Gurpide, A. (Alfonso)

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    Resultados a medio y largo plazo de la utilización de videotoracoscopia en la cirugía de resección de las metástasis pulmonares
    (Gobierno de Navarra. Departamento de Salud, 2005) Torre, W. (Wenceslao); Rodriguez-Spiteri, N. (Natalia); Lopez-Picazo, J.M. (José M.); Gurpide, A. (Alfonso); Villalobos, W. (W.); Fernandez-Hidalgo, Ó. (Óscar)
    The surgical resection of pulmonary metastases is a method of treatment accepted as habitual in thoracic surgery. However, it continues to be a source of controversy if this resection must be realised by thoracotomy or by modern video-assisted techniques. With the aim of finding a response to this controversy in our work milieu, a review was made of the surgical interventions carried out in order to resect pulmonary metastases. Between January 1997 and December 2001, 56 patients were found whose pulmonary metastases had been resected by videothorascopy out of a total of 252 metastasectomies (22.2%). The primary tumours were classified in 4 groups: sarcoma (n=11); colorectal (n=25); renal (n=5); and others (n=15). Videothoroscopy was carried out on the right hemithorax (n=28), left hemithorax (n=22) or on both at once (n=6). Operational mortality was nil and the only morbidity attributable to the technique was a defect of re-expansion following the removal of the thoracic drainage in one patient. Using the Kaplan-Meier method, the probability of survival in this series of patients was 60.4% after 5 years, with an average survival time of 48 months. All of this data supports the use of videothorascopy in our milieu on patients with pulmonary metastases. However, in the light of the results, it is important in using this technique to place special emphasis on obtaining good margins of resection, due to the real risk of local recurrence on these margins in the medium term.
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    Tratamiento del cáncer de próstata en función de la esperanza de vida, la comorbilidad y las guías de práctica clínica
    (Gobierno de Navarra, 2015) Perez-Gracia, J.L. (Jose Luis); Rodriguez-Ruiz, M.E. (María Esperanza); Fusco, J.P. (Juan Pablo); Gurpide, A. (Alfonso)
    En un número anterior de la revista de Anales del Sistema Sanitario de Navarra, Barceló y col realizaron una interesante y útil revisión de los pacientes con cáncer de próstata tratados en un gran centro hospitalario español durante un año, centrándose en sus características basales, el tratamiento realizado y el grado de seguimiento de las Guías de Práctica Clínica (GPC) y las complicaciones asociadas a los tratamientos realizados.
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    Carcinoma microcítico de pulmón
    (Ediciones Universidad de Navarra, 2007) Perez-Gracia, J.L. (Jose Luis); Martin-Algarra, S. (Salvador); Lopez-Picazo, J.M. (José M.); Gurpide, A. (Alfonso); Garcia-Foncillas, J. (Jesús); Viteri, S. (S.)
    El cáncer microcítico de pulmón es uno de los tumores sólidos más agresivos, por su rápido crecimiento y por su tendencia a metastatizar desde fases tempranas. Sin embargo, también es uno de los tumores más sensibles a los tratamientos de quimioterapia y radioterapia, con los cuales algunos pacientes con enfermedad limitada pueden sobre- vivir a largo plazo. Estas características han hecho de este tumor un modelo clínico sobre el cual se han probado múltiples estrategias de tratamiento, incluyendo tratamientos concomitantes con quimioterapia y radioterapia, esquemas de quimioterapia alternante o de altas dosis con soporte hematológico o la utilización de radioterapia holocraneal profi láctica. Además en los últimos años el cáncer microcítico de pulmón también se ha empleado como plataforma de desarrollo de tratamientos dirigidos contra dianas específi cas o de inmunoterapia. INGLÉS: Small cell lung cancer is one of the most aggressive solid tumors because of its rapid growth and early tendency to spread to distant organs. Nonetheless, it is also one of the most sensitive tumors to chemotherapy and radiotherapy, which can give patients with limited disease a chance to become long-term survivors. These characteristics have made this tumor a clinical model to explore various treatment strategies, including concomitant chemotherapy and radiotherapy, alternant chemotherapy, high-dose chemotherapy with hematologic support, or use of whole-brain prophylactic radiotherapy. In addition, in recent years, small cell lung cancer has been used as a platform to develop some new targeted therapy agents or immunotherapeutic approaches.
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    Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes
    (Cancer Research UK, 2009) Dubrot, J. (Juan); Alfaro, C. (Carlos); Solano, S. (Sarai); Perez-Gracia, J.L. (Jose Luis); Lopez-Picazo, J.M. (José M.); Gonzalez-Hernandez, A. (Alvaro); Gurpide, A. (Alfonso); Hervas-Stubbs, S. (Sandra); Erro, L. (Lorena); Melero, I. (Ignacio); Palazon, A. (Asís); Suarez, N. (Natalia); Grande-Pulido, E. (E.)
    Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.
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    PSA reactivity in extracellular microvesicles to commercial immunoassays
    (2023) Alegre-Martinez, E. (Estibaliz); Perez-Gracia, J.L. (Jose Luis); Rodriguez-Ruiz, M.E. (María Esperanza); Gonzalez-Hernandez, A. (Alvaro); Sandúa-Condado, A. (Amaia); Gurpide, A. (Alfonso); Fernandez-Sanmamed, M. (Miguel); Ancizu-Marckert, J. (Javier)
    Aims: Characterization of PSA in extracellular microvesicles (EVs) and its reactivity to commercial methods. Materials and methods: EVs derived from serum of 47 prostate cancer (PCa) patients, 27 benign prostatic hyperplasia (BPH) patients and 42 healthy controls were analyzed. EVs isolation and quantification of PSA immunoreactive to total (ev-T-PSA) or free (ev-F-PSA) PSA immunoassays, were performed using commercial assays. PSA in CD81+ or CD63+ EVs was determined directly in serum by an immunocapture-ELISA (IC-ELISA). Results: Ev-T-PSA immunoreactive to Elecsys assay was detected in all samples. Median T-PSA ev/srm ratio was 2.20 % (Q1-Q3: 0.80-4.00 %), although in some samples this ratio reached 59 %. T-PSA ev/srm ratio was higher in those samples with serum T-PSA below 4 µg/L than in those exceeding that cut-off (p < 0.001). T-PSA ev/srm ratio was lower in PCa patients compared to healthy controls and BPH patients (p < 0.001). Elecsys immunoassays detected higher concentrations of ev-T-PSA and ev-F-PSA than Immulite (p < 0.001). PSA was detected by IC-ELISA more intensely in CD81+ EVs than in CD63+ EVs, and ev-T-PSA correlated with PSA+ CD63+ (p < 0.001) but not with PSA+ CD81+. Conclusion: EVs-bound PSA is another form of circulating PSA whose measurement could be easily performed in clinical laboratories by automated immunoassays.
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    The dynamic use of EGFR mutation analysis in cell-free DNA as a follow-up biomarker during different treatment lines in non-small-cell lung cancer patients
    (Hindawi Limited, 2019) Gil-Bazo, I. (Ignacio); Alegre-Martinez, E. (Estibaliz); Patiño-García, A. (Ana); Perez-Gracia, J.L. (Jose Luis); Alkorta-Aranburu, G. (Gorka); Lopez-Picazo, J.M. (José M.); Gurpide, A. (Alfonso); Andueza, M.P. (Maria P.); Mateos, B. (Beatriz); Macías, M. (Mónica); González, Á. (Álvaro)
    Epidermal growth factor receptor (EGFR) mutational testing in advanced non-small-cell lung cancer (NSCLC) is usually performed in tumor tissue, although cfDNA (cell-free DNA) could be an alternative. We evaluated EGFR mutations in cfDNA as a complementary tool in patients, who had already known EGFR mutations in tumor tissue and were treated with either EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy. We obtained plasma samples from 21 advanced NSCLC patients with known EGFR tumor mutations, before and during therapy with EGFR-TKIs and/or chemotherapy. cfDNA was isolated and EGFR mutations were analyzed with the multiple targeted cobas EGFR Mutation Test v2. EGFR mutations were detected at baseline in cfDNA from 57% of patients. The semiquantitative index (SQI) significantly decreased from the baseline (median = 11, IQR = 9 5-13) to the best response (median = 0, IQR = 0-0, p < 0 01), followed by a significant increase at progression (median = 11, IQR = 11-15, p < 0 01) in patients treated with either EGFR-TKIs or chemotherapy. The SQI obtained with the cobas EGFR Mutation Test v2 did not correlate with the concentration in copies/mL determined by droplet digital PCR. Resistance mutation p.T790M was observed at progression in patients with either type of treatment. In conclusion, cfDNA multiple targeted EGFR mutation analysis is useful for treatment monitoring in tissue of EGFR-positive NSCLC patients independently of the drug received.
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    Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma
    (Public Library of Science, 2014) Carles, J. (Joan); Gallardo, E. (Enrique); Arranz, J.A. (Jose Ángel); Lozano, M.D. (María Dolores); Prior, C. (Celia); Perez-Gracia, J.L. (Jose Luis); Climent, M.A. (Miguel Ángel); Bellmunt, J. (Joaquim); Rodriguez-Antona, C. (Cristina); Lopez-Picazo, J.M. (José M.); Esteban-Gutiérrez, E. (Emilio); Gonzalez-Hernandez, A. (Alvaro); Gurpide, A. (Alfonso); Garcia-Donas, J. (Jesús); Moreno, F. (Fernando); Gonzalez-del-Alba, A. (Aránzazu); Font, A. (Albert); Suárez, C. (Cristina); Guruceaga, E. (Elizabeth); Mellado, B. (Begoña); Martinez, E. (Esther); Castellano, D. (Daniel); Calvo-González, A. (Alfonso); Puente, J. (Javier)
    We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.
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    Randomized pharmacokinetic study comparing subcutaneous and intravenous palonosetron in cancer patients treated with platinum based chemotherapy
    (Public Library of Science, 2014) Campanero, M.A. (Miguel Angel); Gomez-Guiu, A. (Almudena); Perez-Gracia, J.L. (Jose Luis); Martin-Algarra, S. (Salvador); Blanco-Prieto, M.J. (María José); Barrio, A. (Anabel) del; Lopez-Picazo, J.M. (José M.); Gurpide, A. (Alfonso); Guillen-Grima, F. (Francisco); Sadaba, B. (Belén); Azanza, J.R. (José Ramón)
    BACKGROUND: Palonosetron is a potent second generation 5- hydroxytryptamine-3 selective antagonist which can be administered by either intravenous (IV) or oral routes, but subcutaneous (SC) administration of palonosetron has never been studied, even though it could have useful clinical applications. In this study, we evaluate the bioavailability of SC palonosetron. PATIENTS AND METHODS: Patients treated with platinum-based chemotherapy were randomized to receive SC or IV palonosetron, followed by the alternative route in a crossover manner, during the first two cycles of chemotherapy. Blood samples were collected at baseline and 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 h after palonosetron administration. Urine was collected during 12 hours following palonosetron. We compared pharmacokinetic parameters including AUC0-24h, t1/2, and Cmax observed with each route of administration by analysis of variance (ANOVA). RESULTS: From October 2009 to July 2010, 25 evaluable patients were included. AUC0-24h for IV and SC palonosetron were respectively 14.1 and 12.7 ng × h/ml (p = 0.160). Bioavalability of SC palonosetron was 118% (95% IC: 69-168). Cmax was lower with SC than with IV route and was reached 15 minutes following SC administration. CONCLUSIONS: Palonosetron bioavailability was similar when administered by either SC or IV route. This new route of administration might be specially useful for outpatient management of emesis and for administration of oral chemotherapy.
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    First-line management of metastatic urothelial cancer: Current and future perspectives after the EV-302 and CcheckMate-901 studies
    (Elsevier, 2023) Barbas-Bernardos, G. (Guillermo); Fata, F.R. (Fernando Ramón) de; Perez-Gracia, J.L. (Jose Luis); Aristu-Mendioroz, J.J. (José Javier); Andrés, G. (Guillermo); Fenor-de-la-Maza, M.D. (Maria Dolores); Gurpide, A. (Alfonso); Villacampa, F. (Felipe); Villacampa, G. (Guillermo); Cambeiro, M. (Mauricio); González-Padilla, D.A. (Daniel A.); Sanz, J. (Julián); Miñana, B. (Bernardino)
    The standard of care for the first-line management of metastatic urothelial carcinoma has been recently challenged, with the combination of pembrolizumab and enfortumab vedotin (P-EV) strongly arising as a practice-changing option from classical platinum-based chemotherapies. With this paradigm shift on the horizon new questions, including the most suitable second line of treatment for these patients, and the role that the molecular characterization of these tumours will have when selecting these therapies will inevitably arise. Furthermore, after the negative results of the Keynote 361 and IMvigor 130 trials, the combination of nivolumab with platinum-based chemotherapy followed by nivolumab maintenance (Nivo GC-Nivo) has also shown positive results when compared with chemotherapy alone. Translational studies at a molecular, cellular, and functional level will be key to better explain these discordant results. In this Current Perspective, we discuss the potential impact of these results in clinical practice and propose specific guidance for prospective translational research.
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    Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer
    (UICC, 2019) Brich, S. (Silvia); Patiño-García, A. (Ana); Pio, R. (Rubén); Lozano, M.D. (María Dolores); Colecchia, M. (Maurizio); Agorreta, J. (Jackeline); Perez-Gracia, J.L. (Jose Luis); Minucci, S. (Saverio); Elgendy, M. (Mohamed); Rodriguez-Ruiz, M.E. (María Esperanza); Renne, S.L. (Salvatore Lorenzo); Fusco, J.P. (Juan Pablo); Diez-Valle, R. (Ricardo); Velis, J.M. (José María); Gurpide, A. (Alfonso); Andueza, M.P. (Maria P.); Calvo-Alonso, A. (Alfonso); Melero, I. (Ignacio); Abengozar-Muela, M. (Marta); Guruceaga, E. (Elizabeth); Echeveste, J.I. (José I.); Pascual, J.I. (Juan Ignacio); Segura, V. (Víctor); Miñana, B. (Bernardino); Fernandez-Sanmamed, M. (Miguel)
    Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.