Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16,

Design and applications of flexible photonic membranes

ADF acknowledges support from EPSRC (EP/I004602/1 and EP/J004200/1).In this paper we present the design and applications of flexible photonic membranes. We discuss their use as versatile photonic layers in the framework of lab-on-fibre applications, specifically focusing on the design of angular robust spectral filters. We also show alternative routes to their fabrication, highlighting the opportunities and limitations associated to each approach. Finally we present our preliminary results on the all-optical control over flexible membranes, as a potential method to fine-tune their opto-mechanical properties to the required application.Publisher PD

Reproducible surface-enhanced Raman quantification of biomarkers in multicomponent mixtures

A.C.D.L. is supported by an AIRC Start-up Grant 11454 and a FIR project RBFR12WAPY. A.D.F. is supported by an EPSRC Career Acceleration Fellowship (EP/I004602/1). D.C. is supported by an AIRC Grant IG10341 and the projects PON01-00117 and PON01-00862. S.M. is supported by a PRIN project 2012CK5RPF_05.Direct and quantitative detection of unlabeled glycerophosphoinositol (GroPIns), an abundant cytosolic phosphoinositide derivative, would allow rapid evaluation of several malignant cell transformations. Here we report label-free analysis of GroPIns via surface-enhanced Raman spectroscopy (SERS) with a sensitivity of 200 nM, well below its apparent concentration in cells. Crucially, our SERS substrates, based on lithographically defined gold nanofeatures, can be used to predict accurately the GroPIns concentration even in multicomponent mixtures, avoiding the preliminary separation of individual compounds. Our results represent a critical step toward the creation of SERS-based biosensor for rapid, label-free, and reproducible detection of specific molecules, overcoming limits of current experimental methods.PostprintPeer reviewe

Flexible membranes for nanoplasmonic applications

Nanoplasmonics has provided a way to control light with extremely high precision, into nanoscale volumes. In many circumstances, the nanoplasmonic devices which can be realised are fabricated using processing techniques which rely on planar technologies. This thesis provides a general method to make nanoplasmonic devices on a flexible membrane structure, which can be free standing, extremely thin (less than the wavelength of visible light), but retains the ability to be manipulated without loss of optical function. These devices are very pliant and conformable. Flexibility allows the integration of nanoplasmonic devices into many new applications where curved surfaces or the ability to conform to another object is required, as well as providing a route for post-fabrication tunability. Two specific applications are considered: lab-on-fibre technology and surface enhanced Raman spectroscopy. Lab-on-fibre technologies have been advancing the ability to miniaturise experiments which would normally require a whole laboratory. Fabricating a membrane and then later applying it to the fibre decouples the choice of fibre from the design of the device. Surface enhanced Raman spectroscopy is a powerful diagnostic tool which can uniquely identify an optical fingerprint of different molecules. The technique has been held back from widespread clinical adoption because of the difficulty of reproducibility of the substrates used. A repeatable and reliable rigid substrate is demonstrated, which can identify the concentration of a three component mixture of physiologically relevant biomolecules. This same design is then shown in a flexible form factor, which is applied to a non-planar landscape where it can identify the locations where a molecule of interest has been deposited. This thesis details the development of the fabrication protocol, the construction of experimental apparatus for characterisation, and the use of numerical modelling to advance the flexible nanoplasmonic membrane platform

Optical guided mode resonance filter on a flexible substrate

We demonstrate the operation of a flexible optical filter based on guided mode resonances that operates in the visible regime. The filter is fabricated on a free standing polymeric membrane of 1.3 μm thickness and we show how the geometrical design parameters of the filter determine its optical properties, and how various types of filter can be made with this scheme. To highlight the versatility and robustness of the approach, we mount a filter onto a collimated fibre output and demonstrate successful wavelength filtering.Publisher PDFPeer reviewe

Optical guided mode resonance filter on a flexible substrate

We demonstrate the operation of a flexible optical filter based on guided mode resonances that operates in the visible regime. The filter is fabricated on a free standing polymeric membrane of 1.3 μm thickness and we show how the geometrical design parameters of the filter determine its optical properties, and how various types of filter can be made with this scheme. To highlight the versatility and robustness of the approach, we mount a filter onto a collimated fibre output and demonstrate successful wavelength filtering

Biomolecular sensing for cancer diagnostics using highly reproducible SERS substrates

We developed a SERS biosensor based on gold fishnets fabricated by using e-beam lithography. This device is used for glycerophosphoinositol (GroPIns) molecule sensing. GroPIns is an abundant component of cell cytosol and high GroPIns levels have been reported in several tumour cells. We demonstrate that our SERS sensor is able to accurately and quantitatively determine the concentration of GroPIns. These results indicate that SERS may provide a novel platform technology to identify GroPIns profiles in disease pathogenesis.</p