56 research outputs found
A multicentre, randomised phase III trial comparing protracted venous infusion (PVI) 5-fluorouracil (5-FU) with PVI 5-FU plus mitomycin C in patients with inoperable oesophago-gastric cancer
No full textBackground: this randomised study compared protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin C (MMC) in patients with advanced oesophago-gastric cancer.Patients and methods: two hundred and fifty-four patients with adenocarcinoma, squamous cell carcinoma or undifferentiated carcinoma involving the oesophagus, oesophago-gastric junction or the stomach were randomised. The major end points were tumour response, survival, toxicity and quality of life.Results: the median age of patients treated was 72 years and the two arms were well-balanced for baseline demographic factors. The overall response rate was 16.1% [95% confidence interval (CI) 9.5% to 22.7%] in patients treated with PVI 5-FU alone compared with 19.1% (95% CI 12.0% to 26.0%) for those treated with PVI 5-FU plus MMC (P = 0.555). Median time to treatment failure was 3.9 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC (P = 0.195). Median survival was 6.3 months for PVI 5-FU and 5.3 months for PVI 5-FU plus MMC (P = 1.0).Toxicity was mild for both treatments. Symptomatic benefit measured by improvement in pain control, weight loss, dysphagia and oesophageal reflux was observed in over 64% of patients in each arm. Quality of life scores were comparable in each arm.Conclusions: PVI 5-FU is a safe, effective form of palliation for patients with advanced oesophago-gastric cancer although the addition of MMC adds little extra benefit
Using bevacizumab with different chemotherapeutic regimens in metastatic colorectal cancer: balancing utility with low toxicity
No full textThe addition of bevacizumab to currently available treatment options for metastatic colorectal cancer has changed the traditional chemotherapy-based paradigm. In this review we cover published clinical trials pertaining to the toxicity and efficacy of bevacizumab for metastatic colorectal cancer. Several randomized trials have studied combinations of irinotecan, oxaliplatin, 5-fluorouracil or capecitabine with bevacizumab. Efficacy in terms of progression-free survival and overall survival has been improved to varying degrees with the addition of bevacizumab. Bevacizumab’s distinctive toxicity profile has been well demonstrated in these trials, and has been shown to be manageable. However, certain patient groups, such as the elderly, may require particular toxicity considerations with bevacizumab. The optimal timing, dose and duration of bevacizumab-containing therapy have yet to be fully determined. Further randomized data, particularly for patients with potentially resectable liver metastases, are required in order to fully define the role of bevacizumab in the increasingly complex management paradigm for this disease
The effect of low and high-intensity cycling in diesel exhaust on flow-mediated dilation, circulating NOx, endothelin-1 and blood pressure
No full textINTRODUCTION:
Exposure to air pollution impairs aspects of endothelial function such as flow-mediated dilation (FMD). Outdoor exercisers are frequently exposed to air pollution, but how exercising in air pollution affects endothelial function and how these effects are modified by exercise intensity are poorly understood.
OBJECTIVES:
Therefore, the purpose of this study was to determine the effects of low-intensity and high-intensity cycling with diesel exhaust (DE) exposure on FMD, blood pressure, plasma nitrite and nitrate (NOx) and endothelin-1.
METHODS:
Eighteen males performed 30-minute trials of low or high-intensity cycling (30% and 60% of power at VO2peak) or a resting control condition. For each subject, each trial was performed once while breathing filtered air (FA) and once while breathing DE (300ug/m3 of PM2.5, six trials in total). Preceding exposure, immediately post-exposure, 1 hour and 2 hours post-exposure, FMD, blood pressure and plasma endothelin-1 and NOx concentrations were measured. Data were analyzed using repeated-measures ANOVA and linear mixed model.
RESULTS:
Following exercise in DE, plasma NOx significantly increased and was significantly greater than FA (p<0.05). Two hours following DE exposure, endothelin-1 was significantly less than FA (p = 0.037) but exercise intensity did not modify this response. DE exposure did not affect FMD or blood pressure.
CONCLUSION:
Our results suggest that exercising in DE did not adversely affect plasma NOX, endothelin-1, FMD and blood pressure. Therefore, recommendations for healthy individuals to moderate or avoid exercise during bouts of high pollution appear to have no acute protective effect.Peer reviewedFinal article published
Current opinion on optimal treatment for colorectal cancer
No full textThe medical treatment of colorectal cancer (CRC) has evolved greatly in the last 10 years, involving complex combined chemotherapy protocols and, in more recent times, new biologic agents. Advances in adjuvant therapy have been limited to the addition of oxaliplatin and the substitution of oral fluoropyrimidine (e.g., capecitabine) for intravenous 5-fluorouracil with no evidence for improved outcome with biological agents. Clinical benefit from the use of the targeted monoclonal antibodies, bevacizumab, cetuximab and panitumumab, in the treatment of metastatic CRC is now well established, but the optimal timing of their use requires careful consideration to derive the maximal benefit. Evidence to date suggests potentially distinct roles for bevacizumab and EGF receptor-targeted biological agents (cetuximab and panitumumab) in the treatment of metastatic CRC. This article reviews the evidence in support of modern treatments for CRC and the decision-making behind the treatment choices, their benefits and toxicities.Timothy J Price, Eva Segelov, Matthew Burge, Daniel G Haller, Stephen P Ackland, Niall C Tebbutt, Christos S Karapetis, Nick Pavlakis, Alberto F Sobrero, David Cunningham and Jeremy D Shapir
Current opinion on optimal systemic treatment for metastatic colorectal cancer: outcome of the ACTG/AGITG expert meeting ECCO 2013
No full textThe treatment of metastatic colorectal cancer has evolved greatly in the last 15 years, involving combined chemotherapy protocols and, in more recent times, new biologic agents. Clinical benefit from the use of targeted therapy with bevacizumab, aflibercept, cetuximab, panitumumab and regorafenib in the treatment of metastatic colorectal cancer is now well established with median overall survival accepted as over 24 months, and with super selection for extended RAS patients higher again. The optimal timing of treatment options requires careful consideration of predictive biomarkers, and importantly the potential for interactions, to derive the maximal benefit. A group of colorectal subspecialty medical oncologists from Australia, the USA, the Netherlands and Germany met during ECCO 2013 to discuss current practice. Subsequent new data from the American Society of Clinical Oncology were also reviewed. This article reviews the evidence discussed in support of modern treatments for colorectal cancer and the decision-making behind the treatment choices, with their benefits and risks.Timothy J Price, Eva Segelov, Matthew Burge, Daniel G Haller, Niall C Tebbutt, Christos S Karapetis, Cornelis JA Punt, Nick Pavlakis, Dirk Arnold, Peter Gibbs and Jeremy D Shapir
Effects of low-intensity and high-intensity cycling with diesel exhaust exposure on soluble P-selectin, E-selectin, I-CAM-1, VCAM-1 and complete blood count
No full textBackground: Exposure to particulate matter 2.5 μm or less (PM2.5) that contains transition metals may play a role in systemic oxidative stress and inflammation. Exposure to diesel exhaust (DE) can increase adhesion molecules, which are important in the inflammatory response; however, it is unclear how exercising in DE affects adhesion molecules and how exercise intensity modulates this response.
Aim: To determine how DE exposure during exercise of varying intensities affects adhesion molecules and markers of systemic inflammation.
Methods: Eighteen males performed 30 min cycling bouts at low intensity and high intensity (30% and 60% of power at VO2peak (peak oxygen consumption) and a control condition (rest)). Each trial was performed once breathing filtered air (FA) and once breathing DE (300 μg/m3 of PM2.5, six trials in total). Prior to, immediately post, 1 and 2 hours post exposure, blood was drawn to measure parameters of a complete blood count and soluble (s) platelet-Selectin, endothelin-Selectin, intracellular cell adhesion molecule (sICAM)-1 and vascular cell adhesion molecule (sVCAM)-1. Data were analysed using repeated-measures analysis of variance.
Results: Two hours following high-intensity exercise, sICAM-1 was significantly less in DE compared with FA (p=0.008). Immediately following rest (p=0.013) and high-intensity exercise (p=0.042) in DE, sICAM-1 was significantly greater than immediately following low-intensity exercise in DE. There were no significant differences in other markers between DE and FA.
Conclusions: Based on this study, healthy individuals may not experience an acute increase in adhesion molecules and systemic inflammatory markers from exercising in DE compared with FA, and higher exercise intensities do not appear to increase the likelihood that DE will affect adhesion molecules and systemic inflammatory markers.Peer reviewedFinal article published.adhesion moleculesair pollutionexerciseexercise intensityinflammator
Angiopoietin-like 4 enhances the proliferation and migration of tendon fibroblasts
No full textPurpose: Angiopoietin-like 4 (ANGPTL4) is known to play a variety of roles in the response to exercise, and more recently has been shown to enhance the healing of tendon, a fibrous load-bearing tissue required for efficient movement. The objective of the current study was to further explore the mechanisms of ANGPTL4's effect on tendon cells using a gene array approach.
Methods: Human tendon fibroblasts were treated with recANGPTL4 and their global transcriptome response analyzed after 4 and 24 h. We also conducted functional studies using tendon fibroblasts derived from human subjects, cultured in the presence or absence of applied cyclic stretch and/or siRNA for ANGPTL4, and as confirmation we also used tendon cells from wild type (ANGPTL4 +/+) or knockout (ANGPTL4-/-) mice.
Results: The leading functions of ANGPTL4 predicted by the resulting pathway analysis were cell movement and proliferation. The experiments demonstrated that ANGPTL4 significantly enhanced tendon cell proliferation and the cell cycle progression, as well as adhesion and migration.
Conclusion: Taken together, these findings provide novel molecular insights into the effect of ANGPTL4, a multifunctional protein that regulates the physiological response to exercise, on fundamental tendon cell functions.Peer reviewedfinal article publishedCell cycleTenocytesANGPTL4Microarra
Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer
No full textIMPORTANCE Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS).OBJECTIVE To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer.DESIGN, SETTING, AND PARTICIPANTS Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industrysponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti-epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer.MAIN OUTCOMES AND MEASURES Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size-weighted coefficients of determination (R-2), with values closer to 1.00 indicating stronger association. At the patient level, the correlationwas assessed between modeled relative tumor-size change and OS.RESULTS For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.300.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R-2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 antiepidermal growth factor receptor comparisons (2684 patients), corresponding values of R-2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78).CONCLUSIONS AND RELEVANCE In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer
Risk of arterial thromboembolic events in patients with advanced colorectal cancer receiving bevacizumab
No full textBackground: Bevacizumab is an antiangiogenic mAb with efficacy against several cancers, but it is associated with risk of arterial thromboembolism (ATE). Further data are needed to determine the safety of bevacizumab. Patients and methods: We recorded grade 3, 4, or 5 ATE events and other data (including age, baseline cardiovascular risk factors, history of ATE, and aspirin use) from 471 patients with metastatic colorectal cancer in the MAX (Mitomycin, Avastin, Xeloda) trial of capecitabine monotherapy versus capecitabine with bevacizumab with or without mitomycin C. Results: Bevacizumab-treated patients had 12 grade 3, 4, or 5 ATEs (3.8% incidence). ATEs occurred in 2.1% of patients >65 years, 5% of those with a history of ATE, and 5% of those with cardiac risk factors. Age, history of ATE, or vascular risk factors did not increase risk. Aspirin users had a higher incidence than nonusers (8.9% versus 2.7%) but had higher rates of vascular risk factors. Conclusions: Bevacizumab was associated with a modestly higher risk of ATE, but safety was not significantly worse in older patients or patients with a history of ATE or vascular risk factors. The effect of aspirin in preventing ATE in patients receiving bevacizumab could not be determined from this study.N. C. Tebbutt, F. Murphy, D. Zannino, K. Wilson, M. M. Cummins, E. Abdi, A. H. Strickland, R. M. Lowenthal, G. Marx, C. Karapetis, J. Shannon, D. Goldstein, S. S. Nayagam, R. Blum, L. Chantrill, R. J. Simes & T. J. Price on behalf of the Australasian Gastro-Intestinal Trials Grou
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