RESUMEN
A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patología , Microambiente Tumoral/genética , Neoplasias Encefálicas/patología , Recurrencia Local de Neoplasia/genética , Perfilación de la Expresión Génica , TranscriptomaRESUMEN
WHO grade I meningiomas occasionally show regrowth after radiosurgical treatment, which cannot be predicted by clinical features. There is increasing evidence that certain biomarkers are associated with regrowth of meningiomas. The aim of this retrospective study was to asses if these biomarkers could be of value to predict regrowth of WHO grade I meningiomas after additive radiosurgery. Forty-four patients with WHO grade I meningiomas who underwent additive radiosurgical treatment between 2002 and 2015 after Simpson IV resection were included in this study, of which 8 showed regrowth. Median follow-up time was 64 months (range 24-137 months). Tumors were analyzed for the proliferation marker Ki-67 by immunohistochemistry and for deletion of 1p36 by fluorescence in situ hybridization (FISH). Furthermore, genomic DNA was analyzed for promoter hypermethylation of the genes NDRG1-4, SFRP1, HOXA9 and MGMT. Comparison of meningiomas with and without regrowth after radiosurgery revealed that loss of 1p36 (p = 0.001) and hypermethylation of NDRG1 (p = 0.046) were correlated with regrowth free survival. Loss of 1p36 was the only parameter that was significantly associated with meningioma regrowth after multivariate analysis (p = 0.01). Assessment of 1p36 loss in tumor tissue prior to radiosurgery might be considered an indicator of prognosis/regrowth. However, this finding has to be validated in an independent larger set of tumors.
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Deleción Cromosómica , Cromosomas Humanos Par 1 , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/radioterapia , Meningioma/patología , Meningioma/radioterapia , Recurrencia Local de Neoplasia/patología , Radiocirugia/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Organización Mundial de la SaludRESUMEN
BACKGROUND: Recent studies suggest a relationship between the APOE ε4 allele and cognitive outcome in patients treated for malignant brain tumors. Still, longitudinal investigations that include a pretreatment cognitive assessment are lacking and APOE's effects in patients with benign tumors are understudied. This study investigated presurgical cognitive performance and postsurgical change in ε4-carrying and non-carrying patients with glioma and meningioma. METHODS: Neuropsychological test scores (CNS Vital Signs battery [seven measures], Digit Span Forward/Backward, Letter Fluency test) were obtained as part of a prospective study in which patients with meningioma and glioma underwent cognitive assessment 1 day before (T0, n = 505) and 3 (T3, n = 418) and 12 months after (T12, n = 167) surgery. APOE isoforms were identified retrospectively. ε4 carriers and non-carriers were compared with regard to pretreatment cognitive performance on the group and individual level. Changes in performances over time were compared with longitudinal mixed model analysis in the total sample and the subgroup receiving adjuvant treatment. RESULTS: Carriers and non-carriers did not differ with regard to pretreatment performance. No significant main effect of ε4 carrier status or interaction between time (T0-T12) and carrier status was found on any of the tests in the whole sample nor in the sample receiving adjuvant treatment. CONCLUSIONS: This study found no evidence of increased vulnerability for pretreatment cognitive dysfunction or cognitive decline within 1 year after surgery in APOE ε4-carrying meningioma and glioma patients. Investigations that include larger samples at longer-term follow-up are recommended to investigate potential late treatment effects.
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Apolipoproteína E4 , Neoplasias Encefálicas , Alelos , Apolipoproteína E4/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirugía , Cognición , Genotipo , Humanos , Pruebas Neuropsicológicas , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Gamma Knife radiosurgery (GKRS) has been proven to be a successful primary treatment for metastatic brain tumors (BM). BM can come in cystic lesions and are often too large for GKRS. An alternative approach to treat cystic BM is stereotactic cyst aspiration (SCA) for volume reduction, making it suitable for GKRS afterwards. OBJECTIVE: Our objective is evaluation of volumetric reduction after SCA, tumor control, and complications after SCA directly followed by GKRS. METHODS: We performed a retrospective analysis of all patients who underwent SCA directly followed by GKRS at the Gamma Knife Center of the Elisabeth-Tweesteden Hospital in Tilburg between 2002 and 2015. In total, 54 patients had undergone this combined approach. Two patients were excluded because of prior intracranial treatment. The other 52 patients were included for analysis. RESULTS: SCA resulted in a mean volumetric reduction of 56.5% (range 5.50-87.00%). In 83.6% of the tumors (46 tumors), SCA led to sufficient volumetric reduction making GKRS possible. The overall local tumor control (OLTC) of the aspirated lesions post-GKRS was 60.9% (28 out of 46 tumors). Median progression-free survival (PFS) and overall survival (OS) for all patients were 3 (range 5 days-14 months) and 12 months (range 5 days-58 months), respectively. Leptomeningeal disease was reported in 5 (9.6%) cases. CONCLUSION: SCA directly followed by GKRS is an effective and time-efficient treatment for large cystic BM in selected patients in which surgery is contraindicated and those with deeply located lesions.
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Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/mortalidad , Quistes/mortalidad , Quistes/cirugía , Femenino , Humanos , Masculino , Neoplasias Meníngeas/cirugía , Persona de Mediana Edad , Supervivencia sin Progresión , Radiocirugia/métodos , Estudios Retrospectivos , Succión , Resultado del TratamientoRESUMEN
PURPOSE: Precision medicine trials in glioblastoma (GBM) are often conducted at tumor recurrence. However, second surgeries for recurrent GBM are not routinely performed, and therefore, molecular data for trial inclusion are predominantly derived from the primary sample. This study aims to establish whether molecular targets change during tumor progression and, if so, whether this affects precision medicine trial design. MATERIALS AND METHODS: We collected 186 pairs of primary-recurrent GBM samples from patients receiving chemoradiotherapy with temozolomide and sequenced approximately 300 cancer genes. MGMT, TERT, and EGFRvIII status was individually determined. RESULTS: The molecular profile of our cohort was identical to that of other GBM cohorts (IDH wild-type [WT], 95%; EGFR amplified, approximately 50%), indicating that patients amenable to second surgery do not represent a specific molecular subtype. Molecular events in IDH WT GBMs were stable in approximately 80% of events, but changes in mutation status were observed for all examined genes (range, approximately 90% and 60% for TERT and EGFR mutations, respectively), and such changes strongly affected targeted trial size and design. A similar pattern of GBM driver instability was observed within MGMT promoter-methylated tumors. MGMT promoter methylation status remained prognostic at tumor recurrence. The observation that hypermutation at GBM recurrence was rare (8%) and not correlated with outcome was relevant for immunotherapy-based treatments. CONCLUSION: This large cohort of matched primary and recurrent IDH WT tumors establishes the frequency of GBM driver instability after chemoradiotherapy with temozolomide. This allows per gene or pathway calculation of trial size at tumor recurrence, using molecular data of the primary tumor only. We also identify genes for which repeat surgery is necessary because of low mutation retention rate.
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Neoplasias Encefálicas/terapia , Glioblastoma/genética , Glioblastoma/terapia , Isocitrato Deshidrogenasa/genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/terapia , Medicina de Precisión/métodos , Adolescente , Adulto , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/genética , Estudios de Casos y Controles , Quimioradioterapia , Protocolos Clínicos , Ensayos Clínicos como Asunto , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Evolución Molecular , Femenino , Glioblastoma/enzimología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/enzimología , Regiones Promotoras Genéticas , Temozolomida/administración & dosificación , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
BACKGROUND: At current prognostication of low grade glioma remains suboptimal and might be improved with additional markers. These may guide treatment decisions, in particular on early adjuvant therapy versus wait and see after surgery. METHODS: We used a targeted Next-Generation Sequencing panel to assess mutational and copy number status of selected genes and chromosomes in a consecutive series of adult grade II supratentorial glioma, and assessed the impact of molecular markers of interest on overall survival. RESULTS: 207 IDH mutated grade II glioma samples were analyzed with a median follow-up of 6.9 years. Loss of region 9p21.3 did not show a correlation with outcome in IDH mutated 1p/19q-codeleted oligodendroglioma or IDH mutated astrocytoma. We found a significant shorter overall survival with univariable analysis in IDH mutated astrocytoma patients with trisomy of chromosome 7 (Log rank P = 0.044) and in IDH mutated 1p/19q-codeleted oligodendroglioma patients with a PTEN mutation (Log rank P = 0.033). We could not validate these findings in multivariate analysis or in the TCGA dataset. CONCLUSIONS: Loss of 9p21.3 is not associated with outcome in a molecularly defined cohort of grade II glioma and therefore it remains unclear if loss of 9p21.3 can be used as additional marker of anaplasia or to guide treatment decisions. Trisomy of chromosome 7 in IDH mutated astrocytoma and PTEN mutations in IDH mutated oligodendroglioma are potential markers of poor prognosis, but require confirmation in larger series.
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Neoplasias del Sistema Nervioso Central/genética , Variaciones en el Número de Copia de ADN , Glioma/genética , Isocitrato Deshidrogenasa/genética , Mutación , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias del Sistema Nervioso Central/enzimología , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias del Sistema Nervioso Central/patología , Cromosomas Humanos Par 7 , Cromosomas Humanos Par 9 , Femenino , Estudios de Seguimiento , Glioma/enzimología , Glioma/mortalidad , Glioma/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Análisis de Supervivencia , TrisomíaRESUMEN
Background: Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes. Methods: We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model. Results: Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1-5.0 cm3) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002-1.02; P = 0.016) per cm3 increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1-5.0 cm) already negatively affected OS. Conclusion: Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.
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Astrocitoma/cirugía , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirugía , Glioma/cirugía , Procedimientos Neuroquirúrgicos/efectos adversos , Adulto , Astrocitoma/mortalidad , Neoplasias Encefálicas/genética , Femenino , Glioma/mortalidad , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Procedimientos Neuroquirúrgicos/métodos , Modelos de Riesgos Proporcionales , Resultado del TratamientoRESUMEN
INTRODUCTION: The completeness of the pathological examination of resected colon cancer specimens is important for further clinical management. We reviewed the pathological reports of 356 patients regarding the five factors (pT-stage, tumor differentiation grade, lymphovascular invasion, tumor perforation and lymph node metastasis status) that are used to identify high-risk stage II colon cancers, as well as their impact on overall survival (OS). METHODS: All patients with stage II colon cancer who were included in the first five years of the MATCH study (1 July 2007 to 1 July 2012) were selected (n = 356). The hazard ratios of relevant risk factors were calculated using Cox Proportional Hazards analyses. RESULTS: In as many as 69.1% of the pathology reports, the desired information on one or more risk factors was considered incomplete. In multivariable analysis, age (HR: 1.07, 95%CI 1.04-1.10, p < .001), moderately- (HR: 0.35, 95%CI 0.18-0.70, p = .003) and well (HR 0.11, 95%CI 0.01-0.89, p = .038) differentiated tumors were significantly associated with OS. CONCLUSIONS: Pathology reports should better describe the five high-risk factors, in order to enable proper patient selection for further treatment. Chemotherapy may be offered to stage II patients only in select instances, yet a definitive indication is still unavailable.
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Neoplasias del Colon/patología , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Colectomía , Neoplasias del Colon/mortalidad , Neoplasias del Colon/terapia , Colonoscopía , Terapia Combinada , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Older asthmatic patients may develop fixed airway obstruction and clinical signs of chronic obstructive pulmonary disease (COPD). We investigated the added value of pathological evaluation of bronchial biopsies to help differentiate asthma from COPD, taking into account smoking, age, and inhaled corticosteroid (ICS) use. Asthma and COPD patients (24 of each category) were matched for ICS use, age, FEV(1), and smoking habits. Five pulmonary and five general pathologists examined bronchial biopsies using an interactive website, without knowing patient information. They were asked to diagnose asthma or COPD on biopsy findings in both a pairwise and randomly mixed order of cases during four different phases, with intervals of 4-6 weeks, covering a maximal period of 36 weeks. Clinically concordant diagnoses of asthma or COPD varied between 63 %-73 %, without important differences between pairwise vs randomly mixed examination or between general vs pulmonary pathologists. The highest percentage of concordant diagnoses was in young asthmatic patients without ICS use and in COPD patients with ICS use. In non ICS users with fixed airway obstruction, a COPD diagnosis was favored if abnormal presence of glands, squamous metaplasia, and submucosal infiltrate was present and an asthma diagnosis in case of abnormal presence of goblet cells. In ICS users with fixed airway obstruction, abnormal presence of submucosal infiltrates, basement membrane thickening, eosinophils, and glands was associated with asthma. Histological characteristics in bronchial biopsies are reproducibly recognized by pathologists, yet the differentiation by histopathology between asthma and COPD is difficult without information about ICS use.
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Asma/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Anciano , Asma/complicaciones , Diagnóstico Diferencial , Eosinófilos/patología , Femenino , Humanos , Pulmón , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Fumar/efectos adversosRESUMEN
BACKGROUND: The disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aberrations (CNAs). The purpose of this study is to identify CNAs that are indicative of aggressive tumor behavior and can thereby complement the prognostically favorable 1p/19q co-deletion. RESULTS: Genome-wide, 50 base pair single-end sequencing was performed to detect CNAs in a clinically well-characterized cohort of 98 formalin-fixed paraffin-embedded low-grade gliomas. CNAs are correlated with overall survival as an endpoint. Seventy-five additional samples from spatially distinct regions and paired recurrent tumors of the discovery cohort were analyzed to interrogate the intratumoral heterogeneity and spatial evolution. Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis. A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients. Loss of 10q25.2-qter arises in a longitudinal manner in paired recurrent tumor specimens, whereas the prognostically favorable 1p/19q co-deletion is the only CNA that is stable across spatial regions and recurrent tumors. CONCLUSIONS: CNAs in low-grade gliomas display extensive intratumoral heterogeneity. Distal loss of 10q is a late onset event and a marker for reduced overall survival in low-grade glioma patients. Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.
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Neoplasias Encefálicas/genética , Deleción Cromosómica , Glioma/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Cromosomas Humanos Par 10 , Análisis por Conglomerados , Variaciones en el Número de Copia de ADN , Femenino , Glioma/mortalidad , Glioma/patología , Humanos , Estimación de Kaplan-Meier , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
OBJECTIVE: Despite refinement of surgical techniques and adjuvant radiotherapy, the prognosis for patients with a chordoma remains poor. Identification of prognostic factors related to tumor biology might improve this assessment and result in molecular markers for targeted therapy. Limited studies have been performed to unravel the impact of cell-cycle markers in chordoma, and those performed have shown inconclusive results. In the current study, we aimed to discover the impact of cyclin-dependent kinase 4 (CDK4) expression and its relation to prognosis and other cell-cycle markers in chordoma. METHODS: Twenty-five human formalin-fixed, paraffin-embedded chordoma specimens were examined by immunohistochemistry for the expression of CDK4, protein 53 (p53), and murine double minute 2 (MDM2). The MIB-1 labeling index and mitotic index were used for the examination of proliferation. We collected detailed demographic and clinical data. RESULTS: Overexpression of CDK4, p53, and MDM2 was found in five (20%), seven (28%), and 14 (56%) of the cases, respectively. All three cell-cycle markers showed a significant correlation with MIB1 labeling index. Expression of CDK4 (P = 0.02) and p53 (P < 0.01) were both significantly correlated with poor overall survival. Also, histologically observed necrosis (P < 0.05) and a dedifferentiated tumor subtype (P < 0.01) were related to adverse patient outcome. CONCLUSION: Our results show that the expression of CDK4 and p53 are related to cell proliferation capacity and worse outcome in patients with chordoma.
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Biomarcadores de Tumor/sangre , Proteínas de Ciclo Celular/sangre , Cordoma/sangre , Neoplasias de la Base del Cráneo/sangre , Neoplasias de la Columna Vertebral/sangre , Adulto , Anciano , Cordoma/terapia , Intervalos de Confianza , Quinasa 4 Dependiente de la Ciclina/sangre , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Antígeno Ki-67/sangre , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adhesión en Parafina , Pronóstico , Proteínas Proto-Oncogénicas c-mdm2/sangre , Región Sacrococcígea , Neoplasias de la Base del Cráneo/terapia , Neoplasias de la Columna Vertebral/terapia , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/sangre , Adulto JovenRESUMEN
Choroid plexus papillomas (CPP) are rare tumours and spinal metastases of CPP are even less common. We report a 50-year-old woman with spinal drop metastases at Th9 and S1-2 6 years after total resection of a posterior fossa CPP. The metastasis at S1-2 was resected and histological examination showed transformation to an atypical CPP. Atypical transformation in a metastasis years after resection of a benign posterior fossa CPP has been described once. We would like to advocate craniospinal MRI at the time of initial diagnosis as well as periodic follow-up after total and subtotal resection of a posterior fossa CPP in adults at least once in 1 or 2 years, depending on the histological grading of the primary CPP. In our case report, this could have resulted in earlier diagnosis of the locoregional recurrence or of the spinal drop metastasis.
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Recurrencia Local de Neoplasia/radioterapia , Papiloma del Plexo Coroideo/patología , Sacro/patología , Neoplasias de la Columna Vertebral/patología , Craneotomía , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Papiloma del Plexo Coroideo/secundario , Papiloma del Plexo Coroideo/terapia , Neoplasias de la Columna Vertebral/radioterapia , Neoplasias de la Columna Vertebral/secundarioRESUMEN
A young man presented with progressive motor weakness and atrophy of the ulnar muscles of his left hand over a period of more than 2 years. Electrodiagnostic studies indicated an ulnar nerve lesion, but it was not localized. High-resolution sonography of the ulnar nerve revealed an enlarged and hypoechogenic ulnar nerve at an unusual location, namely 12.5 cm proximal to the medial epicondyle. Histology showed that this was an intraneural perineurioma. High-resolution sonography of the ulnar nerve is very useful in the discovery of this unusual location of nerve pathology and may assist in its early detection.