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1.
J Clin Endocrinol Metab ; 105(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32449514

RESUMO

CONTEXT: Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells. OBJECTIVE: To investigate SOAT1 protein expression as a marker of treatment response to mitotane. PATIENTS: A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens. SETTING: Retrospective study at 12 ACC referral centers. MAIN OUTCOME MEASURE: Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). RESULTS: Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different. CONCLUSIONS: SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.

2.
Appl Immunohistochem Mol Morphol ; 28(1): 10-16, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31809310

RESUMO

Anaplastic large cell lymphomas (ALCL) encompass several subgroups that differ in their clinical presentation, genetic features, and prognosis. We characterized the genetic subgroups of 74 patients with ALCL and correlated programmed death ligand 1 (PD-L1) protein expression and compared the densities and ratios of FOXP3+ T regulatory cells and CD8+ tumor-infiltrating lymphocytes (TILs) in tumor cells and the immune microenvironment. The subgroups included anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL and ALK-negative (ALK-) ALCL and DUSP22-rearranged and nonrearranged ALK- ALCL. None of our cases represented the TP63-rearrangement ALK- ALCL subgroup. Our results showed that ALK+ ALCL had a higher expression of PD-L1 in the tumor cells, in contrast to ALK- ALCL, which expressed high PD-L1 in tumor-associated macrophages (TAMs). DUSP22-rearranged ALK- ALCL lacked PD-L1 expression in the tumor cells and instead expressed PD-L1 only in TAMs. There was a significant positive correlation of PD-L1 expression between tumor and TAMs in ALK+ ALCL with a negative correlation in ALK- ALCL. Systemic ALCL subgroups had similar densities of CD8+ tumor-infiltrating lymphocytes and FOXP3 T regulatory cells, but differences were observed in the ratio of CD8/FOXP3. Our results suggest that alterations in tumor microenvironment and immune responses exist among systemic ALCL subgroups and these features may account for different clinical behavior and prognosis.

3.
Diagn Pathol ; 14(1): 115, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640798

RESUMO

BACKGROUND: Primary cutaneous CD30+ lymphoproliferative disorders (pc-CD30-LPD) are a group of clonal T cell lymphoproliferative disorders that despite very similar tumor histology follow different and characteristic clinical courses, suggesting a homeostatic role of the tumor microenvironment. Little is known about tumor microenvironment and there is almost no literature about PD-L1 expression in pc-CD30-LPD. METHODS: This retrospective study presents a fully clinicopathologically characterized series of pc-CD30-LPDs from an academic medical center in Brazil, including 8 lymphomatoid papulomatosis (LyP), 9 primary cutaneous anaplastic large cell lymphoma (pcALCL) and 4 borderline lesions. All the cases were scored for FOXP3+ regulatory T-cells (Treg) and CD8+ cytotoxic tumor infiltrating lymphocytes (TIL) densities, as well as PD-L1 expression in tumor cells and tissue associated macrophages. The CD8+/FOXP3+ ratio was also evaluated. RESULTS: Among the 21 cases of pc-CD30-LPD, PD-L1 expression is frequent in both tumor cells and tissue associated macrophages in pc-CD30-LPD across categories, suggesting that the PD-L1 axis may be a common feature of pc-CD30-LPDs. While reactive T cell infiltrates vary widely from case to case, a common feature across pc-CD30-LPDs is higher density of CD8 than FOXP3 + T cells. The distribution of T cells within the lesions however differed between LyP and pcALCL: we found that LyP lesions tend to be permeated by CD8+ and FOXP3+ T cells, whereas pcALCL tend to be surrounded by a rim of CD8+ TIL and FOXP3+ Tregs with relatively lower density infiltrates in the center of the lesion. CONCLUSIONS: LyP has a trend to have denser immune cells throughout the lesion, with higher FOXP3+ Treg and CD8+ TIL in the center than the edge comparing with pcALCL. PD-L1+ is frequent in tumor cells and tissue associated macrophages in pc-CD30-LPD. The differential distribution of CD8+ and FOXP3+ TILs in LyP as compared to pcALCL could provide a clue to the relapsing/remitting course of LyP as compared to the less frequent spontaneous regression of pcALCL.


Assuntos
Antígeno Ki-1/imunologia , Transtornos Linfoproliferativos/patologia , Dermatopatias/patologia , Neoplasias Cutâneas/patologia , Microambiente Tumoral/fisiologia , Centros Médicos Acadêmicos , Adulto , Idoso , Brasil , Feminino , Humanos , Antígeno Ki-1/análise , Linfócitos do Interstício Tumoral/patologia , Linfoma de Células T Periférico/patologia , Transtornos Linfoproliferativos/diagnóstico , Masculino , Pessoa de Meia-Idade , Dermatopatias/diagnóstico , Neoplasias Cutâneas/diagnóstico
4.
Hum Pathol ; 80: 138-144, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29898383

RESUMO

Forkhead box P3 (FOXP3) is a specific marker for regulatory T-cells (Tregs). We report 6 cases of T-cell lymphomas with Treg phenotype based on diffuse positivity for FOXP3 in tumor cells. The patients showed a median age of 56 years with a male predominance. Sites of disease included lymph nodes (4), skin (2), subcutaneous tissue (1) and bone marrow (1). All cases showed monomorphic large cells, some with Hodgkin-like or anaplastic cells. All cases expressed pan T-cell markers and lacked cytotoxic markers; one case showed diffuse PD1 staining. Only one case harbored human T-lymphotrophic virus (HTLV)-1 DNA within tumor cells and was classified as adult T-cell leukemia/lymphoma (ATLL). Among 5 HTLV1-negative cases, 3 were classified as peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) and 2 fulfilled criteria for ALK-negative anaplastic large cell lymphoma (ALCL) with diffuse and strong CD30 positivity. We concluded that Treg phenotype may be rarely seen in HTLV1-negative cases, such as PTCL, NOS and ALK-negative ALCL. Our findings expand the spectrum of T-cell lymphomas with regulatory phenotype and suggest that consideration should be given to HTLV1 DNA testing in the appropriate clinical setting to rule out ATLL.


Assuntos
Quinase do Linfoma Anaplásico/imunologia , Fatores de Transcrição Forkhead/imunologia , Linfoma Anaplásico de Células Grandes/genética , Linfoma de Células T/patologia , Adulto , Idoso , Biomarcadores/análise , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Linfoma Anaplásico de Células Grandes/imunologia , Linfoma Anaplásico de Células Grandes/patologia , Linfoma de Células T/imunologia , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Receptores Proteína Tirosina Quinases/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
5.
Oncotarget ; 8(38): 63835-63845, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28969033

RESUMO

BACKGROUND: Discrimination between benign and malignant tumors is a challenging process in pediatric adrenocortical tumors. New insights in the metabolic profile of pediatric adrenocortical tumors may contribute to this distinction, predict prognosis, as well as identify new molecular targets for therapy. The aim of this work is to characterize the expression of the metabolism-related proteins MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX in a series of pediatric adrenocortical tumors. METHODS: A total of 50 pediatric patients presenting adrenocortical tumors, including 41 clinically benign and 9 clinically malignant tumors, were included. Protein expression was evaluated using immunohistochemistry in samples arranged in tissue microarrays. RESULTS: The immunohistochemical analysis showed a significant increase in plasma membrane expression of GLUT1 in malignant lesions, when compared to benign lesions (p=0.004), being the expression of this protein associated with shorter overall and disease-free survival (p=0.004 and p=0.001, respectively). Although significant differences were not observed for proteins other than GLUT1, MCT1, MCT4 and CD147 were highly expressed in pediatric adrenocortical neoplasias (around 90%). CONCLUSION: GLUT1 expression was differentially expressed in pediatric adrenocortical tumors, with higher expression in clinically malignant tumors, and associated with shorter survival, suggesting a metabolic remodeling towards a hyperglycolytic phenotype in this malignancy.

6.
Oncotarget ; 6(42): 44403-21, 2015 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-26587828

RESUMO

Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis.


Assuntos
Neoplasias do Córtex Suprarrenal/química , Adenoma Adrenocortical/química , Carcinoma Adrenocortical/química , Biomarcadores Tumorais/análise , Metabolismo Energético , Adolescente , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/terapia , Adenoma Adrenocortical/mortalidade , Adenoma Adrenocortical/patologia , Adenoma Adrenocortical/terapia , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/análise , Basigina/análise , Anidrase Carbônica IX , Anidrases Carbônicas/análise , Intervalo Livre de Doença , Feminino , Transportador de Glucose Tipo 1/análise , Humanos , Receptores de Hialuronatos/análise , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Transportadores de Ácidos Monocarboxílicos/análise , Proteínas Musculares/análise , Gradação de Tumores , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Simportadores/análise , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
7.
J Clin Endocrinol Metab ; 100(2): E308-18, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25389632

RESUMO

CONTEXT: The phenotype of familial pheochromocytoma (PHEO) associated with germline TMEM127 mutations (TMEM127-related PHEO) has not been clearly defined. OBJECTIVE: This study aimed to investigate the penetrance, full phenotypic spectrum and effectiveness of clinical/genetic screening in TMEM127-related PHEO. DESIGN, SETTING, AND PARTICIPANTS: Clinical and genetic screening, and genetic counseling were offered to 151 individuals from a six-generation family carrying a TMEM127 germline mutation in a referral center. INTERVENTION AND MAIN OUTCOME MEASURES: TMEM127 genetic testing was offered to at-risk relatives and clinical surveillance for pheochromocytoma was performed in mutation-positive carriers. RESULTS: Forty seven individuals carried the c.410-2A>C TMEM127 mutation. Clinical data were obtained from 34 TMEM127-mutation carriers followed up for 8.7 ± 8.1 years (range, 1-20 y). Pheochromocytoma was diagnosed in 11 carriers (32%) at a median age of 43 years. In nine patients, symptoms started at 29 years (range, 10-55 y) and two cases were asymptomatic. Tumors were multicentric in five (45%) and bilateral in five (45%) patients. Six patients (54%) had at least one adrenomedullary nodule less than 10 mm. No paragangliomas, distant metastases, or other manifestations were detected. Cumulative penetrance of pheochromocytoma was 0% at 0-20 years, 3% at 21-30 years, 15% at 31-40 years, 24% at 41-50 years, and 32% at 51-65 years. The youngest case was diagnosed at 22 years and the earliest symptoms were reported at age 10. CONCLUSIONS: Tumor multicentricity, nodular adrenomedullary hyperplasia, and the occurrence of symptoms more than a decade earlier than the age at diagnosis are novel findings in TMEM127-related PHEO. The high penetrance of pheochromocytoma in this condition validates the benefits of genetic testing of at-risk relatives. We thus recommend that TMEM127 genetic testing should be offered to at-risk individuals at age 22 years and mutation carriers should undergo clinical surveillance annually.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Mutação em Linhagem Germinativa , Proteínas de Membrana/genética , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idade de Início , Família , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Penetrância , Fenótipo , Feocromocitoma/patologia , Adulto Jovem
8.
Cancer ; 105(3): 139-44, 2005 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-15803491

RESUMO

BACKGROUND: Plasmablastic lymphomas (PBLs) were originally described exclusively in human immunodeficiency virus (HIV)-positive patients who presented with jaw or oral mucosa involvement. Recent studies have reported this neoplasm also in patients without HIV infection and involving sites other than head and neck. This lymphoma has a heterogeneous morphologic presentation but distinct phenotype. METHODS: Cytologic features from four cases of histologically confirmed PBL were evaluated. The cytology specimens were evaluated for criteria as follow: cellularity, cell size and shape, pleomorphism, cytoplasmic characteristics, chromatin pattern, nucleolar features, and mitotic figures. RESULTS: Specimens evaluated were two head and neck fine needle aspiration specimens, one anal smear, and one cerebrospinal fluid specimen. Atypical lymphocytes ranged from intermediate to large in size and demonstrated slight nuclear pleomorphism. The cytoplasm varied from scant to moderate in the alcohol-fixed slides. Nuclei were round with vesicular chromatin. Nucleoli varied from a prominent one to multiple small ones. Multinucleated cells and mitotic figures were easily identified in three of four cases. Tingible-body histiocytes were seen in one case. Ancillary studies in two cases demonstrated expression of CD138 with lack of CD20 expression. CONCLUSION: PBL is a variant of large cell lymphoma with heterogeneous cytologic findings but distinct immunophenotype. Knowledge of the cytomorphologic spectrum of PBLs and detection of CD138 expression by flow cytometry can be helpful in achieving a correct diagnosis.


Assuntos
Citodiagnóstico/métodos , Linfoma Imunoblástico de Células Grandes/patologia , Biópsia por Agulha , Estudos de Coortes , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Sistema de Registros , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Manejo de Espécimes , Técnicas de Cultura de Tecidos
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