and CINE).

Clinical outcome of biomarker-guided therapies in adult patients with tumors of the nervous system.

Background: The clinical utility of molecular profiling and targeted therapies for neuro-oncology patients outside of clinical trials is not established. We aimed at investigating feasibility and clinical utility of molecular profiling and targeted therapy in adult patients with advanced tumors in the nervous system within a prospective observational study. Methods: molecular tumor board (MTB)@ZPM (NCT03503149) is a prospective observational precision medicine study for patients with advanced tumors. After inclusion of patients, we performed comprehensive molecular profiling, formulated ranked biomarker-guided therapy recommendations based on consensus by the MTB, and collected prospective clinical outcome data. Results: Here, we present initial data of 661 adult patients with tumors of the nervous system enrolled by December 31, 2021. Of these, 408 patients were presented at the MTB. Molecular-instructed therapy recommendations could be made in 380/408 (93.1%) cases and were prioritized by evidence levels. Therapies were initiated in 86/380 (22.6%) cases until data cutoff. We observed a progression-free survival ratio >1.3 in 31.3% of patients. Conclusions: Our study supports the clinical utility of biomarker-guided therapies for neuro-oncology patients and indicates clinical benefit in a subset of patients. Our data might inform future clinical trials, translational studies, and even clinical care.

Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions.

Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.

Adult intracranial ependymoma-relevance of DNA methylation profiling for diagnosis, prognosis, and treatment.

BACKGROUND: A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. METHODS: Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from 8 diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS). RESULTS: The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6%, and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE, and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (GTR) (P = .009) and postoperative radiotherapy (P = .007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of the prognosis within molecularly defined ependymoma classes. CONCLUSIONS: DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. GTR and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.

Correction: Gonçalves et al. Macrophage and Lymphocyte Infiltration Is Associated with Volumetric Tumor Size but Not with Volumetric Growth in the Tübingen Schwannoma Cohort. Cancers 2021, 13, 466.

The authors would like to make a correction to their published paper [...].