Quality assurance for mixed electron-photon beam radiation therapy using treatment log files and MapCHECK.

BACKGROUND: Mixed photon-electron beam radiotherapy (MBRT) is a technique that combines the use of both photons and electrons in one single treatment plan to exploit their advantageous and complimentary characteristics. Compared to other photon treatment modalities, it has been shown that the MBRT technique contributes to better target coverage and organ-at-risk (OAR) sparing. However, the use of combined photons and electrons in one delivery makes the technique more complex and a well-established quality assurance (QA) protocol for MBRT is essential. PURPOSE: To investigate the feasibility of using MapCHECK and log file-dose reconstruction for MBRT plan verification and to recommend a patient-specific quality assurance (PSQA) protocol for MBRT. METHODS: MBRT plans were robustly optimized for five soft-tissue sarcoma (STS) patients. Each plan comprised step-and-shoot deliveries of a six MV photon beam and a combination of five electron beam energies at an SAD of 100 cm. The plans were delivered to the MapCHECK device with collapsed gantry angle and the 2D dose distributions at the detector depth were measured. To simulate the expected dose distribution delivered to the MapCHECK, a MapCHECK computational phantom was modeled in EGSnrc based on vendor-supplied blueprint information. The dose to the detectors in the model was scored using the DOSXYZnrc user code. The agreement between the measured and the simulated dose distribution was evaluated using 2D gamma analysis with a gamma criterion of 3%/2 mm and a low dose threshold of 10%. One of the plans was selected and delivered with a rotating gantry angle for trajectory log file collection. To evaluate the potential interlinac and intralinac differences, the plan was delivered repeatedly on three linacs. From the collected log files, delivery parameters were retrieved to recalculate the 3D dose distributions in the patient's anatomy with DOSXYZnrc. The recalculated mean dose to the clinical target volume (CTV) and OARs from all deliveries were computed and compared with the planned dose in terms of percentage difference. To validate the accuracy of log file-based QA, the log file-recalculated dose was also compared with film measurement. RESULTS: The agreement of the total dose distribution between the MapCHECK measurement and simulation showed gamma passing rates of above 97% for all five MBRT plans. In the log file-dose recalculation, the difference between the recalculated and the planned dose to the CTV and OARs was below 1% for all deliveries. No significant inter- or intralinac differences were observed. The log file-dose had a gamma passing rate of 98.6% compared to film measurement. CONCLUSION: Both the MapCHECK measurements and log file-dose recalculations showed excellent agreement with the expected dose distribution. This study demonstrates the potential of using MapCHECK and log files as MBRT QA tools.

Robust mixed electron-photon radiation therapy planning for soft tissue sarcoma.

BACKGROUND: Mixed electron-photon beam radiation therapy (MBRT) is an emerging technique in which external electron and photon beams are simultaneously optimized into a single treatment plan. MBRT exploits the steep dose falloff and high surface dose of electrons while maintaining target conformity by leveraging the sharp penumbra of photons. PURPOSE: This study investigates the dosimetric benefits of MBRT for soft tissue sarcoma (STS) patients. MATERIAL AND METHODS: A retrospective cohort of 22 STS of the lower extremity treated with conventional photon-based Volumetric Modulated Arc Therapy (VMAT) were replanned with MBRT. Both VMAT and MBRT treatments were planned on the Varian TrueBeam linac using the Millenium multi-leaf collimator. No electron applicator, cutout or additional collimating devices were used for electron beams of MBRT plans. MBRT plans were optimized to use a combination of 6 MV photons and five electron energies (6, 9, 12, 16, 20 MeV) by a robust column generation algorithm. Electron beams in this study were planned at standard 100 cm source-axis distance (SAD). The dose to the clinical target volume (CTV), bone, normal tissue strip and other organs-at-risk (OARs) were compared using a Wilcoxon signed-rank test. RESULTS: As part of the original VMAT treatment, tissue-equivalent bolus was required in 10 of the 22 patients. MBRT plans did not require bolus by virtue of the higher electron entrance dose. CTV coverage by the prescription dose was found to be clinically equivalent between plans of either modality: V 50Gy $V_{\text{50Gy}}$ (MBRT) = 97.9 ± 0.2% versus V 50Gy $V_{\text{50Gy}}$ (VMAT) = 98.1 ± 0.6% (p=0.34). Evaluating the absolute paired difference between doses to OARs in MBRT and VMAT plans, we observed lower V 20Gy $V_{\text{20Gy}}$ to normal tissue in MBRT plans by 14.9 ± 3.2% ( p < 10 - 6 $p<10^{-6}$ ). Similarly, V 50Gy $V_{\text{50Gy}}$ to bone was found to be decreased by 8.2 ± 4.0% ( p < 10 - 3 $p<10^{-3}$ ) of the bone volume. CONCLUSION: For STS with subcutaneous involvement, MBRT offers statistically significant sparing of OARs without sacrificing target coverage when compared to VMAT. MBRT plans are deliverable on conventional linacs without the use of electron applicators, shortened source-to-surface distance (SSD) or bolus. This study shows that MBRT is a logistically feasible technique with clear dosimetric benefits.

Applying the column generation method to the intensity modulated high dose rate brachytherapy inverse planning problem.

Objective.Intensity modulated high dose rate brachytherapy (IMBT) is a rapidly developing application of brachytherapy where anisotropic dose distributions can be produced at each source dwell position. This technique is made possible by placing rotating metallic shields inside brachytherapy needles or catheters. By dynamically directing the radiation towards the tumours and away from the healthy tissues, a more conformal dose distribution can be obtained. The resulting treatment planning involves optimizing dwell position and shield angle (DPSA). The aim of this study was to investigate the column generation method for IMBT treatment plan optimization.Approach.A column generation optimization algorithm was developed to optimize the dwell times and shield angles. A retrospective study was performed on 10 prostate cases using RapidBrachyMCTPS. At every iteration, the plan was optimized with the chosen DPSA which would best improve the cost function that was added to the plan. The optimization process was stopped when the remaining DPSAs would not add value to the plan to limit the plan complexity.Main results.The average number of DPSAs and voxels were 2270 and 7997, respectively. The column generation approach yielded near-optimal treatment plans by using only 11% of available DPSAs on average in ten prostate cases. The coverage and organs at risk constraints passed in all ten cases.Significance.The column generation method produced high-quality deliverable prostate IMBT plans. The treatment plan quality reached a plateau, where adding more DPSAs had a minimal effect on dose volume histogram parameters. The iterative nature of the column generation method allows early termination of the treatment plan creation process as soon as the dosimetric indices from dose volume histogram satisfy the clinical requirements or if their values stabilize.

Graph neural networks and deep reinforcement learning for simultaneous beam orientation and trajectory optimization of Cyberknife.

Objective. Despite the high-quality treatment, the long treatment time of the Cyberknife system is believed to be a drawback. The high flexibility of its robotic arm requires meticulous path-finding algorithms to deliver the prescribed dose in the shortest time.Approach. We proposed a Deep Q-learning based on Graph Neural Networks to find the subset of the beams and the order to traverse them. A complex reward function is defined to minimize the distance covered by the robotic arm while avoiding the selection of close beams. Individual beam scores are also generated based on their effect on the beam intensity and are incorporated in the reward function. Main results. The performance of the presented method is evaluated on three clinical cases suffering from lung cancer. Applying this approach leads to an average of 35% reduction in the treatment time while delivering the prescribed dose provided by the physicians.Significance. Shorter treatment times result in a better treatment experience for individual patients, reduces discomfort and the sides effects of inadvertent movements for them. Additionally, it creates the opportunity to treat a higher number of patients in a given time period at the radiation therapy centers.

Ion chamber and film-based quality assurance of mixed electron-photon radiation therapy.

PURPOSE: In previous work, we demonstrated that mixed electron-photon radiation therapy (MBRT) produces treatment plans with improved normal tissue sparing and similar target coverage, when compared to photon-only plans. The purpose of this work was to validate the MBRT delivery process on a Varian TrueBeam accelerator and laying the groundwork for a patient-specific quality assurance (QA) protocol based on ion chamber point measurements and 2D film measurements. METHODS: MC beam models used to calculate the MBRT dose distributions of each modality (photons/electrons) were validated with a single-angle beam MBRT treatment plan delivered on a slab of Solid Water phantom with a film positioned at a depth of 2 cm. The measured film absorbed dose was compared to the calculated dose. To validate clinical deliveries, a polymethyl methacrylate (PMMA) cylinder was machined and holes were made to fit an ionization chamber. A complex MBRT plan involving a photon arc and three electron delivery angles was created with the aim of reproducing a clinically realistic dose distribution in typical soft tissue sarcoma tumours of the extremities. The treatment plan was delivered on the PMMA cylinder. Point measurements were taken with an Exradin A1SL chamber at two nominal depths: 1.4 cm and 2.1 cm. The plan was also delivered on a second identical phantom with an insert at 2 cm depth, where a film was placed. An existing EGSnrc user-code, SPRRZnrc, was modified to calculate the stopping power ratios between any materials in the same voxelized geometry used for dose calculation purposes. This modified code, called SPRXYZnrc, was used to calculate a correction factor, k MBRT , accounting for the differences in electron fluence spectrum at the measurement point compared to that at reference conditions. The uncertainty associated with neglecting potential ionization chamber fluence perturbation correction factors using this approach was estimated. RESULTS: The film measurement from the Solid Water phantom treatment plan was in good agreement with the simulated dose distribution, with a gamma pass rate of 96.1% for a 3%/2 mm criteria. For the PMMA phantom delivery, for the same gamma criteria, the pass rate was 97.3%. The ion chamber measurements of the total delivered dose agreed with the MC-simulated dose within 2.1%. The beam quality correction factors amounted to, at most, a 4% correction on the ion chamber measurement. However, individual contribution of low electron energies proved difficult to precisely measure due to their steep dose gradients, with disagreements of up to 28% ± 15% at 2.1 cm depth (6 MeV). Ion chamber measurement procedure of electron beams was achieved in less than 5 min, and the entire validation process including phantom setup was performed in less than 30 min. CONCLUSION: The agreement between measured and simulated MBRT doses indicates that the dose distributions obtained from the MBRT treatment planning algorithm are realistically achievable. The SPRXYZnrc MC code allowed for convenient calculations of k MBRT simultaneously with the dose distributions, laying the groundwork for patient-specific QA protocol practical for clinical use. Further investigation is needed to establish the accuracy of our ionization chamber correction factors k MBRT calculations at low electron energies.

Large-scale dosimetric assessment of Monte Carlo recalculated doses for lung robotic stereotactic body radiation therapy.

Owing to its short computation time and simplicity, the Ray-Tracing algorithm (RAT) has long been used to calculate dose distributions for the CyberKnife system. However, it is known that RAT fails to fully account for tissue heterogeneity and is therefore inaccurate in the lung. The aim of this study is to make a dosimetric assessment of 219 non-small cell lung cancer CyberKnife plans by recalculating their dose distributions using an independent Monte Carlo (MC) method. For plans initially calculated by RAT without heterogeneity corrections, target coverage was found to be significantly compromised when considering MC doses. Only 35.4% of plans were found to comply to their prescription doses. If the normal tissue dose limits were respected in the treatment planning dose, the MC recalculated dose did not exceed these limits in over 97% of the plans. Comparison of RAT and recalculated-MC doses confirmed the overestimation of RAT doses observed in previous studies. An inverse correlation between the RAT/MC dose ratio and the target size was also found to be statistically significant (p<10-4), consistent with other studies. In addition, the inaccuracy and variability in target coverage incurred from dose calculations using RAT without heterogeneity corrections was demonstrated. On average, no clinically relevant differences were observed between MC-calculated dose-to-water and dose-to-medium for all tissues investigated (⩽1%). Patients receiving a dose D95% larger than 119 Gy in EQD210 (or ≈52 Gy in 3 fractions) as recalculated by MC were observed to have significantly superior loco-regional progression-free survival rates (p=0.02) with a hazard ratio of 3.45 (95%CI: 1.14-10.5).

Simultaneous trajectory generation and volumetric modulated arc therapy optimization.

PURPOSE: Trajectory-based treatment planning involves the combination of a gantry-couch trajectory with volumetric modulated arc therapy (VMAT) treatment plan optimization. This work presents the implementation of an optimization methodology that generates a trajectory simultaneous with treatment plan optimization (simTr-VMAT). METHODS: The optimization algorithm is based on the column generation approach, in which a treatment plan is iteratively constructed through the solution of a subproblem called the "pricing problem." The property of the pricing problem to rank candidate apertures based on their associated price is leveraged to select an optimal aperture while simultaneously determining the trajectory path. A progressively increasing gantry-couch grid resolution is used to provide an initial coarse sampling of the angular solution space while maintaining fine control point spacing with the final treatment plan. The trajectory optimization was applied and compared to coplanar VMAT treatment plans for a lung patient, a glioblastoma patient, and a prostate patient. Algorithm validation was performed through the generation of 5000 random trajectories and optimization using column generation VMAT for each patient case, representing the solution space for the trajectory optimization problem. The simTr-VMAT trajectories were compared against these random trajectories based on a quality metric that prefers trajectories with few control points and low objective function value over long, inefficient trajectories. RESULTS: For the lung patient, the simTr-VMAT plan resulted in a decrease of the mean dose of 1.5 and 1.0 Gy to the heart and ipsilateral lung, respectively. For the glioblastoma patient, the simTr-VMAT plan resulted in improved planning target volume coverage with a decrease in mean dose to the eyes, lens, nose, and contralateral temporal lobe between 2 and 7 Gy. The prostate patient showed no clinically relevant dosimetric improvement. The simTr-VMAT treatment plans ranked at the 99.6, 96.3, and 99.4 percentiles compared to the distribution of randomly generated trajectories for the lung, glioblastoma, and prostate patients, respectively. CONCLUSION: The simTr-VMAT optimization methodology resulted in treatment plans with equivalent or improved dosimetric outcomes compared to coplanar VMAT treatment plans, with the trajectories resulting from the optimization ranking among the optimal trajectories for each patient case.

Trajectory-based VMAT for cranial targets with delivery at shortened SAD.

INTRODUCTION: Trajectory-based volumetric modulated arc therapy (tr-VMAT) treatment plans enable the option for noncoplanar delivery yielding steeper dose gradients and increased sparing of critical structures compared to conventional treatment plans. The addition of translational couch motion to shorten the effective source-to-axis distance (SAD) may result in improved delivery precision and an increased effective dose rate. In this work, tr-VMAT treatment plans using a noncoplanar "baseball stitch" trajectory were implemented, applied to patients presented with cranial targets, and compared to the clinical treatment plans. METHODS: A treatment planning workflow was implemented: (a) beamlet doses were calculated for control points defined along a baseball stitch trajectory using a collapsed-cone convolution-superposition algorithm; (b) VMAT treatment plans were optimized using the column generation approach; (c) a final dose distribution was calculated in Varian Eclipse using the analytical anisotropic algorithm by importing the optimized treatment plan parameters. Tr-VMAT plans were optimized for ten patients presented with cranial targets at both standard and shortened SAD, and compared to the clinical treatment plans through isodose distributions, dose-volume histograms, and dosimetric indices. The control point specifications of the optimized tr-VMAT plans were used to estimate the delivery time. RESULTS: The optimized tr-VMAT plans with both shortened and standard SAD delivery yielded a comparable plan quality to the clinical treatment plans. A statistically significant benefit was observed for dose gradient index and monitor unit efficiency for shortened SAD tr-VMAT plans, while improved target volume conformity was observed for the clinical treatment plan (P ≤ 0.05). A clear dosimetric benefit was not demonstrated between tr-VMAT delivery at shortened SAD compared to standard SAD, but shortened SAD delivery yielded a fraction size-dependent reduction in the estimated delivery time. CONCLUSION: The implementation of "baseball stitch" tr-VMAT treatment plans to patients presented with cranial targets demonstrated comparable plan quality to clinical treatment plans. The delivery at shortened SAD produced a fraction size-dependent decrease in estimated delivery time.

Robust mixed electron-photon radiation therapy optimization.

PURPOSE: Mixed beam electron-photon radiation therapy (MBRT) is an emerging technique that has the potential to reduce dose to normal tissue while improving target coverage for cancer sites with superficial tumors. Advances in optimization algorithms and robotic linear accelerators have made the creation and delivery of complex MBRT plans realistic without the need for special additional collimators, devices, or resetup of the patient. However, no study has been performed on the robustness of MBRT dose distributions to patient setup errors. Intensity-modulated delivery of other charged particles such as protons have been shown to require robust planning techniques to maintain adequate target coverage under positioning errors. We therefore assess the sensitivity of MBRT treatment plans to positioning uncertainties when created under the traditional planning target volume (PTV)-based planning paradigm and present a novel optimization model for the creation of robust MBRT plans. METHODS: The column generation method was applied to robust MBRT treatment planning by deriving the pricing problem for stochastic and "worst case" minimax optimization models, two common formulations of robustness. Robust treatment plans were created for two patient cases representative of the cancer sites which stand to benefit from MBRT: soft tissue sarcoma (STS) irradiation and chest wall irradiation with deep-seated internal mammary, axillary, and supraclavicular nodes (CW-N). For both patient cases, beamlet dose distributions for electrons and photons were generated for positioning shifts in six directions, ± 5 mm ( x ^ , y ^ , z ^ ) in addition to a nominal unshifted scenario, for a total of seven sets of beamlets. Robust plans were created by specifying dose coverage constraints to the clinical target volume (CTV), as opposed to the PTV. Comparisons were performed against traditional PTV-based plans created with a single set of unshifted beamlets. RESULTS: The dose distributions of traditional PTV-based MBRT plans showed significant degradation in target coverage homogeneity when patient positioning errors were considered. For both cancer sites, cold spots below 95% and hot spots above 108% of the prescription dose appeared within the CTV when shifting the patient by 5 mm, corresponding to the margin added to the CTV to form the PTV. In contrast, CTV-based robust plans created with the new optimization model maintained target coverage within the 95%-108% limits, for all positioning errors. CONCLUSION: The quality of MBRT treatment plans created using a traditional PTV-based optimization model was highly sensitive to patient positioning errors. For both patient cases, positioning errors resulted in perturbations to the nominal dose distributions which would have rendered PTV-based plans clinically unacceptable. In contrast, CTV-based robust plans were able to maintain adequate target coverage under all positioning error scenarios considered. We therefore conclude that to ensure the fidelity of the dose distribution delivered to the patient, robust optimization is critical when creating MBRT plans.

Monte Carlo calculated kilovoltage x-ray arc therapy plans for three lung cancer patients.

Purpose: The intent of this work was to evaluate the ability of our 200 kV kilovoltage arc therapy (KVAT) system to treat realistic lung tumors without exceeding dose constraints to organs-at-risk (OAR).Methods and Materials: Monte Carlo (MC) methods and the McO optimization framework generated and inversely optimized KVAT treatment plans for 3 SABR lung cancer patients. The KVAT system was designed to treat deep-seated lesions with kilovoltage photons. KVAT delivers dose to roughly spherical PTVs and therefore non-spherical PTVs were divided into spherical sub-volumes. A prescription dose of 12 Gy/fx × 4 fractions was planned to 90% of the PTV volume. KVAT plans were compared to VMC++ calculated, 6 MV stereotactic ablative radiotherapy (SABR) treatment plans. Dose distributions, dose volume histograms, gradient index (GI), planned mean doses and plan treatment times were calculated. Dose constraints for organs-at-risk (OAR) were taken from RTOG 101.Results: All plans, with the exception of the rib dose calculated in one of the KVAT plans for a peripheral lesion, were within dose-constraints. In general, KVAT plans had higher planned doses to OARs. KVAT GI values were 5.7, 7.2 and 8.9 and SABR values were 4.6, 4.1, and 4.7 for patient 1, 2 and 3, respectively. KVAT plan treatment times were 49, 65 and 17 min for patients 1, 2 and 3, respectively.Conclusions: Inverse optimization and MC methods demonstrated the ability of KVAT to produce treatment plans without exceeding TG 101 dose constraints to OARs for 2 out of 3 investigated lung cancer patients.

RapidBrachyMCTPS: a Monte Carlo-based treatment planning system for brachytherapy applications.

Despite being considered the gold standard for brachytherapy dosimetry, Monte Carlo (MC) has yet to be implemented into a software for brachytherapy treatment planning. The purpose of this work is to present RapidBrachyMCTPS, a novel treatment planning system (TPS) for brachytherapy applications equipped with a graphical user interface (GUI), optimization tools and a Geant4-based MC dose calculation engine, RapidBrachyMC. Brachytherapy sources and applicators were implemented in RapidBrachyMC and made available to the user via a source and applicator library in the GUI. To benchmark RapidBrachyMC, TG-43 parameters were calculated for the microSelectron v2 (192Ir) and SelectSeed (125I) source models and were compared against previously validated MC brachytherapy codes. The performance of RapidBrachyMC was evaluated for a prostate high dose rate case. To assess the accuracy of RapidBrachyMC in a heterogeneous setup, dose distributions with a cylindrical shielded/unshielded applicator were validated against film measurements in a Solid WaterTM phantom. TG-43 parameters calculated using RapidBrachyMC generally agreed within 1%-2% of the results obtained in previously published work. For the prostate case, clinical dosimetric indices showed general agreement with Oncentra TPS within 1%. Simulation times were on the order of minutes on a single core to achieve uncertainties below 2% in voxels within the prostate. The calculation time was decreased further using the multithreading features of Geant4. In the comparison between MC-calculated and film-measured dose distributions, at least 95% of points passed the 3%/3 mm gamma index criteria in all but one case. RapidBrachyMCTPS can be used as a post-implant dosimetry toolkit, as well as for MC-based brachytherapy treatment planning. This software is especially well suited for the development of new source and applicator models.

Inverse optimization of low-cost kilovoltage x-ray arc therapy plans.

PURPOSE: The objective of this work was to investigate the benefits of using inverse optimization treatment planning for kilovoltage arc therapy (KVAT) and to assess the dosimetric limitations of KVAT. METHODS: Monte Carlo (MC) calculated, inversely optimized KVAT plans of spherical, idealized breast, lung, and prostate lesions were calculated using the EGSnrc/BEAMnrc and DOSXYZnrc MC codes. The dose delivered with the KVAT system, which generates 200-225 kV photon beamlets, was calculated and inversely optimized using an optimization framework developed at McGill University. KVAT dose distributions were compared with inversely optimized and MC generated megavoltage (MV) volumetric modulated arc therapy (VMAT) plans as a reference. Prescription doses delivered to 95% of the planning target volume (PTV) were 38.5 (10 fractions), 60 (30 fractions) and 73.8 (41 fractions) Gy for the breast, lung and prostate patients, respectively. Dose distributions, dose volume histograms, and PTV homogeneity indices were used to evaluate KVAT and VMAT plans based on RTOG protocols. RESULTS: All organ-at-risk (OAR) doses were within prescribed dose limits for KVAT and VMAT plans. Generally, KVAT plans delivered higher doses to OARs. For example, due to the lower energy of KVAT, 50% of the rib volume received 12.9 Gy from KVAT while only receiving 2.5 Gy from VMAT. OAR doses were especially high for the KVAT prostate plan due to the presence of large volumes of bony anatomy, which illustrates a limitation of the KVAT system. The KVAT treatment times per fraction for the breast, lung and prostate patients were 2.8, 2.6 and 5.5 min, respectively. CONCLUSIONS: The inversely optimized KVAT plans presented in this work have demonstrated the ability of our novel low-cost, kilovoltage x-ray therapy system to safely treat deep-seated spherical lesions in breast and lung patients while meeting RTOG dose constraints on OARs.

On mixed electron-photon radiation therapy optimization using the column generation approach.

PURPOSE: Despite considerable increase in the number of degrees of freedom handled by recent radiotherapy optimisation algorithms, treatments are still typically delivered using a single modality. Column generation is an iterative method for solving large optimisation problems. It is well suited for mixed-modality (e.g., photon-electron) optimisation as the aperture shaping and modality selection problem can be solved rapidly, and the performance of the algorithm scales favourably with increasing degrees of freedom. We demonstrate that the column generation method applied to mixed photon-electron planning can efficiently generate treatment plans and investigate its behaviour under different aperture addition schemes. MATERIALS AND METHODS: Column generation was applied to the problem of mixed-modality treatment planning for a chest wall case and a leg sarcoma case. 6 MV beamlets (100 cm SAD) were generated for the photon components along with 5 energies for electron beamlets (6, 9, 12, 16 and 20 MeV), simulated as shortened-SAD (80 cm) beams collimated with a photon MLC. For the chest wall case, IMRT-only, modulated electron radiation therapy (MERT)-only, and mixed electron-photon (MBRT) treatment plans were created using the same planning criteria. For the sarcoma case, MBRT and MERT plans were created to study the behaviour of the algorithm under two different sets of planning criteria designed to favour specific modalities. Finally, the efficiency and plan quality of four different aperture addition schemes was analysed by creating chest wall MBRT treatment plans which incorporate more than a single aperture per iteration of the column generation loop based on a heuristic aperture ranking scheme. RESULTS: MBRT plans produced superior target coverage and homogeneity relative to IMRT and MERT plans created using the same optimisation criteria, all the while preserving the normal tissue-sparing advantages of electron therapy. Adjusting the planning criteria to favour a specific modality in the sarcoma case resulted in the algorithm correctly emphasizing the appropriate modality. As expected, adding a single aperture per iteration yielded the lowest (best) cost function value per aperture included in the treatment plan. However, a greedier scheme was able to converge to approximately the same cost function after 125 apertures in one third of the running time. Electron apertures were on average 50-100% larger than photon apertures for all aperture addition schemes. The distribution of intensities among the available modalities followed a similar trend for all schemes, with the dominant modalities being 6 MV photons along with 6, 9 and 20 MeV electrons. CONCLUSION: The column generation method applied to mixed modality treatment planning was able to produce clinically realistic treatment plans and combined the advantages of photon and electron radiotherapy. The running time of the algorithm depended heavily on the choice of mixing scheme. Adding the highest ranked aperture for each modality provided the best trade-off between running time and plan quality for a fixed number of apertures. This work contributes an efficient methodology for the planning of mixed electron-photon treatments.

Pulmonary toxoplasmosis in immunocompromised patients with interstitial pneumonia: a single-centre prospective study assessing PCR-based diagnosis.

AIMS: Pulmonary toxoplasmosis has become a very rare parasitic infection since the advent of highly active antiretroviral therapies. It is generally diagnosed by the direct microscopic observation of Toxoplasma gondii tachyzoites in bronchoalveolar lavage fluid (BALF). The aim of this study was to assess possible improvements in diagnostic performance associated with the use of real-time PCR. METHODS: This prospective study was carried out on BALFs obtained from immunocompromised patients over a 2-year period. We systematically compared the results of conventional staining with those of molecular detection. RESULTS: Two cases of pulmonary toxoplasmosis were diagnosed for a total of 336 samples. PCR did not detect any additional cases and was more time-consuming than conventional staining. CONCLUSIONS: Conventional staining is a reliable technique and is probably the most appropriate method for experienced microbiology laboratories, whereas T. gondii-specific PCR may be useful for laboratories with less experience in parasitology. TRIAL REGISTRATION NUMBER: 2015_030, May 27th 2015.

Latent uncertainties of the precalculated track Monte Carlo method.

PURPOSE: While significant progress has been made in speeding up Monte Carlo (MC) dose calculation methods, they remain too time-consuming for the purpose of inverse planning. To achieve clinically usable calculation speeds, a precalculated Monte Carlo (PMC) algorithm for proton and electron transport was developed to run on graphics processing units (GPUs). The algorithm utilizes pregenerated particle track data from conventional MC codes for different materials such as water, bone, and lung to produce dose distributions in voxelized phantoms. While PMC methods have been described in the past, an explicit quantification of the latent uncertainty arising from the limited number of unique tracks in the pregenerated track bank is missing from the paper. With a proper uncertainty analysis, an optimal number of tracks in the pregenerated track bank can be selected for a desired dose calculation uncertainty. METHODS: Particle tracks were pregenerated for electrons and protons using EGSnrc and geant4 and saved in a database. The PMC algorithm for track selection, rotation, and transport was implemented on the Compute Unified Device Architecture (cuda) 4.0 programming framework. PMC dose distributions were calculated in a variety of media and compared to benchmark dose distributions simulated from the corresponding general-purpose MC codes in the same conditions. A latent uncertainty metric was defined and analysis was performed by varying the pregenerated track bank size and the number of simulated primary particle histories and comparing dose values to a "ground truth" benchmark dose distribution calculated to 0.04% average uncertainty in voxels with dose greater than 20% of Dmax. Efficiency metrics were calculated against benchmark MC codes on a single CPU core with no variance reduction. RESULTS: Dose distributions generated using PMC and benchmark MC codes were compared and found to be within 2% of each other in voxels with dose values greater than 20% of the maximum dose. In proton calculations, a small (≤ 1 mm) distance-to-agreement error was observed at the Bragg peak. Latent uncertainty was characterized for electrons and found to follow a Poisson distribution with the number of unique tracks per energy. A track bank of 12 energies and 60000 unique tracks per pregenerated energy in water had a size of 2.4 GB and achieved a latent uncertainty of approximately 1% at an optimal efficiency gain over DOSXYZnrc. Larger track banks produced a lower latent uncertainty at the cost of increased memory consumption. Using an NVIDIA GTX 590, efficiency analysis showed a 807 × efficiency increase over DOSXYZnrc for 16 MeV electrons in water and 508 × for 16 MeV electrons in bone. CONCLUSIONS: The PMC method can calculate dose distributions for electrons and protons to a statistical uncertainty of 1% with a large efficiency gain over conventional MC codes. Before performing clinical dose calculations, models to calculate dose contributions from uncharged particles must be implemented. Following the successful implementation of these models, the PMC method will be evaluated as a candidate for inverse planning of modulated electron radiation therapy and scanned proton beams.

Double umbilical cord blood transplantation for hematological malignancies: a long-term analysis from the SFGM-TC registry.

Allogeneic hematopoietic stem cell (HSC) transplantation is a curative treatment for many hematologic malignancies for which umbilical cord blood (UCB) represents an alternative source of HSCs. To overcome the low cellularity of one UCB unit, double UCB transplantation (dUCBT) has been developed in adults. We have analyzed the outcome of 136 patients who underwent dUCBT reported to the SFGM-TC registry between 2005 and 2007. Forty-six patients received myeloablative regimens, and 90 patients received reduced-intensity conditioning regimens. There were 84 cases of leukemia, 17 cases of non-Hodgkin lymphoma, 11 cases of myeloma, and 24 other hematologic malignancies. At transplantation, 40 (29%) patients were in complete remission. At day 60 after transplantation, the cumulative incidence of neutrophil recovery was 91%. We observed one UCB unit domination in 88% of cases. The cumulative incidence of day 100 acute graft-versus-host disease, chronic graft-versus-host disease, transplant-related mortality, and relapse at 2 years were 36%, 23%, 27%, and 28% respectively. After a median follow-up of 49.5 months, the 3-year probabilities of overall and progression-free survival were 41% and 35%, respectively, with a significant overall survival advantage when male cord engrafted male recipients. We obtained a long-term plateau among patients in complete remission, which makes dUCBT a promising treatment strategy for these patients.

Direct aperture optimization for FLEC-based MERT and its application in mixed beam radiotherapy.

PURPOSE: Despite promising research in modulated electron radiotherapy (MERT), an applicator to produce modulated electron beams and associated treatment planning software is still not commercially available. This work investigated an optimization process in treatment planning for the McGill few leaf electron collimator (FLEC) MERT delivery device. In addition, the possibility of combining MERT with photon fields was examined to investigate mixed beam radiotherapy. METHODS: A FLEC direct aperture optimization (DAO) method, in which FLEC apertures and weights were iteratively optimized was created. The authors evaluated the performance of DAO against our previous technique for generating FLEC plans and with commercially available photon beam optimization algorithms using a basic target and organ at risk geometry. The authors applied the DAO technique on a sarcoma treatment to evaluate clinical parameters. Finally, the authors examined the merit of mixing the DAO generated FLEC electron fields with photon fields to improve the dosimetry of the sarcoma treatment. RESULTS: In relation to the alternative plans, the DAO generated sarcoma MERT plan was competitive in its ability to reduce the dose to OAR but weaker in its ability to highly conform the dose to the target volume. The addition of photon fields improved the quality of the MERT plan in terms of OAR sparing and target conformality. CONCLUSIONS: The DAO approach yielded deliverable FLEC-based MERT plans with a limited number of fields. The approach combined with photon optimization added flexibility, where the mutual benefits of each radiation type was used in unison to improve plan quality.

Analysis of risk factors for outcomes after unrelated cord blood transplantation in adults with lymphoid malignancies: a study by the Eurocord-Netcord and lymphoma working party of the European group for blood and marrow transplantation.

PURPOSE: To determine risk factors of umbilical cord blood transplantation (UCBT) for patients with lymphoid malignancies. PATIENTS AND METHODS: We evaluated 104 adult patients (median age, 41 years) who underwent unrelated donor UCBT for lymphoid malignancies. UCB grafts were two-antigen human leukocyte antigen-mismatched in 68%, and were composed of one (n = 78) or two (n = 26) units. Diagnoses were non-Hodgkin's lymphoma (NHL, n = 61), Hodgkin's lymphoma (HL, n = 29), and chronic lymphocytic leukemia (CLL, n = 14), with 87% having advanced disease and 60% having experienced failure with a prior autologous transplant. Sixty-four percent of patients received a reduced-intensity conditioning regimen and 46% low-dose total-body irradiation (TBI). Median follow-up was 18 months. RESULTS: Cumulative incidence of neutrophil engraftment was 84% by day 60, with greater engraftment in recipients of higher CD34(+) kg/cell dose (P = .0004). CI of non-relapse-related mortality (NRM) was 28% at 1 year, with a lower risk in patients treated with low-dose total-body irradiation (TBI; P = .03). Cumulative incidence of relapse or progression was 31% at 1 year, with a lower risk in recipients of double-unit UCBT (P = .03). The probability of progression-free survival (PFS) was 40% at 1 year, with improved survival in those with chemosensitive disease (49% v 34%; P = .03), who received conditioning regimens containing low-dose TBI (60% v 23%; P = .001), and higher nucleated cell dose (49% v 21%; P = .009). CONCLUSION: UCBT is a viable treatment for adults with advanced lymphoid malignancies. Chemosensitive disease, use of low-dose TBI, and higher cell dose were factors associated with significantly better outcome.

Activation of Cdk2 stimulates proteasome-dependent truncation of tyrosine phosphatase SHP-1 in human proliferating intestinal epithelial cells.

SHP-1 is expressed in the nuclei of intestinal epithelial cells (IECs). Increased SHP-1 expression and phosphatase activity coincide with cell cycle arrest and differentiation in these cells. Suspecting the tumor-suppressive properties of SHP-1, a yeast two-hybrid screen of an IEC cDNA library was conducted using the full-length SHP-1 as bait. Characterization of many positive clones revealed sequences identical to a segment of the Cdk2 cDNA sequence. Interaction between SHP-1 and Cdk2 was confirmed by co-immunoprecipitations whereby co-precipitated Cdk2 phosphorylated SHP-1 protein. Inhibition of Cdk2 (roscovitine) or proteasome (MG132) was associated with an enhanced nuclear punctuate distribution of SHP-1. Double labeling localization studies with signature proteins of subnuclear domains revealed a co-localization between the splicing factor SC35 and SHP-1 in bright nucleoplasmic foci. Using Western blot analyses with the anti-SHP-1 antibody recognizing the C terminus, a lower molecular mass species of 45 kDa was observed in addition to the full-length 64-65-kDa SHP-1 protein. Treatment with MG132 led to an increase in expression of the full-length SHP-1 protein while concomitantly leading to a decrease in the levels of the lower mass 45-kDa molecular species. Further Western blots revealed that the 45-kDa protein corresponds to the C-terminal portion of SHP-1 generated from proteasome activity. Mutational analysis of Tyr(208) and Ser(591) (a Cdk2 phosphorylation site) residues on SHP-1 abolished the expression of the amino-truncated 45-kDa SHP-1 protein. In conclusion, our results indicate that Cdk2-associated complexes, by targeting SHP-1 for proteolysis, counteract the ability of SHP-1 to block cell cycle progression of IECs.

Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

This retrospective study analyzed the impact of demographic and transplantation variables on outcomes of 1108 patients who have undergone allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning (RIC HSCT) for hematological malignancies and were reported to the Société Française de Greffe de Moelle et de Thérapie Cellulaire registry between November 1994 and December 2004. Only 442 patients (40%) were in complete remission (CR) at time of transplantation. Peripheral blood stem cells were used in the majority of patients (n = 878; 79%), 255 patients received fludarabine and low-dose total body irradiation, while 465 patients (42%) fludarabine and busulfan with rabbit anti-thymocyte globulins (ATG). The impact of demographic and transplant variables was studied on overall (OS) and event-free survival (EFS) in univariate and multivariate analysis. With a median follow-up of 21 months, 3-year probability of OS and EFS was 42% and 30%, respectively, and treatment-related mortality was 15% at 2 years. The multivariate analysis showed a significant negative impact on OS and EFS of the absence of CR status before transplantation; conditioning regimen, including >10 mg/kg ATG; and minor ABO incompatibility. In conclusion, this study highlights the major impact on RIC HSCT outcome of disease status before transplantation, ATG dose and ABO incompatibility.