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  • 1
    Abstract: PURPOSE: The interactions of neoplastic cells with each other and the microenvironment are complex. To understand intratumoral heterogeneity, subtle differences should be quantified. Main factors contributing to heterogeneity include the gradient ischemic level within neoplasms, action of microenvironment, mechanisms of intercellular transfer of genetic information, and differential mechanisms of modifications of genetic material/proteins. This may reflect on the expression of biomarkers in the context of prognosis/stratification. Hence, a rigorous approach for assessing the spatial intratumoral heterogeneity of histological biomarker expression with accuracy and reproducibility is required, since patterns in immunohistochemical images can be challenging to identify and describe. METHODS: A quantitative method that is useful for characterizing complex irregular structures is lacunarity; it is a multiscale technique that exhaustively samples the image, while the decay of its index as a function of window size follows characteristic patterns for different spatial arrangements. In histological images, lacunarity provides a useful measure for the spatial organization of a biomarker when a sampling scheme is employed and relevant features are computed. The proposed approach quantifies the segmented proliferative cells and not the textural content of the histological slide, thus providing a more realistic measure of heterogeneity within the sample space of the tumor region. The aim is to investigate in whole sections of primary pancreatic neuroendocrine neoplasms (pNENs), using whole-slide imaging and image analysis, the spatial intratumoral heterogeneity of Ki-67 immunostains. Unsupervised learning is employed to verify that the approach can partition the tissue sections according to distributional heterogeneity. RESULTS: The architectural complexity of histological images has shown that single measurements are often insufficient. Inhomogeneity of distribution depends not only on percentage content of proliferation phase but also on how the phase fills the space. Lacunarity curves demonstrate variations in the sampled image sections. Since the spatial distribution of proliferation in each case is different, the width of the curves changes too. Image sections that have smaller numerical variations in the computed features correspond to neoplasms with spatially homogeneous proliferation, while larger variations correspond to cases where proliferation shows various degrees of clumping. Grade 1 (uniform/nonuniform: 74%/26%) and grade 3 (uniform: 100%) pNENs demonstrate a more homogeneous proliferation with grade 1 neoplasms being more variant, while grade 2 tumor regions render a more diverse landscape (50%/50%). Hence, some cases show an increased degree of spatial heterogeneity comparing to others with similar grade. Whether this is a sign of different tumor biology and an association with a more benign/malignant clinical course needs to be investigated further. The extent and range of spatial heterogeneity has the potential to be evaluated as a prognostic marker. CONCLUSIONS: The association with tumor grade as well as the rationale that the methodology reflects true tumor architecture supports the technical soundness of the method. This reflects a general approach which is relevant to other solid tumors and biomarkers. Drawing upon the merits of computational biomedicine, the approach uncovers salient features for use in future studies of clinical relevance.
    Type of Publication: Journal article published
    PubMed ID: 27277043
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    Abstract: PURPOSE: Dynamic CT perfusion (CTP) consists in repeated acquisitions of the same volume in different time steps, slightly before, during and slightly afterwards the injection of contrast media. Important functional information can be derived for each voxel, which reflect the local hemodynamic properties and hence the metabolism of the tissue. Different approaches are being investigated to exploit data redundancy and prior knowledge for noise reduction of such datasets, ranging from iterative reconstruction schemes to high dimensional filters. METHODS: We propose a new spatial bilateral filter which makes use of the k-means clustering algorithm and of an optimal calculated guiding image. We named the proposed filter as k-means clustering guided bilateral filter (KMGB). In this study, the KMGB filter is compared with the partial temporal non-local means filter (PATEN), with the time-intensity profile similarity (TIPS) filter, and with a new version derived from it, by introducing the guiding image (GB-TIPS). All the filters were tested on a digital in-house developed brain CTP phantom, were noise was added to simulate 80 kV and 200 mAs (default scanning parameters), 100 mAs and 30 mAs. Moreover, the filters performances were tested on 7 noisy clinical datasets with different pathologies in different body regions. The original contribution of our work is two-fold: first we propose an efficient algorithm to calculate a guiding image to improve the results of the TIPS filter, secondly we propose the introduction of the k-means clustering step and demonstrate how this can potentially replace the TIPS part of the filter obtaining better results at lower computational efforts. RESULTS: As expected, in the GB-TIPS, the introduction of the guiding image limits the over-smoothing of the TIPS filter, improving spatial resolution by more than 50%. Furthermore, replacing the time-intensity profile similarity calculation with a fuzzy k-means clustering strategy (KMGB) allows to control the edge preserving features of the filter, resulting in improved spatial resolution and CNR both for CT images and for functional maps. In the phantom study, the PATEN filter showed overall the poorest results, while the other filters showed comparable performances in terms of perfusion values preservation, with the KMGB filter having overall the best image quality. CONCLUSION: In conclusion, the KMGB filter leads to superior results for CT images and functional maps quality improvement, in significantly shorter computational times compared to the other filters. Our results suggest that the KMGB filter might be a more robust solution for halved-dose CTP datasets. For all the filters investigated, some artifacts start to appear on the BF maps if one sixth of the dose is simulated, suggesting that no one of the filters investigated in this study might be optimal for such a drastic dose reduction scenario.
    Type of Publication: Journal article published
    PubMed ID: 28437011
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    Abstract: PURPOSE: Range uncertainties limit the potential of charged particle therapy. In vivo and online range verification techniques could increase the confidence in the dose delivery distribution and lead to more conformal treatments. Prompt gamma imaging and prompt gamma spectroscopy (PGS) have been demonstrated for such a purpose. The successful application of these techniques requires the development of a dedicated detector system optimized to the radiation energy ranges and the intensity. In this work, we investigated a detector system based on CeBr3 crystals capable of performing spectroscopy of the prompt gamma radiation induced by (4) He beams. METHODS: We performed Monte Carlo simulations to optimize the detector system. The study was carried out both with the Geant4 toolkit and the FLUKA package. The simulated system consisted of a primary crystal for spectroscopy and secondary crystals for noise reduction in anticoincidence (AC). For comparison purposes, we considered a configuration without AC crystals. We first defined the dimensions of the primary cerium bromide (CeBr3 ) crystal and the secondary bismuth germanate (BGO) or CeBr3 crystals. We then evaluated their detection performance for monoenergetic gamma radiation up to 7 MeV in such way that the probability of the photo-peak detection was maximized in comparison to the number of escape peak and Compton events. We simulated realistic prompt gamma radiation spectra induced by (4) He beams on homogeneous targets (water, graphite, and aluminum) and on implants (water with an aluminum insert). Finally, we tested the performances of the optimized systems in the detection of the realistic gamma spectra. The quantitative analysis was accomplished by comparing the signal-to-noise ratio between the different configurations and the ability to resolve the discrete reactions. RESULTS: We present the optimized dimensions for the primary CeBr3 crystals with and without AC shielding. The specific values are given over a wide range of crystal volumes. The results show an optimal primary CeBr3 crystal with an approximately diameter to length ratio of 1 without AC shielding and 0.5 with AC shielding. The secondary BGO and CeBr3 should have a transverse dimension of 3 and 4.56 cm, respectively. The analysis of the prompt gamma spectra from (4) He beams highlighted the presence of specific discrete reactions not observed in (1) H studies, for example, (12) C transition 0(+) (7.65 MeV) --〉2(+) (4.44 MeV). This reaction is responsible for the generation of the 3.21 MeV prompt gamma peak. The optimized primary crystal provides a significant increase in the signal-to-noise ratio together with an improved resolution of the discrete gamma lines, especially in the high-energy region. The detection configuration with an optimized anticoincidence crystal improved the signal-to-noise ratio up to a factor of 3.5. CONCLUSIONS: This work provides the optimal geometry for primary and secondary crystals to be used in range verification through PGS. The simulations show that such a PGS system may allow for the simultaneous detection of the discrete lines from a thin metal implant within a water phantom.
    Type of Publication: Journal article published
    PubMed ID: 29411400
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  • 6
    Abstract: PURPOSE: To investigate the extent of MR image distortions in the pelvis caused by susceptibility-induced field inhomogeneities in MR images in the context of a study on MR-guided radiotherapy. METHODS: Using a high-bandwidth double-echo gradient echo sequence, field maps and distortion maps of the pelvis were calculated and evaluated for 219 exams (92 of female and 127 of male patients) to investigate patient-related image distortions caused by susceptibility differences in an ongoing study on MR-guided radiotherapy. The evaluation of distortions in the regions "rectum", "prostate", "cervix", and in a reference region in the gluteus maximus was based on masks drawn by two readers. RESULTS: Distortions in the prostate and cervix were smaller than 0.03 px (0.1 mm) for 99% of voxels, and reached a maximum value of 0.09 px (0.3 mm). In the reference region, maximum distortions were smaller than in the prostate and cervix. CONCLUSIONS: Using a geometric uncertainty of 0.2 px (0.6 mm) in margin definition for organs that are close to the rectum like the prostate and the cervix would be a cautious choice to account for susceptibility-induced distortions that can arise during MR-based treatment guidance for the imaging setting used in this study. Since distortions are inversely proportional to the readout bandwidth of the sequence, safety margins need to be adapted adequately. Additional sources of image distortions like gradient nonlinearities are not included in our margin recommendations and should be considered separately.
    Type of Publication: Journal article published
    PubMed ID: 29394448
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  • 7
    Abstract: PURPOSE: We show that it is possible to explicitly incorporate fractionation effects into closed-form probabilistic treatment plan analysis and optimization for intensity-modulated proton therapy with analytical probabilistic modeling (APM). We study the impact of different fractionation schemes on the dosimetric uncertainty induced by random and systematic sources of range and setup uncertainty for treatment plans that were optimized with and without consideration of the number of treatment fractions. METHODS: The APM framework is capable of handling arbitrarily correlated uncertainty models including systematic and random errors in the context of fractionation. On this basis, we construct an analytical dose variance computation pipeline that explicitly considers the number of treatment fractions for uncertainty quantitation and minimization during treatment planning. We evaluate the variance computation model in comparison to random sampling of 100 treatments for conventional and probabilistic treatment plans under different fractionation schemes (1, 5, 30 fractions) for an intracranial, a paraspinal and a prostate case. The impact of neglecting the fractionation scheme during treatment planning is investigated by applying treatment plans that were generated with probabilistic optimization for 1 fraction in a higher number of fractions and comparing them to the probabilistic plans optimized under explicit consideration of the number of fractions. RESULTS: APM enables the construction of an analytical variance computation model for dose uncertainty considering fractionation at negligible computational overhead. It is computationally feasible (a) to simultaneously perform a robustness analysis for all possible fraction numbers and (b) to perform a probabilistic treatment plan optimization for a specific fraction number. The incorporation of fractionation assumptions for robustness analysis exposes a dose to uncertainty trade-off, i.e., the dose in the organs at risk is increased for a reduced fraction number and/or for more robust treatment plans. By explicit consideration of fractionation effects during planning, we demonstrate that it is possible to exploit this trade-off during optimization. APM optimization considering the fraction number reduced the dose in organs at risk compared to conventional probabilistic optimization neglecting the fraction number. CONCLUSION: APM enables computationally efficient incorporation of fractionation effects in probabilistic uncertainty analysis and probabilistic treatment plan optimization. The consideration of the fractionation scheme in probabilistic treatment planning reveals the trade-off between number of fractions, nominal dose, and treatment plan robustness.
    Type of Publication: Journal article published
    PubMed ID: 29393506
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    Abstract: PURPOSE: To evaluate the accuracy of relative stopping power and spatial resolution of images reconstructed with simulated helium CT (HeCT) in comparison to proton CT (pCT). METHODS: A Monte Carlo (MC) study with the TOPAS tool was performed to compare the accuracy of relative stopping power (RSP) reconstruction and spatial resolution of low-fluence HeCT to pCT, both using 200 MeV/u particles. An ideal setup consisting of a flat beam source and a totally absorbing energy-range detector was implemented to estimate the theoretically best achievable RSP accuracy for the calibration and reconstruction methods currently used for pCT. The phantoms imaged included a cylindrical water phantom with inserts of different materials, sizes, and positions, a Catphan phantom with a module containing high-contrast line pairs (CTP528) and a module with cylindrical inserts of different RSP (CTP404), as well as a voxelized 10-year-old female phantom. Dose to the cylindrical water phantom was also calculated. The RSP accuracy was studied for all phantoms except the CTP528 module. The latter was used for the estimation of the spatial resolution, evaluated as the modulation transfer function (MTF) at 10%. RESULTS: An overall error under 0.5% was achieved for HeCT for the water phantoms with the different inserts, in all cases better than that for pCT, in some cases by a factor 3. The inserts in the CTP404 module were reconstructed with an average RSP accuracy of 0.3% for HeCT and 0.2% for pCT. Anatomic structures (brain, bones, air cavities, etc.) in the digitized head phantom were well recognizable and no artifacts were visible with both HeCT and pCT. The three main tissue materials (soft tissue, brain, and cranium) were well identifiable in the reconstructed RSP-volume distribution with both imaging modalities. Using 360 projection angles, the spatial resolution was 4 lp/cm for HeCT and 3 lp/cm for pCT. Generally, spatial resolution increased with the number of projection angles and was always higher for HeCT than for pCT for the same number of projections. When HeCT and pCT scan were performed to deliver the same dose in the phantom, the resolution for HeCT was higher than pCT. CONCLUSION: MC simulations were used to compare HeCT and pCT image reconstruction. HeCT images had similar or better RSP accuracy and higher spatial resolution compared to pCT. Further investigation of the potential of helium ion imaging is warranted.
    Type of Publication: Journal article published
    PubMed ID: 29727481
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  • 10
    Abstract: PURPOSE: In this work, a combined body coil array with eight transmit/receive (Tx/Rx) meander elements and with 24 receive-only (Rx) loops (8Tx/32Rx) was developed and evaluated in comparison with an 8-channel transmit/receive body array (8Tx/Rx) based on meander elements serving as the reference standard. METHODS: Systematic evaluation of the RF array was performed on a body-sized phantom. Body imaging at 7T was performed in six volunteers in the body regions pelvis, abdomen, and heart. Coil characteristics such as signal-to-noise ratio, acceleration capability, g-factors, S-parameters, noise correlation, and B1+ maps were assessed. Safety was ensured by numerical simulations using a coil model validated by dosimetric field measurements. RESULTS: Meander elements and loops are intrinsically well decoupled with a maximum coupling value of -20.5 dB. Safe use of the 8Tx/32Rx array could be demonstrated. High gain in signal-to-noise ratio (33% in the subject's center) could be shown for the 8Tx/32Rx array compared to the 8Tx/Rx array. Improvement in acceleration capability in all investigations could be demonstrated. For example, the 8Tx/32Rx array provides lower g-factors in the right-left and anterior-posterior directions with R = 3 undersampling as compared to the 8Tx/Rx array using R = 2. Both arrays are very similar regarding their RF transmit performance. Excellent image quality in the investigated body regions could be achieved with the 8Tx/32Rx array. CONCLUSION: In this work, we show that a combination of eight meander elements and 24 loop receive elements is possible without impeding transmit performance. Improved SNR and g-factor performance compared to an RF array without these loops is demonstrated. Body MRI at 7T with the 8Tx/32Rx array could be accomplished in the heart, abdomen, and pelvis with excellent image quality.
    Type of Publication: Journal article published
    PubMed ID: 29679498
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