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In Vivo (Athens, Greece) 2024Gliomas are highly heterogeneous malignancies originating from diverse cell types within the brain. Although their precise etiology is frequently unknown, risk factors,...
BACKGROUND/AIM
Gliomas are highly heterogeneous malignancies originating from diverse cell types within the brain. Although their precise etiology is frequently unknown, risk factors, such as chemical exposure, radiation, and specific uncommon genetic disorders have been identified. Diagnosis typically entails imaging tests, such as magnetic resonance imaging and computed tomography, complemented by a biopsy for confirmation, which may be further validated through genetic testing.
CASE REPORT
Next-generation sequencing technology revealed germline co-deletion deletion of cyclin-dependent kinase inhibitor 2 A and B genes (CDKN2A and CDKN2B) in a patient diagnosed with pleomorphic xanthoastrocytoma based on the tumor's molecular characteristics. Following this result, we performed focused genetic analysis with use of multiplex ligation-dependent probe amplification technology for the mother that revealed the same co-deletion. Moreover, due to the father's neuroendocrine pancreatic cancer, application of the NGS technology detected a pathogenic variant in the BRCA1-interacting helicase 1 (BRIP1) gene. Comprehensive multi-gene testing conducted within the familial context, marked by a varied spectrum of cancer type, revealed a constellation of genetic predispositions.
CONCLUSION
This case study underscores the critical importance of molecular testing for tumor characterization and highlights the pivotal role of genetic testing in facilitating early intervention and screening for at-risk family members. Furthermore, the identification of germline co-deletions in cancer lays the foundation for the development of targeted therapeutic strategies aimed at restoring normal cellular regulation and improving patient management.
Topics: Humans; Cyclin-Dependent Kinase Inhibitor p16; Astrocytoma; Cyclin-Dependent Kinase Inhibitor p15; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Genetic Predisposition to Disease; Male; Female; Adult; Brain Neoplasms; Pedigree; Magnetic Resonance Imaging; Gene Deletion
PubMed: 38936911
DOI: 10.21873/invivo.13617 -
European Journal of Cancer (Oxford,... Jun 2024Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric... (Review)
Review
Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.
PubMed: 38936103
DOI: 10.1016/j.ejca.2024.114145 -
JCO Precision Oncology Jun 2024The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II...
Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.
PURPOSE
The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor.
METHODS
As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS).
RESULTS
Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with -altered CNS tumors achieved stable disease >6 months.
CONCLUSION
Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.
Topics: Humans; Adolescent; Child; Female; Male; Young Adult; Child, Preschool; Neoplasms; Infant; United States; Mitogen-Activated Protein Kinases; National Cancer Institute (U.S.); MAP Kinase Signaling System; Aminopyridines; Pyrroles
PubMed: 38935895
DOI: 10.1200/PO.24.00103 -
PloS One 2024Neurotrophic receptor tyrosine kinases (NTRKs) belong to the receptor tyrosine kinase (RTK) family. NTRKs are responsible for the activation of multiple downstream...
Neurotrophic receptor tyrosine kinases (NTRKs) belong to the receptor tyrosine kinase (RTK) family. NTRKs are responsible for the activation of multiple downstream signaling pathways that regulate cell growth, proliferation, differentiation, and apoptosis. NTRK-associated mutations often result in oncogenesis and lead to aberrant activation of downstream signaling pathways including MAPK, JAK/STAT, and PLCγ1. This study characterizes the NACC2-NTRK2 oncogenic fusion protein that leads to pilocytic astrocytoma and pediatric glioblastoma. This fusion joins the BTB domain (Broad-complex, Tramtrack, and Bric-a-brac) domain of NACC2 (Nucleus Accumbens-associated protein 2) with the transmembrane helix and tyrosine kinase domain of NTRK2. We focus on identifying critical domains for the biological activity of the fusion protein. Mutations were introduced in the charged pocket of the BTB domain or in the monomer core, based on a structural comparison of the NACC2 BTB domain with that of PLZF, another BTB-containing protein. Mutations were also introduced into the NTRK2-derived portion to allow comparison of two different breakpoints that have been clinically reported. We show that activation of the NTRK2 kinase domain relies on multimerization of the BTB domain in NACC2-NTRK2. Mutations which disrupt BTB-mediated multimerization significantly reduce kinase activity and downstream signaling. The ability of these mutations to abrogate biological activity suggests that BTB domain inhibition could be a potential treatment for NACC2-NTRK2-induced cancers. Removal of the transmembrane helix leads to enhanced stability of the fusion protein and increased activity of the NACC2-NTRK2 fusion, suggesting a mechanism for the oncogenicity of a distinct NACC2-NTRK2 isoform observed in pediatric glioblastoma.
Topics: Humans; Oncogene Proteins, Fusion; Receptor, trkB; Protein Domains; Mutation; Membrane Glycoproteins; Glioblastoma; Signal Transduction; Protein Multimerization
PubMed: 38935636
DOI: 10.1371/journal.pone.0301730 -
Neuromolecular Medicine Jun 2024Glioma is the most common primary intracranial tumor with high mortality and poor prognosis. The purpose of this study was to investigate how single-nucleotide...
Glioma is the most common primary intracranial tumor with high mortality and poor prognosis. The purpose of this study was to investigate how single-nucleotide polymorphisms (SNPs) of the NID2 gene affect glioma risk and prognosis. Four candidate SNPs of NID2 in 529 glioma patients and 478 healthy controls were successfully genotyped by Agena MassARRAY mass spectrometer. Logistic regression was utilized to assess the associations between NID2 SNPs and glioma risk under different genetic models. Furthermore, the relationship between risk-related SNPs in NID2 and the prognosis of glioma patients was explored through Kaplan-Meier (KM) survival curve and Cox proportional hazard regression analysis. The results showed that rs11846847 (OR 1.24, p = 0.017) and rs1874569 (OR 1.22, p = 0.026) were significantly associated with an increased risk of glioma, and rs11846847 also had a risk-increasing effect on glioma in participants ≤ 40 years old. The interaction model of rs11846847 and rs1874569 could be more suitable for forecasting glioma risk. We also discovered a significant association between rs1874569 and poor prognosis in glioma patients (HR 1.32, p = 0.039) and especially CC genotype was relevant to shorter overall survival (OS) and progression-free survival (PFS) in patients with high-grade glioma. Additionally, the study demonstrated that gross total resection or chemotherapy improve glioma prognosis in the Chinese Han population. This study is the first to provide evidence for the association of NID2 SNPs with glioma risk and prognosis, suggesting that NID2 variants might be potential factors for glioma.
Topics: Humans; Polymorphism, Single Nucleotide; Glioma; Female; Male; Brain Neoplasms; Prognosis; Adult; Middle Aged; Asian People; Genetic Predisposition to Disease; Calcium-Binding Proteins; China; Case-Control Studies; Kaplan-Meier Estimate; Genotype; Proportional Hazards Models; Risk Factors; East Asian People; Cell Adhesion Molecules
PubMed: 38935278
DOI: 10.1007/s12017-024-08795-0 -
Journal of Computational Biology : a... Jun 2024The prompt and precise identification and delineation of tumor regions within glioma brain images are critical for mitigating the risks associated with this...
The prompt and precise identification and delineation of tumor regions within glioma brain images are critical for mitigating the risks associated with this life-threatening ailment. In this study, we employ the UNet convolutional neural network (CNN) architecture for glioma tumor detection. Our proposed methodology comprises a transformation module, a feature extraction module, and a tumor segmentation module. The spatial domain representation of brain magnetic resonance imaging images undergoes decomposition into low- and high-frequency subbands via a non-subsampled shearlet transform. Leveraging the selective and directive characteristics of this transform enhances the classification efficacy of our proposed system. Shearlet features are extracted from both low- and high-frequency subbands and subsequently classified using the UNet-CNN architecture to identify tumor regions within glioma brain images. We validate our proposed glioma tumor detection methodology using publicly available datasets, namely Brain Tumor Segmentation (BRATS) 2019 and The Cancer Genome Atlas (TCGA). The mean classification rates achieved by our system are 99.1% for the BRATS 2019 dataset and 97.8% for the TCGA dataset. Furthermore, our system demonstrates notable performance metrics on the BRATS 2019 dataset, including 98.2% sensitivity, 98.7% specificity, 98.9% accuracy, 98.7% intersection over union, and 98.5% disc similarity coefficient. Similarly, on the TCGA dataset, our system achieves 97.7% sensitivity, 98.2% specificity, 98.7% accuracy, 98.6% intersection over union, and 98.4% disc similarity coefficient. Comparative analysis against state-of-the-art methods underscores the efficacy of our proposed glioma brain tumor detection approach.
PubMed: 38934096
DOI: 10.1089/cmb.2023.0339 -
Frontiers in Oncology 2024To review our single-institution experience in the surgical management of foramen magnum tumors via a far-lateral approach using an oblique straight incision.
OBJECTIVE
To review our single-institution experience in the surgical management of foramen magnum tumors via a far-lateral approach using an oblique straight incision.
METHODS
From October 2023 to January 2024, four cases of tumors in the foramen magnum area treated at the Capital Medical University-affiliated XuanWu hospital neurosurgery department were involved in this study. All cases were managed with a far-lateral approach using an oblique straight incision. We retrospectively reviewed the clinical and imaging data, as well as the surgical strategies employed.
RESULTS
Three cases of foramen magnum meningiomas and one case of glioma of the ventral medulla. All cases underwent a far-lateral approach using an oblique straight incision; all cases had a gross total resection, and the wounds healed well without cerebral fluid leakage or scalp hydrops. Except for one case of right foramen magnum meningioma, which had dysphagia and pneumothorax, the other cases were without any postoperative complications.
CONCLUSION
A far-lateral approach using an oblique straight incision can preserve muscle integrity and minimize subcutaneous exposure, allowing for complete anatomical reduction of muscles. This craniectomy method is simple and replicable, making it worthy of further clinical practice.
PubMed: 38933447
DOI: 10.3389/fonc.2024.1391002 -
Frontiers in Computational Neuroscience 2024The necessity of prompt and accurate brain tumor diagnosis is unquestionable for optimizing treatment strategies and patient prognoses. Traditional reliance on Magnetic...
BACKGROUND
The necessity of prompt and accurate brain tumor diagnosis is unquestionable for optimizing treatment strategies and patient prognoses. Traditional reliance on Magnetic Resonance Imaging (MRI) analysis, contingent upon expert interpretation, grapples with challenges such as time-intensive processes and susceptibility to human error.
OBJECTIVE
This research presents a novel Convolutional Neural Network (CNN) architecture designed to enhance the accuracy and efficiency of brain tumor detection in MRI scans.
METHODS
The dataset used in the study comprises 7,023 brain MRI images from figshare, SARTAJ, and Br35H, categorized into glioma, meningioma, no tumor, and pituitary classes, with a CNN-based multi-task classification model employed for tumor detection, classification, and location identification. Our methodology focused on multi-task classification using a single CNN model for various brain MRI classification tasks, including tumor detection, classification based on grade and type, and tumor location identification.
RESULTS
The proposed CNN model incorporates advanced feature extraction capabilities and deep learning optimization techniques, culminating in a groundbreaking paradigm shift in automated brain MRI analysis. With an exceptional tumor classification accuracy of 99%, our method surpasses current methodologies, demonstrating the remarkable potential of deep learning in medical applications.
CONCLUSION
This study represents a significant advancement in the early detection and treatment planning of brain tumors, offering a more efficient and accurate alternative to traditional MRI analysis methods.
PubMed: 38933391
DOI: 10.3389/fncom.2024.1418546 -
Nuclear Medicine and Molecular Imaging Jun 2024Positron emission tomography/computed tomography (PET/CT) has dramatically altered the landscape of noninvasive glioma evaluation, offering complementary insights to... (Review)
Review
Positron emission tomography/computed tomography (PET/CT) has dramatically altered the landscape of noninvasive glioma evaluation, offering complementary insights to those gained through magnetic resonance imaging (MRI). PET/CT scans enable a multifaceted analysis of glioma biology, supporting clinical applications from grading and differential diagnosis to mapping the full extent of tumors and planning subsequent treatments and evaluations. With a broad array of specialized radiotracers, researchers and clinicians can now probe various biological characteristics of gliomas, such as glucose utilization, cellular proliferation, oxygen deficiency, amino acid trafficking, and reactive astrogliosis. This review aims to provide a recent update on the application of versatile PET/CT radiotracers in glioma research and clinical practice.
PubMed: 38932755
DOI: 10.1007/s13139-024-00847-4 -
Pharmaceutics Jun 2024EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic...
EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic single-stranded oligonucleotides that bind to biochemical target molecules with high binding affinity and specificity. This study examined the potential of the Ga-NOTA-EGFRvIII aptamer as a nuclear imaging probe for visualizing EGFRvIII-expressing glioblastoma by positron emission tomography (PET). EGFRvIII aptamer was selected using the SELEX technology, and flow cytometry and fluorescence microscopy verified the high binding affinity to EGFRvIII positive U87MG vIII 4.12 glioma cells but not to EGFRvIII negative U87MG cells. The EGFRvIII aptamer was conjugated with a chelator (1,4,7-triazanonane-1,4,7-triyl)triacetic acid (NOTA) for Ga-labeling. The Ga-NOTA-EGFRvIII aptamer was prepared using the preconcentration-based labeling method with a high radiolabeling yield at room temperature. Ex vivo biodistribution analyses confirmed the significantly higher tumor uptake of the Ga-NOTA-EGFRvIII aptamer in EGFRvIII-expressing xenograft tumors than that in EGFRvIII negative tumors, confirming the specific tumor uptake of the Ga-NOTA-EGFRvIII aptamer in vivo. PET imaging studies revealed a high retention rate of the Ga-NOTA-EGFRvIII aptamer in U87MG vIII 4.12 tumors but only low uptake levels in U87-MG tumors, suggesting that the Ga-NOTA-EGFRvIII aptamer may be used as a PET imaging agent for EGFRvIII-expressing glioblastoma.
PubMed: 38931935
DOI: 10.3390/pharmaceutics16060814