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PURPOSE: Intracerebral metastases present a substantial risk of tumor-associated intracerebral hemorrhage (ICH). This study aimed to investigate the risk of hemorrhagic events in brain metastases (BM) from various primary tumor sites and evaluate the safety and outcomes of surgical tumor removal. METHODS: A retrospective, single-center review of medical records was conducted for patients who underwent BM removal between January 2016 and December 2017. Patients with hemorrhagic BM were compared to those with non-hemorrhagic BM. Data on preoperative predictors, perioperative management, and postoperative outcomes were collected and analyzed. RESULTS: A total of 229 patients met the inclusion criteria. Melanoma metastases were significantly associated with preoperative hemorrhage, even after adjusting for confounding factors (p = 0.001). Poor clinical status (p = 0.001), larger tumor volume (p = 0.020), and unfavorable prognosis (p = 0.001) independently predicted spontaneous hemorrhage. Importantly, preoperative use of anticoagulant medications was not linked to increased hemorrhagic risk (p = 0.592). Surgical removal of hemorrhagic BM, following cessation of blood-thinning medication, did not significantly affect intraoperative blood loss, surgical duration, or postoperative rebleeding risk (p > 0.096). However, intra-tumoral hemorrhage was associated with reduced overall survival (p = 0.001). CONCLUSION: This study emphasizes the safety of anticoagulation in patients with BM and highlights the safety of neurosurgical treatment in patients with hemorrhagic BM when blood-thinning medication is temporarily paused. The presence of intra-tumoral hemorrhage negatively impacts survival, highlighting its prognostic significance in BM patients. Further research with larger cohorts is warranted to validate these findings and elucidate underlying mechanisms.
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Neoplasias Encefálicas , Hemorragia Cerebral , Humanos , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Hemorragia Cerebral/etiología , Anciano , Pronóstico , Resultado del Tratamiento , Adulto , Procedimientos Neuroquirúrgicos/efectos adversos , Factores de RiesgoRESUMEN
Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In our study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n = 67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA and histone H3 as compared to serum EVs from healthy volunteers (P value range: <.0001 to .08). For two independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44 and histone H3 upon tumor progression, but not in patients with stable disease. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. Measurement of CD29, CD44, CD81, C1QA and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, has the potential to improve detection of true tumor progression and thus could be a useful biomarker for clinical decision making.
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Vesículas Extracelulares , Glioblastoma , Humanos , Histonas , Proteínas Sanguíneas , Integrina beta1RESUMEN
Gold nanoparticles (AuNPs) are currently the most studied radiosensitizers in proton therapy (PT) applicable for the treatment of solid tumors, where they amplify production of reactive oxygen species (ROS). However, it is underexplored how this amplification is correlated with the AuNPs' surface chemistry. To clarify this issue, we fabricated ligand-free AuNPs of different mean diameters by laser ablation in liquids (LAL) and laser fragmentation in liquids (LFL) and irradiated them with clinically relevant proton fields by using water phantoms. ROS generation was monitored by the fluorescent dye 7-OH-coumarin. Our findings reveal an enhancement of ROS production driven by I) increased total particle surface area, II) utilization of ligand-free AuNPs avoiding sodium citrate as a radical quencher ligands, and III) a higher density of structural defects generated by LFL synthesis, indicated by surface charge density. Based on these findings it may be concluded that the surface chemistry is a major and underexplored contributor to ROS generation and sensitizing effects of AuNPs in PT. We further highlight the applicability of AuNPs inâ vitro in human medulloblastoma cells.
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Nanopartículas del Metal , Terapia de Protones , Fármacos Sensibilizantes a Radiaciones , Humanos , Oro/química , Nanopartículas del Metal/química , Especies Reactivas de OxígenoRESUMEN
INTRODUCTION: This study aimed to test the diagnostic significance of FET-PET imaging combined with machine learning for the differentiation between multiple sclerosis (MS) and glioma II°-IV°. METHODS: Our database was screened for patients in whom FET-PET imaging was performed for the diagnostic workup of newly diagnosed lesions evident on MRI and suggestive of glioma. Among those, we identified patients with histologically confirmed glioma II°-IV°, and those who later turned out to have MS. For each group, tumor-to-brain ratio (TBR) derived features of FET were determined. A support vector machine (SVM) based machine learning algorithm was constructed to enhance classification ability, and Receiver Operating Characteristic (ROC) analysis with area under the curve (AUC) metric served to ascertain model performance. RESULTS: A total of 41 patients met selection criteria, including seven patients with MS and 34 patients with glioma. TBR values were significantly higher in the glioma group (TBRmax glioma vs. MS: p = 0.002; TBRmean glioma vs. MS: p = 0.014). In a subgroup analysis, TBR values significantly differentiated between MS and glioblastoma (TBRmax glioblastoma vs. MS: p = 0.0003, TBRmean glioblastoma vs. MS: p = 0.0003) and between MS and oligodendroglioma (ODG) (TBRmax ODG vs. MS: p = 0.003; TBRmean ODG vs. MS: p = 0.01). The ability to differentiate between MS and glioma II°-IV° increased from 0.79 using standard TBR analysis to 0.94 using a SVM based machine learning algorithm. CONCLUSIONS: FET-PET imaging may help differentiate MS from glioma II°-IV° and SVM based machine learning approaches can enhance classification performance.
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Neoplasias Encefálicas/diagnóstico por imagen , Glioma/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador/métodos , Aprendizaje Automático , Esclerosis Múltiple/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiofármacos , Tirosina/análogos & derivadosRESUMEN
PURPOSE: The aim of the present study based on the PriCoTTF-phase I/II trial is the quantification of skin-normal tissue complication probabilities of patients with newly diagnosed glioblastoma multiforme treated with Tumor Treating Field (TTField) electrodes, concurrent radiotherapy, and temozolomide. Furthermore, the skin-sparing effect by the clinically applied strategy of repetitive transducer array fixation around their center position shall be examined. MATERIAL AND METHODS: Low-dose cone-beam computed tomography (CBCT) scans of all fractions of the first seven patients of the PriCoTTF-phase I/II trial, used for image guidance, were applied for the dosimetric analysis, for precise TTField transducer array positioning and contour delineation. Within this trial, array positioning was varied from fixation-to-fixation period with a standard deviation of 1.1 cm in the direction of the largest variation of positioning and 0.7 cm in the perpendicular direction. Physical TTField electrode composition was examined and a respective Hounsfield Unit attributed to the TTField electrodes. Dose distributions in the planning CT with TTField electrodes in place, as derived from prefraction CBCTs, were calculated and accumulated with the algorithm Acuros XB. Dose-volume histograms were obtained for the first and second 2 mm scalp layer with and without migrating electrodes and compared with those with fixed electrodes in an average position. Skin toxicity was quantified according to Lyman's model. Minimum doses in hot-spots of 0.05 cm2 and 25 cm2 ( Δ D0.05cm 2 , Δ D25cm 2 ) size in the superficial skin layers were analyzed. RESULTS: Normal tissue complication probabilities (NTCPs) for skin necrosis ranged from 0.005% to 1.474% (median 0.111%) for the different patients without electrodes. NTCP logarithms were significantly dependent on patient (P < 0.0001) and scenario (P < 0.0001) as classification variables. Fixed positioning of TTField arrays increased skin-NTCP by a factor of 5.50 (95%, CI: 3.66-8.27). The variation of array positioning increased skin-NTCP by a factor of only 3.54 (95%, CI: 2.36-5.32) (P < 0.0001, comparison to irradiation without electrodes; P = 0.036, comparison to irradiation with fixed electrodes). NTCP showed a significant rank correlation with D25cm2 over all patients and scenarios (rs = 0.76; P < 0.0001). CONCLUSION: Skin-NTCP calculation uncovers significant interpatient heterogeneity and may be used to stratify patients into high- and low-risk groups of skin toxicity. Array position variation may mitigate about one-third of the increase in surface dose and skin-NTCP by the TTField electrodes.
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Glioblastoma , Planificación de la Radioterapia Asistida por Computador , Electrodos , Glioblastoma/diagnóstico por imagen , Glioblastoma/radioterapia , Humanos , Radiometría , Dosificación RadioterapéuticaRESUMEN
Glioblastoma is a devastating disease, for which biomarkers allowing a prediction of prognosis are urgently needed. microRNAs have been described as potentially valuable biomarkers in cancer. Here, we studied a panel of microRNAs in extracellular vesicles (EVs) from the serum of glioblastoma patients and evaluated their correlation with the prognosis of these patients. The levels of 15 microRNAs in EVs that were separated by size-exclusion chromatography were studied by quantitative real-time PCR, followed by CD44 immunoprecipitation (SEC + CD44), and compared with those from the total serum of glioblastoma patients (n = 55) and healthy volunteers (n = 10). Compared to total serum, we found evidence for the enrichment of miR-21-3p and miR-106a-5p and, conversely, lower levels of miR-15b-3p, in SEC + CD44 EVs. miR-15b-3p and miR-21-3p were upregulated in glioblastoma patients compared to healthy subjects. A significant correlation with survival of the patients was found for levels of miR-15b-3p in total serum and miR-15b-3p, miR-21-3p, miR-106a-5p, and miR-328-3p in SEC + CD44 EVs. Combining miR-15b-3p in serum or miR-106a-5p in SEC + CD44 EVs with any one of the other three microRNAs in SEC + CD44 EVs allowed for a prognostic stratification of glioblastoma patients. We have thus identified four microRNAs in glioblastoma patients whose levels, in combination, can predict the prognosis for these patients.
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Biomarcadores de Tumor/sangre , Glioblastoma/sangre , Receptores de Hialuranos/sangre , MicroARNs/sangre , Adulto , Anciano , Supervivencia sin Enfermedad , Vesículas Extracelulares/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Glioblastoma/genética , Glioblastoma/patología , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Molecularly targeted therapies using receptor inhibitors, small molecules or monoclonal antibodies are routinely applied in oncology. Verification of target expression should be mandatory prior to initiation of therapy, yet, determining the expression status is most challenging in recurrent glioblastoma (GBM) where most patients are not eligible for second-line surgery. Because very little is known on the consistency of expression along the clinical course we here explored common drug targets in paired primary vs. recurrent GBM tissue samples. METHODS: Paired surgical tissue samples were derived from a homogeneously treated cohort of 34 GBM patients. All patients received radiotherapy and temozolomide chemotherapy. Verification of common drug targets included immunohistological analysis of PDGFR-ß, FGFR-2, FGFR-3, and mTOR-pathway component (phospho-mTORSer2448) as well as molecular, MLPA-based analysis of specific copy number aberrations at the gene loci of ALK, PDGFRA, VEGFR2/KDR, EGFR, MET, and FGFR1. RESULTS: Paired tumor tissue exhibited significant changes of expression in 9 of the 10 investigated druggable targets (90%). Only one target (FGFR1) was found "unchanged", since dissimilar expression was observed in only one of the 34 paired tumor tissue samples. All other targets were variably expressed with an 18-56% discordance rate between primary and recurrent tissue. CONCLUSIONS: The high incidence of dissimilar target expression status in clinical samples from primary vs. recurrent GBM suggests clinically relevant heterogeneity along the course of disease. Molecular target expression, as determined at primary diagnosis, may not necessarily present rational treatment clues for the clinical care of recurrent GBM. Further studies need to analyze the therapeutic impact of longitudinal heterogeneity in GBM.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/terapia , Heterogeneidad Genética , Glioblastoma/terapia , Terapia Molecular Dirigida/métodos , Recurrencia Local de Neoplasia/terapia , Adulto , Anciano , Antineoplásicos/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Progresión de la Enfermedad , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/fisiología , Femenino , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/patología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/tendencias , Recurrencia Local de Neoplasia/genética , Planificación de Atención al Paciente , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Leptomeningeal metastasis (LM) is a predominantly late stage, devastating complication of a variety of malignant solid tumors. Diagnosis relies predominantly on neurological, radiographic, and cerebrospinal fluid (CSF) assessments. Recently, liquid biopsy tests derived from CSF has shown to be a feasible, noninvasive promising approach to tumor molecular profiling for proper brain cancer diagnostic treatment, thereby providing an opportunity for CSF-based personalized medicine. However, LM is typically misleadingly assumed to originate from only one primary tumor type. CASE PRESENTATION: In this case report, we provide first evidence of the co-occurrence of LM originating from more than one primary tumor types. DISCUSSION AND CONCLUSIONS: Based on this patient case profile, the co-occurrence of LM from two or more primary tumor types should be accounted for when deriving diagnostic conclusions from liquid biopsy tests.
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Adenocarcinoma del Pulmón/secundario , Neoplasias Pulmonares/patología , Melanoma/secundario , Neoplasias Meníngeas/secundario , Adenocarcinoma del Pulmón/líquido cefalorraquídeo , Adenocarcinoma del Pulmón/terapia , Anciano , Resultado Fatal , Femenino , Humanos , Biopsia Líquida , Neoplasias Pulmonares/terapia , Melanoma/líquido cefalorraquídeo , Melanoma/terapia , Neoplasias Meníngeas/líquido cefalorraquídeo , Neoplasias Meníngeas/terapiaRESUMEN
Glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor that contributes to this poor prognosis is the highly invasive character of the tumor. GBM is characterized by microscopic infiltration of tumor cells throughout the brain, whereas non-neural metastases, as well as select lower grade gliomas, develop as self-contained and clearly delineated lesions. Illustrated by rodent xenograft tumor models as well as pathological human patient specimens, we present evidence that one fundamental switch between these two distinct pathologies--invasion and noninvasion--is mediated through the tumor extracellular matrix. Specifically, noninvasive lesions are associated with a rich matrix containing substantial amounts of glycosylated chondroitin sulfate proteoglycans (CSPGs), whereas glycosylated CSPGs are essentially absent from diffusely infiltrating tumors. CSPGs, acting as central organizers of the tumor microenvironment, dramatically influence resident reactive astrocytes, inducing their exodus from the tumor mass and the resultant encapsulation of noninvasive lesions. Additionally, CSPGs induce activation of tumor-associated microglia. We demonstrate that the astrogliotic capsule can directly inhibit tumor invasion, and its absence from GBM presents an environment favorable to diffuse infiltration. We also identify the leukocyte common antigen-related phosphatase receptor (PTPRF) as a putative intermediary between extracellular glycosylated CSPGs and noninvasive tumor cells. In all, we present CSPGs as critical regulators of brain tumor histopathology and help to clarify the role of the tumor microenvironment in brain tumor invasion.
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Neoplasias Encefálicas/metabolismo , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Glioma/metabolismo , Microambiente Tumoral , Adulto , Animales , Astrocitos/metabolismo , Astrocitos/patología , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Células Cultivadas , Niño , Proteoglicanos Tipo Condroitín Sulfato/genética , Femenino , Glioma/patología , Glicosilación , Humanos , Masculino , Ratones , Microglía/metabolismo , Microglía/patología , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cellular heterogeneity, for example, the intratumoral coexistence of cancer cells with and without stem cell characteristics, represents a potential root of therapeutic resistance and a significant challenge for modern drug development in glioblastoma (GBM). We propose here that activation of the innate immune system by stimulation of innate immune receptors involved in antiviral and antitumor responses can similarly target different malignant populations of glioma cells. We used short-term expanded patient-specific primary human GBM cells to study the stimulation of the cytosolic nucleic acid receptors melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). Specifically, we analyzed cells from the tumor core versus "residual GBM cells" derived from the tumor resection margin as well as stem cell-enriched primary cultures versus specimens without stem cell properties. A portfolio of human, nontumor neural cells was used as a control for these studies. The expression of RIG-I and MDA5 could be induced in all of these cells. Receptor stimulation with their respective ligands, p(I:C) and 3pRNA, led to in vitro evidence for an effective activation of the innate immune system. Most intriguingly, all investigated cancer cell populations additionally responded with a pronounced induction of apoptotic signaling cascades revealing a second, direct mechanism of antitumor activity. By contrast, p(I:C) and 3pRNA induced only little toxicity in human nonmalignant neural cells. Granted that the challenge of effective central nervous system (CNS) delivery can be overcome, targeting of RIG-I and MDA5 could thus become a quintessential strategy to encounter heterogeneous cancers in the sophisticated environments of the brain.
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Antineoplásicos/farmacología , Citosol/inmunología , ARN Helicasas DEAD-box/inmunología , Glioblastoma/tratamiento farmacológico , Glioblastoma/inmunología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/inmunología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Citosol/efectos de los fármacos , Citosol/metabolismo , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Helicasa Inducida por Interferón IFIH1 , Ligandos , Receptores Inmunológicos , Transducción de Señal/efectos de los fármacos , Células Madre/efectos de los fármacos , Células Madre/inmunología , Células Madre/metabolismoRESUMEN
BACKGROUND: After the failure of radiotherapy and temozolomide, there is no established standard therapy for patients with recurrent glioblastoma (GBM). Based on the promising data of a previous trial (NOA-01) for primary GBM and some retrospective case series for GBM recurrence, the combination of nimustine and teniposide (VM26) was commonly used in this setting. When nimustine was no longer available in Europe, we switched to intrvaveneous carmustine (BCNU). Data on the toxicity and efficacy of BCNU and VM26 in recurrent GBM are lacking. METHODS: In our neurooncological center, all patients with recurrent GBM or with progressed glioma and a typical MRI lesion suggesting GBM treated with BCNU (130-150 mg/m(2), day 1/42) and VM26 (45-60 mg/m(2), days 1-3/42) were analyzed retrospectively for progression-free survival, overall survival and toxicity. RESULTS: Fifteen patients (median age 52 years) were identified. Median progression-free survival was 2 months and median overall survival was 4 months. Two patients (14%) developed grade 3/4 hematotoxicity. Nonhematological toxicity ≥grade 3 was not observed. CONCLUSION: Our data do not support the application of BCNU/VM26 in patients with late stages of recurrent GBM.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Carmustina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Glioma/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Estudios Retrospectivos , Tenipósido/administración & dosificaciónRESUMEN
The tyrosine kinase c-Met promotes the formation and malignant progression of multiple cancers. It is well known that c-Met hyperactivation increases tumorigenicity and tumor cell resistance to DNA damaging agents, properties associated with tumor-initiating stem cells. However, a link between c-Met signaling and the formation and/or maintenance of neoplastic stem cells has not been previously identified. Here, we show that c-Met is activated and functional in glioblastoma (GBM) neurospheres enriched for glioblastoma tumor-initiating stem cells and that c-Met expression/function correlates with stem cell marker expression and the neoplastic stem cell phenotype in glioblastoma neurospheres and clinical glioblastoma specimens. c-Met activation was found to induce the expression of reprogramming transcription factors (RFs) known to support embryonic stem cells and induce differentiated cells to form pluripotent stem (iPS) cells, and c-Met activation counteracted the effects of forced differentiation in glioblastoma neurospheres. Expression of the reprogramming transcription factor Nanog by glioblastoma cells is shown to mediate the ability of c-Met to induce the stem cell characteristics of neurosphere formation and neurosphere cell self-renewal. These findings show that c-Met enhances the population of glioblastoma stem cells (GBM SCs) via a mechanism requiring Nanog and potentially other c-Met-responsive reprogramming transcription factors.
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Glioblastoma/metabolismo , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Transducción de Señal , Antígeno AC133 , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Reprogramación Celular , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Glioblastoma/patología , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Immunoblotting , Indoles/farmacología , Ratones , Ratones SCID , Proteína Homeótica Nanog , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Células Madre Neoplásicas/patología , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Péptidos/genética , Péptidos/metabolismo , Fenotipo , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Sulfonamidas/farmacología , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
(1) Background: Although the incidence of glioblastoma (GB) has a peak in patients aged 75-84 years, no standard treatment regimen for elderly patients has been established so far. The goal of this study was to analyze the outcome of GB patients ≥ 65 years to detect predictors with relevant impacts on overall survival (OS) and progression-free survival (PFS). (2) Methods: Medical records referred to our institution from 2006 to 2020 were analyzed. Adult GB patients with clinical data, postoperative MRI data, and ≥1 follow-up investigation after surgical resection were included. The complete cohort was divided into a younger (<65) and an elderly group (≥65 years). Multiple factors regarding OS and PFS were scanned using univariate and multivariable regression with p < 0.05. (3) Results: 1004 patients were included with 322 (61.0%) male individuals in the younger and 267 (56.1%) males in the older cohort. The most common tumor localization was frontal in both groups. Gross total resection (GTR) was the most common surgical procedure in both groups, followed by subtotal resection (STR) (145; 27.5%) in the younger group, and biopsy (156; 32.8%) in the elderly group. Multivariate analyses detected that in the younger cohort, MGMT promoter methylation and GTR were predictors for a longer OS, while MGMT methylation, GTR, and hypofractionated radiation were significantly associated with a longer OS in the elderly group. (4) Conclusions: Elderly patients benefit from surgical resection of GB when they show MGMT promoter methylation, undergo GTR, and receive hypofractionated radiation. Furthermore, MGMT methylation seems to be associated with a longer PFS in elderly patients. Further investigations are required to confirm these findings, especially within prospective radiation therapy studies and molecular examinations.
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Pituitary adenomas are one of the most common mass lesions of the brain and are associated with a reduced quality of life. While transnasal and transsphenoidal endoscopic approaches are considered to deliver similar recovery rates for sino-nasal health (SNH), the impact of radiological tumor growth patterns on SNH has not been evaluated. In the present study, the influence of radiological tumor growth on SNH was examined before and after endoscopic transsphenoidal tumor resection. Patient data were prospectively collected between August 1, 2016 and August 31, 2022. The Knosp and Hardy classifications were used to dichotomize pituitary adenoma lesions into low- and high-graded lesions. SNH was assessed shortly before surgery and at follow-up examinations 3-6 months after operation using the Sino-Nasal Outcome Test for Neurosurgery (SNOT-NC) questionnaire. Fully completed SNOT-NC questionnaires were collected before and after surgery from a total of 101 patients. Independent t-tests showed significantly higher rates of deterioration after surgery in patients with Knosp low-graded lesions compared with those with high-graded tumors for the SNOT-NC total score P=0.048, nasal discomfort P=0.034, sleep problems P=0.024 and visual impairment P=0.042. Pre- and post-operative comparisons for the Knosp low-graded tumor cohort showed an increase of nasal discomfort (P=0.004), while the Knosp high-graded tumor cohort reported decreased visual impairment (P=0.016) after surgery. Assessing the Hardy classification, increased nasal discomfort was reported in patients with high-graded infrasellar tumors after surgery (P=0.046). Growth characteristics of pituitary adenomas based on Knosp and Hardy classifications may influence SNH. Patients with less invasive lesions were revealed to be more prone to experiencing a decrease in SNH, which went beyond the assumed deterioration of 1-3 months. These findings indicate the importance of detailed information regarding SNH as part of every pre-operative patient briefing.
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Despite their unique histologic features, gliosarcomas belong to the group of glioblastomas and are treated according to the same standards. Fibroblast activation protein (FAP) is a component of a tumor-specific subpopulation of fibroblasts that plays a critical role in tumor growth and invasion. Some case studies suggest an elevated expression of FAP in glioblastoma and a particularly strong expression in gliosarcoma attributed to traits of predominant mesenchymal differentiation. However, the prognostic impact of FAP and its diagnostic and therapeutic potential remain unclear. Here, we investigate the clinical relevance of FAP expression in gliosarcoma and glioblastoma and how it correlates with 68Ga-FAP inhibitor (FAPI)-46 PET uptake. Methods: Patients diagnosed with gliosarcoma or glioblastoma without sarcomatous differentiation with an overall survival of less than 2.5 y were enrolled. Histologic examination included immunohistochemistry and semiquantitative scoring of FAP (0-3, with higher values indicating stronger expression). Additionally, 68Ga-FAPI-46 PET scans were performed in a subset of glioblastomas without sarcomatous differentiation patients. The clinical SUVs were correlated with FAP expression levels in surgically derived tumor tissue and relevant prognostic factors. Results: Of the 61 patients who were enrolled, 13 of them had gliosarcoma. Immunohistochemistry revealed significantly more FAP in gliosarcomas than in glioblastomas without sarcomatous differentiation of tumor tissue (P < 0.0001). In the latter, FAP expression was confined to the perivascular space, whereas neoplastic cells additionally expressed FAP in gliosarcoma. A significant correlation of immunohistochemical FAP with SUVmean and SUVpeak of 68Ga-FAPI-46 PET indicates that clinical tracer uptake represents FAP expression of the tumor. Although gliosarcomas express higher levels of FAP than do glioblastomas without sarcomatous differentiation, overall survival does not significantly differ between the groups. Conclusion: The analysis reveals a significant correlation between SUVmean and SUVpeak in 68Ga-FAPI-46 PET and immunohistochemical FAP expression. This study indicates that FAP expression is much more abundant in the gliosarcoma subgroup of glioblastomas. This could open not only a diagnostic but also a therapeutic gap, since FAP could be explored as a theranostic target to enhance survival in a distinct subgroup of high-risk brain tumor patients with poor survival prognosis.
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Glioblastoma , Gliosarcoma , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Endopeptidasas , Gelatinasas/metabolismo , Glioblastoma/diagnóstico por imagen , Glioblastoma/metabolismo , Glioblastoma/patología , Gliosarcoma/diagnóstico por imagen , Gliosarcoma/metabolismo , Gliosarcoma/patología , Proteínas de la Membrana/metabolismo , Tomografía de Emisión de Positrones , Pronóstico , Quinolinas , Serina Endopeptidasas/metabolismo , Análisis de SupervivenciaRESUMEN
Adaptive plasticity to the standard chemotherapeutic temozolomide (TMZ) leads to glioblastoma progression. Here, we examine early stages of this process in patient-derived cellular models, exposing the human lysine-specific demethylase 5B (KDM5B) as a prospective indicator for subclonal expansion. By integration of a reporter, we show its preferential activity in rare, stem-like ALDH1A1+ cells, immediately increasing expression upon TMZ exposure. Naive, genetically unmodified KDM5Bhigh cells phosphorylate AKT (pAKT) and act as slow-cycling persisters under TMZ. Knockdown of KDM5B reverses pAKT levels, simultaneously increasing PTEN expression and TMZ sensitivity. Pharmacological inhibition of PTEN rescues the effect. Interference with KDM5B subsequent to TMZ decreases cellular vitality, and clonal tracing with DNA barcoding demonstrates high individual levels of KDM5B to predict subclonal expansion already before TMZ exposure. Thus, KDM5Bhigh treatment-naive cells preferentially contribute to the dynamics of drug resistance under TMZ. These findings may serve as a cornerstone for future biomarker-assisted clinical trials.
RESUMEN
The ecosystem of brain tumors is considered immunosuppressed, but our current knowledge may be incomplete. Here we analyzed clinical cell and tissue specimens derived from patients presenting with glioblastoma or nonmalignant intracranial disease to report that the cranial bone (CB) marrow, in juxtaposition to treatment-naive glioblastoma tumors, harbors active lymphoid populations at the time of initial diagnosis. Clinical and anatomical imaging, single-cell molecular and immune cell profiling and quantification of tumor reactivity identified CD8+ T cell clonotypes in the CB that were also found in the tumor. These were characterized by acute and durable antitumor response rooted in the entire T cell developmental spectrum. In contrast to distal bone marrow, the CB niche proximal to the tumor showed increased frequencies of tumor-reactive CD8+ effector types expressing the lymphoid egress marker S1PR1. In line with this, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker indicating focal association with improved progression-free survival. The data of this study advocate preservation and further exploitation of these cranioencephalic units for the clinical care of glioblastoma.
RESUMEN
The extracellular matrix (ECM) protein tenascin-C (TN-C) is upregulated within glioma tissues and cultured glioma cell lines. TN-C possesses a multi-modular structure and a variety of functional properties have been reported for its domains. We describe five novel monoclonal antibodies identifying different domains of TN-C. The epitopes for these antibodies were investigated by using recombinantly expressed fibronectin type III domains of TN-C. The biological effects of TN-C fragments on glioma cell proliferation and adhesion were analyzed. The expression pattern of TN-C in human glioma tissue sections and in glioma cell lines was studied with the novel library of monoclonal antibodies. The immunocytochemical analyses of the established human glioma cell lines U-251-MG, U-373-MG and U-87-MG revealed distinct staining patterns for each antibody. Robust expression of TN-C was found within the tumor mass of surgery specimens from glioblastoma. In many cases, the expression of this ECM molecule was clearly associated with blood vessels, particularly with microvessels. Three of the new antibodies highlighted individual TN-C-expressing single cells in glioma tissues. The effect of TN-C domains on glioma cells was examined by a BrdU-proliferation assay and an adhesion assay. Short fragments of constitutively expressed TN-C-domains did not exert significant effects on the proliferation of glioma cells, whereas the intact molecule increased cell division rates. In contrast, the long fragment TNfnALL containing all of the FNIII domains of TN-C decreased proliferation. Additionally, we found strong differences between the adhesion-influencing properties of the recombinant fragments on glioma cells.
Asunto(s)
Neoplasias Encefálicas/irrigación sanguínea , Neoplasias del Sistema Nervioso Central/irrigación sanguínea , Glioma/irrigación sanguínea , Tenascina/análisis , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Regulación Neoplásica de la Expresión Génica , Glioblastoma/irrigación sanguínea , Glioblastoma/genética , Glioblastoma/patología , Glioma/genética , Glioma/patología , Humanos , Inmunohistoquímica , Tenascina/genéticaRESUMEN
OBJECTIVES: In this study, we analyzed the prognostic value of different MRI progression patterns for survival in patients with recurrent malignant glioma treated with the vascular endothelial growth factor antibody bevacizumab. PATIENTS AND METHODS: Twenty-six adult patients with recurrent malignant glioma treated with bevacizumab or bevacizumab/irinotecan were retrospectively analyzed for the development of contrast-enhanced (T1-weighted MRI) and T2/FLAIR lesions. According to the progression pattern, patients were divided into 3 subgroups: (1) patients with primarily progressive contrast-enhanced lesions in the first MRI after initiation of therapy ('primary PD group'); (2) patients with stable or regressive enhanced lesions but progressive FLAIR lesions ('FLAIR-only PD group'), and (3) patients with stable or regressive contrast-enhanced T1 and FLAIR lesions ('no PD group'). RESULTS: Overall survival (OS) in the 6 patients in the FLAIR-only PD group was not significantly different from the 11 patients in the no PD group (median 311 vs. 254 days, respectively). In contrast, survival in the FLAIR-only PD group was significantly better (p = 0.025) than in the primary PD group. CONCLUSION: FLAIR-only progression is not an independent prognostic factor negatively influencing OS in recurrent glioblastoma treated with bevacizumab and should not lead to discontinuation of bevacizumab therapy.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Adulto , Análisis de Varianza , Bevacizumab , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Progresión de la Enfermedad , Femenino , Alemania/epidemiología , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Irinotecán , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Background: Glioblastoma is the most aggressive primary brain cancer with a poor prognosis. Despite numerous studies in the past 17 years, effective treatment options for glioblastoma remain limited. In this study, we aimed to identify and compare phase III clinical trials for glioblastoma in terms of efficacy and baseline characteristics. Methods: A systematic literature search was conducted using PubMed and ClinicalTrials.gov to identify phase III clinical trials for glioblastoma in adult patients. The target population included adult patients aged 18 years and above (younger cohort) and patients ≥60 years of age (elderly cohort). The search results were screened based on predefined inclusion criteria, and the included trials were analyzed for their study design, baseline characteristics, and survival results. Results: Eleven trials met the inclusion criteria in the younger cohort. Of these, three reported a statistically significant improvement in overall survival (OS), including the EORTC/NCIC study (NCT00006353), EF-14 (NCT00916409), and CeTeG (NCT01149109). Of the 11 trials, eight were open-label randomized trials, including all of the positive ones, while three negative trials employed treatment blinding and a placebo control. The baseline characteristics of the trials [such as extent of resection, age, gender, and O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status] did not significantly differ between positive and negative trials. Isocitrate dehydrogenase (IDH) mutation status was analyzed in only two trials, with a small percentage of IDH-mutated tumors in each. Additionally, three more trials in the elderly cohort showed a statistically significant improvement of OS, the NOA-08 trial, the ISRCTN81470623-trial by Malmström et al. and NCT00482677-trial by Perry et al. Their baseline characteristics and implications are also analyzed. Conclusion: This analysis of phase III clinical trials for glioblastoma conducted since 2005 showed that the majority of trials did not result in a significant improvement in OS. Among the trials included in this analysis, only the EORTC/NCIC, EF-14, and CeTeG studies demonstrated a positive OS outcome in the younger cohort.