MARIA APARECIDA NAGAI
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Radiologia, Faculdade de Medicina - Docente
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
7 resultados
Resultados de Busca
Agora exibindo 1 - 7 de 7
- Concomitant TP53 mutation in early-stage resected EGFR-mutated non-small cell lung cancer: a narrative approach in a genetically admixed Brazilian cohort(2023) MACHADO-RUGOLO, J.; BALDAVIRA, C. M.; PRIETO, T. G.; OLIVIERI, E. H. R.; FABRO, A. T.; RAINHO, C. A.; CASTELLI, E. C.; RIBOLLA, P. E. M.; AB'SABER, A. M.; TAKAGAKI, T.; NAGAI, M. A.; CAPELOZZI, V. L.TP53 mutations are frequent in non-small cell lung cancer (NSCLC) and have been associated with poor outcome. The prognostic and predictive relevance of EGFR/TP53 co-mutations in NSCLC is controversial. We analyzed lung tissue specimens from 70 patients with NSCLC using next-generation sequencing to determine EGFR and TP53 status and the association between these status with baseline patient and tumor characteristics, adjuvant treatments, relapse, and progression-free (PFS) and overall survival (OS) after surgical resection. We found the EGFR mutation in 32.9% of patients (20% classical mutations and 12.9% uncommon mutations). TP53 missense mutations occurred in 25.7% and TP53/EGFR co-mutations occurred in 43.5% of patients. Stage after surgical resection was significantly associated with OS (P=0.028). We identified an association between progression-free survival and poor outcome in patients with distant metastases (P=0.007). We found a marginally significant difference in OS between genders (P=0.057) and between mutant and wild type TP53 (P=0.079). In univariate analysis, distant metastases (P=0.027), pathological stage (IIIA-IIIB vs I-II; P=0.028), and TP53 status (borderline significance between wild type and mutant; P=0.079) influenced OS. In multivariable analysis, a significant model for high risk of death and poor OS (P=0.029) selected patients in stage IIIA-IIIB, with relapse and distant metastases, non-responsive to platin-based chemotherapy and erlotinib, with tumors harboring EGFR uncommon mutations, with TP53 mutant, and with EGFR/TP53 co-mutations. Our study suggested that TP53 mutation tends to confer poor survival and a potentially negative predictive effect associated with a non-response to platinum-based chemotherapy and erlotinib in early -stage resected EGFR-mutated NSCLC.
- The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma(2021) BALDAVIRA, Camila M.; MACHADO-RUGOLO, Juliana; PRIETO, Tabatha G.; BASTOS, Daniel R.; BALANCIN, Marcelo; AB'SABER, Alexandre M.; YAEGASHI, Lygia B.; SOUZA, Paola C.; FARHAT, Cecilia; TAKAGAKI, Teresa Y.; NAGAI, Maria Ap; CAPELOZZI, Vera L.Background: Pleckstrin homology domain family A (PHLDA) genes play important roles in cancer cellular processes, including inhibiting Akt activation, repressing growth factor signaling, inhibiting the negative feedback of EGFR/ErbB2 signaling cells, and inducing apoptosis. However, the prognostic significance of PHLDA in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MM) remains unclear. The present study investigates the associations between PHLDA expression patterns and their prognostic value in lung adenocarcinoma (LUAD) and MM. Methods: We analyzed PHLDA family members at the genomic level in silico to explore their mRNA expression pattern and predictive significance in LUAD and MM. We then created a PHLDA-drug interaction network and a protein-protein interaction (PPI) network using different databases. Finally, we immunohistochemically assessed the protein expression of each PHLDA family member on tissue microarrays (TMAs) in both LUAD and MM cohorts with long-term follow-up. Results: While PHLDA1 mRNA expression in both LUAD and MM was lower than that of normal tissue, PHLDA2 mRNA was significantly overexpressed in LUAD, and PHLDA3 mRNA was overexpressed in MM. In NSCLC, both low PHLDA1 mRNA expression and high PHLDA3 mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high PHLDA2 mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high PHLDA1 and PHLDA2 mRNA expression had poor OS (P=0.01 and P<0.01, respectively). In addition, the PHLDA-drug interaction network indicated that several common drugs could potentially modulate PHLDA expression, and the PPI network suggested that PHLDA1 interacts with Notch family members, whereas PHLDA3 interacts with TP53. Our results also showed that the expression of PHLDA2 and PHLDA3 was significantly higher in LUAD and MM than that of PHLDA1 (P<0.05) and was associated with the risk of death. While patients with PHLDA2 >85.09 cells/mm(2) had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm(2) had a high risk of death (P=0.03) and a median survival time of 34 months. Conclusions: We shed light on the role of the PHLDA family as promising predictive biomarkers and potential therapeutic targets in LUAD and MM.
- Usefulness of complementary next-generation sequencing and quantitative immunohistochemistry panels for predicting brain metastases and selecting treatment outcomes of non-small cell lung cancer(2019) MACHADO-RUGOLO, Juliana; FABRO, Alexandre Todorovic; ASCHERI, Daniel; FARHAT, Cecilia; AB'SABER, Alexandre Muxfeldt; SA, Vanessa Karen de; NAGAI, Maria Aparecida; TAKAGAKI, Teresa; TERRA, Ricardo; PARRA, Edwin Roger; CAPELOZZI, Vera LuizaTo demonstrate the usefulness of complementary next-generation sequencing (NGS) and immunohistochemistry (IHC) counting, we analyzed 196 patients with non-small cell lung cancer who underwent surgical resection and adjuvant chemotherapy. Formalin-fixed, paraffin-embedded samples of adenocarcinoma (ADC), squamous cell carcinoma, and large cell carcinoma were used to prepare tissue microarrays and were examined by protein H-score IHC image analysis and NGS for oncogenes and proto-oncogenes and genes of tumor suppressors, immune checkpoints, epithelial-mesenchymal transition factors, tyrosine kinase receptors, and vascular endothelial growth factors. In patients with brain metastases, primary tumors expressed lower PIK3CA protein levels. Overexpression of p53 and a higher PD-LI protein H-score were detected in patients who underwent surgical treatment followed by chemotherapy as compared with those who underwent only surgical treatment The absence of brain metastases was associated with wild-type sequences of genes EGFR, CD267, CTLA-4, and ZEBI. The combination of protein overexpression according to IHC and mutation according to NGS was rare (ie, represented by a very low percentage of concordant cases), except for p53 and vascular endothelial growth factor. Our data suggest that protein levels detected by IHC may be a useful complementary tool when mutations are not detected by NGS and also support the idea to expand this approach beyond ADC to include squamous cell carcinoma and even large cell carcinoma, particularly for patients with unusual clinical characteristics. Conversely, well-pronounced immunogenotypic features seemed to predict the clinical outcome after univariate and multivariate analyses. Patients with a solid ADC subtype and mutated genes EGFR, CTLA4, PDCDILG2, or ZEBI complemented with PD-L1 or p53 protein lower expression that only underwent surgical treatment who develop brain metastases may have the worst prognosis.
- Clinical outcome of Brazilian patients with non-small cell lung cancer in early stage harboring rare mutations in epidermal growth factor receptor(2022) MACHADO-RUGOLO, J.; BALDAVIRA, C. M.; PRIETO, T. G.; OLIVIERI, E. H. R.; FABRO, A. T.; RAINHO, C. A.; CASTELLI, E. C.; RIBOLLA, P. E. M.; AB'SABER, A. M.; TAKAGAKI, T.; NAGAI, M. A.; CAPELOZZI, V. L.The common epidermal growth factor receptor (EGFR) mutations, such as the L858R point mutation in exon 21 and the in-frame deletional mutation in exon 19, have been definitively associated with response to EGFR-tyrosine kinase inhibitors (EGFR-TKI). However, the clinical outcome and response to treatment for many other rarer mutations are still unclear. In this study, we report the results of Brazilian patients in stage IB-IIIA non-small cell lung cancer (NSCLC) following complete resection with minimal residual disease and EGFR mutations treated with adjuvant chemotherapy and/or EGFR-TKIs. The frequency of EGFR mutations was investigated in 70 cases of early stage NSCLC. Mutations in exons 18 and 20, uncommon mutations in exons 19 and 21, as well as in exons 3, 7, 14, 16, 22, 27, and 28, and/or the presence of different mutations in a single tumor (complex mutations) are considered rare. EGFR mutations were detected in 23 tumors (32.9%). Fourteen cases carried rare mutations and were treated with platinum-based chemotherapy and two cases were treated with erlotinib. The clinical outcome is described case by case with references to the literature. Notably, we found two rare EGFR mutations and one of them with an unknown response to chemotherapy and/or EGFR-TKIs. We have provided complementary information concerning the clinical outcome and treatment of patients with early stage NSCLC for several rare EGFR mutations not previously or only rarely reported. Description of cases harboring rare mutations can support the decision-making process in this subset of patients.
- The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma(2023) LABERIANO-FERNANDEZ, Caddie; BALDAVIRA, Camila Machado; MACHADO-RUGOLO, Juliana; TAMEGNON, Auriole; PANDURENGAN, Renganayaki Krishna; AB'SABER, Alexandre Muxfeldt; BALANCIN, Marcelo Luiz; TAKAGAKI, Teresa Yae; NAGAI, Maria Aparecida; CAPELOZZI, Vera Luiza; PARRA, Edwin RogerSimple Summary Identifying biomarkers to guide immunotherapy regimens remains an unmet clinical need in malignant pleural mesothelioma. A potential source of such markers is tumor-associated macrophages (TAMs), which contribute to the immunosuppressive microenvironment of mesothelioma. By examining distinct subsets of pleural macrophages to identify their gene signatures and protein expression, we found that TAMs preferentially contribute to M2a and M2b phenotypes, and M2a, M2b, and M2c more specifically contributed to immune tolerance. CD206, ARG1, CD274, CD163, and MRP8-14 are potential therapeutic targets in this disease.Abstract Background: Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design. Methods: We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments. Results: The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors. Conclusions: The interactions between TAMs in situ and, particularly, CD206+ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.
conferenceObject Clinical Relevant Oncogenic Drivers in Advanced Adenocarcinoma Discloses New Therapeutic Targets in Negative EGFR/ALK/KRAS Patients(2017) MACHADO, Juliana; ASCHERI, Daniel; LEAO, Patricia; MILSONI, Priscila; OLIVEIRA, Rogerio; PARRA, Edwin; SA, Vanessa; FARHAT, Cecilia; RAINHO, Claudia; AB'SABER, Alexandre; NAGAI, Maria; TAKAGAKI, Teresa; FABRO, Alexandre; CAPELOZZI, VeraconferenceObject Protein and Molecular Alterations in EMT Pathways of Lung Cancer: A Comparative Analysis between NSCLCs(2017) MACHADO, Juliana; ASCHERI, Daniel; LEAO, Patricia; MILSONI, Priscila; OLIVEIRA, Rogerio; PARRA, Edwin; SA, Vanessa; FARHAT, Cecilia; AB'SABER, Alexandre; NAGAI, Maria; TAKAGAKI, Teresa; FABRO, Alexandre; CAPELOZZIL, Vera