The assessment of gliomas by
F-FDOPA PET imaging as an adjunct to MRI showed high performance by combining static and dynamic features to noninvasively predict the isocitrate dehydrogenase (IDH) ...mutations and the 1p/19q codeletion, which the World Health Organization classified as significant parameters in 2016. The current study evaluated whether other
F-FDOPA PET radiomics features further improve performance and the contributions of each of these features to performance.
Our study included 72 retrospectively selected, newly diagnosed glioma patients with
F-FDOPA PET dynamic acquisitions. A set of 114 features, including conventional static features and dynamic features, as well as other radiomics features, were extracted and machine-learning models trained to predict IDH mutations and the 1p/19q codeletion. Models were based on a machine-learning algorithm built from stable, relevant, and uncorrelated features selected by hierarchic clustering followed by a bootstrapped feature selection process. Models were assessed by comparing area under the curve using a nested cross-validation approach. Feature importance was assessed using Shapley additive explanations values.
The best models were able to predict IDH mutations (logistic regression with L2 regularization) and the 1p/19q codeletion (support vector machine with radial basis function kernel) with an area under the curve of 0.831 (95% CI, 0.790-0.873) and 0.724 (95% CI, 0.669-0.782), respectively. For the prediction of IDH mutations, dynamic features were the most important features in the model (time to peak, 35.5%). In contrast, other radiomics features were the most useful for predicting the 1p/19q codeletion (up to 14.5% of importance for the small-zone low-gray-level emphasis).
F-FDOPA PET is an effective tool for the noninvasive prediction of glioma molecular parameters using a full set of amino-acid PET radiomics features. The contribution of each feature set shows the importance of systematically integrating dynamic acquisition for prediction of the IDH mutations as well as developing the use of radiomics features in routine practice for prediction of the 1p/19q codeletion.
Abstract
INTRODUCTION
Low-grade gliomas (LGGs) are slow growing tumors that often cause infiltration and/or compression of the white matter pathways. Regular imaging modalities are no capable of ...revealing such a pathologic condition. Furthermore, up-to-date there is no reliable noninvasive imaging method to address this issue. Here we report that the local connectome fingerprint, an along track density measurement derived from diffusion MRI (dMRI), is capable of revealing the tumor compression effect on the surrounding white matter pathways.
METHODS
We acquired high angular resolution dMRI data on 16 patients diagnosed of LGG (WHO grade II). Peritumoral fiber tracts underwent qualitative and quantitative evaluation. Contralateral hemisphere counterparts were used for comparison. The local connectome fingerprint of peritumoral tract segment and their ratio to healthy side were visualized and calculated in comparison with 842 normal subjects from the Human Connectome Project.
RESULTS
>Our results showed significant increase in the ratios to the normal side among displaced tracts and decreases among the infiltrated tracts when compared to their healthy counterpart. Qualitative analysis of 65 peritumoral tracts revealed 9 (13.8%) unaffected, 24 (36.9%) displaced, 13 (20%) infiltrated and 19 (29.2%) tracts with a combination of displacement and infiltration. There were no disrupted tracts. The along tracks local connectome fingerprint further localizes the track segments with compression effect caused by the tumor mass. This feature cannot be observed in conventional tensor and diffusivity analysis.
CONCLUSION
The unique capability of local connectome fingerprint in revealing the compression and infiltration effect can provide potential diagnostic and prognostic applications in clinical intervention of patients with WHO grade-II low-grade gliomas.
Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system
. We have previously shown that ...the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells
, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 10
GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly
. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.
Los nuevos procedimientos quirúrgicos han beneficiado a los pacientes con Gliomas de Bajo Grado (GBG), quienes tienen una mayor esperanza de vida. Por este motivo existe un creciente interés en ...proteger la cognición y mejorar su calidad de vida. Los objetivos del estudio fueron: (1) Construir y administrar una batería neuropsicológica que permita examinar el perfil cognitivo prequirúrgico en pacientes con GBG y determinar los efectos posquirúrgicos. (2) Diseñar una intervención intraquirúrgica para pacientes con lesiones en el hemisferio izquierdo a fin de minimizar posibles déficits posteriores. Se evaluaron 19 pacientes con una batería prequirúrgica que evalúa los distintos dominios cognitivos: memoria, lenguaje, atención, funciones ejecutivas, habilidades visuoespaciales, cognición social, praxias y gnosias. Asimismo, los pacientes completaron cuestionarios neuropsiquiátricos con el fin de valorar funcionalidad, estado anímico y calidad de vida. Los pacientes presentaron déficit en múltiples dominios cognitivos en la evaluación pre-quirúrgica, al comparar su rendimiento con valores normativos ajustados por edad, sexo y educación. Los resultados del presente estudio demuestran la importancia de la administración de la batería neuropsicológica específicamente diseñada para pacientes con GBG y la evaluación de los dominios cognitivos para lograr la detección y el seguimiento de posibles trastornos cognitivos.
Altered cellular metabolism is a hallmark of gliomas. Propelled by a set of recent technological advances, new insights into the molecular mechanisms underlying glioma metabolism are rapidly ...emerging. In this Review, we focus on the dynamic nature of glioma metabolism and how it is shaped by the interaction between tumour genotype and brain microenvironment. Recent advances integrating metabolomics with genomics are discussed, yielding new insight into the mechanisms that drive glioma pathogenesis. Studies that shed light on interactions between the tumour microenvironment and tumour genotype are highlighted, providing important clues as to how gliomas respond to and adapt to their changing tissue and biochemical contexts. Finally, a road map for the discovery of potential new glioma drug targets is suggested, with the goal of translating these new insights about glioma metabolism into clinical benefits for patients.
A neurotropic herpes simplex virus that was genetically inactivated to prevent replication in normal cells was injected into the brain tumors of 12 patients with tumors that had progressed during ...previous treatment. Eleven patients had some radiographic or clinical responses, with inflammation detected in some PET scans. The median survival was 12.2 months, and 4 of 11 patients were still alive 18 months after treatment.
A high tumour mutational burden (hypermutation) is observed in some gliomas
; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly ...understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs are a barrier to emerging immunotherapies. It is unknown to what extent macrophages derived from peripheral ...blood adopt the phenotype of brain-resident microglia in pre-treatment gliomas. The relative proportions of blood-derived macrophages and microglia have been poorly quantified in clinical samples due to a paucity of markers that distinguish these cell types in malignant tissue.
We perform single-cell RNA-sequencing of human gliomas and identify phenotypic differences in TAMs of distinct lineages. We isolate TAMs from patient biopsies and compare them with macrophages from non-malignant human tissue, glioma atlases, and murine glioma models. We present a novel signature that distinguishes TAMs by ontogeny in human gliomas. Blood-derived TAMs upregulate immunosuppressive cytokines and show an altered metabolism compared to microglial TAMs. They are also enriched in perivascular and necrotic regions. The gene signature of blood-derived TAMs, but not microglial TAMs, correlates with significantly inferior survival in low-grade glioma. Surprisingly, TAMs frequently co-express canonical pro-inflammatory (M1) and alternatively activated (M2) genes in individual cells.
We conclude that blood-derived TAMs significantly infiltrate pre-treatment gliomas, to a degree that varies by glioma subtype and tumor compartment. Blood-derived TAMs do not universally conform to the phenotype of microglia, but preferentially express immunosuppressive cytokines and show an altered metabolism. Our results argue against status quo therapeutic strategies that target TAMs indiscriminately and in favor of strategies that specifically target immunosuppressive blood-derived TAMs.
Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma
. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours ...a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II
. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)
tumours in syngeneic MHC-humanized mice
. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)
astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG
and CXCL13
T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.
The WHO 2007 glioma classification system (based primarily on tumour histology) resulted in considerable interobserver variability and substantial variation in patient survival within grades. ...Furthermore, few risk factors for glioma were known. Discoveries over the past decade have deepened our understanding of the molecular alterations underlying glioma and have led to the identification of numerous genetic risk factors. The advances in molecular characterization of glioma have reframed our understanding of its biology and led to the development of a new classification system for glioma. The WHO 2016 classification system comprises five glioma subtypes, categorized by both tumour morphology and molecular genetic information, which led to reduced misclassification and improved consistency of outcomes within glioma subtypes. To date, 25 risk loci for glioma have been identified and several rare inherited mutations that might cause glioma in some families have been discovered. This Review focuses on the two dominant trends in glioma science: the characterization of diagnostic and prognostic tumour markers and the identification of genetic and other risk factors. An overview of the many challenges still facing glioma researchers is also included.
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