In recent years, a wide range of cancer immunotherapies have been developed and have become increasingly important in cancer treatment across multiple oncologic diseases. In particular, immune ...checkpoint inhibitors (ICIs) offer promising options to improve patient outcomes. However, a major limitation of these treatments consists in the development of immune-related adverse events (irAEs) occurring in potentially any organ system and affecting up to 76% of the patients. The most frequent toxicities involve the skin, gastrointestinal tract, and endocrine system. Although mostly manageable, potentially life-threatening events, particularly due to neuro-, cardiac, and pulmonary toxicity, occur in up to 30% and 55% of the patients treated with ICI-monotherapy or -combination therapy, respectively. Imaging, in particular computed tomography (CT), magnetic resonance imaging (MRI), and 2-deoxy-2-
Ffluoro-D-glucose positron emission tomography/computed tomography (
F-FDG-PET/CT), plays an important role in the detection and characterization of these irAEs. In some patients, irAEs can even be detected on imaging before the onset of clinical symptoms. In this context, it is particularly important to distinguish irAEs from true disease progression and specific immunotherapy related response patterns, such as pseudoprogression. In addition, there are irAEs which might be easily confused with other pathologies such as infection or metastasis. However, many imaging findings, such as in immune-related pneumonitis, are nonspecific. Thus, accurate diagnosis may be delayed underling the importance for adequate imaging features characterization in the appropriate clinical setting in order to provide timely and efficient patient management.
F-FDG-PET/CT and radiomics have demonstrated to reliably detect these toxicities and potentially have predictive value for identifying patients at risk of developing irAEs. The purpose of this article is to provide a review of the main immunotherapy-related toxicities and discuss their characteristics on imaging.
In recent years, various systemic immunotherapies have been developed for cancer treatment, such as monoclonal antibodies (mABs) directed against immune checkpoints (immune checkpoint inhibitors, ...ICIs), oncolytic viruses, cytokines, cancer vaccines, and adoptive cell transfer. While being estimated to be eligible in 38.5% of patients with metastatic solid or hematological tumors, ICIs, in particular, demonstrate durable disease control across many oncologic diseases (e.g., in melanoma, lung, bladder, renal, head, and neck cancers) and overall survival benefits. Due to their unique mechanisms of action based on T-cell activation, response to immunotherapies is characterized by different patterns, such as progression prior to treatment response (pseudoprogression), hyperprogression, and dissociated responses following treatment. Because these features are not encountered in the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), which is the standard for response assessment in oncology, new criteria were defined for immunotherapies. The most important changes in these new morphologic criteria are, firstly, the requirement for confirmatory imaging examinations in case of progression, and secondly, the appearance of new lesions is not necessarily considered a progressive disease. Until today, five morphologic (immune-related response criteria (irRC), immune-related RECIST (irRECIST), immune RECIST (iRECIST), immune-modified RECIST (imRECIST), and intra-tumoral RECIST (itRECIST)) criteria have been developed to accurately assess changes in target lesion sizes, taking into account the specific response patterns after immunotherapy. In addition to morphologic response criteria, 2-deoxy-2-
Ffluoro-D-glucose positron emission tomography/computed tomography (
F-FDG-PET/CT) is a promising option for metabolic response assessment and four metabolic criteria are used (PET/CT Criteria for Early Prediction of Response to Immune Checkpoint Inhibitor Therapy (PECRIT), PET Response Evaluation Criteria for Immunotherapy (PERCIMT), immunotherapy-modified PET Response Criteria in Solid Tumors (imPERCIST5), and immune PERCIST (iPERCIST)). Besides, there is evidence that parameters on
F-FDG-PET/CT, such as the standardized uptake value (SUV)max and several radiotracers, e.g., directed against PD-L1, may be potential imaging biomarkers of response. Moreover, the emerge of human intratumoral immunotherapy (HIT-IT), characterized by the direct injection of immunostimulatory agents into a tumor lesion, has given new importance to imaging assessment. This article reviews the specific imaging patterns of tumor response and progression and available imaging response criteria following immunotherapy.
This Letter reports the successful use of feedback from a spin polarization measurement to the revolution frequency of a 0.97 GeV/c bunched and polarized deuteron beam in the Cooler Synchrotron ...(COSY) storage ring in order to control both the precession rate (≈121 kHz) and the phase of the horizontal polarization component. Real time synchronization with a radio frequency (rf) solenoid made possible the rotation of the polarization out of the horizontal plane, yielding a demonstration of the feedback method to manipulate the polarization. In particular, the rotation rate shows a sinusoidal function of the horizontal polarization phase (relative to the rf solenoid), which was controlled to within a 1 standard deviation range of σ=0.21 rad. The minimum possible adjustment was 3.7 mHz out of a revolution frequency of 753 kHz, which changes the precession rate by 26 mrad/s. Such a capability meets a requirement for the use of storage rings to look for an intrinsic electric dipole moment of charged particles.
The field of beam physics touches many areas of physics, engineering, and the sciences. In general terms, beams describe ensembles of particles with initial conditions similar enough to be treated ...together as a group so that the motion is a weakly nonlinear perturbation of a chosen reference particle. Particle beams are used in a variety of areas,
A method for the nonlinear propagation of uncertainties in Celestial Mechanics based on differential algebra is presented. The arbitrary order Taylor expansion of the flow of ordinary differential ...equations with respect to the initial condition delivered by differential algebra is exploited to implement an accurate and computationally efficient Monte Carlo algorithm, in which thousands of pointwise integrations are substituted by polynomial evaluations. The algorithm is applied to study the close encounter of asteroid Apophis with our planet in 2029. To this aim, we first compute the high order Taylor expansion of Apophis’ close encounter distance from the Earth by means of map inversion and composition; then we run the proposed Monte Carlo algorithm to perform the statistical analysis.
A frontier challenge in implementing femtosecond electron microscopy is to gain precise optical control of intense beams to mitigate collective space charge effects for significantly improving the ...throughput. Here, we explore the flexible uses of an RF cavity as a longitudinal lens in a high-intensity beam column for condensing the electron beams both temporally and spectrally, relevant to the design of ultrafast electron microscopy. Through the introduction of a novel atomic grating approach for characterization of electron bunch phase space and control optics, we elucidate the principles for predicting and controlling the phase space dynamics to reach optimal compressions at various electron densities and generating conditions. We provide strategies to identify high-brightness modes, achieving ∼100 fs and ∼1 eV resolutions with 106 electrons per bunch, and establish the scaling of performance for different bunch charges. These results benchmark the sensitivity and resolution from the fundamental beam brightness perspective and also validate the adaptive optics concept to enable delicate control of the density-dependent phase space structures to optimize the performance, including delivering ultrashort, monochromatic, high-dose, or coherent electron bunches.
Frequently the design of schemes for correction of aberrations or the determination of possible operating ranges for beamlines and cells in synchrotrons exhibit multitudes of possibilities for their ...correction, usually appearing in disconnected regions of parameter space which cannot be directly qualified by analytical means. In such cases, frequently an abundance of optimization runs are carried out, each of which determines a local minimum depending on the specific chosen initial conditions. Practical solutions are then obtained through an often extended interplay of experienced manual adjustment of certain suitable parameters and local searches by varying other parameters.
However, in a formal sense this problem can be viewed as a global optimization problem, i.e. the determination of all solutions within a certain range of parameters that lead to a specific optimum. For example, it may be of interest to find all possible settings of multiple quadrupoles that can achieve imaging; or to find ahead of time all possible settings that achieve a particular tune; or to find all possible manners to adjust nonlinear parameters to achieve correction of high order aberrations. These tasks can easily be phrased in terms of such an optimization problem; but while mathematically this formulation is often straightforward, it has been common belief that it is of limited practical value since the resulting optimization problem cannot usually be solved.
However, recent significant advances in modern methods of rigorous global optimization make these methods feasible for optics design for the first time. The key ideas of the method lie in an interplay of rigorous local underestimators of the objective functions, and by using the underestimators to rigorously iteratively eliminate regions that lie above already known upper bounds of the minima, in what is commonly known as a branch-and-bound approach.
Recent enhancements of the Differential Algebraic methods used in particle optics for the computation of aberrations allow the determination of particularly sharp underestimators for large regions. As a consequence, the subsequent progressive pruning of the allowed search space as part of the optimization progresses is carried out particularly effectively. The end result is the rigorous determination of the single or multiple optimal solutions of the parameter optimization, regardless of their location, their number, and the starting values of optimization.
The methods are particularly powerful if executed in interplay with genetic optimizers generating their new populations within the currently active unpruned space. Their current best guess provides rigorous upper bounds of the minima, which can then beneficially be used for better pruning. Examples of the method and its performance will be presented, including the determination of all operating points of desired tunes or chromaticities, etc. in storage ring lattices.
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