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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. Source

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. Source

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. Source

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. Source

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. Source

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