Biologically consistent dose accumulation using daily patient imaging.

BACKGROUND: This work addresses a basic inconsistency in the way dose is accumulated in radiotherapy when predicting the biological effect based on the linear quadratic model (LQM). To overcome this inconsistency, we introduce and evaluate the concept of the total biological dose, bEQDd. METHODS: Daily computed tomography imaging of nine patients treated for prostate carcinoma with intensity-modulated radiotherapy was used to compute the delivered deformed dose on the basis of deformable image registration (DIR). We compared conventional dose accumulation (DA) with the newly introduced bEQDd, a new method of accumulating biological dose that considers each fraction dose and tissue radiobiology. We investigated the impact of the applied fractionation scheme (conventional/hypofractionated), uncertainties induced by the DIR and by the assigned α/ß-value. RESULTS: bEQDd was systematically higher than the conventionally accumulated dose with difference hot spots of 3.3-4.9 Gy detected in six out of nine patients in regions of high dose gradient in the bladder and rectum. For hypofractionation, differences are up to 8.4 Gy. The difference amplitude was found to be in a similar range to worst-case uncertainties induced by DIR and was higher than that induced by α/ß. CONCLUSION: Using bEQDd for dose accumulation overcomes a potential systematic inaccuracy in biological effect prediction based on accumulated dose. Highest impact is found for serial-type late responding organs at risk in dose gradient regions and for hypofractionation. Although hot spot differences are in the order of several Gray, in dose-volume parameters there is little difference compared with using conventional or biological DA. However, when local dose information is used, e.g. dose surface maps, difference hot spots can potentially change outcomes of dose-response modelling and adaptive treatment strategies.

An end-to-end test for MR-guided online adaptive radiotherapy.

In the evolving field of adaptive MR guided radiotherapy, the need for dedicated procedures for acceptance and quality assurance is increasing. Research has been devoted to MR compatible dosimeters and phantoms, but to date no end-to-end test has been presented that covers an MRgRT workflow. Such an end-to-end test should comprise each step of the workflow and include all associated uncertainties. The purpose of this study was to investigate the usability of an anthropomorphic deformable and multimodal pelvis (ADAM-pelvis) phantom in combination with film dosimetry for end-to-end testing of an MRgRT adaptive workflow. The ADAM-pelvis phantom included surrogates for muscle tissue, adipose and bone, as well as deformable silicone organs mimicking a prostate patient. At the interfaces of the critical structures (bladder and rectum), small pieces of GafChromic EBT3 films were placed to measure delivered dose. Pre-treatment MR imaging of the phantom was used to delineate the prostate, rectum and bladder and to generate a treatment plan to deliver 2 Gy to the prostate. Electron density (ED) map from CT imaging was used for dose calculation after deformable image registration (DIR) to the pre-treatment MR scan. At each fraction, bladder- and rectum filling was varied and a new adapted plan was generated. Dose calculation was performed using both a DIR-based ED map and a CT-based ED map after acquisition of a new CT scan of the phantom at each fraction. All dose calculations were performed taking into account the magnetic field. A good agreement between measured and calculated dose was found using both, the CT-derived and the DIR-based ED map (2.0% and 2.8% dose difference, respectively). The gamma index pass-rate (3%/2 mm) varied from 96.4% to 100%.The ADAM-pelvis phantom was suitable for end-to-end testing in MR-guided radiotherapy and a very good agreement with the calculated dose was achieved.

End-to-end empirical validation of dose accumulation in MRI-guided adaptive radiotherapy for prostate cancer using an anthropomorphic deformable pelvis phantom.

BACKGROUND AND PURPOSE: This work evaluates the accuracy of deformable dose accumulation for organs at risk (OAR) in MR-guided prostate SBRT using an anthropomorphic deformable phantom. MATERIALS AND METHODS: Six MR-guided prostate SBRT treatment courses were simulated using volumetric OAR (bladder and rectum) information derived from actual patient data. Deformed OAR contours, geometrical landmarks and GafChromic EBT3 film strips (1.25 × 2.0 cm2) placed at the surface of the OARs were used to validate DIR-based dose accumulation in MRgRT. Two DIR methods were applied: an intensity-based deformation (IB-D) applied to the whole image, and a contour-based deformation (CB-D), resulting in a separate deformation and dose accumulation for each OAR. Dosimetric accuracy was evaluated by quantifying the dose differences, and performing a gamma-index analysis between measured and DIR-derived accumulated dose for both OARs. Geometrical accuracy was assessed by measuring the Dice similarity coefficient (DSC), Hausdorff distance (HDD) and residual distance error (RDE) for all markers at each fraction. RESULTS: CB-D resulted in an average dose deviation from film measurements for rectum and bladder surfaces of 0.6% and 0.3%, respectively. IB-D led to worse results resulting in an overall average dose accumulation inaccuracy of 7.2% and 2.5% for rectum and bladder. CB-D also showed a higher geometrical accuracy than IB-D with significantly higher DSC values and lower RDE and HDD deviations. CONCLUSION: Empirical validation of dose accumulation in MR-guided SBRT for prostate cancer obtained a good agreement with reference film measurements when using a contour-based DIR approach.

Generation of synthetic CT data using patient specific daily MR image data and image registration.

To fully exploit the advantages of magnetic resonance imaging (MRI) for radiotherapy (RT) treatment planning, a method is required to overcome the problem of lacking electron density information. We aim to establish and evaluate a new method for computed tomography (CT) data generation based on MRI and image registration. The thereby generated CT data is used for dose accumulation. We developed a process flow based on an initial pair of rigidly co-registered CT and T2-weighted MR image representing the same anatomical situation. Deformable image registration using anatomical landmarks is performed between the initial MRI data and daily MR images. The resulting transformation is applied to the initial CT, thus fractional CT data is generated. Furthermore, the dose for a photon intensity modulated RT (IMRT) or intensity modulated proton therapy (IMPT) plan is calculated on the generated fractional CT and accumulated on the initial CT via inverse transformation. The method is evaluated by the use of phantom CT and MRI data. Quantitative validation is performed by evaluation of the mean absolute error (MAE) between the measured and the generated CT. The effect on dose accumulation is examined by means of dose-volume parameters. One patient case is presented to demonstrate the applicability of the method introduced here. Overall, CT data derivation lead to MAEs with a median of 37.0 HU ranging from 29.9 to 66.6 HU for all investigated tissues. The accuracy of image registration showed to be limited in the case of unexpected air cavities and at tissue boundaries. The comparisons of dose distributions based on measured and generated CT data agree well with the published literature. Differences in dose volume parameters kept within 1.6% and 3.2% for photon and proton RT, respectively. The method presented here is particularly suited for application in adaptive RT in current clinical routine, since only minor additional technical equipment is required.

Technical Note: Radiological properties of tissue surrogates used in a multimodality deformable pelvic phantom for MR-guided radiotherapy.

PURPOSE: Phantom surrogates were developed to allow multimodal [computed tomography (CT), magnetic resonance imaging (MRI), and teletherapy] and anthropomorphic tissue simulation as well as materials and methods to construct deformable organ shapes and anthropomorphic bone models. METHODS: Agarose gels of variable concentrations and loadings were investigated to simulate various soft tissue types. Oils, fats, and Vaseline were investigated as surrogates for adipose tissue and bone marrow. Anthropomorphic shapes of bone and organs were realized using 3D-printing techniques based on segmentations of patient CT-scans. All materials were characterized in dual energy CT and MRI to adapt CT numbers, electron density, effective atomic number, as well as T1- and T2-relaxation times to patient and literature values. RESULTS: Soft tissue simulation could be achieved with agarose gels in combination with a gadolinium-based contrast agent and NaF to simulate muscle, prostate, and tumor tissues. Vegetable oils were shown to be a good representation for adipose tissue in all modalities. Inner bone was realized using a mixture of Vaseline and K2HPO4, resulting in both a fatty bone marrow signal in MRI and inhomogeneous areas of low and high attenuation in CT. The high attenuation of outer bone was additionally adapted by applying gypsum bandages to the 3D-printed hollow bone case with values up to 1200 HU. Deformable hollow organs were manufactured using silicone. Signal loss in the MR images based on the conductivity of the gels needs to be further investigated. CONCLUSIONS: The presented surrogates and techniques allow the customized construction of multimodality, anthropomorphic, and deformable phantoms as exemplarily shown for a pelvic phantom, which is intended to study adaptive treatment scenarios in MR-guided radiation therapy.

An anthropomorphic multimodality (CT/MRI) head phantom prototype for end-to-end tests in ion radiotherapy.

With the increasing complexity of external beam therapy "end-to-end" tests are intended to cover every step from therapy planning through to follow-up in order to fulfill the higher demands on quality assurance. As magnetic resonance imaging (MRI) has become an important part of the treatment process, established phantoms such as the Alderson head cannot fully be used for those tests and novel phantoms have to be developed. Here, we present a feasibility study of a customizable multimodality head phantom. It is initially intended for ion radiotherapy but may also be used in photon therapy. As basis for the anthropomorphic head shape we have used a set of patient computed tomography (CT) images. The phantom recipient consisting of epoxy resin was produced by using a 3D printer. It includes a nasal air cavity, a cranial bone surrogate (based on dipotassium phosphate), a brain surrogate (based on agarose gel), and a surrogate for cerebrospinal fluid (based on distilled water). Furthermore, a volume filled with normoxic dosimetric gel mimicked a tumor. The entire workflow of a proton therapy could be successfully applied to the phantom. CT measurements revealed CT numbers agreeing with reference values for all surrogates in the range from 2 HU to 978 HU (120 kV). MRI showed the desired contrasts between the different phantom materials especially in T2-weighted images (except for the bone surrogate). T2-weighted readout of the polymerization gel dosimeter allowed approximate range verification.

Hematopoietic development from human induced pluripotent stem cells.

A decade of research on human embryonic stem cells (ESC) has paved the way for the discovery of alternative approaches to generating pluripotent stem cells. Combinatorial overexpression of a limited number of proteins linked to pluripotency in ESC was recently found to reprogram differentiated somatic cells back to a pluripotent state, enabling the derivation of isogenic (patient-specific) pluripotent stem cell lines. Current research is focusing on improving reprogramming protocols (e.g., circumventing the use of retroviral technology and oncoproteins), and on methods for differentiation into transplantable tissues of interest. In mouse ESC, we have previously shown that the embryonic morphogens BMP4 and Wnt3a direct blood formation via activation of Cdx and Hox genes. Ectopic expression of Cdx4 and HoxB4 enables the generation of mouse ESC-derived hematopoietic stem cells (HSC) capable of multilineage reconstitution of lethally irradiated adult mice. Here, we explore hematopoietic development from human induced pluripotent stem (iPS) cells generated in our laboratory. Our data show robust differentiation of iPS cells to mesoderm and to blood lineages, as shown by generation of CD34(+)CD45(+) cells, hematopoietic colony activity, and gene expression data, and suggest conservation of blood patterning pathways between mouse and human hematopoietic development.