Search

Your search keyword '"Maughan, Timothy"' showing total 9 results
Start Over Author "Maughan, Timothy" Publisher bmj publishing group
9 results on '"Maughan, Timothy"'

1. Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer

Author

Corry, Shania M., McCorry, Amy M.B., Lannagan, Tamsin R.M., Leonard, Niamh A., Fisher, Natalie C., Byrne, Ryan M., Tsantoulis, Petros, Cortes-Lavaud, Xabier, Amirkhah, Raheleh, Redmond, Keara L., McCooey, Aoife J., Malla, Sudhir B., Rogan, Emily, Sakhnevych, Svetlana, Gillespie, Michael A., White, Mark, Richman, Susan D., Jackstadt, Rene-Filip, Campbell, Andrew D., Maguire, Sarah, McDade, Simon S., Longley, Daniel B., Loughrey, Maurice B., Coleman, Helen G., Kerr, Emma M., Tejpar, Sabine, Maughan, Timothy, Leedham, Simon J., Small, Donna M., Ryan, Aideen E., Sansom, Owen J., Lawler, Mark, and Dunne, Philip D.

Subjects
STAGE-II, INTERFERONS, CLASSIFICATION, COLORECTAL-CANCER, SDG 3 - Good Health and Well-being, COLON CARCINOGENESIS, Biomarkers, Tumor, Humans, HETEROGENEITY, CELL, COLORECTAL CANCER, Science & Technology, Gastroenterology & Hepatology, Gastroenterology, POOR-PROGNOSIS SUBTYPES, Prognosis, CANCER, Colonic Neoplasms, CONSENSUS MOLECULAR SUBTYPES, ADJUVANT TREATMENT, Stromal Cells, Neoplasm Recurrence, Local, Life Sciences & Biomedicine, TUMOR MICROENVIRONMENT, RESPONSES
Abstract

ObjectiveStroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy.DesignTo address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series ofin vitroand stroma-richin vivomodels to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours.ResultsBy performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Usingin silico, in vitroandin vivomodels, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype acrossin vitroandin vivomodels. In anin vivomodel of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (pConclusionThis study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC.

Published
2022

2. Image-based consensus molecular subtype (imCMS) classification of colorectal cancer using deep learning

Author

Sirinukunwattana, Korsuk, Domingo, Enric; https://orcid.org/0000-0003-4390-8767, Richman, Susan D, Redmond, Keara L, Blake, Andrew, Verrill, Clare, Leedham, Simon J, Chatzipli, Aikaterini, Hardy, Claire, Whalley, Celina M, Wu, Chieh-Hsi, Beggs, Andrew D; https://orcid.org/0000-0003-0784-2967, McDermott, Ultan, Dunne, Philip D; https://orcid.org/0000-0001-9160-283X, Meade, Angela, Walker, Steven M, Murray, Graeme I, Samuel, Leslie, Seymour, Matthew, Tomlinson, Ian; https://orcid.org/0000-0003-3037-1470, Quirke, Phil, Maughan, Timothy; https://orcid.org/0000-0002-0580-5065, Rittscher, Jens; https://orcid.org/0000-0002-8528-8298, Koelzer, Viktor H; https://orcid.org/0000-0001-9206-4885, S:CORT consortium, Sirinukunwattana, Korsuk, Domingo, Enric; https://orcid.org/0000-0003-4390-8767, Richman, Susan D, Redmond, Keara L, Blake, Andrew, Verrill, Clare, Leedham, Simon J, Chatzipli, Aikaterini, Hardy, Claire, Whalley, Celina M, Wu, Chieh-Hsi, Beggs, Andrew D; https://orcid.org/0000-0003-0784-2967, McDermott, Ultan, Dunne, Philip D; https://orcid.org/0000-0001-9160-283X, Meade, Angela, Walker, Steven M, Murray, Graeme I, Samuel, Leslie, Seymour, Matthew, Tomlinson, Ian; https://orcid.org/0000-0003-3037-1470, Quirke, Phil, Maughan, Timothy; https://orcid.org/0000-0002-0580-5065, Rittscher, Jens; https://orcid.org/0000-0002-8528-8298, Koelzer, Viktor H; https://orcid.org/0000-0001-9206-4885, and S:CORT consortium

Abstract

OBJECTIVE Complex phenotypes captured on histological slides represent the biological processes at play in individual cancers, but the link to underlying molecular classification has not been clarified or systematised. In colorectal cancer (CRC), histological grading is a poor predictor of disease progression, and consensus molecular subtypes (CMSs) cannot be distinguished without gene expression profiling. We hypothesise that image analysis is a cost-effective tool to associate complex features of tissue organisation with molecular and outcome data and to resolve unclassifiable or heterogeneous cases. In this study, we present an image-based approach to predict CRC CMS from standard H&E sections using deep learning. DESIGN Training and evaluation of a neural network were performed using a total of n=1206 tissue sections with comprehensive multi-omic data from three independent datasets (training on FOCUS trial, n=278 patients; test on rectal cancer biopsies, GRAMPIAN cohort, n=144 patients; and The Cancer Genome Atlas (TCGA), n=430 patients). Ground truth CMS calls were ascertained by matching random forest and single sample predictions from CMS classifier. RESULTS Image-based CMS (imCMS) accurately classified slides in unseen datasets from TCGA (n=431 slides, AUC)=0.84) and rectal cancer biopsies (n=265 slides, AUC=0.85). imCMS spatially resolved intratumoural heterogeneity and provided secondary calls correlating with bioinformatic prediction from molecular data. imCMS classified samples previously unclassifiable by RNA expression profiling, reproduced the expected correlations with genomic and epigenetic alterations and showed similar prognostic associations as transcriptomic CMS. CONCLUSION This study shows that a prediction of RNA expression classifiers can be made from H&E images, opening the door to simple, cheap and reliable biological stratification within routine workflows.

Published
2021

3. Pre-trial inter-laboratory analytical validation of the FOCUS4 personalised therapy trial

Author

Richman, Susan D., Adams, Richard Alexander, Quirke, Phil, Butler, Rachel, Hemmings, Gemma, Chambers, Phil, Roberts, Helen, James, Michelle D., Wozniak, Sue, Bathia, Riya, Pugh, Cheryl, Maughan, Timothy Stanley, and Jasani, Bharat

Subjects
Observer Variation, COLORECTAL CANCER, Laboratory Proficiency Testing, Wales, Biopsy, Patient Selection, DNA Mutational Analysis, Reproducibility of Results, Immunohistochemistry, LABORATORY TESTS, Phenotype, England, Molecular Diagnostic Techniques, Predictive Value of Tests, ANTIBODIES, Mutation, Biomarkers, Tumor, Humans, Original Article, Genetic Predisposition to Disease, Precision Medicine, Colorectal Neoplasms, MOLECULAR PATHOLOGY
Abstract

Introduction Molecular characterisation of tumours is increasing personalisation of cancer therapy, tailored to an individual and their cancer. FOCUS4 is a molecularly stratified clinical trial for patients with advanced colorectal cancer. During an initial 16-week period of standard first-line chemotherapy, tumour tissue will undergo several molecular assays, with the results used for cohort allocation, then randomisation. Laboratories in Leeds and Cardiff will perform the molecular testing. The results of a rigorous pre-trial inter-laboratory analytical validation are presented and discussed.\ud \ud Methods Wales Cancer Bank supplied FFPE tumour blocks from 97 mCRC patients with consent for use in further research. Both laboratories processed each sample according to an agreed definitive FOCUS4 laboratory protocol, reporting results directly to the MRC Trial Management Group for independent cross-referencing.\ud \ud Results Pyrosequencing analysis of mutation status at KRAS codons12/13/61/146, NRAS codons12/13/61, BRAF codon600 and PIK3CA codons542/545/546/1047, generated highly concordant results. Two samples gave discrepant results; in one a PIK3CA mutation was detected only in Leeds, and in the other, a PIK3CA mutation was only detected in Cardiff. pTEN and mismatch repair (MMR) protein expression was assessed by immunohistochemistry (IHC) resulting in 6/97 discordant results for pTEN and 5/388 for MMR, resolved upon joint review. Tumour heterogeneity was likely responsible for pyrosequencing discrepancies. The presence of signet-ring cells, necrosis, mucin, edge-effects and over-counterstaining influenced IHC discrepancies.\ud \ud Conclusions Pre-trial assay analytical validation is essential to ensure appropriate selection of patients for targeted therapies. This is feasible for both mutation testing and immunohistochemical assays and must be built into the workup of such trials.\ud \ud Trial registration number ISRCTN90061564.

Published
2015

5. Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab.

Author

Madi, Ayman, Fisher, David, Maughan, Timothy S., Colley, James P., Meade, Angela M., Tejpar, Sabine, Van den Bosch, Ben, Maynard, Julie, Humphreys, Vikki, Wasan, Harpreet, Adams, Richard A., Idziaszczyk, Shelley, Harris, Rebecca, Kaplan, Richard S., and Cheadle, Jeremy P.

Abstract

Background Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesised that common germline variants within these pathways may also play similar roles.Methods We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 patients with aCRC treated with oxaliplatin–fluoropyrimidine chemotherapy plus cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%.Results We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab—in patients with KRAS wild-type CRCs, 36.4% with one allele encoding proline responded, as compared with 71.2% homozygous for allele encoding serine (OR 0.23, 95% CI 0.09 to 0.56, p=0.0014), and this association was predictive for cetuximab (pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated.Conclusions Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
View/download PDF

6. Pre-trial inter-laboratory analytical validation of the FOCUS4 personalised therapy trial.

Author

Richman, Susan D., Adams, Richard, Quirke, Phil, Butler, Rachel, Hemmings, Gemma, Chambers, Phil, Roberts, Helen, James, Michelle D., Wozniak, Sue, Bathia, Riya, Pugh, Cheryl, Maughan, Timothy, and Jasani, Bharat

Subjects
INDIVIDUALIZED medicine, CANCER treatment, CLINICAL trials, CLINICAL pathology, DIAGNOSIS
Abstract

Introduction Molecular characterisation of tumours is increasing personalisation of cancer therapy, tailored to an individual and their cancer. FOCUS4 is a molecularly stratified clinical trial for patients with advanced colorectal cancer. During an initial 16-week period of standard first-line chemotherapy, tumour tissue will undergo several molecular assays, with the results used for cohort allocation, then randomisation. Laboratories in Leeds and Cardiff will perform the molecular testing. The results of a rigorous pre-trial inter-laboratory analytical validation are presented and discussed. Methods Wales Cancer Bank supplied FFPE tumour blocks from 97 mCRC patients with consent for use in further research. Both laboratories processed each sample according to an agreed definitive FOCUS4 laboratory protocol, reporting results directly to the MRC Trial Management Group for independent crossreferencing. Results Pyrosequencing analysis of mutation status at KRAS codons12/13/61/146, NRAS codons12/13/61, BRAF codon600 and PIK3CA codons542/545/546/1047, generated highly concordant results. Two samples gave discrepant results; in one a PIK3CA mutation was detected only in Leeds, and in the other, a PIK3CA mutation was only detected in Cardiff. pTEN and mismatch repair (MMR) protein expression was assessed by immunohistochemistry (IHC) resulting in 6/97 discordant results for pTEN and 5/388 for MMR, resolved upon joint review. Tumour heterogeneity was likely responsible for pyrosequencing discrepancies. The presence of signet-ring cells, necrosis, mucin, edgeeffects and over-counterstaining influenced IHC discrepancies. Conclusions Pre-trial assay analytical validation is essential to ensure appropriate selection of patients for targeted therapies. This is feasible for both mutation testing and immunohistochemical assays and must be built into the workup of such trials. [ABSTRACT FROM AUTHOR]

Published
2016
Full Text
View/download PDF

7. LETTERS.

Author

Johnson, Richard C., Fligelstone, Louis J., Maughan, Timothy S., Kale, V.R., Notaras, M.J., Milroy, S.J., Quinn, A.C., Fawcett, W.J., Douglas, J.D.M., Connolly, M.J., Haddad, Peter M., O'Neill, William M., Howells, Roger, Youlten, Lawrence J.F., Henriksen, Tine Brink, Wilcox, Allen, Langhorne, Peter, and Dixon, J. Michael

Subjects
LETTERS, MEDICINE
Abstract

Presents letters on medicine. Hypothesis on dissemination of undiagnosed tumor by minimally invasive surgery; Risk of bile leak after laparoscopic cholecystectomy; Benefit from the laparoscopic repair of an inguinal hernia.

Published
1994

8. Ethics of PCT decision making on funding cancer treatments.

Author

Maughan, Timothy S. and Rule, Joanne

Subjects
*LETTERS to the editor, *MEDICAL care financing
Abstract

A letter to the editor is presented in response to the article "The World is Watching" by F. Goodlee in the July 28, 2008 issue.

Published
2008

Catalog

Books, media, physical & digital resources
See catalog results