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Postoperative radiotherapy remains the gold standard for malignant glioma treatment. Clinical limitations, including tumor growth between surgery and radiotherapy and the emergence of radioresistance, reduce treatment effectiveness and result in local disease progression. This study aimed to develop a local drug delivery system to inhibit tumor growth before radiotherapy and enhance the subsequent anticancer effects of limited-dose radiotherapy. We developed a compound of carboplatin-loaded hydrogel (CPH) incorporated with carboplatin-loaded calcium carbonate (CPCC) to enable two-stage (peritumoral and intracellular) release of carboplatin to initially inhibit tumor growth and to synergize with limited-dose radiation (10 Gy in a single fraction) to eliminate malignant glioma (ALTS1C1 cells) in a C57BL/6 mouse subcutaneous tumor model. The doses of carboplatin in CPH and CPCC treatments were 150 µL (carboplatin concentration of 5 mg/mL) and 15 mg (carboplatin concentration of 4.1 µg/mg), respectively. Mice receiving the combination of CPH-CPCC treatment and limited-dose radiation exhibited significantly reduced tumor growth volume compared to those receiving double-dose radiation alone. Furthermore, combining CPH-CPCC treatment with limited-dose radiation resulted in significantly longer progression-free survival than combining CPH treatment with limited-dose radiation. Local CPH-CPCC delivery synergized effectively with limited-dose radiation to eliminate mouse glioma, offering a promising solution for overcoming clinical limitations.
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Carbonato de Calcio , Carboplatino , Glioma , Hidrogeles , Ratones Endogámicos C57BL , Animales , Glioma/patología , Glioma/tratamiento farmacológico , Glioma/radioterapia , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Carboplatino/farmacología , Hidrogeles/química , Línea Celular Tumoral , Carbonato de Calcio/química , Ratones , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapiaRESUMEN
Background: Diffuse astrocytomas preferentially infiltrate eloquent areas affecting the outcome. A preoperative understanding of isocitrate dehydrogenase (IDH) status may offer opportunities for specific targeted therapies impacting treatment management. The aim of this study was to analyze clinical, topographical, radiological in WHO 2 astrocytomas with different IDH status and the long-term patient's outcome. Methods: A series of confirmed WHO 2 astrocytoma patients (between 2005 and 2015) were retrospectively analyzed. MRI sequences (FLAIR) were used for tumor volume segmentation and to create a frequency map of their locations into the Montreal Neurological Institute (MNI) space. The Brain-Grid (BG) system (standardized radiological tool of intersected lines according to anatomical landmarks) was used as an overlay for infiltration analysis of each tumor. Long-term follow-up was used to perform a survival analysis. Results: Forty patients with confirmed IDH status (26 IDH-mutant, IDHm/14 IDH-wild type, IDHwt) according to WHO 2021 classification were included with a mean follow-up of 7.8 years. IDHm astrocytomas displayed a lower number of BG-voxels (P < 0.05) and were preferentially located in the anterior insular region. IDHwt group displayed a posterior insular and peritrigonal location. IDHwt group displayed a shorter OS compared with IDHm (P < 0.05), with the infiltration of 7 or more BG-voxels as an independent factor predicting a shorter OS. Conclusions: IDHm and IDHwt astrocytomas differed in preferential location, number of BG-voxels and OS at long follow-up time. The number of BG-voxels affected the OS in IDHwt was possibly reflecting higher tumor invasiveness. We encourage the systematic use of alternative observational tools, such as gradient maps and the Brain-Grid analysis, to better detect differences of tumor invasiveness in diffuse low-grade gliomas subtypes.
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Astrocitoma , Neoplasias Encefálicas , Isocitrato Deshidrogenasa , Imagen por Resonancia Magnética , Humanos , Isocitrato Deshidrogenasa/genética , Astrocitoma/patología , Astrocitoma/diagnóstico por imagen , Astrocitoma/genética , Femenino , Masculino , Estudios Retrospectivos , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Pronóstico , Persona de Mediana Edad , Adulto , Mutación , Anciano , Invasividad Neoplásica , Análisis de Supervivencia , Adulto JovenRESUMEN
Brain tumors pose significant global health concerns due to their high mortality rates and limited treatment options. These tumors, arising from abnormal cell growth within the brain, exhibits various sizes and shapes, making their manual detection from magnetic resonance imaging (MRI) scans a subjective and challenging task for healthcare professionals, hence necessitating automated solutions. This study investigates the potential of deep learning, specifically the DenseNet architecture, to automate brain tumor classification, aiming to enhance accuracy and generalizability for clinical applications. We utilized the Figshare brain tumor dataset, comprising 3,064 T1-weighted contrast-enhanced MRI images from 233 patients with three prevalent tumor types: meningioma, glioma, and pituitary tumor. Four pre-trained deep learning models-ResNet, EfficientNet, MobileNet, and DenseNet-were evaluated using transfer learning from ImageNet. DenseNet achieved the highest test set accuracy of 96%, outperforming ResNet (91%), EfficientNet (91%), and MobileNet (93%). Therefore, we focused on improving the performance of the DenseNet, while considering it as base model. To enhance the generalizability of the base DenseNet model, we implemented a fine-tuning approach with regularization techniques, including data augmentation, dropout, batch normalization, and global average pooling, coupled with hyperparameter optimization. This enhanced DenseNet model achieved an accuracy of 97.1%. Our findings demonstrate the effectiveness of DenseNet with transfer learning and fine-tuning for brain tumor classification, highlighting its potential to improve diagnostic accuracy and reliability in clinical settings.
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Neoplasias Encefálicas , Aprendizaje Profundo , Imagen por Resonancia Magnética , Humanos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/clasificación , Imagen por Resonancia Magnética/métodos , Meningioma/diagnóstico por imagen , Meningioma/patología , Glioma/diagnóstico por imagen , Glioma/patología , Glioma/clasificación , Masculino , Femenino , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/clasificaciónRESUMEN
Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse models tested. We show these myeloid populations communicate with H3-mutant cells, mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients.
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Neoplasias Encefálicas , Glioma , Histonas , Mutación , Células Mieloides , Microambiente Tumoral , Animales , Glioma/genética , Glioma/inmunología , Glioma/patología , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Células Mieloides/metabolismo , Células Mieloides/inmunología , Histonas/metabolismo , Histonas/genética , Ratones , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Humanos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Regulación Neoplásica de la Expresión Génica , Análisis de la Célula IndividualRESUMEN
Glioblastoma (GBM) represents an aggressive brain tumor, characterized by intra- and inter-tumoral heterogeneity and therapy resistance, leading to unfavourable prognosis. An increasing number of studies pays attention on the regulation of ferroptosis, an iron-dependent cell death, as a strategy to reverse drug resistance in cancer. However, the debate on whether this strategy may have important implications for the treatment of GBM is still ongoing. In the present study, we used ferric ammonium citrate and erastin to evaluate ferroptosis induction effects on two human GBM cell lines, U-251 MG, with proneural characteristics, and T98-G, with a mesenchymal profile. The response to ferroptosis induction was markedly different between cell lines, indeed T98-G cells showed an enhanced antioxidant defence, with increased glutathione levels, as compared to U-251 MG cells. Moreover, using bioinformatic approaches and analysing publicly available datasets from patients' biopsies, we found that GBM with a mesenchymal phenotype showed an up-regulation of several genes involved in antioxidant mechanisms as compared to proneural subtype. Thus, our results suggest that GBM subtypes differently respond to ferroptosis induction, emphasizing the significance of further molecular studies on GBM to better discriminate between various tumor subtypes and progressively move towards personalized therapy.
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Antioxidantes , Ferroptosis , Glioblastoma , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Humanos , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Línea Celular Tumoral , Antioxidantes/farmacología , Antioxidantes/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Regulación Neoplásica de la Expresión Génica , Compuestos Férricos/farmacología , Compuestos de Amonio Cuaternario/farmacología , Glutatión/metabolismo , PiperazinasRESUMEN
OBJECTIVE: The E3 ubiquitin ligase is well recognized as a significant contributor to glioblastoma (GBM) progression and has promise as a prospective therapeutic target. This study explores the contribution of E3 ubiquitin ligase RNF122 in the GBM progression and the related molecular mechanisms. METHODS: RNF122 expression levels were evaluated using qRT-PCR, WB, and IHC, while functional assays besides animal experiments were used to assess RNF122's effect on GBM progression. We also tested the RNF122 impact on JAK2/STAT3/c-Myc signaling using WB. RESULTS: RNF122 was upregulated in GBM and correlated to the advanced stage and poor clinical outcomes, representing an independent prognostic factor. Based on functional assays, RNF122 promotes GBM growth and cell cycle, which was validated further in subsequent analyses by JAK2/STAT3/c-Myc pathway activation. Moreover, JAK2/STAT3 signaling pathway inhibitor WP1066 can weaken the effect of overexpression RNF122 on promoting GBM progression. CONCLUSION: Our results revealed that RNF122 caused an aggressive phenotype to GBM and was a poor prognosticator; thus, targeting RNF122 may be effectual in GBM treatment.
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Neoplasias Encefálicas , Glioblastoma , Janus Quinasa 2 , Proteínas Proto-Oncogénicas c-myc , Factor de Transcripción STAT3 , Transducción de Señal , Ubiquitina-Proteína Ligasas , Humanos , Glioblastoma/metabolismo , Glioblastoma/patología , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT3/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Masculino , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Femenino , Animales , Línea Celular Tumoral , Ratones Desnudos , Persona de Mediana Edad , Ratones , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Ratones Endogámicos BALB C , Péptidos y Proteínas de Señalización IntracelularRESUMEN
BACKGROUND: The radiogenomic analysis has provided valuable imaging biomarkers with biological insights for gliomas. The radiogenomic markers for molecular profile such as DNA methylation remain to be uncovered to assist the molecular diagnosis and tumor treatment. METHODS: We apply the machine learning approaches to identify the magnetic resonance imaging (MRI) features that are associated with molecular profiles in 146 patients with gliomas, and the fitting models for each molecular feature (MoRad) are developed and validated. To provide radiological annotations for the molecular profiles, we devise two novel approaches called radiomic oncology (RO) and radiomic set enrichment analysis (RSEA). RESULTS: The generated MoRad models perform well for profiling each molecular feature with radiomic features, including mutational, methylation, transcriptional, and protein profiles. Among them, the MoRad models have a remarkable performance in quantitatively mapping global DNA methylation. With RO and RSEA approaches, we find that global DNA methylation could be reflected by the heterogeneity in volumetric and textural features of enhanced regions in T2-weighted MRI. Finally, we demonstrate the associations of global DNA methylation with clinicopathological, molecular, and immunological features, including histological grade, mutations of IDH and ATRX, MGMT methylation, multiple methylation-high subtypes, tumor-infiltrating lymphocytes, and long-term survival outcomes. CONCLUSIONS: Global DNA methylation is highly associated with radiological profiles in glioma. Radiogenomic global methylation is an imaging-based quantitative molecular biomarker that is associated with specific consensus molecular subtypes and immune features.
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Neoplasias Encefálicas , Metilación de ADN , Glioma , Imagen por Resonancia Magnética , Humanos , Glioma/genética , Glioma/inmunología , Metilación de ADN/genética , Femenino , Masculino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Persona de Mediana Edad , Adulto , Aprendizaje Automático , Fenotipo , Anciano , Biomarcadores de Tumor/genéticaRESUMEN
Stereotactic needle biopsy stands as a crucial method for diagnosing intracranial lesions unsuitable for surgical intervention. Nonetheless, the potential for sampling errors lead to innovative approaches to enhance diagnostic precision. This study contrasts the outcomes of patients undergoing fluorescein-assisted frameless stereotactic needle biopsy with those receiving traditional biopsies to evaluate the impact on diagnostic accuracy and safety. This study included patients with contrast-enhancing intracranial lesions, comprising a prospective group undergoing fluorescein-assisted biopsies and a retrospective group undergoing conventional biopsies at the same institution. We've collected data on demographics, procedural specifics, diagnostic outcomes, and postoperative events. A comparative analysis involved 43 patients who received fluorescein-assisted biopsies against 77 patients who underwent conventional biopsies. The average age was 60.5 years. The fluorescein group exhibited a 93% success rate in diagnosis, markedly higher than the 70.1% in the non-fluorescein group (OR = 5.67; 95%IC: 1.59-20.24; p < 0.01). The rate of complications was statistically similar across both cohorts. Despite its established value, stereotactic needle biopsy is susceptible to inaccuracies and complications. The application of fluorescence-based adjuncts like 5-ALA and fluorescein has been investigated to improve diagnostic fidelity and reduce risks. These technologies potentially minimize the necessity for multiple biopsies, decrease surgical duration, and provide immediate verification of tumor presence. Fluorescein-assisted stereotactic biopsy emerges as an effective, secure alternative to conventional methods.
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Neoplasias Encefálicas , Fluoresceína , Humanos , Persona de Mediana Edad , Femenino , Masculino , Anciano , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/diagnóstico , Biopsia con Aguja/métodos , Biopsia con Aguja/efectos adversos , Adulto , Estudios Retrospectivos , Técnicas Estereotáxicas , Anciano de 80 o más Años , Estudios ProspectivosRESUMEN
Over the last decades, extracellular vesicles (EVs) have become increasingly popular for their roles in various pathologies, including cancer and neurological and immunological disorders. EVs have been considered for a long time as a means for normal cells to get rid of molecules it no longer needs. It is now well established that EVs play their biological roles also following uptake or by the interaction of EV surface proteins with cellular receptors and membranes. In this review, we summarize the current status of EV production and secretion in glioblastoma, the most aggressive type of glioma associated with high mortality. The main purpose is to shed light on the EVs as a universal mediator of interkingdom and intrakingdom communication in the context of tumor microenvironment heterogeneity. We focus on the immunomodulatory EV functions in glioblastoma-immune cross-talk to enhance immune escape and reprogram tumor-infiltrating immune cells. We critically examine the evidence that GBM-, immune cell-, and microbiome-derived EVs impact local tumor microenvironment and host immune responses, and can enter the circulatory system to disseminate and drive premetastatic niche formation in distant organs. Taking into account the current state of the art in intratumoral microbiome studies, we discuss the emerging role of bacterial EV in glioblastoma and its response to current and future therapies including immunotherapies.
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Neoplasias Encefálicas , Vesículas Extracelulares , Glioblastoma , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Glioblastoma/inmunología , Glioblastoma/patología , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Animales , Escape del Tumor , Comunicación Celular/inmunología , Inmunoterapia/métodos , Microbiota/inmunologíaRESUMEN
The stiffness of human cancers may be correlated with their pathology, and can be used as a biomarker for diagnosis, malignancy prediction, molecular expression, and postoperative complications. Neurosurgeons perform tumor resection based on tactile sensations. However, it takes years of surgical experience to appropriately distinguish brain tumors from surrounding parenchymal tissue. Haptics is a technology related to the touch sensation. Haptic technology can amplify, transmit, record, and reproduce real sensations, and the physical properties (e.g., stiffness) of an object can be quantified. In the present study, glioblastoma (SF126-firefly luciferase-mCherry [FmC], U87-FmC, U251-FmC) and malignant meningioma (IOMM-Lee-FmC, HKBMM-FmC) cell lines were transplanted into nude mice, and the stiffness of tumors and normal brain tissues were measured using our newly developed surgical forceps equipped with haptic technology. We found that all five brain tumor tissues were stiffer than normal brain tissue (p < 0.001), and that brain tumor pathology (three types of glioblastomas, two types of malignant meningioma) was significantly stiffer than normal brain tissue (p < 0.001 for all). Our findings suggest that tissue stiffness may be a useful marker to distinguish brain tumors from surrounding parenchymal tissue during microsurgery, and that haptic forceps may help neurosurgeons to sense minute changes in tissue stiffness.
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Neoplasias Encefálicas , Glioblastoma , Meningioma , Ratones Desnudos , Microcirugia , Animales , Humanos , Microcirugia/métodos , Microcirugia/instrumentación , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patología , Glioblastoma/cirugía , Glioblastoma/patología , Ratones , Meningioma/cirugía , Meningioma/patología , Línea Celular Tumoral , Instrumentos QuirúrgicosRESUMEN
Tumor-associated macrophages/microglia (TAMs) are highly plastic and heterogeneous immune cells that can be immune-supportive or tumor-supportive depending of the microenvironment. TAMs are the most abundant immune cells in glioblastoma (GB), and play a key role in immunosuppression. Therefore, TAMs reprogramming toward immune-supportive cells is a promising strategy to overcome immunosuppression. By leveraging scRNAseq human GB databases, we identified that Inhibitor of Apoptosis Proteins (IAP) were expressed by TAMs. To investigate their role in TAMs-related immunosuppression, we antagonized IAP using the central nervous system permeant SMAC mimetic GDC-0152 (SMg). On explants and cultured immune cells isolated from human GB samples, SMg modified TAMs activity. We showed that SMg treatment promoted microglia pro-apoptotic and anti-tumoral function via caspase-3 pro-inflammatory cleavage and the inhibition of tumoroids growth. Then we designed a relevant immunogenic mouse GB model to decipher the spatio-temporal densities, distribution, phenotypes and function of TAMs with or without SMg treatment. We used 3D imaging techniques, a transgenic mouse with fluorescent TAM subsets and mass cytometry. We confirmed that SMg promoted microglia activation, antigen-presenting function and tumor infiltration. In addition, we observed a remodeling of blood vessels, a decrease in anti-inflammatory macrophages and an increased level of monocytes and their mo-DC progeny. This remodeling of the TAM landscape is associated with an increase in CD8 T cell density and activation. Altogether, these results demonstrated that SMg drives the immunosuppressive basal microglia toward an active phenotype with pro-apoptotic and anti-tumoral function and modifies the GB immune landscape. This identifies IAP as targets of choice for a potential mechanism-based therapeutic strategy and SMg as a promising molecule for this application.
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Glioblastoma , Microglía , Fenotipo , Microambiente Tumoral , Glioblastoma/inmunología , Glioblastoma/patología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/inmunología , Humanos , Ratones , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Proteínas Reguladoras de la Apoptosis/metabolismo , Ratones Endogámicos C57BL , Proteínas Mitocondriales/metabolismo , Línea Celular Tumoral , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones TransgénicosRESUMEN
Objectives: This study aims to develop brain-targeted temozolomide (TMZ) nanograins using the biodegradable polymer material PEG-PLA as a carrier. The model drug TMZ was encapsulated within the polymer using targeted nanotechnology. Key characteristics such as appearance, particle size, size distribution, drug loading capacity, in vitro release rate, stability, and anti-tumor effects were systematically evaluated through in vitro experiments. Methods: Transmission electron microscopy (TEM) and Malvern size analyzer were employed to observe the morphological and particle size features of the TMZ nanospheres at various time points to assess stability. The effects of TMZ nanograins on glioma cell viability and apoptosis were evaluated using MTT assays and flow cytometry. Results: The targeted TMZ nano-micelles were successfully synthesized. After loading and targeted modifications, the particle size increased from 50.7 to 190 nm, indicating successful encapsulation of TMZ. The average particle size of the nano-micelles remained stable around 145 ± 10 nm at 1 day, 15 days, and 30 days post-preparation. The release rate of the nano-micelles was monitored at 2 h, 12 h, 24 h, and 48 h post-dialysis, ultimately reaching 95.8%. Compared to TMZ alone, the TMZ-loaded PEG-PLA nano-micelles exhibited enhanced cytotoxicity and apoptosis in glioma cells. This was accompanied by increased mitochondrial membrane potential and reactive oxygen species (ROS) levels following treatment with the TMZ nano-micelles. Conclusions: TMZ-loaded nano-micelles demonstrated a gradual release profile and significantly enhanced inhibitory effects on human glioma U251 cells compared to TMZ alone. The findings suggest that TMZ-loaded PEG-PLA nano-micelles may offer a more effective therapeutic approach for glioma treatment.
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Antineoplásicos Alquilantes , Apoptosis , Glioma , Micelas , Tamaño de la Partícula , Polietilenglicoles , Temozolomida , Temozolomida/farmacología , Temozolomida/química , Humanos , Glioma/tratamiento farmacológico , Glioma/patología , Glioma/metabolismo , Línea Celular Tumoral , Polietilenglicoles/química , Polietilenglicoles/farmacología , Apoptosis/efectos de los fármacos , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/química , Transferrina/química , Portadores de Fármacos/química , Supervivencia Celular/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Nanopartículas/química , Poliésteres/químicaRESUMEN
Tissue-agnostic, molecularly targeted therapies are becoming increasingly common in cancer treatment. The molecular drivers of some classes and subclasses of tumors are rapidly being uncovered in an era of deep tumor sequencing occurring at the time of diagnosis. When and how targeted therapies should fit within up-front cytotoxic chemotherapy and radiation paradigms is yet to be determined, because many of them have been studied in single-arm studies in patients with relapsed or refractory cancer. Infant high-grade gliomas (HGGs) are biologically and clinically distinct from older child and adult HGGs, and are divided into 3 molecular subgroups. Group 1 infant HGGs are driven by receptor tyrosine kinase fusions, most commonly harboring an ALK, ROS1, NTRK, or MET fusion. Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. This report discusses an 11-month-old female who presented with infantile spasms, found to have an unresectable, NTRK fusion-positive infant HGG. Larotrectinib was prescribed when the NTRK fusion was identified at diagnosis, and without additional intervention to date, the patient has continued with stable disease for >3 years. The only adverse event experienced was grade 1 aspartate transaminase and alanine transaminase elevations. The patient has a normal neurologic examination, is developing age-appropriately in all domains (gross motor, fine motor, cognitive, language, and social-emotional). She is no longer on antiseizure medications. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.
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Glioma , Inhibidores de Proteínas Quinasas , Pirazoles , Pirimidinas , Receptor trkB , Humanos , Femenino , Lactante , Pirazoles/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/patología , Receptor trkB/genética , Receptor trkB/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas de Fusión Oncogénica/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Clasificación del Tumor , Resultado del Tratamiento , Glicoproteínas de Membrana/genéticaRESUMEN
While multiple factors impact disease, artificial intelligence (AI) studies in medicine often use small, non-diverse patient cohorts due to data sharing and privacy issues. Federated learning (FL) has emerged as a solution, enabling training across hospitals without direct data sharing. Here, we present FL-PedBrain, an FL platform for pediatric posterior fossa brain tumors, and evaluate its performance on a diverse, realistic, multi-center cohort. Pediatric brain tumors were targeted due to the scarcity of such datasets, even in tertiary care hospitals. Our platform orchestrates federated training for joint tumor classification and segmentation across 19 international sites. FL-PedBrain exhibits less than a 1.5% decrease in classification and a 3% reduction in segmentation performance compared to centralized data training. FL boosts segmentation performance by 20 to 30% on three external, out-of-network sites. Finally, we explore the sources of data heterogeneity and examine FL robustness in real-world scenarios with data imbalances.
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Inteligencia Artificial , Neoplasias Encefálicas , Humanos , Niño , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Adolescente , Femenino , Masculino , Preescolar , Difusión de la Información/métodosRESUMEN
This study examined to evaluate the predictive value of a nomogram with Ki-67 in overall and disease-free survival in glioma patients, a total of 76 patients diagnosed with glioma by pathology in Tengzhou Central People's Hospital were enrolled. The baseline data and follow ups were retrospectively collected from medical records. The associations between Ki-67 and survival status were examined using log-rank test, univariate and multivariate Cox proportional hazard regression models. Calibrations were performed to validate the established nomograms. Ki-67 negative group showed of a longer OS survival time and a longer PFS survival time with log-rank test (x2 = 16.101, P < 0.001 and x2 = 16.961, P < 0.001). Age older than 50 years (HR = 2.074, 95% CI 1.097-3.923), abnormal treatment (HR = 2.932, 95% CI 1.343-6.403) and Ki-67 positive (HR = 2.722, 95% CI 1.097-6.755) were the independent predictive factors of death. High grade pathology (HR = 2.453, 95% CI 1.010-5.956) and Ki-67 positive (HR = 2.200, 95% CI 1.043-4.639) were the independent predictive factors of recurrence. The C-index for the nomogram of OS and PFS were 0.745 and 0.723, respectively. The calibration results showed that the nomogram could predict the overall and disease-free 1-year survival of glioma patients. In conclusion, the nomograms with Ki-67 as independent risk factor for OS and PFS could provide clinical consultation in the treatment and follow-up of malignant glioma.
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Neoplasias Encefálicas , Glioma , Antígeno Ki-67 , Recurrencia Local de Neoplasia , Nomogramas , Humanos , Glioma/mortalidad , Glioma/cirugía , Glioma/metabolismo , Glioma/patología , Antígeno Ki-67/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Adulto , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patología , Estudios Retrospectivos , Anciano , Pronóstico , Supervivencia sin Enfermedad , Modelos de Riesgos ProporcionalesAsunto(s)
Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Secuenciación de Nanoporos/métodos , Masculino , Linfoma/líquido cefalorraquídeo , Linfoma/diagnóstico , Linfoma/patología , Linfoma/genética , Femenino , Persona de Mediana Edad , Anciano , CitologíaRESUMEN
Chromosomal instability (CIN) is a pivotal factor in gliomas, contributing to their complexity, progression, and therapeutic challenges. CIN, characterized by frequent genomic alterations during mitosis, leads to genetic abnormalities and impacts cellular functions. This instability results from various factors, including replication errors and toxic compounds. While CIN's role is well documented in cancers like ovarian cancer, its implications for gliomas are increasingly recognized. CIN influences glioma progression by affecting key oncological pathways, such as tumor suppressor genes (e.g., TP53), oncogenes (e.g., EGFR), and DNA repair mechanisms. It drives tumor evolution, promotes inflammatory signaling, and affects immune interactions, potentially leading to poor clinical outcomes and treatment resistance. This review examines CIN's impact on gliomas through a narrative approach, analyzing data from PubMed/Medline, EMBASE, the Cochrane Library, and Scopus. It highlights CIN's role across glioma subtypes, from adult glioblastomas and astrocytomas to pediatric oligodendrogliomas and astrocytomas. Key findings include CIN's effect on tumor heterogeneity and its potential as a biomarker for early detection and monitoring. Emerging therapies targeting CIN, such as those modulating tumor mutation burden and DNA damage response pathways, show promise but face challenges. The review underscores the need for integrated therapeutic strategies and improved bioinformatics tools like CINdex to advance understanding and treatment of gliomas. Future research should focus on combining CIN-targeted therapies with immune modulation and personalized medicine to enhance patient outcomes.
Asunto(s)
Neoplasias Encefálicas , Inestabilidad Cromosómica , Progresión de la Enfermedad , Glioma , Humanos , Glioma/genética , Glioma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologíaRESUMEN
BACKGROUND: Glioblastoma (GBM) is an immunosuppressive, universally lethal cancer driven by glioblastoma stem cells (GSCs). The interplay between GSCs and immunosuppressive microglia plays crucial roles in promoting the malignant growth of GBM; however, the molecular mechanisms underlying this crosstalk are unclear. This study aimed to investigate the role of POSTN in maintaining GSCs and the immunosuppressive phenotype of microglia. METHODS: The expression of POSTN in GBM was identified via immunohistochemistry, quantitative real-time PCR, and immunoblotting. Tumorsphere formation assay, Cell Counting Kit-8 assay and immunofluorescence were used to determine the key role of POSTN in GSC maintenance. ChIP-seq and ChIP-PCR were conducted to confirm the binding sequences of ß-catenin in the promoter region of FOSL1. Transwell migration assays, developmental and functional analyses of CD4+ T cells, CFSE staining and analysis, enzyme-linked immunosorbent assays and apoptosis detection tests were used to determine the key role of POSTN in maintaining the immunosuppressive phenotype of microglia and thereby promoting the immunosuppressive tumor microenvironment. Furthermore, the effects of POSTN on GSC maintenance and the immunosuppressive phenotype of microglia were investigated in a patient-derived xenograft model and orthotopic glioma mouse model, respectively. RESULTS: Our findings revealed that POSTN secreted from GSCs promotes GSC self-renewal and tumor growth via activation of the αVß3/PI3K/AKT/ß-catenin/FOSL1 pathway. In addition to its intrinsic effects on GSCs, POSTN can recruit microglia and upregulate CD70 expression in microglia through the αVß3/PI3K/AKT/NFκB pathway, which in turn promotes Treg development and functionality and supports the formation of an immunosuppressive tumor microenvironment. In both in vitro models and orthotopic mouse models of GBM, POSTN depletion disrupted GSC maintenance, decreased the recruitment of immunosuppressive microglia and suppressed GBM growth. CONCLUSION: Our findings reveal that POSTN plays critical roles in maintaining GSCs and the immunosuppressive phenotype of microglia and provide a new therapeutic target for treating GBM.