Author
Dion Morton
Other affiliations: University of Warwick, University of Leicester, Central Manchester University Hospitals NHS Foundation Trust ...read more
Bio: Dion Morton is an academic researcher from University of Birmingham. The author has contributed to research in topics: Colorectal cancer & Population. The author has an hindex of 45, co-authored 160 publications receiving 9932 citations. Previous affiliations of Dion Morton include University of Warwick & University of Leicester.
Papers published on a yearly basis
Papers
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TL;DR: Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk, and cardiovascular mortality was similar in the two groups.
Abstract: background Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. methods A total of 2586 patients with a history of colorectal adenomas underwent randomization: 1287 were assigned to receive 25 mg of rofecoxib daily, and 1299 to receive placebo. All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee. results A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups. conclusions Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk.
2,471 citations
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Imperial College London1, The Royal Marsden NHS Foundation Trust2, University of Western Australia3, Queensland University of Technology4, St. Vincent's Health System5, University of New South Wales6, Charles University in Prague7, University of Paris8, French Institute of Health and Medical Research9, Max Planck Society10, Ludwig Maximilian University of Munich11, National and Kapodistrian University of Athens12, University of Massachusetts Boston13, University of Hong Kong14, Royal College of Surgeons in Ireland15, University of Palermo16, Kanazawa University17, University of Fukui18, Tokyo Medical and Dental University19, Dokkyo Medical University20, Maastricht University21, Rikshospitalet–Radiumhospitalet22, Tan Tock Seng Hospital23, Autonomous University of Barcelona24, Linköping University25, University of Lausanne26, National Cheng Kung University27, University of Leeds28, University of Edinburgh29, University of Birmingham30, AstraZeneca31, University of Glasgow32, University of Manchester33, Cancer Research UK34, Yale University35, Brown University36, University of Pittsburgh37, Vanderbilt University38, Yeshiva University39, Military Medical Academy40
TL;DR: In this paper, the effect of the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer was investigated using a multivariate analysis.
Abstract: Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras incolorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P=0.004, HR 1.3) and overall survival (P=0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P=0.008, HR 1.5, overall survival P=0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P=0.46, HR 1.12, overall survival P=0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. ⌐ 2001 Cancer Research Campaign.
753 citations
01 Jan 2006
TL;DR: In this randomized trial, rofecoxib significantly reduced the risk of colorectal adenomas, but also had serious toxicity.
Abstract: BACKGROUND & AIMS
In human and animal studies, nonsteroidal anti-inflammatory drugs have been associated with a reduced risk of colorectal neoplasia. Although the underlying mechanisms are unknown, inhibition of cyclooxygenase (COX), particularly COX-2, is thought to play a role. We conducted a randomized, placebo-controlled, double-blind trial to assess whether use of the selective COX-2 inhibitor rofecoxib would reduce the risk of colorectal adenomas.
METHODS
We randomized 2587 subjects with a recent history of histologically confirmed adenomas to receive daily placebo or 25 mg rofecoxib. Randomization was stratified by baseline use of cardioprotective aspirin. Colonoscopic follow-up evaluation was planned for 1 and 3 years after randomization. The primary end point was all adenomas diagnosed during 3 years' treatment. In a modified intent-to-treat analysis, we computed the relative risk of any adenoma after randomization, using Mantel-Haenszel statistics stratified by low-dose aspirin use at baseline.
RESULTS
Adenoma recurrence was less frequent for rofecoxib subjects than for those randomized to placebo (41% vs 55%; P < .0001; relative risk [RR], 0.76; 95% confidence interval [CI], 0.69-0.83). Rofecoxib also conferred a reduction in risk of advanced adenomas (P < .01). The chemopreventive effect was more pronounced in the first year (RR, 0.65; 95% CI, 0.57-0.73) than in the subsequent 2 years (RR, 0.81; 95% CI, 0.71-0.93). As reported previously, rofecoxib was associated with increased risks of significant upper gastrointestinal events and serious thrombotic cardiovascular events.
CONCLUSIONS
In this randomized trial, rofecoxib significantly reduced the risk of colorectal adenomas, but also had serious toxicity.
403 citations
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TL;DR: In this article, a randomized, placebo-controlled, double-blind trial was conducted to assess whether use of the selective COX-2 inhibitor rofecoxib would reduce the risk of colorectal adenomas.
395 citations
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TL;DR: The FOxTROT trial aims to investigate the feasibility, safety, and efficacy of preoperative chemotherapy for colon cancer, and to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome.
Abstract: Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and efficacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with >= 5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m(2), l-folinic acid 175 mg, fluorouracil 400 mg/m(2) bolus, then 2400 mg/m(2) by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the first 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratification variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3-4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no significant differences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0.81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0.10). Preoperative therapy resulted in significant downstaging of TNM5 compared with the postoperative group (p=0.04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0.0001), resection margin involvement (4% [four of 99] vs 20% [ten of 50], p=0.002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0.0001). Interpretation Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate. Funding Cancer Research UK.
331 citations
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TL;DR: The evidence is recounted that atherosclerosis, the main cause of CAD, is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the arterial tree.
Abstract: ecent research has shown that inflammation plays a key role in coronary artery disease (CAD) and other manifestations of atherosclerosis. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes. This review highlights the role of inflammation in the pathogenesis of atherosclerotic CAD. It will recount the evidence that atherosclerosis, the main cause of CAD, is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the arterial tree. A decade ago, the treatment of hypercholesterolemia and hypertension was expected to eliminate CAD by the end of the 20th century. Lately, however, that optimistic prediction has needed revision. Cardiovascular diseases are expected to be the main cause of death globally within the next 15 years owing to a rapidly increasing prevalence in developing countries and eastern Europe and the rising incidence of obesity and diabetes in the Western world. 1 Cardiovascular diseases cause 38 percent of all deaths in North America and are the most common cause of death in European men under 65 years of age and the second most common cause in women. These facts force us to revisit cardiovascular disease and consider new strategies for prediction, prevention, and treatment.
7,551 citations
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TL;DR: The If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction is evaluated as well as patients with Diabetes mellitus for Optimal management of Multivessel disease.
Abstract: 99mTc
: technetium-99m
201TI
: thallium 201
ABCB1
: ATP-binding cassette sub-family B member 1
ABI
: ankle-brachial index
ACC
: American College of Cardiology
ACCF
: American College of Cardiology Foundation
ACCOMPLISH
: Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension
ACE
: angiotensin converting enzyme
ACIP
: Asymptomatic Cardiac Ischaemia Pilot
ACS
: acute coronary syndrome
ADA
: American Diabetes Association
ADP
: adenosine diphosphate
AHA
: American Heart Association
ARB
: angiotensin II receptor antagonist
ART
: Arterial Revascularization Trial
ASCOT
: Anglo-Scandinavian Cardiac Outcomes Trial
ASSERT
: Asymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the atrial fibrillation Reduction atrial pacing Trial
AV
: atrioventricular
BARI 2D
: Bypass Angioplasty Revascularization Investigation 2 Diabetes
BEAUTIFUL
: Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction
BIMA
: bilateral internal mammary artery
BMI
: body mass index
BMS
: bare metal stent
BNP
: B-type natriuretic peptide
BP
: blood pressure
b.p.m.
: beats per minute
CABG
: coronary artery bypass graft
CAD
: coronary artery disease
CAPRIE
: Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events
CASS
: Coronary Artery Surgery Study
CCB
: calcium channel blocker
CCS
: Canadian Cardiovascular Society
CFR
: coronary flow reserve
CHARISMA
: Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management and Avoidance
CI
: confidence interval
CKD
: chronic kidney disease
CKD-EPI
: Chronic Kidney Disease Epidemiology Collaboration
CMR
: cardiac magnetic resonance
CORONARY
: The CABG Off or On Pump Revascularization Study
COURAGE
: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation
COX-1
: cyclooxygenase-1
COX-2
: cyclooxygenase-2
CPG
: Committee for Practice Guidelines
CT
: computed tomography
CTA
: computed tomography angiography
CV
: cardiovascular
CVD
: cardiovascular disease
CXR
: chest X-ray
CYP2C19*2
: cytochrome P450 2C19
CYP3A
: cytochrome P3A
CYP3A4
: cytochrome P450 3A4
CYP450
: cytochrome P450
DANAMI
: Danish trial in Acute Myocardial Infarction
DAPT
: dual antiplatelet therapy
DBP
: diastolic blood pressure
DECOPI
: Desobstruction Coronaire en Post-Infarctus
DES
: drug-eluting stents
DHP
: dihydropyridine
DSE
: dobutamine stress echocardiography
EACTS
: European Association for Cardiothoracic Surgery
EECP
: enhanced external counterpulsation
EMA
: European Medicines Agency
EASD
: European Association for the Study of Diabetes
ECG
: electrocardiogram
Echo
: echocardiogram
ED
: erectile dysfunction
EF
: ejection fraction
ESC
: European Society of Cardiology
EXCEL
: Evaluation of XIENCE PRIME or XIENCE V vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization
FAME
: Fractional Flow Reserve vs. Angiography for Multivessel Evaluation
FDA
: Food & Drug Administration (USA)
FFR
: fractional flow reserve
FREEDOM
: Design of the Future Revascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease
GFR
: glomerular filtration rate
HbA1c
: glycated haemoglobin
HDL
: high density lipoprotein
HDL-C
: high density lipoprotein cholesterol
HR
: hazard ratio
HRT
: hormone replacement therapy
hs-CRP
: high-sensitivity C-reactive protein
HU
: Hounsfield units
ICA
: invasive coronary angiography
IMA
: internal mammary artery
IONA
: Impact Of Nicorandil in Angina
ISCHEMIA
: International Study of Comparative Health Effectiveness with Medical and Invasive Approaches
IVUS
: intravascular ultrasound
JSAP
: Japanese Stable Angina Pectoris
KATP
: ATP-sensitive potassium channels
LAD
: left anterior descending
LBBB
: left bundle branch block
LIMA
: Left internal mammary artery
LDL
: low density lipoprotein
LDL-C
: low density lipoprotein cholesterol
LM
: left main
LMS
: left main stem
LV
: left ventricular
LVEF
: left ventricular ejection fraction
LVH
: left ventricular hypertrophy
MACE
: major adverse cardiac events
MASS
: Medical, Angioplasty, or Surgery Study
MDRD
: Modification of Diet in Renal Disease
MERLIN
: Metabolic Efficiency with Ranolazine for Less Ischaemia in Non-ST-Elevation Acute Coronary Syndromes
MERLIN-TIMI 36
: Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes: Thrombolysis In Myocardial Infarction
MET
: metabolic equivalents
MI
: myocardial infarction
MICRO-HOPE
: Microalbuminuria, cardiovascular and renal sub-study of the Heart Outcomes Prevention Evaluation study
MPI
: myocardial perfusion imaging
MRI
: magnetic resonance imaging
NO
: nitric oxide
NSAIDs
: non-steroidal anti-inflammatory drugs
NSTE-ACS
: non-ST-elevation acute coronary syndrome
NYHA
: New York Heart Association
OAT
: Occluded Artery Trial
OCT
: optical coherence tomography
OMT
: optimal medical therapy
PAR-1
: protease activated receptor type 1
PCI
: percutaneous coronary intervention
PDE5
: phosphodiesterase type 5
PES
: paclitaxel-eluting stents
PET
: positron emission tomography
PRECOMBAT
: Premier of Randomized Comparison of Bypass Surgery vs. Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease
PTP
: pre-test probability
PUFA
: polyunsaturated fatty acid
PVD
: peripheral vascular disease
QoL
: quality of life
RBBB
: right bundle branch block
REACH
: Reduction of Atherothrombosis for Continued Health
RITA-2
: Second Randomized Intervention Treatment of Angina
ROOBY
: Veterans Affairs Randomized On/Off Bypass
SAPT
: single antiplatelet therapy
SBP
: systolic blood pressure
SCAD
: stable coronary artery disease
SCORE
: Systematic Coronary Risk Evaluation
SCS
: spinal cord stimulation
SES
: sirolimus-eluting stents
SIMA
: single internal mammary artery
SPECT
: single photon emission computed tomography
STICH
: Surgical Treatment for Ischaemic Heart Failure
SWISSI II
: Swiss Interventional Study on Silent Ischaemia Type II
SYNTAX
: SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery
TC
: total cholesterol
TENS
: transcutaneous electrical neural stimulation
TERISA
: Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina
TIME
: Trial of Invasive vs. Medical therapy
TIMI
: Thrombolysis In Myocardial Infarction
TMR
: transmyocardial laser revascularization
TOAT
: The Open Artery Trial
WOEST
: What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing
Guidelines summarize and evaluate all evidence available, at the time of the writing process, on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well …
3,879 citations
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TL;DR: Owing to the importance of these tumour-associated phenotypes in metastasis and cancer-related mortality, targeting the products of such cellular plasticity is an attractive but challenging approach that is likely to lead to improved clinical management of cancer patients.
Abstract: Transitions between epithelial and mesenchymal states have crucial roles in embryonic development. Emerging data suggest a role for these processes in regulating cellular plasticity in normal adult tissues and in tumours, where they can generate multiple, distinct cellular subpopulations contributing to intratumoural heterogeneity. Some of these subpopulations may exhibit more differentiated features, whereas others have characteristics of stem cells. Owing to the importance of these tumour-associated phenotypes in metastasis and cancer-related mortality, targeting the products of such cellular plasticity is an attractive but challenging approach that is likely to lead to improved clinical management of cancer patients.
3,101 citations
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TL;DR: Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors, and KRAS status should be considered in selecting patients withmCRC as candidates for panitumuab mon Therapy.
Abstract: Purpose Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. Patients and Methods KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. Results KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Conclusion Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.
3,040 citations
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TL;DR: The hypothesis is put forward that activation of nuclear factor-κB by the classical, IKK-β (inhibitor-of-NF-β kinase-β)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.
Abstract: There has been much effort recently to probe the long-recognized relationship between the pathological processes of infection, inflammation and cancer. For example, epidemiological studies have shown that approximately 15% of human deaths from cancer are associated with chronic viral or bacterial infections. This Review focuses on the molecular mechanisms that connect infection, inflammation and cancer, and it puts forward the hypothesis that activation of nuclear factor-kappaB (NF-kappaB) by the classical, IKK-beta (inhibitor-of-NF-kappaB kinase-beta)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.
2,746 citations