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1.
BMC Cancer ; 21(1): 239, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676425

RESUMO

BACKGROUND: Cancer-associated fibroblasts (CAFs) are some of the most abundant components of the tumour microenvironment. A recent study suggested that in some cancers, CAFs express programmed death ligand 1 (PD-L1), which can act as a prognostic marker. The aim of this study was to investigate the clinicopathological significance of CAF PD-L1 expression in patients with triple-negative breast cancer (TNBC) and to identify the most suitable primary antibody for immunostaining for CAF PD-L1. METHODS: Immunohistochemical staining (primary antibodies of 73-10, SP142, and E1L3N) and tissue microarrays were used to analyse the expression profiles of PD-L1 in CAF in 61 patients with TNBC who underwent surgery. Overall survival (OS) was compared based on CAF PD-L1 expression, and the risk factors for OS were analysed. The relationship between clinicopathological parameters and survival was also examined. RESULTS: Thirty-four (55.7%) patients were positive for CAF PD-L1 (73-10) expression. Compared with CAF PD-L1 negativity, there was a significant correlation between CAF PD-L1 positivity and better OS (p = 0.029). CAF PD-L1 expression, evaluated using SP-142 or E1L3N, did not correlate with OS. CAF PD-L1-positivity (73-10) correlated significantly with better prognosis in multivariate analyses (hazard ratio: 0.198; 95% confidence interval: 0.044-0.891; p = 0.035). CONCLUSIONS: CAF PD-L1 expression is a novel marker for a better prognosis of patients with TNBC, and the 73-10 assay may be suitable for immunostaining CAF PD-L1.


Assuntos
Fibroblastos Associados a Câncer/imunologia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias de Mama Triplo Negativas/mortalidade , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Antígeno B7-H1/metabolismo , Mama/imunologia , Mama/patologia , Mama/cirurgia , Fibroblastos Associados a Câncer/metabolismo , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
2.
Am J Surg Pathol ; 45(5): 701-707, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33739790

RESUMO

Suppression of the immune system is intimately linked to the development and progression of malignancy, and immune modulating treatment options have shown promise in a variety of tumor types, including some triple-negative breast cancers (TNBC). The most dramatic therapeutic success has been seen with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand, PD-L1. Difficulty remains, however, in appropriate patient selection for treatment, as many PD-L1-positive cancers fail to show durable responses to PD-1/PD-L1 inhibition. Checkpoint inhibitor targeting of the adaptive immune response relies on the presence of major histocompatibility complex (MHC) class I molecules on the tumor cell surface for tumor antigen presentation. MHC class I loss has been previously described in breast cancer and represents a putative mechanism of immunotherapeutic resistance in this tumor type. One hundred seventeen invasive primary breast carcinomas with a range of histologic subtypes were evaluated on tissue microarrays containing formalin-fixed paraffin-embedded tissue. Loss of MHC class I expression was common among breast cancers, with greater than half of cases demonstrating either subclonal or diffuse loss. Fifty-nine percent of TNBC demonstrated loss of MHC class I, including 46% of those meeting the Food and Drug Administration-approved threshold of 1% for tumor-associated immune cell PD-L1 expression. MHC class I loss was particularly common in the apocrine subtype of TNBC (78%). MHC class I's employment as a predictive biomarker should be considered, as its loss may represent a barrier to successful enhancement of the antitumor adaptive immune response by PD-1/PD-L1 inhibition.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Antígenos de Histocompatibilidade Classe I/análise , Receptor de Morte Celular Programada 1/análise , Neoplasias de Mama Triplo Negativas/imunologia , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/antagonistas & inibidores , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Seleção de Pacientes , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise Serial de Tecidos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral
3.
ACS Appl Mater Interfaces ; 13(7): 8026-8041, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33577301

RESUMO

Photodynamic therapy (PDT) is a promising strategy for cancer treatment. It can not only generate reactive oxygen species (ROS) to cause the chemical damage of tumor cells in the presence of enough oxygen but also promote the antitumor immunity of T cells through enhancing the production of interferon γ (IFN-γ). However, one phenomenon is ignored so far that the enhanced production of IFN-γ caused by PDT may significantly increase the expression of programmed death-ligand 1 (PD-L1) on the tumor cell membrane and thus could inhibit the immune killing effects of T cells. Herein, we report the construction of a composite by loading metformin (Met) and IR775 into a clinically usable liposome as a two-in-one nanoplatform (IR775@Met@Lip) to solve this problem. The IR775@Met@Lip could reverse tumor hypoxia to enhance ROS production to elicit more chemical damage. Besides, the overexpression of PD-L1 by PDT was also effectively down-regulated. These therapeutic benefits including decreased PD-L1 expression, alleviated T cell exhaustion, and reversed tumor hypoxia successfully suppressed both the primary and abscopal tumor growth in bladder and colon cancers, respectively. Combining with its excellent biocompatibility, our results indicate that this IR775@Met@Lip system has great potential to become a highly effective cancer therapy modality.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Imunoterapia , Metformina/farmacologia , Fotoquimioterapia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Antígeno B7-H1/análise , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Indóis/química , Indóis/farmacologia , Lipossomos/química , Lipossomos/farmacologia , Masculino , Metformina/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Imagem Óptica , Tamanho da Partícula , Propriedades de Superfície , Hipóxia Tumoral/efeitos dos fármacos
4.
Medicine (Baltimore) ; 100(1): e23691, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429737

RESUMO

ABSTRACT: HERV-H LTR -associating 2 (HHLA2) is a recently discovered member of the B7-family of immune checkpoint molecules that is overexpressed in several types of cancer. The aim of the present study was to investigate the expression of HHLA2 in cervical adenocarcinoma (AC) and the relationship between its expression and clinicopathological factors to assess its use as a potential marker for AC prognosis.This study included 76 patients diagnosed with cervical AC. Their resected specimens were obtained and a tissue microarray was constructed. Expression of HHLA2 was detected by the immunohistochemistry. Based on the follow-up data, correlation of HHLA2 expression and clinicopathological features, including overall survival (OS) and disease-free survival, was evaluated. Furthermore, we investigated the correlation between the expression of HHLA2 and programmed death ligand 1 (PD-L1).A total of 76 cases of invasive cervical AC were evaluated. High HHLA2 expression was detected in 62 cases (81.6%) and low HHLA2 expression was presented in 14 cases (18.4%). HHLA2 expression showed a significant negative correlation with lymph node metastasis (P = .011). Disease free survival was 75.0% and 49.0% in high-expression and the low expression group, respectively (P = .057). Although there was no statistical significance, an improved OS was observed in the high expression group (83.1% vs 64.9%, P = .479). Further, the expression of HHLA2 and PD-L1 correlated positively (P = .005). Thus, an improved OS was observed in the PD-L1 expression group (90.7% vs 66.2%, P = .037).High expression of HHLA2 is related to tumor progression and prognosis in patients with cervical AC. Therefore, HHLA2 may be a potential biomarker for predicting prognosis of cervical AC.


Assuntos
Imunoglobulinas/análise , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Antígeno B7-H1/análise , Feminino , Humanos , Pessoa de Meia-Idade , República da Coreia , Estudos Retrospectivos , Análise de Sobrevida
5.
Int J Clin Oncol ; 26(4): 659-669, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33415571

RESUMO

BACKGROUND: The expression of programmed cell death-ligand 1 (PD-L1) is a biomarker for administering immune check point inhibitors in patients with advanced stage non-small cell lung cancer. Although the consolidation therapy of durvalumab after definitive chemoradiotherapy has become the new standard of care for patients with unresectable stage III non-small cell lung cancer, the prevalence and prognostic role of PD-L1 expression in this population remain unclear. METHODS: We retrospectively reviewed data from patients with unresectable stage III non-small cell lung cancer who received definitive chemoradiotherapy at our institution between 2012 and 2017. Levels of PD-L1 were assessed using 22C3 antibody, and associations of progression-free and overall survival rates with PD-L1 statuses at a tumor proportion score cutoff of 1% were analyzed. RESULTS: Among the 104 patients enrolled, PD-L1 statuses were as follows: tumor proportion score < 1%, 73 (70.2%); 1-49%, 21 (20.2%); and ≥ 50%, 10 (9.6%). The number of patients with stage III non-small cell lung cancer with pretreatment PD-L1 tumor proportion score ≥ 1% was less than the number with advanced stage disease. There was no association between patient characteristics and PD-L1 status, and no significant differences were observed in progression-free and overall survival rates relative to PD-L1 status. CONCLUSION: Expression of PD-L1 in patients with stage III non-small cell cancer before chemoradiotherapy should be assessed because of the low prevalence of tumors with tumor proportion scores ≥ 1%. Further studies are needed to clarify whether durvalumab improves survival after definitive chemoradiotherapy, irrespective of tumor PD-L1 expression.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Apoptose , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Quimiorradioterapia , Humanos , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos
6.
Medicine (Baltimore) ; 99(45): e23172, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33158004

RESUMO

This study aimed to investigate the prognostic value of PD-L1 in Chinese patients with non-small cell lung carcinoma (NSCLC).In this retrospective study, 97 patients with NSCLC were consecutively recruited. The expression profiling of PD-1, PD-L1, p53 and Ki-67 was detected by immunohistochemistry. Median survival time was estimated by Kaplan-Meier survival curve with log-rank test. Risk factors were evaluated by Cox Proportional Hazards regression models.The median tumor size was larger (3.5 cm) among patients with positive PD-L1 expression, compared to those with negative expression (2.0 cm; P < .01). Compared to those with negative PD-L1 expression, patients with positive PD-L1 expression had significantly higher rates of nerve invasion (26.3% vs 5.0%; P < .01), blood vessel invasion (47.4% vs 20.0%; P < .01) and lymph node metastasis (64.9% vs 27.5%; P < .01), more advanced tumor stage (P < .01) and Ki-67 index (P < .01). PD-L1 expression status was not significantly associated with disease-free (DFS) or overall survival (OS). However, for patients with advanced disease, PD-L1 positive expression was related to worse outcome (HR: 4.13; 95% CI: 1.06-16.12).Positive PD-L1 expression is associated with more aggressive pathological features and poorer prognosis in advanced stage NSCLC.


Assuntos
Antígeno B7-H1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Idoso , Antígeno B7-H1/análise , Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
7.
Medicine (Baltimore) ; 99(46): e22323, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181636

RESUMO

RATIONALE: Patients reporting high PD-L1 expression have shown to respond well to immunotherapy; however, some patients develop hyperprogressive disease upon initiation of immune checkpoint inhibitors. We report a patient with lung cancer and 100% PD-L1 expression who developed hyperprogressive disease while treated with pembrolizumab and responded well to salvage chemotherapy with carboplatin and pemetrexed. PATIENT CONCERNS: A 66-year-old African American female with 25-pack year smoking history, diabetes mellitus type 2, essential thrombocytosis, and a history of papillary thyroid carcinoma developed relapsed lung adenocarcinoma after 13 months of no evidence of disease. DIAGNOSIS: Surveillance imagine showed subcarinal and hilar lymphadenopathy, which was confirmed as recurrent lung adenocarcinoma via bronchoscopy. In addition, a brain scan showed a 5 mm enhancing left insular lesion. PD-L1 was reported as 100% expression. Staging was reported as stage IVB TxN3M1c lung adenocarcinoma. INTERVENTIONS: One fraction of radiation with a total dose of 20 Gray was delivered to the left insular lesion. The patient initiated pembrolizumab (200 mg) every 3 weeks. She was then treated with salvage chemotherapy consisting of carboplatin (AUC 5) and pemetrexed (500 mg/m) every 3 weeks for 3 cycles. OUTCOMES: The brain lesion resolved after the radiation therapy. The patient developed hyperprogression with a large pericardial effusion and right pleural effusion after 2 treatments of pembrolizumab. Her PD-L1 expression decreased from 100% to 0% over a 10-week period. Salvage chemotherapy with carboplatin and pemetrexed resulted with 20 months of ongoing to evidence of disease. LESSONS: Immune checkpoint inhibitor-related hyperprogressive disease may respond to second-line salvage chemotherapy. Complete PD-L1 expression loss was observed after the patient's treatment and could be a marker of hyperprogressive disease or tumor immunoevasion.


Assuntos
Antígeno B7-H1/análise , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Serina-Treonina Quinases/análise , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Tratamento Farmacológico/métodos , Tratamento Farmacológico/normas , Feminino , Expressão Gênica/genética , Humanos , Proteínas Serina-Treonina Quinases/genética
8.
Zhonghua Fu Chan Ke Za Zhi ; 55(8): 529-534, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32854477

RESUMO

Objective: To examine the expression of programmed cell death 1 (PD-1) and its ligand (PD-L1) in epithelial ovarian cancer (EOC) tissues, and investigate the correlation among their expression, clinicopathological features and prognosis. Methods: The specimens of 180 patients with EOC treated in the First Affiliated Hospital of Dalian Medical University from October 2002 to December 2013 were confirmed by pathological examination. The pathological tissue specimens of subtypes ,included 120 cases of serous carcinoma, 30 cases of mucinous carcinoma, 20 cases of endometrioid carcinoma, and 20 cases of clear cell carcinoma. The normal paracancerous tissues of 50 cases randomly selected from the 180 patients as control group. Immunohistochemical SP method was used to detect the expressions of both PD-1 and PD-L1 in epithelial ovarian cancer tissues, and the relationships among their expressions,the clinicopathological parameters and prognosis were respectively analyzed. Results: (1) PD-1 was expressed in lymphocytes infiltrated in EOC tissues, and PD-L1 was expressed in the cell membranes of cancer tissues. In all EOC cases, 33 cases (18.3%, 33/180) of both PD-1 and PD-L1 were highly expressed, and only 1 (2.0%, 1/50) of control group showed high expression. There was statistically significant difference between two groups (P<0.01). (2) Among the four subtypes tissue specimens of EOC, the high expression rate of PD-1 was 25.0% (30/120) for serous carcinoma, 3/15 for endometrioid carcinoma, 0 (0/30) for mucinous carcinoma, and 0 (0/15) for clear cell carcinoma. The high expression rate of PD-L1 was 23.3% (28/120) for serous carcinoma, 3.3% (1/30) for mucinous carcinoma, 2/15 for endometrioid carcinoma, and 2/15 for clear cell carcinoma. Both PD-1 and PD-L1 expressions in the four sub-types of tissue specimens were significantly different (P<0.05). The high expression rate of both PD-1 and PD-L1 was 9.2% (8/87) in the early stage and 26.9% (25/93) in the late stage. There was a statistically significant difference between the two groups (P<0.01). Similarly, the expression of both PD-1 and PD-L1 were significantly higher in the cases of high-grade EOC (type Ⅱ) than those of low-grade (type Ⅰ) and in the cases of EOC distributed bilaterally than that distributed unilaterally, and there were statistically significant differences (P<0.05). (3) The Kaplan-Meier survival analysis showed that the survival time were respectively 35 and 36 months in the cases with high expressions of both PD-1 and PD-L1, and the survival time were the same as 61 months in the cases with low expression of both PD-1 and PD-L1, and the comparison was statistically significant (P<0.05). Conclusions: The expression levels of PD-1 and PD-L1 in EOC tissues are higher than those in adjacent tissues, especially in serous carcinomas. The expression of both PD-1 and PD-L1 is higher in specimens of the patients with advanced stages. The results showed that the high expression of both PD-1 and PD-L1 is an indicator of poor prognosis of patients suffering from EOC.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Recidiva Local de Neoplasia/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , Receptor de Morte Celular Programada 1 , RNA Mensageiro/genética
9.
Am J Surg Pathol ; 44(10): 1353-1366, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32649320

RESUMO

It is becoming increasingly important to obtain detailed diagnostic information on small-volume tissue biopsies, such as core needle biopsies. This is particularly crucial in the workup and diagnosis of classic Hodgkin lymphoma (CHL) and other morphologically similar lymphomas such as T-cell/histiocyte-rich large B-cell lymphoma (THRLBL), where small-volume lymph node biopsies often represent the frontline tissue source, and the differential diagnosis includes a reactive process. Immunohistochemical markers could be helpful to differentiate CHL from reactive lymph node changes (RLN) in this setting. The use of programmed cell death-1 (PD-1) and its ligand (PD-L1) immunohistochemistry has historically focused on prognostic and therapeutic value when evaluating CHL. However, the present study seeks to determine the diagnostic utility of these markers in core needle biopsies of CHL (25), THRLBL (3), and RLN (31). The cases of CHL and THRLBL were previously diagnosed and confirmed with standard immunohistochemistry, allowing the utility of PD-1 and PD-L1 to be tested in this setting. Different PD-1 and PD-L1 expression patterns were observed between the reactive process of RLN and the malignant lymphomas (CHL and THRLBL). CHL cases overall showed the greatest expression of PD-L1 within the malignant Reed-Sternberg cell population, with 40% of CHL cases exhibiting >50% PD-L1 expression. This degree of PD-L1 expression was not seen in the lymphocytic cell population of any RLN (P<0.001). Conversely, CHL cases showed an overall lower expression of PD-1, as 96% of CHLs had <5% PD-1 expression in Reed-Sternberg cells compared with only 10% expression within the lymphocytic population of RLN (P<0.001). THRLBL cases followed a similar trend to CHL. These results demonstrate that upfront PD-1 and PD-L1 immunohistochemistry can aid in the diagnosis of CHL in small-volume tissue biopsies.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Doença de Hodgkin/diagnóstico , Receptor de Morte Celular Programada 1/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia com Agulha de Grande Calibre , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica/métodos , Linfoma de Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
JAMA Netw Open ; 3(6): e207205, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32511721

RESUMO

Importance: Initial approval for immune checkpoint inhibitors (ICIs) for treatment of advanced non-small cell lung cancer (NSCLC) was limited to patients with high levels of programmed cell death ligand 1 (PD-L1) expression. However, in the period after approval, it is not known how new evidence supporting efficacy of these treatments in patients with low or negative PD-L1 expression was incorporated into real-world practice. Objective: To evaluate the association between PD-L1 testing and first-line ICI use. Design, Setting, and Participants: This retrospective cohort study (January 1, 2011, to December 31, 2018) used a deidentified nationwide electronic health record-derived database reflecting real-world care at more than 280 US community and academic cancer clinics (approximately 800 sites of care). Patients included those with advanced NSCLC without other identifiable variations diagnosed in the period after the US Food and Drug Administration's initial first-line approval of ICIs for patients with high PD-L1 expression (≥50%). Exposure: First-line ICI treatment. Main Outcomes and Measures: Patterns of PD-L1 testing and first-line ICI treatment among all patients and patients stratified by tumor histologic type (squamous vs nonsquamous). Results: A total of 45 631 patients (mean [SD] age, 68.4 [9.6] years; 21 614 [47.4%] female) with advanced NSCLC were included in the study. PD-L1 testing increased from 468 (7.2%) in 2015 to 4202 (73.2%) in 2018. Within a subset of 7785 patients receiving first-line treatment in the period after first-line approval of pembrolizumab, those who received PD-L1 testing had a greater odds of receiving an ICI (odds ratio, 2.11; 95% CI, 1.89-2.36). Among patients with high PD-L1 expression (≥50%), 1541 (83.5%) received first-line ICI treatment; 776 patients (40.3%) with low PD-L1 expression (1%-49%) and 348 (32.3%) with negative PD-L1 expression (0%) also received ICIs. In addition, 755 untested patients (32.8%) were treated with a first-line ICI. The proportion of patients who received ICIs without PD-L1 testing increased during the study period (59 [17%] in quarter 4 of 2016 to 141 [53.8%] in quarter 4 of 2018). Conclusions and Relevance: In this study, use of first-line ICI treatment increased among patients with advanced NSCLC with negative, low, or untested PD-L1 expression status in 2016 through 2018. These findings suggest that national practice was rapidly responsive to new clinical evidence rather than adhering to regulatory guidance in place at the time.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/análise , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
J Clin Pathol ; 73(10): 656-664, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32591352

RESUMO

AIMS: Programmed death-1/programmed death ligand 1 (PD-1/PD-L1) inhibitor therapy is accompanied by companion or complementary PD-L1 testing in some tumour types. We investigated utilisation of the Dako PD-L1 IHC 28-8 and 22C3 pharmDx assays and the Ventana PD-L1 (SP142) assay and evaluated concordance between the 28-8 and 22C3 assays in a real-world cohort of patients tested at a single US national reference laboratory. METHODS: NeoGenomics Laboratories performed PD-L1 testing on tumour samples between October 2015 and March 2018. PD-L1 test results were matched with patient characteristics using unique identifiers. Concordance between the 28-8 and 22C3 assays was evaluated in matched tumour samples. Data were evaluated across multiple tumour types and in subgroups of patients with lung cancer, melanoma, squamous cell carcinoma of the head and neck, and urothelial carcinoma. RESULTS: 62 180 individual PD-L1 tests were conducted on samples from 55 652 patients. PD-L1 test volume increased ~10-fold over the period evaluated. Test failure rates were typically low, and test turnaround time (TAT) ranged between 2 and 4 days. Concordance between the 28-8 and 22C3 assays was strong in the overall population and across tumour type subgroups (Kendall's tau correlations of 0.94 and 0.92-0.98, respectively). CONCLUSIONS: Test failure rates for PD-L1 tests were low and TAT remained reasonable despite marked increases in test volume. Concordance was high between the 28-8 and 22C3 assays across a range of tumour types and biopsy locations. These findings add to the literature showing high concordance between the 28-8 and 22C3 assays.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Imuno-Histoquímica , Humanos , Imuno-Histoquímica/métodos , Imuno-Histoquímica/normas , Imuno-Histoquímica/estatística & dados numéricos , Neoplasias/metabolismo , Reprodutibilidade dos Testes
12.
Acta Cytol ; 64(6): 577-587, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32599583

RESUMO

BACKGROUND: Programmed death ligand-1 (PD-L1) assessed by immunohistochemistry (IHC) is used as biomarker for pembrolizumab therapy in advanced stage lung cancer patients. However, data permitting direct performance comparison between cytology and surgical specimen types are limited since both specimens from a single tumor site are infrequently available. In addition, alcohol fixation used with cytology specimens requires technical validation of the PD-L1 IHC assay before clinical use. We here report our experience with implementation of the PD-L1 22C3 IHC pharmDxTM assay for cytologic samples at a large tertiary cancer center. STUDY DESIGN: Archival formalin-fixed (FF), paraffin-embedded cell blocks (CBs) and subsequent lung tumor resections (LTRs) from the same anatomical site were used for a direct comparison of PD-L1 tumor proportion scores (TPSs). TPS values were independently determined by one surgical lung pathologist and two cytopathologists blinded to the specimen pairs. An interim analysis was performed to facilitate the pooling of expertise among observers. After PD-L1 22C3 IHC pharmDxTM implementation for FF cytology specimens, dual-processed samples were used for a prospective technical validation of CytoLyt® prefixation (CF). Digital image analysis was performed for a subset of dual-processed specimens. RESULTS: Eighty-one CBs and LTRs were included for comparison of the specimen types. PD-L1 assessment in CBs had an accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 88.9/72.8, 66.7/73.5, 95.2/72.3, 80.0/65.8, and 90.9/79.1% for the ≥50/≥1% cutoff, respectively. The intraclass correlation coefficient was 0.84 (95% confidence interval [CI]: 0.76, 0.90), and it improved after interim analysis (before: 0.79 and after: 0.92). The overall concordance between CF and FF for the categories defined by the ≥50/≥1% cutoff values was 90.4% (95% CI: 79.0, 96.8). Similar assay performance was confirmed by digital analysis. CONCLUSIONS: PD-L1 22C3 IHC pharmDxTM shows good reliability if used with CB preparations. CF does not impact assay results significantly. Clinical validation with outcome data is needed, and digital methods of assessment should be further investigated.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Imuno-Histoquímica , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Humanos , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
13.
Hum Pathol ; 100: 15-23, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32387103

RESUMO

Synovial sarcoma (SS) is a soft-tissue malignancy that most often affects patients aged between 15 and 40 years, and the prognosis for patients with metastatic disease is generally poor. This study was performed to evaluate checkpoint blockade immunotherapy markers in SS, including tumor mutational burden (TMB), DNA mismatch repair (MMR) status, and PDL-1 (programmed cell death ligand 1), PD1 (programmed cell death 1), and CD8 expression by normal-tumor paired whole-exome sequencing (WES) and immunohistochemistry (IHC). Outcomes evaluated included event-free and overall survival. Twenty one (21) FISH (Fluorescence In Situ Hybridization)-confirmed SS cases (11 F, 10 M) were studied, with age ranging from 8 to 89 years at diagnosis and follow-up ranging from 1 to 16 years. TMB (n = 16) ranged from 0.83 to 212/Mb (median, 1.7). Only one case showed a high TMB of 212/Mb and missense variants of MMR genes in the primary tumor, while the other 15 cases had a low TMB of less than 5/Mb. IHC was performed on all 21 tumor samples for PD-L1, PD1, CD8, and MMR proteins. PD-L1 membranous staining was detected in 3 of 21 cases (14.3%), ranging from 1 to 5% for tumor proportion score and 1-10 for combined positive score. PD1 was detected in 15 of 21 cases (71.4%), ranging from 1 to 25/HPF (high power field) (median, 2). CD8 stain was seen in all cases, ranging from 2 to 60/HPF (median, 5). PD1 staining results correlated with CD8 staining results (P < 0.0001). No correlation of TMB or IHC markers was found with survival. No fixed pattern of TMB or IHCs between primary and metastatic tumors was observed; there was no correlation between TMB or IHCs and age, location, or diagnosis subtype. All of the cases tested showed retained expression of MMR proteins. The results show that for SS, a tumor with strong driver translocation, most cases have a low TMB, but occasionally a high TMB may be present, as observed in 1 of the 16 (6.25%) cases. The demonstration of a subgroup of SS cases with high TMB might explain the 10% response rate to checkpoint immunotherapy observed in clinical trials in patients with SS.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais , Antígenos CD8/análise , Mutação , Receptor de Morte Celular Programada 1/análise , Sarcoma Sinovial/genética , Sarcoma Sinovial/imunologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Criança , Reparo de Erro de Pareamento de DNA , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Intervalo Livre de Progressão , Estudos Retrospectivos , Sarcoma Sinovial/secundário , Sarcoma Sinovial/terapia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
J Surg Res ; 253: 201-213, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32380346

RESUMO

BACKGROUND: Most tumors responding to immunotherapy with monoclonal antibodies targeting programmed cell death protein1 (PD1) and programmed death ligand-1 (PD-L1) show surface expression of PD-L1. Neuroblastoma has been reported to show low PD-L1 surface expression. METHODS: The effect of immune checkpoint inhibitor on mouse neuroblastoma was investigated, and host immune cells were analyzed in the tumor microenvironment. Expression of co-stimulatory molecules by Neuro-2a mouse neuroblastoma cells was analyzed using flow cytometer. Neuro-2a cells were inoculated subcutaneously into A/J mice, followed by intraperitoneal injection of antibodies targeting PD-1 and PD-L1. Mice were sacrificed for the measurement of tumor weights on day 14 following tumor inoculation, and tumor-infiltrating cells were analyzed using a flow cytometer. RESULTS: Dim expression of PD-L1 was observed on the cell surface of cultured Neuro-2a cells. Growth of subcutaneous tumors was significantly suppressed, and PD-L1-expressing tumor cells were depleted by the antibody treatment. We confirmed that Neuro-2a cells opsonized by the anti-PD-L1 antibody were phagocytosed in the in vitro setting. In the treated tumor microenvironments, CD8α+ lymphocyte and CD11c+ MHC II+ cells were significantly accumulated in comparison with the control group. These CD11c+ MHC II+ cells expressed CD80, CD86, CD14, and CD40, but not CD205, PD-L1, or CTLA4. PD-1 expression was detected dimly. Immune suppressive effects of CD11b+Gr-1+ myeloid-derived suppressor cells by the administration of anti-PD-1 and PD-L1 antibodies were not observed in spleen, regional lymph nodes, or tumor microenvironment. CONCLUSIONS: Our findings raise the possibility that co-administration of anti-PD-1 and anti-PD-L1 antibodies have a synergistic effect on inhibition of tumor growth and could be an effective therapy against neuroblastoma with dim expression of PD-L1.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/análise , Células Dendríticas/imunologia , Neuroblastoma/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral/transplante , Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Humanos , Camundongos , Neuroblastoma/imunologia , Neuroblastoma/patologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
15.
Am J Surg Pathol ; 44(8): 1050-1060, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32384321

RESUMO

The prevalence and significance of programmed death-1 ligand (PD-L1) expression in different types of tubo-ovarian carcinoma have not been well defined. We evaluated PD-L1 expression and CD8 tumor-infiltrating lymphocyte (TIL) density in whole tissue sections of 189 cases of tubo-ovarian carcinoma, including high-grade serous carcinoma (HGSC, n=100), clear cell carcinoma (CCC, n=24), endometrioid carcinoma (EmC, n=40), and mucinous carcinomas (MC, n=25). Using the tumor proportion score (TPS) with a 1% cutoff, PD-L1 expression was present in 21% of HGSC, 16.7% of CCC, 2.5% of EmC, and 4% of MC. Using the combined positive score (CPS) with a cutoff of 1, PD-L1 expression was present in 48% of HGSC, 25% of CCC, 20% of EmC, and 24% of MC. HGSC demonstrated significantly higher CD8 TIL density than CCC (P=0.013238), EmC (P=0.01341), or MC (P=0.004556). In HGSC, CD8 TIL density was directly correlated with PD-L1 positivity using either TPS (P=0.0008) or CPS (P=0.00011). Survival analysis of patients with high stage (stage III to IV) HGSC revealed PD-L1 positivity by TPS to be associated with improved progression-free survival (adjusted hazard ratio: 0.4912 vs. 2.036, P=0.0378). Although not statistically significant, a similar trend was observed in overall survival (adjusted hazard ratio: 0.3387 vs. 2.953, P=0.0548). In contrast, with CPS, no significant difference was identified between PD-L1-positive and negative groups in either progression-free survival (P=0.5086) or overall survival (P=0.7823). Neoadjuvant chemotherapy was associated with higher PD-L1 expression by TPS (P=0.00407) but not CPS. No significant difference in PD-L1 expression was detected in tumors from patients with germline BRCA1/2 mutations compared with germline mutation-negative tumors by either TPS or CPS. In conclusion, the prevalence of PD-L1 expression is variable in different types of tubo-ovarian carcinoma and is highest in HGSC. In high-stage HGSC, PD-L1 positivity in tumor cells is associated with an increased immune response and improved survival.


Assuntos
Adenocarcinoma de Células Claras/imunologia , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Linfócitos T CD8-Positivos/imunologia , Carcinoma Endometrioide/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Ovarianas/imunologia , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Císticas, Mucinosas e Serosas/terapia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Intervalo Livre de Progressão , Fatores de Tempo , Adulto Jovem
16.
Virchows Arch ; 477(5): 687-696, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32424767

RESUMO

Pancreatic carcinoma remains one of the leading cancer-related causes of death worldwide and is generally characterized by a dismal prognosis and limited potential for oncologic treatment. A rare subvariant of pancreatic cancer, undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), has an unpredictable prognosis according to many previous studies, with unexpectedly long survival in individual cases. In this study, we collected, retrospectively, 13 cases of well-documented UCOGCs and performed immunohistochemistry focused on the expression of the programmed death-ligand 1 (PD-L1) and several other potential therapeutic and predictive markers (PanTRK, p53, MSH2, PMS2, and the number of tumor-infiltrating lymphocytes), to explore their correlation with the follow-up of the patients. As a control group, we examined 24 cases of conventional pancreatic ductal adenocarcinoma (PDAC). In our results, PanTRK was negative in all 24 cases. P53 did not show any significant differences between UCOGCs and PDACs, and the entire cohort was MSH2, MLH1, PMS2, and MSH6 positive. Significant differences were present in the analysis of PD-L1: UCOGCs were found to express PD-L1 significantly more frequently and have a higher number of tumor-infiltrating lymphocytes than PDAC. The expression of PD-L1 was related to significantly shorter survival in patients with UCOGC and in the entire cohort. Patients with PD-L1 negative UCOGCs displayed surprisingly long survival in comparison to PD-L1 positive UCOGCs and PDACs (both PD-L1+ and PD-L1-). We compared our results with previously published data, and, after statistical analysis, we were able to identify PD-L1 as an effective prognostic marker of UCOGC and suggest a strong need for a clinical trial of immune checkpoint immunotherapy in patients with advanced PD-L1 positive UCOGC.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/imunologia , Diferenciação Celular , Células Gigantes/imunologia , Osteoclastos/imunologia , Neoplasias Pancreáticas/imunologia , Adulto , Idoso , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Feminino , Células Gigantes/patologia , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Osteoclastos/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco
17.
PLoS One ; 15(4): e0231936, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32339189

RESUMO

BACKGROUND: Studies have indicated that programmed death ligand 1 (PD-L1) expression may have utility as a predictive biomarker in patients with advanced/metastatic urothelial carcinoma (UC). Different immunohistochemical (IHC) assays are in development to assess PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs). METHODS: In this post hoc analysis of the single-arm, phase 1/2 Study 1108 (NCT01693562), PD-L1 expression was evaluated from tumor samples obtained prior to second-line treatment with durvalumab in patients with advanced/metastatic UC using the VENTANA (SP263) IHC Assay. The primary objective was to determine whether the TC ≥ 25%/IC ≥ 25% algorithm (i.e., cutoff of ≥ 25% TC or ≥ 25% IC with PD-L1 staining at any intensity above background) was optimal for predicting response to durvalumab. PD-L1 expression data were available from 188 patients. RESULTS: After a median follow-up of 15.8 and 14.6 months, higher PD-L1 expression was associated with longer overall survival (OS) and progression-free survival (PFS), respectively, with significant separation in survival curves for PD-L1-high and-low expressing patients for the TC ≥ 25%/IC ≥ 25% cutoff (median OS: 19.8 vs 4.8 months; hazard ratio: 0.46; 90% confidence interval: 0.33, 0.639). OS was also prolonged for PD-L1-high compared with-low patients when samples were categorized using TC/IC combined positive score ≥ 10 and IC≥ 5% cutoffs. In multivariate analysis, IC but not TC PD-L1 expression was significantly associated with OS, PFS, and objective response rate (P < 0.001 for each), although interaction analysis showed similar directionality of benefit for ICs and TCs. CONCLUSIONS: These findings support the utility of a combined TC/IC algorithm for predicting response to durvalumab in patients with UC, with the TC≥ 25%/IC≥ 25% cutoff optimal when used with the VENTANA (SP263) IHC Assay.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/análise , Neoplasias Urológicas/tratamento farmacológico , Adulto , Algoritmos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Resultado do Tratamento , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologia
18.
PLoS One ; 15(4): e0222551, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294103

RESUMO

We assessed the frequency of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) in a cohort of 522 sarcomas from 457 patients, incuding a subset of 46 patients with 63 matched samples from local recurrence or metastases with primary tumours and/or metachronous metastases. We also investigated the correlation of PD-L1 with the presence and degree of tumour-infiltrating lymphocytes (TILs) in a subset of cases. IHC was performed using the PD-L1 SP263 companion kit (VENTANA) on tissue microarrays from an archival cohort. Evaluation of PD-L1 and TILs was performed on full sections for a subset of 23 cases. Fisher's exact and Mann Whitney test were used to establish significance (P <0.05). PD-L1 positive expression (≥1%) was identified in 31% of undifferentiated pleomorphic sarcomas, 29% of angiosarcomas, 26% of rhabdomyosarcomas, 18% of myxofibrosarcomas, 11% of leiomyosarcomas and 10% of dedifferentiated liposarcomas. Negative expression was present in all atypical lipomatous tumous/well-differentiated lipoasarcomas, myxoid liposarcomas, synovial sarcomas, pleomorphic liposarcomas, and Ewing sarcomas. PD-L1 IHC was concordant in 81% (38 of 47) of matched/paired samples. PD-L1 IHC was discordant in 19% (9 of 47 matched/paired samples), displaying differences in the proportion of cells expressing PD-L1 amongst paired samples with the percentage of PD-L1-positive cells increasing in the metastatic/recurrent site compared to the primary in 6 of 9 cases (67%). Significant correlation between PD-L1 expression and the degree of TILs was exclusively identified in the general cohort of leiomyosarcomas, but not in other sarcoma subtypes or in metastatic/recurrent samples. We conclude that the prevalence of PD-L1 expression in selected sarcomas is variable and likely to be clone dependent. Importantly, we demonstrated that PD-L1 can objectively increase in a small proportion of metastases/recurrent sarcomas, offering the potential of treatment benefit to immune checkpoint inhibitors in this metastatic setting.


Assuntos
Antígeno B7-H1/análise , Sarcoma/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Prevalência
19.
Hum Pathol ; 99: 88-97, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32246989

RESUMO

Combined anti-VEGF/anti-programmed death ligand 1 (PD-L1) therapy synergistically improves treatment outcomes in advanced renal cell carcinoma (RCC) compared with anti-PD-L1 or anti-vascular endothelial growth factor (VEGF) monotherapy. Here, we analyzed the expression of VEGF and PD-L1 (SP142) in a retrospective cohort of 513 patients with clear-cell (cc) RCC. PD-L1 expression on tumor cells (TCs) and immune cells (ICs) was evaluated by immunohistochemistry (IHC) with a positive threshold value of ≥1%. Positive staining for PD-L1 on ICs and TCs was found in 115 (22.4%) and 7 (1.4%) cases, respectively. Moderate or strong staining for VEGF on TCs was found in 217 (42.3%) patients. PD-L1 expression on ICs and TCs was positively associated with VEGF expression on TCs. Both VEGF and PD-L1 (IC) positivity (VEGF/PD-L1 [IC]: +/+) was observed in 65 (12.7%) cases. Patients in this subgroup exhibited more aggressive clinicopathologic features, including older age, higher World Health Organization/International Society of Urological Pathology (ISUP) grade, angiolymphatic invasion, tumor necrosis, and sarcomatoid differentiation (P < 0.05). Kaplan-Meier analysis indicated that expression of VEGF and PD-L1 on ICs was positively correlated with tumor recurrence (P < 0.001), whereas expression of PD-L1 on TCs was not (P = 0.554). Tumors with positivity for both antibodies (VEGF/PD-L1 [IC]: +/+) exhibited the worst recurrence-free survival (P < 0.001), and double positivity independently predicted tumor recurrence in ccRCC. The present study provides comprehensive and basic information about VEGF and PD-L1 expression for new combined therapy in primary ccRCC.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/química , Neoplasias Renais/química , Fator A de Crescimento do Endotélio Vascular/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrectomia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Adulto Jovem
20.
Eur J Cancer ; 129: 97-106, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32145474

RESUMO

AIM: The KEYNOTE-659 study evaluated the efficacy and safety of pembrolizumab in combination with chemotherapy as the first-line treatment in Japanese patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer. In this paper, we report results from cohort 1 (S-1 plus oxaliplatin [SOX] with pembrolizumab). METHODS: This was a non-randomised, multicentre, open-label phase IIb study in patients with advanced programmed death-ligand 1 (PD-L1)-positive, human epidermal growth factor receptor 2-negative G/GEJ tumours. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. Exploratory analyses were performed based on the PD-L1 combined positive score (CPS) status. RESULTS: Fifty-four patients were evaluated. The median follow-up was 10.1 months. ORR and DCR by BICR were 72.2% (95% confidence interval [CI] 58.4-83.5) and 96.3% (95% CI 87.3-99.5), respectively. Median DOR, TTR, PFS and OS were as follows: not reached, 1.5 months, 9.4 months and not reached. The ORR was 73.9% in patients with CPS ≥1 to <10 and 71.0% in those with CPS ≥10. Grade ≥3 treatment-related adverse events (TRAEs) were reported by 57.4% of patients. The most common grade ≥3 TRAEs were decreased platelet count (14.8%), decreased neutrophil count (13.0%), colitis (5.6%) and adrenal insufficiency (5.6%). CONCLUSIONS: SOX with pembrolizumab showed encouraging efficacy and a manageable safety profile for the first-line treatment of advanced G/GEJ cancer. TRIAL REGISTRATION: NCT03382600/JapicCTI-183829.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno B7-H1/análise , Neoplasias Esofágicas/tratamento farmacológico , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Combinação de Medicamentos , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/imunologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Intervalo Livre de Progressão , Receptor ErbB-2/análise , Receptor ErbB-2/metabolismo , Indução de Remissão/métodos , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem , Tegafur/efeitos adversos
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