المؤلفون: Patel, Sandip, Alonso-Gordoa, Teresa, Banerjee, Susana, Wang, Ding, Naidoo, Jarushka, Standifer, Nathan, Palmer, Doug, Cheng, Lin-Yang, Kourtesis, Panagiotis, Ascierto, Maria, Das, Mayukh, Diamond, Jennifer, Hellmann, Matthew, Carneiro, Benedito

المصدر: Journal for ImmunoTherapy of Cancer. 12(2)

مصطلحات موضوعية: Adaptive Immunity, Immunity, Innate, Natural Killer T-Cells, Programmed Cell Death 1 Receptor, Tumor Microenvironment, Female, Humans, Adolescent, Adult, Carcinoma, Non-Small-Cell Lung, Ligands, Lung Neoplasms, Tumor Microenvironment, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized

الوصف: BACKGROUND: The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors. MAIN BODY: Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8+ T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8+ and granzyme B+ cells were observed. CONCLUSIONS: Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME. TRIAL REGISTRATION NUMBER: NCT02671435.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2888m63bTest

المؤلفون: Patel, Sandip P, Alonso-Gordoa, Teresa, Banerjee, Susana, Wang, Ding, Naidoo, Jarushka, Standifer, Nathan E, Palmer, Doug C, Cheng, Lin-Yang, Kourtesis, Panagiotis, Ascierto, Maria L, Das, Mayukh, Diamond, Jennifer R, Hellmann, Matthew D, Carneiro, Benedito A

المصدر: Hematology/Oncology Articles

مصطلحات موضوعية: Female, Humans, Adolescent, Adult, Carcinoma, Non-Small-Cell Lung, Ligands, Lung Neoplasms, Tumor Microenvironment, Antibodies, Monoclonal, Humanized

الوصف: BACKGROUND: The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors. MAIN BODY: Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8(+) T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif ...

العلاقة: https://scholarlycommons.henryford.com/hematologyoncology_articles/347Test; http://sfxhosted.exlibrisgroup.com/hfhs?sid=Entrez:PubMed&id=pmid:38309722Test

الإتاحة: https://scholarlycommons.henryford.com/hematologyoncology_articles/347Test
http://sfxhosted.exlibrisgroup.com/hfhs?sid=Entrez:PubMed&id=pmid:38309722Test

المؤلفون: McDermott, David F., Lee, Jae Lyun, Bjarnason, Georg A., Larkin, James M.G., Gafanov, Rustem A., Kochenderfer, Mark D., Jensen, Niels Viggo, Donskov, Frede, Malik, Jahangeer, Poprach, Alexandr, Tykodi, Scott S., Alonso-Gordoa, Teresa, Cho, Daniel C., Geertsen, Poul F., Climent Duran, Miguel Angel, DiSimone, Christopher, Silverman, Rachel Kloss, Perini, Rodolfo F., Schloss, Charles, Atkins, Michael B.

المصدر: McDermott , D F , Lee , J L , Bjarnason , G A , Larkin , J M G , Gafanov , R A , Kochenderfer , M D , Jensen , N V , Donskov , F , Malik , J , Poprach , A , Tykodi , S S , Alonso-Gordoa , T , Cho , D C , Geertsen , P F , Climent Duran , M A , DiSimone , C , Silverman , R K , Perini , R F , Schloss , C & Atkins , M B 2021 , ' Open-Label, ....

مصطلحات موضوعية: Adult, Aged, 80 and over, Antibodies, Monoclonal, Humanized/therapeutic use, Antineoplastic Agents, Immunological/therapeutic use, Carcinoma, Renal Cell/drug therapy, Female, Follow-Up Studies, Humans, Kidney Neoplasms/drug therapy, Male, Middle Aged, Non-Randomized Controlled Trials as Topic, Prognosis, Survival Rate

الوصف: PURPOSE: Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS: In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS: In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION: Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.

وصف الملف: application/pdf

العلاقة: https://pure.au.dk/portal/en/publications/bae5aee9-7f1b-4552-855b-cfdb62d318f9Test

الإتاحة: https://doi.org/10.1200/JCO.20.02363Test
https://pure.au.dk/portal/en/publications/bae5aee9-7f1b-4552-855b-cfdb62d318f9Test
https://pure.au.dk/ws/files/274416924/jco.20.02363.pdfTest
http://www.scopus.com/inward/record.url?scp=85103228704&partnerID=8YFLogxKTest

المؤلفون: Motzer, Robert, Alekseev, Boris, Rha, Sun-Young, Porta, Camillo, Eto, Masatoshi, Powles, Thomas, Grünwald, Viktor, Hutson, Thomas E, Kopyltsov, Evgeny, Méndez-Vidal, María J, Kozlov, Vadim, Alyasova, Anna, Hong, Sung-Hoo, Kapoor, Anil, Alonso Gordoa, Teresa, Merchan, Jaime R, Winquist, Eric, Maroto, Pablo, Goh, Jeffrey C, Kim, Miso, Gurney, Howard, Patel, Vijay, Peer, Avivit, Procopio, Giuseppe, Takagi, Toshio, Melichar, Bohuslav, Rolland, Frederic, De Giorgi, Ugo, Wong, Shirley, Bedke, Jens, Schmidinger, Manuela, Dutcus, Corina E, Smith, Alan D, Dutta, Lea, Mody, Kalgi, Perini, Rodolfo F, Xing, Dongyuan, Choueiri, Toni K, Galamaga, Rob

المصدر: ENT and Skull Base Surgery

مصطلحات موضوعية: Adult, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Renal Cell, Everolimus, Female, Humans, Kidney Neoplasms, Male, Middle Aged, Phenylurea Compounds, Programmed Cell Death 1 Receptor, Progression-Free Survival, Protein Kinase Inhibitors, Quinolines, Sunitinib, Survival Analysis

الوصف: BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

العلاقة: https://scholar.barrowneuro.org/ent-and-skull-base-surgery/23Test

الإتاحة: https://doi.org/10.1056/NEJMoa2035716Test
https://scholar.barrowneuro.org/ent-and-skull-base-surgery/23Test

المؤلفون: Carmona-Bayonas, Alberto, Jiménez-Fonseca, Paula, Lamarca, Ángela, Barriuso, Jorge, Castaño, Ángel, Benavent, Marta, Alonso, Vicente, Riesco-Martínez, María Del Carmen, Alonso-Gordoa, Teresa, Custodio, Ana, Sánchez Cánovas, Manuel, Hernando Cubero, Jorge, López, Carlos, Lacasta, Adelaida, Fernández Montes, Ana, Marazuela, Mónica, Crespo, Guillermo, Escudero, Pilar, Diaz, José Ángel, Feliciangeli, Eduardo, Gallego, Javier, Llanos, Marta, Segura, Ángel, Vilardell, Felip, Percovich, Juan Carlos, Grande, Enrique, Capdevila, Jaume, Valle, Juan W, García-Carbonero, Rocío

مصطلحات موضوعية: Adolescent, Adult, Cohort Studies, Female, Hormones, Humans, Male, Neuroendocrine Tumors, Progression-Free Survival, Retrospective Studies, Somatostatin, Survival Analysis, Young Adult

الوصف: Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in ...

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/10668/14373Test; PMC6768612; https://doi.org/10.1200/jco.19.00980Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768612/pdfTest

الإتاحة: https://doi.org/10.1200/JCO.19.00980Test
https://doi.org/10.1200/jco.19.00980Test
http://hdl.handle.net/10668/14373Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768612/pdfTest

المؤلفون: Solis-Hernandez, Mª Pilar, Fernandez Del Valle, Ana, Carmona-Bayonas, Alberto, Garcia-Carbonero, Rocio, Custodio, Ana, Benavent, Marta, Alonso Gordoa, Teresa, Nuñez-Valdovino, Bárbara, Sanchez Canovas, Manuel, Matos, Ignacio, Alonso, Vicente, Lopez, Carlos, Viudez, Antonio, Izquierdo, Marta, Calvo-Temprano, David, Grande, Enrique, Capdevila, Jaume, Jimenez-Fonseca, Paula

مصطلحات موضوعية: Adult, Aged, 80 and over, Antineoplastic Agents, Confidence Intervals, Female, Humans, Male, Middle Aged, Neuroendocrine Tumors, Pancreatic Neoplasms, Progression-Free Survival, Proportional Hazards Models, Prospective Studies, Response Evaluation Criteria in Solid Tumors, Sunitinib, Tomography, X-Ray Computed, Tumor Burden, Young Adult

الوصف: The purpose of our study was to analyse the usefulness of Choi criteria versus RECIST in patients with pancreatic neuroendocrine tumours (PanNETs) treated with sunitinib. A multicentre, prospective study was conducted in 10 Spanish centres. Computed tomographies, at least every 6 months, were centrally evaluated until tumour progression. One hundred and seven patients were included. Median progression-free survival (PFS) by RECIST and Choi were 11.42 (95% confidence interval [CI], 9.7-15.9) and 15.8 months (95% CI, 13.9-25.7). PFS by Choi (Kendall's τ = 0.72) exhibited greater correlation with overall survival (OS) than PFS by RECIST (Kendall's τ = 0.43). RECIST incorrectly estimated prognosis in 49.6%. Partial response rate increased from 12.8% to 47.4% with Choi criteria. Twenty-four percent of patients with progressive disease according to Choi had stable disease as per RECIST, overestimating treatment effect. Choi criteria predicted PFS/OS. Changes in attenuation occurred early and accounted for 21% of the variations in tumour volume. Attenuation and tumour growth rate (TGR) were associated with improved survival. Choi criteria were able to capture sunitinib's activity in a clinically significant manner better than RECIST; their implementation in standard clinical practice shall be strongly considered in PanNET patients treated with this drug.

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/10668/14466Test; PMC6889276; https://www.nature.com/articles/s41416-019-0558-7.pdfTest; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889276/pdfTest

الإتاحة: https://doi.org/10.1038/s41416-019-0558-7Test
http://hdl.handle.net/10668/14466Test
https://www.nature.com/articles/s41416-019-0558-7.pdfTest
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889276/pdfTest

المؤلفون: Ruiz-Pinto, Sara, Pita, Guillermo, Martín, Miguel, Alonso-Gordoa, Teresa, Barnes, Daniel R, Alonso, María R, Herraez, Belén, García-Miguel, Purificación, Alonso, Javier, Pérez-Martínez, Antonio, Cartón, Antonio J, Gutiérrez-Larraya, Federico, García-Sáenz, José A, Benítez, Javier, Easton, Douglas F, Patiño-García, Ana, González-Neira, Anna

مصطلحات موضوعية: Anthracyclines, Chronic cardiotoxicity, ETFB, Long-term cancer survivors, Low-frequency variants, Adult, Aged, Breast Neoplasms, Cancer Survivors, Cardiotoxicity, Electron-Transferring Flavoproteins, Exome, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Heart Failure, Humans, Middle Aged, Mitochondria

الوصف: PURPOSE: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial β-oxidation and ATP production (P = 4.16 × 10-4) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10-4, 95% CI 2.83-28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.

وصف الملف: Print-Electronic; application/pdf

العلاقة: https://www.repository.cam.ac.uk/handle/1810/271330Test

الإتاحة: https://doi.org/10.17863/CAM.17690Test
https://www.repository.cam.ac.uk/handle/1810/271330Test