Author: "Robert C Rintoul" / Publication Year Range: Last 50 years - Searchworks@Jio Institute Digital Library Search Results

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210 results on '"Robert C Rintoul"'

1. Protocol for a systematic review and individual participant data meta-analysis for risk factors for lung cancer in individuals with lung nodules identified by low-dose CT screening

Author: Matthew Callister, Harry J de Koning, Robert C Rintoul, Carolyn Horst, Arjun Nair, John K Field, Christine D Berg, Samantha Quaife, Rhian Gabe, Stephen Duffy, Sam Janes, Philip AJ Crosbie, Mark M Hammer, Panos Alexandris, and Michael PA Davies
Subjects: Medicine
Abstract: Background Worldwide, lung cancer (LC) is the second most frequent cancer and the leading cause of cancer related mortality. Low-dose CT (LDCT) screening reduced LC mortality by 20–24% in randomised trials of high-risk populations. A significant proportion of those screened have nodules detected that are found to be benign. Consequently, many individuals receive extra imaging and/or unnecessary procedures, which can have a negative physical and psychological impact, as well as placing a financial burden on health systems. Therefore, there is a need to identify individuals who need no interval CT between screening rounds.Methods and analysis The aim of this study is to identify risk factors predictive of LC, which are known at the time of the scan, in patients with LDCT screen-detected lung nodules. The MEDLINE and EMBASE databases will be searched and articles that are on cohorts or mention cohorts of screenees with nodules will be identified. A data extraction framework will ensure consistent extraction across studies. Individual participant data (IPD) will be collected to perform a one-stage IPD meta-analysis using hierarchical univariate models. Clustering will be accounted for by having separate intercept terms for each cohort. Where IPD is not available, the effects of risk factors will be extracted from publications, if possible. Effects from IPD cohorts and aggregate data will be reported and compared. The PROBAST (Prediction model Risk Of Bias ASsessment Tool) will be used for assessment of quality of the studies.Ethics and dissemination Ethical approval was not required as this study is a secondary analysis. The results will be disseminated through publication in peer-reviewed journals and presentations at relevant conferences.PROSPERO registration number CRD42022309515
Published: 2025
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2. Dynamic contrast-enhanced CT compared with positron emission tomography CT to characterise solitary pulmonary nodules: the SPUtNIk diagnostic accuracy study and economic modelling

Author: Fiona J Gilbert, Scott Harris, Kenneth A Miles, Jonathan R Weir-McCall, Nagmi R Qureshi, Robert C Rintoul, Sabina Dizdarevic, Lucy Pike, Donald Sinclair, Andrew Shah, Rosemary Eaton, Andrew Clegg, Valerio Benedetto, James E Hill, Andrew Cook, Dimitrios Tzelis, Luke Vale, Lucy Brindle, Jackie Madden, Kelly Cozens, Louisa A Little, Kathrin Eichhorst, Patricia Moate, Chris McClement, Charles Peebles, Anindo Banerjee, Sai Han, Fat Wui Poon, Ashley M Groves, Lutfi Kurban, Anthony J Frew, Matthew E Callister, Philip Crosbie, Fergus V Gleeson, Kavitasagary Karunasaagarar, Osei Kankam, and Steve George
Subjects: solitary pulmonary nodule (spn), dce-ct, pet/ct, diagnostic imaging, lung cancer, diagnostic accuracy trial, cost-effectiveness, Medical technology, R855-855.5
Abstract: Background: Current pathways recommend positron emission tomography–computerised tomography for the characterisation of solitary pulmonary nodules. Dynamic contrast-enhanced computerised tomography may be a more cost-effective approach. Objectives: To determine the diagnostic performances of dynamic contrast-enhanced computerised tomography and positron emission tomography–computerised tomography in the NHS for solitary pulmonary nodules. Systematic reviews and a health economic evaluation contributed to the decision-analytic modelling to assess the likely costs and health outcomes resulting from incorporation of dynamic contrast-enhanced computerised tomography into management strategies. Design: Multicentre comparative accuracy trial. Setting: Secondary or tertiary outpatient settings at 16 hospitals in the UK. Participants: Participants with solitary pulmonary nodules of ≥ 8 mm and of ≤ 30 mm in size with no malignancy in the previous 2 years were included. Interventions: Baseline positron emission tomography–computerised tomography and dynamic contrast-enhanced computer tomography with 2 years’ follow-up. Main outcome measures: Primary outcome measures were sensitivity, specificity and diagnostic accuracy for positron emission tomography–computerised tomography and dynamic contrast-enhanced computerised tomography. Incremental cost-effectiveness ratios compared management strategies that used dynamic contrast-enhanced computerised tomography with management strategies that did not use dynamic contrast-enhanced computerised tomography. Results: A total of 380 patients were recruited (median age 69 years). Of 312 patients with matched dynamic contrast-enhanced computer tomography and positron emission tomography–computerised tomography examinations, 191 (61%) were cancer patients. The sensitivity, specificity and diagnostic accuracy for positron emission tomography–computerised tomography and dynamic contrast-enhanced computer tomography were 72.8% (95% confidence interval 66.1% to 78.6%), 81.8% (95% confidence interval 74.0% to 87.7%), 76.3% (95% confidence interval 71.3% to 80.7%) and 95.3% (95% confidence interval 91.3% to 97.5%), 29.8% (95% confidence interval 22.3% to 38.4%) and 69.9% (95% confidence interval 64.6% to 74.7%), respectively. Exploratory modelling showed that maximum standardised uptake values had the best diagnostic accuracy, with an area under the curve of 0.87, which increased to 0.90 if combined with dynamic contrast-enhanced computerised tomography peak enhancement. The economic analysis showed that, over 24 months, dynamic contrast-enhanced computerised tomography was less costly (£3305, 95% confidence interval £2952 to £3746) than positron emission tomography–computerised tomography (£4013, 95% confidence interval £3673 to £4498) or a strategy combining the two tests (£4058, 95% confidence interval £3702 to £4547). Positron emission tomography–computerised tomography led to more patients with malignant nodules being correctly managed, 0.44 on average (95% confidence interval 0.39 to 0.49), compared with 0.40 (95% confidence interval 0.35 to 0.45); using both tests further increased this (0.47, 95% confidence interval 0.42 to 0.51). Limitations: The high prevalence of malignancy in nodules observed in this trial, compared with that observed in nodules identified within screening programmes, limits the generalisation of the current results to nodules identified by screening. Conclusions: Findings from this research indicate that positron emission tomography–computerised tomography is more accurate than dynamic contrast-enhanced computerised tomography for the characterisation of solitary pulmonary nodules. A combination of maximum standardised uptake value and peak enhancement had the highest accuracy with a small increase in costs. Findings from this research also indicate that a combined positron emission tomography–dynamic contrast-enhanced computerised tomography approach with a slightly higher willingness to pay to avoid missing small cancers or to avoid a ‘watch and wait’ policy may be an approach to consider. Future work: Integration of the dynamic contrast-enhanced component into the positron emission tomography–computerised tomography examination and the feasibility of dynamic contrast-enhanced computerised tomography at lung screening for the characterisation of solitary pulmonary nodules should be explored, together with a lower radiation dose protocol. Study registration: This study is registered as PROSPERO CRD42018112215 and CRD42019124299, and the trial is registered as ISRCTN30784948 and ClinicalTrials.gov NCT02013063. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 17. See the NIHR Journals Library website for further project information.
Published: 2022
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3. Mesothelioma and Radical Surgery 2 (MARS 2): protocol for a multicentre randomised trial comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication for patients with malignant pleural mesothelioma

Author: Liz Darlison, John Edwards, Apostolos Nakas, Nick A Maskell, Wendy Underwood, Chris Rogers, Matthew Callister, David Waller, Richard Milton, Victoria Ashford-Turner, Paul Taylor, Claire Matthews, Victoria Hughes, Kelvin Lau, Alan Kirk, Robert C Rintoul, Elizabeth A Stokes, Kate Ashton, Daisy Elliott, Rosie Harris, Marie Kirwan, Juliette Novasio, Sara Waplington, Eric Lim, Holly Mckeon, Charlotte Jacobs, Laura White, Mary O’Brien, Judith Moore, Louise Li, Nicola Mills, Sanjay Popat, Suzanne Miller, Nadia Yousaf, D A Fennell, Clinton Ali, Andrea Bille, Liz Fuller, Andreea Ionescu, Manjusha Keni, Pek Koh, Talal Mansy, Dakshinamoorthy Muthukumar, Tony Pope, Amy Roy, Riyaz Shah, Jonathan Shamash, Zacharias Tasigiannopoulos, Sarah Treece, Katherine Joyce, Barbara Warnes, Athanasia Gravani, Rachel Brophy, Nicola Farrar, Jane Elliott, Philip Noyes, Louise Nelson, Sara Tenconi, Laura Socci, Hilary Wood, Helena Hanratty, Helena Stanley, Robert Rintoul, Amy Gladwell, Jenny Castedo, Amanda Stone, Charlotte Ingle, Hayley Hewer, Eleanor Aynsley, Andrea Watson, Alison Hassall, Masuma Begum, Christopher Worth, Ellie Piggott, Elizabeth Nadin, Yvonne Summers, Raffaele Califano, Laura Cove-Smith, Matt Evison, Maria Blinston, Amal Ismail, Rachel Chant, Asmita Desai, Ian Morgan, Victoria Lake, Nichola Harris, Simon Hodge, Nadza Tokaca, Adam Januszewski, Avani Athauda, Anisha Ramessur, Emily Grist, Niamh Colman, Michael Flynn, Joan Joyce, Sarah Vaughan, Maria Piga, Derya Sahin, Agnieszka Yongue, Emma Turay, Jaishree Bhosle, Rajiv Kumar, Charlotte Milner-Watts, Jessica Brown, David Walder, Alexandros Georgiou, Xiaorong Wu, Naila Kaudeer, Kroopa Joshi, Michael Davidson, Shelize Khakoo, Bee Ayite, Kathryn Priest, James Dobbyn, Vasanthi Prathapan, Deborah McCrimmon, Natalie Ash, Alison Norton, Bianca Peet, Libby Hennessy, and Rosemary Johnson
Subjects: Medicine
Abstract: Introduction Mesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with mesothelioma is 12.1 months, surgery is an important consideration to improve survival and/or quality of life. Currently, only two surgical trials have been performed which found that neither extensive (extra-pleural pneumonectomy) or limited (partial pleurectomy) surgery improved survival (although there was some evidence of improved quality of life). Therefore, clinicians are now looking to evaluate pleurectomy decortication, the only radical treatment option left.Methods and analysis The MARS 2 study is a UK multicentre open parallel group randomised controlled trial comparing the effectiveness and cost-effectiveness of surgery—(extended) pleurectomy decortication—versus no surgery for the treatment of pleural mesothelioma. The study will test the hypothesis that surgery and chemotherapy is superior to chemotherapy alone with respect to overall survival. Secondary outcomes include health-related quality of life, progression-free survival, measures of safety (adverse events) and resource use to 2 years. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment.Ethics and dissemination Research ethics approval was granted by London – Camberwell St. Giles Research Ethics Committee (reference 13/LO/1481) on 7 November 2013. We will submit the results for publication in a peer-reviewed journal.Trial registration numbers ISRCTN—ISRCTN44351742 and ClinicalTrials.gov—NCT02040272.
Published: 2020
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4. The UK Lung Cancer Screening Trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer

Author: John K Field, Stephen W Duffy, David R Baldwin, Kate E Brain, Anand Devaraj, Tim Eisen, Beverley A Green, John A Holemans, Terry Kavanagh, Keith M Kerr, Martin Ledson, Kate J Lifford, Fiona E McRonald, Arjun Nair, Richard D Page, Mahesh KB Parmar, Robert C Rintoul, Nicholas Screaton, Nicholas J Wald, David Weller, David K Whynes, Paula R Williamson, Ghasem Yadegarfar, and David M Hansell
Subjects: united kingdom lung cancer screening trial, pilot, randomised controlled trial, low-dose computed tomography, risk prediction modelling, screening, detection, lung cancer, psychological impact, cost-effectiveness modelling, Medical technology, R855-855.5
Abstract: Background: Lung cancer kills more people than any other cancer in the UK (5-year survival
Published: 2016
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5. Smoking-associated gene expression alterations in nasal epithelium reveal immune impairment linked to lung cancer risk

Author: Maria Stella de Biase, Florian Massip, Tzu-Ting Wei, Federico M. Giorgi, Rory Stark, Amanda Stone, Amy Gladwell, Martin O’Reilly, Daniel Schütte, Ines de Santiago, Kerstin B. Meyer, Florian Markowetz, Bruce A. J. Ponder, Robert C. Rintoul, and Roland F. Schwarz
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract Background Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to modifiable lifestyle risk in the form of tobacco smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, 40% of which occur more than 15 years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk remain unclear. We thus set out to examine whether risk stratification in the clinic and in the general population can be improved upon by the addition of genetic data and to explore the mechanisms of the persisting risk in former smokers. Methods We analysed transcriptomic data from accessible airway tissues of 487 subjects, including healthy volunteers and clinic patients of different smoking statuses. We developed a computational model to assess smoking-associated gene expression changes and their reversibility after smoking is stopped, comparing healthy subjects to clinic patients with and without lung cancer. Results We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune- and interferon-related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. Conclusions Our results provide initial evidence for germline-mediated personalized smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.
Published: 2024
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6. Diagnostic Accuracy of a Convolutional Neural Network Assessment of Solitary Pulmonary Nodules Compared With PET With CT Imaging and Dynamic Contrast-Enhanced CT Imaging Using Unenhanced and Contrast-Enhanced CT Imaging

Author: Jonathan R. Weir-McCall, Elise Debruyn, Scott Harris, Nagmi R. Qureshi, Robert C. Rintoul, Fergus V. Gleeson, Fiona J. Gilbert, Anindo Banerjee Lucy Brindle, Matthew Callister, Andrew Clegg, Andrew Cook, Kelly Cozens, Philip Crosbie, Sabina Dizdarevic, Rosemary Eaton, Kathrin Eichhorst, Anthony Frew, Ashley Groves, Sai Han, Jeremy Jones, Osie Kankam, Kavitasagary Karunasaagarar, Lutfi Kurban, Louisa Little, Jackie Madden, Chris McClement, Ken Miles, Patricia Moate, Charles Peebles, Lucy Pike, Fat-Wui Poon, Donald Sinclair, Andrew Shah, Luke Vale, Steve George, Richard Riley, Andrea Lodge, John Buscombe, Theresa Green, Amanda Stone, Neal Navani, Robert Shortman, Gabriella Azzopardi, Sarah Doffman, Janice Bush, Jane Lyttle, Kenneth Jacob, Joris van der Horst, Joseph Sarvesvaran, Barbara McLaren, Lesley Gomersall, Ravi Sharma, Kathleen Collie, Steve O’Hickey, Jayne Tyler, Sue King, John O’Brien, Rajiv Srivastava, Hugh Lloyd-Jones, Sandra Beech, Andrew Scarsbrook, Victoria Ashford-Turner, Elaine Smith, Susan Mbale, Nick Adams, and Gail Pottinger
Subjects: Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Abstract: Solitary pulmonary nodules (SPNs) measuring 8 to 30 mm in diameter require further workup to determine the likelihood of malignancy.What is the diagnostic performance of a lung cancer prediction convolutional neural network (LCP-CNN) in SPNs using unenhanced and contrast-enhanced CT imaging compared with the current clinical workup?This was a post hoc analysis of the Single Pulmonary Nodule Investigation: Accuracy and Cost-Effectiveness of Dynamic Contrast Enhanced Computed Tomography in the Characterisation of Solitary Pulmonary Nodules trial, a prospective multicenter study comparing the diagnostic accuracy of dynamic contrast-enhanced (DCE) CT imaging with PET imaging in SPNs. The LCP-CNN was designed and validated in an external cohort. LCP-CNN-generated risk scores were created from the noncontrast and contrast-enhanced CT scan images from the DCE CT imaging. The gold standard was histologic analysis or 2 years of follow-up. The area under the receiver operating characteristic curves (AUC) were calculated using LCP-CNN score, maximum standardized uptake value, and DCE CT scan maximum enhancement and were compared using the DeLong test.Two hundred seventy participants (mean ± SD age, 68.3 ± 8.8 years; 49% women) underwent PET with CT scan imaging and DCE CT imaging with CT scan data available centrally for LCP-CNN analysis. The accuracy of the LCP-CNN on the noncontrast images (AUC, 0.83; 95% CI, 0.79-0.88) was superior to that of DCE CT imaging (AUC, 0.76; 95% CI, 0.69-0.82; P = .03) and equal to that of PET with CT scan imaging (AUC, 0.86; 95% CI, 0.81-0.90; P = .35). The presence of contrast resulted in a small reduction in diagnostic accuracy, with the AUC falling from 0.83 (95% CI, 0.79-0.88) on the noncontrast images to 0.80 to 0.83 after contrast (P .05 for 240 s after contrast only).An LCP-CNN algorithm provides an AUC equivalent to PET with CT scan imaging in the diagnosis of solitary pulmonary nodules.ClinicalTrials.gov Identifier; No.: NCT02013063.
Published: 2023
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7. Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options.Significance:Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494
Published: 2023
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8. Table S3 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Table S3 contains the karyotypes of 16 genome-wide LOH MPM cases from the BWH cohort.
Published: 2023
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9. 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: John K. Field, Stephen W. Duffy, David M. Hansell, Jonathan Myles, Paula R. Williamson, David Weller, Nicholas Wald, Mahesh Parmar, Richard Page, Keith M. Kerr, David Whynes, Kate Lifford, Christopher J. Hands, Robert C. Rintoul, Nicholas Screaton, Martin Ledson, John A. Holemans, Tim Eisen, Kate E. Brain, Anand Devaraj, David R. Baldwin, Ghasem Yadegarfar, and Fiona E. McRonald
Abstract: PDF file - 372K, Figure S1: Trial Recruitment Process for UKLS Pilot Study. Figure S2: Social Demographics of UKLS sample: Distribution of individuals within IMD National Quintiles, by area. Table S1: Smoking status by IMD quintile for all UKLS positive responders, n=23,794. Table S2: Smoking status by IMD quintile for all UKLS negative responders, n=23,794. Table S3: Population figures for smoking status according to IMD quintile, age matched (in five-year bands) to the UKLS sample (Data extracted from Health Survey for England, 2010; accessed via Economic and Social Data Service.
Published: 2023
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10. Supplementary Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Supplementary materials and methods, as well as supplementary figures S1-S7.
Published: 2023
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11. Supplementary Methods from Two Novel Determinants of Etoposide Resistance in Small Cell Lung Cancer

Author: Gillian Murphy, Robert C. Rintoul, James D. Brenton, Roslin Russell, Doris M. Rassl, Natalie M. Cummings, and Malcolm H. Lawson
Abstract: Supplementary Methods from Two Novel Determinants of Etoposide Resistance in Small Cell Lung Cancer
Published: 2023
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12. Supplementary Figure 1 from CD133+ Cancer Stem-like Cells in Small Cell Lung Cancer Are Highly Tumorigenic and Chemoresistant but Sensitive to a Novel Neuropeptide Antagonist

Author: Tariq Sethi, Christopher D. Gregory, Stuart J. Forbes, Wei Wang, Doris M. Rassl, Robert C. Rintoul, Mark Bradley, Nicolaos Avlonitis, Alison C. Mackinnon, and Sana Sarvi
Abstract: PDF file - 519KB, Apoptosis in etoposide treated H345 cells and etoposide treated mouse tumors immunostained for CD133 and GRP-R.
Published: 2023
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13. Data from CD133+ Cancer Stem-like Cells in Small Cell Lung Cancer Are Highly Tumorigenic and Chemoresistant but Sensitive to a Novel Neuropeptide Antagonist

Author: Tariq Sethi, Christopher D. Gregory, Stuart J. Forbes, Wei Wang, Doris M. Rassl, Robert C. Rintoul, Mark Bradley, Nicolaos Avlonitis, Alison C. Mackinnon, and Sana Sarvi
Abstract: Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor survival rates, with initial responses nearly invariably followed by rapid recurrence of therapy-resistant disease. Drug resistance in SCLC may be attributable to the persistence of a subpopulation of cancer stem-like cells (CSC) that exhibit multiple drug resistance. In this study, we characterized the expression of CD133, one important marker of CSC in other cancers, in SCLC cancer cells. CD133 expression correlated with chemoresistance and increased tumorigenicity in vitro and in vivo accompanied by increased expression of Akt/PKB and Bcl-2. CD133 expression was increased in mouse and human SCLC after chemotherapy, an observation confirmed in clinical specimens isolated longitudinally from a patient receiving chemotherapy. We discovered in CD133+ SCLC cells, an increased expression of the mitogenic neuropeptide receptors for gastrin-releasing peptide and arginine vasopressin. Notably, these cells exhibited increased sensitivity to the growth inhibitory and proapoptotic effects of a novel broad spectrum neuropeptide antagonist (related to SP-G), which has completed a phase I clinical trial for SCLC. Our results offer evidence that this agent can preferentially target chemoresistant CD133+ cells with CSC character in SCLC, emphasizing its potential utility for improving therapy in this setting. Cancer Res; 74(5); 1554–65. ©2014 AACR.
Published: 2023
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14. Supplementary Table 1 from CD133+ Cancer Stem-like Cells in Small Cell Lung Cancer Are Highly Tumorigenic and Chemoresistant but Sensitive to a Novel Neuropeptide Antagonist

Author: Tariq Sethi, Christopher D. Gregory, Stuart J. Forbes, Wei Wang, Doris M. Rassl, Robert C. Rintoul, Mark Bradley, Nicolaos Avlonitis, Alison C. Mackinnon, and Sana Sarvi
Abstract: PDF file - 82KB, IC50 values in uM of H345 and H69 cells treated with substance-P analogues.
Published: 2023
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15. Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma

Author: Joanna Obacz, Reshma Nibhani, Taylor S. Adams, Jonas C. Schupp, Jose Antonio Valer, Niki Veale, Giuseppe Aresu, Aman S. Coonar, Adam Peryt, Giulia Biffi, Naftali Kaminski, Hayley Francies, Doris M. Rassl, Matthew J Garnett, Robert C. Rintoul, and Stefan J. Marciniak
Abstract: The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here we present the first comprehensive single cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiplein vitromodels of benign and malignant mesothelial cells, and characterise these through comparison within vivotranscriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at single cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. For example, it has already enabled us to shed light on the transdifferentiation of mesothelial cells allowing us to develop a simple method for prolonging mesothelial cell differentiation in vitro.
Published: 2022
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16. Respiratory cytology in malignant lung disease – The thoracic oncologist’s perspective

Author: Niki Veale, Laura Succony, Robert C. Rintoul, and Doris Rassl
Subjects: Oncology, Endoscopic ultrasound, medicine.medical_specialty, Sputum Cytology, Lung Neoplasms, Histology, Genomic profiling, Cytodiagnosis, Malignancy, Pathology and Forensic Medicine, Cytology, Thoracic Oncology, Internal medicine, Bronchoscopy, Humans, Medicine, Lung cancer, Endoscopic Ultrasound-Guided Fine Needle Aspiration, Oncologists, medicine.diagnostic_test, business.industry, Mediastinum, General Medicine, medicine.disease, Lung disease, Lymph Nodes, business
Abstract: Respiratory cytology continues to play a central role in the diagnosis and staging of thoracic malignancy, although over time indications have changed. Historically, sputum cytology and endobronchial brushings and washings figured prominently, but with the advent of endobronchial and endoscopic ultrasound much greater emphasis is placed on fine needle aspirates from lymph nodes. The advent of targeted sequencing panels for genomic profiling to identify driver mutations and PD-L1 directed immunotherapy means that there is a need to extract increasing amounts of diagnostic and predictive information from ever smaller amounts of diagnostic material. Recent work has demonstrated that cytology samples are well suited to delivering the information required, but in order to understand the limitations of clinical and laboratory techniques, a close working relationship between pathologist and thoracic oncologist is needed to optimise sample procurement and utilisation.
Published: 2021
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17. Biological basis for novel mesothelioma therapies

Author: Stefan J. Marciniak, David Fairen-Jimenez, Xiewen Liu, Robert C. Rintoul, Marie Shamseddin, Marko Nikolic, Arsalan A. Azad, Joanna Obacz, Emily Linnane, Doris Rassl, Henry Yung, Obacz, Joanna [0000-0002-4539-9946], Fairen-Jimenez, David [0000-0002-5013-1194], Nikolić, Marko Z. [0000-0001-6304-6848], Marciniak, Stefan J. [0000-0001-8472-7183], Apollo - University of Cambridge Repository, Nikolić, Marko Z [0000-0001-6304-6848], and Marciniak, Stefan J [0000-0001-8472-7183]
Subjects: 0301 basic medicine, Oncology, Mesothelioma, Cancer Research, medicine.medical_specialty, Review Article, medicine.disease_cause, Asbestos, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Gene Regulatory Networks, business.industry, Nutrient stress, review-article, Aggressive cancer, medicine.disease, Prognosis, Combined Modality Therapy, humanities, respiratory tract diseases, 030104 developmental biology, Mechanisms of disease, 030220 oncology & carcinogenesis, 631/67/1641, Conventional chemotherapy, 631/80/304, business
Abstract: Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351, Funder: Royal Society through a University Research Fellowship and the Engineering and Physical Sciences Research Council (EPRSC), Funder: China Scholarship Council (CSC); doi: https://doi.org/10.13039/501100004543, Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.
Published: 2021

18. Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom

Author: M Estée Török, Benjamin R Underwood, Mark Toshner, Claire Waddington, Emad Sidhom, Katherine Sharrocks, Rachel Bousfield, Charlotte Summers, Caroline Saunders, Zoe McIntyre, Helen Morris, Jo Piper, Gloria Calderon, Sarah Dennis, Tracy Assari, Anita Marguerie de Rotrou, Ashley Shaw, John Bradley, John O’Brien, Robert C Rintoul, Ian Smith, Ed Bullmore, Krishna Chatterjee, Carla Ribeiro, Lorinda Pickup, Ranalie de Jesus, Karen Brookes, Phoebe Vargas, Caroline McMahon, Chiara Macor, Ciro Pasquale, Areti Bermperi, Evgenia Kourampa, Marivic Fabiculcana, Julie Ann Zerudo, Vivien Mendoza, Stewart Fuller, Claire Glemas, Sharon Baker, Greta Lyons, Marina Bishop, Siobhan Coleman, Naomi Thomas, Vince Mlilo, Edward Stanton, Rachel Michel, Julie Philips, Heidi Rice, Lucie Garner, Francesca Rosa, Saji Victor, Julie Zamikula, Sue Mepham, Fatima Hajee, Juan Carlos Quijano-Campos, Laura Watson, Christopher Georgiou, Jieniean Worsley, Djamilla Shamtally-Amode, Ferishta Rahimi, Heather Jones, Isabel Cruz, Gayle Lindsay, Christian Sparke, Anna Chapman, Katie Keating-Fedders, Codie Fahey, Danielle Johnson, Lucy Worboys, Simone Hargreaves, Ashlea Bucke, Lindsay Carr, Jackie Hampshire, Tracy Richardson, Jenny Sharpe, Lynne Whitehead, Naval Vyse, Stephen Kelleher, Mary-Beth Sherwood, Vicki Hughes, Kim Giraud, Török, M Estée [0000-0001-9098-8590], and Apollo - University of Cambridge Repository
Subjects: medicine.medical_specialty, COVID-19 Vaccines, Design, Best practice, coronavirus, 01 natural sciences, State Medicine, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, vaccine, Political science, Pandemic, medicine, Humans, 030212 general & internal medicine, 0101 mathematics, Pandemics, Pharmacology, Clinical Trials as Topic, Medical education, SARS-CoV-2, business.industry, pandemic, Public health, Teleconference, Vaccine trial, COVID-19, Information technology, clinical trial, General Medicine, Project team, United Kingdom, 3. Good health, Clinical trial, business
Abstract: The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency.
Published: 2021
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19. A tumour-promoting senescent secretome triggered by platinum chemotherapy exploits a targetable TGFβR1/Akt-mTOR axis in lung cancer

Author: Estela González-Gualda, David Macias, Samir Morsli, José Ezequiel Martín, Hui-Ling Ou, Mary Denholm, Ioana Olan, Reuben Hoffmann, Mark Dane, Dimitris Veroutis, Guillermo Medrano, Francisca Mulero, Carla P. Martins, Mariano Barbacid, Vassilis Gorgoulis, James E. Korkola, Doris M. Rassl, Gary J. Doherty, Robert C. Rintoul, Masashi Narita, and Daniel Muñoz-Espín
Abstract: Platinum-based chemotherapy is commonly used for non-small cell lung cancer (NSCLC) treatment, yet clinical outcomes remain poor. Cellular senescence and its associated secretory phenotype (SASP) can have multiple tumour-promoting activities, although these are largely unexplored in lung cancer. Here we show that cisplatin-derived SASP enhances the malignant phenotype of lung cancer cells. Using xenograft, orthotopic and KrasG12V-driven murine NSCLC models, we demonstrate that cisplatin-induced senescent cells strongly promote tumour progression. Mechanistically, we find that a TGF-β-enriched SASP drives pro-proliferative effects through TGFβR1 and Akt/mTOR pathway activation. We validate the translational relevance of chemotherapy-induced SASP using clinical NSCLC samples from patients who received neoadjuvant platinum-based chemotherapy. Importantly, TGFβR1 inhibition with galunisertib or senolytic treatment significantly reduces tumour promotion driven by cisplatin-induced senescence. Finally, we demonstrate, using distinct murine NSCLC models, that addition of TGFBR1 inhibitors to platinum-based chemotherapy reduces tumour burden and improves survival, providing pre-clinical proof-of-concept for future trial designs.
Published: 2022
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20. Author Correction: Integrated genomics point to immune vulnerabilities in pleural mesothelioma

Author: Anca Nastase, Amit Mandal, Shir Kiong Lu, Hima Anbunathan, Deborah Morris‑Rosendahl, Yu Zhi Zhang, Xiao‑Ming Sun, Spyridon Gennatas, Robert C. Rintoul, Matthew Edwards, Alex Bowman, Tatyana Chernova, Tim Benepal, Eric Lim, Anthony Newman Taylor, Andrew G. Nicholson, Sanjay Popat, Anne E. Willis, Marion MacFarlane, Mark Lathrop, Anne M. Bowcock, Miriam F. Moffatt, and William O. C. M. Cookson
Subjects: Multidisciplinary
Published: 2022
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21. Determinants of expression of SARS-CoV-2 entry-related genes in upper and lower airways

Author: K Malmström, A. Faiz, Maria Stella de Biase, Corry-Anke Brandsma, Michele A. Grimbaldeston, Gaik W. Tew, Basil Khuder, Cheng-Jian Xu, G. H. Koppelman, Pieter S. Hiemstra, Cancan Qi, Sile Hu, Roland F. Schwarz, Hananeh Aliee, Paul A. Reyfman, Florian Massip, Robert C. Rintoul, N. H. Hacken, Fabian J. Theis, Ian M. Adcock, Xiaoyu Zhang, Nazanin Zounemat Kermani, Bruce A.J. Ponder, Mika J. Mäkelä, Martijn C. Nawijn, Elin T G Kersten, Jos van Nijnatten, Judith M. Vonk, Roel Vermeulen, Kai Sun, Yike Guo, W. Timens, Margaret Neighbors, Maarten van den Berge, Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), HUS Inflammation Center, Department of Dermatology, Allergology and Venereology, Commission of the European Communities, Medical Research Council (MRC), and Engineering & Physical Science Research Council (EPSRC)
Subjects: 0303 health sciences, 2019-20 coronavirus outbreak, Science & Technology, Letter, Coronavirus disease 2019 (COVID-19), Allergy, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, INER-Ciencias Mexican Lung Program, Virology, Cambridge Lung Cancer Early Detection Programme, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, 1107 Immunology, 3121 General medicine, internal medicine and other clinical medicine, Immunology and Allergy, Medicine, U-BIOPRED study group, Letters, business, Gene, Life Sciences & Biomedicine, 030304 developmental biology
Abstract: The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed at preventing spread of the virus and reducing progression to severe disease, detailed knowledge of the cell types and regulating factors driving cellular entry is urgently needed. Here we assess the expression patterns in genes required for COVID-19 entry into cells and replication, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Matched samples from the upper and lower airways show a clear increased expression of these genes in the nose compared to the bronchi and parenchyma. Cellular deconvolution indicates a clear association of these genes with the proportion of secretory epithelial cells. Smoking status was found to increase the majority of COVID-19 related genes including ACE2 and TMPRSS2 but only in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of current smokers. Both acute and second hand smoke were found to increase ACE2 expression in the bronchus. Inhaled corticosteroids decrease ACE2 expression in the lower airways. No significant effect of genetics on ACE2 expression was observed, but a strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified in the bronchus.
Published: 2022

22. Integrated genomics point to immune vulnerabilities in pleural mesothelioma

Author: Hima Anbunathan, Anne M. Bowcock, Yu Zhi Zhang, William O.C.M. Cookson, Miriam F. Moffatt, Tatyana Chernova, S. Gennatas, Anne E. Willis, Mark Lathrop, I. Alex Bowman, Eric Lim, A. Mandal, Marion MacFarlane, Anthony Newman Taylor, Sanjay Popat, Tim Benepal, A. Nastase, Matthew S. Edwards, Deborah J. Morris-Rosendahl, Robert C. Rintoul, Andrew G. Nicholson, Xiao-Ming Sun, Shir Kiong Lu, Guys & St Thomas NHS Foundation Trust, Department of Health, Rintoul, Robert [0000-0003-3875-3780], Willis, Anne [0000-0002-1470-8531], Apollo - University of Cambridge Repository, Mandal, Amit [0000-0002-2530-8103], and Willis, Anne E [0000-0002-1470-8531]
Subjects: Male, Molecular biology, medicine.medical_treatment, Biopsy, Aurora kinase, CDKN2A, Medicine, Mesothelioma, Cancer, YAP1, Aged, 80 and over, Multidisciplinary, 631/250, article, Genomics, Middle Aged, Gene Expression Regulation, Neoplastic, Oncology, Pleura, Female, 631/337, medicine.drug, 631/67, DNA Copy Number Variations, Science, Pleural Neoplasms, Immunology, 692/308, Primary Cell Culture, Antineoplastic Agents, Malignancy, 692/4028, Medical research, 692/53, Biomarkers, Tumor, Humans, Hippo Signaling Pathway, Hedgehog, Aged, Whole Genome Sequencing, business.industry, Gene Expression Profiling, Mesothelioma, Malignant, Immunotherapy, medicine.disease, Computational biology and bioinformatics, Mutation, Cancer research, 631/114, business, Biomarkers, Interferon type I
Abstract: Funder: Libor Fund grant from the UK Department of Health, by the British Lung Foundation and by the Asmarley Foundation, Funder: UK Medical Research Council, Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.
Published: 2021
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23. Smoking-dependent expression alterations in nasal epithelium reveal immune impairment linked to germline variation and lung cancer risk

Author: Maria Stella de Biase, Florian Massip, Tzu-Ting Wei, Federico M. Giorgi, Rory Stark, Amanda Stone, Amy Gladwell, MarJn O’Reilly, Daniel Schütte, Ines de Santiago, Kerstin B. Meyer, Florian Markowetz, Bruce A J Ponder, Robert C Rintoul, and Roland F Schwarz
Subjects: Oncology, medicine.medical_specialty, education.field_of_study, Lung, business.industry, Incidence (epidemiology), medicine.medical_treatment, Population, medicine.disease, Germline, Transcriptome, Immune system, medicine.anatomical_structure, Internal medicine, medicine, Smoking cessation, Lung cancer, education, business
Abstract: Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to modifiable lifestyle risk in the form of tobacco smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk are unclear.To examine whether risk stratification in the clinic and in the general population can be improved upon by the addition of genetic data, and to explore the mechanisms of the persisting risk in former smokers, we have analysed transcriptomic data from accessible airway tissues of 487 subjects, including healthy volunteers and clinic patients of different smoking status. We developed a model to assess smoking associated gene expression changes and their reversibility after smoking is stopped, comparing healthy subjects to clinic patients with and without lung cancer. We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune and interferon related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier.Our results provide initial evidence for germline-mediated personalised smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.
Published: 2021
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24. S98 Dissecting human pleura at single-cell resolution

Author: Stefan J. Marciniak, Robert C. Rintoul, Giuseppe Aresu, Joanna Obacz, Naftali Kaminski, Taylor Adams, A Peryt, AS Coonar, Doris Rassl, and Jonas C. Schupp
Subjects: Optics, business.industry, Resolution (electron density), Medicine, business
Published: 2021
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25. Multimodality Approaches to Screening for Lung Cancer

Author: L. Succony, Nitzan Rosenfeld, and Robert C. Rintoul
Subjects: Oncology, medicine.medical_specialty, Text mining, business.industry, Internal medicine, Medicine, Radiology, Nuclear Medicine and imaging, business, Lung cancer, medicine.disease, Multimodality
Published: 2019
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26. Prophylactic Irradiation of Tracts in Patients With Malignant Pleural Mesothelioma: An Open-Label, Multicenter, Phase III Randomized Trial

Author: Andrew Bates, Corinne Faivre-Finn, Liz Darlison, Talal Mansy, Linda Ashcroft, Apurna Jegannathen, N. Bayman, Laura S Pemberton, Veni Ezhil, W David J Ryder, Matthew Hatton, Michael D Peake, David R Baldwin, Paul Taylor, M. Snee, W. Appel, David Gilligan, Robert C. Rintoul, and John G. Edwards
Subjects: Cancer Research, medicine.medical_specialty, business.industry, Pleural mesothelioma, medicine.disease, law.invention, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Oncology, Multicenter study, Randomized controlled trial, law, 030220 oncology & carcinogenesis, medicine, In patient, Mesothelioma, Radiology, Open label, business
Abstract: PURPOSE Prophylactic irradiation to the chest wall after diagnostic or therapeutic procedures in patients with malignant pleural mesothelioma (MPM) has been a widespread practice across Europe, although the efficacy of this treatment is uncertain. In this study, we aimed to determine the efficacy of prophylactic radiotherapy in reducing the incidence of chest wall metastases (CWM) after a procedure in MPM. METHODS After undergoing a chest wall procedure, patients with MPM were randomly assigned to receive prophylactic radiotherapy (within 42 days of the procedure) or no radiotherapy. Open thoracotomies, needle biopsies, and indwelling pleural catheters were excluded. Prophylactic radiotherapy was delivered at a dose of 21 Gy in three fractions over three consecutive working days, using a single electron field adapted to maximize coverage of the tract from skin surface to pleura. The primary outcome was the incidence of CWM within 6 months from random assignment, assessed in the intention-to-treat population. Stratification factors included epithelioid histology and intention to give chemotherapy. RESULTS Between July 30, 2012, and December 12, 2015, 375 patients were recruited from 54 centers and randomly assigned to receive prophylactic radiotherapy (n = 186) or no prophylactic radiotherapy (n = 189). Participants were well matched at baseline. No significant difference was seen in the incidence of CWM at 6 months between the prophylactic radiotherapy and no radiotherapy groups (no. [%]: 6 [3.2] v 10 [5.3], respectively; odds ratio, 0.60; 95% CI, 0.17 to 1.86; P = .44). Skin toxicity was the most common radiotherapy-related adverse event in the prophylactic radiotherapy group, with 96 patients (51.6%) receiving grade 1; 19 (10.2%), grade 2; and 1 (0.5%) grade 3 radiation dermatitis (Common Terminology Criteria for Adverse Events, version 4.0). CONCLUSION There is no role for the routine use of prophylactic irradiation to chest wall procedure sites in patients with MPM.
Published: 2019
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27. ctDNA detection by personalised assays in early-stage NSCLC

Author: Susan Harden, Wendi Qian, Wan Jcm, Katrin Heider, Timothy Eisen, K. Howarth, Rundell, Robert C. Rintoul, David Gilligan, Nagmi R. Qureshi, Castedo J, Charles E. Massie, Doris Rassl, Knock H, Florent Mouliere, Andrea Ruiz-Valdepeñas, Emma Green, Nitzan Rosenfeld, James Morris, Christopher Smith, Jerome Wulff, Wendy N. Cooper, and Davina Gale
Subjects: Oncology, medicine.medical_specialty, business.industry, Hazard ratio, Cancer, medicine.disease, Internal medicine, Cohort, medicine, Adenocarcinoma, Non small cell, Stage (cooking), business, Exome, Exome sequencing
Abstract: Blood-based assays have shown increasing ability to detect circulating tumour DNA (ctDNA) in patients with early-stage cancer. However, detection of ctDNA in patients with non-small cell lung cancer (NSCLC) has continued to prove challenging. We performed retrospective analysis to quantify ctDNA levels in a cohort of 100 patients with early-stage NSCLC prior to treatment with curative intent enrolled in the LUCID study (NCT04153526). Where tumour tissue was available for whole exome sequencing, mutations identified were used to define patient-specific sequencing assays. For those 90 patients, plasma cell-free DNA was sequenced to high depth across capture panels targeting a median of 328 mutations specific to each patient. Data was analysed using Integration of Variant Reads (INVAR), detecting ctDNA in 66.7% of patients, including 52.7% (29 of 55) patients with stage I disease and >88% detection for patients with stage II and III disease (16/18 and 15/17). ctDNA was detected in plasma at fractional concentrations as low as 9.1×10−6, and in patients with tumour volumes as low as 0.23 cm3. A 36-gene sequencing panel (InVisionFirst-Lung™) was used to analyse plasma DNA in 27 samples including the 10 cases without tumour exome data, and detected ctDNA in 59% of samples tested (16 of 27). Across the entire cohort, detection rates were higher in squamous cell carcinoma patients compared to adenocarcinoma patients (81% vs. 59%). Detection of ctDNA prior to treatment was associated with significantly shorter time free from relapse, across all patients and in patient subgroups, with Hazard Ratios >11 for selected patient subsets. Our analysis indicates that for patients with stage I NSCLC, the median ctDNA fraction in plasma is approx. 12 parts per million (0.0012%). This indicates the limits of detection that would be required for ctDNA-based liquid biopsies to detect ctDNA in the majority of patients with early-stage NSCLC.
Published: 2021
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28. Impact of solitary pulmonary nodule size on qualitative and quantitative assessment using 18F-fluorodeoxyglucose PET/CT:the SPUTNIK trial

Author: Sabina Dizdarevic, Nagmi R. Qureshi, Lucy Pike, Kenneth A. Miles, Robert C. Rintoul, Jonathan R. Weir-McCall, Heok Cheow, Fiona J. Gilbert, Scott Harris, Weir-McCall, JR [0000-0001-5842-842X], and Apollo - University of Cambridge Repository
Subjects: Lung Neoplasms, Cost effectiveness, PET/CT, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography, Biopsy, medicine, Medical imaging, Humans, Radiology, Nuclear Medicine and imaging, Prospective Studies, Lung cancer, Retrospective Studies, PET-CT, Solitary pulmonary nodule, medicine.diagnostic_test, business.industry, Mediastinum, Solitary Pulmonary Nodule, Nodule (medicine), General Medicine, medicine.disease, DCE-CT, medicine.anatomical_structure, Positron-Emission Tomography, Diagnostic accuracy trial, Diagnostic imaging, Original Article, Cost-effectiveness, Solitary pulmonary nodule (SPN), medicine.symptom, Radiopharmaceuticals, Nuclear medicine, business
Abstract: Purpose To compare qualitative and semi-quantitative PET/CT criteria, and the impact of nodule size on the diagnosis of solitary pulmonary nodules in a prospective multicentre trial. Methods Patients with an SPN on CT ≥ 8 and ≤ 30 mm were recruited to the SPUTNIK trial at 16 sites accredited by the UK PET Core Lab. Qualitative assessment used a five-point ordinal PET-grade compared to the mediastinal blood pool, and a combined PET/CT grade using the CT features. Semi-quantitative measures included SUVmax of the nodule, and as an uptake ratio to the mediastinal blood pool (SURBLOOD) or liver (SURLIVER). The endpoints were diagnosis of lung cancer via biopsy/histology or completion of 2-year follow-up. Impact of nodule size was analysed by comparison between nodule size tertiles. Results Three hundred fifty-five participants completed PET/CT and 2-year follow-up, with 59% (209/355) malignant nodules. The AUCs of the three techniques were SUVmax 0.87 (95% CI 0.83;0.91); SURBLOOD 0.87 (95% CI 0.83; 0.91, p = 0.30 versus SUVmax); and SURLIVER 0.87 (95% CI 0.83; 0.91, p = 0.09 vs. SUVmax). The AUCs for all techniques remained stable across size tertiles (p > 0.1 for difference), although the optimal diagnostic threshold varied by size. For nodules 16 mm, an SUVmax ≥ 3.6 or visual PET uptake greater than the mediastinum was the most accurate. Conclusion In this multicentre trial, SUVmax was the most accurate technique for the diagnosis of solitary pulmonary nodules. Diagnostic thresholds should be altered according to nodule size. Trial registration ISRCTN - ISRCTN30784948. ClinicalTrials.gov - NCT02013063
Published: 2021
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29. Communicating uncertainty:contrasting the communication experiences of patients with advanced COPD and incurable lung cancer

Author: Morag Farquhar, Scott A Murray, Nothando B. Ngwenya, Stephen Barclay, Lori D Calvert, Robert C. Rintoul, Ravi Mahadeva, Clare Crang, Ngwenya, Nothando [0000-0002-5630-6389], and Apollo - University of Cambridge Repository
Subjects: Advance care planning, medicine.medical_specialty, Lung Neoplasms, media_common.quotation_subject, Disease, Secondary care, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Health care, medicine, health communication, Humans, Conversation, 030212 general & internal medicine, Intensive care medicine, Lung cancer, chronic obstructive pulmonary disease (COPD), Health communication, Qualitative Research, media_common, COPD, business.industry, 030503 health policy & services, Communication, Palliative Care, Uncertainty, medicine.disease, respiratory tract diseases, primary health care, lung cancer, 0305 other medical science, Family Practice, business
Abstract: Due to the uncertain disease trajectory and variable rate of progression in chronic obstructive pulmonary disease (COPD), health care professionals (HCPs) are challenged in explaining what the future may hold for patients compared to those with lung cancer (LC). Support and communication of timely information can significantly improve health outcomes.This study sought to identify factors that impact communication and support and recommend ways to improve patients' understanding of living with life-threatening illness.Semi-structured interviews with patients with LC (n = 22) and advanced COPD (n = 18), their informal carers (21 LC and 18 COPD) and HCPs (n = 51). Patients were recruited from primary and secondary care in the East of England, UK, during 2010-12.Directness and clarity characterized communication in LC, whereas uncertainty and limited explanations predominated in COPD. Discussions on how the disease might impact on decisions and preferences to be made in the future were less common in COPD. Information for LC patients was mainly from hospital clinicians and any information for COPD patients mainly from primary care clinicians.The experience of COPD patients could be improved by professionals soon after diagnosis explaining to them the typical pattern of decline in COPD, highlighting the inherent uncertainties about when exacerbations and death may occur. This conversation should lead to planning for the different challenges that the patient and informal carer recognize as most important to them. This contrasts with the 'breaking bad news' conversation that oncologists are highly trained to deliver.People living with lung cancer (LC) or chronic obstructive pulmonary disease (COPD) have poor health-related quality of life. However, more people with LC receive holistic palliative care (which involves supportive advance care planning) than those with COPD. We interviewed patients with LC or COPD, their informal carers (family/friends who support them) and health care professionals (HCPs) about their experiences and our findings confirmed this: HCPs said the uncertainty of COPD prognosis made starting advance care planning conversations challenging. The level of uncertainty and unpredictability is very different in LC and COPD: the cancer diagnosis is made at a single point in time with mortality immediately on the agenda, while COPD is a chronic condition that develops over many years. We urge clinicians to share this uncertainty with patients and to try to explain and communicate it sooner than later. These conversations should also continue as a recognized part of ongoing care so that COPD patients can benefit from understanding the uncertainties they are dealing and living with. LC and COPD should be approached differently to meet patients’ condition-specific needs in order that the existing disparity in holistic care can be remedied.
Published: 2021
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30. SARS-CoV-2-induced senescence as a potential therapeutic target

Author: Mary Denholm, Robert C. Rintoul, and Daniel Muñoz-Espín
Subjects: Pulmonary and Respiratory Medicine, Phenotype, Mutagenesis, SARS-CoV-2, viruses, fungi, COVID-19, Humans, Pneumonia, Original Research Article
Abstract: Background SARS-CoV-2 infection of the respiratory system can progress to a multi-systemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named as senescence-associated secretory phenotype (SASP). We investigated whether COVID-19 disease is associated with cellular senescence and SASP. Methods Autopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID controls with similar comorbidities were analysed by immunohistochemistry for SARS-CoV-2, markers of senescence and key SASP cytokines. Virally-induced senescence was functionally recapitulated in vitro, by infecting epithelial Vero-E6 cells and a three-dimensional alveosphere system of alveolar type 2 (AT2) cells with SARS-CoV-2 strains isolated from COVID-19 patients. Results SARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in AT2 cells. Infected AT2 cells expressed the angiotensin-converting-enzyme 2 (ACE2) and exhibited increased senescence (p16INK4A and SenTraGorTM positivity) and IL-1β and IL-6 expression. In vitro, infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGorTM), DNA damage (γ-H2AX) and increased cytokine (IL-1β, IL-6, CXCL8) and Apolipoprotein B mRNA-editing (APOBEC) enzyme expression. Next-generation-sequencing analysis of progenies obtained from infected/senescent Vero-E6 cells demonstrated APOBEC-mediated SARS-CoV-2 mutations. Dissemination of the SARS-CoV-2-infection and senescence was confirmed in extra-pulmonary sites (kidney and liver) of a COVID-19 patient. Conclusions We demonstrate that in severe COVID-19, AT2 cells infected by SARS-CoV-2 exhibit senescence and a proinflammatory phenotype. In vitro, SARS-CoV-2 infection induces senescence and inflammation. Importantly, infected senescent cells may act as a source of SARS-CoV-2 mutagenesis mediated by APOBEC enzymes. Therefore, SARS-CoV-2-induced senescence may be an important molecular mechanism of severe COVID-19, disease persistence and mutagenesis.
Published: 2022
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31. Use of preclinical models for malignant pleural mesothelioma

Author: Hayley E. Francies, Stefan J. Marciniak, Marie Shamseddin, Joanna Obacz, Robert C. Rintoul, Mathew J. Garnett, Rintoul, Robert Campbell [0000-0003-3875-3780], Marciniak, Stefan John [0000-0001-8472-7183], and Apollo - University of Cambridge Repository
Subjects: Pulmonary and Respiratory Medicine, Mesothelioma, Lung Neoplasms, Pleural Neoplasms, Disease, 03 medical and health sciences, Pleural disease, Mice, 0302 clinical medicine, pleural disease, State of the Art Review, Medicine, asbestos induced lung disease, Animals, 030304 developmental biology, 0303 health sciences, business.industry, Pleural mesothelioma, Mesothelioma, Malignant, Cancer, Aggressive cancer, Asbestos, medicine.disease, 030220 oncology & carcinogenesis, Pleural fluid, Cancer research, business, Median survival
Abstract: Malignant pleural mesothelioma (MPM) is an aggressive cancer most commonly caused by prior exposure to asbestos. Median survival is 12–18 months, since surgery is ineffective and chemotherapy offers minimal benefit. Preclinical models that faithfully recapitulate the genomic and histopathological features of cancer are critical for the development of new treatments. The most commonly used models of MPM are two-dimensional cell lines established from primary tumours or pleural fluid. While these have provided some important insights into MPM biology, these cell models have significant limitations. In order to address some of these limitations, spheroids and microfluidic chips have more recently been used to investigate the role of the three-dimensional environment in MPM. Efforts have also been made to develop animal models of MPM, including asbestos-induced murine tumour models, MPM-prone genetically modified mice and patient-derived xenografts. Here, we discuss the available in vitro and in vivo models of MPM and highlight their strengths and limitations. We discuss how newer technologies, such as the tumour-derived organoids, might allow us to address the limitations of existing models and aid in the identification of effective treatments for this challenging-to-treat disease.
Published: 2021
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32. Biomarkers in lung cancer screening: the importance of study design

Author: Robert Steele, Robert C. Rintoul, Philip A.J. Crosbie, Matthew E.J. Callister, David R Baldwin, E. O'Dowd, and Hilary A. Robbins
Subjects: Pulmonary and Respiratory Medicine, Research design, Oncology, medicine.medical_specialty, China, Lung Neoplasms, Cost effectiveness, Lung Neoplasms/diagnosis, Population, MEDLINE, Methylation, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Carcinoma, Non-Small-Cell Lung, Biomarkers, Tumor, Medicine, Humans, 030212 general & internal medicine, Prospective Studies, Lung cancer, education, Lung, Early Detection of Cancer, education.field_of_study, business.industry, Lung Cancer, Original Articles, medicine.disease, respiratory tract diseases, Ct screening, 030228 respiratory system, Research Design, business, Lung cancer screening
Abstract: Aim Lung cancer screening reduces mortality. We aim to validate the performance of Lung EpiCheck, a six-marker panel methylation-based plasma test, in the detection of lung cancer in European and Chinese samples. Methods A case–control European training set (n=102 lung cancer cases, n=265 controls) was used to define the panel and algorithm. Two cut-offs were selected, low cut-off (LCO) for high sensitivity and high cut-off (HCO) for high specificity. The performance was validated in case–control European and Chinese validation sets (cases/controls 179/137 and 30/15, respectively). Results The European and Chinese validation sets achieved AUCs of 0.882 and 0.899, respectively. The sensitivities/specificities with LCO were 87.2%/64.2% and 76.7%/93.3%, and with HCO they were 74.3%/90.5% and 56.7%/100.0%, respectively. Stage I nonsmall cell lung cancer (NSCLC) sensitivity in European and Chinese samples with LCO was 78.4% and 70.0% and with HCO was 62.2% and 30.0%, respectively. Small cell lung cancer (SCLC) was represented only in the European set and sensitivities with LCO and HCO were 100.0% and 93.3%, respectively. In multivariable analyses of the European validation set, the assay's ability to predict lung cancer was independent of established risk factors (age, smoking, COPD), and overall AUC was 0.942. Conclusions Lung EpiCheck demonstrated strong performance in lung cancer prediction in case–control European and Chinese samples, detecting high proportions of early-stage NSCLC and SCLC and significantly improving predictive accuracy when added to established risk factors. Prospective studies are required to confirm these findings. Utilising such a simple and inexpensive blood test has the potential to improve compliance and broaden access to screening for at-risk populations., Lung EpiCheck, a simple blood test, detected 85% of early-stage lung cancers with specificity of 64% in high-risk population, reaching AUC of 0.942 when combined with risk factors. This could improve efficiency of implementing lung cancer screening. https://bit.ly/3jWhLOn
Published: 2021
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33. Lesson of the month: novel method to quantify neutrophil uptake in early lung cancer using SPECT-CT

Author: Laurence S C Lok, Sarah Heard, Charlotte Summers, A. Michael Peters, John R. Buscombe, Stephen D. Preston, Uta Hill, Daniel Gillett, Mark Southwood, Edwin R. Chilvers, Chrystalla Loutsios, Nicola Tregay, Doris Rassl, Neda Farahi, Robert C. Rintoul, Preston, Stephen Denis [0000-0002-6836-3591], Rintoul, Robert Campbell [0000-0003-3875-3780], Chilvers, Edwin R [0000-0002-4230-9677], and Apollo - University of Cambridge Repository
Subjects: Pulmonary and Respiratory Medicine, Adult, Male, Pathology, medicine.medical_specialty, Lung Neoplasms, Chest clinic, Neutrophils, Early lung cancer, Biopsy, Respiratory System, digestive system, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Lung cancer, 030304 developmental biology, Neoplasm Staging, chemistry.chemical_classification, Tomography, Emission-Computed, Single-Photon, 0303 health sciences, biology, business.industry, Indium Radioisotopes, neutrophil biology, 1103 Clinical Sciences, imaging/CT MRI etc, medicine.disease, 3. Good health, lung cancer, chemistry, Transferrin, 030220 oncology & carcinogenesis, Myeloperoxidase, biology.protein, Female, Non small cell, Lung tumours, business
Abstract: Neutrophils play an important role in the lung tumour microenvironment. We hypothesised that radiolabelled neutrophils coupled to single-photon emission CT (SPECT) may non-invasively quantify neutrophil uptake in tumours from patients with non-small cell lung cancer. We demonstrated increased uptake of radiolabelled neutrophils from the blood into tumours compared with non-specific uptake using radiolabelled transferrin. Moreover, indium-111-neutrophil activity in the tumour biopsies also correlated with myeloperoxidase (MPO)-positive neutrophils. Our data support the utility of imaging with In-111-labelled neutrophils and SPECT-CT to quantify neutrophil uptake in lung cancer.
Published: 2020

34. Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways

Author: Fabian J. Theis, S. Hu, Gaik W. Tew, E. T. G. Kersten, Cheng-Jian Xu, Mika J. Mäkelä, Corry-Anke Brandsma, Yike Guo, Martijn C. Nawijn, Ian M. Adcock, M. van den Berge, Paul A. Reyfman, Xiaoyu Zhang, Bruce A.J. Ponder, Cancan Qi, Hananeh Aliee, J. L. van Nijnatten, Nazanin Zounemat Kermani, Robert C. Rintoul, Wim Timens, Margaret Neighbors, N.H.T. ten Hacken, Florian Massip, Basil Khuder, K. Malmstrom, Gerard H. Koppelman, Roland F. Schwarz, M. Stella de Biase, Alen Faiz, Judith M. Vonk, Roel Vermeulen, Pieter S. Hiemstra, Kaiyuan Sun, and Michele A. Grimbaldeston
Subjects: Cancer Research, Cell type, Respiratory System, Virus, Article, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Parenchyma, medicine, Humans, 030212 general & internal medicine, Epigenetics, Respiratory system, 030304 developmental biology, 0303 health sciences, Bronchus, business.industry, SARS-CoV-2, Serine Endopeptidases, COVID-19, respiratory system, 3. Good health, respiratory tract diseases, medicine.anatomical_structure, Immunology, business, Respiratory tract
Abstract: BackgroundThe recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. A subset of COVID-19 patients progresses to severe disease, with high mortality and limited treatment options. Detailed knowledge of the expression regulation of genes required for viral entry into respiratory epithelial cells is urgently needed.MethodsHere we assess the expression patterns of genes required for SARS-CoV-2 entry into cells, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi).FindingsGenes encoding viral receptors and activating protease are increased in the nose compared to the bronchi in matched samples and associated with the proportion of secretory epithelial cells in cellular deconvolution analyses. Current or ex-smoking was found to increase expression of these genes only in lower airways, which was associated with a significant increase in the predicted proportion of goblet cells. Both acute and second hand smoke exposure were found to increase ACE2 expression while inhaled corticosteroids decrease ACE2 expression in the lower airways. A strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified.InterpretationGenes associated with SARS-CoV-2 viral entry into cells are high in upper airways, but strongly increased in lower airways by smoke exposure. In contrast, ICS decreases ACE2 expression, indicating that inhaled corticosteroids are unlikely to increase the risk for more severe COVID-19 disease.FundingThis work was supported by a Seed Network grant from the Chan Zuckerberg Initiative to M.C.N. and by the European Union’s H2020 Research and Innovation Program under grant agreement no. 874656 (discovAIR) to M.C.N. U BIOPRED was supported by an Innovative Medicines Initiative Joint Undertaking (No. 115010), resources from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution (www.imi.europa.eu). Longfonds Junior Fellowship. We acknowledge the contribution of the whole U-BIOPRED team as listed in the Appendix S1.’ SDB, FM and RFS would like to thank the Helmholtz Association, Germany, for support.” NIH K08HL146943; Parker B. Francis Fellowship; ATS Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. RCR is part funded by Cancer Research UK Cambridge Centre and the Cambridge NIHR Biomedical Research Centre. BAP was funded by programme support from Cancer Research UK. The CRUKPAP Study was supported by the CRUK Cambridge Cancer Centre, by the NIHR Cambridge Biomedical Research Centre and by the Cambridge Bioresource. PIAMA was supported by The Netherlands Organization for Health Research and Development; The Netherlands Organization for Scientific Research; The Netherlands Lung Foundation (with methylation studies supported by AF 4.1.14.001); The Netherlands Ministry of Spatial Planning, Housing, and the Environment; and The Netherlands Ministry of Health, Welfare, and Sport. Dr. Qi is supported by a grant from the China Scholarship Council.
Published: 2020

35. A hypercoagulable state leading to venous limb gangrene associated with occult lung adenocarcinoma

Author: David Gilligan, Stephen D. Preston, Martin Besser, Paul D. Hayes, Anthony W Martinelli, Matthew Waite, Adam Peryt, Emily Symington, Robert C. Rintoul, Emma Gudgin, Patrick A. Coughlin, Waite, Matthew MA [0000-0002-6528-5022], Preston, Stephen D [0000-0002-6836-3591], and Apollo - University of Cambridge Repository
Subjects: medicine.medical_specialty, Case Report, Case Reports, 030204 cardiovascular system & hematology, Argatroban, Dabigatran, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, argatroban, dabigatran, Gangrene, Hematology, Lung, Crizotinib, business.industry, hematology, Idarucizumab, General Medicine, medicine.disease, lung adenocarcinoma, respiratory, medicine.anatomical_structure, hypercoagulability, 030220 oncology & carcinogenesis, Radiology, Occult Lung Adenocarcinoma, business, medicine.drug
Abstract: Key Clinical Message We report a case of lung adenocarcinoma‐associated hypercoagulability leading to venous limb gangrene, managed successfully with argatroban and then dabigatran. Use of idarucizumab permitted diagnostic investigations, leading to targeted antineoplastic therapy with crizotinib, surgical resection with curative intent, and continued survival over 2 years after the index event.
Published: 2019

36. ctDNA monitoring using patient-specific sequencing and integration of variant reads

Author: Carlos Caldas, Irena Hudecova, Katrin Heider, Richard Mair, Pippa Corrie, Charles E. Massie, Christopher Smith, Eyal Fisher, Constantine Alifrangis, Kevin M. Brindle, Amer Durrani, Ultan McDermott, Pui Ying Chan, Mark R. Middleton, Andrew B. Gill, Suzanne Murphy, Grant D. Stewart, Andrea Marshall, Dineika Chandrananda, Robert C. Rintoul, Jean Abraham, Andrea Ruiz-Valdepeñas, Florent Mouliere, Gemma Young, Ferdia A. Gallagher, Jonathan C. M. Wan, Angela Santonja, Doris Rassl, Nitzan Rosenfeld, Wendy N. Cooper, Emily Barker, Francesco Marass, James Morris, Davina Gale, Christine Parkinson, Pathology, CCA - Cancer biology and immunology, Wan, Jonathan CM [0000-0003-0001-1802], Heider, Katrin [0000-0003-4035-1668], Gale, Davina [0000-0002-4521-8199], Fisher, Eyal [0000-0003-3546-6153], Mouliere, Florent [0000-0001-7043-0514], Santonja, Angela [0000-0001-9367-7632], Chandrananda, Dineika [0000-0002-8834-9500], Marshall, Andrea [0000-0002-6610-5812], Gill, Andrew B [0000-0002-9287-9563], Chan, Pui Ying [0000-0001-7804-4482], Barker, Emily [0000-0001-6682-0392], Cooper, Wendy N [0000-0003-3416-9982], Hudecova, Irena [0000-0003-3823-9896], Marass, Francesco [0000-0002-8993-7320], Mair, Richard [0000-0001-8235-5689], Brindle, Kevin M [0000-0003-3883-6287], Stewart, Grant D [0000-0003-3188-9140], Abraham, Jean E [0000-0003-0688-4807], Caldas, Carlos [0000-0003-3547-1489], Alifrangis, Constantine [0000-0002-5876-6696], Middleton, Mark R [0000-0003-0167-1685], Gallagher, Ferdia A [0000-0003-4784-5230], McDermott, Ultan [0000-0001-9032-4700], Smith, Christopher G [0000-0001-7357-2737], Massie, Charles [0000-0003-2314-4843], Corrie, Pippa G [0000-0003-4875-7021], Rosenfeld, Nitzan [0000-0002-2825-4788], and Apollo - University of Cambridge Repository
Subjects: Sequencing data, Computational biology, Biology, Circulating Tumor DNA, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Biomarkers, Tumor, Humans, Liquid biopsy, Genotyping, 030304 developmental biology, 0303 health sciences, Melanoma, Liquid Biopsy, Cancer, High-Throughput Nucleotide Sequencing, General Medicine, DNA, Neoplasm, Patient specific, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Mutation, RC
Abstract: Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >105 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to parts per million. This resulted in median area under the curve (AUC) values of 0.98 in advanced cancers and 0.80 in early-stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that INVAR may be applied without requiring personalized sequencing panels so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.
Published: 2020
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37. Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Author: Joshua D. Campbell, Christina Yau, Reanne Bowlby, Yuexin Liu, Kevin Brennan, Huihui Fan, Alison M. Taylor, Chen Wang, Vonn Walter, Rehan Akbani, Lauren Averett Byers, Chad J. Creighton, Cristian Coarfa, Juliann Shih, Andrew D. Cherniack, Olivier Gevaert, Marcos Prunello, Hui Shen, Pavana Anur, Jianhong Chen, Hui Cheng, D. Neil Hayes, Susan Bullman, Chandra Sekhar Pedamallu, Akinyemi I. Ojesina, Sara Sadeghi, Karen L. Mungall, A. Gordon Robertson, Christopher Benz, Andre Schultz, Rupa S. Kanchi, Carl M. Gay, Apurva Hegde, Lixia Diao, Jing Wang, Wencai Ma, Pavel Sumazin, Hua-Sheng Chiu, Ting-Wen Chen, Preethi Gunaratne, Larry Donehower, Janet S. Rader, Rosemary Zuna, Hikmat Al-Ahmadie, Alexander J. Lazar, Elsa R. Flores, Kenneth Y. Tsai, Jane H. Zhou, Anil K. Rustgi, Esther Drill, Ronglei Shen, Christopher K. Wong, Joshua M. Stuart, Peter W. Laird, Katherine A. Hoadley, John N. Weinstein, Myron Peto, Curtis R. Pickering, Zhong Chen, Carter Van Waes, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Paul Spellman, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Toshinori Hinoue, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, onathan Stretch, Maria Synott, John Thompson, James Wilmott, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, SAIC-F-Frederick, Inc, and Leidos Biomedical Research, Inc.
Subjects: 0301 basic medicine, Genetics and Molecular Biology (all), ANTITUMOR-ACTIVITY, Cancer Genome Atlas Research Network, Biochemistry, transcriptomics, FANCF, HUMAN HEAD, lung squamous cell carcinoma, PHOSPHORYLATION, human papillomavirus, lcsh:QH301-705.5, Regulation of gene expression, INHIBITOR, Genomics, Chromatin, esophageal squamous cell carcinoma, Gene Expression Regulation, Neoplastic, DNA methylation, Carcinoma, Squamous Cell, Life Sciences & Biomedicine, Metabolic Networks and Pathways, EXPRESSION, GENES, Epithelial-Mesenchymal Transition, CANCERS, PROTEINS, Biology, head and neck squamous cell carcinoma, General Biochemistry, Genetics and Molecular Biology, Article, bladder carcinoma with squamous differentiation, cervical squamous cell carcinoma, genomics, proteomics, Biochemistry, Genetics and Molecular Biology (all), 03 medical and health sciences, Cell Line, Tumor, microRNA, Humans, Science & Technology, Polymorphism, Genetic, Oncogene, MUTAÇÃO GENÉTICA, Cell Biology, CELL CARCINOMA, DNA Methylation, Immune checkpoint, stomatognathic diseases, 030104 developmental biology, lcsh:Biology (General), FANCONI-ANEMIA, Cancer research, biology.protein, Demethylase
Abstract: Summary: This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches. : Campbell et al. reveal that squamous cell cancers from different tissue sites may be distinguished from other cancers and subclassified molecularly by recurrent alterations in chromosomes, DNA methylation, messenger and microRNA expression, or by mutations. These affect squamous cell pathways and programs that provide candidates for therapy. Keywords: genomics, transcriptomics, proteomics, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, bladder carcinoma with squamous differentiation, human papillomavirus
Published: 2018

38. Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas

Author: Gregory P. Way, Francisco Sanchez-Vega, Konnor La, Joshua Armenia, Walid K. Chatila, Augustin Luna, Chris Sander, Andrew D. Cherniack, Marco Mina, Giovanni Ciriello, Nikolaus Schultz, Yolanda Sanchez, Casey S. Greene, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Debyani Chakravarty, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Marc Ladanyi, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, Cancer Genome Atlas Research Network, Caesar-Johnson, S.J., Demchok, J.A., Felau, I., Kasapi, M., Ferguson, M.L., Hutter, C.M., Sofia, H.J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J.C., Zhang, J.J., Chudamani, S., Liu, J., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Cho, J., DeFreitas, T., Frazer, S., Gehlenborg, N., Getz, G., Heiman, D.I., Kim, J., Lawrence, M.S., Lin, P., Meier, S., Noble, M.S., Saksena, G., Voet, D., Zhang, H., Bernard, B., Chambwe, N., Dhankani, V., Knijnenburg, T., Kramer, R., Leinonen, K., Liu, Y., Miller, M., Reynolds, S., Shmulevich, I., Thorsson, V., Zhang, W., Akbani, R., Broom, B.M., Hegde, A.M., Ju, Z., Kanchi, R.S., Korkut, A., Li, J., Liang, H., Ling, S., Liu, W., Lu, Y., Mills, G.B., Ng, K.S., Rao, A., Ryan, M., Wang, J., Weinstein, J.N., Zhang, J., Abeshouse, A., Armenia, J., Chakravarty, D., Chatila, W.K., de Bruijn, I., Gao, J., Gross, B.E., Heins, Z.J., Kundra, R., La, K., Ladanyi, M., Luna, A., Nissan, M.G., Ochoa, A., Phillips, S.M., Reznik, E., Sanchez-Vega, F., Sander, C., Schultz, N., Sheridan, R., Sumer, S.O., Sun, Y., Taylor, B.S., Anur, P., Peto, M., Spellman, P., Benz, C., Stuart, J.M., Wong, C.K., Yau, C., Hayes, D.N., Parker, J.S., Wilkerson, M.D., Ally, A., Balasundaram, M., Bowlby, R., Brooks, D., Carlsen, R., Chuah, E., Dhalla, N., Holt, R., Jones, SJM, Kasaian, K., Lee, D., Ma, Y., Marra, M.A., Mayo, M., Moore, R.A., Mungall, A.J., Mungall, K., Robertson, A.G., Sadeghi, S., Schein, J.E., Sipahimalani, P., Tam, A., Thiessen, N., Tse, K., Wong, T., Berger, A.C., Beroukhim, R., Cherniack, A.D., Cibulskis, C., Gabriel, S.B., Gao, G.F., Ha, G., Meyerson, M., Schumacher, S.E., Shih, J., Kucherlapati, M.H., Kucherlapati, R.S., Baylin, S., Cope, L., Danilova, L., Bootwalla, M.S., Lai, P.H., Maglinte, D.T., Van Den Berg, D.J., Weisenberger, D.J., Auman, J.T., Balu, S., Bodenheimer, T., Fan, C., Hoadley, K.A., Hoyle, A.P., Jefferys, S.R., Jones, C.D., Meng, S., Mieczkowski, P.A., Mose, L.E., Perou, A.H., Perou, C.M., Roach, J., Shi, Y., Simons, J.V., Skelly, T., Soloway, M.G., Tan, D., Veluvolu, U., Fan, H., Hinoue, T., Laird, P.W., Shen, H., Zhou, W., Bellair, M., Chang, K., Covington, K., Creighton, C.J., Dinh, H., Doddapaneni, H., Donehower, L.A., Drummond, J., Gibbs, R.A., Glenn, R., Hale, W., Han, Y., Hu, J., Korchina, V., Lee, S., Lewis, L., Li, W., Liu, X., Morgan, M., Morton, D., Muzny, D., Santibanez, J., Sheth, M., Shinbrot, E., Wang, L., Wang, M., Wheeler, D.A., Xi, L., Zhao, F., Hess, J., Appelbaum, E.L., Bailey, M., Cordes, M.G., Ding, L., Fronick, C.C., Fulton, L.A., Fulton, R.S., Kandoth, C., Mardis, E.R., McLellan, M.D., Miller, C.A., Schmidt, H.K., Wilson, R.K., Crain, D., Curley, E., Gardner, J., Lau, K., Mallery, D., Morris, S., Paulauskis, J., Penny, R., Shelton, C., Shelton, T., Sherman, M., Thompson, E., Yena, P., Bowen, J., Gastier-Foster, J.M., Gerken, M., Leraas, K.M., Lichtenberg, T.M., Ramirez, N.C., Wise, L., Zmuda, E., Corcoran, N., Costello, T., Hovens, C., Carvalho, A.L., de Carvalho, A.C., Fregnani, J.H., Longatto-Filho, A., Reis, R.M., Scapulatempo-Neto, C., Silveira, HCS, Vidal, D.O., Burnette, A., Eschbacher, J., Hermes, B., Noss, A., Singh, R., Anderson, M.L., Castro, P.D., Ittmann, M., Huntsman, D., Kohl, B., Le, X., Thorp, R., Andry, C., Duffy, E.R., Lyadov, V., Paklina, O., Setdikova, G., Shabunin, A., Tavobilov, M., McPherson, C., Warnick, R., Berkowitz, R., Cramer, D., Feltmate, C., Horowitz, N., Kibel, A., Muto, M., Raut, C.P., Malykh, A., Barnholtz-Sloan, J.S., Barrett, W., Devine, K., Fulop, J., Ostrom, Q.T., Shimmel, K., Wolinsky, Y., Sloan, A.E., De Rose, A., Giuliante, F., Goodman, M., Karlan, B.Y., Hagedorn, C.H., Eckman, J., Harr, J., Myers, J., Tucker, K., Zach, L.A., Deyarmin, B., Hu, H., Kvecher, L., Larson, C., Mural, R.J., Somiari, S., Vicha, A., Zelinka, T., Bennett, J., Iacocca, M., Rabeno, B., Swanson, P., Latour, M., Lacombe, L., Têtu, B., Bergeron, A., McGraw, M., Staugaitis, S.M., Chabot, J., Hibshoosh, H., Sepulveda, A., Su, T., Wang, T., Potapova, O., Voronina, O., Desjardins, L., Mariani, O., Roman-Roman, S., Sastre, X., Stern, M.H., Cheng, F., Signoretti, S., Berchuck, A., Bigner, D., Lipp, E., Marks, J., McCall, S., McLendon, R., Secord, A., Sharp, A., Behera, M., Brat, D.J., Chen, A., Delman, K., Force, S., Khuri, F., Magliocca, K., Maithel, S., Olson, J.J., Owonikoko, T., Pickens, A., Ramalingam, S., Shin, D.M., Sica, G., Van Meir, E.G., Eijckenboom, W., Gillis, A., Korpershoek, E., Looijenga, L., Oosterhuis, W., Stoop, H., van Kessel, K.E., Zwarthoff, E.C., Calatozzolo, C., Cuppini, L., Cuzzubbo, S., DiMeco, F., Finocchiaro, G., Mattei, L., Perin, A., Pollo, B., Chen, C., Houck, J., Lohavanichbutr, P., Hartmann, A., Stoehr, C., Stoehr, R., Taubert, H., Wach, S., Wullich, B., Kycler, W., Murawa, D., Wiznerowicz, M., Chung, K., Edenfield, W.J., Martin, J., Baudin, E., Bubley, G., Bueno, R., De Rienzo, A., Richards, W.G., Kalkanis, S., Mikkelsen, T., Noushmehr, H., Scarpace, L., Girard, N., Aymerich, M., Campo, E., Giné, E., Guillermo, A.L., Van Bang, N., Hanh, P.T., Phu, B.D., Tang, Y., Colman, H., Evason, K., Dottino, P.R., Martignetti, J.A., Gabra, H., Juhl, H., Akeredolu, T., Stepa, S., Hoon, D., Ahn, K., Kang, K.J., Beuschlein, F., Breggia, A., Birrer, M., Bell, D., Borad, M., Bryce, A.H., Castle, E., Chandan, V., Cheville, J., Copland, J.A., Farnell, M., Flotte, T., Giama, N., Ho, T., Kendrick, M., Kocher, J.P., Kopp, K., Moser, C., Nagorney, D., O'Brien, D., O'Neill, B.P., Patel, T., Petersen, G., Que, F., Rivera, M., Roberts, L., Smallridge, R., Smyrk, T., Stanton, M., Thompson, R.H., Torbenson, M., Yang, J.D., Zhang, L., Brimo, F., Ajani, J.A., Gonzalez, AMA, Behrens, C., Bondaruk, J., Broaddus, R., Czerniak, B., Esmaeli, B., Fujimoto, J., Gershenwald, J., Guo, C., Lazar, A.J., Logothetis, C., Meric-Bernstam, F., Moran, C., Ramondetta, L., Rice, D., Sood, A., Tamboli, P., Thompson, T., Troncoso, P., Tsao, A., Wistuba, I., Carter, C., Haydu, L., Hersey, P., Jakrot, V., Kakavand, H., Kefford, R., Lee, K., Long, G., Mann, G., Quinn, M., Saw, R., Scolyer, R., Shannon, K., Spillane, A., Stretch, J., Synott, M., Thompson, J., Wilmott, J., Al-Ahmadie, H., Chan, T.A., Ghossein, R., Gopalan, A., Levine, D.A., Reuter, V., Singer, S., Singh, B., Tien, N.V., Broudy, T., Mirsaidi, C., Nair, P., Drwiega, P., Miller, J., Smith, J., Zaren, H., Park, J.W., Hung, N.P., Kebebew, E., Linehan, W.M., Metwalli, A.R., Pacak, K., Pinto, P.A., Schiffman, M., Schmidt, L.S., Vocke, C.D., Wentzensen, N., Worrell, R., Yang, H., Moncrieff, M., Goparaju, C., Melamed, J., Pass, H., Botnariuc, N., Caraman, I., Cernat, M., Chemencedji, I., Clipca, A., Doruc, S., Gorincioi, G., Mura, S., Pirtac, M., Stancul, I., Tcaciuc, D., Albert, M., Alexopoulou, I., Arnaout, A., Bartlett, J., Engel, J., Gilbert, S., Parfitt, J., Sekhon, H., Thomas, G., Rassl, D.M., Rintoul, R.C., Bifulco, C., Tamakawa, R., Urba, W., Hayward, N., Timmers, H., Antenucci, A., Facciolo, F., Grazi, G., Marino, M., Merola, R., de Krijger, R., Gimenez-Roqueplo, A.P., Piché, A., Chevalier, S., McKercher, G., Birsoy, K., Barnett, G., Brewer, C., Farver, C., Naska, T., Pennell, N.A., Raymond, D., Schilero, C., Smolenski, K., Williams, F., Morrison, C., Borgia, J.A., Liptay, M.J., Pool, M., Seder, C.W., Junker, K., Omberg, L., Dinkin, M., Manikhas, G., Alvaro, D., Bragazzi, M.C., Cardinale, V., Carpino, G., Gaudio, E., Chesla, D., Cottingham, S., Dubina, M., Moiseenko, F., Dhanasekaran, R., Becker, K.F., Janssen, K.P., Slotta-Huspenina, J., Abdel-Rahman, M.H., Aziz, D., Bell, S., Cebulla, C.M., Davis, A., Duell, R., Elder, J.B., Hilty, J., Kumar, B., Lang, J., Lehman, N.L., Mandt, R., Nguyen, P., Pilarski, R., Rai, K., Schoenfield, L., Senecal, K., Wakely, P., Hansen, P., Lechan, R., Powers, J., Tischler, A., Grizzle, W.E., Sexton, K.C., Kastl, A., Henderson, J., Porten, S., Waldmann, J., Fassnacht, M., Asa, S.L., Schadendorf, D., Couce, M., Graefen, M., Huland, H., Sauter, G., Schlomm, T., Simon, R., Tennstedt, P., Olabode, O., Nelson, M., Bathe, O., Carroll, P.R., Chan, J.M., Disaia, P., Glenn, P., Kelley, R.K., Landen, C.N., Phillips, J., Prados, M., Simko, J., Smith-McCune, K., VandenBerg, S., Roggin, K., Fehrenbach, A., Kendler, A., Sifri, S., Steele, R., Jimeno, A., Carey, F., Forgie, I., Mannelli, M., Carney, M., Hernandez, B., Campos, B., Herold-Mende, C., Jungk, C., Unterberg, A., von Deimling, A., Bossler, A., Galbraith, J., Jacobus, L., Knudson, M., Knutson, T., Ma, D., Milhem, M., Sigmund, R., Godwin, A.K., Madan, R., Rosenthal, H.G., Adebamowo, C., Adebamowo, S.N., Boussioutas, A., Beer, D., Giordano, T., Mes-Masson, A.M., Saad, F., Bocklage, T., Landrum, L., Mannel, R., Moore, K., Moxley, K., Postier, R., Walker, J., Zuna, R., Feldman, M., Valdivieso, F., Dhir, R., Luketich, J., Pinero, EMM, Quintero-Aguilo, M., Carlotti, C.G., Dos Santos, J.S., Kemp, R., Sankarankuty, A., Tirapelli, D., Catto, J., Agnew, K., Swisher, E., Creaney, J., Robinson, B., Shelley, C.S., Godwin, E.M., Kendall, S., Shipman, C., Bradford, C., Carey, T., Haddad, A., Moyer, J., Peterson, L., Prince, M., Rozek, L., Wolf, G., Bowman, R., Fong, K.M., Yang, I., Korst, R., Rathmell, W.K., Fantacone-Campbell, J.L., Hooke, J.A., Kovatich, A.J., Shriver, C.D., DiPersio, J., Drake, B., Govindan, R., Heath, S., Ley, T., Van Tine, B., Westervelt, P., Rubin, M.A., Lee, J.I., Aredes, N.D., Mariamidze, A., SAIC-F-Frederick, Inc, and Leidos Biomedical Research, Inc.
Subjects: 0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Genetics and Molecular Biology (all), PATHOGENESIS, pan-cancer, PROTEIN, Cancer Genome Atlas Research Network, medicine.disease_cause, computer.software_genre, Genome, Biochemistry, Transcriptome, Gene expression, HRAS, KRAS, NF1, NRAS, Ras, TCGA, drug sensitivity, machine learning, Neoplasms, PRECISION ONCOLOGY, lcsh:QH301-705.5, Regulation of gene expression, PREVIOUSLY TREATED PATIENTS, 3. Good health, Gene Expression Regulation, Neoplastic, PHASE-II, Life Sciences & Biomedicine, Signal Transduction, Biology, Machine learning, General Biochemistry, Genetics and Molecular Biology, Article, BRAF, 03 medical and health sciences, Cell Line, Tumor, medicine, Biochemistry, Genetics and Molecular Biology (all), Humans, Gene, SIGNATURES, Science & Technology, business.industry, Genome, Human, MUTATIONS, EXPRESSÃO GÊNICA, Cell Biology, SELUMETINIB, GENE, 030104 developmental biology, lcsh:Biology (General), Selumetinib, ras Proteins, Artificial intelligence, business, computer
Abstract: SUMMARY Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these “hidden responders” may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders., In Brief Way et al. develop a machine-learning approach using PanCanAtlas data to detect Ras activation in cancer. Integrating mutation, copy number, and expression data, the authors show that their method detects Ras-activating variants in tumors and sensitivity to MEK inhibitors in cell lines.
Published: 2018

39. Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers

Author: Xinxin Peng, Zhongyuan Chen, Farshad Farshidfar, Xiaoyan Xu, Philip L. Lorenzi, Yumeng Wang, Feixiong Cheng, Lin Tan, Kamalika Mojumdar, Di Du, Zhongqi Ge, Jun Li, George V. Thomas, Kivanc Birsoy, Lingxiang Liu, Huiwen Zhang, Zhongming Zhao, Calena Marchand, John N. Weinstein, Oliver F. Bathe, Han Liang, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, SAIC-F-Frederick, Inc, and Leidos Biomedical Research, Inc.
Subjects: Genetics and Molecular Biology (all), 0301 basic medicine, MICRORNAS, Somatic cell, Cancer Genome Atlas Research Network, MYC, therapeutic targets, Biochemistry, Neoplasms, HETEROGENEITY, lcsh:QH301-705.5, media_common, Gene knockdown, Metabolic heterogeneity, ATLAS, 3. Good health, Core Binding Factor Alpha 2 Subunit, SURVIVAL, GLIOMA, somatic drivers, Life Sciences & Biomedicine, Metabolic Networks and Pathways, Drug, media_common.quotation_subject, The Cancer Genome Atlas, 610 Medicine & health, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Downregulation and upregulation, Cell Line, Tumor, Humans, carbohydrate metabolism, Clinical significance, drug sensitivity, HALLMARKS, Science & Technology, master regulator, Lipid metabolism, METABOLISMO DOS CARBOIDRATOS, Cell Biology, prognostic markers, tumor subtypes, Biochemistry, Genetics and Molecular Biology (all), 030104 developmental biology, HEK293 Cells, lcsh:Biology (General), Drug Resistance, Neoplasm, SNAI1, PATTERNS, Cancer research, Snail Family Transcription Factors, Transcriptome
Abstract: SUMMARY Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes—modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility., In Brief Peng et al. analyze a cohort of 9,125 TCGA samples across 33 cancer types to characterize tumor subtypes based on the expression of seven metabolic pathways. They find metabolic expression subtypes are associated with patient survivals and suggest the therapeutic and predictive relevance of subtype-related master regulators.
Published: 2018
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40. Lung cancer mortality reduction by LDCT screening: UKLS randomised trial results and international meta-analysis

Author: Nicholas Screaton, Fiona E. McRonald, David R Baldwin, Stephen W. Duffy, Nicholas J Wald, Tim Eisen, John K. Field, Mahesh K. B. Parmar, Terry Kavanagh, Arjun Nair, Kate Lifford, John A Holemans, Michael P.A. Davies, Gasham Yadegarfar, David Weller, Katherine Emma Brain, Richard D. Page, Anand Devaraj, Paula R Williamson, John R. Gosney, Martin Ledson, Keith M. Kerr, David K. Whynes, Beverley A Green, Daniel Vulkan, Rhian Gabe, Robert C. Rintoul, and Doris Rassl
Subjects: CT Screening, medicine.medical_specialty, Framingham Risk Score, business.industry, Health Policy, Lung Cancer, Mortality reduction, medicine.disease, Meta-analysis, Risk groups, Primary outcome, Lung Cancer Mortality, Oncology, Internal medicine, Usual care, Internal Medicine, medicine, Lung cancer, business, Lung cancer screening, Research Paper
Abstract: BackgroundThe 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.MethodsFrom 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.Findings1 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.InterpretationThe 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.FundingNIHR Health Technology Assessment programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation.
Published: 2021
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41. SOX2 Drives Bronchial Dysplasia in a Novel Organotypic Model of Early Human Squamous Lung Cancer

Author: Gerard I. Evan, Doris M Rassl, Frank McCaughan, Peter McErlean, Emma L. Rawlins, Julien Bauer, Tariq Sethi, Hassan Farah, Paul Lavender, Trevor D. Littlewood, Jo-Anne Johnson, Lucia L. Correia, and Robert C. Rintoul
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung Neoplasms, business.industry, SOXB1 Transcription Factors, Early lung cancer, Cell Culture Techniques, Original Articles, Critical Care and Intensive Care Medicine, medicine.disease, Models, Biological, Surgery, 03 medical and health sciences, 030104 developmental biology, Research centre, Family medicine, Cancer centre, Carcinoma, Squamous Cell, Humans, Medicine, Bronchial dysplasia, business, Lung cancer, Bronchopulmonary Dysplasia
Abstract: Improving the early detection and chemoprevention of lung cancer are key to improving outcomes. The pathobiology of early squamous lung cancer is poorly understood. We have shown that amplification of sex-determining region Y-box 2 (SOX2) is an early and consistent event in the pathogenesis of this disease, but its functional oncogenic potential remains uncertain. We tested the impact of deregulated SOX2 expression in a novel organotypic system that recreates the molecular and microenvironmental context in which squamous carcinogenesis occurs.(1) To develop an in vitro model of bronchial dysplasia that recapitulates key molecular and phenotypic characteristics of the human disease; (2) to test the hypothesis that SOX2 deregulation is a key early event in the pathogenesis of bronchial dysplasia; and (3) to use the model for studies on pathogenesis and chemoprevention.We engineered the inducible activation of oncogenes in immortalized bronchial epithelial cells. We used three-dimensional tissue culture to build an organotypic model of bronchial dysplasia.We recapitulated human bronchial dysplasia in vitro. SOX2 deregulation drives dysplasia, and loss of tumor promoter 53 is a cooperating genetic event that potentiates the dysplastic phenotype. Deregulated SOX2 alters critical genes implicated in hallmarks of cancer progression. Targeted inhibition of AKT prevents the initiation of the dysplastic phenotype.In the appropriate genetic and microenvironmental context, acute deregulation of SOX2 drives bronchial dysplasia. This confirms its oncogenic potential in human cells and affords novel insights into the impact of SOX2 deregulation. This model can be used to test therapeutic agents aimed at chemoprevention.
Published: 2017
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42. Dynamic contrast-enhanced computed tomography for the diagnosis of solitary pulmonary nodules: a systematic review and meta-analysis

Author: James W. MacKay, Kenneth A. Miles, Jonathan R. Weir-McCall, Stella Joyce, Nagmi R. Qureshi, Gabrielle C Baxter, Robert C. Rintoul, Andrew Clegg, Fiona J. Gilbert, Lena-Marie Dendl, Weir-McCall, Jonathan [0000-0001-5842-842X], MacKay, James [0000-0001-7558-3800], Baxter, Gabrielle [0000-0002-8242-1559], Rintoul, Robert [0000-0003-3875-3780], Gilbert, Fiona [0000-0002-0124-9962], and Apollo - University of Cambridge Repository
Subjects: medicine.medical_specialty, Multi-detector computed tomography, Solitary pulmonary nodule, I510, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Biopsy, medicine, Radiology, Nuclear Medicine and imaging, Neuroradiology, medicine.diagnostic_test, business.industry, Contrast media, Nodule (medicine), General Medicine, Odds ratio, medicine.disease, Meta-analysis, Positron emission tomography, 030220 oncology & carcinogenesis, Diagnostic odds ratio, Radiology, medicine.symptom, Lung cancer, business
Abstract: A systematic review and meta-analysis were performed to determine the diagnostic performance of dynamic contrast–enhanced computed tomography (DCE-CT) for the differentiation between malignant and benign pulmonary nodules. Ovid MEDLINE and EMBASE were searched for studies published up to October 2018 on the diagnostic accuracy of DCE-CT for the characterisation of pulmonary nodules. For the index test, studies with a minimum of a pre- and post-contrast computed tomography scan were evaluated. Studies with a reference standard of biopsy for malignancy, and biopsy or 2-year follow-up for benign disease were included. Study bias was assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies). The sensitivities, specificities, and diagnostic odds ratios were determined along with 95% confidence intervals (CIs) using a bivariate random effects model. Twenty-three studies were included, including 2397 study participants with 2514 nodules of which 55.3% were malignant (1389/2514). The pooled accuracy results were sensitivity 94.8% (95% CI 91.5; 96.9), specificity 75.5% (69.4; 80.6), and diagnostic odds ratio 56.6 (24.2–88.9). QUADAS 2 assessment showed intermediate/high risk of bias in a large proportion of the studies (52–78% across the domains). No difference was present in sensitivity or specificity between subgroups when studies were split based on CT technique, sample size, nodule size, or publication date. DCE-CT has a high diagnostic accuracy for the diagnosis of pulmonary nodules although study quality was indeterminate in a large number of cases. • The pooled accuracy results were sensitivity 95.1% and specificity 73.8% although individual studies showed wide ranges of values. • This is comparable to the results of previous meta-analyses of PET/CT (positron emission tomography/computed tomography) diagnostic accuracy for the diagnosis of solitary pulmonary nodules. • Robust direct comparative accuracy and cost-effectiveness studies are warranted to determine the optimal use of DCE-CT and PET/CT in the diagnosis of SPNs.
Published: 2020
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43. Integrated genomics identify novel immunotherapy targets for malignant mesothelioma

Author: I. Alex Bowman, Anthony Newman Taylor, Shir Kiong Lu, Anne M. Bowcock, Anne E. Willis, Tim Benepal, Mark Lathrop, Xiao-Ming Sun, Matthew S. Edwards, Deborah J. Morris-Rosendahl, Sanjay Popat, A. Mandal, Miriam F. Moffatt, William O.C.M. Cookson, Yu Zhi Zhang, Eric Lim, Robert C. Rintoul, A. Nastase, S. Gennatas, Marion MacFarlane, Andrew G. Nicholson, Tatyana Chernova, and Hima Anbunathan
Subjects: YAP1, business.industry, medicine.medical_treatment, Immunotherapy, medicine.disease, Malignancy, Aurora kinase, CDKN2A, medicine, Cancer research, Mesothelioma, business, Hedgehog, Interferon type I, medicine.drug
Abstract: BackgroundMalignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective therapies.MethodsIn order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells.ResultsPreviously unrecognised losses of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary MPM cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin.ConclusionsOur results suggest new therapeutic avenues in MPM and provide targets and biomarkers for immunotherapy.
Published: 2020
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44. Dynamic contrast-enhanced computed tomography for the diagnosis of solitary pulmonary nodules: a systematic review and meta-analysis

Author: Jonathan R, Weir-McCall, Stella, Joyce, Andrew, Clegg, James W, MacKay, Gabrielle, Baxter, Lena-Marie, Dendl, Robert C, Rintoul, Nagmi R, Qureshi, Ken, Miles, and Fiona J, Gilbert
Subjects: Lung Neoplasms, Fluorodeoxyglucose F18, Humans, Multiple Pulmonary Nodules, Solitary Pulmonary Nodule, Radiopharmaceuticals, Tomography, X-Ray Computed
Abstract: A systematic review and meta-analysis were performed to determine the diagnostic performance of dynamic contrast-enhanced computed tomography (DCE-CT) for the differentiation between malignant and benign pulmonary nodules.Ovid MEDLINE and EMBASE were searched for studies published up to October 2018 on the diagnostic accuracy of DCE-CT for the characterisation of pulmonary nodules. For the index test, studies with a minimum of a pre- and post-contrast computed tomography scan were evaluated. Studies with a reference standard of biopsy for malignancy, and biopsy or 2-year follow-up for benign disease were included. Study bias was assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies). The sensitivities, specificities, and diagnostic odds ratios were determined along with 95% confidence intervals (CIs) using a bivariate random effects model.Twenty-three studies were included, including 2397 study participants with 2514 nodules of which 55.3% were malignant (1389/2514). The pooled accuracy results were sensitivity 94.8% (95% CI 91.5; 96.9), specificity 75.5% (69.4; 80.6), and diagnostic odds ratio 56.6 (24.2-88.9). QUADAS 2 assessment showed intermediate/high risk of bias in a large proportion of the studies (52-78% across the domains). No difference was present in sensitivity or specificity between subgroups when studies were split based on CT technique, sample size, nodule size, or publication date.DCE-CT has a high diagnostic accuracy for the diagnosis of pulmonary nodules although study quality was indeterminate in a large number of cases.• The pooled accuracy results were sensitivity 95.1% and specificity 73.8% although individual studies showed wide ranges of values. • This is comparable to the results of previous meta-analyses of PET/CT (positron emission tomography/computed tomography) diagnostic accuracy for the diagnosis of solitary pulmonary nodules. • Robust direct comparative accuracy and cost-effectiveness studies are warranted to determine the optimal use of DCE-CT and PET/CT in the diagnosis of SPNs.
Published: 2019

45. Sequential screening for lung cancer in a high-risk group: randomised controlled trial: LungSEARCH: a randomised controlled trial of Surveillance using sputum and imaging for the EARly detection of lung Cancer in a High-risk group

Author: Penny Shaw, Richard Booton, Matthew E.J. Callister, John F. Allen, Marco Novelli, Paul Dhillon, Michael D Peake, Nicholas Counsell, Yenting Ngai, Robert C. Rintoul, Allan Hackshaw, Victoria Ashford-Turner, Simon P. G. Padley, Pamela Rabbitts, Dahmane Oukrif, Andrew G. Nicholson, Asia Ahmed, Kishore Sridharan, Nicholas D. Magee, Sarah Lewis, Mary Falzon, Sam M. Janes, Gabrijela Kocjan, Jeremy George, Nyasha Chinyanganya, Stephen G. Spiro, Chris Griffiths, Pallav L. Shah, Magali Taylor, Shah, Pallav L [0000-0002-9052-4638], Janes, Samuel [0000-0002-6634-5939], Booton, Richard [0000-0003-4512-2899], and Apollo - University of Cambridge Repository
Subjects: Pulmonary and Respiratory Medicine, Male, Sputum Cytology, medicine.medical_specialty, Lung Neoplasms, Cytological Techniques, Adenocarcinoma of Lung, Risk Assessment, Sensitivity and Specificity, law.invention, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Carcinoma, Non-Small-Cell Lung, Bronchoscopy, medicine, Carcinoma, Humans, 030212 general & internal medicine, Carcinoma, Small Cell, Lung cancer, Early Detection of Cancer, Neoplasm Staging, COPD, business.industry, Lung Cancer, Optical Imaging, Sputum, Original Articles, Middle Aged, medicine.disease, United Kingdom, respiratory tract diseases, 030228 respiratory system, Relative risk, Carcinoma, Squamous Cell, Carcinoma, Large Cell, Female, medicine.symptom, business, Tomography, X-Ray Computed, Lung cancer screening
Abstract: Background Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. Methods LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). Results 1568 participants were randomised during 2007–2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75–1.95) or 0.82 (95% CI 0.52–1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. Conclusions Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening., While low-dose CT is now preferred for lung cancer screening, our randomised trial of smokers with COPD showed that a proposed sequential policy using sputum testing to select who receives low-dose CT and autofluorescence bronchoscopy was ineffective http://bit.ly/2JZujnx
Published: 2019

46. DNA Repair Biomarker for Lung Cancer Risk and its Correlation With Airway Cells Gene Expression

Author: Bruce A.J. Ponder, Tamar Paz-Elizur, Ronen Fluss, Martin O'Reilly, Robert C. Rintoul, Federico M. Giorgi, Laurence S. Freedman, Hyunjin Kim, Zvi Livneh, Yael Leitner-Dagan, Barak Markus, Yentl Evgy, Kerstin B. Meyer, Paz-Elizur, Tamar, Leitner-Dagan, Yael, Meyer, Kerstin B, Markus, Barak, Giorgi, Federico M, O'Reilly, Martin, Kim, Hyunjin, Evgy, Yentl, Fluss, Ronen, Freedman, Laurence S, Rintoul, Robert C, Ponder, Bruce, Livneh, Zvi, Rintoul, Robert [0000-0003-3875-3780], and Apollo - University of Cambridge Repository
Subjects: Oncology, Cancer Research, medicine.medical_specialty, DNA repair, Population, 32 Biomedical and Clinical Sciences, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, DNA Damage Repair, Internal medicine, Genetics, medicine, Risk factor, Lung cancer, education, Lung, Cancer, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, Prevention, 3 Good Health and Well Being, Odds ratio, 3211 Oncology and Carcinogenesis, medicine.disease, 4.1 Discovery and preclinical testing of markers and technologies, 3. Good health, 030220 oncology & carcinogenesis, Respiratory, Biomarker (medicine), 4.4 Population screening, 4 Detection, screening and diagnosis, business, 4.2 Evaluation of markers and technologies
Abstract: Background Improving lung cancer risk assessment is required because current early-detection screening criteria miss most cases. We therefore examined the utility for lung cancer risk assessment of a DNA Repair score obtained from OGG1, MPG, and APE1 blood tests. In addition, we examined the relationship between the level of DNA repair and global gene expression. Methods We conducted a blinded case-control study with 150 non–small cell lung cancer case patients and 143 control individuals. DNA Repair activity was measured in peripheral blood mononuclear cells, and the transcriptome of nasal and bronchial cells was determined by RNA sequencing. A combined DNA Repair score was formed using logistic regression, and its correlation with disease was assessed using cross-validation; correlation of expression to DNA Repair was analyzed using Gene Ontology enrichment. Results DNA Repair score was lower in case patients than in control individuals, regardless of the case’s disease stage. Individuals at the lowest tertile of DNA Repair score had an increased risk of lung cancer compared to individuals at the highest tertile, with an odds ratio (OR) of 7.2 (95% confidence interval [CI] = 3.0 to 17.5; P Conclusions The DNA Repair score, previously shown to be a lung cancer risk factor in the Israeli population, was validated in this independent study as a mechanism-based cancer risk biomarker and can substantially improve current lung cancer risk prediction, assisting prevention and early detection by computed tomography scanning.
Published: 2019

47. Incidence of second and higher order smoking-related primary cancers following lung cancer: a population-based cohort study

Author: Sarah Jefferies, Fiona M Walter, Robert C. Rintoul, Michael D Peake, Georgios Lyratzopoulos, Matthew Barclay, Barclay, Matthew [0000-0003-1148-1922], Lyratzopoulos, Georgios [0000-0002-2873-7421], Walter, Fiona [0000-0002-7191-6476], Rintoul, Robert [0000-0003-3875-3780], and Apollo - University of Cambridge Repository
Subjects: Pulmonary and Respiratory Medicine, Oncology, Adult, Male, medicine.medical_specialty, Lung Neoplasms, Time Factors, Cancer registration, 03 medical and health sciences, symbols.namesake, Population based cohort, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, 030212 general & internal medicine, Poisson regression, Lung cancer, non-small cell lung cancer, Aged, Retrospective Studies, Aged, 80 and over, Lung, business.industry, Incidence (epidemiology), Public health, Incidence, Smoking, Neoplasms, Second Primary, Second primary cancer, clinical epidemiology, Middle Aged, medicine.disease, Prognosis, Survival Rate, lung cancer, medicine.anatomical_structure, England, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, symbols, Female, business, Follow-Up Studies
Abstract: BackgroundLung cancer 5-year survival has doubled over 15 years. Although the risk of second primary cancer is recognised, quantification over time is lacking. We describe the incidence of second and higher order smoking-related primary cancers in lung cancer survivors, identifying high-incidence groups and how incidence changes over time from first diagnosis.MethodsData on smoking-related primary cancers (lung, laryngeal, head and neck, oesophageal squamous cell carcinoma and bladder) diagnosed in England between 2000 and 2014 were obtained from Public Health England National Cancer Registration and Analysis Service. We calculated absolute incidence rates and standardised incidence rate ratios, both overall and for various subgroups of second primary cancer for up to 10 years from the initial diagnosis of lung cancer, using Poisson regression.ResultsElevated incidence of smoking-related second primary cancer persists for at least 10 years from first lung cancer diagnosis with those aged 50 and 79 at first diagnosis at particularly high risk. The most frequent type of second malignancy was lung cancer although the highest standardised incidence rate ratios were for oesophageal squamous cell carcinoma (2.4) and laryngeal cancers (2.8) and consistently higher in women than in men. Over the last decade, the incidence of second primary lung cancer has doubled.ConclusionLung cancer survivors have increased the incidence of subsequent lung, laryngeal, head and neck and oesophageal squamous cell carcinoma for at least a decade from the first diagnosis. Consideration should be given to increasing routine follow-up from 5 years to 10 years for those at highest risk, alongside surveillance for other smoking-related cancers.
Published: 2019

48. Adenocarcinoma spectrum lesions of the lung: Detection, pathology and treatment strategies

Author: Robert C. Rintoul, L Succony, Frank McCaughan, AP Barker, and Doris Rassl
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Lung Neoplasms, Adenocarcinoma of Lung, Disease, medicine.disease_cause, Lesion, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Neoplasm Invasiveness, Radiology, Nuclear Medicine and imaging, Stage (cooking), Lung cancer, Lung, business.industry, General Medicine, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Adenocarcinoma, KRAS, medicine.symptom, Tomography, X-Ray Computed, business, Lung cancer screening
Abstract: Adenocarcinoma has become the most prevalent lung cancer sub-type and its frequency is increasing. The earliest stages in the development of lung adenocarcinomas are visible using modern computed tomography (CT) as ground glass nodules. These pre-invasive nodules can progress over time to become invasive lung adenocarcinomas. Lesions in this developmental pathway are termed 'adenocarcinoma spectrum' lesions. With the introduction of lung cancer screening programs there has been an increase in the detection of these lesions raising questions about natural history, surveillance and treatment. Here we review how the radiological appearance of an adenocarcinoma spectrum lesion relates to its underlying pathology and explore the natural history and factors driving lesion progression. We examine the molecular changes that occur at each stage of adenocarcinoma spectrum lesion development, including the effects of the driver mutations, EGFR and KRAS, that are key to invasive adenocarcinoma pathology. A better understanding of the development of pre-invasive disease will create treatment targets. Our understanding of how tumours interact with the immune system has led to the development of new therapeutic strategies. We review the role of the immune system in the development of adenocarcinoma spectrum lesions. With a clear preinvasive phase there is an opportunity to treat early adenocarcinoma spectrum lesions before an invasive lung cancer develops. We review current management including surveillance, surgical resection and oncological therapy as well as exploring potential future treatment avenues.
Published: 2021
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49. Lung cancer treatment during a pandemic: how have multi-disciplinary teams changed?

Author: T. Newsom-Davis, James Hargrave, Lorraine Dallas, Claire Hastings, J. Fenemore, and Robert C. Rintoul
Subjects: Pulmonary and Respiratory Medicine, Cancer Research, medicine.medical_specialty, Oncology, Multi disciplinary, business.industry, Pandemic, medicine, Intensive care medicine, business, Lung cancer, medicine.disease
Published: 2021
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50. Quantifying the impact of Covid-19 on lung cancer: an urgent need for restoration

Author: Berkay Karahacioglu, Neal Navani, Elizabeth Fuller, Robert C. Rintoul, Laura Succony, E. O'Dowd, Amyn Bhamani, Ian Woolhouse, David R Baldwin, Matthew Evison, Sam M. Janes, and Sinan Eccles
Subjects: Pulmonary and Respiratory Medicine, Cancer Research, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.disease, Oncology, medicine, COVID and Cancer, Lung cancer, Intensive care medicine, business
Published: 2021
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