Patient-specific stopping power calibration for proton therapy planning based on single-detector proton radiography.

A simple robust optimizer has been developed that can produce patient-specific calibration curves to convert x-ray computed tomography (CT) numbers to relative stopping powers (HU-RSPs) for proton therapy treatment planning. The difference between a digitally reconstructed radiograph water-equivalent path length (DRRWEPL) map through the x-ray CT dataset and a proton radiograph (set as the ground truth) is minimized by optimizing the HU-RSP calibration curve. The function of the optimizer is validated with synthetic datasets that contain no noise and its robustness is shown against CT noise. Application of the procedure is then demonstrated on a plastic and a real tissue phantom, with proton radiographs produced using a single detector. The mean errors using generic/optimized calibration curves between the DRRWEPL map and the proton radiograph were 1.8/0.4% for a plastic phantom and -2.1/ - 0.2% for a real tissue phantom. It was then demonstrated that these optimized calibration curves offer a better prediction of the water equivalent path length at a therapeutic depth. We believe that these promising results are suggestive that a single proton radiograph could be used to generate a patient-specific calibration curve as part of the current proton treatment planning workflow

A methodology to extract outcomes from routine healthcare data for patients with locally advanced non-small cell lung cancer

BACKGROUND: Outcomes for patients in UK with locally advanced non-small cell lung cancer (LA NSCLC) are amongst the worst in Europe. Assessing outcomes is important for analysing the effectiveness of current practice. However, data quality is inconsistent and regular large scale analysis is challenging. This project investigates the use of routine healthcare datasets to determine progression free survival (PFS) and overall survival (OS) of patients treated with primary radical radiotherapy for LA NSCLC. METHODS: All LA NSCLC patients treated with primary radical radiotherapy in a 2 year period were identified and paired manual and routine data generated for an initial pilot study. Manual data was extracted information from hospital records and considered the gold standard. Key time points were date of diagnosis, recurrence, death or last clinical encounter. Routine data was collected from various data sources including, Hospital Episode Statistics, Personal Demographic Service, chemotherapy data, and radiotherapy datasets. Relevant event dates were defined by proxy time points and refined using backdating and time interval optimization. Dataset correlations were then tested on key clinical outcome indicators to establish if routine data could be used as a reliable proxy measure for manual data. RESULTS: Forty-three patients were identified for the pilot study. The manual data showed a median age of 67 years (range 46- 89 years) and all patients had stage IIIA/B disease. Using the manual data, the median PFS was 10.78 months (range 1.58-37.49 months) and median OS was 16.36 months (range 2.69-37.49 months). Based on routine data, using proxy measures, the estimated median PFS was 10.68 months (range 1.61-31.93 months) and estimated median OS was 15.38 months (range 2.14-33.71 months). Overall, the routine data underestimated the PFS and OS of the manual data but there was good correlation with a Pearson correlation coefficient of 0.94 for PFS and 0.97 for OS. CONCLUSIONS: This is a novel approach to use routine datasets to determine outcome indicators in patients with LA NSCLC that will be a surrogate to analysing manual data. The ability to enable efficient and large scale analysis of current lung cancer strategies has a huge potential impact on the healthcare system

A methodology to extract outcomes from routine healthcare data for patients with locally advanced non-small cell lung cancer

BACKGROUND: Outcomes for patients in UK with locally advanced non-small cell lung cancer (LA NSCLC) are amongst the worst in Europe. Assessing outcomes is important for analysing the effectiveness of current practice. However, data quality is inconsistent and regular large scale analysis is challenging. This project investigates the use of routine healthcare datasets to determine progression free survival (PFS) and overall survival (OS) of patients treated with primary radical radiotherapy for LA NSCLC. METHODS: All LA NSCLC patients treated with primary radical radiotherapy in a 2 year period were identified and paired manual and routine data generated for an initial pilot study. Manual data was extracted information from hospital records and considered the gold standard. Key time points were date of diagnosis, recurrence, death or last clinical encounter. Routine data was collected from various data sources including, Hospital Episode Statistics, Personal Demographic Service, chemotherapy data, and radiotherapy datasets. Relevant event dates were defined by proxy time points and refined using backdating and time interval optimization. Dataset correlations were then tested on key clinical outcome indicators to establish if routine data could be used as a reliable proxy measure for manual data. RESULTS: Forty-three patients were identified for the pilot study. The manual data showed a median age of 67 years (range 46- 89 years) and all patients had stage IIIA/B disease. Using the manual data, the median PFS was 10.78 months (range 1.58-37.49 months) and median OS was 16.36 months (range 2.69-37.49 months). Based on routine data, using proxy measures, the estimated median PFS was 10.68 months (range 1.61-31.93 months) and estimated median OS was 15.38 months (range 2.14-33.71 months). Overall, the routine data underestimated the PFS and OS of the manual data but there was good correlation with a Pearson correlation coefficient of 0.94 for PFS and 0.97 for OS. CONCLUSIONS: This is a novel approach to use routine datasets to determine outcome indicators in patients with LA NSCLC that will be a surrogate to analysing manual data. The ability to enable efficient and large scale analysis of current lung cancer strategies has a huge potential impact on the healthcare system

Investigation into the effects of high-Z nano materials in proton therapy

High-Z nano materials have been previously shown to increase the amount of dose deposition within the tumour due to an increase in secondary electrons. This study evaluates the effects of high-Z nano materials in combination with protons, and the impact of proton energy, nanoparticle material and concentration. These effects were studied in silico through Monte Carlo simulation and experimentally through a phantom study, with particular attention to macroscale changes to the Bragg peak in the presence of nanoparticles. Three nanoparticle materials were simulated (gold, silver and platinum) at three concentrations (0.01, 0.1 and 6.5 mg ml(-1)) at two clinical proton energies (60 and 226 MeV). Simulations were verified experimentally using Gafchromic film measurements of gold nanoparticles suspended in water at two available high concentrations (5.5 mg ml(-1) and 1.1 mg ml(-1)). A significant change to Bragg peak features was evident, where at 226 MeV and 6.5 mg ml(-1), simulations of gold showed a 4.7 mm longitudinal shift of the distal edge and experimentally at 5.5 mg ml(-1), a shift of 2.2 mm. Simulations showed this effect to be material dependent, where platinum having the highest physical density caused the greatest shift with increasing concentration. A dose enhancement of 6%  ±  0.05 and 5%  ±  0.15 (60 MeV and 226 MeV, respectively) was evident with gold at 6.5 mg ml(-1) to water alone, compared to the 21%  ±  0.53 observed experimentally as dose to film with 5.5 mg ml(-1) of gold nanoparticles suspended in water at 226 MeV. The introduction of nanoparticles has strong potential to enhance dose in proton therapy, however the changes to the Bragg peak distribution that occur with high concentrations need to be accounted for to ensure tumour coverage

The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy : a systematic review and economic evaluation

Peer reviewedPublisher PD

Ixazomib for relapsed or refractory multiple myeloma : review from an evidence review group on a NICE single technology appraisal

Ixazomib is an oral proteasome inhibitor used in combination with lenalidomide plus dexamethasone (IXA-LEN-DEX) and licensed for relapsed or refractory multiple myeloma. As part of a single technology appraisal (ID807) undertaken by the National Institute of Health and Care Excellence, the Evidence Review Group, Warwick Evidence was invited to independently review the evidence submitted by the manufacturer of ixazomib, Takeda UK Ltd. The main source of clinical effectiveness data about IXA-LEN-DEX came from the Tourmaline-MM1 randomized controlled trial in which 771 patients with relapsed or refractory multiple myeloma received either IXA-LEN-DEX or placebo-LEN-DEX as their second-, third-, or fourth-line treatment. Takeda estimated the cost effectiveness of IXA-LEN-DEX using a de-novo partitioned-survival model with three health states (pre-progression, post-progression, and dead). In their first submission, this model was used to estimate the cost effectiveness of IXA-LEN-DEX vs. bortezomib plus dexamethasone (BORT-DEX) in second-line treatment, and of IXA-LEN-DEX vs. LEN-DEX in third-line treatment. To estimate the relative clinical performance of IXA-LEN-DEX vs. BORT-DEX, Takeda conducted network meta-analyses for important outcomes. The network meta-analysis for overall survival was found to be flawed in several respects, but mainly because a hazard ratio input for one of the studies in the network had been inverted, resulting in a large inflation of the claimed superiority of IXA-LEN-DEX over BORT-DEX and a considerable overestimation of its cost effectiveness. In subsequent submissions, Takeda withdrew second-line treatment as an option for IXA-LEN-DEX. The manufacturer’s first submission comparing IXA-LEN-DEX with LEN-DEX for third-line therapy employed Tourmaline-MM1 data from third- and fourth-line patients as proxy for a third-line population. The appraisal committee did not consider this reasonable because randomization in Tourmaline-MM1 was stratified according to one previous treatment and two or more previous treatments. A further deficiency was considered to be the manufacturer’s use of interim survival data rather than the most mature data available. A second submission from the company focussed on IXA-LEN-DEX vs. LEN-DEX as third- or fourth-line treatment (the two or more previous lines population) and a new patient access scheme was introduced. Covariate modeling of survival outcomes was proposed using the most mature survival data. The Evidence Review Group’s main criticisms of the new evidence included: the utility associated with the pre-progression health state was overestimated, treatment costs of ixazomib were underestimated, survival models were still associated with great uncertainty, leading to clinically implausible anomalies and highly variable incremental cost-effectiveness ratio estimates, and the company had not explored a strong assumption that the survival benefit of IXA-LEN-DEX over LEN-DEX would be fully maintained for a further 22 years beyond the observed data, which encompassed only approximately 2.5 years of observation. The appraisal committee remained unconvinced that ixazomib represented a cost-effective use of National Health Service resources. Takeda’s third submission offered new base-case parametric models for survival outcomes, a new analysis of utilities, and proposed a commercial access agreement. In a brief critique of the third submission, the Evidence Review Group agreed that the selection of appropriate survival models was problematic and at the request of the National Institute for Health Care and Excellence investigated external sources of evidence regarding survival outcomes. The Evidence Review Group considered that some cost and utility estimates in the submission may have remained biased in favor of ixazomib. As a result of their third appraisal meeting, the committee judged that for the two to three prior therapies population, and at the price agreed in a commercial access agreement, ixazomib had the potential to be cost effective. It was referred to the Cancer Drugs Fund so that further data could accrue with the aim of diminishing the clinical uncertainties

The Hubble Ultra Deep Field

This paper presents the Hubble Ultra Deep Field (HUDF), a one million second exposure of an 11 square minute-of-arc region in the southern sky with the Hubble Space Telescope. The exposure time was divided among four filters, F435W (B435), F606W (V606), F775W (i775), and F850LP (z850), to give approximately uniform limiting magnitudes mAB~29 for point sources. The image contains at least 10,000 objects presented here as a catalog. Few if any galaxies at redshifts greater than ~4 resemble present day spiral or elliptical galaxies. Using the Lyman break dropout method, we find 504 B-dropouts, 204 V-dropouts, and 54 i-dropouts. Using these samples that are at different redshifts but derived from the same data, we find no evidence for a change in the characteristic luminosity of galaxies but some evidence for a decrease in their number densities between redshifts of 4 and 7. The ultraviolet luminosity density of these samples is dominated by galaxies fainter than the characteristic luminosity, and the HUDF reveals considerably more luminosity than shallower surveys. The apparent ultraviolet luminosity density of galaxies appears to decrease from redshifts of a few to redshifts greater than 6. The highest redshift samples show that star formation was already vigorous at the earliest epochs that galaxies have been observed, less than one billion years after the Big Bang.Comment: 44 pages, 18 figures, to appear in the Astronomical Journal October 200

Fluence correction factor for graphite calorimetry in a clinical high-energy carbon-ion beam

The aim of this work is to develop and adapt a formalism to determine absorbed dose to water from graphite calorimetry measurements in carbon-ion beams. Fluence correction factors, kfl, needed when using a graphite calorimeter to derive dose to water, were determined in a clinical high-energy carbon-ion beam. Measurements were performed in a 290 MeV/n carbon-ion beam with a field size of 11 x 11 cm2, without modulation. In order to sample the beam, a plane-parallel Roos ionization chamber was chosen for its small collecting volume in comparison with the field size. Experimental information on fluence corrections was obtained from depth-dose measurements in water. This procedure was repeated with graphite plates in front of the water phantom. Fluence corrections were also obtained with Monte Carlo simulations through the implementation of three methods based on (i) the fluence distributions differential in energy, (ii) a ratio of calculated doses in water and graphite at equivalent depths and (iii) simulations of the experimental setup. The kfl term increased in depth from 1.00 at the entrance toward 1.02 at a depth near the Bragg peak, and the average difference between experimental and numerical simulations was about 0.13%. Compared to proton beams, there was no reduction of the kfl due to alpha particles because the secondary particle spectrum is dominated by projectile fragmentation. By developing a practical dose conversion technique, this work contributes to improving the determination of absolute dose to water from graphite calorimetry in carbon-ion beams