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Breast cancer (BC) is the most common cancer in women, with incidence rates increasing globally in recent years. Therefore, it is important to find new molecules with prognostic and therapeutic value to improve therapeutic response and quality of life. The polyunsaturated fatty acids (PUFAs) metabolic pathway participates in various physiological processes, as well as in the development of malignancies. Although aberrancies in the PUFAs metabolic pathway have been implicated in carcinogenesis, the functional and clinical relevance of this pathway has not been well explored in BC. To evaluate the clinical significance of soluble epoxide hydrolase (EPHX2) expression in Mexican patients with BC using tissue microarrays (TMAs) and digital pathology (DP). Immunohistochemical analyses were performed on 11 TMAs with 267 BC samples to quantify this enzyme. Using DP, EPHX2 protein expression was evaluated solely in tumor areas. The association of EPHX2 with overall survival (OS) was detected through bioinformatic analysis in public databases and confirmed in our cohort via Cox regression analysis. Clear nuclear expression of EPHX2 was identified. Receiver operating characteristics (ROC) curves revealed the optimal cutoff point at 2.847062 × 10-3 pixels, with sensitivity of 69.2% and specificity of 67%. Stratification based on this cutoff value showed elevated EPHX2 expression in multiple clinicopathological features, including older age and nuclear grade, human epidermal growth factor receptor 2 (HER2) and triple negative breast cancer (TNBC) subtypes, and recurrence. Kaplan-Meier curves demonstrated how higher nuclear expression of EPHX2 predicts shorter OS. Consistently, multivariate analysis confirmed EPHX2 as an independent predictor of OS, with a hazard ratio (HR) of 3.483 and a 95% confidence interval of 1.804-6.724 (p < 0.001). Our study demonstrates for the first time that nuclear overexpression of EPHX2 is a predictor of poor prognosis in BC patients. The DP approach was instrumental in identifying this significant association. Our study provides valuable insights into the potential clinical utility of EPHX2 as a prognostic biomarker and therapeutic target in BC.
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Biomarcadores Tumorais , Neoplasias da Mama , Epóxido Hidrolases , Humanos , Epóxido Hidrolases/metabolismo , Epóxido Hidrolases/genética , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/genética , Pessoa de Meia-Idade , Prognóstico , Biomarcadores Tumorais/metabolismo , Idoso , Adulto , Núcleo Celular/metabolismo , Regulação para Cima , Regulação Neoplásica da Expressão Gênica , Curva ROC , Idoso de 80 Anos ou mais , Estimativa de Kaplan-MeierRESUMO
Currently, immunotherapy based on PD-1/PD-L1 pathway blockade has improved survival of non-small cell lung cancer (NSCLC) patients. However, differential responses have been observed by sex, where men appear to respond better than women. Additionally, adverse effects of immunotherapy are mainly observed in women. Studies in some types of hormone-dependent cancer have revealed a role of sex hormones in anti-tumor response, tumor microenvironment and immune evasion. Estrogens mainly promote immune tolerance regulating T-cell function and modifying tumor microenvironment, while androgens attenuate anti-tumor immune responses. The precise mechanism by which sex and sex hormones may modulate immune response to tumor, modify PD-L1 expression in cancer cells and promote immune escape in NSCLC is still unclear, but current data show how sexual differences affect immune therapy response and prognosis. This review provides update information regarding anti-PD-1/PD-L immunotherapeutic efficacy in NSCLC by sex, analyzing potential roles for sex hormones on PD-L1 expression, and discussing a plausible of sex and sex hormones as predictive response factors to immunotherapy.
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BACKGROUND: Epidemiological evidence associates chronic exposure to particulate matter (PM) with respiratory damage and lung cancer. Inhaled PM may induce systemic effects including inflammation and metastasis. This study evaluated whether PM induces expression of adhesion molecules in lung cancer cells promoting interaction with monocytes. METHODS: The expression of early and late adhesion molecules and their receptors was evaluated in A549 (human lung adenocarcinoma) cells using a wide range of concentrations of PM2.5 and PM10. Then we evaluated cellular adhesion between A549 cells and U937 (human monocytes) cells after PM exposure. RESULTS: We found higher expression of both early and late adhesion molecules and their ligands in lung adenocarcinoma cells exposed to PM2.5 and PM10 particles present in the air pollution at Mexico City from 0.03 µg/cm2 with a statistically significant difference (p ≤ 0.05). PM10 had stronger effect than PM2.5. Both PM also stimulated cellular adhesion between tumor cells and monocytes. CONCLUSIONS: This study reveals a comprehensive expression profile of adhesion molecules and their ligands upregulated by PM2.5 and PM10 in A549 cells. Additionally these particles induced cellular adhesion of lung cancer cells to monocytes. This highlights possible implications of PM in two cancer hallmarks i.e. inflammation and metastasis, underlying the high cancer mortality associated with air pollution.
Assuntos
Adenocarcinoma de Pulmão , Poluentes Atmosféricos , Poluição do Ar , Neoplasias Pulmonares , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/análise , Linhagem Celular , Cidades , Humanos , México , Material Particulado/análise , Material Particulado/toxicidadeRESUMO
OBJECTIVE: CD47 is an antiphagocytic molecule that contributes to tumor cell resistance in host immune surveillance. CD47 overexpression correlated with tumor progression and shorter survival in lung cancer. However, the expression and functional significance of CD47 in Non-Small Cell Lung Cancer (NSCLC) has not been completely understood. MATERIALS AND METHODS: In this retrospective study, CD47 expression was immunohistochemically examined in tumor biopsies from 169 NSCLC patients. The association of CD47 levels (H-score) with clinicopathological characteristics and survival outcomes was evaluated. RESULTS: CD47 protein was detected in 84% of patients with a median expression of 80% (0-100). Tumor CD47 levels above 1% and 50% were found in 84% and 65.7% of patients, respectively. While, median CD47 staining index was 160 (0-300). Patients were divided into two groups according to CD47 expression (high or low), using a cutoff value of 150. High CD47 expression was associated with wood smoke exposure (71.1% vs 28.9%, P = .013) and presence of EGFR (+) mutations (66.7% vs 33.3%, P = .04). Survival analysis carried out in the whole population did not show any association of CD47 expression and survival outcome. However, in patients with EGFR (+) mutations, CD47 expression was associated with higher progression-free survival (PFS) (12.2 vs. 4.4 months, P = .032). When the survival analysis was performed according to CD47 levels (cut off value: 150), both, PFS and overall survival (OS) were shortened in patients with a high expression of CD47 (10.7 vs. NR, P = .156) and (29.2 vs. NR months P = .023), respectively. CONCLUSIONS: CD47 overexpression is not a prognostic factor for PFS and OS in NSCLC patients. However, the presence of EGFR mutations and high expression of CD47 were associated with shortened PFS and OS. Coexpression of these markers represents a potential biomarker and characterizes a therapeutic niche for lung cancer.
Assuntos
Adenocarcinoma de Pulmão/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Antígeno CD47/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/mortalidade , Neoplasias Pulmonares/mortalidade , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Antígeno CD47/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
OBJECTIVE: Targeted next-generation sequencing (t-NGS) has revolutionized clinical diagnosis allowing multiplexed detection of genomic alterations. This study evaluated the profile of somatic mutations by t-NGS in Mexican patients with nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Genomic DNA was extracted from 90 lung adenocarcinomas and sequences were generated for a panel of 48 cancer genes. Epidermal Growth Factor Receptor (EGFR) mutations were detected in parallel by quantitative PCR. RESULTS: The mutational profile of NSCLC revealed alterations in 27 genes, where TP53 (47.8%) and EGFR (36.7%) exhibited the highest mutation rates. EGFR Q787 mutations were present in 14 cases (15.6%), 10 cases had exon 19 deletions (11.1%), seven cases had L858R (7.8%). The mutational frequency for genes like EGFR, MET, HNF1A, HER2 and GUSB was different compared to caucasian population. CONCLUSIONS: t-NGS improved NSCLC treatments efficacy due to its sensitivity and specificity. A distinct pattern of somatic mutations was found in Mexican population.
OBJETIVO: La secuenciación dirigida de nueva generación (SNG) permite la detección múltiple de mutaciones. Este estudio evalúa el perfil de mutaciones somáticas por SNG en pacientes mexicanos con cáncer de pulmón de células no pequeñas(CPCNP). MATERIAL Y MÉTODOS: Se aisló ADN de 90 muestras de pacientes con CPCNP y se analizarón 48 genes relacionados con cáncer. Las mutaciones del receptor del factor de crecimiento epidérmico (EGFR) se detectaron por PCR cuantitativa. RESULTADOS: Se detectaron alteraciones en 27 genes. Las mutaciones más frecuentes fueron TP53 (47.8%) y EGFR (36.7%). En el gen EGFR, 14 casos fueron mutaciones Q787 (15.6%), 10 presentaron microdeleciones en el exón 19 (11.1%), y siete en L858R (7.8%). La frecuencia de mutación en EGFR, MET, HNF1A, HER2 y GUSB fue diferente en comparación con población caucásica. CONCLUSIONES: NGS modifica el tratamiento del paciente con CPCNP por su sensibilidad y especificidad para detectar mutaciones. La población mexicana presenta un perfil mutacional particula.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Pulmonares/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sequência de DNARESUMO
Lung cancer (LC) is the first cause of cancer-related deaths worldwide. Elucidating the pathogenesis of LC will give information on key elements of tumor initiation and development while helping to design novel targeted therapies. LC is an heterogeneous disease that has the second highest mutation rate surpassed only by melanoma, since 90% of LC occurs in tobacco smokers. However, only a small percent of smokers develops LC, indicating an inherent genomic instability. Additionally, LC in never smokers suggests other molecular mechanisms not causally linked to tobacco carcinogens. This review presents a current outlook of the connection between LC and genomic instability at the molecular and clinical level summarizing its implications for diagnosis, therapy, and prognosis. The genomic landscape of LC shows widespread alterations such as DNA methylation, point mutations, copy number variation, chromosomal translocations, and aneuploidy. Genome maintenance mechanisms including cell cycle control, DNA repair, and mitotic checkpoints open a window to translational research for finding novel diagnostic biomarkers and targeted therapies in LC.
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Abstract: Objective: Targeted next-generation sequencing (t-NGS) has revolutionized clinical diagnosis allowing multiplexed detection of genomic alterations. This study evaluated the profile of somatic mutations by t-NGS in Mexican patients with non-small cell lung cancer (NSCLC). Materials and methods: Genomic DNA was extracted from 90 lung adenocarcinomas and sequences were generated for a panel of 48 cancer genes. Epidermal Growth Factor Receptor (EGFR) mutations were detected in parallel by quantitative PCR. Results: The mutational profile of NSCLC revealed alterations in 27 genes, where TP53 (47.8%) and EGFR (36.7%) exhibited the highest mutation rates. EGFR Q787 mutations were present in 14 cases (15.6%), 10 cases had exon 19 deletions (11.1%), seven cases had L858R (7.8%). The mutational frequency for genes like EGFR, MET, HNF1A, HER2 and GUSB was different compared to caucasian population. Conclusion: t-NGS improved NSCLC treatments efficacy due to its sensitivity and specificity. A distinct pattern of somatic mutations was found in Mexican population.
Resumen: Objetivo: La secuenciación dirigida de nueva generación (SNG) permite la detección múltiple de mutaciones. Este estudio evalúa el perfil de mutaciones somáticas por SNG en pacientes mexicanos con cáncer de pulmón de células no pequeñas (CPCNP). Material y métodos: Se aisló ADN de 90 muestras de pacientes con CPCNP y se analizarón 48 genes relacionados con cáncer. Las mutaciones del receptor del factor de crecimiento epidérmico (EGFR) se detectaron por PCR cuantitativa. Resultados. Se detectaron alteraciones en 27 genes. Las mutaciones más frecuentes fueron TP53 (47.8%) y EGFR (36.7%). En el gen EGFR, 14 casos fueron mutaciones Q787 (15.6%), 10 presentaron microdeleciones en el exón 19 (11.1%), y siete en L858R (7.8%). La frecuencia de mutación en EGFR, MET, HNF1A, HER2 y GUSB fue diferente en comparación con población caucásica. Conclusión: NGS modifica el tratamiento del paciente con CPCNP por su sensibilidad y especificidad para detectar mutaciones. La población mexicana presenta un perfil mutacional particular.
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Pulmonares/genética , Mutação , Estudos Prospectivos , Análise de Sequência de DNA , MéxicoRESUMO
Triple-negative breast cancer (TNBC) is one of the most aggressive tumors, with poor prognosis and high metastatic capacity. The aggressive behavior may involve inflammatory processes characterized by deregulation of molecules related to the immunological responses in which interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) are involved. It is known that calcitriol, the active vitamin D metabolite, modulates the synthesis of immunological mediators; however, its role in the regulation of IL-1ß and TNF-α in TNBC has been scarcely studied. In the present study, we showed that TNBC cell lines SUM-229PE and HCC1806 expressed vitamin D, IL-1ß, and TNF-α receptors. Moreover, calcitriol, its analogue EB1089, IL-1ß, and TNF-α inhibited cell proliferation. In addition, we showed that synthesis of both IL-1ß and TNF-α was stimulated by calcitriol and its analogue. Interestingly, the antiproliferative activity of calcitriol was significantly abrogated when the cells were treated with anti-IL-1ß receptor 1 (IL-1R1) and anti-TNF-α receptor type 1 (TNFR1) antibodies. Furthermore, the combination of calcitriol with TNF-α resulted in a greater antiproliferative effect than either agent alone, in the two TNBC cell lines and an estrogen receptor-positive cell line. In summary, this study demonstrated that calcitriol exerted its antiproliferative effects in part by inducing the synthesis of IL-1ß and TNF-α through IL-1R1 and TNFR1, respectively, in TNBC cells, highlighting immunomodulatory and antiproliferative functions of calcitriol in TNBC tumors.
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Calcitriol/farmacologia , Proliferação de Células/efeitos dos fármacos , Interleucina-1beta/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Fator de Necrose Tumoral alfa/imunologia , Calcitriol/análogos & derivados , Linhagem Celular Tumoral , Feminino , Humanos , Fatores Imunológicos/farmacologia , Interleucina-1beta/genética , Receptores Tipo I de Interleucina-1/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Lung cancer (LC) has a high rate of anorexia, which negatively affects quality-of-life and prognosis; however prevalence values may vary as per diagnostic test. There is no standard for anorexia diagnosis, currently the anorexia cachexia scale (A/CS) has been proposed as a tool for diagnosing anorexia with a consensus cutoff value of ≤24, nonetheless a validated cutoff value is required. The A/CS was evaluated in advanced Non-Small Cell Lung Cancer (NSCLC) patients to establish a cutoff value. The appetite item from the QLQ-C30 questionnaire and survival served as a standard reference. The cutoff value was associated with clinical and nutritional characteristics along with quality-of-life. Three hundred and twelve (312) NSCLC patients were evaluated. The mean A/CS value was 31 ± 9 and the identified cutoff value was 32.5 (sensitivity: 80.3% and specificity: 85%). The proportion of anorexia accurately diagnosed with the cutoff value of 24 was 26%, while with 32 it was 50%. The A/CS cutoff value of 32 was associated with clinical parameters, nutritional consumption, and quality-of-life, and independently associated with overall survival. A score of ≤32 in the A/CS is proposed for anorexia diagnosis in order to identify patients at risk of complications involving malnutrition related to LC.
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Anorexia/diagnóstico , Caquexia/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/complicações , Neoplasias Pulmonares/complicações , Adenocarcinoma/complicações , Adenocarcinoma/tratamento farmacológico , Idoso , Anorexia/terapia , Apetite , Caquexia/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Comportamento Alimentar , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Valores de Referência , Inquéritos e QuestionáriosRESUMO
Adenocarcinomas of the ampulla of Vater account for 0.5% of malignant neoplasms of the gastrointestinal tract and 6% to 20% of malignant periampullary neoplasms, with most patients being candidates for elective surgery. Our objective was to evaluate the clinicopathological prognostic factors of ampullary adenocarcinomas after surgical resection in a Mexican population. From the records of the Department of Pathology at the Instituto Nacional de Cancerología, México, cases diagnosed as adenocarcinomas of the ampulla of Vater were selected over a period of 11 years, from January 2005 to September 2015. Cases with a pancreaticoduodenectomy report were included, and from each case, demographic and pathological data of the surgical specimen were obtained. Univariate and multivariate statistical analyses were performed using the log-rank test and Cox regression. Of 157 cases diagnosed as ampullary adenocarcinomas, 104 patients were excluded as not eligible for surgical treatment at the time of diagnosis. In the remaining 53 patients, a pancreaticoduodenectomy was performed. The mean age of the entire group was 55.4 years, and most were men. Intestinal-type adenocarcinomas were more frequent (77.4%) than pancreatobiliary-type (15.1%), with most being without perineural invasion, well to moderately differentiated, and less than 3 cm in size. Lymph node metastasis and age greater than 65 years had a negative impact on overall survival of the patients. The most convenient classification of malignant epithelial tumors of the Vaterian system is according to the histopathologic phenotype grouped into intestinal-, pancreatobiliary-, and mixed-type adenocarcinomas, as well as uncommon variants.
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Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias do Ducto Colédoco/patologia , Neoplasias Duodenais/patologia , Adenocarcinoma/mortalidade , Adulto , Idoso , Ampola Hepatopancreática/patologia , Carcinoma Ductal Pancreático/mortalidade , Neoplasias do Ducto Colédoco/mortalidade , Estudos Transversais , Neoplasias Duodenais/mortalidade , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , PrognósticoRESUMO
Curcumin has protective effects against toxic agents and shows preventive properties for various diseases. Particulate material with an aerodynamic diameter of ≤10 µm (PM10) and titanium dioxide nanoparticles (TiO2-NPs) induce endothelial dysfunction and activation. We explored whether curcumin is able to attenuate different events related to endothelial activation. This includes adhesion, expression of adhesion molecules and oxidative stress induced by PM10 and TiO2-NPs. Human umbilical vein endothelial cells (HUVEC) were treated with 1, 10 and 100 µM curcumin for 1 h and then exposed to PM10 at 3 µg/cm2 or TiO2-NPs at 10 µg/cm2. Cell adhesion was evaluated by co-culture with U937 human myelomonocytic cells. Adhesion molecules expression was measured by flow cytometry after 3 or 24 h of exposure. Oxidative stress was determined by 2,7-dichlorodihydrofluorescein (H2DCF) oxidation. PM10 and TiO2-NPs induced the adhesion of U937 cells and the expression of E- and P-selectins, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1). The expression of E- and P-selectins matched the adhesion of monocytes to HUVEC after 3 h. In HUVEC treated with 1 or 10 µM curcumin, the expression of adhesion molecules and monocytes adhesion was significantly diminished. Curcumin also partially reduced the H2DCF oxidation induced by PM10 and TiO2-NPs. Our results suggest an anti-inflammatory and antioxidant role by curcumin attenuating the activation caused on endothelial cells by exposure to particles. Therefore, curcumin could be useful in the treatment of diseases where an inflammatory process and endothelial activation are involved.
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Antioxidantes/farmacologia , Curcumina/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Nanopartículas/toxicidade , Material Particulado/antagonistas & inibidores , Biomarcadores/metabolismo , Adesão Celular/efeitos dos fármacos , Cidades , Técnicas de Cocultura , Selectina E/genética , Selectina E/metabolismo , Fluoresceínas/química , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , México , Estresse Oxidativo/efeitos dos fármacos , Selectina-P/genética , Selectina-P/metabolismo , Material Particulado/farmacologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Titânio/farmacologia , Células U937 , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
BACKGROUND: C-met and its ligand, hepatocyte growth factor (HGF) have been associated with the resistance mechanism of EGFR-TKIs. HGF was evaluated as a clinical-marker of response in NSCLC patients treated with afatinib. METHODS: Sixty-six patients with stage IIIB/IV lung adenocarcinoma and progression to any-line chemotherapy received afatinib 40 mg/day. Mutational EGFR and HER2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Serum HGF content was measured by ELISA before and 2 months after the start of treatment. HGF levels were assessed with the objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS). This trial was registered on ClinicalTrials.gov: NCT01542437. RESULTS: Fifty patients (75 %) were EGFR mutation positive. Response was achieved in 59 % of all patients and 78 % of EGFR mutated patients. Median PFS was 10 [95 % CI 6.8-13.1] and 14.5 months [10.9-18.9] for all and EGFR mutated patients, respectively. Median OS was 22.8 [17.5-28.1] and 32.4 months [18.3-46.6] for all and EGFR mutated patients, respectively. Patients with reduced serum HGF levels had improved ORR (75 % vs 44 %; p = 0.011), PFS (15.1 [2.9-27.3] vs 6.5 months [3.9-9.1]; p = 0.005) and OS (NR vs 14.5 months [7.8 - 21.3] p = 0.007). A reduction in serum HGF levels was an independent factor associated with longer PFS (HR 0.40; p = 0.021) and OS (HR 0.31; p = 0.006) in all and EGFR mutated patients. CONCLUSIONS: A reduction in serum HGF levels was associated with improved outcomes in patients treated with afatinib. These results suggest HGF might have a role as a mechanism of resistance to EGFR-TKIs. HGF could represent a potential therapeutic target to prevent or reverse resistance particularly in EGFR mutated patients.
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Adenocarcinoma/tratamento farmacológico , Fator de Crescimento de Hepatócito/sangue , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Adenocarcinoma de Pulmão , Afatinib , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Quinazolinas/administração & dosagem , Quinazolinas/farmacologia , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/farmacologia , Resultado do TratamentoRESUMO
Inflammation is a component of the tumor microenvironment and represents the 7th hallmark of cancer. Chronic inflammation plays a critical role in tumorigenesis. Tumor infiltrating inflammatory cells mediate processes associated with progression, immune suppression, promotion of neoangiogenesis and lymphangiogenesis, remodeling of extracellular matrix, invasion and metastasis, and, lastly, the inhibition of vaccine-induced antitumor T cell response. Accumulating evidence indicates a critical role of myeloid cells in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages (TAMs), the significance of granulocytes in cancer has only recently begun to emerge with the characterization of tumor-associated neutrophils (TANs). Recent studies show the importance of CD47 in the interaction with macrophages inhibiting phagocytosis and promoting the migration of neutrophils, increasing inflammation which can lead to recurrence and progression in lung cancer. Currently, therapies are targeted towards blocking CD47 and enhancing macrophage-mediated phagocytosis. However, antibody-based therapies may have adverse effects that limit its use.
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Mediadores da Inflamação/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Animais , Antígeno CD47/metabolismo , Humanos , Neutrófilos/metabolismo , Microambiente Tumoral/imunologiaRESUMO
OBJECTIVE: Sixteen percent of US population is Hispanic, mostly Mexican. Recently, two independent American reports demonstrated a higher overall survival (OS) in Hispanic populations compared with non-Hispanic-white populations (NHW) with non-small-cell lung cancer (NSCLC), even when most Hispanic patients are diagnosed at advanced disease stages and have lower income status. We analyzed the clinical, pathological, and molecular characteristics as well as outcomes in a cohort of NSCLC Hispanic patients from the National Cancer Institute of Mexico that could explain this "Hispanic Paradox". MATERIAL AND METHODS: A cohort of 1260 consecutive NSCLC patients treated at the National Cancer Institute of Mexico from 2007 to 2014 was analyzed. Their clinical-pathological characteristics, the presence of EGFR and KRAS mutations and the prognosis were evaluated. RESULTS: Patients presented with disease stages II, IIIa, IIIb and IV at rates of 0.6, 4.8, 18.4 and 76.3%, respectively. NSCLC was associated with smoking in only 56.5% of the patients (76.7% of male vs. 33.0% of female patients). Wood smoke exposure (WSE) was associated with 37.2% of the cases (27.3% in men vs. 48.8% in women). The frequency of EGFR mutations was 27.0% (18.5% in males vs. 36.9% in females, p<0.001) and the frequency for KRAS mutations was 10.5% (10.3% men vs. 10.1% in women p=0.939). The median OS for all patients was 23.0 [95% CI 19.4-26.2], whereas for patients at stage IV, it was 18.5 months [95% CI 15.2-21.8]. The independent factors associated with the OS were the ECOG, disease stage, EGFR and KRAS mutation status. CONCLUSION: The high frequency of EGFR mutations and low frequency of KRAS mutations in Hispanic populations and different prevalence in lung cancer-related-developing risk factors compared with Caucasian populations, such as the lower frequency of smoking exposure and higher WSE, particularly in women, might explain the prognosis differences between foreign-born-Hispanics, US-born-Hispanics and NHWs.
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Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Receptores ErbB/genética , Feminino , Hispânico ou Latino , Humanos , Masculino , México , Pessoa de Meia-Idade , Prognóstico , Fumaça/efeitos adversos , Fumar/efeitos adversos , Adulto Jovem , Proteínas ras/genéticaRESUMO
We studied the endophytic mycoflora associated with Taxus globosa, the Mexican yew. The study localities; Las Avispas (LA), San Gaspar (SG), and La Mina (LM) were three segments of cloud forest within the range of Sierra Gorda Biosphere Reserve, México. Overall, 245 endophytes were isolated and 105 representative Ascomycota (morphotaxons) were chosen for phylogenetic and genotypic characterization. Maximum likelihood analyses of large subunit of ribosomal RNA (LSU) rDNA showed well-supported clades of Dothideomycetes, Eurotiomycetes, Leotiomycetes, Pezizomycetes, and Sordariomycetes. Analyses of ITS rDNA groups showed 57 genotypes (95% sequence similarity), in general consistent with the phylogenetically delimitated taxa based on LSU rDNA sequences. The endophyte diversity measured by Fisher's α, Shanonn, and Simpson indices was ca. three-fold and ca. two-fold greater in LM than in LA and SG respectively. A screening for paclitaxel using a competitive inhibition enzyme immunoassay showed 16 positive isolates producing between 65 and 250 ng l(-1). The isolates included Acremonium, Botryosphaeria, Fusarium, Gyromitra, Nigrospora, Penicillium, three novel Pleosporales, and Xylaria.