Factores de riesgo para el desarrollo de complicaciones tras tratamiento quirúrgico del carcinoma broncopulmonar / Risk factors for the development of complications after surgical treatment for bronchopulmonary carcinoma

INTRODUCCIÓN: El tratamiento más adecuado en la mayoría de los pacientes con cáncer de pulmón en estadio inicial es la resección quirúrgica. A pesar de evaluar anteriormente que el estado de cada paciente sea el adecuado para detectar posibles complicaciones inherentes a la intervención quirúrgica, no se ha alcanzado ningún consenso sobre los factores que son de «alto riesgo» en esos pacientes. Nuestro estudio tuvo como objetivo analizar la morbilidad y la incidencia de mortalidad asociada con esta intervención quirúrgica en nuestro entorno con un estudio multicéntrico y descubrir los parámetros de riesgo. MÉTODOS: Se trata de un estudio de análisis prospectivo con 3.307 pacientes operados de carcinoma broncopulmonar en 24 hospitales. Las variables de estudio fueron edad, sistema TNM, sexo, estadio, tabaquismo, abordaje quirúrgico, resección quirúrgica, escala ECOG, tratamiento neoadyuvante, comorbilidad, valores espirométricos y morbimortalidad intra- y postoperatoria. Se realizó un análisis de regresión logística multivariante de los factores pronósticos de morbilidad y mortalidad. RESULTADOS: Registramos el 34,2% de morbilidad postoperatoria y el 2,1% de mortalidad postoperatoria. Sexo, infarto de miocardio, angina, ECOG ≥ 1, EPOC, DLCO < 60%, estado clínico patológico, resección quirúrgica y abordaje quirúrgico aparecieron como factores pronósticos de morbilidad y mortalidad en cirugía de cáncer de pulmón en nuestra serie. CONCLUSIONES: Las principales variables que deben tenerse en cuenta al evaluar a pacientes con cáncer de pulmón para realizarles una intervención quirúrgica son sexo, infarto de miocardio, angina, ECOG, EPOC, DLCO, estado clínico patológico, resección quirúrgica y abordaje quirúrgico

INTRODUCTION: The most suitable treatment in most early-stage lung cancer patients is surgical resection. Despite previously assessing each patient's status being relevant to detect possible complications inherent to surgery, no consensus has been reached on which factors are "high risk" in such patients. Our study aimed to analyse the morbidity and the mortality incidence associated with this surgery in our setting with a multicentre study and to detect risk parameters. METHODS: A prospective analysis study with 3,307 patients operated for bronchopulmonary carcinoma in 24 hospitals. Study variables were age, TNM, gender, stage, smoking habit, surgery approach, surgical resection, ECOG, neoadjuvant therapy, comorbidity, spirometric values, and intraoperative and postoperative morbidity and mortality. A multivariate logistic regression analysis of the morbidity and mortality predictor factors was done. RESULTS: We recorded 34.2% postoperative morbidity and 2.1% postoperative mortality. Gender, myocardial infarction, angina, ECOG ≥1, COPD, DLCO <60%, clinical pathological status, surgical resection and surgery approach were shown as morbidity and mortality predictor factors in lung cancer surgery in our series. CONCLUSIONS: The main variables to consider when assessing the lung cancer patients to undergo surgery are gender, myocardial infarction, angina, ECOG, COPD, DLCO, clinical pathological status, surgical resection and surgery approach

Risk factors for the development of complications after surgical treatment for bronchopulmonary carcinoma. / Factores de riesgo para el desarrollo de complicaciones tras tratamiento quirúrgico del carcinoma broncopulmonar.

INTRODUCTION: The most suitable treatment in most early-stage lung cancer patients is surgical resection. Despite previously assessing each patient's status being relevant to detect possible complications inherent to surgery, no consensus has been reached on which factors are "high risk" in such patients. Our study aimed to analyse the morbidity and the mortality incidence associated with this surgery in our setting with a multicentre study and to detect risk parameters. METHODS: A prospective analysis study with 3,307 patients operated for bronchopulmonary carcinoma in 24 hospitals. Study variables were age, TNM, gender, stage, smoking habit, surgery approach, surgical resection, ECOG, neoadjuvant therapy, comorbidity, spirometric values, and intraoperative and postoperative morbidity and mortality. A multivariate logistic regression analysis of the morbidity and mortality predictor factors was done. RESULTS: We recorded 34.2% postoperative morbidity and 2.1% postoperative mortality. Gender, myocardial infarction, angina, ECOG ≥1, COPD, DLCO <60%, clinical pathological status, surgical resection and surgery approach were shown as morbidity and mortality predictor factors in lung cancer surgery in our series. CONCLUSIONS: The main variables to consider when assessing the lung cancer patients to undergo surgery are gender, myocardial infarction, angina, ECOG, COPD, DLCO, clinical pathological status, surgical resection and surgery approach.

CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC.

Although EGFR mutant-selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via ß-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI-resistant persister cells. Many patients with non-small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC. SIGNIFICANCE: Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non-small cell lung cancer through reactivation of ERK signaling.

Clinical Significance of Molecular Micrometastasis in the Sentinel Lymph Node of Early-stage Non-Small Cell Lung Cancer Patients.

OBJECTIVES: Metastatic affectation of lymph node is the main prognostic factor in localized lung cancer. A pathologic study of the obtained samples, even after adequate lymphadenectomy, showed tumor relapses for 20% of stage I patients after oncological curative surgery. We evaluated the prognostic value of molecular micrometastasis in the sentinel lymph node of patients with early-stage lung cancer. PATIENTS AND METHODS: The sentinel node was marked immediately after performing thoracotomy by peritumorally injecting 0.25 mCi of nanocoloid of albumin (Nanocol1) labeled with Tc-99m in 0.3 mL. Guided by a Navigator1 gammagraphic sensor, we proceeded to its resection. The RNA of the tissue was extracted, and the presence of genes CEACAM5, BPIFA1, and CK7 in mRNA was studied. The significant association between the presence of micrometastasis, clinicopathologic characteristics, and patients' outcome was assessed. RESULTS: Eighty-nine stage I-II non-small cell lung cancer patients were included in the study. Of the 89 analyzed sentinel lymph nodes, 44 (49.4%) were positive for CK7, 24 (26.9%) for CEACAM5, and 17 (19.1%) for BPIFA1, whereas 10 (11.2%) were positive for the 3 analyzed genes. A survival analysis showed no significant relation between the presence of molecular micrometastasis in the sentinel node and patients' progression. CONCLUSIONS: The molecular analysis of the sentinel node in patients with early-stage lung cancer shows node affectation in cases staged as stage I/II by hematoxylin-eosin or an immunohistochemical analysis. However, this nodal affectation was not apparently related to patients' outcome.

[Genetic analysis of a family with Von Hippel-Lindau syndrome]. / Análisis genético en una familia con síndrome de Von Hippel-Lindau.

Von Hippel-Lindau syndrome (VHL) is an autosomal dominant inherited disease associated with mutations in the VHL tumour suppressor gene located on chromosome 3p25. VHL is characterized by the development of multiple malignant and benign tumours in the central nervous system and internal organs, including liver, pancreas and the adrenal gland. More than 823 different mutations of the VHL gene have currently been identified. In the present study we describe the case of a family affected by VHL treated at the University Hospital of La Ribera and the results of the genetic analysis of three relatives, identifying the mutation R167G in exon 3 of VHL gene as the cause of VHL syndrome in this family.

Proliferation of Interstitial Cells in the Cyclophosphamide-Induced Cystitis and the Preventive Effect of Imatinib.

Cyclophosphamide- (CYP-) induced cystitis in the rat is a well-known model of bladder inflammation that leads to an overactive bladder, a process that appears to involve enhanced nitric oxide (NO) production. We investigated the changes in the number and distribution of interstitial cells (ICs) and in the expression of endothelial NO synthase (eNOS) in the bladder and urethra of rats subjected to either intermediate or chronic CYP treatment. Pronounced hyperplasia and hypertrophy of ICs were evident within the lamina propria and in the muscle layer. IC immunolabeling with CD34, PDGFRα, and vimentin was enhanced, as reflected by higher colocalization indexes of the distinct pairs of markers. Moreover, de novo expression of eNOS was evident in vimentin and CD34 positive ICs. Pretreatment with the receptor tyrosine kinase inhibitor Imatinib prevented eNOS expression and ICs proliferation, as well as the increased voiding frequency and urinary tract weight provoked by CYP. As similar results were obtained in the urethra, urethritis may contribute to the uropathology of CYP-induced cystitis.

Análisis genético en una familia con síndrome de Von Hippel-Lindau / Genetic analysis of a family with Von Hippel-Lindau syndrome

El síndrome de Von Hippel-Lindau (VHL) es una enfermedad hereditaria autosómica dominante asociada a mutaciones en el gen supresor de tumores VHL localizado en el cromosoma 3p25. El VHL se caracteriza por el desarrollo de múltiples tumores malignos y benignos en el sistema nervioso central y órganos internos, incluyendo el hígado, el páncreas y la glándula adrenal. Actualmente se conocen más de 823mutaciones distintas del gen VHL. En el presente estudio describimos el caso clínico de una familia afecta por VHL tratada en el Hospital Universitario de la Ribera y los resultados del análisis genético de 3 de sus miembros, permitiendo identificar como causa de la enfermedad a la mutación R167G en el exón 3 del gen VHL (AU)

Von Hippel-Lindau syndrome (VHL) is an autosomal dominant inherited disease associated with mutations in the VHL tumour suppressor gene located on chromosome 3p25. VHL is characterized by the development of multiple malignant and benign tumours in the central nervous system and internal organs, including liver, pancreas and the adrenal gland. More than 823 different mutations of the VHL gene have currently been identified. In the present study we describe the case of a family affected by VHL treated at the University Hospital of La Ribera and the results of the genetic analysis of three relatives, identifying the mutation R167G in exon 3 of VHL gene as the cause of VHL syndrome in this family (AU)

Association of PD-1, PD-L1, and CTLA-4 Gene Expression and Clinicopathologic Characteristics in Patients With Non-Small-Cell Lung Cancer.

INTRODUCTION: Recent studies show a potential benefit of therapies that target programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitory checkpoints in a subgroup of patients with non-small-cell lung cancer (NSCLC), without the clinicopathologic characteristics related to positive responses to these treatments being well determined. The aim of this study was to determine PD-1, PD-L1, and CTLA-4 gene expression at the mRNA level in tumoral tissue from patients with NSCLC and analyze their possible relationship with the clinicopathological characteristics and their potential prognostic role. PATIENTS AND METHODS: PD-1, PD-L1, and CTLA-4 expression levels were analyzed using real-time quantitative reverse transcriptase polymerase chain reaction in fresh-frozen tumor and normal adjacent lung tissue samples from 78 patients with NSCLC. Later, a significant association between mRNA levels, clinicopathologic characteristics, and patient's survival was assessed. RESULTS: No significant correlation between gene expression levels and sex, age, histological type, smoking status, pathologic stage, or tumor differentiation was found. However, higher levels of PD-1 were significantly associated with worse prognosis in patients with NSCLC, and PD-L1 overexpression was associated with a worse prognosis in stage I patients and in Grade 1 to 2 tumors. CONCLUSION: Alterations in PD-1/PD-L1 and CTLA-4 expression in lung tumoral tissue seem not to be related to age, sex, smoking status, histological type, pathological stage, or tumor differentiation degree. However, PD-1 and PD-L1 overexpression might predict worse survival in patients with stage I NSCLC and in well differentiated tumors.

Prevalencia mutacional de los genes BRCA1 y BRCA2 en pacientes con cáncer de mama y ovario atendidos en el Área de Salud de La Ribera (Comunidad Valenciana, España) / Mutational prevalence of BRCA1 and BRCA2 genes in patients with breast and ovarian cancer treated in the Health Area of La Ribera (Comunidad Valenciana, Spain)

El cáncer de mama es la neoplasia más frecuente en la mujer, estando implicadas mutaciones en la línea germinal de los genes BRCA1 y BRCA2 en un 5-10% de los casos. El análisis genético precoz en familias portadoras de mutaciones en BRCA permite la detección de pacientes de riesgo en los que llevar a cabo unas adecuadas medidas de seguimiento o profilácticas. Se han descrito más de 3.000 mutaciones distintas en BRCA relacionadas con la enfermedad, variando su prevalencia alélica según el área geográfica analizada. El objetivo de este trabajo ha sido determinar mediante secuenciación masiva (NGS) qué mutaciones patológicas en los genes BRCA1 y BRCA2 son las prevalentes en los pacientes atendidos en la Unidad de Riesgo de Cáncer de Mama Familiar del Hospital de La Ribera y cuáles son sus características clinicopatológicas. Nuestro estudio muestra que los pacientes con mutaciones en BRCA fueron principalmente mujeres premenopáusicas con algún tipo de cáncer y con antecedentes familiares. La mutación con mayor prevalencia detectada en nuestra población de estudio fue c.9026_9030delATCAT del exón 23 en el gen BRCA2 (AU)

Breast cancer is the most frequent neoplasia in women, with BRCA1 and BRCA2 germline mutations being involved in 5%-10% of cases. Early genetic analyses in families affected by this disease are crucial for the identification of family members at risk and thus candidates for surveillance programmes. More than 3,000 different mutations in BRCA gene have been described with different allelic prevalence depending on the geographic area analyzed. The aim of this study was to determine, by massive sequencing (NGS), which pathological mutations in BRCA1 and BRCA2 genes are prevalent in patients treated in the Health Area of La Ribera (Comunidad Valenciana, Spain) and its relation with clinic-pathological characteristics. Our data show that patients with BRCA mutations are mainly premenopausal women with cancer and a family history. The predominant detected mutation in our region is c.9026_9030delATCAT in exon 23 of BRCA2 gene (AU)

Características clinicopatológicas de pacientes con cáncer de pulmón no microcítico con mutaciones en el gen del receptor del factor de crecimiento epidérmico en el Área de Salud de La Ribera (Comunidad Valenciana) / Clinicopathological characteristics of non-small cell lung cancer patients with mutations in epidermal growth factor receptor gene in the Health Area of La Ribera (Comunidad Valenciana)

Actualmente los pacientes que presentan cáncer de pulmón no microcítico (CPNM) portadores de mutaciones en el gen receptor del factor de crecimiento epidérmico (EGFR) pueden recibir un tratamiento específico a partir de la detección de dicha mutación en el tejido tumoral, pues estas mutaciones se consideran un factor predictivo de eficacia al tratamiento con inhibidores de la tirosina quinasa (ITK) de EGFR (ITK-EGFR). En el presente trabajo analizamos qué características clinicopatológicas presentan mayoritariamente los pacientes con CPNM EGFR mutado en el Área de Salud de La Ribera (Comunidad Valenciana) entre marzo de 2012 y noviembre de 2014. Nuestros datos muestran una predominancia del género femenino (70%), de pacientes no fumadores (60%), mayores de 65 años (65%) y en estadio avanzado de la enfermedad (75%). Las mutaciones predominantes son la deleción en el exón 19 y la mutación L858R en el exón 21 del gen EGFR (AU)

Currently, patients suffering from non-small cell lung cancer (NSCLC) with mutations in EGFR gene (epidermal growing factor receptor) can benefit from specific treatment based on the detection of these mutations in the tumour tissue. Mutated EGFR is considered as a positive predictor factor of efficacy for EGFR tyrosine kinase inhibitor (ITK) treatment. In the present study we analyzed the predominant clinicopathological characteristics from NSCLC patients with EGFR mutations in the Health Area of La Ribera (Comunidad Valenciana, Spain) between March 2012 and November 2014. Our data show a predominance of females (70%), non-smokers (60%), and patients older than 65 (65%) and in an advanced stage of the disease (75%). Predominant detected mutations are deletion in exon 19 and L858R mutation in exon 21 in EGFR gene (AU)