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Dive into the research topics where Duncan C. Gilbert is active.

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Featured researches published by Duncan C. Gilbert.


The Journal of Pathology | 2009

Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents

Duncan C. Gilbert; Ian Chandler; Alan McIntyre; N. C. Goddard; Rhian Gabe; Robert Huddart; Janet Shipley

Interaction between the chemokine CXCL12 (SDF1) and the G‐protein coupled receptor CXCR4 is responsible for the maintenance of adult stem cell niches and is known to play an important role in utero in the migration of primordial germ cells. We demonstrate expression of CXCL12 by Sertoli cells and confirm CXCR4 expression by the germ cell population of the adult human testes. CXCR4 is also known to mediate organ‐specific patterns of metastases in a range of common cancers. We identify consistent expression of CXCR4 mRNA and protein in testicular germ cell tumours (TGCT) that accounts for their patterns of relapse in sites of known CXCL12 expression. Extragonadal primary germ cell tumours express CXCR4 and their sites of occurrence are coincident with areas of known CXCL12 expression in utero. We show that CXCL12 stimulates the invasive migration of a TGCT cell line in vitro in a CXCR4‐dependent fashion and activates ERK. Furthermore, we demonstrate that expression of CXCL12 in stage I non‐seminomas is significantly associated with organ‐confined disease post‐orchidectomy and reduced risk of relapse (p = 0.003). This may be through the loss of CXCL12 gradients that might otherwise attract cells away from the primary tumour. We propose CXCL12 expression as a potential predictor of subsequent relapse that could lead to avoiding unnecessary treatment and associated late toxicities. Our observations support a role for CXCL12/CXCR4 in the adult germ cell population and demonstrate pathological function in germ cell tumour development and metastasis that may have clinical utility. Copyright


Nature Reviews Cancer | 2011

Testicular germ cell tumours: predisposition genes and the male germ cell niche

Duncan C. Gilbert; Elizabeth A. Rapley; Janet Shipley

Testicular germ cell tumours (TGCTs) of adults and adolescents are putatively derived from primordial germ cells or gonocytes. Recently reported genome-wide association studies implicate six gene loci that predispose to TGCT development. Remarkably, the functions of proteins encoded by genes within these regions bridge our understanding between the pathways involved in primordial germ cell physiology, male germ cell development and the molecular pathology of TGCTs. Furthermore, this improved understanding of the mechanisms underlying TGCT development and dissemination has clinical relevance for the management of patients with these tumours.


British Journal of Cancer | 2008

Evidence-based pragmatic guidelines for the follow-up of testicular cancer: optimising the detection of relapse

N. van As; Duncan C. Gilbert; Julian Money-Kyrle; David Bloomfield; Sharon Beesley; David P. Dearnaley; A. Horwich; Robert Huddart

Testicular germ cell tumours (TGCTs) are the most common cause of cancer in men between the ages of 15 and 40 years, and, overall, the majority of patients should expect to be cured. The European Germ Cell Cancer Consensus Group has provided clear guidelines for the primary treatment of both seminoma and nonseminomatous germ cell tumours. There is, however, no international consensus on how best to follow patients after their initial management. This must promptly and reliably identify relapses without causing further harm. The standardising of follow-up would result in optimising risk-benefit ratios for individual patients, while ensuring economic use of resources. We have identified the seven common scenarios in managing seminomas and nonseminomas of the various stages and discuss the pertinent issues around relapse and follow-up. We review the available literature and present our comprehensive TGCT follow-up guidelines. Our protocols provide a pragmatic, easily accessible user-friendly basis for other centres to use or to adapt to suit their needs. Furthermore, this should enable future trials to address specific issues around follow-up giving meaningful and useful results.


British Journal of Cancer | 2012

Topoisomerase I inhibition in colorectal cancer: biomarkers and therapeutic targets

Duncan C. Gilbert; Anthony J. Chalmers; Sherif F. El-Khamisy

The topoisomerase I (Top 1) poison irinotecan is an important component of the modern treatment of colorectal cancer. By stabilising Top 1-DNA complexes, irinotecan generates Top 1-linked DNA single-strand breaks that can evolve into double-strand breaks and ultimately cause cell death. However, cancer cells may overcome cell killing by releasing the stalled topoisomerase from DNA termini, thereby reducing the efficacy of Top 1 poisons in clinics. Thus, understanding the DNA repair mechanisms involved in the repair of Top 1-mediated DNA damage provides a useful tool to identify potential biomarkers that predict response to this class of chemotherapy. Furthermore, targeting these pathways could enhance the therapeutic benefits of Top 1 poisons. In this review, we describe the cellular mechanisms and consequences of targeting Top 1 activity in cells. We summarise preclinical data and discuss the potential clinical utility of small-molecule inhibitors of the key proteins.


Genes, Chromosomes and Cancer | 2008

Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults

Alan McIntyre; Duncan C. Gilbert; N. C. Goddard; Leendart Looijenga; Janet Shipley

Testicular germ cell tumors (TGCTs) of adults and adolescents are thought to be derived from primordial germ cells or gonocytes. TGCTs develop postpuberty from precursor lesions known as intratubular germ cell neoplasia undifferentiated. The tumors can be divided into two groups based on their histology and clinical behavior; seminomas resemble primordial germ cells or gonocytes and nonseminomas resemble embryonic or extraembryonic tissues at various stages of differentiation. The most undifferentiated form of nonseminoma, embryonal carcinoma, resembles embryonic stem cells in terms of morphology and expression profiling, both mRNAs and microRNAs. Evidence supports both environmental factors and genetic predisposition underlying the development of TGCTs. Various models of development have been proposed and are discussed. In TGCTs, gain of material from the short arm of chromosome 12 is invariable: genes from this region include the proto‐oncogene KRAS, which has activating mutations in ∼10% of tumors or is frequently overexpressed. A number of different approaches to increase the understanding of the development and progression of TGCTs have highlighted the involvement of KIT, RAS/RAF/MAPK, STAT, and PI3K/AKT signaling. We review the role of these signaling pathways in this process and the potential influence of environmental factors in the development of TGCTs.


European Journal of Cancer | 2015

High-sensitivity human papilloma virus genotyping reveals near universal positivity in anal squamous cell carcinoma: Different implications for vaccine prevention and prognosis

Ivona Baricevic; Xiaotong He; Bipasha Chakrabarty; Anthony W. Oliver; Charles Bailey; Jeff Summers; Lynne Hampson; Ian N. Hampson; Duncan C. Gilbert; Andrew G. Renehan

BACKGROUND Characterisation of human papilloma virus (HPV) infection in anal squamous cell carcinoma (ASCC) may have dual importance: first, aetiological; second, prognostic, informing outcome after chemo-radiotherapy (CRT). We undertook HPV genotyping, and allelic characterisations, to evaluate the aetiological role of HPV while simultaneously evaluating the impact of HPV genotyping on relapse-free (RFS) and overall survival (OS). METHOD Dual-primer HPV genotyping (subtypes 6, 11, 16, 18, 31, 33, 45, 52, 58) and DNA sequencing of HPV 16 positive tumours were analysed in 151 consecutively referred ASCCs, previously characterised by immunohistochemistry for p16 expression. In 110 patients treated with CRT, factors influencing RFS and OS were evaluated using univariate and multivariate models. RESULTS HPV positivity was observed in 95%. HPV 16 accounted for 89%; of these, 64% harboured the T350G E6 variant. HPV 16 positivity was significantly correlated with improved 5-year RFS (62% versus 40%; p = 0.027) and OS (59% versus 38%; p = 0.019). p16 expression was also significantly correlated with improved 5-year RFS (positive versus negative: 65% versus 16%; p < 0.0001) and OS (63% versus 13%; p < 0.0001). In multivariable models that included HPV 16 status, p16 status, sex, and age, p16 expression remained an independent prognostic factor for RFS (p < 0.0001) and OS (p = 0.002). CONCLUSION In ASCC, near-universal HPV detection rates were demonstrated, higher than generally reported in the literature, and supporting the development of multivalent HPV vaccinations for prevention. By contrast, p16 negatively, but not HPV 16 genotype, is an independent adverse prognosticator after chemo-radiotherapy in patients with ASCC.


Current Medicinal Chemistry | 2012

DNA repair and resistance to topoisomerase I inhibitors: mechanisms, biomarkers and therapeutic targets.

Meryem Alagoz; Duncan C. Gilbert; Sherif F. El-Khamisy; Anthony J. Chalmers

Irinotecan and topotecan are derivatives of the naturally occurring cytotoxic compound camptothecin that are used in the treatment of patients with colorectal cancer, either as single agents or in combination with radiotherapy and/or other chemotherapy drugs. They are inhibitors of DNA topoisomerase I (Top I) and exert their cytotoxic effects in replicating cells by inducing DNA strand breaks. A wide range of DNA repair proteins is involved in the recognition and repair of these breaks, and depletion or inhibition of some of these proteins increases the cytotoxic effects of Top I inhibitors. Building on these laboratory observations, ongoing translational research is aiming to establish whether this mechanistic information can be used to improve the treatment of patients with certain types of cancer. Two potential strategies are under investigation: (1) individualising treatment by evaluating levels and/or patterns of expression of DNA repair proteins that predict clinical response to Top I inhibitors, and (2) developing small molecule inhibitors of these repair enzymes to overcome tumour resistance and improve outcomes. This review summarises the current status of these research endeavours, focusing on the key roles of tyrosyl DNA phosphodiesterase 1 (Tdp1) and poly(ADP-ribose) polymerase (PARP), and examines the pre-clinical and clinical data that support the potential value of these and other DNA repair proteins as predictive markers and therapeutic targets. Since irinotecan is increasingly being combined with radiotherapy, the potential for these proteins to act as predictive biomarkers for both Top I inhibitors and radiation is proposed, and the possibility of synergistic potentiation of chemoradiation regimes by Tdp1 and/or PARP inhibitors is considered.


BJUI | 2006

Treating stage I nonseminomatous germ cell tumours with a single cycle of chemotherapy.

Duncan C. Gilbert; Andrew R. Norman; Judith Nicholl; David P. Dearnaley; A. Horwich; Robert Huddart

To estimate the rate of relapse in men with stage I nonseminomatous germ cell tumours (NSGCT) of the testis treated with one cycle of chemotherapy instead of the usual two cycles.


Contemporary Clinical Trials | 2016

ADD-ASPIRIN: A phase III, double-blind, placebo controlled, randomised trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common non-metastatic solid tumours

Christopher Coyle; Fay H. Cafferty; Samuel Rowley; Mairead MacKenzie; Lindy Berkman; Sudeep Gupta; C.S. Pramesh; Duncan C. Gilbert; Howard Kynaston; David Cameron; Richard Wilson; Alistair Ring; Ruth E. Langley

Background There is a considerable body of pre-clinical, epidemiological and randomised data to support the hypothesis that aspirin has the potential to be an effective adjuvant cancer therapy. Methods Add-Aspirin is a phase III, multi-centre, double-blind, placebo-controlled randomised trial with four parallel cohorts. Patients who have undergone potentially curative treatment for breast (n = 3100), colorectal (n = 2600), gastro-oesophageal (n = 2100) or prostate cancer (n = 2120) are registered into four tumour specific cohorts. All cohorts recruit in the United Kingdom, with the breast and gastro-oesophageal cohort also recruiting in India. Eligible participants first undertake an active run-in period where 100 mg aspirin is taken daily for approximately eight weeks. Participants who are able to adhere and tolerate aspirin then undergo a double-blind randomisation and are allocated in a 1:1:1 ratio to either 100 mg aspirin, 300 mg aspirin or a matched placebo to be taken daily for at least five years. Those participants ≥ 75 years old are only randomised to 100 mg aspirin or placebo due to increased toxicity risk. Results The primary outcome measures are invasive disease-free survival for the breast cohort, disease-free survival for the colorectal cohort, overall survival for the gastro-oesophageal cohort, and biochemical recurrence-free survival for the prostate cohort, with a co-primary outcome of overall survival across all cohorts. Secondary outcomes include adherence, toxicity including serious haemorrhage, cardiovascular events and some cohort specific measures. Conclusions The Add-Aspirin trial investigates whether regular aspirin use after standard therapy prevents recurrence and prolongs survival in participants with four non-metastatic common solid tumours.


British Journal of Cancer | 2016

Tumour-infiltrating lymphocyte scores effectively stratify outcomes over and above p16 post chemo-radiotherapy in anal cancer

Duncan C. Gilbert; Eva Serup-Hansen; Dorte Linnemann; Estrid Høgdall; Charles Bailey; Jeff Summers; Hanne Havsteen; Gareth J. Thomas

Background:The majority (90%) of anal cancers are human papillomavirus (HPV)-driven, identified using immunochemistry for p16. Compared with HPV− patients, those with HPV+ disease generally show improved survival, although relapse rates around 25% indicate a need for further stratification of this group.Methods:Using two cohorts of anal cancer, previously characterised for p16, we assessed the prognostic value of tumour-infiltrating lymphocytes (TILs).Results:Tumour-infiltrating lymphocyte scores were used to stratify p16+ cases, where tumours with absent/low levels of TIL had a relapse-free rate of 63%, as opposed to 92% with high levels of TIL (log rank P=0.006).Conclusions:Assessment of TIL adds to p16 status in the prognosis of anal cancer following chemo-radiotherapy and provides evidence of the clinical importance of the immune response.

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Robert Huddart

The Royal Marsden NHS Foundation Trust

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Janet Shipley

Institute of Cancer Research

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A. Horwich

The Royal Marsden NHS Foundation Trust

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N. C. Goddard

Institute of Cancer Research

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Ruth E. Langley

University College London

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David P. Dearnaley

Institute of Cancer Research

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Ian Chandler

Royal Devon and Exeter Hospital

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