Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 200
Filtrar
1.
Cancer Immunol Immunother ; 69(5): 779-788, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32052078

RESUMO

Dendritic cells are crucial for the initiation and regulation of immune responses against cancer and pathogens. DCs are heterogeneous and highly specialized antigen-presenting cells. Human DCs comprise several subsets with different phenotypes and functional properties. In the steady state, human DC subsets have been well studied. However, the components of DC subsets and their immune functions during the inflamed setting are poorly understood. We identified and characterized DC subsets in the malignant pleural effusions of NSCLC patients. We analyzed the capacity of these DC subsets to induce T-cell differentiation. We observed the presence of inflammatory DCs (infDCs) and macrophages in the malignant pleural effusions of NSCLC patients, as identified by the CD11C+HLA-DR+CD16-BDCA1+ and CD11C+HLA-DR+CD16+BDCA1- phenotypes, respectively. InfDCs represented approximately 1% of the total light-density cells in the pleural effusion and were characterized by the expression of CD206, CD14, CD11b, and CD1α, which were absent on blood DCs. InfDCs also expressed CD80, although at a low level. As infDCs did not express CD40, CD83 and CD275, they remained functionally immature. We found that TLR agonists promoted the maturation of infDCs. Compared with macrophages, infDCs had a weaker capacity to phagocytose necrotic tumor cell lysates. However, only infDCs induced autologous memory CD4+ T-cell differentiation into Th1 cells. For the first time, we found that infDCs were present in the malignant pleural effusions of NSCLC patients. We conclude that infDCs represent a distinct human DC subset and induce Th1 cell differentiation in the presence of TLR agonists.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Células Dendríticas/imunologia , Neoplasias Pulmonares/patologia , Derrame Pleural Maligno/imunologia , Células Th1/imunologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Dendríticas/metabolismo , Humanos , Imidazóis/farmacologia , Lipopolissacarídeos/farmacologia , Neoplasias Pulmonares/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Cultura Primária de Células , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo , Células Tumorais Cultivadas
2.
Medicine (Baltimore) ; 98(38): e17253, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567996

RESUMO

BACKGROUND: Malignant pleural effusion (MPE) and tuberculosis pleural effusion (TPE) are 2 kinds of common pleural diseases. Finding efficient and accurate biomarkers to distinguish the 2 is of benefit to basic and clinical research. In the present study, we carried out the first high-throughput autoantibody chip to screen the beneficial biomarker with samples of MPE and TPE and the corresponding serum. METHODS: We collected pleural effusion and serum of patients with MPE (n = 10) and TPE (n = 10) who had been in Beijing Chao-Yang hospital from June 2013 to August 2014. Using RayBio Human Protein Array-G2 to measure the concentration of 487 defined autoantibodies. RESULTS: Fold changes of Bcl-2-like protein 11 (BIM) autoantibody in MPE-serum/TPE-serum and MPE/TPE groups were 10 (P = .019) and 6 (P = .001); for decorin autoantibody, MPE-serum/TPE-serum ratio was 0.6 (P = .029), and MPE/TPE ratio was 0.3 (P < .001). CONCLUSION: BIM autoantibody is a promising MPE biomarker by high-throughput autoantibody analysis in MPE and TPE.


Assuntos
Autoanticorpos/sangue , Derrame Pleural Maligno/sangue , Derrame Pleural/sangue , Tuberculose Pleural/sangue , Autoanticorpos/imunologia , Proteína 11 Semelhante a Bcl-2/sangue , Proteína 11 Semelhante a Bcl-2/imunologia , Biomarcadores/sangue , Feminino , Ensaios de Triagem em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/diagnóstico , Derrame Pleural/imunologia , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/imunologia , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/imunologia
3.
J Coll Physicians Surg Pak ; 29(1): 33-36, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30630566

RESUMO

OBJECTIVE: To differentiate between adenocarcinoma cells and reactive mesothelial cells (RMC) in serous effusions using a limited immuno-panel of Ber-EP4 and Calretinin. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Pathology, Allama Iqbal Medical College, Lahore, in collaboration with the Departments of Surgery, Pulmonology and Oncology, Jinnah Hospital, Lahore, from March 2015 to March 2016. METHODOLOGY: Ninety-seven clinically and radiologically proven cases of peritoneal and pleural effusion and peritoneal wash of patients with suspicion of malignancy were included in the present study. Diagnostic accuracy of a limited immuno-panel of Calretinin and Ber-EP4 for diagnosis of malignant effusions was calculated using histopathology as gold standard. RESULTS: The sensitivity of Ber-EP4 for malignant cases was 98.6%, specificity 100%, positive predictive value (PPV) 100%, negative predictive value (NPV) 96%, and diagnostic accuracy 98.9%. Sensitivity of Calretinin as positive staining for RMC was 79.2%, specificity and positive predictive value (PPV) 100%, negative predictive value (NPV) 93.6%, and diagnostic accuracy 94.8%. CONCLUSION: Limited immuno-panel of Calretinin and Ber-EP4 had a high positive and negative predictive value and is cost-effective in resource limited set-up for identification of adenocarcinoma cells and reactive mesothelial cells in challenging cases of serous effusions.


Assuntos
Biomarcadores Tumorais/imunologia , Calbindina 2/imunologia , Mesotelioma/diagnóstico , Mesotelioma/patologia , Derrame Pericárdico/patologia , Derrame Pleural Maligno/patologia , Derrame Pleural/diagnóstico , Adenocarcinoma/diagnóstico , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Biópsia , Calbindina 2/metabolismo , Células Epiteliais/metabolismo , Epitélio/patologia , Humanos , Imuno-Histoquímica , Mesotelioma/metabolismo , Derrame Pericárdico/diagnóstico , Derrame Pleural/patologia , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/imunologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade
4.
Sci Transl Med ; 11(474)2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626714

RESUMO

Cell membrane-derived microparticles (MPs), the critical mediators of intercellular communication, have gained much interest for use as natural drug delivery systems. Here, we examined the therapeutic potential of tumor cell-derived MPs (TMPs) in the context of malignant pleural effusion (MPE). TMPs packaging the chemotherapeutic drug methotrexate (TMPs-MTX) markedly restricted MPE growth and provided a survival benefit in MPE models induced by murine Lewis lung carcinoma and colon adenocarcinoma cells. On the basis of the potential benefit and minimal toxicity of TMPs-MTX, we conducted a human study of intrapleural delivery of a single dose of autologous TMPs packaging methotrexate (ATMPs-MTX) to assess their safety, immunogenicity, and clinical activity. We report our findings on 11 advanced lung cancer patients with MPE. We found that manufacturing and infusing ATMPs-MTX were feasible and safe, without evidence of toxic effects of grade 3 or higher. Evaluation of the tumor microenvironment in MPE demonstrated notable reductions in tumor cells and CD163+ macrophages in MPE after ATMP-MTX infusion, which then translated into objective clinical responses. Moreover, ATMP-MTX treatment stimulated CD4+ T cells to release IL-2 and CD8+ cells to release IFN-γ. Our initial experience with ATMPs-MTX in advanced lung cancer with MPE suggests that ATMPs targeting malignant cells and the immunosuppressive microenvironment may be a promising therapeutic platform for treating malignancies.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Derrame Pleural Maligno/complicações , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Micropartículas Derivadas de Células/ultraestrutura , Modelos Animais de Doenças , Endocitose , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Camundongos Endogâmicos C57BL , Estadiamento de Neoplasias , Derrame Pleural Maligno/imunologia , Derrame Pleural Maligno/patologia , Distribuição Tecidual/efeitos dos fármacos , Transplante Autólogo , Microambiente Tumoral/efeitos dos fármacos
5.
Lung ; 197(1): 53-60, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30523401

RESUMO

BACKGROUND: Malignant pleural effusion (MPE) is a sign of advanced disease of poor prognosis. As natural killer (NK) cells are involved in the first line of tumour defence, we aimed to validate a new diagnostic and prognostic indicator for MPE based on NK subpopulations of pleural fluid (PF) and peripheral blood (PB). METHODS: NK subpopulations were determined in PF and PB in 71 patients with malignant, paramalignant or benign pleural effusion. The receiver operating characteristic (ROC) curves, Kaplan-Meier, multivariable Cox model and decision trees created with the CHAID (Chi-square automatic interaction detector) methodology were employed. RESULTS: We demonstrated that the PF/PB ratios of the CD56 bright CD16- and CD56 dim CD16- NK subpopulations were higher (p = 0.013 and p = 0.003, respectively) in MPEs and paramalignant pleural effusions (PPEs) than in benign ones, with an AUC of 0.757 and 0.741, respectively. The PF/PB ratio of CD16+ NK and CD57+ NK obtained a higher hazard ratio (HR) in the crude Cox's regression analysis. In the adjusted Cox's regression analysis, the PF/PB ratio of CD16+ NK gave the highest HR (HR 6.1 [1.76-21.1]) (p = 0.004). In the decision tree created for the MPE prognosis, we observed that the main predictor variable among the studied clinical, radiological, and analytical variables was lung mass, and that 92.9% of the patients who survived had a PF/PB ratio of the CD56 dim CD16+ NK subpopulation ≤ 0.43. CONCLUSIONS: Our data suggest that both the PF/PB ratios of cytotoxic subpopulations CD57+ NK and CD16+ NK are useful as a prognostic factor of MPE. Other subpopulations (CD56 bright CD16- and CD56 dim CD16- NK) could help to diagnose MPE.


Assuntos
Imunofenotipagem/métodos , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Derrame Pleural Maligno/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Antígeno CD56/sangue , Antígenos CD57/sangue , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Derrame Pleural Maligno/sangue , Derrame Pleural Maligno/imunologia , Derrame Pleural Maligno/terapia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Receptores de IgG/sangue
6.
Am J Physiol Lung Cell Mol Physiol ; 315(3): L443-L455, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29847991

RESUMO

Inflammatory signaling networks between tumor cells and immune cells contribute to the development of malignant pleural effusion (MPE). B cells have been found in MPE; however, little is known about their roles there. In the present study, by using mouse MPE models, we noted that although the total B cells in MPE were decreased as compared with the corresponding blood and spleen, the percentage of activated naïve B cells expressing higher levels of CD80, CD86, myosin heavy chain-II, CD44, CD69, and programmed cell death-ligand 1 (PD-L1) molecules were increased in wild-type mouse MPE. Compared with wild-type mice, decreased T helper (TH)1 cells and increased TH17 cells were present in B cell-deficient mouse MPE, which paralleled to the reduced MPE volume and longer survival time. Adoptive transfer of activated naïve B cells into B cell-deficient mice was able to increase TH1 cells and decrease TH17 cells in MPE and shorten the survival of mice bearing MPE. Furthermore, we demonstrated that activated naïve B cells inhibited TH17-cell expansion via the PD-1/PD-L1 pathway and promoted naïve CD4+ T-cell differentiation into TH1/TH17 cells through secreting IL-27/IL-6 independent of the PD-1/PD-L1 pathway. Collectively, our data uncovered a mechanism by which naïve B cells promote MPE formation by regulating TH1/TH17 cell responses, making these B cells an attractive target for therapeutic intervention in the fight against cancer.


Assuntos
Linfócitos B/imunologia , Derrame Pleural Maligno/imunologia , Transdução de Sinais/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Linfócitos B/patologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/patologia , Transdução de Sinais/genética , Células Th1/patologia , Células Th17/patologia
7.
Cell Immunol ; 331: 1-8, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29903664

RESUMO

Adoptive cell therapy (ACT) of autologous tumor-infiltrating lymphocytes (TILs) has shown an effect on mediating tumor regression in some patients with highly advanced, refractory metastatic malignancy. Here, the in vitro generation of TILs isolated from malignant pleural effusion and ascites was compared with which using engineered cells for costimulatory enhancement (ECCE) and 3 common γ-chain cytokines, interleukin (IL)-2, IL-7, and IL-15, alone or in combination. We showed the robust clinical-scale production of TILs with a less differentiated 'young' phenotype by expansion in the presence of ECCE combined with IL-2/7/15. Furthermore, a major fraction of the TILs generated in this fashion was shown to produce much more IFN-γ and TNF-α, and displayed cytolytic activity against target cells expressing the relevant antigens. To our knowledge, this is the first time that the combination of ECCE and IL-2/7/15 has been applied for the generation of TILs isolated from malignant pleural effusion and ascites.


Assuntos
Ascite/imunologia , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Derrame Pleural Maligno/imunologia , Ligante 4-1BB/genética , Ligante 4-1BB/imunologia , Ligante 4-1BB/metabolismo , Adulto , Idoso , Ascite/patologia , Divisão Celular/imunologia , Células Cultivadas , Feminino , Humanos , Imunoterapia Adotiva/métodos , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-2/metabolismo , Interleucina-7/genética , Interleucina-7/imunologia , Interleucina-7/metabolismo , Células K562 , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Derrame Pleural Maligno/patologia
8.
J Immunol Res ; 2018: 2438598, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29713652

RESUMO

Natural killer (NK) cells are crucial in tumor recognition and eradication, but their activity is impaired in cancer patients, becoming poorly cytotoxic. A particular type of NK cells, from the decidua, has low cytotoxicity and shows proangiogenic functions. We investigated whether NK cells from peripheral blood (PB) and pleural effusions of patients develop decidual-like NK phenotype and whether exposure to IL-2 can restore their killing ability in the presence of pleural fluids. NK cells from pleural effusion of patients with inflammatory conditions (iPE, n = 18), primary tumor (ptPE, n = 18), and metastatic tumor (tmPE, n = 27) acquired the CD56brightCD16- phenotype. NK cells from both ptPE and tmPE showed increased expression for the CD49a and CD69 decidual-like (dNK) markers and decreased levels of the CD57 maturation marker. NK from all the PE analyzed showed impaired degranulation capability and reduced perforin release. PE-NK cells efficiently responded to IL-2 stimulation in vitro. Addition of TGFß or cell-free pleural fluid to IL-2 in the culture medium abrogated NK cell CD107a and IFNγ expression even in healthy donors (n = 14) NK. We found that tmPE-NK cells produce VEGF and support the formation of capillary-like structures in endothelial cells. Our results suggest that the PE tumor microenvironment can shape NK cell polarization towards a low cytotoxic, decidual-like, highly proangiogenic phenotype and that IL-2 treatment is not sufficient to limit this process.


Assuntos
Células Endoteliais/fisiologia , Células Matadoras Naturais/imunologia , Derrame Pleural Maligno/imunologia , Idoso , Idoso de 80 Anos ou mais , Antígeno CD56/metabolismo , Degranulação Celular , Diferenciação Celular , Células Cultivadas , Citotoxicidade Imunológica , Decídua/patologia , Feminino , Humanos , Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Neovascularização Fisiológica , Perforina/metabolismo , Receptores de IgG/metabolismo , Microambiente Tumoral
9.
J Immunol Res ; 2018: 9876014, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29785404

RESUMO

Cancer metastatic spread to serous cavity causes malignant pleural effusions (MPEs), indicating dismal prognosis. Tumor microenvironment can implement suppressive activity on host immune responses. Thus, we investigated the prevalence of Tregs and the relationship between them and TGF-ß and IL-10 concentrations and measured expression of FOXP3, CTLA-4, CD28, and GITR genes, as well as protein expression of selected genes in benign effusions and MPEs. The percentage of Tregs was determined by means of multicolor flow cytometry system. TGF-ß and IL-10 concentrations were measured using human TGF-ß1 and IL-10 ELISA kit. Relative mRNA expression of studied genes was analyzed by real-time PCR. The frequency of Tregs was significantly higher in MPEs compared to benign effusions; however, the level of TGF-ß and IL-10 in analyzed groups was comparable, and no correlation between concentrations of TGF-ß and IL-10 and percentage of Tregs was observed. Relative mRNA expression of all the genes was higher in CD4+CD25+ compared to CD4+CD25- cells. In CD4+CD25+ cells from MPEs, relative mRNA expression of FOXP3, CTLA-4, and CD28 genes was significantly higher than in benign effusions; however, the level of CD4+CD25+CTLA-4+ cells in analyzed groups showed no significant differences. We found numerous genes correlations in an entire CD4+CD25+ cell subset and CD4+CD25+ cells from MPEs. Enhanced suppressive activity of Tregs is observed in the microenvironment of MPEs. Understanding of relations between cellular and cytokine immunosuppressive factors in tumor microenvironment may determine success of anticancer response.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Neoplasias Pulmonares/imunologia , Derrame Pleural Maligno/imunologia , Linfócitos T Reguladores/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Células Cultivadas , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Humanos , Interleucina-10/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Metástase Neoplásica , Estadiamento de Neoplasias , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral
10.
Cytopathology ; 29(2): 172-178, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29575419

RESUMO

INTRODUCTION: Acute lymphoblastic leukaemia/lymphoma (ALL/LBL) is an aggressive entity of precursor lymphoid neoplasm and may cause malignant serous effusion (SE). The current study aimed to analyse the characteristics of SE cytology of ALL/LBL including cytomorphology, immunophenotyping, clonality and evaluate the effectiveness of SE cytology as a diagnostic method for ALL/LBL. METHODS: SE specimens with final diagnosis of ALL/LBL from 2006 to 2016 were reviewed for clinical data, cytomorphological features and ancillary studies. Cytodiagnoses were compared with histodiagnoses, and the discordant cases were analysed. RESULTS: A total of 49 specimens including 47 pleural fluids and 2 pericardial fluids from 49 patients were evaluated. Cytomorphology revealed lymphoblasts varied from small size with scant cytoplasm, condensed nuclear chromatin and indistinct nucleoli to large size with dispersed nuclear chromatin and multiple variably prominent nucleoli. Nuclear clefts and hand mirror-shaped blasts were demonstrated. The positive rates of CD99 and terminal deoxynucleotidyl transferase were 90.9% and 81.6%, respectively. Both monoclonal immunoglobulin (Ig)H and T-cell receptor-γ gene rearrangements were demonstrated in 1 of 3 cases. Monoclonal T-cell receptor-γ gene rearrangement was found in 10 of 11 cases. Monoclonal IgH and/or Ig? gene rearrangements were revealed in 2 of 3 cases. Cytodiagnoses included 4 ALL/LBL, 3 B-ALL/LBL and 42 T-ALL/LBL. Histodiagnoses were available in 24 cases including 2 ALL/LBL, 2 B-ALL/LBL and 20 T-ALL/LBL. The concordance rates of cytological-histological diagnoses were 66.7%, 0% and 95.2% in the three categories, respectively. There were 3 cases with discrepancies of cell lineages. CONCLUSIONS: SE cytological evaluation is a reliable and effective method for the diagnosis of ALL/LBL.


Assuntos
Núcleo Celular , Linfócitos , Derrame Pericárdico , Derrame Pleural Maligno , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Núcleo Celular/imunologia , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Criança , Pré-Escolar , Citodiagnóstico , Feminino , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/imunologia , Derrame Pericárdico/metabolismo , Derrame Pericárdico/patologia , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/imunologia , Derrame Pleural Maligno/metabolismo , Derrame Pleural Maligno/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
11.
Mol Ther ; 26(5): 1198-1205, 2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29550074

RESUMO

Gene-mediated cytotoxic immunotherapy (GMCI) is an immune strategy implemented through local delivery of an adenovirus-based vector expressing the thymidine kinase gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug valacyclovir. A phase I dose escalation trial of GMCI followed by chemotherapy was conducted in patients with malignant pleural effusion (MPE). AdV-tk was administered intrapleurally (IP) in three cohorts at a dose of 1 × 1012 to 1013 vector particles. Primary endpoint was safety; secondary endpoints included response rate, progression-free survival, and overall survival. Nineteen patients were enrolled: median age 67 years; 14 with malignant mesothelioma, 4 non-small-cell lung cancer (NSCLC), and 1 breast cancer. There were no dose limiting toxicities. All 3 patients in cohort 2 experienced transient cytokine release syndrome (CRS). Addition of celecoxib in cohort 3 reduced the incidence and severity of CRS (none > grade 2). Three patients are alive (23-33 months after GMCI), and 3 of 4 NSCLC patients had prolonged disease stabilization; one is alive 29 months after GMCI, 3.6 years after initial diagnosis. GMCI was safe and well tolerated in combination with chemotherapy in patients with MPE and showed encouraging response. Further studies are warranted to determine efficacy.


Assuntos
Terapia Genética , Imunoterapia , Derrame Pleural Maligno/imunologia , Derrame Pleural Maligno/terapia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Adenoviridae/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Terapia Combinada , Feminino , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos/genética , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Testes de Função Respiratória , Resultado do Tratamento
12.
Support Care Cancer ; 26(5): 1525-1531, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29188375

RESUMO

PURPOSE: Concerns for infections resulting from antineoplastic therapy-associated immunosuppression may deter referral for symptom palliation with a tunneled pleural catheter (TPC) in patients with malignant/para-malignant pleural effusions (MPE/PMPE). While rates of TPC-related infections range from 1 to 21%, those in patients receiving antineoplastic therapy with correlation to immune status has not been established. We aimed to assess TPC-related infection rates in patients on antineoplastic therapy, determine relation to immune system competency, and assess impact on the patient. METHODS: Patients with a MPE/PMPE undergoing TPC management associated with antineoplastic therapy, from 2008 to 2016, were reviewed and categorized into those with an immunocompromised versus immunocompetent immune status. RESULTS: Of the 150 patients, a TPC-related infection developed in 13 (9%): pleural space in 11 (7%) and superficial in 2 (1%). Ninety-three percent (139/150) were identified to be immunocompromised during their antineoplastic therapy. No difference in TPC-related infections was seen in patients with an immunocompromised (9%, 12/139) versus immunocompetent status (9%, 1/11); p = 0.614. The presence of a catheter-related infection did not negatively impact overall survival over a median follow-up of 144 days (interquartile range 41-341); p = 0.740. CONCLUSIONS: These results suggest that antineoplastic therapy may not significantly increase the overall risk of TPC-related infections, as the rate remains low and comparable to rates in patients not undergoing antineoplastic therapy. Regardless of immune status, the presence of a catheter-related infection did not negatively impact overall survival. These results should reassure clinicians that the need to initiate antineoplastic therapy should not delay definitive pleural palliation with a TPC.


Assuntos
Infecções Relacionadas a Cateter/etiologia , Cateteres de Demora/efeitos adversos , Neoplasias/terapia , Derrame Pleural Maligno/terapia , Idoso , Infecções Relacionadas a Cateter/imunologia , Infecções Relacionadas a Cateter/microbiologia , Drenagem/efeitos adversos , Drenagem/instrumentação , Drenagem/métodos , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/microbiologia , Cuidados Paliativos , Derrame Pleural Maligno/imunologia , Derrame Pleural Maligno/microbiologia , Pleurodese/efeitos adversos , Pleurodese/instrumentação , Pleurodese/métodos , Estudos Retrospectivos , Resultado do Tratamento
14.
Respiration ; 95(2): 98-105, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29131120

RESUMO

BACKGROUND: Haematological malignancy is an important cause of pleural effusion. Pleural effusions secondary to haematological malignancy are usually lymphocyte predominant. However, several other conditions such as carcinoma, tuberculosis, and chronic heart failure also cause lymphocytic effusions. Lymphocyte subset (LS) analysis may be a useful test to identify haematological malignancy in patients with lymphocytic effusions. However, research into their utility in pleural effusion diagnostic algorithms has not yet been published. OBJECTIVES: We aimed to determine the clinical utility of pleural fluid LS analysis and whether it can be applied to a diagnostic algorithm to identify effusions secondary to haematological malignancy. The secondary aim was to evaluate the diagnostic value of pleural fluid differential cell count. METHODS: Consecutive consenting patients presenting to our pleural service between 2008 and 2013 underwent thoracentesis and differential cell count analysis. We proposed an algorithm which selected patients with lymphocytic effusions (>50%) to have further fluid sent for LS analysis. Two independent consultants agreed on the cause of the original effusion after a 12-month follow-up period. RESULTS: A total of 60 patients had samples sent for LS analysis. LS analysis had an 80% sensitivity (8/10) and a 100% specificity for the diagnosis of haematological malignancy. The positive and negative predictive values were 100 and 96.1%, respectively. Overall 344 differential cell counts were analysed; 16% of pleural effusions with a malignant aetiology were neutrophilic or eosinophilic at presentation. A higher neutrophil and eosinophil count was associated with benign diagnoses, whereas a higher lymphocyte count was associated with malignant diagnoses. CONCLUSIONS: LS analysis may identify haematological malignancy in a specific cohort of patients with undiagnosed pleural effusions. A pleural fluid differential cell count provides useful additional information to streamline patient pathway decisions.


Assuntos
Subpopulações de Linfócitos , Derrame Pleural Maligno/diagnóstico , Algoritmos , Humanos , Contagem de Leucócitos , Derrame Pleural Maligno/citologia , Derrame Pleural Maligno/imunologia , Estudos Prospectivos
15.
Front Immunol ; 9: 2916, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619280

RESUMO

Preclinical and clinical studies have shown that prior receipt of radiotherapy enhances antitumor immune responses, a phenomenon we call the "radio-memory effect." However, all of the evidence regarding this effect to date comes from work with PD1/PDL1 inhibitors. Here we explored whether this effect also occurs with other forms of immune therapy, specifically interleukin-2 (IL-2). We retrospectively assessed outcomes in patients with malignant pleural effusion (MPE) who had previously received radiotherapy for non-small-cell lung cancer (NSCLC) within 18 months before the intrapleural infusion of IL-2 or cisplatin. Radiotherapy sites included lungs, thoracic lymph nodes, and intracranial. All patients received intrapleural infusion of IL-2 or cisplatin, and most had had several cycles of standard chemotherapy for NSCLC. We identified 3,747 patients with MPE (median age 64 years [range 29-88)) treated at one of several institutions from August 2009 through February 2015; 642 patients had been treated with IL-2 and 1102 with cisplatin and had survived for at least 6 months afterward. Among those who received IL-2, 288 had no radiotherapy, 324 had extracranial (i.e., thoracic) radiotherapy, and 36 had intracranial radiotherapy. The median follow-up time for surviving patients was 38 months. Patients who had received extracranial radiotherapy followed by IL-2 had significantly longer PFS than patients who had not received extracranial radiotherapy (i.e., either no radiotherapy or intracranial radiotherapy). Patients who had received intracranial or extracranial radiotherapy followed by IL-2 had significantly longer OS than did other patients. No survival advantage was noted for prior radiotherapy among patients who received intrapleural cisplatin. We speculate that previous radiotherapy could enhance the efficacy of subsequent intrapleural infusion of IL-2, a "radio-memory" effect that could be beneficial in future studies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Cisplatino/uso terapêutico , Memória Imunológica/efeitos da radiação , Interleucina-2/uso terapêutico , Neoplasias Pulmonares/radioterapia , Derrame Pleural Maligno/tratamento farmacológico , Radioterapia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Memória Imunológica/imunologia , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural Maligno/imunologia , Estudos Retrospectivos , Fatores de Tempo
16.
Immunobiology ; 222(3): 499-505, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27773662

RESUMO

Tumors exert suppressive effects on the host immune system and tumor progression can be linked to functional impairments of immune cells. Regulatory T cells (Treg) are a subpopulation of T lymphocytes and play a key role in suppressing immune responses against autoimmune diseases and cancer. The aim of the study was to investigate the prevalence of Treg in malignant and benign pleural effusions and to evaluate the relationship between Treg frequency and disease advance. Pleural effusions from 76 patients were subjected to a routine laboratory diagnosis and analyzed by conventional cytology. Biological materials were divided into three groups: malignant pleural effusions with malignant cells, effusions from patients with malignancy but without malignant cells, and non-malignant pleural effusions. The frequency of Treg in malignant pleural effusions was significantly higher compared to non-malignant effusions. In general, the increase in Treg frequency was correlated with a decrease in the percentage of lymphocytes and an increase in T CD4+ and T CD4+ CD25+ cells. The highest percentage of Treg was observed among patients with the most advanced clinical stage of lung cancer in terms of size and location of a primary tumor, T4. A Kaplan-Meier survival analysis showed a statistically significant trend towards an adverse outcome for patients representing higher Treg counts. Overall, our results support the extraordinary potential of Treg control in future anticancer therapy.


Assuntos
Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Derrame Pleural Maligno/imunologia , Derrame Pleural Maligno/patologia , Linfócitos T Reguladores/imunologia , Biomarcadores , Progressão da Doença , Feminino , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Contagem de Linfócitos , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Carga Tumoral
17.
Am J Respir Cell Mol Biol ; 56(3): 342-352, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27767332

RESUMO

Toll-like receptor (TLR) 2 has a well-known role in sensing multiple ligands that include microbial products, endotoxin, and some extracellular matrix molecules; however, its role in the development of malignant pleural effusion (MPE) remains unknown. We performed the present study to explore the impact of TLR2 signaling on the development of MPE and to define the underlying mechanisms by which TLR2 works. Development of MPE was compared between TLR2-/- and wild-type (WT) mice. The effect of TLR2 on differentiation of T helper type 17 (Th17), Th9, and Th2 cells in MPE was explored. The mechanisms of TLR2 on survival of mice bearing MPE were also investigated. MPE volume in TLR2-/- mice was lower than that in WT mice, and the survival of TLR2-/- mice bearing MPE was longer than that of WT mice. TLR2 deficiency increased, and TLR2 activation decreased, Th17 cells in MPE, whereas TLR2 signaling showed the contrary effects on Th2 cells. Th9 cells were increased in MPE of TLR2-/- mice but were not influenced by TLR2 signaling. Intraperitoneal injection of anti-IL-17 monoclonal antibody (mAb), anti-IL-9 mAb, or recombinant mouse IL-4 accelerated the death of TLR2-/- mice bearing MPE, and intraperitoneal injection anti-IL-17 mAb in TLR2-/- mice was associated with a significantly shorter survival time than in WT mice. We have demonstrated, for the first time, that TLR2 signaling promotes the development of MPE and accelerates the death of mice bearing MPE by directly suppressing Th17 cell differentiation and directly promoting Th2 cell differentiation, and also by indirectly suppressing Th9 cell differentiation via an IL-17-dependent mechanism.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Derrame Pleural Maligno/imunologia , Receptor 2 Toll-Like/metabolismo , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Interleucina-17/farmacologia , Camundongos Endogâmicos C57BL , Derrame Pleural Maligno/patologia , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Receptor 2 Toll-Like/agonistas
18.
Lung Cancer ; 107: 36-40, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27168021

RESUMO

OBJECTIVES: Clinical studies have proven the potential of immunotherapy in malignancies. To increase efficacy, a prerequisite is that treatment is tailored, so precision immune-oncology is the logical next step. In order to tailor treatment, characterization of the patient's tumor environment is key. Pleural effusion (PE) often accompanies malignant pleural mesothelioma (MPM) and is an important part of the MPM environment. Furthermore, the composition of PE is used as surrogate for the tumor. In this study, we provide an insight in the dynamics of the MPM environment through characterization of PE composition over time and show that the immunological characteristics of PE do not necessarily mirror those of the tumor. MATERIALS AND METHODS: From 5 MPM patients, PE and tumor biopsies were acquired at the same time point. From one of these patients multiple PEs were obtained. PEs were acquired performing thoracocenteses and total cell amounts were determined. Immunohistochemistry was performed to quantify immune cell composition (T cells, macrophages) and tumor cells in PE derived cytospins and tumor biopsies. RESULTS: The PE amount and (immune) cellular composition varied considerably over time between multiple (n=10) thoracocenteses. These dynamics could in part be attributed to the treatment regimen consisting of standard chemotherapy and dendritic cell (DC)-based immunotherapy. In addition, the presence of T cells and macrophages in PE did not necessarily mirror the infiltration of these immune cells within tumor biopsies in 4 out of 5 patients. CONCLUSIONS: In this proof-of-concept study with limited sample size, we demonstrate that the composition of PE is dynamic and influenced by treatment. Furthermore, the immune cell composition of PE does not automatically reflect the properties of tumor tissue. This has major consequences when applying precision immunotherapy based on PE findings in patients. Furthermore, it implies a regulated trafficking of immune regulating cells within the tumor environment.


Assuntos
Imunoterapia/métodos , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Derrame Pleural Maligno/imunologia , Neoplasias Pleurais/imunologia , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Macrófagos/metabolismo , Mesotelioma/complicações , Mesotelioma/tratamento farmacológico , Mesotelioma/imunologia , Derrame Pleural Maligno/patologia , Derrame Pleural Maligno/terapia , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/patologia , Neoplasias Pleurais/terapia , Medicina de Precisão , Linfócitos T/imunologia , Toracentese/métodos , Microambiente Tumoral/imunologia
20.
Emerg Microbes Infect ; 5(8): e83, 2016 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-27485497

RESUMO

The differential diagnosis of tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) remains difficult despite the availability of numerous diagnostic tools. The current study aimed to evaluate the performance of the whole blood QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and conventional laboratory biomarkers in differential diagnosis of TPE and MPE in high tuberculosis prevalence areas. A total of 117 patients with pleural effusions were recruited, including 91 with TPE and 26 with MPE. All of the patients were tested with QFT-GIT, and the conventional biomarkers in both blood and pleural effusion were detected. The level of antigen-stimulated QFT-GIT in the whole blood of TPE patients was significantly higher than that of MPE (2.89 vs 0.33 IU/mL, P<0.0001). The sensitivity and specificity of QFT-GIT for the diagnosis of TPE were 93.0% and 60.0%, respectively. Among the biomarkers in blood and pleural effusion, pleural adenosine deaminase (ADA) was the most prominent biomarker, with a cutoff value of 15.35 IU/L. The sensitivity and specificity for the diagnosis of TPE were 93.4% and 96.2%, respectively. The diagnostic classification tree from the combination of these two biomarkers was 97.8% sensitive and 92.3% specific. Ultimately, the combination of whole blood QFT-GIT with pleural ADA improved both the specificity and positive predictive value to 100%. Thus, QFT-GIT is not superior to pleural ADA in the differential diagnosis of TPE and MPE. Combined whole blood QFT-GIT and pleural ADA detection can improve the diagnosis of TPE.


Assuntos
Adenosina Desaminase/análise , Biomarcadores/sangue , Testes de Liberação de Interferon-gama , Interferon gama/sangue , Derrame Pleural Maligno/diagnóstico , Derrame Pleural/enzimologia , Tuberculose Pleural/diagnóstico , Adolescente , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Interferon gama/imunologia , Masculino , Derrame Pleural/imunologia , Derrame Pleural Maligno/imunologia , Kit de Reagentes para Diagnóstico , Sensibilidade e Especificidade , Tuberculose Pleural/imunologia , Tuberculose Pleural/microbiologia , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA