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We introduce a novel approach for comprehensive molecular profiling in biological samples. Our single-section methodology combines quantitative mass spectrometry imaging (Q-MSI) and a single step extraction protocol enabling lipidomic and proteomic liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis on the same tissue area. The integration of spatially correlated lipidomic and proteomic data on a single tissue section allows for a comprehensive interpretation of the molecular landscape. Comparing Q-MSI and Q-LC-MS/MS quantification results sheds new light on the effect of MSI and related sample preparation. Performing MSI before Q-LC-MS on the same tissue section led to fewer protein identifications and a lower correlation between lipid quantification results. Also, the critical role and influence of internal standards in Q-MSI for accurate quantification is highlighted. Testing various slide types and the evaluation of different workflows for single-section spatial multiomics analysis emphasized the need for critical evaluation of Q-MSI data. These findings highlight the necessity for robust quantification methods comparable to current gold-standard LC-MS/MS techniques. The spatial information from MSI allowed region-specific insights within heterogeneous tissues, as demonstrated for glioblastoma multiforme. Additionally, our workflow demonstrated the efficiency of a single step extraction for lipidomic and proteomic analyses on the same tissue area, enabling the examination of significantly altered proteins and lipids within distinct regions of a single section. The integration of these insights into a lipid-protein interaction network expands the biological information attainable from a tissue section, highlighting the potential of this comprehensive approach for advancing spatial multiomics research.
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Lipidômica , Espectrometria de Massas em Tandem , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Cromatografia Líquida , Fluxo de Trabalho , Espectrometria de Massa com Cromatografia Líquida , Proteômica/métodos , Lipídeos/análiseRESUMO
OBJECTIVES: Accurate presurgical brain mapping enables preoperative risk assessment and intraoperative guidance. This cross-sectional study investigated whether constrained spherical deconvolution (CSD) methods were more accurate than diffusion tensor imaging (DTI)-based methods for presurgical white matter mapping using intraoperative direct electrical stimulation (DES) as the ground truth. METHODS: Five different tractography methods were compared (three DTI-based and two CSD-based) in 22 preoperative neurosurgical patients undergoing surgery with DES mapping. The corticospinal tract (CST, N = 20) and arcuate fasciculus (AF, N = 7) bundles were reconstructed, then minimum distances between tractograms and DES coordinates were compared between tractography methods. Receiver-operating characteristic (ROC) curves were used for both bundles. For the CST, binary agreement, linear modeling, and posthoc testing were used to compare tractography methods while correcting for relative lesion and bundle volumes. RESULTS: Distance measures between 154 positive (functional response, pDES) and negative (no response, nDES) coordinates, and 134 tractograms resulted in 860 data points. Higher agreement was found between pDES coordinates and CSD-based compared to DTI-based tractograms. ROC curves showed overall higher sensitivity at shorter distance cutoffs for CSD (8.5 mm) compared to DTI (14.5 mm). CSD-based CST tractograms showed significantly higher agreement with pDES, which was confirmed by linear modeling and posthoc tests (PFWE < .05). CONCLUSIONS: CSD-based CST tractograms were more accurate than DTI-based ones when validated using DES-based assessment of motor and sensory function. This demonstrates the potential benefits of structural mapping using CSD in clinical practice.
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Mapeamento Encefálico , Imagem de Tensor de Difusão , Estimulação Elétrica , Humanos , Imagem de Tensor de Difusão/métodos , Imagem de Tensor de Difusão/normas , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Transversais , Estimulação Elétrica/métodos , Mapeamento Encefálico/métodos , Mapeamento Encefálico/normas , Tratos Piramidais/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto Jovem , Cuidados Pré-Operatórios/métodos , Cuidados Pré-Operatórios/normas , IdosoRESUMO
OBJECTIVES: Standard of care treatment for glioblastoma (GBM) involves surgical resection followed by chemoradiotherapy. However, variations in treatment decisions and outcomes exist across hospitals and physicians. In Belgium, where oncological care is dispersed, the impact of hospital volume on GBM outcomes remains unexplored. This nationwide study aims to analyse interhospital variability in 30-day postoperative mortality and 1-/2-year survival for GBM patients. METHODS: Data collected from the Belgian Cancer Registry, identified GBM patients diagnosed between 2016 and 2019. Surgical resection and biopsy cases were identified, and hospital case load was determined. Associations between hospital volume and mortality and survival probabilities were analysed, considering patient characteristics. Statistical analysis included logistic regression for mortality and Cox proportional hazard models for survival. RESULTS: A total of 2269 GBM patients were identified (1665 underwent resection, 662 underwent only biopsy). Thirty-day mortality rates post-resection/post-biopsy were 5.1%/11.9% (target < 3%/<5%). Rates were higher in elderly patients and those with worse WHO-performance scores. No significant difference was found based on hospital case load. Survival probabilities at 1/2 years were 48.6% and 21.3% post-resection; 22.4% and 8.3% post-biopsy. Hazard ratio for all-cause death for low vs. high volume centres was 1.618 in first 0.7 year post-resection (p < 0.0001) and 1.411 in first 0.8 year post-biopsy (p = 0.0046). CONCLUSION: While 30-day postoperative mortality rates were above predefined targets, no association between hospital volume and mortality was found. However, survival probabilities demonstrated benefits from treatment in higher volume centres, particularly in the initial months post-surgery. These variations highlight the need for continuous improvement in neuro-oncological practice and should stimulate reflection on the neuro-oncological care organisation in Belgium.
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PURPOSE: Glioblastoma (GBM) is the most common malignant primary brain tumor with a dismal prognosis of less than 2 years under maximal therapy. Despite the poor prognosis, small fractions of GBM patients seem to have a markedly longer survival than the vast majority of patients. Recently discovered intertumoral heterogeneity is thought to be responsible for this peculiarity, although the exact underlying mechanisms remain largely unknown. Here, we investigated the epigenetic contribution to survival. METHODS: GBM treatment-naïve samples from 53 patients, consisting of 12 extremely long-term survivors (eLTS) patients and 41 median-term survivors (MTS) patients, were collected for DNA methylation analysis. 865 859 CpG sites were examined and processed for detection of differentially methylated CpG positions (DMP) and regions (DMR) between both survival groups. Gene Ontology (GO) and pathway functional annotations were used to identify associated biological processes. Verification of these findings was done using The Cancer Genome Atlas (TCGA) database. RESULTS: We identified 67 DMPs and 5 DMRs that were associated with genes and pathways - namely reduced interferon beta signaling, in MAPK signaling and in NTRK signaling - which play a role in survival in GBM. CONCLUSION: In conclusion, baseline DNA methylation differences already present in treatment-naïve GBM samples are part of genes and pathways that play a role in the survival of these tumor types and therefore may explain part of the intrinsic heterogeneity that determines prognosis in GBM patients.
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Glioblastoma (GBM) is the most common and fatal primary tumor of the central nervous system (CNS) and current treatments have limited success. Chemokine signaling regulates both malignant cells and stromal cells of the tumor microenvironment (TME), constituting a potential therapeutic target against brain cancers. Here, we investigated the C-C chemokine receptor type 7 (CCR7) and the chemokine (C-C-motif) ligand 21 (CCL21) for their expression and function in human GBM and then assessed their therapeutic potential in preclinical mouse GBM models. In GBM patients, CCR7 expression positively associated with a poor survival. CCL21-CCR7 signaling was shown to regulate tumor cell migration and proliferation while also controlling tumor associated microglia/macrophage recruitment and VEGF-A production, thereby controlling vascular dysmorphia. Inhibition of CCL21-CCR7 signaling led to an increased sensitivity to temozolomide-induced tumor cell death. Collectively, our data indicate that drug targeting of CCL21-CCR7 signaling in tumor and TME cells is a therapeutic option against GBM.
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Glioblastoma , Microglia , Animais , Camundongos , Humanos , Glioblastoma/tratamento farmacológico , Receptores CCR7/genética , Macrófagos , Sistema Nervoso Central , Microambiente Tumoral , Quimiocina CCL21RESUMO
BACKGROUND: Functional profiling of freshly isolated glioblastoma (GBM) cells is being evaluated as a next-generation method for precision oncology. While promising, its success largely depends on the method to evaluate treatment activity which requires sufficient resolution and specificity. METHODS: Here, we describe the 'precision oncology by single-cell profiling using ex vivo readouts of functionality' (PROSPERO) assay to evaluate the intrinsic susceptibility of high-grade brain tumor cells to respond to therapy. Different from other assays, PROSPERO extends beyond life/death screening by rapidly evaluating acute molecular drug responses at single-cell resolution. RESULTS: The PROSPERO assay was developed by correlating short-term single-cell molecular signatures using mass cytometry by time-of-flight (CyTOF) to long-term cytotoxicity readouts in representative patient-derived glioblastoma cell cultures (n = 14) that were exposed to radiotherapy and the small-molecule p53/MDM2 inhibitor AMG232. The predictive model was subsequently projected to evaluate drug activity in freshly resected GBM samples from patients (n = 34). Here, PROSPERO revealed an overall limited capacity of tumor cells to respond to therapy, as reflected by the inability to induce key molecular markers upon ex vivo treatment exposure, while retaining proliferative capacity, insights that were validated in patient-derived xenograft (PDX) models. This approach also allowed the investigation of cellular plasticity, which in PDCLs highlighted therapy-induced proneural-to-mesenchymal (PMT) transitions, while in patients' samples this was more heterogeneous. CONCLUSION: PROSPERO provides a precise way to evaluate therapy efficacy by measuring molecular drug responses using specific biomarker changes in freshly resected brain tumor samples, in addition to providing key functional insights in cellular behavior, which may ultimately complement standard, clinical biomarker evaluations.
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Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Medicina de Precisão , Antineoplásicos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular TumoralRESUMO
The biomedical use of nanoparticles (NPs) has been the focus of intense research for over a decade. As most NPs are explored as carriers to alter the biodistribution, pharmacokinetics and bioavailability of associated drugs, the delivery of these NPs to the tissues of interest remains an important topic. To date, the majority of NP delivery studies have used tumor models as their tool of interest, and the limitations concerning tumor targeting of systemically administered NPs have been well studied. In recent years, the focus has also shifted to other organs, each presenting their own unique delivery challenges to overcome. In this review, we discuss the recent advances in leveraging NPs to overcome four major biological barriers including the lung mucus, the gastrointestinal mucus, the placental barrier, and the blood-brain barrier. We define the specific properties of these biological barriers, discuss the challenges related to NP transport across them, and provide an overview of recent advances in the field. We discuss the strengths and shortcomings of different strategies to facilitate NP transport across the barriers and highlight some key findings that can stimulate further advances in this field.
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Nanopartículas , Neoplasias , Gravidez , Humanos , Feminino , Portadores de Fármacos/uso terapêutico , Distribuição Tecidual , Placenta/patologia , Neoplasias/tratamento farmacológico , Sistemas de Liberação de MedicamentosRESUMO
INTRODUCTION: The objective of this study was to cross-check and, if necessary, adjust registered ICD-O-3 topography and morphology codes with the findings in pathology reports available at the Belgian Cancer Registry (BCR) for glioma patients. Additionally, integration of molecular markers in the pathological diagnosis and concordance with WHO 2016 classification is investigated. METHODS: Since information regarding molecular tests and corresponding conclusions are not available as structured data at population level, a manual screening of all pseudonymized pathology reports available at the BCR for registered glioma patients (2017-2019) was conducted. ICD-O-3 morphology and topography codes from the BCR database (based on information as provided by hospital oncological care programmes and pathology laboratories), were, at tumour level, cross-checked with the data from the pathology reports and, if needed, specified or corrected. Relevant molecular markers (IDH1/2, 1p19q codeletion, promoter region of the MGMT gene [MGMTp]) were manually extracted from the pathology reports. RESULTS: In 95.3% of gliomas, the ICD-O-3 morphology code was correct. Non-specific topography codes were specified in 9.3%, while 3.3% of specific codes were corrected. The IDH status was known in 75.2% of astrocytic tumours. The rate of correct integrated diagnoses varied from 47.6% to 56.4% among different gliomas. MGMTp methylation status was available in 32.2% of glioblastomas. CONCLUSION: Both the integration of molecular markers in the conclusion of the pathology reports and the delivery of those reports to the BCR can be improved. The availability of distinct ICD-O-3 codes for each molecularly defined tumour entity within the WHO classification would increase the consistency of cancer registration, facilitate population level research and international benchmarking.
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Neoplasias Encefálicas , Glioma , Humanos , Bélgica , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/diagnóstico , Glioma/genética , Biomarcadores , Organização Mundial da Saúde , Isocitrato Desidrogenase/genética , MutaçãoRESUMO
BACKGROUND: Awake mapping has been associated with decreased neurological deficits and increased extent of resection in eloquent glioma resections. However, its effect within clinically relevant glioblastoma subgroups remains poorly understood. We aimed to assess the benefit of this technique in subgroups of patients with glioblastomas based on age, preoperative neurological morbidity, and Karnofsky Performance Score (KPS). METHODS: In this propensity score-matched analysis of an international, multicentre, cohort study (GLIOMAP), patients were recruited at four tertiary centres in Europe (Erasmus MC, Rotterdam and Haaglanden MC, The Hague, Netherlands, and UZ Leuven, Leuven, Belgium) and the USA (Brigham and Women's Hospital, Boston, MA). Patients were eligible if they were aged 18-90 years, undergoing resection, had a histopathological diagnosis of primary glioblastoma, their tumour was in an eloquent or near-eloquent location, and they had a unifocal enhancing lesion. Patients either underwent awake mapping during craniotomy, or asleep resection, as per treating physician or multidisciplinary tumour board decision. We used propensity-score matching (1:3) to match patients in the awake group with those in the asleep group to create a matched cohort, and to match patients from subgroups stratified by age (<70 years vs ≥70 years), preoperative National Institute of Health Stroke Scale (NIHSS) score (score of 0-1 vs ≥2), and preoperative KPS (90-100 vs ≤80). We used Cox proportional hazard regressions to analyse the effect of awake mapping on the primary outcomes including postoperative neurological deficits (measured by deterioration in NIHSS score at 6 week, 3 months, and 6 months postoperatively), overall survival, and progression-free survival. We used logistic regression to analyse the predictive value of awake mapping and other perioperative factors on postoperative outcomes. FINDINGS: Between Jan 1, 2010, and Oct 31, 2020, 3919 patients were recruited, of whom 1047 with tumour resection for primary eloquent glioblastoma were included in analyses as the overall unmatched cohort. After propensity-score matching, the overall matched cohort comprised 536 patients, of whom 134 had awake craniotomies and 402 had asleep resection. In the overall matched cohort, awake craniotomy versus asleep resection resulted in fewer neurological deficits at 3 months (26 [22%] of 120 vs 107 [33%] of 323; p=0·019) and 6 months (30 [26%] of 115 vs 125 [41%] of 305; p=0·0048) postoperatively, longer overall survival (median 17·0 months [95% CI 15·0-24·0] vs 14·0 months [13·0-16·0]; p=0·00054), and longer progression-free survival (median 9·0 months [8·0-11·0] vs 7·3 months [6·0-8·8]; p=0·0060). In subgroup analyses, fewer postoperative neurological deficits occurred at 3 months and at 6 months with awake craniotomy versus asleep resection in patients younger than 70 years (3 months: 22 [21%] of 103 vs 93 [34%] of 272; p=0·016; 6 months: 24 [24%] of 101 vs 108 [42%] of 258; p=0·0014), those with an NIHSS score of 0-1 (3 months: 22 [23%] of 96 vs 97 [38%] of 254; p=0·0071; 6 months: 27 [28%] of 95 vs 115 [48%] of 239; p=0·0010), and those with a KPS of 90-100 (3 months: 17 [19%] of 88 vs 74 [35%] of 237; p=0·034; 6 months: 24 [28%] of 87 vs 101 [45%] of 223, p=0·0043). Additionally, fewer postoperative neurological deficits were seen in the awake group versus the asleep group at 3 months in patients aged 70 years and older (two [13%] of 16 vs 15 [43%] of 35; p=0·033; no difference seen at 6 months), with a NIHSS score of 2 or higher (3 months: three [13%] of 23 vs 21 [36%] of 58; p=0·040) and at 6 months in those with a KPS of 80 or lower (five [18%] of 28 vs 34 [39%] of 88; p=0·043; no difference seen at 3 months). Median overall survival was longer for the awake group than the asleep group in the subgroups younger than 70 years (19·5 months [95% CI 16·0-31·0] vs 15·0 months [13·0-17·0]; p<0·0001), an NIHSS score of 0-1 (18·0 months [16·0-31·0] vs 14·0 months [13·0-16·5]; p=0·00047), and KPS of 90-100 (19·0 months [16·0-31·0] vs 14·5 months [13·0-16·5]; p=0·00058). Median progression-free survival was also longer in the awake group than in the asleep group in patients younger than 70 years (9·3 months [95% CI 8·0-12·0] vs 7·5 months [6·5-9·0]; p=0·0061), in those with an NIHSS score of 0-1 (9·5 months [9·0-12·0] vs 8·0 months [6·5-9·0]; p=0·0035), and in those with a KPS of 90-100 (10·0 months [9·0-13·0] vs 8·0 months [7·0-9·0]; p=0·0010). No difference was seen in overall survival or progression-free survival between the awake group and the asleep group for those aged 70 years and older, with NIHSS scores of 2 or higher, or with a KPS of 80 or lower. INTERPRETATION: These data might aid neurosurgeons with the assessment of their surgical strategy in individual glioblastoma patients. These findings will be validated and further explored in the SAFE trial (NCT03861299) and the PROGRAM study (NCT04708171). FUNDING: None.
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Neoplasias Encefálicas , Glioblastoma , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Estudos de Coortes , Craniotomia/efeitos adversos , Craniotomia/métodos , Feminino , Glioblastoma/cirurgia , Humanos , Pontuação de Propensão , Estudos Retrospectivos , VigíliaRESUMO
Immunogenic cell death (ICD) has emerged as a key component of therapy-induced anti-tumor immunity. Over the past few years, ICD was found to play a pivotal role in a wide variety of novel and existing treatment modalities. The clinical application of these techniques in cancer treatment is still in its infancy. Glioblastoma (GBM) is the most lethal primary brain tumor with a dismal prognosis despite maximal therapy. The development of new therapies in this aggressive type of tumors remains highly challenging partially due to the cold tumor immune environment. GBM could therefore benefit from ICD-based therapies stimulating the anti-tumor immune response. In what follows, we will describe the mechanisms behind ICD and the ICD-based (pre)clinical advances in anticancer therapies focusing on GBM.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Morte Celular Imunogênica , PrognósticoRESUMO
BACKGROUND: Quality Indicators (QIs) are important tools to assess the quality and variability of oncological care. However, their application in neuro-oncology is limited so far. The objective of this study was to develop a set of QIs for glioma, covering process and outcome indicators. METHODS: A systematic review was conducted to identify both QIs in the field of adult glioma care, and guidelines or recommendations that could be translated into QIs. Also reports from national and international healthcare agencies and scientific associations ("grey literature") were taken into account. After conversion of these recommendations into QIs, merging with existing QIs found in the literature and rationalization, a two-round Delphi survey was conducted to gain consensus on relevance for the proposed QIs. RESULTS: In total 240 recommendations and 30 QIs were retrieved from the literature. After conversion, merging and rationalization, 147 QIs were evaluated in the Delphi survey and eventually consensus was gained on 47 QIs in the following 7 domains: Diagnosis and Imaging, Surgery, Pathology, Radio/Chemotherapy, Recurrence, Supportive Treatments (Epilepsy, Thromboembolism, Steroid Use and Rehabilitation) and Survival. CONCLUSION: This study defined a set of 47 QIs for assessing quality of care in adult glioma patients, distributed amongst 7 crucial phases in the patient's care trajectory. These QIs are readily applicable for use in diverse health care systems, depending on the availability of population-based health care data enabling (inter)national benchmarking.
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Glioma , Indicadores de Qualidade em Assistência à Saúde , Consenso , Atenção à Saúde , Técnica Delphi , Glioma/diagnóstico , Glioma/terapia , HumanosRESUMO
PURPOSE: Due to the lack of consensus on the management of glioblastoma patients, there exists variability amongst surgeons and centers regarding treatment decisions. Though, objective data about the extent of this heterogeneity is still lacking. We aim to evaluate and analyze the similarities and differences in neurosurgical practice patterns. METHODS: The survey was distributed to members of the neurosurgical societies of the Netherlands (NVVN), Europe (EANS), the United Kingdom (SBNS) and the United States (CNS) between January and March 2021 with questions about the selection of surgical modality and decision making in glioblastoma patients. RESULTS: Survey respondents (224 neurosurgeons) were from 41 countries. Overall, the most notable differences observed were the presence and timing of a multidisciplinary tumor board; the importance and role of various perioperative factors in the decision-making process, and the preferred treatment in various glioblastoma cases and case variants. Tumor boards were more common at academic centers. The intended extent of resection for glioblastoma resections in eloquent areas was limited more often in European neurosurgeons. We found a strong relationship between the surgeon's theoretical survey answers and their actual approach in presented patient cases. In general, the factors which were found to be theoretically the most important in surgical decision making were confirmed to influence the respondents' decisions to the greatest extent in practice as well. DISCUSSION: This survey illustrates the theoretical and practical heterogeneity among surgeons and centers in their decision making and treatment selection for glioblastoma patients. These data invite further evaluations to identify key variables that can be optimized and may therefore benefit from consensus.
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Tomada de Decisão Clínica , Glioblastoma , Neurocirurgiões , Procedimentos Neurocirúrgicos , Glioblastoma/cirurgia , Pesquisas sobre Atenção à Saúde , Humanos , Internacionalidade , Neurocirurgiões/psicologia , Procedimentos Neurocirúrgicos/métodosRESUMO
Cerebrospinal fluid (CSF) leakage is a major complication after elective neurosurgical procedures. The aim of this systematic literature review is to summarize the incidence rates of postoperative cerebrospinal fluid leakage for neurosurgical procedures, classified by surgical approach. The Pubmed, Cochrane, Embase, and Web of Science databases were searched for studies reporting the outcome of patients undergoing elective neurosurgical procedures. The number of patients, surgical approach, and indication for surgery were recorded for each study. Outcomes related to CSF leakage such as clinical manifestation and treatment were reported as well. One hundred and thirteen studies were included, reporting 94,695 cases. Overall, CSF leaks were present in 3.8% of cases. Skull base surgery had the highest rate of CSF leakage with 6.2%. CSF leakage occurred in 5.9% of anterior skull base procedures, 6.4% of middle fossa, and 5.2% of transpetrosal surgeries. 5.8% of reported infratentorial procedures were complicated by CSF leakage versus 2.9% of supratentorial surgeries. CSF leakage remains a common serious adverse event after cranial surgery. There exists a need for standardized procedures to reduce the incidence of postoperative CSF leakage, as this serious adverse event may lead to increased health care costs.
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Vazamento de Líquido Cefalorraquidiano , Complicações Pós-Operatórias , Vazamento de Líquido Cefalorraquidiano/epidemiologia , Vazamento de Líquido Cefalorraquidiano/etiologia , Vazamento de Líquido Cefalorraquidiano/cirurgia , Humanos , Incidência , Procedimentos Neurocirúrgicos/efeitos adversos , Complicações Pós-Operatórias/etiologia , Período Pós-Operatório , Estudos Retrospectivos , Base do Crânio/cirurgiaRESUMO
PURPOSE: Patients with a benign meningioma often have a long survival following the treatment of their meningioma. Since radiotherapy is frequently part of the treatment, long-term side effects are of considerable concern. A controversial long-term side effect of radiotherapy is stroke. Due to its severity, it is important to know the frequency of this side effect. The aim of this study was to assess the stroke incidence and risk factors among patients receiving radiotherapy for their benign meningioma. METHODS: We performed a retrospective database study of patients who underwent primary or adjuvant radiotherapy for their benign meningioma at University Hospitals Leuven from January 2003 to December 2017. RESULTS: We included 169 patients with a median age of 51 years (range 22-84). Every patient received fractionated radiotherapy using photons with a median dose of 56 Gy (range 54-56) in fractions of 2 Gy (range 1.8-2). The median follow-up was 5.3 years (range 0.1-14). The cumulative stroke incidence function showed an incidence of 11.6% after 9 years of follow-up, translating to a stroke incidence per year of 1.29%. We found two significant risk factors for stroke: medically treated arterial hypertension (p = 0.005) and history of previous stroke or transient ischemic attack (p < 0.001). 5-year local control and overall survival rates were respectively 97.4% and 91.2%. Other late grade III/IV toxicities occurred in 16.0% (27/169) of patients. CONCLUSION: Our study shows a higher incidence of stroke in patients who received radiotherapy for their benign meningioma compared to the general population.
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Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Radioterapia/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Fracionamento da Dose de Radiação , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologiaRESUMO
Cutibacterium (C) acnes, a Gram-positive bacterium that is part of the commensal flora, is increasingly noticed as an opportunistic pathogen in serious infections in both immunocompromised and immunocompetent patients. The indolent character and often difficult identification because of its slow growth contribute to delayed diagnosis or underdiagnosis. This report highlights a unique case of a lung transplant recipient with a C acnes intracerebral abscess, and we recommend including this organism in such differential diagnosis. A 66-year-old woman, 2 years after bilateral lung transplantation for chronic obstructive pulmonary disease, presented with frontal headache, without other complaints, and with normal neurological examination. Magnetic resonance imaging showed an extensive lesion in the right frontal lobe with extensive perilesional edema. Given the broad differential diagnosis, stereotactic brain biopsy was performed and culture became positive for C acnes. She was treated with intravenous ceftriaxone for 8 weeks and per oral clindamycin for 6 months, as well as corticosteroids in tapered dose. There was a rapid favorable clinical and radiographic evolution.
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Infecções por Bactérias Gram-Positivas , Transplante de Pulmão , Idoso , Abscesso Encefálico , Ceftriaxona , Feminino , Humanos , Propionibacterium acnesRESUMO
Blockade of the immune checkpoint molecule programmed-cell-death-protein-1 (PD-1) yielded promising results in several cancers. To understand the therapeutic potential in human gliomas, quantitative data describing the expression of PD-1 are essential. Moreover, due the immune-specialized region of the brain in which gliomas arise, differences between tumor-infiltrating and circulating lymphocytes should be acknowledged. In this study we have used flow cytometry to quantify PD-1 expression on tumor-infiltrating T cells of 25 freshly resected glioma cell suspensions (10 newly and 5 relapsed glioblastoma, 10 lower grade gliomas) and simultaneously isolated circulating T cells. A strong upregulation of PD-1 expression in the tumor microenvironment compared to the blood circulation was seen in all glioma patients. Additionally, circulating T cells were isolated from 15 age-matched healthy volunteers, but no differences in PD-1 expression were found compared to glioma patients. In the murine GL261 malignant glioma model, there was a similar upregulation of PD-1 on brain-infiltrating lymphocytes. Using a monoclonal PD-1 blocking antibody, we found a marked prolonged survival with 55% of mice reaching long-term survival. Analysis of brain-infiltrating cells 21 days after GL261 tumor implantation showed a shift in infiltrating lymphocyte subgroups with increased CD8+ T cells and decreased regulatory T cells. Together, our results suggest an important role of PD-1 in glioma-induced immune escape, and provide translational evidence for the use of PD-1 blocking antibodies in human malignant gliomas.
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Anticorpos Monoclonais/administração & dosagem , Glioma/tratamento farmacológico , Linfócitos do Interstício Tumoral/patologia , Receptor de Morte Celular Programada 1/genética , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/imunologia , Glioma/patologia , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Posttraumatic pontomedullary rents have been described mainly as postmortem histopathological findings in patients who died immediately or within the first hours after trauma. To the best of our knowledge, no long-term survivors of this condition have been described, and those surviving initially were always severely impaired. We present the first patient with this condition and with corresponding lesions on imaging who survived longer than 3 months. Moreover, the patient regained almost complete independence 1 year after the trauma. We briefly discuss the proposed mechanisms of this injury. We conclude that this lesion, when incomplete, is not always lethal and can exceptionally have a good clinical outcome. Prevention of respiratory failure is of utmost importance in these patients.