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Contains fulltext : 287919.pdf (Publisher’s version ) (Open Access) BACKGROUND: In 2016, the International Consortium for Health Outcomes Measurement (ICHOM) defined an international consensus recommendation of the most important outcomes for lung cancer patients. The European Health Outcomes Observatory (H2O) initiative aimed to develop an updated patient-centered core outcome set (COS) for lung cancer, to capture the patient perspective of the impact of lung cancer and (novel) treatments using a combination of patient-reported outcome (PRO) instruments and clinical data as a means to drive value-based health-care. MATERIAL AND METHODS: An international, expert team of patient representatives, multidisciplinary healthcare professionals, academic researchers and pharmaceutical industry representatives (n = 17) reviewed potential outcomes generated through literature review. A broader group of patients/patient representatives (n = 31), healthcare professionals / academic researchers (n = 83), pharmaceutical industry representatives (n = 26), and health authority representatives (n = 6) participated in a Delphi study. In two survey rounds, participants scored the relevance of outcomes from a preliminary list. The threshold for consensus was defined as ≥ 70 % of participants scoring an outcome as 'highly relevant'. In concluding consensus-meeting rounds, the expert multidisciplinary team finalized the COS. RESULTS: The preliminary list defined by the core group consisted of 102 outcomes and was prioritized in the Delphi procedure to 64. The final lung cancer COS includes: 1) case-mix factors (n = 27); 2) PROs related to health-related quality of life (HRQoL) (n = 25); 3) clinical outcomes (n = 12). Patient-reported symptoms beyond domains included in the ICHOM lung cancer set in 2016 were insomnia, nausea, vomiting, anxiety, depression, lack of appetite, gastric problems, constipation, diarrhoea, dysphagia, and haemoptysis. CONCLUSIONS: We will implement the lung cancer COS in Europe within the H2O initiative by collecting the outcomes through a combination of clinician-reported measures and PRO measures. The COS will support the adoption and reporting of lung cancer measures in a standardized way across Europe and empower patients with lung cancer to better manage their health care.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an important regulator of extracellular matrix turnover that has been traditionally regarded as a potential tumor suppressor owing to its inhibitory effects of matrix metalloproteinases. Intriguingly, this interpretation has been challenged by the consistent observation that increased expression of TIMP-1 is associated with poor prognosis in virtually all cancer types including lung cancer, supporting a tumor-promoting function. However, how TIMP-1 is dysregulated within the tumor microenvironment and how it drives tumor progression in lung cancer is poorly understood. We analyzed the expression of TIMP-1 and its cell surface receptor CD63 in two major lung cancer subtypes: lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), and defined the tumor-promoting effects of their interaction. We found that TIMP-1 is aberrantly overexpressed in tumor-associated fibroblasts (TAFs) in ADC compared to SCC. Mechanistically, TIMP-1 overexpression was mediated by the selective hyperactivity of the pro-fibrotic TGF-β1/SMAD3 pathway in ADC-TAFs. Likewise, CD63 was upregulated in ADC compared to SCC cells. Genetic analyses revealed that TIMP-1 secreted by TGF-β1-activated ADC-TAFs is both necessary and sufficient to enhance growth and invasion of ADC cancer cells in culture, and that tumor cell expression of CD63 was required for these effects. Consistently, in vivo analyses revealed that ADC cells co-injected with fibroblasts with reduced SMAD3 or TIMP-1 expression into immunocompromised mice attenuated tumor aggressiveness compared to tumors bearing parental fibroblasts. We also found that high TIMP1 and CD63 mRNA levels combined define a stronger prognostic biomarker than TIMP1 alone. Our results identify an excessive stromal TIMP-1 within the tumor microenvironment selectively in lung ADC, and implicate it in a novel tumor-promoting TAF-carcinoma crosstalk, thereby pointing to TIMP-1/CD63 interaction as a novel therapeutic target in lung cancer.

Introduction: Fibrotic interstitial lung disease (ILD) is a frequent and severe complication of connective tissue disease (CTD). Areas covered: In this narrative review, we update the most relevant differential characteristics of fibrotic ILD associated with CTD (CTD-ILD) and propose a diagnostic and therapeutic approach based on a review of the articles published between 2002 and 2022 through PubMed. Expert opinion: The subset of ILD, mainly the radiological/histological pattern and the degree of fibrotic component, usually determines the prognosis and therapeutic strategy for these patients. Some patients with CTD-ILD can develop progressive pulmonary fibrosis (PPF) with severe deterioration of lung function, rapid progression to chronic respiratory failure, and high mortality. PPF has been described in many CTDs, mainly in systemic sclerosis and rheumatoid arthritis, and requires a multidisciplinary diagnostic and therapeutic approach to improve patient outcomes.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR-activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21_L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed.

Chronic obstructive pulmonary disease (COPD) and lung cancer are common global causes of morbidity and mortality. Because both diseases share several predisposing risks, the 2 diseases may occur concurrently in susceptible individuals. The diagnosis of COPD has important implications for the diagnostic approach and treatment options if lesions concerning for lung cancer are identified during screening. Importantly, the presence of COPD has significant implications on prognosis and management of patients with lung cancer. In this monograph, we review the mechanistic linkage between lung cancer and COPD, the impact of lung cancer screening on patients at risk, and the implications of the presence of COPD on the approach to the diagnosis and treatment of lung cancer. This manuscript succinctly reviews the epidemiology and common pathogenetic factors for the concurrence of COPD and lung cancer. Importantly for the clinician, it summarizes the indications, benefits, and complications of lung cancer screening in patients with COPD, and the assessment of risk factors for patients with COPD undergoing consideration of various treatment options for lung cancer.

Fibrillar collagens are the most abundant extracellular matrix components in nonesmall cell lung cancer (NSCLC). However, the potential of collagen fiber descriptors as a source of clinically relevant biomarkers in NSCLC is largely unknown. Similarly, our understanding of the aberrant collagen organization and associated tumor-promoting effects is very scarce. To address these limitations, we identified a digital pathology approach that can be easily implemented in pathology units based on CT-FIRE software (version 2; https://loci.wisc.edu/software/ctfire) analysis of Picrosirius red (PSR) stains of fibrillar collagens imaged with polarized light (PL). CT-FIRE settings were pre-optimized to assess a panel of collagen fiber descriptors in PSR-PL images of tissue microarrays from surgical NSCLC patients (106 adenocarcinomas [ADC] and 89 squamous cell carcinomas [SCC]). Using this approach, we identified straightness as the single high-accuracy diagnostic collagen fiber descriptor (average area under the curve ¼ 0.92) and fiber density as the single descriptor consistently associated with a poor prognosis in both ADC and SCC independently of the gold standard based on the TNM staging (hazard ratio, 2.69; 95% CI, 1.55-4.66; P

Background: Robotic-assisted thoracic surgery (RATS) has seen increasing interest in the last few years, with most procedures primarily being performed in the conventional multiport manner. Our team has developed a new approach that has the potential to convert surgeons from uniportal video-assisted thoracic surgery (VATS) or open surgery to robotic-assisted surgery, uniportal-RATS (U-RATS). We aimed to evaluate the outcomes of one single incision, uniportal robotic-assisted thoracic surgery (U-RATS) against standard multiport RATS (M-RATS) with regards to safety, feasibility, surgical technique, immediate oncological result, postoperative recovery, and 30-day follow-up morbidity and mortality. Methods: We performed a large retrospective multi-institutional review of our prospectively curated database, including 101 consecutive U-RATS procedures performed from September 2021 to October 2022, in the European centers that our main surgeon operates in. We compared these cases to 101 consecutive M-RATS cases done by our colleagues in Barcelona between 2019 to 2022. Results: Both patient groups were similar with respect to demographics, smoking status and tumor size, but were significantly younger in the U-RATS group [M-RATS =69 (range, 39-81) years; U-RATS =63 years (range, 19-82) years; P

Breast cancer (BC) is the most common malignancy in women worldwide. While the main systemic treatment option is anthracycline-containing chemotherapy, chemoresistance continues to be an obstacle to patient survival. Carnitine palmitoyltransferase 1C (CPT1C) has been described as a poor-prognosis marker for several tumour types, as it favours tumour growth and hinders cells from entering senescence. At the molecular level, CPT1C has been associated with lipid metabolism regulation and important lipidome changes. Since plasma membrane (PM) rigidity has been associated with reduced drug uptake, we explored whether CPT1C expression could be involved in PM remodelling and drug chemoresistance. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) lipid analysis of PM-enriched fractions of MDA-MB-231 BC cells showed that CPT1C silencing increased PM phospholipid saturation, suggesting a rise in PM rigidity. Moreover, CPT1C silencing increased cell survival against doxorubicin (DOX) treatment in different BC cells due to reduced drug uptake. These findings, further complemented by ROC plotter analysis correlating lower CPT1C expression with a lower pathological complete response to anthracyclines in patients with more aggressive types of BC, suggest CPT1C as a novel predictive biomarker for BC chemotherapy., This study was funded by the Spanish Ministry of Science and Innovation (MCIN) (PID2020-114953RB-C22 to N.C.) and co-funded by the European Regional Development Fund, and the CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN) (Grant CB06/03/0001 to N.C.).

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p

Interleukin-8 (IL-8/CXCL8) is a pro-angiogenic and pro-inflammatory chemokine that plays a role in cancer development. Non-small cell lung carcinoma (NSCLC) produces high amounts of IL-8, which is associated with poor prognosis and resistance to chemo-radio and immunotherapy. However, the signaling pathways that lead to IL-8 production in NSCLC are unresolved. Here, we show that expression and release of IL-8 are regulated autonomously by TRAIL death receptors in several squamous and adenocarcinoma NSCLC cell lines. NSCLC constitutively secrete IL-8, which could be further enhanced by glucose withdrawal or by treatment with TRAIL or TNFα. In A549 cells, constitutive and inducible IL-8 production was dependent on NF-κB and MEK/ERK MAP Kinases. DR4 and DR5, known regulators of these signaling pathways, participated in constitutive and glucose deprivation-induced IL-8 secretion. These receptors were mainly located intracellularly. While DR4 signaled through the NF-κB pathway, DR4 and DR5 both regulated the ERK-MAPK and Akt pathways. FADD, caspase-8, RIPK1, and TRADD also regulated IL-8. Analysis of mRNA expression data from patients indicated that IL-8 transcripts correlated with TRAIL, DR4, and DR5 expression levels. Furthermore, TRAIL receptor expression levels also correlated with markers of angiogenesis and neutrophil infiltration in lung squamous carcinoma and adenocarcinoma. Collectively, these data suggest that TRAIL receptor signaling contributes to a pro-tumorigenic inflammatory signature associated with NSCLC.

[eng] Treatment landscape in early-stage NSCLC is rapidly changing after approval of anti-PD-1/PD-L1 in the neoadjuvant and adjuvant settings, respectively. However, biomarkers for patient selection, to predict response and to inform immunotherapeutic resistance are not available. Here we interrogate the expression patterns of CD73 in malignant cells and examined host anti-tumor immune response in order to describe and elucidate potential tumor mechanisms that promote immune evasion. We also assess immune biomarkers in early stage NSCLC surgical specimens. Finally, we evaluate immune features that promote response after chemotherapy or chemoimmunotherapy treatment, with the aim to uncover immune predictive and prognostic biomarkers in early-stage lung cancer. Our results pointed to the potential role of CD73, and other members of the adenosine signaling pathway, as potential mechanisms of tumor immune evasion and resistance to ICI, thus providing additional rationale for propagating anti-CD73 antibodies in new combinatorial immunotherapeutic regimens. We found that CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lung adenocarcinoma (LUAD). We observed that differential CD73 localization was associated with distinct clinicopathological and molecular features in LUAD. CD73 expression was positively associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Additionally, and using targeted gene sequencing analysis and immunohistochemistry, we characterized immune programs across patients that underwent upfront surgery, neoadjuvant chemotherapy, or neoadjuvant chemoimmunotherapy. We identified immune gene programs that are unique to PD-L1 positive and PD-L1 negative NSCLCs as well as those that are shared between both groups. Using IHC, we observed that PD-L1 positive (≥1%) LUADs exhibited an augmented infiltration of T cells (CD3+, CD4+, CD8+ cells) along with increase of FOXP3+ cells, resident memory cells (CD103+) and macrophages (CD68+). Spatial distribution of CD8+ T cells unveiled distinctive TIME phenotypes whose frequencies differed based on TNM stage, PD-L1 expression, and mutational burden. Inflamed and PD-L1+/TILs+ NSCLCs displayed significantly amplified lev- els of immune signatures, with the excluded group representing an intermediate immune state. Subgroup analysis based on the expression of tumor PD-L1, and resident memory immune cells (CD103+ cells) showed an enrichment of immune cell infiltrates (CD3+, CD4+, CD8+, CD68+ cells) in tumors harboring higher levels of CD103+ immune cells along with an increase of CD80+ cells, essential for T cell activation. Longitudinal analysis of patients following neoadjuvant chemoimmunotherapy showed strong upregulation of immune cells signatures within the TIME. In this cohort, pathologic response to chemoimmunotherapy was positively associated with higher expression of genes involved in immune activation, chemotaxis, as well as T and natural killer cells. Comparative analysis between the three cohorts, underscored immune programs and signatures that overall were progressively modulated along the spectrum of treatment-naïve, neoadjuvant chemotherapy-treated, up to those treated with chemoimmunotherapy, pointing to an association between perturbation of an expanded repertoire of immune gene sets with neoadjuvant chemoimmunotherapy. In conclusion, our findings suggest that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early-stage lung adenocarcinoma. Additionally, our results highlight immune gene programs and IHC markers that may underlie host tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in resectable NSCLC., [spa] El escenario del tratamiento del cáncer de pulmón en estadios localizados está cambiando rápidamente después de la aprobación de anti-PD-1/PD-L1 como tratamiento neoadyuvante o adyuvante, respectivamente. Sin embargo, no disponemos de biomarcadores para la selección de pacientes que ayuden a predecir la respuesta y para informar la resistencia a la inmunoterapia. En este trabajo, evaluamos los patrones de expresión de CD73 en las células malignas, así como la respuesta inmunitaria antitumoral del huésped con el objetivo de describir y dilucidar algunos de los mecanismos tumorales que promueven la evasión inmunitaria, así como las características inmunitarias que desencadenan la respuesta después del tratamiento con quimioterapia o quimioinmunoterapia, con el objetivo de revelar biomarcadores inmunes en el cáncer de pulmón en etapa temprana. Nuestros resultados señalan el papel de CD73 y otros miembros de la vía de señalización de la adenosina como mecanismos potenciales de evasión inmune por parte de los tumores y de resistencia a la inmunoterapia, proporcionando una justificación adicional para el desarrollo de anticuerpos anti-CD73 en combinación con inmunoterapia. Además, encontramos que la expresión de CD73 aumenta significativa y progresivamente a lo largo de tejido pulmonar de apariencia normal, hiperplasia atípica adenomatosa, adenocarcinoma in situ, adenocarcinoma mínimamente invasivo y, finalmente, adenocarcinoma de pulmón. Observamos también que la localización diferencial de CD73 se asocia con distintas características clinicopatológicas y moleculares en adenocarcinomas de pulmón. La expresión de CD73 se asocia positivamente con un aumento en la expresión de PD-L1 en células tumorales y un aumento de células inmunitarias intratumorales. Además, mediante el uso de análisis de secuenciación de genes específicos y por inmunohistoquímica (IHC), caracterizamos los perfiles inmunes en pacientes que se sometieron a cirugía, quimioterapia neoadyuvante o quimioinmunoterapia neoadyuvante. Identificamos perfiles de genes inmunitarios que son exclusivos de tumores PD-L1 positivos y PD-L1 negativos, así como los que comparten ambos grupos. Usando IHC, observamos que los adenocarcinomas de pulmón positivos para PD-L1 (≥1%) exhiben una infiltración aumentada de células T (células CD3+, CD4+, CD8+) junto con un aumento de células FOXP3+, células de memoria residentes (CD103+) y macrófagos (CD68+). La distribución espacial de las células T CD8+ revela distintos fenotipos de microambientes tumorales cuyas frecuencias difieren según el estadio TNM, la expresión de PD-L1 y la carga mutacional. Los tumores inflamados y PD-L1+/TILs+ muestran niveles significativamente aumentados de marcadores inmunes, mientras que el fenotipo excluido representa un estado inmunitario intermedio. El análisis de subgrupos basado en la expresión tumoral de PD-L1 y la presencia de células inmunitarias de memoria residentes (células CD103+) muestra un enriquecimiento de infiltrados de células inmunitarias (células CD3+, CD4+, CD8+, CD68+) en tumores que albergan niveles elevados de células inmunitarias CD103+ junto con un aumento de células CD80+, esenciales para la activación de los linfocitos T. El análisis longitudinal de los pacientes después de quimioinmunoterapia neoadyuvante muestra un aumento de los marcadores inmunes intratumorales. En esta cohorte, la respuesta patológica a la quimioinmunoterapia se asocia positivamente con una mayor expresión de genes implicados en la activación inmune, la quimiotaxis, así como genes característicos de células T y células natural killer. El análisis comparativo entre las tres cohortes subraya los perfiles inmunes que, en general, se modulan progresivamente a lo largo del espectro de los pacientes tratados con cirugía de entrada, quimioterapia neoadyuvante, hasta los tratados con quimioinmunoterapia, lo que señala el papel de la quimioinmunoterapia neoadyuvante como desencadenante de una respuesta inmunitaria antitumoral. En conclusión, nuestros hallazgos sugieren que una mayor expresión de CD73 se asocia con una respuesta inmune aumentada, con potenciales implicaciones en la patobiología inmune de los adenocarcinomas de pulmón en estadio iniciales. Además, nuestros resultados destacan perfiles de genes inmunitarios y marcadores por IHC que caracterizan la inmunidad anti-tumoral del huésped y de respuesta a tratamientos con quimioterapia o quimioinmunoterapia neoadyuvantes en el cáncer de pulmón resecable.

Objective: Few published studies have described multidisciplinary therapeutic strategies for lung cancer. This study aims to describe the different approaches used for treating lung cancer in Catalonia in 2014 and 2018 and to assess the associated cost and impact on patient survival. Methods: A retrospective observational cohort study using data of patients with lung cancer from health care registries in Catalonia was carried out. We analyzed change in treatment patterns, costs and survival according to the year of treatment initiation (2014 vs. 2018). The Kaplan–Meier method was used to estimate survival, with the follow-up until 2021. Results: From 2014 to 2018, the proportion of patients undergoing surgery increased and treatments for unresectable tumors decreased, mainly in younger patients. Immunotherapy increased by up to 9% by 2018. No differences in patient survival were observed within treatment patterns. The mean cost per patient in the first year of treatment increased from EUR 14,123 (standard deviation [SD] 4327) to EUR 14,550 (SD 3880) in surgical patients, from EUR 4655 (SD 3540) to EUR 5873 (SD 6455) in patients receiving curative radiotherapy and from EUR 4723 (SD 7003) to EUR 6458 (SD 10,116) in those treated for unresectable disease. Conclusions: From 2014 to 2018, surgical approaches increased in younger patients. The mean cost of treating patients increased, especially in pharmaceutical expenditure, mainly related to the use of several biomarker-targeted treatments. While no differences in overall patient survival were observed, it seems reasonable to expect improvements in this outcome in upcoming years as more patients receive innovative treatments.

[eng] The composition and architecture of the extracellular matrix (ECM), and their dynamic alterations, play an essential regulatory role in numerous cellular processes. Furthermore, structural, and biochemical properties of the ECM are central in regulating cell response via mechanical, chemical, and topological cues detected by receptors on the cell membrane, which induce cytoskeleton and/or cell nucleus rearrangements affecting gene expression. Indeed, distinct ECM architectures in the native stroma depend on tissue type, function, and composition. For instance, ECM anisotropy and stiffness are associated with altered ECM degradation and remodeling in cancer. In turn, abnormal ECM architecture favors tumor progression and invasion. Moreover, numerous diseases are associated with mutations in genes encoding ECM components, leading to deficient mechanical properties and altered ECM structure. Thus, there is an increasing interest to exploit and consolidate this knowledge to improve patients’ diagnosis, treatment, and care. In this work, we examined the use of cutting-edge open-source software to characterize the properties of ECM fibers and fibril bundles in patients’ samples and in vitro model tissues. We focused on Collagen I-III in lung cancer and on Collagen VI-related muscular dystrophies (COL6-RMD) because these pathologies present a clear link between altered ECM architecture and patients’ outcomes, which requires further investigation and may be exploited at the clinical level. For this purpose, we initially generated phantom images of fibrils networks (created artificially in silico or obtained from bioengineered models in vitro mimicking isotropic/anisotropic ECM) to test and validate the analysis of ECM fibrils with different bioengineering tools. Then, we focused on ECM images obtained from patient cell cultures or tissue biopsies and evaluated ECM descriptors as novel potential biomarkers. We collaborated with the Institut de Recerca Sant Joan De Déu (IRSJD) to analyze ECM models obtained from fibroblasts of patients affected by COL6-RMD. This is a rare subset of neuromuscular diseases related to deficiency in collagen type VI (COL6) expression, which affects young patients causing a broad range of severe disabilities, which worsen with time and shorten their lifespan. Currently, analysis of in vitro cultures of patients’ fibroblasts is employed as the first screening to select cases of COL6-RMD, and image-based classification has been suggested to improve this assay. Employing similar protocols, fibroblasts of different sources and malignant origin have been used to obtain decellularized cell-derived matrices (CDM), which retain topography and biochemical features, preserving their native microenvironment. Therefore, we produced and analyzed patients’ CDM to provide new in vitro personalized ECM models and improve early recognition of COL6-RMD subtypes with novel fiber-based ECM descriptors. In parallel, in collaboration with the CIBERES (Centro de Investigación Biomédica en Red de Enfermedades Respiratorias), we characterized the fibrillar properties of Non-Small Cell Lung Cancer (NSCLC) patients’ tissues. NSCLC is among the tumors with the highest death rate and recurrence; therefore, novel biomarkers may provide helpful complementary data with clinical impact. Fiber descriptors extracted by CT-FIRE have been demonstrated to capture relevant prognostic changes in the collagen structure of several tumors. In NSCLC, collagen architecture influences immune system activation, and increased fibrosis is already reported to correlate with patients’ prognosis. Therefore, we studied alterations of collagen fiber networks in the two most common NSCLC subtypes, Adenocarcinoma and Squamous Cell Carcinoma, to provide novel collagen structure-based biomarkers. Ultimately this work, along with the tools presented, paves the way for addressing the need for novel ECM-based descriptors, to stratify patients and evaluate their response to experimental treatments., [spa] La composición y arquitectura de la matriz extracelular (MEC), y sus alteraciones dinámicas, juegan un papel regulador importante en numerosos procesos patológicos. Por ejemplo, la anisotropía y la rigidez de la MEC están asociadas con la remodelación alterada de la MEC en el cáncer. A su vez, esta arquitectura favorece la progresión e invasión tumoral. Además, numerosas enfermedades están asociadas con mutaciones en los genes que codifican los componentes de la MEC, lo que conduce a propiedades mecánicas deficientes y una estructura alterada de la MEC. Por lo tanto, existe un interés creciente por explotar y consolidar este conocimiento para mejorar la atención de los pacientes. En este trabajo, nos centramos en las distrofias musculares relacionadas con el colágeno VI (COL6-RMD) y el cáncer de pulmón de células no pequeñas (NSCLC), para investigar biomarcadores relacionados con la MEC in vitro y en los tejidos de los pacientes que se implementarán en el entorno clínico. Empleamos la segmentación automática de imágenes para cuantificar las características fibrilares e investigamos la asociación con la información clinicopatológica de los pacientes. Por lo tanto, producimos y analizamos matrices derivadas de células de pacientes para proporcionar nuevos modelos de ECM personalizados in vitro y nuevos descriptores de ECM basados en fibra de los subtipos COL6-RMD. Se ha demostrado que los descriptores de fibra basados en imágenes capturan cambios pronósticos relevantes en la estructura del colágeno de varios tumores. En el NSCLC, la arquitectura del colágeno influye en la activación del sistema inmunitario y ya se reconoce que el aumento de la fibrosis se correlaciona con el pronóstico de los pacientes. Por lo tanto, estudiamos las alteraciones de las redes de fibras de colágeno en los dos subtipos de NSCLC más comunes, el adenocarcinoma y el carcinoma de células escamosas, y demostramos que los descriptores de la estructura del colágeno son posibles biomarcadores basados en imágenes con aplicaciones de diagnóstico y pronóstico. En última instancia, este análisis, junto con las herramientas presentadas, es prometedor para abordar la necesidad de nuevos descriptores, para estratificar a los pacientes y evaluar su respuesta a los tratamientos experimentales.

Background: The aim of this study was to evaluate the safety and survival outcomes of anti-programmed cell death (PD)-1/programmed cell death-ligand 1 (PD-L1) monotherapy in patients with advanced nonsmall cell lung cancer (NSCLC) and different hepatitis B virus (HBV) infection status. Methods: Patients with advanced NSCLC and both chronic and/or resolved HBV infection who were treated with anti-PD-(L)1 monotherapy were retrospectively enrolled. The primary endpoint was the safety of PD-1/PD-L1 monotherapy, while the secondary endpoints included the survival outcomes. Results: Of the 62 eligible patients, 10 (16.1%) were hepatitis B surface antigen (HBsAg) positive [chronic hepatitis B (CHB) infection] and 52 (83.9%) were HBsAg negative and HBcAb positive [resolved hepatitis B (RHB) infection]; 42 (67.7%) patients had at least 1 treatment-related adverse event (AE), with 4 patients (6.5%) developing grade 3 AEs and 6 (9.7%) developing hepatic AEs. One CHB patient experienced HBV reactivation during anti-PD-1 immunotherapy due to the interruption of antiviral prophylaxis. The objective response rate and durable clinical benefit (DCB) rate were 17.7% and 29.0%, respectively. Median overall survival (OS) and progression-free survival (PFS) were 23.6 months [95% confidence interval (CI): 14.432.8] and 2.1 months (95% CI: 1.2-3.0), respectively. The DCB rate was significantly higher in the CHB group than in the RHB group (60% vs. 23.1%; P=0.048). Patients with CHB experienced a longer PFS (8.3 vs. 2.0 months; P=0.103) and OS (35.0 vs. 18.2 months, P=0.119) than did RHB patients. Conclusions: Anti-PD-(L)1 monotherapy was safe and effective in patients with NSCLC and HBV infection. This population should not be excluded from receiving immunotherapy in routine clinical practice or within clinical trials if HBV biomarkers are monitored and antiviral prophylaxis is properly used.

Introduction: The aim of this study was to determine whether preoperative nutritional status and inflammatory status, specifically polyunsaturated acids and the omega 6/3 ratio, would affect postoperative outcomes and complications in patients with lung cancer undergoing lung resection. Methods: This prospective observational study included 68 patients with early-stage non-small-cell lung cancer who were candidates for radical surgery. A complete nutritional assessment was performed. The primary study variable was postoperative complications and mortality in the first 30 days. Descriptive, bivariate, and logistic regression analyses were carried out. Results: A total of 50 men (73.53%) and 18 women (26.47%) underwent surgery, with a median age of 64.2 (±9.74) years. The mean omega 6/3 ratio was 17.39 (±9.45). A complication occurred in 39.7% of the study sample (n = 27), the most common being persistent air leak in 23.53% (n = 16). After performing the bivariate analysis, the only variable that remained significant was the omega 6/3 ratio; we observed that it had a prognostic value for persistent air leak (p = 0.001) independent of age, sex, comorbidity, preoperative respiratory function, and approach or type of surgery. The remaining nutritional and inflammatory markers did not have a statistically significant association (p > 0.05) with postoperative complications. However, this significance was not maintained in the multivariate analysis by a small margin (p = 0.052; 95% CI: 0.77–1.41). Conclusions: Omega 6/3 ratio may be a prognostic factor for air leak, independent of the patient’s clinical and pathological characteristics.

Background Circular RNAs (circRNAs) are non-coding RNAs with a circular structure that have recently emerged as important regulators of tumorogenesis. Recently, several circRNAS, including circ-10720 have been related to epithelial-mesenchymal transition (EMT) process. In the present study, we have analyzed the role of circ-10720 in non-small-cell lung cancer (NSCLC) and studied its prognostic relevance in resected stage I-IIIa NSCLC patients. Methods Circ-10720 expression was analyzed using a custom TaqMan assay in four NSCLC cell lines (HCC44, A549, H23 and H1299) and in the normal immortalized lung cell line BEAS2B. Silencing of circ-10720 was performed using two custom siRNAs which were transfected using lipofectamine 2000. Protein levels were evaluated by Western blot and immunofluorescence. Wound healing and invasion assays were performed to evaluate the impact the circRNA on cell motility. Apoptosis was analyzed by evaluation of Caspase 3-7 activity and proliferation by MTS assay. Moreover, the expression levels of the circRNA were studied in 119 resected NSCLC patients. The expression in tumor tissue was correlated with the main clinicopathological characteristics and with time to relapse (TTR). Results Circ-10720 was overexpressed in HCC44 and A549 and underexpressed in H23 and H1299 NSCLC cell lines in comparison to BEAS2B normal immortalized lung cell line. CircRNA knockdown in the two circ-10720 overexpressing cell lines was associated with a decrease of Vimentin (VIM) and an increase of E-cadherin (CDH1) protein levels, loss of mesenchymal phenotype, and a significant reduction of migration and invasion capacity. After silencing circ-10720, the apoptosis rate increased and the proliferation was significantly reduced. Furthermore, circ-10720 was upregulated in tumor vs. normal tissue from 119 resected NSCLC patients. In the group of patients not receiving adjuvant treatment, those with high levels of circ-10720 had a shorter TTR than those with low levels and emerged as an independent prognostic value in the multivariate analysis. In tumor tissue, circ-10720 levels positively correlated with the EMT gene Twist1 levels. Conclusions Circ-10720 regulates EMT, apoptosis and proliferation and acts as a biomarker of relapse in NSCLC.

El càncer de pulmó és la primera causa de mort per càncer a escala mundial. A Europa, és un problema sanitari de gran magnitud, ja que cada any aquesta malaltia es diagnostica a 2,6 milions de persones i posa fi a la vida d'altres 1,2 milions de persones, segons informa la Comissió Europea. Encara que el tabac és el factor de risc principal, existeixen altres factors prevalents, tant intrínsecs (predisposició genètica), com extrínsecs o carcinògens (gas radó, agents laborals, etc.), sent molts d'ells sinèrgics amb el tabac. No obstant això, aquesta informació no es registra i estudia de manera detallada en oncologia toràcica i avui dia, es desconeix quin perfil de malaltia s'associa als diferents factors intrínsecs i extrínsecs, més enllà del tabac i el que és més rellevant, si aquests tenen un impacte clínic en l'evolució i supervivència de pacients amb càncer de pulmó. Aquest projecte té com a objectiu desenvolupar una eina per l'estudi d'un d'aquests factors extrínsecs. Concretament, es construirà una aplicació per a la comparació de dades de càncer de pulmó amb dades d'origen ambiental amb el propòsit final de què aquesta pugui ser emprada per l'equip d'oncologia de l'Hospital Clínic per a analitzar possibles relacions entre zones d'altes emissions contaminants i zones amb alts índexs de càncer de pulmó. El resultat ha sigut una aplicació web duta a terme amb Dash, un framework dissenyat per a crear i desplegar aplicacions de dades amb interfícies d'usuari personalitzades, i MongoDB, una base de dades no relacional escalable i d'alt rendiment. L'aplicació final permet visualitzar, actualitzar i descarregar les dades segons les necessitats de l'equip. Lung cancer is the leading cause of cancer deaths worldwide. In Europe, it is a major health problem, with 2.6 million people diagnosed with the disease each year, killing another 1.2 million people, according to the European Commission. Although tobacco is the main risk factor, there are other prevalent factors, both intrinsic (genetic predisposition) and extrinsic or carcinogenic (radon gas, occupational agents, etc.), many of which are synergistic with tobacco. However, this information is not recorded and studied in thoracic oncology and today, it is not known what disease profile is associated with the different intrinsic and extrinsic factors, beyond tobacco and, more importantly, whether they have a clinical impact on the evolution and survival of patients with lung cancer. This project aims to develop a tool for the study of one of these extrinsic factors. Specifically, an application will be built to compare lung cancer data with data of environmental origin with the aim that it can be used by the oncology team of the Hospital Clínic to analyse possible relationships between areas with high pollutant emissions and areas with high rates of lung cancer. The result has been a web application developed with Dash, a framework designed to create and deploy data applications with customised user interfaces, and MongoDB, a scalable, high-performance, non-relational database. The final application allows data to be viewed, updated and downloaded according to the team's needs.

[eng] Tumours grow in a self-imposed hypoglycaemic microenvironment due to their exacerbated metabolic needs. To thrive in these harsh conditions, malignant cells must adapt their own metabolic routes and hijack the host nutrient supply infrastructure through extracellular signalling. This study aimed at characterising the secretory response of tumoral cells in response to glucose deprivation, both the molecular signalling leading to this response and the consequences of this response for the tumour. In particular, this study focused on a cytokine never before linked to glucose deprivation: LIF. Through use of in silico, in vitro, and in vivo approaches we made two novel findings: firstly, we determined that LIF induction happens through non-canonical N-glycosylation dependent signalling, in the context of glucose deprivation. Furthermore, we have determined that the signalling mechanism leading to LIF production encompasses a complex combination of transcriptional and post-transcriptional signals that involve PERK but none of its canonical transcription factors. Secondly, we discovered a novel pro-tumorigenic role for this cytokine as an angiogenic. Our findings addressed the gap in literature regarding the mechanism for LIF production in tumours, providing insight relevant to future development of therapeutic approaches. And most importantly, we provide an integrative view of not only how glucose deprivation leads to production of LIF, but also how this cytokine could lead to the resolution of the local hypoglycaemia via angiogenesis., [spa] Los tumores imponen un microambiente de constante hipoglicemia debido a su rápida proliferación y al exacerbado consumo de metabolitos que esto conlleva. Para prosperar en estas circunstancias, las células cancerosas alteran su metabolismo y sus rutas de señalización de forma que puedan abusar de la infraestructura de aporte de nutrientes del organismo. El objetivo de este estudio es caracterizar la respuesta secretora del tumor en respuesta a la falta de glucosa, tanto al nivel de la señalización molecular que integra esta respuesta como al nivel de las consecuencias externas que estas señales tienen para el tumor. En particular, este estudio se centra en una citoquina que nunca antes se había relacionado con la falta de glucosa: LIF (por sus siglas en inglés: Factor Inhibidor de la Leucemia). A través del uso de técnicas in silico, in vitro e in vivo hemos alcanzado dos descubrimientos. En primer lugar, hemos determinado que la producción de LIF está inducida a través de una ruta no-canónica de detección de la falta de glucosa basada en la falta de N-glicosilación. Además, hemos determinado que el mecanismo que sigue a este fallo en la glicosilación incluye una compleja combinación de señales transcripcionales y postranscripcionales dependientes de PERK, pero no de los factores de transcripción tradicionalmente asociados a esta quinasa. En segundo lugar, hemos descubierto un nuevo rol pro-tumorigénico de esta citoquina como factor pro-angiogénico. Nuestros hallazgos cubren un vacío en la literatura en lo relativo al mecanismo que causa la producción de LIF por parte del tumor, lo cual podría servir de base para nuevas aproximaciones terapéuticas. Además, hemos desarrollado una visión unificada que explica cómo la falta de glucosa resulta en la producción de esta citoquina, y cómo LIF a su vez puede actuar para resolver la hipoglicemia local restaurando el riego sanguíneo mediante la angiogénesis.

Introducción: El objetivo del estudio es valorar el rendimiento diagnóstico de la tomografía computarizada (TC) y la tomografía por emisión de positrones (PET) en la estadificación clínica mediastínica del cáncer pulmonar quirúrgico según los datos de la cohorte prospectiva del Grupo Español de Cirugía Torácica Videoasistida (GEVATS). Métodos: Se han analizado 2.782 pacientes intervenidos por carcinoma pulmonar primario. Se ha estudiado el acierto diagnóstico en la estadificación mediastínica (cN2). Se ha realizado un análisis bivariante y multivariante de los factores que influyen en el acierto. Se ha estudiado el riesgo de pN2 inesperado en los factores con los que se recomienda una prueba invasiva de estadificación: cN1, tumor central o tamaño mayor de 3cm. Resultados: El acierto global de la TC y PET en conjunto es del 82,9% con VPP y VPN de 0,21 y 0,93. En tumores mayores de 3cm y a mayor SUVmax del mediastino, el acierto es menor, OR de 0,59 (0,44 - 0,79) y 0,71 (0,66 - 0,75), respectivamente. En el abordaje VATS el acierto es mayor, OR de 2,04 (1,52 - 2,73). El riesgo de pN2 inesperado aumenta con el número de los factores cN1, tumor central o tamaño mayor de 3cm: entre el 4,5% (0 factores) y 18,8% (3 factores), pero no hay diferencias significativas con la realización de prueba invasiva. Conclusiones: La TC y PET en conjunto tienen un elevado valor predictivo negativo. Su acierto global es menor en tumores mayores de 3cm y SUVmax del mediastino elevado, y mayor en el abordaje VATS. El riesgo de pN2 inesperado es mayor si cN1, tumor central o mayor de 3cm y no varía significativamente con prueba invasiva.

In resected non-small cell lung cancer (NSCLC), post-surgical recurrence occurs in around 40% of patients, highlighting the necessity to identify relapse biomarkers. An analysis of the extracellular vesicle (EV) cargo from a pulmonary tumor-draining vein (TDV) can grant biomarker identification. We studied the pulmonary TDV EV-miRNAome to identify relapse biomarkers in a two-phase study (screening and validation). In the screening phase, a 17-miRNA relapse signature was identified in 18 selected patients by small RNAseq. The most expressed miRNA from the signature (EV-miR-203a-3p) was chosen for further validation. Pulmonary TDV EV-miR-203a-3p was studied by qRT-PCR in a validation cohort of 70 patients, where it was found to be upregulated in relapsed patients (p = 0.0194) and in patients with cancer spread to nearby lymph nodes (N+ patients) (p = 0.0396). The ROC curve analysis showed that TDV EV-miR-203a-3p was able to predict relapses with a sensitivity of 88% (AUC: 0.67; p = 0.022). Moreover, patients with high TDV EV-miR-203a-3p had a shorter time to relapse than patients with low levels (43.6 vs. 97.6 months; p = 0.00703). The multivariate analysis showed that EV-miR-203a-3p was an independent, predictive and prognostic post-surgical relapse biomarker. In conclusion, pulmonary TDV EV-miR-203a-3p is a promising new relapse biomarker for resected NSCLC patients.

Overcoming resistance is one of the most challenging features in current anticancer therapy. Autophagy is a cellular process that confers resistance in some advanced tumors, since it enables cancer cells to adapt to stressful situations, such as anticancer treatments. Hence, the inhibition of this cytoprotective autophagy leads to tumor cells sensitization and death. In this regard, we designed a novel potent anionophore compound that specifically targets lysosomes, called LAI-1 (late-stage autophagy inhibitor-1), and evaluated its role in blocking autophagy and its potential anticancer effects in three lung cancer cell lines from different histological subtypes. Compared to other autophagy inhibitors, such as chloroquine and 3-Methyladenine, the LAI-1 treatment induced more potent anticancer effects in all tested cancer cells. LAI-1 was able to efficiently target and deacidify lysosomes, while acidifying cytoplasmic pH. Consequently, LAI-1 efficiently blocked autophagy, indicated by the increased LC3-II/I ratio and p62/SQSTM1 levels. Moreover, no colocalization was observed between autophagosomes, marked with LC3 or p62/SQSTM1, and lysosomes, stained with LAMP-1, after the LAI-1 treatment, indicating the blockage of autophagolysosome formation. Furthermore, LAI-1 induced cell death by activating apoptosis (enhancing the cleavage of caspase-3 and PARP) or necrosis, depending on the cancer cell line. Finally, LAI-1 sensitized cancer cells to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a new late-stage autophagy inhibitor that causes lysosomal dysfunction and the blockage of autophagolysosome formation, as well as potently induces cancer cell death and sensitization to conventional treatments at lower concentrations than other known autophagy inhibitors, appearing as a potential new therapeutic approach to overcome cancer resistance., This research was supported by Consejería de Educación de la Junta de Castilla y León (grant BU067P20), MCIN/AEI/10.13039/501100011033 (grant PID2020-117610RB-I00) and Instituto de Salud Carlos III (grant PI18/00441), co-funded by the European Regional Development Fund. ERDF, a way to build Europe. P.F., D.A.-C. and I.C.-B. thank Consejería de Educación de la Junta de Castilla y León, European Social Fund and ERDF for their predoctoral (D.A.-C.) and postdoctoral (P.F. and I.C.-B.) contracts. C.B.-G. thanks the University of Barcelona for a predoctoral fellowship.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease accounting for approximately 85% of all lung cancers. Only 17% of patients are diagnosed at an early stage. Treatment is multidisciplinary and radiotherapy plays a key role in all stages of the disease. More than 50% of patients with NSCLC are treated with radiotherapy (curative-intent or palliative). Technological advances-including highly conformal radiotherapy techniques, new immobilization and respiratory control systems, and precision image verification systems-allow clinicians to individualize treatment to maximize tumor control while minimizing treatment-related toxicity. Novel therapeutic regimens such as moderate hypofractionation and advanced techniques such as stereotactic body radiotherapy (SBRT) have reduced the number of radiotherapy sessions. The integration of SBRT into routine clinical practice has radically altered treatment of early-stage disease. SBRT also plays an increasingly important role in oligometastatic disease. The aim of the present guidelines is to review the role of radiotherapy in the treatment of localized, locally-advanced, and metastatic NSCLC. We review the main radiotherapy techniques and clarify the role of radiotherapy in routine clinical practice. These guidelines are based on the best available evidence. The level and grade of evidence supporting each recommendation is provided.

[cat] ANTECEDENTS: Quan els gens responsables del desenvolupament embrionari normal s'expressen de manera anormal en adults, pot derivar en l’aparició del tumor. Això pot suggerir que el mateix mecanisme que controla la diferenciació embrionària també podria controlar la diferenciació del tumor. Per tant, es va hipotetitzar que el fenotip maligne de les cèl·lules canceroses de pulmó podria adquirir característiques benignes al posar-se en contacte amb un microambient pulmonar embrionari. MÈTODES: Es va crear un medi condicionat de cèl·lules mesenquimals de pulmó embrionari humà (hEML-CM). A continuació, es van cultivar les línies cel·lulars d’adenocarcinoma pulmonar, A549 i H1299, en hEML-CM i en un medi condicionat control. Posteriorment, els canvis morfològics es van analitzar amb microscòpia electrònica òptica i de transmissió. Els canvis funcionals es van avaluar mitjançant l’anàlisi de la proliferació, la migració, la capacitat de formació de colònies en 2D i 3D, i la capacitat de creixement del tumor in vivo. Els canvis moleculars i de diferenciació es van estudiar per l'expressió dels gens de pluripotència OSKM, el marcador d'adenocarcinoma NKX2-1, les SFTPs, les DNMT3A/3B, els marcadors mesenquimals VIM i α-SMA, i el marcador de miofibroblasts MYH. Per últim, l'anàlisi transcriptòmic es va realitzar mitjançant matrius d’Affymetrix. RESULTATS: Les cèl·lules A549 i H1299 cultivades en hEML-CM van perdre la seva morfologia epitelial, van adquirir un fenotip mesodèrmic i van disminuir les seves característiques funcionals malignes. L'expressió d'OSKM, NKX2-1 i SFTP va disminuir, mentre que la de DNMT3A/3B, VIM, α-SMA i MYH va augmentar. L'anàlisi transcriptòmic va mostrar que les cèl·lules condicionades estaven més a prop dels mioblasts i del fibroblast de pulmó humà que de les cèl·lules pulmonars epitelials normals; el que va permetre identificar gran quantitat de gens diferencialment expressats entre les cèl·lules control i les condicionades. CONCLUSIONS: Pel que se sap, aquest és el primer estudi en el que s’ha observat que els estímuls del mesènquima pulmonar embrionari poden modular el fenotip maligne de les cèl·lules canceroses de pulmó, controlar-ne la capacitat de creixement i activar la seva diferenciació en miofibroblasts. Aquestes troballes podrien conduir a noves estratègies per al tractament del càncer de pulmó., [eng] BACKGROUND: When genes responsible for normal embryonic development are abnormally expressed in adults, it can lead to tumor development. This can suggest that the same mechanism that controls embryonic differentiation can also control tumor differentiation. We hypothesize that the malignant phenotype of lung cancer cells could acquire benign characteristics when in contact with an embryonic lung microenvironment. We cultured two lung cancer cell lines in embryonic lung mesenchyme-conditioned medium and evaluated morphological, functional and molecular changes. METHODS: The human embryonic mesenchymal lung-conditioned medium (hEML-CM) was obtained by culturing lung cells from embryos in the pseudoglandular stage of development. The NSCLC cell lines A549 and H1299 we cultured in the hEML-CM and in a tumor-conditioned medium. Morphological changes were analyzed with optical and transmission electron microscopy. To evaluate the functional effect of conditioned medium in tumor cells, we analyzed cell proliferation, migration, colony formation capacity in 2D and 3D and in vivo tumor growth capacity. The expression of the pluripotency genes OSKM, the adenocarcinoma marker NKX2-1, the lung surfactant proteins SFTP, the myofibroblast marker MYH and DNMT3A/3B was analyzed with qRT-PCR and the presence of the myofibroblast markers vimentin and α-SMA with immunofluorescence. Transcriptomic analysis was performed using Affymetrix arrays. RESULTS: The A549 and H1299 cells cultured in hEML-CM lost their epithelial morphology, acquired mesodermal characteristics, and decreased proliferation, migration, and colony formation capacity in 2D and 3D, as well as reduced its capacity to growth in vivo. The expression of OSKM, NKX2-1 and SFTP decreased, while that of DNMT3A/3B, vimentin, α-SMA and MYH increased. Distant matrix analysis based on transcriptomic profile showed that conditioned cells were closer to myoblast and human lung fibroblast than to normal epithelial immortalized lung cells. A total of 1631 for A549 and 866 for H1299 differentially expressed genes between control and conditioned cells were identified. CONCLUSIONS: To the best of our knowledge, this is the first study to report that stimuli from the embryonic lung can modulate the malignant phenotype of lung cancer cells, control their growth capacity and activate their differentiation into myofibroblasts. These findings could lead to new strategies for lung cancer management.

Among early‐stage non‐small‐cell lung cancer (NSCLC) patients, cg05293407TRIM27 was significantly and exclusively associated with survival of lung squamous cell carcinoma patients, who had higher smoking intensity compared to lung adenocarcinoma patients. Generally, the significant association between cg05293407TRIM27 and survival only remained in NSCLC patients having medium‐to‐high pack‐year of smoking. The cg05293407TRIM27‐smoking synergistic interaction might account for histologically heterogeneous effects of TRIM27 DNA methylation on NSCLC survival., Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non‐small‐cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early‐stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407TRIM27 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30–2.09, P = 4.52 × 10−5), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87–1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407TRIM27 methylation in NSCLC. LUSC patients had a higher average pack‐year of smoking (37.49LUAD vs 54.79LUSC, P = 1.03 × 10−19) and included a higher proportion of current smokers than LUAD patients (28.24%LUAD vs 34.09%LUSC, P = 0.037). cg05293407TRIM27 was significantly associated with overall survival only in NSCLC patients with medium–high pack‐year of smoking (HR = 1.58, 95% CI: 1.26–1.96, P = 5.25 × 10−5). We conclude that cg05293407TRIM27 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.

Objective: This study aimed to describe the current status of lung cancer in Spain, including patient characteristics and in-hospital mortality, and to revise disease management and the direct medical costs of secondary care. Methods: A retrospective observational study was set to analyse anonymized primary and secondary care records of patients admitted with lung cancer in Spain between 2011 and 2016. Data were obtained from the Primary Care Dataset and the Centralised Hospital Discharge Database (...)

[eng] Increased expression of TIMP-1 is associated with poor prognosis in virtually all cancer types, including lung cancer. However, how TIMP-1 is regulated in lung cancer and how it drives tumor progression is poorly defined. In the first part of this thesis, we analyze the expression of TIMP-1 and its cell surface receptor CD63 in two major lung cancer subtypes: lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). We report that TIMP-1 is aberrantly overproduced in tumor-associated fibroblasts (TAFs) in ADC compared to SCC-TAFs, and identify the selective hyperactivity of the pro-fibrotic TGF- β1/SMAD3 pathway in ADC-TAFs as a major mechanism driving the excessive secretion of TIMP-1 in ADC-TAFs. In contrast, CD63 was markedly downregulated in SCC cells compared to ADC cells. In the second part of this thesis, we define the tumor-promoting effects of the heterotypic crosstalk, specific for ADC patients, between TIMP-1 secreted by TAFs and CD63 in cancer cells. Functional assays revealed that TIMP-1 within the pro- tumoral secretome of TGF-β1-activated ADC-TAFs is necessary and sufficient to promote the growth and invasion of ADC cells in culture. Concomitantly, tumor cell expression of CD63 was required for the tumor-promoting effects of TIMP-1. Consistently, in vivo analyses revealed that ADC cells co-injected with fibroblasts with reduced TIMP-1 expression into immunocompromised mice exhibited a lower tumor volume together with a less invasive growth pattern compared to tumors bearing parental fibroblasts. Finally, we studied the relationship of TIMP-1/CD63 crosstalk with the resistance mechanism of SCC patients to nintedanib, which is an antifibrotic drug that has been selectively approved for the treatment of ADC patients. Of note, nintedanib strongly inhibited TIMP-1 secretion in TAFs. Moreover, we observed that TIMP-1 deficient TAFs are resistant to the nintedanib inhibition of their pro-tumoral traits, both in vitro and in vivo, compared to parental TAFs. This work identifies the first tumor-promoting TAF- carcinoma crosstalk that is selective for lung ADC, provides new insights on the pathologic role of stromal TIMP-1 in lung cancer, identifies a novel resistance mechanism to nintedanib in SCC, and points to the TIMP-1/CD63 interaction as a novel therapeutic target., [cat] L’expressió elevada de TIMP-1 està associada a un mal pronòstic en gairebé tots els tipus de càncer, inclòs el càncer de pulmó. No obstant, es desconeix com es regula l’expressió de TIMP-1 en càncer de pulmó ni mitjançant quins mecanismes promou la progressió tumoral. En la primera part d’aquesta tesi, s’han analitzat els nivells de TIMP-1 i CD63, el seu receptor de membrana, en els dos subtipus majoritaris de càncer de pulmó: l’adenocarcinoma (ADC) i el carcinoma escatós (CE). Hem trobat que en els fibroblasts associats al tumor (TAFs de l’anglès) del subtipus ADC hi ha una secreció aberrant de TIMP-1 en comparació amb els TAFs de CE. Aquesta excessiva secreció de TIMP-1 en ADC es deu a la hiperactivació selectiva de la via del TGF-β1/SMAD3 en aquest subtipus de TAFs. D’altra banda, els nivells de CD63 són més baixos en les cèl·lules canceroses de CE que en les d’ADC. En la segona part d’aquesta tesi, hem descrit els efectes pro- tumorals d’un mecanisme de comunicació creuada entre el TIMP-1 secretat pels TAFs i el CD63 de les cèl·lules canceroses que és específic per als pacients amb ADC. El TIMP- 1 secretat pels TAFs d’ADC és necessari i suficient per promoure el creixement i la invasió en les cèl·lules de càncer. Simultàniament, l’expressió de CD63 en les cèl·lules tumorals es necessària per observar aquests efectes pro-tumorals del TIMP-1. De manera consistent, in vivo hem observat que la inhibició de la secreció del TIMP-1 redueix tant el volum tumoral com el creixement invasiu en ratolins co-injectats amb cèl·lules canceroses i TAFs. Finalment, hem estudiat la relació d’aquesta comunicació creuada amb la resistència al nintedanib trobada en pacients amb CE, el qual és un fàrmac antifibròtic aprovat selectivament en pacients amb ADC. Hem observat que en els TAFs en els quals s’ha inhibit genèticament la secreció de TIMP-1, hi ha una menor resposta a nintedanib. Aquest treball identifica per primer cop un mecanisme de comunicació creuada entre TAFs i cèl·lules canceroses que és específic per pacients amb ADC, aporta nous coneixements sobre el rol patològic del TIMP-1 en càncer de pulmó, descriu un nou mecanisme de resistència al nintedanib en CE i apunta la interacció TIMP-1/CD63 com a nova diana terapèutica.

Background Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are still lacking. Here we show that a zebrafish tumor xenograft (ZTX) platform based on implantation of PDX tissue fragments recapitulate both treatment outcome and tumor invasiveness/dissemination in patients, within an assay time of only 3 days. Methods Using a panel of 39 non-small cell lung cancer PDX models, we developed a combined mouse-zebrafish PDX platform based on direct implantation of cryopreserved PDX tissue fragments into zebrafish embryos, without the need for pre-culturing or expansion. Clinical proof-of-principle was established by direct implantation of tumor samples from four patients. Results The resulting ZTX models responded to Erlotinib and Paclitaxel, with similar potency as in mouse-PDX models and the patients themselves, and resistant tumors similarly failed to respond to these drugs in the ZTX system. Drug response was coupled to elevated expression of EGFR, Mdm2, Ptch1 and Tsc1 (Erlotinib), or Nras and Ptch1 (Paclitaxel) and reduced expression of Egfr, Erbb2 and Foxa (Paclitaxel). Importantly, ZTX models retained the invasive phenotypes of the tumors and predicted lymph node involvement of the patients with 91% sensitivity and 62% specificity, which was superior to clinically used tests. The biopsies from all four patient tested implanted successfully, and treatment outcome and dissemination were quantified for all patients in only 3 days. Conclusions We conclude that the ZTX platform provide a fast, accurate, and clinically relevant system for evaluation of treatment outcome and invasion/dissemination of PDX models, providing an attractive platform for combined mouse-zebrafish PDX trials and personalized medicine.

La càrrega de les alteracions del nombre de còpies somàtiques (SCNAs charge) és un biomarcador de benefici clínic en pacients amb càncer de pulmó no microcític avançat tractats amb inhibidors de punt de control d’anticossos. Es vol demostrar tant el seu ús en teixit com en biòpsia líquida. La carga de las alteraciones del número de copias somáticas (SCNAs burden) es un biomarcador de beneficio clínico en pacientes con cáncer de pulmón no microcítico avanzado tratados con inhíbidores de punto de control inmunológico.Se quiere demostrar tanto su uso en tejido como en biopsia líquida. The load of somatic copy number alterations (SCNAs load) is a biomarker of clinical benefit in patients with advanced non-small cell lung cancer treated with antibody checkpoint inhibitors. We want to demonstrate its use in both tissue and biopsy liquid. Universitat Autònoma de Barcelona. Programa de Doctorat en Medicina

The algorithm for calculating absorbed dose in external radiotherapy Acuros XB (AXB), based on the solution of the Boltzmann equation, has shown to achieve a higher level of accuracy than the preceding convolution/superposition algorithm AAA, especially in volumetric-modulated arc therapy (VMAT) in head and neck (H&N) patients or lung stereotactic radiation therapy (SBRT). Adopting AXB in clinical practice requires a detailed study of the differences in the calculation of doses with respect to AAA. This study assesses the dosimetric impact of switching from AAA to AXB, reporting dose-to-medium and dose-to-water, in 110 H&N VMAT and 54 lung SBRT patients, determines whether planning-target-volume dose prescriptions and organ-at-risk constraints should be modified, and, for the H&N cohort, establishes the relationship between maximum doses to the mandible and osteoradionecrosis (ORN) incidence for the two algorithms and reporting modes. We obtain that differences between AXB and AAA are below the threshold of clinical detectability, except for structures that include bone, such as the mandible in H&N VMAT and the ribs in lung SBRT. On the other hand, we obtain that AXB reporting dose-to-water can be the best combination to predict ORN of the mandible. The results of this research may facilitate decision-making when switching to the AXB algorithm in clinical practice and provide tools to facilitate studies about the clinical impact of its differences with respect to AAA at a multicentric level L’algorisme de càlcul de dosi absorbida en radioteràpia externa Acuros XB (AXB), basat en la solució de l’equació de Boltzmann, ha demostrat assolir un nivell de precisió superior al de l’algorisme de convolució/superposició anterior AAA, especialment en tècniques com l’arc-teràpia de modulació volumètrica (VMAT) en pacients de cap i coll (CC) o la radioteràpia estereotàxica (SBRT) pulmonar. L’adopció d’AXB a la pràctica clínica requereix un estudi detallat de les diferències en el càlcul de dosi respecte de AAA. Aquest estudi avalua l'impacte dosimètric de canviar de AAA a AXB, reportant la dosi en medi i en aigua, en 110 pacients de VMAT de CC i 54 pacients de SBRT de pulmó, determina si les prescripcions de dosi als volums blanc de planificació i les restriccions als òrgans de risc s’han de modificar i, per la cohort de cap i coll, estableix la relació entre les dosis màximes a la mandíbula i la incidència d’osteoradionecrosi (ORN) pels dos algorismes i maneres de reportar la dosi. Obtenim que les diferències entre AXB i AAA estan per sota del llindar de detectabilitat clínica, excepte per estructures que inclouen os, com la mandíbula en VMAT de cap i coll i les costelles en SBRT pulmonar. D’altra banda, obtenim que AXB reportant la dosi en aigua pot ser la millor combinació per predir l’ORN mandibular. Els resultats d’aquesta recerca faciliten la presa de decisions al canviar a l'algorisme AXB a la pràctica clínica i aporten eines per facilitar estudis sobre l’impacte clínic de les seves diferències respecte AAA a nivell multicèntric Programa de Doctorat en Biologia Molecular, Biomedicina i Salut

Los tratamientos quimioterapéuticos en pacientes oncológicos no solo reflejan secuelas físicas, también producen secuelas a nivel cognitivo; lo que se conoce como "chemobrain". Por ello, para profundizar sobre las características de este fenómeno, se ha escogido el caso una paciente real de 62 años de edad diagnosticada de cáncer de pulmón en estadio IV desde el año 2014. A causa de su enfermedad, ha recibido, entre otros tratamientos, quimioterapia; y a raíz de este evento refiere ciertas alteraciones cognitivas como déficits de memoria y enlentecimiento de la velocidad de procesamiento. Así como alteraciones emocionales y conductuales. Se lleva a cabo una evaluación neuropsicológica mediante la administración de pruebas estandarizadas y cuestionarios sobre calidad de vida y estado emocional, donde los resultados muestran la presencia de este fenómeno en nuestra paciente. Pues refleja alteraciones en procesos de memoria y de la capacidad de aprendizaje, déficits atencionales, velocidad de procesamiento enlentecida y dificultades en el funcionamiento ejecutivo. Del mismo modo, presenta manifestaciones clínicas ansioso- depresivas, apatía, irritabilidad y fatiga. Por lo tanto, se propone un programa de rehabilitación cognitiva durante un periodo de 6 meses, centrado en enlentecer la progresión de la sintomatología presente; proporcionando una mejora y un mantenimiento del funcionamiento cognitivo global. Este programa incluye, además, sesiones de psicoterapia e intervención familiar. Al finalizar el programa se espera obtener una mejora general del funcionamiento cognitivo, emocional y conductual; disminuyendo las alteraciones del desarrollo de su vida diaria. Chemotherapeutic treatments in oncological patients not only reflect physical sequelae, also produce sequelae at the cognitive level; what is known as "chemobrain". Therefore, to delve into the characteristics of this phenomenon, we have chosen the case of a real 62-year-old patient diagnosed with stage IV lung cancer since 2014. Because of her disease, she has received, among other treatments, chemotherapy; and as a result of this event she refers certain cognitive alterations such as memory deficits and slowing of processing speed. As well as emotional and behavioral alterations. A neuropsychological evaluation is carried out by administering standardized tests and questionnaires on quality of life and emotional state, where the results show the presence of this phenomenon in our patient. It reflects alterations in memory processes and learning ability, attentional deficits, slowed processing speed and difficulties in executive functioning. Likewise, she presents clinical manifestations of anxiety and depression, apathy, irritability and fatigue. Therefore, a cognitive rehabilitation program is proposed for a period of 6 months focused on slowing down the progression of the present symptomatology; providing an improvement and maintenance of global cognitive functioning. This program also includes psychotherapy sessions and family intervention. At the end of the program it is expected to obtain a general improvement of cognitive, emotional and behavioral functioning; decreasing the alterations in the development of their daily life. Els tractaments quimioterapèutics en pacients oncològics no sols reflecteixen seqüeles físiques, també produeixen seqüeles a nivell cognitiu; el que es coneix com "chemobrain". Per això, per a aprofundir sobre les característiques d'aquest fenomen, s'ha triat el cas una pacient real de 62 anys d'edat diagnosticada de càncer de pulmó en estadi IV des de l'any 2014. A causa de la seva malaltia, ha rebut, entre altres tractaments, quimioteràpia; i arran d'aquest esdeveniment refereix unes certes alteracions cognitives com a dèficits de memòria i alentiment de la velocitat de processament. Així com alteracions emocionals i conductuals. Es duu a terme una avaluació neuropsicològica mitjançant l'administració de proves estandarditzades i qüestionaris sobre qualitat de vida i estat emocional, on els resultats mostren la presència d'aquest fenomen en la nostra pacient. Perquè reflecteix alteracions en processos de memòria i de la capacitat d'aprenentatge, dèficits atencionales, velocitat de processament alentida i dificultats en el funcionament executiu. De la mateixa manera, presenta manifestacions clíniques ansiós- depressives, apatia, irritabilitat i fatiga. Per tant, es proposa un programa de rehabilitació cognitiva durant un període de 6 mesos, centrat en alentir la progressió de la simptomatologia present; proporcionant una millora i un manteniment del funcionament cognitiu global. Aquest programa inclou, a més, sessions de psicoteràpia i intervenció familiar. En finalitzar el programa s'espera obtenir una millora general del funcionament cognitiu, emocional i conductual; disminuint les alteracions del desenvolupament de la seva vida diària.

Background The TGF-β1 transcription factor SMAD3 is epigenetically repressed in tumour-associated fibroblasts (TAFs) from lung squamous cell carcinoma (SCC) but not adenocarcinoma (ADC) patients, which elicits a compensatory increase in SMAD2 that renders SCC-TAFs less fibrotic. Here we examined the effects of altered SMAD2/3 in fibroblast migration and its impact on the desmoplastic stroma formation in lung cancer. Methods We used a microfluidic device to examine descriptors of early protrusions and subsequent migration in 3D collagen gels upon knocking down SMAD2 or SMAD3 by shRNA in control fibroblasts and TAFs. Results High SMAD3 conditions as in shSMAD2 fibroblasts and ADC-TAFs exhibited a migratory advantage in terms of protrusions (fewer and longer) and migration (faster and more directional) selectively without TGF-β1 along with Erk1/2 hyperactivation. This enhanced migration was abrogated by TGF-β1 as well as low glucose medium and the MEK inhibitor Trametinib. In contrast, high SMAD2 fibroblasts were poorly responsive to TGF-β1, high glucose and Trametinib, exhibiting impaired migration in all conditions. Conclusions The basal migration advantage of high SMAD3 fibroblasts provides a straightforward mechanism underlying the larger accumulation of TAFs previously reported in ADC compared to SCC. Moreover, our results encourage using MEK inhibitors in ADC-TAFs but not SCC-TAFs.

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P

Projekt DEAL; National Institutes of Health [7U19CA203654-02/397 114564-5111078]; National Cancer Institute, National Institutes of Health [U01 CA063673, UM1 CA167462, R01 CA 111703, RO1 CA 151989, U01 CA167462]; Fred Hutchinson Cancer Research Center; NCI [5U01CA209414.]; Open Access Publication Funds of the Gottingen University, Rosenberger A, Muttray N, Hung RJ, Christiani DC, Caporaso NE, Liu G, Bojesen SE, Le Marchand L, Albanes D, Aldrich MC, Tardon A, Fernández-Tardón G, Rennert G, Field JK, Davies MPA, Liloglou T, Kiemeney LA, Lazarus P, Wendel B, Haugen A, Zienolddiny S, Lam S, Schabath MB, Andrew AS, Duell EJ, Arnold SM, Goodman GE, Chen C, Doherty JA, Taylor F, Cox A, Woll PJ, Risch A, Muley TR, Johansson M, Brennan P, Landi MT, Shete SS, Amos CI, Bickeböller H; INTEGRAL-ILCCO Consortium

Background: Nutrition is an important factor in the outcome of any disease process. We evaluated the relationship of nutritional status and inflammatory status of non-small cell lung cancer (NSCLC) patients undergoing robotic-assisted thoracic surgery (RATS) with postoperative complications. Methods: This prospective cohort study included 107 NSCLC patients undergoing surgical treatment, between 2019 and 2021. Nutritional status and inflammatory status were assessed before pulmonary resection using anthropometric assessment, blood tests, and body mass index (BMI). Results: The BMI was 27.5 ± 4.4. Based on BMI, 29% (n = 31) were classified as normal weight, 43% (n = 46) as overweight, and 28% (n = 30) as obese. The mean neutrophil/lymphocyte ratio (NLR) was 2.16 ± 0.85, the platelet/lymphocyte ratio (PLR) was 121.59 ± 44.21, and the lymphocyte/monocyte ratio (LMR) was 3.52 ± 1.17. There was no increase in the number of intraoperative complications or bleeding (p = 0.696), postoperative complications (p = 0.569), mean hospital stay (p = 0.258) or duration of chest drain (p = 0.369). Higher inflammatory status, with an NLR > 1.84, was associated with more overall postoperative complications (p = 0.028), only in univariate analysis, but this significance was not maintained on multivariate analysis. Conclusions: BMI was not a predictor of increased postoperative risk in this cohort; therefore, weight should not deter surgeons from using RATS for pulmonary resection.

Lung cancer remains one the most common cancers in Europe and ranks first in terms of cancer mortality in both sexes. Incidence rates vary by region and depend above all on the prevalence of tobacco consumption. In this study we describe recent trends in lung cancer incidence by sex, age and histological type in Catalonia and project changes according to histology by 2025. Bayesian age-period-cohort models were used to predict trends in lung cancer incidence according to histological type from 2012 to 2025, using data from the population-based Catalan cancer registries. Data suggest a decrease in the absolute number of new cases in men under the age of 70 years and an increase in women aged 60 years or older. Adenocarcinoma was the most common type in both sexes, while squamous cell carcinoma and small cell carcinoma were decreasing significantly among men. In both sexes, the incident cases increased by 16% for patients over 70 years. Increases in adenocarcinoma and rising incidence in elderly patients suggest the need to prioritize strategies based on multidisciplinary teams, which should include geriatric specialists.

Objectives: Robust economic evaluations are needed to identify efficient strategies for lung cancer prevention that combine brief and intensive smoking cessation intervention programmes with screening using low-dose computed tomography (LDCT) at different ages, frequencies, and coverages. We aimed to assess the cost-effectiveness of smoking cessation approaches combined with lung cancer screening in the European context at a population level from a societal perspective. Materials and Methods: A microsimulation model that describes the natural history of lung cancer and incorporates several prevention strategies was developed. Discounted lifetime QALYs and costs at a rate of 3% were used to calculate incremental cost-effectiveness ratios, defined as additional costs in 2017 Euros per QALY gained. Results: Smoking cessation interventions reduce the incidence of lung cancer by 8%-46% and are consistently more effective and cost-effective when starting at younger ages. Screening reduces lung cancer mortality by 1%-24% and is generally less effective and more costly than smoking cessation interventions. The most cost-effective strategy would be to implement intensive smoking cessation interventions at ages 35, 40 and 45, combined with screening every three years between the ages of 55 and 65. Conclusions: Combining smoking cessation interventions with LDCT screening is a very attractive prevention strategy that substantially diminishes the burden of lung cancer. These combined prevention strategies, especially when providing several intensive interventions for smoking cessation at early ages, are more cost-effective than both approaches separately and allow for a more intensified LDCT without losing efficiency. info:eu-repo/semantics/publishedVersion

Simple Summary It is already known that DNA alterations do not fully recapitulate the complex nature of a tumor or its potential interaction with specific treatments. Therefore, in order to establish more precise and effective therapeutic approaches for non-small cell lung cancer, tumors will have to be characterized in a more accurate and comprehensive way. In this regard, transcription profiling has already demonstrated its utility in further stratifying patients in a much more refined way than genomic alterations. Examples of this include the definition of intrinsic subtypes in colorectal cancer, breast, or non-small cell lung cancer tumors based on their expression patterns. Moreover, the characterization of the activity levels of the pathways involved in tumor progression and development is bound to better predict the specific response to a certain therapy than isolated biomarkers such as specific DNA alterations or the expression of single genes. This is especially relevant in the context of patients not harboring targetable alterations or those developing resistance after treatment. Abstract Recent technological advances and the application of high-throughput mutation and transcriptome analyses have improved our understanding of cancer diseases, including non-small cell lung cancer. For instance, genomic profiling has allowed the identification of mutational events which can be treated with specific agents. However, detection of DNA alterations does not fully recapitulate the complexity of the disease and it does not allow selection of patients that benefit from chemo- or immunotherapy. In this context, transcriptional profiling has emerged as a promising tool for patient stratification and treatment guidance. For instance, transcriptional profiling has proven to be especially useful in the context of acquired resistance to targeted therapies and patients lacking targetable genomic alterations. Moreover, the comprehensive characterization of the expression level of the different pathways and genes involved in tumor progression is likely to better predict clinical benefit from different treatments than single biomarkers such as PD-L1 or tumor mutational burden in the case of immunotherapy. However, intrinsic technical and analytical limitations have hindered the use of these expression signatures in the clinical setting. In this review, we will focus on the data reported on molecular classification of non-small cell lung cancer and discuss the potential of transcriptional profiling as a predictor of survival and as a patient stratification tool to further personalize treatments.

Simple Summary Nintedanib is an anti-angiogenic agent that has received approval in the European Union for the treatment of non-small cell lung cancer (NSCLC) after first-line chemotherapy. Here, we explore the possibility that the flavonolignan silibinin—the major bioactive component from the seeds of the milk thistle herb (Silybum marianum)—can provide clinical benefit in patients with advanced NSCLC treated with nintedanib. In vitro studies revealed that silibinin targets biological functions important for the therapeutic efficacy of nintedanib; specifically, activation of the transcription factor STAT3 and sequestration into lysosomal “safe houses”. Supplementation with the silibinin-based nutraceutical Legasil® to patients with NSCLC receiving nintedanib/docetaxel was associated with increased clinical responses and a significantly longer time to treatment failure. Our findings provide a biological and clinical rationale for combining silibinin with nintedanib in a patient population for whom few effective second-line chemotherapy regimens are available. Abstract The anti-angiogenic agent nintedanib has been shown to prolong overall and progression-free survival in patients with advanced non-small-cell lung cancer (NSCLC) who progress after first-line platinum-based chemotherapy and second-line immunotherapy. Here, we explored the molecular basis and the clinical benefit of incorporating the STAT3 inhibitor silibinin—a flavonolignan extracted from milk thistle—into nintedanib-based schedules in advanced NSCLC. First, we assessed the nature of the tumoricidal interaction between nintedanib and silibinin and the underlying relevance of STAT3 activation in a panel of human NSCLC cell lines. NSCLC cells with poorer cytotoxic responses to nintedanib exhibited a persistent, nintedanib-unresponsive activated STAT3 state, and deactivation by co-treatment with silibinin promoted synergistic cytotoxicity. Second, we tested whether silibinin could impact the lysosomal sequestration of nintedanib, a lung cancer cell-intrinsic mechanism of nintedanib resistance. Silibinin partially, but significantly, reduced the massive lysosomal entrapment of nintedanib occurring in nintedanib-refractory NSCLC cells, augmenting the ability of nintedanib to reach its intracellular targets. Third, we conducted a retrospective, observational multicenter study to determine the efficacy of incorporating an oral nutraceutical product containing silibinin in patients with NSCLC receiving a nintedanib/docetaxel combination in second- and further-line settings (n = 59). Overall response rate, defined as the combined rates of complete and partial responses, was significantly higher in the study cohort receiving silibinin supplementation (55%) than in the control cohort (22%, p = 0.011). Silibinin therapy was associated with a significantly longer time to treatment failure in multivariate analysis (hazard ratio 0.43, p = 0.013), despite the lack of overall survival benefit (hazard ratio 0.63, p = 0.190). Molecular mechanisms dictating the cancer cell-intrinsic responsiveness to nintedanib, such as STAT3 activation and lysosomal trapping, are amenable to pharmacological intervention with silibinin. A prospective, powered clinical trial is warranted to confirm the clinical relevance of these findings in patients with advanced NSCLC.

Simple Summary Lung cancer is the leading cause of cancer death among both men and women, partly due to limited therapy responses. New avenues of knowledge are indicating that lung cancer cells do not form a tumor in isolation but rather obtain essential support from their surrounding host tissue rich in altered fibroblasts. Notably, there is growing evidence that tumor progression and even the current limited responses to therapies could be prevented by rescuing the normal behavior of fibroblasts, which are critical housekeepers of normal tissue function. For this purpose, it is key to improve our understanding of the molecular mechanisms driving the pathologic alterations of fibroblasts in cancer. This work provides a comprehensive review of the main molecular mechanisms involved in fibroblast transformation based on epigenetic reprogramming, and summarizes emerging therapeutic approaches to prevent or overcome the pathologic effects of tumor-associated fibroblasts. Abstract Lung cancer is the leading cause of cancer-related death worldwide. The desmoplastic stroma of lung cancer and other solid tumors is rich in tumor-associated fibroblasts (TAFs) exhibiting an activated/myofibroblast-like phenotype. There is growing awareness that TAFs support key steps of tumor progression and are epigenetically reprogrammed compared to healthy fibroblasts. Although the mechanisms underlying such epigenetic reprogramming are incompletely understood, there is increasing evidence that they involve interactions with either cancer cells, pro-fibrotic cytokines such as TGF-β, the stiffening of the surrounding extracellular matrix, smoking cigarette particles and other environmental cues. These aberrant interactions elicit a global DNA hypomethylation and a selective transcriptional repression through hypermethylation of the TGF-β transcription factor SMAD3 in lung TAFs. Likewise, similar DNA methylation changes have been reported in TAFs from other cancer types, as well as histone core modifications and altered microRNA expression. In this review we summarize the evidence of the epigenetic reprogramming of TAFs, how this reprogramming contributes to the acquisition and maintenance of a tumor-promoting phenotype, and how it provides novel venues for therapeutic intervention, with a special focus on lung TAFs.

Before initiating treatment of advanced non-small-cell lung cancer with tyrosine kinase inhibitors (eg, erlotinib, gefitinib, osimertinib, and afatinib), which inhibit the catalytic activity of epidermal growth factor receptor (EGFR), clinical guidelines require determining the EGFR mutational status for activating (EGFR exons 18, 19, 20, or 21) and resistance (EGFR exon 20) mutations. The EGFR resistance mutation T790M should be monitored at cancer progression. The Idylla EGFR Mutation Assay, performed on the Idylla molecular diagnostics platform, is a fully automated (

Introduction p21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCι) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKCι-PAK1 signaling pathway approach can be an efficient target in different types of NSCLC cell and mouse models. Methods The effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification. In addition, for clinical availability, screening for new PAK1 inhibitors was carried out and the compound OTSSP167 was evaluated in combination with auranofin in cell and mice models. Results The combination of IPA-3 or OTSSP167 plus auranofin showed high synergism for inhibiting cell viability and colony formation in three cell lines. Mechanistic characterization revealed that this drug combination abrogated expression and activation of membrane receptors and downstream signaling proteins crucial in lung cancer: EGFR, MET, PAK1, PKCι, ERK1/2, AKT, YAP1 and mTOR. A nude mouse xenograft assay demonstrated that this drug combination strongly suppressed tumor volume compared with single drug treatment. Conclusions Combination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models. It is of interest to further test the targeting of PKCι-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients.

Highlights • EV HOTTIP analysis during post-surgical follow-up allows early recurrence detection. • Detection of an increment of EV HOTTIP level in first post-surgical sample predicts recurrence with a sensitivity of 87.5% and specificity of 90.9%. • Detection of an increment of EV HOTTIP level in first post-surgical sample predicts worse patient outcome. • EV HOTTIP could be considered as a follow-up biomarker for monitoring recurrence in NSCLC., In resected non-small cell lung cancer (NSCLC), postsurgical recurrence is the major factor affecting long-term survival. The identification of biomarkers in extracellular vesicles (EV) obtained from serial blood samples after surgery could enhance early detection of relapse and improve NSCLC outcome. Since EV cargo contains long non-coding RNAs (lncRNAs), we aimed to analyze whether the oncogenic lncRNA HOTTIP, which higher expression in tumor tissue was related to worse outcome in NSCLC, could be detected in EV from NSCLC patients and serve as recurrence biomarker. After purification of EVs by ultracentrifugation in 52 serial samples from 18 NSCLC patients, RNA was isolated and HOTTIP was quantified by Real time PCR. We observed that patients that relapsed after surgery displayed increased postsurgical EV HOTTIP levels in comparison with presurgical levels. In the relapsed patients with several samples available between surgery and relapse, we observed an increment in the EV HOTTIP levels when approaching to relapse, which indicated its potential utility for monitoring disease recurrence. When we focused in EV HOTTIP levels in the first post-surgical sample, we observed that the detection of an increment of the expression levels in comparison to presurgical sample, predicted recurrence with high sensitivity (85.7%) and specificity (90.9%) and that patients had shorter time to relapse and shorter overall survival. In conclusion, our pilot study showed that EV HOTTIP is a potential biomarker for monitoring disease recurrence after surgery in NSCLC.

Nanocàpsules anfòteres; Tractament del càncer de pulmó; Sistemes de lliurament de medicaments dirigits Nanocápsulas anfóteras; Tratamiento del cáncer de pulmón; Sistemas de administración de fármacos dirigidos Amphoteric nanocapsules; Lung cancer treatment; Targeted drug delivery systems Cancer is one of the leading causes of mortality worldwide due, in part, to limited success of some current therapeutic approaches. The clinical potential of many promising drugs is restricted by their systemic toxicity and lack of selectivity towards cancer cells, leading to insufficient drug concentration at the tumor site. To overcome these hurdles, we developed a novel drug delivery system based on polyurea/polyurethane nanocapsules (NCs) showing pH-synchronized amphoteric properties that facilitate their accumulation and selectivity into acidic tissues, such as tumor microenvironment. We have demonstrated that the anticancer drug used in this study, a hydrophobic anionophore named T21, increases its cytotoxic activity in acidic conditions when nanoencapsulated, which correlates with a more efficient cellular internalization. A biodistribution assay performed in mice has shown that the NCs are able to reach the tumor and the observed systemic toxicity of the free drug is significantly reduced in vivo when nanoencapsulated. Additionally, T21 antitumor activity is preserved, accompanied by tumor mass reduction compared to control mice. Altogether, this work shows these NCs as a potential drug delivery system able to reach the tumor microenvironment, reducing the undesired systemic toxic effects. Moreover, these nanosystems are prepared under scalable methodologies and straightforward process, and provide tumor selectivity through a smart mechanism independent of targeting ligands. This research was funded by Consejería de Educación de la Junta de Castilla y León (BU092U16 and BU067P20), Instituto de Salud Carlos III (grants PI18/00441 and DTS20/00018), ACCIÓ (Agency for business competitiveness; Generalitat de Catalunya) (Nuclis d’R+D EMC/2755/2017); co-funded by the European Regional Development Fund (ERDF); Asociación Española Contra el Cáncer (LABAE18009SEGU), and supported by the “Pla de Doctorats Industrials de la Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya (grant number 2013 DI 028).

Simple Summary Although microcalcifications can be considered one of the first indicators of suspicious cancer lesions, depending on their morphology and distribution, the formation of hydroxyapatite calcifications and their relationship with malignancy remains unknown. In this work, we investigate in depth the biochemical composition of breast cancer microcalcifications, combining Raman spectroscopy imaging and advanced multivariate analysis. We demonstrate that DNA is naturally adsorbed and encapsulated inside hydroxyapatite found in breast cancer tissue. Furthermore, we also show the encapsulation of other relevant biomolecules such as lipids, proteins, cytochrome C and polysaccharides. The demonstration of the natural DNA biomineralization in cancer tissues represents an unprecedented advance in the field, as it can pave the way to understanding the role of hydroxyapatite in malignant tissues. Microcalcifications are detected through mammography screening and, depending on their morphology and distribution (BI-RADS classification), they can be considered one of the first indicators of suspicious cancer lesions. However, the formation of hydroxyapatite (HAp) calcifications and their relationship with malignancy remains unknown. In this work, we report the most detailed three-dimensional biochemical analysis of breast cancer microcalcifications to date, combining 3D Raman spectroscopy imaging and advanced multivariate analysis in order to investigate in depth the molecular composition of HAp calcifications found in 26 breast cancer tissue biopsies. We demonstrate that DNA has been naturally adsorbed and encapsulated inside HAp microcalcifications. Furthermore, we also show the encapsulation of other relevant biomolecules in HAp calcifications, such as lipids, proteins, cytochrome C and polysaccharides. The demonstration of natural DNA biomineralization, particularly in the tumor microenvironment, represents an unprecedented advance in the field, as it can pave the way to understanding the role of HAp in malignant tissues.

Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRAS G12C, the most common mutation, is found in ~13% of patients. While KRAS was long considered ‘undruggable’, several novel direct KRAS G12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy.

Large cell carcinoma (LCC) is a rare and aggressive lung cancer subtype with poor prognosis and no targeted therapies. Tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we identify MMP1 as overexpressed specifically in LCC cell lines, and we show that expression of MMP1 by LCC cells is necessary for induction of fibroblast senescence and consequent tumor promotion in both cell culture and mouse models. We also show that MMP1, in combination with TGF-β1, is sufficient to induce fibroblast senescence and consequent LCC promotion. Furthermore, we implicate PAR-1 and oxidative stress in MMP1/TGF-β1-induced TAF senescence. Our results establish an entirely new role for MMP1 in cancer, and support a novel therapeutic strategy in LCC based on targeting senescent TAFs., This work was further supported by grants from the Agencia Estatal de Investigaci´on (AEI/FEDER) (PI13/02368, SAF2016-79527-R and PID2019-110944RB-I00 (AEI/ 10.13039/501100011033) to JA, PI16/ 00890 to NR), Fundaci´o Privada Cellex (to JA), National Institutes of Health (grant R01 GM132100 to ER), Generalitat de Catalunya (AGAUR SGR661 and CERCA Programme to JA), Junta Provincial de Barcelona de l’Associaci´o Espanyola Contra el C`ancer (AECC-B16-917 to JA), Italian Ministry of Health (RF-2016-02362946 to LR), Italian Association for Cancer Research (AIRC-IG21431 to LR), Sociedad Espa˜nola de Neumología y Cirugía Tor´acica – SEPAR (SEPAR 437 to NR), COST Action (PROTEOSTASIS BM1307), and by fellowships from Ciˆencia sem Fronteiras CNPq (to RI), and Universitat de Barcelona/beca APIF (to PD).