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1. Adapting the design of the ongoing RAMPART trial in response to external evidence: An example for trials which take many years to run and report

Author

Meade, Angela, Frangou, Elena, Choodari-Oskooei, Babak, Larkin, James, Powles, Tom, Stewart, Grant D., Albiges, Laurence, Bex, Axel, Choueiri, Toni K., Davis, Ian D., Eisen, Tim, Fielding, Alison, Gedye, Craig, Harrison, David J., Kaplan, Rick, Mulhere, Salena, Nathan, Paul, Patel, Grisma, Patel, Jay, Plant, Hannah, Ritchie, Alastair, Rush, Hannah, Shakeshaft, Clare, Stockler, Martin R., Suarez, Cristina, Thompson, Jemima, Thorogood, Nat, Venugopal, Balaji, and Parmar, Mahesh K.B.

Published
2024
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2. A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA)

Author

Stewart, Grant D., Welsh, Sarah J., Ursprung, Stephan, Gallagher, Ferdia A., Jones, James O., Shields, Jacqui, Smith, Christopher G., Mitchell, Thomas J., Warren, Anne Y., Bex, Axel, Boleti, Ekaterini, Carruthers, Jade, Eisen, Tim, Fife, Kate, Hamid, Abdel, Laird, Alexander, Leung, Steve, Malik, Jahangeer, Mendichovszky, Iosif A., Mumtaz, Faiz, Oades, Grenville, Priest, Andrew N., Riddick, Antony C. P., Venugopal, Balaji, Welsh, Michelle, Riddle, Kathleen, Hopcroft, Lisa E. M., and Jones, Robert J.

Published
2022
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3. Temporary treatment cessation compared with continuation of tyrosine kinase inhibitors for adults with renal cancer: the STAR non-inferiority RCT.

Author

Collinson, Fiona, Royle, Kara-Louise, Swain, Jayne, Ralph, Christy, Maraveyas, Anthony, Eisen, Tim, Nathan, Paul, Jones, Robert, Meads, David, Wah, Tze Min, Martin, Adam, Bestall, Janine, Kelly-Morland, Christian, Linsley, Christopher, Oughton, Jamie, Chan, Kevin, Theodoulou, Elisavet, Arias-Pinilla, Gustavo, Kwan, Amy, and Daverede, Luis

Published
2024
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4. The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer – a study protocol

Author

Ursprung, Stephan, Mossop, Helen, Gallagher, Ferdia A., Sala, Evis, Skells, Richard, Sipple, Jamal A. N., Mitchell, Thomas J., Chhabra, Anita, Fife, Kate, Matakidou, Athena, Young, Gemma, Walker, Amanda, Thomas, Martin G., Ortuzar, Mireia Crispin, Sullivan, Mark, Protheroe, Andrew, Oades, Grenville, Venugopal, Balaji, Warren, Anne Y., Stone, John, Eisen, Tim, Wason, James, Welsh, Sarah J., and Stewart, Grant D.

Published
2021
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5. Data from The UK Lung Screen (UKLS): Demographic Profile of First 88,897 Approaches Provides Recommendations for Population Screening

Author

McRonald, Fiona E., primary, Yadegarfar, Ghasem, primary, Baldwin, David R., primary, Devaraj, Anand, primary, Brain, Kate E., primary, Eisen, Tim, primary, Holemans, John A., primary, Ledson, Martin, primary, Screaton, Nicholas, primary, Rintoul, Robert C., primary, Hands, Christopher J., primary, Lifford, Kate, primary, Whynes, David, primary, Kerr, Keith M., primary, Page, Richard, primary, Parmar, Mahesh, primary, Wald, Nicholas, primary, Weller, David, primary, Williamson, Paula R., primary, Myles, Jonathan, primary, Hansell, David M., primary, Duffy, Stephen W., primary, and Field, John K., primary

Published
2023
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6. Supplementary Figures 1 - 2, Tables 1 - 3 from The UK Lung Screen (UKLS): Demographic Profile of First 88,897 Approaches Provides Recommendations for Population Screening

Author

McRonald, Fiona E., primary, Yadegarfar, Ghasem, primary, Baldwin, David R., primary, Devaraj, Anand, primary, Brain, Kate E., primary, Eisen, Tim, primary, Holemans, John A., primary, Ledson, Martin, primary, Screaton, Nicholas, primary, Rintoul, Robert C., primary, Hands, Christopher J., primary, Lifford, Kate, primary, Whynes, David, primary, Kerr, Keith M., primary, Page, Richard, primary, Parmar, Mahesh, primary, Wald, Nicholas, primary, Weller, David, primary, Williamson, Paula R., primary, Myles, Jonathan, primary, Hansell, David M., primary, Duffy, Stephen W., primary, and Field, John K., primary

Published
2023
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7. Data from Prognostic Model for Survival in Patients with Metastatic Renal Cell Carcinoma: Results from the International Kidney Cancer Working Group

Author

Manola, Judith, primary, Royston, Patrick, primary, Elson, Paul, primary, McCormack, Jennifer Bacik, primary, Mazumdar, Madhu, primary, Négrier, Sylvie, primary, Escudier, Bernard, primary, Eisen, Tim, primary, Dutcher, Janice, primary, Atkins, Michael, primary, Heng, Daniel Y.C., primary, Choueiri, Toni K., primary, Motzer, Robert, primary, and Bukowski, Ronald, primary

Published
2023
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8. supplementary data from A Genetic Polymorphism in CTLA-4 Is Associated with Overall Survival in Sunitinib-Treated Patients with Clear Cell Metastatic Renal Cell Carcinoma

Author

Liu, Xiaoyan, primary, Swen, Jesse J., primary, Diekstra, Meta H.M., primary, Boven, Epie, primary, Castellano, Daniel, primary, Gelderblom, Hans, primary, Mathijssen, Ron H.J., primary, Vermeulen, Sita H., primary, Oosterwijk, Egbert, primary, Junker, Kerstin, primary, Roessler, Max, primary, Alexiusdottir, Kristin, primary, Sverrisdottir, Asgerdur, primary, Radu, Marius T., primary, Ambert, Valentin, primary, Eisen, Tim, primary, Warren, Anne, primary, Rodríguez-Antona, Cristina, primary, García-Donas, Jesus, primary, Böhringer, Stefan, primary, Koudijs, Karel K.M., primary, Kiemeney, Lambertus A.L.M., primary, Rini, Brian I., primary, and Guchelaar, Henk-Jan, primary

Published
2023
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9. Supplementary Figure 1 from Prognostic Model for Survival in Patients with Metastatic Renal Cell Carcinoma: Results from the International Kidney Cancer Working Group

Author

Manola, Judith, primary, Royston, Patrick, primary, Elson, Paul, primary, McCormack, Jennifer Bacik, primary, Mazumdar, Madhu, primary, Négrier, Sylvie, primary, Escudier, Bernard, primary, Eisen, Tim, primary, Dutcher, Janice, primary, Atkins, Michael, primary, Heng, Daniel Y.C., primary, Choueiri, Toni K., primary, Motzer, Robert, primary, and Bukowski, Ronald, primary

Published
2023
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10. Supplementary Tables and Figures from Angiokines Associated with Targeted Therapy Outcomes in Patients with Non–Clear Cell Renal Cell Carcinoma

Author

Armstrong, Andrew J., primary, Nixon, Andrew B., primary, Carmack, Andrea, primary, Yang, Qian, primary, Eisen, Tim, primary, Stadler, Walter M., primary, Jones, Robert J., primary, Garcia, Jorge A., primary, Vaishampayan, Ulka N., primary, Picus, Joel, primary, Hawkins, Robert E., primary, Hainsworth, John D., primary, Kollmannsberger, Christian K., primary, Logan, Theodore F., primary, Puzanov, Igor, primary, Pickering, Lisa M., primary, Ryan, Christopher W., primary, Protheroe, Andrew, primary, George, Daniel J., primary, and Halabi, Susan, primary

Published
2023
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11. Supplementary Figure 2 from Prognostic Model for Survival in Patients with Metastatic Renal Cell Carcinoma: Results from the International Kidney Cancer Working Group

Author

Manola, Judith, primary, Royston, Patrick, primary, Elson, Paul, primary, McCormack, Jennifer Bacik, primary, Mazumdar, Madhu, primary, Négrier, Sylvie, primary, Escudier, Bernard, primary, Eisen, Tim, primary, Dutcher, Janice, primary, Atkins, Michael, primary, Heng, Daniel Y.C., primary, Choueiri, Toni K., primary, Motzer, Robert, primary, and Bukowski, Ronald, primary

Published
2023
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12. Supplementary Figure 4a from Angiokines Associated with Targeted Therapy Outcomes in Patients with Non–Clear Cell Renal Cell Carcinoma

Author

Armstrong, Andrew J., primary, Nixon, Andrew B., primary, Carmack, Andrea, primary, Yang, Qian, primary, Eisen, Tim, primary, Stadler, Walter M., primary, Jones, Robert J., primary, Garcia, Jorge A., primary, Vaishampayan, Ulka N., primary, Picus, Joel, primary, Hawkins, Robert E., primary, Hainsworth, John D., primary, Kollmannsberger, Christian K., primary, Logan, Theodore F., primary, Puzanov, Igor, primary, Pickering, Lisa M., primary, Ryan, Christopher W., primary, Protheroe, Andrew, primary, George, Daniel J., primary, and Halabi, Susan, primary

Published
2023
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13. Supplementary Tables 1-7 from Prognostic Model for Survival in Patients with Metastatic Renal Cell Carcinoma: Results from the International Kidney Cancer Working Group

Author

Manola, Judith, primary, Royston, Patrick, primary, Elson, Paul, primary, McCormack, Jennifer Bacik, primary, Mazumdar, Madhu, primary, Négrier, Sylvie, primary, Escudier, Bernard, primary, Eisen, Tim, primary, Dutcher, Janice, primary, Atkins, Michael, primary, Heng, Daniel Y.C., primary, Choueiri, Toni K., primary, Motzer, Robert, primary, and Bukowski, Ronald, primary

Published
2023
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14. Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib

Author

Diekstra, Meta HM, Swen, Jesse J, Van Der Zanden, Loes FM, Vermeulen, Sita H, Boven, Epie, Mathijssen, Ron HJ, Fukunaga, Koya, Mushiroda, Taisei, Hongo, Fumiya, Oosterwijk, Egbert, Cambon-Thomsen, Anne, Castellano, Daniel, Fritsch, Achim, Donas, Jesus Garcia, Rodriguez-Antona, Cristina, Ruijtenbeek, Rob, Radu, Marius T, Eisen, Tim, Junker, Kerstin, Roessler, Max, Jaehde, Ulrich, Miki, Tsuneharu, Böhringer, Stefan, Kubo, Michiaki, Kiemeney, Lambertus ALM, Guchelaar, Henk-Jan, Medical Oncology, Internal medicine, Diekstra, Meta HM [0000-0002-9368-3650], Swen, Jesse J [0000-0002-3965-5552], van der Zanden, Loes FM [0000-0003-3914-7491], Mathijssen, Ron HJ [0000-0001-5667-5697], Cambon-Thomsen, Anne [0000-0001-8793-3644], Eisen, Tim [0000-0001-9663-4873], Guchelaar, Henk-Jan [0000-0002-7085-1383], and Apollo - University of Cambridge Repository

Subjects
Cancer Research, sunitinib, clear cell renal cell carcinoma, urologic and male genital diseases, metastatic renal cell carcinoma, genome wide association study, pharmacogenetics, single nucleotide polymorphism, Oncology, SDG 3 - Good Health and Well-being, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Renal disorders Radboud Institute for Health Sciences [Radboudumc 11]
Abstract

Contains fulltext : 251723.pdf (Publisher’s version ) (Open Access) Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10(-8)) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10(-10), HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10(-8), HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

Published
2022
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15. Logical Imputation to Optimize Prognostic Risk Classification in Metastatic Renal Cell Cancer

Author

Maurits, Jake S.F., primary, van der Zanden, Loes F.M., additional, Diekstra, Meta H.M., additional, Ambert, Valentin, additional, Castellano, Daniel, additional, Garcia-Donas, Jesus, additional, Troyas, Rosa Guarch, additional, Guchelaar, Henk-Jan, additional, Jaehde, Ulrich, additional, Junker, Kerstin, additional, Martinez-Cardus, Anna, additional, Radu, Marius T., additional, Rodriguez-Antona, Cristina, additional, Roessler, Max, additional, Warren, Anne, additional, Eisen, Tim, additional, Oosterwijk, Egbert, additional, Kiemeney, Lambertus A.L.M., additional, and Vermeulen, Sita H., additional

Published
2022
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16. Neoadjuvant and Adjuvant Therapy for Renal Cell Carcinoma

Author

Haas, Naomi B., primary, Shevach, Jeffrey, additional, Davis, Ian D., additional, Eisen, Tim, additional, Gross-Gupil, Marine, additional, Kapoor, Anil, additional, Master, Viraj A., additional, Ryan, Christopher W., additional, and Schimdinger, Manuela, additional

Published
2022
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17. Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma-A Proof of Principle Study

Author

Ursprung, Stephan, Woitek, Ramona, McLean, Mary, Priest, Andrew N, Crispin-Ortuzar, Mireia, Brodie, Cara R, Gill, Andrew, Gehrung, Marcel, Beer, Lucian, Riddick, Antony CP, Field-Rayner, Johanna, Grist, James T, Deen, Surrin S, Riemer, Frank, Kaggie, Joshua, Zaccagna, Fulvio, Duarte, Joao AG, Locke, Matthew J, Frary, Amy, Aho, Tevita F, Armitage, James N, Casey, Ruth, Mendichovszky, Iosif A, Welsh, Sarah, Barrett, Tristan, Graves, Martin, Eisen, Tim, Mitchell, Thomas J, Warren, Anne, Brindle, Kevin, Sala, Evis, Stewart, Grant, Gallagher, Ferdia, Ursprung, Stephan [0000-0003-2476-178X], McLean, Mary [0000-0002-3752-0179], Priest, Andrew N [0000-0002-9771-4290], Gill, Andrew [0000-0002-9287-9563], Beer, Lucian [0000-0003-4388-7580], Deen, Surrin S [0000-0002-6206-7337], Riemer, Frank [0000-0002-3805-5221], Kaggie, Joshua [0000-0001-6706-3442], Zaccagna, Fulvio [0000-0001-6838-9532], Frary, Amy [0000-0002-4373-3517], Welsh, Sarah [0000-0001-5690-2677], Barrett, Tristan [0000-0002-1180-1474], Graves, Martin [0000-0003-4327-3052], Eisen, Tim [0000-0001-9663-4873], Warren, Anne [0000-0002-1170-7867], Brindle, Kevin [0000-0003-3883-6287], Sala, Evis [0000-0002-5518-9360], Stewart, Grant [0000-0003-3188-9140], Gallagher, Ferdia [0000-0003-4784-5230], Apollo - University of Cambridge Repository, Ursprung S., Woitek R., McLean M.A., Priest A.N., Crispin-Ortuzar M., Brodie C.R., Gill A.B., Gehrung M., Beer L., Riddick A.C.P., Field-Rayner J., Grist J.T., Deen S.S., Riemer F., Kaggie J.D., Zaccagna F., Duarte J.A.G., Locke M.J., Frary A., Aho T.F., Armitage J.N., Casey R., Mendichovszky I.A., Welsh S.J., Barrett T., Graves M.J., Eisen T., Mitchell T.J., Warren A.Y., Brindle K.M., Sala E., Stewart G.D., Gallagher F.A., Gill, Andrew B [0000-0002-9287-9563], Kaggie, Joshua D [0000-0001-6706-3442], Welsh, Sarah J [0000-0001-5690-2677], Brindle, Kevin M [0000-0003-3883-6287], Stewart, Grant D [0000-0003-3188-9140], and Gallagher, Ferdia A [0000-0003-4784-5230]

Subjects
Cancer Research, renal cell carcinoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, cancer metabolism, monocarboxylate transporter, Article, Hyperpolarized, hyperpolarized 13C magnetic resonance imaging, Oncology, C magnetic resonance imaging, RC254-282
Abstract

Simple Summary We evaluated renal cancer with varying aggressive appearances on histology, using an emerging form of non-invasive metabolic MRI. This imaging technique assesses the uptake and metabolism of a breakdown product of glucose (pyruvate) labelled with hyperpolarized carbon-13. We show that pyruvate metabolism is dependent on the aggressiveness of an individual tumor and we provide a mechanism for this finding from tissue analysis of molecules influencing pyruvate metabolism, suggesting a role for its membrane transporter. Abstract Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1-13C]pyruvate (HP-13C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP-13C-MRI and conventional proton (1H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant (kPL) between 13C-pyruvate and 13C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing kPL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset (p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP-13C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP-13C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.

Published
2022

18. Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib

Author

Diekstra, Meta H.M., Swen, Jesse J., van der Zanden, Loes F.M., Vermeulen, Sita H., Boven, Epie, Mathijssen, Ron H.J., Fukunaga, Koya, Mushiroda, Taisei, Hongo, Fumiya, Oosterwijk, Egbert, Cambon-Thomsen, Anne, Castellano, Daniel, Fritsch, Achim, Donas, Jesus Garcia, Rodriguez-Antona, Cristina, Ruijtenbeek, Rob, Radu, Marius T., Eisen, Tim, Junker, Kerstin, Roessler, Max, Jaehde, Ulrich, Miki, Tsuneharu, Böhringer, Stefan, Kubo, Michiaki, Kiemeney, Lambertus A.L.M., Guchelaar, Henk Jan, Diekstra, Meta H.M., Swen, Jesse J., van der Zanden, Loes F.M., Vermeulen, Sita H., Boven, Epie, Mathijssen, Ron H.J., Fukunaga, Koya, Mushiroda, Taisei, Hongo, Fumiya, Oosterwijk, Egbert, Cambon-Thomsen, Anne, Castellano, Daniel, Fritsch, Achim, Donas, Jesus Garcia, Rodriguez-Antona, Cristina, Ruijtenbeek, Rob, Radu, Marius T., Eisen, Tim, Junker, Kerstin, Roessler, Max, Jaehde, Ulrich, Miki, Tsuneharu, Böhringer, Stefan, Kubo, Michiaki, Kiemeney, Lambertus A.L.M., and Guchelaar, Henk Jan

Abstract

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8 ) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

Published
2022

19. External Validation of the 2003 Leibovich Prognostic Score in Patients Randomly Assigned to SORCE, an International Phase III Trial of Adjuvant Sorafenib in Renal Cell Cancer

Author

Oza, Bhavna, primary, Eisen, Tim, additional, Frangou, Eleni, additional, Stewart, Grant D., additional, Bex, Axel, additional, Ritchie, Alastair W.S., additional, Kaplan, Rick, additional, Smith, Benjamin, additional, Davis, Ian D., additional, Stockler, Martin R., additional, Albiges, Laurence, additional, Escudier, Bernard, additional, Larkin, James, additional, Joniau, Steven, additional, Hancock, Barry, additional, Hermann, Gregers G., additional, Bellmunt, Joaquim, additional, Parmar, Mahesh K.B., additional, Royston, Patrick, additional, and Meade, Angela, additional

Published
2022
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20. Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma—A Proof of Principle Study

Author

Ursprung, Stephan, primary, Woitek, Ramona, additional, McLean, Mary A., additional, Priest, Andrew N., additional, Crispin-Ortuzar, Mireia, additional, Brodie, Cara R., additional, Gill, Andrew B., additional, Gehrung, Marcel, additional, Beer, Lucian, additional, Riddick, Antony C. P., additional, Field-Rayner, Johanna, additional, Grist, James T., additional, Deen, Surrin S., additional, Riemer, Frank, additional, Kaggie, Joshua D., additional, Zaccagna, Fulvio, additional, Duarte, Joao A. G., additional, Locke, Matthew J., additional, Frary, Amy, additional, Aho, Tevita F., additional, Armitage, James N., additional, Casey, Ruth, additional, Mendichovszky, Iosif A., additional, Welsh, Sarah J., additional, Barrett, Tristan, additional, Graves, Martin J., additional, Eisen, Tim, additional, Mitchell, Thomas J., additional, Warren, Anne Y., additional, Brindle, Kevin M., additional, Sala, Evis, additional, Stewart, Grant D., additional, and Gallagher, Ferdia A., additional

Published
2022
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21. Results from the randomised UKLS trial: Lung cancer mortality reduction by LDCT screening confirmed in an international meta-analysis

Author

Field, John K., Vulkan, Daniel, Davies, Micahel P.A., Baldwin, David R., Brain, Kate E., Devaraj, Anand, Eisen, Tim, Holemans, John A., Kavanagh, Terry, Kerr, Keith M., Ledson, Martin, Lifford, Kate J., McRonald, Fiona E., Nair, Arjun, Page, Richard D., Parmar, Mahesk K.B., Rassi, Doris M., Rintoul, Robert C., Wald, Nicolas J., Weler, David, Whynes, David K., Williamson, Paul R., Yadegarfar, Casham, Gabe, Rhian, and Duffy, Stephen W.

Abstract

Background\ud \ud The NLST reported a significant 20% reduction in lung cancer mortality with three annual low-dose CT (LDCT) screens and the Dutch-Belgian NELSON trial indicates a similar reduction. We present the results of the UKLS trial.\ud Methods\ud \ud From October 2011 to February 2013, we randomly allocated 4 055 participants to either a single invitation to screening with LDCT or to no screening (usual care). Eligible participants (aged 50–75) had a risk score (LLPv2) ≥ 4.5% of developing lung cancer over five years. Data were collected on lung cancer cases to 31 December 2019 and deaths to 29 February 2020 through linkage to national registries. The primary outcome was mortality due to lung cancer. We included our results in a random-effects meta-analysis to provide a synthesis of the latest randomised trial evidence.\ud Findings\ud \ud 1 987 participants in the intervention and 1 981 in the usual care arms were followed for a median of 7.3 years (IQR 7.1–7.6), 86 cancers were diagnosed in the LDCT arm and 75 in the control arm. 30 lung cancer deaths were reported in the screening arm, 46 in the control arm, (relative rate 0.65 [95% CI 0.41–1.02]; p=0.062). The meta-analysis indicated a significant reduction in lung cancer mortality with a pooled overall relative rate of 0.84 (95% CI 0.76–0.92) from nine eligible trials.\ud Interpretation\ud \ud The UKLS trial of single LDCT indicates a reduction of lung cancer death of similar magnitude to the NELSON and NLST trials and was included in a meta-analysis of nine randomised trials which provides unequivocal support for lung cancer screening in identified risk groups.\ud Funding\ud \ud NIHR Health Technology Assessment programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation.\ud Keywords\ud Lung Cancer\ud CT Screening\ud Lung Cancer Mortality\ud Meta-analysis

Published
2021

24. External Validation of the 2003 Leibovich Prognostic Score in Patients Randomly Assigned to SORCE, an International Phase III Trial of Adjuvant Sorafenib in Renal Cell Cancer

Author

Bhavna Oza, Tim Eisen, Eleni Frangou, Grant D. Stewart, Axel Bex, Alastair W.S. Ritchie, Rick Kaplan, Benjamin Smith, Ian D. Davis, Martin R. Stockler, Laurence Albiges, Bernard Escudier, James Larkin, Steven Joniau, Barry Hancock, Gregers G. Hermann, Joaquim Bellmunt, Mahesh K.B. Parmar, Patrick Royston, Angela Meade, Oza, Bhavna [0000-0003-3860-1349], Eisen, Tim [0000-0001-9663-4873], Frangou, Eleni [0000-0002-5978-292X], Stewart, Grant D [0000-0003-3188-9140], Bex, Axel [0000-0002-8499-2662], Kaplan, Rick [0000-0002-0189-8348], Smith, Benjamin [0000-0002-7079-4956], Davis, Ian D [0000-0002-9066-8244], Stockler, Martin R [0000-0003-3793-8724], Albiges, Laurence [0000-0002-5734-3480], Larkin, James [0000-0001-5569-9523], Joniau, Steven [0000-0003-3195-9890], Hermann, Gregers G [0000-0002-8413-5919], Bellmunt, Joaquim [0000-0003-2328-3421], Parmar, Mahesh KB [0000-0003-0166-1700], Meade, Angela [0000-0001-6424-0554], and Apollo - University of Cambridge Repository

Subjects
Cancer Research, Oncology, Recurrence, Humans, Sorafenib, urologic and male genital diseases, Prognosis, Carcinoma, Renal Cell, Nephrectomy, Kidney Neoplasms
Abstract

PURPOSE The 2003 Leibovich score guides prognostication and selection to adjuvant clinical trials for patients with locally advanced renal cell carcinoma (RCC) after nephrectomy. We provide a robust external validation of the 2003 Leibovich score using contemporary data from SORCE, an international, randomized trial of sorafenib after excision of primary RCC. METHODS Data used to derive the 2003 Leibovich score were compared with contemporary data from SORCE. Discrimination and calibration of the metastasis-free survival outcome were assessed in data from patients with clear-cell RCC, using Cox proportional hazards regression, Kaplan-Meier curves, and calculation of Harrell's c indexes. Secondary analyses involved three important SORCE groups: patients with any non–clear-cell subtype, papillary, and chromophobe carcinomas. RESULTS Four hundred seven recurrences occurred in 982 patients in the Leibovich cohort and 520 recurrences were recorded in 1,445 patients in the primary SORCE cohort. Clear discrimination between intermediate-risk and high-risk SORCE cohorts was shown; hazard ratio 2.74 (95% CI, 2.29 to 3.28), c-index 0.63 (95% CI, 0.61 to 0.65). A hazard ratio of 0.61 (95% CI, 0.53 to 0.70) confirmed poor calibration of the two cohorts. Discrimination was observed in secondary populations, with c-indexes of 0.64 (95% CI, 0.59 to 0.69) for non–clear-cell RCC, 0.63 (95% CI, 0.56 to 0.69) for papillary RCC, and 0.65 (95% CI, 0.55 to 0.76) for chromophobe RCC. CONCLUSION The 2003 Leibovich score discriminates between intermediate-risk and high-risk clear-cell and non–clear-cell RCC groups in contemporary data, supporting its use for risk stratification in adjuvant clinical trials. Over time, metastasis-free survival for patients with locally advanced RCC has improved. Contemporary data from adjuvant RCC trials should be used to improve prognostication for patients with RCC.

Published
2022

25. Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma

Author

Ferdia A. Gallagher, Wendi Qian, Fulvio Zaccagna, Stephan Ursprung, Grant D. Stewart, Anne Y. Warren, Sarah J. Welsh, Tristan Barrett, Timothy Eisen, Andrew N. Priest, Andrea Machin, Ursprung, Stephan [0000-0003-2476-178X], Priest, Andrew N. [0000-0002-9771-4290], Warren, Anne Y. [0000-0002-1170-7867], Apollo - University of Cambridge Repository, Priest, Andrew N [0000-0002-9771-4290], Stewart, Grant [0000-0003-3188-9140], Warren, Anne [0000-0002-1170-7867], Eisen, Tim [0000-0001-9663-4873], Welsh, Sarah [0000-0001-5690-2677], Gallagher, Ferdia [0000-0003-4784-5230], Barrett, Tristan [0000-0002-1180-1474], Ursprung S., Priest A.N., Zaccagna F., Qian W., Machin A., Stewart G.D., Warren A.Y., Eisen T., Welsh S.J., Gallagher F.A., Barrett T., and Warren, Anne Y [0000-0002-1170-7867]

Subjects
Male, medicine.medical_treatment, Cancer Treatment, urologic and male genital diseases, Nephrectomy, Metastasis, Diagnostic Radiology, Renal cell carcinoma, Basic Cancer Research, Medicine and Health Sciences, Sunitinib, ComputingMilieux_MISCELLANEOUS, Brain Mapping, Multidisciplinary, medicine.diagnostic_test, Radiology and Imaging, Middle Aged, Magnetic Resonance Imaging, Kidney Neoplasms, Neoadjuvant Therapy, Treatment Outcome, Oncology, Nephrology, Renal Cancer, Medicine, Female, Perfusion, medicine.drug, MRI, Research Article, medicine.medical_specialty, Imaging Techniques, Brain Morphometry, Science, Urology, Surgical and Invasive Medical Procedures, Neuroimaging, Antineoplastic Agents, Research and Analysis Methods, Urinary System Procedures, Diagnostic Medicine, medicine, Humans, Multiparametric Magnetic Resonance Imaging, Carcinoma, Renal Cell, Aged, Surgical Excision, business.industry, Diffusion Weighted Imaging, Carcinoma, Renal Cell Carcinoma, Cancer, Cancers and Neoplasms, Biology and Life Sciences, Magnetic resonance imaging, medicine.disease, Clinical trial, Genitourinary Tract Tumors, business, Neuroscience
Abstract

Funder: NIHR Cambridge Biomedical Research Centre, Funder: Addenbrooke’s Charitable Trust, Funder: National Institute for Health Research (NIHR), Funder: Mark Foundation For Cancer Research, Funder: Cambridge Commonwealth, European and International Trust, Funder: Cancer Research UK, Funder: Cambridge Clinical Trials Unit, Funder: Cancer Research UK Cambridge Centre, Funder: Engineering and Physical Sciences Research Council Cancer Imaging Centre in Cambridge and Manchester, Funder: Cambridge Experimental Cancer Medicine Centre, PURPOSE: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. METHOD: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. RESULTS: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p

Published
2022
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26. Hyperpolarized 13 C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma-A Proof of Principle Study.

Author

Ursprung S, Woitek R, McLean MA, Priest AN, Crispin-Ortuzar M, Brodie CR, Gill AB, Gehrung M, Beer L, Riddick ACP, Field-Rayner J, Grist JT, Deen SS, Riemer F, Kaggie JD, Zaccagna F, Duarte JAG, Locke MJ, Frary A, Aho TF, Armitage JN, Casey R, Mendichovszky IA, Welsh SJ, Barrett T, Graves MJ, Eisen T, Mitchell TJ, Warren AY, Brindle KM, Sala E, Stewart GD, and Gallagher FA

Abstract

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1- 13 C]pyruvate (HP- 13 C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP- 13 C-MRI and conventional proton ( 1 H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant ( k PL ) between 13 C-pyruvate and 13 C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing k PL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1 H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset ( p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP- 13 C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP- 13 C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.

Published
2022
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