Publications by authors named "J Lorente"

407 Publications

Case Studies in Physiology: Physiological and clinical effects of temporary diaphragm pacing in 2 patients with ventilator-induced diaphragm dysfunction.

J Appl Physiol (1985) 2021 Apr 8. Epub 2021 Apr 8.

Critical Care, Hospital Universitario de Getafe, Spain.

IntroductionVentilator-induced diaphragm dysfunction (VIDD) is increasingly recognized as an important side-effect of invasive ventilation in critically ill patients and is associated with poor outcomes. Whether patients with VIDD benefit from temporary diaphragm pacing is uncertain.Material and MethodsIntramuscular diaphragmatic electrodes were implanted for temporary stimulation with a pacing device (TransAeris{trade mark, serif} System) in two patients with VIDD. The electrodes were implanted via laparoscopy (first patient), or via bilateral thoracoscopy (second patient). Stimulation parameters were titrated according to tolerance. Diaphragm thickening fraction by ultrasound, maximum inspiratory pressure (Pi) and diaphragm electromyography (EMGdi) signal analysis were used to monitor the response to diaphragm pacing.ResultsBoth patients tolerated diaphragm pacing. In the first patient improvements in diaphragm excursions were noted once pacing was initiated, and diaphragm thickening fraction did not further deteriorate over time. The diaphragm thickening fraction improved in the second patient, and Pi as well as EMGdi analysis suggested improved muscle function. This patient could be fully weaned from the ventilator.DiscussionThese case reports present the first experience with temporary diaphragm pacing in critically ill patients with VIDD. Our results should be taken cautiously given the reduced sample size, but provide the proof of concept to put forward the hypothesis that a course of diaphragm pacing may be associated with improved diaphragmatic function. Our findings of the tolerance to the procedure and the beneficial physiological effects are not prove of safety and efficacy, but may set the ground to design and conduct larger studies.
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http://dx.doi.org/10.1152/japplphysiol.00543.2020DOI Listing
April 2021

Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation.

Cancers (Basel) 2021 Mar 23;13(6). Epub 2021 Mar 23.

GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Gene Regulation, Stem Cells & Development Lab, PTS Granada, Avenida de la Ilustracion 114, 18016 Granada, Spain.

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms ( and ) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of full-length and AR target genes, but not necessarily and/or isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment.
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http://dx.doi.org/10.3390/cancers13061483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004828PMC
March 2021

Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia.

Int J Mol Sci 2021 Mar 15;22(6). Epub 2021 Mar 15.

Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain.

Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient's amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease.
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http://dx.doi.org/10.3390/ijms22062990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002209PMC
March 2021

Intraoperative crystalloid utilization variability and association with postoperative outcomes: A post hoc analysis of two multicenter prospective cohort studies.

Rev Esp Anestesiol Reanim 2021 Mar 19. Epub 2021 Mar 19.

Departamento de Anestesia y Medicina Perioperatoria, Hospital Universitario Infanta Leonor, Madrid, España; Spanish Perioperative Audit and Research Network (REDGERM), Zaragoza, España; Grupo Español de Rehabilitación Multimodal (GERM), Zaragoza, España.

Background: The optimal regimen for intravenous administration of intraoperative fluids remains unclear. Our goal was to analyze intraoperative crystalloid volume administration practices and their association with postoperative outcomes.

Methods: We extracted clinical data from two multicenter observational studies including adult patients undergoing colorectal surgery and total hip (THA) and knee arthroplasty (TKA). We analyzed the distribution of intraoperative fluid administration. Regression was performed using a general linear model to determine factors predictive of fluid administration. Patient outcomes and intraoperative crystalloid utilization were summarized for each surgical cohort. Regression models were developed to evaluate associations of high or low intraoperative crystalloid with the likelihood of increased postoperative complications, mainly acute kidney injury (AKI) and hospital length of stay (LOS).

Results: 7,580 patients were included. The average adjusted intraoperative crystalloid infusion rate across all surgeries was to 7.9 (SD 4) mL/kg/h. The regression model strongly favored the type of surgery over other patient predictors. We found that high fluid volume was associated with 40% greater odds ratio (OR 1.40; 95% confidence interval1.01-1.95, p = 0.044) of postoperative complications in patients undergoing THA, while we found no associations for the other types of surgeries, AKI and LOS CONCLUSIONS: A wide variability was observed in intraoperative crystalloid volume administration; however, this did not affect postoperative outcomes.
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http://dx.doi.org/10.1016/j.redar.2020.10.011DOI Listing
March 2021

Antioxidants for the Treatment of Breast Cancer: Are We There Yet?

Antioxidants (Basel) 2021 Jan 31;10(2). Epub 2021 Jan 31.

Instituto de Investigación Biosanitaria Ibs.GRANADA, University Hospitals of Granada-University of Granada, 18100 Granada, Spain.

Breast cancer is the most frequent cancer and the leading cause of cancer death in women. Oxidative stress and the generation of reactive oxygen species (ROS) have been related to cancer progression. Compared to their normal counterparts, tumor cells show higher ROS levels and tight regulation of REDOX homeostasis to maintain a low degree of oxidative stress. Traditionally antioxidants have been extensively investigated to counteract breast carcinogenesis and tumor progression as chemopreventive agents; however, there is growing evidence indicating their potential as adjuvants for the treatment of breast cancer. Aimed to elucidate whether antioxidants could be a reality in the management of breast cancer patients, this review focuses on the latest investigations regarding the ambivalent role of antioxidants in the development of breast cancer, with special attention to the results derived from clinical trials, as well as their potential use as plausible agents in combination therapy and their power to ameliorate the side effects attributed to standard therapeutics. Data retrieved herein suggest that antioxidants play an important role in breast cancer prevention and the improvement of therapeutic efficacy; nevertheless, appropriate patient stratification based on "redoxidomics" or tumor subtype is mandatory in order to define the dosage for future standardized and personalized treatments of patients.
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http://dx.doi.org/10.3390/antiox10020205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911462PMC
January 2021

Oxygen-sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension.

Antioxidants (Basel) 2021 Jan 21;10(2). Epub 2021 Jan 21.

Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, 28040 Madrid, Spain.

Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.
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http://dx.doi.org/10.3390/antiox10020155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911835PMC
January 2021

Goal-Directed Fluid Therapy and Postoperative Outcomes in an Enhanced Recovery Program for Colorectal Surgery: A Propensity Score-Matched Multicenter Study.

Am Surg 2020 Dec 19:3134820973365. Epub 2020 Dec 19.

Department of Anesthesiology and Critical Care Medicine, 1501Johns Hopkins Hospital, MD, USA.

Introduction: Goal-directed fluid therapy (GDFT) has increasingly been utilized in major surgery as a key component to ensure fluid optimization and adequate tissue perfusion, showing improvements in the rate of morbidity and mortality under conventional care. It is unclear if patients derive similar benefit as part of an enhanced recovery program (ERP). Our group sought to assess the association between GDFT and postoperative outcomes within an ERP for colorectal surgery.

Methods: A propensity score-matched analysis, based upon demographic characteristics, comorbidities, and ERP components, was utilized to assess the association between GDFT and outcomes in a multicenter prospective ERP for colorectal surgery cohort study. Outcomes included pulmonary edema, acute kidney injury (AKI), ileus, surgical site infection (SSI), and anastomotic dehiscence. The calipmatch module was used to match patients who received GDFT to non-GDFT in a 1-to-1 propensity score fashion.

Results: A total of 151 matched pairs were included in the analysis (n = 302, 23%). Both groups had comparable baseline demographics, as well as similar rates of compliance with enhanced recovery after surgery (ERAS) components. Goal-directed fluid therapy patients received significantly more colloid (237 ± 320 mL vs. 140 ± 245 mL, < .01) than non-GDFT counterparts. Goal-directed fluid therapy was not associated with improved rates of postoperative AKI (odds ratios (OR) 1.00, 95% confidence intervals (CI) .39-2.59, = 1.00), ileus (OR 1.40, 95% CI .82-2.41, = .22), SSI (OR 1.06, 95% CI .54-2.08, = .86), or length of hospital stay (LOS) (10.8 ± 8.9 vs. 11.1±13.2 days, = .84).

Conclusions: There was no associated between GDFT and major postoperative outcomes within an ERAS program for colorectal surgery. Additional large-scale or pragmatic randomized trials are necessary to determine whether GDFT has a role in ERP for colorectal surgery.
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http://dx.doi.org/10.1177/0003134820973365DOI Listing
December 2020

Liver-lung interactions in acute respiratory distress syndrome.

Intensive Care Med Exp 2020 Dec 18;8(Suppl 1):48. Epub 2020 Dec 18.

Department of Critical Care Medicine, Hospital Universitario de Getafe, Madrid, Spain.

Patients with liver diseases are at high risk for the development of acute respiratory distress syndrome (ARDS). The liver is an important organ that regulates a complex network of mediators and modulates organ interactions during inflammatory disorders. Liver function is increasingly recognized as a critical determinant of the pathogenesis and resolution of ARDS, significantly influencing the prognosis of these patients. The liver plays a central role in the synthesis of proteins, metabolism of toxins and drugs, and in the modulation of immunity and host defense. However, the tools for assessing liver function are limited in the clinical setting, and patients with liver diseases are frequently excluded from clinical studies of ARDS. Therefore, the mechanisms by which the liver participates in the pathogenesis of acute lung injury are not totally understood. Several functions of the liver, including endotoxin and bacterial clearance, release and clearance of pro-inflammatory cytokines and eicosanoids, and synthesis of acute-phase proteins can modulate lung injury in the setting of sepsis and other severe inflammatory diseases. In this review, we summarized clinical and experimental support for the notion that the liver critically regulates systemic and pulmonary responses following inflammatory insults. Although promoting inflammation can be detrimental in the context of acute lung injury, the liver response to an inflammatory insult is also pro-defense and pro-survival. A better understanding of the liver-lung axis will provide valuable insights into new diagnostic targets and therapeutic strategies for clinical intervention in patients with or at risk for ARDS.
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http://dx.doi.org/10.1186/s40635-020-00337-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746785PMC
December 2020

Outcome of Acute Hypoxaemic Respiratory Failure. Insights from the Lung Safe Study.

Eur Respir J 2020 Dec 17. Epub 2020 Dec 17.

Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Unity Heath Toronto, Toronto, Ontario, Canada.

Background: The current incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in intensive care unit are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS).

Methods: An international, multicentre, prospective cohort study of patients presenting with hypoxemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with PaO/FiO ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure (PEEP) of at least 5 cm HO. ICU prevalence, causes of hypoxemia, hospital survival, factors associated with hospital mortality were measured. Patients with unilateral bilateral opacities were compared.

Findings: 12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (8.2%, CHF). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality but similar adjusted mortality than ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only 2 quadrants involved.

Interpretation: More than one third of the patients receiving mechanical ventilation have hypoxaemia and new infiltrates with an hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.
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http://dx.doi.org/10.1183/13993003.03317-2020DOI Listing
December 2020

[ISAR Score (Identification of Seniors At Risk) predicts mortality in patients older than 75 years admitted in Intensive Care].

Rev Esp Geriatr Gerontol 2021 Jan-Feb;56(1):5-10. Epub 2020 Dec 11.

Servicio de Medicina Intensiva y Grandes Quemados, Hospital Universitario de Getafe, Getafe, Madrid, España; CIBER de Enfermedades Respiratorias, Madrid, Universidad Europea, Madrid, España.

Background And Objectives: Currently, the patient's baseline situation is a more important prognostic factor than age. The purpose of this study is to estimate the prognostic value of the ISAR score (Identification of Senior at Risk) in patients ≥75 years admitted to intensive care (ICU).

Patients And Methods: Prospective multicenter study including patients ≥75 years admitted to the ICU > 24hours. On admission, 28 days and 6 months after discharge from the ICU, mortality and baseline were evaluated using the ISAR score, the Lawton and Brody scale (LB) and the Barthel index (BI), the Frail fragility scale. scale (FS), the Charlson comorbidity index (ICC), Dementia rating score (DRC).

Results: 38 of 94 patients (40%) were high risk (ISAR ≥ 3) and were characterized by BI 90 (65-100), LB 4 (3-5), and CDR 1 (0-2), ICC 7.5 (6-10). 58% had FS ≥ 3. In the long term, they were in a situation of dependency [BI 50 (2.5-77.5), LB 3 (0-4), CDR 1 (0-1.5)]. The ICU mortality at 28 days and 6 months was 18.4%, 25.7% and 35.3%, respectively, being statistically significant. The area under the ISAR score ROC curve was 0.749 to 0.797, in all the mortality periods studied, although the difference with other predictive variables was not significant, but the p value was the lowest.

Conclusions: The ISAR score predicts mortality in critically elderly patients with a discriminative capacity comparable to other predictive variables.
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http://dx.doi.org/10.1016/j.regg.2020.09.009DOI Listing
December 2020

Sandwich-Type Electrochemical Paper-Based Immunosensor for Claudin 7 and CD81 Dual Determination on Extracellular Vesicles from Breast Cancer Patients.

Anal Chem 2021 01 10;93(2):1143-1153. Epub 2020 Dec 10.

INQUISAL, Departamento de Química, Universidad Nacional de San Luis, CONICET, Chacabuco 917, D5700BWS San Luis, Argentina.

This study is focused on identifying novel epithelial markers in circulating extracellular vesicles (EVs) through the development of a dual sandwich-type electrochemical paper-based immunosensor for Claudin 7 and CD81 determination, as well as its validation in breast cancer (BC) patients. This immunosensor allows for rapid, sensitive, and label-free detection of these two relevant BC biomarkers. Under optimum conditions, the limit of detection for Claudin 7 was 0.4 pg mL, with a wide linear range of 2 to 1000 pg mL, while for CD81, the limit of detection was 3 pg mL, with a wide linear range of 0.01 to 10 ng mL. Finally, we validated Claudin 7 and CD81 determination in EVs from 60 BC patients and 20 healthy volunteers, reporting higher diagnostic accuracy than the one observed with classical diagnostic markers. This analysis provides a low-cost, specific, versatile, and user-friendly strategy as a robust and reliable tool for early BC diagnosis.
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http://dx.doi.org/10.1021/acs.analchem.0c04180DOI Listing
January 2021

The Polemic Diagnostic Role of Mutations in Liquid Biopsies from Breast, Colon and Lung Cancers.

Cancers (Basel) 2020 Nov 12;12(11). Epub 2020 Nov 12.

GENYO Centre for Genomics and Oncological Research, formed by Pfizer, the University of Granada and the Andalusian Regional Government, PTS Granada, Liquid Biopsy and Cancer Interception Group, Av. de la Ilustración, 114, 18016 Granada, Spain.

Being minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding mutation status analysis, liquid biopsies have not yet substituted tissue samples, mainly due to the lack of concordance between the two types of biopsies. This needs to be examined in a study-dependent manner, taking into account the particular type of liquid biopsy analyzed, that is, circulating tumor cells (CTCs) or cell-free DNA (cfDNA), its involvement in the tumor biology and evolution and, finally, the technology used to analyze each biopsy type. Here, we review the main studies analyzing mutations in either CTCs or cfDNA in the three more prevalent solid tumors: breast, colon and lung cancers. We evaluate the correlation for mutation status between liquid biopsies and tumor tissue, suggesting possible sources of discrepancies, as well as evaluating the clinical utility of using liquid biopsies for the analysis of mutation status and the future actions that need to be undertaken to make liquid biopsy analysis a reality for the evaluation of mutations.
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http://dx.doi.org/10.3390/cancers12113343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696715PMC
November 2020

Therapy-Induced Modulation of the Tumor Microenvironment: New Opportunities for Cancer Therapies.

Front Oncol 2020 23;10:582884. Epub 2020 Oct 23.

Otorhinolaryngology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.

Advances in immunotherapy have achieved remarkable clinical outcomes in tumors with low curability, but their effects are limited, and increasing evidence has implicated tumoral and non-tumoral components of the tumor microenvironment as critical mediators of cancer progression. At the same time, the clinical successes achieved with minimally invasive and optically-guided surgery and image-guided and ablative radiation strategies have been successfully implemented in clinical care. More effective, localized and safer treatments have fueled strong research interest in radioimmunotherapy, which has shown the potential immunomodulatory effects of ionizing radiation. However, increasingly more observations suggest that immunosuppressive changes, metabolic remodeling, and angiogenic responses in the local tumor microenvironment play a central role in tumor recurrence. In this review, we address challenges to identify responders vs. non-responders to the immune checkpoint blockade, discuss recent developments in combinations of immunotherapy and radiotherapy for clinical evaluation, and consider the clinical impact of immunosuppressive changes in the tumor microenvironment in the context of surgery and radiation. Since the therapy-induced modulation of the tumor microenvironment presents a multiplicity of forms, we propose that overcoming microenvironment related resistance can become clinically relevant and represents a novel strategy to optimize treatment immunogenicity and improve patient outcome.
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http://dx.doi.org/10.3389/fonc.2020.582884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645077PMC
October 2020

TSPAN1: A Novel Protein Involved in Head and Neck Squamous Cell Carcinoma Chemoresistance.

Cancers (Basel) 2020 Nov 5;12(11). Epub 2020 Nov 5.

Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute (VHIR), Autonomous University of Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.

Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial-mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 with EMT and metastasis. Immunohistochemical analysis of HNSCC specimens further revealed that TSPAN1 expression was correlated with phospho-SRC (pSRC), and inversely with E-cadherin, thus reinforcing TSPAN1 association with EMT. Overall, TSPAN1 emerges as a novel oncogenic protein and a promising target for HNSCC therapy.
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http://dx.doi.org/10.3390/cancers12113269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694336PMC
November 2020

Strategies for Isolation and Phenotypic, Genetic, and Functional Characterization of Circulating Tumor Cells.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Liquid Biopsy & Cancer Interception Group, GENYO Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain.

From the medical and scientific point of view, we are witnessing important changes in the way we approach diseases, and consequently in the way we manage patients [...].
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http://dx.doi.org/10.3390/cancers12113257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694253PMC
November 2020

Drug Repurposing for Triple-Negative Breast Cancer.

J Pers Med 2020 Oct 29;10(4). Epub 2020 Oct 29.

GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Avenida de la Ilustración, 18016 Granada, Spain.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.
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http://dx.doi.org/10.3390/jpm10040200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711505PMC
October 2020

Precision Prevention and Cancer Interception: The New Challenges of Liquid Biopsy.

Cancer Discov 2020 Nov 9;10(11):1635-1644. Epub 2020 Oct 9.

Clinical and Translational Oncology Group, Clínica del Country, Bogotá, Colombia.

Despite major therapeutic progress, most advanced solid tumors are still incurable. Cancer interception is the active way to combat cancer onset, and development of this approach within high-risk populations seems a logical first step. Until now, strategies for the identification of high-risk subjects have been based on low-sensitivity and low-specificity assays. However, new liquid biopsy assays, "the Rosetta Stone of the new biomedicine era," with the ability to identify circulating biomarkers with unprecedented sensitivity, promise to revolutionize cancer management. This review focuses on novel liquid biopsy approaches and the applications to cancer interception. Cancer interception involves the identification of biomarkers associated with developing cancer, and includes genetic and epigenetic alterations, as well as circulating tumor cells and circulating epithelial cells in individuals at risk, and the implementation of therapeutic strategies to prevent the beginning of cancer and to stop its development. Large prospective studies are needed to confirm the potential role of liquid biopsy for early detection of precancer lesions and tumors.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0466DOI Listing
November 2020

High plasma levels of soluble P-Selectin and Factor VIII predict venous thromboembolism in non-small cell lung cancer patients: The Thrombo-Nsclc risk score.

Thromb Res 2020 12 16;196:349-354. Epub 2020 Sep 16.

Legal Medicine Department, School of Medicine, Av. Investigación, 11-PTS., Universidad de Granada, 18016 Granada, Spain.

Introduction: Venous thromboembolism (VTE) is common in non-small cell lung cancer (NSCLC) patients undergoing systemic chemotherapy. The usefulness of Khorana score (KRS) to predict risk in lung cancer patients is limited, and the identification of patients who would benefit most from thromboprophylaxis is challenging. We aimed to identify variables whose values before chemotherapy helped in predicting VTE occurrence, and build a model to assess VTE risk.

Materials And Methods: A cohort of newly diagnosed NSCLC patients to undergo outpatient chemotherapy, not under anticoagulant treatment, was recruited. Pre-chemotherapy demographic, clinical, analytical and tumor-specific variables were collected. Patients were prospectively followed-up for 12 months to record VTE events. Bivariate and multivariate analyses were performed to identify VTE-associated variables, and a prediction model was built and compared with KRS.

Results: 90 patients were recruited, 18 of whom had a VTE event during follow-up. High baseline levels of factor VIII (FVIII) and, especially, soluble P-selectin (sP-selectin), were independently associated with VTE risk (hazard ratio [HR] 4.15, 95% confidence interval [CI] 1.17-14.71, and 66.40 [8.70-506.69], respectively). Our so-called Thrombo-NSCLC risk score, which assigns 1 and 3 points to high FVIII and sP-selectin values, respectively, was significantly better than KRS in predicting VTE (area under the curve [AUC] 0.93 vs. 0.55, sensitivity 94.4 vs. 35.0%, specificity 93.1 vs. 60.0%). Our prediction model showed significant discriminating capacity between high risk vs. intermediate/low risk patients, while KRS did not.

Conclusions: The Thrombo-NSCLC risk score may be useful to identify those NSCLC patients who would benefit most from thromboprophylaxis.
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http://dx.doi.org/10.1016/j.thromres.2020.09.021DOI Listing
December 2020

DatAC: A visual analytics platform to explore climate and air quality indicators associated with the COVID-19 pandemic in Spain.

Sci Total Environ 2021 Jan 4;750:141424. Epub 2020 Aug 4.

GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain; Department of Statistics, University of Granada, 18071 Granada, Spain. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic has caused an unprecedented global health crisis, with several countries imposing lockdowns to control the coronavirus spread. Important research efforts are focused on evaluating the association of environmental factors with the survival and spread of the virus and different works have been published, with contradictory results in some cases. Data with spatial and temporal information is a key factor to get reliable results and, although there are some data repositories for monitoring the disease both globally and locally, an application that integrates and aggregates data from meteorological and air quality variables with COVID-19 information has not been described so far to the best of our knowledge. Here, we present DatAC (Data Against COVID-19), a data fusion project with an interactive web frontend that integrates COVID-19 and environmental data in Spain. DatAC is provided with powerful data analysis and statistical capabilities that allow users to explore and analyze individual trends and associations among the provided data. Using the application, we have evaluated the impact of the Spanish lockdown on the air quality, observing that NO, CO, PM, PM and SO levels decreased drastically in the entire territory, while O levels increased. We observed similar trends in urban and rural areas, although the impact has been more important in the former. Moreover, the application allowed us to analyze correlations among climate factors, such as ambient temperature, and the incidence of COVID-19 in Spain. Our results indicate that temperature is not the driving factor and without effective control actions, outbreaks will appear and warm weather will not substantially limit the growth of the pandemic. DatAC is available at https://covid19.genyo.es.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399783PMC
January 2021

Corrigendum to "Challenges and opportunities of cfDNA analysis implementation in clinical practice: Perspective of the International Society of Liquid Biopsy (ISLB)" [Crit. Rev. Oncol. Hematol. 151 (July) (2020) 102978].

Crit Rev Oncol Hematol 2020 Oct 18;154:103058. Epub 2020 Aug 18.

Centre for Genomics and Oncological Research - GENYO, Pfizer, University of Granada, Andalusian Regional Government, Granada, Spain; Bio-Health Research Institute (Instituto de Investigación Biosanitaria ibs. GRANADA), Spain; Complejo Hospitalario Universitario Granada (CHUG), Department of Medical Oncology, University of Granada, Granada, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.critrevonc.2020.103058DOI Listing
October 2020

Risk factors for acute kidney injury in an enhanced recovery pathway for colorectal surgery.

Surg Today 2021 Apr 12;51(4):537-544. Epub 2020 Aug 12.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purposes: Enhanced recovery pathways (ERPs) have been disseminated worldwide to improve the perioperative patient outcomes while lowering direct healthcare costs. Recent evidence has revealed a potential association between ERPs for colorectal surgery and acute kidney injury (AKI). We, therefore, sought to identify the risk factors associated with postoperative AKI among patients in an ERP for colorectal surgery.

Methods: We analyzed the data resulting from a large multicenter, prospective cohort study of patients in an ERP for colorectal surgery. A multivariable analysis was performed to identify factors independently associated with postoperative AKI. The receiver operating characteristic (ROC) curves and contour representations were plotted for the diagnostic prediction analysis.

Results: Among those patients included in the analysis (n = 1652), the overall incidence of postoperative AKI was 7.7% (95% CI 6.5-9.1%). After adjustment, the independent risk factors for AKI included age > 60 (OR 1.03, 95% CI 1.01-1.05), male gender (OR 2.33, 95% CI 1.36-4.02), ASA III-IV (OR 2.43, 95% CI 1.39-4.26), CKD (OR 2.45, 95% CI 1.42-4.23), open surgical approach (OR 2.62, 95% CI 1.63-4.21) and serum albumin < 3.5 g/dL (OR 1.68, 95% CI 1.02-2.79). An ROC analysis revealed that the composite of albumin, creatinine and age was a strong predictor of postoperative AKI [area under the curve (AUC) 0.756; 95% CI 0.705-0.808].

Conclusion: Postoperative AKI is common in the setting of ERPs for colorectal surgery and it is associated with a poor clinical outcome. Of those characteristics associated with postoperative AKI, one modifiable factor is a low preoperative albumin level. Screening for malnourished patients or optimizing the nutritional status may be a useful preoperative intervention to prevent postoperative AKI and associated complications.
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http://dx.doi.org/10.1007/s00595-020-02107-2DOI Listing
April 2021

Pain-induced alterations in the dynorphinergic system within the mesocorticolimbic pathway: Implication for alcohol addiction.

J Neurosci Res 2020 Aug 7. Epub 2020 Aug 7.

Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of València, Burjassot, Spain.

Latest studies have revealed that pain negatively impacts on reward processing and motivation leading to negative affective states and stress. These states not only reduce quality of life of patients by increasing the appearance of psychiatric comorbidities, but also have an important impact on vulnerability to drug abuse, including alcohol. In fact, clinical, epidemiological but also preclinical studies have revealed that the presence of pain is closely related to alcohol use disorders (AUDs). All this evidence suggests that pain is a factor that increases the risk of suffering AUD, predicting heavy drinking behavior and relapse drinking in those patients with a previous history of AUD. The negative consequences of chronic pain and its impact on stress and AUD are likely mediated by alterations in the central nervous system, especially in the stress and reward systems. Therefore, pain and stress impact on dopaminergic mesolimbic pathway can lead to an increase in drug abuse liability. In this mini review we analyze the interaction between pain, stress, and alcohol addiction, and how dynamic changes in the kappa opioid system might play a crucial role in the development of compulsive alcohol drinking in chronic pain patients.
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http://dx.doi.org/10.1002/jnr.24703DOI Listing
August 2020

Mesenchymal stromal/stem cells modulate response to experimental sepsis-induced lung injury via regulation of miR-27a-5p in recipient mice.

Thorax 2020 07 16;75(7):556-567. Epub 2020 Jun 16.

Critical Care Medicine, The Keenan Research Centre for Biomedical Science of Saint Michael's Hospital, Toronto, Ontario, Canada

Introduction: Mesenchymal stromal cell (MSC) therapy mitigates lung injury and improves survival in murine models of sepsis. Precise mechanisms of therapeutic benefit remain poorly understood.

Objectives: To identify host-derived regulatory elements that may contribute to the therapeutic effects of MSCs, we profiled the microRNAome (miRNAome) and transcriptome of lungs from mice randomised to experimental polymicrobial sepsis-induced lung injury treated with either placebo or MSCs.

Methods And Results: A total of 11 997 genes and 357 microRNAs (miRNAs) expressed in lungs were used to generate a statistical estimate of association between miRNAs and their putative mRNA targets; 1395 miRNA:mRNA significant association pairs were found to be differentially expressed (false discovery rate ≤0.05). MSC administration resulted in the downregulation of miR-27a-5p and upregulation of its putative target gene VAV3 (adjusted p=1.272E-161) in septic lungs. In human pulmonary microvascular endothelial cells, miR-27a-5p expression levels were increased while VAV3 was decreased following lipopolysaccharide (LPS) or tumour necrosis factor (TNF) stimulation. Transfection of miR-27a-5p mimic or inhibitor resulted in increased or decreased VAV3 message, respectively. Luciferase reporter assay demonstrated specific binding of miR-27a-5p to the 3'UTR of VAV3. miR27a-5p inhibition mitigated TNF-induced (1) delayed wound closure, increased (2) adhesion and (3) transendothelial migration but did not alter permeability. In vivo, cell infiltration was attenuated by intratracheal coinstillation of the miR-27a-5p inhibitor, but this did not protect against endotoxin-induced oedema formation.

Conclusions: Our data support involvement of miR-27a-5p and VAV3 in cellular adhesion and infiltration during acute lung injury and a potential role for miR-27a-based therapeutics for acute respiratory distress syndrome.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361025PMC
July 2020

Challenges and opportunities of cfDNA analysis implementation in clinical practice: Perspective of the International Society of Liquid Biopsy (ISLB).

Crit Rev Oncol Hematol 2020 Jul 5;151:102978. Epub 2020 May 5.

Centre for Genomics and Oncological Research - GENYO, Pfizer, University of Granada, Andalusian Regional Government, Granada, Spain; Bio-Health Research Institute (Instituto de Investigación Biosanitaria ibs. GRANADA), Spain; Complejo Hospitalario Universitario Granada (CHUG), Department of Medical Oncology, University of Granada, Granada, Spain. Electronic address:

Precision medicine was born with the development of new diagnostic techniques and targeted drugs, yielding better outcomes in cancer care. With the evolution and increasing sensitivity for detecting oncogenic drivers, liquid biopsies (LBs), specifically cell-free DNA (cfDNA) analysis, have been proposed as a minimally-invasive technique for genomic profiling. Ranging from sequencing techniques to PCR-based methods and other more complex strategies, this approach, currently applicable in some solid tumors with robust evidence, is showing promising opportunities in other cancers. However, difficulties in validating their clinical utility exist within limitation at different levels among several techniques, reporting of the results, lack of appropriate clinical trial designs, and unknown economic impact. One of the aims of the ISLB is to create recommendations to develop reliable and sustainable diagnostic, prognostic and predictive tools using LBs. This paper is addressing these objectives, helping the healthcare providers and scientific community to understand the potential of LB.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102978DOI Listing
July 2020

Impaired alcohol-induced dopamine release in the nucleus accumbens in an inflammatory pain model: behavioral implications in male rats.

Pain 2020 09;161(9):2203-2211

Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of València, Spain.

Abstract: Recent studies have drawn the attention to the link between alcohol use disorder and the presence of pain. Indeed, the correct management of pain in patients with a previous history of alcohol use disorder has been reported to decrease the risk of relapse in alcohol drinking, suggesting that in this prone population, pain may increase the vulnerability to relapse. Previous data in male rats revealed that inflammatory pain desensitizes mu-opioid receptors in the ventral tegmental area and increases intake of high doses of heroin. Owing to the relevant role of mu-opioid receptors in alcohol effects, we hypothesize that pain may also alter alcohol reinforcing properties and therefore affect alcohol relapse in male rats. Our microdialysis studies show that the presence of inflammatory pain blunted the increase of extracellular dopamine levels in the nucleus accumbens induced by 1.5 g/kg of ethanol (s.c.). Moreover, we also revealed that the administration of 52 nmol of ethanol into the ventral tegmental area failed to induce place preference only in inflammatory pain-suffering animals, and a higher dose (70 nmol) was necessary to reverse this effect. Finally, we evaluated the effect of inflammatory pain on the alcohol deprivation effect in long-term ethanol-experienced male rats. After 4 cycles of free ethanol intake and abstinence periods, inflammatory pain induced alcohol deprivation effect without affecting its magnitude. These intriguing data reveal the impact of pain on neurochemical and behavioral effects after alcohol administration but also underscore the necessity of finding an appropriate paradigm to determine the long-term behavioral consequences.
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http://dx.doi.org/10.1097/j.pain.0000000000001915DOI Listing
September 2020

A Legal and Forensic Medicine Approach to Police Physical Intervention Techniques in High-Risk Situations.

Int J Environ Res Public Health 2020 04 19;17(8). Epub 2020 Apr 19.

Department of Physical Chemistry, Faculty of Sciences, INBIO, University of Cadiz, 11510 Puerto Real, Spain.

: The physical intervention techniques (PITs) typically used by the police in troublesome situations are examined in terms of injuring potential depending on whether they target a body zone of high, medium or low vulnerability. Based on legal and forensic considerations, and principles of congruence, opportunity and proportionality, a need exists to favor opponent locking and arrest techniques targeting non-vulnerable zones to minimize the risk of severe damage. : A search of the training manuals for the different kind of law of enforcement officers was carried out. Revision of injuries was available from electronic databases of academic o medical journals. : Three different locking and arrest PITs based on operational tactical procedures (OTP) that avoid zones of high or medium vulnerability are proposed. The new techniques use blocking, diverting and grabbing of the upper and lower limbs, followed by dislocation and locking of the same targets. : The damaging potential of such PITs was assessed in terms of anatomical region and most were found to have a high risk of severe damage. The alternative PITs proposed here, which rely on OTP, improve in legal and forensic medical terms on existing choices and dramatically reduce the risk of injuring arrestees.
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http://dx.doi.org/10.3390/ijerph17082809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215352PMC
April 2020

Intraoperative management of arterial hypertension in non-cardiac surgery.

Rev Esp Anestesiol Reanim 2020 May 12;67 Suppl 1:14-19. Epub 2020 Mar 12.

Unidad de Gestión Clínica de Cuidados Intensivos, Hospital Universitario SAS de Jerez, Jerez de la Frontera, Cádiz, España.

High blood pressure is very common and predisposes to cardiovascular events, renal failure, cognitive risk and premature death. There are insufficient data to provide guidance on the ideal blood pressure values for elective anesthesia and surgery. In this review, we will examine the physiology of blood pressure and its regulation, the implications of high blood pressure for anesthesia and surgery, as well as the pathophysiology of perioperative hypertension.
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http://dx.doi.org/10.1016/j.redar.2020.01.004DOI Listing
May 2020

Efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in mechanically ventilated intensive care patients-a randomized clinical trial.

Crit Care 2020 03 4;24(1):74. Epub 2020 Mar 4.

Centro de Investigacion Biomedica en Red (CIBERES), Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Background: Pseudomonas aeruginosa infections are a serious threat in intensive care units (ICUs). The aim of this confirmatory, randomized, multicenter, placebo-controlled, double-blind, phase 2/3 study was to assess the efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in non-surgical ICU patients.

Methods: Eight hundred patients aged 18 to 80 years admitted to the ICU with expected need for mechanical ventilation for ≥ 48 h were randomized 1:1 to either IC43 100 μg or saline placebo, given in two vaccinations 7 days apart. The primary efficacy endpoint was all-cause mortality in patients 28 days after the first vaccination. Immunogenicity and safety were also evaluated.

Findings: All-cause mortality rates at day 28 were 29.2% vs 27.7% in the IC43 and placebo groups, respectively (P = .67). Overall survival (Kaplan-Meier survival estimates, P = .46) and proportion of patients with ≥ one confirmed P. aeruginosa invasive infection or respiratory tract infection also did not differ significantly between both groups. The geometric mean fold increase in OprF/I titers was 1.5 after the first vaccination, 20 at day 28, after the second vaccination, and 2.9 at day 180. Significantly more patients in the placebo group (96.5%) had ≥ one adverse event (AE) versus the IC43 100 μg group (93.1%) (P = .04). The most frequently reported severe AEs in the IC43 and placebo groups were respiratory failure (6.9% vs 5.7%, respectively), septic shock (4.1% vs 6.5%), cardiac arrest (4.3% vs 5.7%), multiorgan failure (4.6% vs 5.5%), and sepsis (4.6% vs 4.2%). No related serious AEs were reported in the IC43 group.

Interpretation: The IC43 100 μg vaccine was well tolerated in this large population of medically ill, mechanically ventilated patients. The vaccine achieved high immunogenicity but provided no clinical benefit over placebo in terms of overall mortality.

Trial Registration: https://clinicaltrials.gov (NCT01563263). Registration was sent to ClinicalTrials.gov on March 14, 2012, but posted by ClinicalTrials.gov on March 26, 2012. The first subject was included in the trial on March 22, 2012.
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http://dx.doi.org/10.1186/s13054-020-2792-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057595PMC
March 2020

Post-Surgery Circulating Tumor Cells and Overexpression as New Poor Prognostic Biomarkers in Resected Lung Adenocarcinoma.

Cancers (Basel) 2019 Nov 7;11(11). Epub 2019 Nov 7.

GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Liquid Biopsy and Metastasis Research Group, PTS Granada, Avenida de la Ilustración 114, 18016 Granada, Spain.

Background: The prognosis of early stage non-small cell lung cancer (NSCLC) is quite disappointing and the benefits of adjuvant therapy are relatively small. Thus, there is an urgent need to identify novel prognostic and predictive biomarkers. Lung adenocarcinoma has distinct clinical-pathological characteristics and novel therapeutic strategies are under active evaluation in the adjuvant setting. Here, we investigated the prognostic impact of circulating tumor cells (CTCs) and gene and miRNA tissue expression in resectable NSCLC.

Patients And Methods: We assessed the association between CTC subpopulations and the outcome of resected early stage lung adenocarcinoma (ADC) patients at three different time-points (CTC1-3) (before surgery, after one month, and after six months) in comparison to squamous cell carcinoma (SCC). Furthermore, gene and miRNA tissue expression, immunoprofiling, and epithelial-to-mesenchymal transition (EMT) markers were correlated with outcome.

Results: ADC (n = 47) and SCC (n = 50) revealed different tissue expression profiles, resulting in the presence of different CTC subpopulations. In ADC, miR-155 correlated with AXL and IL6R expression, which were related to the presence of EMT CTC1 (p = 0.014 and p = 0.004). In the multivariate analysis, CTC2 was an independent prognostic factor for relapse-free survival, and CTC3 and AXL were independent prognostic for overall survival only in ADC. Neither the surgery nor the adjuvant treatment influenced the prognosis of these patients.

Conclusions: Our study elucidate the prognostic impact of tissue expression and the presence of CTCs after surgery in adenocarcinoma patients. Tissue expression and CTC EMT activation could potentially represent biomarkers for the stratification of ADC patients that might benefit from new adjuvant therapies.
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http://dx.doi.org/10.3390/cancers11111750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896005PMC
November 2019