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1.
RMD Open ; 9(4)2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-38123480

RESUMO

OBJECTIVE: Undifferentiated, early inflammatory arthritis (EIA) can differentiate into seropositive or seronegative rheumatoid arthritis (RA), peripheral spondyloarthritis (SpA) or remain as seronegative undifferentiated inflammatory arthritis (UIA). Little is known about immune pathways active in the early stages of SpA and seronegative UIA, in contrast to detailed knowledge of seropositive RA. The aim of this study was to examine if specific immune pathways were active in synovial CD4+ and CD8+ T cells in EIA. METHODS: Synovial fluid (SF) samples from 30 patients with EIA were analysed for expression of IL-17A, IFNγ and TNFα in CD8+ or CD4+ T cells. Final clinical diagnoses were made at least 12 months after sample collection, by two independent clinicians blind to the study data. RESULTS: Flow cytometry analysis of all EIA samples indicated considerable variation in synovial IL-17A+CD8+ T cells (Tc17) cell frequencies between patients. The group with a final diagnosis of SpA (psoriatic arthritis or peripheral SpA, n=14) showed a significant enrichment in the percentage of synovial Tc17 cells compared with the group later diagnosed with seronegative UIA (n=10). The small number of patients later diagnosed with seropositive RA (n=6) patients had few Tc17 cells, similar to our previous findings in established disease. In contrast, RA SF contained a significantly higher percentage of CD8+IFNγ+ T cells compared with SpA or seronegative UIA. CONCLUSION: These results suggest that adaptive T cell cytokine pathways differ not only between RA and SpA but also seronegative UIA early in the disease process, with a particular activation of Tc17 pathways in early SpA.


Assuntos
Artrite Psoriásica , Artrite Reumatoide , Espondilartrite , Humanos , Interleucina-17 , Líquido Sinovial/metabolismo , Espondilartrite/diagnóstico , Artrite Psoriásica/metabolismo
2.
Arthritis Rheumatol ; 75(10): 1793-1797, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37163452

RESUMO

OBJECTIVE: To characterize the presentation and outcomes of patients with atopic dermatitis (AD) who developed musculoskeletal symptoms after treatment with dupilumab, a human IgG4 monoclonal antibody that blocks the functions of interleukin-4 (IL-4) and IL-13, key pathologic pathways in AD. METHODS: This article reports an observational cohort of patients receiving dupilumab who developed new-onset musculoskeletal symptoms after dupilumab therapy at our center. All patients had a comprehensive rheumatologic history and examination, with imaging by ultrasonography (US) or magnetic resonance imaging (MRI) in most patients. RESULTS: Between October 2018 and February 2021, we recorded 470 patients with AD commencing dupilumab treatment from routine clinical care records. Of 36 patients referred for rheumatologic assessment, we identified 26 patients (14 male, 12 female) with a musculoskeletal syndrome of inflammatory enthesitis, arthritis, and/or tenosynovitis. Clinical findings were confirmed by US and MRI. All patients had very good response to dupilumab treatment, and no specific predictors of musculoskeletal syndrome were noted. Symptoms were mild in 16 patients, moderate in 6 patients, and severe in 4 patients. Receipt of nonsteroidal antiinflammatory drugs or cyclooxygenase 2 inhibitors, reduction of dupilumab dose/frequency, and cessation of dupilumab therapy led to improvement, but moderate or severe symptoms persisted for many months. CONCLUSION: We report a new musculoskeletal syndrome of inflammatory enthesitis/arthritis/tenosynovitis in some patients receiving the IL-4 receptor antagonist dupilumab. This response to a cytokine-targeting therapy provides key insights into the pathogenesis of enthesitis.


Assuntos
Artrite Reumatoide , Dermatite Atópica , Tenossinovite , Humanos , Masculino , Feminino , Dermatite Atópica/complicações , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/diagnóstico , Interleucina-4/uso terapêutico , Inibidores de Interleucina , Resultado do Tratamento , Índice de Gravidade de Doença
4.
Arthritis Rheumatol ; 68(1): 103-16, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26314565

RESUMO

OBJECTIVE: Conflicting evidence exists regarding the suppressive capacity of Treg cells in the peripheral blood (PB) of patients with rheumatoid arthritis (RA). The aim of this study was to determine whether Treg cells are intrinsically defective in RA. METHODS: Using a range of assays on PB samples from patients with chronic RA and healthy controls, CD3+CD4+CD25+CD127(low) Treg cells from the CD45RO+ or CD45RA+ T cell compartments were analyzed for phenotype, cytokine expression (ex vivo and after in vitro stimulation), suppression of Teff cell proliferation and cytokine production, suppression of monocyte-derived cytokine/chemokine production, and gene expression profiles. RESULTS: No differences between RA patients and healthy controls were observed with regard to the frequency of Treg cells, ex vivo phenotype (CD4, CD25, CD127, CD39, or CD161), or proinflammatory cytokine profile (interleukin-17 [IL-17], interferon-γ [IFNγ], or tumor necrosis factor [TNF]). FoxP3 expression was slightly increased in Treg cells from RA patients. The ability of Treg cells to suppress the proliferation of T cells or the production of cytokines (IFNγ or TNF) upon coculture with autologous CD45RO+ Teff cells and monocytes was not significantly different between RA patients and healthy controls. In PB samples from some RA patients, CD45RO+ Treg cells showed an impaired ability to suppress the production of certain cytokines/chemokines (IL-1ß, IL-1 receptor antagonist, IL-7, CCL3, or CCL4) by autologous lipopolysaccharide-activated monocytes. However, this was not observed in all patients, and other cytokines/chemokines (TNF, IL-6, IL-8, IL-12, IL-15, or CCL5) were generally suppressed. Finally, gene expression profiling of CD45RA+ or CD45RO+ Treg cells from the PB revealed no statistically significant differences between RA patients and healthy controls. CONCLUSION: Our findings indicate that there is no global defect in either CD45RO+ or CD45RA+ Treg cells in the PB of patients with chronic RA.


Assuntos
Artrite Reumatoide/imunologia , Citocinas/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Antígenos CD4/imunologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-17/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Antígenos Comuns de Leucócito/imunologia , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
5.
Arthritis Rheumatol ; 66(5): 1272-81, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24470327

RESUMO

OBJECTIVE: Psoriatic arthritis (PsA) is associated with HLA class I genes, in contrast to the association with HLA class II in rheumatoid arthritis (RA). Since IL-17+ cells are considered important mediators of synovial inflammation, we sought to determine whether IL-17-producing CD8+ T cells may be found in the joints of patients with PsA and whether these cells might contribute to the disease process. METHODS: Mononuclear cells from paired samples of synovial fluid (SF) and peripheral blood (PB) from patients with PsA or patients with RA were stimulated ex vivo, and CD4- T cells were examined by flow cytometry for cytokine expression, cytotoxic markers, and frequencies of γ/δ or mucosal-associated invariant T cells. Clinical measures of arthritis activity (C-reactive protein [CRP] level, erythrocyte sedimentation rate [ESR], Disease Activity Score in 28 joints [DAS28]) and power Doppler ultrasound (PDUS) scores for the presence of active synovitis in the aspirated knee were recorded and assessed for correlations with immunologic markers. RESULTS: Within the CD3+ T cell compartment, both IL-17+CD4- (predominantly CD8+) and IL-17+CD4+ T cells were significantly enhanced in the SF compared to the PB of patients with PsA (P = 0.0003 and P = 0.002, respectively; n = 21), whereas in patients with RA, only IL-17+CD4+ T cells were increased in the SF compared to the PB (P = 0.008; n = 14). The frequency of IL-17+CD4- T cells in PsA SF was positively correlated with the CRP level (r = 0.52, P = 0.01), ESR (r = 0.59, P = 0.004), and DAS28 (r = 0.52, P = 0.01), and was increased in patients with erosive disease (P < 0.05). In addition, the frequency of IL-17+CD4- T cells positively correlated with the PDUS score, a marker for active synovitis (r = 0.49, P = 0.04). CONCLUSION: These results show, for the first time, that the PsA joint, but not the RA joint, is enriched for IL-17+CD8+ T cells. Moreover, the findings reveal that the levels of this T cell subset are correlated with disease activity measures and the radiographic erosion status after 2 years, suggesting a previously unrecognized contribution of these cells to the pathogenesis of PsA.


Assuntos
Artrite Psoriásica/metabolismo , Artrite Psoriásica/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Progressão da Doença , Interleucina-17/metabolismo , Índice de Gravidade de Doença , Adulto , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Contagem de Células , Proliferação de Células , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Articulações/diagnóstico por imagem , Articulações/metabolismo , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Ultrassonografia Doppler
6.
Eur J Immunol ; 43(8): 2043-54, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23677517

RESUMO

Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are "plastic", and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL-1ß, but not IL-6. "IL-17 potential" is restricted to population III (CD4(+) CD25(hi) CD127(lo) CD45RA(-) ) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17. Finally, we show that CD161(+) population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites. As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary.


Assuntos
Interleucina-17/biossíntese , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto , Idoso , Antígenos CD4/biossíntese , Células Cultivadas , Feminino , Fatores de Transcrição Forkhead/biossíntese , Humanos , Interleucina-1beta/metabolismo , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Interleucina-6/metabolismo , Subunidade alfa de Receptor de Interleucina-7/biossíntese , Antígenos Comuns de Leucócito/biossíntese , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Fator de Transcrição STAT3/genética
7.
Arthritis Rheum ; 65(3): 627-38, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23280063

RESUMO

OBJECTIVE: Despite the high frequency of CD4+ T cells with a regulatory phenotype (CD25+CD127(low) FoxP3+) in the joints of patients with rheumatoid arthritis (RA), inflammation persists. One possible explanation is that human Treg cells are converted into proinflammatory interleukin-17 (IL-17)-producing cells by inflammatory mediators and thereby lose their suppressive function. The aim of this study was to investigate whether activated monocytes, which are potent producers of inflammatory cytokines and are abundantly present in the rheumatic joint, induce proinflammatory cytokine expression in human Treg cells and impair their regulatory function. METHODS: The presence and phenotype of CD4+CD45RO+CD25+CD127(low) T cells (memory Treg cells) and CD14+ monocytes in the peripheral blood (PB) and synovial fluid (SF) of patients with RA were investigated by flow cytometry. Memory Treg cells obtained from healthy control subjects underwent fluorescence-activated cell sorting and then were cocultured with autologous activated monocytes and stimulated with anti-CD3 monoclonal antibodies. Intracellular cytokine expression, phenotype, and function of cells were determined by flow cytometry, enzyme-linked immunosorbent assay, and proliferation assays. RESULTS: In patients with RA, the frequencies of CD4+CD45RO+CD25+CD127(low) Treg cells and activated CD14+ monocytes were higher in SF compared with PB. In vitro-activated monocytes induced an increase in the percentage of IL-17-positive, interferon-γ (IFNγ)-positive, and tumor necrosis factor α (TNFα)-positive Treg cells as well as IL-10-positive Treg cells. The observed increase in IL-17-positive and IFNγ-positive Treg cells was driven by monocyte-derived IL-1ß, IL-6, and TNFα and was mediated by both CD14+CD16- and CD14+CD16+ monocyte subsets. Despite enhanced cytokine expression, cells maintained their CD25+FoxP3+CD39+ Treg cell phenotype and showed an enhanced capacity to suppress T cell proliferation and IL-17 production. CONCLUSION: Treg cells exposed to a proinflammatory environment show increased cytokine expression as well as enhanced suppressive activity.


Assuntos
Artrite Reumatoide/imunologia , Citocinas/metabolismo , Tolerância Imunológica/imunologia , Memória Imunológica/imunologia , Monócitos/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Artrite Reumatoide/patologia , Antígenos CD4/metabolismo , Comunicação Celular/imunologia , Células Cultivadas , Técnicas de Cocultura , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Imunofenotipagem , Interleucina-17/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-6/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/metabolismo , Receptores de IgG/metabolismo , Membrana Sinovial/citologia , Membrana Sinovial/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
J Autoimmun ; 38(1): 29-38, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22197557

RESUMO

Conclusive resolution of an immune response is critical for the prevention of autoimmunity and chronic inflammation. We report that following co-culture with autologous CD4+CD25- responder T cells, human CD14+ monocytes and monocyte-derived macrophages become activated but also significantly more prone to apoptosis than monocytes/macrophages cultured alone. In contrast, in the presence of CD4+CD25+ regulatory T cells (Tregs), monocytes and macrophages survive whilst adopting an anti-inflammatory phenotype. The induction of monocyte death requires responder T cell activation and cell-contact between responder T cells and monocytes. We demonstrate a critical role for FAS/FAS-L ligation in responder T cell-induced monocyte killing since responder T cells, but not Tregs, upregulate FAS-ligand (FAS-L) mRNA, and induce FAS expression on monocytes. Furthermore, responder T cell-induced monocyte apoptosis is blocked by neutralising FAS/FAS-L interaction, and is not observed when monocytes from an autoimmune lymphoproliferative syndrome (ALPS) patient with complete FAS-deficiency are used as target cells. Finally, we show that responder T cell-induced killing of monocytes is impaired in patients with active rheumatoid arthritis (RA). Our data suggest that resolution of inflammation in the course of a healthy immune response is aided by the unperturbed killing of monocytes with inflammatory potential by responder T cells and the induction of longer-lived, Treg-induced, anti-inflammatory monocytes.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteína Ligante Fas/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Linfócitos T Reguladores/imunologia , Receptor fas/imunologia , Apoptose/imunologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Técnicas de Cocultura , Citotoxicidade Imunológica/imunologia , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Citometria de Fluxo , Expressão Gênica , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
11.
Pediatr Blood Cancer ; 52(2): 215-7, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18855905

RESUMO

AIMS: The aims of this study were to review the presenting features, treatment and outcome for Malaysian children with retinoblastoma currently. SUBJECTS AND METHODS: This was a prospective study, conducted at the General Hospital Kuala Lumpur from August 2001 until October 2007. Clinical data were collected at presentation and follow-up. RESULTS: One hundred five children were diagnosed to have retinoblastoma. There were 55 males and 50 females, ranging in age from 1 month to 14 years (median 20 months). Seventy-six children were Malay in ethnic origin (73%), 14 Chinese (13%), 12 Indian (11%), and other races (3%). Sixty-four children presented with leukocoria (61%), followed by 23 with proptosis (22%), 13 with squint (12%), and 3 with orbital cellulitis (3%). Thirty-three children (31%) deferred treatment for 6 months or more. Overall, 56 children had extraocular disease (55%), 52 at presentation, 4 later. Seventy-one children (68%) underwent primary enucleation, 76 received chemotherapy (72%), and 23 radiotherapy (22%). Fifty-seven children are alive (54%), of whom 3 are blind (5%). Twenty-seven children were lost to follow-up (26%) and 21 have died (20%). CONCLUSION: Retinoblastoma in Malaysia is still characterized by predominantly extraocular disease due to late presentation and high rates of abandonment.


Assuntos
Retinoblastoma/patologia , Adolescente , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Etnicidade , Exoftalmia/etiologia , Enucleação Ocular , Feminino , Seguimentos , Humanos , Lactente , Malásia/epidemiologia , Masculino , Celulite Orbitária/etiologia , Estudos Prospectivos , Radioterapia , Retinoblastoma/epidemiologia , Retinoblastoma/mortalidade , Retinoblastoma/terapia , Estrabismo/etiologia , Taxa de Sobrevida
12.
Artigo em Inglês | MEDLINE | ID: mdl-19058612

RESUMO

The aims of this study were to determine the types of cancers and hematological disorders in patients attending a pediatric hematology-oncology clinic. This was a prospective study at the Pediatric Institute, General Hospital Kuala Lumpur, Malaysia from June 2005-November 2006. During the 18-month study, 803 patients attended the clinic, 730 had oncological problems and 73 had hematological problems. The age range was from 2 months to 28 years (median 6 years). The patients were Malay (66%), Chinese (23%), Indian (10%) and other races (1%). Of the oncological patients, 51% had either leukemia (n=293) or lymphoma (n=77). The other most common diagnoses were retinoblastoma, followed by Wilm's tumor and germ cell tumors. Six patients (0.8%) developed a second malignant neoplasm. Of the hematological patients, 60% had platelet disorders, most commonly chronic immune thrombocytopenic purpura. Twenty-four per cent had bone marrow failure and 16% had red cell disorders.


Assuntos
Neoplasias Hematológicas/epidemiologia , Neoplasias/epidemiologia , Adolescente , Adulto , Institutos de Câncer , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Malásia/epidemiologia , Masculino , Estudos Prospectivos , Adulto Jovem
14.
J Palliat Med ; 11(10): 1301-3, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19115887

RESUMO

AIMS: The aims of this study were to review the deaths of Malaysian pediatric oncology patients in order to determine the major causes and the proportion of patients who received palliative care. SUBJECTS AND METHODS: This was a retrospective review from 2001-2007 of deaths at the Pediatric Institute, General Hospital Kuala Lumpur. Clinical data such as age, gender, disease, cause, and place of death were collected. The patients were divided into two groups: those who received palliative care and those who received curative treatment. RESULTS: Two hundred forty-seven patients were included. There were 148 males and 99 females. The age ranged from 2 months to 22 years (median, 4 years). One hundred thirty cases (53%) were still in the curative phase of treatment at the time of death. The most common cause of death was septicemia (62%), followed by hemorrhage (18%) and underlying cancer (14%). One hundred seventeen cases (47%) were in the palliative phase at the time of death. All palliative care deaths occurred in the oncology ward with one exception. CONCLUSION: Nearly half of all inpatient pediatric cancer deaths were palliative in nature. Septicemia and hemorrhage were the major causes of death in the others.


Assuntos
Neoplasias/mortalidade , Cuidados Paliativos/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Adulto Jovem
15.
J Pediatr Hematol Oncol ; 29(1): 2-4, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17230058

RESUMO

In the last decade, chemotherapy in combination with focal therapy (chemoreduction) has been increasingly used in intraocular retinoblastoma to avoid enucleation and radiotherapy. The aim of this study was to assess the feasibility and outcome of chemoreduction in Malaysian children with retinoblastoma. This was a prospective study from August 2001 to January 2006. Twenty children (25 eyes) were given 4 cycles of chemoreduction, after which the response was assessed. Fourteen eyes showed a complete response, 10 eyes showed a partial response, and 1 eye had progressive disease. Twelve eyes developed progressive disease later, 9 after an initial complete response and 3 after a partial response. Overall, progressive disease occurred in 52%. There were 2 treatment failures, in Reese-Elsworth groups 3 and 4. Both eyes required enucleation. One eye in group 5 required second line chemotherapy to achieve a complete response. No eyes were irradiated. Five children (25%) defaulted follow-up, one of whom returned with disseminated disease. In conclusion, 4 cycles of chemoreduction achieved a durable complete response in only 12% of eyes. Chemoreduction is feasible in Malaysia but requires good patient compliance and close follow-up.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Retina/terapia , Retinoblastoma/terapia , Carboplatina/administração & dosagem , Terapia Combinada , Crioterapia , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Lactente , Terapia a Laser , Malásia , Masculino , Estudos Prospectivos , Retinoblastoma/mortalidade , Vincristina/administração & dosagem
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