Piñero Madrona, A.

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Piñero Madrona, A.

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Piñero Madrona, A.

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Universidad de Murcia. Departamento de Cirugía, Pediatría, Obstetriciay Ginecología

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Open Access
Ex vivo engineering of phagocytic signals in breast cancer cells for a whole tumor cell-based vaccine
(2025-07-01) Martí Díaz, Román; Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Hernández Caselles, Trinidad; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Piñero Madrona, A.; Bioquímica y Biología Molecular A
Background Today, cell therapies are constantly evolving and providing new options for cancer patients. These therapies are mostly based on the inoculation of immune cells extracted from a person’s own tumor; however, some studies using whole tumor cell-based vaccines are approaching the level of maturity required for clinical use. Although these latest therapies will have to be developed further and adapted to overcome many ethical barriers, there is no doubt that therapeutic cancer vaccines are the next frontier of immunotherapy. Methods Ionizing radiation and CD47 knockout via CRISPR-Cas9 genome editing were used to optimize the macrophage-mediated phagocytosis of breast cancer cells. These cells were subsequently used in several mouse models to determine their potential as novel whole-cell-based vaccines to drive antitumor immunity. To improve the recognition of tumor cells by activated immune cells, this cellular therapy was combined with anti-PD-1 antibody treatments. Results Here, we showed that irradiation of 4T1 breast cancer cells increases their immunogenicity and, when injected into the blood of immunocompetent mice, elicits a complete antitumor immune response mediated, in part, by the adaptive immune system. Next, to improve the macrophage-mediated phagocytosis of breast cancer cells, we knocked out CD47 in 4T1 cells. When injected in the bloodstream, irradiated CD47 knockout cells activated both the adaptive and the innate immune systems. Therefore, we used these ex vivo engineered cells as a whole tumor cellbased vaccine to treat breast tumors in immunocompetent mice. A better response was obtained when these cells were combined with an anti-PD-1 antibody. Conclusion These results suggest that tumor cells obtained from surgical samples of a breast cancer patient could be engineered ex vivo and used as a novel cell therapy to drive antitumor immunity.
Open Access
Clinical impact of patient-specific 3D models in neonatal surgery: a case-based review of applications and future directions
(MDPI, 2025-09-09) Girón Vallejo, Óscar; Garcia Nuñez, Bernardo; Narbona Arias, Isidoro; Siles Hinojosa, Alexander; Murcia Pascual, Francisco Javier; Azzubi, Moutasem; Gorriti, Ignacio; García Calderón, Darío; Piñero Madrona, A.; Krauel, Lucas; Cirugía, Pediatría y Obstetricia y Ginecología
Three-dimensional (3D) modeling and printing technologies are increasingly used in pediatric surgery, offering improved anatomical visualization, surgical planning, and personalized approaches to complex conditions. Compared to standard imaging, patient-specific 3D models—virtual or printed—provide a more intuitive spatial understanding of congenital anomalies, tumors, and vascular anomalies. This review compiles evidence from pediatric surgical fields including oncology, abdominal, and thoracic surgery, highlighting the clinical relevance of 3D applications. The technological workflow—from image segmentation to computer-aided design (CAD) modeling and multimaterial printing—is described, emphasizing accuracy, reproducibility, and integration into hospital systems. Several clinical cases are presented: neuroblastoma, cloacal malformation, conjoined twins, and two cases of congenital diaphragmatic hernia (one with congenital pulmonary airway malformation, CPAM). In each, 3D modeling enhanced anatomical clarity, increased surgeon confidence, and supported safer intraoperative decision-making. Models also improved communication with families and enabled effective multidisciplinary planning. Despite these advantages, challenges remain, such as production time, cost variability, and lack of standardization. Future directions include artificial intelligence-based automation, expanded use of virtual and mixed reality, and prospective validation studies in pediatric cohorts. Overall, 3D modeling represents a significant advance in pediatric precision surgery, with growing evidence supporting its safety, clinical utility, and educational value.
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Características inmunohistoquímicas del cáncer de mama: ¿hacia una nueva clasificación?
(Elsevier, 2008-09) Polo-García, Luis; Alonso-Romero, José Luis; Salinas-Ramos, Juan; Canteras-Jordana, Manuel; Sola-Pérez, Joaquín; Galindo-Fernández, Pedro J.; Illana-Morenoa, Julián; Bermejo-López, Juan; Navarrete-Montoya, Agustín; Parrilla-Paricio, Pascual; Piñero Madrona, A.; Medicina
Introducción. El objetivo de este trabajo es determinar la posible asociación de cinco perfiles diferentes de expresión inmunohistoquímica con variables clínicas, histopatológicas e inmunohistoquímicas de conocido valor pronóstico en el cáncer de mama. Material y método. Se estudiaron 194 muestras de carcinoma ductal infiltrante de mama. Se definieron 5 perfiles inmunohistoquímicos basados en la expresión de receptores hormonales (estrogénicos o de progesterona) y/o Her2neu (luminal A, luminal B, mixto, Her2neu y triple negativo) y se estudió si había diferencias entre ellos en relación con variables clínicas, histopatológicas e inmunohistoquímicas de conocido valor pronóstico. Resultados. En la serie se encontraron 134 (69%) casos correspondientes a un inmunofenotipo luminal, de los que 98 (50,5%) fueron del grupo luminal A y 36 (18,6%) del luminal B; 29 (15,9%) casos fueron triples negativos, en 18 (9,3%) se daba un tipo mixto y en 13 (6,7%), del tipo Her2neu. Destaca la relación entre los inmunofenotipos triple negativos y Her2neu con formas histológicas peor diferenciadas (el 62 y el 60%, respectivamente) y del grupo luminal A con tumores bien diferenciados (p = 0,008). La expresión de ki67 fue mayor en el grupo triple negativo (73,9%) y baja en el luminal A (26,3%) (p = 0,001). La expresión de p53 también fue mayor para los grupos Her2neu (55,5%) y triple negativo (60,8%) (p = 0,0005) respecto a los otros. Conclusiones. Los subgrupos sin expresión de receptores hormonales, con sobreexpresión de Her2neu o sin ella (triple negativo) presentan características asociadas con variables de peor pronóstico. La pérdida de expresión de receptores a progesterona también parece asociarse con ellas.
Open Access
Directed Phenotype Switching as an Effective Antimelanoma Strategy
(Cell Press, 2013-06-20) Sáez Ayala, Magalí; Fernández Pérez, María Piedad; Chazarra Parres, Soledad; Freter, Rasmus; Middleton, Mark; Cabezas Herrera, Juan; Goding, Colin R.; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Piñero Madrona, A.; Bioquímica y Biología Molecular A; Cirugía, Pediatría y Obstetricia y Ginecología
Therapeutic resistance in melanoma and other cancers arises via irreversible genetic, and dynamic phenotypic, heterogeneity. Here, we use directed phenotype switching in melanoma to sensitize melanoma cells to lineage-specific therapy. We show that methotrexate (MTX) induces microphthalmia-associated transcription factor (MITF) expression to inhibit invasiveness and promote differentiation-associated expression of the melanocyte-specific Tyrosinase gene. Consequently, MTX sensitizes melanomas to a tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(−)-epicatechin (TMECG), that inhibits the essential enzyme DHFR with high affinity. The combination of MTX and TMECG leads to depletion of thymidine pools, double-strand DNA breaks, and highly efficient E2F1-mediated apoptosis in culture and in vivo. Importantly, this drug combination delivers an effective and tissue-restricted antimelanoma therapy in vitro and in vivo irrespective of BRAF, MEK, or p53 status.
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Usefulness of lymphocyte-to-monocyte, neutrophil-to-monocyte and neutrophil-to-lymphocyte ratios as prognostic markers in breast cancer patients treated with neoadjuvant chemotherapy
(Springer, 2017-08-07) Marín Hernández, C.; Galindo Fernández, P. J.; Alonso-Romero, José Luis; Parrilla Paricio, P.; Gil Vázquez, P. J.; Ruiz Merino, Guadalupe; Piñero Madrona, A.; Medicina
Background: Nowadays, neoadjuvant chemotherapy (nCT) in breast cancer is more and more standardized, not only in advanced tumours but also in those for which there is an attempt to achieve breast-conserving surgery. In literature, we can find evidences of the relationship between several types of tumours and systemic inflammatory response. Our objective is to analyse the prognostic value of blood parameters (lymphocytes, neutrophils, monocytes, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-monocyte ratio (NMR) and neutrophil-to-lymphocyte ratio (NLR) in breast cancer (BC) patients treated with nCT. Methods: A retrospective cohort of 150 breast cancer patients treated with nCT and subsequently with surgery was analysed. Data about the patients, histology, response to chemotherapy and peripheral blood values of lymphocytes, monocytes and neutrophils was collected, and used to calculate the LMR, NMR and NLR. Univariate and multivariate analyses were performed for the variables to see the relationship of the ratios to disease-free survival (DFS) and overall survival (OS). Results: Patients with high LMR (≥5.46) and low NLR (<3.33) were associated with a lower percentage of relapse (P = 0.048 and P = 0.015, respectively) and, above all, NLR was associated with a better survival (P = 0.024), being those factors that predict a good progress. Conclusion: High LMR and low NLR can be considered as favourable prognostic factors in BC patients treated with nCT.
Open Access
Past, present and future of primary systemic treatment in breast cancer
(Baishideng Publishing Group, 2013-05-10) Alonso-Romero, José Luis; Piñero Madrona, A.; Medicina
Primary systemic treatment is a fundamental part of breast cancer therapy, and it is applied to non-surgical and locally advanced tumours as well as surgical tumours to increase the likelihood of conservative treatment. Its aim is to achieve the best possible survival with better cosmetic results and with the lowest number of treatment-related secondary effects. Before treatment is started, it is necessary to attain the best knowledge of the biological features and locoregional extension of the tumour. To do so, it is necessary to obtain a biopsy of the lesion with a wide bore needle, as well as good radiological knowledge of the disease. Therefore, currently, the use of a dynamic magnetic resonance imaging (MRI) of the breast should be included in all cases. In addition, before it is started, especially in those tumours in which conservative treatment is considered, one or several radiopaque markers should be put into place to make it possible to locate the area to be treated if there is a considerable or complete response. Systemic treatment is mainly based on combined chemotherapy with anthracyclins and taxanes, in addition to some biological agents with demonstrated efficiency for increasing the likelihood of complete disease response (trastuzumab in patients with Her-2/neu overexpression). However, there is room for neoadjuvant hormone treatment, in patients with hormone receptor overexpression, especially in those cases in which chemotherapy is contraindicated as well as in elderly patients with a relatively short life expectancy. The assessment of preoperative treatment should be based on adequate radiological tests, and nowad these should include MRI before taking decisions about adequate surgical treatment. The objective of primary treatment is to be able to increase survival and improve the chances of local treatment in the case of locally advanced treatment, achieving results that are at least equal to those of adjuvant treatment in the case of surgical tumours, but with greater chances of conservative surgery. Although the objective is survival, achieving complete pathological response seems to be a reasonable related objective, although these are more closely linked in some tumour subtypes.
Open Access
A new treatment for mammillary fistulas using ultrasound-guided percutaneous needle electrolysis
(MDPI, 2020-02-28) García Vidal, José Antonio; Escolar Reina, María P.; Medina Mirapeix, Francesc; Guzmán Aroca, Florentina; Berná Mestre, Juan de Dios; Berná Serna, Juan De Dios; Piñero Madrona, A.; Fisioterapia
The aim of this study was to investigate the efficacy of ultrasound-guided percutaneous needle electrolysis (PNE) in mammillary fistulas (MFs). A prospective study was performed in 18 patients with MF who were treated with the PNE technique. The technique was repeated in the case of no response or recurrence. The results obtained show that MFs revealing an elongated appearance with the ultrasound (US) are generally resolved with two sessions of PNE, whereas ovoid MFs require several sessions of PNE for complete resolution and they tend to recur. Success of the treatment with PNE was observed in 88.8% of the patients (16/18), and failure, after five or six sessions in two cases (11.2%), which were referred for surgery. Conclusions: To the best of our knowledge this is the first study to reveal that the PNE technique is safe, effective, quick, and well-tolerated by patients.
Open Access
MITF induces escape from innate immunity in melanoma
(BMC, 2021) Martí-Díaz, Román; González-Guerrero, Rebeca; Martínez-Barba, Enrique; Cabezas-Herrera, Juan; Goding, Colin R.; Montenegro Arce, María Fernanda; Hernández Caselles, Trinidad; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Piñero Madrona, A.; Bioquímica y Biología Molecular B e Inmunología
Background: The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair. Whether MITF also controls the immune response is unknown. Methods: By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response. ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene. Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing. Results: Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells. By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system. Consequently, while melanoma MITFLow cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance. Conclusion: Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.
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La reconstrucción posmastectomía y su relación con la radioterapia adyuvante en el tratamiento del cáncer invasivo de mama: ¿asunto cerrado?
(Elsevier, 2024-10) Císcar García, Irene; Fuente Muñoz, Isabel de la; Sánchez Henarejos, Pilar; Marín Rodríguez, Pedro; Marín Hernández, Caridad; Servet Pérez de Lema, Carmen María; Alonso Romero, José Luis; Piñero Madrona, A.; Medicina
Introducción la radioterapia posmastectomía es crucial en el tratamiento del cáncer de mama, mejorando la supervivencia. La reconstrucción mamaria posmastectomía influye en la calidad de vida, pero la radioterapia adyuvante es controvertida por las complicaciones que genera sobre la misma. Se examina la relación entre la radioterapia y las complicaciones en la reconstrucción, considerando el momento y la técnica empleadas. Métodos se realizó un estudio retrospectivo en un solo centro con 273 pacientes tratadas con mastectomía y reconstrucción. La radioterapia fue evaluada como variable independiente en relación con las complicaciones. Se analizaron variables demográficas, anatomopatológicas, quirúrgicas y de tratamiento. Resultados la incidencia general de complicaciones fue del 42,2%, siendo la necrosis grasa y la contractura capsular las más comunes. No hubo asociación significativa entre la radioterapia y las complicaciones en general, pero hubo una tendencia a más complicaciones con las reconstrucciones inmediatas. La reconstrucción autóloga se asoció con menos complicaciones que la heteróloga, especialmente con radioterapia. Discusión aunque estudios previos sugieren una asociación entre la radioterapia y la morbilidad en la reconstrucción posmastectomía, este estudio no encontró una conexión directa. Se destacó la importancia de distinguir entre las complicaciones en el sitio donante y receptor. La reconstrucción inmediata mostró más complicaciones con radioterapia, apoyando la recomendación de posponerla. La reconstrucción autóloga se destacó como la opción preferida. Conclusiones el estudio no encontró una asociación directa entre la radioterapia en pacientes reconstruidas posmastectomía y las complicaciones en general. Sin embargo, reveló una correlación entre las complicaciones y las técnicas heterólogas, subrayando la preferencia por reconstrucciones autólogas.
Open Access
Suppression of antifolate resistance by targeting the myosin va trafficking pathway in melanoma
(Elsevier, 2014-02-28) Fernández Pérez, Maria Piedad; Sáez Ayala, Magalí; Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Piñero Madrona, A.; Bioquímica y Biología Molecular A
Human melanoma is a significant clinical problem. As most melanoma patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is one of the highest priorities to improve melanoma therapy. Melanosomal sequestration and the cellular exportation of cytotoxic drugs have been proposed to be important melanoma-specific mechanisms that contribute to multidrug resistance in melanoma. Concretely, we found that treatment of melanoma with methotrexate (MTX) altered melanogenesis and accelerated the exportation of melanosomes; however, the cellular and molecular processes by which MTX is trapped into melanosomes and exported out of cells have not been elucidated. In this study, we identified myosin Va (MyoVa) as a possible mediator of these cellular processes. The results demonstrated that melanoma treatment with MTX leads to Akt2-dependent MyoVa phosphorylation, which enhances its ability to interact with melanosomes and accelerates their exportation. To understand the mechanism(s) by which MTX activates Akt2, we examined the effects of this drug on the activity of protein phosphatase 2A, an Akt inhibitor activated by the methylation of its catalytic subunit. Taken together, this study identified a novel trafficking pathway in melanoma that promotes tumor resistance through Akt2/MyoVa activation. Because of these findings, we explored several MTX combination therapies to increase the susceptibility of melanoma to this drug. By avoiding MTX exportation, we observed that the E2F1 apoptotic pathway is functional in melanoma, and its induction activates p73 and apoptosis protease-activating factor 1 following a p53-autonomous proapoptotic signaling event.