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* Context.--The diagnosis and clinical management of patients with diffuse gliomas (DGs) have evolved rapidly over the past decade with the emergence of molecular biomarkers that are used to classify, stratify risk, and predict treatment response for optimal clinical care. Objective.--To develop evidence-based recommendations for informing molecular biomarker testing for pediatric and adult patients with DGs and provide guidance for appropriate laboratory test and biomarker selection for optimal diagnosis, risk stratification, and prediction. Design.--The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. A systematic review of literature was conducted to address the overarching question, "What ancillary tests are needed to classify DGs and sufficiently inform the clinical management of patients?" Recommendations were derived from quality of evidence, open comment feedback, and expert panel consensus. Results.--Thirteen recommendations and 3 good practice statements were established to guide pathologists and treating physicians on the most appropriate methods and molecular biomarkers to include in laboratory testing to inform clinical management of patients with DGs. Conclusions.--Evidence-based incorporation of laboratory results from molecular biomarker testing into integrated diagnoses of DGs provides reproducible and clinically meaningful information for patient management. [ABSTRACT FROM AUTHOR]

Advances in our understanding of the biological basis and molecular characteristics of ependymal tumors since the latest iteration of the World Health Organization (WHO) classification of CNS tumors (2016) have prompted the cIMPACT‐NOW group to recommend a new classification. Separation of ependymal tumors by anatomic site is an important principle of the new classification and was prompted by methylome profiling data to indicate that molecular groups of ependymal tumors in the posterior fossa and supratentorial and spinal compartments are distinct. Common recurrent genetic or epigenetic alterations found in tumors belonging to the main molecular groups have been used to define tumor types at intracranial sites; C11orf95 and YAP1 fusion genes for supratentorial tumors and two types of posterior fossa ependymoma defined by methylation group, PFA and PFB. A recently described type of aggressive spinal ependymoma with MYCN amplification has also been included. Myxopapillary ependymoma and subependymoma have been retained as histopathologically defined tumor types, but the classification has dropped the distinction between classic and anaplastic ependymoma. While the cIMPACT‐NOW group considered that data to inform assignment of grade to molecularly defined ependymomas are insufficiently mature, it recommends assigning WHO grade 2 to myxopapillary ependymoma and allows grade 2 or grade 3 to be assigned to ependymomas not defined by molecular status. [ABSTRACT FROM AUTHOR]

Both high levels of copy number variations (CNV) and somatic mutations have been associated with higher histologic grade among IDH-mutant astrocytomas and with shorter overall survival in patients with WHO grade II or III IDH-mutant astrocytomas [[1], [9], [28]]. IDH-mutant astrocytomas that lack significant mitotic activity, histologic anaplasia, microvascular proliferation, necrosis and I CDKN2A/B i homozygous deletion are referred to as Astrocytoma, IDH-mutant, grade 2. An IDH-mutant astrocytoma that contains elevated mitotic activity and histologic anaplasia, yet lacks microvascular proliferation, necrosis and I CDKN2A/B i homozygous deletion, currently fits into the designation of Astrocytoma, IDH-mutant, grade 3. [Extracted from the article]

The article focuses on "cIMPACT-NOW" update 3 provided by World Health Organization, which offers diagnostic criteria for diffuse astrocytic glioma, IDH‑wildtype, with molecular features of glioblastoma.

Recent advances in genomic technology have led to a better understanding of key molecular alterations that underlie glioblastoma (GBM). The current WHO-based classification of GBM is mainly based on histologic features of the tumor, which frequently do not reflect the molecular differences that describe the diversity in the biology of these lesions. The current WHO definition of GBM relies on the presence of high-grade astrocytic neoplasm with the presence of either microvascular proliferation and/or tumor necrosis. High-throughput analyses have identified molecular subtypes and have led to progress in more accurate classification of GBM. These findings, in turn, would result in development of more effective patient stratification, targeted therapeutics, and prediction of patient outcome. While consensus has not been reached on the precise nature and means to sub-classify GBM, it is clear that IDH-mutant GBMs are clearly distinct from GBMs without IDH1/2 mutation with respect to molecular and clinical features, including prognosis. In addition, recent findings in pediatric GBMs regarding mutations in the histone H3F3A gene suggest that these tumors may represent a 3rd major category of GBM, separate from adult primary ( IDH1/2 wt), and secondary ( IDH1/2 mut) GBMs. In this review, we describe major clinically relevant genetic and epigenetic abnormalities in GBM-such as mutations in IDH1/2, EGFR, PDGFRA, and NF1 genes-altered methylation of MGMT gene promoter, and mutations in hTERT promoter. These markers may be incorporated into a more refined classification system and applied in more accurate clinical decision-making process. In addition, we focus on current understanding of the biologic heterogeneity and classification of GBM and highlight some of the molecular signatures and alterations that characterize GBMs as histologically defined. We raise the question whether IDH-wild type high grade astrocytomas without microvascular proliferation or necrosis might best be classified as GBM, even if they lack the histologic hallmarks as required in the current WHO classification. Alternatively, an astrocytic tumor that fits the current histologic definition of GBM, but which shows an IDH mutation may in fact be better classified as a distinct entity, given that IDH-mutant GBM are quite distinct from a biological and clinical perspective. [ABSTRACT FROM AUTHOR]

Context.—Significant interobserver variability exists with respect to the diagnosis of oligodendroglial neoplasms, especially their distinction from astrocytoma and mixed oligoastrocytoma. Combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 has been shown to be both relatively specific to oligodendroglioma and, when present, a marker of improved prognosis in patients with these tumors. In addition, 1p/19q loss has been shown to be a marker of ‘classic’ oligodendroglial histology. These findings raise questions as to the role of 1p/19q testing in clinical practice, both as a prognostic marker and as a potential diagnostic marker among infiltrating glial neoplasms. Objective.—This review discusses the issues raised above and tries to clarify the current status of 1p/19q evaluation in the diagnosis of oligodendroglioma. Data Sources.—Sources for this review include recent literature as well as the experience of 3 practicing neuropathologists. Conclusions.—1p/19q status is an important marker in oligodendroglioma. Loss of 1p/19q is associated with classic oligodendroglioma histology as well as improved prognosis. The combined 1p/19q marker will continue to be a clinically useful marker of prognosis and could potentially be incorporated into diagnostic criteria in the future. [ABSTRACT FROM AUTHOR]

Grade II astrocytoma is defined as a low-grade tumor, yet patients have a wide range of survival and tumors can quickly progress to high-grade astrocytoma/glioblastoma. Previous studies using comparative genomic hybridization (CGH) failed to demonstrate frequent copy number aberrations (CNA) in these tumors. This may be related to technical difficulties because infiltrating astrocytic tumors are often intermixed with normal brain tissue. We developed methods to exclude most normal tissue and use small amounts of DNA for CGH by microdissecting small regions of tumor from paraffin sections and amplifying extracted DNA using degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR). Using this method, we examined 30 grade II astrocytoma cases. We found CNA in 25 cases (83%), with a mean of two CNA per case. The most frequent CNA were gains on 7q (12 cases), 5p (5 cases), 9 (5 cases), and 19p (3 cases), and losses on 19q (7 cases), 1p (6 cases), and Xp (3 cases). Gain on 7q and losses on 1p/19q were mutually exclusive. This is the first report on the genetic characterization of low-grade astrocytomas using CGH from microdissected and formalin-fixed tissue. The comparatively large number of cases in this study allows us to suggest that these tumors are genetically subgrouped. [Copyright &y& Elsevier]

Presents information on a study which focused on the in vivo distribution and biochemical characteristics of human brain KCNQ2 and KCNQ3, two potassium channel subunits that are mutated in epilepsy. Immunolocalization of the channel genes in human cortex and hippocampal formation; Materials and methods of the study; Results and discussion.

Simple Summary: Radiation therapy (RT) plans deviating from the standard could likely compromise the efficacy of a pre-specified intervention for any clinical trial due either to insufficient coverage of the target area and/or excessive radiation doses to healthy tissues. Knowledge-based machine learning tools utilize high-quality data and generate patient-specific optimization objectives that produce RT plans that comply better with treatment protocol specifications. In this study, we investigated the use of a knowledge-based planning (KBP) model to evaluate the quality of RT plans in two clinical trials, one for glioblastoma and the other for head and neck cancer. The outcomes of this research indicate that this tool can assist RT quality assessments in multi-center clinical trials. The quality of radiation therapy (RT) treatment plans directly affects the outcomes of clinical trials. KBP solutions have been utilized in RT plan quality assurance (QA). In this study, we evaluated the quality of RT plans for brain and head/neck cancers enrolled in multi-institutional clinical trials utilizing a KBP approach. The evaluation was conducted on 203 glioblastoma (GBM) patients enrolled in NRG-BN001 and 70 nasopharyngeal carcinoma (NPC) patients enrolled in NRG-HN001. For each trial, fifty high-quality photon plans were utilized to build a KBP photon model. A KBP proton model was generated using intensity-modulated proton therapy (IMPT) plans generated on 50 patients originally treated with photon RT. These models were then applied to generate KBP plans for the remaining patients, which were compared against the submitted plans for quality evaluation, including in terms of protocol compliance, target coverage, and organ-at-risk (OAR) doses. RT plans generated by the KBP models were demonstrated to have superior quality compared to the submitted plans. KBP IMPT plans can decrease the variation of proton plan quality and could possibly be used as a tool for developing improved plans in the future. Additionally, the KBP tool proved to be an effective instrument for RT plan QA in multi-center clinical trials. [ABSTRACT FROM AUTHOR]

Provides information on a study investigating an oncogenic form of p53 confer of a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Methodology and materials used to conduct the study; Results of the study.

Introduction: Chordoma is a rare slow-growing tumor that occurs along the length of the spinal axis and arises from primitive notochordal remnants (Stepanek et al., Am J Med Genet 75:335–336, 1998). Most chordomas are sporadic, but a small percentage of cases are due to hereditary cancer syndromes (HCS) such as tuberous sclerosis 1 and 2 (TSC1/2), or constitutional variants in the gene encoding brachyury T (TBXT) (Pillay et al., Nat Genet 44:1185–1187, 2012; Yang et al., Nat Genet 41:1176–1178, 2009). Purpose: The genetic susceptibility of these tumors is not well understood; there are only a small number of studies that have performed germline genetic testing in this population. Methods: We performed germline genetic in chordoma patients using genomic DNA extracted by blood or saliva. Conclusion: We report here a chordoma cohort of 24 families with newly found germline genetic mutations in cancer predisposing genes. We discuss implications for genetic counseling, clinical management, and universal germline genetic testing for cancer patients with solid tumors. [ABSTRACT FROM AUTHOR]

In the evolving landscape of ependymoma classification, which integrates histological, molecular, and anatomical context, we detail a rare case divergent from the usual histopathological spectrum. We present the case of a 37‐year‐old man with symptomatic spinal cord compression at the L3–L4 level. Neuroradiological evaluation revealed an intradural, encapsulated mass. Histologically, the tumor displayed atypical features: bizarre pleomorphic giant cells, intranuclear inclusions, mitotic activity, and a profusion of eosinophilic cytoplasm with hyalinized vessels, deviating from the characteristic perivascular pseudorosettes or myxopapillary patterns. Immunohistochemical staining bolstered this divergence, marking the tumor cells positive for glial fibrillary acidic protein and epithelial membrane antigen with a characteristic ring‐like pattern, and CD99 but negative for Olig‐2. These markers, alongside methylation profiling, facilitated its classification as a myxopapillary ependymoma (MPE), despite the atypical histologic features. This profile underscores the necessity of a multifaceted diagnostic process, especially when histological presentation is uncommon, confirming the critical role of immunohistochemistry and molecular diagnostics in classifying morphologically ambiguous ependymomas and exemplifying the histological diversity within MPEs. [ABSTRACT FROM AUTHOR]

It is recognized that the tumor microenvironment (TME) plays a critical role in the biology of cancer. To better understand the role of immune cell components in CNS tumors, we applied a deconvolution approach to bulk DNA methylation array data in a large set of newly profiled samples (n = 741) as well as samples from external data sources (n = 3311) of methylation-defined glial and glioneuronal tumors. Using the cell-type proportion data as input, we used dimensionality reduction to visualize sample-wise patterns that emerge from the cell type proportion estimations. In IDH-wildtype glioblastomas (n = 2,072), we identified distinct tumor clusters based on immune cell proportion and demonstrated an association with oncogenic alterations such as EGFR amplification and CDKN2A/B homozygous deletion. We also investigated the immune cluster-specific distribution of four malignant cellular states (AC-like, OPC-like, MES-like and NPC-like) in the IDH-wildtype cohort. We identified two major immune-based subgroups of IDH-mutant gliomas, which largely aligned with 1p/19q co-deletion status. Non-codeleted gliomas showed distinct proportions of a key genomic aberration (CDKN2A/B loss) among immune cell-based groups. We also observed significant positive correlations between monocyte proportion and expression of PD-L1 and PD-L2 (R = 0.54 and 0.68, respectively). Overall, the findings highlight specific roles of the TME in biology and classification of CNS tumors, where specific immune cell admixtures correlate with tumor types and genomic alterations. [ABSTRACT FROM AUTHOR]

Intracranial mesenchymal tumor (IMT), FET::CREB fusion-positive is a provisional tumor type in the 2021 WHO classification of central nervous system tumors with limited information available. Herein, we describe five new IMT cases from four females and one male with three harboring an EWSR1::CREM fusion and two featuring an EWSR1::ATF1 fusion. Uniform manifold approximation and projection of DNA methylation array data placed two cases to the methylation class "IMT, subclass B", one to "meningioma-benign" and one to "meningioma-intermediate". A literature review identified 74 cases of IMTs (current five cases included) with a median age of 23 years (range 4–79 years) and a slight female predominance (female/male ratio = 1.55). Among the confirmed fusions, 25 (33.8%) featured an EWSR1::ATF1 fusion, 24 (32.4%) EWSR1::CREB1, 23 (31.1%) EWSR1::CREM, one (1.4%) FUS::CREM, and one (1.4%) EWSR1::CREB3L3. Among 66 patients with follow-up information available (median: 17 months; range: 1–158 months), 26 (39.4%) experienced progression/recurrences (median 10.5 months; range 0–120 months). Ultimately, three patients died of disease, all of whom underwent a subtotal resection for an EWSR1::ATF1 fusion-positive tumor. Outcome analysis revealed subtotal resection as an independent factor associated with a significantly shorter progression free survival (PFS; median: 12 months) compared with gross total resection (median: 60 months; p < 0.001). A younger age (< 14 years) was associated with a shorter PFS (median: 9 months) compared with an older age (median: 49 months; p < 0.05). Infratentorial location was associated with a shorter overall survival compared with supratentorial (p < 0.05). In addition, the EWSR1::ATF1 fusion appeared to be associated with a shorter overall survival compared with the other fusions (p < 0.05). In conclusion, IMT is a locally aggressive tumor with a high recurrence rate. Potential risk factors include subtotal resection, younger age, infratentorial location, and possibly EWSR1::ATF1 fusion. Larger case series are needed to better define prognostic determinants in these tumors. [ABSTRACT FROM AUTHOR]

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas. [ABSTRACT FROM AUTHOR]

We further assembled two molecular cohorts with 258 H3K27M-DMG patients (208 STS patients) with clinical and genomic profiles (see OR) and 20 STS H3K27M-DMG patients (MNP2.0 cohort) with clinical, genomic, and tumor DNA methylation profiles. This combined retrospective molecular cohort may be a closer reflection of the prevalence of patients with LTS and MAPK alterations in the general H3K27M-DMG population (5-10%). A control cohort of 453 patients with confirmed H3K27M-DMG and OS < 18 months (short-term survival [STS]) with detailed histology, demographic, and CNS tumor location from Pratt et al. [[4]] was utilized. [Extracted from the article]

Glioma-associated mutations in IDH1 or IDH2 lead to aberrant DNA methylation. A recent paper shows that loss of methylation-sensitive CTCF binding in IDH mutant cells leads to disruption of enhancer boundary function, which results in aberrant activation of PDGFRA expression via an enhancer associated with an adjacent gene. [ABSTRACT FROM AUTHOR]

cIMPACT‐NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT‐NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles—relating to classification categories, approaches to classification, nomenclature, and grading—that the group hopes will also inform the future classification of CNS neoplasms. [ABSTRACT FROM AUTHOR]

Genomic alterations that occur early in tumorigenesis represent fundamental diver lesions and are perhaps of highest priority as a means to intervene therapeutically. In this issue of Cancer Cell, Ozawa and colleagues apply an algorithm to identify early events in glioblastoma and validate their findings in a rigorous manner. [ABSTRACT FROM AUTHOR]

Pediatric diffuse gliomas are rare but aggressive brain tumors for which effective therapies are unavailable. New studies identify recurrent mutations of the ACVR1 gene in these tumors, identify molecular subtypes and highlight differences between gliomas affecting children and adults. [ABSTRACT FROM AUTHOR]

Globally decreased histone 3, lysine 27 tri-methylation (H3K27me3) is a hallmark of H3K27-altered diffuse midline gliomas (DMGs) and group-A posterior fossa ependymomas (PFAs). H3K27-altered DMGs are largely characterized by lysine-to-methionine mutations in histone 3 at position 27 (H3K27M). Most PFAs overexpress EZH inhibitory protein (EZHIP), which possesses a region of similarity to the mutant H3K27M. Both H3K27M and EZHIP inhibit the function of the polycomb repressive complex 2 (PRC2) responsible for H3K27me3 deposition. These tumors often arise in neighboring regions of the brainstem and posterior fossa. In rare cases PFAs harbor H3K27M mutations, and DMGs overexpress EZHIP. These findings together raise the possibility that certain cell populations in the developing hindbrain/posterior fossa are especially sensitive to modulation of H3K27me3 states. We identified shared molecular features by comparing genomic, bulk transcriptomic, chromatin-based profiles, and single-cell RNA-sequencing (scRNA-seq) data from the two tumor classes. Our approach demonstrated that 1q gain, a key biomarker in PFAs, is prognostic in H3.1K27M, but not H3.3K27M gliomas. Conversely, Activin A Receptor Type 1 (ACVR1), which is associated with mutations in H3.1K27M gliomas, is overexpressed in a subset of PFAs with poor outcome. Despite diffuse H3K27me3 reduction, previous work shows that both tumors maintain genomic H3K27me3 deposition at select sites. We demonstrate heterogeneity in shared patterns of residual H3K27me3 for both tumors that largely segregated with inferred anatomic tumor origins and progenitor populations of tumor cells. In contrast, analysis of genes linked to H3K27 acetylation (H3K27ac)-marked enhancers showed higher expression in astrocytic-like tumor cells. Finally, common H3K27me3-marked genes mapped closely to expression patterns in the human developing hindbrain. Overall, our data demonstrate developmentally relevant molecular similarities between PFAs and H3K27M DMGs and support the overall hypothesis that deregulated mechanisms of hindbrain development are central to the biology of both tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Our study investigates the well-known observation/quandary that cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. This has motivated us to explore whether these sex biases may have a common basis. To study that, we assembled and analyzed a large collection of cancer and AID incidence datasets, including matched data from 29 countries. We first, quite strikingly, find that the sex biases observed in the incidence of AIDs and cancers that occur in the same tissue are positively correlated across human tissues. To our knowledge, this is the first time this across-tissue relationship has been quantitatively demonstrated. Second, we find by analyzing healthy human tissue gene expression data that the sex bias in the expression of mitochondrial-encoded genes stands out as the common key factor whose levels across human tissues are most strongly and positively associated with both cancer and AID incidence rate sex biases, pointing to the key potential role of these genes in determining sex bias in both disorders. These findings may further prompt researchers to explore how pertaining findings in cancer studies could cross fertilize AID studies and vice versa, potentially enhancing our ability to prevent and treat these diseases. Cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 167 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-matched cancer-AID incidence rate sex bias data pairs, we find that, indeed, the sex biases observed in the incidence of AIDs and cancers that occur in the same tissue are positively correlated across human tissues. The common key factor whose levels across human tissues are most strongly associated with these incidence rate sex biases is the sex bias in the expression of the 37 genes encoded in the mitochondrial genome. [ABSTRACT FROM AUTHOR]

Mutations disabling the retinoblastoma (Rb) pathway are among the most common in human cancers, including brain cancer. These mutations promote tumor development through deregulated control of the E2F family of transcription factors. E2F1 belongs to a class of E2F's identified as transcriptional activators and involved in the G1/S phase transition of the cell. However, E2F-1 presents with a paradox as it is considered to have membership in two gene classes, functioning as both an oncogene and a tumor suppressor. This unusual trait generates a degree of uncertainty on the role that E2F1 plays in the development or maintenance of any given tumor. Here we show that E2F1 functions as an oncogene in brain tumors through the generation of mice engineered to overexpress E2F1 specifically within glial cells and neuronal progenitors as directed by the GFAP promoter. Mice carrying the transgene develop with high penetrance a phenotype characterized by neurological deficits including paresia, ataxia, head tilt and seizures. MRI imagining of tgE2F1 mice reveal a low incidence of mild hydrocephalus, and most notably, histological analysis demonstrates that 20% of tgE2F1 mice present with the spontaneous formation of malignant brain tumors. Overall these neoplasms show histological features from a wide range of aggressive brain cancers including medulloblastoma, choroid plexus carcinoma, primary neuroectodermic tumor and malignant gliomas. Mouse age as related to tumoral type forces a comparison to the human disease with juvenile mice presenting embryonal tumors typically identified in children, and older mice revealed gliomas similar to the clinical findings in adults. In this regard, this study suggests a global role for E2F1 in the formation and maintenance of multilineage brain tumors, irrefutably establishing E2F1 as an oncogne in the brain. Further characterization of the tgE2F1 mouse should propel the development of a preclinical brain tumor model for the testing of cell-cycle or apoptosis-targetd therapies against brain cancer.Molecular Therapy (2006) 13, S122–S122; doi: 10.1016/j.ymthe.2006.08.377 [ABSTRACT FROM AUTHOR]

These data suggest a remarkably wide range of different gene fusions that drive tumors within this epigenetic group and in parallel highlights attractive therapeutic targets in particular for patients with incomplete surgical resection or tumor progressions. Given their morphological overlap with other GNTs and the lack of a pathognomonic alteration, we provisionally suggest the term "glioneuronal tumor kinase-fused" (GNT KinF A) to describe this novel group of tumors. To identify novel epigenetic subgroups of GNTs, we used an unsupervised visualization approach with a comprehensive dataset of DNA methylation profiles covering the entire spectrum of existing molecular CNS tumor classes [[2]]. [Extracted from the article]

The article presents a study which explores the cross-species identification of cancer resistance–associated genes that may mediate human cancer risk. It mentions that cancer as a predominant disease across animals. It discusses that study describes a cross-species genomic analysis pointing to candidate genes that may mediate human cancer risk.

Introduction: Isocitrate dehydrogenase (IDH) mutation status and grade define subgroups of diffuse gliomas differing based on age, tumor location, presentation, and prognosis. While some biologic differences between IDH mutated (IDHmut) and wild-type (IDHwt) gliomas are clear, the distinct alterations associated with progression of the two subtypes to glioblastoma (GBM, Grade IV) have not been well described. We analyzed copy number alterations (CNAs) across grades (Grade II-III and GBM) in both IDHmut and IDHwt infiltrating gliomas using molecular inversion probe arrays. Results: Ninety four patient samples were divided into four groups: Grade II-III IDHwt (n = 17), Grade II-III IDHmut (n = 28), GBM IDHwt (n = 25), and GBM IDHmut (n = 24). We validated prior observations that IDHwt GBM have a high frequency of chromosome 7 gain (including EGFR) and chromosome 10 loss (including PTEN) compared with IDHmut GBM. Hierarchical clustering of IDHmut gliomas demonstrated distinct CNA patterns distinguishing lower grade gliomas versus GBM. However, similar hierarchical clustering of IDHwt gliomas demonstrated no CNA distinction between lower grade glioma and GBM. Functional analyses showed that IDHwt gliomas had more chromosome gains in regions containing receptor tyrosine kinase pathways. In contrast, IDHmut gliomas more commonly demonstrated amplification of cyclins and cyclin dependent kinase genes. One of the most common alterations associated with transformation of lower grade to GBM IDHmut gliomas was the loss of chromosomal regions surrounding PTEN. IDHmut GBM tumors demonstrated significantly higher levels of overall CNAs compared to lower grade IDHmut tumors and all grades of IDHwt tumors, and IDHmut GBMs also demonstrated significant increase in incidence of chromothripsis. Conclusions: Taken together, these analyses demonstrate distinct molecular ontogeny between IDHwt and IDHmut gliomas. Our data also support the novel findings that malignant progression of IDHmut gliomas to GBM involves increased genomic instability and genomic catastrophe, while IDHwt lower grade tumors are virtually identical to GBMs at the level of DNA copy number alterations. [ABSTRACT FROM AUTHOR]

SHH medulloblastoma from GNAS mutation (molecular profiling confirmation) with osteoma cutis & syndromic features. [ABSTRACT FROM AUTHOR]

Background: The mechanism underlying EGF receptor (EGFR) activation-promoted glioblastoma (GBM) cell invasion remains elusive. Results: EGFR activation resulted in PKC∈- and NF-κB-dependent VCAM-1 up-regulation, which subsequently promoted the interaction between macrophages and GBM cells, as well as GBM cell invasion. Conclusion: EGF-induced VCAM-1 up-regulation plays an instrumental role in EGFR activation-promoted macrophagetumor cell interaction and tumor cell invasion. Significance: VCAM-1 expression is a potential target for GBM therapy. [ABSTRACT FROM AUTHOR]

Keywords: angiocentric glioma; DNA methylation; epilepsy; glioma EN angiocentric glioma DNA methylation epilepsy glioma 1 3 3 01/16/23 20230101 NES 230101 CLINICAL HISTORY A 64-year-old woman with a 29-year history of drug resistant epilepsy presented to the NIH Clinical Center for surgical evaluation. UMAP clustering analysis of DNA methylation profile data classified this tumor as low-grade glioma (F). gl DNA methylation microarrays classifier analysis (V11) of this case indicated a match to low-grade glioma, MYB/MYBL1 (calibrated score 0.99). According to the 5th edition of the WHO international classification of human tumors, angiocentric glioma is classified under glioma, glioneuronal tumors and neuronal tumors, and is a subtype of pediatric-type diffuse low-grade glioma. [Extracted from the article]

The tumor micro-environment (TME) plays an important role in various cancers, including gliomas. We estimated immune cell type-specific gene expression profiles in 3 large clinically annotated glioma datasets using CIBERSORTx and LM22/LM10 blood-based immune signatures and found that the proportions and estimated gene expression patterns of specific immune cells significantly varied according to IDH mutation status. When IDH-WT and IDH-MUT tumors were considered separately, cluster-of-cluster analyses of immune cell gene expression identified groups with distinct survival outcomes. We confirmed and extended these findings by applying a signature matrix derived from single-cell RNA-sequencing data derived from 19 glioma tumor samples to the bulk profiling data, validating findings from the LM22/LM10 results. To link immune cell signatures with outcomes in checkpoint therapy, we then showed a significant association of monocytic lineage cell gene expression clusters with patient survival and with mesenchymal gene expression scores. Integrating immune cell-based gene expression with previously described malignant cell states in glioma demonstrated that macrophage M0 abundance significantly correlated with mesenchymal state in IDH-WT gliomas, with evidence of a previously implicated role of the Oncostatin-M receptor and macrophages in the mesenchymal state. Among IDH-WT tumors that were enriched for the mesenchymal cell state, the estimated M0 macrophage expression signature coordinately also trended to a mesenchymal signature. We also examined IDH-MUT tumors stratified by 1p/19q status, showing that a mesenchymal gene expression signature the M0 macrophage fraction was enriched in IDH-MUT, non-codeleted tumors. Overall, these results highlight the biological and clinical significance of the immune cell environment related to IDH mutation status, patient prognosis and the mesenchymal state in diffuse gliomas. [ABSTRACT FROM AUTHOR]

SHH medulloblastoma from GNAS mutation (molecular profiling confirmation) with osteoma cutis & syndromic features. [ABSTRACT FROM AUTHOR]

These cases extend the molecular spectrum of anaplastic PXA to include tumors harboring I CDKN2A/B i homozygous deletion with accompanying RTK fusions rather than MAP kinase alterations. Patient #1, H&E sections revealed a high-grade glial neoplasm composed of pleomorphic tumor cells (a), along with areas of necrosis and an increased mitotic index (b). Patient #2, H&E sections revealed a solid glial neoplasm with frequent multinucleated cells (g) with GFAP-positivity (h), ALK-positivity (i), and lack of p16 protein expression by immunohistochemistry (j). [Extracted from the article]

The association between human cytomegalovirus (HCMV) infection and glioblastoma has been a source of debate in recent years because of conflicting laboratory reports concerning the presence of the virus in glioma tissue. HCMV is a ubiquitous herpesvirus that exhibits tropism for glial cells and has been shown to transform cells in vitro. Using sensitive immunohistochemical and in situ hybridization methods in 50 glioma samples, we detected HCMV antigen and DNA in 21/21 cases of glioblastoma, 9/12 cases of anaplastic gliomas and 14/17 cases of low-grade gliomas. Reactivity against the HCMV IE1 antigen (72 kDa) exhibited histology-specific patterns with more nuclear staining for anaplastic and low-grade gliomas, while GBMs showed nuclear and cytoplasmic staining that likely occurs with latent infection. Using IHC, the number of HCMV-positive cells in GBMs was 79% compared to 48% in lower grade tumors. Non-tumor areas of the tissue contained only four and 1% of HCMV-positive cells for GBMs and lower grade tumors, respectively. Hybridization to HCMV DNA in infected cells corresponded to patterns of immunoreactivity. Our findings support previous reports of the presence of HCMV infection in glioma tissues and advocate optimization of laboratory methods for the detection of active HCMV infections. This will allow for detection of low-level latent infections that may play an important role in the initiation and/or promotion of malignant gliomas. [ABSTRACT FROM AUTHOR]

High-density short oligonucleotide microarrays have become a widely used tool for measuring gene expression on a large scale[SUP1,2]. However, details of the mechanism of binding on microarrays remain unclear[SUP3]. Short oligonucleotide probes currently synthesized on microarrays are often ineffective as a result of limited sequence specificity or low sensitivity. Here, we describe a model of binding interactions on microarrays that reveals how probe signals depend on probe sequences and why certain probes are ineffective. The model indicates that the amount of nonspecific binding can be estimated from a simple rule. Using this model, we have developed an improved measure of gene expression for use in data analysis. [ABSTRACT FROM AUTHOR]

Overall, our results suggest that a subset of F3T3-positive high-grade tumors with histological low-grade look but molecular features of IDH-wildtype GBM, may exhibit a distinct methylation profile and better patient outcome compared to conventional GBMs. GBM-F3T3-O cases showed significantly better patient survival when compared to the remaining F3T3-positive GBMs (Fig. [Extracted from the article]

PURPOSE: This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX , CIC , FUBP1 , TERT , and TP53 , in NRG/RTOG 0424 using long-term follow-up data. METHODS: Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. RESULTS: We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDH mutant/co-deleted, 28 (35%) were IDH mutant/non-co-deleted, and 26 (32.5%) were IDH wild-type. Upon single-marker MVA, both IDH mutant subgroups were associated with significantly better OS and PFS (P values <.001), compared with the IDH wild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS (P value <.001) and PFS (P value =.003). In a multimarker MVA, one WHO subgroup comparison (IDH mutant/co-deleted v IDH wild-type) was significant for OS (P value =.045), whereas MGMT methylation did not retain significance. CONCLUSION: This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status. IDH and 1p/19q serve as strong prognostic biomarkers in high-risk grade II glioma patients treated on NRG/RTOG 0424. [ABSTRACT FROM AUTHOR]

To this end, we mined the survival and TMB information of patients with melanoma in three additional patient cohorts: the first treated with anti-CTLA4 (N = 174[12],[13]), the second treated with an anti-PD1/PDL1 and anti-CTLA4 combination (N = 115[3]), and the third treated with different chemotherapies (N = 322[14]). The association between high TMB status and survival of melanoma patients after anti-PD1/PDL1 treatment is dependent on the sex of the patients. [Extracted from the article]

To this end, we mined the survival and TMB information of patients with melanoma in three additional patient cohorts: the first treated with anti-CTLA4 (N = 174[12],[13]), the second treated with an anti-PD1/PDL1 and anti-CTLA4 combination (N = 115[3]), and the third treated with different chemotherapies (N = 322[14]). The association between high TMB status and survival of melanoma patients after anti-PD1/PDL1 treatment is dependent on the sex of the patients. [Extracted from the article]

PURPOSE: This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX , CIC , FUBP1 , TERT , and TP53 , in NRG/RTOG 0424 using long-term follow-up data. METHODS: Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. RESULTS: We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDH mutant/co-deleted, 28 (35%) were IDH mutant/non-co-deleted, and 26 (32.5%) were IDH wild-type. Upon single-marker MVA, both IDH mutant subgroups were associated with significantly better OS and PFS (P values <.001), compared with the IDH wild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS (P value <.001) and PFS (P value =.003). In a multimarker MVA, one WHO subgroup comparison (IDH mutant/co-deleted v IDH wild-type) was significant for OS (P value =.045), whereas MGMT methylation did not retain significance. CONCLUSION: This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status. IDH and 1p/19q serve as strong prognostic biomarkers in high-risk grade II glioma patients treated on NRG/RTOG 0424. [ABSTRACT FROM AUTHOR]

One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs. [ABSTRACT FROM AUTHOR]

A novel ATXN1-DUX4 fusion expands the spectrum of "CIC-rearranged sarcoma" of the CNS to include non-CIC alterations 5139621 19 Sugita S, Arai Y, Aoyama T, Asanuma H, Mukai W, Hama N. NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma. *Previously published cases include ATXN1-NUTM1 [[17]], CIC frameshift deletion [[18]], and CIC in-frame deletion in the PFSK-1 cell line [[5]] independently profiled from two separate studies [[6], [10]] Initially described as a "Ewing-like" sarcoma [[13]], the molecular features of I CIC i -rearranged sarcomas have only recently come into focus. Collectively, these alterations led to the designation of " I CIC i -rearranged sarcoma" for both peripheral and CNS-based sarcomas harboring a I CIC i gene fusion. [Extracted from the article]

We report a novel group of clinically aggressive spinal cord ependymomas characterized by Grade III histology, MYCN amplification, an absence of NF2 alterations or other recurrent pathogenic mutations, and a unique methylation classifier profile. Seven cases were found to have MYCN amplification in the course of routine mutational profiling of 552 patients with central nervous system tumors between December 2016 and July of 2019 and an eighth patient was identified from an unrelated set of cases. Methylation array analysis revealed that none of the 8 cases clustered with any of the nine previously described ependymoma methylation subgroups, and 7 of 8 formed their own tight unique cluster. Histologically all cases showed grade III features, and all demonstrated aggressive clinical behavior. These findings are presented in the context of data from three other studies describing similar cases. Therefore, a combined total of 27 MYCN amplified spinal cord ependymoma cases have now been reported in the literature, warranting their consideration as a distinctive subtype of spinal cord ependymoma (SP-EPN-MYCN) with their unique molecular characteristics and aggressive clinical behavior. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic caused by SARS‐CoV‐2 has is a global health challenge. Angiotensin‐converting enzyme 2 (ACE2) is the host receptor for SARS‐CoV‐2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID‐19 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2‐upregulating drugs, while antineoplastic agents are enriched for ACE2‐downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID‐19, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators. Synopsis: Analyzing large‐scale in vitro and in vivo publicly available transcriptomic data of drug treatments, we identify the effects of hundreds of clinically approved drugs on expression of ACE2, the host receptor of SARS‐CoV‐2. ACE inhibitors are enriched for ACE2‐upregulating drugs among antihypertensives, while antineoplastic agents are enriched for ACE2‐down-regulating drugs.Dexamethasone significantly upregulates ACE2 both in vitro and in vivo.Additionally, the top ranked up‐regulators include vorinostat, erlotinib and vancomycin; top down‐regulators include isotretinoin, bleomycin and probenecid. [ABSTRACT FROM AUTHOR]

Background: Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM.Methods: Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS).Results: After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms.Conclusion: The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) contains a subpopulation of cells, GBM stem cells (GSCs), that maintain the bulk tumor and represent a key therapeutic target. Norrin is a Wnt ligand that binds Frizzled class receptor 4 (FZD4) to activate canonical Wnt signaling. Although Norrin, encoded by NDP, has a well-described role in vascular development, its function in human tumorigenesis is largely unexplored. Here, we show that NDP expression is enriched in neurological cancers, including GBM, and its levels positively correlated with survival in a GBM subtype defined by low expression of ASCL1, a proneural factor. We investigated the function of Norrin and FZD4 in GSCs and found that it mediated opposing tumor-suppressive and -promoting effects on ASCL1lo and ASCL1hi GSCs. Consistent with a potential tumor-suppressive effect of Norrin suggested by the tumor outcome data, we found that Norrin signaling through FZD4 inhibited growth in ASCL1lo GSCs. In contrast, in ASCL1hi GSCs Norrin promoted Notch signaling, independently of WNT, to promote tumor progression. Forced ASCL1 expression reversed the tumor-suppressive effects of Norrin in ASCL1lo GSCs. Our results identify Norrin as a modulator of human brain cancer progression and reveal an unanticipated Notch-mediated function of Norrin in regulating cancer stem cell biology. This study identifies an unanticipated role of Norrin in human brain cancer progression. In addition, we provide preclinical evidence suggesting Norrin and canonical Wnt signaling as potential therapeutic targets for GBM subtype-restricted cancer stem cells. [ABSTRACT FROM AUTHOR]

We performed genome‐wide methylation analysis on 136 pediatric low‐grade gliomas, identifying a unique cluster consisting of three tumors with oligodendroglioma‐like histology, BRAF p.V600E mutations and recurrent whole chromosome gains of 7 and loss of 10. Morphologically, all showed similar features, including a diffusely infiltrative glioma composed of round nuclei with perinuclear halos, a chicken‐wire pattern of branching capillaries and microcalcification. None showed astrocytic features or characteristics suggestive of high‐grade tumors including necrosis or mitotic figures. All tumors harbored multiple chromosomal copy number abnormalities (>10 chromosomes altered), but none showed 1p/19q co‐deletion or IDH1 p.R132H mutation. Hierarchical clustering and t‐stochastic neighbor embedding analyses from DNA methylation data cluster them more closely to previously described pediatric‐type low‐grade gliomas and separate from adult gliomas. These tumors exhibit distinct clinical features; they are temporal lobe lesions occurring in adolescents and young adults with a prolonged history of seizures and all are alive with no recurrence (follow‐up 3.2 to 13.2 years). We encountered another young adult case with quite similar pathological appearance and molecular status except for TERT promoter mutation. Although the series is small, these may represent a new category of IDH wild‐type low‐grade gliomas which may be confused with "molecular GBM." Further, they highlight the heterogeneity of IDH wild‐type gliomas and the relatively indolent behavior of "pediatric‐type" gliomas. [ABSTRACT FROM AUTHOR]

Diffuse brainstem gliomas, historically termed diffuse intrinsic pontine glioma (DIPG), account for approximately 75% of pediatric brainstem tumors and have a particularly poor prognosis with a median survival of only 10 months [[8], [10]]. To further assess the methylation profile of this tumor in relation to other CNS entities, we performed unsupervised clustering on the DKFZ cohort that comprises the 82 tumor methylation classes used in the Classifier (v11b4). The "EPN, PF A" tumor class contains tumors arising solely within the fourth ventricle and/or cerebellum. EZHIP (CXorf67) immunohistochemistry showed increased nuclear expression in tumor cells (d) and served to highlight individual tumor cells percolating surrounding normal-appearing brain (e-f). [Extracted from the article]

cIMPACT‐NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. From 2016 to 2019 (Round 1), cIMPACT published four updates. Update 1 clarified the use of the term NOS (Not Otherwise Specified) and proposed use of the additional term NEC (Not Elsewhere Classified). Update 2 issued clarifications regarding two diagnoses: Diffuse Midline Glioma, H3 K27M‐mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH‐mutant. Update 3 proposed molecular criteria that could be used in the setting of an IDH‐wildtype diffuse or anaplastic astrocytic glioma without histological features of glioblastoma to infer that the tumor would behave similarly to a grade IV glioblastoma. Update 4 suggested that, in children and young adults, subtypes of IDH‐wildtype/H3‐wildtype diffuse gliomas may have distinct clinical features in the setting of a BRAFV600E mutation, FGFR1 alteration, other MAPK pathway alteration, or a MYB or MYBL1 rearrangement. The practical diagnostic relevance of these cIMPACT proposals is highlighted in this summary. [ABSTRACT FROM AUTHOR]

Background: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ).Methods: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design.Results: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%.Conclusions: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma. [ABSTRACT FROM AUTHOR]