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1
Park, Jong-Whi. "Metabolic Rewiring in Adult-Type Diffuse Gliomas." International Journal of Molecular Sciences 24, no. 8 (April 16, 2023): 7348. http://dx.doi.org/10.3390/ijms24087348.
Повний текст джерелаАнотація:
Multiple metabolic pathways are utilized to maintain cellular homeostasis. Given the evidence that altered cell metabolism significantly contributes to glioma biology, the current research efforts aim to improve our understanding of metabolic rewiring between glioma’s complex genotype and tissue context. In addition, extensive molecular profiling has revealed activated oncogenes and inactivated tumor suppressors that directly or indirectly impact the cellular metabolism that is associated with the pathogenesis of gliomas. The mutation status of isocitrate dehydrogenases (IDHs) is one of the most important prognostic factors in adult-type diffuse gliomas. This review presents an overview of the metabolic alterations in IDH-mutant gliomas and IDH-wildtype glioblastoma (GBM). A particular focus is placed on targeting metabolic vulnerabilities to identify new therapeutic strategies for glioma.
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Wong, Shu Chyi, Muhamad Noor Alfarizal Kamarudin, and Rakesh Naidu. "Anticancer Mechanism of Flavonoids on High-Grade Adult-Type Diffuse Gliomas." Nutrients 15, no. 4 (February 4, 2023): 797. http://dx.doi.org/10.3390/nu15040797.
Повний текст джерелаАнотація:
High-grade adult-type diffuse gliomas are the most common and deadliest malignant adult tumors of the central nervous system. Despite the advancements in the multimodality treatment of high-grade adult-type diffuse gliomas, the five-year survival rates still remain poor. The biggest challenge in treating high-grade adult-type diffuse gliomas is the intra-tumor heterogeneity feature of the glioma tumors. Introducing dietary flavonoids to the current high-grade adult-type diffuse glioma treatment strategies is crucial to overcome this challenge, as flavonoids can target several molecular targets. This review discusses the anticancer mechanism of flavonoids (quercetin, rutin, chrysin, apigenin, naringenin, silibinin, EGCG, genistein, biochanin A and C3G) through targeting molecules associated with high-grade adult-type diffuse glioma cell proliferation, apoptosis, oxidative stress, cell cycle arrest, migration, invasion, autophagy and DNA repair. In addition, the common molecules targeted by the flavonoids such as Bax, Bcl-2, MMP-2, MMP-9, caspase-8, caspase-3, p53, p38, Erk, JNK, p38, beclin-1 and LC3B were also discussed. Moreover, the clinical relevance of flavonoid molecular targets in high-grade adult-type diffuse gliomas is discussed with comparison to small molecules inhibitors: ralimetinib, AMG232, marimastat, hydroxychloroquine and chloroquine. Despite the positive pre-clinical results, further investigations in clinical studies are warranted to substantiate the efficacy and safety of the use of flavonoids on high-grade adult-type diffuse glioma patients.
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Rao, Aparna, Xiaoran Zhang, Christopher Deibert, Paola Sette, Paola Grandi, and Nduka Amankulor. "IDH Mutant Gliomas Escape Natural Killer Cell Immune Surveillance by Downregulation of NKG2D Ligand Expression." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 142.11. http://dx.doi.org/10.4049/jimmunol.196.supp.142.11.
Повний текст джерелаАнотація:
Abstract Background Diffuse gliomas are fatal primary brain tumors that are poorly immunogenic. The basis for insufficient anti-tumor immunity in diffuse gliomas is not understood. Mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. Methods We analyzed the TCGA database for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligands expression levels and NK cell-mediated lysis were measured in patient-derived glioma stem cells and in genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent Decitabine as a potential NK cell sensitizing agent in IDH mutant cells. Results All IDH mutant glioma stem-like cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes were resistant to NK cell-mediated lysis. The hypomethylating agent Decitabine increased NKG2D ligand expression, and restored NK- mediated lysis of IDH mutant cells in an NKG2D-dependent manner. Conclusions IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULPB3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell-mediated immune surveillance in patients with IDH mutated diffuse gliomas.
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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.
Повний текст джерелаАнотація:
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.
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Nguyen, Anthony V., Jose M. Soto, Sarah-Marie Gonzalez, Jennifer Murillo, Eric R. Trumble, Frank Y. Shan, and Jason H. Huang. "H3G34-Mutant Gliomas—A Review of Molecular Pathogenesis and Therapeutic Options." Biomedicines 11, no. 7 (July 15, 2023): 2002. http://dx.doi.org/10.3390/biomedicines11072002.
Повний текст джерелаАнотація:
The 2021 World Health Organization Classification of Tumors of the Central Nervous System reflected advances in understanding of the roles of oncohistones in gliomagenesis with the introduction of the H3.3-G34R/V mutant glioma to the already recognized H3-K27M altered glioma, which represent the diagnoses of pediatric-type diffuse hemispheric glioma and diffuse midline glioma, respectively. Despite advances in research regarding these disease entities, the prognosis remains poor. While many studies and clinical trials focus on H3-K27M-altered-glioma patients, those with H3.3-G34R/V mutant gliomas represent a particularly understudied population. Thus, we sought to review the current knowledge regarding the molecular mechanisms underpinning the gliomagenesis of H3.3-G34R/V mutant gliomas and the diagnosis, treatment, long-term outcomes, and possible future therapeutics.
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Nuechterlein, Nicholas, and Patrick Cimino. "PATH-24. COPY NUMBER ALTERATIONS IN NOTCH PATHWAY GENES ARE PROGNOSTIC IN A SUBSET OF DIFFUSE ASTROCYTIC GLIOMAS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi120. http://dx.doi.org/10.1093/neuonc/noab196.476.
Повний текст джерелаАнотація:
Abstract Inactivating mutations in NOTCH1 occur in many cancer types and are frequently observed in IDH-mutant, 1p/19q-codeleted oligodendroglioma. Although the role of NOTCH1 as a tumor suppressor in diffuse glioma has become appreciated in human tissue and small animal models, the spectrum of inactivating mutations in Notch pathway genes in diffuse astrocytic gliomas has not been well described. To address this, we queried the TCGA lower-grade glioma and glioblastoma datasets to establish the extent of inactivation of Notch pathway genes, specifically by cataloging single nucleotide variants and those with copy number loss or deletion. Key alteration frequencies were found to be similar in two-independent glioma cohorts (Col, MSK). Notch pathway genes with inactivating alterations (overwhelmingly copy number loss) were present in 77% of TCGA diffuse gliomas. Across all diffuse gliomas, DLL3 loss was the most common alteration (TCGA 31%). For IDH-mutant diffuse astrocytic gliomas, JAG2 loss was the most common alteration (TCGA 23.0%, Col 35%, MSK 27%). DLL1 loss and MAML1 loss were mutually exclusive (p< 0.001) in TCGA IDH-mutant astrocytomas with a combined frequency of 39% (Col 47%, MSK 56%). The presence of any alteration in the top 10 altered Notch pathway genes indicated a shorter progression-free survival (p = 0.028) for TCGA IDH-mutant diffuse astrocytomas. For IDH-wildtype diffuse astrocytic gliomas, EP300 loss was the most common inactivating alteration (TCGA 35.4%, Col 49%, MSK 38%). EP300 loss, DLL1 loss, DLL4 loss were mutually exclusive (p = 0.006) in TCGA IDH-wildtype diffuse astrocytic gliomas with a combined frequency of 61% (Col 72%, MSK 66%). The presence of alterations in any of these three genes indicated a decreased overall survival (p = 0.045) in TCGA IDH-wildtype diffuse astrocytic gliomas. Overall, loss of differential Notch pathway genes has prognostic implications in both IDH-wildtype and IDH-mutant diffuse astrocytic gliomas.
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Campos Paiva, Aline, João Luiz Vitorino Araujo, Guilherme Brasileiro de Aguiar, Gabriel Rezende Batistella, Marcos Maldaum, and José Esteves veiga. "SURG-11. NEOADJUVANT CHEMOTHERAPY FOR DIFFUSE GLIOMAS: A FEASIBLE OPTION?" Neuro-Oncology 22, Supplement_2 (November 2020): ii205. http://dx.doi.org/10.1093/neuonc/noaa215.858.
Повний текст джерелаАнотація:
Abstract BACKGROUND Diffuse gliomas are slow-growing tumors with predilection for deep and eloquent structures such as supplementary motor area and insula. They can reach huge dimensions which is a surgical challenging. OBJECTIVE Describe indications and limitations of neoadjuvant chemotherapy for diffuse gliomas. METHODS Systematic review was performed in November/2019 using Pubmed, Bireme and Cochrane databases. The following combinations were used: “Chemotherapy” AND “neoadjuvant” AND “diffuse glioma”, “Chemotherapy” AND “neoadjuvant” AND “low grade glioma”, “Chemotherapy” AND “preoperative” AND “diffuse glioma”, “Neoadjuvant” AND “Chemotherapy” AND “temozolomide” AND “diffuse glioma”. RESULTS After carefully analysis, 7 papers were selected. They had mixed surgical interventions and used different drugs. In general, it was observed that neoadjuvant Temozolomide for Oligodendrogliomas 1p19q codeleted with MGMT methylation had better response than other molecular groups. Tumor reduction was significant. CONCLUSIONS Quality of life is a main goal in neurooncology. Tumor reduction using chemotherapy is a promising therapeutic. Surgery, especially in eloquent areas, could remove more tumors with less morbidity. Recent publications are using this approach with good outcomes, however further studies with more patients and uniformization are required to stablish this approach.
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Soni, Vaishali Walke, Deepti Joshi, Tanya Sharma, Adesh Shrivastava, and Amit Agrawal. "The spectrum of microvascular patterns in adult diffuse glioma and their correlation with tumor grade." Journal of Pathology and Translational Medicine 58, no. 3 (May 15, 2024): 127–33. http://dx.doi.org/10.4132/jptm.2024.03.11.
Повний текст джерелаАнотація:
Background: Primary brain tumors constitute the leading cause of cancer-related mortality. Among them, adult diffuse gliomas are the most common type, affecting the cerebral hemispheres and displaying a diffuse infiltrative pattern of growth in the surrounding neuropil that accounts for about 80% of all primary intracranial tumors. The hallmark feature of gliomas is blood vessel proliferation, which plays an important role in tumor growth, tumor biological behavior, and disease outcome. High-grade gliomas exhibit increased vascularity, the worst prognosis, and lower survival rates. Several angiogenic receptors and factors are upregulated in glioblastomas and stimulate angiogenesis signaling pathways by means of activating oncogenes and/or down-regulating tumor-suppressor genes. Existing literature has emphasized that different microvascular patterns (MVPs) are displayed in different subtypes of adult diffuse gliomas. Methods: We examined the distribution and biological characteristics of different MVPs in 50 patients with adult diffuse gliomas. Haematoxylin and eosin staining results, along with periodic acid–Schiff and CD34 dual-stained sections, were examined to assess the vascular patterns and correlate with different grades of diffuse glioma. Results: The present observational study on adult diffuse glioma evaluated tumor grade and MVPs. Microvascular sprouting was the most common pattern, while a bizarre pattern (type 2) was associated with the presence of a high-grade glioma. Vascular mimicry was observed in 6% of cases, all of which were grade 4 gliomas. Conclusions: This study supplements the role of neo-angiogenesis and aberrant vasculature patterns in the grading and progression of adult diffuse gliomas, which can be future targets for planning treatment strategies.
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Dellaretti, Marcos, Nicolas Reyns, Gustavo Touzet, François Dubois, Sebastião Gusmão, Júlio Leonardo Barbosa Pereira, and Serge Blond. "Diffuse brainstem glioma: prognostic factors." Journal of Neurosurgery 117, no. 5 (November 2012): 810–14. http://dx.doi.org/10.3171/2012.7.jns111992.
Повний текст джерелаАнотація:
Object Brainstem gliomas were regarded as a single entity prior to the advent of MRI; however, several studies investigating MRI have recognized that these lesions are a heterogeneous group, and certain subgroups have a better prognosis for long-term survival. The aim of this study was to conduct a retrospective analysis of prognostic factors of patients with brainstem gliomas confirmed by histopathological diagnosis, particularly regarding assessment of whether histological grade, age, and MRI findings are prognostic factors for patient survival. Methods The study evaluated 100 patients diagnosed with brainstem glioma. There were 63 adults (40 men and 23 women; age range 18–75 years, mean 41 years) and 37 children (19 boys and 18 girls; age range 2–12 years, mean 6.9 years). Results The mean overall survival of this population, measured from the date of biopsy, was 57 months for diffuse low-grade glioma and 13.8 months for diffuse high-grade glioma (p < 0.001). The mean survival among patients with nonenhancing contrast lesions on MRI was 54.2 months, whereas for patients with enhancing lesions, it was 21.7 months (p < 0.001). Comparisons between the Kaplan-Meier survival curves of adults and children revealed similar median survival periods of 25 and 16 months, respectively (p > 0.05). The multivariate analysis (Cox proportional hazards regression) revealed that only histological grade was a significant prognostic factor (p < 0.001). Conclusions The study revealed that histological grade and MRI features were significant prognostic factors for survival in these patients, but in multivariate analysis, only histological grade remained a significant factor.
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Sarangi, Sasmit, and Eric Wong. "HOUT-05. COMPARING OUTCOMES OF ADULT DIFFUSE MIDLINE GLIOMAS TO GLIOBLASTOMA (GBM) IN YOUNG PATIENTS." Neuro-Oncology 21, Supplement_6 (November 2019): vi112—vi113. http://dx.doi.org/10.1093/neuonc/noz175.470.
Повний текст джерелаАнотація:
Abstract Diffuse midline gliomas are a diagnostic entity with astrocytic tumors in a midline location and in the pediatric age group they have been associated with poor outcomes. There is ongoing debate if adults with diffuse midline gliomas also have a poor prognosis particularly as complete surgical resection is often not achievable in these patients. One of the limitations of looking at case-series based outcomes with these patients is that the incidence of these tumors has a skew towards younger patients and recent case-series with observed better than expected outcomes, might be subject to influence from this parameter. To better compare outcomes of these patients we reviewed our institutional tumor registry to identify 31 patients with diffuse midline gliomas from January 2010 to December 2017. We also identified a contemporaneous consecutive series of 46 patients of age ≤ 55 with a diagnosis of GBM, as the control group for comparison. Both groups were comparable in median age (53 vs 50), gender distribution and median Karnofsky Performance Status (80 vs 90). But fewer resections were performed on diffuse midline gliomas (35.5% vs 80%). Our results indicate that patients with a diffuse midline glioma have a higher likelihood of a poorer outcome with a median overall survival of 52 vs 91 weeks in the control. The hazard ratio for death in the diffuse midline glioma cohort as compared to the control was 1.68 (95% CI – 0.97–2.91, log-rank P value = 0.038). The 2-year survival rate was also lower in the diffuse midline glioma with 22.6% vs 39.1% in the control. This poorer outcome could be related to the slightly lower median performance status or the lack of complete resection in diffuse midline glioma patients. Additional analysis is being planned to genetically differentiate these patients and identify possible prognostic indicators.
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Paracha, Awais, Mohamed S. Abdelbaki, and Pournima Navalkele. "DIPG-63. Therapies for diffuse gliomas in pediatric patients: a systematic review and meta-analysis." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i33. http://dx.doi.org/10.1093/neuonc/noac079.120.
Повний текст джерелаАнотація:
Abstract Diffuse gliomas are one of the most challenging pediatric brain tumors of the current era. The new WHO classification has brought in a paradigm shift in the diagnosis and management of diffuse gliomas. Although these tumors are not surgically resectable, an integrated molecular analysis could make them more amenable to targeted agents. We conducted a thorough systematic review and meta-analysis of therapies for diffuse gliomas in pediatric patients. Methods: Using PRISMA guidelines, PubMed, (Medline), Cochrane, and Google Scholar database searches are being conducted using search terms “diffuse midline glioma”, “diffuse midline astrocytoma” and “diffuse glioma management”. PubMed search filters used to find relevant articles were “human” species, “English” language, and “age birth to 18 years”. Results: Interim analysis using the PubMed database has revealed 387 articles of which 32 articles describe details of therapies used in pediatric patients. We found 8 case reports, 17 case series, and 7 clinical trials elucidating therapies for diffuse gliomas. Comprehensive analysis of modalities of therapies including neurosurgery, chemotherapy, and radiation therapy, along with survival analysis for these patients stratified by H3.3K27M mutant status is ongoing.
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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.
Повний текст джерелаАнотація:
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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den Hartog, Sanne J., Anja van der Kolk, Annette Bruggink, Tatjana Seute, Pieter Wesseling, and Joyce Wilbers. "Pathology-proven extradural (“distant”) metastases of gliomas in adults in the Netherlands between 1971 and 2018: a systematic case series." Neuro-Oncology Practice 8, no. 3 (January 22, 2021): 317–24. http://dx.doi.org/10.1093/nop/npab006.
Повний текст джерелаАнотація:
Abstract Background Diffuse gliomas are the most frequent primary tumors originating in the central nervous system parenchyma. Although the majority of these tumors are highly malignant, extradural metastases (EDM) are extremely rare. We aimed to perform a systematic review of patients with pathology-proven EDM of diffuse gliomas in the Netherlands. Methods From the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands information on all cases with EDM between 1971 and October 2018 was retrieved. Patients aged < 18 years or with a diagnosis of ependymoma or continuous tumor growth from intradural to extradural were excluded. Demographics, initial tumor diagnosis, treatment characteristics, location of the EDM, and survival data were collected. IDH1 R132H immunohistochemistry was performed on cases in which a paraffin block of the metastatic tumor could be retrieved. Results Twenty-five patients with diffuse glioma and pathology-proven EDM were identified. Median age at diagnosis of glioma was 46 years (IQR: 35-59); 21 patients (84%) were male. Histopathologic diagnosis was glioblastoma in 17 patients (68%) and lower-grade tumor in eight patients. In 3 out of 12 patients of which a paraffin block could be retrieved immunohistochemistry revealed an IDH1-mutant glioma. Most frequent EDM locations were bone/bone marrow (14/25 patients; 56%), and lymph nodes (6/25 patients; 24%). Conclusion EDM of diffuse glioma are rare. They occur most frequently in patients with glioblastoma, however, they can also originate from lower-grade, IDH-mutant gliomas. In daily practice, EDM of diffuse glioma should be considered in patients with tumefactive lesions of the bone or lymph nodes.
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Im, Sanghyuk, Jonghwan Hyeon, Eunyoung Rha, Janghyeon Lee, Ho-Jin Choi, Yuchae Jung, and Tae-Jung Kim. "Classification of Diffuse Glioma Subtype from Clinical-Grade Pathological Images Using Deep Transfer Learning." Sensors 21, no. 10 (May 17, 2021): 3500. http://dx.doi.org/10.3390/s21103500.
Повний текст джерелаАнотація:
Diffuse gliomas are the most common primary brain tumors and they vary considerably in their morphology, location, genetic alterations, and response to therapy. In 2016, the World Health Organization (WHO) provided new guidelines for making an integrated diagnosis that incorporates both morphologic and molecular features to diffuse gliomas. In this study, we demonstrate how deep learning approaches can be used for an automatic classification of glioma subtypes and grading using whole-slide images that were obtained from routine clinical practice. A deep transfer learning method using the ResNet50V2 model was trained to classify subtypes and grades of diffuse gliomas according to the WHO’s new 2016 classification. The balanced accuracy of the diffuse glioma subtype classification model with majority voting was 0.8727. These results highlight an emerging role of deep learning in the future practice of pathologic diagnosis.
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Norris, Gregory, Andrew Donson, Sarah Milgrom, Alisa Gaskell, Nicholas Willard, Nicholas Foreman, Ahmed Gilani, and Nathan Dahl. "HGG-17. Novel Fusion in Congenital Brainstem Diffuse High-Grade Glioma." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i64. http://dx.doi.org/10.1093/neuonc/noac079.232.
Повний текст джерелаАнотація:
Abstract BACKGROUND: Infant-type hemispheric glioma, previously termed infantile glioblastoma multiforme, is a rare infantile neoplasm with improved survival and distinct molecular features when compared to other pediatric and adult-type high-grade glioma. Infant-type high-grade gliomas are typically located in the cerebral hemispheres and are characterized by ALK, ROS1, MET, and NTRK fusions. Typical brainstem gliomas (diffuse midline glioma, H3 K27-altered or diffuse intrinsic pontine glioma) are comparatively rare in this age group. As a result, the biology of brainstem congenital high-grade gliomas is poorly described. RESULTS: A 3 month old female who initially presented with failure to thrive had an apneic event and was found to have an infiltrative mass in the medulla with expansion into the pons and cervical spine on magnetic resonance imaging. She underwent surgical biopsy with pathology revealing diffuse high-grade glioma, WHO grade 4. Next generation sequencing showed no alterations to H3F3A, IDH, or fusions involving BRAF, ALK, ROS1, MET, or NTRK. Whole-transcriptome sequencing revealed a novel fusion of PDGFRB:APOBEC3C. She received chemotherapy with 2 cycles of carboplatin/etoposide and 2 cycles of carboplatin/etoposide/imatinib before having disease progression. She then underwent palliative radiation (35 Gy in 10 fractions) with near complete regression of her disease. Surprisingly, our patient has not had any progression of disease or new lesions now two years from her last therapy. CONCLUSION: Congenital high-grade glioma is a rare, unique entity that greatly differs from its adult and childhood counterparts. Here, we discuss a previously-unreported fusion of PDGFB:APOBEC3C in a patient with congenital brainstem diffuse high-grade glioma with a favorable clinical course. This highlights the importance of routine molecular characterization, both to better understand the complex biology of this rare disease and to guide prognosis and clinical decision making for individual patients and families.
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Budd, Kaitlin, Chang-Hyuk Kwon, Lawryn H. Kasper, Christopher Roberts, Jordan Roach, Jennifer Ocasio-Adorno, Jon D. Larson, and Suzanne J. Baker. "Abstract IA007: Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): IA007. http://dx.doi.org/10.1158/1538-7445.cancepi22-ia007.
Повний текст джерелаАнотація:
Abstract Pediatric diffuse high-grade gliomas (HGGs) are a heterogeneous spectrum of disease with abysmal survival rates. Approximately half of diffuse high-grade gliomas in children arise in midline structures predominantly the brainstem, but also thalamus, cerebellum and spinal cord. Approximately 80% of these tumors harbor H3 K27M mutations, which result in dramatic depletion of the post-translational modification H3K27me3. Alternative mutations in diffuse midline gliomas can result in similar reduction of H3K27me3, leading to a redefined classification of this collection of tumors as diffuse midline glioma, H3 K27-altered. In contrast, distinct histone H3 mutations, H3.3 G34R/V, are found in approximately 30% of diffuse gliomas arising in the cerebral hemispheres of older adolescents and young adults, defining the tumor subgroup of diffuse hemispheric glioma, H3 G34-mutant. The striking spatiotemporal pattern of these histone mutations, termed oncohistones, indicates an intimate association between epigenetic dysregulation, brain development, and tumorigenesis. We will discuss use of genetically engineered and patient-derived models to investigate the contribution of oncohistone mutations to disrupted development, epigenetic dysregulation and gliomagenesis. Citation Format: Kaitlin Budd, Chang-Hyuk Kwon, Lawryn H. Kasper, Christopher Roberts, Jordan Roach, Jennifer Ocasio-Adorno, Jon D. Larson, Suzanne J. Baker. Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA007.
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Kitano, Yotaro, Kosuke Aoki, Takao Yasui, Kazuya Motomura, Fumiharu Ohka, Kuniaki Tanahashi, Masaki Hirano, et al. "PATH-36. MACHINE LEARNING TO DETECT GLIOMAS IN URINE-BASED LIQUID BIOPSY." Neuro-Oncology 21, Supplement_6 (November 2019): vi151. http://dx.doi.org/10.1093/neuonc/noz175.632.
Повний текст джерелаАнотація:
Abstract BACKGROUND Diffuse gliomas are the most common primary malignant brain tumors, whose overall prognosis is quite dismal. Tumor-cell-secreted extracellular vesicles (EVs) participate in physiological and pathological processes and have potential applications to diagnostics of malignant tumors including diffuse gliomas. Because urine is less invasive to collect, development of early diagnosis based on urine EVs is eagerly awaited. In this study, we captured urine EVs of patients with gliomas efficiently with the nanowire device and compared expression profile of microRNAs (miRNAs) within urine EVs with that of healthy donors to identify diagnostic accuracy by a machine learning algorithm. METHODS 62 patients with diffuse gliomas, including 27 glioblastoma and 35 lower grade gliomas, and 100 healthy donors were analyzed, along with orthotopic transplant mouse model. Urinary EVs were obtained with the nanowire device which could collect EVs more efficiently than the conventional ultracentrifugation method (Yasui et.al., Science Adv.2017). Machine learning methods were performed to select the miRNAs which could distinguish patients with gliomas from healthy control. RESULTS More than 2400 miRNAs were obtained from all urine samples. We identified miRNA panels that provided high diagnostic accuracy of diffuse gliomas (92.5%). There were 440 miRNAs whose expression increased by more than 1.5 fold (p< 0.05) as compared to healthy donor samples (glioma-upregulated miRNAs), whereas the expression of 87 miRNAs decreased to less than 2/3-fold (p< 0.05) (glioma-downregulated miRNAs). Mouse miRNAs which were homologous to glioma-upregulated and -downregulated miRNAs showed significantly high and low level expressions, respectively, in glioma mouse models as compared to normal control mice, confirming the reliability of urine miRNA-based diagnosis. Furthermore, some of these glioma-upregulated miRNAs has been reported to be involved in tumor progression. CONCLUSIONS miRNAs obtained from urine could be biomarkers for detection of gliomas by machine learning and some of these could be associated with tumor progression.
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Zhang, Lu, Sabrina Fritah, Petr V. Nazarov, Tony Kaoma, and Eric Van Dyck. "Impact of IDH Mutations, the 1p/19q Co-Deletion and the G-CIMP Status on Alternative Splicing in Diffuse Gliomas." International Journal of Molecular Sciences 24, no. 12 (June 6, 2023): 9825. http://dx.doi.org/10.3390/ijms24129825.
Повний текст джерелаАнотація:
By generating protein diversity, alternative splicing provides an important oncogenic pathway. Isocitrate dehydrogenase (IDH) 1 and 2 mutations and 1p/19q co-deletion have become crucial for the novel molecular classification of diffuse gliomas, which also incorporates DNA methylation profiling. In this study, we have carried out a bioinformatics analysis to examine the impact of the IDH mutation, as well as the 1p/19q co-deletion and the glioma CpG island methylator phenotype (G-CIMP) status on alternative splicing in a cohort of 662 diffuse gliomas from The Cancer Genome Atlas (TCGA). We identify the biological processes and molecular functions affected by alternative splicing in the various glioma subgroups and provide evidence supporting the important contribution of alternative splicing in modulating epigenetic regulation in diffuse gliomas. Targeting the genes and pathways affected by alternative splicing might provide novel therapeutic opportunities against gliomas.
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de la Fuente, Macarena I. "Adult-type Diffuse Gliomas." CONTINUUM: Lifelong Learning in Neurology 29, no. 6 (December 2023): 1662–79. http://dx.doi.org/10.1212/con.0000000000001352.
Повний текст джерелаАнотація:
ABSTRACT OBJECTIVE This article highlights key aspects of the diagnosis and management of adult-type diffuse gliomas, including glioblastomas and IDH-mutant gliomas relevant to the daily practice of the general neurologist. LATEST DEVELOPMENTS The advances in molecular characterization of gliomas have translated into more accurate prognostication and tumor classification. Gliomas previously categorized by histological appearance solely as astrocytomas or oligodendrogliomas are now also defined by molecular features. Furthermore, ongoing clinical trials have incorporated these advances to tailor more effective treatments for specific glioma subtypes. ESSENTIAL POINTS Despite recent insights into the molecular aspects of gliomas, these tumors remain incurable. Care for patients with these complex tumors requires a multidisciplinary team in which the general neurologist has an important role. Efforts focus on translating the latest data into more effective therapies that can prolong survival.
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Yin, Luxin, and Liwei Zhang. "Correlation Between MRI Findings and Histological Diagnosis of Brainstem Glioma." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 40, no. 3 (May 2013): 348–54. http://dx.doi.org/10.1017/s0317167100014293.
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Objective:In most studies, treatment decisions of brainstem glioma are based solely on MRI features and do not incorporate a histopathological diagnosis. In the current study, we sought to compare MRI characteristics with histopathological findings of bainstem glioma.Methods:From April 2003 through April 2012, 150 patients were diagnosed with brainstem gliomas by MRI and microsurgically treated in Tiantan Hospital, Beijing, China. All the MRI and histopathological findings of these patients were respectively reviewed.Results:Of the 150 patients, 65 were female and 85 were male, 120 were adults and 30 were children (age < 18 years), 108 were low-grade glioma (72.0%), 35 were high-grade glioma (23.3%). The accuracy of the MRI diagnosis for brainstem glioma was 95.3%. Data analysis of the MRI findings revealed that a focal lesion was associated with a more favorable histopathological diagnosis in intrinsic (P=0.005) and exophytic (P=0.001) brainstem glioma patients. In the intrinsic diffuse type, tumors without enhancement had more favorable pathological findings (P=0.009).Conclusions:To our knowledge, this is the largest case series of this nature reported in the literature to date. The results of this study suggest that MRI features of brainstem gliomas could predict some pathological features and guide prognosis, choice of biopsy and treatment modalities. The pathology of tumors with a focal appearance on MRI was associated with a prognosis that was significantly better than their diffuse counterparts. For the intrinsic diffuse gliomas, non-enhancing tumors had pathology suggestive of a favorable prognosis.
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Aabedi, Alexander, Benjamin Lipkin, Jacob S. Young, Leighton Hinkley, Anne Findlay, Andy Daniel, Saritha Krishna, et al. "CNSC-05. ELECTROPHYSIOLOGICAL PATTERNS OF GLIOMA-INDUCED NEURONAL NETWORK REMODELING ARE CONSERVED ACROSS TUMOR SUBTYPE." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii22. http://dx.doi.org/10.1093/neuonc/noac209.086.
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Abstract Recent evidence indicates that diffuse gliomas engage with neurons at the single-unit and circuit level through differing mechanisms. Certain malignant gliomas form glioma-neuron excitatory glutamatergic synapses and modulate neuron-neuron synapses through activity-dependent paracrine signaling, while others establish glioma-glioma connections via tumor microtubes. It is therefore possible that diffuse gliomas remodel neuronal circuits in a defined and predictable manner and demonstrate distinct electrophysiological profiles with prognostic and therapeutic significance. Here we apply machine learning principles in 140 patients across glioma subtypes to uncover unique electrophysiological features non-invasively via magnetoencephalography (discovery dataset) followed by feature validation using subdural electrocorticography (validation dataset). Following spatial-temporal registration, we fit an elastic net logistic regression classifier to distinguish between power spectra arising from glioma-remodeled cortex and within-subject control conditions. Model significance was determined non-parametrically by re-training each model 1,000 times with randomly permuted class labels and testing the true phi coefficient against the null distribution. In the discovery dataset, we were able to classify glioma infiltration based on tumor intrinsic neuronal activity (p < 0.05) in 127 patients (90.7%). We identified 30 electrophysiological features which revealed increased power in the delta range (1-4 Hz) and decreased power in the beta range (12-20 Hz) as a unique signature of glioma remodeling (p < 0.05) which was preserved in the validation dataset as well as across WHO 2021 diffuse glioma subtypes. In order to identify gene expression programs and signaling mechanisms that may contribute to glioma-induced remodeling but are potentially not identified in the current clinical classification scheme, we assessed targeted, next generation sequencing and DNA mutations as covariates, which again demonstrated the significance of the delta-beta spectral features. These data support converging mechanisms of glioma-induced neuronal network remodeling across tumor subtypes, setting the stage for novel therapies such as neuromodulation.
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Morgacheva, D. A., D. A. Sitovskaia, and Yu V. Dinikina. "Diagnostic and therapeutical approaches to H3K27M-altered diffuse midline glioma in children: a review." Oncohematology 18, no. 4 (December 8, 2023): 104–14. http://dx.doi.org/10.17650/1818-8346-2023-18-4-104-114.
Повний текст джерелаАнотація:
H3K27M-altered diffuse midline gliomas are the most devastating pediatric brain tumors. These tumors are characterized by lesion of central nervous system midline structures, diffuse infiltrative growth and fatal prognosis. The pathogenesis of H3K27M-altered diffuse midline glioma is based on unique epigenetic and genetic changes which are associated with histone 3 (H3) alterations. Clinical disease course usually is non-specific, that could hamper diagnosis establishment and defines high prevalence of disseminated tumor stages. Diagnostic approach includes neuroimaging, various laboratory and molecular methods, including high throughput sequencing, which allows finding potential targets for precise therapy. Despite the availability of anti-tumor technologies, including targeted therapy and immunotherapy, the standard of care for H3K27M-altered diffuse midline glioma is radiation therapy, which does not allow achieving long-term event-free survival. A dismal prognosis and absence of curative options for these tumors determine the necessity of new treatment methods search that could improve patients’ outcome. In this article we present current worldwide data of the diagnosis and treatment trends in H3K27M-altered diffuse midline glioma.
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Onishi, Shumpei, Fumiyuki Yamasaki, Motoki Takano, Ushio Yonezawa, Kazuhiko Sugiyama, and Kaoru Kurisu. "NI-17 T2-FLAIR MISMATCH SIGN IN DIFFUSE GLIOMA AND DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR." Neuro-Oncology Advances 1, Supplement_2 (December 2019): ii28. http://dx.doi.org/10.1093/noajnl/vdz039.128.
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Abstract BACKGROUND T2-FLAIR mismatch sign was reported as a specific imaging marker for diffuse astrocytoma with IDH-mutant and 1p/19q non-codeletion. However, most of the previous studies for T2-FLAIR mismatch were confirmed only among low grade glioma. The purpose of this study is to assess the T2-FLAIR mismatch sign in supratentorial diffuse glioma, diffuse midline glioma and dysembryoplastic neuroepithelial tumor (DNT) to unveil the exception rules of the sign. METHODS In total, 51 patients were included in this study; 33 supratentorial diffuse glioma (18 diffuse astrocytoma with IDH mutant (IDHmut-Noncodel), 12 oligodendroglioma with IDH-mutant and 1p19q codeletion (IDHmut-Codel), 3 diffuse astrocytoma with IDH wildtype (IDHwt)), 18 diffuse midline glioma and 11 DNT. The tumors were evaluated by 2 independent reviewers to assess presence or absence of T2-FLAIR mismatch sign. RESULT Ten out of 18 cases of IDHmut-Noncodel presented T2-FLAIR mismatch sign. None of the other supratentorial diffuse glioma (IDHmut-Codel and IDHwt) presented T2-FLAIR mismatch. The T2-FLAIR mismatch sign for IDHmut-Noncodel presented 100% positive predictive values among supratentorial diffuse glioma. However, 8 out of 18 cases of diffuse midline glioma and 8 out of 11 cases of DNT also presented the T2-FLAIR mismatch. CONCLUSION The T2-FLAIR mismatch sign was specific marker for IDHmut-NonCodel among supratentorial diffuse glioma. Physicians need to be aware that diffuse midline glioma and DNT could present the T2-FLAIR mismatch sign.
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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.
Повний текст джерелаАнотація:
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).
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Reinecke, James, Catherine Cottrell, Sarah Rush, Alexis Judd, Joshua Palmer, Christopher Pierson, Margot Lazow, and Yelena Wilson. "HGG-31. Unique case of a bithalamic H3K27-wildtype diffuse midline glioma, EGFR-altered with methylated MGMT." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i67. http://dx.doi.org/10.1093/neuonc/noac079.246.
Повний текст джерелаАнотація:
Abstract BACKGROUND: Diffuse midline gliomas are aggressive pediatric brain tumors frequently associated with somatic mutations in histone genes H3F3A (H3.3) and HIST1H3B (H3.1), which promote gliomagenesis through reprograming of the epigenetic landscape by inhibiting the tri-methylation of H3K27 (H3K27-me3). H3K27M-mutant gliomas comprise over 80% of diffuse midline gliomas, and are characterized by dismal outcomes as well as near-ubiquitous absence of MGMT promoter methylation. The subset of H3K27-wildtype diffuse midline gliomas remains incompletely understood with regards to underlying pathogenesis, therapeutic targets, and prognosis. We present the clinical, imaging, histopathologic, and molecular characteristics of a pediatric patient with a bithalamic H3K27-wildtype diffuse midline glioma, EGFR-altered with methylated MGMT. CASE: A 10-year-old female presented with an infiltrative bithalamic T2-hyperintense mass lacking diffusion restriction or contrast enhancement on MRI. Initial pathological inspection from biopsy was consistent with high-grade neuroepithelial tumor favoring high-grade glioma, however, immunohistochemistry was negative for H3K27M and demonstrated reduced H3K27-me3. DNA sequencing uncovered mutations in EGFR (exon 20 insertion) and TP53 (R175H), with overexpression of EGFR and CDK6 (but not EZHIP) identified by RNA-sequencing. Methylation profiling was consistent with high-grade glioma, matching closest with glioblastoma, IDH-wildtype, with positive MGMT promoter methylation. Treatment was initiated with focal chemoradiotherapy with concurrent temozolomide, with plans for adjuvant temozolomide/ lomustine.DISCUSSION: Our case adds to growing evidence suggesting bithalamic tumors represent a distinct genetic and epigenetic subset of diffuse midline gliomas often defined by H3K27-wildtype status, loss of H3K27-me3, and EGFR receptor alterations. Our patient’s H3K27-wildtype, EGFR-altered tumor had reduced H3K27-me3 as well as positive MGMT promoter methylation, a molecular characteristic that has not been well-studied in H3K27-wildtype bithalamic gliomas, but is suspected to confer sensitivity to alkylating chemotherapy. The prevalence, prognostic impact, and therapeutic implications of MGMT promoter methylation in bithalamic H3K27-wildtype diffuse midline gliomas, including potential association with EGFR aberrations, requires further exploration.
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Faraji-Rad, Mohammad. "Epidemiological Study of Molecular and Genetic Classification in Adult Diffuse Glioma." International Journal of Surgery & Surgical Techniques 6, no. 2 (2022): 1–5. http://dx.doi.org/10.23880/ijsst-16000171.
Повний текст джерелаАнотація:
Background: Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are frequent in lowgrade and high-grade gliomas. However, the diagnostic criteria, in particular for gliomas, are highly various. The aim of our study was to establish genetic profiles for mutation and calcification of diffuse gliomas and to evaluate their predictive factors. Methods: We estimate the different clinical and molecular characterization between IDH1, IDH2 mutant gliomas, p53, ATRX and 1p19q. In addition, whole-transcriptome sequencing and DNA extraction data were used to evaluate the distribution of genetic changes in IDH1 and IDH2 mutant gliomas in a Iranian high grade glioma. Results: Between 2016-2019, among 53 gliomas in our study, 29 cases (54.7% %) harbored an IDH1,2 mutation, 21 cases (39.6 %) harbored an p53 mutation and 19 cases (35.8 %) harbored an ATRX. In addition, 1p19q co-deletion mutation was found in 7 cases (12.2%). We found that IDH1 and IDH2 are mutually entirely in gliomas. There was no significant relation between histopathology, tumor location and clinical finding with diagnosed mutations. Conclusion: Our study discloses an associated distinction between IDH1 and IDH2 mutant gliomas nearly in half of patients, followed by p53. These mutations should be reviewed separately because their differences could have indication for the diagnosis and treatment of IDH1/2 mutant gliomas.
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Dellaretti, Marcos, Gustavo Touzet, Nicolas Reyns, François Dubois, Sebastião Gusmão, Júlio Leonardo Barbosa Pereira, and Serge Blond. "Correlation among magnetic resonance imaging findings, prognostic factors for survival, and histological diagnosis of intrinsic brainstem lesions in children." Journal of Neurosurgery: Pediatrics 8, no. 6 (December 2011): 539–43. http://dx.doi.org/10.3171/2011.9.peds1167.
Повний текст джерелаАнотація:
Object The aim of this study was to compare MR imaging characteristics with histopathological findings of intrinsic brainstem lesions and also to show the prognostic factors in patients with diffuse brainstem glioma. Methods Between February 1988 and August 2007, 44 brainstem biopsies were performed at the Roger Salengro Hospital in Lille, France, in children with intrinsic brainstem lesions not amenable to excision. Twenty-six were female and 18 male, and the mean age was 6 years. Results Histological evaluation revealed diffuse brainstem glioma in all patients with diffuse nonenhancing brainstem lesions. Diffuse brainstem glioma was found in 18 patients (90%) with diffuse enhancing brainstem lesions. Pathological entities different from diffuse glioma were verified in 2 patients (10%)—1 with ependymoma and 1 with ganglioglioma. In 4 of 5 patients with a focal nonenhancing brainstem lesion, the histopathological diagnosis was diffuse low-grade glioma. In 6 of 10 patients with focal enhancing brainstem lesion, the diagnosis was diffuse brainstem glioma, and pathological entities different from diffuse brainstem glioma were verified in 2 (20%), both with pilocytic astrocytoma. The mean 1-year actuarial survival rates for patients classified with low-grade and high-grade glioma were 80.4% ± 0.08% and 48.6% ± 0.14%, respectively. Conclusions The impact of stereotactic biopsy on intrinsic brainstem lesions was greater in patients with MR imaging–documented enhancing lesions in whom the diagnosis of diffuse glioma was less frequent. Patients with low-grade glioma seem to have longer survival than those with high-grade glioma.
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Verburg, Niels, Thomas Koopman, Maqsood M. Yaqub, Otto S. Hoekstra, Adriaan A. Lammertsma, Frederik Barkhof, Petra J. W. Pouwels, et al. "Improved detection of diffuse glioma infiltration with imaging combinations: a diagnostic accuracy study." Neuro-Oncology 22, no. 3 (September 24, 2019): 412–22. http://dx.doi.org/10.1093/neuonc/noz180.
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Abstract Background Surgical resection and irradiation of diffuse glioma are guided by standard MRI: T2/fluid attenuated inversion recovery (FLAIR)–weighted MRI for non-enhancing and T1-weighted gadolinium-enhanced (T1G) MRI for enhancing gliomas. Amino acid PET has been suggested as the new standard. Imaging combinations may improve standard MRI and amino acid PET. The aim of the study was to determine the accuracy of imaging combinations to detect glioma infiltration. Methods We included 20 consecutive adults with newly diagnosed non-enhancing glioma (7 diffuse astrocytomas, isocitrate dehydrogenase [IDH] mutant; 1 oligodendroglioma, IDH mutant and 1p/19q codeleted; 1 glioblastoma IDH wildtype) or enhancing glioma (glioblastoma, 9 IDH wildtype and 2 IDH mutant). Standardized preoperative imaging (T1-, T2-, FLAIR-weighted, and T1G MRI, perfusion and diffusion MRI, MR spectroscopy and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET) was co-localized with multiregion stereotactic biopsies preceding resection. Tumor presence in the biopsies was assessed by 2 neuropathologists. Diagnostic accuracy was determined using receiver operating characteristic analysis. Results A total of 174 biopsies were obtained (63 from 9 non-enhancing and 111 from 11 enhancing gliomas), of which 129 contained tumor (50 from non-enhancing and 79 from enhancing gliomas). In enhancing gliomas, the combination of apparent diffusion coefficient (ADC) with [18F]FET PET (area under the curve [AUC], 95% CI: 0.89, 0.79‒0.99) detected tumor better than T1G MRI (0.56, 0.39‒0.72; P < 0.001) and [18F]FET PET (0.76, 0.66‒0.86; P = 0.001). In non-enhancing gliomas, no imaging combination detected tumor significantly better than standard MRI. FLAIR-weighted MRI had an AUC of 0.81 (0.65–0.98) compared with 0.69 (0.56–0.81; P = 0.019) for [18F]FET PET. Conclusion Combining ADC and [18F]FET PET detects glioma infiltration better than standard MRI and [18F]FET PET in enhancing gliomas, potentially enabling better guidance of local therapy.
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Schulte, Jessica, Robin Buerki, Sarah Lapointe, Annette Molinaro, Yalan Zhang, Javier Villanueva-Meyer, Arie Perry, et al. "PATH-30. CLINICAL AND GENETIC CHARACTERISTICS OF HISTONE H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMAS IN ADULTS." Neuro-Oncology 22, Supplement_2 (November 2020): ii170—ii171. http://dx.doi.org/10.1093/neuonc/noaa215.711.
Повний текст джерелаАнотація:
Abstract BACKGROUND “Diffuse midline glioma, H3 K27M-mutant” is a new tumor entity established in the 2016 WHO Classification of Tumors of the CNS that comprises a set of diffuse gliomas arising in midline structures that is molecularly defined by a recurrent K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited. Given the more frequent origin in the thalamus or spinal cord in adults versus the brainstem in children, gliomas with this mutation may encompass a heterogeneous population of tumor subtypes that vary based on patient age, anatomic site of origin, and concurrent genetic alterations. METHODS The 60 patients included were 18 years or older at initial diagnosis, during the period of 2014-2019 at UCSF. Cases were identified using immunohistochemistry with a H3 K27M-mutant specific antibody and/or next-generation sequencing of histone 3 genes H3F3A, HIST1H3B and HIST1H3C. Targeted NGS was performed on tumors from 21 patients, utilizing an UCSF institutional panel or a variety of commercial sources. RESULTS Patients presented primarily in the 3rd decade of life, and 57% of tumors were located in the thalamus. Genomic profiling revealed p.K27M mutations exclusively in H3F3A and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric diffuse midline gliomas. Additionally, these adult H3 K27M-mutant diffuse midline gliomas are universally IDH-wildtype, and have frequent mutations in TP53, PPM1D, FGFR1, NF1, and ATRX. The overall survival of this adult cohort is longer than historical averages for both H3 K27M-mutant diffuse midline glioma in children and IDH-wildtype glioblastomas in adults. CONCLUSIONS Together, these findings indicate that H3 K27M-mutant diffuse midline glioma represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in children versus adults.
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Mamatjan, Yasin, Mathew Voisin, Farshad Nassiri, Fabio Moraes, Severa Bunda, Mira Salih, Kenneth Aldape, and Gelareh Zadeh. "MOMC-3. Hypermethylation and overexpression of HOX genes are poor prognosticators in Lower-Grade Glioma." Neuro-Oncology Advances 3, Supplement_2 (July 1, 2021): ii4. http://dx.doi.org/10.1093/noajnl/vdab070.013.
Повний текст джерелаАнотація:
Abstract Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Molecular characterization of these tumors led to the development of new classification system comprising specific glioma subtypes. While this provides novel molecular insight into gliomas it does not fully explain the variability in patient outcome. To identify and characterize a predictive signature of outcome in diffuse gliomas, we utilized an integrative molecular analysis (methylation, mRNA, copy number variation (CNV) and mutation data) using multiple molecular platforms, including a total of 310 IDH mutant glioma samples from University Health Network (UHN) and German Cancer Research Center (DKFZ) together with 419 samples from The Cancer Genome Atlas (TCGA). Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival (p-value < 0.0001). The CpG-based signatures were reliably validated using two independent datasets from TCGA and DKFZ cohorts (both p-values < 0.0001). The results show that the methylation signatures that predict poor outcome also correlated with G-CIMP low status, elevated CNV instability and hypermethylation of a set of HOX gene probes. Further study in diffuse lower-grade glioma (LGG) using integrated mRNA and methylation (iRM) analyses showed that parallel HOX gene overexpression and hypermethylation in the same direction were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value < 0.0001). Furthermore, this iRM high group was characterized by a 7-HOX gene signature showed significant survival differences not only in IDH mutant LGG but also in IDH wildtype LGG. These results demonstrate the importance of HOX genes in predicting the outcome of diffuse gliomas to identify relevant molecular subtyping independent of histology.
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Mobark, Nahla Ali, Musa Alharbi, Yasser S. Bayoumi, Aymn Albanyan, Ali Abdullah O. Balbaid, Wael abdel Rahman Aljabarat, and Malak Abedalthagafi. "DIPG-35. Personalized treatment for molecularly heterogeneous Diffuse midline glioma, H3 k27-altered Paediatric case." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i26. http://dx.doi.org/10.1093/neuonc/noac079.092.
Повний текст джерелаАнотація:
Abstract Diffuse midline glioma, H3 k27-altered (DMG) is a type of Paediatric- type diffuse high grade gliomas according to the 2021 WHO CNS tumors Classification. Diffuse intrinsic pontine glioma (DIPG) is another acceptable related term when it located in the pons with fatal prognosis. The combination of H3K27M with BRAF V600 mutations rarely reported in DMG although more commonly in Paediatric-type low grade gliomas (Diffuse low-grade glioma, MAPK pathway-altered). We present a twenty-month-old boy, previously healthy, presented with 2 weeks history of unsteady gait, drooling, cranial nerves palsy MRI imaging showed diffuse pontine mass with classic radiological features of DIPG. 2.6 x 1.6 x 3.2 (AP x TV x CC) with no evidence for spinal metastases. Patient underwent right retro sigmoid approach and open biopsy of lesion he received focal Radiation Therapy 54GY/30fx as stander of care of DIPG with mild neurogical improvement Pathological & molecular Diagnosis was Diffuse midline glioma, H3 k27-altered with Co-occurrence BRAF V600E mutation. Two months after end of radiation, he presented with vomiting, and neurological deterioration with new right-side hemiplegia. Imaging studies showed interval increase in the pontine lesion with increased edema causing narrowing of the fourth ventricle, no active hydrocephalus. He was started on combination therapy BRAF inhibitor Dabrafenib and MEK Inhibitor Trametinib as maintenance therapy the patient gradually showed Marked neurological and clinical improvement. A 6-month MRI after start of targeted therapy showed favorable treatment response with complete resolution of the previous diffusion restriction, reduced tumor volume on MR perfusion ,reduced perilesional edema otherwise almost stabilization of nonenhancing pontine lesion. The poor prognosis of recurrent DIPG is well known but our patient is clinically and radiologically stable with excellent quality of life and well tolerating the therapy . Our case show that personalized treatment approach that address molecular heterogeneity of H3K27M glioma are safe and feasible
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Hollon, Todd, Cheng Jiang, Mustafa Nasir-Moin, Akhil Kondepudi, Asadur Chowdury, Wajd Al-Holou, Maria Castro, et al. "NIMG-30. AI-BASED MOLECULAR CLASSIFICATION OF DIFFUSE GLIOMAS USING RAPID, LABEL-FREE OPTICAL HISTOLOGY." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii169. http://dx.doi.org/10.1093/neuonc/noac209.648.
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Abstract INTRODUCTION Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. Access to timely molecular diagnostic testing for brain tumor patients is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. OBJECTIVE We aim to develop a rapid (< 90 seconds), AI-based diagnostic screening system that can provide molecular classification of diffuse gliomas and report its use in a prospective, multicenter, international clinical trial of diffuse glioma patients (n = 153). METHODS By combining stimulated Raman histology (SRH), a rapid, label-free, non-consumptive, optical imaging method, and deep learning-based image classification, we are able to predict the molecular genetic features used by the World Health Organization (WHO) to define the adult-type diffuse glioma taxonomy, including IDH-1/2, 1p19q-codeletion, and ATRX loss. We developed a multimodal deep neural network training strategy that uses both SRH images and large-scale, public diffuse glioma genomic data in order to achieve optimal molecular classification performance. RESULTS One institution was used for model training (University of Michigan) and four institutions (NYU, UCSF, Medical University of Vienna, and University Hospital Cologne) were included for prospective patient enrollment and model testing. Using our system, called DeepGlioma, we achieved an average molecular genetic classification accuracy of 93.2% and identified the correct diffuse glioma molecular subgroup with 91.5% accuracy. DeepGlioma outperformed conventional IDH1-R132H immunohistochemistry (94.2% versus 91.4% accuracy, respectively) as a first-line molecular diagnostic screening method for diffuse gliomas, detecting canonical and non-canonical IDH mutations with high accuracy. CONCLUSION Our results demonstrate how artificial intelligence and optical histology can be used to provide a rapid and scalable alternative to wet lab methods for the molecular diagnosis of brain tumor patients during surgery.
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Yamamura, Toshihiro, Kaoru Tamura, Daisuke Kobayashi, Motoki Inaji, Yoji Tanaka, and Taketoshi Maehara. "PEDT-1 Integrated diagnoses of pediatric gliomas in our institute by cIMPACT-NOW recommendations." Neuro-Oncology Advances 3, Supplement_6 (December 1, 2021): vi10—vi11. http://dx.doi.org/10.1093/noajnl/vdab159.038.
Повний текст джерелаАнотація:
Abstract Purpose:Since many genetic abnormalities in glioma have been revealed in recent years, Integrated diagnoses are necessary in the updated fourth edition of the WHO Classification of Tumors of the Central Nervous System(CNS) published in 2016. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classification. We retrospectively classified pediatric gliomas in our hospital in accordance with cIMPACT-NOW recommendations. Methods: This study includes 13 consecutive glioma patients under the age of 18 who underwent surgical resection at our hospital from 2000 to 2021. Histopathological diagnoses and molecular status such as IDH, H3F3A and BRAF were analyzed. Results: There were four females and nine males, ranging in age from 0 to 17 years, median 9.0 years. Three pilocytic astrocytomas (PA) and a polymorphous low-grade neuroepithelial tumor of the young (PLNTY) had BRAF fusion. Four cases were classified as Diffuse midline glioma, H3K27M-altered. Two cases were classified as Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. No genetic alteration was observed in two diffuse astrocytoma cases. An anaplastic oligodendroglioma case with PDGFRA amplification could not be classified as any new entity. All three PA cases with BRAF fusion occurred in cerebellum and all four H3K27M altered cases occurred in midline location such as thalamus, brainstem and cervical spinal cord. Six cases which were classified as pediatric-type diffuse high grade gliomas had poor prognosis. Conclusion:Genetic status is associated to tumor location and patients prognosis. Integrated diagnoses are important in pediatric glioma patients.
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Kwikima, Ugumba. "GLIOMA-04 BRIDGING THE GAP ON ADULT GLIOMA IMAGING, DIAGNOSIS AND FOLLOW UP IN SUB-SAHARAN AFRICA." Neuro-Oncology Advances 5, Supplement_4 (October 31, 2023): iv1. http://dx.doi.org/10.1093/noajnl/vdad121.003.
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Abstract Cerebral Gliomas are the most common and devastating primary brain tumors. Prior to 2016 WHO CNS tumor classification update, the grading of gliomas, mainly relied on histological features, including cellularity, nuclear atypia, mitotic activity, vascularity, and necrosis, observed on light microscopy with the aid of immunohistochemistry. A number of studies confirmed that diffuse gliomas demonstrates different growth pattern, clinical behavior, and prognostication based on their genomic alterations, these findings necessitated incorporation of molecular subtypes in glioma classification, and leads to 2016 WHO CNS tumors Classification update. Introduction of molecular criteria into the classification of gliomas has given rise to interesting, wide-ranging implications regarding glioma management. In the current classification, all diffuse gliomas have been grouped based on their growth pattern, clinical behavior, and specifically sharing of the mutational state of the gene that codes for isocitrate dehydrogenase (IDH) in its isoforms (IDH1 and IDH2). Regardless of grade, the first phase in glioma molecular characterization is IDH testing. Mutations in IDH1 and IDH2 are associated with significant increase in progression free survival and overall survival. Immunohistochemistry, Molecular subtyping, Both FISH and genetic sequencing have significant implications in gliomas management and clinical outcome, yet they are not available in our low resource settings. Advanced MRI techniques (DTI, MR Perfussion, MR Spectroscopy, and Functional MRI) have a significant impact in presurgical planning and follow up of glioma patients after surgery and chemo radiation treatment. Radiographic findings can bridge the gap on accurate glioma diagnosis in sub-Saharan Africa through predicting Glioma Molecular subtypes based on clinical presentation and utilizing conventional MRI as a radio genomic tool. Also to emphasis in the utilization of available advanced MRI techniques (DTI, MR Perfussion, and MR spectroscopy) for presurgical planning and follow up of patients after Glioma treatment.
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Nikitin, Pavel V., Guzel R. Musina, Stanislav I. Pekov, Andrey A. Kuzin, Igor A. Popov, Artem Y. Belyaev, Gregory L. Kobyakov, Dmitry Y. Usachev, Viktor N. Nikolaev, and Valentin P. Mikhailov. "Cell-Population Dynamics in Diffuse Gliomas during Gliomagenesis and Its Impact on Patient Survival." Cancers 15, no. 1 (December 26, 2022): 145. http://dx.doi.org/10.3390/cancers15010145.
Повний текст джерелаАнотація:
Diffuse gliomas continue to be an important problem in neuro-oncology. To solve it, studies have considered the issues of molecular pathogenesis from the intratumoral heterogeneity point. Here, we carried out a comparative dynamic analysis of the different cell populations’ content in diffuse gliomas of different molecular profiles and grades, considering the cell populations’ functional properties and the relationship with patient survival, using flow cytometry, immunofluorescence, multiparametric fluorescent in situ hybridization, polymerase chain reaction, and cultural methods. It was shown that an increase in the IDH-mutant astrocytomas and oligodendrogliomas malignancy is accompanied by an increase in stem cells’ proportion and mesenchymal cell populations’ appearance arising from oligodendrocyte-progenitor-like cells with cell plasticity and cells’ hypoxia response programs’ activation. In glioblastomas, malignancy increase is accompanied by an increase in both stem and definitive cells with mesenchymal differentiation, while proneuronal glioma stem cells are the most likely the source of mesenchymal glioma stem cells, which, in hypoxic conditions, further give rise to mesenchymal-like cells. Clinical confirmation was a mesenchymal-like cell and mesenchymal glioma stem cell number, and the hypoxic and plastic molecular programs’ activation degree had a significant effect on relapse-free and overall survival. In general, we built a multi-vector model of diffuse gliomas’ pathogenetic tracing up to the practical plane.
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Barron, Tara, Vilina Mehta, Pamelyn Woo, and Michelle Monje. "HGG-04. TARGETING GABAERGIC NEURON-GLIOMA SYNAPSES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) THROUGH ANTI-EPILEPTIC DRUG REPURPOSING." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i17—i18. http://dx.doi.org/10.1093/neuonc/noab090.070.
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Abstract Pediatric high-grade gliomas, including diffuse intrinsic pontine glioma (DIPG), are the leading cause of brain cancer-related death in children. While enormous progress has been made in recent years for many forms of cancer, high-grade gliomas remain seemingly intractable, indicating that fundamental aspects of glioma growth are not yet sufficiently understood. Neuronal activity drives glioma growth both through paracrine signaling and through direct neuron-to-glioma synapses. Recently glutamatergic, AMPA receptor-dependent synapses were discovered between microenvironmental neurons and malignant glioma cells. The depolarizing current that results from synaptic and other forms of electrical neuron-glioma signaling promotes pediatric high-grade glioma proliferation and regulates growth. Neuron-glioma cell synapses mediated by other neurotransmitters remain largely unexplored, though glioma cells express genes encoding neurotransmitter receptors such as GABAA receptor subunits. Using whole-cell patch clamp electrophysiology in patient-derived DIPG xenografts, we have identified functional GABAergic neuron-to-glioma synapses mediated by GABAA receptors. GABAergic input has a depolarizing effect on glioma cells, but the magnitude of depolarization is heterogeneous between high-grade glioma subtypes and between patient-derived DIPG xenograft models. As membrane depolarization increases glioma proliferation, depolarizing GABAergic inputs to glioma cells could promote DIPG progression. Drugs that stimulate GABA signaling, such as benzodiazepines, are often given to pediatric glioma patients to treat nausea, seizures or anxiety. In patient-derived DIPG xenograftn models, lorazepam, a benzodiazepine that increases GABAA receptor conductance, increases glioma growth. Conversely, levetiracetam, an anti-epileptic drug that reduces synaptic transmission including at GABAergic neuron-glioma synapses, reduces glioma proliferation in patient-derived DIPG xenografts. This emerging understanding of brain cancer neurophysiology reveals new therapeutic targets and highlights commonly used drugs about which more study is required in this disease context.
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Joshi, Sabendra, Yuan-Kui Wu, Yi-Kai Xu, Xiao-Min Liu, and Hao Zhang. "Comparative study of diffuse midline glioma and glioblastoma: Magnetic Resonance Imaging (MRI) in the characteristics and demography." Nepal Journal of Neuroscience 19, no. 2 (July 7, 2022): 32–36. http://dx.doi.org/10.3126/njn.v19i2.43724.
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Introduction: Diffuse midline glioma and glioblastoma are classified as grade IV CNS tumors (WHO). The entity ‘diffuse midline glioma, H3 K27 mutant’ was introduced in the 4th revised edition of the 2016 WHO classification of brain tumors; however, there are only a few reports on Magnetic Resonance Imaging of these tumors. Thus, we conducted a retrospective study focused on Magnetic Resonance Imaging features of diffuse midline glioma compared to glioblastoma. This study aims to evaluate and compare the demographic characteristics, anatomic location of lesions, and MRI characteristics of diffuse midline glioma and glioblastoma. Methods: We histologically confirmed 30 patients with diffuse midline glioma and 70 patients with glioblastoma were enrolled in this retrospective study. Pretreatment MRI of each patient was reviewed by a neuroradiology issuing physician and neuroradiology reporting physician for MRI characteristics of tumors. Comparative analysis was performed of the imaging pattern to show differences between diffuse midline glioma and glioblastoma with the p-value. Results: The age of patients with diffuse midline glioma (mean age =24.7 ±10.4) was significantly lower than in those with glioblastoma (mean age =48.2 ±1). The majority of patients with diffuse midline glioma (56.7%) and glioblastoma (51.4%) were ≤ 25 and ≥ 50 years age group respectively. The most common location of diffuse midline glioma and glioblastoma were the thalamus (73.3%) and frontal lobe (37.1%) respectively. The presence of hydrocephalus, edema, and invasion were statistically significantly differences in patients with diffuse midline glioma (hydrocephalus = 46.7%, edema = 53.3%, and invasion =30%) than in those with glioblastoma (hydrocephalus = 12.9%, edema = 88.6%, and invasion =5.7%) (P < 0.05 each). Conclusions: Despite having similar imaging features, diffuse midline glioma exhibited marked differences in age, edema, invasion, and hydrocephalus in MRI compared to Glioblastoma.
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Kalidindi, Navya, Rosemarylin Or, Sam Babak, and Warren Mason. "Molecular Classification of Diffuse Gliomas." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 47, no. 4 (January 10, 2020): 464–73. http://dx.doi.org/10.1017/cjn.2020.10.
Повний текст джерелаАнотація:
ABSTRACT:Technological advances in the field of molecular genetics have improved the ability to classify brain tumors into subgroups with distinct clinical features and important therapeutic implications. The World Health Organization’s newest update on classification of gliomas (2016) incorporated isocitrate dehydrogenase 1 and 2 mutations, ATRX loss, 1p/19q codeletion status, and TP53 mutations to allow for improved classification of glioblastomas, low-grade and anaplastic gliomas. This paper reviews current advances in the understanding of diffuse glioma classification and the impact of molecular markers and DNA methylation studies on survival of patients with these tumors. We also discuss whether the classification and grading of diffuse gliomas should be based on histological findings, molecular markers, or DNA methylation subgroups in future iterations of the classification system.
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Yoel, Abigail, Shazia Adjumain, Yuqing Liang, Paul Daniel, Ron Firestein, and Vanessa Tsui. "Emerging and Biological Concepts in Pediatric High-Grade Gliomas." Cells 13, no. 17 (September 5, 2024): 1492. http://dx.doi.org/10.3390/cells13171492.
Повний текст джерелаАнотація:
Primary central nervous system tumors are the most frequent solid tumors in children, accounting for over 40% of all childhood brain tumor deaths, specifically high-grade gliomas. Compared with pediatric low-grade gliomas (pLGGs), pediatric high-grade gliomas (pHGGs) have an abysmal survival rate. The WHO CNS classification identifies four subtypes of pHGGs, including Grade 4 Diffuse midline glioma H3K27-altered, Grade 4 Diffuse hemispheric gliomas H3-G34-mutant, Grade 4 pediatric-type high-grade glioma H3-wildtype and IDH-wildtype, and infant-type hemispheric gliomas. In recent years, we have seen promising advancements in treatment strategies for pediatric high-grade gliomas, including immunotherapy, CAR-T cell therapy, and vaccine approaches, which are currently undergoing clinical trials. These therapies are underscored by the integration of molecular features that further stratify HGG subtypes. Herein, we will discuss the molecular features of pediatric high-grade gliomas and the evolving landscape for treating these challenging tumors.
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Kessler, Jacqueline, Tim Hohmann, Antje Güttler, Marina Petrenko, Christian Ostheimer, Urszula Hohmann, Matthias Bache, Faramarz Dehghani, and Dirk Vordermark. "Radiosensitization and a Less Aggressive Phenotype of Human Malignant Glioma Cells Expressing Isocitrate Dehydrogenase 1 (IDH1) Mutant Protein: Dissecting the Mechanisms." Cancers 11, no. 6 (June 25, 2019): 889. http://dx.doi.org/10.3390/cancers11060889.
Повний текст джерелаАнотація:
The presence of an isocitrate dehydrogenase 1 (IDH1) mutation is associated with a less aggressive phenotype, increased sensitivity to radiation, and increased overall survival in patients with diffuse glioma. Based on in vitro experimentations in malignant glioma cell lines, the consequences on cellular processes of IDH1R132H expression were analyzed. The results revealed that IDH1R132H expression enhanced the radiation induced accumulation of residual γH2AX foci and decreased the amount of glutathione (GSH) independent of the oxygen status. In addition, expression of the mutant IDH1 caused a significant increase of cell stiffness and induced an altered organization of the cytoskeleton, which has been shown to reinforce cell stiffness. Furthermore, IDH1R132H expression decreased the expression of vimentin, an important component of the cytoskeleton and regulator of the cell stiffness. The results emphasize the important role of mutant IDH1 in treatment of patients with diffuse gliomas especially in response to radiation. Hence, detection of the genetic status of IDH1 before therapy massively expands the utility of immunohistochemistry to accurately distinguish patients with a less aggressive and radiosensitive IDH1-mutant diffuse glioma suitable for radiotherapy from those with a more aggressive IDH1-wildtype diffuse glioma who might benefit from an individually intensified therapy comprising radiotherapy and alternative medical treatments.
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Odia, Yazmin, Ashley Love Sumrall, Timothy Francis Cloughesy, Phioanh Leia Leia Nghiemphu, Matthew David Hall, Doured Daghistani, Minesh P. Mehta, et al. "Single agent activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e14037-e14037. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e14037.
Повний текст джерелаАнотація:
e14037 Background: H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti-cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201. Methods: We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, though excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata). Results: Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness. Conclusions: These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.
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Odia, Yazmin, Ashley Sumrall, Timothy Cloughesy, Phioanh Nghiemphu, Matthew Hall, Doured Daghistani, Minesh Mehta, et al. "CTNI-27. SINGLE AGENT ACTIVITY OF ONC201 IN NON-MIDLINE H3 K27M-MUTANT DIFFUSE GLIOMAS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi65. http://dx.doi.org/10.1093/neuonc/noab196.252.
Повний текст джерелаАнотація:
Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti- cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201. METHODS We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata). RESULTS Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness. CONCLUSIONS These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.
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Wang, Daniel, Mauli Shah, Srividya Arjuna, Antonio Dono, Chirag Patel, Jason Huse, Brittany Parker Kerrigan, et al. "BIOM-67. DIFFERENTIAL DNA METHYLATION PATTERNS IN THE CSF OF PATIENTS WITH DIFFUSE GLIOMAS." Neuro-Oncology 26, Supplement_8 (November 1, 2024): viii35. http://dx.doi.org/10.1093/neuonc/noae165.0139.
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Abstract Studies have shown that different central nervous system (CNS) tumor types exhibit unique DNA methylation profiles. DNA methylation-based machine learning classification of CNS tumor tissue has been demonstrated to be highly-accurate in differentiating between tumor types, including between diffuse glioma subtypes. While similar analyses have been performed using cell-free DNA (cfDNA) from blood, few studies have looked at the potential of DNA methylation as a biomarker for diffuse gliomas using CSF-derived cfDNA. In this study, we analyzed CSF cfDNA methylation patterns in diffuse glioma patients. DNA methylation profiling of CSF of patients with glioblastoma, IDH-wildtype (GBM) (n=37), IDH-mutant diffuse gliomas (n=12), and non-neoplastic conditions (n=5) was performed using cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq). Methylation quantification was estimated for each genomic region. Significance testing was performed between diagnostic groups to discover differentially-methylated regions (DMRs). The 300 most differentially-methylated regions (DMRs) for each comparison (IDH-wildtype vs. IDH-mutant, IDH-mutant vs. control, IDH-wildtype vs. control), for a total of 900 DMRs, were utilized as features in dimensionality reduction analysis and machine learning. Out of ~1×107 defined genomic regions, there were ~7×105 DMRs between GBM and control samples and ~1.5×106 DMRs between GBM and IDH-mutant samples, accounting for ~7% and ~15% of the genome, respectively. Uniform manifold approximation and projection (UMAP) and hierarchical clustering analysis revealed that samples were mostly clustered by diagnosis. Random forest analysis of the 900 DMRs with an 80/20 train/test split resulted in an overall accuracy of 0.815. In conclusion, CSF cfDNA methylation profiles of diffuse glioma patients exhibit differential methylation patterns between IDH-mutant and IDH-wildtype tumors, as well as between tumor and control, and could be informative biomarkers for the diagnosis of patients with diffuse gliomas.
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Hennika, Tammy, and Oren J. Becher. "Diffuse Intrinsic Pontine Glioma." Journal of Child Neurology 31, no. 12 (July 20, 2016): 1377–85. http://dx.doi.org/10.1177/0883073815601495.
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Aziz-Bose, Razina, and Michelle Monje. "Diffuse intrinsic pontine glioma." Current Opinion in Oncology 31, no. 6 (November 2019): 522–30. http://dx.doi.org/10.1097/cco.0000000000000577.
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Esparragosa, Inés, Ricardo Díez-Valle, Sonia Tejada, and Jaime Gállego Pérez-Larraya. "Management of diffuse glioma." La Presse Médicale 47, no. 11-12 (November 2018): e199-e212. http://dx.doi.org/10.1016/j.lpm.2018.04.014.
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Punt, J., and M. Cartmill. "Diffuse brain stem glioma." Child's Nervous System 15, no. 5 (May 20, 1999): 235–37. http://dx.doi.org/10.1007/s003810050379.
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Ross, Jennifer, Adriana Olar, and Christine Fuller. "A Pediatric Case of Diffuse Glioma Diagnosed at Autopsy." Academic Forensic Pathology 7, no. 4 (December 2017): 657–66. http://dx.doi.org/10.23907/2017.056.
Повний текст джерелаАнотація:
Sudden death from an undiagnosed primary intracranial neoplasm is extremely uncommon and even rarer in the pediatric population. Gliomatosis cerebri (GC) represents a growth pattern demonstrable by a variety of gliomas, predominating in adults. Herein we present a rare occurrence of diagnosis of a pediatric glioma with a GC pattern of infiltration at autopsy and compare the immunohistochemical results and molecular characteristics in this tumor to the small amount of published knowledge available about pediatric diffuse gliomas with widespread brain invasion.
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Barthel, Floris, Kevin C. Johnson, Frederick Varn, Anzhela Moskalik, Georgette Tanner, Emre Kocakavuk, Kevin Anderson, et al. "GENE-28. LONGITUDINAL MOLECULAR TRAJECTORIES OF DIFFUSE GLIOMA IN ADULTS." Neuro-Oncology 21, Supplement_6 (November 2019): vi103. http://dx.doi.org/10.1093/neuonc/noz175.430.
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Abstract Treatment options for adult patients with glioma has remained largely unchanged over the past three decades. Targeted inhibitors and immunotherapies have improved outcomes for many cancer types but their relevance in glioma is unclear. The inevitability of glioma disease recurrence demands an understanding of mechanisms driving therapy resistance. The Glioma Longitudinal Analysis (GLASS) Consortium was initiated to establish a definitive portrait of the recurrence process and to discover vulnerabilities that render the tumor sensitive to therapeutic intervention. GLASS is a community-driven effort that seeks to overcome the logistical challenges in constructing adequately powered longitudinal genomic glioma datasets by pooling data from patients treated at institutions worldwide. Currently, the GLASS Data Resource comprises DNA sequencing data (exome and/or whole-genome) from 288 patients of whom high-quality data in at least two time points are present from 222 patients (n = 134 IDHwt, n = 63 IDHmutant-noncodel, n = 25 IDHmutant-codel). We inferred longitudinal mutation, copy number, clonal frequency, and neoantigen profiles and demonstrated that driver genes found at initial disease persisted into recurrence. Treatment with alkylating-agents resulted in a hypermutator phenotype at different rates across glioma subtypes, most frequently among IDHmutant-noncodels, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent IDHmutant-noncodel gliomas and further converged with acquired cell cycle pathway alterations and poor outcomes. We showed that the clonal architecture of each tumor remains largely intact over time and that genetic drift was associated with increased survival. Finally, we found that neoantigens were exposed to stable selective pressures throughout a tumor’s progression. Our results collectively suggest that the strongest selective pressures occur early during glioma development and that current therapies shape this evolution in a largely stochastic manner. The GLASS Data Resource provides a genomic reference to study the patterns of glioma evolution.
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van den Bent, Martin J., Marion Smits, Johan M. Kros, and Susan M. Chang. "Diffuse Infiltrating Oligodendroglioma and Astrocytoma." Journal of Clinical Oncology 35, no. 21 (July 20, 2017): 2394–401. http://dx.doi.org/10.1200/jco.2017.72.6737.
Повний текст джерелаАнотація:
The new 2016 WHO brain tumor classification defines different diffuse gliomas primarily according to the presence or absence of IDH mutations ( IDH-mt) and combined 1p/19q loss. Today, the diagnosis of anaplastic oligodendroglioma requires the presence of both IDH-mt and 1p/19q co-deletion, whereas anaplastic astrocytoma is divided into IDH wild-type ( IDH-wt) and IDH-mt tumors. IDH-mt tumors have a more favorable prognosis, and tumors with low-grade histology especially tend evolve slowly. IDH-wt tumors are not a homogeneous entity and warrant further molecular testing because some have glioblastoma-like molecular features with poor clinical outcome. Treatment consists of a resection that should be as extensive as safely possible, radiotherapy, and chemotherapy. Trials of patients with newly diagnosed grade II or III glioma have shown survival benefit from adding chemotherapy to radiotherapy compared with initial treatment using radiotherapy alone. Both temozolomide and the combination of procarbazine, lomustine, and vincristine provide survival benefit. In contrast, trials that compare single modality treatment of chemotherapy alone with radiotherapy alone did not observe survival differences. Currently, for patients with grade II or III gliomas who require postsurgical treatment, the preferred treatment consists of a combination of radiotherapy and chemotherapy. Low-grade gliomas with favorable characteristics are slow-growing tumors. When deciding on the timing of postsurgical treatment with radiotherapy and chemotherapy, both clinical and molecular factors should be taken into account, but a more conservative approach can be considered initially in some of these patients. The factor that best predicts benefit of chemotherapy in grade II and III glioma remains to be established.