Marian Axente

Clinical evaluation of the iterative metal artifact reduction algorithm for CT simulation in radiotherapy

PURPOSE To clinically evaluate an iterative metal artifact reduction (IMAR) algorithm prototype in the radiation oncology clinic setting by testing for accuracy in CT number retrieval, relative dosimetric changes in regions affected by artifacts, and improvements in anatomical and shape conspicuity of corrected images. METHODS A phantom with known material inserts was scanned in the presence/absence of metal with different configurations of placement and sizes. The relative change in CT numbers from the reference data (CT with no metal) was analyzed. The CT studies were also used for dosimetric tests where dose distributions from both photon and proton beams were calculated. Dose differences and gamma analysis were calculated to quantify the relative changes between doses calculated on the different CT studies. Data from eight patients (all different treatment sites) were also used to quantify the differences between dose distributions before and after correction with IMAR, with no reference standard. A ranking experiment was also conducted to analyze the relative confidence of physicians delineating anatomy in the near vicinity of the metal implants. RESULTS IMAR corrected images proved to accurately retrieve CT numbers in the phantom study, independent of metal insert configuration, size of the metal, and acquisition energy. For plastic water, the mean difference between corrected images and reference images was -1.3 HU across all scenarios (N = 37) with a 90% confidence interval of [-2.4, -0.2] HU. While deviations were relatively higher in images with more metal content, IMAR was able to effectively correct the CT numbers independent of the quantity of metal. Residual errors in the CT numbers as well as some induced by the correction algorithm were found in the IMAR corrected images. However, the dose distributions calculated on IMAR corrected images were closer to the reference data in phantom studies. Relative spatial difference in the dose distributions in the regions affected by the metal artifacts was also observed in patient data. However, in absence of a reference ground truth (CT set without metal inserts), these differences should not be interpreted as improvement/deterioration of the accuracy of calculated dose. With limited data presented, it was observed that proton dosimetry was affected more than photons as expected. Physicians were significantly more confident contouring anatomy in the regions affected by artifacts. While site specific preferences were detected, all indicated that they would consistently use IMAR corrected images. CONCLUSIONS IMAR correction algorithm could be readily implemented in an existing clinical workflow upon commercial release. While residual errors still exist in IMAR corrected images, these images present with better overall conspicuity of the patient/phantom geometry and offer more accurate CT numbers for improved local dosimetry. The variety of different scenarios included herein attest to the utility of the evaluated IMAR for a wide range of radiotherapy clinical scenarios.

High-Resolution Radioluminescence Microscopy of 18F-FDG Uptake by Reconstructing the β-Ionization Track

Radioluminescence microscopy is a new method for imaging radionuclide uptake by single live cells with a fluorescence microscope. Here, we report a particle-counting scheme that improves spatial resolution by overcoming the β-range limit. Methods: Short frames (10 μs−1 s) were acquired using a high-gain camera coupled to a microscope to capture individual ionization tracks. Optical reconstruction of the β-ionization track (ORBIT) was performed to localize individual β decays, which were aggregated into a composite image. The new approach was evaluated by imaging the uptake of 18F-FDG in nonconfluent breast cancer cells. Results: After image reconstruction, ORBIT resulted in better definition of individual cells. This effect was particularly noticeable in small clusters (2–4 cells), which occur naturally even for nonconfluent cell cultures. The annihilation and Bremsstrahlung photon background signal was markedly lower. Single-cell measurements of 18F-FDG uptake that were computed from ORBIT images more closely matched the uptake of the fluorescent glucose analog (Pearson correlation coefficient, 0.54 vs. 0.44, respectively). Conclusion: ORBIT can image the uptake of a radiotracer in living cells with spatial resolution better than the β range. In principle, ORBIT may also allow for greater quantitative accuracy because the decay rate is measured more directly, with no dependency on the β-particle energy.

Comprehensive Approach to Coregistration of Autoradiography and Microscopy Images Acquired from a Set of Sequential Tissue Sections

Histopathologic validation of a PET tracer requires assessment of colocalization of the tracer with its intended biologic target. Using thin tissue section autoradiography, it is possible to visualize the spatial distribution of the PET tracer uptake and compare it with the distribution of the intended biologic target (as visualized with immunohistochemistry). The purpose of this study was to develop and evaluate an objective methodology for deformable coregistration of autoradiography and microscopy images acquired from a set of sequential tissue sections. Methods: Tumor-bearing animals were injected with 3′-deoxy-3′-18F-fluorothymidine (18F-FLT), 14C-FDG, and other markers of tumor microenvironment including Hoechst 33342 (blood-flow surrogate). After sacrifice, tumors were excised, frozen, and sectioned. Multiple stacks of sequential 8 μm sections were collected from each tumor. From each stack, the middle (reference) sections were used to obtain images of 18F-FLT and 14C-FDG uptake distributions using dual-tracer autoradiography. Sections adjacent to the reference were used to acquire all histopathologic data (e.g., images of cell proliferation, hematoxylin and eosin). Hoechst images were acquired from all sections. To correct for deformations and misalignments induced by tissue processing and image acquisition, the Hoechst image of each nonreference section was deformably registered to the reference Hoechst image. This transformation was then applied to all images acquired from the same tissue section. In this way, all microscopy images were registered to the reference Hoechst image. The Hoechst-to-autoradiography image registration was done using rigid point-set registration based on external markers visible in both images. Results: The mean error of Hoechst to 18F-FLT autoradiography registration (both images acquired from the same section) was 30.8 ± 20.1 μm. The error of Hoechst-based deformable registration of histopathologic images (acquired from sequential tissue sections) was 23.1 ± 17.9 μm. Total error of registration of autoradiography images to the histopathologic images acquired from adjacent sections was evaluated at 44.9 μm. This coregistration precision supersedes current rigid registration methods with reported errors of 100–200 μm. Conclusion: Deformable registration of autoradiography and histopathology images acquired from sequential sections is feasible and accurate when performed using corresponding Hoechst images.

An alternative approach to histopathological validation of PET imaging for radiation therapy image-guidance: A proof of concept

PURPOSE In radiotherapy, PET images can be used to guide the delivery of selectively escalated doses to biologically relevant tumour subvolumes. Validation of PET for such applications requires demonstration of spatial coincidence between PET tracer uptake pattern and the histopathologically confirmed target. This study introduces a novel approach to histopathological validation of PET image segmentation for radiotherapy guidance. METHODS AND MATERIALS Sequential tissue sections from surgically excised whole-tumour specimens were used to acquire full 3D-sets of both histopathological images (microscopy) and PET tracer distribution images (autoradiography). After these datasets were accurately registered, a full 3D autoradiographic distribution of PET tracer was reconstructed and used to obtain synthetic PET images (sPET) by simulating the image deterioration induced by processes involved in PET image formation. To illustrate the method, sPET images were used in this study to investigate spatial coincidence between high FDG uptake areas and the distribution of viable tissue in two small animal tumour models. RESULTS The reconstructed 3D autoradiographic distribution of the PET tracer was spatially coherent, as indicated by the high average value of the normalised pixel-by-pixel correlation of intensities between successive slices (0.84 ± 0.05 and 0.94 ± 0.02). The loss of detail in the sPET images versus the 3D autoradiography was significant as indicated by Dice coefficient values corresponding to the two tumours (0 and 0.1 at 70% threshold). The maximum overlap between the FDG segmented volumes and the extent of the viable tissue as indicated by Dice coefficient values, was 0.8 for one tumour (for the image thresholded at 22% of max intensity) and 0.88 for the other (threshold of 14% of max intensity). CONCLUSION It was demonstrated that the use of synthetic PET images for histopathological validation allows for bypassing a technically challenging and error-prone step of registering non-invasive PET images with histopathology.

On autoradiographic studies comparing the distributions of 18F- and 14C-labeled compounds in tumor tissue specimens

To the Editor, We read with great interest the paper by Christian et al. [1] where the authors studied the degree of concordance between the spatial patterns of F-FDG and C-EF3 uptake in SCCVII and FSAII tumors using the dice similarity index. Although the study was meticulously performed, there are several concerns with the methodology that we believe are worth mentioning herein. The authors state they used 1 mm-thick slab of tissue to perform F-FDG and C-EF3 autoradiography. To selectively image F-FDG uptake, a layer of plastic was inserted between the tissue and the phosphor plate. This layer was sufficiently thick to block the low-energy electrons emitted by C (maximum energy 156 keV, range 0.28 mm), while allowing higher energy positrons emitted by F to penetrate. Since the maximum range of b emitted by F is 2 mm (maximum energy 634 keV), the F autoradiographic image is formed by the positrons emitted by F-FDG trapped throughout the whole 1 mm-thick slab of tissue, as was also observed in another study by Christian et al. [2]. Following complete decay of F, C-EF3 autoradiography was performed. In this case, due to the low penetrating power of C-emissions, only the electrons emanating from a very thin layer of tissue closest to the phosphor plate contribute to the image. These differences between C and F autoradiography result in a substantial reduction in the physical resolution of F-FDG autoradiograms relative to that of C-EF3 autoradiograms. As was previously demonstrated by a very insightful paper published earlier by the same group [3], such a loss of resolution results in a significant reduction of the dice similarity index, even when imaging the same underlying tracer distribution. Most importantly, the chaotic nature of tumor morphology ought to be taken into account. Tumors, unlike normal tissue, are characterized by a very irregular vasculature and highly heterogeneous microenvironment with a typical feature size of 100– 200 lm [4,5]. Therefore, throughout 1 mm of tissue thickness, the oxygenation status can easily change from normoxic to hypoxic and back. The layer of tissue located 1 mm away from the phosphor plate can potentially be characterized by the microenvironmental and oxygenation patterns completely different from those in the layer of tissue closest to the phosphor plate. Therefore, we conclude that the poor dice similarity index reported in the paper may be as much a consequence of the ambiguity of the radiotracer distribution, resulting from thick section autoradiography, as the spatial discrepancies between the F-FDG and C-EF3 microdistributions. It is for these reasons we suggest utilizing thin tissue sections (20 lm or thinner) for the correlative studies utilizing autoradiography for visualization of F-labeled tracer distribution in tumor tissue. Also, we believe that for dual tracer autoradiography it is better to avoid using additional layers of blocking material and rely on the differences in physical half lives of the isotopes instead. In this way it is possible to minimize the bias that can be induced by both the differential loss of image resolution and the chaotic nature of tumor microenvironment.

Single-fraction simulation of relative cell survival in response to uniform versus hypoxia-targeted dose escalation

The purpose of this study was to investigate the increase in cell kill that can be achieved by tumor irradiation with heterogeneous dose distributions targeting hypoxic regions that can be visualized with non-invasive imaging. Starting with a heterogeneous distribution of microvessels, a microscopic two-dimensional model of tumor oxygenation was developed using planar simulation of oxygen diffusion. Non-invasive imaging of hypoxia was simulated taking partial volume effect into account. A dose-modulation scheme was implemented with the goal of delivering higher doses to the hypoxic pixels, as seen in simulated hypoxia images. To determine the relative cell kill in response to hypoxia-targeting irradiation, tumor cell survival fractions were compared to those resulting from treatments delivering the same average dose to the lesion in a spatially uniform fashion. It was shown that hypoxia-targeting dose modulation may be better suited for tumors with low α/β, low hypoxic fraction and spatially aggregated hypoxic features. Most importantly, it was determined that at low fraction doses there is no cell kill increase from targeting hypoxic regions alone versus escalating the total tumor dose. However, for higher doses per fraction (≥8 Gy/fraction), the effectiveness of hypoxia-targeting irradiation increases, resulting in the tumoricidal effect of up to 30% higher than that of uniform tumor irradiation delivering the same average tumor dose.

Imaging dose in variable pitch body perfusion CT scans: an analysis using TG111 formalism.

PURPOSE To investigate the variation of imaging dose with tube potential in variable pitch body CT perfusion (CTp) protocols using the TG111 dosimetric formalism. METHODS TG111 recommendations were followed in choosing the phantom, dosimetric equipment, and methodology. Specifically, equilibrium doses (D(eq)) were measured centrally and peripherally in a long PMMA phantom. Reference planar average equilibrium doses were determined for each tube potential, for a reference set of exposure parameters (collimation, pitch, filtration) on a Siemens Definition CT scanner. These reference values were utilized to predict the imaging dose during perfusion scans using interpretations of the TG111 formalism. As a gold reference, the midscan average planar perfusion doses (D(CTp)) were obtained directly from central and peripheral D(eq) measurements for body CTp scans (144 and 271 mm) using variable pitch acquisition. Measurement-based D(CTp) values obtained using a thimble chamber were compared to the TG111-predicted values, and to CTDI(vol) reported at the console. RESULTS Reference planar average equilibrium dose values measured for reference uniform pitch helical scans were consistently higher than console-reported or measured values for CTDI(vol). The measurement-based perfusion dose D(CTp) was predicted accurately by the reported CTDI(vol) for the 144 mm scan. The 271 mm scans delivered systematically larger dose than reported. The TG111-based dose estimates were proven to be conservative, as they were systematically higher than both the measured and the reported imaging doses. CONCLUSIONS Upon successful implementation of TG111 formalism, standard imaging dose was measured for a body CTp protocol using the variable pitch helical acquisition. The TG111 formalism is not directly applicable to this type of acquisition. Measurement of dose for all variable pitch protocols is strongly suggested.

TU‐E‐141‐07: Clinical Evaluation of the Iterative Metal Artifact Reduction Algorithm for CT Simulation in Radiotherapy

PURPOSE The iterative metal artifact reduction (IMAR) algorithm has been proposed for commercial implementation in upcoming Siemens platforms. The purpose of this study is to evaluate the performance of this algorithm in radiation oncology settings. METHODS Mean CT numbers and noise (standard-deviation) within delineated regions of interest were compared before/after IMAR correction on standard electron-density phantom images. Patient IMAR-corrected images were evaluated by 4 observers and ranked based on conspicuity of structures near artifacts (0-5 scale, 5 best score). The dosimetric impact of utilizing IMAR-corrected patient images for planning was analyzed by comparing original dose distributions and those recalculated on IMAR-corrected images. All images were acquired on a Siemens Definition scanner. In order to reference the observations herein, all analyses were also conducted on images corrected with a second algorithm: metal deletion technique (MDT), available for public use. RESULTS IMAR accurately recovers CT numbers. CT number percent differences were reduced on average from 62% to 18%, while average noise percent differences were minimally reduced (146% before, 140% after). MDT performed worse retrieving mean CT numbers (62% to 27%), and better at reducing noise (146% to 24%). After visually inspecting the images, physicians agreed that IMAR-corrected images offered better confidence at reading patient anatomy than original images. The MDT-corrected images scored 4.3 on average while IMAR-corrected images scored 4 with reviewing physicians (p = 0.052). Local dose differences up to ±20-30cGy were noted, but γ-analysis (3%/3mm) did not indicate major overall differences between plans calculated on original images and those calculated on IMAR-corrected images. CONCLUSION The IMAR algorithm accurately recovered CT numbers (better than MDT), while minimally reducing noise values (worse than MDT). No clinically significant differences were detected between dose distributions calculated on original CT images and those planned on IMAR-corrected images. Initial analysis indicates that IMAR images could be used for treatment planning. Siemens Healthcare.

WE‐E‐108‐11: PET‐Guided Selective Dose Escalation for a Small Animal Tumor Model

PURPOSE To develop methods for pre-clinical validation of PET image-guided selective dose escalation in IMRT treatment using the Small Animal Radiation Research Platform (SARRP, Xstrahl). METHODS Nude mice bearing subcutaneous FaDu human head and neck tumor xenografts were imaged with 18F-FDG using a Siemens Inveon PET/CT. The PET image was used to create an image-guided radiation treatment plan treating the entirety of the tumor with a 10Gy uniform radiation dose while sparing as much normal tissue as possible using a 15mm collimator. A dose escalation of 10 Gy was planned to treat the volume of highest FDG uptake within the tumor. To ensure localized dose distribution, the boost was to be delivered using dynamic arc techniques with a 5mm collimator. The isocenters for both fields were recorded on the planning PET image. The following day, the animals were anaesthetized, positioned in the SARRP irradiator, and imaged using on-board cone-beam to obtain an image in the treatment position. The planning CT was then deformably registered to the treatment CT using the BRAINSFit b-spline algorithm in SLICER 3D. Finally, the transform was applied to the planning PET and isocenters for the treatment fields were transferred to the treatment CT while the animal was still under anesthesia. The animal was then irradiated according to the original PET/CT-guided treatment plan. RESULTS SARRP allows for selective dose escalation treatments to small animal tumor models. In this study a subcutaneously grown tumor of 12mm in diameter was irradiated to 10Gy. The volume of the tumor characterized by increased FDG uptake received an additional 10Gy in the form of a 5mm-diameter boost delivered with non-coplanar arc field. CONCLUSION The Small Animal Radiation Research Platform (SARRP) combined with a dedicated small animal PET/CT scanner enables pre-clinical validation of PET image-guided selective dose escalation in IMRT treatment.

TH‐E‐BRA‐02: A Novel Approach to Histopathological Validation of PET Tracers for Image Guidance in Radiotherapy

Purpose: It has been proposed that PETimages can be used to guide the delivery of selectively escalated doses to biologically‐relevant tumor subvolumes. Histopathological validation of PETimaging is challenging due to difficulties associated with precise registration of non‐invasive in‐vivo images to histopathological ex‐vivo images. The aim of this study is to develop an alternative method of PETimaging validation for image‐guidance applications. The method is applied to evaluation of the feasibility of FDG PET‐based delineation of viable tissue in animaltumormodels.Methods: Tumor‐bearing mice were injected with 14C‐FDG. Whole‐tumor specimens were sectioned, obtaining 8μm thick sections every 120μm throughout the tumor. These sections were used to obtain 14C‐FDG autoradiography and H&E microscopy images. Viable tumortissue was delineated on each H&E image. Based on sequential digital photography images of the tissue block acquired during sectioning, the true 3D distributions of 14C‐FDG and viable tissue were reconstituted. To simulate generation of a PETimage, the 3D activity map was convolved with a 3D point‐spread‐function of Siemens Inveon small‐animal PET scanner. Threshold‐based analysis was used to evaluate the degree of coincidence between the areas of high FDG uptake in the simulated PETimage and 3D distribution of viable tissue.Results: Averaging effects associated with PETimaging altered the true 3D spatial pattern of FDG intratumoral uptake. ROC analysis indicated good sensitivity of FDG PETimage‐segmentation for the detection of the viable tissue (AUC = 0.74). However, the specificity was low, as indicated by the low threshold value at which the maximum overlap occurred (22% of maximum uptake). Conclusion: A novel method of histopathological validation of PETimaging for image‐guidance in radiotherapy was developed. Using this method, it was demonstrated that for the tumors with high viable tissue content, FDG‐thresholding can be used for viable tissue detection.