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2. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study

Author

Wierda, William G, Shah, Nirav N, Cheah, Chan Y, Lewis, David, Hoffmann, Marc S, Coombs, Catherine C, Lamanna, Nicole, Ma, Shuo, Jagadeesh, Deepa, Munir, Talha, Wang, Yucai, Eyre, Toby A, Rhodes, Joanna M, McKinney, Matthew, Lech-Maranda, Ewa, Tam, Constantine S, Jurczak, Wojciech, Izutsu, Koji, Alencar, Alvaro J, Patel, Manish R, Seymour, John F, Woyach, Jennifer A, Thompson, Philip A, Abada, Paolo B, Ho, Caleb, McNeely, Samuel C, Marella, Narasimha, Nguyen, Bastien, Wang, Chunxiao, Ruppert, Amy S, Nair, Binoj, Liu, Hui, Tsai, Donald E, Roeker, Lindsey E, and Ghia, Paolo

Published
2024
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5. Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2

Author

Kudo, Masatoshi, Galle, Peter R., Brandi, Giovanni, Kang, Yoon-Koo, Yen, Chia-Jui, Finn, Richard S., Llovet, Josep M., Assenat, Eric, Merle, Philippe, Chan, Stephen L., Palmer, Daniel H., Ikeda, Masafumi, Yamashita, Tatsuya, Vogel, Arndt, Huang, Yi-Hsiang, Abada, Paolo B., Yoshikawa, Reigetsu, Shinozaki, Kenta, Wang, Chunxiao, Widau, Ryan C., and Zhu, Andrew X.

Published
2021
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7. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Zhu, Andrew X, Kang, Yoon-Koo, Yen, Chia-Jui, Finn, Richard S, Galle, Peter R, Llovet, Josep M, Assenat, Eric, Brandi, Giovanni, Pracht, Marc, Lim, Ho Yeong, Rau, Kun-Ming, Motomura, Kenta, Ohno, Izumi, Merle, Philippe, Daniele, Bruno, Shin, Dong Bok, Gerken, Guido, Borg, Christophe, Hiriart, Jean-Baptiste, Okusaka, Takuji, Morimoto, Manabu, Hsu, Yanzhi, Abada, Paolo B, and Kudo, Masatoshi

Published
2019
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8. Cisplatin induces resistance by triggering differentiation of testicular embryonal carcinoma cells.

Author

Abada, Paolo B and Howell, Stephen B

Subjects
Cell Line, Tumor, Humans, Neoplasms, Germ Cell and Embryonal, Testicular Neoplasms, Cisplatin, Tretinoin, Homeodomain Proteins, Fibronectins, Membrane Proteins, Blotting, Western, Cell Differentiation, Cell Survival, Drug Resistance, Neoplasm, Male, Octamer Transcription Factor-3, Real-Time Polymerase Chain Reaction, Nestin, Nanog Homeobox Protein, Rare Diseases, Cancer, Stem Cell Research, Urologic Diseases, Cell Line, Tumor, Neoplasms, Germ Cell and Embryonal, Blotting, Western, Drug Resistance, Neoplasm, General Science & Technology
Abstract

Although testicular germ cell tumors are generally quite responsive to treatment with cisplatin, a small fraction of them acquire resistance during therapy. Even when cisplatin treatment is successful the patient is often left with a residual teratoma at the site of the primary tumor suggesting that cisplatin may trigger differentiation in some tumors. Using the human embryonal carcinoma cell line NTera2/D1, we confirmed that exposure to the differentiating agent retinoic acid produced a reduction in pluripotency markers NANOG and POU5F1 (Oct3/4) and an acute concentration-dependent increase in resistance to both cisplatin and paclitaxel that reached as high as 18-fold for cisplatin and 61-fold for paclitaxel within four days. A two day exposure to cisplatin also produced a concentration-dependent decrease in the expression of the NANOG and POU5F1 and increased expression of three markers whose levels increase with differentiation including Nestin, SCG10 and Fibronectin. In parallel, exposure to cisplatin induced up to 6.2-fold resistance to itself and 104-fold resistance to paclitaxel. Paclitaxel did not induce differentiation or resistance to either itself or cisplatin. Neither retinoic acid nor cisplatin induced resistance in cervical or prostate cancer cell lines or other germ cell tumor lines in which they failed to alter the expression of NANOG and POU5F1. Forced expression of NANOG prevented the induction of resistance to cisplatin by retinoic acid. We conclude that cisplatin can acutely induce resistance to itself and paclitaxel by triggering a differentiation response in pluripotent germ cell tumor cells.

Published
2014

9. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study

Author

Chau, Ian, Peck-Radosavljevic, Markus, Borg, Christophe, Malfertheiner, Peter, Seitz, Jean Francois, Park, Joon Oh, Ryoo, Baek-Yeol, Yen, Chia-Jui, Kudo, Masatoshi, Poon, Ronnie, Pastorelli, Davide, Blanc, Jean-Frederic, Chung, Hyun Cheol, Baron, Ari D., Okusaka, Takuji, Bowman, L., Cui, Zhanglin Lin, Girvan, Allicia C., Abada, Paolo B., Yang, Ling, and Zhu, Andrew X.

Published
2017
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10. Alpha-fetoprotein kinetics in patients with hepatocellular carcinoma receiving ramucirumab or placebo: an analysis of the phase 3 REACH study

Author

Chau, Ian, Park, Joon Oh, Ryoo, Baek-Yeol, Yen, Chia-Jui, Poon, Ronnie, Pastorelli, Davide, Blanc, Jean-Frédéric, Kudo, Masatoshi, Pfiffer, Tulio, Hatano, Etsuro, Chung, Hyun Cheol, Kopeckova, Katerina, Phelip, Jean-Marc, Brandi, Giovanni, Ohkawa, Shinichi, Li, Chung-Pin, Okusaka, Takuji, Hsu, Yanzhi, Abada, Paolo B., and Zhu, Andrew X.

Published
2018
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11. Abstract CT167: Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: Results from the phase 1/2 BRUIN study

Author

Rhodes, Joanna, primary, Lewis, David, additional, Ghia, Paolo, additional, Shah, Nirav N., additional, Coombs, Catherine C., additional, Cheah, Chan Y., additional, Woyach, Jennifer, additional, Lamanna, Nicole, additional, Hoffmann, Marc S., additional, Ma, Shuo, additional, Eyre, Toby A., additional, Munir, Talha, additional, Patel, Manish R., additional, Alencar, Alvaro J., additional, Tam, Constantine S., additional, Seymour, John F., additional, Jurczak, Wojciech, additional, Lech-Maranda, Ewa, additional, Roeker, Lindsey E., additional, Thompson, Philip A., additional, Abada, Paolo B., additional, Wang, Chunxiao, additional, Nair, Binoj, additional, Liu, Hui, additional, Tsai, Donald E., additional, Mato, Anthony R., additional, and Wierda, William G., additional

Published
2023
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12. Pirtobrutinib preclinical characterization: a highly selective, non-covalent (reversible) BTK inhibitor

Author

Gomez, Eliana B, primary, Ebata, Kevin, additional, Randeria, Hetal S, additional, Rosendahl, Mary S, additional, Cedervall, Ernst Peder, additional, Morales, Tony H, additional, Hanson, Lauren M, additional, Brown, Nicholas E, additional, Gong, Xueqian, additional, Stephens, Jennifer Rachelle, additional, Wu, Wenjuan, additional, Lippincott, Isabel, additional, Ku, Karin S., additional, Walgren, Richard A, additional, Abada, Paolo B, additional, Ballard, Joshua A, additional, Allerston, Charles K, additional, and Brandhuber, Barbara J, additional

Published
2023
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13. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

Author

Zhu, Andrew X, Park, Joon Oh, Ryoo, Baek-Yeol, Yen, Chia-Jui, Poon, Ronnie, Pastorelli, Davide, Blanc, Jean-Frederic, Chung, Hyun Cheol, Baron, Ari D, Pfiffer, Tulio Eduardo Flesch, Okusaka, Takuji, Kubackova, Katerina, Trojan, Jorg, Sastre, Javier, Chau, Ian, Chang, Shao-Chun, Abada, Paolo B, Yang, Ling, Schwartz, Jonathan D, and Kudo, Masatoshi

Published
2015
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15. Efficacy of Pirtobrutinib in Covalent BTK-Inhibitor Pre-Treated Relapsed / Refractory CLL/SLL: Additional Patients and Extended Follow-up from the Phase 1/2 BRUIN Study

Author

Mato, Anthony R., primary, Woyach, Jennifer A., additional, Brown, Jennifer R., additional, Ghia, Paolo, additional, Patel, Krish, additional, Eyre, Toby A., additional, Munir, Talha, additional, Lech-Marańda, Ewa, additional, Lamanna, Nicole, additional, Tam, Constantine S., additional, Seymour, John F., additional, Shah, Nirav N., additional, Coombs, Catherine C., additional, Ujjani, Chaitra S., additional, Patel, Manish R., additional, Fakhri, Bita, additional, Cheah, Chan Y., additional, Alencar, Alvaro J., additional, Cohen, Jonathon B., additional, Gerson, James N., additional, Flinn, Ian W., additional, Ma, Shuo, additional, Jagadeesh, Deepa, additional, Rhodes, Joanna M., additional, Hernandez-Ilizaliturri, Francisco, additional, Zinzani, Pier Luigi, additional, Balbas, Minna, additional, Nair, Binoj, additional, Abada, Paolo B., additional, Wang, Chunxiao, additional, Wang, Denise, additional, Tsai, Donald E., additional, Wierda, William G., additional, and Jurczak, Wojciech, additional

Published
2022
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16. Efficacy of Pirtobrutinib in Covalent BTK-Inhibitor Pre-Treated Relapsed / Refractory Mantle Cell Lymphoma: Additional Patients and Extended Follow-up from the Phase 1/2 BRUIN Study

Author

Wang, Michael L., primary, Shah, Nirav N., additional, Jurczak, Wojciech, additional, Zinzani, Pier Luigi, additional, Eyre, Toby A., additional, Cheah, Chan Y., additional, Ujjani, Chaitra S., additional, Koh, Youngil, additional, Izutsu, Koji, additional, Gerson, James N., additional, Flinn, Ian W., additional, Tessoulin, Benoit, additional, Alencar, Alvaro J., additional, Ma, Shuo, additional, Lech-Marańda, Ewa, additional, Rhodes, Joanna M., additional, Patel, Krish, additional, Woyach, Jennifer A., additional, Lamanna, Nicole, additional, Wang, Yucai, additional, Tam, Constantine S., additional, Seymour, John F., additional, Munir, Talha, additional, Nagai, Hirokazu, additional, Hernandez-Ilizaliturri, Francisco, additional, Kumar, Anita, additional, Zelenetz, Andrew D., additional, Jain, Preetesh, additional, Nair, Binoj, additional, Tsai, Donald E., additional, Balbas, Minna, additional, Walgren, Richard A., additional, Abada, Paolo B., additional, Wang, Chunxiao, additional, Zhao, Junjie, additional, and Mato, Anthony R., additional

Published
2022
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17. Efficacy of Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Richter Transformation: Results from the Phase 1/2 BRUIN Study

Author

Wierda, William G., primary, Lewis, David John, additional, Ghia, Paolo, additional, Shah, Nirav N., additional, Coombs, Catherine C., additional, Cheah, Chan Y., additional, Lamanna, Nicole, additional, Rhodes, Joanna M., additional, Hoffmann, Marc, additional, Ma, Shuo, additional, Eyre, Toby A., additional, Munir, Talha, additional, Patel, Manish R., additional, Alencar, Alvaro J., additional, Tam, Constantine S., additional, Seymour, John F., additional, Jurczak, Wojciech, additional, Lech-Marańda, Ewa, additional, Roeker, Lindsey E., additional, Thompson, Philip A., additional, Abada, Paolo B., additional, Wang, Chunxiao, additional, Nair, Binoj, additional, Liu, Hui, additional, Tsai, Donald E., additional, and Mato, Anthony R., additional

Published
2022
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18. Ramucirumab as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma: Analysis of REACH Trial Results by Child-Pugh Score

Author

Zhu, Andrew X., Baron, Ari David, Malfertheiner, Peter, Kudo, Masatoshi, Kawazoe, Seiji, Pezet, Denis, Weissinger, Florian, Brandi, Giovanni, Barone, Carlo A., Okusaka, Takuji, Wada, Yoshiyuki, Park, Joon Oh, Ryoo, Baek-Yeol, Cho, Jae Yong, Chung, Hyun Cheol, Li, Chung-Pin, Yen, Chia-Jui, Lee, Kuan-Der, Chang, Shao-Chun, Yang, Ling, Abada, Paolo B., and Chau, Ian

Published
2017
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20. Clinical development and evaluation of a VEGF-D assay in plasma from patients with metastatic colorectal cancer in the RAISE study

Author

Taniguchi, Hiroya, primary, Yoshino, Takayuki, additional, Yamaguchi, Kensei, additional, Yamazaki, Kentaro, additional, Nixon, Andrew B., additional, Tabernero, Josep, additional, Van Cutsem, Eric, additional, Robling, Kim R., additional, Abada, Paolo B., additional, Hozak, Rebecca R., additional, Siegel, Robert, additional, Fill, Jeffrey A., additional, Wijayawardana, Sameera, additional, Walgren, Richard A., additional, Giles, Brendan, additional, Jones, Abby, additional, Pitts, Kelly R., additional, Drove, Nora, additional, and Muro, Kei, additional

Published
2021
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21. Impact of baseline hepatitis B viremia and management on outcomes in advanced hepatocellular carcinoma and elevated alpha-fetoprotein: outcomes from REACH-2

Author

Peter Robert Galle, Kudo, Masatoshi, Llovet, Josep M., Finn, Richard, Karwal, Mark, Denis, Pezet, Kim, Tae-You, Yang, Tsai-Sheng, Zagonel, Vittorina, Tomasek, Jiri, Phelip, Jean-Marc, Touchefeu, Yann, Koh, Su-Jin, Stirnimann, Guido, Wang, Chunxiao, Ogburn, Kenyon, Abada, Paolo B., Widau, Ryan, and Zhu, Andrew

Subjects
Hepatology, 610 Medicine & health
Published
2020
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22. Impact of baseline hepatitis B viremia and management on outcomes in advanced hepatocellular carcinoma and elevated alpha-fetoprotein: outcomes from REACH-2

Author

Galle, Peter, primary, Kudo, Masatoshi, additional, Llovet, Josep M., additional, Finn, Richard, additional, Karwal, Mark, additional, Denis, Pezet, additional, Kim, Tae-You, additional, Yang, Tsai-Sheng, additional, Zagonel, Vittorina, additional, Tomasek, Jiri, additional, Phelip, Jean-Marc, additional, Touchefeu, Yann, additional, Koh, Su-Jin, additional, Stirnimann, Guido, additional, Wang, Chunxiao, additional, Ogburn, Kenyon, additional, Abada, Paolo B., additional, Widau, Ryan, additional, and Zhu, Andrew, additional

Published
2020
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24. Issue Cover

Author

Galle, Peter R., primary, Foerster, Friedrich, additional, Kudo, Masatoshi, additional, Chan, Stephen L., additional, Llovet, Josep M., additional, Qin, Shukui, additional, Schelman, William R., additional, Chintharlapalli, Sudhakar, additional, Abada, Paolo B., additional, Sherman, Morris, additional, and Zhu, Andrew X., additional

Published
2019
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25. Biology and significance of alpha‐fetoprotein in hepatocellular carcinoma

Author

Galle, Peter R., primary, Foerster, Friedrich, additional, Kudo, Masatoshi, additional, Chan, Stephen L., additional, Llovet, Josep M., additional, Qin, Shukui, additional, Schelman, William R., additional, Chintharlapalli, Sudhakar, additional, Abada, Paolo B., additional, Sherman, Morris, additional, and Zhu, Andrew X., additional

Published
2019
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26. GS-09-Ramucirumab for patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein following sorafenib: Outcomes by liver disease aetiology from two randomised, placebo-controlled phase 3 studies (REACH-2 and REACH)

Author

Galle, Peter, primary, Kudo, Masatoshi, additional, Llovet, Josep M., additional, Finn, Richard, additional, Karwal, Mark, additional, Denis, Pezet, additional, Kim, Tae-You, additional, Yang, Tsai-Sheng, additional, Zagonel, Vittorina, additional, Tomasek, Jiri, additional, Phelip, Jean-Marc, additional, Touchefeu, Yann, additional, Koh, Su-Jin, additional, Stirnimann, Guido, additional, Wang, Chunxiao, additional, Widau, Ryan, additional, Hsu, Yanzhi, additional, Abada, Paolo B., additional, and Zhu, Andrew, additional

Published
2019
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29. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

Author

Dufour, Jean-François, Schwartz, Jonathan D, Zhu, Andrew X, Pastorelli, Davide, Chau, Ian, REACH Trial, Investigators., Chang, Shao-Chun, Okusaka, Takuji, Ryoo, Baek-Yeol, Chung, Hyun Cheol, Blanc, Jean-Frederic, Trojan, Jorg, Sastre, Javier, Kubackova, Katerina, Abada, Paolo B, Yen, Chia-Jui, Yang, Ling, Pfiffer, Tulio Eduardo Flesch, Kudo, Masatoshi, Baron, Ari D, Poon, Ronnie, Park, Joon Oh, Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J, Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD, Kudo M, REACH Trial Investigator, Brandi G., Zhu A.X., Park J.O., Ryoo B.-Y., Yen C.-J., Poon R., Pastorelli D., Blanc J.-F., Chung H.C., Baron A.D., Pfiffer T.E.F., Okusaka T., Kubackova K., Trojan J., Sastre J., Chau I., Chang S.-C., Abada P.B., Yang L., Schwartz J.D., Kudo M., and Craxì Antonio.

Subjects
Male, Time Factors, Kaplan-Meier Estimate, Gastroenterology, Liver disease, Clinical endpoint, 610 Medicine & health, ramucirumab, sorafenib, HCC, Aged, 80 and over, education.field_of_study, Liver Neoplasms, Remission Induction, Antibodies, Monoclonal, Middle Aged, Sorafenib, Treatment Outcome, Oncology, Liver Neoplasm, Hepatocellular carcinoma, Female, Survival Analysi, Human, medicine.drug, Adult, Niacinamide, Phenylurea Compound, medicine.medical_specialty, Carcinoma, Hepatocellular, Time Factor, Population, Antibodies, Monoclonal, Humanized, Placebo, Disease-Free Survival, Drug Administration Schedule, Follow-Up Studie, Ramucirumab, Double-Blind Method, Internal medicine, Confidence Intervals, medicine, Carcinoma, Humans, education, Proportional Hazards Models, Aged, Dose-Response Relationship, Drug, business.industry, Phenylurea Compounds, Patient Selection, medicine.disease, Survival Analysis, digestive system diseases, Surgery, Proportional Hazards Model, business, Confidence Interval, Follow-Up Studies
Abstract

Background: VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. Methods: In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. Findings: Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [

Published
2015
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30. Corrigendum to ‘Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study’ [Eur J Canc 81 (2017) 17–25]

Author

Chau, Ian, primary, Peck-Radosavljevic, Markus, additional, Borg, Christophe, additional, Malfertheiner, Peter, additional, Seitz, Jean Francois, additional, Park, Joon Oh, additional, Ryoo, Baek-Yeol, additional, Yen, Chia-Jui, additional, Kudo, Masatoshi, additional, Poon, Ronnie, additional, Pastorelli, Davide, additional, Blanc, Jean-Frederic, additional, Chung, Hyun Cheol, additional, Baron, Ari D., additional, Okusaka, Takuji, additional, Bowman, L., additional, Cui, Zhanglin Lin, additional, Girvan, Allicia C., additional, Abada, Paolo B., additional, Yang, Ling, additional, and Zhu, Andrew X., additional

Published
2018
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32. Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): Japanese subgroup analysis of the phase III REACH trial

Author

Ohkawa, Shinichi, primary, Okusaka, Takuji, additional, Kudo, Masatoshi, additional, Hatano, Etsuro, additional, Fujii, Hirofumi, additional, Masumoto, Akihide, additional, Furuse, Junji, additional, Wada, Yoshiyuki, additional, Ishii, Hiroshi, additional, Obi, Shuntaro, additional, Arai, Kuniaki, additional, Kawazoe, Seiji, additional, Yokosuka, Osamu, additional, Ikeda, Masafumi, additional, Ukai, Katsuaki, additional, Morita, Sojiro, additional, Asou, Hiroya, additional, Abada, Paolo B., additional, Yang, Ling, additional, and Zhu, Andrew X., additional

Published
2015
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37. Pirtobrutinib preclinical characterization: a highly selective, noncovalent (reversible) BTK inhibitor

Author

Gomez, Eliana B., Ebata, Kevin, Randeria, Hetal S., Rosendahl, Mary S., Cedervall, E. Peder, Morales, Tony H., Hanson, Lauren M., Brown, Nicholas E., Gong, Xueqian, Stephens, Jennifer, Wu, Wenjuan, Lippincott, Isabel, Ku, Karin S., Walgren, Richard A., Abada, Paolo B., Ballard, Joshua A., Allerston, Charles K., and Brandhuber, Barbara J.

Abstract

•Pirtobrutinib, a potent, noncovalent (reversible), highly selective inhibitor of BTK and C481-mutant BTK.•Pirtobrutinib is efficacious in B-cell models in vitro and in vivo, including patient-derived CLL cells.

Published
2023
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39. Second-line ramucirumab therapy for advanced hepatocellular carcinoma (REACH): an East Asian and non-East Asian subgroup analysis

Author

Park, Joon Oh, Ryoo, Baek-Yeol, Yen, Chia-Jui, Kudo, Masatoshi, Yang, Ling, Abada, Paolo B., Cheng, Rebecca, Orlando, Mauro, Zhu, Andrew X., and Okusaka, Takuji

Subjects
Asians, alpha-fetoprotein, clinical trial, liver neoplasms, vascular endothelial growth factor receptor-2
Abstract

Purpose REACH investigated second-line ramucirumab therapy for advanced hepatocellular carcinoma. Results: Median overall survival was 8.2 months for ramucirumab and 6.9 months for placebo (HR, 0.835; 95% CI, 0.634–1.100; p = 0.2046) for East Asians, and 10.1 months for ramucirumab and 8.0 months for placebo (HR, 0.895; 95% CI, 0.690–1.161; p = 0.4023) for non-East Asians. Median overall survival in patients with baseline alpha-fetoprotein ≥ 400 ng/mL was 7.8 months for ramucirumab and 4.2 months for placebo (HR, 0.749; 95% CI, 0.519–1.082; p = 0.1213) for East Asians (n = 139), and 8.2 months for ramucirumab and 4.5 months for placebo (HR, 0.579; 95% CI, 0.371–0.904; p = 0.0149) for non-East Asians (n = 111). The most common grade ≥ 3 treatment-emergent adverse events in East Asians and non-East Asians included hypertension and malignant neoplasm progression. Materials and methods A post-hoc analysis of East Asians (N = 252) and non-East Asians (N = 313) in the intent-to-treat population was performed. Conclusions: In East Asians and non-East Asians, ramucirumab did not significantly prolong overall survival. In patients with baseline alpha-fetoprotein ≥ 400 ng/mL, a potentially larger survival benefit was observed in both subgroups. Safety for East Asians was similar to non-East Asians.

Published
2016
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40. Copper Transporter 2 Regulates Endocytosis and Controls Tumor Growth and Sensitivity to Cisplatin In Vivo

Author

Blair, Brian G., Larson, Christopher A., Adams, Preston L., Abada, Paolo B., Pesce, Catherine E., Safaei, Roohangiz, and Howell, Stephen B.

Abstract

Copper transporter 2 (CTR2) is one of the four copper transporters in mammalian cells that influence the cellular pharmacology of cisplatin and carboplatin. CTR2 was knocked down using a short hairpin RNA interference. Robust expression of CTR2 was observed in parental tumors grown in vivo, whereas no staining was found in the tumors formed from cells in which CTR2 had been knocked down. Knockdown of CTR2 reduced growth rate by 5.8-fold, increased the frequency of apoptotic cells, and decreased the vascular density, but it did not change copper content. Knockdown of CTR2 increased the tumor accumulation of cis-diamminedichloroplatinum(II) [cisplatin (cDDP)] by 9.1-fold and greatly increased its therapeutic efficacy. Because altered endocytosis has been implicated in cDDP resistance, uptake of dextran was used to quantify the rate of macropinocytosis. Knockdown of CTR2 increased dextran uptake 2.5-fold without reducing exocytosis. Inhibition of macropinocytosis with either amiloride or wortmannin blocked the increase in macropinocytosis mediated by CTR2 knockdown. Stimulation of macropinocytosis by platelet-derived growth factor coordinately increased dextran and cDDP uptake. Knockdown of CTR2 was associated with activation of the Rac1 and cdc42 GTPases that control macropinocytosis but not activation of the phosphoinositide-3 kinase pathway. We conclude that CTR2 is required for optimal tumor growth and that it is an unusually strong regulator of cisplatin accumulation and cytotoxicity. CTR2 regulates the transport of cDDP in part through control of the rate of macropinocytosis via activation of Rac1 and cdc42. Selective knockdown of CTR2 in tumors offers a strategy for enhancing the efficacy of cDDP.

Published
2011

41. Alpha-fetoprotein kinetics in patients with hepatocellular carcinoma receiving ramucirumab or placebo: an analysis of the phase 3 REACH study

Author

Paolo Abada, Baek Yeol Ryoo, Takuji Okusaka, Jean-Marc Phelip, Etsuro Hatano, Chia Jui Yen, Shinichi Ohkawa, Ronnie T.P. Poon, Tulio Eduardo Flesch Pfiffer, Davide Pastorelli, Jean-Frédéric Blanc, Masatoshi Kudo, Hyun Cheol Chung, Andrew X. Zhu, Ian Chau, Chung Pin Li, Yanzhi Hsu, Joon Oh Park, Katerina Kopeckova, Giovanni Brandi, Chau, Ian, Park, Joon Oh, Ryoo, Baek-Yeol, Yen, Chia-Jui, Poon, Ronnie, Pastorelli, Davide, Blanc, Jean-Frédéric, Kudo, Masatoshi, Pfiffer, Tulio, Hatano, Etsuro, Chung, Hyun Cheol, Kopeckova, Katerina, Phelip, Jean-Marc, Brandi, Giovanni, Ohkawa, Shinichi, Li, Chung-Pin, Okusaka, Takuji, Hsu, Yanzhi, Abada, Paolo B., and Zhu, Andrew X.

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Carcinoma, Hepatocellular, Kaplan-Meier Estimate, Antibodies, Monoclonal, Humanized, Placebo, Gastroenterology, Disease-Free Survival, Article, Ramucirumab, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Carcinoma, Humans, neoplasms, Aged, business.industry, Liver Neoplasms, digestive, oral, and skin physiology, Antibodies, Monoclonal, Middle Aged, medicine.disease, digestive system diseases, Radiography, Clinical trial, Oncology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, embryonic structures, Monoclonal, Female, 030211 gastroenterology & hepatology, alpha-Fetoproteins, Alpha-fetoprotein, business
Abstract

Background Post-hoc analyses of AFP response and progression and their relationship with objective measures of response and survival were performed in patients from REACH. Methods Serum AFP was measured at baseline and every 3 cycles (2 weeks/cycle). Associations between AFP and radiographic progression and efficacy end points were analysed. Results Median percent AFP increase from baseline was smaller in the ramucirumab than in the placebo arm throughout treatment. Time to AFP progression (HR 0.621; P P P P = 0.0002). AFP response was higher with ramucirumab compared with placebo (P P Conclusions Treatment with ramucirumab prolonged time to AFP progression, slowed AFP increase and was more likely to induce AFP response. Similar benefits in radiographic progression and response correlated with AFP changes.

Published
2018
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42. THU496 - Impact of baseline hepatitis B viremia and management on outcomes in advanced hepatocellular carcinoma and elevated alpha-fetoprotein: outcomes from REACH-2.

Author

Galle, Peter, Kudo, Masatoshi, Llovet, Josep M., Finn, Richard, Karwal, Mark, Denis, Pezet, Kim, Tae-You, Yang, Tsai-Sheng, Zagonel, Vittorina, Tomasek, Jiri, Phelip, Jean-Marc, Touchefeu, Yann, Koh, Su-Jin, Stirnimann, Guido, Wang, Chunxiao, Ogburn, Kenyon, Abada, Paolo B., Widau, Ryan, and Zhu, Andrew

Subjects
*HEPATITIS B, *ALPHA fetoproteins, *VIREMIA, *CHRONIC hepatitis B
Published
2020
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43. Mutagenesis and peptide analysis of the DRY motif in the <f>α2A</f> adrenergic receptor: evidence for alternate mechanisms in G protein-coupled receptors

Author

Chung, Duane A., Wade, Susan M., Fowler, Carol B., Woods, Danielle D., Abada, Paolo B., Mosberg, Henry I., and Neubig, Richard R.

Subjects
*G proteins, *ADRENERGIC receptors, *GENETIC mutation
Abstract

In G protein-coupled receptors (GPCRs), a conserved aspartic acid in the DRY motif at the cytoplasmic end of helix 3 regulates the transition to the active state, while the adjacent arginine is crucial for G protein activation. To examine the functions of these two residues, we made D130I and R131Q mutations in the α2A adrenergic receptor (AR). We demonstrate that, unlike other GPCRs, the α2A AR is not constitutively activated by the D130I mutation, although the mutation increases agonist affinity. While the R131Q mutation severely disrupts function, it decreases rather than increasing agonist affinity as seen in other GPCRs. We then investigated the molecular effects of the same mutations in a peptide model and showed that Arg131 is not required for peptide-mediated G protein activation. These results indicate that the α2A AR does not follow the conventional GPCR mechanistic paradigm with respect to the function of the DRY motif. [Copyright &y& Elsevier]

Published
2002
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44. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2) : A randomised, double-blind, placebo-controlled, phase 3 trial

Author

Marc Pracht, Kenta Motomura, Philippe Merle, Richard S. Finn, Jean-Baptiste Hiriart, Takuji Okusaka, Christophe Borg, Paolo Abada, Masatoshi Kudo, Dong Bok Shin, Guido Gerken, Eric Assenat, Chia Jui Yen, Izumi Ohno, Yoon-Koo Kang, Kun-Ming Rau, Bruno Daniele, Yanzhi Hsu, Andrew X. Zhu, Josep M. Llovet, Peter R. Galle, Manabu Morimoto, Giovanni Brandi, Ho Yeong Lim, Zhu, Andrew X, Kang, Yoon-Koo, Yen, Chia-Jui, Finn, Richard S, Galle, Peter R, Llovet, Josep M, Assenat, Eric, Brandi, Giovanni, Pracht, Marc, Lim, Ho Yeong, Rau, Kun-Ming, Motomura, Kenta, Ohno, Izumi, Merle, Philippe, Daniele, Bruno, Shin, Dong Bok, Gerken, Guido, Borg, Christophe, Hiriart, Jean-Baptiste, Okusaka, Takuji, Morimoto, Manabu, Hsu, Yanzhi, Abada, Paolo B, Kudo, Masatoshi, Harvard Medical School [Boston] (HMS), Asan Medical Center [Seoul], University of Ulsan, National Cheng Kung University (NCKU), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University Medical Center [Mainz], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Centre Eugène Marquis (CRLCC), Sungkyunkwan University [Suwon] (SKKU), Chang Gung Memorial Hospital [Taipei] (CGMH), Fukuoka University, University of Tokyo [Kashiwa Campus], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), G Rummo Hospital, Ospedale del Mare, Gachon University Gil Medical Center [Incheon, Republic of Korea], Universität Duisburg-Essen [Essen], Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Tokyo Medical University, Yokohama University School of Medecine, Eli Lilly and Company [Indianapolis], and Kindai University

Subjects
Sorafenib, Male, medicine.medical_specialty, Carcinoma, Hepatocellular, Medizin, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Placebo, Antibodies, Monoclonal, Humanized, Gastroenterology, Ramucirumab, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Internal medicine, medicine, Clinical endpoint, Carcinoma, Humans, Aged, Neoplasm Staging, Intention-to-treat analysis, business.industry, Hazard ratio, Liver Neoplasms, MESH: Alpha-Fetoproteins / analysis, Middle Aged, medicine.disease, digestive system diseases, 3. Good health, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Female, alpha-Fetoproteins, MESH: Carcinoma, Hepatocellular / drug therapy, Liver Neoplasms / blood, Liver Neoplasms / drug therapy, Sorafenib / administration & dosage, business, medicine.drug, MESH: Antibodies, Monoclonal, Humanized /administration & dosage, Antineoplastic Agents / administration & dosage, Carcinoma, Hepatocellular / blood
Abstract

Background: Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher. Methods: REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433. Findings: Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0–12·5), median overall survival (8·5 months [95% CI 7·0–10·6] vs 7·3 months [5·4–9·1]; hazard ratio [HR] 0·710 [95% CI 0·531–0·949]; p=0·0199) and progression-free survival (2·8 months [2·8–4·1] vs 1·6 months [1·5–2·7]; 0·452 [0·339–0·603]; p

Published
2019
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45. Ramucirumab as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma: Analysis of REACH Trial Results by Child-Pugh Score

Author

Florian Weissinger, Paolo Abada, Ling Yang, Baek Yeol Ryoo, Denis Pezet, Carlo Barone, Giovanni Brandi, Ari David Baron, Chung Pin Li, Jae Yong Cho, Shao Chun Chang, Joon Oh Park, Ian Chau, Kuan Der Lee, Takuji Okusaka, Masatoshi Kudo, Peter Malfertheiner, Chia Jui Yen, Hyun Cheol Chung, Andrew X. Zhu, Seiji Kawazoe, Yoshiyuki Wada, Zhu, Andrew X, Baron, Ari David, Malfertheiner, Peter, Kudo, Masatoshi, Kawazoe, Seiji, Pezet, Deni, Weissinger, Florian, Brandi, Giovanni, Barone, Carlo A, Okusaka, Takuji, Wada, Yoshiyuki, Park, Joon Oh, Ryoo, Baek-Yeol, Cho, Jae Yong, Chung, Hyun Cheol, Li, Chung-Pin, Yen, Chia-Jui, Lee, Kuan-Der, Chang, Shao-Chun, Yang, Ling, Abada, Paolo B, and Chau, Ian

Subjects
Cancer Research, medicine.medical_specialty, Randomization, Population, Chronic liver disease, Placebo, Ramucirumab, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, HCC, education, Survival analysis, education.field_of_study, Settore MED/06 - ONCOLOGIA MEDICA, business.industry, Hazard ratio, medicine.disease, digestive system diseases, Surgery, Oncology, Tolerability, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, business
Abstract

Importance REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline α-fetoprotein (αFP). Objective To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. Design, Settings, and Participants Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis; 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). Interventions Ramucirumab (8 mg/kg) or placebo intravenously plus best supportive care every 2 weeks. Main Outcomes and Measures Overall survival (OS), defined as time from randomization to death from any cause. Results In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80; 95% CI, 0.63-1.02; P = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline αFP levels of 400 ng/mL (to convert ng/mL to μg/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61; 95% CI, 0.43-0.87; P = .01) and Child-Pugh 6 (HR, 0.64; 95% CI, 0.42-0.98; P = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment–emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. Conclusions and Relevance In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline αFP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline αFP levels of 400 ng/mL or more. Trial Registration clinicaltrials.gov Identifier:NCT01140347

Published
2017

46. Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2.

Author

Kudo M, Galle PR, Brandi G, Kang YK, Yen CJ, Finn RS, Llovet JM, Assenat E, Merle P, Chan SL, Palmer DH, Ikeda M, Yamashita T, Vogel A, Huang YH, Abada PB, Yoshikawa R, Shinozaki K, Wang C, Widau RC, and Zhu AX

Abstract

Background & Aims: The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this post hoc analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC., Methods: Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle., Results: Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 vs. 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051])., Conclusions: Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade., Lay Summary: Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate ramucirumab did not impair liver function when compared with placebo., Competing Interests: M.K.: conflict with Daiichi Sankyo, Otsuka, Taiho, Astellas Pharma, Chugai, AbbVie, BMS, EA Pharma, Takeda, Gilead, Eisai, Ono, Bayer, MSD, BMS, and Eli Lilly and Company. P.G.: conflict with Bayer, BMS, MSD, Merck, SIRTEX, AstraZeneca, Sillajen, Eli Lilly and Company, Ipsen, Roche, and Eisai. G.B.: declares no conflicts of interest that pertain to this work. Y-K.K.: conflict with ONO, BMS, Eli Lilly and Company, Roche, Daehwa, and Taiho. C-J. Yen: declares no conflicts of interest that pertain to this work. R.S.F.: conflict with Astra Zeneca, Bayer, BMS, Eli Lilly and Company, Pfizer, Merck, Novartis, Roche/Genentech, and Eisai. J.M.L.: conflict with Bayer, Eisai Inc, BMS, IPSEN, Eli Lilly and Company, Celsion Corp, Elelixis, Merck, Glycotest, Can-Fite, Blueprint, Incyte, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech Inc, and Spring Bank Pharmaceuticals. E.A.: received honoraria from IPSEN, Bayer, Terasphere, Sirtex, Sanofi, Novartis, and Servier; served as an advisor and consultant for IPSEN, Bayer, Terasphere, Sirtex, Sanofi, Novartis, and Servier; and reports receipt of research grant and funding from Eli Lilly and Company. P.M.: conflict with Bayer, Ipsen/Exelixis, BMS, Onxeo, MSD, AstraZeneca, Eisai, and Roche. S.L.C.: conflict with Eisai, Merck, and AstraZeneca. D.H.P.: conflict with Bayer, Eisai, BMS, and Sirtex. M.I.: conflict with Bayer, Bristol-Myers Squibb, Eisai, Sumitomo Dainippon, EA Pharma, Takeda Pharmaceutical, AstraZeneca, Chugai, Merck Serono, Gilead, ASLAN, Daiichi Sankyo, Novartis, Teijin Pharma, Kyowa Hakko Kirin, NanoCarrier, Shire, Yakult, Taiho, Baxalta, Nobelpharma, Otsuka, Ono, MSD, J-Pharma, Mylan, NIHON SERVIER, and Eli Lilly and Company. T.Y.: received personal fees from Eli Lilly and Eisai. A.V.: conflict with Eli Lilly and Company, EISAI, Roche, BMS, MSD, Bayer, BTG, AstraZeneca, Ipsen, Novartis; Y-H. Huang: Eisai, BMS, Merck, AstraZeneca, Bayer, Gilead, Abbvie, Roche, Eli Lilly, and IPSEN. P.B.A.: employed by Eli Lilly and Company, stocks held in Eli Lilly and Company. R.Y.: Eli Lilly Japan KK, stocks held in Eli Lilly and Company. K.S.: Eli Lilly Japan KK. C.W.: employed by Eli Lilly and Company, stocks held in Eli Lilly and Company. R.C.W.: employed by Eli Lilly and Company, stocks held in Eli Lilly and Company. A.X.Z.: conflict with Eisai, BMS, Merck, Novartis, Sanofi, AstraZeneca, Bayer, Roche, Eli Lilly and Company, and Exelixis. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Authors.)

Published
2020
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