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1.
J Cell Mol Med ; 24(12): 6916-6927, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32390293

RESUMO

Glioblastomas and brain metastases (BM) of solid tumours are the most common central nervous system neoplasms associated with very unfavourable prognosis. In this study, we report the association of prostate-specific membrane antigen (PSMA) with various clinical parameters in a large cohort of primary and secondary brain tumours. A tissue microarray containing 371 cases of ascending grades of gliomas pertaining to astrocytic origin and samples of 52 cases of primary lung carcinomas with matching BM with follow-up time accounting to 10.4 years was evaluated for PSMA expression using immunohistochemistry. In addition, PSMA expression was studied in BM arising from melanomas and breast carcinomas. Neovascular expression of PSMA was evident alongside with high expression in the proliferating microvasculature of glioblastomas when compared to the tumour cell expression. This result correlated with the results obtained from the in silico (cancer genome databases) analyses. In gliomas, only the vascular expression of PSMA associated with poor overall survival but not the tumour cell expression. In the matched primary lung cancers and their BM (n = 52), vascular PSMA expression in primary tumours associated with significantly accelerated metastatic dissemination to the brain with a tendency towards poor overall survival. Taken together, we report that the vascular expression of PSMA in the primary and secondary brain tumours globally associates with the malignant progression and poor outcome of the patients.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/patologia , Antígeno Prostático Específico/metabolismo , Adulto , Idoso , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/irrigação sanguínea , Glioma/patologia , Glutamato Carboxipeptidase II/genética , Glutamato Carboxipeptidase II/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
2.
Acta Oncol ; 58(8): 1087-1094, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31002007

RESUMO

Background: Predictive biomarkers for immunotherapy in lung cancer are intensively investigated; however, correlations between PD-L1/PD-1 expressions and clinical features or histopathological tumor characteristics determined on hematoxylin and eosin stained sections have not extensively been studied. Material and methods: We determined PD-L1 expression of tumor cells (TC) and immune cells (IC), and PD-1 expression of IC by immunohistochemistry in 268 lung adenocarcinoma (LADC) patients, and correlated the data with smoking, COPD, tumor grade, necrosis, lepidic growth pattern, vascular invasion, density of stromal IC, and EGFR/KRAS status of the tumors. Results: There was a positive correlation between PD-L1 expression of TC and IC, as well as PD-L1 and PD-1 expression of IC. Tumor necrosis was associated with higher PD-L1 expression of TC and PD-1 expression of IC. A negative correlation was observed between lepidic growth pattern and PD-L1 expression of TC and PD-L1/PD-1 expression of IC. EGFR mutation seemed to negatively correlate with PD-1 expression of IC, but this tendency could not be verified when applying corrections for multiple comparisons. No significant effect of the KRAS mutation on any of the studied variables could be established. Conclusion: Here we first demonstrate that the presence of necrosis correlates with higher PD-L1 expression of TC and PD-1 expression of IC in LADC. Further studies are required to determine the predictive value of this observation in LADC patients receiving immunotherapy.


Assuntos
Adenocarcinoma de Pulmão/patologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/patologia , Pulmão/patologia , Receptor de Morte Celular Programada 1/metabolismo , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pulmão/citologia , Pulmão/cirurgia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Necrose , Pneumonectomia
3.
Transl Lung Cancer Res ; 12(1): 27-41, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36762067

RESUMO

Background: BRAF is a critical member of proliferation pathways in cancer, and a mutation is present in only 2-4% of lung adenocarcinomas (LADC). There is no data available on the expression pattern of BRAF RNA that might result in enhanced signalling and drug resistance. Methods: LADC tissue samples (n=64) were fixed and processed into paraffin blocks. Tissue microarrays (TMA) were constructed, and RNAScope® in situ hybridization (ISH) assay was performed for wild-type (WT) BRAF RNA. Apart from pathological assessment of tumor samples (grade, necrosis, vascular involvement and peritumoral infiltration), anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 (PD-1) immunohistochemistry and validation in public databases [The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA)] were carried out. Results: WT BRAF RNA is expressed in LADC, with no significant expressional difference between early-stage (I-II) and advanced-stage (III-IV) patients (P=0.317). Never smokers exhibited significantly increased BRAF expression (compared to current and ex-smokers, P<0.01) and tumor necrosis correlated significantly with BRAF expression (P=0.014). PD-L1 expression was assessed on tumor cells and immune cells, PD-1 expression was evaluated on immune cells. There was no significant difference in BRAF RNA expression between tumor cell PD-L1-high vs. low patients (P=0.124), but it was decreased in immune cell PD-L1-high patients (P=0.03). Kaplan-Meier survival analysis showed that high BRAF expression was associated with significantly decreased OS (P<0.01) and was an independent negative prognostic factor according to multivariate Cox hazard regression (P=0.024). TCGA validation cohort confirmed our findings regarding OS in early-stage patients (P=0.034). Conclusions: We found an increased expression of BRAF RNA in all stages in LADC. High BRAF expression was associated with tumor necrosis, distinct immune checkpoint biology and outcomes. We recommend further evaluating the potential of targeting overexpressed BRAF pathways in LADC.

4.
Transl Lung Cancer Res ; 10(2): 662-674, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33718012

RESUMO

BACKGROUND: Although lung adenocarcinoma (LADC) with sensitizing mutations of the epidermal growth factor receptor (EGFR) is highly sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs), in most cases disease progression inevitably occurs. Our aim was to investigate the predictive and prognostic significance of adjusted tumoral EGFR variant allele frequency (EGFR-aVAF) in the above setting. METHODS: Eighty-nine Caucasian advanced-stage LADC patients with known exon-specific EGFR mutations undergoing EGFR-TKI treatment were included. The correlations of EGFR-aVAF with clinicopathological variables including progression-free and overall survival (PFS and OS, respectively) were retrospectively analyzed. RESULTS: Of 89 EGFR-mutant LADC patients, 46 (51.7%) had exon 19 deletion, while 41 (46.1%) and 2 (2.2%) patients had exon 21- and exon 18-point mutations, respectively. Tumoral EGFR-aVAF was significantly higher in patients harboring EGFR exon 19 mutations than in those with exon 21-mutant tumors (P<0.001). Notably, patients with EGFR exon 19 mutant tumors demonstrated significantly improved PFS (P=0.003) and OS (P=0.02) compared to patients with exon 21 mutations. Irrespective of specific exon mutations, a statistically significant positive linear correlation was found between EGFR-aVAF of tumoral tissue and PFS (r=0.319; P=0.002). High (≥70%) EGFR-aVAF was an independent predictor of longer PFS [vs. low (<70%) EGFR-aVAF; median PFSs were 52 vs. 26 weeks, respectively; P<0.001]. Additionally, patients with high EGFR-aVAF also had significantly improved OS than those with low EGFR-aVAF (P=0.011). CONCLUSIONS: Our study suggests that high (≥70%) EGFR-aVAF of tumoral tissue predicts benefit from EGFR-TKI treatment in advanced LADC and, moreover, that exon 19 EGFR mutation is associated with high EGFR-aVAF and improved survival outcomes.

5.
Thorac Cancer ; 11(11): 3193-3204, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32941706

RESUMO

BACKGROUND: Metastatic lung cancer is a debilitating disease, but with the advances in immunotherapy, therapeutic options have vastly increased. Numerous complete blood count parameters (CBC) have been described as easily accessible biomarkers that might predict response to immunotherapy. However, to date, no comprehensive study has been performed on the longitudinal changes of these parameters during cancer progression. METHODS: The clinicopathological variables and CBC parameters of 986 advanced stage lung cancer patients were retrospectively analyzed. Blood tests were performed as part of the routine checkup and the results were recorded at the time of the diagnosis of the primary tumor, the diagnosis of brain or bone metastases, and also during the last available follow-up. RESULTS: In the experimental subcohort, 352 and 466 patients were diagnosed with brain and bone metastases, respectively. The control group consisted of 168 patients without clinically detectable or other distant organ metastases. In our longitudinal analyses, we found significantly decreasing absolute lymphocyte count (ALC: P < 0.001), and significantly increasing absolute neutrophil count (ANC: P < 0.001) levels in all patient subgroups, irrespective of histopathological type and metastatic site. Interestingly, patients with brain metastases had significantly descending-ascending platelet count (PLT) trendlines (P < 0.001), while the bone metastatic subgroup exhibited significantly ascending-descending trendlines (P = 0.043). CONCLUSIONS: Significantly decreasing ALC, significantly increasing ANC and fluctuating PLT levels may be found in brain and bone metastatic lung cancer patients during disease progression. Our findings might contribute to improve personalized healthcare in this devastating malignancy. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Significantly decreasing ALC, and significantly increasing ANC levels can be found in advanced-stage lung cancer patients during disease progression Patients with brain metastases have descending-ascending PLT trendlines, while patients with bone metastases exhibit ascending-descending trendlines during disease progression WHAT THIS STUDY ADDS: The descending values for ALC, and the ascending mean values for PLT and ANC, might be suggestive of poor response to second- or third-line immunotherapy in advanced-stage lung cancer patients. The current study might help to improve patient selection and treatment strategies for brain and/or bone metastatic lung cancer patients.


Assuntos
Neoplasias Pulmonares/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , Feminino , Humanos , Estudos Longitudinais , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos
6.
Magy Onkol ; 63(3): 233-238, 2019 Sep 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31533144

RESUMO

Survival of patients with lung cancer is unfavorable. Distant metastasis is detected in more than half of the patients at diagnosis. In advanced stages, platinum-based chemotherapy has been the main therapeutic approach for a long time, however, in 2004 targeted therapies emerged. Recently, PDL1/ PD-1 inhibitors have been introduced in the treatment of metastatic lung cancers, for which the therapeutic criteria are increasingly outlined. Based on international and Hungarian data, it is likely that determination of PD-L1 expression in the primary tumor samples may be sufficient for the establishment of therapeutic indication, if PD-L1 expression of tumor cells remains the sole criterion. However, if the combined positive score, which takes into account PD-L1 expression of both tumor and immune cells, will be introduced as a therapeutic criterion, testing of all the actual tumor samples may be required to initiate treatment, as conventional oncotherapies may affect the PD-L1 expression of immune cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Humanos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo
7.
J Neuropathol Exp Neurol ; 78(4): 326-339, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30816955

RESUMO

The impact of growth pattern on the distribution of connective tissue and on the vascularization of brain metastases (40 colon, lung and breast carcinoma samples) was analyzed. Most of the cases showed either a "pushing-type" (18/40, mostly colon and lung carcinomas) or a "papillary-type" (19/40, mostly breast carcinomas) growth pattern. There was a striking difference in the growth pattern and vascularization of colon/lung versus breast carcinoma metastases. Pushing-type brain metastases incorporated fewer vessels and accumulated more collagen in the adjacent brain parenchyma, whereas papillary-type brain metastases incorporated more vessels and accumulated collagen in the center of the tumor. We observed duplication of the PDGFRß-positive pericyte layer accompanied by an increase in the amount of collagen within the vessel walls. The outer layer of pericytes and the collagen was removed from the vessel by invasive activity of the tumors, which occurred either peri- or intratumorally, depending on the growth pattern of the metastasis. Our findings suggest that pericytes are the main source of the connective tissue in brain metastases. Vascularization and connective tissue accumulation of the brain metastases largely depend on the growth pattern of the tumors.


Assuntos
Neoplasias Encefálicas/secundário , Carcinoma/secundário , Tecido Conjuntivo/patologia , Metástase Neoplásica/patologia , Neovascularização Patológica/patologia , Pericitos/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias da Mama/patologia , Neoplasias do Colo/patologia , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino
8.
Clin Lung Cancer ; 20(5): 363-369.e2, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31178388

RESUMO

BACKGROUND: Approximately 50% of brain metastases originate from non-small-cell lung cancer. The median survival of patients with brain metastases is 1 month without treatment. Novel immunotherapeutic strategies, such as those targeting the programmed death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) axis, are promising in patients with advanced systemic disease but are often preferentially administered to patients with tumors showing PD-L1 positivity. PATIENTS AND METHODS: Surgically resected paired primary lung adenocarcinoma and brain metastasis samples of 61 patients were analyzed. We compared the paired samples regarding the amount of peritumoral and stromal mononuclear infiltration, PD-L1 expression of tumor and immune cells, and PD-1 expression of immune cells. We investigated the effect of radiotherapy, chemotherapy, and steroid therapy on PD-L1 expression in brain metastases. RESULTS: There was significant positive correlation regarding the PD-L1 expression of tumor cells between the paired primary lung adenocarcinoma and brain metastatic samples with the use of different cutoff levels (1%, 5%, 50%). We found no impact of chemotherapy or steroid therapy on the changes of PD-L1 expression of tumor cells between the 2 sites. There is no or only limited concordance of the proportion of PD-1- or PD-L1-positive tumor-associated immune cells between the paired tumor samples, which suggests that brain metastases develop their own immune environment. CONCLUSION: We observed a strong correlation of PD-L1 positive tumor cells between primary lung adenocarcinoma cases and their corresponding brain metastases, which is not significantly influenced by chemotherapy or steroid therapy.


Assuntos
Adenocarcinoma/genética , Antígeno B7-H1/genética , Neoplasias Encefálicas/genética , Encéfalo/metabolismo , Neoplasias Pulmonares/genética , Pulmão/metabolismo , Linfócitos do Interstício Tumoral/fisiologia , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Encéfalo/patologia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade
9.
J Cancer Res Clin Oncol ; 144(7): 1219-1226, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29675791

RESUMO

OBJECTIVES: While the predictive value of programmed cell death ligand-1 (PD-L1) protein expression for immune checkpoint inhibitor therapy of lung cancer has been extensively studied, the impact of standard platinum-based chemotherapy on PD-L1 or programmed cell death-1 (PD-1) expression is unknown. The aim of this study was to determine the changes in PD-L1 expression of tumor cells (TC) and immune cells (IC), in PD-1 expression of IC, and in the amount of stromal mononuclear cell infiltration after platinum-based chemotherapy in patients with lung cancer. MATERIALS AND METHODS: We determined the amount of stromal mononuclear cells and PD-L1/PD-1 expressions by immunohistochemistry in bronchoscopic biopsy samples including 20 adenocarcinomas (ADC), 15 squamous cell carcinomas (SCC), 2 other types of non-small cell lung cancer, and 4 small cell lung cancers together with their corresponding surgical resection tissues after platinum-based chemotherapy. RESULTS: PD-L1 expression of TC decreased in ten patients (24.4%) and increased in three patients (7.32%) after neoadjuvant chemotherapy (p = 0.051). The decrease in PD-L1 expression, however, was significant only in patients who received cisplatin-gemcitabine combination (p = 0.020), while in the carboplatin-paclitaxel group, no similar tendency could be observed (p = 0.432). There was no difference between ADC and SCC groups. Neither PD-1 expression nor the amount of stromal IC infiltration showed significant changes after chemotherapy. CONCLUSIONS: This is the first study, in which both PD-L1 and PD-1 expression were analyzed together with the amount of stromal IC infiltration in different histological subtypes of lung cancer before and after platinum-based chemotherapy. Our results confirm that chemotherapy decreases PD-L1 expression of TC in a subset of patients, therefore, rebiopsy and re-evaluation of PD-L1 expression may be necessary for the indication of immune checkpoint inhibitor therapy.


Assuntos
Antígeno B7-H1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Biópsia , Broncoscopia , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Imuno-Histoquímica , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/imunologia , Gencitabina
10.
Neuro Oncol ; 19(8): 1058-1067, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28201746

RESUMO

BACKGROUND: Management of lung cancer patients who suffer from brain metastases represents a major challenge. Considering the promising results with immune checkpoint inhibitor treatment, evaluating the status of immune cell (IC) infiltrates in the prognosis of brain metastasis may lead to better therapeutic strategies with these agents. The aim of this study was to characterize the distribution of ICs and determine the expression of the checkpoint molecules programmed death protein 1 (PD-1) and its ligand, PD-L1, in brain metastasis of lung adenocarcinoma (LUAD) patients and to analyze their clinicopathological correlations. METHODS: We determined the presence of peritumoral mononuclear cells (mononuclear ring) and the density of intratumoral stromal mononuclear cells on brain metastasis tissue sections of 208 LUAD patients. PD-L1/PD-1 expressions were analyzed by immunohistochemistry. RESULTS: Mononuclear rings were significantly associated with better survival after brain metastasis surgery. Cases with massive stromal IC infiltration also showed a tendency for better overall survival. Lower expression of PD-1 and PD-L1 was associated with better survival in patients who underwent surgery for the primary tumor and had multiple brain metastases. Steroid administration and chemotherapy appear not to influence the density of IC in brain metastasis. CONCLUSION: This is the first study demonstrating the independent prognostic value of mononuclear rings in LUAD cases with brain metastasis. Our results also suggest that the density of tumor-associated ICs in addition to PD-L1 expression of tumor cells and ICs as well as PD-1 expression of ICs may hold relevant information for the appropriate selection of patients who might benefit from anti-PD-L1 or anti-PD-1 therapy.


Assuntos
Adenocarcinoma/patologia , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/química , Leucócitos Mononucleares/metabolismo , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Adenocarcinoma de Pulmão , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade
11.
Pathol Oncol Res ; 21(3): 821-5, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25698383

RESUMO

Mycosis fungoides (MF) is a common, indolent primary cutaneous T-cell lymphoma (CTCL), with rare, more aggressive variants, such as folliculotropic MF (FMF). A minority of the MF cases may undergo large cell transformation (T-MF) associated with poor prognosis. A selection of microRNAs (miRs) contribute to the pathogenesis and progression of classic MF, and may also be useful in differential diagnostics. However, the molecular background of FMF and the mechanisms involved in large cell transformation are obscure. We analyzed the expression of 11 miRs in 9 FMF and 7 T-MF cases. Three miRs, including miR-93-5p, miR-181a and miR-34a were significantly upregulated in both FMF and T-MF. FMF also showed overexpression of miR-155 and miR-223, while miR-181b and miR-326 were overexpressed in T-MF cases compared to controls. These results by identifying a number of differentially expressed microRNAs add further insight into the molecular pathogenesis of folliculotropic MF and large cell transformation of MF.


Assuntos
Transformação Celular Neoplásica/patologia , MicroRNAs/genética , Micose Fungoide/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Micose Fungoide/patologia , Estadiamento de Neoplasias , Prognóstico , Neoplasias Cutâneas/patologia
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