On dosimetric characteristics of detectors for relative dosimetry in small fields: a multicenter experimental study.

Objective. In this multicentric collaborative study, we aimed to verify whether the selected radiation detectors satisfy the requirements of TRS-483 Code of Practice for relative small field dosimetry in megavoltage photon beams used in radiotherapy, by investigating four dosimetric characteristics. Furthermore, we intended to analyze and complement the recommendations given in TRS-483.Approach. Short-term stability, dose linearity, dose-rate dependence, and leakage were determined for 17 models of detectors considered suitable for small field dosimetry. Altogether, 47 detectors were used in this study across ten institutions. Photon beams with 6 and 10 MV, with and without flattening filters, generated by Elekta Versa HDTMor Varian TrueBeamTMlinear accelerators, were used.Main results. The tolerance level of 0.1% for stability was fulfilled by 70% of the data points. For the determination of dose linearity, two methods were considered. Results from the use of a stricter method show that the guideline of 0.1% for dose linearity is not attainable for most of the detectors used in the study. Following the second approach (squared Pearson's correlation coefficientr2), it was found that 100% of the data fulfill the criteriar2> 0.999 (0.1% guideline for tolerance). Less than 50% of all data points satisfied the published tolerance of 0.1% for dose-rate dependence. Almost all data points (98.2%) satisfied the 0.1% criterion for leakage.Significance. For short-term stability (repeatability), it was found that the 0.1% guideline could not be met. Therefore, a less rigorous criterion of 0.25% is proposed. For dose linearity, our recommendation is to adopt a simple and clear methodology and to define an achievable tolerance based on the experimental data. For dose-rate dependence, a realistic criterion of 1% is proposed instead of the present 0.1%. Agreement was found with published guidelines for background signal (leakage).

A comparison of physical image quality of two hologic digital mammography systems that utilise linear and 2D anti-scatter grids.

Objective. Full-field digital mammography (FFDM) systems manufactured by Hologic that utilise either a 2D or linear anti-scatter grid have recently been installed in our clinic. The manufacturer advise that for matched dose, both grids deliver comparable image quality. The aim of this study was to test the manufacturer's claim using advanced physical image quality metrics and to inform whether the different grids are indeed dose neutral.Approach. Effective detective quantum efficiency (eDQE), effective noise equivalent quanta (eNEQ) and effective dose efficiency (eDE) were measured on a Hologic Dimensions (2D grid) and a Hologic 3Dimensions (linear grid) FFDM system, both calibrated at installation to provide matched threshold contrast, according to the EUREF protocol. eDQE, eNEQ and eDE were calculated and compared using 2, 4, 6 and 7 cm thicknesses of poly (methyl methacrylate) (PMMA) to simulate a clinically appropriate range of breast thicknesses. The beam qualities (target/filter and kilovoltage) chosen were identical between the two systems.Main results. All image quality metrics investigated show that the 2D grid outperforms the linear grid across all spatial frequencies. Furthermore, mean glandular dose (MGD) must be increased by up to 38% on those units that utilise the linear grid if eNEQ is to be matched, although MGD to the standard breast remains within NHSBSP tolerance and below the UK diagnostic reference level. The gradient and shape of each curve was the same irrespective of which grid was used, suggesting that subtle lesions (low frequency information) and micro-calcifications (high frequency information) will be imaged just as efficiently with a linear or 2D grid.Significance. If image quality is to be matched between those units utilising 2D and linear grids, dose must be increased on the latter. This information will be useful to the medical physicist tasked with the optimisation and standardisation of Hologic FFDM units.

Exploring hypoxic biology to improve radiotherapy outcomes.

Ionising radiotherapy is a well-established, effective cancer treatment modality, whose efficacy has improved with the application of newer technological modalities. However, patient outcomes are governed and potentially limited by aspects of tumour biology that are associated with radioresistance. Patients also still endure treatment-associated toxicities owed to the action of ionising radiation in normoxic tissue adjacent to the tumour mass. Tumour hypoxia is recognised as a key component of the tumour microenvironment and is well established as leading to therapy resistance and poor prognosis. In this review, we outline the current understanding of hypoxia-mediated radiotherapy resistance, before exploring targeting tumour hypoxia for radiotherapy sensitisation to improve treatment outcomes and increase the therapeutic window. This includes increasing oxygen availability in solid tumours, the use of hypoxia-activated prodrugs, targeting of hypoxia-regulated or associated signalling pathways, as well as the use of high-LET radiotherapy modalities. Ultimately, targeting hypoxic radiobiology combined with precise radiotherapy delivery modalities and modelling should be associated with improvement to patient outcomes.

Predicting personalised and progressive adaptive dose escalation to gross tumour volume using knowledge-based planning models for inoperable advanced-stage non-small cell lung cancer patients treated with volumetric modulated arc therapy.

Objectives. Increased radiation doses could improve local control and overall survival of lung cancer patients, however, this could be challenging without exceeding organs at risk (OAR) dose constraints, especially for patients with advanced-stage disease. Increasing OAR doses could reduce the therapeutic ratio and quality of life. It is therefore important to investigate methods to increase the dose to target volume without exceeding OAR dose constraints.Methods. Gross tumour volume (GTV) was contoured on synthetic computerised tomography (sCT) datasets produced using the Velocity adaptive radiotherapy software for eleven patients. The fractions where GTV volume decreased compared to that prior to radiotherapy (reference plan) were considered for personalised progressive dose escalation. The dose to the adapted GTV (GTVAdaptive) was increased until OAR doses were affected (as compared to the original clinical plan). Planning target volume (PTV) coverage was maintained for all plans. Doses were also escalated to the reference plan (GTVClinical) using the same method. Adapted, dose-escalated, plans were combined to estimate accumulated dose, D99(dose to 99%) of GTVAdapted, PTV D99and OAR doses and compared with those in the original clinical plans. Knowledge-based planning (KBP) model was developed to predict D99of the adapted GTV with OAR doses and PTV coverage kept similar to the original clinical plans; prediction accuracy and model verification were performed using further data sets.Results. Compared to the original clinical plan, the dose to GTV was significantly increased without exceeding OAR doses. Adaptive dose-escalation increased the average D99to GTVAdaptiveby 15.1Gy and 8.7Gy compared to the clinical plans. The KBP models were verified and demonstrated prediction accuracy of 0.4% and 0.7% respectively.Conclusion. Progressive adaptive dose escalation can significantly increase the dose to GTV without increasing OAR doses or compromising the dose to microscopic disease. This may increase overall survival without increasing toxicities.

Predicting personalised optimal arc parameter using knowledge-based planning model for inoperable locally advanced lung cancer patients to reduce organ at risk doses.

Objectives. Volumetric modulated arc therapy (VMAT) allows for reduction of organs at risk (OAR) volumes receiving higher doses, but increases OAR volumes receiving lower radiation doses and can subsequently increasing associated toxicity. Therefore, reduction of this low-dose-bath is crucial. This study investigates personalizing the optimization of VMAT arc parameters (gantry start and stop angles) to decrease OAR doses.Materials and Methods. Twenty previously treated locally advanced non-small cell lung cancer (NSCLC) patients treated with half-arcs were randomly selected from our database. These plans were re-optimized with seven different arcs parameters; optimization objectives were kept constant for all plans. All resulting plans were reviewed by two clinicians and the optimal plan (lowest OAR doses and adequate target coverage) was selected. Furthermore, knowledge-based planning (KBP) model was developed using these plans as 'training data' to predict optimal arc parameters for individual patients based on their anatomy. Treatment plan complexity scores and deliverability measurements were performed for both optimal and original clinical plans.Results.The results show that different arc geometries resulted in different dose distributions to the OAR but target coverage was mostly similar. Different arc geometries were required for different patients to minimize OAR doses. Comparison of the personalized against the standard (2 half-arcs) plans showed a significant reduction in lung V5(lung volume receiving 5 Gy), mean lung dose and mean heart doses. Reduction in lung V20and heart V30were statistically insignificant. Plan complexity and deliverability measurements show the test plans can be delivered as planned.Conclusions.Our study demonstrated that personalizing arc parameters based on an individual patient's anatomy significantly reduces both lung and heart doses. Dose reduction is expected to reduce toxicity and improve the quality of life for these patients.

Validation of in-house knowledge-based planning model for predicting change in target coverage during VMAT radiotherapy to in-operable advanced-stage NSCLC patients.

Objectives. anatomical changes are inevitable during the course of radiotherapy treatments and, if significant, can severely alter expected dose distributions and affect treatment outcome. Adaptive radiotherapy (ART) is employed to maintain the planned distribution and minimise detriment to predicted treatment outcome. Typically, patients who may benefit from adaptive planning are identified via a re-planning process, i.e., re-simulation, re-contouring, re-planning and treatment plan quality assurance (QA). This time-intensive process significantly increases workload, can introduce delays and increases unnecessary stress to those patients who will not actually gain benefit. We consider it crucial to develop efficient models to predict changes to target coverage and trigger ART, without the need for re-planning.Methods.knowledge-based planning (KBP) models were developed using data for 20 patients' (400 fractions) to predict changes in PTV V95coverageΔV95PTV.Initially, this change in coverage was calculated on the synthetic computerised tomography (sCT) images produced using the Velocity adaptive radiotherapy software. Models were developed using patient (cell death bio-marker) and treatment fraction (PTV characteristic) specific parameters to predictΔV95PTVand verified using five patients (100 fractions) data.Results. three models were developed using combinations of patient and fraction specific terms. The prediction accuracy of the model developed using biomarker (PD-L1 expression) and the difference in 'planning' and 'fraction' PTV centre of the mass (characterised by mean square difference, MSD) had the higher prediction accuracy, predicting theΔV95PTVwithin ± 1.0% for 77% of the total fractions; with 59% for the model developed using, PTV size, PD-L1 and MSD and 48% PTV size and MSD respectively.Conclusion. the KBP models can predictΔV95PTVvery effectively and efficiently for advanced-stage NSCLC patients treated using volumetric modulated arc therapy and to identify patients who may benefit from adaption for a specific fraction.

PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma.

OBJECTIVE: Neoadjuvant chemoradiotherapy (neo-CRT) prior to surgery is the standard of care for oesophageal adenocarcinoma (OAC) patients. Unfortunately, most patients fail to respond to treatment. MiR-187 was previously shown to be downregulated in neo-CRT non-responders, whist in vitro miR-187 overexpression enhanced radiosensitivity and upregulated PTEN. This study evaluates the role of miR-187 and downstream PI3K signalling in radiation response in OAC. METHODS: The effect of miR-187 overexpression on downstream PI3K signalling was evaluated in OAC cell lines by qPCR and Western blotting. PTEN expression was analysed in OAC pre-treatment biopsies of neo-CRT responders and non-responders. Pharmacological inhibition of PI3K using GDC-0941 was evaluated in combination with radiotherapy in two-dimensional and three-dimensional OAC models in vitro and as a single agent in vivo. Radiation response in vitro was assessed via clonogenic assay. RESULTS: PTEN expression was significantly decreased in neo-CRT non-responders. MiR-187 overexpression significantly upregulated PTEN expression and inhibited downstream PI3K signalling in vitro. GDC-0941 significantly reduced viability and enhanced radiation response in vitro and led to tumour growth inhibition as a single agent in vivo. CONCLUSION: Targeting of PI3K signalling is a promising therapeutic strategy for OAC patients who have repressed miR-187 expression and do not respond to conventional neo-CRT. ADVANCES IN KNOWLEDGE: This is the first study evaluating the effect of PI3K inhibition on radiosensitivity in OAC, with a particular focus on patients that do not respond to neo-CRT. We have shown for the first time that targeting of PI3K signalling is a promising alternative therapeutic strategy for OAC patients who do not respond to conventional neo-CRT.

Validation of in-house knowledge-based planning model for advance-stage lung cancer patients treated using VMAT radiotherapy.

OBJECTIVES: Radiotherapy plan quality may vary considerably depending on planner's experience and time constraints. The variability in treatment plans can be assessed by calculating the difference between achieved and the optimal dose distribution. The achieved treatment plans may still be suboptimal if there is further scope to reduce organs-at-risk doses without compromising target coverage and deliverability. This study aims to develop a knowledge-based planning (KBP) model to reduce variability of volumetric modulated arc therapy (VMAT) lung plans by predicting minimum achievable lung volume-dose metrics. METHODS: Dosimetric and geometric data collected from 40 retrospective plans were used to develop KBP models aiming to predict the minimum achievable lung dose metrics via calculating the ratio of the residual lung volume to the total lung volume. Model accuracy was verified by replanning 40 plans. Plan complexity metrics were calculated using locally developed script and their effect on treatment delivery was assessed via measurement. RESULTS: The use of KBP resulted in significant reduction in plan variability in all three studied dosimetric parameters V5, V20 and mean lung dose by 4.9% (p = 0.007, 10.8 to 5.9%), 1.3% (p = 0.038, 4.0 to 2.7%) and 0.9 Gy (p = 0.012, 2.5 to 1.6Gy), respectively. It also increased lung sparing without compromising the overall plan quality. The accuracy of the model was proven as clinically acceptable. Plan complexity increased compared to original plans; however, the implication on delivery errors was clinically insignificant as demonstrated by plan verification measurements. CONCLUSION: Our in-house model for VMAT lung plans led to a significant reduction in plan variability with concurrent decrease in lung dose. Our study also demonstrated that treatment delivery verifications are important prior to clinical implementation of KBP models. ADVANCES IN KNOWLEDGE: In-house KBP models can predict minimum achievable lung dose-volume constraints for advance-stage lung cancer patients treated with VMAT. The study demonstrates that plan complexity could increase and should be assessed prior to clinical implementation.

The usefulness of large sample size patient dose audits for optimisation of CT automatic exposure control (AEC) settings.

The aim of this study was to demonstrate the usefulness of large sample size patient dose audits for optimisation of CT automatic exposure control (AEC) settings, even when the investigation is limited to only three scanners at a single institution. Pre-optimisation patient dose audits of common CT examinations (n > 200 for each protocol) on three CT scanners (two Philips Brilliance and one Toshiba Aquilion) using radiology information system (RIS) data were conducted showing sub-optimal CT AEC performance on the Toshiba scanner. Based on these results, an optimisation exercise was carried out on the non-optimally performing scanner by phantom measurement and investigation of system configuration. Post-optimisation patient dose audits were subsequently carried out to assess the success of the optimisation exercise demonstrating standardisation of doses; median dose-length-product values were reduced by up to 43% on the sub-optimal scanner without any adverse effect on clinical image quality. This study has demonstrated that large sample patient dose audits using RIS data can be instrumental in identifying and rectifying sub-optimal CT AEC performance, even when the investigation is limited to only three scanners at a single institution.

The opportunities of computer simulation training in radiation therapy.

The use of computer simulation is arguably more widespread in other industries than in medicine. However, it has filtered into mainstream use in radiation therapy via a commercial product born from collaborative research partnership based in a radiation therapy department .The benefits and potentials of simulation training is discussed in this editorial from the perspective of an experienced radiation therapy physicist.

Measurement of effective detective quantum efficiency for a photon counting scanning mammography system and comparison with two flat panel full-field digital mammography systems.

Effective detective quantum efficiency (eDQE) describes the resolution and noise properties of an imaging system along with scatter and primary transmission, all measured under clinically appropriate conditions. Effective dose efficiency (eDE) is the eDQE normalised to mean glandular dose and has been proposed as a useful metric for the optimisation of clinical imaging systems. The aim of this study was to develop a methodology for measuring eDQE and eDE on a Philips microdose mammography (MDM) L30 photon counting scanning system, and to compare performance with two conventional flat panel systems. A custom made lead-blocker was manufactured to enable the accurate determination of dose measurements, and modulation transfer functions were determined free-in-air at heights of 2, 4 and 6 cm above the breast support platform. eDQE were calculated for a Philips MDM L30, Hologic Dimensions and Siemens Inspiration digital mammography system for 2, 4 and 6 cm thick poly(methyl methacrylate) (PMMA). The beam qualities (target/filter and kilovoltage) assessed were those selected by the automatic exposure control, and anti-scatter grids were used where available. Measurements of eDQE demonstrate significant differences in performance between the slit- and scan-directions for the photon counting imaging system. MTF has been shown to be the limiting factor in the scan-direction, which results in a rapid fall in eDQE at mid-to-high spatial frequencies. A comparison with two flat panel mammography systems demonstrates that this may limit image quality for small details, such as micro-calcifications, which correlates with a more conventional image quality assessment with the CDMAM phantom. eDE has shown the scanning photon counting system offers superior performance for low spatial frequencies, which will be important for the detection of large low contrast masses. Both eDQE and eDE are proposed as useful metrics that should enable optimisation of the Philips MDM L30.

Measuring the response of human head and neck squamous cell carcinoma to irradiation in a microfluidic model allowing customized therapy.

Radiotherapy is the standard treatment for head and neck squamous cell carcinoma (HNSCC), however, radioresistance remains a major clinical problem despite significant improvements in treatment protocols. Therapeutic outcome could potentially be improved if a patient's tumour response to irradiation could be predicted ex vivo before clinical application. The present study employed a bespoke microfluidic device to maintain HNSCC tissue whilst subjecting it to external beam irradiation and measured the responses using a panel of cell death and proliferation markers. HNSCC biopsies from five newly-presenting patients [2 lymph node (LN); 3 primary tumour (PT)] were divided into parallel microfluidic devices and replicates of each tumour were subjected to single-dose irradiation (0, 5, 10, 15 and 20 Gy). Lactate dehydrogenase (LDH) release was measured and tissue sections were stained for cytokeratin (CK), cleaved-CK18 (cCK18), phosphorylated-H2AX (γH2AX) and Ki­67 by immunohistochemistry. In addition, fragmented DNA was detected using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Compared with non­irradiated controls, higher irradiation doses resulted in elevated CK18-labelling index in two lymph nodes [15 Gy; 34.8% on LN1 and 31.7% on LN2 (p=0.006)] and a single laryngeal primary tumour (20 Gy; 31.5%; p=0.014). Significantly higher levels of DNA fragmentation were also detected in both lymph node samples and one primary tumour but at varying doses of irradiation, i.e., LN1 (20 Gy; 27.6%; p=0.047), LN2 (15 Gy; 15.3%; p=0.038) and PT3 (10 Gy; 35.2%; p=0.01). The γH2AX expression was raised but not significantly in the majority of samples. The percentage of Ki­67 positive nuclei reduced dose-dependently following irradiation. In contrast no significant difference in LDH release was observed between irradiated groups and controls. There is clear inter- and intra-patient variability in response to irradiation when measuring a variety of parameters, which offers the potential for the approach to provide clinically valuable information.

A method to incorporate the effect of beam quality on image noise in a digitally reconstructed radiograph (DRR) based computer simulation for optimisation of digital radiography.

The use of computer simulated digital x-radiographs for optimisation purposes has become widespread in recent years. To make these optimisation investigations effective, it is vital simulated radiographs contain accurate anatomical and system noise. Computer algorithms that simulate radiographs based solely on the incident detector x-ray intensity ('dose') have been reported extensively in the literature. However, while it has been established for digital mammography that x-ray beam quality is an important factor when modelling noise in simulated images there are no such studies for diagnostic imaging of the chest, abdomen and pelvis. This study investigates the influence of beam quality on image noise in a digital radiography (DR) imaging system, and incorporates these effects into a digitally reconstructed radiograph (DRR) computer simulator. Image noise was measured on a real DR imaging system as a function of dose (absorbed energy) over a range of clinically relevant beam qualities. Simulated 'absorbed energy' and 'beam quality' DRRs were then created for each patient and tube voltage under investigation. Simulated noise images, corrected for dose and beam quality, were subsequently produced from the absorbed energy and beam quality DRRs, using the measured noise, absorbed energy and beam quality relationships. The noise images were superimposed onto the noiseless absorbed energy DRRs to create the final images. Signal-to-noise measurements in simulated chest, abdomen and spine images were within 10% of the corresponding measurements in real images. This compares favourably to our previous algorithm where images corrected for dose only were all within 20%.

Accounting for patient size in the optimization of dose and image quality of pelvis cone beam CT protocols on the Varian OBI system.

OBJECTIVE: The purpose of this study was to develop size-based radiotherapy kilovoltage cone beam CT (CBCT) protocols for the pelvis. METHODS: Image noise was measured in an elliptical phantom of varying size for a range of exposure factors. Based on a previously defined "small pelvis" reference patient and CBCT protocol, appropriate exposure factors for small, medium, large and extra-large patients were derived which approximate the image noise behaviour observed on a Philips CT scanner (Philips Medical Systems, Best, Netherlands) with automatic exposure control (AEC). Selection criteria, based on maximum tube current-time product per rotation selected during the radiotherapy treatment planning scan, were derived based on an audit of patient size. RESULTS: It has been demonstrated that 110 kVp yields acceptable image noise for reduced patient dose in pelvic CBCT scans of small, medium and large patients, when compared with manufacturer's default settings (125 kVp). Conversely, extra-large patients require increased exposure factors to give acceptable images. 57% of patients in the local population now receive much lower radiation doses, whereas 13% require higher doses (but now yield acceptable images). CONCLUSION: The implementation of size-based exposure protocols has significantly reduced radiation dose to the majority of patients with no negative impact on image quality. Increased doses are required on the largest patients to give adequate image quality. ADVANCES IN KNOWLEDGE: The development of size-based CBCT protocols that use the planning CT scan (with AEC) to determine which protocol is appropriate ensures adequate image quality whilst minimizing patient radiation dose.

Palliative Radiotherapy in the Presence of Well-Controlled Metastatic Disease after Initial Chemotherapy May Prolong Survival in Patients with Metastatic Esophageal and Gastric Cancer.

PURPOSE: We report the outcomes of patients treated with palliative radiotherapy (pRT) to the primary tumour in the context of well-controlled metastatic disease after initial chemotherapy. MATERIALS AND METHODS: Clinical records of 132 patients with metastatic esophago-gastric (OG) cancer treated with palliative chemotherapy (pCT) between January 2009 and June 2013 were reviewed. Ninetyseven patients had responding or stable disease after 3 months of chemotherapy, of whom 53 patients received pRT to the primary tumour after initial chemotherapy in the presence of well-controlled metastatic disease (group A, pCT-RT). The remaining 44 patients were treated with pCT alone (group B, pCT). Treatment-related outcomes were assessed in above groups including time to local progression (TTLP), progression-free and overall survival. RESULTS: The median overall survival for patients treated with pRT after initial chemotherapy (group A) was 23.3 months (95% confidence interval [CI], 17.70 to 28.89 months) and significantly higher than the 14 months (95% CI, 10.91 to 17.08 months) in patients treated with pCT alone (group B) (p < 0.001). The use of pCT-RT was an independent predictor of OS in multivariate analysis. Local recurrence was observed in 12/53 of patients (23%) in group A compared to 16/44 (36%) in group B. The median TTLP was significantly higher in patients after pCT-RT at 17.3 months (5.23 months to 44.50 months) compared to 8.3 months (range, 4.10 to 25.23 months) in patients treated with pCT alone (p=0.006). CONCLUSION: The possibility of pRT influencing systemic disease in advanced OG cancer has not been reported, and results from the present study present strong arguments for investigation of this therapeutic strategy in a randomized trial.

The updated ESTRO core curricula 2011 for clinicians, medical physicists and RTTs in radiotherapy/radiation oncology.

INTRODUCTION: In 2007 ESTRO proposed a revision and harmonisation of the core curricula for radiation oncologists, medical physicists and RTTs to encourage harmonised education programmes for the professional disciplines, to facilitate mobility between EU member states, to reflect the rapid development of the professions and to secure the best evidence-based education across Europe. MATERIAL AND METHODS: Working parties for each core curriculum were established and included a broad representation with geographic spread and different experience with education from the ESTRO Educational Committee, local representatives appointed by the National Societies and support from ESTRO staff. RESULTS: The revised curricula have been presented for the ESTRO community and endorsement is ongoing. All three curricula have been changed to competency based education and training, teaching methodology and assessment and include the recent introduction of the new dose planning and delivery techniques and the integration of drugs and radiation. The curricula can be downloaded at http://www.estro-education.org/europeantraining/Pages/EuropeanCurricula.aspx. CONCLUSION: The main objective of the ESTRO core curricula is to update and harmonise training of the radiation oncologists, medical physicists and RTTs in Europe. It is recommended that the authorities in charge of the respective training programmes throughout Europe harmonise their own curricula according to the common framework.

Proteomic identification of putative biomarkers of radiotherapy resistance: a possible role for the 26S proteasome?

PURPOSE: We aimed to identify putative predictive protein biomarkers of radioresistance. EXPERIMENTAL DESIGN: Three breast cancer cell lines (MCF7, MDA-MB-231, and T47D) were used as in vitro models to study radioresistance. Inherent radiosensitivities were examined using a clonogenic survival assay. It was revealed that each cell line differed in their response to radiotherapy. These parental breast cancer cell lines were used to establish novel derivatives (MCF7RR, MDA-MB-231RR, and T47DRR) displaying significant resistance to ionizing radiation. Derivative cells were compared with parental cells to identify putative biomarkers associated with the radioresistant phenotype. To identify these biomarkers, complementary proteomic screening approaches were exploited encompassing two-dimensional gel electrophoresis in combination with mass spectrometry, liquid chromatography coupled with tandem mass spectrometry and quantitative proteomics using iTRAQ technology. RESULTS: A large number of potential biomarkers were identified, and several of these were confirmed using Western blot analysis. In particular, a decrease in the expression of the 26S proteasome was found in all radioresistant derivatives when compared with the respective parent cells. Decreased expression of this target was also found to be associated with radioresistant laryngeal tumors (P = .05) in a small pilot immunohistochemical study. CONCLUSIONS: These findings suggest that the 26S proteasome may provide a general predictive biomarker for radiotherapy outcome.

Repeatability of functional MRI for conformal avoidance radiotherapy planning.

PURPOSE: To establish the repeatability of functional magnetic resonance imaging (fMRI) examinations in order to develop an appropriate margin for functional organs at risk (fOAR) in the radiotherapy planning process. MATERIALS AND METHODS: This work investigates the variability of motor cortex activation in the left and right hemispheres of 15 normal subjects. The uncertainty of the absolute position and volume of the activation was determined for each volunteer by repeating the fMRI examination three times in a single scan session. RESULTS: Our study proposes the use of 2.9 mm and 2.2 mm margins for the left and right motor cortices, respectively. CONCLUSION: From the sample of 15 volunteers we established an appropriate planning margin that is considered to represent the uncertainty in spatially measuring the fOAR for a single fMRI examination. The work will be of interest to anyone investigating the clinical robustness of fMRI.

Quality assurance of registration of CT and MRI data sets for treatment planning of radiotherapy for head and neck cancers.

We are implementing the use of magnetic resonance (MR) images for head and neck radiotherapy planning, which involves their registration with computed tomography (CT). The quality assurance (QA) of the registration process was an initial step of this program. A phantom was built, and appropriate materials were identified to produce clinically relevant MR T1 and T2 contrast for its constituent "anatomy". We performed a characterization of the distortion detectable within our phantom. Finally, we assessed the accuracy of image registration by contouring structures in the registered/fused data sets using the treatment planning system. Each structure was contoured using each modality, in turn, blind of the other. The position, area, and perimeter of each structure were assessed as a measure of accuracy of the entire image registration process. Distortion effects in the MR image were shown to be minimized by choosing a suitable (3 +/- 30 kHz) receiver bandwidth. Remaining distortion was deemed clinically acceptable within +/-15 cm of the magnetic field isocenter. A coefficient of agreement (A) analysis gave values to be within 9% of unity, where A = square root(RaRp) and Ra/p is the ratio of the area/perimeter of a particular structure on CT to that on MR. The center of each structure of interest agreed to within 1.8 mm. A QA process has been developed to assess the accuracy of using multimodality image registration in the planning of radiotherapy for the head and neck; we believe its introduction is feasible and safe.