Exploring advanced 2D acquisitions in breast tomosynthesis: T-shaped and Pentagon geometries.

In this study, we investigate the performance of advanced 2D acquisition geometries - Pentagon and T-shaped - in digital breast tomosynthesis (DBT) and compare them against the conventional 1D geometry. Unlike the conventional approach, our proposed 2D geometries also incorporate anterior projections away from the chest wall. Implemented on the Next-Generation Tomosynthesis (NGT) prototype developed by X-ray Physics Lab (XPL), UPenn, we utilized various phantoms to compare three geometries: a Defrise slab phantom with alternating plastic slabs to study low-frequency modulation; a Checkerboard breast phantom (a 2D adaptation of the Defrise phantom design) to study the ability to reconstruct the fine features of the checkerboard squares; and the 360° Star-pattern phantom to assess aliasing and compute the Fourier-spectral distortion (FSD) metric that assesses spectral leakage and the contrast transfer function. We find that both Pentagon and T-shaped scans provide greater modulation amplitude of the Defrise phantom slabs and better resolve the squares of the Checkerboard phantom against the conventional scan. Notably, the Pentagon geometry exhibited a significant reduction in aliasing of spatial frequencies oriented in the right-left (RL) medio-lateral direction, which was corroborated by a near complete elimination of spectral leakage in the FSD plot. Conversely T-shaped scan redistributes the aliasing between both posteroanterior (PA) and RL directions thus maintaining non-inferiority against the conventional scan which is predominantly affected by PA aliasing. The results of this study underscore the potential of incorporating advanced 2D geometries in DBT systems, offering marked improvements in imaging performance over the conventional 1D approach.

Line-based iterative geometric calibration method for a tomosynthesis system.

BACKGROUND: A next generation tomosynthesis (NGT) system, capable of two-dimensional source motion, detector motion in the perpendicular direction, and magnification tomosynthesis, was constructed to investigate different acquisition geometries. Existing position-based geometric calibration methods proved ineffective when applied to the NGT geometries. PURPOSE: A line-based iterative calibration method is developed to perform accurate geometric calibration for the NGT system. METHODS: The proposed method calculates the system geometry through virtual line segments created by pairs of fiducials within a calibration phantom, by minimizing the error between the line equations computed from the true and estimated fiducial projection pairs. It further attempts to correct the 3D fiducial locations based on the initial geometric calibration. The method's performance was assessed via simulation and experimental setups with four distinct NGT geometries: X, T, XZ, and TZ. The X geometry resembles a conventional DBT acquisition along the chest wall. The T geometry forms a "T"-shaped source path in mediolateral (ML) and posteroanterior (PA) directions. A descending detector motion is added to both X and T geometries to form the XZ and TZ geometries, respectively. Simulation studies were conducted to assess the robustness of the method to geometric perturbations and inaccuracies in fiducial locations. Experimental studies were performed to assess the impact of phantom magnification and the performance of the proposed method for various geometries, compared to the traditional position-based method. Star patterns were evaluated for both qualitative and quantitative analyses; the Fourier spectral distortions (FSDs) graphs and the contrast transfer function (CTF) were extracted. The limit of spatial resolution (LSR) was measured at 5% modulation of the CTF. RESULTS: The proposed method presented is highly robust to geometric perturbation and fiducial inaccuracies. After the line-based iterative method, the mean distance between the true and estimated fiducial projections was [X, T, XZ, TZ]: [0.01, 0.01, 0.02, 0.01] mm. The impact of phantom magnification was observed; a contact-mode acquisition of a calibration phantom successfully provided an accurate geometry for 1.85× magnification images of a star pattern, with the X geometry. The FSD graphs for the contact-mode T geometry acquisition presented evidence of super-resolution, with the LSR of [0°-quadrant: 8.57, 90°-quadrant: 8.47] lp/mm. Finally, a contact-mode XZ geometry acquisition and a 1.50× magnification TZ geometry acquisition were reconstructed with three calibration methods-position-based, line-based, and iterative line-based. As more advanced methods are applied, the CTF becomes more isotropic, the FSD graphs demonstrate less spectral leakage as super-resolution is achieved, and the degree of blurring artifacts reduces significantly. CONCLUSIONS: This study introduces a robust calibration method tailored to the unique requirements of advanced tomosynthesis systems. By employing virtual line segments and iterative techniques, we ensure accurate geometric calibration while mitigating the limitations posed by the complex acquisition geometries of the NGT system. Our method's ability to handle various NGT configurations and its tolerance to fiducial misalignment make it a superior choice compared to traditional calibration techniques.

Artificial intelligence-based automated segmentation and radiotherapy dose mapping for thoracic normal tissues.

Background and purpose: Objective assessment of delivered radiotherapy (RT) to thoracic organs requires fast and accurate deformable dose mapping. The aim of this study was to implement and evaluate an artificial intelligence (AI) deformable image registration (DIR) and organ segmentation-based AI dose mapping (AIDA) applied to the esophagus and the heart. Materials and methods: AIDA metrics were calculated for 72 locally advanced non-small cell lung cancer patients treated with concurrent chemo-RT to 60 Gy in 2 Gy fractions in an automated pipeline. The pipeline steps were: (i) automated rigid alignment and cropping of planning CT to week 1 and week 2 cone-beam CT (CBCT) field-of-views, (ii) AI segmentation on CBCTs, and (iii) AI-DIR-based dose mapping to compute dose metrics. AIDA dose metrics were compared to the planned dose and manual contour dose mapping (manual DA). Results: AIDA required âˆ¼2 min/patient. Esophagus and heart segmentations were generated with a mean Dice similarity coefficient (DSC) of 0.80±0.15 and 0.94±0.05, a Hausdorff distance at 95th percentile (HD95) of 3.9±3.4 mm and 14.1±8.3 mm, respectively. AIDA heart dose was significantly lower than the planned heart dose (p = 0.04). Larger dose deviations (>=1Gy) were more frequently observed between AIDA and the planned dose (N = 26) than with manual DA (N = 6). Conclusions: Rapid estimation of RT dose to thoracic tissues from CBCT is feasible with AIDA. AIDA-derived metrics and segmentations were similar to manual DA, thus motivating the use of AIDA for RT applications.

Non-Isocentric Geometry for Next-Generation Tomosynthesis With Super-Resolution.

Our lab at the University of Pennsylvania (UPenn) is investigating novel designs for digital breast tomosynthesis. We built a next-generation tomosynthesis system with a non-isocentric geometry (superior-to-inferior detector motion). This paper examines four metrics of image quality affected by this design. First, aliasing was analyzed in reconstructions prepared with smaller pixelation than the detector. Aliasing was assessed with a theoretical model of r -factor, a metric calculating amplitudes of alias signal relative to input signal in the Fourier transform of the reconstruction of a sinusoidal object. Aliasing was also assessed experimentally with a bar pattern (illustrating spatial variations in aliasing) and 360°-star pattern (illustrating directional anisotropies in aliasing). Second, the point spread function (PSF) was modeled in the direction perpendicular to the detector to assess out-of-plane blurring. Third, power spectra were analyzed in an anthropomorphic phantom developed by UPenn and manufactured by Computerized Imaging Reference Systems (CIRS), Inc. (Norfolk, VA). Finally, calcifications were analyzed in the CIRS Model 020 BR3D Breast Imaging Phantom in terms of signal-to-noise ratio (SNR); i.e., mean calcification signal relative to background-tissue noise. Image quality was generally superior in the non-isocentric geometry: Aliasing artifacts were suppressed in both theoretical and experimental reconstructions prepared with smaller pixelation than the detector. PSF width was also reduced at most positions. Anatomic noise was reduced. Finally, SNR in calcification detection was improved. (A potential trade-off of smaller-pixel reconstructions was reduced SNR; however, SNR was still improved by the detector-motion acquisition.) In conclusion, the non-isocentric geometry improved image quality in several ways.

Spatial dependency of multiplanar reconstruction in digital breast tomosynthesis.

Tomosynthesis acquires projections over a limited angular range, resulting in anisotropic sampling in the Fourier domain. The volume of the sampled space is therefore spatially dependent; different Fourier components are sampled for the same object, depending upon where the object is located relative to the system origin. A next-generation tomosynthesis (NGT) system was developed at the University of Pennsylvania to increase the spatial isotropy in DBT, by incorporating additional system motions. In this work, we investigate the spatial dependency of image quality in tomosynthesis and compare conventional and NGT tomosynthesis in terms of multiplanar reconstruction (MPR). Two test objects, a high-frequency star pattern and a low-frequency octagon phantom, were placed throughout the detector field of view at various obliquities to analyze the anisotropic nature of tomosynthesis. Reconstructions of the star pattern were analyzed both qualitatively and quantitatively using the Fourier distortion metric (FSD). Reconstructions of the octagon phantom were analyzed qualitatively. In a separate experiment, a container filled with water and acrylic beads of various diameters were imaged at various locations to simulate low-contrast objects mimicking breast tissue. We show that the spatial dependency of MPR is unique to the tilt angle, orientation, and frequency of the input. The NGT geometry benefitted the visualization of objects by reducing the out-of-plane artifacts in MPR.

Achieving Isotropic Super-Resolution with a Non-Isocentric Acquisition Geometry in a Next-Generation Tomosynthesis System.

We have constructed a prototype next-generation tomosynthesis (NGT) system that supports a non-isocentric acquisition geometry for digital breast tomosynthesis (DBT). In this geometry, the detector gradually descends in the superior-to-inferior direction. The aim of this work is to demonstrate that this geometry offers isotropic super-resolution (SR), unlike clinical DBT systems which are characterized by anisotropies in SR. To this end, a theoretical model of a sinusoidal test object was developed with frequency exceeding the alias frequency of the detector. We simulated two geometries: (1) a conventional geometry with a stationary detector, and (2) a non-isocentric geometry. The input frequency was varied over the full 360° range of angles in the plane of the object. To investigate whether SR was achieved, we calculated the Fourier transform of the reconstruction. The amplitude of the tallest peak below the alias frequency was measured relative to the peak at the input frequency. This ratio (termed the r-factor) should approach zero to achieve high-quality SR. In the conventional geometry, the r-factor was minimized (approaching zero) if the orientation of the frequency was parallel with the source motion, yet exceeded unity (prohibiting SR) in the orientation perpendicular to the source motion. However, in the non-isocentric geometry, the r-factor was minimized (approaching zero) for all orientations of the frequency, meaning SR was achieved isotropically. In summary, isotropic SR in DBT can be achieved using the non-isocentric acquisition geometry supported by the NGT system.

Cytokine-induced natural killer cell training is dependent on cellular metabolism and is defective in obesity.

Natural killer (NK) cells are a population of innate immune cells that can rapidly kill cancer cells and produce cytokines such as interferon-γ. A key feature of NK cells is their ability to respond without prior sensitization; however, it is now well established that NK cells can possess memory-like features. After activation with cytokines, NK cells demonstrate enhanced effector functions upon restimulation days or weeks later. This demonstrates that NK cells may be trained to be more effective killers and harnessed as more potent cancer immunotherapy agents. We have previously demonstrated that cellular metabolism is essential for NK cell responses, with NK cells upregulating both glycolysis and oxidative phosphorylation upon cytokine stimulation. Limiting NK cell metabolism results in reduced cytotoxicity and cytokine production. We have also demonstrated that defective NK cell responses in obesity are linked to defective cellular metabolism. In the current study, we investigated if cellular metabolism is required during the initial period of NK cell cytokine training and if NK cells from people with obesity (PWO) can be effectively trained. We show that increased flux through glycolysis and oxidative phosphorylation during the initial cytokine activation period is essential for NK cell training, as is the metabolic signaling factor Srebp. We show that NK cells from PWO, which are metabolically defective, display impaired NK cell training, which may have implications for immunotherapy in this particularly vulnerable group.

Metabolic requirements of NK cells during the acute response against retroviral infection.

Natural killer (NK) cells are important early responders against viral infections. Changes in metabolism are crucial to fuel NK cell responses, and altered metabolism is linked to NK cell dysfunction in obesity and cancer. However, very little is known about the metabolic requirements of NK cells during acute retroviral infection and their importance for antiviral immunity. Here, using the Friend retrovirus mouse model, we show that following infection NK cells increase nutrient uptake, including amino acids and iron, and reprogram their metabolic machinery by increasing glycolysis and mitochondrial metabolism. Specific deletion of the amino acid transporter Slc7a5 has only discrete effects on NK cells, but iron deficiency profoundly impaires NK cell antiviral functions, leading to increased viral loads. Our study thus shows the requirement of nutrients and metabolism for the antiviral activity of NK cells, and has important implications for viral infections associated with altered iron levels such as HIV and SARS-CoV-2.

Optimising NK cell metabolism to increase the efficacy of cancer immunotherapy.

Immunotherapy has ushered in an exciting new era for cancer treatment. The recent discovery and success of immune checkpoint blockade and chimeric antigen receptor (CAR) T cell adoptive cell transfer has raised interest in using other immune cells, including Natural Killer (NK) cells, which might overcome some limitations with CAR T cell therapy. In this review article, we discuss the evidence that cellular metabolism is crucial for NK cell effector function. Additionally, potential strategies to optimise the metabolism of therapeutic NK cells for improved function within the metabolically adverse tumour microenvironment will be explored.

Relationship of intraoperative perfusion parameters to the need for immediate extracorporeal support following heart transplantation.

PURPOSE: We sought to assess the relationship of intraoperative perfusion parameters while on cardiopulmonary bypass, including oxygen delivery (DO2), to the need for ECMO following orthotopic heart transplantation (OHT). METHODS: We included all adult (>18 years old) OHTs performed at our institution since implementation of an electronic perfusion record (March 2019-February 2020). Multi-organ transplants were excluded. The primary outcome was the need for immediate venoarterial ECMO in the OR following OHT. Univariable statistics were computed across demographic, clinical, operative, and perfusion variables, including oxygen delivery (DO2) measured each minute. RESULTS: Fifty-three OHT were included with a median age of 54 years (interquartile range, 45-61). The primary outcome occurred in eight patients (15.1%). A significantly greater proportion of patients requiring ECMO had ischemic cardiomyopathy (50.0% (4/8) vs. 15.6% (7/45), p = 0.02) and had preoperative ventricular assist devices (37.5% (3/8) vs. 8.9% (4/45), p = 0.03). Median bypass times were longer in the ECMO group (217 vs. 147 minutes, p = 0.001). Phenylephrine doses were nonsignificantly higher in ECMO patients (4.1 vs. 1.9 mg, p = 0.10). No significant differences were observed in single-point median DO2 (275 vs. 294 mL O2/min/m2 BSA, p = 0.17) and nadir DO2 (226 vs. 222, p = 0.94), but increasing time and depth of DO2 below a threshold of 300 mL O2/min/m2 BSA (i.e. area over the DO2 curve (AOC) but below threshold) was significantly associated with the need for postoperative ECMO (p = 0.04). CONCLUSION: This is the first study to examine the relationship of perfusion parameters, including oxygen delivery, to outcomes following heart transplantation. We note that DO2 < 300-AOC was significantly associated with the need for postoperative ECMO following heart transplant. Further study will clarify whether potential DO2 differences in patients who require post-OHT ECMO reflect vasoplegia, or a more causative relationship which might be leveraged to improve outcomes.

De novo polyamine synthesis supports metabolic and functional responses in activated murine NK cells.

Cellular metabolism is dynamically regulated in NK cells and strongly influences their responses. Metabolic dysfunction is linked to defective NK cell responses in diseases such as obesity and cancer. The transcription factors, sterol regulatory element binding protein (SREBP) and cMyc, are crucial for controlling NK cell metabolic and functional responses, though the mechanisms involved are not fully understood. This study reveals a new role for SREBP in NK cells in supporting de novo polyamine synthesis through facilitating elevated cMyc expression. Polyamines have diverse roles and their de novo synthesis is required for NK cell glycolytic and oxidative metabolism and to support optimal NK cell effector functions. When NK cells with impaired SREBP activity were supplemented with exogenous polyamines, NK cell metabolic defects were not rescued but these NK cells displayed significant improvement in some effector functions. One role for polyamines is in the control of protein translation where spermidine supports the posttranslational hypusination of translation factor eIF5a. Pharmacological inhibition of hypusination also impacts upon NK cell metabolism and effector function. Considering recent evidence that cholesterol-rich tumor microenvironments inhibit SREBP activation and drive lymphocyte dysfunction, this study provides key mechanistic insight into this tumor-evasion strategy.

Development of Magnification Tomosynthesis for Superior Resolution in Diagnostic Mammography.

Our previous work showed that digital breast tomosynthesis (DBT) supports super-resolution (SR). Clinical systems are not yet designed to optimize SR; this can be demonstrated with a high-frequency line-resolution pattern. SR is achieved if frequencies are oriented laterally, but not if frequencies are oriented in the perpendicular direction; i.e., the posteroanterior (PA) direction. We are developing a next-generation tomosynthesis (NGT) prototype with new trajectories for the x-ray source. This system is being designed to optimize SR not just for screening, but also for diagnostic mammography; specifically, for magnification DBT (M-DBT). SR is not achieved clinically in magnification mammography, since the acquisition is 2D. The aim of this study is to investigate SR in M-DBT, and analyze how anisotropies differ from screening DBT (S-DBT). We have a theoretical model of a high-frequency sinusoidal test object. First, a conventional scanning motion (directed laterally) was simulated. In the PA direction, SR was not achieved in either S-DBT or M-DBT. Next, the scanning motion was angled relative to the lateral direction. This motion introduces submillimeter offsets in source positions in the PA direction. Theoretical modeling demonstrated that SR was achieved in M-DBT, but not in S-DBT, in the PA direction. This work shows that, with the use of magnification, anisotropies in SR are more sensitive to small offsets in the source motion, leading to insights into how to design M-DBT systems.

Diverse Immunoregulatory Roles of Oxysterols-The Oxidized Cholesterol Metabolites.

Intermediates of both cholesterol synthesis and cholesterol metabolism can have diverse roles in the control of cellular processes that go beyond the control of cholesterol homeostasis. For example, oxidized forms of cholesterol, called oxysterols have functions ranging from the control of gene expression, signal transduction and cell migration. This is of particular interest in the context of immunology and immunometabolism where we now know that metabolic processes are key towards shaping the nature of immune responses. Equally, aberrant metabolic processes including altered cholesterol homeostasis contribute to immune dysregulation and dysfunction in pathological situations. This review article brings together our current understanding of how oxysterols affect the control of immune responses in diverse immunological settings.

Natural Killer Cells Integrate Signals Received from Tumour Interactions and IL2 to Induce Robust and Prolonged Anti-Tumour and Metabolic Responses.

Natural Killer (NK) cells are lymphocytes with an important role in anti-tumour responses. NK cells bridge the innate and adaptive arms of the immune system; they are primed for immediate anti-tumour function but can also have prolonged actions alongside the adaptive T cell response. However, the key signals and cellular processes that are required for extended NK cell responses are not fully known. Herein we show that murine NK cell interaction with tumour cells induces the expression of CD25, the high affinity IL2 receptor, rendering these NK cells highly sensitive to the T cell-derived cytokine IL2. In response to IL2, CD25high NK cells show robust increases in metabolic signalling pathways (mTORC1, cMyc), nutrient transporter expression (CD71, CD98), cellular growth and in NK cell effector functions (IFNγ, granzyme B). Specific ligation of an individual activating NK cell receptor, NK1.1, showed similar increases in CD25 expression and IL2-induced responses. NK cell receptor ligation and IL2 collaborate to induce mTORC1/cMyc signalling leading to high rates of glycolysis and oxidative phosphorylation (OXPHOS) and prolonged NK cell survival. Disrupting mTORC1 and cMyc signalling in CD25high tumour interacting NK cells prevents IL2-induced cell growth and function and compromises NK cell viability. This study reveals that tumour cell interactions and T cell-derived IL2 cooperate to promote robust and prolonged NK cell anti-tumour metabolic responses.

Clinical Utility of Multi-Energy Spectral Photon-Counting Computed Tomography in Crystal Arthritis.

OBJECTIVE: To determine whether novel multi-energy spectral photon-counting computed tomography (SPCCT) imaging can detect and differentiate between monosodium urate (MSU), calcium pyrophosphate (CPP), and hydroxyapatite (HA) crystal deposits ex vivo. METHODS: A finger with a subcutaneous gouty tophus and a calcified knee meniscus excised at the time of surgery were obtained. The finger was imaged using plain x-ray, dual-energy CT (DECT), and multi-energy SPCCT. Plain x-ray and multi-energy SPCCT images of the meniscus were acquired. For validation purposes, samples of the crystals were obtained from the tophus and meniscus, and examined by polarized light microscopy and/or x-ray diffraction. As further validation, synthetic crystal suspensions of MSU, CPP, and HA were scanned using multi-energy SPCCT. RESULTS: Plain x-ray of the gouty finger revealed bone erosions with overhanging edges. DECT and multi-energy SPCCT both showed MSU crystal deposits; SPCCT was able to show finer detail. Plain x-ray of the calcified meniscus showed chondrocalcinosis consistent with CPP, while SPCCT showed and differentiated CPP and HA. CONCLUSION: Multi-energy SPCCT can not only detect, differentiate, and quantify MSU crystal deposits in a gouty finger ex vivo, but also specifically detect, identify, and quantify CPP within an osteoarthritic meniscus, and distinguish them from HA crystal deposits. There is potential for multi-energy SPCCT to become useful in the diagnosis of crystal arthropathies.