HOPE (SOLTI-1903) breast cancer study: real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer

Background Metastatic breast cancer (mBC) causes nearly all BC-related deaths. Next-generation sequencing (NGS) technologies allow for the application of personalized medicine using targeted therapies that could improve patients' outcomes. However, NGS is not routinely used in the clinical practice and its cost induces access-inequity among patients. We hypothesized that promoting active patient participation in the management of their disease offering access to NGS testing and to the subsequent medical interpretation and recommendations provided by a multidisciplinary molecular advisory board (MAB) could contribute to progressively overcome this challenge. We designed HOPE (SOLTI-1903) breast cancer trial, a study where patients voluntarily lead their inclusion through a digital tool (DT). The main objectives of HOPE study are to empower mBC patients, gather real-world data on the use of molecular information in the management of mBC and to generate evidence to assess the clinical utility for healthcare systems.Trial design After self-registration through the DT, the study team validates eligibility criteria and assists patients with mBC in the subsequent steps. Patients get access to the information sheet and sign the informed consent form through an advanced digital signature. Afterwards, they provide the most recent (preferably) metastatic archival tumor sample for DNA-sequencing and a blood sample obtained at the time of disease progression for ctDNA analysis. Paired results are reviewed by the MAB, considering patient's medical history. The MAB provides a further interpretation of molecular results and potential treatment recommendations, including ongoing clinical trials and further (germline) genetic testing. Participants self-document their treatment and disease evolution for the next 2 years. Patients are encouraged to involve their physicians in the study. HOPE also includes a patient empowerment program with educational workshops and videos about mBC and precision medicine in oncology. The primary endpoint of the study was to describe the feasibility of a patient-centric precision oncology program in mBC patients when a comprehensive genomic profile is available to decide on a subsequent line of treatment

El trasplante de células alveolares tipo II disminuye la migración de fibrocitos en la fibrosis pulmonar

Póster presentado en el 46º Congreso NacionaL SEPAR (Sociedad Española de Neumología y Cirugía Torácica), celebrado del 14 al 17 de junio de 2013 en Barcelona (España)Peer Reviewe

Alveolar type II cells transplantation decrease fibrocyte migration in pulmonary fibrosis

Póster presentado en el 23rd Annual Congress European Respiratory Society (ERS) celebrado del 7 al 11 de septiembre de 2013 en Barcelona (España)Abstract publicado en "European Respiratory Journal" 42 (Suppl 57): 115s (2013)One of the most important features of the pathogenesis of pulmonary fibrosis is epithelial cell injury and fibroblast proliferation. The original source of this aberrant fibroblast overpopulation might proceed from the lung resident fibroblasts, or could come from circulating fibrocytes migration and its subsequent differentiation to fibroblasts/myofibroblasts. In a previous study our group demonstrated that intratraqueal transplantation of alveolar type II cells (ATII) can reverse the fibrotic process in a rat model of bleomycin-induced lung fibrosis. The objective of this study was to determine whether ATII transplant was able to inhibit fibrocyte recruitment into the fibrotic lung. Lung fibrosis was induced by intratraqueal instillation of bleomycin (3.5U/kg). The animals were transplanted with ATII (2.5x106 cells/animal) 15 days after bleomycin instillation and were sacrificed 21 days after the induction of fibrosis. The expression of CXCL12/CXR4 axis, involved in the recruitment of fibrocytes, was assessed by real time RT-PCR in peripheral blood, lung tissue and isolated cells (macrophages and fibroblasts). Protein synthesis was analyzed by immunohistochemistry in tissue slices. Fibrotic animals showed increased expression of CXCR4 in both peripheral blood and lung tissue. ATII transplantation was able to significantly reduce these increments. Furthermore, although fibrotic animals also showed increases in CXCL12 expression in pulmonary macrophages, these increases were inhibited in the fibrotic transplanted animals. In conclusion ATII transplantation is able to inhibit the fibrocyte recruitment reducing the fibrocyte infiltration to lung tissue and then stopping fibrosisPeer Reviewe

Role of macrophage activation in type II alveolar cells transplantation for the treatment of idiopathic pulmonary fibrosis

Póster presentado en el 23rd Annual Congress European Respiratory Society (ERS) celebrado del 7 al 11 de septiembre de 2013 en Barcelona (España)Abstract publicado en "European Respiratory Journal" 42 (Suppl 57): 676s (2013)In previous experimental studies, we found that alveolar type II cells (ATII) are successful in reversing lung fibrosis. Recently it has been reported that alternatively activated macrophages (M2) play a critical role in idiopathic pulmonary fibrosis (IPF), and appear to be involved in lung tissue remodelling and extracellular matrix deposition. The purpose of this study is to investigate whether intratracheal transplantation of ATII can inhibit M2 polarized human alveolar macrophages or shifts them to a classic activation or M1 phenotype. This could play a significant role in the inhibition of pulmonary fibrosis progression. We included 15 patients with IPF diagnosed in the last 3 years, who underwent ATII trasplantation by fiberoptic bronchoscopy. Bronchoalveolar lavage cell isolation was performed 1 month before and 2 months after the ATII transplantation. The alveolar macrophages were isolated and purified in culture plates. We investigated the expression levels of M1 markers proteins TNF-alpha, IL-1beta and iNOS, and M2 markers proteins IL-10, Arginase-I, FOLR2 and TGF-beta using the real-time RT-PCR. Alveolar macrophages from transplanted patients released higher amounts of the three investigated M1 marker proteins TNF-alpha, IL-1beta and iNOS, compared to cells from pre-transplanted patients. Moreover, a decrease in expression of M2 marker proteins TGF-beta and Arginase-I was revealed, without any change in IL-10 or FOLR2 levels. In conclusion, we have demonstrated that ATII transplantation may produce a shift of alveolar macrophages activation to a M1 phenotype. This shift could thus modulate the fibrotic response and end up the progression of IPF in transplanted patientsPeer Reviewe

Estudio de la activación de macrófagos asociada al trasplante de celulas alveolares tipo II para el tratamiento de pacientes con fibrosis pulmonar idiopática

Póster presentado en el 46º Congreso NacionaL SEPAR (Sociedad Española de Neumología y Cirugía Torácica), celebrado del 14 al 17 de junio de 2013 en Barcelona (España)Peer Reviewe

Efecto del trasplante de células alveolares tipo II en la activación de los macrófagos pulmonares durante la fibrosis pulmonar.

Póster presentado en el 46º Congreso NacionaL SEPAR (Sociedad Española de Neumología y Cirugía Torácica), celebrado del 14 al 17 de junio de 2013 en Barcelona (España)Introducción: La activación de los macrófagos se clasifica en clásica (M1) cuando adquieren un fenotipo pro-inflamatorio y en alternativa (M2) cuando están implicados en la remodelación tisular. El fenotipo que adopten los macrófagos alveolares (MA) y los intersticiales (MI) determinará la progresión de la fibrosis. Nuestro grupo de investigación ha demostrado que el trasplante de células alveolares tipo II (ATII) es capaz de revertir la fibrosis pulmonar. Por ello, el objetivo de este estudio fue evaluar el efecto del trasplante de ATII en la activación de los macrófagos en un modelo experimental de fibrosis pulmonar. Material y métodos: La inducción de fibrosis se realizó en ratas mediante la administración intratraqueal de bleomicina (0,35 U/kg). Las ATII se trasplantaron en animales fibróticos (2,5 × 106 células/animal) 15 días después de la administración de bleomicina. Los animales se sacrificaron 21 días después de la inducción de fibrosis. El número de macrófagos se determinó mediante el anticuerpo anti-CD68 específico de MA y anti-CD163 específico de MI. La obtención de los MA se realizó mediante lavado broncoalveolar y la de los MI mediante digestión por tripsina. La activación de los macrófagos se determinó por RT-PCR analizando los marcadores TNF-a e IL-1b específicos para M1 y arginasa-I, receptor de manosa (RM), IL-10 y TGF-b específicos para M2. Resultados: Durante la fibrosis el número de macrófagos aumentó significativamente y el trasplante de ATII revirtió este aumento. En los MA la expresión de marcadores M1 no mostró cambios en ningún grupo. En cambio, la expresión de los marcadores M2 como la arginasa-I, la IL-10 y el TGF-b aumentó significativamente en el grupo fibrótico. El trasplante de ATII fue capaz de disminuir la expresión de estos marcadores. Por contra, en los MI la expresión de todos los marcadores M1 aumentó significativamente en el grupo fibrótico. En el grupo trasplantado solo aumentó el TNF-a. Respecto a la activación M2, el grupo fibrótico mostró un aumento significativo en comparación con el grupo control en todos los marcadores analizados. El trasplante de ATII disminuyó significativamente la expresión de arginasa-I, IL-10 y TGF-b, manteniendo inalterada la expresión del RM. Conclusiones: Durante la fibrosis los macrófagos adoptan un fenotipo M2 característico del remodelado tisular. El trasplante de ATII disminuye el fenotipo M2 de las dos poblaciones de macrófagos, lo que podría estar relacionado en la reversión de la fibrosisFinanciación: FIS-PS09/02362, SEPAR y MTV3 538/U/2012Peer Reviewe

Alveolar type II cells transplantation in pulmonary fibrosis: effect on the lung macrophage activation

Póster presentado en el ERS (European Respiratory Society) Annual Congress, celebrado del 7 al 11 de septiembre de 2013 en Barcelona (España)The phenotype adopted by alveolar macrophages (AM) and interstitial macrophages (IM) could determine the progression of fibrosis. Macrophages activation is classified into M1 or M2. M1 is a proinflammatory phenotype and M2 is involved in tissue remodeling. Our group has shown that alveolar type II cells (ATII) transplantation is able to reverse pulmonary fibrosis. Therefore, the objective of the study was to evaluate the effect of ATII transplantation in macrophages activation in an experimental model of pulmonary fibrosis. The induction of fibrosis was performed in rats by the intratracheal instillation of bleomycin (3.5U/kg). The animals were transplanted with ATII (2.5x106 cells/animal) 15 days after bleomycin instillation and were sacrificed 21 days after the induction of fibrosis. AM were obtained by bronchoalveolar lavage and IM by digestion of the lung tissue. Macrophages activation was determined by RT-PCR of TNFα and IL1β specific M1 markers and arginase-I, mannose receptor (MR), IL10 and TGFβ specific M2 markers. In AM, the expression of M2 markers as arginase-I, IL10 and TGFβ significantly increased in the fibrotic group. ATII transplantation was able to decrease the expression of all these markers. In contrast, M1 markers were unchanged. In IM, expression of all M1 and M2 markers increased significantly in the fibrotic group. ATII transplantation was able to decreased the expression of IL1β, arginase-I, IL10 and TGFβ. During pulmonary fibrosis, all the macrophages adopted a M2 phenotype characteristic of tissue remodeling. ATII transplantation decreases M2 phenotype of both macrophage populations, which could be related to the reduction of fibrotic lesionsPeer Reviewe