The Cambridge Breast Intensity-modulated Radiotherapy Trial: Comparison of Clinician- versus Patient-reported Outcomes.

AIMS: Breast radiotherapy-associated toxicity is often reported using clinical and photographic assessments. The addition of patient-reported outcome measures (PROMs) is becoming more common. This study investigated the concordance between clinician- and patient-reported outcomes. MATERIALS AND METHODS: The Cambridge Breast Intensity-modulated Radiotherapy (IMRT) trial prospectively collected data on clinician assessment and PROMs at 2 and 5 years after breast radiotherapy. Clinician assessment included physical examination and photographic assessment. PROMs included European Organization for Research and Treatment of Cancer (EORTC) BR23 questionnaire and four breast radiotherapy-specific questions. The correlation between patient and clinician scores were analysed on an independent patient basis using percentage agreement, Cohen's kappa coefficient (k) and Bowker's test of symmetry. The analysis was repeated after stratifying patients based on age, baseline Hospital Anxiety and Depression Score (HADS) and baseline body image score. RESULTS: At 2 and 5 years, a weak level of concordance was seen between the clinician-based assessment and PROMS for all the five toxicity end points (k = 0.05-0.21), with individual patient-based agreement of 32.9-78.3% and a highly discordant Bowker's test of symmetry (P < 0.001). The most frequently reported moderate-severe toxicity by patients was change in breast appearance (14% at both 2 and 5 years), whereas it was breast induration (36% and 25% at 2 and 5 years, respectively) by the clinicians. The lack of concordance was not affected by patient's age, baseline HADS and baseline body image score. CONCLUSIONS: This study found that moderate-severe toxicity reported by patients is low and the overall concordance between clinicians and patients is low. This could be due to methodological limitations or alternatively reflects the subjective nature of PROMs. Incorporation of a patient's perception on treatment-related toxicity will have important implications for treatment decisions and follow-up care.

Waveguide lasers in ytterbium-doped tantalum pentoxide on silicon.

A waveguide laser in an ytterbium-doped tantalum pentoxide film is reported. The waveguide is formed of a rib of sputtered tantalum pentoxide on top of oxidized silicon with an over-cladding of silica. Emission at a wavelength of 1025 nm was achieved with an absorbed pump power threshold and slope efficiency of ≈29 mW and 27%, respectively, for a cavity formed by a high reflector mirror and an estimated 12% Fresnel reflection from the bare end-face at the output.

Association of breast tumour bed seroma with post-operative complications and late normal tissue toxicity: results from the Cambridge Breast IMRT trial.

AIMS: There are two main surgical techniques for managing the tumour bed after breast cancer excision. Firstly, closing the defect by suturing the cavity walls together and secondly leaving the tumour bed open thus allowing seroma fluid to collect. There is debate regarding which technique is preferable, as it has been reported that a post-operative seroma increase post-operative infection rates and late normal tissue side effects. METHODS: Data from 648 patients who participated in the Cambridge Breast IMRT trial were used. Seromas were identified on axial CT images at the time of radiotherapy planning and graded as not visible/subtle or easily visible. An association was sought between the presence of seroma and the development of post-operative infection, post-operative haematoma and 2 and 5 years normal tissue toxicity (assessed using serial photographs, clinical assessment and self assessment questionnaire). RESULTS: The presence of easily visible seroma was associated with increased risk of post-operative infection (OR = 1.80; p = 0.004) and post-operative haematoma (OR = 2.1; p = 0.02). Breast seroma was an independent risk factor for whole breast induration and tumour bed induration at 2 and 5 years. The presence of breast seroma was also associated with inferior overall cosmesis at 5 years. There was no significant association between the presence of seroma and the development of either breast shrinkage or breast pain. CONCLUSION: The presence of seroma at the time of radiotherapy planning is associated with increased rates of post-operative infection and haematoma. It is also an independent risk factor for late normal tissue toxicity. This study suggests that full thickness surgical closure may be desirable for patients undergoing breast conservation and radiotherapy.

Hollow-bottle optical microresonators.

Selective excitation of whispering-gallery and bottle modes in a robust hollow-bottle optical microresonator, fabricated from a silica microcapillary by a pressure-compensated, "soften-and-compress" method, is demonstrated. Characteristic resonance spectra of bottle modes were obtained by using a tapered fiber coupled at different locations along the hollow bottle. The spectral characteristics (Q-factor, excitation efficiency) are shown to have high tolerance to angular misalignment of the tapered fiber. In addition, introduction of localized losses on the outer surface of the resonator results in selective clean-up of the transmission spectrum and superior performance. A theoretical analysis of modal turning points and associated resonant wavelengths is used to explain the mechanism of mode-suppression and the resultant spectral cleaning.

The Cambridge Breast Intensity-modulated Radiotherapy Trial: patient- and treatment-related factors that influence late toxicity.

AIMS: The effect of patient- and treatment-related factors in the development of late normal tissue toxicity after radiotherapy is not yet fully established. The aim of this study was to elucidate the relative importance of such factors in the development of late toxicity after breast-conserving surgery and adjuvant breast radiotherapy. MATERIALS AND METHODS: Patient- and treatment-related factors were analysed in 1014 patients who had received adjuvant radiotherapy to the breast in the Cambridge Breast Intensity-modulated Radiotherapy (IMRT) Trial. Late toxicity data were collected using photographic and clinical assessments and patient-reported questionnaires at 2 years after radiotherapy. RESULTS: On multivariate analysis, a larger breast volume was statistically significantly associated with the development of breast shrinkage assessed by serial photographs (odds ratio per litre increase in breast volume = 1.98, 95% confidence interval 1.41, 2.78; P < 0.0005), telangiectasia (odds ratio = 3.94, 95% confidence interval 2.49, 6.24; P < 0.0005), breast oedema (odds ratio = 3.65, 95% confidence interval 2.54, 5.24; P < 0.0005) and pigmentation (odds ratio = 1.75, 95% confidence interval 1.21, 2.51; P = 0.003). Current smokers had an increased risk of developing pigmentation (odds ratio = 2.09, 95% confidence interval 1.23, 3.54; P = 0.006). Patients with a moderate or poor post-surgical cosmesis had a greatly increased risk of moderate or poor overall cosmesis (odds ratio = 38.19; 95% confidence interval 21.9, 66.7; P < 0.0005). Postoperative infection requiring antibiotics was associated with increased risk of telangiectasia (odds ratio = 3.39, 95% confidence interval 1.94, 5.91; P < 0.0005) and breast oversensitivity (odds ratio = 1.78, 95% confidence interval 1.27, 2.49; P = 0.001). CONCLUSIONS: In this study, the greatest risk factors for the development of late toxicity 2 years after breast-conserving surgery and adjuvant radiotherapy were larger breast volume, baseline pre-radiotherapy surgical cosmesis, postoperative infection and possibly smoking. These factors seem to be more important than relatively small differences in dose inhomogeneity and the addition of boost radiotherapy at 2 years after the completion of radiotherapy. The modification of potentially preventable risk factors, such as postoperative infection and smoking, may limit the development of late toxicity after breast radiotherapy.

Multi-modal particle manipulator to enhance bead-based bioassays.

By sequentially pushing micro-beads towards and away from a sensing surface, we show that ultrasonic radiation forces can be used to enhance the interaction between a functionalised glass surface and polystyrene micro-beads, and identify those that bind to the surface by illuminating bound beads using an evanescent field generated by guided light. The movement towards and immobilisation of streptavidin coated beads onto a biotin functionalised waveguide surface is achieved by using a quarter-wavelength mode pushing beads onto the surface, while the removal of non-specifically bound beads uses a second quarter-wavelength mode which exhibits a kinetic energy maximum at the boundary between the carrier layer and fluid, drawing beads towards this surface. This has been achieved using a multi-modal acoustic device which exhibits both of these quarter-wavelength resonances. Both 1-D acoustic modelling and finite element analysis has been used to design this device and to investigate the spatial uniformity of the field. We demonstrate experimentally that 90% of specifically bound beads remain attached after applying ultrasound, with 80% of non-specifically bound control beads being successfully removed acoustically. This approach overcomes problems associated with lengthy sedimentation processes used for bead-based bioassays and surface (electrostatic) forces, which delay or prevent immobilisation. We explain the potential of this technique in the development of DNA and protein assays in terms of detection speed and multiplexing.

Titanium clip placement to allow accurate tumour bed localisation following breast conserving surgery: audit on behalf of the IMPORT Trial Management Group.

INTRODUCTION: Accurate tumour bed (TB) localisation is a key requirement for the UK IMPORT (Intensity Modulated Partial Organ Radiotherapy) trial. We audited the value of titanium clips for TB localisation following breast conserving surgery (BCS) in breast radiotherapy (RT) planning. PATIENTS AND METHODS: At surgery, paired clips were positioned around the TB as follows: 1. Medial, lateral, superior and inferior: half-way between skin and fascia; 2. Posterior: at the pectoral fascia; 3. Anterior: close to the suture line. Thirty consecutive patients with clips inserted were audited at the time of RT planning. Audit standards were set as follows: (i) 5/6 pairs of clips identified on RT planning computed tomography (CT) scan - 100%; (ii) possible clip migration: <10%; (iii) TB localisation improved with clips: >50%. Inter- and intra-observer variability in clinician outlining of the TB was studied in a subset of 12 randomly selected patients to see if this impacted on positioning of radiotherapy field borders. RESULTS: Five or six pairs of clips were identified in all 30 cases. The TB could be successfully identified using CT seroma alone in only 8/30 (27%) patients. Clips were essential for the TB localisation of the other 22/30 (73%) patients. There was no evidence of clip migration. TB localisation led to modified RT field borders in 18/30 (60%) patients. Five of these patients had highly visible seromas, so the addition of clips modified field borders in 13/30 (43%) patients. Both inter- and intra-observer variability was reasonable and did not impact on positioning of radiotherapy field borders. CONCLUSION: Titanium clips provide an accurate and reliable method of TB localisation following BCS. We anticipate that the audit results will lead to clips being adopted as best practice by the Association of Breast Surgeons (ABS) at BASO (British Association of Surgical Oncology).

Whispering gallery mode spectra of channel waveguide coupled microspheres.

Evanescent coupling of light from glass channel waveguides into the whispering gallery modes of glass microspheres of radius 15?m and 100?m is studied experimentally at wavelengths near 1550 nm. Fitting the positions, widths and heights of resonances in the experimental spectra to the characteristic equation for microsphere modes and to universal coupled microresonator theory, we establish sphere radius and index, identify mode numbers, and determine losses. The results provide detailed information for the design of optical devices incorporating microsphere resonators in planar lightwave circuits.

Optical manipulation of microspheres along a subwavelength optical wire.

The propulsion of 3 microm polystyrene spheres along a subwavelength optical wire is demonstrated. Velocities in the range of 7-15 microm/s are observed. Simulations are carried out to evaluate the evanescent field at the waveguide-water suspension interface.

Submicron patterning of DNA oligonucleotides on silicon.

The covalent attachment of DNA oligonucleotides onto crystalline silicon (100) surfaces, in patterns with submicron features, in a straightforward, two-step process is presented. UV light exposure of a hydrogen-terminated silicon (100) surface coated with alkenes functionalized with N-hydroxysuccinimide ester groups resulted in the covalent attachment of the alkene as a monolayer on the surface. Submicron-scale patterning of surfaces was achieved by illumination with an interference pattern obtained by the transmission of 248 nm excimer laser light through a phase mask. The N-hydroxysuccinimide ester surface acted as a template for the subsequent covalent attachment of aminohexyl-modified DNA oligonucleotides. Oligonucleotide patterns, with feature sizes of 500 nm, were reliably produced over large areas. The patterned surfaces were characterized with atomic force microscopy, scanning electron microscopy, epifluorescence microscopy and ellipsometry. Complementary oligonucleotides were hybridized to the surface-attached oligonucleotides with a density of 7 x 10(12) DNA oligonucleotides per square centimetre. The method will offer much potential for the creation of nano- and micro-scale DNA biosensor devices in silicon.

Waveguide surface plasmon resonance studies of surface reactions on gold electrodes.

We describe the fabrication and characterisation of gold-coated graded index channel waveguide sensors designed for simultaneous electrochemical and surface plasmon resonance studies. The active sensing electrode area is a thin gold film between 0.5 and 5 mm in length and 200 microm wide deposited on top of a 3 microm wide waveguide which forms one arm of a Y-junction while the other arm of the Y-junction serves as a reference. Using these devices we have measured simultaneously the changes in transmittance through the device whilst carrying out cyclic voltammetry in either sulfuric or perchloric acid solution or during the deposition of an UPD layer of copper at the gold surface. In all cases we obtain stable and reproducible results which demonstrate the very high sensitivity of the devices to sub-monolayer changes occurring at the gold electrode surface. The response of these integrated optoelectrochemical devices is discussed in terms of a numerical model for the propagation of light within the waveguide structure.

Superstrate index control of waveguide grating reflectivity.

Control of reflectivity of a relief grating in a high-index film overlaid on a monomode glass waveguide was achieved by adjustment of the superstrate refractive index with liquids. Weak gratings reflecting at 1531 nm were inscribed by UV laser ablation. The grating reflectivity was measured as the ratio of the transmission outside the reflection band, at 1536 nm, to that at the Bragg wavelength. Reflectivity with an air superstrate was <0.3 dB for both polarizations. In the TE polarization the grating strength increased to 20.5 dB after application of a liquid of index 1.45. In the TM polarization the strength increased to 27 dB with a superstrate index of 1.50. Good agreement was found with a theoretical model based on beam propagation.

Planar waveguides in multicomponent glasses fabricated by field-driven differential drift of cations.

The fabrication of planar waveguides by a constant-current thermal poling procedure in multicomponent glasses rich in alkali or alkaline earth ions is described. Near the anode, the dc electric field applied to the substrate separates the mobile cations into regions according to their mobility. Each region presents a different refractive index, allowing a waveguide to be formed. This method produces waveguides with an index increase greater than 10(-2) in soda-lime glass with no external ion source, and the waveguides are buried beneath the substrate surface without an additional step.

Waveguide surface plasmon resonance sensor for electrochemically controlled surface reactions.

Electrochemical oxidation of the surface of a thin gold film overlaid on an optical waveguide and placed in a cell containing sulfuric acid is monitored by integrated optical surface plasmon resonance (IOSPR) combined with cyclic voltammetry. Waveguide transmittance correlates well with the charge transferred to and from the electrode to oxidize and reduce the surface, with a 60% reduction in transmittance being observed for complete formation of the surface oxide. IOSPR sensors combined with electrochemical measurement and control show potential for sensitive and robust integrated multisensors for electroactive species.

Gallium-diffused waveguides in sapphire.

The fabrication and characterization of gallium-diffused planar waveguides in sapphire are reported. Waveguides were fabricated by diffusion of 60-200-nm-thick films of gallium oxide into c -cut sapphire at 1600 degrees C for times ranging from 6 to 16 h. Near-field intensity profiles of the guided modes were measured at wavelengths from 488 to 850 nm, and the surface-index elevation was estimated to be up to (0.6+/-0.02)x10(-2) . Potential applications for low-threshold Ti:sapphire waveguide lasers and for optical integrated circuits with passive and active elements in sapphire are discussed.

Ion-exchanged tapered-waveguide laser in neodymium-doped BK7 glass.

We report what is to our knowledge the first operation of a planar dielectric tapered-waveguide laser. The waveguide laser is fabricated by potassium-ion exchange in Nd(3+) -doped BK7 glass and consists of a single-mode channel waveguide of a few micrometers' width followed by a linear taper up to a broad region with a width of ~180microm . A slope efficiency of 42% is found both in the tapers and in standard channel waveguides fabricated upon the same substrate, indicating that the tapers and the channels have similar internal losses; hence the low-loss nature of the tapered beam expansion. The output from either end of the tapered structure is found to be nearly diffraction limited.

Integrated optical surface plasmon resonance immunoprobe for simazine detection.

This paper presents the detailed design and characterisation of a regenerable integrated optical surface plasmon resonance immunoprobe as a detector for the triazine herbicide simazine. A sensor design theoretically optimised for use in the aqueous environment is presented and its fabrication described. Experimental results on the sensitivity to changes in bulk refractive index of the analyte and on non-specific binding of ovalbumin are presented. Binding inhibition immunoassays were conducted for simazine and the lower limit of detection determined to be 0.16 microgram/l using anti-simazine IgG antibodies and 0.11 microgram/l using anti-simazine Fab fragments. A sample test cycle of 20 min was established.

Sensitivity enhancement of integrated optical sensors by use of thin high-index films.

The proportion of power carried in the superstrate medium by the guided modes of integrated optical waveguides can be increased by the addition of a thin high-index film. Enhanced refractive-index sensing is demonstrated with channel waveguide Mach-Zehnder interferometers with Ta(2)O(5) overlays. Sensitivity increases by a factor greater than 50, and a detection limit better than 5 x 10(-7) is obtained. This approach is broadly applicable to sensing at waveguide surfaces where the strength of evanescent fields dictates performance.

Indium tin oxide overlayered waveguides for sensor applications.

The use of indium tin oxide (ITO) thin films as electrodes for integrated optical electrochemical sensor devices is discussed. The effect of various thicknesses of ITO overlayers exhibiting low resistivity and high transparency on potassium ion-exchanged waveguides fabricated in glass substrates is investigated over the wavelength range 500-900 nm. ITO overlayers are formed by reactive thermal evaporation in oxygen, followed by annealing in air to a maximum temperature of 320 degrees C. With air as the superstrate, losses in the waveguides were found to increase dramatically above 30-nm ITO thickness for TE polarization and above 50-nm thickness for TM. Losses were increased over the whole wavelength range for a superstrate index close to that of water. A one-dimensional, multilayer waveguide model is used in the interpretation of the experimental results.