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BACKGROUND AND OBJECTIVES: Neurolymphomatosis (NL) refers to lymphomatous infiltration of the peripheral nervous system (PNS). NL diagnosis and treatment are challenging given the broad differential diagnosis of peripheral neuropathy, the lack of larger cohorts, and the subsequent unavailability of prognostic factors or consensus therapy. This study aimed to define characteristics and prognostic factors of NL. METHODS: A systematic review of the literature (2004-2023) was performed using PubMed and Scopus databases and reported following PRISMA guidelines. Studies reporting individual patient data on cases with definitive NL diagnosis were included. Clinical, radiologic, pathologic, and outcome information were extracted. Univariable and multivariable survival analyses were performed using log-rank tests and Cox proportional hazard models. RESULTS: A total of 459 NL cases from 264 studies were accumulated. NL was the first manifestation of malignancy (primary NL) in 197 patients. PNS relapse of known non-Hodgkin lymphoma (secondary NL) occurred in 262 cases after a median 12 months. NL predominantly presented with rapidly deteriorating, asymmetric painful polyneuropathy. Infiltrated structures included peripheral nerves (56%), nerve roots (52%), plexus (33%), and cranial nerves (32%). Diagnosis was established at a median of 3 months after symptom onset with substantial delays in primary NL. It mainly relied on PNS biopsy or FDG-PET, which carried high diagnostic yields (>90%). Postmortem diagnoses were rare (3%). Most cases were classified as B-cell (90%) lymphomas. Tumor-directed therapy was administered in 96% of patients and typically consisted of methotrexate or rituximab-based polychemotherapy. The median overall survival was 18 months. Primary NL without concurrent systemic disease outside the nervous system (hazard ratio [HR]: 0.44; 95% CI 0.25-0.78; p = 0.005), performance status (ECOG <2, HR: 0.30; 95% CI 0.18-0.52; p < 0.0001), and rituximab-based treatment (HR: 0.46; 95% CI 0.28-0.73; p = 0.001) were identified as favorable prognostic markers on multivariable analysis when adjusting for clinical and sociodemographic parameters. DISCUSSION: Advances in neuroimaging modalities, particularly FDG-PET, facilitate NL diagnosis and offer a high diagnostic yield. Yet, diagnostic delays in primary NL remain common. Rituximab-based therapy improves NL outcome. Findings may assist clinicians in early recognition, prognostic stratification, and treatment of NL.
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Neurolinfomatosis , Humanos , Neurolinfomatosis/terapia , Neurolinfomatosis/diagnóstico por imagen , Manejo de la Enfermedad , PronósticoRESUMEN
Background: The purpose of this study was to elucidate the relationship between distinct brain regions and molecular subtypes in glioblastoma (GB), focusing on integrating modern statistical tools and molecular profiling to better understand the heterogeneity of Isocitrate Dehydrogenase wild-type (IDH-wt) gliomas. Methods: This retrospective study comprised 441 patients diagnosed with new IDH-wt glioma between 2009 and 2020 at Heidelberg University Hospital. The diagnostic process included preoperative magnetic resonance imaging and molecular characterization, encompassing IDH-status determination and subclassification, through DNA-methylation profiling. To discern and map distinct brain regions associated with specific methylation subtypes, a support-vector regression-based lesion-symptom mapping (SVR-LSM) was employed. Lesion maps were adjusted to 2 mm³ resolution. Significance was assessed with beta maps, using a threshold of Pâ <â .005, with 10 000 permutations and a cluster size minimum of 100 voxels. Results: Of 441 initially screened glioma patients, 423 (95.9%) met the inclusion criteria. Following DNA-methylation profiling, patients were classified into RTK II (40.7%), MES (33.8%), RTK I (18%), and other methylation subclasses (7.6%). Between molecular subtypes, there was no difference in tumor volume. Using SVR-LSM, distinct brain regions correlated with each subclass were identified: MES subtypes were associated with left-hemispheric regions involving the superior temporal gyrus and insula cortex, RTK I with right frontal regions, and RTK II with 3 clusters in the left hemisphere. Conclusions: This study linked molecular diversity and spatial features in glioblastomas using SVR-LSM. Future studies should validate these findings in larger, independent cohorts to confirm the observed patterns.
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PURPOSE: To propose a novel recursive partitioning analysis (RPA) classification model in patients with IDH-wildtype glioblastomas that incorporates the recently expanded conception of the extent of resection (EOR) in terms of both supramaximal and total resections. EXPERIMENTAL DESIGN: This multicenter cohort study included a developmental cohort of 622 patients with IDH-wildtype glioblastomas from a single institution (Severance Hospital) and validation cohorts of 536 patients from three institutions (Seoul National University Hospital, Asan Medical Center, and Heidelberg University Hospital). All patients completed standard treatment including concurrent chemoradiotherapy and underwent testing to determine their IDH mutation and MGMTp methylation status. EORs were categorized into either supramaximal, total, or non-total resections. A novel RPA model was then developed and compared to a previous RTOG RPA model. RESULTS: In the developmental cohort, the RPA model included age, MGMTp methylation status, KPS, and EOR. Younger patients with MGMTp methylation and supramaximal resections showed a more favorable prognosis (class I: median overall survival [OS] 57.3 months), while low-performing patients with non-total resections and without MGMTp methylation showed the worst prognosis (class IV: median OS 14.3 months). The prognostic significance of the RPA was subsequently confirmed in the validation cohorts, which revealed a greater separation between prognostic classes for all cohorts compared to the previous RTOG RPA model. CONCLUSIONS: The proposed RPA model highlights the impact of supramaximal versus total resections and incorporates clinical and molecular factors into survival stratification. The RPA model may improve the accuracy of assessing prognostic groups.
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Delays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown etiology. Participants underwent genotyping of CSF-derived DNA using a qPCR-based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7/33 (21.2%) cases of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median 3 vs 12 days; p = 0.027). This assay was then implemented in a Clinical Laboratory Improvement Amendments (CLIA) environment, with 2-day median turnaround for diagnosis of central nervous system lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.
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Background: This study investigates the influence of diffusion-weighted Magnetic Resonance Imaging (DWI-MRI) on radiomic-based prediction of glioma types according to molecular status and assesses the impact of DWI intensity normalization on model generalizability. Methods: Radiomic features, compliant with image biomarker standardization initiative standards, were extracted from preoperative MRI of 549 patients with diffuse glioma, known IDH, and 1p19q-status. Anatomical sequences (T1, T1c, T2, FLAIR) underwent N4-Bias Field Correction (N4) and WhiteStripe normalization (N4/WS). Apparent diffusion coefficient (ADC) maps were normalized using N4 or N4/z-score. Nine machine-learning algorithms were trained for multiclass prediction of glioma types (IDH-mutant 1p/19q codeleted, IDH-mutant 1p/19q non-codeleted, IDH-wild type). Four approaches were compared: Anatomical, anatomicalâ +â ADC naive, anatomicalâ +â ADC N4, and anatomicalâ +â ADC N4/z-score. The University of California San Francisco (UCSF)-glioma dataset (nâ =â 409) was used for external validation. Results: Naïve-Bayes algorithms yielded overall the best performance on the internal test set. Adding ADC radiomics significantly improved AUC from 0.79 to 0.86 (Pâ =â .011) for the IDH-wild-type subgroup, but not for the other 2 glioma subgroups (Pâ >â .05). In the external UCSF dataset, the addition of ADC radiomics yielded a significantly higher AUC for the IDH-wild-type subgroup (Pâ ≤â .001): 0.80 (N4/WS anatomical alone), 0.81 (anatomicalâ +â ADC naive), 0.81 (anatomicalâ +â ADC N4), and 0.88 (anatomicalâ +â ADC N4/z-score) as well as for the IDH-mutant 1p/19q non-codeleted subgroup (Pâ <â .012 each). Conclusions: ADC radiomics can enhance the performance of conventional MRI-based radiomic models, particularly for IDH-wild-type glioma. The benefit of intensity normalization of ADC maps depends on the type and context of the used data.
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PURPOSE: Surgery for recurrent glioma provides cytoreduction and tissue for molecularly informed treatment. With mostly heavily pretreated patients involved, it is unclear whether the benefits of repeat surgery outweigh its potential risks. METHODS: Patients receiving surgery for recurrent glioma WHO grade 2-4 with the goal of tissue sampling for targeted therapies were analyzed retrospectively. Complication rates (surgical, neurological) were compared to our institutional glioma surgery cohort. Tissue molecular diagnostic yield, targeted therapies and post-surgical survival rates were analyzed. RESULTS: Between 2017 and 2022, tumor board recommendation for targeted therapy through molecular diagnostics was made for 180 patients. Of these, 70 patients (38%) underwent repeat surgery. IDH-wildtype glioblastoma was diagnosed in 48 patients (69%), followed by IDH-mutant astrocytoma (n = 13; 19%) and oligodendroglioma (n = 9; 13%). Gross total resection (GTR) was achieved in 50 patients (71%). Tissue was processed for next-generation sequencing in 64 cases (91%), and for DNA methylation analysis in 58 cases (83%), while immunohistochemistry for mTOR phosphorylation was performed in 24 cases (34%). Targeted therapy was recommended in 35 (50%) and commenced in 21 (30%) cases. Postoperatively, 7 patients (11%) required revision surgery, compared to 7% (p = 0.519) and 6% (p = 0.359) of our reference cohorts of patients undergoing first and second craniotomy, respectively. Non-resolving neurological deterioration was documented in 6 cases (10% vs. 8%, p = 0.612, after first and 4%, p = 0.519, after second craniotomy). Median survival after repeat surgery was 399 days in all patients and 348 days in GBM patients after repeat GTR. CONCLUSION: Surgery for recurrent glioma provides relevant molecular diagnostic information with a direct consequence for targeted therapy under a reasonable risk of postoperative complications. With satisfactory postoperative survival it can therefore complement a multi-modal glioma therapy approach.
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Neoplasias Encefálicas , Glioma , Humanos , Reoperación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patología , Estudios Retrospectivos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/cirugía , Medicina de Precisión , Glioma/genética , Glioma/cirugía , Glioma/patologíaRESUMEN
BACKGROUND: The extended acquisition times required for MRI limit its availability in resource-constrained settings. Consequently, accelerating MRI by undersampling k-space data, which is necessary to reconstruct an image, has been a long-standing but important challenge. We aimed to develop a deep convolutional neural network (dCNN) optimisation method for MRI reconstruction and to reduce scan times and evaluate its effect on image quality and accuracy of oncological imaging biomarkers. METHODS: In this multicentre, retrospective, cohort study, MRI data from patients with glioblastoma treated at Heidelberg University Hospital (775 patients and 775 examinations) and from the phase 2 CORE trial (260 patients, 1083 examinations, and 58 institutions) and the phase 3 CENTRIC trial (505 patients, 3147 examinations, and 139 institutions) were used to develop, train, and test dCNN for reconstructing MRI from highly undersampled single-coil k-space data with various acceleration rates (R=2, 4, 6, 8, 10, and 15). Independent testing was performed with MRIs from the phase 2/3 EORTC-26101 trial (528 patients with glioblastoma, 1974 examinations, and 32 institutions). The similarity between undersampled dCNN-reconstructed and original MRIs was quantified with various image quality metrics, including structural similarity index measure (SSIM) and the accuracy of undersampled dCNN-reconstructed MRI on downstream radiological assessment of imaging biomarkers in oncology (automated artificial intelligence-based quantification of tumour burden and treatment response) was performed in the EORTC-26101 test dataset. The public NYU Langone Health fastMRI brain test dataset (558 patients and 558 examinations) was used to validate the generalisability and robustness of the dCNN for reconstructing MRIs from available multi-coil (parallel imaging) k-space data. FINDINGS: In the EORTC-26101 test dataset, the median SSIM of undersampled dCNN-reconstructed MRI ranged from 0·88 to 0·99 across different acceleration rates, with 0·92 (95% CI 0·92-0·93) for 10-times acceleration (R=10). The 10-times undersampled dCNN-reconstructed MRI yielded excellent agreement with original MRI when assessing volumes of contrast-enhancing tumour (median DICE for spatial agreement of 0·89 [95% CI 0·88 to 0·89]; median volume difference of 0·01 cm3 [95% CI 0·00 to 0·03] equalling 0·21%; p=0·0036 for equivalence) or non-enhancing tumour or oedema (median DICE of 0·94 [95% CI 0·94 to 0·95]; median volume difference of -0·79 cm3 [95% CI -0·87 to -0·72] equalling -1·77%; p=0·023 for equivalence) in the EORTC-26101 test dataset. Automated volumetric tumour response assessment in the EORTC-26101 test dataset yielded an identical median time to progression of 4·27 months (95% CI 4·14 to 4·57) when using 10-times-undersampled dCNN-reconstructed or original MRI (log-rank p=0·80) and agreement in the time to progression in 374 (95·2%) of 393 patients with data. The dCNN generalised well to the fastMRI brain dataset, with significant improvements in the median SSIM when using multi-coil compared with single-coil k-space data (p<0·0001). INTERPRETATION: Deep-learning-based reconstruction of undersampled MRI allows for a substantial reduction of scan times, with a 10-times acceleration demonstrating excellent image quality while preserving the accuracy of derived imaging biomarkers for the assessment of oncological treatment response. Our developments are available as open source software and hold considerable promise for increasing the accessibility to MRI, pending further prospective validation. FUNDING: Deutsche Forschungsgemeinschaft (German Research Foundation) and an Else Kröner Clinician Scientist Endowed Professorship by the Else Kröner Fresenius Foundation.
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Aprendizaje Profundo , Glioblastoma , Humanos , Inteligencia Artificial , Biomarcadores , Estudios de Cohortes , Glioblastoma/diagnóstico por imagen , Imagen por Resonancia Magnética , Estudios RetrospectivosRESUMEN
Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. However, the determination of TM-interconnectivity in individual tumors is challenging and the impact on patient survival unresolved. Here, we establish a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells using a dye uptake methodology, and validate it with recording of cellular calcium epochs and clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, TM-network connectivity correlates with the mesenchymal subtype and dismal patient survival. CHI3L1 gene expression serves as a robust molecular marker of connectivity and functionally influences TM networks. The connectivity signature allows insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients' prognosis, and serves as a robust prognostic biomarker.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/genética , Glioma/genética , Neoplasias Encefálicas/genética , Proteína 1 Similar a Quitinasa-3RESUMEN
Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.
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BACKGROUND: Glioblastoma is the most frequent and a particularly malignant primary brain tumor with no efficacy-proven standard therapy for recurrence. It has recently been discovered that excitatory synapses of the AMPA-receptor subtype form between non-malignant brain neurons and tumor cells. This neuron-tumor network connectivity contributed to glioma progression and could be efficiently targeted with the EMA/FDA approved antiepileptic AMPA receptor inhibitor perampanel in preclinical studies. The PerSurge trial was designed to test the clinical potential of perampanel to reduce tumor cell network connectivity and tumor growth with an extended window-of-opportunity concept. METHODS: PerSurge is a phase IIa clinical and translational treatment study around surgical resection of progressive or recurrent glioblastoma. In this multicenter, 2-arm parallel-group, double-blind superiority trial, patients are 1:1 randomized to either receive placebo or perampanel (n = 66 in total). It consists of a treatment and observation period of 60 days per patient, starting 30 days before a planned surgical resection, which itself is not part of the study interventions. Only patients with an expected safe waiting interval are included, and a safety MRI is performed. Tumor cell network connectivity from resected tumor tissue on single cell transcriptome level as well as AI-based assessment of tumor growth dynamics in T2/FLAIR MRI scans before resection will be analyzed as the co-primary endpoints. Secondary endpoints will include further imaging parameters such as pre- and postsurgical contrast enhanced MRI scans, postsurgical T2/FLAIR MRI scans, quality of life, cognitive testing, overall and progression-free survival as well as frequency of epileptic seizures. Further translational research will focus on additional biological aspects of neuron-tumor connectivity. DISCUSSION: This trial is set up to assess first indications of clinical efficacy and tolerability of perampanel in recurrent glioblastoma, a repurposed drug which inhibits neuron-glioma synapses and thereby glioblastoma growth in preclinical models. If perampanel proved to be successful in the clinical setting, it would provide the first evidence that interference with neuron-cancer interactions may indeed lead to a benefit for patients, which would lay the foundation for a larger confirmatory trial in the future. TRIAL REGISTRATION: EU-CT number: 2023-503938-52-00 30.11.2023.
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Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/cirugía , Calidad de Vida , Recurrencia Local de Neoplasia/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Nitrilos/uso terapéutico , Piridonas/uso terapéutico , Resultado del Tratamiento , Método Doble CiegoRESUMEN
PURPOSE: Primary central nervous system (CNS) gliomas can be classified by characteristic genetic alterations. In addition to solid tissue obtained via surgery or biopsy, cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) is an alternative source of material for genomic analyses. EXPERIMENTAL DESIGN: We performed targeted next-generation sequencing of CSF cfDNA in a representative cohort of 85 patients presenting at two neurooncological centers with suspicion of primary or recurrent glioma. Copy-number variation (CNV) profiles, single-nucleotide variants (SNV), and small insertions/deletions (indel) were combined into a molecular-guided tumor classification. Comparison with the solid tumor was performed for 38 cases with matching solid tissue available. RESULTS: Cases were stratified into four groups: glioblastoma (n = 32), other glioma (n = 19), nonmalignant (n = 17), and nondiagnostic (n = 17). We introduced a molecular-guided tumor classification, which enabled identification of tumor entities and/or cancer-specific alterations in 75.0% (n = 24) of glioblastoma and 52.6% (n = 10) of other glioma cases. The overlap between CSF and matching solid tissue was highest for CNVs (26%-48%) and SNVs at predefined gene loci (44%), followed by SNVs/indels identified via uninformed variant calling (8%-14%). A molecular-guided tumor classification was possible for 23.5% (n = 4) of nondiagnostic cases. CONCLUSIONS: We developed a targeted sequencing workflow for CSF cfDNA as well as a strategy for interpretation and reporting of sequencing results based on a molecular-guided tumor classification in glioma. See related commentary by Abdullah, p. 2860.
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Biomarcadores de Tumor , Ácidos Nucleicos Libres de Células , Variaciones en el Número de Copia de ADN , Glioma , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Glioma/genética , Glioma/líquido cefalorraquídeo , Glioma/patología , Glioma/diagnóstico , Femenino , Persona de Mediana Edad , Masculino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Anciano , Adulto , Biomarcadores de Tumor/líquido cefalorraquídeo , Biomarcadores de Tumor/genética , Ácidos Nucleicos Libres de Células/líquido cefalorraquídeo , Ácidos Nucleicos Libres de Células/genética , Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/patología , Polimorfismo de Nucleótido Simple , Adulto Joven , Anciano de 80 o más Años , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnósticoRESUMEN
OBJECTIVES: Radiomic features have demonstrated encouraging results for non-invasive detection of molecular biomarkers, but the lack of guidelines for pre-processing MRI-data has led to poor generalizability. Here, we assessed the influence of different MRI-intensity normalization techniques on the performance of radiomics-based models for predicting molecular glioma subtypes. METHODS: Preoperative MRI-data from n = 615 patients with newly diagnosed glioma and known isocitrate dehydrogenase (IDH) and 1p/19q status were pre-processed using four different methods: no normalization (naive), N4 bias field correction (N4), N4 followed by either WhiteStripe (N4/WS), or z-score normalization (N4/z-score). A total of 377 Image-Biomarker-Standardisation-Initiative-compliant radiomic features were extracted from each normalized data, and 9 different machine-learning algorithms were trained for multiclass prediction of molecular glioma subtypes (IDH-mutant 1p/19q codeleted vs. IDH-mutant 1p/19q non-codeleted vs. IDH wild type). External testing was performed in public glioma datasets from UCSF (n = 410) and TCGA (n = 160). RESULTS: Support vector machine yielded the best performance with macro-average AUCs of 0.84 (naive), 0.84 (N4), 0.87 (N4/WS), and 0.87 (N4/z-score) in the internal test set. Both N4/WS and z-score outperformed the other approaches in the external UCSF and TCGA test sets with macro-average AUCs ranging from 0.85 to 0.87, replicating the performance of the internal test set, in contrast to macro-average AUCs ranging from 0.19 to 0.45 for naive and 0.26 to 0.52 for N4 alone. CONCLUSION: Intensity normalization of MRI data is essential for the generalizability of radiomic-based machine-learning models. Specifically, both N4/WS and N4/z-score approaches allow to preserve the high model performance, yielding generalizable performance when applying the developed radiomic-based machine-learning model in an external heterogeneous, multi-institutional setting. CLINICAL RELEVANCE STATEMENT: Intensity normalization such as N4/WS or N4/z-score can be used to develop reliable radiomics-based machine learning models from heterogeneous multicentre MRI datasets and provide non-invasive prediction of glioma subtypes. KEY POINTS: ⢠MRI-intensity normalization increases the stability of radiomics-based models and leads to better generalizability. ⢠Intensity normalization did not appear relevant when the developed model was applied to homogeneous data from the same institution. ⢠Radiomic-based machine learning algorithms are a promising approach for simultaneous classification of IDH and 1p/19q status of glioma.
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Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Radiómica , Glioma/diagnóstico por imagen , Glioma/genética , Imagen por Resonancia Magnética/métodos , Biomarcadores , Isocitrato Deshidrogenasa/genética , Mutación , Estudios RetrospectivosRESUMEN
BACKGROUND: While the association between diffusion and perfusion magnetic resonance imaging (MRI) and survival in glioblastoma is established, prognostic models for patients are lacking. This study employed clustering of functional imaging to identify distinct functional phenotypes in untreated glioblastomas, assessing their prognostic significance for overall survival. METHODS: A total of 289 patients with glioblastoma who underwent preoperative multimodal MR imaging were included. Mean values of apparent diffusion coefficient normalized relative cerebral blood volume and relative cerebral blood flow were calculated for different tumor compartments and the entire tumor. Distinct imaging patterns were identified using partition around medoids (PAM) clustering on the training dataset, and their ability to predict overall survival was assessed. Additionally, tree-based machine-learning models were trained to ascertain the significance of features pertaining to cluster membership. RESULTS: Using the training dataset (231/289) we identified 2 stable imaging phenotypes through PAM clustering with significantly different overall survival (OS). Validation in an independent test set revealed a high-risk group with a median OS of 10.2 months and a low-risk group with a median OS of 26.6 months (Pâ =â 0.012). Patients in the low-risk cluster had high diffusion and low perfusion values throughout, while the high-risk cluster displayed the reverse pattern. Including cluster membership in all multivariate Cox regression analyses improved performance (Pâ ≤â 0.004 each). CONCLUSIONS: Our research demonstrates that data-driven clustering can identify clinically relevant, distinct imaging phenotypes, highlighting the potential role of diffusion, and perfusion MRI in predicting survival rates of glioblastoma patients.
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Neoplasias Encefálicas , Imagen de Difusión por Resonancia Magnética , Glioblastoma , Humanos , Glioblastoma/patología , Glioblastoma/diagnóstico por imagen , Glioblastoma/mortalidad , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Pronóstico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Imagen de Difusión por Resonancia Magnética/métodos , Análisis por Conglomerados , Adulto , Tasa de Supervivencia , Circulación Cerebrovascular , Aprendizaje Automático , Adulto Joven , Estudios de SeguimientoRESUMEN
BACKGROUND: To assess compound muscle action potential (CMAP) amplitudes as electrophysiologic markers in relation to clinical outcome in adult patients with 5q-linked spinal muscular atrophy (SMA) before and during treatment with risdiplam. METHODS: In this monocentric longitudinal cohort study, CMAP of 18 adult patients with SMA type 2 or 3 were assessed at baseline (T0 ) and after 10 months (T10 ) of risdiplam treatment. CMAP amplitudes of the median, ulnar, peroneal, and tibial nerves were compared with established clinical outcome scores, and with the course of disease before start of treatment. RESULTS: During a pharmacotherapy-naive pre-treatment period of 328 ± 46 days, Revised Upper Limb Module (RULM) score and peroneal nerve CMAP amplitudes decreased, while CMAP of tibial and upper limb nerves remained unchanged. CMAP amplitudes positively correlated with clinical scores (Hammersmith Functional Motor Scale-Expanded [HFMSE], RULM) at T0 . During risdiplam treatment, HFMSE and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores increased, paralleled by marked increase of CMAP amplitudes in both median nerves (T10 -T0 ; right: Δ = 1.4 ± 1.4 mV, p = 0.0003; left: Δ = 1.3 ± 1.4 mV, p = 0.0007), but not in ulnar, peroneal, or tibial nerves. A robust increase of median nerve CMAP amplitudes correlated well with an increase in the HFMSE score (T10 -T0 ). Median nerve CMAP amplitudes at T0 were associated with subsequent risdiplam-related improvement of HFMSE and CHOP INTEND scores at T10 . CONCLUSIONS: Median nerve CMAP amplitudes increase with risdiplam treatment in adult SMA patients, and should be further evaluated as potential easy-to-use electrophysiologic markers in assessing and monitoring clinical response to therapy.
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Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Adulto , Niño , Lactante , Humanos , Estudios Longitudinales , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Evaluación de Resultado en la Atención de SaludRESUMEN
BACKGROUND: Concurrent malignant brain tumors in patients with multiple sclerosis (MS) constitute a rare but paradigmatic phenomenon for studying neuroimmunological mechanisms from both molecular and clinical perspectives. METHODS: A multicenter cohort of 26 patients diagnosed with both primary brain tumors and multiple sclerosis was studied for disease localization, tumor treatment-related MS activity, and molecular characteristics specific for diffuse glioma in MS patients. RESULTS: MS neither predisposes nor protects from the development of gliomas. Patients with glioblastoma WHO grade 4 without isocitratdehydrogenase (IDH) mutations have a longstanding history of MS, whereas patients diagnosed with IDH-mutant astrocytoma WHO grade 2 receive multiple sclerosis diagnosis mostly at the same time or later. Concurrent MS is associated with a lesser extent of tumor resection and a worse prognosis in IDH-mutant glioma patients (PFS 32 vs. 64 months, p = 0.0206). When assessing tumor-intrinsic differences no distinct subgroup-defining methylation pattern is identified in gliomas of MS patients compared to other glioma samples. However, differential methylation of immune-related genetic loci including human leukocyte antigen locus on 6p21 and interleukin locus on 5q31 is found in MS patients vs. matched non-MS patients. In line, inflammatory disease activity increases in 42% of multiple sclerosis patients after brain tumor radiotherapy suggesting a susceptibility of multiple sclerosis brain tissue to pro-inflammatory stimuli such as ionizing radiation. CONCLUSIONS: Concurrent low-grade gliomas should be considered in multiple sclerosis patients with slowly progressive, expansive T2/FLAIR lesions. Our findings of typically reduced extent of resection in MS patients and increased MS activity after radiation may inform future treatment decisions.
Brain tumors such as gliomas can evade attacks by the immune system. In contrast, some diseases of the central nervous system such as multiple sclerosis (MS) are caused by an overactive immune system. Our study looks at a cohort of rare patients with both malignant glioma and concurrent MS and examines how each disease and their treatments affect each other. Our data suggest that even in patients with known MS, if medical imaging findings are unusual, a concurrent brain tumor should be excluded at an early stage. Radiotherapy, as is the standard of care for malignant brain tumors, may worsen the inflammatory disease activity in MS patients, which may be associated with certain genetic risk factors. Our findings may help to inform treatment of patients with brain tumors and MS.
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Substitution of lysine 27 to methionine in histone H3 (H3K27M) defines an aggressive subtype of diffuse glioma. Previous studies have shown that a H3K27M-specific long peptide vaccine (H3K27M-vac) induces mutation-specific immune responses that control H3K27M+ tumors in major histocompatibility complex-humanized mice. Here we describe a first-in-human treatment with H3K27M-vac of eight adult patients with progressive H3K27M+ diffuse midline glioma on a compassionate use basis. Five patients received H3K27M-vac combined with anti-PD-1 treatment based on physician's discretion. Repeat vaccinations with H3K27M-vac were safe and induced CD4+ T cell-dominated, mutation-specific immune responses in five of eight patients across multiple human leukocyte antigen types. Median progression-free survival after vaccination was 6.2 months and median overall survival was 12.8 months. One patient with a strong mutation-specific T cell response after H3K27M-vac showed pseudoprogression followed by sustained complete remission for >31 months. Our data demonstrate safety and immunogenicity of H3K27M-vac in patients with progressive H3K27M+ diffuse midline glioma.
Asunto(s)
Neoplasias Encefálicas , Glioma , Vacunas , Humanos , Adulto , Animales , Ratones , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Histonas/genética , Glioma/genética , Glioma/terapia , Mutación/genéticaRESUMEN
PURPOSE: The EORTC-26101 study was a randomized phase II and III clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allow for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma. EXPERIMENTAL DESIGN: We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable with the overall study cohort in regard to baseline characteristics, study treatment, and survival. RESULTS: Of patients' samples, 295/380 (78%) were classified into one of the main glioblastoma groups, receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared with mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment. CONCLUSIONS: Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Metilación de ADN , Pronóstico , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Lomustina , Metilasas de Modificación del ADN/genética , O(6)-Metilguanina-ADN Metiltransferasa/genética , Enzimas Reparadoras del ADN/genética , Biomarcadores , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV+) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies. In this study, a comprehensive genetic analysis of 22 EBV+ PCNSL, therefore, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. EBV+ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24-217) and 2 insertions/deletions (range 0-22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79-53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV- PCNSL. Instead, EBV+ PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV+ PCNSL. In addition to novel insights into the pathobiology of EBV+ PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Linfoma , Humanos , Herpesvirus Humano 4/genética , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/metabolismo , Mutación , Pronóstico , Linfoma/genética , Microambiente TumoralRESUMEN
BACKGROUND: Glioblastomas are characterized by aggressive and infiltrative growth, and by striking heterogeneity. The aim of this study was to investigate whether tumor cell proliferation and invasion are interrelated, or rather distinct features of different cell populations. METHODS: Tumor cell invasion and proliferation were longitudinally determined in real-time using 3D in vivo 2-photon laser scanning microscopy over weeks. Glioblastoma cells expressed fluorescent markers that permitted the identification of their mitotic history or their cycling versus non-cycling cell state. RESULTS: Live reporter systems were established that allowed us to dynamically determine the invasive behavior, and previous or actual proliferation of distinct glioblastoma cells, in different tumor regions and disease stages over time. Particularly invasive tumor cells that migrated far away from the main tumor mass, when followed over weeks, had a history of marked proliferation and maintained their proliferative capacity during brain colonization. Infiltrating cells showed fewer connections to the multicellular tumor cell network, a typical feature of gliomas. Once tumor cells colonized a new brain region, their phenotype progressively transitioned into tumor microtube-rich, interconnected, slower-cycling glioblastoma cells. Analysis of resected human glioblastomas confirmed a higher proliferative potential of tumor cells from the invasion zone. CONCLUSIONS: The detection of glioblastoma cells that harbor both particularly high proliferative and invasive capabilities during brain tumor progression provides valuable insights into the interrelatedness of proliferation and migration-2 central traits of malignancy in glioma. This contributes to our understanding of how the brain is efficiently colonized in this disease.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/patología , Invasividad Neoplásica/genética , Neoplasias Encefálicas/patología , Proliferación Celular , Movimiento Celular , Línea Celular TumoralRESUMEN
Mass spectrometry imaging vows to enable simultaneous spatially resolved investigation of hundreds of metabolites in tissues, but it primarily relies on traditional ion images for non-data-driven metabolite visualization and analysis. The rendering and interpretation of ion images neither considers nonlinearities in the resolving power of mass spectrometers nor does it yet evaluate the statistical significance of differential spatial metabolite abundance. Here, we outline the computational framework moleculaR ( https://github.com/CeMOS-Mannheim/moleculaR ) that is expected to improve signal reliability by data-dependent Gaussian-weighting of ion intensities and that introduces probabilistic molecular mapping of statistically significant nonrandom patterns of relative spatial abundance of metabolites-of-interest in tissue. moleculaR also enables cross-tissue statistical comparisons and collective molecular projections of entire biomolecular ensembles followed by their spatial statistical significance evaluation on a single tissue plane. It thereby fosters the spatially resolved investigation of ion milieus, lipid remodeling pathways, or complex scores like the adenylate energy charge within the same image.