Development of patient-specific 3D models from histopathological samples for applications in radiation therapy.

The biological effects of ionizing radiation depend on the tissue, tumor type, radiation quality, and patient-specific factors. Inter-patient variation in cell/nucleus size may influence patient-specific dose response. However, this variability in dose response is not well investigated due to lack of available cell/nucleus size data. The aim of this study was to develop methods to derive cell/nucleus size distributions from digital images of 2D histopathological samples and use them to build digital 3D models for use in cellular dosimetry. Nineteen of sixty hematoxylin and eosin stained lung adenocarcinoma samples investigated passed exclusion criterion to be analyzed in the study. A difference of gaussians blob detection algorithm was used to identify nucleus centers and quantify cell spacing. Hematoxylin content was measured to determine nucleus radius. Pouring simulations were conducted to generate one-hundred 3D models containing volumes of equivalent cell spacing and nuclei radius to those in histopathological samples. The nuclei radius distributions of non-tumoral and cancerous regions appearing in the same slide were significantly different (p < 0.01) in all samples analyzed. The median nuclear-cytoplasmic ratio was 0.36 for non-tumoral cells and 0.50 for cancerous cells. The average cellular and nucleus packing densities in the 3D models generated were 65.9% (SD: 1.5%) and 13.3% (SD: 0.3%) respectively. Software to determine cell spacing and nuclei radius from histopathological samples was developed. 3D digital tissue models containing volumes with equivalent cell spacing, nucleus radius, and packing density to cancerous tissues were generated.

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.

Water equivalent PRESAGE® for synchrotron radiation therapy dosimetry.

PURPOSE: Synchrotron Radiation Therapy techniques are currently being trialed and commissioned at synchrotrons around the world. The patient treatment planning systems (TPS) developed for these treatments use simulated data of the synchrotron x-ray beam to produce the dosimetry in the treatment plan. The purpose of this study was to investigate a water equivalent PRESAGE® dosimeter capable of 3D dosimetry over an energy range suitable for synchrotron x-ray beams. METHODS: Water equivalent PRESAGE® dosimeters were fabricated with a radiological effective atomic number similar to water over an energy range of 10 keV to 10 MeV. The dosimeters were irradiated at various energies, scanned using optical CT (OCT) scanning and compared to ion chamber measurements. Percentage depth dose and beam profiles of the synchrotron beam were compared to Monte Carlo (MC) model simulations. RESULTS: The PDD profiles of the water equivalent PRESAGE® agreed with ion chamber measurements and MC calculations within 2% for all keV energies investigated. The PRESAGE® also showed good agreement to the MC model for depths below 5 mm of the synchrotron beam where ion chamber data do not exist. The spatial resolution of the OCT was not sufficient to accurately measure the penumbra of the synchrotron beams compared to MC calculations or EBT3 film; however, the water equivalent PRESAGE® was able to verify dose profile characteristics of the MC model. CONCLUSIONS: The radiological response of a water equivalent PRESAGE® dosimeter has been validated for synchrotron x-ray beam energies along with the ability to independently verify dose distributions of a MC model.

Image guidance protocol for synchrotron microbeam radiation therapy.

The protocol for image-guided microbeam radiotherapy (MRT) developed for the Australian Synchrotron's Imaging and Medical Beamline (IMBL) is described. The protocol has been designed for the small-animal MRT station of IMBL to enable future preclinical trials on rodents. The image guidance procedure allows for low-dose monochromatic imaging at 50 keV and subsequent semi-automated sample alignment in 3D with sub-100 µm accuracy. Following the alignment, a beamline operation mode change is performed and the relevant beamline components are automatically aligned for the treatment (pink) beam to be delivered on the sample. Here, the small-animal MRT station, the parameters and procedures for the image guidance protocol, as well as the experimental imaging results using phantoms are described. Furthermore, the experimental validation of the protocol using 3D PRESAGE(®) dosimeters is reported. It is demonstrated that the sample alignment is maintained after the mode change and the treatment can be delivered within the same spatial accuracy of 100 µm. The results indicate that the proposed approach is viable for preclinical trials of small-animal MRT.

A feasibility study for using ABS plastic and a low-cost 3D printer for patient-specific brachytherapy mould design.

This feasibility study aims to determine if a low-cost 3D printer (BitsFromBytes 3D Touch) with ABS plastic can print custom mould structures and catheter channels defined in a brachytherapy treatment planning system (Nucletron Oncentra) for patient-specific treatment. Printer accuracy was evaluated through physical measurement, and print quality was investigated by adjusting print parameters (print speed, layer thickness, percentage infill). Catheter positioning and reproducibility were measured over repeated insertions. ABS plastic water equivalency was investigated by comparing Ir-192 HDR source dose distributions, measured with radiochromic film, in ABS plastic and in water. Structures and catheter channels were printed accurately to within 0.5 mm laterally and 1 mm in the vertical print direction. Adjusting print parameters could reduce print time, albeit with reduced print quality. 3.5 mm channel diameters allowed for easy catheter insertion. Catheter positioning was reproducible to within 0.5 mm but, because of catheter flex within the channel, was on average 1 mm offset from defined TPS positions. This offset could be accounted for by repeating the treatment planning CT scan with the printed mould positioned on the patient. Dose attenuation in ABS plastic and in water was equivalent to within the measurement limitations. While clinical uses for this particular low-cost printer and ABS plastic are limited by print size restrictions and non-certification for biocompatibility, it has been demonstrated that a low-cost 3D printer set-up can accurately create custom moulds and catheter channels potentially acceptable for clinical use.

Determination of subcellular compartment sizes for estimating dose variations in radiotherapy.

The variation in specific energy absorbed to different cell compartments caused by variations in size and chemical composition is poorly investigated in radiotherapy. The aim of this study was to develop an algorithm to derive cell and cell nuclei size distributions from 2D histology samples, and build 3D cellular geometries to provide Monte Carlo (MC)-based dose calculation engines with a morphologically relevant input geometry. Stained and unstained regions of the histology samples are segmented using a Gaussian mixture model, and individual cell nuclei are identified via thresholding. Delaunay triangulation is applied to determine the distribution of distances between the centroids of nearest neighbour cells. A pouring simulation is used to build a 3D virtual tissue sample, with cell radii randomised according to the cell size distribution determined from the histology samples. A slice with the same thickness as the histology sample is cut through the 3D data and characterised in the same way as the measured histology. The comparison between this virtual slice and the measured histology is used to adjust the initial cell size distribution into the pouring simulation. This iterative approach of a pouring simulation with adjustments guided by comparison is continued until an input cell size distribution is found that yields a distribution in the sliced geometry that agrees with the measured histology samples. The thus obtained morphologically realistic 3D cellular geometry can be used as input to MC-based dose calculation programs for studies of dose response due to variations in morphology and size of tumour/healthy tissue cells/nuclei, and extracellular material.

Dual acquisition of (18)F-FMISO and (18)F-FDOPA.

Metabolic imaging using positron emission tomography (PET) has found increasing clinical use for the management of infiltrating tumours such as glioma. However, the heterogeneous biological nature of tumours and intrinsic treatment resistance in some regions means that knowledge of multiple biological factors is needed for effective treatment planning. For example, the use of (18)F-FDOPA to identify infiltrative tumour and (18)F-FMISO for localizing hypoxic regions. Performing multiple PET acquisitions is impractical in many clinical settings, but previous studies suggest multiplexed PET imaging could be viable. The fidelity of the two signals is affected by the injection interval, scan timing and injected dose. The contribution of this work is to propose a framework to explicitly trade-off signal fidelity with logistical constraints when designing the imaging protocol. The particular case of estimating (18)F-FMISO from a single frame prior to injection of (18)F-FDOPA is considered. Theoretical experiments using simulations for typical biological scenarios in humans demonstrate that results comparable to a pair of single-tracer acquisitions can be obtained provided protocol timings are carefully selected. These results were validated using a pre-clinical data set that was synthetically multiplexed. The results indicate that the dual acquisition of (18)F-FMISO and (18)F-FDOPA could be feasible in the clinical setting. The proposed framework could also be used to design protocols for other tracers.

Recent advances in radiotherapy for thoracic tumours.

Radiation Oncology technology has continued to advance at a rapid rate and is bringing significant benefits to patients. This review outlines some of the advances in technology and radiotherapy treatment of thoracic cancers including brachytherapy, stereotactic radiotherapy, tomotherapy and intensity modulated radiotherapy. The importance of functional imaging with PET and management of movement are highlighted. Most of the discussion relates to non-small cell lung cancer but management of mesothelioma and small cell lung cancer are also covered. This technology has substantial benefits to patients in terms of decreasing toxicity both in the short and longer term.