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3. A phase II study of pembrolizumab in combination with doxorubicin in advanced, recurrent or metastatic endometrial cancer

Author

R. Serrano, J.M. Piulats Rodriguez, M Ocariz Diez, Ignacio A. Romero, Andrés Redondo, A. Yubero Esteban, A. González Martín, M J Rubio Perez, A. Gallego Martínez, Jesús García-Donas, M. Gil Martin, L. Fariñas Madrid, Ana Oaknin, M D Fenor De La Maza Lopez Olmedo, V. Rodriguez Freixinos, and M.L. Sanchez Lorenzo

Subjects
business.industry, Hematology, Management, Oncology, Honorarium, Advanced disease, Overall survival, Medicine, In patient, Until Disease Progression, business, Objective response, Metastatic endometrial cancer, Predictive biomarker
Abstract

Background New approaches are needed for patients with advanced endometrial cancer (EC) since there is no standard second-line therapy after failure to platinum-based chemotherapy. The TCGA subtypes, POLE and MSI, show high tumour mutation burden (TMB) that correlates with PD-L1 expression. Pembrolizumab (anti-PD-1 antibody) conferred a 13% objective response rate (ORR) in patients with advanced EC whose tumors expressed PD-L1. However, the majority of patients with advanced disease belong to the serous-like or CN-low subtypes, with fewer potential neoantigens and may experience less benefit from immunotherapy. We hypothesize that combining pembrolizumab with an inducer of immunogenic cell death such as doxorubicin could improve clinical responses in all EC subtypes. The purpose of this trial is to determine the efficacy/safety of the combination and to identify predictive biomarkers of response. Trial design This investigator-initiated, single-arm, multicenter, phase 2 study aims to enroll 41 to 51 patients with relapsed/metastatic EC (endometrioid, serous, squamous, clear-cell, and an exploratory cohort of carcinosarcoma). Patients must have received one prior line of platinum-based chemotherapy, have an ECOG PS ≤ 1, and tumor specimen available for biomarker analysis. Patients will receive IV doxorubicin (60 mg/m2) plus IV pembrolizumab (200 mg) every 3 weeks up to 9 cycles; treatment with pembrolizumab will continue in 3-week cycles until disease progression, unacceptable toxicity, or 35 administrations (approximately 2 years). The primary endpoint is investigator assessed progression-free survival (PFS) rate by RECIST v1.1 at 6 months. Key secondary endpoints include duration of response, PFS, ORR, overall survival, and the association with TCGA subtypes. An exploratory translational analysis will be also performed on tumour samples to investigate genetic predictors of response, such as distribution of PD-L1, tumour-stroma immune-regulatory gene expression, and TMB.The study is actively recruiting. At the time of submission, the safety run-in part with 6 patients had been completed with no safety concerns and 30 patients enrolled. Clinical trial information: NCT03276013. Legal entity responsible for the study Vall d’Hebron Institute of Oncology (VHIO). Funding MSD. Disclosure A. Oaknin: Full / Part-time employment: Vall d’Hebron Univeristy Hospital; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Travel / Accommodation / Expenses: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Immunogen; Advisory / Consultancy: Genmab. L. Farinas Madrid: Advisory / Consultancy: Tesaro; Speaker Bureau / Expert testimony: Roche. A. Redondo: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Eisai. A. Gonzalez Martin: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Clovis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Speaker Bureau / Expert testimony: PharmaMar; Advisory / Consultancy: GenMab. I. Romero: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Clovis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Tesaro; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: PharmaMar. J. Garcia-Donas: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: GammaMabs; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol Meiers; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Squibb; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BioClin. A. Gallego Martinez: Advisory / Consultancy: PharmaMar; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Tesaro. M.D. Fenor de la Maza Lopez Olmedo: Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (institution): Pierre Fabre; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Janssen. V. Rodriguez Freixinos: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: PharmaMar. J.M. Piulats Rodriguez: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy: Roche; Advisory / Consultancy: BeiGene; Advisory / Consultancy: VCN Biosciences; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.

Published
2019
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4. A phase II study of pembrolizumab in combination with doxorubicin in advanced, recurrent or metastatic endometrial cancer

Author

Oaknin, A., primary, Perez, M J Rubio, additional, Madrid, L Fariñas, additional, Redondo, A., additional, Esteban, A Yubero, additional, Martín, M Gil, additional, Martín, A González, additional, Romero, I., additional, Garcia-Donas, J., additional, Serrano, R., additional, Martínez, A Gallego, additional, Diez, M Ocariz, additional, Lorenzo, M L Sanchez, additional, De La Maza Lopez Olmedo, M D Fenor, additional, Freixinos, V Rodriguez, additional, and Rodriguez, J M Piulats, additional

Published
2019
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5. Impact of cigarette smoking on Volatile Organic Compound (VOC) blood levels in the U.S. Population: NHANES 2003–2004

Author

Benjamin C. Blount, David M. Chambers, Jessica M. Ocariz, and Maureen F. McGuirk

Subjects
National Health and Nutrition Examination Survey, Population, Xylenes, Ethylbenzene, chemistry.chemical_compound, Cigarette smoking, Interquartile range, Environmental health, Linear regression, Benzene Derivatives, Humans, Cigarette smoke, Volatile organic compound, education, Styrene, lcsh:Environmental sciences, General Environmental Science, chemistry.chemical_classification, lcsh:GE1-350, Air Pollutants, Volatile Organic Compounds, education.field_of_study, Chemistry, Smoking, Benzene, Environmental Exposure, Nutrition Surveys, United States, Environmental chemistry, Tobacco Smoke Pollution, Toluene
Abstract

The impact of cigarette smoking on volatile organic compound (VOC) blood levels is studied using 2003–2004 National Health and Nutrition Examination Survey (NHANES) data. Cigarette smoke exposure is shown to be a predominant source of benzene, toluene, ethylbenzene, xylenes and styrene (BTEXS) measured in blood as determined by (1) differences in central tendency and interquartile VOC blood levels between daily smokers [≥1 cigarette per day (CPD)] and less-than-daily smokers, (2) correlation among BTEXS and the 2,5-dimethylfuran (2,5-DMF) smoking biomarker in the blood of daily smokers, and (3) regression modeling of BTEXS blood levels versus categorized CPD. Smoking status was determined by 2,5-DMF blood level using a cutpoint of 0.014 ng/ml estimated by regression modeling of the weighted data and confirmed with receiver operator curve (ROC) analysis. The BTEXS blood levels among daily smokers were moderately-to-strongly correlated with 2,5-DMF blood levels (correlation coefficient, r, ranging from 0.46 to 0.92). Linear regression of the geometric mean BTEXS blood levels versus categorized CPD showed clear dose–response relationship (correlation of determination, R2, ranging from 0.81 to 0.98). Furthermore, the pattern of VOCs in blood of smokers is similar to that reported in mainstream cigarette smoke. These results show that cigarette smoking is a primary source of benzene, toluene and styrene and an important source of ethylbenzene and xylene exposure for the U.S. population, as well as the necessity of determining smoking status and factors affecting dose (e.g., CPD, time since last cigarette) in assessments involving BTEXS exposure. Keywords: Benzene, Toluene, Ethylbenzene, Xylene (BTEX), Blood, Cigarette smoke, National Health and Nutrition Examination Survey (NHANES), Volatile organic compound (VOC)

Published
2011

6. [PRIMARY ADENOCARCINOMA OF THE APPENDIX]

Author

M, CUESTASILVA, A, HEIDENREICH, and M, OCARIZ

Subjects
Radiography, Appendiceal Neoplasms, Surgical Procedures, Operative, Pathology, Appendectomy, Humans, Neoplasms, Glandular and Epithelial, Adenocarcinoma, Appendix
Published
1963

8. PD-1 is expressed in cytotoxic granules of NK cells and rapidly mobilized to the cell membrane following recognition of tumor cells.

Author

Pesini C, Hidalgo S, Arias MA, Santiago L, Calvo C, Ocariz-Díez M, Isla D, Lanuza PM, Agustín MJ, Galvez EM, Ramírez-Labrada A, and Pardo J

Subjects
Cell Membrane metabolism, Humans, Immunotherapy, Killer Cells, Natural metabolism, Lymphocyte Activation, Antineoplastic Agents, Neoplasms
Abstract

The contribution of the T cell-related inhibitory checkpoint PD-1 to the regulation of NK cell activity is still not clear with contradictory results concerning its expression and role in the modulation of NK cell cytotoxicity. We provide novel key findings on the mechanism involved in the regulation of PD-1 expression on NK cell membrane and its functional consequences for the elimination of cancer cells. In contrast to freshly isolated NK cells from cancer patients, those from healthy donors did not express PD-1 on the cell membrane. However, when healthy NK cells were incubated with tumor target cells, membrane PD-1 expression increased, concurrent with the CD107a surface mobilization. This finding suggested that PD-1 was translocated to the cell membrane during NK cell degranulation after contact with target cells. Indeed, cytosolic PD-1 was expressed in freshly-isolated-NK cells and partly co-localized with CD107a and GzmB, confirming that membrane PD-1 corresponded to a pool of preformed PD-1. Moreover, NK cells that had mobilized PD-1 to the cell membrane presented a significantly reduced anti-tumor activity on PD-L1-expressing-tumor cells in vitro and in vivo , which was partly reversed by using anti-PD-1 blocking antibodies. Our results indicate that NK cells from healthy individuals express cytotoxic granule-associated PD-1, which is rapidly mobilized to the cell membrane after interaction with tumor target cells. This novel finding helps to understand how PD-1 expression is regulated on NK cell membrane and the functional consequences of this expression during the elimination of tumor cells, which will help to design more efficient NK cell-based cancer immunotherapies., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Published
2022
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9. How Could Antibiotics, Probiotics, and Corticoids Modify Microbiota and Its Influence in Cancer Immune Checkpoint Inhibitors: A Review.

Author

Cruellas M, Yubero A, Zapata M, Galvez EM, Gascón M, Isla D, Lastra R, Martínez-Lostao L, Ocariz M, Pardo J, Ramírez A, Sesma A, Torres-Ramón I, and Paño JR

Subjects
Adrenal Cortex Hormones therapeutic use, Animals, Anti-Bacterial Agents therapeutic use, Humans, Immune Checkpoint Inhibitors pharmacology, Immunomodulation drug effects, Microbial Interactions drug effects, Microbial Interactions immunology, Neoplasms etiology, Treatment Outcome, Adrenal Cortex Hormones pharmacology, Anti-Bacterial Agents pharmacology, Host Microbial Interactions drug effects, Host Microbial Interactions immunology, Immune Checkpoint Inhibitors therapeutic use, Microbiota drug effects, Neoplasms drug therapy, Probiotics
Abstract

Immunotherapy has become a new paradigm in oncology, improving outcomes for several types of cancer. However, there are some aspects about its management that remain uncertain. One of the key points that needs better understanding is the interaction between immunotherapy and gut microbiome and how modulation of the microbiome might modify the efficacy of immunotherapy. Consequently, the negative impact of systemic antibiotics and corticosteroids on the efficacy of immunotherapy needs to be clarified.

Published
2021
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10. [PRIMARY ADENOCARCINOMA OF THE APPENDIX].

Author

CUESTASILVA M, HEIDENREICH A, and OCARIZ M

Subjects
Humans, Adenocarcinoma, Appendectomy, Appendiceal Neoplasms, Appendix, Neoplasms, Glandular and Epithelial, Pathology, Radiography, Surgical Procedures, Operative
Published
1963

11. [Obstructive complications of transvesicular adenomectomy].

Author

Sanchez Sañudo L, Marquez F, Ponte L, Ocariz M, and Bartolucci J

Subjects
Humans, Male, Ureteral Obstruction etiology, Postoperative Complications, Prostatic Hyperplasia surgery, Urinary Bladder Neck Obstruction etiology
Published
1969

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