41 research outputs found
Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC
No full textThe efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response
Cross-method comparison for BRAF p.V600 mutation cfDNA testing in Melanoma: BRAFI study
No full textMelanoma; Mutació BRAF; Biòpsia líquidaMelanoma; Mutación BRAF; Biopsia líquidaMelanoma; BRAF mutation; Liquid biopsyBackground
BRAF p.V600 mutation is the most frequent molecular driver alteration in melanoma. Detection of BRAF mutations in circulating-free DNA (cfDNA) reflects the shedding of tumor DNA and offers a potential non-invasive biomarker for disease monitoring and prognosis. However, the lack of standardized methodologies and inter-assay variability hinders its clinical implementation.
Methods
The sensitivity, agreement and concordance of seven BRAF mutation detection assays were assessed across four laboratories. BRAF p.V600 mutation in pretreatment plasma samples was analyzed in 51 patients diagnosed with advanced stage melanoma using two digital PCR-based assays (droplet digital PCR -ddPCR- Bio-Rad and microfluidic digital PCR -Absolute Q, ThermoFisher Scientific-), three RT-PCR based assays (Idylla®, Cobas®, PNA-Q-PCR) and two NGS based assays (Oncomine™ Pan-Cancer Cell-Free Assay and Illumina Platforms).
Results
digital PCR-based assays and Cobas® exhibited the highest sensitivity (51.0 %), followed by NGS Illumina® (45.1 %), Oncomine NGS / PNA-Q-PCR (43.1 %) and Idylla® (37.2 %). Results of different techniques showed a moderate to strong agreement, except for the comparison of Cobas with Idylla that was poor (Kappa=0.57). There was near-perfect agreement on detection of BRAF mutation between both NGS platforms and the NGS Illumina® with PNA-Q-PCR (Kappa = 0.92). Concordance of the quantitative results in terms of mutant allele frequency was near-perfect between NGS Illumina and ddPCR Bio-Rad assays (ICC = 0.99).
Conclusions
Our study demonstrates substantial agreement among multiple cfDNA BRAF mutation detection assays, particularly between NGS and digital PCR assays. These findings support the potential utility of different techniques for BRAF testing in cfDNA.This study was supported by the Novartis Group
BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer
No full textAltres ajuts: Fellowship Award of the International Association for the Study of Lung Cancer i grant of the Italian Association for Cancer Research (AIRC My First AIRC Grant n° 14282).Altres ajuts: RTICC/RD12/0036/0072Abstract.BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR
Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients
No full textBackground: Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8 + T-cells were also evaluated. Progression-free survival and overall survival were estimated. Results: A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression. Conclusions: IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1
Prospective Investigation of Nanoplastic Accumulation in Healthy Subjects, Autoimmune Diseases, Hematological Malignancies, Lung Cancer, and Murine Models
No full textNanoplastics (NPs) and microplastics (MPs) are an emerging threat to global health. They negatively impact ecosystems and many physiological processes, causing alterations in xenobiotic metabolism, nutrient uptake, energy metabolism, or cytotoxicity. In humans, we are beginning to analyze these plastics for the mechanisms by which they enter the organism, accumulate and diffuse, and for their pathogenic potential. NP accumulation has been demonstrated in human tissues, such as blood or placenta, while in others it remains largely unstudied. In this work, we have detected NP accumulation in bronchoalveolar lavage fluids (BALF), cerebrospinal fluids (CSF), lymph nodes (LN), urine, pleural fluids (PF), ascitic fluids (AF) and peripheral blood (PB) by combining fluorescence and nanocytometry techniques. NP analysis has been compared with mouse animal models, suggesting that inhalation is the main route of NP accumulation
Prospective Investigation of Nanoplastic Accumulation in Healthy Subjects, Autoimmune Diseases, Hematological Malignancies, Lung Cancer, and Murine Models
No full textNanoplastics (NPs) and microplastics (MPs) are an emerging threat to global health. They negatively impact ecosystems and many physiological processes, causing alterations in xenobiotic metabolism, nutrient uptake, energy metabolism, or cytotoxicity. In humans, we are beginning to analyze these plastics for the mechanisms by which they enter the organism, accumulate, and diffuse as well as for their pathogenic potential. NP accumulation has been demonstrated in human tissues, such as blood or placenta, while in others it remains largely unstudied. In this work, we detected NP accumulation in bronchoalveolar lavage fluids (BALFs), cerebrospinal fluids (CSFs), lymph nodes (LNs), urine, pleural fluids (PFs), ascitic fluids (AFs), and peripheral blood (PB) by combining fluorescence and nanocytometry techniques. NP analysis was compared with two strains of mice, and the results support that inhalation is the main route of NP accumulation
BRAF mutations classes I, II, and III in NSCLC patients included in the SLLIP trial : The need for a new pre-clinical treatment rationale
No full textBRAF V600 mutations have been found in 1-2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50-80% of BRAF mutations in lung cancer are non-V600, and can be class II, with intermediate to high kinase activity and RAS independence, or class III, with impaired kinase activity, upstream signaling dependence, and consequently, sensitivity to receptor tyrosine kinase (RTK) inhibitors. Plasma cell-free DNA (cfDNA) of 185 newly diagnosed advanced lung adenocarcinoma patients (Spanish Lung Liquid versus Invasive Biopsy Program, SLLIP, NCT03248089) was examined for BRAF and other alterations with a targeted cfDNA next-generation sequencing (NGS) assay (Guardant360®, Guardant Health Inc., CA, USA), and results were correlated with patient outcome. Cell viability with single or combined RAF, MEK, and SHP2 inhibitors was assessed in cell lines with BRAF class I, II, and III mutations. Out of 185 patients, 22 had BRAF alterations (12%) of which seven patients harbored amplifications (32%) and 17 had BRAF mutations (77%). Of the BRAF mutations, four out of 22 (18%) were V600E and 18/22 (82%) were non-V600. In vitro results confirmed sensitivity of class III and resistance of class I and II BRAF mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III BRAF-mutant cell line. Our study indicates that the class of the BRAF mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decision
El papel mediador de la disregulación emocional en la adherencia al tratamiento en adolescentes con diabetes mellitus tipo 1.
No full textntroducción:
La Diabetes Mellitus tipo 1 (DM1) es una enfermedad crónica que
requiere de un estrecho seguimiento y control terapéutico para la
prevención de complicaciones. Un peor funcionamiento ejecutivo
contribuye a un peor cumplimiento terapéutico y a un peor manejo de la
diabetes. El fenotipo de disregulación emocional se ha señalado como
un indicador de autorregulación deficiente, psicopatología general,
gravedad de los síntomas, exposición a la adversidad psicosocial y
deterioro funcional. Se desconoce el papel de la disregulación
emocional en la adherencia al tratamiento de la DM1.
Hipótesis y objetivos:
El objetivo del presente estudio es determinar el papel de l fenotipo
de disregulación emocional en la adherencia al tratamiento de la DM1.
Se hipotetiza que el fenotipo de disregulación emocional mediará la
relación entre las funciones ejecutivas y la adherencia al tratamiento
de la DM1.
Población y método:
Se reclutaron 55 pacientes entre 10 y 18 años con un diagnóstico de
DM1 de al menos 3 años de evolución atendidos en el Servicio de
endocrinología infantil de los Hospitales Universitarios Gregorio
Marañón y Fundación Jiménez Díaz.
Se evaluó la adherencia al tratamiento a la DM1 con la escala de vida
relacionada con la DM1 (PedsQL- heteroinformada), las funciones
ejecutivas con un cuestionario heteroaplicado (BRIEF-2) y la
disregulación emocional con la subescala del Cuestionario de
Capacidades y Dificultades (SDQ-Dysregulation Profile).
Se desarrollaron modelos de mediación para evaluar el papel de la
disregulación emocional como variable de mediación en la relación
entre las funciones ejecutivas y la adherencia al tratamiento de la
DM1. Los modelos de mediación se analizaron mediante métodos de
muestreo Bootstrap.
Resultados:
Se halló una correlación estadísticamente significativa entre la
variable Independiente (BRIEF-2) y el mediador propuesto (SDQ-DP). Los
resultados apoyan el modelo de mediación total de la disregulación
emocional en la relación entre las funciones ejecutivas y la
adherencia al tratamiento de la DM1. El efecto indirecto mediante
bootstrapping apoya el modelo de mediación ya que el efecto indirecto
es significativamente diferente de cero en p<.05 (0.098).
Discusión:
Este estudio es pionero en presentar la disregulación emocional como
un potencial factor de riesgo en la adherencia al tratamiento de la
DM1. El fenotipo de disregulación emocional medido por el SDQ-DP
parece mediar de forma completa la asociación establecida entre
alteraciones en la función ejecutiva y la adherencia al tratamiento en
la DM1
Conclusiones:
El objetivo principal del tratamiento en la DM1 es proporcionar al
paciente las herramientas necesarias para lograr el mejor control de
su enfermedad a fin de evitar, retardar o detener las complicaciones
agudas y a largo plazo. El perfil de disregulación emocional podría
ser un factor de riesgo en la adherencia al tratamiento de la DM1. Se
requieren más estudios y diseños prospectivos para confirmar el papel
mediador de la disregulación emocional de las funciones ejecutivas y
la adherencia al tratamiento en la DM1.
Bibliografía:
Hilliard ME, Harris MA, Weissberg-Benchell J. Diabetes resilience: a
model of risk and protection in type 1 diabetes. Curr Diab Rep. 2012
Dec;12(6):739-48.
Sildorf SM, Breinegaard N, Lindkvist EB, Tolstrup JS, Boisen KA,
Teilmann GK, Skovgaard AM, Svensson J. Poor Metabolic Control in
Children and Adolescents With Type 1 Diabetes and Psychiatric
Comorbidity. Diabetes Care. 2018 Nov;41(11):2289-2296
Carballo JJ, Serrano-Drozdowskyj E, García Nieto R, Díaz de
Neira-Hernando M, Pérez-Fominaya M, Molina-Pizarro CA, De
León-Martínez V, Baca-García E. Prevalence and correlates of
psychopathology in children and adolescents evaluated with the
strengths and difficulties questionnaire dysregulation profile in a
clinical setting. Psychopathology. 2014;47(5):303-11.2022-2
Prognostic Significance of PD-L1 Expression on Circulating Myeloid-Derived Suppressor Cells in NSCLC Patients Treated with Anti-PD-1/PD-L1 Checkpoint Inhibitors
No full textEven though anti-PD-1/PD-L1 immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) have improved survival, a high percentage of patients still do not respond to ICIs. Myeloid-derived suppressor cells (MDSCs) are circulating cells that express PD-L1 and can infiltrate and proliferate in the tumor microenvironment, inducing immunosuppression. By evaluating changes in PD-L1 expression of live peripheral blood MDSCs, we are able to define a new PD-L1 index, useful in predicting ICI escape in NSCLC patients before initiating anti-PD-1/PD-L1 immunotherapy. In this study, a cohort of 37 NSCLC patients was prospectively analyzed, obtaining independent PD-L1 indexes. In patients with a PD-L1 index > 5.88, progressive disease occurred in 58.33% of patients [median progression-free survival (PFS) = 5.73 months; 95%CI = 2.67–20.53], showing significant differences when compared with patients with a PD-L1 index ≤ 5.88, in whom 7.69% progressed and median PFS was not reached (NR); p-value = 0.0042. Overall survival (OS) was significantly worse in patients with a high vs. low PD-L1 index (41.67% vs. 76.92%; median OS = 18.03 months, 95%CI = 6.77–25.23 vs. NR, 95%CI = 1.87-NR; p-value = 0.035). The PD-L1 index can be applied to stratify NSCLC patients according to their probability of response to ICIs at baseline. In addition to quantifying tumoral expression, this index could be used to compare nonresponse to treatment
