Monica Serban

A deformable phantom for 4D radiotherapy verification: Design and image registration evaluation

Motion of thoracic tumors with respiration presents a challenge for three-dimensional (3D) conformal radiation therapy treatment. Validation of techniques aimed at measuring and minimizing the effects of respiratory motion requires a realistic deformable phantom for use as a gold standard. The purpose of this study was to develop and study the characteristics of a reproducible, tissue equivalent, deformable lung phantom. The phantom consists of a Lucite cylinder filled with water containing a latex balloon stuffed with dampened natural sponges. The balloon is attached to a piston that mimics the human diaphragm. Nylon wires and Lucite beads, emulating vascular and bronchial bifurcations, were uniformly glued at various locations throughout the sponges. The phantom is capable of simulating programmed irregular breathing patterns with varying periods and amplitudes. A tissue equivalent tumor, suitable for holding radiochromic film for dose measurements was embedded in the sponge. To assess phantom motion, eight 3D computed tomography data sets of the static phantom were acquired for eight equally spaced positions of the piston. The 3D trajectories of 12 manually chosen point landmarks and the tumor center-of-mass were studied. Motion reproducibility tests of the deformed phantom were established on seven repeat scans of three different states of compression. Deformable image registration (DIR) of the extreme breathing phases was performed. The accuracy of the DIR was evaluated by visual inspection of image overlays and quantified by the distance-to-agreement (DTA) of manually chosen point landmarks and triangulated surfaces obtained from 3D contoured structures. In initial tests of the phantom, a 20-mm excursion of the piston resulted in deformations of the balloon of 20 mm superior-inferior, 4 mm anterior-posterior, and 5 mm left-right. The change in the phantom mean lung density ranged from 0.24 (0.12 SD) g/cm3 at peak exhale to 0.19 (0.12 SD) g/cm3 at peak inhale. The SI displacement of the landmarks varied between 94% and 3% of the piston excursion for positions closer and farther away from the piston, respectively. The reproducibility of the phantom deformation was within the image resolution (0.7 x 0.7 x 1.25 mm3). Vector average registration accuracy based on point landmarks was found to be 0.5 (0.4 SD) mm. The tumor and lung mean 3D DTA obtained from triangulated surfaces were 0.4 (0.1 SD) mm and 1.0 (0.8 SD) mm, respectively. This phantom is capable of reproducibly emulating the physically realistic lung features and deformations and has a wide range of potential applications, including four-dimensional (4D) imaging, evaluation of deformable registration accuracy, 4D planning and dose delivery.

Dosimetric effects near implanted vascular access ports: an examination of external photon beam dose calculations

Vascular access ports are used widely in the administering of drugs for radiation oncology patients. Their dosimetric effect on radiation therapy delivery in photon beams has not been rigorously established. In this work, the effects on external beam fields when any of a variety of vascular access ports were included in the path of a high energy beam are studied. This study specifically identifies sidescatter and backscatter consequences as well as attenuation effects. The study was divided into two parts. First, a total of 18 ports underwent extended HU range CT scanning followed by 3D computer treatment planning, where homogeneous and heterogeneous plans were created for photon beams of energy 6 MV and 18 MV using a Pencil Beam Convolution (PBC) algorithm. Dose points were analyzed at locations around each device. A total of 1,440 points were reviewed in this section of the study. A replicate of the largest vascular access port was created in the treatment planning workspace for further investigation with alternative treatment planning algorithms. Then, plans were generated identical to the above and compared to the results of dose computation between the Pencil Beam Convolution algorithm, the Analytical Anisotropic Algorithm (AAA), and the EGSnrc Monte Carlo algorithm with user code DOSRZnrc (MC). A total of 300 points were reviewed in this part of the study. It was concluded that ports with more bulky construction and those with partial metal composition create the largest changes. Similar effects were observed for similar port configurations. Considerable differences between the PBC and AAA in comparison to MC are noted and discussed. By thorough examination of planning system results, the presented vascular access ports may now be ranked according to the greatest amount of change exhibited within a treatment planning system. Effects of backscatter, lateral scatter, and attenuation are up to 5.0%, 3.4% and 16.8% for 6 MV and 7.0%, 7.7% and 7.2% for 18 MV, respectively. PACS numbers: 87.56.bd, 61.82.Bg, 41.50.+h, 87.19.Hh, 87.55.Gh, 87.55.K−, 87.55.N−, 87.55.−x, 81.40.Wx, 87.55.−x, 87.53.Bn, and 87.59.bd

Tracking of Mesenchymal Stem Cells with Fluorescence Endomicroscopy Imaging in Radiotherapy-Induced Lung Injury

Mesenchymal stem cells (MSCs) have potential for reducing inflammation and promoting organ repair. However, limitations in available techniques to track them and assess this potential for lung repair have hindered their applicability. In this work, we proposed, implemented and evaluated the use of fluorescence endomicroscopy as a novel imaging tool to track MSCs in vivo. MSCs were fluorescently labeled and injected into a rat model of radiation-induced lung injury via endotracheal (ET) or intravascular (IV) administration. Our results show that MSCs were visible in the lungs with fluorescence endomicroscopy. Moreover, we developed an automatic cell counting algorithm to quantify the number of detected cells in each condition. We observed a significantly higher number of detected cells in ET injection compared to IV and a slight increase in the mean number of detected cells in irradiated lungs compared to control, although the latter did not reach statistical significance. Fluorescence endomicroscopy imaging is a powerful new minimally invasive and translatable tool that can be used to track and quantify MSCs in the lungs and help assess their potential in organ repair.

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.

Patient-specific compensation for Co-60 TBI treatments based on Monte Carlo design: A feasibility study.

PURPOSE To develop an AP-PA treatment technique for the delivery of total body irradiation (TBI) at extended SSD using a modified Co-60 unit equipped with flattening filter and patient-specific compensators supported by Monte Carlo (MC) simulations and measurements. METHODS An existing Eldorado-78 Co-60 teletherapy unit was stripped of its original collimator and equipped with two beam-defining cerrobend blocks. An acrylic flattening filter was numerically designed based on detailed mapping of the dose distribution of the large open field at a 10 cm depth in water using a primary radiation attenuation calculation. An EGSnrc/BEAMnrc MC model of the resulting unit was developed and experimentally validated and was used to calculate MC dose distributions in whole-body supine and prone CT images of a patient. AP-PA patient-specific compensators were designed based on the supine and prone mid-plane dose distributions. RESULTS The designed flattening filter flattens the beam to within ±2% over a 200 cm × 70 cm area at 10 cm depth in water. Experimental validation of the calculated dose profiles in the open and flattened beams shows agreement of better than 2% and 1%, respectively. Patient MC dose calculations in the flattened, uncompensated beam showed dose deviations from prescription dose most notably in lung, neck and extremities ranging from -5% to +25%. The use of patient-specific compensators reduced inhomogeneities to within -5% to +10%. CONCLUSIONS This work demonstrates that a Co-60 TBI setup upgraded with patient-specific compensators, numerically designed using MC patient dose calculations, is feasible and considerably improves the dose homogeneity.

Mesenchymal Stem Cells Adopt Lung Cell Phenotype in Normal and Radiation-induced Lung Injury Conditions.

Lung tissue exposure to ionizing irradiation can invariably occur during the treatment of a variety of cancers leading to increased risk of radiation-induced lung disease (RILD). Mesenchymal stem cells (MSCs) possess the potential to differentiate into epithelial cells. However, cell culture methods of primary type II pneumocytes are slow and cannot provide a sufficient number of cells to regenerate damaged lungs. Moreover, effects of ablative radiation doses on the ability of MSCs to differentiate in vitro into lung cells have not been investigated yet. Therefore, an in vitro coculture system was used, where MSCs were physically separated from dissociated lung tissue obtained from either healthy or high ablative doses of 16 or 20 Gy whole thorax irradiated rats. Around 10±5% and 20±3% of cocultured MSCs demonstrated a change into lung-specific Clara and type II pneumocyte cells when MSCs were cocultured with healthy lung tissue. Interestingly, in cocultures with irradiated lung biopsies, the percentage of MSCs changed into Clara and type II pneumocytes cells increased to 40±7% and 50±6% at 16 Gy irradiation dose and 30±5% and 40±8% at 20 Gy irradiation dose, respectively. These data suggest that MSCs to lung cell differentiation is possible without cell fusion. In addition, 16 and 20 Gy whole thorax irradiation doses that can cause varying levels of RILD, induced different percentages of MSCs to adopt lung cell phenotype compared with healthy lung tissue, providing encouraging outlook for RILD therapeutic intervention for ablative radiotherapy prescriptions.

A comparative analysis of longitudinal computed tomography and histopathology for evaluating the potential of mesenchymal stem cells in mitigating radiation-induced pulmonary fibrosis

Radiation-induced pulmonary fibrosis (RIPF) is a debilitating side effect that occurs in up to 30% of thoracic irradiations in breast and lung cancer patients. RIPF remains a major limiting factor to dose escalation and an obstacle to applying more promising new treatments for cancer cure. Limited treatment options are available to mitigate RIPF once it occurs, but recently, mesenchymal stem cells (MSCs) and a drug treatment stimulating endogenous stem cells (GM-CSF) have been investigated for their potential in preventing this disease onset. In a pre-clinical rat model, we contrasted the application of longitudinal computed tomography (CT) imaging and classical histopathology to quantify RIPF and to evaluate the potential of MSCs in mitigating RIPF. Our results on histology demonstrate promises when MSCs are injected endotracheally (but not intravenously). While our CT analysis highlights the potential of GM-CSF treatment. Advantages and limitations of both analytical methods are contrasted in the context of RIPF.

MO‐E‐BRA‐02: Computer Aided Design and Monte Carlo Validation of a Patient‐Specific Co‐60 TBI Treatment Unit

Purpose: To modify and characterize a teletherapy 60Co unit for total body irradiation (TBI) treatments at extended SSD using experiments and a Monte Carlo (MC)model and to propose the design of custom compensators based on MCdose in the patient. Methods and Materials: An existing Eldorado T78 60Co teletherapy unit was stripped from its original collimator and equipped with beam‐defining cerrobend blocks for extended SSD TBI treatments. An acrylic flattening filter was numerically designed based on detailed mapping of the dose distribution of the large open field at 10 cm depth in water and using a primary radiation attenuation calculation. An EGSnrc MCmodel of the resulting unit was developed and validated. Dose distributions measured using ionization chambers were compared to MCdose distribution in air and phantom. The validated model was used to calculate dose in a whole‐body patient CTimage. A compensator, designed to make the patient mid‐plane dose uniform was proposed. Results: The designed filter flattens the beam to within ±2% over an area of 200 × 70 cm2 at patient mid‐plane. The agreement between measured and calculated dose profiles in the open and the filtered beams is at the sub 2% and sub 1% level, respectively. Surface dose in the filtered beam is 78.5% and mean photon energy of the primary fluence is 0.94 MeV independent of position in the field. Patient‐specific calculations show excess dose in lung and the area of neck and extremities relative to prescription dose, by up to 20% and 30%, respectively. These excess doses can be reduced by introducing compensators, designed from the mid‐plane dose distribution, following similar techniques as for the design of the filter. Conclusions: This work shows that extended SSD 60Co irradiation equipment and patient‐specific compensators designed based on realistic dose distributions, can improve TBI delivery.

Investigating the role of functional imaging in the management of soft-tissue sarcomas of the extremities

Highlights • We acquired FDG-PET, FMISO-PET, DW-MRI and DCE-MRI for 18 soft-tissue sarcomas.• We investigated the complementarity and evolution of imaging data over time.• We used textural biomarkers to identify patients who could benefit from dose boosts.• We showed the technical feasibility of double boost doses to sub-GTV regions.

Image-Guided Fluorescence Endomicroscopy: From Macro- to Micro-Imaging of Radiation-Induced Pulmonary Fibrosis

Radiation-induced pulmonary fibrosis (RIPF) is a debilitating side effect of radiation therapy (RT) of several cancers including lung and breast cancers. Current clinical methods to assess and monitor RIPF involve diagnostic computed tomography (CT) imaging, which is restricted to anatomical macroscopic changes. Confocal laser endomicroscopy (CLE) or fluorescence endomicroscopy (FE) in combination with a fibrosis-targeted fluorescent probe allows to visualize RIPF in real-time at the microscopic level. However, a major limitation of FE imaging is the lack of anatomical localization of the endomicroscope within the lung. In this work, we proposed and validated the use of x-ray fluoroscopy-guidance in a rat model of RIPF to pinpoint the location of the endomicroscope during FE imaging and map it back to its anatomical location in the corresponding CT image. For varying endomicroscope positions, we observed a positive correlation between CT and FE imaging as indicated by the significant association between increased lung density on CT and the presence of fluorescent fiber structures with FE in RT cases compared to Control. Combining multimodality imaging allows visualization and quantification of molecular processes at specific locations within the injured lung. The proposed image-guided FE method can be extended to other disease models and is amenable to clinical translation for assessing and monitoring fibrotic damage.