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Diagnostic and Interventional Radiology... Jun 2024This study aimed to detect supratentorial cortical and subcortical morphological changes in pediatric patients with infratentorial tumors.
PURPOSE
This study aimed to detect supratentorial cortical and subcortical morphological changes in pediatric patients with infratentorial tumors.
METHODS
The study included 24 patients aged 4-18 years who were diagnosed with primary infratentorial tumors and 41 age- and gender-matched healthy controls. Synthetic magnetization-prepared rapid gradient echo images of brain magnetic resonance imaging were generated using deep learning algorithms applied to T2-axial images. The cortical thickness, surface area, volume, and local gyrification index (LGI), as well as subcortical gray matter volumes, were automatically calculated. Surface-based morphometry parameters for the patient and control groups were compared using the general linear model, and volumes between subcortical structures were compared using the t-test and Mann-Whitney U test.
RESULTS
In the patient group, cortical thinning was observed in the left supramarginal, and cortical thickening was observed in the left caudal middle frontal (CMF), left fusiform, left lateral orbitofrontal, left lingual gyrus, right CMF, right posterior cingulate, and right superior frontal ( < 0.050). The patient group showed a volume reduction in the pars triangularis, paracentral, precentral, and supramarginal gyri of the left hemisphere ( < 0.05). A decreased surface area was observed in the bilateral superior frontal and cingulate gyri ( < 0.05). The patient group exhibited a decreased LGI in the right precentral and superior temporal gyri, left supramarginal, and posterior cingulate gyri and showed an increased volume in the bilateral caudate nucleus and hippocampus, while a volume reduction was observed in the bilateral putamen, pallidum, and amygdala ( < 0.05). The ventricular volume and tumor volume showed a positive correlation with the cortical thickness in the bilateral CMF while demonstrating a negative correlation with areas exhibiting a decreased LGI ( < 0.05).
CONCLUSION
Posterior fossa tumors lead to widespread morphological changes in cortical structures, with the most prominent pattern being hypogyria.
CLINICAL SIGNIFICANCE
This study illuminates the neurological impacts of infratentorial tumors in children, providing a foundation for future therapeutic strategies aimed at mitigating these adverse cortical and subcortical changes and improving patient outcomes.
PubMed: 38836466
DOI: 10.4274/dir.2024.242652 -
Neuro-oncology Jun 2024Neurocognition can be severely affected in pediatric brain tumor survivors. We analyzed the association of cognitive functioning with radiotherapy dose, postoperative...
BACKGROUND
Neurocognition can be severely affected in pediatric brain tumor survivors. We analyzed the association of cognitive functioning with radiotherapy dose, postoperative cerebellar mutism syndrome (pCMS), hydrocephalus, intraventricular methotrexate (MTX) application, tumor localization and biology in pediatric survivors of a posterior fossa tumor.
METHODS
Subdomain-specific neurocognitive outcome data from 279 relapse-free survivors of the HIT-2000 trial (241 medulloblastoma and 38 infratentorial ependymoma) using the Neuropsychological Basic Diagnostic (NBD) tool based on Cattell-Horn-Carroll's model for intelligence were analyzed.
RESULTS
Cognitive performance 5.14 years (mean; range=1.52-13.02) after diagnosis was significantly below normal for all subtests. Processing speed and psychomotor abilities were most affected. Influencing factors were domain-specific: CSI-dose had strong impact on most subtests. pCMS was associated with psychomotor abilities (β=-0.25 to -0.16) and processing speed (β=-0.32). Postoperative hydrocephalus correlated with crystallized intelligence (β=-0.20) and short-term memory (β=-0.15), age with crystallized intelligence (β=0.15) and psychomotor abilities (β=-0.16 and β=-0.17). Scores for fluid intelligence (β=-0.23), short-term memory (β=-0.17) and visual processing (β=-0.25) declined, and scores for selective attention improved (β=0.29) with time after diagnosis.
CONCLUSION
Dose of CSI was strongly associated with neurocognitive outcome. Low psychomotor abilities and processing speed both in patients treated with and without CSI suggest a strong contribution of the tumor and its surgery on these functions. Future research therefore should analyze strategies to both reduce CSI-dose and toxicity caused by other treatment modalities.
PubMed: 38835160
DOI: 10.1093/neuonc/noae092 -
Developmental Cell May 2024Normal cells coordinate proliferation and differentiation by precise tuning of gene expression based on the dynamic shifts of the epigenome throughout the developmental...
Normal cells coordinate proliferation and differentiation by precise tuning of gene expression based on the dynamic shifts of the epigenome throughout the developmental timeline. Although non-mutational epigenetic reprogramming is an emerging hallmark of cancer, the epigenomic shifts that occur during the transition from normal to malignant cells remain elusive. Here, we capture the epigenomic changes that occur during tumorigenesis in a prototypic embryonal brain tumor, medulloblastoma. By comparing the epigenomes of the different stages of transforming cells in mice, we identify nuclear factor I family of transcription factors, known to be cell fate determinants in development, as oncogenic regulators in the epigenomes of precancerous and cancerous cells. Furthermore, genetic and pharmacological inhibition of NFIB validated a crucial role of this transcription factor by disrupting the cancer epigenome in medulloblastoma. Thus, this study exemplifies how epigenomic changes contribute to tumorigenesis via non-mutational mechanisms involving developmental transcription factors.
PubMed: 38834071
DOI: 10.1016/j.devcel.2024.05.013 -
Journal of Imaging Informatics in... Jun 2024The aim of this study was to validate a novel medical virtual reality (VR) platform used for medical image segmentation and contouring in radiation oncology and 3D...
A Pilot Clinical and Technical Validation of an Immersive Virtual Reality Platform for 3D Anatomical Modeling and Contouring in Support of Surgical and Radiation Oncology Treatment Planning.
The aim of this study was to validate a novel medical virtual reality (VR) platform used for medical image segmentation and contouring in radiation oncology and 3D anatomical modeling and simulation for planning medical interventions, including surgery. The first step of the validation was to verify quantitatively and qualitatively that the VR platform can produce substantially equivalent 3D anatomical models, image contours, and measurements to those generated with existing commercial platforms. To achieve this, a total of eight image sets and 18 structures were segmented using both VR and reference commercial platforms. The image sets were chosen to cover a broad range of scanner manufacturers, modalities, and voxel dimensions. The second step consisted of evaluating whether the VR platform could provide efficiency improvements for target delineation in radiation oncology planning. To assess this, the image sets for five pediatric patients with resected standard-risk medulloblastoma were used to contour target volumes in support of treatment planning of craniospinal irradiation, requiring complete inclusion of the entire cerebral-spinal volume. Structures generated in the VR and the commercial platforms were found to have a high degree of similarity, with dice similarity coefficient ranging from 0.963 to 0.985 for high-resolution images and 0.920 to 0.990 for lower resolution images. Volume, cross-sectional area, and length measurements were also found to be in agreement with reference values derived from a commercial system, with length measurements having a maximum difference of 0.22 mm, angle measurements having a maximum difference of 0.04°, and cross-sectional area measurements having a maximum difference of 0.16 mm. The VR platform was also found to yield significant efficiency improvements, reducing the time required to delineate complex cranial and spinal target volumes by an average of 50% or 29 min.
PubMed: 38831190
DOI: 10.1007/s10278-024-01048-3 -
Clinical Neurology and Neurosurgery Jul 2024Cerebellar mutism syndrome (CMS) is a serious complication of posterior fossa surgeries affecting mainly pediatric age group. The pathophysiology is still not fully... (Review)
Review
INTRODUCTION
Cerebellar mutism syndrome (CMS) is a serious complication of posterior fossa surgeries affecting mainly pediatric age group. The pathophysiology is still not fully understood. It adversely affects the recovery of patients. There is no definitive and standardized management for CMS. However pharmacological therapy has been used in reported cases with variable effectiveness. We aim through this review to summarize the available evidence on pharmacological agents used to treat CMS.
METHOD
A thorough systematic review until December 2022, was conducted using PubMed Central, Embase, and Web of Science, databases to identify case reports and case series of CMS patients who underwent posterior fossa surgery and received pharmacological treatment. Patients with pathologies other than posterior fossa lesions were excluded from the study.
RESULTS
Of 592 initial studies, 8 studies met our eligibility criteria for inclusion, with 3 more studies were added through manual search; reporting on 13 patients. The median age of 13 years (Standard deviation SD=10.60). The most frequent agent used was Bromocriptine. Other agents were fluoxetine, midazolam, zolpidem, and arpiprazole. Most patients recovered within 48 hours of initiating medical therapy. The median follow-up period was 4 months (SD=13.8). All patients showed complete recovery at the end of follow-up period.
CONCLUSION
Cerebellar mutism syndrome is reported after posterior fossa surgeries, despite attempts to identify risk factors, pathophysiology, and management of CMS, it remains a challenging condition with significant morbidity. Different Pharmacological treatments have been proposed with promising results. Further studies and formalized clinical trials are needed to evaluate available options and their effectiveness.
Topics: Humans; Mutism; Neurosurgical Procedures; Postoperative Complications; Cranial Fossa, Posterior; Cerebellar Diseases; Child; Adolescent
PubMed: 38823197
DOI: 10.1016/j.clineuro.2024.108352 -
Bioengineering & Translational Medicine May 2024Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) is an effective tumor treatment capable of eliciting an antitumor immune response. Motivated by the...
Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) is an effective tumor treatment capable of eliciting an antitumor immune response. Motivated by the ability of PBNP-PTT to potentiate endogenous immune responses, we recently demonstrated that PBNP-PTT could be used ex vivo to generate tumor-specific T cells against glioblastoma (GBM) cell lines as an adoptive T cell therapy (ATCT). In this study, we further developed this promising T cell development platform. First, we assessed the phenotype and function of T cells generated using PBNP-PTT. We observed that PBNP-PTT facilitated CD8+ T cell expansion from healthy donor PBMCs that secreted IFNγ and TNFα and upregulated CD107a in response to engagement with target U87 cells, suggesting specific antitumor T cell activation and degranulation. Further, CD8+ effector and effector memory T cell populations significantly expanded after co-culture with U87 cells, consistent with tumor-specific effector responses. In orthotopically implanted U87 GBM tumors in vivo, PBNP-PTT-derived T cells effectively reduced U87 tumor growth and generated long-term survival in >80% of tumor-bearing mice by Day 100, compared to 0% of mice treated with PBS, non-specific T cells, or T cells expanded from lysed U87 cells, demonstrating an enhanced antitumor efficacy of this ATCT platform. Finally, we tested the generalizability of our approach by generating T cells targeting medulloblastoma (D556), breast cancer (MDA-MB-231), neuroblastoma (SH-SY5Y), and acute monocytic leukemia (THP-1) cell lines. The resulting T cells secreted IFNγ and exerted increased tumor-specific cytolytic function relative to controls, demonstrating the versatility of PBNP-PTT in generating tumor-specific T cells for ATCT.
PubMed: 38818122
DOI: 10.1002/btm2.10639 -
Journal of Neuropathology and... May 2024
PubMed: 38812094
DOI: 10.1093/jnen/nlae051 -
BioRxiv : the Preprint Server For... May 2024Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase...
Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB) , the most common embryonal brain tumor in children, and pineoblastoma . These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST . However, their mechanism of action remains unresolved. Here, we elucidate the mechanistic basis by which KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2, the direct neomorphic target of the substrate receptor. Using deep mutational scanning, we systematically map the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy (cryo-EM) analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat propeller domains. The interface between HDAC1 and one of the KBTBD4 propellers is stabilized by the MB mutations, which directly insert a bulky side chain into the active site pocket of HDAC1. Our structural and mutational analyses inform how this hotspot E3-neo-substrate interface can be chemically modulated. First, our results unveil a converging shape complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface, the aberrant degradation of CoREST, and the growth of KBTBD4-mutant MB models. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions and pharmacological strategies to modulate their action for therapeutic applications.
PubMed: 38798357
DOI: 10.1101/2024.05.14.593970 -
BioRxiv : the Preprint Server For... May 2024Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB subtype accounts for about 25% of MB diagnoses and is associated with the most unfavorable...
BACKGROUND
Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB subtype accounts for about 25% of MB diagnoses and is associated with the most unfavorable outcomes. Herein, we report that more than half of group 3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are tumor antigens, expressed in several types of adult cancers and associated with poorer prognosis and therapy resistance; however, their expression in pediatric cancers is mostly unknown. The aim of this study was to determine whether are activated in pediatric MB.
METHODS
To determine frequency in pediatric MB, we obtained formalin-fixed paraffin-embedded tissue (FFPE) samples of 34 patients, collected between 2008 - 2015, from the Children's Medical Center Dallas pathology archives and applied our validated reverse transcription quantitative PCR (RT-qPCR) assay to measure the relative expression of 23 cancer-testis antigen genes. To validate our data, we analyzed several published datasets from pediatric MB patients and patient-derived orthotopic xenografts, totaling 860 patients. We then examined how expression affects the growth and oncogenic potential of medulloblastoma cells by CRISPR-Cas9- and siRNA-mediated gene depletion.
RESULTS
Our RT-qPCR analysis suggested that were expressed in group 3/4 medulloblastoma. Further mining of bulk and single-cell RNA-sequencing datasets confirmed that 50-75% of group 3 tumors activate a subset of genes. Depletion of MAGEAs, B2, and Cs alter MB cell survival, viability, and clonogenic growth due to decreased proliferation and increased apoptosis.
CONCLUSIONS
These results indicate that targeting MAGEs in medulloblastoma may be a potential therapeutic option for group 3 medulloblastomas.
KEY POINTS
Several Type I CTAs are expressed in >60% of group 3 MBs. Type I MAGEs affect MB cell proliferation and apoptosis. are potential biomarkers and therapeutic targets for group 3 MBs.
IMPORTANCE OF THE STUDY
This study is the first comprehensive analysis of all Type I CTAs ( , , and subfamily members) in pediatric MBs. Our results show that more than 60% of group 3 MBs express genes, which are required for the viability and growth of cells in which they are expressed. Collectively, these data provide novel insights into the antigen landscape of pediatric MBs. The activation of genes in group 3 MBs presents potential stratifying and therapeutic options.
PubMed: 38798351
DOI: 10.1101/2024.05.14.594201 -
Pharmaceutics May 2024Medulloblastomas (MBs) represent the most prevalent malignant solid tumors in kids. The conventional treatment regimen for MBs includes surgical removal of the tumor,...
Medulloblastomas (MBs) represent the most prevalent malignant solid tumors in kids. The conventional treatment regimen for MBs includes surgical removal of the tumor, followed by radiation and chemotherapy. However, this approach is associated with significant morbidity and detrimental side effects. Consequently, there is a critical demand for more precise and less harmful treatments to enhance the quality of life for survivors. CEP-18770, a novel proteasome inhibitor that targets the 20S subunit, has emerged as a promising candidate, due to its anticancer activity in metastatic solid tumors and multiple myeloma, coupled with an acceptable safety profile. In this study, we aimed to assess the anticancer efficacy of CEP-18770 by employing a variety of MB patient-derived cells and cell lines. Our preclinical investigations revealed that CEP-18770 effectively inhibits proteasome activity and induces apoptosis in MBs cells. Furthermore, we discovered that CEP-18770 and cisplatin, a current component of MB therapy, exhibit a synergistic apoptotic effect. This paper shows that CEP-18770 holds potential as an adjunctive treatment for MB tumors, thereby paving the way for more targeted and less toxic therapeutic strategies.
PubMed: 38794334
DOI: 10.3390/pharmaceutics16050672