Myocarditis Associated with Immune Checkpoint Inhibitors: An Expert Consensus on Data Gaps and a Call to Action.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for cancer. Due to the mechanism of action of ICIs, inflammatory reactions against normal tissue were an anticipated side effect of these agents; these immune-related adverse events have been documented and are typically low grade and manageable. Myocarditis has emerged as an uncommon but potentially life-threatening adverse reaction in patients treated with ICIs. Assessment and characterization of ICI-associated myocarditis is challenging because of its low incidence and protean manifestations. Nevertheless, the seriousness of ICI-associated myocarditis justifies a coordinated effort to increase awareness of this syndrome, identify patients who may be at risk, and enable early diagnosis and appropriate treatment. The "Checkpoint Inhibitor Safety Working Group," a multidisciplinary committee of academic, industry, and regulatory partners, convened at a workshop hosted by Project Data Sphere, LLC, on December 15, 2017. This meeting aimed to evaluate the current information on ICI-associated myocarditis, determine methods to collect and share data on this adverse reaction, and establish task forces to close the identified knowledge gaps. In this report, we summarize the workshop findings and proposed steps to address the impact of ICI-associated myocarditis in patients with cancer.

Tribute to Donald Metcalf.

A collection of tributes and remembrances from esteemed colleagues, mentees, and friends on the life and work of "the father of hematopoietic cytokines".

Editorial: Our top 10 developments in stem cell biology over the last 30 years.

To celebrate 30 years of peer-reviewed publication of cutting edge stem cell research in Stem Cells, the first journal devoted to this promising field, we pause to review how far we have come in the three-decade lifetime of the Journal. To do this, we will present our views of the 10 most significant developments that have advanced stem cell biology where it is today. With the increasing rate of new data, it is natural that the bulk of these developments would have occurred in recent years, but we must not think that stem cell biology is a young science. The idea of a stem cell has actually been around for quite a long time having appeared in the scientific literature as early as 1868 with Haeckels' concept of a stamzelle as an uncommitted or undifferentiated cell responsible for producing many types of new cells to repair the body [Naturliche Schopfungsgeschichte, 1868; Berlin: Georg Reimer] but it took many years to obtain hard evidence in support of this theory. Not until the work of James Till and Ernest McCulloch in the 1960s did we have proof of the existence of stem cells and until the derivation of embryonal carcinoma cells in the 1960s-1970s and the first embryonic stem cell in 1981, such adult or tissue-specific stem cells were the only known class. The first issue of Stem Cells was published in 1981; no small wonder that most of its papers were devoted to hematopoietic progenitors. More recently, induced pluripotent stem cells (iPSCs) have been developed, and this is proving to be a fertile area of investigation as shown by the volume of publications appearing not only in Stem Cells but also in other journals over the last 5 years. The reader will note that many of the articles in this special issue are concerned with iPSC; however, this reflects the current surge of interest in the topic rather than any deliberate attempt to ignore other areas of stem cell investigation.

A method to estimate the effect of deformable image registration uncertainties on daily dose mapping.

PURPOSE: To develop a statistical sampling procedure for spatially-correlated uncertainties in deformable image registration and then use it to demonstrate their effect on daily dose mapping. METHODS: Sequential daily CT studies are acquired to map anatomical variations prior to fractionated external beam radiotherapy. The CTs are deformably registered to the planning CT to obtain displacement vector fields (DVFs). The DVFs are used to accumulate the dose delivered each day onto the planning CT. Each DVF has spatially-correlated uncertainties associated with it. Principal components analysis (PCA) is applied to measured DVF error maps to produce decorrelated principal component modes of the errors. The modes are sampled independently and reconstructed to produce synthetic registration error maps. The synthetic error maps are convolved with dose mapped via deformable registration to model the resulting uncertainty in the dose mapping. The results are compared to the dose mapping uncertainty that would result from uncorrelated DVF errors that vary randomly from voxel to voxel. RESULTS: The error sampling method is shown to produce synthetic DVF error maps that are statistically indistinguishable from the observed error maps. Spatially-correlated DVF uncertainties modeled by our procedure produce patterns of dose mapping error that are different from that due to randomly distributed uncertainties. CONCLUSIONS: Deformable image registration uncertainties have complex spatial distributions. The authors have developed and tested a method to decorrelate the spatial uncertainties and make statistical samples of highly correlated error maps. The sample error maps can be used to investigate the effect of DVF uncertainties on daily dose mapping via deformable image registration. An initial demonstration of this methodology shows that dose mapping uncertainties can be sensitive to spatial patterns in the DVF uncertainties.

Optimized knot placement for B-splines in deformable image registration.

PURPOSE: To develop an automatic knot placement algorithm to enable the use of NonUniform Rational B-Splines (NURBS) in deformable image registration. METHODS: The authors developed a two-step approach to fit a known displacement vector field (DVF). An initial fit was made with uniform knot spacing. The error generated by this fit was then assigned as an attractive force pulling on the knots, acting against a resistive spring force in an iterative equilibration scheme. To demonstrate the accuracy gain of knot optimization over uniform knot placement, we compared the sum of the squared errors and the frequency of large errors. RESULTS: Fits were made to a one-dimensional DVF using 1-20 free knots. Given the same number of free knots, the optimized, nonuniform B-spline fit produced a smaller error than the uniform B-spline fit. The accuracy was improved by a mean factor of 4.02. The optimized B-spline was found to greatly reduce the number of errors more than 1 standard deviation from the mean error of the uniform fit. The uniform B-spline had 15 such errors, while the optimized B-spline had only two. The algorithm was extended to fit a two-dimensional DVF using control point grid sizes ranging from 8 x 8 to 15 x 15. Compared with uniform fits, the optimized B-spline fits were again found to reduce the sum of squared errors (mean ratio = 2.61) and number of large errors (mean ratio = 4.50). CONCLUSIONS: Nonuniform B-splines offer an attractive alternative to uniform B-splines in modeling the DVF. They carry forward the mathematical compactness of B-splines while simultaneously introducing new degrees of freedom. The increased adaptability of knot placement gained from the generalization to NURBS offers increased local control as well as the ability to explicitly represent topological discontinuities.

Reconstruction of brachytherapy seed positions and orientations from cone-beam CT x-ray projections via a novel iterative forward projection matching method.

PURPOSE: To generalize and experimentally validate a novel algorithm for reconstructing the 3D pose (position and orientation) of implanted brachytherapy seeds from a set of a few measured 2D cone-beam CT (CBCT) x-ray projections. METHODS: The iterative forward projection matching (IFPM) algorithm was generalized to reconstruct the 3D pose, as well as the centroid, of brachytherapy seeds from three to ten measured 2D projections. The gIFPM algorithm finds the set of seed poses that minimizes the sum-of-squared-difference of the pixel-by-pixel intensities between computed and measured autosegmented radiographic projections of the implant. Numerical simulations of clinically realistic brachytherapy seed configurations were performed to demonstrate the proof of principle. An in-house machined brachytherapy phantom, which supports precise specification of seed position and orientation at known values for simulated implant geometries, was used to experimentally validate this algorithm. The phantom was scanned on an ACUITY CBCT digital simulator over a full 660 sinogram projections. Three to ten x-ray images were selected from the full set of CBCT sinogram projections and postprocessed to create binary seed-only images. RESULTS: In the numerical simulations, seed reconstruction position and orientation errors were approximately 0.6 mm and 5 degrees, respectively. The physical phantom measurements demonstrated an absolute positional accuracy of (0.78 +/- 0.57) mm or less. The theta and phi angle errors were found to be (5.7 +/- 4.9) degrees and (6.0 +/- 4.1) degrees, respectively, or less when using three projections; with six projections, results were slightly better. The mean registration error was better than 1 mm/6 degrees compared to the measured seed projections. Each test trial converged in 10-20 iterations with computation time of 12-18 min/iteration on a 1 GHz processor. CONCLUSIONS: This work describes a novel, accurate, and completely automatic method for reconstructing seed orientations, as well as centroids, from a small number of radiographic projections, in support of intraoperative planning and adaptive replanning. Unlike standard back-projection methods, gIFPM avoids the need to match corresponding seed images on the projections. This algorithm also successfully reconstructs overlapping clustered and highly migrated seeds in the implant. The accuracy of better than 1 mm and 6 degrees demonstrates that gIFPM has the potential to support 2D Task Group 43 calculations in clinical practice.

Localizing intracavitary brachytherapy applicators from cone-beam CT x-ray projections via a novel iterative forward projection matching algorithm.

PURPOSE: To present a novel method for reconstructing the 3D pose (position and orientation) of radio-opaque applicators of known but arbitrary shape from a small set of 2D x-ray projections in support of intraoperative brachytherapy planning. METHODS: The generalized iterative forward projection matching (gIFPM) algorithm finds the six degree-of-freedom pose of an arbitrary rigid object by minimizing the sum-of-squared-intensity differences (SSQD) between the computed and experimentally acquired autosegmented projection of the objects. Starting with an initial estimate of the object's pose, gIFPM iteratively refines the pose parameters (3D position and three Euler angles) until the SSQD converges. The object, here specialized to a Fletcher-Weeks intracavitary brachytherapy (ICB) applicator, is represented by a fine mesh of discrete points derived from complex combinatorial geometric models of the actual applicators. Three pairs of computed and measured projection images with known imaging geometry are used. Projection images of an intrauterine tandem and colpostats were acquired from an ACUITY cone-beam CT digital simulator. An image postprocessing step was performed to create blurred binary applicators only images. To quantify gIFPM accuracy, the reconstructed 3D pose of the applicator model was forward projected and overlaid with the measured images and empirically calculated the nearest-neighbor applicator positional difference for each image pair. RESULTS: In the numerical simulations, the tandem and colpostats positions (x,y,z) and orientations (alpha, beta, gamma) were estimated with accuracies of 0.6 mm and 2 degrees, respectively. For experimentally acquired images of actual applicators, the residual 2D registration error was less than 1.8 mm for each image pair, corresponding to about 1 mm positioning accuracy at isocenter, with a total computation time of less than 1.5 min on a 1 GHz processor. CONCLUSIONS: This work describes a novel, accurate, fast, and completely automatic method to localize radio-opaque applicators of arbitrary shape from measured 2D x-ray projections. The results demonstrate approximately 1 mm accuracy while compared against the measured applicator projections. No lateral film is needed. By localizing the applicator internal structure as well as radioactive sources, the effect of intra-applicator and interapplicator attenuation can be included in the resultant dose calculations. Further validation tests using clinically acquired tandem and colpostats images will be performed for the accurate and robust applicator/sources localization in ICB patients.

4D Cone-beam CT reconstruction using a motion model based on principal component analysis.

PURPOSE: To provide a proof of concept validation of a novel 4D cone-beam CT (4DCBCT) reconstruction algorithm and to determine the best methods to train and optimize the algorithm. METHODS: The algorithm animates a patient fan-beam CT (FBCT) with a patient specific parametric motion model in order to generate a time series of deformed CTs (the reconstructed 4DCBCT) that track the motion of the patient anatomy on a voxel by voxel scale. The motion model is constrained by requiring that projections cast through the deformed CT time series match the projections of the raw patient 4DCBCT. The motion model uses a basis of eigenvectors that are generated via principal component analysis (PCA) of a training set of displacement vector fields (DVFs) that approximate patient motion. The eigenvectors are weighted by a parameterized function of the patient breathing trace recorded during 4DCBCT. The algorithm is demonstrated and tested via numerical simulation. RESULTS: The algorithm is shown to produce accurate reconstruction results for the most complicated simulated motion, in which voxels move with a pseudo-periodic pattern and relative phase shifts exist between voxels. The tests show that principal component eigenvectors trained on DVFs from a novel 2D/3D registration method give substantially better results than eigenvectors trained on DVFs obtained by conventionally registering 4DCBCT phases reconstructed via filtered backprojection. CONCLUSIONS: Proof of concept testing has validated the 4DCBCT reconstruction approach for the types of simulated data considered. In addition, the authors found the 2D/3D registration approach to be our best choice for generating the DVF training set, and the Nelder-Mead simplex algorithm the most robust optimization routine.

A neural network based 3D/3D image registration quality evaluator for the head-and-neck patient setup in the absence of a ground truth.

PURPOSE: To develop a neural network based registration quality evaluator (RQE) that can identify unsuccessful 3D/3D image registrations for the head-and-neck patient setup in radiotherapy. METHODS: A two-layer feed-forward neural network was used as a RQE to classify 3D/3D rigid registration solutions as successful or unsuccessful based on the features of the similarity surface near the point-of-solution. The supervised training and test data sets were generated by rigidly registering daily cone-beam CTs to the treatment planning fan-beam CTs of six patients with head-and-neck tumors. Two different similarity metrics (mutual information and mean-squared intensity difference) and two different types of image content (entire image versus bony landmarks) were used. The best solution for each registration pair was selected from 50 optimizing attempts that differed only by the initial transformation parameters. The distance from each individual solution to the best solution in the normalized parametrical space was compared to a user-defined error threshold to determine whether that solution was successful or not. The supervised training was then used to train the RQE. The performance of the RQE was evaluated using the test data set that consisted of registration results that were not used in training. RESULTS: The RQE constructed using the mutual information had very good performance when tested using the test data sets, yielding the sensitivity, the specificity, the positive predictive value, and the negative predictive value in the ranges of 0.960-1.000, 0.993-1.000, 0.983-1.000, and 0.909-1.000, respectively. Adding a RQE into a conventional 3D/3D image registration system incurs only about 10%-20% increase of the overall processing time. CONCLUSIONS: The authors' patient study has demonstrated very good performance of the proposed RQE when used with the mutual information in identifying unsuccessful 3D/3D registrations for daily patient setup. The classifier had very good generality and required only to be trained once for each implementation. When the RQE is incorporated with an automated 3D/3D image registration system, it can improve the robustness of the system.

Assessing the intrinsic precision of 3D/3D rigid image registration results for patient setup in the absence of a ground truth.

PURPOSE: To assess the precision and robustness of patient setup corrections computed from 3D/3D rigid registration methods using image intensity, when no ground truth validation is possible. METHODS: Fifteen pairs of male pelvic CTs were rigidly registered using four different in-house registration methods. Registration results were compared for different resolutions and image content by varying the image down-sampling ratio and by thresholding out soft tissue to isolate bony landmarks. Intrinsic registration precision was investigated by comparing the different methods and by reversing the source and the target roles of the two images being registered. RESULTS: The translational reversibility errors for successful registrations ranged from 0.0 to 1.69 mm. Rotations were less than 1 degrees. Mutual information failed in most registrations that used only bony landmarks. The magnitude of the reversibility error was strongly correlated with the success/ failure of each algorithm to find the global minimum. CONCLUSIONS: Rigid image registrations have an intrinsic uncertainty and robustness that depends on the imaging modality, the registration algorithm, the image resolution, and the image content. In the absence of an absolute ground truth, the variation in the shifts calculated by several different methods provides a useful estimate of that uncertainty. The difference observed by reversing the source and target images can be used as an indication of robust convergence.

Reconstruction of a cone-beam CT image via forward iterative projection matching.

PURPOSE: To demonstrate the feasibility of reconstructing a cone-beam CT (CBCT) image by deformably altering a prior fan-beam CT (FBCT) image such that it matches the anatomy portrayed in the CBCT projection data set. METHODS: A prior FBCT image of the patient is assumed to be available as a source image. A CBCT projection data set is obtained and used as a target image set. A parametrized deformation model is applied to the source FBCT image, digitally reconstructed radiographs (DRRs) that emulate the CBCT projection image geometry are calculated and compared to the target CBCT projection data, and the deformation model parameters are adjusted iteratively until the DRRs optimally match the CBCT projection data set. The resulting deformed FBCT image is hypothesized to be an accurate representation of the patient's anatomy imaged by the CBCT system. The process is demonstrated via numerical simulation. A known deformation is applied to a prior FBCT image and used to create a synthetic set of CBCT target projections. The iterative projection matching process is then applied to reconstruct the deformation represented in the synthetic target projections; the reconstructed deformation is then compared to the known deformation. The sensitivity of the process to the number of projections and the DRR/CBCT projection mismatch is explored by systematically adding noise to and perturbing the contrast of the target projections relative to the iterated source DRRs and by reducing the number of projections. RESULTS: When there is no noise or contrast mismatch in the CBCT projection images, a set of 64 projections allows the known deformed CT image to be reconstructed to within a nRMS error of 1% and the known deformation to within a nRMS error of 7%. A CT image nRMS error of less than 4% is maintained at noise levels up to 3% of the mean projection intensity, at which the deformation error is 13%. At 1% noise level, the number of projections can be reduced to 8 while maintaining CT image and deformation errors of less than 4% and 13%, respectively. The method is sensitive to contrast mismatch between the simulated projections and the target projections when the soft-tissue contrast in the projections is low. CONCLUSIONS: By using prior knowledge available in a FBCT image, the authors show that a CBCT image can be iteratively reconstructed from a comparatively small number of projection images, thus saving acquisition time and reducing imaging dose. This will enable more frequent daily imaging during radiation therapy. Because the process preserves the CT numbers of the FBCT image, the resulting 3D image intensities will be more accurate than a CBCT image reconstructed via conventional backprojection methods. Reconstruction errors are insensitive to noise at levels beyond what would typically be found in CBCT projection data, but are sensitive to contrast mismatch errors between the CBCT projection data and the DRRs.

A method to map errors in the deformable registration of 4DCT images.

PURPOSE: To present a new approach to the problem of estimating errors in deformable image registration (DIR) applied to sequential phases of a 4DCT data set. METHODS: A set of displacement vector fields (DVFs) are made by registering a sequence of 4DCT phases. The DVFs are assumed to display anatomical movement, with the addition of errors due to the imaging and registration processes. The positions of physical landmarks in each CT phase are measured as ground truth for the physical movement in the DVF. Principal component analysis of the DVFs and the landmarks is used to identify and separate the eigenmodes of physical movement from the error eigenmodes. By subtracting the physical modes from the principal components of the DVFs, the registration errors are exposed and reconstructed as DIR error maps. The method is demonstrated via a simple numerical model of 4DCT DVFs that combines breathing movement with simulated maps of spatially correlated DIR errors. RESULTS: The principal components of the simulated DVFs were observed to share the basic properties of principal components for actual 4DCT data. The simulated error maps were accurately recovered by the estimation method. CONCLUSIONS: Deformable image registration errors can have complex spatial distributions. Consequently, point-by-point landmark validation can give unrepresentative results that do not accurately reflect the registration uncertainties away from the landmarks. The authors are developing a method for mapping the complete spatial distribution of DIR errors using only a small number of ground truth validation landmarks.

Clinical application and validation of an iterative forward projection matching algorithm for permanent brachytherapy seed localization from conebeam-CT x-ray projections.

PURPOSE: To experimentally validate a new algorithm for reconstructing the 3D positions of implanted brachytherapy seeds from postoperatively acquired 2D conebeam-CT (CBCT) projection images. METHODS: The iterative forward projection matching (IFPM) algorithm finds the 3D seed geometry that minimizes the sum of the squared intensity differences between computed projections of an initial estimate of the seed configuration and radiographic projections of the implant. In-house machined phantoms, containing arrays of 12 and 72 seeds, respectively, are used to validate this method. Also, four 103Pd postimplant patients are scanned using an ACUITY digital simulator. Three to ten x-ray images are selected from the CBCT projection set and processed to create binary seed-only images. To quantify IFPM accuracy, the reconstructed seed positions are forward projected and overlaid on the measured seed images to find the nearest-neighbor distance between measured and computed seed positions for each image pair. Also, the estimated 3D seed coordinates are compared to known seed positions in the phantom and clinically obtained VariSeed planning coordinates for the patient data. RESULTS: For the phantom study, seed localization error is (0.58 +/- 0.33) mm. For all four patient cases, the mean registration error is better than 1 mm while compared against the measured seed projections. IFPM converges in 20-28 iterations, with a computation time of about 1.9-2.8 min/ iteration on a 1 GHz processor. CONCLUSIONS: The IFPM algorithm avoids the need to match corresponding seeds in each projection as required by standard back-projection methods. The authors' results demonstrate approximately 1 mm accuracy in reconstructing the 3D positions of brachytherapy seeds from the measured 2D projections. This algorithm also successfully localizes overlapping clustered and highly migrated seeds in the implant.

Development of a population-based model of surface segmentation uncertainties for uncertainty-weighted deformable image registrations.

PURPOSE: To develop a population-based model of surface segmentation uncertainties for uncertainty-weighted surface-based deformable registrations. METHODS: The contours of the prostate, the bladder, and the rectum were manually delineated by five observers on fan beam CT images of four prostate cancer patients. First, patient-specific representations of structure segmentation uncertainties were derived by determining the interobserver variability (i.e., standard deviation) of the structure boundary delineation. This was achieved by (1) generating an average structure surface mesh from the structure contours drawn by different observers, and (2) calculating three-dimensional standard deviation surface meshes (SDSMs) based on the perpendicular distances from the individual boundary surface meshes to the average surface mesh computed above. Then an average structure surface mesh was constructed to be the reference mesh for the population-based model. The average structure meshes of the other patients were deformably registered to the reference mesh. The calculated deformable vector fields were used to map the patient-specific SDSMs to the reference mesh to obtain the registered SDSMs. Finally, the population-based SDSM was derived by taking the average of the registered SDSMs in quadrature. RESULTS: Population-based structure surface statistical models of the prostate, the bladder, and the rectum were created by mapping the patient-specific SDSMs to the population surface model. Graphical visualization indicates that the boundary uncertainties are dependent on anatomical location. CONCLUSIONS: The authors have developed and demonstrated a general method for objectively constructing surface maps of uncertainties derived from topologically complex structure boundary segmentations from multiple observers. The computed boundary uncertainties have significant spatial variations. They can be used as weighting factors for surface-based probabilistic deformable registration.

Comparisons of multiple automated anatomy-based image-guidance methods for patient setup before head/neck external beam radiotherapy.

The purpose was to assess the variability in automated translational head/neck setup corrections computed from several different imaging modalities and rigid registration methods using patient anatomy. Shifts were calculated using three commercial and one in-house automated rigid registration methods for nine head/neck patients who were imaged with three different image-guidance systems. The mean difference between the daily isocenter shifts determined by the four methods ranged from 2.8 to 12.5 mm for all of the test cases.These differences are much greater than the variability observed for a rigid imaging phantom. Image-guided setup procedures have an uncertainty that depends on the imaging modality, the registration algorithm, the image resolution and the image content. In the absence of an absolute ground truth, the variation in the shifts calculated by several different methods provides a useful estimate of that uncertainty.