Royal Marsden NHS Trust

London, United Kingdom

Royal Marsden NHS Trust

London, United Kingdom
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James S.,University of London | Jhanji S.,Royal Marsden NHS Trust | Smith A.,Barts Health NHS Trust | O'Brien G.,Materials Misericordiae University Hospital | And 3 more authors.
British Journal of Anaesthesia | Year: 2014

Background. Current approaches to risk assessment before major surgery have important limitations. The aim of this pilot study was to compare predictive accuracy of preoperative scoring systems, plasma biomarkers, and cardiopulmonary exercise testing (CPET) for complications after major non-cardiac surgery. Methods. Single-centre, observational study of patients aged ≥40 yr undergoing major elective non-cardiac surgery. Before surgery, risk scores were calculated and blood samples collected for measurement of plasma biomarkers. Patients underwent CPET for measurement of anaerobic threshold (AT) and peak oxygen consumption (VO2 peak). After surgery, patients were followed for 28 days to evaluate complications and major adverse cardiac events (MACE). Data are presented as area under the receiver operating characteristic curve (AUROC) with 95% confidence intervals. Results. A total of 100 patients were recruited between April 2009 and October 2010; 17 of whom did not proceed to surgery. CPET variables suggested good predictive accuracy for MACE [AT: AUROC 0.83 (0.69-0.96); VO2 peak AUROC 0.81 (0.69-0.96)] and poor predictive accuracy for all complications [AT: AUROC 0.64 (0.52-0.77); VO 2 peak AUROC 0.64 (0.52-0.77)]. There was a trend towards predictive accuracy of the plasma biomarkers B-type natriuretic peptide and estimated glomerular filtration rate (calculated from serum creatinine) for MACE but not all complications. C-reactive protein, ASA score, and revised cardiac risk index had little or no predictive value. Conclusions. These pilot data suggest that CPET and plasma biomarkers may improve risk assessment before surgery. Only large clinical studies can confirm this observation and define the optimal use of these tests in clinical practice. © 2013 © The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.

Cuzick J.,Queen Mary, University of London | Sestak I.,Queen Mary, University of London | Forbes J.F.,University of Newcastle | Knox J.,Queen Mary, University of London | And 10 more authors.
The Lancet | Year: 2014

Background Aromatase inhibitors eff ectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. We assessed the effi cacy and safety of the aromatase inhibitor anastrozole for prevention of breast cancer in postmenopausal women who are at high risk of the disease. Methods Between Feb 2, 2003, and Jan 31, 2012, we recruited postmenopausal women aged 40-70 years from 18 countries into an international, double-blind, randomised placebo-controlled trial. To be eligible, women had to be at increased risk of breast cancer (judged on the basis of specifi c criteria). Eligible women were randomly assigned (1:1) by central computer allocation to receive 1 mg oral anastrozole or matching placebo every day for 5 years. Randomisation was stratifi ed by country and was done with blocks (size six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation; only the trial statistician was unmasked. The primary endpoint was histologically confi rmed breast cancer (invasive cancers or non-invasive ductal carcinoma in situ). Analyses were done by intention to treat. This trial is registered, number ISRCTN31488319. Findings 1920 women were randomly assigned to receive anastrozole and 1944 to placebo. After a median follow-up of 5.0 years (IQR 3.0-7.1), 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (hazard ratio 0.47, 95% CI 0.32-0.68, p<0.0001). The predicted cumulative incidence of all breast cancers after 7 years was 5.6% in the placebo group and 2.8% in the anastrozole group. 18 deaths were reported in the anastrozole group and 17 in the placebo group, and no specifi c causes were more common in one group than the other (p=0.836). Interpretation Anastrozole eff ectively reduces incidence of breast cancer in high-risk postmenopausal women. This fi nding, along with the fact that most of the side-eff ects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer. Funding Cancer Research UK, the National Health and Medical Research Council Australia, Sanofi -Aventis, and AstraZeneca.

Khattak M.,Royal Marsden NHS Trust | Fisher R.,Royal Marsden NHS Trust | Turajlic S.,Institute of Cancer Research | Larkin J.,Royal Marsden NHS Trust
Therapeutic Advances in Medical Oncology | Year: 2013

Metastatic melanoma is one of the most challenging malignancies to treat and often has a poor outcome. Until recently, systemic treatment options were limited, with poor response rates and no survival advantage. However, the treatment of metastatic melanoma has been revolutionized by developments in targeted therapy and immunotherapy; the BRAF inhibitor, vemurafenib, and anticytotoxic T-lymphocyte antigen 4 antibody, ipilimumab, are the first agents to demonstrate a survival benefit. Despite the success of these treatments, most patients eventually progress, and research into response and resistance mechanisms, rationally designed combination therapies and evaluation of the role of these agents in the adjuvant setting is critically important. © 2012 The Author(s).

Weigelt B.,Cancer Research UK Research Institute | Banerjee S.,Royal Marsden NHS Trust
Current Opinion in Oncology | Year: 2012

Purpose of Review: Endometrial cancer is the most common gynaecological malignancy in the western world. Two clinicopathological subtypes are recognized: type I (endometrioid) and type II (nonendometrioid) carcinomas. This review describes the molecular alterations in endometrial cancer and how this knowledge is leading to the development of novel treatments in this area. Recent Findings: Molecularly targeted agents have entered clinical trials in endometrial cancer. So far, mechanistic target of rapamycin (mTOR) inhibitors and antiangiogenic agents appear promising and are being pursued further in addition to other targeted approaches. Summary: The clinicopathological and molecular heterogeneity of endometrial cancer needs to be taken into account in the design of future clinical trials as well as the incorporation of robust biomarkers for the success of therapeutic strategies in endometrial cancer. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Banerjee S.,Royal Marsden NHS Trust
Steroids | Year: 2011

Despite effective treatments for oestrogen receptor-positive breast cancers, drug resistance is common and remains a significant clinical challenge. Targeting tumour vasculature by blockade of the vascular endothelial growth factor (VEGF) has proved successful in a variety of cancers. Phase III clinical trials of bevacizumab in combination with chemotherapy showed some efficacy in breast cancer. Concomitant targeting of the VEGF and oestrogen signalling pathways has the potential to provide enhanced therapeutic benefit in oestrogen receptor-positive breast cancer, and this strategy is under evaluation in clinical trials. This article summarises the rationale for this approach and clinical studies so far. © 2011 Elsevier Inc. All rights reserved.

Khattak M.A.,Royal Marsden NHS Trust | Fisher R.,Royal Marsden NHS Trust | Hughes P.,Royal Marsden NHS Trust | Gore M.,Royal Marsden NHS Trust | Larkin J.,Royal Marsden NHS Trust
Melanoma Research | Year: 2013

Uveal melanoma (UM) is a rare disease with a distinct molecular profile. About half of the patients with UM eventually develop metastatic disease. The prognosis of these patients remains poor. Treatment options are limited and none of them have been able to show a survival benefit. Ipilimumab was the first agent to show a survival benefit in patients with cutaneous melanoma in a randomized trial; however, there is limited published evidence for its role in the management of advanced UM. Here, we report our experience of ipilimumab in five patients with advanced UM treated at an academic cancer centre in the UK. Two patients had durable stable disease and three developed progressive disease. Of the patients with stable disease, one maintained disease control at 11 months from the commencement of treatment with ∼10% reduction in tumour volume compared with the baseline, and the second patient progressed after 15 months. We also examined the tumour kinetics and response patterns that resembled that of ipilimumab in cutaneous melanoma. Given the lack of randomized trial data, our findings indicate that ipilimumab might be a reasonable treatment option for patients with advanced UM. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Jennings A.L.,Royal Marsden NHS Trust
Cochrane database of systematic reviews (Online) | Year: 2012

Breathlessness is a common symptom in people with advanced disease. The most effective treatments are aimed at treating the underlying cause of the breathlessness but this may not be possible and symptomatic treatment is often necessary. Strategies for the symptomatic treatment of breathlessness have never been systematically evaluated. Opioids are commonly used to treat breathlessness: the mechanisms underlying their effectiveness are not completely clear and there have been few good-sized trials in this area. To determine the effectiveness of opioid drugs given by any route in relieving the symptom of breathlessness in patients who are being treated palliatively. An electronic search was carried out of Medline, Embase, CINAHL, T he Cochrane L ibrary, Dissertation Abstracts, Cancercd and SIGLE. Review articles and reference lists of retrieved articles were hand searched. Date of most recent search: May 1999. Randomised double-blind, controlled trials comparing the use of any opioid drug against placebo for the relief of breathlessness were included. Patients with any illness suffering from breathlessness were included and the intervention was any opioid, given by any route, in any dose. Studies identified by the search were imported into a reference manager database. The full texts of the relevant studies were retrieved and data were independently extracted by two review authors. Studies were quality scored according to the Oxford Quality scale. The primary outcome measure used was breathlessness and the secondary outcome measure was exercise tolerance. Studies were divided into non-nebulised and nebulised and were analysed both separately and together. A qualitative analysis was carried out of adverse effects of opioids. Where appropriate, meta-analysis was carried out. Eighteen studies were identified of which nine involved the non-nebulised route of administration and nine the nebulised route. A small but statistically significant positive effect of opioids was seen on breathlessness in the analysis of studies using non-nebulised opioids. There was no statistically significant positive effect seen for exercise tolerance in either group of studies or for breathlessness in the studies using nebulised opioids. There is evidence to support the use of oral or parenteral opioids to palliate breathlessness although numbers of patients involved in the studies were small. No evidence was found to support the use of nebulised opioids. Further research with larger numbers of patients, using standardised protocols and with quality of life measures is needed.

Seifert H.,Royal Marsden NHS Trust
Melanoma Research | Year: 2015

The BRAF inhibitor vemurafenib is an effective drug in patients with BRAF mutant metastatic melanoma, but resistance occurs after a median of 6 months. The anti-CTLA4-antibody, ipilimumab, is a standard first-line and second-line treatment option in Europe, with a median time to response of 2–3 months, but some patients show rapid clinical deterioration before that. The aim of this analysis was to identify prognostic markers for survival after failure of vemurafenib treatment to identify patients who have a sufficient life expectancy to respond to new immunotherapy treatments. We retrospectively analysed 101 consecutive unselected patients treated with vemurafenib for metastatic melanoma at a single institution. The association between clinical parameters and death within 3 months after cessation of vemurafenib (n=69) was assessed by binary logistic and Cox regression. Of the patients, 45% died within 3 months of progression on vemurafenib. Elevated baseline serum lactate dehydrogenase, absence of normalization of serum lactate dehydrogenase on vemurafenib therapy, performance status of at least 2 at progression and time from primary tumour to metastatic disease less than 5 years were identified as poor prognostic markers. In an exploratory tumour growth kinetics analysis (n=16), we found that following cessation of vemurafenib, approximately a third each showed a stable, decelerated or accelerated rate of tumour growth. Patients with these poor prognostic markers are unlikely to have sufficient life expectancy to complete ipilimumab treatment after failure with vemurafenib. Consideration needs to be given to the elective use of immunotherapy before patients become resistant to vemurafenib. This requires prospective randomized evaluation. Our tumour growth kinetics analysis requires confirmation; however, it may suggest that intermittent vemurafenib treatment should be investigated in clinical trials. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Khattak M.,Royal Marsden NHS Trust | Larkin J.,Royal Marsden NHS Trust
World Journal of Urology | Year: 2014

Renal cell carcinoma comprises 2-3 % of all adult malignancies and its incidence is increasing. Overall survival of patients with advanced disease has increased over the last decade due to the development of many effective targeted agents. Unfortunately, most patients inevitably develop resistance to these agents. While our understanding of the underlying resistance mechanisms has improved, there remain multiple challenges in order to overcome resistance to targeted agents. Sequential and combination therapy with a variety of novel drugs has been evaluated to maintain ongoing clinical benefit and potentially overcome drug resistance. Retrospective data suggest that further anti-angiogenic therapy may be beneficial in advanced renal cell carcinoma after prior progression on two targeted agents with a similar or different mechanism of action. However, further randomised data are needed to better define the role of these agents beyond second-line therapy in the treatment of renal cell carcinoma. © 2013 Springer-Verlag Berlin Heidelberg.

Hirata E.,Cancer Research UK Research Institute | Girotti M.R.,Cancer Research UK Research Institute | Viros A.,Cancer Research UK Research Institute | Hooper S.,Cancer Research UK Research Institute | And 5 more authors.
Cancer Cell | Year: 2015

Intravital imaging of BRAF-mutant melanoma cells containing an ERK/MAPK biosensor reveals how the tumor microenvironment affects response to BRAF inhibition by PLX4720. Initially, melanoma cells respond to PLX4720, but rapid reactivation of ERK/MAPK is observed in areas of high stromal density. This is linked to"paradoxical" activation of melanoma-associated fibroblasts by PLX4720 and the promotion of matrix production and remodeling leading to elevated integrin β1/FAK/Src signaling in melanoma cells. Fibronectin-rich matrices with 3-12kPa elastic modulus are sufficient to provide PLX4720 tolerance. Co-inhibition of BRAF and FAK abolished ERK reactivation and led to more effective control of BRAF-mutant melanoma. We propose that paradoxically activated MAFs provide a "safe haven" for melanoma cells to tolerate BRAF inhibition. © 2015 The Authors.

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