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Non-small cell lung cancer (NSCLC) driven by activating mutations in epidermal growth factor receptor (EGFR) constitutes up to 10% of NSCLC cases. According to the NCCN recommendations, all patients (with the exception of smoking patients with squamous cell lung cancer) should be screened for the presence of activating EGFR mutations, i.e. deletion in exon 19 or point mutation L858R in exon 21, in order to select the group that benefits from EGFR tyrosine kinase inhibitors (EGFR TKIs) treatment. Among approved agents there are the 1st generation reversible EGFR TKIs, erlotinib and gefitinib, and the 2nd generation irreversible EGFR TKI, afatinib. The objective response rates to these drugs in randomised clinical trials were in the range of 56-74%, and median time to progression 9-13 months. The most common determinant of resistance to these drugs is the clonal expansion of cancer cells with T790M mutation (Thr790Met) in exon 20 of EGFR. Osimertinib (Tagrisso™), a 3rd generation, irreversible EGFR tyrosine kinase inhibitor, constitutes a novel, highly efficacious treatment for NSCLC patients progressing on EGFR TKIs with T790M mutation confirmed as the resistance mechanism. Resistance mutation can be determined in tissue or liquid biopsy obtained after progression on EGFR TKIs. Osimertinib has a favourable toxicity profile, with mild rash and diarrhoea being the most common. In this article, we present three cases that were successfully treated with osimertinib after progression on 1st and 2nd generation EGFR TKIs.
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Colorectal carcinoma (CRC) is one of the leading causes of cancer-related deaths worldwide. Alterations in keratin expression, including keratin 7 (K7), are frequent findings in multiple cancers, and they constitute a prognostic factor. The aim of our study was to evaluate the prognostic significance of K7 in the primary tumour and lymph node metastases in two separate cohorts of patients: the first one with lymph node involvement (LN+, 129 cases) and the second one free of LN metastases (LN-, 85 cases). Keratin 7 expression in CRC was analysed on tissue microarrays with immunohistochemistry and evaluated using the h-score. In the LN+ group K7 positivity was identified in 7/129 (5.4%) of primary tumours (PT) and lymph node metastases (LNM); concordance between them was 94% (ï«ï ï½ 0.396). Keratin 7 was expressed in 8/85 cases (9.4%) in the LN- group. K7 expression in LNM of the LN+ cohort correlated with shorter overall survival (OS) (p = 0.047) and presence of distant metastases at diagnosis (p = 0.005). Expression of K7 in the primary tumour in both cohorts did not correlate with survival. We conclude that the status of K7 expression in metastatic lymph nodes from CRC is a poor prognostic factor.
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Adenocarcinoma/patología , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/patología , Queratina-7/biosíntesis , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Queratina-7/análisis , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Matrices TisularesRESUMEN
BACKGROUND: The development of a more refined prognostic methodology for early non-small cell lung cancer (NSCLC) is an unmet clinical need. An accurate prognostic tool might help to select patients at early stages for adjuvant therapies. RESULTS: A new integrated bioinformatics searching strategy, that combines gene copy number alterations and expression, together with clinical parameters was applied to derive two prognostic genomic signatures. The proposed methodology combines data from patients with and without clinical data with a priori information on the ability of a gene to be a prognostic marker. Two initial candidate sets of 513 and 150 genes for lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), respectively, were generated by identifying genes which have both: a) significant correlation between copy number and gene expression, and b) significant prognostic value at the gene expression level in external databases. From these candidates, two panels of 7 (ADC) and 5 (SCC) genes were further identified via semi-supervised learning. These panels, together with clinical data (stage, age and sex), were used to construct the ADC and SCC hazard scores combining clinical and genomic data. The signatures were validated in two independent datasets (n = 73 for ADC, n = 97 for SCC), confirming that the prognostic value of both clinical-genomic models is robust, statistically significant (P = 0.008 for ADC and P = 0.019 for SCC) and outperforms both the clinical models (P = 0.060 for ADC and P = 0.121 for SCC) and the genomic models applied separately (P = 0.350 for ADC and P = 0.269 for SCC). CONCLUSION: The present work provides a methodology to generate a robust signature using copy number data that can be potentially used to any cancer. Using it, we found new prognostic scores based on tumor DNA that, jointly with clinical information, are able to predict overall survival (OS) in patients with early-stage ADC and SCC.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Dosificación de Gen/genética , Proteínas de Neoplasias/genética , Pronóstico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Femenino , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Genómica , Humanos , Estimación de Kaplan-Meier , Masculino , Proteínas de Neoplasias/biosíntesis , Estadificación de NeoplasiasRESUMEN
Significance: Chemotherapy is a primary method to treat cancer. While chemotherapeutic drugs are designed to target rapidly dividing cancer cells, they can also affect other cell types. In the case of dermal cells and macrophages involved in wound healing, cytotoxicity often leads to the development of chronic wounds. The situation becomes even more severe when chemotherapy is combined with surgical tumor excision. Recent Advances: Despite its significant impact on patients' recovery from surgery, the issue of delayed wound healing in individuals undergoing chemotherapy remains inadequately explored. Critical Issues: This review aims to analyze the harmful impact of chemotherapy on wound healing. The analysis showed that chemotherapy drugs could inhibit cellular metabolism, cell division, and angiogenesis and lead to nerve damage. They impede the migration of cells into the wound and reduce the production of extracellular matrix. At the molecular level, they interfere with replication, transcription, translation, and cell signaling. This work reviews skin problems that patients may experience during and after chemotherapy and demonstrates insights into the cellular and molecular mechanisms of these pathologies. Future Directions: In the future, the problem of impaired wound healing in patients treated with chemotherapy may be addressed by cell therapies like autologous keratinocyte transplantation, which has already proved effective in this case. Epigenetic intervention to mitigate the side effects of chemotherapy is also worth considering, but epigenetic consequences of chemotherapy on skin cells are largely unknown and should be investigated.
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Queratinocitos , Cicatrización de Heridas , Humanos , Cicatrización de Heridas/fisiología , Matriz ExtracelularRESUMEN
The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.
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Inestabilidad Cromosómica , Receptores ErbB , Neoplasias Pulmonares , Mutación , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Ratones , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Terapia Molecular Dirigida/métodos , Femenino , Variaciones en el Número de Copia de ADN , MasculinoRESUMEN
Background and Objective: Lung cancer remains the leading cause of cancer-related mortality and constitutes a significant societal burden. Recent advancements in targeted therapies and immunotherapy have considerably broadened therapeutic options in lung cancer, particularly in non-small-cell lung cancer (NSCLC). However, these novel methods necessitate sophisticated molecular diagnostics. Liquid biopsy, which refers to the cytological and molecular analysis of cancer markers shed by the tumor into the body fluids, may offer an attractive diagnostic tool at the individual patient level. This approach is particularly relevant for lung cancer, as the anatomical location of tumor lesions frequently makes them inaccessible for tissue biopsy. Apart from minimal invasiveness, the major advantages of liquid biopsy include better reflection of the tumor clonal heterogeneity (spatial heterogeneity), the possibility of sequential sampling, and real-time monitoring of tumor load and its evolving mutational status (temporal heterogeneity). Methods: This article reviews the available data in this field, current applications, and future perspectives in accordance with the Narrative Review reporting rules. Key Content and Findings: We discuss the most used approaches, i.e., circulating DNA and tumor cells, but also emerging liquid biopsy techniques, such as plasma DNA methylation, plasma metabolites and RNA, extracellular vesicles, and tumor-educated platelets in NSCLC. Finally, we highlight the current limitations of liquid biopsy techniques hampering their clinical applications. Conclusions: Due to their advantages, liquid biopsy-based approaches have recently gained immense interest in oncology. Potential applications of this method include early detection, informing precision medicine-based individualized treatment, and real-time monitoring of disease evolution and treatment. The development of next-generation sequencing has vastly extended genetic profiling, thus enabling better identification of druggable alterations. However, the clinical application of liquid biopsy techniques is still limited due to their suboptimal specificity and sensitivity, lack of standardization, and relatively high costs. Addressing these issues may allow further integration of liquid biopsies in the routine clinical setting, thus making a profound and permanent change in NSCLC management.
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Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Masculino , Humanos , Caquexia/complicaciones , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteómica , Recurrencia Local de Neoplasia/patología , Composición Corporal , Peso Corporal , Músculo Esquelético/metabolismo , Antígenos de Neoplasias/metabolismo , Proteínas de NeoplasiasRESUMEN
MicroRNAs (miRs) are short RNA chains that regulate gene expression by inhibition of mRNA translation. Their expression is often deranged in cancer. Increasing evidence indicates that these molecules play an important role in oncogenesis and cancer progression. This review focuses on the clinical application of miRs in lung cancer, with the emphasis on detection of early lung cancer, prognostication and chemotherapy sensitivity prediction. Methodological aspects of studies on prognostic markers in early NSCLC are outlined in detail. Finally, modulation of miR expression in lung cancer as a therapeutic possibility is discussed.
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Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , MicroARNs , Animales , Antineoplásicos/uso terapéutico , Biomarcadores/metabolismo , Ensayos Clínicos como Asunto , Detección Precoz del Cáncer/métodos , Humanos , PronósticoRESUMEN
PURPOSE: Current staging methods are imprecise for predicting prognosis of early-stage non-small-cell lung cancer (NSCLC). We aimed to develop a gene expression profile for stage I and stage II NSCLC, allowing identification of patients with a high risk of disease recurrence within 2 to 3 years after initial diagnosis. EXPERIMENTAL DESIGN: We used whole-genome gene expression microarrays to analyze frozen tumor samples from 172 NSCLC patients (pT1-2, N0-1, M0) from five European institutions, who had undergone complete surgical resection. Median follow-up was 89 months (range, 1.2-389) and 64 patients developed a recurrence. A random two thirds of the samples were assigned as the training cohort with the remaining samples set aside for independent validation. Cox proportional hazards models were used to evaluate the association between expression levels of individual genes and patient recurrence-free survival. A nearest mean analysis was used to develop a gene-expression classifier for disease recurrence. RESULTS: We have developed a 72-gene expression prognostic NSCLC classifier. Based on the classifier score, patients were classified as either high or low risk of disease recurrence. Patients classified as low risk showed a significantly better recurrence-free survival both in the training set (P < 0.001; n = 103) and in the independent validation set (P < 0.01; n = 69). Genes in our prognostic signature were strongly enriched for genes associated with immune response. CONCLUSIONS: Our 72-gene signature is closely associated with recurrence-free and overall survival in early-stage NSCLC patients and may become a tool for patient selection for adjuvant therapy.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Perfilación de la Expresión Génica , Neoplasias Pulmonares/genética , Estadificación de Neoplasias/métodos , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Humanos , Neoplasias Pulmonares/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Tasa de SupervivenciaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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PURPOSE: Clinical staging does not adequately risk stratify patients with early stage non-small cell lung cancer. We sought to generate a real-time PCR (RT-PCR)-based prognostic model in patients with early stage lung adenocarcinoma, the dominant histology of lung cancer in the United States. EXPERIMENTAL DESIGN: We studied gene expression of 61 candidate genes in 107 patients with completely surgically resected lung adenocarcinoma using RT-PCR. We used crossvalidation methods to select and validate a prognostic model based on the expression of a limited number of genes. A risk score was generated based on model coefficients, and survival of patients with high- and low-risk scores were analyzed. RESULTS: We generated a four-gene model based on expression of WNT3a, ERBB3, LCK, and RND3. Risk score predicted mortality better than clinical stage or tumor size (adjusted hazard ratio, 6.7; 95% confidence interval, 1.6-28.9; P=0.001). Among 70 patients with stage I disease, 5-year overall survival was 87% among patients with low-risk scores, and 38% among patients with high-risk scores (P=0.0002). Among all patients, 5-year overall survival was 62% and 41%, respectively (P=0.0054). Disease-free survival was also significantly different among low- and high-risk score patients. CONCLUSIONS: This multigene assay predicts overall and disease-free survival significantly better than clinical stage and tumor size in patients with early stage lung adenocarcinoma and performs especially well in patients with stage I disease. Prospective clinical trials are needed to determine whether high-risk patients with stage I disease benefit from adjuvant chemotherapy.
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Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/mortalidad , Anciano , Femenino , Expresión Génica , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Riesgo , Análisis de SupervivenciaRESUMEN
PURPOSE: Adjuvant treatment may improve survival in early-stage squamous cell carcinoma (SCC) of the lung; however, the absolute gain is modest and mainly limited to stage II-IIIA. Current staging methods are imprecise indications of prognosis, but high-risk patients can be identified by gene expression profiling and considered for adjuvant therapy. EXPERIMENTAL DESIGN: The expression of 29 genes was assessed by reverse transcriptase quantitative PCR in frozen primary tumor specimens obtained from 66 SCC patients who had undergone surgical resection. Expression values were dichotomized using the median as a cutoff value. We used a risk score to develop a gene expression model for the prediction of survival. RESULTS: The univariate analysis of gene expression in the training cohort identified 10 genes with significant prognostic value: CSF1, EGFR, CA IX, PH4, KIAA0974, ANLN, VEGFC, NTRK1, FN1, and INR1. In the multivariate Cox model, CSF1 (hazard ratio, 3.5; P = 0.005), EGFR (hazard ratio, 2.7; P = 0.02), CA IX (hazard ratio, 0.2; P < 0.0001), and tumor size >4 cm (hazard ratio, 2.7; P = 0.02) emerged as significant markers for survival. The high prognostic value of a risk score based on the expression of the three genes (CSF1, EGFR, and CA IX) was positively validated in a separate cohort of 26 patients in an independent laboratory (P = 0.05). CONCLUSIONS: The three-gene signature is strongly associated with prognosis in early-stage SCC. Positive independent validation suggests its suitability for selecting SCC patients with an increased risk of death who might benefit from adjuvant treatment.
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Antígenos de Neoplasias/biosíntesis , Anhidrasas Carbónicas/biosíntesis , Carcinoma de Células Escamosas/metabolismo , Receptores ErbB/biosíntesis , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/metabolismo , Factor Estimulante de Colonias de Macrófagos/biosíntesis , Adulto , Anciano , Anhidrasa Carbónica IX , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodosRESUMEN
PURPOSE OF REVIEW: Thoracic malignancies are amongst the most lethal of all cancers. Cancer cachexia lacks unanimously accepted diagnostic criteria, and therefore is referenced to as a conceptual framework whereby cancer cachexia is 'an ongoing loss of skeletal muscle mass (termed sarcopenia), with or without loss of fat mass that cannot be reversed by conventional nutritional support and leads to progressive functional impairment'. This review summarises the current evidence base in this field, including imaging techniques currently used to define sarcopenia, inflammatory and metabolic changes associated with the syndrome and ongoing research into potential treatment strategies. RECENT FINDINGS: Sarcopenia is a key component of the cancer cachexia syndrome. It is common in patients with both early-stage and advanced NSCLC. Patients with sarcopenia have more treatment-related side effects and poorer overall survival compared with nonsarcopenic patients. SUMMARY: Early identification of cancer cachexia may facilitate stratification of patients most-at-risk and initiation of emerging anticachexia treatments. If these are proven to be effective, this strategy has the potential to improve tolerance to anti-cancer therapies, improving the quality of life, and perhaps the survival, of patients with thoracic malignancies.
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Caquexia/etiología , Caquexia/fisiopatología , Sarcopenia/etiología , Sarcopenia/fisiopatología , Neoplasias Torácicas/complicaciones , Anorexia/etiología , Anorexia/fisiopatología , Composición Corporal/fisiología , Caquexia/diagnóstico , Caquexia/terapia , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Metabolismo Energético , Humanos , Mediadores de Inflamación/metabolismo , Neoplasias Pulmonares/complicaciones , Músculo Esquelético/metabolismo , Obesidad/etiología , Obesidad/fisiopatología , Cuidados Paliativos , Sarcopenia/diagnóstico , Sarcopenia/terapiaRESUMEN
Resistance to chemotherapy remains a critical barrier to effective cancer treatment. Although cisplatin is one of the most commonly used chemotherapeutic agents in the treatment of non-small cell lung cancer (NSCLC), mechanisms of resistance to this drug are not fully understood. Here, we report a novel cisplatin-resistance mechanism involving SET Domain Containing 2 (SETD2), a histone H3 lysine 36 (H3K36) trimethyltransferase, and cAMP-responsive element-binding protein 1 (CREB1). A549 cells selected in vivo to give brain metastases exhibited cisplatin resistance and decreased expression of phosphorylated CREB1. Next-generation sequencing (NGS) analysis identified a missense mutation in SETD2 (p.T1171K), and we demonstrated that SETD2-mediated trimethylation of H3K36 (H3K36me3) and CREB1 phosphorylation are critical for cellular sensitivity to cisplatin. Moreover, we showed that suppression of SETD2 or CREB1 and ectopic expression of mutant SETD2 conferred cisplatin resistance through inhibition of H3K36me3 and ERK activation in NSCLC cells. Our results provide evidence that SETD2 and CREB1 contribute to cisplatin cytotoxicity via regulation of the ERK signaling pathway, and their inactivation may lead to cisplatin resistance.
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Carcinoma de Pulmón de Células no Pequeñas/patología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Resistencia a Antineoplásicos/genética , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias Pulmonares/patología , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cisplatino/farmacología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MutaciónRESUMEN
An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2-6. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.
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Evolución Clonal/genética , Neoplasias Pulmonares/genética , Pronóstico , Transcriptoma/genética , Anciano , Biomarcadores de Tumor/genética , Variaciones en el Número de Copia de ADN/genética , Supervivencia sin Enfermedad , Exoma/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Heterogeneidad Genética , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Factores de Riesgo , Secuenciación del ExomaRESUMEN
Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) is rapidly becoming a basic method in lung cancer research. Analysis of transcriptional activity of tumor cells or detection of tumor markers by this technique has the potential to change lung cancer diagnosis and treatment. Quantitative RT-PCR is characterized by unparalleled sensitivity and specificity, with very reliable reproducibility. Its prime advantage for gene expression analysis is its broad dynamic range of 10(7)-fold. Moreover, it is cost-effective, feasible in every day laboratory routine and efficient in terms of biological material consumption. Still, there are a number of methodological aspects that need to be carefully considered before it can sensibly be implemented into clinical practice. Three major technical issues: the choice of chemistries, gene expression data normalization and statistical processing of the results will be specifically highlighted in this review. Further, clinical applications of qRT-PCR will be thoroughly discussed: detection and staging of lung cancer and construction and validation of prognostic and predictive gene expression signatures.
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Biomarcadores de Tumor/genética , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Humanos , Neoplasias Pulmonares/diagnóstico , Pronóstico , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: The safety profile of venom immunotherapy is a relevant issue. We evaluated the frequency of severe adverse events (SAE), associated risk factors, retrospective comparison of pretreatment protocols including solely H1 receptor blockers and a combination of H1 and H2 receptor blockers during rush Hymenoptera venom immunotherapy. METHODS: The study group comprised 118 patients. The treatment was initiated according to a 5-day rush protocol with the use of standardized venom allergens of either wasp or honeybee. RESULTS: During the rush induction, side effects occurred in 18 patients (15.2%), whereas SAE were present in 7 patients (5.9%). Twelve out of 18 (66.6%) developed anaphylactic reactions on the fourth day of the rush protocol, with the majority of cases at a dose of 40 or 60 microg of the venom extract (p = 0.001). The frequency of SAE was also significantly higher on the fourth day than thereafter (p = 0.0001) as well as in patients allergic to bee venom (p = 0.049). All systemic side effects were more frequent in women (p = 0.0065). However, this relation was not true when SAE were consider (p = 0.11). A higher percentage of SAE was observed in the subjects pretreated with both H1 and H2 receptor antagonists than in those pretreated with H1 blocker only (8.8 vs. 4.1%); however, the difference was not significant. CONCLUSIONS: Considerable severity of allergic adverse events requires particular attention to patients allergic to bee venom and during rush phase, especially when rapidly increasing doses are administered. Pretreatment with H2 blockers is debatable and warrants further investigation.
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Venenos de Abeja/efectos adversos , Desensibilización Inmunológica/efectos adversos , Antagonistas de los Receptores Histamínicos H1 , Himenópteros/inmunología , Venenos de Avispas/efectos adversos , Adolescente , Adulto , Anciano , Anafilaxia/etiología , Anafilaxia/prevención & control , Anafilaxia/terapia , Animales , Venenos de Abeja/administración & dosificación , Venenos de Abeja/inmunología , Desensibilización Inmunológica/métodos , Femenino , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Mordeduras y Picaduras de Insectos/complicaciones , Mordeduras y Picaduras de Insectos/terapia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Resultado del Tratamiento , Venenos de Avispas/administración & dosificación , Venenos de Avispas/inmunologíaRESUMEN
The majority of stage III NSCLC patients managed with a combination of radiotherapy and chemotherapy will develop a locoregional or distant relapse. Concomitant radiochemotherapy allows for improved local control but has no impact on extrathoracic recurrences. To ameliorate this inefficiency the concept of consolidation treatment has been put forward, whereby systemically active doses of chemotherapy, targeted therapy or immune therapy are administered after completion of radiochemotherapy. Randomized trials failed to provide support for consolidation chemotherapy or anti-EGFR therapies. Recently durvalumab, an anti-PD-L1 checkpoint inhibitor, administered as consolidation treatment, was shown to substantially improve progression-free survival. This article critically reviews major studies addressing the role of consolidation systemic therapies following definitive concurrent radiochemotherapy and discusses prospects for future research.
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Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Quimioradioterapia/métodos , Quimioterapia de Consolidación/métodos , Neoplasias Pulmonares/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patología , Estadificación de NeoplasiasRESUMEN
OBJECTIVES: Overexpression of miR-192, miR-192* and miR-662 was previously found to correlate with poor prognosis of early-stage squamous cell lung cancer (SCC) patients. In this study, we investigated the relevance of these miRNAs to cancer cell biology and chemoresistance. MATERIALS AND METHODS: MiRNA expression profile was analysed in 10 non-small cell lung cancer (NSCLC) cell lines using RT-qPCR. H520 and H1703 cells were transfected with miRNA inhibitors (anti-miR-192, -192* and -662) for functional studies. Chemoresistance to cisplatin and etoposide was evaluated using MTT colorimetric assay. H520 cells were subjected to 3D soft-agar colony formation assay and H1703 cells to wound healing assay. Whole transcriptome analysis was used to assess the effect of miR-192 and miR-662 inhibition on gene expression. RESULTS: SCC cell lines, H520 and H1703, differed in miRNA expression and phenotypic features. MiR-192 and miR-662 inhibition decreased clonogenicity and motility of SCC cells. MiR-192 and miR-662 inhibition sensitized SCC cells to etoposide but not to cisplatin. Whole transcriptome analysis revealed genes regulated by miR-192 and miR-662 in SCC, relevant to maintaining chemoresistance, invasiveness, epithelial-mesenchymal transition (EMT) and immune evasion. CONCLUSIONS: We showed for the first time that miR-192 and miR-662 have functional role in SCC cells. Our findings suggest that targeting these miRNAs may impact both chemoresistance and invasiveness of SCC, and add to the evidence linking these aspects of tumour biology. Overexpression of miR-192 and miR-662 might be useful as a marker of resistance to etoposide.
Asunto(s)
Neoplasias Pulmonares/genética , MicroARNs/genética , Neoplasias de Células Escamosas/genética , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , Etopósido/uso terapéutico , Perfilación de la Expresión Génica , Humanos , Evasión Inmune/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Invasividad Neoplásica/genética , Neoplasias de Células Escamosas/tratamiento farmacológico , Neoplasias de Células Escamosas/patologíaRESUMEN
Mastocytosis is an uncommon disease classified as a myeloproliferative neoplasm, however, its symptoms are broad and place patients at crossroads between dermatology, hematology and allergology. Patients with mastocytosis often suffer from symptoms resulting from the activation and release of mediators from the mast cells, such as generalized itching, redness, headache, abdominal cramps, diarrhea, bone pain or arthritis, hypotension and shock. The possible severe, fatal or near fatal reactions caused by food hypersensitivity are reasons for the research focused on marker identification. The aim of the study was to analyse the gene expression differences in mastocytosis patients with and without food and drug hypersensitivity and insect venom allergy (IVA). A total of 57 Caucasian patients with mastocytosis were studied [median age 41.8; range 18-77 years; 15 (26.3 %) males and 42 (73.7 %) females]. Quantitative RT-PCRs of 11 genes plus ribosomal 18S RNA were run. Symptoms of food hypersensitivity were found in 12 patients (21 %), including 3 patients (13 %) with cutaneous mastocytosis (CM), and 9 (28 %) with indolent systemic mastocytosis (ISM). IVA was confirmed in 13 patients (22.8 %) including 6 patients (10.5 %) with CM, and 7 patients (12.3 %) with ISM. Drug hypersensitivity was diagnosed in 10 patients (17.5 %). Significant differences in the gene expression were found for TRAF4 (p = 0.008) in the comparison of the mastocytosis patients with and without concomitant food hypersensitivity. Furthermore significant differences were found in gene expression for B3GAT1 (p = 0.003) in patients with IVA compared to patients without insect sting anaphylaxis in the medical history. The expression of studied genes did not differ according to the presence of drug hypersensitivity. The TRAF4 expression was higher in mastocytosis patients with food hypersensitivity in their medical history, the B3GAT1 expression was lower in mastocytosis patients with IVA in history.