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PURPOSE: Reprogramming of amino acid metabolism is relevant for initiating and fueling tumor formation and growth. Therefore, there has been growing interest in anticancer therapies targeting amino acid metabolism. While developing personalized therapeutic approaches to glioma, in vivo proton magnetic resonance spectroscopy (MRS) is a valuable tool for non-invasive monitoring of tumor metabolism. Here, we evaluated MRS-detected brain amino acids and myo-inositol as potential diagnostic and prognostic biomarkers in glioma. METHOD: We measured alanine, glycine, glutamate, glutamine, and myo-inositol in 38 patients with MRI-suspected glioma using short and long echo-time single-voxel PRESS MRS sequences. The detectability of alanine, glycine, and myo-inositol and the (glutamate + glutamine)/total creatine ratio were evaluated against the patients' IDH mutation status, CNS WHO grade, and overall survival. RESULTS: While the detection of alanine and non-detection of myo-inositol significantly correlated with IDH wildtype (p = 0.0008, p = 0.007, respectively) and WHO grade 4 (p = 0.01, p = 0.04, respectively), glycine detection was not significantly associated with either. The ratio of (glutamate + glutamine)/total creatine was significantly higher in WHO grade 4 than in 2 and 3. We found that the overall survival was significantly shorter in glioma patients with alanine detection (p = 0.00002). CONCLUSION: Focusing on amino acids in MRS can improve its diagnostic and prognostic value in glioma. Alanine, which is visible at long TE even in the presence of lipids, could be a relevant indicator for overall survival.
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BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating disease with high morbidity and mortality. Neuroprotective effects of the noble gas argon have been shown in animal models of ischemia. The aim of this study was to investigate the effects of argon in the immediate early phase of SAH in a rat model. METHODS: A total of 19 male Wistar rats were randomly assigned to three treatment groups. SAH was induced using a endovascular filament perforation model. Cerebral blood flow, mean arterial blood pressure (MAP), and body temperature were measured continuously. Group A received 2 h of ventilation by 50% argon/50% O2 (n = 7) immediately following SAH. Group B underwent a sham operation and was also ventilated by 50% argon/50% O2 (n = 6). Group C underwent SAH and 50% O2/50% N2 ventilation (n = 6). Preoperative and postoperative neurological and behavioral testing were performed. Histology and immunohistochemistry were used to evaluate the extent of brain injury and vasospasm. RESULTS: The cerebral blood flow dropped in both treatment groups after SAH induction (SAH, 63.0 ± 11.6% of baseline; SAH + argon, 80.2 ± 8.2% of baseline). During SAH, MAP increased (135.2 ± 10.5%) compared with baseline values (85.8 ± 26.0 mm Hg) and normalized thereafter. MAP in both groups showed no significant differences (p = 0.3123). Immunohistochemical staining for neuronal nuclear antigen demonstrated a decrease of hippocampal immunoreactivity after SAH in the cornu ammonis region (CA) 1-3 compared with baseline hippocampal immunoreactivity (p = 0.0127). Animals in the argon-ventilated group showed less neuronal loss compared with untreated SAH animals (p < 0.0001). Ionized calcium-binding adaptor molecule 1 staining showed a decreased accumulation after SAH + argon (CA1, 2.57 ± 2.35%; CA2, 1.89 ± 1.89%; CA3, 2.19 ± 1.99%; DG, 2.6 ± 2.24%) compared with untreated SAH animals (CA1, 5.48 ± 2.39%; CA2, 4.85 ± 4.06%; CA3, 4.22 ± 3.01%; dentate gyrus (DG), 3.82 ± 3.23%; p = 0.0007). The neuroscore assessment revealed no treatment benefit after SAH compared with baseline (p = 0.385). CONCLUSION: In the present study, neuroprotective effects of argon occurred early after SAH. Because neurological deterioration was similar in the preadministration and absence of argon, it remains uncertain if neuroprotective effects translate in improved outcome over time.
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PURPOSE: While epigenetic profiling discovered biomarkers in several tumor entities, its application in prostate cancer is still limited. We explored DNA methylation-based deconvolution of benign and malignant prostate tissue for biomarker discovery and the potential of radiomics as a non-invasive surrogate. METHODS: We retrospectively included 30 patients (63 [58-79] years) with prostate cancer (PCa) who had a multiparametric MRI of the prostate before radical prostatectomy between 2014 and 2019. The control group comprised four patients with benign prostate tissue adjacent to the PCa lesions and four patients with benign prostatic hyperplasia. Tissue punches of all lesions were obtained. DNA methylation analysis and reference-free in silico deconvolution were conducted to retrieve Latent Methylation Components (LCMs). LCM-based clustering was analyzed for cellular composition and correlated with clinical disease parameters. Additionally, PCa and adjacent benign lesions were analyzed using radiomics to predict the epigenetic signatures non-invasively. RESULTS: LCMs identified two clusters with potential prognostic impact. Cluster one was associated with malignant prostate tissue (p < 0.001) and reduced immune-cell-related signatures (p = 0.004) of CD19 and CD4 cells. Cluster one comprised exclusively malignant prostate tissue enriched for significant prostate cancer and advanced tumor stages (p < 0.03 for both). No radiomics model could non-invasively predict the epigenetic clusters. CONCLUSION: Epigenetic clusters were associated with prognostically and clinically relevant metrics in prostate cancer. Further, immune cell-related signatures differed significantly between prognostically favorable and unfavorable clusters. Further research is necessary to explore potential diagnostic and therapeutic implications.
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Biomarcadores Tumorais , Metilação de DNA , Epigênese Genética , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Idoso , Prognóstico , Pessoa de Meia-Idade , Estudos Retrospectivos , Biomarcadores Tumorais/genética , ProstatectomiaRESUMO
BACKGROUND: Emerging evidence suggests that fasting could play a key role in cancer treatment. Its metabolic effects on gliomas require further investigation. PURPOSE: To design a multi-voxel 1H/31P MR-spectroscopic imaging (MRSI) protocol for noninvasive metabolic monitoring of cerebral, fasting-induced changes on an individual patient/tumor level, and to assess its technical reliability/reproducibility. STUDY TYPE: Prospective. POPULATION: MRS phantom. Twenty-two patients (mean age = 61, 6 female) with suspected WHO grade II-IV glioma examined before and after 72-hour-fasting prior to biopsy/resection. FIELD STRENGTH/SEQUENCE: 3-T, 1H decoupled 3D 31P MRSI, 2D 1H sLASER MRSI at an echo time of 144 msec, 2D 1H MRSI (as water reference), T1-weighted, T1-weighted contrast-enhanced, T2-weighted, and FLAIR. sLASER and PRESS sequences were used for phantom measurements. ASSESSMENT: Phantom measurements and spectral simulations were performed with various echo-times for protocol optimization. In vivo spectral analyses were conducted using LCModel and AMARES, obtaining quality/fitting parameters (linewidth, signal-to-noise-ratio, and uncertainty measures of fitting) and metabolite intensities. The volume of glioma sub-regions was calculated and correlated with MRS findings. Ex-vivo spectra of necrotic tumor tissues were obtained using high-resolution magic-angle spinning (HR-MAS) technique. STATISTICAL TESTS: Wilcoxon signed-rank test, Bland-Altman plots, and coefficient of variation were used for repeatability analysis of quality/fitting parameters and metabolite concentrations. Spearman ρ correlation for the concentration of ketone bodies with volumes of glioma sub-regions was determined. A P-value <0.05 was considered statistically significant. RESULTS: 1H and 31P repeatability measures were highly consistent between the two sessions. ß-hydroxybutyrate and acetoacetate were detectable (fitting-uncertainty <50%) in glioma sub-regions of all patients who completed the 72-hour-fasting cycle. ß-hydroxybutyrate accumulation was significantly correlated with the necrotic/non-enhancing tumor core volume (ρ = 0.81) and validated using ex-vivo 1H HR-MAS. DATA CONCLUSION: We propose a comprehensive MRS protocol that may be used for monitoring cerebral, fasting-induced changes in patients with glioma. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 4.
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Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stemcell-like cells in high-neural glioblastoma, primarily of the neural lineage. These cells are further classified as neural-progenitor-cell-like, astrocyte-like and oligodendrocyte-progenitor-like, alongside oligodendrocytes and excitatory neurons. In line with these findings, high-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetencephalography and resting-state magnet resonance imaging and can be detected via DNA analytes and brain-derived neurotrophic factor in patients' plasma. The prognostic importance of the neural signature was further validated in patients diagnosed with diffuse midline glioma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant. High-neural gliomas likely require a maximized surgical resection approach for improved outcomes.
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Neoplasias Encefálicas , Epigênese Genética , Glioma , Humanos , Prognóstico , Glioma/genética , Glioma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Metilação de DNA/genética , Animais , Camundongos , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Pessoa de Meia-Idade , Neurônios/patologia , Neurônios/metabolismo , Adulto , Análise de Célula Única , Linhagem Celular Tumoral , Transcriptoma , Gradação de TumoresRESUMO
OBJECTIVE: Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population. METHODS: This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017. RESULTS: The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult-type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1-57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1-46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post-SE at discharge (p < 0.001). Mortality at discharge was 17.3% (n = 36), with the greatest occurring in patients with metastatic disease (26.4%, p = 0.031) and those that met the radiological criteria for tumor progression (25%, p < 0.001). Long-term mortality at one year (65.9%) was highest in those diagnosed with adult-type diffuse gliomas (68.1%) and metastatic disease (79.2%). Refractory status epilepticus cases showed lower survival rates than non-refractory SE patients (log-rank p = 0.02) and those with signs of tumor progression (log-rank p = 0.001). CONCLUSIONS: SE occurrence contributed to a decline in functional status in all cases, regardless of tumor type, tumor progression status, and SE refractoriness, while long-term mortality was increased in those with malignant tumor entities, tumor progressions, and refractory SE. SE prevention may preserve functional status and improve survival in individuals with brain tumors.
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DNA methylation analysis based on supervised machine learning algorithms with static reference data, allowing diagnostic tumour typing with unprecedented precision, has quickly become a new standard of care. Whereas genome-wide diagnostic methylation profiling is mostly performed on microarrays, an increasing number of institutions additionally employ nanopore sequencing as a faster alternative. In addition, methylation-specific parallel sequencing can generate methylation and genomic copy number data. Given these diverse approaches to methylation profiling, to date, there is no single tool that allows (1) classification and interpretation of microarray, nanopore and parallel sequencing data, (2) direct control of nanopore sequencers, and (3) the integration of microarray-based methylation reference data. Furthermore, no software capable of entirely running in routine diagnostic laboratory environments lacking high-performance computing and network infrastructure exists. To overcome these shortcomings, we present EpiDiP/NanoDiP as an open-source DNA methylation and copy number profiling suite, which has been benchmarked against an established supervised machine learning approach using in-house routine diagnostics data obtained between 2019 and 2021. Running locally on portable, cost- and energy-saving system-on-chip as well as gpGPU-augmented edge computing devices, NanoDiP works in offline mode, ensuring data privacy. It does not require the rigid training data annotation of supervised approaches. Furthermore, NanoDiP is the core of our public, free-of-charge EpiDiP web service which enables comparative methylation data analysis against an extensive reference data collection. We envision this versatile platform as a useful resource not only for neuropathologists and surgical pathologists but also for the tumour epigenetics research community. In daily diagnostic routine, analysis of native, unfixed biopsies by NanoDiP delivers molecular tumour classification in an intraoperative time frame.
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Epigenômica , Neoplasias , Humanos , Aprendizado de Máquina não Supervisionado , Computação em Nuvem , Neoplasias/diagnóstico , Neoplasias/genética , Metilação de DNARESUMO
For CNS lymphomas (CNSL), there is a high need for minimally invasive and easily obtainable diagnostic markers. Intrathecal IgM synthesis can easily be determined in routine CSF diagnostics. The aim of this study was to systematically investigate the diagnostic potential of intrathecal IgM synthesis in primary and secondary CNSL (PCNSL and SCNSL). In this retrospective study, patients with a biopsy-proven diagnosis of PCNSL or SCNSL were compared with patients with other neurological diseases in whom CNSL was initially the primary radiological differential diagnosis based on MRI. Sensitivity and specificity of intrathecal IgM synthesis were calculated using receiver operating characteristic curves. Seventy patients with CNSL were included (49 PCNSL and 21 SCNSL) and compared to 70 control patients. The sensitivity and specificity for the diagnosis of CNSL were 49% and 87%, respectively, for the entire patient population and 66% and 91% after selection for cases with tumor access to the CSF system and isolated intrathecal IgM synthesis. In cases with MRI-based radiological suspicion of CNSL, intrathecal IgM synthesis has good specificity but limited sensitivity. Because of its low-threshold availability, analysis of intrathecal IgM synthesis has the potential to lead to higher diagnostic accuracy, especially in resource-limited settings, and deserves further study.
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Neoplasias do Sistema Nervoso Central , Imunoglobulina M , Linfoma , Humanos , Imunoglobulina M/líquido cefalorraquidiano , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/imunologia , Idoso , Linfoma/líquido cefalorraquidiano , Linfoma/diagnóstico , Adulto , Biomarcadores Tumorais/líquido cefalorraquidiano , Imageamento por Ressonância Magnética , Idoso de 80 Anos ou mais , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: The IDH-wildtype glioblastoma (GBM) patients have a devastating prognosis. Here, we analyzed the potential prognostic value of global DNA methylation of the tumors. METHODS: DNA methylation of 492 primary samples and 31 relapsed samples, each treated with combination therapy, and of 148 primary samples treated with radiation alone were compared with patient survival. We determined the mean methylation values and estimated the immune cell infiltration from the methylation data. Moreover, the mean global DNA methylation of 23 GBM cell lines was profiled and correlated to their cellular radiosensitivity as measured by colony formation assay. RESULTS: High mean DNA methylation levels correlated with improved survival, which was independent from known risk factors (MGMT promoter methylation, age, extent of resection; Pâ =â 0.009) and methylation subgroups. Notably, this correlation was also independent of immune cell infiltration, as higher number of immune cells indeed was associated with significantly better OS but lower mean methylation. Radiosensitive GBM cell lines had a significantly higher mean methylation than resistant lines (Pâ =â 0.007), and improved OS of patients treated with radiotherapy alone was also associated with higher DNA methylation (Pâ =â 0.002). Furthermore, specimens of relapsed GBM revealed a significantly lower mean DNA methylation compared to the matching primary tumor samples (Pâ =â 0.041). CONCLUSIONS: Our results indicate that mean global DNA methylation is independently associated with outcome in glioblastoma. The data also suggest that a higher DNA methylation is associated with better radiotherapy response and less aggressive phenotype, both of which presumably contribute to the observed correlation with OS.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Prognóstico , Metilação de DNA , Metilases de Modificação do DNA/genética , Proteínas Supressoras de Tumor/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/radioterapia , Enzimas Reparadoras do DNA/genéticaRESUMO
The current state-of-the-art analysis of central nervous system (CNS) tumors through DNA methylation profiling relies on the tumor classifier developed by Capper and colleagues, which centrally harnesses DNA methylation data provided by users. Here, we present a distributed-computing-based approach for CNS tumor classification that achieves a comparable performance to centralized systems while safeguarding privacy. We utilize the t-distributed neighborhood embedding (t-SNE) model for dimensionality reduction and visualization of tumor classification results in two-dimensional graphs in a distributed approach across multiple sites (DistSNE). DistSNE provides an intuitive web interface (https://gin-tsne.med.uni-giessen.de) for user-friendly local data management and federated methylome-based tumor classification calculations for multiple collaborators in a DataSHIELD environment. The freely accessible web interface supports convenient data upload, result review, and summary report generation. Importantly, increasing sample size as achieved through distributed access to additional datasets allows DistSNE to improve cluster analysis and enhance predictive power. Collectively, DistSNE enables a simple and fast classification of CNS tumors using large-scale methylation data from distributed sources, while maintaining the privacy and allowing easy and flexible network expansion to other institutes. This approach holds great potential for advancing human brain tumor classification and fostering collaborative precision medicine in neuro-oncology.
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Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Humanos , Metilação de DNA , Neoplasias do Sistema Nervoso Central/genética , Neoplasias Encefálicas/genéticaRESUMO
PURPOSE: The prognosis of patients ≥ 75 years suffering from glioblastoma is poor. Novel therapies are usually reserved for patients ≤ 70 years. In an aging population, treatment of very elderly patients remains a challenge. METHODS: Between 2010 and 2018, a total of 977 glioblastoma patients were treated at our institution. Of these, 143 patients were ≥ 75 years at diagnosis. Primary procedure was surgical resection or biopsy followed by adjuvant treatment, whenever possible. We retrospectively investigated overall survival (OS) and potential prognostic factors influencing survival, including Karnofsky Performance Status (KPS), surgical therapy, adjuvant therapy as well as MGMT promotor status. RESULTS: In very elderly patients, median age was 79 years (range: 75-110). Biopsy only was performed in 104 patients; resection was performed in 39 patients. Median OS for the entire cohort was 5.9 months. Univariate analysis showed that KPS at presentation (≥ 70 vs. ≤60), surgery vs. biopsy, adjuvant chemotherapy and adjuvant radiotherapy were significantly associated with OS (6 vs. 3, p < 0.0111; 12 vs. 4, p = 0.0011; 11 vs. 4, p = 0.0003 and 10 vs. 1.5 months, p < 0.0001, respectively). Multivariate analysis confirmed adjuvant radiotherapy (p < 0.0001) and chemotherapy (p = 0.0002) as independent factors influencing OS. CONCLUSION: For very elderly patients, the natural course of disease without treatment is devastating. These patients benefit from multimodal treatment including adjuvant radiotherapy and chemotherapy. A beneficial effect of resection has not been demonstrated. Treatment options and outcomes should be thoughtfully discussed before treatment decisions are made.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Idoso , Glioblastoma/tratamento farmacológico , Temozolomida/uso terapêutico , Resultado do Tratamento , Estudos Retrospectivos , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Prognóstico , Terapia CombinadaRESUMO
Background: The biological understanding of glioblastoma (GB) with gliomatosis cerebri (GC) pattern is poor due to the absence of GC-specific studies. Here, we aimed to identify molecular or clinical parameters that drive GC growth. Methods: From our methylome database of IDH (isocitrate dehydrogenase)-wildtype GB, we identified 158 non-GC and 65 GC cases. GC cases were subdivided into diffuse-infiltrative (subtype 1), multifocal (subtype 2), or tumors with 1 solid mass (subtype 3). We compared clinical, histological, and molecular parameters and conducted a reference-free tumor deconvolution of DNA methylation data based on latent methylation components (LMC). Results: GC subtype 1 less frequently showed contrast-enhancing tumors, and more frequently lacked morphological GB criteria despite displaying GB DNA methylation profile. However, the tumor deconvolution did not deliver a specific LMC cluster for either of the GC subtypes. Employing the reference-based analysis MethylCIBERSORT, we did not identify significant differences in tumor cell composition. The majority of both GC and non-GC patients received radiochemotherapy as first-line treatment, but there was a major imbalance for resection. The entire GC cohort had significantly shorter overall survival (OS) and time to treatment failure (TTF) than the non-GC cohort. However, when filtering for cases in which only stereotactic biopsy was performed, the comparison of OS and TTF lost statistical significance. Conclusions: Our study offers clinically relevant information by demonstrating a similar outcome for GB with GC growth pattern in the surgically matched analysis. The limited number of cases in the GC subgroups encourages the validation of our DNA methylation analysis in larger cohorts.
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Induction of alternative, non-apoptotic cell death programs such as cell-lethal autophagy and mitophagy represent possible strategies to combat glioblastoma (GBM). Here we report that VLX600, a novel iron chelator and oxidative phosphorylation (OXPHOS) inhibitor, induces a caspase-independent type of cell death that is partially rescued in adherent U251 ATG5/7 (autophagy related 5/7) knockout (KO) GBM cells and NCH644 ATG5/7 knockdown (KD) glioma stem-like cells (GSCs), suggesting that VLX600 induces an autophagy-dependent cell death (ADCD) in GBM. This ADCD is accompanied by decreased oxygen consumption, increased expression/mitochondrial localization of BNIP3 (BCL2 interacting protein 3) and BNIP3L (BCL2 interacting protein 3 like), the induction of mitophagy as demonstrated by diminished levels of mitochondrial marker proteins [e.g., COX4I1 (cytochrome c oxidase subunit 4I1)] and the mitoKeima assay as well as increased histone H3 and H4 lysine tri-methylation. Furthermore, the extracellular addition of iron is able to significantly rescue VLX600-induced cell death and mitophagy, pointing out an important role of iron metabolism for GBM cell homeostasis. Interestingly, VLX600 is also able to completely eliminate NCH644 GSC tumors in an organotypic brain slice transplantation model. Our data support the therapeutic concept of ADCD induction in GBM and suggest that VLX600 may be an interesting novel drug candidate for the treatment of this tumor.NEW & NOTEWORTHY Induction of cell-lethal autophagy represents a possible strategy to combat glioblastoma (GBM). Here, we demonstrate that the novel iron chelator and OXPHOS inhibitor VLX600 exerts pronounced tumor cell-killing effects in adherently cultured GBM cells and glioblastoma stem-like cell (GSC) spheroid cultures that depend on the iron-chelating function of VLX600 and on autophagy activation, underscoring the context-dependent role of autophagy in therapy responses. VLX600 represents an interesting novel drug candidate for the treatment of this tumor.
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Antineoplásicos , Glioblastoma , Humanos , Mitofagia/fisiologia , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Autofagia , Antineoplásicos/farmacologia , Apoptose , Proteínas Mitocondriais/metabolismo , Quelantes de Ferro/farmacologia , Ferro , Proteínas Proto-Oncogênicas c-bcl-2 , Linhagem Celular TumoralRESUMO
Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.
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BACKGROUND: Glioblastoma (GB) is incurable at present without established treatment options for recurrent disease. In this phase I first-in-human clinical trial we investigated safety and feasibility of adoptive transfer of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2, which is expressed at elevated levels by a subset of glioblastomas. METHODS: Nine patients with recurrent HER2-positive GB were treated with single doses of 1 × 107, 3 × 107, or 1 × 108 irradiated CAR-NK cells injected into the margins of the surgical cavity during relapse surgery. Imaging at baseline and follow-up, peripheral blood lymphocyte phenotyping and analyses of the immune architecture by multiplex immunohistochemistry and spatial digital profiling were performed. RESULTS: There were no dose-limiting toxicities, and none of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Five patients showed stable disease after relapse surgery and CAR-NK injection that lasted 7 to 37 weeks. Four patients had progressive disease. Pseudoprogression was found at injection sites in 2 patients, suggestive of a treatment-induced immune response. For all patients, median progression-free survival was 7 weeks, and median overall survival was 31 weeks. Furthermore, the level of CD8+ T-cell infiltration in recurrent tumor tissue prior to CAR-NK cell injection positively correlated with time to progression. CONCLUSIONS: Intracranial injection of HER2-targeted CAR-NK cells is feasible and safe in patients with recurrent GB. 1 × 108 NK-92/5.28.z cells was determined as the maximum feasible dose for a subsequent expansion cohort with repetitive local injections of CAR-NK cells.
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Glioblastoma , Receptores de Antígenos Quiméricos , Humanos , Glioblastoma/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Células Matadoras Naturais , Recidiva , Imunoterapia Adotiva/métodosRESUMO
Tumours of the peripheral nervous system occur sporadically in adults and except for a minority of entities, these tumours are usually benign. The most common are nerve sheath tumours. Because these tumours grow in direct proximity or even invade peripheral nerve bundles, they can lead to severe pain and motion deficits. From the neurosurgical perspective these tumours are technically challenging, and especially for tumours with an invasive growth pattern complete resection may not be possible. Peripheral nervous system tumours that are associated with tumour syndromes such as neurofibromatosis type 1 and 2 or schwannomatosis are a particular clinical challenge. The goal of the current article is to present histological and molecular characteristics of peripheral nervous system tumours. Furthermore, future targeted therapy strategies are presented.
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Neoplasias de Bainha Neural , Neurilemoma , Neurofibromatoses , Neurofibromatose 1 , Neoplasias do Sistema Nervoso Periférico , Humanos , Neurilemoma/genética , Neoplasias de Bainha Neural/genética , Neoplasias do Sistema Nervoso Periférico/genética , Neurofibromatose 1/diagnósticoRESUMO
BACKGROUND: Hirschsprung disease (HD) is an aganglionosis of variable length starting at the rectosigmoid colon with surgery as sole therapeutic option. The length of the resected bowel segment is a crucial information for the treating surgeons and influences the prognosis of the patient. It is often artificially altered due to post operative tissue shrinkage. The objective of this study is to quantify the extent tissue shrinkage of HD specimens. MATERIAL AND METHODS: Colorectal HD specimens were measured at the time of surgery and at the time of cut-up, either fresh or after formalin fixation and statistically analyzed. RESULTS: Sixteen colorectal specimens were included. Following formalin fixation the specimen length decreased by 22.7% (P < .001). Without formalin fixation the specimens shrank by an average of 24.9% (P = .05). There was no significant difference in the extent of tissue shrinkage with or without formalin fixation (P = .76). CONCLUSION: This study showed that there is significant tissue shrinkage in HD specimens. The 2 different cohorts revealed that tissue shrinkage is mostly caused by tissue retraction/alteration after organ removal but also to a lesser extent by fixation with formalin. Surgeons and (neuro-)pathologists should be aware of the sizeable shrinking artifact to avoid unnecessary confusion.