27 results on '"Valverde, Claudia"'
Search Results
2. A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor
- Author
-
Pantaleo, Maria A., Heinrich, Michael C., Italiano, Antoine, Valverde, Claudia, Schöffski, Patrick, Grignani, Giovanni, Reyners, Anna K. L., Bauer, Sebastian, Reichardt, Peter, Stark, Daniel, Berhanu, Ghimja, Brandt, Ulrike, Stefanelli, Tommaso, and Gelderblom, Hans
- Published
- 2022
- Full Text
- View/download PDF
3. A phase II trial of weekly nab-paclitaxel for progressive and symptomatic desmoid tumors
- Author
-
Martin-Broto, Javier, Redondo, Andres, Moura, David S., Valverde, Claudia, Morales, Jose Manuel, Lopez-Pousa, Antonio, Martinez-Trufero, Javier, Gutierrez, Antonio, Díaz-Beveridge, Roberto, Luna, Pablo, Martinez-Marin, Virginia, Marcilla, David, Arribas, Ivan, Ledesma, Patricio, Lopez-Martin, Jose Antonio, Di Lernia, Davide, Zamora, Jorge, and Hindi, Nadia
- Published
- 2022
- Full Text
- View/download PDF
4. Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors
- Author
-
Serrano, César, Vivancos, Ana, López-Pousa, Antonio, Matito, Judit, Mancuso, Francesco M., Valverde, Claudia, Quiroga, Sergi, Landolfi, Stefania, Castro, Sandra, Dopazo, Cristina, Sebio, Ana, Virgili, Anna C., Menso, María M., Martín-Broto, Javier, Sansó, Miriam, García-Valverde, Alfonso, Rosell, Jordi, Fletcher, Jonathan A., George, Suzanne, Carles, Joan, and Arribas, Joaquín
- Published
- 2020
- Full Text
- View/download PDF
5. Genomic Profiling and Clinical Outcomes of Targeted Therapies in Adult Patients with Soft Tissue Sarcomas.
- Author
-
Kokkali, Stefania, Georgaki, Eleni, Mandrakis, Georgios, Valverde, Claudia, and Theocharis, Stamatios
- Subjects
SARCOMA ,NUCLEOTIDE sequencing ,EPITHELIAL tumors ,GASTROINTESTINAL stromal tumors ,TREATMENT effectiveness ,ISOLATION perfusion - Abstract
Genomic profiling has improved our understanding of the pathogenesis of different cancers and led to the development of several targeted therapies, especially in epithelial tumors. In this review, we focus on the clinical utility of next-generation sequencing (NGS) to inform therapeutics in soft tissue sarcoma (STS). The role of NGS is still controversial in patients with sarcoma, given the low mutational burden and the lack of recurrent targetable alterations in most of the sarcoma histotypes. The clinical impact of genomic profiling in STS has not been investigated prospectively. A limited number of retrospective, mainly single-institution, studies have addressed this issue using various NGS technologies and platforms and a variety of criteria to define a genomic alteration as actionable. Despite the detailed reports on the different gene mutations, fusions, or amplifications that were detected, data on the use and efficacy of targeted treatment are very scarce at present. With the exception of gastrointestinal stromal tumors (GISTs), these targeted therapies are administered either through off-label prescription of an approved drug or enrollment in a matched clinical trial. Based mainly on anecdotal reports, the outcome of targeted therapies in the different STS histotypes is discussed. Prospective studies are warranted to assess whether genomic profiling improves the management of STS patients. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. Working to improve the management of sarcoma patients across Europe: a policy checklist
- Author
-
Kasper, Bernd, Lecointe-Artzner, Estelle, Wait, Suzanne, Boldon, Shannon, Wilson, Roger, Gronchi, Alessandro, Valverde, Claudia, Eriksson, Mikael, Dumont, Sarah, Drove, Nora, Kanli, Athanasia, and Wartenberg, Markus
- Published
- 2018
- Full Text
- View/download PDF
7. Uterine sarcomas: clinical practice guidelines for diagnosis, treatment, and follow-up, by Spanish group for research on sarcomas (GEIS).
- Author
-
Pérez-Fidalgo, Jose Alejandro, Ortega, Eugenia, Ponce, Jordi, Redondo, Andres, Sevilla, Isabel, Valverde, Claudia, Isern Verdum, Josep, de Alava, Enrique, Galera López, Mar, Marquina, Gloria, and Sebio, Ana
- Abstract
Uterine sarcomas are very infrequent and heterogeneous entities. Due to its rarity, pathological diagnosis, surgical management, and systemic treatment are challenging. Treatment decision process in these tumors should be taken in a multidisciplinary tumor board. Available evidence is low and, in many cases, based on case series or clinical trials in which these tumors have been included with other soft tissue sarcoma. In these guidelines, we have tried to summarize the most relevant evidence in the diagnosis, staging, pathological disparities, surgical management, systemic treatment, and follow-up of uterine sarcomas. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
8. Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial
- Author
-
Martín Broto, Javier, Hindi, Nadia, Grignani, Giovanni, Martínez Trufero, Javier, Redondo, Andrés, Valverde, Claudia, Encinas Tobajas, Víctor, Álava Casado, Enrique de, López Martín, José A., Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica, Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología, and Universidad de Sevilla. CTS1035: Patología Molecular del Cáncer Sólido
- Subjects
PD-1/ PD-L1 axis (nivolumab) ,Sarcomas ,Test the double inhibition of angiogenesis (sunitinib) ,PD-1 inhibitors ,Immune response - Abstract
Background: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab). Methods: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5mg daily from day 1, plus nivolumab 3mg/kg intravenously on day 15, and then every 2weeks; and level −1 with sunitinib 37.5mg on the first 14 days (induction) and then 25mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II). Results: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5mg as induction and then 25mg in combination with nivolumab. After a median follow-up of 17months (4–26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3–4 adverse events included transaminitis (17.3%) and neutropenia (11.5%). Conclusions: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6months. GEIS ISG BMS Pfizer
- Published
- 2020
9. Optimization of the Therapeutic Approach to Patients with Sarcoma: Delphi Consensus
- Author
-
Álvarez Álvarez, Rosa, Cruz Jurado, Josefina, del Muro Solans, Xavier García, Giner, Javier Lavernia, López Pousa, Antonio, Martín-Broto, Javier, and Valverde, Claudia María
- Subjects
Article Subject - Abstract
Soft tissue sarcomas (STS) constitute a heterogeneous group of rare solid tumors associated with significant morbidity and mortality. The evaluation and treatment of STS require a multidisciplinary team with extensive experience in the management of these types of tumors. National and international clinical practice guidelines for STS do not always provide answers to a great many situations that specialists have to contend with in their everyday practice. This consensus provides a series of specific recommendations based on available scientific evidence and the experience of a group of experts to assist in decision-making by all the specialists involved in the management of STS.
- Published
- 2019
- Full Text
- View/download PDF
10. Ripretinib in gastrointestinal stromal tumor: the long-awaited step forward.
- Author
-
Lostes-Bardaji, M. Julia, García-Illescas, David, Valverde, Claudia, and Serrano, César
- Abstract
Gastrointestinal stromal tumor (GIST) represents a paradigm for clinically effective targeted inhibition of oncogenic driver mutations in cancer. Five drugs are currently positioned as the standard of care for the treatment of advanced or metastatic GIST patients. This is the result of continuous, deep understanding of KIT and PDGFRA GIST oncogenic drivers as well as the resistance mechanisms associated to tumor progression. However, the complexity of GIST molecular heterogeneity is an evolving field, and critical questions remain open. Specifically, the clinical benefit of approved and/or investigated targeted agents is strikingly modest at advanced stages of the disease when compared with the activity of first-line imatinib. Ripretinib is a novel switch-pocket inhibitor with broad activity against KIT and PDGFRA oncoproteins and has recently demonstrated antitumoral activity across phase I to phase III clinical trials. Therefore, ripretinib has emerged as a new standard of care for advanced, multi-resistant GIST patients. Based on this data, the Food and Drug Administration has granted in 2020 the approval of ripretinib for GIST patients after progression to imatinib, sunitinib and regorafenib. This, in turn, constitutes a major breakthrough in sarcoma drug development, as there have not been new treatment approvals in GIST for nearly a decade. Herein, we provide a critical review on the preclinical and clinical development of ripretinib in GIST. Furthermore, we seek to assess the biological and clinical impact of this new standard of care on the course of the disease, aiming to provide an insight on future treatments strategies for the next coming years. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
11. Clinical practice guidelines for the diagnosis and treatment of patients with soft tissue sarcoma by the Spanish group for research in sarcomas (GEIS)
- Author
-
Garcia del Muro, Xavier, de Alava, Enrique, Artigas, Vicenç, Bague, Silvia, Braña, Alejandro, Cubedo, Ricardo, Cruz, Josefina, Mulet-Margalef, Nuria, Narvaez, Jose A, Martinez Tirado, Oscar, Valverde, Claudia, Verges, Ramona, Viñals, Joan, Martin-Broto, Javier, Spanish Group for Research on Sarcoma, [Garcia del Muro, Xavier] Inst Catala Oncol Hosp, Barcelona, Spain, [Mulet-Margalef, Nuria] Inst Catala Oncol Hosp, Barcelona, Spain, [de Alava, Enrique] Hosp Univ Virgen del Rocio, Seville, Spain, [Martin-Broto, Javier] Hosp Univ Virgen del Rocio, Seville, Spain, [Artigas, Vicenc] Hosp Santa Creu & Sant Pau, Barcelona, Spain, [Bague, Silvia] Hosp Santa Creu & Sant Pau, Barcelona, Spain, [Brana, Alejandro] Univ Oviedo, Hosp Cent Asturias, E-33080 Oviedo, Spain, [Cubedo, Ricardo] Hosp Puerta Hierro Majadahonda, Madrid, Spain, [Cruz, Josefina] Hosp Univ Canarias, Santa Cruz De Tenerife, Spain, [Narvaez, Jose A.] Hosp Univ Bellvitge, Barcelona, Spain, [Vinals, Joan] Hosp Univ Bellvitge, Barcelona, Spain, [Martinez Tirado, Oscar] Inst Invest Biomed Bellvitge IDIBELL, Barcelona, Spain, [Valverde, Claudia] Hosp Univ Vall Hebron, Barcelona, Spain, and [Verges, Ramona] Hosp Univ Vall Hebron, Barcelona, Spain
- Subjects
Cancer Research ,medicine.medical_specialty ,Soft Tissue Neoplasm ,Core-needle-biopsy ,medicine.medical_treatment ,Antineoplastic Agents ,Soft Tissue Neoplasms ,Disease ,Isolated limb perfusion ,030230 surgery ,Toxicology ,Targeted therapy ,03 medical and health sciences ,Inflammatory myofibroblastic tumor ,0302 clinical medicine ,Biopsy ,Multidisciplinary management ,medicine ,Humans ,Pharmacology (medical) ,Doxorubicin plus ifosfamide ,Pharmacology ,Randomized phase-ii ,Soft tissue sarcoma ,medicine.diagnostic_test ,business.industry ,General surgery ,Soft tissue ,Prognostic-factors ,Sarcoma ,Evidence-based medicine ,medicine.disease ,Clear-cell sarcoma ,Surgery ,Solitary fibrous tumor ,Adjuvant chemotherapy ,Treatment ,Oncology ,Chemotherapy, Adjuvant ,Spain ,030220 oncology & carcinogenesis ,Original Article ,business ,Clinical practice guidelines ,High-dose doxorubicin - Abstract
The authors would like to thank Ron Clapp, and GEIS Clinical Research Center for their assistance in the preparation of the manuscript, Garcia Del Muro, X., De Alava, E., Artigas, V., Bague, S., Braña, A., Cubedo, R., Cruz, J., Mulet-Margalef, N., Narvaez, J.A., Martinez Tirado, O., Valverde, C., Verges, R., Viñals, J., Martin-Broto, J.
- Published
- 2015
12. GEIS guidelines for gastrointestinal sarcomas (GIST)
- Author
-
Poveda, Andrés, García Del Muro, Xavier, López-Guerrero, Jose Antonio, Cubedo, Ricardo, Martínez, Virginia, Romero, Ignacio, Serrano, César, Valverde, Claudia, Martín-Broto, Javier, and GEIS (Grupo Español de Investigación en Sarcomas/Spanish Group for Sarcoma Research)
- Subjects
0301 basic medicine ,Oncology ,Indoles ,Pyridines ,medicine.medical_treatment ,Targeted therapy ,chemistry.chemical_compound ,0302 clinical medicine ,Sunitinib ,Molecular Targeted Therapy ,Mesentery ,Gastrointestinal Neoplasms ,Regorafenib ,biology ,GiST ,KIT ,General Medicine ,Combined Modality Therapy ,PDGFRA ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,medicine.drug ,GIST ,medicine.medical_specialty ,Gastrointestinal Stromal Tumors ,Antineoplastic Agents ,CD117 ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Pyrroles ,neoplasms ,GEIS ,business.industry ,Phenylurea Compounds ,Imatinib ,DOG1 ,digestive system diseases ,030104 developmental biology ,chemistry ,biology.protein ,business - Abstract
Gastrointestinal stromal sarcomas (GISTs) are the most common mesenchymal tumours originating in the digestive tract. They have a characteristic morphology, are generally positive for CD117 (c-kit) and are primarily caused by activating mutations in the KIT or PDGFRA genes(1). On rare occasions, they occur in extravisceral locations such as the omentum, mesentery, pelvis and retroperitoneum. GISTs have become a model of multidisciplinary work in oncology: the participation of several specialties (oncologists, pathologists, surgeons, molecular biologists, radiologists…) has forested advances in the understanding of this tumour and the consolidation of a targeted therapy, imatinib, as the first effective molecular treatment in solid tumours. Following its introduction, median survival of patients with advanced or metastatic GIST increased from 18 to more than 60months. Sunitinib and Regorafenib are two targeted agents with worldwide approval for second- and third-line treatment, respectively, in metastatic GIST.
- Published
- 2017
13. Relevance of Reference Centers in Sarcoma Care and Quality Item Evaluation: Results from the Prospective Registry of the Spanish Group for Research in Sarcoma (GEIS).
- Author
-
Martin‐Broto, Javier, Hindi, Nadia, Cruz, Josefina, Martinez‐Trufero, Javier, Valverde, Claudia, De Sande, Luis M., Sala, Angeles, Bellido, Lorena, De Juan, Ana, Rubió‐Casadevall, Jordi, Diaz‐Beveridge, Roberto, Cubedo, Ricardo, Tendero, Oscar, Salinas, Diego, Gracia, Isidro, Ramos, Rafael, Baguè, Silvia, Gutierrez, Antonio, Duran‐Moreno, José, and Lopez‐Pousa, Antonio
- Subjects
BIOPSY ,CANCER chemotherapy ,REPORTING of diseases ,HEALTH facilities ,LONGITUDINAL method ,SARCOMA ,SOFT tissue tumors ,TUMOR classification ,TREATMENT effectiveness ,PREOPERATIVE period ,PERIOPERATIVE care ,TUMOR risk factors ,CANCER risk factors - Abstract
Background: Reference centers (RCs) are a key point for improving the survival of patients with soft‐tissue sarcomas (STS). The aim of this study was to evaluate selected items in the management of patients with STS, comparing results between RC and local hospitals (LHs). Materials and Methods: Diagnostic and therapeutic data from patients diagnosed between January 2004 and December 2011 were collected. Correlation with outcome was performed. Results: A total of 622 sarcomas were analyzed, with a median follow‐up of 40 months. Imaging of primary tumor preoperatively (yes vs. no) correlated with a higher probability of free surgical margins (77.4% versus 53.7%; p =.006). The provenance of the biopsy (RC vs. LH) significantly affected relapse‐free survival (RFS; 3‐year RFS 66% vs. 46%, respectively; p =.019). Likewise, 3‐year RFS was significantly worse in cases with infiltrated (55.6%) or unknown (43.4%) microscopic surgical margins compared with free margins (63.6%; p <.001). Patients managed by RCs had a better 3‐year overall survival compared with those managed by LHs (82% vs. 70.4%, respectively; p =.003). Perioperative chemotherapy in high‐risk STS, more frequently administered in RCs than in LHs, resulted in significantly better 3‐year RFS (66% vs. 44%; p =.011). In addition, patients with stage IV disease treated in RCs survived significantly longer compared with those in LHs (30.4 months vs. 18.5 months; p =.036). Conclusion: Our series indicate that selected quality‐of‐care items were accomplished better by RCs over LHs, all with significant prognostic value in patients with STS. Early referral to an RC should be mandatory if the aim is to improve the survival of patients with STS. Implications for Practice: This prospective study in patients diagnosed with soft‐tissue sarcoma shows the prognostic impact of reference centers in the management of these patients. The magnitude of this impact encompasses all steps of the process, from the initial management (performing diagnostic biopsy) to the advanced disease setting. This is the first prospective evidence showing improvement in outcomes of patients with metastatic disease when they are managed in centers with expertise. This study provides extra data supporting referral of patients with sarcoma to reference centers. Management of soft‐tissue sarcoma is challenging. This article reports on sarcoma clinical management in cancer centers in Spain, based on information from a prospective registry launched by the Spanish Group for Research in Sarcoma. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
14. Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib.
- Author
-
Serrano, César, García‐del‐Muro, Xavier, Valverde, Claudia, Sebio, Ana, Durán, José, Manzano, Aránzazu, Pajares, Isabel, Hindi, Nadia, Landolfi, Stefania, Jiménez, Laura, Rubió‐Casadevall, Jordi, Estival, Anna, Lavernia, Javier, Safont, María José, Pericay, Carles, Díaz‐Beveridge, Roberto, Martínez‐Marín, Virginia, Vicente‐Baz, David, Vivancos, Ana, and Hernández‐Losa, Javier
- Subjects
GASTROINTESTINAL tumors ,CYTOGENETICS ,SARCOMA ,DRUG side effects ,SYMPTOMS ,TREATMENT effectiveness ,TREATMENT duration ,CANCER patients ,METASTASIS ,CONNECTIVE tissue tumors ,LONGITUDINAL method ,IMATINIB ,GENETIC mutation ,DISEASE progression - Abstract
Background: Oncogenic KIT/PDGFRA signaling inhibition with imatinib achieves disease control in most patients with advanced/metastatic gastrointestinal stromal tumor (GIST), but resistance eventually develops after 20–24 months. Notably, a small subset of these patients obtain durable benefit from imatinib therapy. Methods: We analyzed clinical, pathological, and molecular characteristics and long‐term outcomes in patients with metastatic GIST treated with continuous daily dosing of frontline imatinib in a cohort of patients benefiting for ≥5 years. A control group was obtained from the national Spanish Group for Sarcoma Research database and used as comparator. Results: Sixty‐four imatinib long‐term responders (LTRs) and 70 control cases were identified. Compared with controls, LTRs at baseline had better performance status (PS) 0–1 (100% vs. 81%), lower mitotic count (median, 8 vs. 15), and tumor burden (number of metastases, 3 vs. 7). KIT exon 11 was the only region found mutated in LTRs. LTRs achieved 34% complete responses and a median progression‐free survival of 11 years, compared with 4% and 2 years, respectively, in the control cohort. Prognostic factors that independently predicted long‐term benefit with imatinib were PS, number of metastases prior to imatinib, and response to imatinib. Fifteen LTR patients developed new side effects attributable to imatinib after ≥5 years of continuous treatment. No resistance mutations were found in metastatic samples from three patients progressing on imatinib. Conclusion: GISTs in LTRs are a distinctive entity with less aggressive behavior and marked sensitivity to KIT inhibition. Patients reaching 5 or more years on imatinib have a higher chance of remaining progression free over time. Implications for Practice: This work demonstrates that clinical and inherent tumor characteristics define a subset of patients with gastrointestinal stromal tumor (GIST) with increased likelihood to achieve durable response to first‐line imatinib therapy. Patients reaching ≥5 years on imatinib have a greater chance of remaining progression free over time, although the disease is unlikely to be cured. Imatinib is well tolerated for >5 years, and emergent toxicities are overall manageable. Resistance to imatinib emerging in patients with GISTs after long‐term imatinib treatment does not involve polyclonal expansion of KIT secondary mutations. This article identifies distinctive clinicopathological and molecular features in long‐term responders to imatinib treatment compared with patients with gastrointestinal stromal tumors reaching the usual median progression‐free survival. Clinical insights from this subgroup collected during the long‐term follow‐up are also provided. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
15. Dovitinib in patients with gastrointestinal stromal tumour refractory and/or intolerant to imatinib.
- Author
-
Joensuu, Heikki, Blay, Jean-Yves, Comandone, Alessandro, Martin-Broto, Javier, Fumagalli, Elena, Grignani, Giovanni, Del Muro, Xavier Garcia, Adenis, Antoine, Valverde, Claudia, Pousa, Antonio Lopez, Bouché, Olivier, Italiano, Antoine, Bauer, Sebastian, Barone, Carlo, Weiss, Claudia, Crippa, Stefania, Camozzi, Maura, Castellana, Ramon, Le Cesne, Axel, and Bouché, Olivier
- Subjects
CLINICAL trials ,COMPARATIVE studies ,DRUG resistance in cancer cells ,HETEROCYCLIC compounds ,LONGITUDINAL method ,RESEARCH methodology ,MEDICAL cooperation ,PROGNOSIS ,QUINOLONE antibacterial agents ,RESEARCH ,TUMOR classification ,GASTROINTESTINAL tumors ,EVALUATION research ,SALVAGE therapy ,PROTEIN kinase inhibitors ,PHARMACODYNAMICS - Abstract
Background: This multicentre phase II trial (DOVIGIST) evaluated the antitumour activity of dovitinib as second-line treatment of patients with gastrointestinal stromal tumour (GIST) refractory to imatinib or who do not tolerate imatinib.Methods: Patients received oral dovitinib 500 mg day-1, 5 days on/2 days off, until GIST progression or unacceptable toxicity, with an objective to evaluate efficacy, assessed as the disease control rate (DCR) at 12 weeks. Tumour assessment and response to dovitinib therapy were evaluated by Response Evaluation Criteria In Solid Tumours (RECIST v1.1) and the Choi criteria. Secondary objectives included assessment of progression-free survival (PFS), safety and tolerability, and DCR at the end of treatment.Results: Thirty-eight of the 39 patients enrolled had histologically confirmed GIST. The DCR at 12 weeks was 52.6% (90% confidence interval (CI), 38.2-66.7%) meeting the preset efficacy criterion for the primary end point. The objective response rate (complete response+partial response) was 2.6% (1 of 38; 90% CI, 0.1-11.9%), and 5.3% (n=2; 90% CI, 0.9-15.7%) at the end of the study. The median PFS was 4.6 months (90% CI, 2.8-7.4 months). Dose interruption was required in 26 patients (66.7%), of which 18 (69.2%) were due to adverse events. The most frequently observed grade 3 adverse events included hypertension (n=7), fatigue (n=5), vomiting (n=4), hypertriglyceridaemia (n=4), and γ-glutamyltransferase increase (n=4).Conclusions: Dovitinib is an active treatment for patients with GIST who are intolerant to imatinib or whose GIST progresses on imatinib. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
16. Prognostic Significance of Venous Thromboembolic Events in Disseminated Germ Cell Cancer Patients.
- Author
-
Gonzalez-Billalabeitia, Enrique, Castellano, Daniel, Sobrevilla, Nora, Guma, Josep, Hervas, David, Luengo, Maria I., Aparicio, Jorge, Sanchez-Munoz, Alfonso, Mellado, Begona, Saenz, Alberto, Valverde, Claudia, Fernandez, Antonio, Margeli, Mireia, Duran, Ignacio, Fernandez, Sara, Sastre, Javier, Ros, Silverio, Maroto, Pablo, Manneh, Ray, and Cerezuela, Pablo
- Subjects
GERM cells ,CANCER prognosis ,THROMBOEMBOLISM ,VENOUS thrombosis ,CANCER chemotherapy ,CANCER ,ANTINEOPLASTIC agents ,BLEOMYCIN ,CISPLATIN ,COMPARATIVE studies ,ETOPOSIDE ,LONGITUDINAL method ,GERM cell tumors ,RESEARCH methodology ,MEDICAL cooperation ,PROGNOSIS ,RESEARCH ,SURVIVAL ,VEINS ,EVALUATION research ,ACQUISITION of data ,PROPORTIONAL hazards models ,DISEASE complications ,DIAGNOSIS - Abstract
Background: Disseminated germ cell cancers are at high risk of developing thromboembolic complications. We evaluated the prognostic value of venous thromboembolic events (VTE) in disseminated germ cell cancer.Methods: Patients with germ cell cancer receiving upfront platinum-containing chemotherapy between 2004 and 2014 were pooled from the Spanish Germ Cell Cancer Group (SGCCG) registry and reviewed for the presence of VTE. Results were validated in an independent international group of patients. We used a penalized Cox proportional hazards model including VTE as a time-varying covariate to identify and validate prognostic factors. All statistical tests were two-sided.Results: The SGCCG registry identified 416 patients from 14 referral institutions. With a median follow-up of 49 months, VTEs were observed in 9% of patients (n = 38). Events occurred at diagnosis, during chemotherapy, and after chemotherapy in 2.6%, 5.0%, and 1.4% of patients, respectively. VTE was associated with shorter progression-free survival (PFS; hazard ratio [HR] = 2.29, 95% confidence interval [CI] = 1.18 to 4.47, P = .02) and overall survival (OS; HR = 5.14, 95% CI = 2.22 to 11.88, P < .001). In multivariable analysis, the effect was consistent in the intermediate-risk group, both for PFS (HR = 9.52 95% CI = 2.48 to 36.58, P < .001) and OS (HR = 12.84, 95% CI = 2.01 to 82.02, P = .007). VTE at diagnosis is also an adverse prognostic variable for progression-free survival (HR = 4.64, 95% CI = 2.04 to 10.54, P < .001) and for overall survival (HR = 6.28, 95% CI = 1.68 to 17.10, P = .01). These results were validated in an independent international cohort that included 241 patients from four hospitals.Conclusions: VTE is an independent adverse prognostic factor in disseminated germ cell cancers, in particular for the intermediate prognostic group of the International Germ Cell Cancer Collaborative Group classification. The presence of VTE at diagnosis has also prognostic significance and should be further explored in future prognostic classifications. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
17. Phosphorylated-insulin growth factor I receptor (p-IGF1R) and metalloproteinase-3 (MMP3) expression in advanced gastrointestinal stromal tumors (GIST). A GEIS 19 study.
- Author
-
Maurel, Joan, López-Pousa, Antonio, Calabuig, Silvia, Bagué, Silvia, Garcia del Muro, Xavier, Sanjuan, Xavier, Rubió-Casadevall, Jordi, Cuatrecasas, Miriam, Martinez-Trufero, Javier, Horndler, Carlos, Fra, Joaquin, Valverde, Claudia, Redondo, Andrés, Poveda, Andrés, Sevilla, Isabel, Lainez, Nuria, Rubini, Michele, García-Albéniz, Xabier, Martín-Broto, Javier, and de Alava, Enrique
- Subjects
INSULIN research ,METALLOPROTEINASES - Abstract
Background: Most GISTs have mutations in KIT or PDGFRA. Patients with advanced GIST with KIT exon 9, PDGFRA mutation or WT for KIT and PDGFRA have a worse progression-free survival (PFS) compared to patients with KIT exon 11 mutated tumors. We evaluated the immunohistochemical (IHC) expression of p-IGF1R (Y1316) and MMP3 as predictors of PFS or overall survival (OS). Methods: Ninety-two advanced GIST patients included in GEIS-16 study with KIT and PDGFRA mutational information were examined for p-IGF1R (Y1316) and MMP3 expression in a tissue micro-array. To study activation of the IGF1R system, we have used an antibody (anti-pY1316) that specifically recognizes the active phosphorylated form of the IGF1R. DNA was extracted from paraffin-embedded tissues and intronic PCR primers were used to amplify exons 9, 11, 13 and 17 of KIT, 12 and 18 of PDGFRA. Bidirectional sequencing with specific primers was performed on a ABI3100 sequencer using the Big Dye Terminator v3.1 kit. Multivariate model was built using a stepwise automated variable selection approach with criterion to enter the variable in the model of p < 0.10 and criterion to keep the variable in the model of p < 0.05. PFS was computed as the date of imatinib initiation to progression or death. Overall survival was defined as the time from imatinib initiation to death. Results: Phospho-IGF1R was expressed only in 9 % (2/22) of cases without KIT mutation. MMP3 expression was detected in 2/5 patients (40 %) with PDGFRA mutation, 1/16 patients (6 %) with WT genotype and 7/71 patients (10 %) of KIT mutant patients. At univariate analysis KIT exon 11/13 mutation had better PFS than patients with exon 9 mutation, PDGFRA mutation or WT genotype (p = 0.021; HR: 0.46; 95 %CI (0.28-0.76). Less than 24 months disease free-interval (HR 24.2, 95 % CI 10.5-55.8), poor performance status (PS) (HR 6.3, 95 % CI 2.5-15.9), extension of disease; >1 organ (HR 1.89; 95 % CI 1.03-3.4) and genotype analysis (HR 0.57, 95 % CI 0.37-0.97) but not immunophenotype analysis (HR 1.53; 95 % CI 0.76-3.06) were the strongest prognostic factors for PFS in the multivariate analysis. Conclusions: Our results do not support p-IGF-1R and MMP3 evaluation in non-selected GIST patients but evaluation of this immunophenotype in WT and mutant PDGFR mutation in larger group of GIST patients, deserve merits. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
18. Novel targets in gastric and esophageal cancer
- Author
-
Valverde, Claudia María, Macarulla, Teresa, Casado, Esther, Ramos, Francisco Javier, Martinelli, Erika, and Tabernero, Josep
- Subjects
- *
CANCER treatment , *ESOPHAGEAL cancer , *THERAPEUTICS , *APOPTOSIS - Abstract
Abstract: Esophageal cancer (EC) and gastric cancer (GC) constitute a major cause of cancer deaths worldwide. Recent improvements in both surgical techniques and adjuvant/neoadjuvant chemotherapy, radiotherapy or both have increased the survival of patients with loco-regional disease. However, most patients with GC or EC have advanced disease either at diagnosis or during the follow-up, and despite recent advances, these patients still do poorly. Understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. In this review we describe the current status of targeted therapies in the treatment of EC and GC, including EGFR inhibitors, antiangiogenic agents, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinases inhibitors. The emerging data from the clinical development of these compounds has provided novel opportunities in the treatment of EC and GC that will probably translate into clinical benefit for patients with these common malignancies. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
- View/download PDF
19. Prognostic Significance of Venous Thromboembolic Events in Disseminated Germ Cell Cancer Patients
- Author
-
Antonio Fernández, Jose Luis Aguilar, Pablo Cerezuela, A. Saenz, S. Ros, Alberto Carmona-Bayonas, Sara Fernández, Claudia Valverde, Daniel Castellano, Mireia Margeli, David Hervás, Xavier Garcia del Muro, Grupo Germinal, Francisco Ayala de la Peña, Josep Guma, Javier Sastre, Ignacio Duran, Begoña Mellado, Samuel Rivera, Nora Sobrevilla, Alfonso Sanchez-Muñoz, Jose R. Germa-Lluch, Enrique Gonzalez-Billalabeitia, Ray Manneh, Maria Isabel Luengo, Pablo Maroto, Jorge Aparicio, [Gonzalez-Billalabeitia, Enrique] Hosp Univ Morales Meseguer IMIB, Murcia, Spain, [Luengo, Maria I.] Hosp Univ Morales Meseguer IMIB, Murcia, Spain, [Gonzalez-Billalabeitia, Enrique] Univ Catolica San Antonio Murcia UCAM, Murcia, Spain, [Castellano, Daniel] Hosp Univ 12 Octubre, Madrid, Spain, [Manneh, Ray] Hosp Univ 12 Octubre, Madrid, Spain, [Sobrevilla, Nora] Inst Nacl Cancerol, Mexico City, DF, Mexico, [Guma, Josep] URV, Hosp San Joan de Reus, IISSPV, Tarragona, Spain, [Hervas, David] Inst Invest Sanitaria La Fe, Valencia, Spain, [Aparicio, Jorge] Hosp Univ La Fe, Valencia, Spain, [Sanchez-Munoz, Alfonso] Hos Univ Reg & Virgen de la Victoria Malaga, Invest Clin & Traslac Canc, Inst Invest Biomed Malaga IBIMA, Malaga, Spain, [Mellado, Begona] Hosp Clin Barcelona, IDIBAPS, Serv Oncol Med, Barcelona, Spain, [Saenz, Alberto] Hosp Clin Lozano Blesa, Zaragoza, Spain, [Valverde, Claudia] Hosp Univ Vall dHebron, Barcelona, Spain, [Fernandez, Antonio] Complejo Hosp Univ Albacete, Albacete, Spain, [Margeli, Mireia] Hosp Badalona Germans Trias & Pujol, Inst Catala Oncol, Badalona, Spain, [Duran, Ignacio] Hosp Univ Virgen del Rocio, Seville, Spain, [Fernandez, Sara] Hosp Cent Asturias, Oviedo, Spain, [Sastre, Javier] Hosp Clin San Carlos, Madrid, Spain, [Ros, Silverio] Hosp Virgen Arrixaca, Murcia, Spain, [Maroto, Pablo] Hosp Santa Creu & Sant Pau, Barcelona, Spain, and [Cerezuela, Pablo] Hosp Santa Lucia, Cartagena, Spain
- Subjects
Risk ,0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Prognostic variable ,Survival ,Adolescent ,medicine.medical_treatment ,Disease-Free Survival ,03 medical and health sciences ,Bleomycin ,Young Adult ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Registries ,Young adult ,Child ,Survival rate ,Tumors ,Aged ,Etoposide ,Proportional Hazards Models ,Chemotherapy ,business.industry ,Proportional hazards model ,Hazard ratio ,Venous Thromboembolism ,Middle Aged ,Neoplasms, Germ Cell and Embryonal ,Prognosis ,Confidence interval ,Cisplatin-based chemotherapy ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Female ,Cisplatin ,business ,Follow-Up Studies - Abstract
Background: Disseminated germ cell cancers are at high risk of developing thromboembolic complications. We evaluated the prognostic value of venous thromboembolic events (VTE) in disseminated germ cell cancer. Methods: Patients with germ cell cancer receiving upfront platinum-containing chemotherapy between 2004 and 2014 were pooled from the Spanish Germ Cell Cancer Group (SGCCG) registry and reviewed for the presence of VTE. Results were validated in an independent international group of patients. We used a penalized Cox proportional hazards model including VTE as a time-varying covariate to identify and validate prognostic factors. All statistical tests were two-sided. Results: The SGCCG registry identified 416 patients from 14 referral institutions. With a median follow-up of 49 months, VTEs were observed in 9% of patients (n = 38). Events occurred at diagnosis, during chemotherapy, and after chemotherapy in 2.6%, 5.0%, and 1.4% of patients, respectively. VTE was associated with shorter progression-free survival (PFS; hazard ratio [HR] = 2.29, 95% confidence interval [CI] = 1.18 to 4.47, P = .02) and overall survival (OS; HR = 5.14, 95% CI = 2.22 to 11.88, P < .001). In multivariable analysis, the effect was consistent in the intermediate-risk group, both for PFS (HR = 9.52 95% CI = 2.48 to 36.58, P < .001) and OS (HR = 12.84, 95% CI = 2.01 to 82.02, P = .007). VTE at diagnosis is also an adverse prognostic variable for progression-free survival (HR = 4.64, 95% CI = 2.04 to 10.54, P < .001) and for overall survival (HR = 6.28, 95% CI = 1.68 to 17.10, P = .01). These results were validated in an independent international cohort that included 241 patients from four hospitals. Conclusions: VTE is an independent adverse prognostic factor in disseminated germ cell cancers, in particular for the intermediate prognostic group of the International Germ Cell Cancer Collaborative Group classification. The presence of VTE at diagnosis has also prognostic significance and should be further explored in future prognostic classifications.
- Published
- 2017
20. The observational EURACAN prospective clinical registry dedicated to epithelioid hemangioendothelioma: The protocol of an international and collaborative effort on an ultra-rare entity.
- Author
-
Frezza AM, Leonard H, Aggerholm-Pedersen N, Badalamenti G, Baili P, Baldi GG, Bauer S, Bazzurri S, Benzonelli I, Bertuzzi A, Blay JY, Bianchi G, Bonfarnuzzo S, Bouvier C, Boye K, Martin Broto J, Brunello A, Campanacci D, Casali PG, Cicala C, Crotti E, D'Ambrosio L, Dei Tos AP, Dieckmann N, Dufresne A, Elston S, Ferraresi V, Gabellini S, Giani C, Giannusa V, Gil Sanjines M, Grassani T, Gronchi A, Lasalvia P, Lindskog S, Hindi N, Ingrosso M, Ivanescu A, Jones R, Lugowska I, Ketzer J, Mariuk-Jarema A, Mazzocca A, Monteleone L, Morosi C, Napolitano A, Nardozza F, Neri E, Nilsson M, Papakonstantinou A, Pasquali S, Sbaraglia M, Scolari F, Szkandera J, Valverde C, Vincenzi B, Vizzaccaro S, Zuccheri F, Stacchiotti S, and Trama A
- Subjects
- Humans, Prospective Studies, Adult, Prognosis, Male, Female, Registries, Hemangioendothelioma, Epithelioid pathology, Hemangioendothelioma, Epithelioid mortality, Hemangioendothelioma, Epithelioid therapy, Hemangioendothelioma, Epithelioid diagnosis
- Abstract
Introduction: Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease., Study Design: Registry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE., Objectives: To improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern., Methods: Settings and participantsIt is an hospital-based registry established in centers with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for routine patient follow-up. VariablesFull details on patients and disease features, treatment and outcome will be collected, according to common clinical practice guidelines developed and shared with all the contributing centers. In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will also be collected. Statistical methodsThe data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression., Results: The registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual., Competing Interests: Anna Maria Frezza declares institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Alexia Bertuzzi declares support for attending meeting and/or travels from Pharmamar and Istituto Gentili; support for scientific activities from Istituto Gentili. Antonella Brunello declares consulting fees or serving on advisory boards for Eli Lilly, Roche, GSK, Eisai, Pharmamar, Boehringer Ingelheim, Deciphera; payment or honoraria for educational events by GSK and Pharmamar; travel grants by Pharmamar, Istituto Gentili. Giacomo G. Baldi declares consulting fees from Eli Lilly, Pharmamar, AboutEvents; honoraria from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai, IstitutoGentili; support for attending meetings and/or travels from Novartis, Pharmamar, Eli Lilly; participation on the advisory board from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai. Paolo G. Casali declares institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Virginia Ferraresi declares consultancy fees or honoraria from PharmaMar, Boehringer Ingelheim, Gentili e Serb Pharmaceuticals. Matilde Ingrosso reports institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Laura Monteleone reports institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Johanna Szkandera reports participation in advisory boards or invited speaker fees for PharmaMar, Bayer, Roche, Lilly, Amgen; travel expenses coverage from PharmaMar, Roche, Lilly, Amgen, Bristol Myers Squibb; research funding from PharmaMar, Roche, Eisai. Bruno Vincenzi reports consulting fees from Eisai, Lilly, Bayer, Deciphera, PharmaMar, Blueprint, Pfizer, GSK, Accord, Abbott and research support from PharmaMar, Novartis, Lilly Silvia Stacchiotti declares advisory board roles with Bayer, Boehringer, Daiichi, Ikena, Nec Oncology, Pharma Essentia, Regeneron, Servier; invited speaker roles for Bayer, Boehringer, Gentili, Pharmamar; institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Carlo Cicala, Lorenzo D’Ambrosio, Angelo Paolo Dei Tos, Alessandro Gronchi, Nadia Hindi, Robin Jones, Iwona Lugowska, Julia Ketzer, Anna Mariuk-Jarema, Andrea Napolitano, Andri Papakonstantinou, Sandro Pasquali, Marta Sbaraglia, Federico Scolari, Elisa Crotti, Irene Benzonelli, Jean-Yves Blay, Christophe Bouvier, Javier Martin Broto, Hugh Leonard, Ninna Aggerholm-Pedersen, Andri Papakonstantinou, Giuseppe Bianchi, Federica Zuccheri, Paolo Baili, Simone Bonfarnuzzo, Domenico Campanacci, Armelle Dufresne, Sebastian Bauer, Serena Bazzurri, Stefano Gabellini, Claudia Giani, Vincenzo Giannusa, Melissa Gil-Sanjines, Teresa Grassani, Paolo Lasalvia, Stefan Lindskog, Salvatore Vizzaccaro, Nils Dieckmann, Alessandro Mazzocca, Andrei Ivanescu, Giuseppe Badalamenti, Carlo Morosi, Stephanie Elston, Kyetil Boye, Francesca Nardozza, Elisabetta Neri, Maria Nilsson and Annalisa Trama declares no conflict of interest., (Copyright: © 2024 Frezza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
- Full Text
- View/download PDF
21. Predictive Value of MRP-1 in Localized High-Risk Soft Tissue Sarcomas: A Translational Research Associated to ISG-STS 1001 Randomized Phase III Trial.
- Author
-
Martin-Broto J, Lopez-Alvarez M, Moura DS, Ramos R, Collini P, Romagosa C, Bagué S, Renne SL, Barisella M, Velasco V, Coindre JM, Lopez-Lopez D, Dopazo J, Gambarotti M, Braglia L, Merlo DF, Palmerini E, Stacchiotti S, Quagliuolo VL, Lopez-Pousa A, Grignani G, Blay JY, Brunello A, Gutierrez A, Valverde C, Hindi N, Dei Tos AP, Picci P, Casali PG, and Gronchi A
- Subjects
- Female, Humans, Male, Multidrug Resistance-Associated Proteins pharmacology, Predictive Value of Tests, Prognosis, Multidrug Resistance-Associated Proteins therapeutic use, Sarcoma drug therapy, Translational Research, Biomedical methods
- Abstract
MRP-1 is implicated in multidrug resistance and was described as prognostic in high-risk patients with soft-tissue sarcoma (STS) in a previous study. The current research aimed to validate MRP-1 prognostic/predictive value in localized sarcomas treated with anthracyclines plus ifosfamide within the ISG-1001 phase III study. In addition, the inhibitory activity on MRP-1 was investigated in preclinical studies to identify new combinations able to increase the efficacy of standard chemotherapy in STS. MRP-1 expression was assessed by IHC in tissue microarrays from patients with STS and tested for correlation with disease-free survival (DFS) and overall survival (OS). In vitro studies tested the efficacy of MRP-1 inhibitors (nilotinib, ripretinib, selumetinib, and avapritinib) in sarcoma cell lines. The effect of combinations of the most active MRP-1 inhibitors and chemotherapy was measured on the basis of apoptosis. MRP-1 was evaluable in 231 of 264 cases who entered the study. MRP-1 expression (strong intensity) was independently associated with worse DFS [HR, 1.78; 95% confidence interval (CI), 1.11-2.83; P = 0.016], in the multivariate analysis, with a trend for a worse OS (HR, 1.78; 95% CI, 0.97-3.25; P = 0.062). In vitro studies showed that the addition of MRP-1 inhibitors (nilotinib or avapritinib) to doxorubicin plus palifosfamide, significantly increased cell death in SK-UT-1 and CP0024 cell lines. MRP-1 is an adverse predictive factor in localized high-risk patients with STS treated with neoadjuvant anthracyclines plus ifosfamide followed by surgery. In vitro findings support the clinical assessment of the combination of chemotherapy and MRP-1 inhibitors as a promising strategy to overcome the drug ceiling effect for chemotherapy., (©2021 American Association for Cancer Research.)
- Published
- 2021
- Full Text
- View/download PDF
22. A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.
- Author
-
Moura DS, Peña-Chilet M, Cordero Varela JA, Alvarez-Alegret R, Agra-Pujol C, Izquierdo F, Ramos R, Ortega-Medina L, Martin-Davila F, Castilla-Ramirez C, Hernandez-Leon CN, Romagosa C, Vaz Salgado MA, Lavernia J, Bagué S, Mayodormo-Aranda E, Vicioso L, Hernández Barceló JE, Rubio-Casadevall J, de Juan A, Fiaño-Valverde MC, Hindi N, Lopez-Alvarez M, Lacerenza S, Dopazo J, Gutierrez A, Alvarez R, Valverde C, Martinez-Trufero J, and Martín-Broto J
- Subjects
- Antineoplastic Agents, Alkylating pharmacology, Antineoplastic Agents, Alkylating therapeutic use, DNA Damage, DNA Repair genetics, Dioxoles adverse effects, Humans, Retrospective Studies, Trabectedin therapeutic use, Sarcoma drug therapy, Sarcoma genetics, Tetrahydroisoquinolines adverse effects
- Abstract
Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Published
- 2021
- Full Text
- View/download PDF
23. Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.
- Author
-
Martin-Broto J, Hindi N, Grignani G, Martinez-Trufero J, Redondo A, Valverde C, Stacchiotti S, Lopez-Pousa A, D'Ambrosio L, Gutierrez A, Perez-Vega H, Encinas-Tobajas V, de Alava E, Collini P, Peña-Chilet M, Dopazo J, Carrasco-Garcia I, Lopez-Alvarez M, Moura DS, and Lopez-Martin JA
- Subjects
- Adult, Aged, Antineoplastic Agents, Immunological pharmacology, Female, Humans, Male, Middle Aged, Nivolumab pharmacology, Sunitinib pharmacology, Young Adult, Antineoplastic Agents, Immunological therapeutic use, Nivolumab therapeutic use, Sarcoma drug therapy, Sunitinib therapeutic use
- Abstract
Background: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab)., Methods: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II)., Results: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%)., Conclusions: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. Trial registration number NCT03277924., Competing Interests: Competing interests: JM-B reports research grants from PharmaMar, Eisai, Immix BioPharma and Novartis, outside the submitted work; honoraria for advisory board participation and expert testimony from PharmaMar, Eli Lilly and Company, Bayer and Eisai; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daiichi Sankyo. NH reports grants, personal fees and non-financial support from PharmaMar, personal fees from Lilly, and grants from Eisai and Novartis, outside the submitted work, and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daiichi Sankyo. GG reports grants and personal fees from PharmaMar, grants from Novartis, and personal fees from Lilly, Pfizer, Bayer and Eisai, outside the submitted work. AR reports grants and personal fees from PharmaMar, personal fees from Lilly, Novartis, Amgen, AstraZeneca and Tesaro, grants and personal fees from Roche, and grants from Eisai, outside the submitted work. SS reports grants and personal fees from Bayer, Lilly and PharmaMar, and grants from GlaxoSmithKline, Novartis and Pfizer, outside the submitted work. EdA reports personal fees and non-financial support from Roche, BMS and PharmaMar, and personal fees from Bayer, outside the submitted work. ML-A declares institutional research grants from PharmaMar, Eisai, Immix BioPharma and Novartis, outside the submitted work. DSM reports institutional research grants from PharmaMar, Eisai, Immix BioPharma and Novartis, outside the submitted work, and travel support from PharmaMar, Eisai, Celgene, Bayer and Pfizer. JAL-M reports honoraria for advisory board participation and travel support from PharmaMar, Eli Lilly and Company, Bayer, Eisai, Novartis, BMS, MSD, Roche, Celgene, Pierre Fabre, Pfizer, GSK, Daiichi Sankyo, Amgen, and Chobani. All other authors declare no relevant relationship to disclose., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
- Full Text
- View/download PDF
24. Sarcoma European and Latin American Network (SELNET) Recommendations on Prioritization in Sarcoma Care During the COVID-19 Pandemic.
- Author
-
Martin-Broto J, Hindi N, Aguiar S Jr, Badilla-González R, Castro-Oliden V, Chacón M, Correa-Generoso R, de Álava E, Donati DM, Eriksson M, Falla-Jimenez M, German G, Gobo Silva ML, Gouin F, Gronchi A, Haro-Varas JC, Jiménez-Brenes N, Kasper B, Lopes de Mello CA, Maki R, Martínez-Delgado P, Martínez-Said H, Martinez-Tlahuel JL, Morales-Pérez JM, Muñoz-Casares FC, Nakagawa SA, Ortiz-Cruz EJ, Palmerini E, Patel S, Moura DS, Stacchiotti S, Sunyach MP, Valverde CM, Waisberg F, and Blay JY
- Subjects
- COVID-19 prevention & control, Consensus, Europe epidemiology, Humans, Latin America epidemiology, Patient Care standards, Practice Guidelines as Topic, SARS-CoV-2, Sarcoma diagnosis, COVID-19 epidemiology, Medical Oncology organization & administration, Medical Oncology standards, Sarcoma therapy
- Abstract
Background: The COVID-19 outbreak has resulted in collision between patients infected with SARS-CoV-2 and those with cancer on different fronts. Patients with cancer have been impacted by deferral, modification, and even cessation of therapy. Adaptive measures to minimize hospital exposure, following the precautionary principle, have been proposed for cancer care during COVID-19 era. We present here a consensus on prioritizing recommendations across the continuum of sarcoma patient care., Material and Methods: A total of 125 recommendations were proposed in soft-tissue, bone, and visceral sarcoma care. Recommendations were assigned as higher or lower priority if they cannot or can be postponed at least 2-3 months, respectively. The consensus level for each recommendation was classified as "strongly recommended" (SR) if more than 90% of experts agreed, "recommended" (R) if 75%-90% of experts agreed and "no consensus" (NC) if fewer than 75% agreed. Sarcoma experts from 11 countries within the Sarcoma European-Latin American Network (SELNET) consortium participated, including countries in the Americas and Europe. The European Society for Medical Oncology-Magnitude of clinical benefit scale was applied to systemic-treatment recommendations to support prioritization., Results: There were 80 SRs, 35 Rs, and 10 NCs among the 125 recommendations issued and completed by 31 multidisciplinary sarcoma experts. The consensus was higher among the 75 higher-priority recommendations (85%, 12%, and 3% for SR, R, and NC, respectively) than in the 50 lower-priority recommendations (32%, 52%, and 16% for SR, R, and NC, respectively)., Conclusion: The consensus on 115 of 125 recommendations indicates a high-level of convergence among experts. The SELNET consensus provides a tool for sarcoma multidisciplinary treatment committees during the COVID-19 outbreak., Implications for Practice: The Sarcoma European-Latin American Network (SELNET) consensus on sarcoma prioritization care during the COVID-19 era issued 125 pragmatical recommendations distributed as higher or lower priority to protect critical decisions on sarcoma care during the COVID-19 pandemic. A multidisciplinary team from 11 countries reached consensus on 115 recommendations. The consensus was lower among lower-priority recommendations, which shows reticence to postpone actions even in indolent tumors. The European Society for Medical Oncology-Magnitude of Clinical Benefit scale was applied as support for prioritizing systemic treatment. Consensus on 115 of 125 recommendations indicates a high level of convergence among experts. The SELNET consensus provides a practice tool for guidance in the decisions of sarcoma multidisciplinary treatment committees during the COVID-19 outbreak., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)
- Published
- 2020
- Full Text
- View/download PDF
25. Preclinical Activity of PI3K Inhibitor Copanlisib in Gastrointestinal Stromal Tumor.
- Author
-
García-Valverde A, Rosell J, Serna G, Valverde C, Carles J, Nuciforo P, Fletcher JA, Arribas J, Politz O, and Serrano C
- Subjects
- Animals, Apoptosis, Cell Proliferation, Female, Gastrointestinal Neoplasms enzymology, Gastrointestinal Neoplasms pathology, Gastrointestinal Stromal Tumors enzymology, Gastrointestinal Stromal Tumors pathology, Humans, Imatinib Mesylate pharmacology, Mice, Mice, Nude, Signal Transduction, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm drug effects, Gastrointestinal Neoplasms drug therapy, Gastrointestinal Stromal Tumors drug therapy, Phosphatidylinositol 3-Kinases chemistry, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Quinazolines pharmacology
- Abstract
KIT or PDGFRA gain-of-function mutations are the primary drivers of gastrointestinal stromal tumor (GIST) growth and progression throughout the disease course. The PI3K/mTOR pathway is critically involved in the transduction of KIT/PDGFRA oncogenic signaling regardless of the type of primary and secondary mutations, and therefore emerges as a relevant targetable node in GIST biology. We evaluated in GIST preclinical models the antitumor activity of copanlisib, a novel pan-class-I PI3K inhibitor with predominant activity against p110α and p110δ isoforms, as single-agent and in combination with first-line KIT inhibitor imatinib. In vitro studies undertaken in one imatinib-sensitive (GIST-T1) and two imatinib-resistant (GIST-T1/670 and GIST430/654) GIST cell models showed that single-agent copanlisib effectively suppressed PI3K pathway activation leading to decreased cell viability and proliferation in both imatinib-sensitive and -resistant cells irrespective of the type of primary or secondary KIT mutations. Simultaneous PI3K and KIT inhibition with copanlisib and imatinib resulted in enhanced impairment of cell viability in both imatinib-sensitive and -resistant GIST cell models, although apoptosis was mostly triggered in GIST-T1. Single-agent copanlisib inhibited GIST growth in vivo , and conjoined inhibition of PI3K and KIT was the most active therapeutic intervention in imatinib-sensitive GIST-T1 xenografts. IHC stain for cleaved-caspase 3 and phospho-S6 support a predominant antiproliferative effect of copanlisib in GIST. In conclusion, copanlisib has single-agent antitumor activity in GIST regardless KIT mutational status or sensitivity to imatinib. Effective KIT inhibition is necessary to achieve synergistic or additive effects with the combination of imatinib and any given PI3K/mTOR pathway inhibition., (©2020 American Association for Cancer Research.)
- Published
- 2020
- Full Text
- View/download PDF
26. Nilotinib as Coadjuvant Treatment with Doxorubicin in Patients with Sarcomas: A Phase I Trial of the Spanish Group for Research on Sarcoma.
- Author
-
Alemany R, Moura DS, Redondo A, Martinez-Trufero J, Calabuig S, Saus C, Obrador-Hevia A, Ramos R, Villar VH, Valverde C, Vaz MA, Medina J, Felipe-Abrio I, Hindi N, Taron M, and Martin-Broto J
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols adverse effects, Apoptosis drug effects, Biomarkers, Tumor, Cell Line, Tumor, Cell Proliferation drug effects, Chemotherapy, Adjuvant, Doxorubicin administration & dosage, Doxorubicin pharmacokinetics, Drug Evaluation, Preclinical, Female, Humans, Male, Mice, Neoplasm Grading, Neoplasm Staging, Pyrimidines administration & dosage, Pyrimidines pharmacokinetics, Sarcoma diagnosis, Sarcoma metabolism, Sarcoma mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Sarcoma drug therapy
- Abstract
Purpose: Nilotinib plus doxorubicin showed to be synergistic regarding apoptosis in several sarcoma cell lines. A phase I/II trial was thus designed to explore the feasibility of nilotinib as coadjuvant of doxorubicin by inhibiting MRP-1/P-gp efflux activity. The phase I part of the study is presented here. Patients and Methods: Nilotinib 400 mg/12 hours was administered in fixed dose from day 1 to 6, and doxorubicin on day 5 of each cycle. Three dose escalation levels for doxorubicin at 60, 65, and 75 mg/m
2 were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma, leiomyosarcoma, and unresectable/metastatic high-grade chondrosarcoma. Results: Thirteen patients were enrolled: 7 chondrosarcoma, 4 liposarcoma, and 2 leiomyosarcoma. In 46 cycles administered, the most relevant grade 3/4 adverse effects per patient were neutropenia 54%, febrile neutropenia 15%, and asthenia 8%. No cardiac toxicity was observed. Only one dose-limiting toxicity (febrile neutropenia) was reported in the third dose level. With regard to efficacy, 1 partial response (1 liposarcoma), 9 stable diseases (5 chondrosarcoma, 2 liposarcoma, 1 leiomyosarcoma), and 3 progressive diseases (2 chondrosarcoma and 1 leiomyosarcoma) were present. ABCB1 and ABCC1 RNA expression levels decreased by 58.47-fold and 1.47-fold, respectively, on day 5 of the cycle. Conclusions: Combination of MRP-1/P-gp inhibitor, nilotinib, as coadjuvant with doxorubicin is feasible; it appears not to add substantial toxicity compared with doxorubicin alone. Pharmacodynamic study supports this concept. The recommended dose for the phase II part for doxorubicin was 75 mg/m2 Clin Cancer Res; 24(21); 5239-49. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
- Full Text
- View/download PDF
27. Prognostic Significance of Venous Thromboembolic Events in Disseminated Germ Cell Cancer Patients.
- Author
-
Gonzalez-Billalabeitia E, Castellano D, Sobrevilla N, Guma J, Hervas D, Luengo MI, Aparicio J, Sanchez-Muñoz A, Mellado B, Saenz A, Valverde C, Fernandez A, Margeli M, Duran I, Fernandez S, Sastre J, Ros S, Maroto P, Manneh R, Cerezuela P, Carmona-Bayonas A, Ayala de la Peña F, Luis Aguilar J, Rivera S, García Del Muro X, and Germà-Lluch JR
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bleomycin administration & dosage, Child, Cisplatin administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasms, Germ Cell and Embryonal diagnosis, Neoplasms, Germ Cell and Embryonal drug therapy, Neoplasms, Germ Cell and Embryonal pathology, Prognosis, Proportional Hazards Models, Registries, Survival Rate, Young Adult, Neoplasms, Germ Cell and Embryonal complications, Venous Thromboembolism complications
- Abstract
Background: Disseminated germ cell cancers are at high risk of developing thromboembolic complications. We evaluated the prognostic value of venous thromboembolic events (VTE) in disseminated germ cell cancer., Methods: Patients with germ cell cancer receiving upfront platinum-containing chemotherapy between 2004 and 2014 were pooled from the Spanish Germ Cell Cancer Group (SGCCG) registry and reviewed for the presence of VTE. Results were validated in an independent international group of patients. We used a penalized Cox proportional hazards model including VTE as a time-varying covariate to identify and validate prognostic factors. All statistical tests were two-sided., Results: The SGCCG registry identified 416 patients from 14 referral institutions. With a median follow-up of 49 months, VTEs were observed in 9% of patients (n = 38). Events occurred at diagnosis, during chemotherapy, and after chemotherapy in 2.6%, 5.0%, and 1.4% of patients, respectively. VTE was associated with shorter progression-free survival (PFS; hazard ratio [HR] = 2.29, 95% confidence interval [CI] = 1.18 to 4.47, P = .02) and overall survival (OS; HR = 5.14, 95% CI = 2.22 to 11.88, P < .001). In multivariable analysis, the effect was consistent in the intermediate-risk group, both for PFS (HR = 9.52 95% CI = 2.48 to 36.58, P < .001) and OS (HR = 12.84, 95% CI = 2.01 to 82.02, P = .007). VTE at diagnosis is also an adverse prognostic variable for progression-free survival (HR = 4.64, 95% CI = 2.04 to 10.54, P < .001) and for overall survival (HR = 6.28, 95% CI = 1.68 to 17.10, P = .01). These results were validated in an independent international cohort that included 241 patients from four hospitals., Conclusions: VTE is an independent adverse prognostic factor in disseminated germ cell cancers, in particular for the intermediate prognostic group of the International Germ Cell Cancer Collaborative Group classification. The presence of VTE at diagnosis has also prognostic significance and should be further explored in future prognostic classifications., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2017
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.