SAS - Hospital Universitario de Jerez de la Frontera
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Publication Vol. 30, nº 20. Perfil de personas con infección por Chlamydia Trachomatis y oportunidades de diagnóstico perdidas en el distrito sanitario Jerez-costa noroeste.(Consejería de Salud y Consumo, 2025-05-30) Servicio de Vigilancia y Salud LaboralEnfermedades de Declaración Obligatoria por provincias. Semana 21/2025 y acumulado desde la semana 01/2025. Datos provisionales. Incluye además el artículo titulado “Perfil de personas con infección por Chlamydia Trachomatis y oportunidades de diagnóstico perdidas en el distrito sanitario Jerez-costa noroeste”, de “Estévanez-Jiménez, Eva; Román-Romera, Isabel; Córdoba-Doña, Juan Antonio”.Publication Vol. 30, nº 04. Atención y seguimiento de las agresiones sexuales en un área de gestión sanitaria: papel de los servicios de medicina preventiva en Andalucía.(Consejería de Salud y Consumo, 2025-01-24) Servicio de Vigilancia y Salud LaboralEnfermedades de Declaración Obligatoria por provincias. Semana 03/2025 y acumulado desde la semana 01/2025. Datos provisionales. Incluye además el artículo titulado “Atención y seguimiento de las agresiones sexuales en un área de gestión sanitaria: papel de los servicios de medicina preventiva en Andalucía”, de “Jorge González Acosta, Ana María Muñoz Martínez, Isabel Pozo Jiménez, Manuel Suárez Vázquez, Álvaro Tejero González, Miguel Daniel Vila Alba, Consuelo Jiménez Castillo, Javier Jiménez Moreno, Juan Antonio Córdoba Doña”.Item Clinical and Ultrasound Thyroid Nodule Characteristics and Their Association with Cytological and Histopathological Outcomes: A Retrospective Multicenter Study in High-Resolution Thyroid Nodule Clinics.(MDPI AG, 2019-12-09) Molina-Vega, Maria; Rodriguez-Perez, Carlos Antonio; Alvarez-Mancha, Ana Isabel; Baena-Nieto, Gloria; Riestra, Maria; Alcazar, Victoria; Romero-Lluch, Ana Reyes; Galofre, Juan C; Fernandez-Garcia, Jose C; Institute of Health Carlos III (ISCIII) co-financed by the European Regional Development Fund (ERDF)Thyroid nodules are a common finding. A high-resolution thyroid nodule clinic (HR-TNC) condenses all tests required for the evaluation of thyroid nodules into a single appointment. We aimed to evaluate the clinical outcomes at HR-TNCs. A retrospective cross-sectional multicenter study including data from four HR-TNCs in Spain. We evaluated fine-needle aspiration (FNA) indications and the association between clinical and ultrasound characteristics with cytological and histopathological outcomes. A total of 2809 thyroid nodules were included; FNA was performed in 82.1%. Thyroid nodules that underwent FNA were more likely larger, isoechoic, with microcalcifications, and in younger subjects. The rate of nondiagnostic FNA was 4.3%. A solid component, irregular margins or microcalcifications, significantly increased the odds of Bethesda IV-V-VI (vs. Bethesda II). Irregular margins and a solid component were independently associated with increased odds of malignancy. Thyroid nodules In this large multicenter study, we found that the presence of a solid component and irregular margins are factors independently related to malignancy in thyroid nodules. Since nodule size ≥40 mm was associated with the lowest odds of malignancy, this cut-off should not be a factor leading to indicate thyroid surgery. HR-TNCs were associated with a low rate of nondiagnostic FNA.Item Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.(Nature Publishing Group, 2019-11-11) Andlauer, Till F M; Guzman-Parra, Jose; Streit, Fabian; Strohmaier, Jana; Gonzalez, Maria Jose; Gil-Flores, Susana; Cabaleiro-Fabeiro, Francisco J; Del-Rio-Noriega, Francisco; Perez-Perez, Fermin ; Haro-Gonzalez, Jesus; Orozco-Diaz, Guillermo; de-Diego-Otero, Yolanda; Moreno-Kustner, Berta; Auburger, Georg; Degenhardt, Franziska; Heilmann-Heimbach, Stefanie; Herms, Stefan; Hoffmann, Per; Frank, Josef; Foo, Jerome C; Treutlein, Jens; Witt, Stephanie H; Cichon, Sven; Kogevinas, Manolis; Rivas, Fabio; Mayoral, Fermin; Muller-Myhsok, Bertram; Forstner, Andreas J; Nothen, Markus M; Rietschel, Marcella; Andalusian regional Health and Innovation Government; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics ConsortiumMultiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.Item Economic Impact and Clinical Outcomes of Omalizumab Add-On Therapy for Patients with Severe Persistent Asthma: A Real-World Study.(Springer, 2019-01-25) Entrenas-Costa, Luis Manuel; Casas-Maldonado, Francisco; Soto-Campos, Jose Gregorio; Padilla-Galo, Alicia; Levy, Alberto; Alvarez Gutierrez, Francisco Javier; Gomez-Bastero-Fernandez, Ana P; Morales-Garcia, Concepcion; Gallego-Dominguez, Rocio; Villegas-Sanchez, Gustavo; Mateos-Caballero, Luis; Pereira-Vega, Antonio; Garcia-Polo, Cayo; Perez-Chica, Gerardo; Martin-Villasclaras, Juan Jose; Novartis Farmacéutica S.A.Omalizumab is a fully humanized monoclonal antibody indicated as add-on therapy to improve asthma control in patients with severe persistent allergic asthma. The aim of this study was to evaluate social, healthcare expenditure and clinical outcomes changes after incorporating omalizumab into standard treatment in the control of severe asthma. In this multicentre retrospective study, a total of 220 patients were included from 15 respiratory medicine departments in the regions of Andalusia and Extremadura (Spain). Effectiveness was calculated as a 3-point increase in the Asthma Control Test (ACT) and a reduction in the annual number of exacerbations. The economic evaluation included both direct and indirect costs. Incremental cost-effectiveness ratio (ICER) was calculated. Results from the year before and the year after incorporation of omalizumab were compared. After adding omalizumab, improvement of lung function, asthma and rhinitis according to patient perception, as well as the number of exacerbations and asthma control measured by the ACT score were observed. Globally, both healthcare resources and pharmacological costs decreased after omalizumab treatment, excluding omalizumab cost. When only direct costs were considered, the ICER was €1712 (95% CI 1487-1995) per avoided exacerbation and €3859 (95% CI 3327-4418) for every 3-point increase in the ACT score. When both direct and indirect costs were considered, the ICER was €1607 (95% CI 1385-1885) for every avoided exacerbation and €3555 (95% CI 3012-4125) for every 3-point increase. Omalizumab was shown to be an effective add-on therapy for patients with persistent severe asthma and allowed reducing key drivers of asthma-related costs.Item Real World Use of Afatinib in NSCLC EGFRm plus Patients Outside Clinical Trials: A FAETT Experience(Elsevier science inc, 2019-10-01) Ramos Garcia, I.; Sanchez, A.; Ortega, A. L.; Pradera, J.; Cobo, M.; Moreno, M. A.; Barneto, I.; Ruiz, S.; Fernandez, I.; Garcia, T.; Toscano, F.; Trigo Perez, J. M.; [Ramos Garcia, I.] Hosp Univ Virgen de La Victoria, Med Oncol, Malaga, Spain; [Ruiz, S.] Hosp Univ Virgen de La Victoria, Med Oncol, Malaga, Spain; [Sanchez, A.] Hosp Virgen Del Rocio, Seville, Spain; [Ortega, A. L.] Complejo Hosp Jaen, Jaen, Spain; [Pradera, J.] Hosp Virgen de Valme, Seville, Spain; [Cobo, M.] Univ Hosp Reg Malaga, Ibima, Malaga, Spain; [Moreno, M. A.] Hosp Univ Puerto Real, Cadiz, Spain; [Barneto, I.] Hosp Univ Reina Sofia, Cordoba, Spain; [Fernandez, I.] Hosp Univ Jerez, Jerez de la Frontera, Spain; [Garcia, T.] Hosp Virgen de La Macarena, Seville, Spain; [Toscano, F.] Hosp Juan Ramon Jimenez, Huelva, Spain; [Trigo Perez, J. M.] Hosp Virgen de La Victoria, Malaga, SpainItem Limited Value of Single Sampling for IgM Antibody Determination as a Diagnostic Approach for Acute Hepatitis E Virus Infection.(American Society for Microbiology, 2021-07-07) Rivero-Juarez, Antonio; Lopez-Lopez, Pedro; Pineda, Juan Antonio; Alados, Juan Carlos; Fuentes-Lopez, Ana; Ramirez-Arellano, Encarnacion; Freyre, Carolina; Perez, Ana Belen; Frias, Mario; Rivero, Antonio; Ministerio de Sanidad; Red de Investigación en SIDA de España ISCIII-RETICThe objective was to evaluate the accuracy of a single determination of IgM antibodies for hepatitis E virus (HEV) diagnosis in patients with acute hepatitis. A prospective study included patients with suspicion of HEV infection, defined as individuals with acute hepatitis showing negative results for serological and molecular markers of other hepatitis viruses. All patients were evaluated for hepatitis E virus infection, including both IgM antibodies and viral RNA determinations. Hepatitis E virus infection was defined as positivity for any of these markers. A total of 182 patients were included in the study, of whom 68 (37.4%) were diagnosed with HEV infection. Of these, 29 (42.6%) were positive for both IgM and HEV RNA, 25 (36.8%) were positive only for IgM antibodies, and 14 (20.6%) were positive only for HEV RNA. Considering only those individuals who were positive for IgM antibodies, 54 of the 68 total cases (79.4%) could be identified, showing a percentage of false-negative individuals of 20.6%. The diagnostic algorithm of hepatitis E virus infection in patients with acute hepatitis should include the determination of both IgM antibodies and HEV RNA because single sampling for IgM antibody determination led to an important proportion of misdiagnosed cases. IMPORTANCE In immunocompetent patients with a suspicion of hepatitis E virus (HEV) infection, single IgM antibody testing is typically applied. In this prospective study, we aimed to evaluate the accuracy of three different HEV screening approaches in patients with acute hepatitis, including approaches based on IgM determination, HEV RNA detection, and the combination of both. Our study shows that any diagnostic algorithm for HEV infection in patients with acute hepatitis should be based on the determination of both markers (IgM antibodies and HEV RNA) because single sampling for IgM antibodies results in an unacceptable number of false-negative results (20%). According to our results, the determination of HEV RNA should not be limited to immunosuppressed individuals because a high proportion of cases could be misdiagnosed.Item HLA class I loss and PD-L1 expression in lung cancer: impact on T-cell infiltration and immune escape.(2017-12-19) Perea, Francisco; Sánchez-Palencia, Abel; Gómez-Morales, Mercedes; Bernal, Mónica; Concha, Ángel; García, Míguela Méndez; González-Ramírez, Amanda Rocío; Kerick, Martin; Martin, Javier; Garrido, Federico; Ruiz-Cabello, Francisco; Aptsiauri, NataliaImmune-checkpoint inhibitors show encouraging results in cancer treatment, but the clinical benefit is limited exclusively to a subset of patients. We analyzed the density and composition of tumor T-cell infiltration in non-small-cell lung carcinoma (NSCLC) in relation to PD-L1 and HLA class I (HLA-I) expression. We found that positive HLA-I expression, independently on PD-L1 status, is the key factor determining the increased density of the immune infiltrate. When both markers were analyzed simultaneously, we identified four phenotypes of HLA-I and PD-L1 co-expression. They demonstrated different patterns of tumor infiltration and clinicopathologic characteristics, including the tumor size and lymphatic spread. All HLA-I+/PD-L1+ tumors had a high degree of intratumoral infiltration with CD8+T-lymphocytes, whereas HLA-I loss was associated with a significantly reduced number of tumor infiltrating T-lymphocytes mostly restrained in the stroma surrounding the tumor nest. HLA-I-negative/PD-L1-positive tumors had bigger size (T) and lower grade of infiltration with CD8+T-cells. It represents a cancer immune escape phenotype that combines two independent mechanisms of immune evasion: loss of HLA-I and upregulation of PD-L1. Using GCH-array analysis of human lung cancer cell lines we found that the loss of heterozygosity (LOH) with complete or partial deletion of HLA-I genes is the principal mechanism of HLA-I alterations. This irreversible defect, which could potentially decrease the clinical efficacy of lung cancer immunotherapy, appears to be underestimated. In conclusion, our results suggest that the analysis of HLA-I is very important for the selection of potential responders to cancer immunotherapy.Item Neural crest derived progenitor cells contribute to tumor stroma and aggressiveness in stage 4/M neuroblastoma.(2017-09-21) Linares-Clemente, Pedro; Aguilar-Morante, Diana; Rodríguez-Prieto, Ismael; Ramírez, Gema; de Torres, Carmen; Santamaría, Vicente; Pascual-Vaca, Diego; Colmenero-Repiso, Ana; Vega, Francisco M; Mora, Jaume; Cabello, Rosa; Márquez, Catalina; Rivas, Eloy; Pardal, RicardoPediatric tumors arise upon oncogenic transformation of stem/progenitor cells during embryonic development. Given this scenario, the existence of non-tumorigenic stem cells included within the aberrant tumoral niche, with a potential role in tumor biology, is an intriguing and unstudied possibility. Here, we describe the presence and function of non-tumorigenic neural crest-derived progenitor cells in aggressive neuroblastoma (NB) tumors. These cells differentiate into neural crest typical mesectodermal derivatives, giving rise to tumor stroma and promoting proliferation and tumor aggressiveness. Furthermore, an analysis of gene expression profiles in stage 4/M NB revealed a neural crest stem cell (NCSC) gene signature that was associated to stromal phenotype and high probability of relapse. Thus, this NCSC gene expression signature could be used in prognosis to improve stratification of stage 4/M NB tumors. Our results might facilitate the design of new therapies by targeting NCSCs and their contribution to tumor stroma.Item Breast cancer is associated to impaired glucose/insulin homeostasis in premenopausal obese/overweight patients.(2017-08-23) Luque, Raúl M; López-Sánchez, Laura M; Villa-Osaba, Alicia; Luque, Isabel M; Santos-Romero, Ana L; Yubero-Serrano, Elena M; Cara-García, María; Álvarez-Benito, Marina; López-Mirand A, José; Gahete, Manuel D; Castaño, Justo PThe association between breast cancer (BCa) presence and altered glucose/insulin metabolism is controversial likely due to an inaccurate insulin resistance (IR) assessment and inappropriate stratification of patients by body-mass index (BMI) and menopausal state. 148 women with suspect of sporadic BCa were stratified by BMI and menopause. Fasting levels of glucose, insulin, glycohemoglobin and selected IR-related and tumor-derived markers were measured. Glucose/insulin levels during OGTT were used to calculate insulin resistance/sensitivity indexes. Analysis of 77 BCa-bearing patients and 71 controls showed an association between BCa and IR as demonstrated by impaired glucose/insulin homeostasis (increased fasting- and OGTT-induced glucose levels) and deteriorated IR indexes, which was especially patent in premenopausal women. The association between BCa presence and IR was markedly influenced by BMI, being obese BCa patients significantly more insulin resistant than controls. BCa presence was associated to elevated levels of IR (glucose, triglycerides) and tumor-derived (VEGF) markers, especially in overweight/obese patients. BCa presence is associated to IR in overweight/obese premenopausal but not in premenopausal normal weight or postmenopausal women. Our data support a bidirectional relationship between dysregulated/imbalanced glucose/insulin metabolism and BCa, as tumor- and IR-markers are correlated with the impairment of glucose/insulin metabolism in overweight/obese premenopausal BCa patients.Item Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets.(2017-08-04) Baldauf, Michaela C; Orth, Martin F; Dallmayer, Marlene; Marchetto, Aruna; Gerke, Julia S; Rubio, Rebeca Alba; Kiran, Merve M; Musa, Julian; Knott, Maximilian M L; Ohmura, Shunya; Li, Jing; Akpolat, Nusret; Akatli, Ayse N; Özen, Özlem; Dirksen, Uta; Hartmann, Wolfgang; de Alava, Enrique; Baumhoer, Daniel; Sannino, Giuseppina; Kirchner, Thomas; Grünewald, Thomas G PEwing sarcoma is an undifferentiated small-round-cell sarcoma. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics. To identify novel diagnostic immunohistochemical markers for Ewing sarcoma, we performed comparative expression analyses in 768 tumors representing 21 entities including Ewing-like sarcomas, which confirmed that CIC-DUX4-, BCOR-CCNB3-, EWSR1-NFATc2-, and EWSR1-ETS-translocated sarcomas are distinct entities, and revealed that ATP1A1, BCL11B, and GLG1 constitute specific markers for Ewing sarcoma. Their high expression was validated by immunohistochemistry and proved to depend on EWSR1-FLI1-binding to highly active proximal super-enhancers. Automated cut-off-finding and combination-testing in a tissue-microarray comprising 174 samples demonstrated that detection of high BCL11B and/or GLG1 expression is sufficient to reach 96% specificity for Ewing sarcoma. While 88% of tested Ewing-like sarcomas displayed strong CD99-immunoreactivity, none displayed combined strong BCL11B- and GLG1-immunoreactivity. Collectively, we show that ATP1A1, BCL11B, and GLG1 are EWSR1-FLI1 targets, of which BCL11B and GLG1 offer a fast, simple, and cost-efficient way to diagnose Ewing sarcoma by immunohistochemistry. These markers may significantly reduce the number of misdiagnosed patients, and thus improve patient care.Item A comprehensive study of circulating tumour cells at the moment of prostate cancer diagnosis: biological and clinical implications of EGFR, AR and SNPs.(2017-07-31) Puche-Sanz, Ignacio; Alvarez-Cubero, María J; Pascual-Geler, Manrique; Rodríguez-Martínez, Alba; Delgado-Rodríguez, Miguel; García-Puche, José L; Expósito, José; Robles-Fernández, Inmaculada; Entrala-Bernal, Carmen; Lorente, José A; Cózar-Olmo, José M; Serrano, María JCirculating tumor cells (CTCs) have been recently accepted as prognostic markers in metastatic prostate cancer (PCa). However, very few studies have analyzed their role in early-stage PCa. The aim of this research is to study the value of CTCs at the moment of PCa diagnosis and to identify different subpopulations of CTCs. Patients with PSA value > 4 ng/ml and clinical suspicion of PCa were included. Samples were collected immediately before prostatic biopsy. CTCs were isolated by immunomagnetic technique using a multi-CK specific antibody. Molecular expression of EGFR and AR in the tissue was analysed by real-time PCR. Up to eight different SNPs in patients' blood DNA were studied. In a total of 86 patients, the CTC detection rate was 18.6%. The sensitivity, specificity, positive and negative predictive values of CTCs to detect PCa was 14.2%, 78.4%, 31.2% and 57.4%, respectively. Up to 75% of CTC-positive patients were AR-negative. A direct association was found between the expression of AR in the prostatic tissue and the presence of CTCs in blood (p 4 ng/ml and clinical suspicion of PCa were included. Samples were collected immediately before prostatic biopsy. CTCs were isolated by immunomagnetic technique using a multi-CK specific antibody. Molecular expression of EGFR and AR in the tissue was analysed by real-time PCR. Up to eight different SNPs in patients' blood DNA were studied. In a total of 86 patients, the CTC detection rate was 18.6%. The sensitivity, specificity, positive and negative predictive values of CTCs to detect PCa was 14.2%, 78.4%, 31.2% and 57.4%, respectively. Up to 75% of CTC-positive patients were AR-negative. A direct association was found between the expression of AR in the prostatic tissue and the presence of CTCs in blood (pItem Inflammation and stem markers association to PIM1/PIM2 kinase-induced tumors in breast and uterus.(2017-07-22) Jiménez-García, Manuel-Pedro; Lucena-Cacace, Antonio; Robles-Frías, María-José; Ferrer, Irene; Narlik-Grassow, Maja; Blanco-Aparicio, Carmen; Carnero, AmancioThe PIM family of Ser/Thr kinase proteins has been implicated in tumorigenesis at different levels. PIM proteins are overexpressed in several tumor types and have been associated with chemoresistance. However, their role in hormone-dependent female tissues has not been explored, especially in the uterus, breast and ovary. We generated conditional transgenic mice with confined expression of human PIM1 or PIM2 genes in these tissues. We characterized the tumoral response to these genetic alterations corroborating their role as oncogenes since they induce hyperproliferation in all tissues and tumors in mammary gland and uterus. Furthermore, we observed a high degree of inflammatory infiltration in these tissues of transgenic mice accompanied by NFAT and mTOR activation and IL6 expression. Moreover, PIM1/2 were overexpressed in human breast, uterine and ovarian tumors, correlating with inflammatory features and stem cell markers. Our data suggest that PIM1/2 kinase overexpression provoke tissue alterations and a large IL6-dependent inflammatory response that may act synergistically during the process of tumorigenesis. The possible end-point is an increased percentage of cancer stem cells, which may be partly responsible for the therapy resistance found in tumors overexpressing PIM kinases.Item Preoperative chemoradiotherapy for rectal cancer: the sensitizer role of the association between miR-375 and c-Myc.(2017-07-19) Conde-Muiño, Raquel; Cano, Carlos; Sánchez-Martín, Victoria; Herrera, Antonio; Comino, Ana; Medina, Pedro P; Palma, Pablo; Cuadros, MartaAdministration of chemoradiation before tumor resection has revolutionized the management of locally advanced rectal cancer, but many patients have proven resistant to this preoperative therapy. Our group recently reported a negative correlation between c-Myc gene expression and this resistance. In the present study, integrated analysis of miRNA and mRNA expression profiles was conducted in 45 pre-treatment rectal tumors in order to analyze the expressions of miRNAs and c-Myc and their relationship with clinicopathological factors and patient survival. Twelve miRNAs were found to be differentially expressed by responders and non-responders to the chemoradiation. Functional classification revealed an association between the differentially expressed miRNAs and c-Myc. Quantitative real-time PCR results showed that miRNA-148 and miRNA-375 levels were both significantly lower in responders than in non-responders. Notably, a significant negative correlation was found between miRNA-375 expression and c-Myc expression. According to these findings, miRNA-375 and its targeted c-Myc may be useful as a predictive biomarker of the response to neoadjuvant treatment in patients with locally advanced rectal cancer.Item Prognostic microRNAs in upper tract urothelial carcinoma: multicenter and international validation study.(2017-05-16) Izquierdo, Laura; Montalbo, Ruth; Ingelmo-Torres, Mercedes; Mallofré, Carme; Ramírez-Backhaus, Miguel; Rubio, Jose; Van der Heijden, Antoine G; Schaafsma, Ewout; Lopez-Beltran, Antonio; Blanca, Ana; Lawrentschuk, Nathan; Alcaraz, Antonio; Mengual, LourdesTo validate previously discovered miRNAs (miR-31-5p and miR-149-5p) as prognostic factors for UTUC in an independent cohort of UTUC patients. Multicenter, international and retrospective study of formalin-fixed paraffin-embedded tissue samples from 103 UTUC patients (45 progressing and 58 non-progressing) who underwent radical nephroureterectomy. Total RNA was isolated and reverse transcribed. The expression of target miRNAs (miR-31-5p and miR-149-5p) and the endogenous control miR-218-5p was evaluated in all samples by reverse transcription quantitative PCR. Normalized miRNA expression values were evaluated by multivariate forward stepwise Cox regression analysis. Kaplan Meier curves were used to discriminate between two groups of patients with a different probability of tumour progression. The mean age (range) of the series was 67 (33-94) years. Overall, 45 patients (43.7%) developed tumour progression and 32 patients (31.2%) died, 20 of these (62.5%) due to their UTUC, after a median follow-up of 36 months. The mean time for tumour progression and cancer-specific survival were 15 and 20 months, respectively. Five year tumour progression free survival and cancer-specific survival were 58% for ≤ pT2, 36% for pT3 and 0% for pT4 and 67.8% for ≤ pT2, 50.6% for pT3 and 0% for pT4, respectively. In the multivariate analysis, expression of miR-31-5p was found to be an independent prognostic factor of tumour progression (HR 1.1; 95% CI 1.039-1.273; p=0.02). Kaplan Meier curve shows that miR-31-5p expression values are able to discriminate between two groups of UTUC patients with a different probability of tumour progression (p=0.007). We have been able to validate our previous results in an independent multicentre international cohort of UTUC patients, suggesting that miRNA-31-5p could be a useful prognostic marker of UTUC progression. The application of miRNA expression values to clinical practice could refine the currently used clinicopathological-based approach for predicting UTUC patients' outcome.Item A phase I study of the SRC kinase inhibitor dasatinib with trastuzumab and paclitaxel as first line therapy for patients with HER2-overexpressing advanced breast cancer. GEICAM/2010-04 study.(2017-04-14) Ocana, Alberto; Gil-Martin, Marta; Martín, Miguel; Rojo, Federico; Antolín, Silvia; Guerrero, Ángel; Trigo, José Manuel; Muñoz, Montse; Pandiella, Atanasio; Diego, Núria Gonzalo; Bezares, Susana; Caballero, Rosalía; Carrasco, Eva; Urruticoechea, AnderThe anti-HER2 antibody trastuzumab have shown clinical activity in combination with chemotherapy in different breast cancer settings. However, most of patients treated with this antibody progress after a period of treatment. Activation of the kinase SRC has been linked with resistance to trastuzumab in several preclinical studies. We designed a phase I clinical study to explore the activity of weekly trastuzumab (2 mg/kg) plus paclitaxel (80 mg/m2) in combination with the anti-SRC kinase inhibitor Dasatinib in the first line treatment of HER2 metastatic breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D); secondary objectives included efficacy, objective response rate (ORR), pharmacokinetics and pharmacodynamics. A "3+3" design guided dose escalation with two oral dose levels of dasatinib: 100mg (DL1) and 140 mg (DL2). 10 patients were included in the phase I part. Dasatinib 100 mg q.d. was established as the recommended RP2D. The median number of administered cycles was 12 (range, 1 to 18). Grade 3 treatment-related AEs at DL1 were diarrhea (n = 2), hyponatremia (n = 1), fatigue (n = 1), and AST/ALT elevation (n = 1). A significant reduction in p-SRC expression on epidermal keratinocytes on sequential skin biopsies was observed. In conclusion, we describe the feasibility of the combination of dasatinib, trastuzumab and paclitaxel, and its effect on proteins involved in trastuzumab resistance. The phase II part of this study is currently evaluating efficacy.Item Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma.(2017) Puente, Javier; Laínez, Nuria; Dueñas, Marta; Méndez-Vidal, María José; Esteban, Emilio; Castellano, Daniel; Martinez-Fernández, Mónica; Basterretxea, Laura; Juan-Fita, María José; Antón, Luis; León, Luis; Lambea, Julio; Pérez-Valderrama, Begoña; Vázquez, Sergio; Suarez, Cristina; Del Muro, Xavier Garcia; Gallardo, Enrique; Maroto, José Pablo; Samaniego, M Luz; Suárez-Paniagua, Beatriz; Sanz, Julián; Paramio, Jesús M; SOGUG (Spanish Oncology Genitourinary Group)Several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation. Multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)≥22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS. 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found. Certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p could be potentially used as biomarkers of sunitinib response.Item Limitations in predicting PAM50 intrinsic subtype and risk of relapse score with Ki67 in estrogen receptor-positive HER2-negative breast cancer.(2017) Fernandez-Martinez, Aranzazu; Pascual, Tomás; Perrone, Giuseppe; Morales, Serafin; de la Haba, Juan; González-Rivera, Milagros; Galván, Patricia; Zalfa, Francesca; Amato, Michela; Gonzalez, Lucia; Prats, Miquel; Rojo, Federico; Manso, Luis; Paré, Laia; Alonso, Immaculada; Albanell, Joan; Vivancos, Ana; González, Antonio; Matito, Judit; González, Sonia; Fernandez, Pedro; Adamo, Barbara; Muñoz, Montserrat; Viladot, Margarita; Font, Carme; Aya, Francisco; Vidal, Maria; Caballero, Rosalía; Carrasco, Eva; Altomare, Vittorio; Tonini, Giuseppe; Prat, Aleix; Martin, MiguelPAM50/Prosigna gene expression-based assay identifies three categorical risk of relapse groups (ROR-low, ROR-intermediate and ROR-high) in post-menopausal patients with estrogen receptor estrogen receptor-positive (ER+)/ HER2-negative (HER2-) early breast cancer. Low risk patients might not need adjuvant chemotherapy since their risk of distant relapse at 10-years is below 10% with endocrine therapy only. In this study, 517 consecutive patients with ER+/HER2- and node-negative disease were evaluated for Ki67 and Prosigna. Most of Luminal A tumors (65.6%) and ROR-low tumors (70.9%) had low Ki67 values (0-10%); however, the percentage of patients with ROR-medium or ROR-high disease within the Ki67 0-10% group was 42.7% (with tumor sizes ≤2 cm) and 33.9% (with tumor sizes > 2 cm). Finally, we found that the optimal Ki67 cutoff for identifying Luminal A or ROR-low tumors was 14%. Ki67 as a surrogate biomarker in identifying Prosigna low-risk outcome patients or Luminal A disease in the clinical setting is unreliable. In the absence of a well-validated prognostic gene expression-based assay, the optimal Ki67 cutoff for identifying low-risk outcome patients or Luminal A disease remains at 14%.Item Critically short telomeres and toxicity of chemotherapy in early breast cancer.(2017) Quintela-Fandino, Miguel; Soberon, Nora; Lluch, Ana; Manso, Luis; Calvo, Isabel; Cortes, Javier; Moreno-Antón, Fernando; Gil-Gil, Miguel; Martinez-Jánez, Noelia; Gonzalez-Martin, Antonio; Adrover, Encarna; de Andres, Raquel; Viñas, Gemma; Llombart-Cussac, Antonio; Alba, Emilio; Mouron, Silvana; Guerra, Juan; Bermejo, Begoña; Zamora, Esther; García-Saenz, Jose Angel; Simon, Sonia Pernas; Carrasco, Eva; Escudero, María José; Campo, Ruth; Colomer, Ramón; Blasco, Maria ACumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres ( 21.9% CSTs) had 2-fold higher number of neuropathy (P = 0.04) or fatigue (P = 0.019) episodes and >3-fold higher number of myalgia episodes (P = 0.005). The average telomere length was unrelated to the incidence of side effects.The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.Item The addition of celecoxib improves the antitumor effect of cetuximab in colorectal cancer: role of EGFR-RAS-FOXM1-β- catenin signaling axis.(2017) Valverde, Araceli; Peñarando, Jon; Cañas, Amanda; López-Sánchez, Laura M; Conde, Francisco; Guil-Luna, Silvia; Hernández, Vanessa; Villar, Carlos; Morales-Estévez, Cristina; de la Haba-Rodríguez, Juan; Aranda, Enrique; Rodríguez-Ariza, AntonioHere we showed that the addition of the COX-2 inhibitor celecoxib improved the antitumor efficacy in colorectal cancer (CRC) of the monoclonal anti-EGFR antibody cetuximab. The addition of celecoxib augmented the efficacy of cetuximab to inhibit cell proliferation and to induce apoptosis in CRC cells. Moreover, the combination of celecoxib and cetuximab was more effective than either treatment alone in reducing the tumor volume in a mouse xenograft model. The combined treatment enhanced the inhibition of EGFR signaling and altered the subcellular distribution of β-catenin. Moreover, knockdown of FOXM1 showed that this transcription factor participates in this enhanced antitumoral response. Besides, the combined treatment decreased β-catenin/FOXM1 interaction and reduced the cancer stem cell subpopulation in CRC cells, as indicated their diminished capacity to form colonospheres. Notably, the inmunodetection of FOXM1 in the nuclei of tumor cells in human colorectal adenocarcinomas was significantly associated with response of patients to cetuximab. In summary, our study shows that the addition of celecoxib enhances the antitumor efficacy of cetuximab in CRC due to impairment of EGFR-RAS-FOXM1-β-catenin signaling axis. Results also support that FOXM1 could be a predictive marker of response of mCRC patients to cetuximab therapy.