Disseminated diffuse midline gliomas, H3K27-altered mimicking diffuse leptomeningeal glioneuronal tumors: a diagnostical challenge!
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SUBMITTER: Tauziede-Espariat A
PROVIDER: S-EPMC9392342 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Project description:Diffuse leptomeningeal glioneuronal tumor is a newly defined entity under the neuronal and mixed neuronal-glial tumors category in the 2016 World Health Organization classification of brain tumors. In this series, we report clinical, radiologic, and histologic findings in 7 cases of diffuse leptomeningeal glioneuronal tumor. Our cases and literature review indicate that the most characteristic imaging finding is diffuse intracranial and intraspinal nodular leptomeningeal thickening and enhancement. This is often associated with small cyst-like, nonenhancing lesions. It should be noted that tumors sometimes bear nontypical features, for example, presenting as a solitary spinal cord mass without leptomeningeal involvement or with a dominant intracranial mass. In children with characteristic imaging findings and without clinical features of infection, the radiologist has an opportunity to promptly raise the possibility of diffuse leptomeningeal glioneuronal tumor, and thereby, affect streamlined diagnostic evaluation.
| S-EPMC7658820 | biostudies-literature
Project description:Diffuse midline glioma with two components: classical glial and ependymal.
| S-EPMC10711257 | biostudies-literature
Project description:BackgroundH3K27-altered diffuse midline glioma (DMG) is the deadliest pediatric brain tumor; despite intensive research efforts, every clinical trial to date has failed. Is this because we are choosing the wrong drugs? Or are drug delivery and other pharmacokinetic variables at play? We hypothesize that the answer is likely a combination, where optimization may result in a much needed novel therapeutic approach.MethodsWe used in vitro drug screening, patient samples, and shRNA knockdown models to identify an upregulated target in DMG. A single small molecule protein kinase inhibitor with translational potential was selected for systemic and direct, loco-regional delivery to patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM). Pharmacokinetic studies were conducted in non-tumor bearing rats.ResultsAurora kinase (AK) inhibitors demonstrated strong antitumor effects in DMG drug screens. Additional in vitro studies corroborated the importance of AK to DMG survival. Systemic delivery of alisertib showed promise in subcutaneous PDX but not intracranial GEMM and PDX models. Repeated loco-regional drug administration into the tumor through convection-enhanced delivery (CED) was equally inefficacious, and pharmacokinetic studies revealed rapid clearance of alisertib from the brain. In an effort to increase the drug to tumor residence time, continuous CED over 7 days improved drug retention in the rodent brainstem and significantly extended survival in both orthotopic PDXs and GEMMs.ConclusionsThese studies provide evidence for increasing drug-tumor residence time of promising targeted therapies via extended CED as a valuable treatment strategy for DMG.
| S-EPMC10148679 | biostudies-literature
Project description:BackgroundDiffuse midline glioma with H3K27-altered (DMG-H3K27a) is a novel tumor entity of the pediatric-type diffuse high-grade tumor in the latest WHO CNS 5. It mostly affects children and is only rarely found in adults. The tumor has a high level of aggressiveness, with a rapid progression and bad prognosis. In adults, the spinal cord is the most common site of DMG-H3K27a. Rare adult cases of primary DMG-H3K27a in the spinal cord were reported in this study, together with clinico-histopathologico-radiographic data.MethodsFrom January 2016 to December 2020, we conducted a retrospective study of five adults with primary DMG-H3K27a in the spinal cord, analyzing their clinical, pathohistological, and radiographic datasets from the first diagnosis to follow-up.ResultsAll five patients were diagnosed for the first time and were given full treatment. In three of the five patients, post-operative follow-up revealed tumor recurrence. The longest survival of the five patients was 45 months at the time of report submission, while the longest progression-free survival (PFS) following surgery was 20 months. Immunohistochemical studies showed the tumors featured aggressive behavior (grade 4) and were positive for the H3K27M mutation. The radiographic appearances were varied, but they were all initially mistaken as benign. DMG-H3K27a in the spinal cord was characterized by isointense/hyperintense on T1WI and isointense/hyperintense on T2WI, as well as cystic necrosis and peripheral spinal cord edema, as well as central canal enlargement and other types of enhancement.ConclusionThis is the first case report focusing on adult DMG-H3K27a of the pediatric-type diffuses high-grade gliomas in the spinal cord. In our cases, we discovered the following: 1) adults had a better prognosis with a longer PFS compared with prior pediatric reports; 2) despite aggressive behavior under the microscope, radiographic appearances of the tumors were less aggressive; and 3) adjuvant treatment, including TCM, may have played a role in the prognosis.
| S-EPMC8694136 | biostudies-literature
Project description:IntroductionDespite much progress, the prognosis for H3K27-altered diffuse midline glioma (DMG), previously known as diffuse intrinsic pontine glioma when located in the brainstem, remains dark and dismal.Areas coveredA wealth of research over the past decade has revolutionized our understanding of the molecular basis of DMG, revealing potential targetable vulnerabilities for treatment of this lethal childhood cancer. However, obstacles to successful clinical implementation of novel therapies remain, including effective delivery across the blood-brain barrier (BBB) to the tumor site. Here, we review relevant literature and clinical trials and discuss direct drug delivery via convection-enhanced delivery (CED) as a promising treatment modality for DMG. We outline a comprehensive molecular, pharmacological, and procedural approach that may offer hope for afflicted patients and their families.Expert opinionChallenges remain in successful drug delivery to DMG. While CED and other techniques offer a chance to bypass the BBB, the variables influencing successful intratumoral targeting are numerous and complex. We discuss these variables and potential solutions that could lead to the successful clinical implementation of preclinically promising therapeutic agents.
| S-EPMC10165636 | biostudies-literature
Project description:IntroductionDiffuse leptomeningeal glioneuronal tumor (DLGNT), a new addition to the 2016 World Health Organization (WHO) classification, is a rare childhood neoplasm presenting with disseminated leptomeningeal enhancement and an occasional intraparenchymal mass. Diagnosis is often impeded by infectious/immunological differentials, necessitating a biopsy to confirm the diagnosis. We report an adult male with DLGNT without hydrocephalus, which is rare in patients with cerebellar masses.Case presentationA 56-year-old man presented with headaches, vertigo, diplopia, impaired hearing, and gait imbalance over 6 months. Magnetic resonance imaging showed a cystic right cerebellar mass with its leptomeningeal dissemination but without hydrocephalus. Cerebrospinal fluid analysis revealed elevated proteins with CD56-positive tumor cells. Cerebellar lesion biopsy verified the diagnosis of DLGNT (WHO Grade 3) with KIAA1549::BRAF fusion and 1p deletion. Radiotherapy was prematurely aborted due to clinical deterioration. The patient was subsequently discharged to palliative home care and lost to follow-up.ConclusionWe conducted the first review of all 34 adult DLGNT cases, including ours (one of the oldest), hitherto published in the literature. The majority presented with signs and symptoms of increased intracranial pressure. 52.0% of adult DLGNT patients were alive at follow-up. DLGNT should be considered in the differential diagnoses of diffuse leptomeningeal enhancement in imaging. Further studies comparing pediatric and adult subgroups of DLGNT are needed to evaluate histopathological prognosticators and standardize therapy for both subpopulations.
| S-EPMC10890803 | biostudies-literature
Project description:We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMG-H3K27M cell fitness. Gene expression studies after VRK3 knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG following VRK3 knockdown. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations, e.g. with the mitochondrial ClpP protease activator ONC201.
| S-EPMC10599138 | biostudies-literature
Project description:Diffuse midline glioma (DMG) is a heterogeneous group of aggressive pediatric brain tumors with a fatal prognosis. The biological hallmark in the major part of the cases is H3K27 alteration. Prognosis remains poor, with median survival ranging from 9 to 12 months from diagnosis. Clinical and radiological prognostic factors only partially change the progression-free survival but they do not improve the overall survival. Despite efforts, there is currently no curative therapy for DMG. Radiotherapy remains the standard treatment with only transitory benefits. No chemotherapeutic regimens were found to significantly improve the prognosis. In the new era of a deeper integration between histological and molecular findings, potential new approaches are currently under investigation. The entire international scientific community is trying to target DMG on different aspects. The therapeutic strategies involve targeting epigenetic alterations, such as methylation and acetylation status, as well as identifying new molecular pathways that regulate oncogenic proliferation; immunotherapy approaches too are an interesting point of research in the oncology field, and the possibility of driving the immune system against tumor cells has currently been evaluated in several clinical trials, with promising preliminary results. Moreover, thanks to nanotechnology amelioration, the development of innovative delivery approaches to overcross a hostile tumor microenvironment and an almost intact blood-brain barrier could potentially change tumor responses to different treatments. In this review, we provide a comprehensive overview of available and potential new treatments that are worldwide under investigation, with the intent that patient- and tumor-specific treatment could change the biological inauspicious history of this disease.
| S-EPMC9497626 | biostudies-literature
Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.
2023-05-25 | PXD036245 | Pride
Project description:Diffuse leptomeningeal glioneuronal tumours (DLGNT) represent rare enigmatic CNS tumours of childhood. Most patients with this disease share common radiological and histopathological features but the clinical course of this disease is variable. A radiological hallmark of this disease is widespread leptomeningeal enhancement that may involve the entire neuroaxis with predilection for the posterior fossa and spine. The classic pathologic features include low- to moderate-density cellular lesions with OLIG2 expression and evidence of 'oligodendroglioma-like' appearance. The MAPK/ERK signaling pathway has recently been reported as a potential driver of tumourigenesis in up to 80% of DLGNT with KIAA1549:BRAF fusions being the most common event seen. Until now, limited analysis of the biological drivers of tumourigenesis has been undertaken via targeted profiling, chromosomal analysis and immunohistochemistry. Our study represents the first examples of comprehensive genomic sequencing in DLGNT and shows that it is not only feasible but crucial to our understanding of this rare disease. Moreover, we demonstrate that DLGNT may be more genomically complex than single-event MAPK/ERK signaling pathway tumours.
| S-EPMC8422739 | biostudies-literature