Relevant bibliographies by topics / Diffuse midline glioma (DMG)

Academic literature on the topic 'Diffuse midline glioma (DMG)'

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Published: 7 July 2024
Last updated: 7 July 2024

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Journal articles on the topic "Diffuse midline glioma (DMG)":

1

Barron, Tara, Belgin Yalçın, Aaron Mochizuki, Evan Cantor, Kiarash Shamardani, Dana Tlais, Andrea Franson, et al. "CNSC-01. GABAERGIC NEURON-TO-GLIOMA SYNAPSES IN DIFFUSE MIDLINE GLIOMAS." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i11. http://dx.doi.org/10.1093/neuonc/noad073.044.

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Abstract High-grade gliomas include clinically and molecularly distinct subtypes that stratify by anatomical location into diffuse midline gliomas (DMG) such as diffuse intrinsic pontine glioma (DIPG) and hemispheric high-grade gliomas. Neuronal activity drives high-grade glioma progression both through paracrine signaling and direct neuron-to-glioma synapses. Glutamatergic, AMPA receptor-dependent synapses between neurons and malignant glioma cells have been demonstrated in both pediatric and adult high-grade gliomas, but neuron-to-glioma synapses mediated by other neurotransmitters remain largely unexplored. Using whole-cell patch clamp electrophysiology, in vivo optogenetics and patient-derived glioma xenograft models, we have now identified functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABAA receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 expression and consequently elevated intracellular chloride concentration in DMG tumor cells. As membrane depolarization increases glioma proliferation, we find that the activity of GABAergic interneurons promotes DMG proliferation in vivo. Increasing GABA signaling with the benzodiazepine lorazepam – a positive allosteric modulator of GABAA receptors commonly administered to children with DMG for nausea or anxiety - increases GABAA receptor conductance and increases glioma proliferation in orthotopic xenograft models of DMG. Conversely, levetiracetam, an anti-epileptic drug that attenuates GABAergic neuron-to-glioma synaptic currents, reduces glioma proliferation in patient-derived DMG xenografts and extends survival of mice bearing DMG xenografts. Concordant with gene expression patterns of GABAA receptor subunit genes across subtypes of glioma, depolarizing GABAergic currents were not found in hemispheric high-grade gliomas. Accordingly, neither lorazepam nor levetiracetam influenced the growth rate of hemispheric high-grade glioma patient-derived xenograft models. Retrospective real-world clinical data are consistent with these conclusions and should be replicated in future prospective clinical studies. Taken together, these findings uncover GABAergic synaptic communication between GABAergic interneurons and DMG cells, underscoring a tumor subtype-specific mechanism of brain cancer neurophysiology with important potential implications for commonly used drugs in this disease context.
2

Al Sharie, Sarah, Dima Abu Laban, Jamil Nazzal, Shahad Iqneibi, Sura Ghnaimat, Abdallah Al-Ani, and Maysa Al-Hussaini. "Midline Gliomas: A Retrospective Study from a Cancer Center in the Middle East." Cancers 15, no. 18 (September 13, 2023): 4545. http://dx.doi.org/10.3390/cancers15184545.

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Midline gliomas are tumors that occur in midline structures and can be circumscribed or diffuse. Classical midline structures include the thalamus, brainstem, and spinal cord. Other midline structures include the corpus callosum, basal ganglia, ventricles, paraventricular structures, and cerebellum. Diffuse midline glioma (DMG) is a diffuse glioma that occurs in the classical midline structures, characterized by a specific genetic alteration, and associated with grim outcome. This study was conducted at King Hussein Cancer Center and reviewed the medical records of 104 patients with circumscribed and diffuse gliomas involving midline structures that underwent biopsy between 2005 and 2022. We included a final cohort of 104 patients characterized by a median age of 23 years and a male-to-female ratio of 1.59-to-1. Diffuse high-grade glioma (DHGG) was the most common pathological variant (41.4%), followed by DMG (28.9%). GFAP was positive in most cases (71.2%). Common positive mutations/alterations detected by surrogate immunostains included H3 K27me3 (28.9%), p53 (25.0%), and H3 K27M (20.2%). Age group, type of treatment, and immunohistochemistry were significantly associated with both the location of the tumor and tumor variant (all; p < 0.05). DMGs were predominantly found in the thalamus, whereas circumscribed gliomas were most commonly observed in the spinal cord. None of the diffuse gliomas outside the classical location, or circumscribed gliomas harbored the defining DMG mutations. The median overall survival (OS) for the entire cohort was 10.6 months. Only the tumor variant (i.e., circumscribed gliomas) and radiotherapy were independent prognosticators on multivariate analysis.
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Ibdah, Haleem, Shervin Pejhan, Lee Ang, Cynthia Hawkins, Barbara Fisher, Joseph Megyesi, and Maria MacDonald. "CEREBELLAR DIFFUSE MIDLINE GLIOMA, H3K27M ALTERED IN A FIFTY-FIVE-YEAR-OLD PATIENT." Neuro-Oncology Advances 5, Supplement_2 (July 1, 2023): i6. http://dx.doi.org/10.1093/noajnl/vdad071.026.

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Abstract H3 K27M mutations were first identified in Pediatric Diffuse Intrinsic Pontine Glioma and are now recognized in gliomas occurring in other midline locations such as the thalamus, spinal cord and cerebellum. These gliomas were renamed to Diffuse Midline Glioma (DMG) H3 K27-altered in the 2021 WHO classification due to the discovery of alternate mechanisms of H3 K27 loss. These gliomas are more commonly found in children but also occur in adolescents and young adults. We present the case of a 55- year-old woman who presented with a 2.5-month history of nausea, vomiting and gait impairment. Imaging revealed a partially cystic, enhancing lesion in the midline of the cerebellum. She had a gross total resection with pathology revealing Diffuse Midline Glioma, H3K27 altered, subgroup DMG, H3 wildtype with EZHIP over-expression, WHO grade 4. The patient completed chemoradiation with temozolomide with plans to enroll in a clinical trial upon progression. However due to loss of ambulation and function she was admitted to hospice. The patient survived 24 months after her surgery, a period longer than the reported median overall survival in DMG with EZIP overexpression which is 16 months. This case illustrates the importance of considering DMG H3K27- altered glioma in adults older than 40 years who present with infiltrative IDH wildtype glioma in midline locations. Recognition of this diagnosis may allow enrollment in clinical trials and should prompt molecular testing for concurrent targetable alterations in the RAS-MAPK-pathway (e.g., mutations in BRAF V600E, FGFR1, NF1 and NTRK) and PI3K-mTOR pathway (e.g., PIK3CA mutation).
4

Choi, Seonah, In-Ho Jung, Jaejoon Lim, Ju Hyung Moon, Eui Hyun Kim, Se Hoon Kim, Seok-Gu Kang, and Jong Hee Chang. "PATH-06. SURVIVAL ANALYSIS FOR ADULT MIDLINE GLIOMA: DO ADULT MIDLINE GLIOMAS WITH THE H3 K27M MUTATION REALLY HAVE POOR PROGNOSIS?" Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii150—vii151. http://dx.doi.org/10.1093/neuonc/noac209.579.

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Abstract PURPOSE Since it is known that midline located glioma with H3K27 mutation in children has a disastrous prognosis, in 2016 WHO classification, these tumors were defined as diffuse midline glioma (DMG) and classified as grade IV. A lot of papers about pediatric DMG have been published, but there are not many papers about adult DMG. In this study, we aimed to identify factors affecting the prognosis of adult midline glioma. This is the first paper to study the prognosis of adult DMG according to histological grade and is the largest study to investigate the survival of adult DMG. METHODS We reviewed the chart of adult patients diagnosed with midline glioma with H3K27M mutation after undergoing resection or biopsy among patients who visited our institution between January 2010 and December 2020. Survival analysis was performed according to tumor location, histological grading, Karnofsky Performance Scale (KPS), and age. RESULTS Among the 125 adult midline gliomas we identified, 45 (36.0%) had the H3K27M mutation. As a result of survival analysis performed on 125 adult midline gliomas, low histological grade, KPS ≥ 80, and age ≤ 60 showed significantly better survival. After adjusting for age, the difference in survival between H3K27M mutation and wildtype group was not significant. As a result of survival analysis performed on 45 DMG, low histological grade, KPS ≥ 80, total resection, and concurrent chemoradiation therapy group showed significantly better survival. CONCLUSION In adult midline glioma, disastrous prognosis due to H3K27M mutation was not observed as in children. The prognosis of adult midline gliomas is determined by histological grade, age, KPS, and extent of tumor resection. Therefore, the current WHO classification, which classifies all H3K27M mutant midline gliomas as grade IV regardless of histological diagnoses, is not suitable for adults.
5

Nakatogawa, Hirokazu, Hiroshi Kawaji, Nobuhide Hayashi, Junya Fukai, Noriyuki Kijima, Tomoko Shofuda, Ema Yoshioka, et al. "10184-BT-14 CLINICAL FEATURE OF HEMISPHERIC GLIOMA WITH H3F3A, PEDIATRIC-TYPE HIGH GRADE GLIOMA, H3 K27-ALTERED, NEC AND DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT, CNS WHO GRADE 4." Neuro-Oncology Advances 5, Supplement_5 (December 1, 2023): v18—v19. http://dx.doi.org/10.1093/noajnl/vdad141.074.

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Abstract INTRODUCTION Diffuse midline glioma (DMG), H3K27-altered, is a CNS WHO grade 4 glioma that usually located mainly in the brainstem, thalamus and spinal cord. However, DMG located in non-midline lesions are now described as pediatric-type high grade glioma, H3K27-altered, NEC (NDMG). On the other hand, diffuse hemispheric glioma, H3G34-mutant (DHG) located in the cerebral hemispheres, and is classified under the WHO 2021 classification. It is unknown that the differences in clinical characteristics of these hemispheric tumors with H3F3A mutations. In the present study, we report a comparative study of the clinical characteristics of two groups of NDMG and DHG. METHODS Among 4128 brain tumor samples collected in the Kansai Network for Molecular Diagnosis of Central Nervous System Tumors, 16 NDMG and 9 DHG cases were examined for comparison of clinical characteristics. RESULTS There were no differences in gender, tumor location, or pathology between NDMG and DHG. The median age was 47.3 years in NDMG and 26.2 years in DHG, and NDMG was significantly older than DHG (p=0.003). There was no significant difference in MGMT promoter methylation between NDMG and DHG (p=0.087). The Kaplan-Meier survival curve showed no significant difference, with a median survival of 495 days for NDMG and 587 days for DHG (p=0.765). There was no significant different survival rate between WHO grade 3 (n=15) and grade 4 (n=9) for pathological diagnosis. DISCUSSION AND CONCLUSION We compared the clinical characteristics of NDMG and DHG. There are some reports that NDMG and DHG gliomas located in non-midline lesion. Removing much tumor volume may improve the prognosis of non-midline glioma. We discuss the gliomas with H3F3A mutations located in a hemispheric lesions by literature review.
6

Morscio, Julie, Sandra Jacobs, and Frederik De Smet. "DIPG-55. DISSECTING THE ECOSYSTEM OF PEDIATRIC DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.108.

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Abstract BACKGROUND Pediatric gliomas are heterogeneous tumors encompassing high grade (pHGG) and low grade (pLGG) subtypes. For tumors not amenable to surgery, in particular high grade H3K27 mutant diffuse midline glioma (DMG), no curative options exist. DMG is characterized by 1) extensive heterogeneity of tumor cells that can exist in different interchangeable cellular states mimicking normal development and 2) extensive heterogeneity of the tumor microenvironment (TME). A better understanding of the DMG ecosystem is needed for therapeutic target identification. METHODS Publicly available single cell RNA seq data of DMG (n=17, Jessa et al. Nat. Genet. 2022), high grade pediatric glioblastoma (GBM, n=16, scPCA) and low grade tumors (ganglioglioma, n=5; pilocytic astrocytoma, n=14, scPCA) were analyzed to define key molecular characteristics and differences between these pediatric brain tumors. Doublet cells were removed from each dataset and tumor and TME cells were discriminated based on marker gene expression and inferred CNVs. RESULTS In DMG, glioma cellular states and TME heterogeneity differed depending on the tumor location. DMG arising in the pons harbored a bigger fraction of astrocyte-like glioma cells whereas oligodendrocyte-like cells were more abundant in thalamic tumors. In line with this observation, Liana cellular communication analysis inferred more intratumoral (autocrine) signaling involving oligodendrocyte-like glioma cells in thalamic tumors (e.g. NCAM1-PTPRZ1, NLGN4X-NRXN1, NTN1-DSCAM) than in pons tumors. Notably, the TME of thalamic tumors contained a bigger fraction of immunotolerant macrophages expressing CD163 or VSIG4. In contrast, pons tumors harbored a unique cluster of VEGFA expressing astrocytes, not found in GBM or pLGG. Liana analysis inferred COPA/APP-CD74 interaction between VEGFA+ astrocytes and CD163/VSIG4+ macrophages and microglia, potentially contributing to an immunotolerant TME in pons DMG. CONCLUSIONS In DMG, patterns of tumor and TME composition associated with tumor location were uncovered. Furthermore, unique TME celltypes could contribute to the particularly aggressive nature of these tumors.
7

Knowles, Truman, Shejuan An, Tina Huang, Jin Qi, and Amanda Saratsis. "DIPG-01. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i12. http://dx.doi.org/10.1093/neuonc/noad073.048.

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Abstract INTRODUCTION Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is an RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines. METHODS All studies were performed on DMG cell lines (n=6) and controls (normal human astrocytes n=1, human neural stem cells n=1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen). RESULTS Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC&gt;2 or &lt;-2, p&lt;0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71. CONCLUSIONS Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
8

Knowles, Truman, Shejuan An, Tina Huang, Jin Qi, and Amanda Saratsis. "CSIG-11. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v42. http://dx.doi.org/10.1093/neuonc/noad179.0167.

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Abstract INTRODUCTION Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is a RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines. METHODS All studies were performed on DMG cell lines (n = 6) and controls (normal human astrocytes n = 1, human neural stem cells n = 1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen). RESULTS Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC&gt;2 or &lt;-2, p&lt; 0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71. CONCLUSIONS Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
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Knowles, Truman, Shejuan An, Tina Huang, Jin Qi, and Amanda Saratsis. "DIPG-02. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.056.

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Abstract BACKGROUND Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is a RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines. METHODS All studies were performed on DMG cell lines (n=6) and controls (normal human astrocytes n=1, human neural stem cells n=1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen). RESULTS Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC&gt;2 or &lt;-2, p&lt;0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71. CONCLUSIONS Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
10

Larsen, Alexandra Giantini, Maricruz Rivera, David Pisapia, Sameer Farouk Sait, Matthias Karajannis, Jeffrey Greenfield, and Mark Souweidane. "DIPG-44. DIFFUSE MIDLINE GLIOMA WITH EXTRACRANIAL METASTASIS." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i23. http://dx.doi.org/10.1093/neuonc/noad073.091.

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Abstract Diffuse midline gliomas (DMGs) are malignant infiltrative gliomas enriched in the pediatric population and characterized by loss of the H3 K27me3 epigenetic marker, most frequently via mutation of the H3F3A gene. Few cases of extracranial DMG metastasis with redemonstrated H3F3A p.K28M (K27M) mutation in metastatic tissue are reported in the literature. Here, we report two such patients, both females (ages 12 and 15), with DMG and extracranial metastasis who died 5 years after initial diagnosis. The first patient with thalamic DMG underwent biopsy, radiation, chemotherapy, and subsequent decompression of spinal metastasis. Initial tumor biopsy demonstrated mutation in BRAF p.V600E, H3F3A K27M, and TERT promoter. The epidural spinal metastasis had mutations in BRAF p.V600E, H3F3A, TERT, and TP53. The second patient with brainstem DMG, diagnosed by radiographic appearance, underwent conventional external beam radiation therapy, chemotherapy including panobinostat and direct delivery of radioimmunotherapy, intra-arterial delivery of bevacizumab, and subsequent decompression of spinal metastasis. The histology and molecular profile for the spinal metastasis was consistent with DMG H3 K27M-mutant, with mutations in BRAF p.G464V, PTPN11 p.R498L, PDGFRA, and KIT. Bone marrow biopsy demonstrated atypical extrinsic cells with strong and diffuse immunolabeling for OLIG2. Autopsy revealed solid organ and osseous metastases. Both patients significantly exceeded the median life expectancy for DMG, raising the possibility that prolonged overall survival permitted progression to a rarely observed disseminated state of disease. There was absence of TP53/p53 modulating pathway mutation seen in classic DMG in the thalamic biopsy of the first patient, as well as the metastatic disease for the second patient, which may contribute to the prolonged survival observed. Molecular analysis of metastatic disease is important, as clinically and prognostically relevant alterations that vary from the primary site of disease may be detected, which shed light on clonal evolution patterns and further our understanding of disease biology.
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Journal articles

Dissertations / Theses on the topic "Diffuse midline glioma (DMG)":

1

Rakotomalala-Andrianasolo, Andria. "Développement et caractérisation de modèles cellulaires pour l'étude du rôle de l'oncohistone H3.3 K27M dans le phénotype agressif et la réponse aux thérapies des gliomes pédiatriques diffus de la ligne médiane." Electronic Thesis or Diss., Université de Lille (2022-....), 2024. http://www.theses.fr/2024ULILS015.

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Le traitement des DMG altérés H3 K27, n’ayant pas connu d’amélioration au cours de ces 50 dernières années, figure parmi les plus grands défis de la neuro-oncologie pédiatrique. En 2012, a été découverte une mutation spécifique de l’histone 3 (oncohistone), dite H3.3 K27M, présentant une prévalence très élevée (70-80% des cas) dans les DMG. Bien que l’impact épigénétique de cette mutation ait été décrit, des études demeurent nécessaires afin de mieux comprendre son rôle dans le phénotype agressif et la réponse aux thérapies des cellules DMG. Afin d’étudier précisément l’impact de la mutation H3.3 K27M sur le phénotype des cellules de DMG,nous avons développé et caractérisé des modèles cellulaires isogéniques complémentaires de gliome pédiatrique de haut grade induits et invalidés pour l’oncohistone. À l’aide de ces modèles, nous souhaitions élucider l’impact de H3.3 K27M sur la biologie des cellules de DMG et leur réponse aux traitements anti-cancéreux, notamment la radiothérapie, unique traitement de référence actuel pour la prise en charge des DMG. Par la caractérisation de nos lignées cellulaires de gliomes pédiatriques sustentoriels induites pourH3.3 K27M, nous avons montré que l’oncohistone impacte la réponse aux radiations ionisantes et à certaines thérapies ciblées de manière dépendante du contexte cellulaire.Sur la base de ce constat, nous avons pris le parti de caractériser les impacts biologiques de l’oncohistone dans un contexte cellulaire plus pertinent de DMG. En ce sens, nous avons établi des modèles cellulaires knock-out pour H3.3 K27M et les avons caractérisés comparativement à leurs lignées cellulaires parentales mutées. Par des caractérisations omiques (transcriptomique et protéomique) et du métabolisme cellulaire de ces modèles, nous avons notamment identifié un impact de la mutation H3.3 K27M sur le métabolisme lipidique des cellules DMG. De surcroit, dans des modèles de sphéroïdes 3D, cette modification du métabolisme lipidique associée à l’oncohistone semblait conditionnée par des facteurs du microenvironnement encore à l’étude.D’autre part, une approche fonctionnelle par criblage pharmacologique nous a permis d’identifier des dépendances à certaines voies de réparation des dommages à l’ADN spécifiquement associées à la mutationH3.3 K27M. De plus, la caractérisation radiobiologique de nos modèles, actuellement en cours, indique une radiosensibilité associée à H3.3 K27M, corrélant avec une diminution de l’efficacité de réparation de l’ADN postirradiation. Au-delà de cet impact sur la réparation des dommages à l’ADN, notre criblage pharmacologique a également révélé une sensibilité exacerbée à certains composés de la famille des glycosides cardiaques induite par H3.3 K27M. Ce résultat apparaît particulièrement intéressant au regard de nos données transcriptomiques montrant un enrichissement en gènes impliqués dans les cardiomyopathies et l’homéostasie ionique parmi les gènes différentiellement exprimés en présence de l’oncohistone. Dans ce contexte, nous avons entrepris l’étude des processus moléculaires et biologiques sous-jacents à cette différence de sensibilité gouvernée parH3.3 K27M.In fine, nous avons utilisé nos modèles cellulaires isogéniques pour montrer que l’oncohistoneH3.3 K27M entraîne des modifications du métabolisme lipidique des cellules de DMG. Ces changements métaboliques pourraient rendre les cellules de DMG altérés H3 K27 plus susceptibles au déclenchement de certaines voies de morts cellulaires (e.g. ferroptose) et affecter la réponse à certaines thérapies. De plus, H3.3K27M semble induire des sensibilités spécifiques, notamment à la radiothérapie et aux glycosides cardiaques [...]
H3K27-altered DMG treatment is one of the most significant challenges in pediatric neuro-oncology,with no improvement in patient survival over the past 50 years. In 2012, it was shown that DMGs harbor a specific histone 3 mutation (oncohistone) called H3.3 K27M with a very high prevalence (70-80% of cases). Although theH3.3 K27M impact on the epigenetic landscape has been well described, studies are needed to understand betterits role in DMG cells’ aggressiveness and response to therapies.To study the H3.3 K27M mutation impact on DMG cell phenotypes precisely, we developed andcharacterized pediatric high-grade glioma isogenic cellular models induced and knock-out for the oncohistone.Using these models, we aimed to decipher the oncohistone impact on DMG cell biology and response to anticancertherapies, including radiation therapy, the only current standard of care for DMGs. Characterization of our H3.3 K27M-induced pediatric supratentorial glioma cell lines reveals that the oncohistone affects the response to ionizing radiations and specific targeted therapies in a cellular context-dependentway. Based on these results, we settled to characterize oncohistone biological impacts in a more relevant cellular context of DMG. In that sense, we established H3.3 K27M knock-out cellular models and characterized them regarding their parental DMG H3.3 K27M mutated cell lines. Through omic (transcriptomic and proteomic)and cell metabolism characterizations of these models, we notably showed the H3.3 K27M mutation impact on DMG cells’ lipid metabolism. In 3D spheroid models, this H3.3 K27M-induced lipid metabolism rewiring appeared conditioned by microenvironment factors still under investigation.On the other hand, a functional pharmacological screen identified H3.3 K27M-driven dependencies tospecific DNA repair pathways. In addition, ongoing radiobiological characterization of our models indicates anH3.3 K27M-associated radiosensitivity correlating with a decrease in DNA repair efficiency following ionizingradiations. Beyond this DNA repair impact, our pharmacological screen also revealed an H3.3 K27M-relatedsensitivity to cardiac glycoside drugs. This result makes sense with our transcriptomic data showing enrichmentin genes involved in cardiomyopathies and ion homeostasis among differentially expressed genes with theoncohistone. In this context, we began unraveling the molecular and biological processes underlying thisH3.3 K27M-driven effect.Finally, we used our isogenic cellular models to show that the H3.3 K27M oncohistone drives lipidmetabolism modifications. These metabolic changes could prime H3K27-altered DMG cells to specific regulatedcell death pathways (e.g., ferroptosis) and affect the response to certain therapies. Moreover, the H3.3 K27Mseems to drive specific sensitivities, notably to radiation therapy and cardiac glycoside drugs. Understanding the underlying molecular mechanisms governing these H3.3 K27M-associated Achille heels could highlight newinsights into the oncohistone role in DMG cells and provide rationales for developing new therapeutic strategies
2

Trisolini, Elena. "Targeted molecular characterization of adult midline and circumscribed gliomas for the identification of new potential targets for personalized therapy." Doctoral thesis, Università del Piemonte Orientale, 2020. http://hdl.handle.net/11579/114872.

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Abstract:
Diffuse midline gliomas (MLG) are primary brain tumours arising from thalamus, hypothalamus, brainstem, cerebellum or spinal cord, mainly occurring in children. In adults, less than 10% of diffuse gliomas arises in midline structures and recent works suggested that this subset of tumours may present with phenotypic and molecular characteristics differing from both pediatric MLG and adult supratentorial gliomas. Circumscribed gliomas (CG) are low-grade tumours but may progress to anaplasia. They have lower genetic complexity than diffuse gliomas and could be better candidate for targeted therapies, when complete surgical resection is not feasible. Unravelling the genomic landscape of MLG and CG will better define the prognostic value of molecular biomarkers and identify new therapeutic strategies that could improve patient care. Adult patients with diagnosis of MLG and CG were retrospectively identified from «Maggiore della Carità» Hospital and GH Pitié-Salpêtrière (Paris). Mutation analysis was performed by Sanger sequencing of the major hot-spots: IDH1, IDH2, H3F3A, HIST1H3B, FGFR1, TERT promoter. FISH analyses of NTRK1-2-3 rearrangements were performed by break-apart probes on tissue microarray of MLG cases. We identified 116 (French) and 47 (Italian) patients. The two cohorts showed a lower percentage of H3F3A mutations (20% vs 33%), the mutation was not associated to a worse prognosis. FGFR1 mutations were identified in 18% of cases and are restricted to MLG. NTRKs analysis in the Italian cohort showed NTRK1 translocations in 15% of cases. We reported a high rate of FGFR1 mutations in optic nerve pilocytic astrocitomas and the presence of alternative BRAF activating mutations (Thr599_Val600insThr and Val600_Lys601>Glu). Our finding of frequent and potentially targetable FGFR1 and BRAF mutations and NTRK1 translocations have important therapeutical implications in the current context of clinical trials, and further reinforces the need for molecular analyses.

Books on the topic "Diffuse midline glioma (DMG)":

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Kleihues, Paul, Elisabeth Rushing, and Hiroko Ohgaki. The 2016 revision of the WHO classification of tumours of the central nervous system. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199651870.003.0001.

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The revised fourth edition of the WHO classification of Tumours of the Central Nervous System, published in 2016, comprises several newly recognized tumour entities, and a significant restructuring of the classification, mainly based on genetic profiling. Glioblastomas are now classified into two major types. Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (primary glioblastoma IDH-wildtype) develops rapidly de novo without a recognizable precursor lesion. IDH-mutant glioblastoma (secondary glioblastoma IDH-mutant) develops more slowly through malignant progression from diffuse or anaplastic astrocytoma. Medulloblastomas are now defined by combining histological patterns (classic, desmoplastic/nodular, extensive nodularity, anaplastic) and genetic hallmarks (WNT-activated; SHH-activated, TP53-mutant; SHH-activated, TP53-wildtype; non-WNT/non-SHH). Other newly recognized tumour entities include diffuse midline glioma, H3 K27M-mutant; ependymoma, RELA fusion-positive; and embryonal tumour with multilayered rosettes. The new classification is a significant step forward and will facilitate the development of novel targeted therapies of brain tumours.

Book chapters on the topic "Diffuse midline glioma (DMG)":

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Noureldine, Mohammad Hassan A., Nir Shimony, and George I. Jallo. "Diffuse Midline Glioma – Diffuse Intrinsic Pontine Glioma." In Brainstem Tumors, 159–93. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-030-38774-7_8.

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Liu, Dongyou. "Chordoid Glioma, Angiocentric Glioma, and Diffuse Midline Glioma." In Tumors and Cancers, 31–36. Boca Raton : Taylor & Francis, 2018. | Series: Pocket guides to biomedical sciences | “A CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Group, the academic division of T&F Informa plc.”: CRC Press, 2017. http://dx.doi.org/10.1201/9781315120522-6.

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Sait, Sameer Farouk, Morgan Freret, and Matthias Karajannis. "Pediatric High-Grade Glioma." In Neuro-Oncology Compendium for the Boards and Clinical Practice, edited by Maciej M. Mrugala, Na Tosha N. Gatson, Sylvia C. Kurz, Kathryn S. Nevel, and Jennifer L. Clarke, 267—C18.P333. Oxford University PressNew York, 2023. http://dx.doi.org/10.1093/med/9780197573778.003.0018.

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Abstract Pediatric high-grade gliomas (pHGGs) represent 8–12% of all pediatric central nervous system tumors and comprise a spectrum of histologies that includes anaplastic astrocytoma (WHO grade 3), glioblastoma (WHO grade 4), and diffuse midline glioma, H3K27M mutant (WHO grade 4). Diffuse intrinsic pontine gliomas (DIPG) are pHGG of the brainstem that are generally diagnosed based on clinical and imaging findings alone, but, if biopsied, pathology most commonly reveals diffuse midline glioma, H3K27M mutant. Evidence from genetic and epigenetic molecular profiling studies has revealed significant molecular diversity among pHGGs. These studies led to a major reclassification of pHGGs into molecular-based tumor subgroups, as compared to earlier primarily histology-based tumor subgroups. Findings show that these molecular subgroups of pHGG correlate with clinically meaningful factors, including tumor location and prognosis. The most important molecular groups are the histone mutations related pHGG (H3.K27-mutated midline and H3.G34-mutated hemispheric pHGG); the rare isocitrate dehydrogenase (IDH1/2)-mutated pHGG occurring mainly in young adults; the BRAFV600E mutant cortical tumors arising from transformation of lower grade tumors, the heterogenous H3/IDH/BRAF wildtype pHGGs and infant HGGs. Another important group occurs in patients with constitutional mismatch repair deficiency, a cancer predisposition syndrome wherein patients develop hypermutant glioblastoma. Standard treatment for pHGG includes maximally safe surgical resection followed by radiation and chemotherapy. This chapter provides a comprehensive review of the clinical, genetic, and therapeutic aspects relevant to oncologists caring for children, adolescents, and young adults with pHGGs.
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Carabenciov, Ivan D., and Michael W. Ruff. "Progressive Bilateral Arm Pain, Gait Disturbance, Constipation, and Urinary Retention." In Mayo Clinic Cases in Neuroimmunology, edited by Andrew McKeon, B. Mark Keegan, and W. Oliver Tobin, 231–32. Oxford University Press, 2021. http://dx.doi.org/10.1093/med/9780197583425.003.0075.

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A 48-year-old woman sought care for progressive right arm and hand pain with radial nerve–distribution sensory loss. She had a past history of multiple prior athletics-associated, musculoskeletal, upper cervical spine injuries. Her symptoms were initially attributed to a right C6 radiculopathy. Over the next several months, the sensory loss spread to involve the entire right hand and subsequently the entire left hand. She had development of diffuse right hand weakness and a sense of imbalance that was particularly prominent while in the dark. Finally, she experienced progressive constipation and urinary retention. Magnetic resonance imaging of the cervical spine showed an expanded cervical spinal cord from C3 through C7-T1 with diffuse T2-hyperintense changes and heterogeneous gadolinium enhancement most prominent at C5-6. In combination with a congenitally small central canal, severe central canal narrowing was seen at C5-6 and moderate narrowing at C4-5. Magnetic resonance imaging of the brain and thoracic spine were normal, and magnetic resonance imaging of the lumbar spine indicated only mild lumbar spondylosis. On suspicion of a spinal cord neoplasm with a secondary compressive myelopathy, C3 through C7 laminectomy and posterior instrumented fusion from C2 through T1 was performed, with a biopsy obtained at the C5-6 level. Postoperatively, her gait and right upper extremity pain improved. The biopsy showed atypical glial cells. Neurofilament staining demonstrated an infiltrative pattern. Atypical cells were positive for glial fibrillary acidic protein, oligodendrocyte transcription factor 2, and a Lys27Met sequence variation of histone H3, with overexpression of p53 on immunohistochemical staining. There was loss of H3 K27-trimethylation on the infiltrating cells, corresponding to the presence of Lys27Met sequence variation of histone H3. These findings were diagnostic for diffuse midline glioma with Lys27Met sequence variation of histone H3 (World Health Organization grade IV). A total of 5,400 cGy of photon radiation was delivered in 30 fractions over 42 days. She was subsequently treated with an oral histone deacetylase inhibitor, panobinostat, for 12 months. During this time, she had clinical response to treatment and reported improvement in balance and numbness. Follow-up magnetic resonance imaging at 3 months showed a slight decrease in the size of the mass, and this response was sustained 1 year post radiotherapy. Diffuse midline gliomas that contain Lys27Met sequence variation of histone H3are incurable, often inoperable, midline brain tumors that are most commonly seen in the pediatric population. These tumors can also occur in adult patients and are considered high grade, even in the absence of features such as necrosis or microvascular proliferation.

Conference papers on the topic "Diffuse midline glioma (DMG)":

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Borsuk, Robyn, Lanlan Zhou, Rishi Lulla, and Wafik El-Deiry. "Abstract 5407: Novel imipridone combination therapies targeting oncohistone H3K27M mutant diffuse midline glioma (DMG)." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-5407.

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Minns, Hanna, Oscar Padilla, Hong-Jian Wei, Robyn D. Gartrell, Andrea Webster-Carrion, Masih Tazhibi, Nicholas McQuillan, et al. "53 Inducing immune response with FLASH and conventional radiation in diffuse midline glioma (DMG)." In SITC 38th Annual Meeting (SITC 2023) Abstracts. BMJ Publishing Group Ltd, 2023. http://dx.doi.org/10.1136/jitc-2023-sitc2023.0053.

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Borsuk, Robyn, Lanlan Zhou, Yiqun Zhang, Varun V. Prabhu, Joshua E. Allen, Nikos Tapinos, Rishi Lulla, and Wafik S. El-Deiry. "Abstract 635: Response to novel imipridone combination therapies targeting H3K27M mutant diffuse midline glioma (DMG)." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-635.

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Cheney, Allison R., Lauren M. Sanders, Lucas Seninge, Holly C. Beale, Ellen Towle Kephart, Jacob Pfeil, Katrina Learned, et al. "Abstract B06: Candidate differentiation stall in epithelial mesenchymal transition in H3K27M diffuse midline glioma." In Abstracts: AACR Special Conference on the Advances in Pediatric Cancer Research; September 17-20, 2019; Montreal, QC, Canada. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.pedca19-b06.

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Weidert, Frances, Christina Von Roemeling, James McGuiness, Jonathan Chardon-Robles, Nagheme Thomas, Anna Devries, Sadeem Qdaisat, et al. "1398 Immune responses and long-term survival with mRNA vaccine targeting diffuse midline glioma." In SITC 38th Annual Meeting (SITC 2023) Abstracts. BMJ Publishing Group Ltd, 2023. http://dx.doi.org/10.1136/jitc-2023-sitc2023.1398.

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Mathes, Stephanie, Nicolas Gerber, Marion Rizo, Michael Grotzer, Ana Guerreiro-Stücklin, Javad Nazarian, and Sabine Müller. "Clinical Research for Pediatric Patients Suffering from a Diffuse Midline Glioma: Limits, Challenges and Perspectives." In RExPO23. REPO4EU, 2023. http://dx.doi.org/10.58647/rexpo.23012.

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Wernicke, Caroline M., Birgit Geoerger, Olaf Witt, Christof Kramm, Stefan Burdach, and Irene Teichert von Luettichau. "Unusual Course of a Diffuse Midline Glioma Exhibits Upcoming Therapeutic Options through Novel Molecular Genetic Analyses." In Abstracts of the 45th Annual Meeting of the Society for Neuropediatrics. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1698205.

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Martinez, Payton, Jane J. Song, Kang-Ho Song, Mark Borden, Genna Nault, Jenna Steiner, Natalie Serkova, et al. "Enhancing Delivery and Efficacy of Panobinostat for Diffuse Midline Glioma through Focused Ultrasound-Mediated Blood-Brain Barrier Opening." In 2023 IEEE International Ultrasonics Symposium (IUS). IEEE, 2023. http://dx.doi.org/10.1109/ius51837.2023.10306559.

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Mount, Christopher W., Robbie Majzner, Shree Sundaresh, Evan P. Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, et al. "Abstract 958: Anti-GD2 chimeric antigen receptor T cells as a potent immunotherapy regimen in xenograft models of histone 3 K27M mutant diffuse midline glioma." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-958.

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