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1. NET-02: a randomised, non-comparative, phase II trial of nal-IRI/5-FU or docetaxel as second-line therapy in patients with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma

Author

McNamara, Mairéad G., Swain, Jayne, Craig, Zoe, Sharma, Rohini, Faluyi, Olusola, Wadsley, Jonathan, Morgan, Carys, Wall, Lucy R., Chau, Ian, Reed, Nick, Sarker, Debashis, Margetts, Jane, Krell, Daniel, Cave, Judith, Sothi, Sharmila, Anthoney, Alan, Bell, Christopher, Patel, Alkesh, Oughton, Jamie B., Cairns, David A., Mansoor, Wasat, Lamarca, Angela, Hubner, Richard A., and Valle, Juan W.

Published
2023
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2. Sangre, esfuerzo, sudor y lágrimas: Resucitación de control de daños en shock hemorrágico.

Author

Roizblatt Krell, Daniel, Ramos Perkins, Juan Pablo, Arellano Graell, Pablo, and Araya Cortez, Patricio

Abstract

Trauma and its morbidity and mortality is a leading public health problem. Since the 1980s, multiple changes have been introduced to the resuscitation of trauma patients, attempting to reduce early mortality, mainly due to hemorrhagic shock. This is how damage control resuscitation arises, a concept that involves treating the trauma patient with a physiological point of view, correcting acidosis, hypocalcemia, hypothermia, and coagulopathy, in addition to emphasizing the resolution of complex problems through simple surgical procedures. This article describes the fundamental concepts of damage control resuscitation that every general surgeon should understand and implement when facing a patient with severe trauma. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Genetic and immune landscape evolution in MMR‐deficient colorectal cancer

Author

Challoner, Benjamin R, primary, Woolston, Andrew, additional, Lau, David, additional, Buzzetti, Marta, additional, Fong, Caroline, additional, Barber, Louise J, additional, Anandappa, Gayathri, additional, Crux, Richard, additional, Assiotis, Ioannis, additional, Fenwick, Kerry, additional, Begum, Ruwaida, additional, Begum, Dipa, additional, Lund, Tom, additional, Sivamanoharan, Nanna, additional, Sansano, Harold B, additional, Domingo‐Arada, Melissa, additional, Tran, Amina, additional, Pandha, Hardev, additional, Church, David, additional, Eccles, Bryony, additional, Ellis, Richard, additional, Falk, Stephen, additional, Hill, Mark, additional, Krell, Daniel, additional, Murugaesu, Nirupa, additional, Nolan, Luke, additional, Potter, Vanessa, additional, Saunders, Mark, additional, Shiu, Kai‐Keen, additional, Guettler, Sebastian, additional, Alexander, James L, additional, Lázare‐Iglesias, Héctor, additional, Kinross, James, additional, Murphy, Jamie, additional, von Loga, Katharina, additional, Cunningham, David, additional, Chau, Ian, additional, Starling, Naureen, additional, Ruiz‐Bañobre, Juan, additional, Dhillon, Tony, additional, and Gerlinger, Marco, additional

Published
2023
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4. Functional analysis of mutations in isocitrate dehydrogenase involved in gliomagenesis

Author

Krell, Daniel and Tomlinson, Ian

Subjects
616.99, Cancer, Oncology, glioma, glioblastoma, Isocitrate Dehydrogenase, Tumour metabolism.
Abstract

The main subject of my thesis is the investigation of mechanisms of glioma tumorigenesis associated with the recently identified mutations in isocitrate dehydrogenase. Gliomas account for 80% of primary brain cancers. They represent a diverse group of tumours, and are graded from I-IV based on histopathological features. Whilst grade I tumours may be curable with surgery alone, grade II and III gliomas inevitably progress to glioblastoma multiforme (GBM), which is highly resistant to current therapies and carries a very poor prognosis. Despite an improved understanding of the pathways and mechanisms involved in the development of glioma and its progression to grade IV disease, current and novel treatments have so far failed to significantly improve outcome. Isocitrate dehydrogenase (IDH) enzymes catalyse the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Somatic mutations in genes encoding IDH1 and IDH2 were first identified in glioma and subsequently in acute myeloid leukemia and other solid tumours. These heterozygous point mutations occur at the arginine residue of the enzymes active site and cause both loss of normal enzyme function and gain-of-function, causing the reduction of α-KG to D-2-hydroxyglutarate (D-2HG), which accumulates. D-2HG may act as an oncometabolite through the inhibition of various α-KG dependent enzymes, stimulating angiogenesis, histone modifications and aberrant DNA methylation. Possibly, IDH1/2 mutations may also cause oncogenic effects through dysregulation of the tricarboxylic acid (TCA) cycle, or by increasing susceptibility to oxidative stress. The exact role of mutant IDH1/2 in tumorigenesis however remains unclear. In the work outlined in this thesis, I have demonstrated that the expression of mutant IDH1/2 in glioma cell lines leads to 2-HG accumultation and a reduction in α-KG production and results in HIF1α accumulation and a reduction in 5hmC production. Furthermore, the brain-specific expression of mutant Idh1 in mice also results in 2-HG accumulation and reduced α-KG production, whilst a reduction in 5hmC levels are also seen. This data appears to support the theory that IDH1/2 mutant activity results in the inhibition of α-KG dependent enzymes, either through the accumulation of 2-HG or due to a reduction in α-KG levels. The brain-specific expression of mutant Idh1 in mice also results in increased cellular proliferation and an increase in the expression of the neural stem cell marker, nestin. However gliomas do not develop, perhaps suggesting that additional mutations are required in conjunction with those occuring in IDH1/2 in order to initiate tumourigenesis. Clinically, IDH1/2 mutations may represent a novel therapeutic target in glioma and may also serve as useful diagnostic, prognostic and predictive biomarkers. However, a better understanding of the pathogenesis of mutant IDH is required, to enable effective IDH1/2 directed therapies to be developed in the future.

Published
2014

8. NET-02 final results: A randomised, phase II trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line (2L) therapy in patients (pts) with progressive poorly differentiated extrapulmonary neuroendocrine carcinoma (PD-EP-NEC).

Author

McNamara, Mairead Geraldine, primary, Swain, Jayne, additional, Craig, Zoe, additional, Sharma, Rohini, additional, Faluyi, Olusola Olusesan, additional, Wadsley, Jonathan, additional, Morgan, Carys, additional, Wall, Lucy R., additional, Chau, Ian, additional, Reed, Nick, additional, Sarker, Debashis, additional, Margetts, Jane, additional, Krell, Daniel, additional, Cave, Judith, additional, Sharmila, Sothi, additional, Anthoney, Alan, additional, Patel, Alkesh, additional, Lamarca, Angela, additional, Hubner, Richard, additional, and Valle, Juan W., additional

Published
2023
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10. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia ( DIPNECH ): Prevalence, clinicopathological characteristics and survival outcome in a cohort of 311 patients with well‐differentiated lung neuroendocrine tumours

Author

Hayes, Aimee R., primary, Luong, Tu Vinh, additional, Banks, Jamie, additional, Shah, Heer, additional, Watkins, Jennifer, additional, Lim, Eric, additional, Patel, Anant, additional, Grossman, Ashley B., additional, Navalkissoor, Shaunak, additional, Krell, Daniel, additional, and Caplin, Martyn E., additional

Published
2022
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11. NET-02: A multicenter, randomized, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).

Author

McNamara, Mairead Geraldine, primary, Swain, Jayne, additional, Craig, Zoe, additional, Sharma, Rohini, additional, Faluyi, Olusola Olusesan, additional, Wadsley, Jonathan, additional, Morgan, Carys, additional, Wall, Lucy R., additional, Chau, Ian, additional, Reed, Nick, additional, Sarker, Debashis, additional, Margetts, Jane, additional, Krell, Daniel, additional, Cave, Judith, additional, Sharmila, Sothi, additional, Anthoney, Alan, additional, Patel, Alkesh, additional, Lamarca, Angela, additional, Hubner, Richard A, additional, and Valle, Juan W., additional

Published
2022
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12. Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer

Author

Challoner, Benjamin Robert, primary, Woolston, Andrew, additional, Lau, David, additional, Buzzetti, Marta, additional, Fong, Caroline, additional, Barber, Louise J, additional, Anandappa, Gayathri, additional, Crux, Richard, additional, Assiotis, Ioannis, additional, Fenwick, Kerry, additional, Begum, Ruwaida, additional, Begum, Dipa, additional, Lund, Tom, additional, Sivamanoharan, Nanna, additional, Sansano, Harold B, additional, Domingo-Arada, Melissa, additional, Tran, Amina, additional, Eccles, Bryony, additional, Ellis, Richard, additional, Falk, Stephen, additional, Hill, Mark, additional, Krell, Daniel, additional, Murugaesu, Nirupa, additional, Nolan, Luke, additional, Potter, Vanessa, additional, Saunders, Mark, additional, Shiu, Kai-Keen, additional, Guettler, Sebastian, additional, Alexander, James L, additional, Lázare-Iglesias, Héctor, additional, Kinross, James, additional, Murphy, Jamie, additional, von Loga, Katharina, additional, Cunningham, David, additional, Chau, Ian, additional, Starling, Naureen, additional, Ruiz-Bañobre, Juan, additional, Dhillon, Tony, additional, and Gerlinger, Marco, additional

Published
2022
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13. Elevated 2HG does not cause features of tumorigenesis

Author

Adam, Julie, primary, Finch, Alina, additional, Sepulveda, Catarina, additional, Ducker, Martin, additional, Torroba, Maria Blanca, additional, Krell, Daniel, additional, Kriaucionis, Skirmantas, additional, Szele, Francis, additional, Ratcliffe, Peter, additional, Soga, Tomoyoshi, additional, Kranc, Kamil, additional, Tomlinson, Ian, additional, and Bardella, Chiara, additional

Published
2021
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14. High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Improved Prognostic Stratification With the New World Health Organization 2019 Classification

Author

Hayes, Aimee R., primary, Furnace, Myles, additional, Shah, Ruchir, additional, Rundell, Caroline, additional, Muller, Gregory, additional, Dehbi, Hakim-Moulay, additional, Luong, Tu Vinh, additional, Toumpanakis, Christos, additional, Caplin, Martyn E., additional, Krell, Daniel, additional, Thirlwell, Christina, additional, and Mandair, Dalvinder, additional

Published
2021
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16. Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis

Author

Bardella, Chiara, Al-Dalahmah, Osama, Krell, Daniel, Brazauskas, Pijus, Al-Qahtani, Khalid, Tomkova, Marketa, Adam, Julie, Serres, Sébastien, Lockstone, Helen, Freeman-Mills, Luke, Pfeffer, Inga, Sibson, Nicola, Goldin, Robert, Schuster-Böeckler, Benjamin, Pollard, Patrick J., Soga, Tomoyoshi, McCullagh, James S., Schofield, Christopher J., Mulholland, Paul, Ansorge, Olaf, Kriaucionis, Skirmantas, Ratcliffe, Peter J., Szele, Francis G., and Tomlinson, Ian

Subjects
Cancer Research, hydroxylase, animal diseases, subventricular zone, Cell Biology, hydroxyglutarate, oncometabolite, stem cell, Wnt, α-ketoglutarate, nervous system, Oncology, glioma, DNA (hydroxy)methylation, isocitrate dehydrogenase, Oncology & Carcinogenesis, 1109 Neurosciences, 1112 Oncology And Carcinogenesis
Abstract

Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.

Published
2016
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18. Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma

Author

Brown, Nicholas, primary, McBain, Catherine, additional, Nash, Stephen, additional, Hopkins, Kirsten, additional, Sanghera, Paul, additional, Saran, Frank, additional, Phillips, Mark, additional, Dungey, Fiona, additional, Clifton-Hadley, Laura, additional, Wanek, Katharina, additional, Krell, Daniel, additional, Jeffries, Sarah, additional, Khan, Iftekhar, additional, Smith, Paul, additional, and Mulholland, Paul, additional

Published
2016
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20. microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis

Author

Frampton, Adam E., primary, Krell, Jonathan, additional, Jamieson, Nigel B., additional, Gall, Tamara M.H., additional, Giovannetti, Elisa, additional, Funel, Niccola, additional, Mato Prado, Mireia, additional, Krell, Daniel, additional, Habib, Nagy A., additional, Castellano, Leandro, additional, Jiao, Long R., additional, and Stebbing, Justin, additional

Published
2015
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23. Health-related quality of life (HRQoL) in patients (pts) with progressive, poorly differentiated, extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC) enrolled in NET-02: A phase II trial of liposomal irinotecan (nal-IRI)/5-fluorouracil...

Author

Craig, Zoe, Swain, Jayne, Sharma, Rohini, Faluyi, Olusola Olusesan, Wadsley, Jonathan, Morgan, Carys, Wall, Lucy R., Chau, Ian, Reed, Nicholas Simon, Sarker, Debashis, Margetts, Jane, Krell, Daniel, Cave, Judith, Sharmila, Sothi, Anthoney, Alan, Patel, Alkesh, Lamarca, Angela, Hubner, Richard A, Valle, Juan W., and McNamara, Mairead Geraldine

Published
2022
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27. Contingency Contacting

Author

Hoch, Theodore A., primary, Babbitt, Roberta L., additional, Ccoe, David A., additional, Krell, Daniel M., additional, and Hackbert, Lucianne, additional

Published
1994
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28. Genetic and immune landscape evolution in MMR-deficient colorectal cancer.

Author

Challoner BR, Woolston A, Lau D, Buzzetti M, Fong C, Barber LJ, Anandappa G, Crux R, Assiotis I, Fenwick K, Begum R, Begum D, Lund T, Sivamanoharan N, Sansano HB, Domingo-Arada M, Tran A, Pandha H, Church D, Eccles B, Ellis R, Falk S, Hill M, Krell D, Murugaesu N, Nolan L, Potter V, Saunders M, Shiu KK, Guettler S, Alexander JL, Lázare-Iglesias H, Kinross J, Murphy J, von Loga K, Cunningham D, Chau I, Starling N, Ruiz-Bañobre J, Dhillon T, and Gerlinger M

Subjects
Humans, B7-H1 Antigen, Phylogeny, Tumor Microenvironment genetics, Colorectal Neoplasms pathology, Colonic Neoplasms
Abstract

Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/β-catenin, mitogen-activated protein kinase, and TGF-β receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Published
2024
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