المؤلفون: Sullivan, Ivana

المساهمون: University/Department: Universitat Autònoma de Barcelona. Departament de Medicina

مرشدي الرسالة: Barnadas i Molins, Agustí, Salazar Blanco, Juliana

المصدر: TDX (Tesis Doctorals en Xarxa)

مصطلحات موضوعية: Cáncer de pulmó no microcític, Cáncer de pulmón no microcítico, Non-small cell lung cancer, Farmacogenètica, Farmacogenética, Pharmacogenetics, Factors pronòstics, Factores pronósticos, Prognostic factors, Ciències de la Salut

الوصف: El cáncer de pulmón no microcítico (CPNM) representa aproximadamente el 90% de los casos de cáncer de pulmón y alrededor de dos tercios de los pacientes se diagnostican en una etapa avanzada de la enfermedad. Su pronóstico global es pobre con una supervivencia a los 5 años entorno al 15%. La cirugía radical es el tratamiento principal en la enfermedad localizada si bien, dependiendo de factores pronósticos clínicos, puede estar indicado un tratamiento adyuvante con quimioterapia y/o radioterapia (QT/RT). En la enfermedad localmente avanzada (estadios IIIA/B), la quimioterapia (QT) combinada con radioterapia (RT) (concomitante o secuencial) es el tratamiento estándar en la mayoría de los pacientes. En el escenario de la enfermedad metastásica, la QT es el tratamiento de elección en más del 80% de los casos. La supervivencia puede variar entre los pacientes a pesar de unas características clínicas y patológicas similares de la enfermedad. Por otra parte, los tratamientos con QT y RT tienen una ventana terapéutica muy estrecha que hace difícil establecer el equilibrio entre dosis y aparición de efectos adversos pudiendo esto condicionar su eficacia. Es por ello que existe la necesidad de identificar biomarcadores genéticos que permitan optimizar los tratamientos para incrementar la supervivencia de los pacientes con CPNM. Las variantes en los genes de reparación del ADN pueden desempeñar un papel en la eficacia de la QT basada en platino en el CPNM. En el primer trabajo, hemos analizado 17 polimorfismos de nucleótido único (SNPs) en 8 genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XRCC1 y XRCC2) involucrados en los mecanismos de reparación del ADN y su asociación con la eficacia, supervivencia y la toxicidad en pacientes con CPNM. Este estudio prospectivo incluyó pacientes con estadios IIIA/B y IV tratados con QT basada en platino asociado a un fármaco de 3ra generación. Los pacientes con un estadio III recibieron adicionalmente RT concomitante o secuencial. Encontramos que en el estadio III la respuesta se asoció significativamente con SNPs en los genes ERCC1 y ERCC3, mientras que la toxicidad derivada de la RT se correlacionó con SNPs en el gen ERCC2. En los pacientes con un estadio IV, la respuesta se asoció con una variante genética en el gen ERCC4 y la supervivencia con un SNP en el gen XRCC1. La vía del VEGF (Vascular Endothelial Growth Factor) ha sido motivo de estudio como factor pronóstico en cáncer, incluido el CPNM. En el segundo trabajo hemos evaluado la relación entre 25 variantes en 16 genes de la vía del VEGF y la supervivencia libre de recaída (SLR) y supervivencia global (SG) en 131 pacientes con CPNM estadios I-III tratados con cirugía radical. Hemos encontrado que las variantes KRAS rs1137282 y PIK3C2A rs4356203 se asociaron significativamente con la SLR, tanto en el análisis univariado como multivariable, sin evidenciarse una asociación entre los SNPs analizados y la SG. Los resultados presentados en estos dos trabajos, además de aportar conocimiento en el área de los biomarcadores en CPNM, abren nuevas vías de investigación en este campo.

الوصف (مترجم): Non-small cell lung cancer (NSCLC) accounts for approximately 90% of lung cancer and about two-thirds of patients are diagnosed at an advanced stage of the disease. The overall prognosis is poor with a 5-year survival rate of about 15%. Radical surgery is the main treatment in localized disease, although, an adjuvant treatment with chemotherapy and/or radiotherapy (CT/RT) could be indicated depending on clinical factors. In locally advanced disease (stages IIIA/B), chemotherapy (CT) combined with radiotherapy (RT) (concomitant or sequential) is the standard treatment in most of the patients. In the scenario of metastatic disease, CT is the usual treatment in more than 80% of cases. Survival may vary among patients despite similar clinical and pathological features of the disease. The efficacy of the treatment with CT and RT is conditioned by the narrow therapeutic window that make it difficult to establish the balance between doses and the appearance of adverse effects. There is a need to identify genetic biomarkers to optimize treatments trying to increase the survival of NSCLC patients. Genetic variants in the DNA repair genes may play a role in the efficacy of platinum-based CT in NSCLC. In the first study, we analyzed 17 single nucleotide polymorphisms (SNPs) in 8 genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XRCC1 and XRCC2) involved in the DNA repair mechanisms and their association with efficacy, survival and toxicity in NSCLC patients. This prospective study included patients with stage IIIA/B and IV treated with platinum-based CT plus a 3rd generation drug. In addition, patients with a stage III received concomitant or sequential RT. We found that in stage III the response was significantly associated with SNPs in the ERCC1 and ERCC3 genes, while the toxicity derived from RT was correlated with SNPs in the ERCC2 gene. In patients with stage IV, the response was associated with a genetic variant in the ERCC4 gene and survival with a SNP in the XRCC1 gene. The VEGF (Vascular Endothelial Growth Factor) pathway has been investigated as a prognostic factor in cancer, including NSCLC. In the second study, we evaluated the relationship between 25 genetic variants in 16 genes involved in the VEGF pathway and the relapse-free survival (RFS) and overall survival (OS) in 131 stage I-III NSCLC patients treated with surgery. We found that the variants KRAS rs1137282 and PIK3C2A rs4356203 were significantly associated with RFS, both in the univariate and multivariable analyzes. No association between the SNPs analyzed and OS was observed. These results provide not only knowledge in the biomarkers area in NSCLC, but the need to improve the research in this field.

وصف الملف: application/pdf

الوصول الحر: http://hdl.handle.net/10803/454809Test

المؤلفون: Calvo de Juan, Virginia, Camps, Carlos, Carcereny, Enric, Cobo, Manuel, Domine Gómez, Manuel, García Campelo, María Rosario, González Larriba, José Luis, Guirado, María, Hernando-Trancho, Florentino, Massutí, Bartomeu, Nadal, Ernest, Rodríguez-Abreu, Delvys, Sánchez, Alfredo, Sullivan, Ivana Gabriela, Provencio Pulla, Mariano

المساهمون: UAM. Departamento de Medicina

مصطلحات موضوعية: barriers, inequity, innovative treatments, medicine access, NSCLC, Spain, Medicina

الوصف: Spanish Lung Cancer Group (SLCG) conducted a review to analyze the barriers to access to innovative targeted therapies for non-small cell lung cancer (NSCLC) in clinical practice in Spain. Review all relevant content published on websites of European Commission, European Medicines Agency, and Spanish Agency of Medicines and Medical Products regarding the authorization and access to oncology treatments. Results: More than 20 targeted therapies are available to treat different molecular alterations in patients with NSCLC. European Commission has approved treatments for genomic alterations involving the following genes: ALK, RET, ROS1, EGFR, BRAF, NTRK, KRAS, MET. However, the availability of these therapies in Spain is not complete, as innovative treatments are not reimbursed or funded late, with only five of these alterations currently covered by National Health System. SLCG considers imperative to improve the access in Spain to innovative treatments for NSCLC to reduce inequity across European countries ; This work was funding by Spanish Lung Cancer Group

وصف الملف: application/pdf

العلاقة: Clinical and Translational Oncology; https://doi.org/10.1007/s12094-023-03303-5Test; Clinical and Translational Oncology 26.3 (2024): 597-612; 1699-048X (print); 1699-3055 (online); http://hdl.handle.net/10486/712889Test; 597; 612; 26

الإتاحة: https://doi.org/10.1007/s12094-023-03303-5Test
http://hdl.handle.net/10486/712889Test

المؤلفون: Calvo, Virginia, Camps Herrero, Carlos, Carcereny, Enric, Cobo, Manuel, Dómine, Manuel, Garcia Campelo, Rosario, González Larriba, Jose Luís, Guirado, Maria, Hernando Trancho, Florentino, Massuti Sureda, Bartomeu, Nadal, Ernest, Rodriguez-Abreu, Delvys, Sánchez, Alfredo, Sullivan, Ivana, Provencio Pulla, Mariano

مصطلحات موضوعية: Càncer, Medicina Pràctica professional, Pulmons Malalties

الوصف: Purpose Spanish Lung Cancer Group (SLCG) conducted a review to analyze the barriers to access to innovative targeted therapies for non-small cell lung cancer (NSCLC) in clinical practice in Spain. Methods Review all relevant content published on websites of European Commission, European Medicines Agency, and Spanish Agency of Medicines and Medical Products regarding the authorization and access to oncology treatments. Results More than 20 targeted therapies are available to treat different molecular alterations in patients with NSCLC. European Commission has approved treatments for genomic alterations involving the following genes: ALK, RET, ROS1, EGFR, BRAF, NTRK, KRAS, MET. However, the availability of these therapies in Spain is not complete, as innovative treatments are not reimbursed or funded late, with only five of these alterations currently covered by National Health System. Conclusion SLCG considers imperative to improve the access in Spain to innovative treatments for NSCLC to reduce inequity across European countries.

وصف الملف: application/pdf

العلاقة: Clinical & Translational Oncology, 2023; Calvo, Virginia Camps Herrero, Carlos Carcereny, Enric Cobo, Manuel Dómine, Manuel Garcia Campelo, Rosario González Larriba, Jose Luís Guirado, Maria Hernando Trancho, Florentino Massuti Sureda, Bartomeu Nadal, Ernest Rodriguez-Abreu, Delvys Sánchez, Alfredo Sullivan, Ivana Provencio Pulla, Mariano 2023 Difficulties on the acces to innovative targeted therapies for lung cancer in Spain Clinical & Translational Oncology; https://hdl.handle.net/10550/89077Test; 161071

الإتاحة: https://doi.org/10.1007/s12094-023-03303-5Test
https://hdl.handle.net/10550/89077Test

المؤلفون: Nadal, Ernest, Rodríguez Abreu, Delvys, Simó, Marta, Massutí, Bartomeu, Juan, Oscar, Huidobro, Gerardo, López, Rafael, Castro, Javier de, Estival, Anna, Mosquera, Joaquín, Sullivan, Ivana, Felip, Enriqueta, Blasco, Ana, Guirado, Maria, Pereira, Eva, Vilariño, Noelia, Navarro, Valentín, Bruna, Jordi

المصدر: Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

مصطلحات موضوعية: Tumors cerebrals, Càncer de pulmó, Brain tumors, Lung cancer

الوصف: PURPOSEThe Atezo-Brain study evaluated atezolizumab combined with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) with untreated brain metastases, a population traditionally excluded from trials.METHODSThis single-arm phase II clinical trial enrolled patients with advanced nonsquamous NSCLC with untreated brain metastases without neurologic symptoms or asymptomatic with medical treatment. Dexamethasone was allowed up to 4 mg once daily. Atezolizumab plus carboplatin and pemetrexed was given for four to six cycles followed by atezolizumab plus pemetrexed until progression for a maximum of 2 years. The primary end points were to determine the progression-free survival (PFS) rate at 12 weeks and the incidence of grade >= 3 adverse events during the first 9 weeks. Intracranial outcomes were assessed using response assessment in neuro-oncology brain metastases criteria.RESULTSForty patients were enrolled and 22 (55%) were receiving corticosteroids at baseline. The overall 12-week PFS rate was 62.2% (95% credibility interval [CrI], 47.1 to 76.2). The rate of grade 3/4 adverse events during the first 9 weeks was 27.5%. Most neurologic events were grade 1 and 2 but five patients (12.5%) experienced grade 3-4 neurologic events. With a median follow-up of 31 months, intracranial median PFS was 6.9 months and response rate was 42.7% (95% CrI, 28.1 to 57.9). Systemic median PFS was 8.9 months and response rate was 45% (95% CrI, 28.1 to 57.9). The median overall survival (OS) was 11.8 months (95% CI, 7.6 to 16.9) and the 2-year OS rate was 27.5% (95% CI, 16.6 to 45.5).CONCLUSIONAtezolizumab plus carboplatin and pemetrexed demonstrates activity in patients with advanced nonsquamous NSCLC with untreated brain metastases with an acceptable safety profile.

وصف الملف: 10 p.; application/pdf

العلاقة: Reproducció del document publicat a: https://doi.org/10.1200/JCO.22.02561Test; Journal of Clinical Oncology, 2023, vol. 41, num. 28, p. 4478-4485; https://doi.org/10.1200/JCO.22.02561Test; http://hdl.handle.net/2445/208722Test

الإتاحة: https://doi.org/10.1200/JCO.22.02561Test
http://hdl.handle.net/2445/208722Test

المؤلفون: Bertran-Alamillo, Jordi, Giménez-Capitán, Ana, Román, Ruth, Talbot, Sara, Whiteley, Rebecca, Floc’h, Nicolas, Martínez-Pérez, Elizabeth, Martin, Matthew J., Smith, Paul D., Sullivan, Ivana, Terp, Mikkel G., Saeh, Jamal, Marino-Buslje, Cristina, Fabbri, Giulia, Guo, Grace, Xu, Man, Tornador, Cristian, Aguilar-Hernández, Andrés, Reguart, Noemí, Ditzel, Henrik J., Martínez-Bueno, Alejandro, Nabau-Moretó, Núria, Gascó, Amaya, Rosell, Rafael, Pease, J. Elizabeth, Polanska, Urszula M., Travers, Jon, Urosevic, Jelena, Molina-Vila, Miguel A.

المصدر: Bertran-Alamillo , J , Giménez-Capitán , A , Román , R , Talbot , S , Whiteley , R , Floc’h , N , Martínez-Pérez , E , Martin , M J , Smith , P D , Sullivan , I , Terp , M G , Saeh , J , Marino-Buslje , C , Fabbri , G , Guo , G , Xu , M , Tornador , C , Aguilar-Hernández , A , Reguart , N , Ditzel , H J , Martínez-Bueno , A , Nabau-Moretó , N , Gascó , A , Rosell , R ....

مصطلحات موضوعية: Abrogation, AURKB inhibitor, BID, Biomarker, CASP-2, Cell cycle, Spindle assembly checkpoint (SAC), TTK inhibitor, Tumor, Aurora Kinase B/genetics, M Phase Cell Cycle Checkpoints, Humans, Neoplasms/drug therapy, Animals, Cell Line, Mice, Cell Cycle Proteins/genetics, Protein Serine-Threonine Kinases/genetics, RNA, Messenger, Protein-Tyrosine Kinases/metabolism

الوصف: Background: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. Methods: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. Results: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. Conclusions: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.

وصف الملف: application/pdf

العلاقة: https://portal.findresearcher.sdu.dk/da/publications/c10f2a0e-c66c-463d-b7c0-50e23449ef85Test

الإتاحة: https://doi.org/10.1186/s12943-023-01815-wTest
https://portal.findresearcher.sdu.dk/da/publications/c10f2a0e-c66c-463d-b7c0-50e23449ef85Test
https://findresearcher.sdu.dk/ws/files/237177716/s12943_023_01815_w.pdfTest

المؤلفون: Giménez‐Capitán, Ana, Sánchez‐Herrero, Estela, Robado de Lope, Lucía, Aguilar‐Hernández, Andrés, Sullivan, Ivana, Calvo, Virginia, Moya‐Horno, Irene, Viteri, Santiago, Cabrera, Carlos, Aguado, Cristina, Armiger, Noelia, Valarezo, Joselyn, Mayo‐de‐las‐Casas, Clara, Reguart, Noemí, Rosell, Rafael, Provencio, Mariano, Romero, Atocha, Molina‐Vila, Miguel A.

المساهمون: European Social Fund

المصدر: Molecular Oncology ; volume 17, issue 9, page 1884-1897 ; ISSN 1574-7891 1878-0261

الوصف: ALK , ROS1 , and RET fusions and MET ∆ex14 variant associate with response to targeted therapies in non‐small‐cell lung cancer (NSCLC). Technologies for fusion testing in tissue must be adapted to liquid biopsies, which are often the only material available. In this study, circulating‐free RNA (cfRNA) and extracellular vesicle RNA (EV‐RNA) were purified from liquid biopsies. Fusion and MET ∆ex14 transcripts were analyzed by nCounter (Nanostring) and digital PCR (dPCR) using the QuantStudio ® System (Applied Biosystems). We found that nCounter detected ALK , ROS1 , RET , or MET ∆ex14 aberrant transcripts in 28/40 cfRNA samples from positive patients and 0/16 of control individuals (70% sensitivity). Regarding dPCR, aberrant transcripts were detected in the cfRNA of 25/40 positive patients. Concordance between the two techniques was 58%. Inferior results were obtained when analyzing EV‐RNA, where nCounter often failed due to a low amount of input RNA. Finally, results of dPCR testing in serial liquid biopsies of five patients correlated with response to targeted therapy. We conclude that nCounter can be used for multiplex detection of fusion and MET ∆ex14 transcripts in liquid biopsies, showing a performance comparable with next‐generation sequencing platforms. dPCR could be employed for disease follow‐up in patients with a known alteration. cfRNA should be preferred over EV‐RNA for these analyses.

الإتاحة: https://doi.org/10.1002/1878-0261.13468Test

المؤلفون: García-Campelo, Rosario, Sullivan, Ivana, Arriola, Edurne, Insa, Amelia, Juan Vidal, Oscar, Cruz-Castellanos, Patricia, Morán, Teresa, Reguart, Noemí, Zugazagoitia, Jon, Dómine, Manuel

المصدر: Clinical and Translational Oncology ; volume 25, issue 9, page 2679-2691 ; ISSN 1699-3055

مصطلحات موضوعية: Cancer Research, Oncology, General Medicine

الوصف: Small-cell lung cancer (SCLC) is a highly aggressive malignancy comprising approximately 15% of lung cancers. Only one-third of patients are diagnosed at limited-stage (LS). Surgical resection can be curative in early stages, followed by platinum–etoposide adjuvant therapy, although only a minority of patients with SCLC qualify for surgery. Concurrent chemo-radiotherapy is the standard of care for LS-SCLC that is not surgically resectable, followed by prophylactic cranial irradiation (PCI) for patients without progression. For extensive-stage (ES)-SCLC, a combination of platinum and etoposide has historically been a mainstay of treatment. Recently, the efficacy of programmed death-ligand 1 inhibitors combined with chemotherapy has become the new front-line standard of care for ES-SCLC. Emerging knowledge regarding SCLC biology, including genomic characterization and molecular subtyping, and new treatment approaches will potentially lead to advances in SCLC patient care.

الإتاحة: https://doi.org/10.1007/s12094-023-03216-3Test

المؤلفون: García-Campelo, Rosario, Sullivan, Ivana, Arriola, Edurne, Insa, Amelia, Juan Vidal, Oscar, Cruz-Castellanos, Patricia, Morán, Teresa, Reguart, Noemí, Zugazagoitia, Jon, Dómine, Manuel

المصدر: Clinical and Translational Oncology ; volume 25, issue 9, page 2760-2762 ; ISSN 1699-3055

مصطلحات موضوعية: Cancer Research, Oncology, General Medicine

الإتاحة: https://doi.org/10.1007/s12094-023-03290-7Test

المؤلفون: De Castro, Javier, Insa, Amelia, Collado-Borrell, Roberto, Escudero-Vilaplana, Vicente, Martínez, Alex, Fernandez, Elena, Sullivan, Ivana, Arrabal, Natalia, Carcedo, David, Manzaneque, Alba

المساهمون: Roche Farma S.A

المصدر: BMC Pulmonary Medicine ; volume 23, issue 1 ; ISSN 1471-2466

مصطلحات موضوعية: Pulmonary and Respiratory Medicine

الوصف: Background There are scarce data of the costs of non-small cell lung cancer (NSCLC) recurrence in Spain. The objective of this study is to assess the economic burden of disease recurrence, for both locoregional and/or metastatic relapses, after appropriate early-stage NSCLC treatment in Spain. Materials and methods A two-round consensus panel of Spanish oncologists and hospital pharmacists was conducted to collect information on patient’s flow, treatments, use of healthcare resources and sick leaves in patients with relapsed NSCLC. A decision-tree model was developed to calculate the economic burden of disease recurrence after appropriate early-stage NSCLC. Both direct and indirect costs were considered. Direct costs included drug acquisition and healthcare resources costs. Indirect costs were estimated using the human-capital approach. Unit costs were obtained from national databases (euros of 2022). A multi-way sensitivity analysis was performed to provide a range to the mean values. Results Among a cohort of 100 patients with relapsed NSCLC, 45 patients would have locoregional relapse (36.3 would eventually progress to metastasis and 8.7 would be considered in remission) and 55 patients would have metastatic relapse. Over time, 91.3 patients would experience a metastatic relapse (55 as first relapse and 36.6 after previous locoregional relapse). The overall cost incurred by the 100-patients cohort is €10,095,846 (€9,336,782 direct costs, €795,064 indirect costs). The average cost of a locoregional relapse is €25,194 (€19,658 direct costs, €5536 indirect costs), while the average cost a patient with metastasis who receives up to 4 lines of treatment is €127,167 (€117,328 direct, €9839 indirect). Conclusions To our knowledge, this is the first study that specifically quantifies the cost of relapse in NSCLC in Spain. Our findings shown that the overall cost of a relapse after appropriate treatment of early-stage NSCLC patients is substantial, and it increases considerably in the metastatic relapse ...

الإتاحة: https://doi.org/10.1186/s12890-023-02356-0Test

المؤلفون: Escudero-Vilaplana, Vicente, Collado-Borrell, Roberto, De Castro, Javier, Insa, Amelia, Martínez, Alex, Fernández, Elena, Sullivan, Ivana, Flores, Andrés, Arrabal, Natalia, Carcedo, David, Manzaneque, Alba

المصدر: Journal of Medical Economics ; volume 26, issue 1, page 445-453 ; ISSN 1369-6998 1941-837X

الإتاحة: https://doi.org/10.1080/13696998.2023.2188844Test