Diffuse coexpression of thyroid transcription factor-1 and p40 in a non-small cell carcinoma of the lung: Second case in the female population / Coexpresión difusa del factor de transcripción tiroidea 1 y p40 en un carcinoma de célula no pequeña del pulmón: segundo caso en la población de sexo femenino

Some non-small cell carcinomas of the lung can express TTF1 and p40 in the same tumor cells. This event has been described in only six cases prior to this one, and only in one other female. It is an extraordinary event that appears as a new entity yet to be defined. The case presented is a woman with a non-small cell lung carcinoma with diffuse coexpression of TTF1 and p40 in the same cells. (AU)

Algunos carcinomas de célula no pequeña del pulmón pueden expresar TTF1 y p40 en las mismas células tumorales. Este evento se ha descrito únicamente en 6 casos anteriores a este, y solo en otra persona del sexo femenino. Se trata de un evento extraordinario que se muestra como una nueva entidad todavía por definir. El caso que se presenta versa sobre una mujer con un carcinoma de pulmón de célula no pequeña con coexpresión difusa en las mismas células de TTF1 y p40. (AU)

Tumor-suppressive action of miR-30a-5p in lung adenocarcinoma correlates with ABL2 inhibition and PI3K/AKT pathway inactivation

Introduction ABL2 contributes to the oncogenic potential of cancers, pointing to its inhibition as a possible strategy against malignant diseases. Bioinformatics prediction of upstream effector miR-30a-5p for ABL2 allowed us to hypothesize and then validate mechanistic actions of miR-30a-5p in lung adenocarcinoma (LUAD). Materials and methods The ABL2 expression in LUAD was analyzed in the TCGA data, clinical samples, and cell lines. The shRNA-mediated silencing of ABL2 was introduced to illustrate its effect on malignant phenotypes of LUAD cells. The binding affinity between ABL2 and miR-30a-5p was verified by luciferase activity and RNA pull-down assay. Ectopic expression, knockdown methods, and PI3K inhibitor LY294002 were used to investigate their effects on in vitro biological characteristics and in vivo tumor growth of LUAD cells. Using nude mouse lung adenocarcinoma in situ and brain metastasis models to validate the inhibitory effect of miR-30a-5p on LUAD by regulating the ABL2/PI3K/AKT signaling axis. Results High expression of ABL2 and poor expression of miR-30a-5p were noticed in LUAD tissues and cell lines. Importantly, miR-30a-5p was demonstrated to target and downregulate ABL2, subsequently inactivating the PI3K/AKT pathway. miR-30a-5p inhibited the malignant phenotypes of LUAD cells by inhibiting ABL2 expression and inactivating the PI3K/AKT pathway. For in vivo experiments, miR-30a-5p was substantiated to thwart tumor tumorigenesis by regulating the ABL2/PI3K/AKT axis. In addition, miR-30a-5p suppresses the occurrence and development of in situ lung cancer and brain metastasis via the ABL2/PI3K/AKT signaling pathway. Conclusion This study underscores the inhibitory role of miR-30a-5p in LUAD through the ABL2/PI3K/AKT axis, which may be a viable target for LUAD treatment (AU)

Proteomics-based clustering of lung adenocarcinoma identifies three subtypes with significantly different clinical and molecular features

Background Lung adenocarcinoma (LUAD) is a predominant subtype of lung cancer. Although molecular classification of LUAD has been widely explored, proteomics-based subtyping of LUAD remains scarce. Methods We proposed a subtyping method for LUAD based on the expression profiles of 500 proteins with the largest expression variability across LUAD. Furthermore, we comprehensively compared molecular and clinical features among the LUAD subtypes. Results Consensus clustering identified three subtypes of LUAD, namely MtE, DrE, and StE. We demonstrated this subtyping method to be reproducible by analyzing two independent LUAD cohorts. MtE was characterized by high enrichment of metabolic pathways, high EGFR mutation rate, low stemness, proliferation, invasion, metastasis and inflammation signatures, favorable prognosis; DrE was characterized by high enrichment of DNA repair pathways, high TP53 mutation rate, and high levels of genomic instability, stemness, proliferation, and intratumor heterogeneity (ITH); and StE was characterized by high enrichment of stroma-related pathways, high KRAS mutation rate, and low levels of genomic instability Conclusions The proteomics-based clustering analysis identified three LUAD subtypes with significantly different molecular and clinical properties. The novel subtyping method offers new perspectives on the cancer biology and holds promise in improving the clinical management of LUAD (AU)

Relationship Between the Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) and Lung Adenocarcinoma Patterns: New Possible Insights

Introduction: This study aimed to evaluate a potential relationship between the diffusing capacity of the lung for carbon monoxide (DLCO) and the aggressiveness of lung adenocarcinoma (ADC). Methods: Patients who underwent radical surgery for lung ADC between 2001 and 2018 were retrospectively reviewed. DLCO values were dichotomized into DLCOlow (<80% of predicted) and DLCOnormal (≥80%). Relationships between DLCO and ADC histopathological features, clinical features, as well as with overall survival (OS), were evaluated. Results: Four-hundred and sixty patients were enrolled, of which 193 (42%) were included in the DLCOlow group. DLCOlow was associated with smoking status, low FEV1, micropapillary and solid ADC, tumour grade 3, high tumour lymphoid infiltrate and presence of tumour desmoplasia. In addition, DLCO values were higher in low-grade ADC and progressively decreased in intermediate and high-grade ADC (p=0.024). After adjusting for clinical variables, at multivariable logistic regression analysis, DLCOlow still showed a significant correlation with high lymphoid infiltrate (p=0.017), presence of desmoplasia (p=0.065), tumour grade 3 (p=0.062), micropapillary and solid ADC subtypes (p=0.008). To exclude the association between non-smokers and well-differentiated ADC, the relationship between DLCO and histopathological ADC patterns was confirmed in the subset of 377 former and current smokers (p=0.021). At univariate analysis, gender, DLCO, FEV1, ADC histotype, tumour grade, stage, pleural invasion, tumour necrosis, tumour desmoplasia, lymphatic and blood invasion were significantly related with OS. At multivariate analysis, only gender (p<0.001), tumour stage (p<0.001) and DLCO (p=0.050) were significantly related with the OS. Conclusions: We found a relationship between DLCO and ADC patterns as well as with tumour grade, tumour lymphoid infiltrate and desmoplasia, suggesting that lung damage may be associated with tumour aggressiveness. (AU)

Identification of a cuproptosis-related lncRNA prognostic signature in lung adenocarcinoma

Purpose Cuproptosis-related long non-coding RNA (lncRNA) diseases are associated with the occurrence and development of tumors. This study aimed to investigate whether cuproptosis-related lncRNA can predict the prognosis of patients with lung adenocarcinoma (LUAD). Methods Cuproptosis-related lncRNA prognosis (CLPS) model was successfully constructed through cox regression and lasso regression analyses. Then, the prognostic value of CLPS model was tested through the survival analysis, the ROC curve and the nomogram. Finally, the correlation of CLPS model with tumor immunity and tumor mutation burden was analyzed, and the potential susceptibility of drugs for LUAD were predicted. Results CLPS model for LUAD (AC090948.1, CRIM1-DT, AC026356.2, AC004832.5, AL161431.1) was successfully constructed, which has an independent prognostic value. Furthermore, the risk score of CLPS model was correlated with tumor immune characteristics and immune escape, which can predict the sensitivity of drugs including Cisplatin, Etoposide, Gemcitabine, and Erlotinib. Conclusions In conclusion, it was found that CLPS model was associated with tumor immunity and tumor mutation load, which also predicted four potentially sensitive drugs for LUAD patients at different risks (AU)

Frequently mutated genes in predicting the relapse of stage I lung adenocarcinoma

Purpose Approximately, 45–65% stage I non-small cell lung cancer (NSCLC) patients with surgical resection relapse within 5 years. Therefore, it is urgent to identify the predictors involved in the relapse of stage I NSCLC. Methods/patients Targeted sequencing was used to examine the mutation of tumor tissues and matched adjacent normal tissues from 35 patients with stage I lung adenocarcinoma (LUAD). Then, tissue microarrays containing tumor tissues from 149 stage I LUAD patients were used to assess protein expression of frequently mutated genes by immunohistochemistry. COX regression model was used to evaluate the impacts of frequently mutated genes and their protein expression on relapse-free survival (RFS) in stage I LUAD. Results and conclusions Three hundred and twenty-nine non-synonymous somatic variants were identified in 161 genes among these 35 patients. EGFR, TP53, LRP1B, RBM10, KRAS, NTRK3, RB1, ALK, APC, FAT2, KEAP1, MED12 and MLL3 were described as frequently mutated genes with prevalence more than 10%. Patients harboring KRAS mutation had more relapse in 1 year after surgical resection. For the expression of these frequently mutated genes in 149 stage I patients, multivariate Cox regression analyses showed that the expression of RBM10 was positively associated with RFS in all patients (HR 0.40, 95% CI 0.15–1.0, p = 0.052), and the expression of APC was negative associated with RFS in patients with EGFR mutations (HR 3.10, 95% CI 1.54–6.26, p = 0.002). Stage I LUAD patients with KRAS mutation or low RBM10 expression are inclined to receive more positive intervention rather than just disease surveillance (AU)

Discordant results for ALK based on immunohistochemistry versus fluorescence in situ hybridization in a cohort of patients diagnosed with lung adenocarcinoma / Discordancia de los resultados para ALK basados en inmunohistoquímica e hibridación fluorescente in situ en una cohorte de pacientes diagnosticados con adenocarcinoma de pulmón

Introduction: Anaplastic lymphoma kinase (ALK) rearrangement located on the short arm of chromosome 2, region 2 and band 3 is frequent in lung cancer patients who respond to targeted therapies with ALK inhibitors Therefore, their identification has become a standard diagnostic test in patients with advanced NSCLS, as such chromosomal alterations may lead to the activation of important signalling pathways involved in cell survival and proliferation. Methods: To investigate the ALK gene status, we performed FISH and IHC assays in 18 lung adenocarcinoma patients, 12 women and 6 men, aged between 29 and 85 years. Paraffin-embedded samples were analyzed in the Pathology Department of the Hospital Universitario San Ignacio. Results: Results between the two techniques in 5 patients showed discordant patterns, being positive for FISH and negative for IHC. The borderline to define ALK positivity was set at 15%, These results present experimental evidence that the techniques differ in specific situations. Conclusions: Our findings show that it is advisable to investigate the ALK gene status in patients with suspected lung cancer using both FISH and IHC in combination.(AU)

Introducción: La reorganización de la (anaplastic lymphoma kinase) ALK ubicada en el brazo corto del cromosoma 2, región 2 y banda 3 es frecuente en los pacientes con cáncer de pulmón que responden a terapias dirigidas con inhibidores de la ALK. Por ello, su identificación se ha establecido como una prueba diagnóstica estándar en pacientes con CPCNP, ya que dichas alteraciones cromosómicas puedan determinar la activación de importantes vías de señalización implicadas en la supervivencia y proliferación celulares. Métodos: Para determinar el estatus de gen ALK se realizaron pruebas FISH e IHC en 18 pacientes con adenocarcinoma pulmonar, 12 mujeres y 6 varones, con edades comprendidas entre 29 y 85 años. Las muestras fueron analizadas en el Departamento de Anatomía Patológica del Hospital Universitario San Ignacio. Resultados: Los resultados entre ambas técnicas mostraron patrones discordantes en 5 pacientes, con positividad de FISH y negatividad con IHC. El límite para definir la positividad de ALK se estableció en el 15%. Estos resultados muestran evidencia experimental que dichas técnicas difieren en situaciones específicas. Conclusiones: Este estudio recomienda la investigación del estatus del gen ALK en los pacientes con sospecha de cáncer de pulmón, mediante la combinación de FISH e IHC.(AU)

Integrated analysis of ALK higher expression in human cancer and downregulation in LUAD using RNA molecular scissors

PurposeAnaplastic lymphoma kinase (ALK) is an endorsed molecular target in ALK-rearranged carcinomas, including lung adenocarcinoma. However, the clinical advantage of targeting ALK using druggable inhibitors is almost universally restricted by the development of drug resistance. Therefore, a strategy for combating ALK overexpression remains paramount for ALK-driven cancer.MethodsWe systemically analyzed the overexpression pattern of ALK and its clinical consequences, genetic alterations, and their significance in cancer hallmark genes, and correlation using integrated multidimensional approaches. The LwCas13a RNA molecular scissors was used to downregulate ALK-rearrangement by leveraging two target guide RNAs in lung adenocarcinoma (LUAD) cells. Immunocytochemistry, immunoblotting, and MTT assays were conducted to validate the downregulation.ResultsWe found elevated levels of ALK in several malignancies, including LUAD, than in normal tissues. Higher expression of ALK was significantly associated with worse or shorter survival than patients with lower expression. We identified numerous genetic alterations in ALK, which potentially alter the cancer hallmark genes, including STAT1 and CTSL, in patients with LUAD. Next, we observed that the LwCas13a molecular scissors robustly downregulated both phosphorylated and total ALK chimera protein expression in LUAD cells compared to the control. Furthermore, we found that downregulation of ALK chimera protein substantially inhibited cell viability and induced cell death, including apoptosis.ConclusionOur findings suggest a basis for ALK as a prognostic biomarker and the LwCas13a molecular scissors successfully downregulated the onco-driver ALK-rearrangement protein, which will potentially pave the way toward the development of novel therapeutic strategies for ALK-driven cancer. (AU)

Nuevos biomarcadores de cáncer de pulmón basados en miRNA / [New biomarkers of lung cancer based on miRNA]

Objetivo: Determinar si existen diferencias de expresión entre los miRNA de tejido sano y tumoral de adenocarcinoma de pulmón y carcinoma epidermoide de pulmón, con lo que podrían ser usados como biomarcadores. Material y métodos: Se ha extraído y secuenciado el miRNA de tejido tumoral y sano adyacente de muestras de adenocarcinoma y carcinoma epidermoide de dieciséis pacientes intervenidos en el Hospital Regional de Málaga. Esas secuencias se han analizado con un flujo de trabajo bioinformático específico que conlleva varios pasos: 1o) preprocesar las lecturas, 2o) mapearlas sobre el genoma humano de referencia, 3o) determinar la expresión de los miRNA en cada una de las muestras, 4o) calcular su expresión diferencial entre el tejido sano y el tumoral de cada paciente, 5o) realizar un análisis funcional de los miRNA encontrados. Resultados: Hemos analizado los miRNA con expresión diferencial en cada uno de los tipos histológicos estudiados. El análisis del adenocarcinoma y carcinoma epidermoide de pulmón ha dado como resultado un total de 82 y 360 miRNA diferencialmente expresados (miDE), respectivamente. Hemos encontrado 50 miRNA comunes a los dos tipos histológicos, y su análisis funcional indica que están implicados en el crecimiento, desarrollo y movimiento celular, que se produce tanto en la célula normal como en el cáncer. Conclusiones: Los miDE encontrados son una fuente de biomarcadores, al tener una reprogramación específica en cáncer, y ser obtenibles de forma no invasiva. (AU)

Objective: Determine if there are differences in expression between the miRNAs of healthy and tumor tissue of lung adenocarcinoma and squamous cell carcinoma of the lung, with which they could be used as biomarkers. Material and methods: miRNA has been extracted and sequenced from tumor and adjacent healthy tissue from samples of adenocarcinoma and squamous cell carcinoma from sixteen patients operated at the Regional Hospital of Malaga. These sequences have been analyzed with a specific bioinformatic workflow that involves several steps: 1st) preprocessing the reads, 2nd) mapping them onto the reference human genome, 3rd) determining the expression of the miRNAs in each of the samples, 4th) calculate its differential expression between the healthy and tumor tissue of each patient, 5th) perform a functional analysis of the miRNAs found. Results: We have analyzed the miRNAs with differential expression in each of the histological types studied. Analysis of adenocarcinoma and squamous cell carcinoma of the lung has resulted in a total of 82 and 360 differentially expressed miRNAs (miDE), respectively. We have found 50 miRNAs common to the two histological types, and their functional analysis indicates that they are involved in cell growth, development and movement, which occurs both in normal cells and in cancer. Conclusions: The miDEs found are a source of biomarkers, as they have a specific reprogramming in cancer, and are obtainable non-invasively. (AU)

Utilidad de la ecografía con contraste para descartar recurrencia local tras radioterapia sobre cáncer de pulmón / Usefulness of Contrast Ultrasound in Ruling Out Local Recurrence After Radiation Therapy for Lung Cancer

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[Translated article] Usefulness of Contrast Ultrasound in Ruling Out Local Recurrence After Radiation Therapy for Lung Cancer / Utilidad de la ecografía con contraste para descartar recurrencia local tras radioterapia sobre cáncer de pulmón

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