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Comins C.,University of Surrey | Spicer J.,Guys and St Thomass Hospital | Protheroe A.,Churchill Hospital | Roulstone V.,Targeted Therapy Laboratory | And 11 more authors.
Clinical Cancer Research | Year: 2010

Purpose: REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer. Experimental Design: Patients received 75 mg/m2 docetaxel (day 1) and escalating doses of reovirus up to 3 × 1010 TCID 50 (days 1-5) every 3 weeks. Results: Twenty-five patients were enrolled, and 24 patients were exposed to treatment, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropenia was seen in one patient, but the maximum tolerated dose was not reached. Antitumor activity was seen with one complete response and three partial responses. A disease control rate (combined complete response, partial response, and stable disease) of 88% was observed. Immunohistochemical analysis of reovirus protein expression was observed in posttreatment tumor biopsies from three patients. Conclusion: The combination of reovirus and docetaxel is safe, with evidence of objective disease response, and warrants further evaluation in a phase II study at a recommended schedule of docetaxel (75 mg/m2, three times weekly) and reovirus (3 × 1010 TCID50, days 1-5, every 3 weeks). ©2010 AACR.

Zaidi A.,University of London | Sheikh N.,University of London | Jongman J.K.,Isala Clinics | Gati S.,University of London | And 6 more authors.
Journal of the American College of Cardiology | Year: 2015

Background Physiological cardiac adaptation to regular exercise, including biventricular dilation and T-wave inversion (TWI), may create diagnostic overlap with arrhythmogenic right ventricular cardiomyopathy (ARVC). Objectives The goal of this study was to assess the accuracy of diagnostic criteria for ARVC when applied to athletes exhibiting electrocardiographic TWI and to identify discriminators between physiology and disease. Methods The study population consisted of athletes with TWI (n = 45), athletes without TWI (n = 35), and ARVC patients (n = 35). Subjects underwent electrocardiography (ECG), signal-averaged electrocardiography (SAECG), echocardiography, cardiac magnetic resonance imaging (CMRI), Holter monitoring, and exercise testing. Results There were no electrical, structural, or functional cardiac differences between athletes exhibiting TWI and athletes without TWI. When athletes were compared with ARVC patients, markers of physiological remodeling included early repolarization, biphasic TWI, voltage criteria for right ventricular (RV) or left ventricular hypertrophy, and symmetrical cardiac enlargement. Indicators of RV pathology included the following: syncope; Q waves or precordial QRS amplitudes <1.8 mV; 3 abnormal SAECG parameters; delayed gadolinium enhancement, RV ejection fraction ≤45%, or wall motion abnormalities at CMRI; >1,000 ventricular extrasystoles (or >500 non-RV outflow tract) per 24 h; and symptoms, ventricular tachyarrhythmias, or attenuated blood pressure response during exercise. Nonspecific parameters included the following: prolonged QRS terminal activation; 2 abnormal SAECG parameters; RV dilation without wall motion abnormalities; RV outflow tract ectopy; and exercise-induced T-wave pseudonormalization. Conclusions TWI and balanced biventricular dilation are likely to represent benign manifestations of training in asymptomatic athletes without relevant family history. Diagnostic criteria for ARVC are nonspecific in such individuals. Comprehensive testing using widely available techniques can effectively differentiate borderline cases. © 2015 American College of Cardiology Foundation.

Howard L.S.,Imperial College Healthcare NHS Trust | Grapsa J.,Imperial College Healthcare NHS Trust | Dawson D.,Imperial College Healthcare NHS Trust | Bellamy M.,Imperial College Healthcare NHS Trust | And 4 more authors.
European Respiratory Review | Year: 2012

Patients with suspected pulmonary hypertension (PH) should be evaluated using a multimodality approach to ensure that they receive a correct diagnosis. The series of investigations required includes clinical evaluation, noninvasive imaging techniques and right heart catheterisation (considered to be the "gold standard" for the diagnosis of PH). Current guidelines recommend that a detailed echocardiographic assessment is performed in all patients with suspected PH. In this review we summarise a protocol adopted by the National Pulmonary Hypertension Centres of UK and Ireland and approved by the British Society of Echocardiography for the evaluation of these patients. The views and measurements described are recommended for diagnosis, assisting in prognosis and providing a noninvasive means of following disease progression or response to therapy. © ERS 2012.

Powell J.T.,Imperial College London | Sweeting M.J.,University of Cambridge | Thompson M.M.,St Georges Vascular Institute | Hinchliffe R.J.,St Georges Vascular Institute | And 5 more authors.
European Heart Journal | Year: 2015

Aims To investigate whether aneurysmshape and extent, which indicate whether a patient with ruptured abdominal aortic aneurysm (rAAA) is eligible for endovascular repair (EVAR), influence the outcome of both EVAR and open surgical repair. Methods and results The influence of sixmorphological parameters (maximumaortic diameter, aneurysm neck diameter, length and conicality, proximalneckangle, andmaximumcommoniliacdiameter)onmortalityandreinterventionswithin30dayswas investigated in rAAApatients randomized beforemorphological assessment in the ImmediateManagement of the Patientwith Rupture: OpenVersus Endovascular strategies (IMPROVE) trial.Patients with a proven diagnosis ofrAAA,whounderwent repair and had their admission computerized tomography scan submitted to the core laboratory, were included.Among 458 patients (364men,mean age 76 years),who had either EVAR(n = 177) oropen repair (n = 281) started, therewere 155 deaths and 88 re-interventionswithin 30 days of randomization analysed according to a pre-specified plan. The mean maximumaortic diameter was 8.6 cm. There were no substantial correlations between the six morphological variables. Aneurysm neck length was shorter in those undergoing open repair (vs. EVAR). Aneurysm neck length (mean 23.3, SD 16.1 mm) was inversely associated with mortality for open repair and overall: adjusted OR 0.72 (95% CI 0.57, 0.92) for each 16 mm (SD) increase in length. There were no convincing associations of morphological parameters with reinterventions. Conclusion Short aneurysm necks adversely influence mortality afteropen repair ofrAAAand preclude conventionalEVAR. Thismay help explain why observational studies, but not randomized trials, have shown an early survival benefit for EVAR. Clinical trial registration: ISRCTN 48334791. © The Author 2014.

Raza S.J.,Roswell Park Cancer Institute | Wilson T.,Beckman Research Institute | Peabody J.O.,Ford Motor Company | Wiklund P.,Karolinska University Hospital | And 17 more authors.
European Urology | Year: 2015

Background Long-term oncologic data on patients undergoing robot-assisted radical cystectomy (RARC) are limited and based largely on single-institution series. Objective Report survival outcomes of patients who underwent RARC ≥5 yr ago. Design, setting, and participants Retrospective review of the prospectively populated International Robotic Cystectomy Consortium multi-institutional database identified 743 patients with RARC performed ≥5 yr ago. Clinical, pathologic, and survival data at the latest follow-up were collected. Patients with palliative RARC were excluded. Final analysis was performed on 702 patients from 11 institutions in 6 countries. Intervention RARC. Outcome measurements and statistical analysis Outcomes of interest, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were plotted using Kaplan-Meier survival curves. A Cox proportional hazards model was used to identify factors that predicted outcomes. Results and limitations Pathologic organ-confined (OC) disease was found in 62% of patients. Soft tissue surgical margins (SMs) were positive in 8%. Median lymph node (LN) yield was 16, and 21% of patients had positive LNs. Median follow-up was 67 mo (interquartile range: 18-84 mo). Five-year RFS, CSS, and OS were 67%, 75%, and 50%, respectively. Non-OC disease and SMs were associated with poorer RFS, CSS, and OS on multivariable analysis. Age predicted poorer CSS and OS. Adjuvant chemotherapy and positive SMs were predictors of RFS (hazard ratio: 3.20 and 2.16; p < 0.001 and p < 0.005, respectively). Stratified survival curves demonstrated poorer outcomes for positive SM, LN, and non-OC disease. Retrospective interrogation and lack of contemporaneous comparison groups that underwent open radical cystectomy were major limitations. Conclusions The largest multi-institutional series to date reported long-term survival outcomes after RARC. Patient summary Patients who underwent robot-assisted radical cystectomy for bladder cancer have acceptable long-term survival. © 2015 European Association of Urology.

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