RESUMO
The health effects of coronavirus disease 2019 (COVID-19) caused by the infection of SARS-CoV2 (severe acute respiratory syndrome coronavirus 2) are becoming increasingly clear as the pandemic spreads. In addition to the lungs, other organs are also affected, which can significantly influence morbidity and mortality. In particular, neurological symptoms involving the central nervous system can lead to acute or long-term consequences. The mechanisms of this neuropathogenesis of SARS-CoV2 infection and its relation to acute and chronic neurological symptoms are the subject of current studies investigating a potential direct and indirect viral infection of the nervous system. The following review summarizes the current status of neuropathological manifestations, molecular pathogenesis, possible infection pathways in the nervous system, and systemic effects. In addition, an overview of the Germany-wide CNS-COVID19 registry and collaborations is presented, which should contribute to a better understanding of the neurological symptoms of COVID-19.
Assuntos
COVID-19 , Alemanha , Humanos , Pandemias , Sistema Nervoso Periférico , SARS-CoV-2RESUMO
In April 2013 our group published a review on predictive molecular pathology in this journal. Although only 2 years have passed many new facts and stimulating developments have happened in diagnostic molecular pathology rendering it worthwhile to present an up-date on this topic. A major technical improvement is certainly given by the introduction of next-generation sequencing (NGS; amplicon, whole exome, whole genome) and its application to formalin-fixed paraffin-embedded (FFPE) tissue in routine diagnostics. Based on this 'revolution' the analyses of numerous genetic alterations in parallel has become a routine approach opening the chance to characterize patients' malignant tumors much more deeply without increasing turn-around time and costs. In the near future this will open new strategies to apply 'off-label' targeted therapies, e.g. for rare tumors, otherwise resistant tumors etc. The clinically relevant genetic aberrations described in this review include mutation analyses of RAS (KRAS and NRAS), BRAF and PI3K in colorectal cancer, KIT or PDGFR alpha as well as BRAF, NRAS and KIT in malignant melanoma. Moreover, we present several recent advances in the molecular characterization of malignant lymphoma. Beside the well-known mutations in NSCLC (EGFR, ALK) a number of chromosomal aberrations (KRAS, ROS1, MET) have become relevant. Only very recently has the clinical need for analysis of BRCA1/2 come up and proven as a true challenge for routine diagnostics because of the genes' special structure and hot-spot-free mutational distribution. The genetic alterations are discussed in connection with their increasingly important role in companion diagnostics to apply targeted drugs as efficient as possible. As another aspect of the increasing number of druggable mutations, we discuss the challenges personalized therapies pose for the design of clinical studies to prove optimal efficacy particularly with respect to combination therapies of multiple targeted drugs and conventional chemotherapy. Such combinations would lead to an extremely high complexity that would hardly be manageable by applying conventional study designs for approval, e.g. by the FDA or EMA. Up-coming challenges such as the application of methylation assays and proteomic analyses on FFPE tissue will also be discussed briefly to open the door towards the ultimate goal of reading a patients' tissue as 'deeply' as possible. Although it is yet to be shown, which levels of biological information are most informative for predictive pathology, an integrated molecular characterization of tumors will likely offer the most comprehensive view for individualized therapy approaches. To optimize cancer treatment we need to understand tumor biology in much more detail on morphological, genetic, proteomic as well as epigenetic grounds. Finally, the complex challenges on the level of drug design, molecular diagnostics, and clinical trials make necessary a close collaboration among academic institutions, regulatory authorities and pharmaceutical companies.
Assuntos
Terapia de Alvo Molecular , Neoplasias/terapia , Antineoplásicos/uso terapêutico , Aberrações Cromossômicas , DNA de Neoplasias/genética , Desenho de Fármacos , Genes Neoplásicos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Mutação , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia , Medicina de Precisão , Proteômica , Análise de Sequência de DNA/métodos , Terapias em EstudoRESUMO
Multiple sclerosis (MS) is usually a chronic and disabling inflammatory disease. Marburg's type of MS is characterized by rapid progression and severe disease course that leads to death within one year after the onset of clinical signs. We describe a fulminant clinical presentation of this malignant subtype of MS and discuss the neuropathological hallmarks as well as differential diagnoses of other fulminant demyelinating diseases. To the best of our knowledge, this is the most fulminant course of this MS variant reported in the literature.
Assuntos
Encéfalo/patologia , Esclerose Múltipla Crônica Progressiva/patologia , Adulto , Autopsia , Doenças Desmielinizantes/diagnóstico , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Esclerose Múltipla Crônica Progressiva/fisiopatologiaRESUMO
The increasing importance of targeting drugs in the treatment of several tumor entities (breast, colon, lung, malignant melanoma (MM), lymphoma, and so on) and the necessity of a companion diagnostic (human epidermal growth factor receptor 2, Kirsten rat sarcoma viral oncogene, epidermal growth factor receptor (EGFR), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), and so on) is leading to new challenges for surgical pathology. As all the biomarkers to be specifically detected are tissue based, a precise and reliable diagnostic is absolutely crucial. To meet this challenge, surgical pathology has adapted a number of molecular methods (semi-quantitative immunohistochemistry, fluorescence in situ hybridization), PCR and its multiple variants, (pyro/Sanger) sequencing, next-generation sequencing, DNA-arrays, methylation analyses, and so on) to be applicable for formalin-fixed paraffin-embedded (FFPE) tissue. To read a patients' tissue as 'deeply' as possible and to obtain information on morphological, genetic, proteomic as well as epigenetic background is the actual task of pathologists and molecular biologists in order to provide the clinicians with information relevant for individualized medicine. The intensified cooperation of clinicians and pathologists will provide the basis of improved clinical drug selection as well as guide development of new cancer gene therapies and molecularly targeted drugs by research units and the pharmaceutical industry. This review will give some information on (1) biomarker detection methods adapted to FFPE tissue, (2) the potency of predictive pathology in tumor detection and treatment and (3) the implications of pathology on the development of new drugs in molecularly targeted and gene therapies.
Assuntos
Terapia de Alvo Molecular , Neoplasias/terapia , Biomarcadores Tumorais/metabolismo , Terapia Genética , Humanos , Técnicas de Diagnóstico Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Medicina de PrecisãoRESUMO
INTRODUCTION: Combined antiangiogenic and cytotoxic treatment represents an appealing treatment approach for malignant glioma. In this study we characterised the antitumoural and microvascular consequences of sunitinib (Su) and temozolomide (TMZ) therapy and verified the ideal treatment protocol, with special focus on a potential therapeutic window for combined scheduling. MATERIALS AND METHODS: O(6)-Methylguanine methyltransferase (MGMT) status was analysed by pyrosequencing. Tumour growth of subcutaneous xenografts was assessed under different treatment protocols (TMZ, SU, SU followed by TMZ, TMZ followed by SU, combined TMZ/SU). Intravital microscopy (dorsal skinfold chamber model) assessed microvascular consequences. Immunohistochemistry included tumour and endothelial cell proliferation, apoptosis and vascular pericyte coverage. Real-time polymerase chain reaction (RT-PCR) analysed the expression of angiogenesis-related pathways in response to therapy. RESULTS: Combined TMZ/SU resulted in significantly reduced tumour growth compared to either monotreatment (TMZ: 106 ± 13 mm(3); SU: 114 ± 53 mm(3); TMZ/SU: 34 ± 7 mm(3)) by additional antiangiogenic effects and synergistic induction of apoptosis versus TMZ monotreatment. Sequential treatment protocols did not show additive antitumour responses. TMZ/SU aggravated vascular resistance mechanisms characterised by significantly higher blood flow rate (TMZ: 74 ± 34 µl/s; SU: 164 ± 36 µl/s; TMZ/SU: 254 ± 95 µl/s), reduced permeability (TMZ: 1.05 ± 0.02; SU: 0.99 ± 0.07; TMZ/SU: 0.89 ± 0.05) and recovery of pericyte-endothelial interactions (TMZ: 89 ± 7%; SU: 67 ± 9%, TMZ/SU:80 ± 10%) versus either monotreatment. Vascular resistance was paralleled by an increase in Ang-1 and Tie-2 and by the downregulation of Dll4. CONCLUSION: Sequential application of TMZ and SU in the angiogenic window does not add antitumour efficacy to monotherapy. Simultaneous application yields beneficial tumour control due to additive antiangiogenic and proapoptotic effects. Combined treatment may aggravate pericyte-mediated vascular resistance mechanisms by altering Ang-1-Tie-2 and Dll4/Notch pathways.
Assuntos
Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Resistência Vascular/efeitos dos fármacos , Inibidores da Angiogênese/administração & dosagem , Animais , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/fisiologia , DNA de Neoplasias/metabolismo , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Glioma/enzimologia , Glioma/patologia , Xenoenxertos , Humanos , Indóis/administração & dosagem , Masculino , Camundongos , Camundongos Nus , Pirróis/administração & dosagem , Sunitinibe , Temozolomida , Células Tumorais CultivadasAssuntos
Doenças por Armazenamento dos Lisossomos/patologia , Doenças Musculares/patologia , Adolescente , Autofagia , Biópsia , Humanos , Imuno-Histoquímica , Doenças por Armazenamento dos Lisossomos/genética , Masculino , Microscopia Eletrônica , Músculo Esquelético/patologia , Doenças Musculares/congênito , Doenças Musculares/genética , Fagossomos/patologia , Vacúolos/patologiaRESUMO
INTRODUCTION: Cerebrospinal fluid (CSF) cell counts are traditionally performed by manual microscopy using the Fuchs-Rosenthal counting chamber. This procedure is time-, labour- and cost-intensive and requires experienced laboratory staff. METHODS: The Sysmex XE-5000 haematology analyzer offers a channel to quantify the total cell count of body fluids. We compared technical sensitivity and specificity, intra-assay variability, turn-around time (TAT) and costs for the determination of CSF cell counts between both methods. RESULTS: The mean coefficients of variation (CV) for total cell counts in CSF of the Fuchs-Rosenthal chamber and the XE-5000 were 15.2% (range: 2.8-47.5%) and 12.5% (range: 1.9-50.6%). Setting the Fuchs-Rosenthal chamber as 'gold standard', our results revealed a sensitivity of 100% and a specificity of 75% for the XE-5000 to detect a pathological cell count (≥ 6 cells/µL), whereas the sensitivity and specificity to detect a severely pathological cell count (≥ 20 cells/µL) were 100% for both. Bland and Altman analysis revealed slightly higher cell counts with the XE-5000. The approximate duration of a single CSF cell count analysis was 635 s for the manual vs. 85 s for the automated method. Total analytical performance costs for the counting chamber were 6.74 EUR per mean analysis and 1.22 EUR for the XE-5000. CONCLUSION: Our study revealed a lower mean CV for the total cell count for the XE-5000 method. The fully automated CSF cell count results in a 7.5-fold reduction in TAT and leads to a significant decrease in total analytical performance costs.
Assuntos
Automação Laboratorial/instrumentação , Líquido Cefalorraquidiano/citologia , Técnicas de Laboratório Clínico/instrumentação , Testes Hematológicos/instrumentação , Automação Laboratorial/normas , Contagem de Células/economia , Contagem de Células/instrumentação , Técnicas de Laboratório Clínico/normas , Análise Custo-Benefício , Testes Hematológicos/normas , Humanos , Pessoal de Laboratório Médico/economia , Pessoal de Laboratório Médico/normas , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Moyamoya disease (MMD) is graded based on digital subtraction angiography (DSA) with limited clinical applications. The aim was to identify clinically relevant parameters that may be used to develop a novel MMD grading system. METHODS: In 40 MMD patients bilateral revascularization surgery was performed. Clinical data including DSA, MRI and regional cerebral blood flow studies were assessed. χ(2) test corrected for dependency of measurements at the same subject and analysis of receiver operating characteristics were used to identify key parameters. Grading system included: DSA (stenosis/occlusion = 1 point; stenosis/occlusion + intracranial compensation = 2 points; stenosis/occlusion + intracranial compensation + extra-intracranial compensation = 3 points), MRI (no sign of ischemia = 0 points; signs of ischemia = 1 point) and cerebrovascular reserve capacity (CVRC > -5% = 0 points; CVRC < -5% = 2 points). MMD grade I referred to 1-2 points, grade II to 3-4 and grade III to 5-6 points. RESULTS: DSA, MRI and CVRC were dependent factors associated with the occurrence of clinical symptoms. Receiver operating characteristics analysis indentified the grading system as superior to each single parameter in predicting clinical symptoms. Fourteen hemispheres were graded as mild (grade I), 35 as moderate (grade II) and 31 as severe (grade III); 21% of grade I, 63% of grade II and 93% of grade III hemispheres were clinically symptomatic. CONCLUSIONS: The proposed grading system allows to stratify for clinical symptomatology in MMD patients. Future studies will have to investigate its value for assessing clinical symptoms and treatment risks.
Assuntos
Angiografia Digital/métodos , Imageamento por Ressonância Magnética/métodos , Doença de Moyamoya/classificação , Doença de Moyamoya/diagnóstico , Adulto , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Artérias Carótidas/fisiopatologia , Circulação Colateral/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The clinical diagnosis of Alzheimer's disease in early stages may be substantiated by the quantification of the biomarkers Abeta42, Abeta40 and total-Tau (t-Tau) in cerebrospinal fluid (CSF). Different commercially available immunosorbent assays yield reliable results, yet the absolute values obtained may differ in between tests. METHODS: We used CSF samples from patients that reported to our memory clinic. Enzyme-linked immunosorbent assays obtained from Innogenetics were used for the quantification of Abeta42 and t-Tau, test kits from IBL International were used to determine Abeta42 and Abeta40 concentrations. The multiplex assay system obtained from Mesoscale Discovery (MSD) Systems was used for the quantification of all three biomarkers. RESULTS: For all biomarkers, the absolute values obtained with different test systems differ. However, the data sets highly correlate for all comparisons, with the MSD test system proving to be slightly more sensitive. Correlation coefficients (c) for the Abeta42 and Abeta40 quantifications lie between c = 0.80 and c = 0.87, and for the t-Tau quantifications we determined c = 0.99. CONCLUSION: We conclude that all assays evaluated give reliable results, yet absolute values obtained have to be assessed differently within the framework of diagnostic procedures, depending on the system used.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Técnicas de Imunoadsorção , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Intervalos de Confiança , Interpretação Estatística de Dados , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoensaio , Modelos Lineares , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
Cells with stem cell properties have been isolated from various areas of the postnatal mammalian brain, most recently from the postnatal mouse cerebellum. We show here that inactivation of the tumor suppressor genes Rb and p53 in these endogenous neural stem cells induced deregulated proliferation and resistance to apoptosis in vitro. Moreover, injection of these cells into mice formed medulloblastomas. Medulloblastomas are the most common malignant brain tumors of childhood, and despite recent advances in treatment they are associated with high morbidity and mortality. They are highly heterogeneous tumors characterized by a diverse genetic make-up and expression profile as well as variable prognosis. Here, we describe a novel ontogenetic pathway of medulloblastoma that significantly contributes to understanding their heterogeneity. Experimental medulloblastomas originating from neural stem cells preferentially expressed stem cell markers Nestin, Sox2 and Sox9, which were not expressed in medulloblastomas originating from granule-cell-restricted progenitors. Furthermore, the expression of these markers identified a subset of human medulloblastomas associated with a poorer clinical outcome.
Assuntos
Neoplasias Cerebelares/patologia , Cerebelo/patologia , Meduloblastoma/patologia , Células-Tronco/patologia , Animais , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Modelos Animais de Doenças , Genes do Retinoblastoma , Genes Supressores de Tumor , Genes p53 , Humanos , Proteínas de Filamentos Intermediários/genética , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/terapia , Camundongos , Proteínas do Tecido Nervoso/genética , Nestina , Neurônios/patologia , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOXB1/genética , Falha de Tratamento , Resultado do TratamentoRESUMO
Diffuse infiltration of glioma cells into normal brain tissue is considered to be a main reason for the unfavorable outcomes of patients with malignant gliomas. Invasion of glioma cells into the brain parenchyma is facilitated by metalloprotease-mediated degradation of the extracellular matrix. Metalloproteases are released as inactive pro-forms and get activated upon cleavage by membrane bound metalloproteases. Here, we show that membrane type 1 metalloprotease (MT1-MMP) is up-regulated in glioma-associated microglia, but not in the glioma cells. Overexpression of MT1-MMP is even lethal for glioma cells. Glioma-released factors trigger the expression and activity of MT1-MMP via microglial toll-like receptors and the p38 MAPK pathway, as deletion of the toll-like receptor adapter protein MyD88 or p38 inhibition prevented MT1-MMP expression and activity in cultured microglial cells. Microglial MT1-MMP in turn activates glioma-derived pro-MMP-2 and promotes glioma expansion, as shown in an ex vivo model using MT1-MMP-deficient brain tissue and a microglia depletion paradigm. Finally, MyD88 deficiency or microglia depletion largely attenuated glioma expansion in 2 independent in vivo models.
Assuntos
Glioma/patologia , Metaloproteinase 14 da Matriz/metabolismo , Microglia/patologia , Animais , Western Blotting , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Precursores Enzimáticos/metabolismo , Feminino , Gelatinases/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 14 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Receptores Toll-Like/metabolismo , Carga Tumoral , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Amyloidoses play an important role in neuropathology, both in autopsies and biopsy specimens. Cerebral amyloidoses are typically characterized by the deposition of beta-amyloid and mostly affect patients >60 years. The cardinal symptom of cerebral amyloid angiopathy (CAA) is spontaneous intracerebral hemorrhage, whereas the clinical presentation of Alzheimer's disease is dementia. Rare familial forms of amyloidoses may affect young patients and need thorough neuropathological assessment, similar to the relatively infrequent prion diseases. Amyloidoses within neuromuscular tissues mainly occur in the setting of systemic amyloid diseases. Detailed evaluation including thorough characterisation of amyloid is essential for ensuring the neuropathological diagnosis.
Assuntos
Peptídeos beta-Amiloides/análise , Amiloidose/patologia , Doenças Neurodegenerativas/patologia , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Amiloide/análise , Amiloide/genética , Peptídeos beta-Amiloides/genética , Amiloidose/genética , Amiloidose Familiar/genética , Amiloidose Familiar/patologia , Encéfalo/patologia , Angiopatia Amiloide Cerebral/genética , Angiopatia Amiloide Cerebral/patologia , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Diagnóstico Diferencial , Humanos , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética , Doenças Neuromusculares/genética , Doenças Neuromusculares/patologia , Nervos Periféricos/patologia , Doenças Priônicas/genética , Doenças Priônicas/patologia , PrognósticoRESUMO
BACKGROUND: Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a recently described, very rare entity, clinically characterized by progressive neurological deficits such as cognitive decline, epileptic seizures, pyramidal, extrapyramidal and cerebellar symptoms/signs. With the exception of two patients with adult onset, in all previously described cases symptoms onset occurred between early infancy and adolescence. RESULTS: We report a case of late onset LCC in a 59-year-old woman presenting with urinary and fecal incontinence and behavioural changes, then rapid progression with hemianopia, hemiparesis, ataxia and cognitive decline. Extensive work-up was performed, including brain magnetic resonance imaging, magnetic resonance spectroscopy, cyst fluid analysis and brain biopsy, confirming the final diagnosis of LCC. CONCLUSION: Our case supports the existence of a late onset adult form of LCC.
Assuntos
Encefalopatias/patologia , Calcinose/patologia , Cistos/patologia , Idade de Início , Encefalopatias/fisiopatologia , Calcinose/fisiopatologia , Cistos/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Microglia activate upon injury, migrate to the injury site, proliferate locally, undergo morphological and gene expression changes, and phagocytose injured and dying cells. Cytokines and proteases secreted by these cells contribute to the injury and edema formed. We studied the injury outcome after local elimination/paralysis of microglia. METHODS: Adult male mice were subjected to intracerebral hemorrhage (ICH) by intra-caudate injection of either collagenase or autologous blood. Mice survived for different periods of time, and were subsequently evaluated for neurological deficits, size of the hematoma, and microglia activation. Mice expressing an fms-GFP transgene or the CD11b-HSVTK transgene were also used. For elimination of monocytes/macrophages, CD11b-HSVTK mice were treated with ganciclovir prior to hemorrhage. Modifiers of microglial activation were also used. RESULTS: Induction of ICH resulted in robust microglia activation and recruitment of macrophages. Inactivation of these cells, genetically or pharmacologically, pointed to a critical role of the time of such inactivation, indicating that their role is distinct at different time points following injury. Edema formation is decreased when microglia activation is inhibited, and neurological outcomes are improved. CONCLUSIONS: Microglia, as immunomodulatory cells, have the ability to modify the final presentation of ICH.
Assuntos
Hemorragia Cerebral/patologia , Microglia/metabolismo , Animais , Antígenos de Diferenciação/metabolismo , Edema Encefálico , Antígeno CD11b/biossíntese , Antígeno CD11b/genética , Proteínas de Ligação ao Cálcio/metabolismo , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/complicações , Colagenases , Modelos Animais de Doenças , Ganciclovir/uso terapêutico , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Masculino , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos , Microglia/efeitos dos fármacos , Doenças do Sistema Nervoso/etiologia , Exame Neurológico , Fatores de TempoRESUMO
AIMS: The distinction between central nervous system (CNS) metastases of clear cell renal cell carcinoma (RCC) and CNS haemangioblastoma still poses a challenge to the pathologist. Since both entities occur in von Hippel-Lindau disease, this aggravates the issue. The antibody renal cell carcinoma marker (RCC-ma) has been suggested to identify primary RCCs specifically, but its value for diagnosing metastases of RCC is controversial. The aim was to assess two distinct clones of the RCC-ma for their potential to: (i) identify primary RCCs and (ii) differentiate between CNS metastases of clear cell RCC and CNS haemangioblastomas. METHODS AND RESULTS: Using tissue microarrays, 77% (n = 363; PN-15) and 66% (n = 355; 66.4C2) of clear cell RCCs, and 93% (PN-15) and 74% (66.4C2) of papillary RCCs (n = 46) were immunopositive for RCC-ma, whereas none of the investigated chromophobe RCCs (n = 22) or any of the oncocytomas (n = 15) showed immunoreactivity. Importantly, 50.9% of CNS metastases of clear cell RCCs (n = 55) exhibited RCC-ma expression, whereas all CNS haemangioblastomas (71) were negative. CONCLUSIONS: Both RCC-ma clones, despite some variation in their sensitivity to detect clear cell and papillary RCCs, are of value in differentiating subtypes of primary RCC and are excellent markers for discriminating clear cell lesions in the brain.
Assuntos
Anticorpos Monoclonais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundário , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/secundário , Hemangioblastoma/diagnóstico , Neoplasias Renais/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Carcinoma de Células Renais/patologia , Neoplasias do Sistema Nervoso Central/patologia , Hemangioblastoma/patologia , Humanos , Neprilisina/imunologia , Análise Serial de TecidosRESUMO
Central nervous system (CNS) atypical teratoid/rhabdoid tumours (AT/RT) are among the paediatric malignant tumours with the worst prognosis and fatal outcome. Insulin-like growth factor I receptor (IGF-IR) protects cancer cells from apoptosis induced by a variety of anticancer drugs and radiation. In the present study, IGF-IR was expressed in 8/8 primary AT/RT as detected by immunohistochemistry. Moreover, we found IGF-I and IGF-II mRNA in BT-16 CNS AT/RT cells and IGF-II mRNA in BT-12 CNS AT/RT cells, and autophosphorylated IGF-IR in both cell lines, indicating the potential presence of an autocrine/paracrine IGF-I/II/IGF-IR loop in CNS AT/RT. IGF-IR antisense oligonucleotide treatment of human CNS AT/RT cells resulted in significant down-regulation of IGF-IR mRNA and protein expression, induction of apoptosis, and chemosensitisation to doxorubicin and cisplatin. These studies provide evidence for the influence of IGF-IR on cellular responses to chemotherapy and raise the possibility that curability of selected CNS AT/RT may be improved by pharmaceutical strategies directed towards the IGF-IR.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Oligorribonucleotídeos Antissenso/uso terapêutico , Receptor IGF Tipo 1/efeitos dos fármacos , Tumor Rabdoide/tratamento farmacológico , Teratoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Cisplatino/uso terapêutico , Regulação para Baixo , Doxorrubicina/uso terapêutico , Feminino , Humanos , Lactente , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Receptor IGF Tipo 1/metabolismo , Tumor Rabdoide/patologia , Teratoma/patologiaAssuntos
Adrenoleucodistrofia/fisiopatologia , Encéfalo/patologia , Doenças Cerebelares/fisiopatologia , Transtornos Mentais/fisiopatologia , Paraparesia Espástica/fisiopatologia , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/patologia , Adulto , Idade de Início , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Transtorno Bipolar/fisiopatologia , Encéfalo/fisiopatologia , Doenças Cerebelares/genética , Doenças Cerebelares/patologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Análise Mutacional de DNA , Progressão da Doença , Evolução Fatal , Feminino , Predisposição Genética para Doença/genética , Heterozigoto , Humanos , Transtornos Mentais/genética , Transtornos Mentais/patologia , Pessoa de Meia-Idade , Mutação , Doenças do Nervo Óptico/genética , Doenças do Nervo Óptico/patologia , Doenças do Nervo Óptico/fisiopatologia , Paraparesia Espástica/genética , Paraparesia Espástica/patologia , Fenótipo , Inativação do Cromossomo X/genéticaRESUMO
We describe a case of a rapidly progressive, sporadic, non-von Hippel-Lindau (VHL) disease associated supratentorial capillary haemangioblastoma. Despite the classical histopathological presentation consisting of stromal cells and abundant capillaries, the tumour showed an unfavourable clinical course.