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1.
Neurol Clin ; 42(2): 389-432, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38575258

RESUMO

Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability making this a disorder of paramount importance to all clinicians. Headache may be an important clue to vasculitic involvement of central nervous system (CNS) vessels. CNS vasculitis may be primary, in which only intracranial vessels are involved in the inflammatory process, or secondary to another known disorder with overlapping systemic involvement. Primary neurologic vasculitides can be diagnosed with assurance after intensive evaluation that incudes tissue confirmation whenever possible.


Assuntos
Cefaleia , Vasculite do Sistema Nervoso Central , Humanos , Cefaleia/diagnóstico , Cefaleia/etiologia , Vasculite do Sistema Nervoso Central/complicações , Vasculite do Sistema Nervoso Central/diagnóstico , Vasculite do Sistema Nervoso Central/patologia , Sistema Nervoso Central/patologia , Inflamação
2.
Zhonghua Xue Ye Xue Za Zhi ; 45(2): 190-194, 2024 Feb 14.
Artigo em Chinês | MEDLINE | ID: mdl-38604797

RESUMO

Clinical data of 15 primary central nervous system lymphoma (PCNSL) children aged ≤18 years admitted to our hospital between May 2013 to May 2023 were retrospectively analyzed. Our goal was to summarize the clinical features of children and investigate the therapeutic effect of a high-dose methotrexate (HD-MTX) based chemotherapy regimen on this disease. The male-to-female ratio was 2.7∶1, and the median age was 7.2 (2.3-16.4) years at diagnosis. The initial clinical symptoms were primarily cranial hypertension, with imaging findings revealing multiple lesions. Pediatric PCNSL with normal immune function has a favorable prognosis with HD-MTX-based chemotherapy. Patients with a stable disease can be treated with minimal or no maintenance. HD-MTX-based chemotherapy remains effective when the disease progresses or recurs after an initial course of non-HD-MTX-based chemotherapy.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma , Humanos , Masculino , Feminino , Criança , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Estudos Retrospectivos , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Metotrexato/uso terapêutico , Linfoma/tratamento farmacológico , Sistema Nervoso Central/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
3.
Zhonghua Bing Li Xue Za Zhi ; 53(4): 364-369, 2024 Apr 08.
Artigo em Chinês | MEDLINE | ID: mdl-38556820

RESUMO

Objective: To investigate the clinicopathological features of Erdheim-Chester disease (ECD) initially diagnosed at extraskeletal locations. Methods: Clinical and pathological data of four cases of ECD diagnosed initially in extraskeletal locations were collected at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2013 to June 2023. BRAF V600E gene was detected by reverse transcription polymerase chain reaction (RT-PCR). Pertinent literatures were reviewed. Results: Four ECD patients included two males and two females ranging in ages from 2 years 11 months to 69 years. The lesions located in the lung (two cases), central nervous system (one case), and the testicle (one case) were collected in the study. One patient had occasional fever at night, one had nausea and vomiting, and two were asymptomatic. Radiologically, the two pulmonary ECD showed diffuse ground-glass nodules in both lungs, and the lesions in central nervous system and testicle both showed solid masses. Microscopically, there were infiltration of foamy histiocyte-like cells and multinucleated giant cells in a fibrotic background, accompanied by varying amounts of lymphocytes and plasma cells. The infiltration of tumor cells in pulmonary ECD was mainly seen in the subpleural area, interlobular septa, and perivascular and peribronchiolar areas. The fibrosis was more pronounced in the pleura and interlobular septa, and less pronounced in the alveolar septa. Immunohistochemical staining showed that all tumor cells expressed CD68, CD163 and Fô€ƒ¼a; one case showed S-100 expression; three cases were positive for BRAF V600E; all were negative for CD1α and Langerin. RT-PCR in all four cases showed BRAF V600E gene mutation. Conclusions: Extraskeletal ECD is often rare and occult, and could be easily misdiagnosed, requiring biopsy confirmation. The radiologic findings of pulmonary ECD is significantly different from other types of ECD, and the histopathological features of pronounced infiltration in the subpleura area, interlobular septa, perivascular and peribronchiolar areas can be helpful in the differential diagnosis from other pulmonary diseases. Detection of BRAF V600E gene mutation by RT-PCR and its expression by immunohistochemical staining are also helpful in the diagnosis.


Assuntos
Doença de Erdheim-Chester , Masculino , Feminino , Humanos , Doença de Erdheim-Chester/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Pulmão/patologia , Histiócitos/patologia , Sistema Nervoso Central/patologia , Mutação
4.
Clin Neuropathol ; 43(2): 53-59, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38517059

RESUMO

Primary T-cell lymphoma (TCL) of the central nervous system (CNS) is a rare and potentially aggressive entity. We describe a case of TCL presenting in the basal ganglia with γδ receptor expression and a remarkably aggressive clinical course. To the best of our knowledge, this is the fifth reported case of γδ TCL presenting in the CNS. We review existing literature, including the previously reported cases of γδ TCL of the CNS. In our case, a 69-year-old male presented with acute onset dysarthria and right-sided weakness, with initial imaging concerning for stroke. Repeat imaging demonstrated a 2.6-cm mass in the left basal ganglia-corona radiata. Pathologic examination of a stereotactic biopsy revealed TCL with γδ receptor phenotype. The patient suffered rapid clinical decline and passed away within 6 weeks of initial diagnosis. This represents an important differential diagnosis and sheds light on the potentially poor prognosis conferred by γδ TCL of the CNS.


Assuntos
Linfoma de Células T , Linfócitos T , Masculino , Humanos , Idoso , Linfócitos T/patologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfoma de Células T/diagnóstico , Linfoma de Células T/patologia , Sistema Nervoso Central/patologia , Biópsia
5.
Clin Neurol Neurosurg ; 239: 108206, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38461672

RESUMO

INTRODUCTION: Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis involving the central nervous system in 5% of cases. Spinal location occurs in less than 1% of extranodal RDD and can be responsible for neurological manifestations. We present a systematic review of cases of isolated spinal RDD. We also report a new case of isolated spinal RDD revealed by spinal cord compression. MATERIALS AND METHODS: The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the MEDLINE and SCOPUS databases and included case reports and case series describing isolated RDD of the spine. RESULTS: There were 53 patients with isolated spinal RDD (including our case). The mean age was 35.85±16.48 years. Neurological deficit was the most frequent clinical presentation (89%). RDD lesions were mainly located in the thoracic spine (51%), then the cervical spine (32%). The lesion was reported to be extradural (57%), intradural extramedullary (26%), intramedullary (7%), and in the vertebral body (10%). Histological examination showed emperipolesis in 73%. Histocytes were positive for S-100 protein in 83%. Treatment was based on surgery 96%), radiotherapy, chemotherapy, and adjunctive steroid therapy were indicated in four, one, and eight cases. After a mean follow-up period of 14.84±13.00 months, recurrence of RDD was noted in 15%. CONCLUSION: Spinal RDD is a rare condition, requiring meticulous histological examination for accurate diagnosis. Complete surgical resection is the treatment of choice. Adjuvant chemotherapy and radiotherapy can also be indicated in patients demonstrating partial improvement following surgery.


Assuntos
Histiocitose Sinusal , Compressão da Medula Espinal , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Histiocitose Sinusal/diagnóstico , Histiocitose Sinusal/cirurgia , Histiocitose Sinusal/patologia , Compressão da Medula Espinal/etiologia , Compressão da Medula Espinal/cirurgia , Vértebras Cervicais/patologia , Sistema Nervoso Central/patologia
6.
J Neuroinflammation ; 21(1): 67, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38481312

RESUMO

Tissue-resident macrophages play an important role in the local maintenance of homeostasis and immune surveillance. In the central nervous system (CNS), brain macrophages are anatomically divided into parenchymal microglia and non-parenchymal border-associated macrophages (BAMs). Among these immune cell populations, microglia have been well-studied for their roles during development as well as in health and disease. BAMs, mostly located in the choroid plexus, meningeal and perivascular spaces, are now gaining increased attention due to advancements in multi-omics technologies and genetic methodologies. Research on BAMs over the past decade has focused on their ontogeny, immunophenotypes, involvement in various CNS diseases, and potential as therapeutic targets. Unlike microglia, BAMs display mixed origins and distinct self-renewal capacity. BAMs are believed to regulate neuroimmune responses associated with brain barriers and contribute to immune-mediated neuropathology. Notably, BAMs have been observed to function in diverse cerebral pathologies, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, ischemic stroke, and gliomas. The elucidation of the heterogeneity and diverse functions of BAMs during homeostasis and neuroinflammation is mesmerizing, since it may shed light on the precision medicine that emphasizes deep insights into programming cues in the unique brain immune microenvironment. In this review, we delve into the latest findings on BAMs, covering aspects like their origins, self-renewal capacity, adaptability, and implications in different brain disorders.


Assuntos
Doenças do Sistema Nervoso Central , Sistema Nervoso Central , Humanos , Sistema Nervoso Central/patologia , Macrófagos/patologia , Microglia/patologia , Encéfalo/patologia
7.
J Transl Med ; 22(1): 257, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461288

RESUMO

BACKGROUND: Neural Tube Defects (NTDs) are congenital malformations of the central nervous system resulting from the incomplete closure of the neural tube during early embryonic development. Neuroinflammation refers to the inflammatory response in the nervous system, typically resulting from damage to neural tissue. Immune-related processes have been identified in NTDs, however, the detailed relationship and underlying mechanisms between neuroinflammation and NTDs remain largely unclear. In this study, we utilized integrated multi-omics analysis to explore the role of neuroinflammation in NTDs and identify potential prenatal diagnostic markers using a murine model. METHODS: Nine public datasets from Gene Expression Omnibus (GEO) and ArrayExpress were mined using integrated multi-omics analysis to characterize the molecular landscape associated with neuroinflammation in NTDs. Special attention was given to the involvement of macrophages in neuroinflammation within amniotic fluid, as well as the dynamics of macrophage polarization and their interactions with neural cells at single-cell resolution. We also used qPCR assay to validate the key TFs and candidate prenatal diagnostic genes identified through the integrated analysis in a retinoic acid-induced NTDs mouse model. RESULTS: Our analysis indicated that neuroinflammation is a critical pathological feature of NTDs, regulated both transcriptionally and epigenetically within central nervous system tissues. Key alterations in gene expression and pathways highlighted the crucial role of STATs molecules in the JAK-STAT signaling pathway in regulating NTDs-associated neuroinflammation. Furthermore, single-cell resolution analysis revealed significant polarization of macrophages and their interaction with neural cells in amniotic fluid, underscoring their central role in mediating neuroinflammation associated with NTDs. Finally, we identified a set of six potential prenatal diagnostic genes, including FABP7, CRMP1, SCG3, SLC16A10, RNASE6 and RNASE1, which were subsequently validated in a murine NTDs model, indicating their promise as prospective markers for prenatal diagnosis of NTDs. CONCLUSIONS: Our study emphasizes the pivotal role of neuroinflammation in the progression of NTDs and underlines the potential of specific inflammatory and neural markers as novel prenatal diagnostic tools. These findings provide important clues for further understanding the underlying mechanisms between neuroinflammation and NTDs, and offer valuable insights for the future development of prenatal diagnostics.


Assuntos
Multiômica , Defeitos do Tubo Neural , Gravidez , Feminino , Animais , Camundongos , Doenças Neuroinflamatórias , Estudos Prospectivos , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/induzido quimicamente , Sistema Nervoso Central/patologia
8.
Nature ; 628(8006): 195-203, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38480879

RESUMO

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.


Assuntos
Complexo I de Transporte de Elétrons , Inflamação , Microglia , Doenças Neuroinflamatórias , Animais , Feminino , Humanos , Masculino , Camundongos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Complexo I de Transporte de Elétrons/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Multiômica , Células Mieloides/metabolismo , Células Mieloides/patologia , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Espécies Reativas de Oxigênio/metabolismo
9.
J Neuroinflammation ; 21(1): 76, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38532383

RESUMO

Japanese encephalitis virus (JEV) is a neurotropic pathogen that causes lethal encephalitis. The high susceptibility and massive proliferation of JEV in neurons lead to extensive neuronal damage and inflammation within the central nervous system. Despite extensive research on JEV pathogenesis, the effect of JEV on the cellular composition and viral tropism towards distinct neuronal subtypes in the brain is still not well comprehended. To address these issues, we performed single-cell RNA sequencing (scRNA-seq) on cells isolated from the JEV-highly infected regions of mouse brain. We obtained 88,000 single cells and identified 34 clusters representing 10 major cell types. The scRNA-seq results revealed an increasing amount of activated microglia cells and infiltrating immune cells, including monocytes & macrophages, T cells, and natural killer cells, which were associated with the severity of symptoms. Additionally, we observed enhanced communication between individual cells and significant ligand-receptor pairs related to tight junctions, chemokines and antigen-presenting molecules upon JEV infection, suggesting an upregulation of endothelial permeability, inflammation and antiviral response. Moreover, we identified that Baiap2-positive neurons were highly susceptible to JEV. Our findings provide valuable clues for understanding the mechanism of JEV induced neuro-damage and inflammation as well as developing therapies for Japanese encephalitis.


Assuntos
Vírus da Encefalite Japonesa (Espécie) , Vírus da Encefalite Japonesa (Subgrupo) , Encefalite Japonesa , Camundongos , Animais , Tropismo Viral , Sistema Nervoso Central/patologia , Encefalite Japonesa/patologia , Inflamação , Análise de Sequência de RNA
10.
Acta Neuropathol ; 147(1): 37, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347231

RESUMO

There are several cellular and acellular structural barriers associated with the brain interfaces, which include the dura, the leptomeninges, the perivascular space and the choroid plexus epithelium. Each structure is enriched by distinct myeloid populations, which mainly originate from erythromyeloid precursors (EMP) in the embryonic yolk sac and seed the CNS during embryogenesis. However, depending on the precise microanatomical environment, resident myeloid cells differ in their marker profile, turnover and the extent to which they can be replenished by blood-derived cells. While some EMP-derived cells seed the parenchyma to become microglia, others engraft the meninges and become CNS-associated macrophages (CAMs), also referred to as border-associated macrophages (BAMs), e.g., leptomeningeal macrophages (MnMΦ). Recent data revealed that MnMΦ migrate into perivascular spaces postnatally where they differentiate into perivascular macrophages (PvMΦ). Under homeostatic conditions in pathogen-free mice, there is virtually no contribution of bone marrow-derived cells to MnMΦ and PvMΦ, but rather to macrophages of the choroid plexus and dura. In neuropathological conditions in which the blood-brain barrier is compromised, however, an influx of bone marrow-derived cells into the CNS can occur, potentially contributing to the pool of CNS myeloid cells. Simultaneously, resident CAMs may also proliferate and undergo transcriptional and proteomic changes, thereby, contributing to the disease outcome. Thus, both resident and infiltrating myeloid cells together act within their microenvironmental niche, but both populations play crucial roles in the overall disease course. Here, we summarize the current understanding of the sources and fates of resident CAMs in health and disease, and the role of the microenvironment in influencing their maintenance and function.


Assuntos
Macrófagos , Proteômica , Camundongos , Animais , Macrófagos/patologia , Sistema Nervoso Central/patologia , Microglia , Meninges
11.
Acta Neuropathol ; 147(1): 38, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347307

RESUMO

Diseases of the central nervous system (CNS) are often associated with vascular disturbances or inflammation and frequently both. Consequently, endothelial cells and macrophages are key cellular players that mediate pathology in many CNS diseases. Macrophages in the brain consist of the CNS-associated macrophages (CAMs) [also referred to as border-associated macrophages (BAMs)] and microglia, both of which are close neighbours or even form direct contacts with endothelial cells in microvessels. Recent progress has revealed that different macrophage populations in the CNS and a subset of brain endothelial cells are derived from the same erythromyeloid progenitor cells. Macrophages and endothelial cells share several common features in their life cycle-from invasion into the CNS early during embryonic development and proliferation in the CNS, to their demise. In adults, microglia and CAMs have been implicated in regulating the patency and diameter of vessels, blood flow, the tightness of the blood-brain barrier, the removal of vascular calcification, and the life-time of brain endothelial cells. Conversely, CNS endothelial cells may affect the polarization and activation state of myeloid populations. The molecular mechanisms governing the pas de deux of brain macrophages and endothelial cells are beginning to be deciphered and will be reviewed here.


Assuntos
Encéfalo , Células Endoteliais , Encéfalo/patologia , Macrófagos , Sistema Nervoso Central/patologia , Microglia
12.
Mycoses ; 67(2): e13697, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38374494

RESUMO

BACKGROUND: The clinical features of central nervous system (CNS) sporotrichosis are derived from case reports and a limited series of cases. Our objective was to carry out a systematic review and meta-analysis of CNS sporotrichosis. METHODS: We searched PubMed/MEDLINE, Embase, Scopus, and LILACS on 9 September 2023. Our inclusion criteria were documentation of Sporothrix and demonstrated CNS involvement. A metaproportion or metamean analysis was performed to estimate a summary proportion with 95% confidence intervals. RESULTS: We included 52 cases of CNS sporotrichosis published from 1966 to 2023. Forty-six patients were male (88%, 95% CI: 77-95), and the mean age was 39 years (95% CI: 36-43). Close contact with cats was reported in 55% of cases (95% CI: 37-72). Thirty-two (61.5%) patients were from Brazil, 18 patients from the United State of America (34.6%). Only two Sporothrix species were reported: S. schenckii (26/41, 63%), and S. brasiliensis (15/41, 37%). The most common neurological symptom was headache. Meningitis was chronic in approximately 80% of cases. A significant majority of the patients were immunocompromised. HIV infection was the primary cause of immunosuppression (85%, 95% CI: 61-95). Overall mortality was 56% (22/39). The comparison of Kaplan-Meier survival curve showed a higher mortality with a statistically significant difference in immunosuppressed patients (p = .019). CONCLUSION: CNS sporotrichosis represents a notable cause of chronic meningitis, especially in individuals living in the Americas with HIV infection and concurrent skin lesions.


Assuntos
Infecções por HIV , Meningite , Sporothrix , Esporotricose , Humanos , Animais , Masculino , Gatos , Adulto , Feminino , Esporotricose/diagnóstico , Esporotricose/tratamento farmacológico , Esporotricose/patologia , Brasil , Sistema Nervoso Central/patologia
13.
Cells ; 13(3)2024 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-38334635

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with poor outcomes. The World Health Organization (WHO) redefined BDCN as a distinct disease entity in 2016. BPDCN arises from plasmacytoid dendritic cells, manifesting primarily in the skin, bone marrow, and lymph nodes, occasionally involving the central nervous system (CNS). This presents challenges in diagnosis and treatment, with CNS involvement often overlooked in standard diagnostic workups due to BPDCN's rarity and patients often being neurologically asymptomatic at diagnosis. CNS involvement typically emerges during relapse, yet clinical trials often exclude such cases, limiting our understanding of its development and treatment. Treatment options for CNS involvement include intrathecal (IT) chemotherapies like methotrexate and cytarabine, often in combination with systemic agents. Tagraxofusp and traditional regimens for acute myeloid leukemia show limited success at preventing CNS relapse, prompting exploration of combined therapies like hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD) with venetoclax and adding IT chemotherapy to other backbones. Ongoing clinical trials investigating emerging therapies offer hope despite limited focus on CNS implications. Trials incorporating CNS-involved patients aim to pioneer novel treatment approaches, potentially reshaping BPDCN management. Understanding CNS involvement's complexities in BPDCN remains crucial for tailored treatments and better patient outcomes.


Assuntos
Transtornos Mieloproliferativos , Neoplasias Cutâneas , Humanos , Sistema Nervoso Central/patologia , Neoplasias Cutâneas/patologia , Transtornos Mieloproliferativos/patologia , Células Dendríticas/patologia , Recidiva
14.
Orphanet J Rare Dis ; 19(1): 73, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365728

RESUMO

BACKGROUND: To date, real-world evidence around the clinical and economic burden related to von Hippel-Lindau (VHL) disease is limited. Therefore, this study characterized the prevalence, healthcare resource utilization (HRU), and economic burden of von Hippel-Lindau-associated central nervous system hemangioblastoma (VHL-CNS-Hb) and pancreatic neuroendocrine tumors (VHL-pNET) in the United States (US). METHODS: Patients with VHL-CNS-Hb or VHL-pNET were identified from Optum's de-identified Clinformatics® Data Mart Database (2007-2020) and matched 1:5 to control patients without VHL disease or CNS-Hb/pNET. Prevalence rates of VHL-CNS-Hb and VHL-pNET (standardized by age and sex) in 2019 were estimated. HRU and healthcare costs (2020 US dollars) were compared between the VHL-CNS-Hb/VHL-pNET and control cohorts. RESULTS: In 2019, US prevalence rates of VHL-CNS-Hb and VHL-pNET were estimated to be 1.12 cases per 100,000 (3,678 patients) and 0.12 cases per 100,000 (389 patients), respectively. Patients with VHL-CNS-Hb (N = 220) had more inpatient, outpatient, and emergency department visits and $49,645 higher annual healthcare costs than controls (N = 1,100). Patients with VHL-pNET (N = 20) had more inpatient and outpatient visits and $56,580 higher annual healthcare costs than controls (N = 100). Costs associated with surgical removal of CNS-Hb and pNET were particularly high. CONCLUSIONS: In this retrospective, claims-based study, both VHL-CNS-Hb and VHL-pNET were associated with substantial HRU and healthcare costs, particularly tumor reduction surgery-related costs. These findings provide important insight for healthcare payers regarding the expected real-world costs that enrollees with VHL-CNS-Hb and VHL-pNET may incur over the course of their disease.


Assuntos
Hemangioblastoma , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Doença de von Hippel-Lindau , Humanos , Doença de von Hippel-Lindau/complicações , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/patologia , Hemangioblastoma/epidemiologia , Estresse Financeiro , Estudos Retrospectivos , Sistema Nervoso Central/patologia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia
15.
J Neuropathol Exp Neurol ; 83(4): 268-275, 2024 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-38350468

RESUMO

Central nervous system (CNS) metastases represent a small portion of pediatric CNS neoplasms and data surrounding this condition with high morbidity is scarce. Single institutional archival institutional pathology records between 1999 and 2022 were searched for patients over 21 years old and younger with CNS, dura, cranial nerve, CSF, or leptomeningeal metastases; 41 cases were identified. We documented primary tumor types and locations, metastasis locations, types of invasion (direct extension vs distant metastasis), times from imaging or pathologic diagnosis to CNS involvement, and outcomes. Distant metastasis was the most common mechanism of metastasis (n = 32, 78%). Interval times to CNS metastasis varied by both tumor type and primary tumor location. In this cohort, osteosarcoma portended the shortest survival following CNS metastasis. This study highlights the diverse mechanisms and locations of CNS involvement in pediatric CNS metastases and illuminates a need for varied monitoring strategies when considering primary tumor type and anatomic location.


Assuntos
Neoplasias do Sistema Nervoso Central , Segunda Neoplasia Primária , Adulto , Criança , Humanos , Adulto Jovem , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/patologia , Estudos Retrospectivos
17.
Brain Res Bull ; 209: 110904, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38387531

RESUMO

The central nervous system (CNS) has been considered an immunologically privileged site. In the past few decades, research on inflammation in CNS diseases has mostly focused on microglia, innate immune cells that respond rapidly to injury and infection to maintain CNS homeostasis. Discoveries of lymphatic vessels within the dura mater and peripheral immune cells in the meningeal layer indicate that the peripheral immune system can monitor and intervene in the CNS. This review summarizes recent advances in the involvement of T lymphocytes in multiple CNS diseases, including brain injury, neurodegenerative diseases, and psychiatric disorders. It emphasizes that a deep understanding of the pathogenesis of CNS diseases requires intimate knowledge of T lymphocytes. Aiming to promote a better understanding of the relationship between the immune system and CNS and facilitate the development of therapeutic strategies targeting T lymphocytes in neurological diseases.


Assuntos
Doenças do Sistema Nervoso Central , Transtornos Mentais , Humanos , Linfócitos T , Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Central/patologia , Microglia/patologia , Transtornos Mentais/patologia
18.
Theranostics ; 14(3): 1168-1180, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38323310

RESUMO

Background: Effector T cell activation, migration, and proinflammatory cytokine production are crucial steps in autoimmune disorders such as multiple sclerosis (MS). While several therapeutic approaches targeting T cell activation and proinflammatory cytokines have been developed for the treatment of autoimmune diseases, there are no therapeutic agents targeting the migration of effector T cells, largely due to our limited understanding of regulatory mechanisms of T cell migration in autoimmune disease. Here we reported that midline-1 (Mid1) is a key regulator of effector T cell migration in experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS. Methods: Mid1-/- mice were generated by Crispr-Cas9 technology. T cell-specific Mid1 knockout chimeric mice were generated by adoptive transfer of Mid1-/- T cells into lymphocyte deficient Rag2-/- mice. Mice were either immunized with MOG35-55 (active EAE) or received adoptive transfer of pathogenic T cells (passive EAE) to induce EAE. In vitro Transwell® assay or in vivo footpad injection were used to assess the migration of T cells. Results: Mid1 was significantly increased in the spinal cord of wild-type (Wt) EAE mice and disruption of Mid1 in T cells markedly suppressed the development of both active and passive EAE. Transcriptomic and flow cytometric analyses revealed a marked reduction in effector T cell number in the central nervous system of Mid1-/- mice after EAE induction. Conversely, an increase in the number of T cells was observed in the draining lymph nodes of Mid1-/- mice. Mice that were adoptively transferred with pathogenic Mid1-/- T cells also exhibited milder symptoms of EAE, along with a lower T cell count in the spinal cord. Additionally, disruption of Mid1 significantly inhibited T-cell migration both in vivo and in vitro. RNA sequencing suggests a suppression in multiple inflammatory pathways in Mid1-/- mice, including mTOR signaling that plays a critical role in cell migration. Subsequent experiments confirmed the interaction between Mid1 and mTOR. Suppression of mTOR with rapamycin or microtubule spindle formation with colcemid blunted the regulatory effect of Mid1 on T cell migration. In addition, mTOR agonists MHY1485 and 3BDO restored the migratory deficit caused by Mid1 depletion. Conclusion: Our data suggests that Mid1 regulates effector T cell migration to the central nervous system via mTOR/microtubule pathway in EAE, and thus may serve as a potential therapeutic target for the treatment of MS.


Assuntos
Encefalomielite Autoimune Experimental , Linfócitos T , Ubiquitina-Proteína Ligases , Animais , Camundongos , Movimento Celular , Sistema Nervoso Central/patologia , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Esclerose Múltipla/metabolismo , Medula Espinal/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Microtúbulos
19.
J Pediatr Hematol Oncol ; 46(2): e180-e183, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38316140

RESUMO

Metastatic central nervous system (CNS) involvement is rare in pediatric primary extracranial Ewing sarcoma (ES). We describe the incidence and course of 6 patients with extracranial ES who developed metastatic CNS lesions treated at a single institution. The median time to CNS disease detection was 16.3 months (10.0-28.3 months). Event-free and overall survival after CNS disease detection were 1.9 months (0.4 to 10.3 months) and 4.6 months (1.1 to 50.9 months), respectively. One patient was alive at the time of analysis. Clinical status and ability to obtain disease control should be considered when making decisions regarding aggressive interventions in these patients with poor prognosis.


Assuntos
Doenças do Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central , Segunda Neoplasia Primária , Sarcoma de Ewing , Criança , Humanos , Sarcoma de Ewing/patologia , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias do Sistema Nervoso Central/secundário , Incidência , Estudos Retrospectivos , Sistema Nervoso Central/patologia
20.
J Vis Exp ; (203)2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38314770

RESUMO

Multiple sclerosis (MS) is an autoimmune disease characterized by the infiltration of immune cells and demyelination in the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) serves as a prototypic animal model for studying MS. In this study, we aimed to investigate the role of CD4 T cells in the initiation and relapse of EAE, focusing on the activation phase and immune response. To create the EAE mice model, female mice were immunized with myelin oligodendrocyte glycoprotein (MOG)35-55 emulsified with complete Freund's adjuvant (CFA). Clinical scores were assessed daily, and results demonstrated that mice in the EAE group exhibited a classic relapsing-remitting pattern. Hematoxylin-eosin (H&E) and luxol fast blue (LFB) staining analysis revealed significant infiltration of inflammatory cells in the CNS and demyelination in EAE mice. Regarding the activation phase, both CD4+CD69+ effector T (Teff) cells and CD4+CD44+CD62L- effector memory T (Tem) cells may contribute to the initiation of EAE, however, the relapse stage was probably dominated by CD4+CD44+CD62L- Tem cells. Additionally, in terms of immune function, helper T (Th)1 cells are primarily involved in initiating the EAE. However, both Th1 and Th17 cells contribute to the relapse stage, and the immunosuppressive function of regulatory T (Treg) cells was inhibited during the EAE pathological process.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Feminino , Animais , Camundongos , Linfócitos T CD4-Positivos , Sistema Nervoso Central/patologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito , Recidiva , Camundongos Endogâmicos C57BL
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