RESUMO
GNAQ is mutated in vascular and melanocytic lesions, including vascular malformations and nevi. No in vivo model of GNAQ activation in endothelial cells has previously been described. We introduce mutant GNAQ into a murine endothelial cell line, MS1. The resultant transduced cells exhibit a novel phenotype in vivo, with extensive vasoformative endothelial cells forming aberrant lumens similar to those seen in vascular malformations. ATAC-seq analysis reveals activation of c-Kit in the novel vascular malformations. We demonstrate that c-Kit is expressed in authentic human Sturge-Weber vascular malformations, indicating a novel druggable target for Sturge-Weber syndrome. Since c-Kit is targeted by the FDA-approved drug imatinib, we tested the ability of imatinib on the phenotype of the vascular malformations in vivo. Imatinib treated vascular malformations are significantly smaller and have decreased supporting stromal cells surrounding the lumen. Imatinib may be useful in the treatment of human vascular malformations that express c-Kit, including Sturge-Weber syndrome.
Assuntos
Biópsia/estatística & dados numéricos , Pacientes Internados/estatística & dados numéricos , Encaminhamento e Consulta/tendências , Pele/patologia , Telemedicina/instrumentação , Biópsia/métodos , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/patologia , COVID-19/virologia , Currículo/tendências , Dermatologia/educação , Dermatologia/métodos , Diagnóstico Diferencial , Feminino , Humanos , Internato e Residência/estatística & dados numéricos , Masculino , Patologia/educação , Patologia/métodos , Melhoria de Qualidade , Estudos Retrospectivos , SARS-CoV-2/genética , Inquéritos e Questionários , Interface Usuário-ComputadorAssuntos
Fibroma/patologia , Idoso , Diagnóstico Diferencial , Feminino , Fibroma/diagnóstico , Fibroma/ultraestrutura , Fibrossarcoma/diagnóstico , Fibrossarcoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mixossarcoma/diagnóstico , Mixossarcoma/patologia , Gradação de Tumores , Estudos Retrospectivos , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/ultraestruturaRESUMO
Soft tissue sarcomas (STS) are malignancies derived from connective tissue, and regional lymph node metastasis (RLNM), while not common, is an important aspect of prognosis and treatment. Various risk factors, in particular the histological subtype, affect the likelihood of nodal involvement, which can be characterized by imaging features such as nodal dimension and morphology. Currently, surveillance and management vary by institution, as concrete societal guidelines have not been established. Common nodal status assessment strategies include physical exam, US CT, MRI, sentinel lymph node biopsy (SLNB) and radical lymphadenectomy. This article summarizes data regarding relevant risk factors of RLNM, imaging features, and any available data regarding surveillance recommendations.
Assuntos
Diagnóstico por Imagem/métodos , Metástase Linfática/diagnóstico por imagem , Sarcoma/diagnóstico por imagem , Humanos , Linfonodos/diagnóstico por imagem , Fatores de RiscoRESUMO
OBJECTIVE: We aimed to evaluate the sensitivity of fine needle aspiration (FNA) for the diagnosis of Hodgkin's lymphoma (HL) in HIV-infected patients. STUDY DESIGN: An electronic search was conducted to retrospectively identify patients diagnosed with HL who underwent FNA followed by confirmatory biopsy. FNAs were categorized as negative, atypical/suspicious/positive, or nondiagnostic. Diagnostic sensitivity in HIV+ and HIV- patients was statistically compared via Fisher's exact test, with a p value <0.05 considered significant. RESULTS: Thirty-six patients meeting inclusion criteria were identified (24 HIV- and 12 HIV+). Average age was 36.0 ± 11.5 and 36.5 ± 7.4 years (means ± SD) in HIV- and HIV+ patients, respectively. The male-to-female ratio was 1.4:1 in HIV- patients versus 3:1 in HIV+ patients. Among these 36 patients, a total of 42 FNAs were performed. Overall sensitivity of FNA was 66.7% (95% confidence interval: 52.4-80.9%). When stratified by HIV status, a statistically significant difference in FNA sensitivity was detected, as sen-sitivity was 84.6% (70.8-98.4%) in HIV- patients versus only 37.5% (13.8-61.2%) in HIV+ patients (p =0.003). CONCLUSION: The diagnostic sensitivity of FNA biopsy was significantly attenuated in the HIV+ cohort. In HIV-infected patients presenting with lymphadenopathy, increased clinical suspicion of HL is critical to avoid misdiagnosis.
Assuntos
Biópsia por Agulha Fina , Infecções por HIV/virologia , Doença de Hodgkin/patologia , Adulto , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/imunologia , Doença de Hodgkin/imunologia , Doença de Hodgkin/virologia , Humanos , Hospedeiro Imunocomprometido , Imuno-Histoquímica , Antígeno Ki-1/análise , Antígenos Comuns de Leucócito/análise , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
A higher number of donor plasmacytoid dendritic cells (pDCs) is associated with increased survival and reduced graft-versus-host disease (GVHD) in human recipients of unrelated donor bone marrow (BM) grafts, but not granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood grafts. We show that in murine models, donor BM pDCs are associated with increased survival and decreased GVHD compared with G-CSF-mobilized pDCs. To increase the content of pDCs in BM grafts, we studied the effect of FMS-like tyrosine kinase 3 ligand (Flt3L) treatment of murine BM donors on transplantation outcomes. Flt3L treatment (300 µg/kg/day) resulted in a schedule-dependent increase in the content of pDCs in the BM. Mice treated on days -4 and -1 had a >5-fold increase in pDC content without significant changes in numbers of HSCs, T cells, B cells, and natural killer cells in the BM graft. In an MHC-mismatched murine transplant model, recipients of Flt3L-treated T cell-depleted (TCD) BM (TCD F-BM) and cytokine-untreated T cells had increased survival and decreased GVHD scores with fewer Th1 and Th17 polarized T cells post-transplantation compared with recipients of equivalent numbers of untreated donor TCD BM and T cells. Gene array analyses of pDCs from Flt3L-treated human and murine donors showed up-regulation of adaptive immune pathways and immunoregulatory checkpoints compared with pDCs from untreated BM donors. Transplantation of TCD F-BM plus T cells resulted in no loss of the graft-versus-leukemia (GVL) effect compared with grafts from untreated donors in 2 murine GVL models. Thus, Flt3L treatment of BM donors is a novel method for increasing the pDC content in allografts, improving survival, and decreasing GVHD without diminishing the GVL effect.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Transplante de Medula Óssea/métodos , Células Dendríticas/imunologia , Proteínas de Membrana/uso terapêutico , Transplante Homólogo/métodos , Adjuvantes Imunológicos/farmacologia , Animais , Humanos , Masculino , Proteínas de Membrana/farmacologia , Camundongos , Doadores de TecidosRESUMO
Soft tissue sarcomas (STS) have minimal expression of PD-L1, a biomarker for PD-1 therapy efficacy. Radiotherapy (RT) has been shown to increase PD-L1 expression pre-clinically. We examined the expression of PD-L1, pre- and post-RT, in 46 Stage II-III STS patients treated with pre-operative RT (50-50.4 Gy in 25-28 fractions) followed by resection. Five additional patients who did not receive RT were utilized as controls. PD-L1 expression on biopsy and resection samples was evaluated by immunochemistry using the anti PD-L1 monoclonal antibody (E1L3 N clone; Cell Signaling). Greater than 1% membranous staining was considered positive PD-L1 expression. Changes in PD-L1 expression were analyzed via the Fisher exact test. Kaplan-Meier statistics were used to correlate PD-L1 expression to distant metastases (DM) rate. The majority of STS were T2b (87.0%), high-grade (80.4%), undifferentiated pleomorphic histology (71.7%), and originated from the extremities (84.6%). Zero patients demonstrated PD-L1 tumor expression pre-RT. Post-RT, 5 patients (10.9%) demonstrated PD-L1 tumor expression (p = 0.056). Tumor associated macrophages (TAM) expression of PD-L1 increased after RT: 15.2% to 45.7% (p = 0.003). Samples from controls demonstrated no baseline (0%) or change in tumor PD-L1 expression. Freedom from DM was lower for patients with PD-L1 TAM expression post-RT (3 years: 49.7% vs. 87.8%, log-rank p = 0.006); TAM PD-L1 positivity remained an independent predictor for DM on multivariate analyses (Hazard ratio - 0.16, 95% confidence interval: 0.034-0.721, p = 0.042). PD-L1 expression on human STS tumor and TAM appears to elevate after pre-operative RT. Expression of PD-L1 on TAM after RT was associated with a higher rate of DM.