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1.
Clin Cancer Res ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199490

RESUMO

PURPOSE: Vascular endothelial growth factor (VEGF) is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase 2 study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma. EXPERIMENTAL DESIGN: Eighty bevacizumab-naive, recurrent glioblastoma patients randomized to pembrolizumab with bevacizumab (cohort A, n=50) or pembrolizumab monotherapy (cohort B, n=30). The primary endpoint was six-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor PD-L1 expression, TIL density, immune activation gene expression signature and plasma cytokines. The Neurologic Assessment in Neuro-Oncology (NANO) scale was used to prospectively assess neurologic function. RESULTS: Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% (95% CI: 16.3, 41.5), median OS was 8.8 months (95% CI: 7.7, 14.2), ORR was 20% and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI: 1.7, 25.4), median OS was 10.3 months (95% CI: 8.5, 12.5) and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased post-therapy plasma VEGF (cohort A) and mutant IDH1, unmethylated MGMT and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment. CONCLUSIONS: Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in GBM immunotherapy trials.

2.
J Immunother Cancer ; 8(2)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33127658

RESUMO

BACKGROUND: Programmed cell death protein 1 (PD-1) and CTLA4 combination blockade enhances clinical efficacy in melanoma compared with targeting either checkpoint alone; however, clinical response improvement is coupled with increased risk of developing immune-related adverse events (irAE). Delineating the mechanisms of checkpoint blockade-mediated irAE has been hampered by the lack of animal models that replicate these clinical events. METHODS: We have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody. RESULTS: Sustained treatment with Fc-effector, but not Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks resulted in enterocolitis. Moreover, combining Fc-null or Fc-mutant CTLA4 antagonists with PD-1 blockade results in potent antitumor combination efficacy indicating that Fc-effector function is not required for combination benefit. CONCLUSION: These data suggest that using CTLA4 antagonists with no Fc-effector function can mitigate gut inflammation associated with anti-CTLA4 antibody therapy yet retain potent antitumor activity in combination with PD-1 blockade.

3.
Sci Immunol ; 5(46)2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332067

RESUMO

Signal transducer and activator of transcription (STAT) proteins have critical roles in the development and function of immune cells. STAT signaling is often dysregulated in patients with inflammatory bowel disease (IBD), suggesting the importance of STAT regulation during the disease process. Moreover, genetic alterations in STAT3 and STAT5 (e.g., deletions, mutations, and single-nucleotide polymorphisms) are associated with an increased risk for IBD. In this study, we elucidated the precise roles of STAT5 signaling in group 3 innate lymphoid cells (ILC3s), a key subset of immune cells involved in the maintenance of gut barrier integrity. We show that mice lacking either STAT5a or STAT5b are more susceptible to Citrobacter rodentium-mediated colitis and that interleukin-2 (IL-2)- and IL-23-induced STAT5 drives IL-22 production in both mouse and human colonic lamina propria ILC3s. Mechanistically, IL-23 induces a STAT3-STAT5 complex that binds IL-22 promoter DNA elements in ILC3s. Our data suggest that STAT5a/b signaling in ILC3s maintains gut epithelial integrity during pathogen-induced intestinal disease.

4.
J Clin Oncol ; 38(1): 20-28, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532724

RESUMO

PURPOSE: To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS). PATIENTS AND METHODS: CITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria. RESULTS: Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature. CONCLUSION: Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Micose Fungoide/tratamento farmacológico , Síndrome de Sézary/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Micose Fungoide/imunologia , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Estadiamento de Neoplasias , Recidiva , Síndrome de Sézary/imunologia , Síndrome de Sézary/metabolismo , Síndrome de Sézary/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
5.
Nat Med ; 25(3): 454-461, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804515

RESUMO

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Procedimentos Cirúrgicos Dermatológicos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos , Quimioterapia Adjuvante , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Neoplasias Cutâneas/patologia , Transcriptoma , Evasão Tumoral
6.
J Immunother Cancer ; 6(1): 99, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30285852

RESUMO

BACKGROUND: We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified. METHODS: Pretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1. RESULTS: Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 µm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1. CONCLUSIONS: While the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Carcinoma de Célula de Merkel/patologia , Feminino , Humanos , Masculino
7.
Immunity ; 49(2): 342-352.e5, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30097293

RESUMO

Interleukin-22 (IL-22)-producing group 3 innate lymphoid cells (ILC3) maintains gut homeostasis but can also promote inflammatory bowel disease (IBD). The regulation of ILC3-dependent colitis remains to be elucidated. Here we show that Foxp3+ regulatory T cells (Treg cells) prevented ILC3-mediated colitis in an IL-10-independent manner. Treg cells inhibited IL-23 and IL-1ß production from intestinal-resident CX3CR1+ macrophages but not CD103+ dendritic cells. Moreover, Treg cells restrained ILC3 production of IL-22 through suppression of CX3CR1+ macrophage production of IL-23 and IL-1ß. This suppression was contact dependent and was mediated by latent activation gene-3 (LAG-3)-an immune checkpoint receptor-expressed on Treg cells. Engagement of LAG-3 on MHC class II drove profound immunosuppression of CX3CR1+ tissue-resident macrophages. Our study reveals that the health of the intestinal mucosa is maintained by an axis driven by Treg cells communication with resident macrophages that withhold inflammatory stimuli required for ILC3 function.


Assuntos
Antígenos CD/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Colite/imunologia , Colite/patologia , Subunidade p19 da Interleucina-23/imunologia , Mucosa Intestinal/patologia , Macrófagos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Fatores de Transcrição Forkhead/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Interleucina-10/imunologia , Interleucina-1beta/imunologia , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/transplante
8.
J Thorac Oncol ; 13(8): 1204-1212, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29702286

RESUMO

INTRODUCTION: Thymic epithelial tumors (TETs) including thymoma and thymic carcinoma are rare tumors with little data available to guide treatment. Immunotherapy with checkpoint blockade has shown promising activity, but data regarding the expression patterns and prognostic implications of programmed death 1 (PD-1) and its ligand (PD-L1) in TETs have yielded conflicting results. Intratumoral heterogeneity of PD-1/L1 expression has been shown in other cancers, but has not been described in the TET literature. METHODS: We performed a retrospective single-center review of 35 patients with resected TET. PD-1/L1 expression was assessed by immunohistochemistry using PD-1 clone: NAT105 and PD-L1 clone: 22C3. Tumor samples from 35 patients were evaluated including 32 patients with thymoma and 3 patients with thymic carcinoma. RESULTS: PD-L1 expression was detected in 83% (29 of 35) tumor samples, including 100% (3 of 3) of thymic carcinoma patients and 81% (26 of 32) of thymoma patients. PD-1 expression was detected in 77% (27 of 35), including 33% (1 of 3) of thymic carcinoma patients and 81% (26 of 32) thymoma patients. High PD-1 expression was associated with lower grade tumors. Unlike prior studies, PD-L1 expression was not associated with higher grade tumors or higher stage. Neither PD-L1 nor PD-1 expression was significantly associated with survival. Three patients with thymoma had multiple tumor sections evaluated for expression of PD-1/L1, with differing expression patterns of both PD-L1 and PD-1 observed in two patients. CONCLUSIONS: This study confirms high expression of PD-L1 and PD-1 in TET and shows for the first time intratumoral heterogeneity of PD-L1 and PD-1 in thymoma patients.


Assuntos
Antígeno B7-H1/biossíntese , Neoplasias Epiteliais e Glandulares/metabolismo , Receptor de Morte Celular Programada 1/biossíntese , Timoma/metabolismo , Neoplasias do Timo/metabolismo , Adulto , Idoso , Antígeno B7-H1/imunologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/imunologia , Neoplasias Epiteliais e Glandulares/patologia , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Timoma/imunologia , Timoma/patologia , Neoplasias do Timo/imunologia , Neoplasias do Timo/patologia
9.
Mod Pathol ; 30(11): 1516-1526, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28752839

RESUMO

The amplification of chromosome 9p24.1 encoding PD-L1, PD-L2, and JAK2 has been reported in multiple types of cancer and is associated with poor outcome, upregulation of PD-L1, and activation of the JAK/STAT pathway. We have developed a novel fluorescence in situ hybridization assay which combines 3 probes mapping to 9p24.1 with a commercial chromosome 9 centromere (CEN9) probe for detection of the JAK2/9p24.1 amplification. JAK2 fluorescence in situ hybridization was compared with array-based comparative genomic hybridization in 34 samples of triple negative breast cancer tumor. By array-based comparative genomic hybridization, 15 had 9p24.1 copy-number gain (log2ratio>0.3) and 19 were classified as non-gain (log2ratio≤0.3). Copy-number gain was defined as JAK2/CEN9 ratio ≥1.1 or average JAK2 signals≥3.0. Twelve of 15 samples with copy-number gain by array-based comparative genomic hybridization were also detected by fluorescence in situ hybridization. Eighteen of 19 samples classified as copy-number non-gain by array-based comparative genomic hybridization were concordant by array-based comparative genomic hybridization. The sensitivity and specificity of the fluorescence in situ hybridization assay was 80% and 95%, respectively (P=0.02). The sample with the highest level of amplification by array-based comparative genomic hybridization (log2ratio=3.6) also scored highest by fluorescence in situ hybridization (ratio=8.2). There was a correlation between the expression of JAK2 and amplification status (Mean 633 vs 393, P=0.02), and there was a trend of association with PD-L1 RNA expression (Mean 46 vs 22, P=0.11). No significant association was observed between PD-L1 immunohistochemistry expression and copy-number gain status. In summary, the novel array-based comparative genomic hybridization assay for detection of chromosome 9p24.1 strongly correlates with the detection of copy-number gain by array-based comparative genomic hybridization. In triple negative breast cancer, this biomarker may identify a relevant subset of patients for targeted molecular therapies.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/análise , Hibridização in Situ Fluorescente/métodos , Janus Quinase 2/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Amplificação de Genes , Humanos , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/diagnóstico
10.
Clin Cancer Res ; 23(12): 3158-3167, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28619999

RESUMO

Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to PD-1-directed immunotherapy. However, PD-L1-negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated.Experimental Design: PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab.Results: PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (P = 0.0012-<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2-positive than PD-L2-negative patients.Conclusions: Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients. Clin Cancer Res; 23(12); 3158-67. ©2017 AACR.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Imunoterapia , Proteína 2 Ligante de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Ligante de Morte Celular Programada 1/genética , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço
11.
Cancer ; 123(17): 3291-3304, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28463396

RESUMO

BACKGROUND: Patients with metastatic sarcomas have poor outcomes and although the disease may be amenable to immunotherapies, information regarding the immunologic profiles of soft tissue sarcoma (STS) subtypes is limited. METHODS: The authors identified patients with the common STS subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), well-differentiated/dedifferentiated liposarcoma, and myxoid/round cell liposarcoma. Gene expression, immunohistochemistry for programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1), and T-cell receptor Vß gene sequencing were performed on formalin-fixed, paraffin-embedded tumors from 81 patients. Differences in liposarcoma subsets also were evaluated. RESULTS: UPS and leiomyosarcoma had high expression levels of genes related to antigen presentation and T-cell infiltration. UPS were found to have higher levels of PD-L1 (P≤.001) and PD-1 (P≤.05) on immunohistochemistry and had the highest T-cell infiltration based on T-cell receptor sequencing, significantly more than SS, which had the lowest (P≤.05). T-cell infiltrates in UPS also were more oligoclonal compared with SS and liposarcoma (P≤.05). A model adjusted for STS histologic subtype found that for all sarcomas, T-cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression levels (P≤.01). CONCLUSIONS: In the current study, the authors provide the most detailed overview of the immune microenvironment in sarcoma subtypes to date. UPS, which is a more highly mutated STS subtype, provokes a substantial immune response, suggesting that it may be well suited to treatment with immune checkpoint inhibitors. The SS and liposarcoma subsets are less mutated but do express immunogenic self-antigens, and therefore strategies to improve antigen presentation and T-cell infiltration may allow for successful immunotherapy in patients with these diagnoses. Cancer 2017;123:3291-304. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.


Assuntos
Receptor de Morte Celular Programada 1/genética , Sarcoma/genética , Sarcoma/mortalidade , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/mortalidade , Linfócitos T/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biópsia por Agulha , Células Clonais , Análise por Conglomerados , Estudos de Coortes , Terapia Combinada , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Sarcoma/patologia , Sarcoma/terapia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia , Análise de Sobrevida , Linfócitos T/imunologia , Adulto Jovem
12.
Arch Pathol Lab Med ; 140(11): 1259-1266, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27788043

RESUMO

CONTEXT: - With the abundance of therapeutics targeted against programmed death receptor-1 and its ligand (PD-L1) that are currently approved or in clinical development, there is interest in identifying those patients most likely to respond to these drugs. Expression of PD-L1 may be an indicator of an initial and robust inflammatory response to the presence of tumor cells. Therefore, tumors that express PD-L1 may be the most likely to respond to therapies that interrupt the negative feedback mechanism that leads to PD-L1 upregulation. OBJECTIVE: - To develop a prototype immunohistochemistry assay using the anti-PD-L1 antibody clone 22C3. DESIGN: - The assay was developed and optimized using commercially available reagents and archival tumor-bank tissue. RESULTS: - The optimized immunohistochemistry method had high precision and reproducibility. Using the prototype assay in 142 non-small cell lung cancer and 79 melanoma archival tumor-bank tissue samples, PD-L1 staining was observed at the plasma membrane of nucleated tumor and nontumor cells and, in some cases, as a distinct lichenoid pattern at the tumor-stroma border. Using a preliminary scoring method, 56% (80 of 142) of non-small cell lung cancer and 53% (42 of 79) of melanoma samples were defined as PD-L1+ based on a modified H-score of 1 or more or the presence of a distinctive staining pattern at the tumor-stroma interface. CONCLUSIONS: - The immunohistochemistry assay using the anti-PD-L1 antibody 22C3 merits further investigation in clinical trials and prevalence assessments to further understand the prognostic and predictive value of PD-L1 expression in cancer.


Assuntos
Anticorpos Monoclonais/metabolismo , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Melanoma/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Especificidade de Anticorpos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Biomarcadores Tumorais/metabolismo , Células CHO , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Membrana Celular/metabolismo , Membrana Celular/patologia , Células Clonais , Cricetulus , Humanos , Imuno-Histoquímica , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Melanoma/diagnóstico , Melanoma/patologia , Camundongos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Bancos de Tecidos
13.
N Engl J Med ; 374(26): 2542-52, 2016 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-27093365

RESUMO

BACKGROUND: Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. METHODS: In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing. RESULTS: A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. CONCLUSIONS: In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Célula de Merkel/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma de Célula de Merkel/patologia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Recidiva , Neoplasias Cutâneas/patologia
14.
PLoS One ; 11(3): e0150968, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26992000

RESUMO

Eosinophilic esophagitis (EoE) is a chronic Th2 and food antigen-mediated disease characterized by esophageal eosinophilic infiltration. Thymic stromal lymphopoetin (TSLP), an epithelial derived cytokine which bridges innate and Th2-type adaptive immune responses in other allergic conditions, is overexpressed in esophageal biopsies of EoE subjects. However, the triggers of TSLP expression in the esophageal epithelium are unknown. The objective of the current study was to characterize TSLP expression in human esophageal epithelium in EoE in vivo and to determine the role of food antigens upon epithelial TSLP expression in vitro. Using immunohistochemistry (IHC), we localized TSLP in esophageal biopsies of active EoE (≥15 eos/hpf), inactive EoE (<15 eos/hpf) and non-EoE control subjects, and found that TSLP expression was restricted to the differentiated suprabasal layer of the epithelium in actively inflamed EoE biopsies. Consistent with these results in vivo, inducible TSLP protein secretion was higher in CaCl2 differentiated telomerase-immortalized esophageal epithelial cells (EPC2-hTERT) compared to undifferentiated cells of the basal phenotype, following stimulation with the TLR3 ligand poly(I:C). To determine whether food antigens could directly induce epithelial TSLP secretion, differentiated and undifferentiated primary esophageal epithelial cells from EoE and non-EoE subjects were challenged with food antigens clinically relevant to EoE: Chicken egg ovalbumin (OVA), wheat, and milk proteins beta-lactoglobulin (blg) and beta-casein. Food antigens failed to induce TSLP secretion by undifferentiated cells; in contrast, only OVA induced TSLP secretion in differentiated epithelial cells from both EoE and control cell lines, an effect abolished by budesonide and NF-κb inhibition. Together, our study shows that specific food antigens can trigger innate immune mediated esophageal TSLP secretion, suggesting that esophageal epithelial cells at the barrier surface may play a significant role in the pathogenesis of EoE by regulating TSLP expression.


Assuntos
Diferenciação Celular , Citocinas/metabolismo , Esofagite Eosinofílica/metabolismo , Células Epiteliais/metabolismo , Esôfago/metabolismo , Antígenos/farmacologia , Budesonida/farmacologia , Linhagem Celular Transformada , Citocinas/imunologia , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Esôfago/imunologia , Esôfago/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , NF-kappa B/antagonistas & inibidores , NF-kappa B/imunologia , NF-kappa B/metabolismo , Poli I-C/farmacologia , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/imunologia , Receptor 3 Toll-Like/metabolismo
15.
Clin Cancer Res ; 22(15): 3791-800, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-26968202

RESUMO

PURPOSE: "In situ vaccination" using immunogene therapy has the ability to induce polyclonal antitumor responses directed by the patient's immune system. EXPERIMENTAL DESIGN: Patients with unresectable malignant pleural mesothelioma (MPM) received two intrapleural doses of a replication-defective adenoviral vector containing the human IFNα2b gene (Ad.IFN) concomitant with a 14-day course of celecoxib followed by chemotherapy. Primary outcomes were safety, toxicity, and objective response rate; secondary outcomes included progression-free and overall survival. Biocorrelates on blood and tumor were measured. RESULTS: Forty subjects were treated: 18 received first-line pemetrexed-based chemotherapy, 22 received second-line chemotherapy with pemetrexed (n = 7) or gemcitabine (n = 15). Treatment was generally well tolerated. The overall response rate was 25%, and the disease control rate was 88%. Median overall survival (MOS) for all patients with epithelial histology was 21 months versus 7 months for patients with nonepithelial histology. MOS in the first-line cohort was 12.5 months, whereas MOS for the second-line cohort was 21.5 months, with 32% of patients alive at 2 years. No biologic parameters were found to correlate with response, including numbers of activated blood T cells or NK cells, regulatory T cells in blood, peak levels of IFNα in blood or pleural fluid, induction of antitumor antibodies, nor an immune-gene signature in pretreatment biopsies. CONCLUSIONS: The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM. OS rate was significantly higher than historical controls in the second-line group. Results of this study support proceeding with a multicenter randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone. Clin Cancer Res; 22(15); 3791-800. ©2016 AACR.


Assuntos
Adenoviridae/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Genética , Vetores Genéticos/genética , Imunoterapia , Interferon-alfa/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mesotelioma/genética , Mesotelioma/terapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Feminino , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Mesotelioma/diagnóstico , Mesotelioma/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do Tratamento
16.
Clin Cancer Res ; 22(2): 470-8, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26373575

RESUMO

PURPOSE: More effective therapy is needed for intrahepatic cholangiocarcinoma (ICC). The encouraging clinical results obtained with checkpoint molecule-specific monoclonal antibodies (mAb) have prompted us to investigate whether this type of immunotherapy may be applicable to ICC. The aims of this study were to determine whether (i) patients mount a T-cell immune response to their ICC, (ii) checkpoint molecules are expressed on both T cells and tumor cells, and (iii) tumor cells are susceptible to recognition by cognate T cells. EXPERIMENTAL DESIGN: Twenty-seven ICC tumors were analyzed for (i) lymphocyte infiltrate, (ii) HLA class I and HLA class II expression, and (iii) PD-1 and PD-L1 expression by T cells and ICC cells, respectively. The results of this analysis were correlated with the clinicopathologic characteristics of the patients investigated. RESULTS: Lymphocyte infiltrates were identified in all tumors. PD-L1 expression and HLA class I antigen expression by ICC cells was observed in 8 and 11, respectively, of the 27 tumors analyzed. HLA class I antigen expression correlated with CD8(+) T-cell infiltrate. Furthermore, positive HLA class I antigen expression in combination with negative/rare PD-L1 expression was associated with favorable clinical course of the disease. CONCLUSIONS: ICC patients are likely to mount a T-cell immune response against their own tumors. Defects in HLA class I antigen expression in combination with PD-L1 expression by ICC cells provide them with an immune escape mechanism. This mechanism justifies the implementation of immunotherapy with checkpoint molecule-specific mAbs in patients bearing ICC tumors without defects in HLA class I antigen expression.


Assuntos
Antígeno B7-H1/imunologia , Neoplasias dos Ductos Biliares/imunologia , Colangiocarcinoma/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Ductos Biliares Intra-Hepáticos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade
17.
Clin Cancer Res ; 22(3): 582-95, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26405194

RESUMO

PURPOSE: Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice. EXPERIMENTAL DESIGN AND RESULTS: Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment. CONCLUSIONS: This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment.


Assuntos
Antineoplásicos/farmacologia , Meduloblastoma/imunologia , Meduloblastoma/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Biomarcadores , Modelos Animais de Doenças , Imunofenotipagem , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Meduloblastoma/tratamento farmacológico , Meduloblastoma/genética , Meduloblastoma/mortalidade , Camundongos , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Receptores Patched , Fenótipo , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Microambiente Tumoral/genética
18.
J Transl Med ; 13: 319, 2015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26419843

RESUMO

BACKGROUND: Characterization of PD-L1 expression within clinically/radiologically negative but microscopically tumor positive sentinel lymph nodes (SLN) is important to our understanding of the relevance of this immune checkpoint pathway for adjuvant therapy. METHODS: Patients included had primary cutaneous melanoma, Breslow thickness of 2.01-4.0 or >4 mm with or without tumor ulceration (T3a, T3b, T4a, T4b). All patients had microscopically tumor positive SLN. Hematoxylin and eosin (H&E) staining was performed, followed by PD-L1 immunohistochemical (IHC) staining using a preliminary IHC assay with anti-PD-L1 antibody clone 22C3. The slides were separately evaluated by two pathologists (JY and CG). Samples containing metastatic melanoma lesions were scored separately for PD-L1 expression in intratumoral and peritumoral locations, by utilizing two scoring methods. RESULTS: Twenty-four patients where metastatic melanoma presence in the SLN was confirmed by H&E review of the cut sections were included in the final analysis of PD-L1 expression. SLN tumor size ranged from 1 to 2 mm. For three patients, the melanin content was too high to confidently assign a PD-L1 score. For the remaining 21 patients, all had some evidence of either intratumoral or peritumoral PD-L1 expression. The frequency of intratumoral tumor-associated PD-L1 expression was: 0 % of tumor cells (3 pts, 14 %); <1 % (5 pts, 24 %); 1-10 % (6 pts, 29 %) and >10 % (7 pts, 33 %). CONCLUSIONS: Tumor-associated PD-L1 expression is readily detectable within melanoma micrometastases in the SLN of the majority of patients. These results support the testing of a therapeutic role for PD1/PD-L1 inhibition in the adjuvant setting, targeting melanoma micrometastases.


Assuntos
Antígeno B7-H1/metabolismo , Metástase Linfática/diagnóstico , Melanoma/metabolismo , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/metabolismo , Adolescente , Adulto , Idoso , Quimioterapia Adjuvante , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema Imunitário , Imuno-Histoquímica , Metástase Linfática/patologia , Masculino , Melanoma/terapia , Pessoa de Meia-Idade , Metástase Neoplásica , Micrometástase de Neoplasia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/terapia , Adulto Jovem
19.
Mod Pathol ; 28(12): 1535-44, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26403784

RESUMO

Melanoma patients with sentinel lymph node metastases have variable 5-year survival rates (39-70%). The prognostic significance of tumor-infiltrating lymphocytes in sentinel lymph node metastases from such patients is currently unknown. Anti-PD-1/PD-L1 inhibitors have significantly improved clinical outcome in unresectable AJCC stage IIIC/IV metastatic melanoma patients, and are being trialed in the adjuvant setting in advanced stage disease, however, their role in early stage (sentinel lymph node positive) metastatic disease remains unclear. The aims of this study were to characterize, in sentinel lymph nodes, the subpopulations of lymphocytes that interact with metastatic melanoma cells and analyze their associations with outcome, and to determine tumor PD-L1 expression as this may provide a rational scientific basis for the administration of adjuvant anti-PD-1/PD-L1 inhibitors in sentinel lymph node positive metastatic melanoma patients. Sentinel lymph nodes containing metastatic melanoma from 60 treatment-naive patients were analyzed for CD3, CD4, CD8, FOXP3, PD-1, and PD-L1 using immunohistochemistry on serial sections. The results were correlated with clinicopathologic features and outcome. Positive correlations between recurrence-free/overall survival with the number of CD3+ tumor-infiltrating lymphocytes (hazard ratio=0.36 (0.17-0.76), P=0.005; hazard ratio=0.29 (0.14-0.61), P=0.0005, respectively), the number of CD4+ tumor-infiltrating lymphocytes (hazard ratio=0.34 (0.15-0.77), P=0.007; hazard ratio=0.32 (0.14-0.74), P=0.005, respectively), and the number of CD8+ tumor-infiltrating lymphocytes (hazard ratio =0.42 (0.21-0.85), P=0.013; hazard ratio =0.32 (0.19-0.78), P=0.006, respectively) were observed. There was also a negative correlation with the number of peritumoral PD-1+ lymphocytes (hazard ratio=2.67 (1.17-6.13), P=0.016; hazard ratio=2.74 (1.14-6.76), P=0.019, respectively). Tumoral PD-L1 expression was present in 26 cases (43%) but did not correlate with outcome. The findings suggest that T-cell subsets in sentinel lymph node metastases can predict melanoma patient outcome. In addition, the relatively high number of PD-L1 positive sentinel lymph node melanoma metastases provides a rationale for anti-PD-1 therapy trials in sentinel lymph node positive melanoma patients, particularly those with peritumoral PD-1+ lymphocytes.


Assuntos
Antígeno B7-H1/biossíntese , Metástase Linfática/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática/patologia , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/biossíntese , Modelos de Riscos Proporcionais , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Adulto Jovem
20.
Lung Cancer ; 89(2): 181-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26024796

RESUMO

OBJECTIVES: Immune checkpoint blockade using inhibitors of programmed death-1 have shown promise in early phase clinical trials in NSCLC and programmed death-ligand 1 (PD-L1) tumoral expression could potentially be a useful predictive marker. Data reporting the prevalence of PD-L1 expression in NSCLC and clinicopathologic associations is very limited. We sought to determine the frequency of PD-L1 expression in NSCLC and investigate associations with clinicopathologic features and patient outcome. MATERIALS AND METHODS: PD-L1 expression was analyzed using immunohistochemistry (Merck; clone 22C3) in 678 stages I-III NSCLC and 52 paired nodal metastases using tissue microarrays. Tumors with ≥50% cells showing positive membrane staining were considered to have high expression of PD-L1. RESULTS: PD-L1 expression of any intensity was identified in 32.8% of cases. High PD-L1 expression was found in 7.4% of NSCLC. Squamous cell carcinomas (8.1%) and large cell carcinomas (12.1%) showed high PD-L1 expression more commonly than adenocarcinomas (5.1%) but this was not statistically significant (p=0.072). High PD-L1 expression was associated with younger patient age and high tumor grade (p<0.05). There was no association with gender, tumor size, stage, nodal status, EGFR or KRAS mutation status. In multivariate analysis, patients with high PD-L1 expression had significantly longer overall survival (p<0.05). CONCLUSIONS: PD-L1 is expressed at high levels in a significant proportion of NSCLC and appears to be a favorable prognostic factor in early stage disease. As there are potential sampling limitations using tissue microarrays to assess heterogeneously expressed biomarkers, and as the results may differ in advanced stage disease, further studies are recommended.


Assuntos
Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Receptores ErbB/genética , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos
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