Patterns of brain atrophy in recently-diagnosed relapsing-remitting multiple sclerosis.

Recurrent neuroinflammation in relapsing-remitting MS (RRMS) is thought to lead to neurodegeneration, resulting in progressive disability. Repeated magnetic resonance imaging (MRI) of the brain provides non-invasive measures of atrophy over time, a key marker of neurodegeneration. This study investigates regional neurodegeneration of the brain in recently-diagnosed RRMS using volumetry and voxel-based morphometry (VBM). RRMS patients (N = 354) underwent 3T structural MRI <6 months after diagnosis and 1-year follow-up, as part of the Scottish multicentre 'FutureMS' study. MRI data were processed using FreeSurfer to derive volumetrics, and FSL for VBM (grey matter (GM) only), to establish regional patterns of change in GM and normal-appearing white matter (NAWM) over time throughout the brain. Volumetric analyses showed a decrease over time (q<0.05) in bilateral cortical GM and NAWM, cerebellar GM, brainstem, amygdala, basal ganglia, hippocampus, accumbens, thalamus and ventral diencephalon. Additionally, NAWM and GM volume decreased respectively in the following cortical regions, frontal: 14 out of 26 regions and 16/26; temporal: 18/18 and 15/18; parietal: 14/14 and 11/14; occipital: 7/8 and 8/8. Left GM and NAWM asymmetry was observed in the frontal lobe. GM VBM analysis showed three major clusters of decrease over time: 1) temporal and subcortical areas, 2) cerebellum, 3) anterior cingulum and supplementary motor cortex; and four smaller clusters within the occipital lobe. Widespread GM and NAWM atrophy was observed in this large recently-diagnosed RRMS cohort, particularly in the brainstem, cerebellar GM, and subcortical and occipital-temporal regions; indicative of neurodegeneration across tissue types, and in accord with limited previous studies in early disease. Volumetric and VBM results emphasise different features of longitudinal lobar and loco-regional change, however identify consistent atrophy patterns across individuals. Atrophy measures targeted to specific brain regions may provide improved markers of neurodegeneration, and potential future imaging stratifiers and endpoints for clinical decision making and therapeutic trials.

Evaluation of the water-equivalence of plastic materials in low- and high-energy clinical proton beams.

The aim of this work was to evaluate the water-equivalence of new trial plastics designed specifically for light-ion beam dosimetry as well as commercially available plastics in clinical proton beams. The water-equivalence of materials was tested by computing a plastic-to-water conversion factor, [Formula: see text]. Trial materials were characterized experimentally in 60 MeV and 226 MeV un-modulated proton beams and the results were compared with Monte Carlo simulations using the FLUKA code. For the high-energy beam, a comparison between the trial plastics and various commercial plastics was also performed using FLUKA and Geant4 Monte Carlo codes. Experimental information was obtained from laterally integrated depth-dose ionization chamber measurements in water, with and without plastic slabs with variable thicknesses in front of the water phantom. Fluence correction factors, [Formula: see text], between water and various materials were also derived using the Monte Carlo method. For the 60 MeV proton beam, [Formula: see text] and [Formula: see text] factors were within 1% from unity for all trial plastics. For the 226 MeV proton beam, experimental [Formula: see text] values deviated from unity by a maximum of about 1% for the three trial plastics and experimental results showed no advantage regarding which of the plastics was the most equivalent to water. Different magnitudes of corrections were found between Geant4 and FLUKA for the various materials due mainly to the use of different nonelastic nuclear data. Nevertheless, for the 226 MeV proton beam, [Formula: see text] correction factors were within 2% from unity for all the materials. Considering the results from the two Monte Carlo codes, PMMA and trial plastic #3 had the smallest [Formula: see text] values, where maximum deviations from unity were 1%, however, PMMA range differed by 16% from that of water. Overall, [Formula: see text] factors were deviating more from unity than [Formula: see text] factors and could amount to a few percent for some materials.

Theoretical and experimental characterization of novel water-equivalent plastics in clinical high-energy carbon-ion beams.

Water-equivalent plastics are frequently used in dosimetry for experimental simplicity. This work evaluates the water-equivalence of novel water-equivalent plastics specifically designed for light-ion beams, as well as commercially available plastics in a clinical high-energy carbon-ion beam. A plastic- to-water conversion factor [Formula: see text] was established to derive absorbed dose to water in a water phantom from ionization chamber readings performed in a plastic phantom. Three trial plastic materials with varying atomic compositions were produced and experimentally characterized in a high-energy carbon-ion beam. Measurements were performed with a Roos ionization chamber, using a broad un-modulated beam of 11 × 11 cm2, to measure the plastic-to-water conversion factor for the novel materials. The experimental results were compared with Monte Carlo simulations. Commercially available plastics were also simulated for comparison with the plastics tested experimentally, with particular attention to the influence of nuclear interaction cross sections. The measured [Formula: see text] correction increased gradually from 0% at the surface to 0.7% at a depth near the Bragg peak for one of the plastics prepared in this work, while for the other two plastics a maximum correction of 0.8%-1.3% was found. Average differences between experimental and numerical simulations were 0.2%. Monte Carlo results showed that for polyethylene, polystyrene, Rando phantom soft tissue and A-150, the correction increased from 0% to 2.5%-4.0% with depth, while for PMMA it increased to 2%. Water-equivalent plastics such as, Plastic Water, RMI-457, Gammex 457-CTG, WT1 and Virtual Water, gave similar results where maximum corrections were of the order of 2%. Considering the results from Monte Carlo simulations, one of the novel plastics was found to be superior in comparison with the plastic materials currently used in dosimetry, demonstrating that it is feasible to tailor plastic materials to be water-equivalent for carbon ions specifically.

Intensity-modulated radiotherapy (IMRT) to prostate and pelvic nodes-is pelvic lymph node coverage adequate with fiducial-based image-guided radiotherapy?

OBJECTIVE: There remains concern regarding the use of fiducial-based image-guided radiotherapy (IGRT) in patients with high-risk prostate cancer also undergoing intensity-modulated radiotherapy (IMRT) to pelvic nodes. By a retrospective study, we aim to ascertain the impact of the use of fiducial-based IGRT on lymph node planned target volume (PTV) coverage. METHODS: 30 consecutive IMRT prostate and pelvic node plans were reviewed, and dose was recalculated with 1-mm increment movements in anterior, posterior, superior, inferior, right and left directions up to 10 mm. All patients were treated with a full bladder after drinking 450-750 ml of water and empty rectum with the use of sodium citrate enemas daily. Dose-volume histogram parameters were recorded at each position, specifically nodal PTV V95%, V99% and V100%. A local IGRT database was used to identify the likelihood of a particular bony to fiducial offset in all directions. The combined data were used to calculate the percentage risk of underdosing the lymph node PTV on any given fraction. RESULTS: The likelihood of an offset in the left, right and anterior directions occurring and resulting in a failure to cover the PTV was <0.25%. The likelihood of a posterior offset occurring and resulting in inadequate coverage was slightly higher but remained <1%. CONCLUSION: This study confirms the safety of fiducial-based image-guided IMRT (IG-IMRT) with a strict bowel and bladder protocol, allowing a reduction of the clinical target volume to PTV margin of the prostate volume and consequent reduction in rectal toxicity. ADVANCES IN KNOWLEDGE: This study strengthens the evidence supporting the safe implementation of fiducial-based IG-IMRT treating the prostate and pelvic nodes in high-risk prostate cancer.

A single plan solution to chest wall radiotherapy with bolus?

OBJECTIVE: Radiotherapy treatments of post-mastectomy chest walls are complex, requiring treatment close to skin, necessitating bolus use. Commonly used 5- and 10-mm-thick boluses develop full skin dose, needing removal for the latter half of treatment and requiring two treatment plans to be generated. Can a thinner bolus be used for all treatment fractions, requiring only one plan? METHODS: Investigation of doses received using (A) a half-time 10-mm-thick Vaseline® bolus (current situation); (B) a brass mesh (Whiting & Davis, Attleboro Falls, MA) and (C) 3- and 5-mm Superflab™ (Mick Radio-Nuclear Instruments, Mount Vernon, NY) for 6 and 15 MV. Dosimetric measurements in Barts WT1 solid water and an anthropomorphic phantom, using ionization chambers and thermoluminescent dosemeters, were used to study the effect of different bolus regimes on the photon depth-dose curves (DDCs) and skin doses. RESULTS: Measured skin doses for the current 10-mm-thick Vaseline bolus, brass mesh and 3-mm bolus were compared (5 mm bolus has been rejected). The brass mesh has the least effect on the DDC, with changes <0.7% for depths greater than dmax. Brass mesh conforms superiorly to skin surfaces. Measurements on an anthropomorphic phantom demonstrate an increased skin dose compared with our current treatment protocol. CONCLUSION: Brass mesh has the smallest effect on the DDC, whilst sufficiently increasing surface dose. It can be removed at any fraction, based on a clinical decision, without the need for generating a new plan. Treating with one plan significantly reduces planning times. ADVANCES IN KNOWLEDGE: Quantification of skin doses required and achieved from wax-on/wax-off treatment compared with alternative available breast boluses.

Stereotactic body radiotherapy in prostate cancer: is rapidarc a better solution than cyberknife?

AIMS: There is increasing interest in stereotactic body radiotherapy (SBRT) for the management of prostate adenocarcinoma, with encouraging initial biological progression-free survival results. However, the limited literature is dominated by the use of the Cyberknife platform. This led to an international phase III study comparing outcomes for Cyberknife SBRT with both surgery and conventionally fractionated intensity-modulated radiotherapy (the PACE study). We aim to compare Cyberknife delivery with Rapidarc, a more widely available treatment platform. MATERIALS AND METHODS: The scans of six previous prostate radiotherapy patients with a range of prostate sizes were chosen. The clinical target volume was defined as the prostate gland, with 3 mm added for the Cyberknife planning target volume (PTV) and 5 mm for the Rapidarc PTV. Accuray multiplan v. 4.5 was used for planning with delivery on a Cyberknife VSI system v9.5; Varian Eclipse v10 was used for Rapidarc planning with delivery using a Varian 21EX linear accelerator. Both systems attempted to deliver at least 35 Gy to the PTV in five fractions with PTV heterogeneity <12%. RESULTS: All organ at risk (OAR) constraints were achieved by both platforms, whereas the Cyberknife failed to achieve the desired PTV homogeneity constraint in two cases. In other OARs without constraints, Cyberknife delivered higher doses. The volume of the 35 Gy isodose was slightly larger with Rapidarc, but conversely at doses <35 Gy normal tissues received higher doses with Cyberknife. The mean planning and delivery time was in favour of Rapidarc. CONCLUSIONS: We have shown that there is no discernible dosimetric advantage to choosing Cyberknife over Rapidarc for SBRT delivery in prostate cancer. Given the significant benefits of Rapidarc in terms of availability, planning and delivery time, the authors suggest that phase III trials of SBRT should include Rapidarc or equivalent rotational delivery platforms.

Not hysteria: ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis.

We report a case of a 33-year-old nulliparous woman who, following a short prodromal illness, experienced a series of psychiatric and behavioural symptoms. These included states of terror, insomnia, delirium, self-harm and suicidal ideation, facial dyskinesias, verbigeration, cognitive impairment, reduced responsiveness, violence and paranoia. A diagnosis of anti-N-methyl-d-aspartate (NMDAR) encephalitis was made 50 days after symptom onset. Early tumour removal is associated with an improved prognosis and a laparoscopic oophorectomy was performed following detection of a dermoid cyst. Within 24 hours of the operation there was marked improvement in cognitive function and appetite.

In vitro and in vivo repeatability of abdominal diffusion-weighted MRI.

OBJECTIVE: To study the in vitro and in vivo (abdomen) variability of apparent diffusion coefficient (ADC) measurements at 1.5 T using a free-breathing multislice diffusion-weighted (DW) MRI sequence. METHODS: DW MRI images were obtained using a multislice spin-echo echo-planar imaging sequence with b-values=0, 100, 200, 500, 750 and 1000 s mm(-2). A flood-field phantom was imaged at regular intervals over 100 days, and 10 times on the same day on 2 occasions. 10 healthy volunteers were imaged on two separate occasions. Mono-exponential ADC maps were fitted excluding b=0. Paired analysis was carried out on the liver, spleen, kidney and gallbladder using multiple regions of interest (ROIs) and volumes of interest (VOIs). RESULTS: The in vitro coefficient of variation was 1.3% over 100 days, and 0.5% and 1.0% for both the daily experiments. In vivo, there was no statistical difference in the group mean ADC value between visits for any organ. Using ROIs, the coefficient of reproducibility was 20.0% for the kidney, 21.0% for the gallbladder, 24.7% for the liver and 28.0% for the spleen. For VOIs, values fall to 7.7%, 6.4%, 8.6% and 9.6%, respectively. CONCLUSION: Good in vitro repeatability of ADC measurements provided a sound basis for in vivo measurement. In vivo variability is higher and when considering single measurements in the abdomen as a whole, only changes in ADC value greater than 23.1% would be statistically significant using a two-dimensional ROI. This value is substantially lower (7.9%) if large three-dimensional VOIs are considered.

First quinquennial review of intensity-modulated radiotherapy at St Bartholomew's Hospital, London.

Intensity-modulated radiotherapy (IMRT) is a relatively new technique of delivering external beam radiotherapy that is becoming increasingly available in the UK. This paper summarises the introduction and initial clinical work in IMRT over the period 2004-2009. Physics aspects of commissioning are described, including the development of a robust method of quality control using a sweeping gap test. Details of the organisational changes necessary to introduce IMRT are given. The clinical selection and practice in head and neck sites are described, together with promising early results on the maintenance of salivary flow after IMRT. A summary of research into optimal planning for pelvic cancer follows. The controversial areas of breast and paediatric IMRT are discussed with recommendations on practice. The potential for concomitant boost therapy is exemplified in the treatment of brain metastatic disease.

A dosimetric comparison between two intensity-modulated radiotherapy techniques: tomotherapy vs dynamic linear accelerator.

This manuscript describes a direct comparison between radiation treatment plans in terms of dosimetric outcomes created by two different IMRT systems: TomoTherapy HiArt and dynamic linac intensity-modulated radiotherapy (dIMRT). Three patient cases were selected (with disease in different anatomical areas): vertebral metastasis re-treatment, radical prostate therapy and an ethmoid sarcoma re-treatment. Each case presents significant and varying dosimetric difficulties with respect to avoidance of adjacent organs. The patients were each planned and treated at the Cromwell Hospital (London, UK) using the TomoTherapy HiArt system, with planning replicated at St Bartholomew's Hospital (London, UK) using Eclipse Treatment Planning System and a 6EX linac with a 120-leaf multileaf collimator (Varian Medical Systems). For both modalities, all treatment plans conformed to the stringent clinical dose constraints set. For the vertebral body re-treatment, both techniques demonstrated adequate and similar planning target volume (PTV) coverage and sparing of the spinal cord. The critical structure sparing and PTV coverage for the prostate treatment was again similar for both modalities. For re-treatment of the paediatric ethmoid sarcoma, tomotherapy was able to produce slightly better organ sparing whilst producing PTV coverage similar to linac dIMRT. The data presented in this manuscript demonstrate subtle dosimetric differences between the two techniques but no marked advantage with either system. Therefore, other factors may need to be considered when making a decision between tomotherapy and linac dIMRT.

Effects of phantom volume and shape on the accuracy of MRI BANG gel dosimetry using BANG3.

Complex radiotherapy techniques call for three-dimensional dosimetric methods with high spatial resolution. Radiation-sensitive polymer gel systems (e.g. commercially available BANG(TM) gel), read using MRI T2 mapping, offer a promising solution. A series of calibration test tubes is traditionally used to calculate the dose delivered to a larger, differently shaped volume of gel. In this work, we investigated the implicit assumption that the sensitivity of the gel is independent of shape and size. Phantoms of different shapes and volumes, and 20 glass test-tubes, were filled with BANG3 gel. T2 mapping of gels was performed pre- and post-irradiation using a 32 echo Carr-Purcell-Meiboom-Gill sequence and single exponential fitting. Gel irradiation was performed with a 6 MV Varian 6EX linear accelerator. The T2 values of both non-irradiated and irradiated gels varied with container volume. For containers of the same shape receiving the same radiation dose, larger volumes exhibited a lower T2 value than did smaller volumes. Containers of the same volume but different shape also showed a smaller variation in response to radiation. The greatest difference in T2 values at the same dose was seen between test-tubes and larger volumes. This would imply that if test-tubes alone are used to calibrate larger volumes, then up to a 35% error could be introduced into radiotherapy plan verification. This can be reduced to <10% error if the gel volume is normalized with an external measurement device. Consequently, the traditional test-tube calibration method would be unacceptable for clinical plan verification.

Using combined x-ray and MR imaging for prostate I-125 post-implant dosimetry: phantom validation and preliminary patient work.

Post-implantation dosimetry is an important element of permanent prostate brachytherapy. This process relies on accurate localization of implanted seeds relative to the surrounding organs. Localization is commonly achieved using CT images, which provide suboptimal prostate delineation. On MR images, conversely, prostate visualization is excellent but seed localization is imprecise due to distortion and susceptibility artefacts. This paper presents a method based on fused MR and x-ray images acquired consecutively in a combined x-ray and MRI interventional suite. The method does not rely on any explicit registration step but on a combination of system calibration and tracking. A purpose-built phantom was imaged using MRI and x-rays, and the images were successfully registered. The same protocol was applied to three patients where combining soft tissue information from MRI with stereoscopic seed identification from x-ray imaging facilitated post-implant dosimetry. This technique has the potential to improve on dosimetry using either CT or MR alone.

Evaluation of the dosimetric performance of BANG3 polymer gel.

New radiotherapy techniques call for three-dimensional dosimetric methods with high spatial resolution. Radiation sensitive gels read out using MRI T(2) mapping provide an extremely promising option, and commercially available BANG polymer gels provide a convenient route into gel dosimetry. Gel dosimetry is dependent on the ability to calibrate gel response against radiation dose. This in turn is dependent on the reproducibility of response both between gels irradiated to the same dose and for a single gel sample over time. This study aims to evaluate the performance of a commercially available BANG gel. Our experimental arrangement gave excellent precision of radiation delivery (<0.2%) and reproducibility of T(2) measurement (<0.5%). Seven groups of 10 test tubes containing BANG3 gel were irradiated in 0.5 Gy steps between 0 and 3 Gy. A further four groups of four samples were irradiated in 2 Gy steps between 4 and 10 Gy. The gel samples were identical and derived from the same manufacturing batch. MR imaging was carried out four days after irradiation and then at weekly intervals for four weeks. Short-term variation in gel response can readily be corrected using reference samples. Longer term systematic drift of the gel calibration curve was observed relative to reference samples prepared in-house for quality assurance purposes. This implies that read-out of the calibration gels and dosimetry phantom must be performed at the same time after irradiation, or errors of up to 25% may be incurred. Precision of gel response did not change significantly over time. The observation of significantly different T(2) values both prior to irradiation and following irradiation to the same dose (variation up to 15%) illustrates the current difficulties associated with BANG3 gel calibration and constrains the practical utility of these commercially available gels for clinical radiation dosimetry.

A systematic review of the precision and accuracy of dose measurements in photon radiotherapy using polymer and Fricke MRI gel dosimetry.

The purpose of this work is to undertake a critical appraisal of the evidence in the published literature concerning the basic parameters of accuracy and precision associated with the use of Fricke and polymer gels (in conjunction with MR imaging) as radiation dosimeters in photon radiotherapy, condensing and analysing the body of published information (to the end of April 2002). A systematic review was undertaken addressing specific issues of precision and accuracy asking defined questions of the published literature. Accuracy and precision in relation to gel dosimetry were defined. Information was obtained from published, peer-reviewed journals. A defined search strategy utilizing MeSH headings and keywords, with extensive use of cross-referencing, identified 115 references dealing with gel dosimetry. Exclusion criteria were used to select only data from publications which would give unequivocal evidence. For accuracy, results had to be compared with an ionization chamber as gold standard and all gel samples had to be manufactured in the same batch. For precision, in addition to gels being from the same batch, samples must all have been irradiated at the same time and scanned simultaneously (or within a short time frame). Many results were found demonstrating 'dose mapping' examples using gels. However, there were very few publications containing firm evidence of precision and accuracy. There was no evidence which fulfilled our criteria about accuracy or precision using Fricke gels. For polymer gels only one paper was found for accuracy (4% (Low et al 1999 Med. Phys. 26 1542-51)) and precision (1.7% (Baldock et al 1998 Phys. Med. Biol. 43695-702)); however, both were carried out at only one dose level. If the exclusion criteria were relaxed to include accuracy results comparing gel to a non gold standard dosimeter (e.g. TLD), results give a median accuracy of 10% (range 8-23.5%) for polymer gel (Cosgrove et al 2000 Phys. Med. Biol. 45 1195-210, De Deene et al 1998 Radiother: Oncol. 48 283-91, Farajollahi et al 2000 Br. J. Radiol. 72 1085-92, McJury et al 1999b Phys. Med. Biol. 44 2431-44, Murphy et al 2000b Phys. Med. Biol. 45 835-45, Oldham et al 2001 Med. Phys. 28 1436-45) and 5% for Fricke gel (Chan and Ayyangar 1995b Med. Phys. 22 1171-5). Evidence also points to accuracy worsening at lower dose levels for both gels. The precision data should be viewed with caution as repeated MR measurements were not performed with the same samples. The only precision data for Fricke gels was 1.5% (Johansson Back et al 1998 Phys. Med. Biol. 43 261-76), but for zero dose. In conclusion, despite the amount of published data, sparse research has been undertaken which provides clear evidence of the accuracy and precision for both gels. That which has been published has used higher doses than would be routine in radiotherapy. The basic radiation dosimeter qualities of accuracy and precision have yet to be fully quantified for polymer and Fricke gels at clinically relevant dose levels.

Merlin, the Drosophila homologue of neurofibromatosis-2, is specifically required in posterior follicle cells for axis formation in the oocyte.

In Drosophila, the formation of the embryonic axes is initiated by Gurken, a transforming growth factor alpha signal from the oocyte to the posterior follicle cells, and an unknown polarising signal back to the oocyte. We report that Drosophila Merlin is specifically required only within the posterior follicle cells to initiate axis formation. Merlin mutants show defects in nuclear migration and mRNA localisation in the oocyte. Merlin is not required to specify posterior follicle cell identity in response to the Gurken signal from the oocyte, but is required for the unknown polarising signal back to the oocyte. Merlin is also required non-autonomously, only in follicle cells that have received the Gurken signal, to maintain cell polarity and limit proliferation, but is not required in embryos and larvae. These results are consistent with the fact that human Merlin is encoded by the gene for the tumour suppressor neurofibromatosis-2 and is a member of the Ezrin-Radixin-Moesin family of proteins that link actin to transmembrane proteins. We propose that Merlin acts in response to the Gurken signal by apically targeting the signal that initiates axis specification in the oocyte.

Isocentric treatment of inclined volumes planned using coronal sections.

The treatment parameters necessary for the isocentric treatment of an inclined volume have to be determined either analytically or through simulation. The derivation of the treatment parameters for the treatment of a transverse plane has been described previously. This work describes the derivation of the treatment parameters necessary for the isocentric treatment of an inclined volume that has been planned from an angled coronal section. Ways of implementing the system in the clinic are described.