Diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body diagnostic CT and MRI in the detection of spinal bone metastases associated with pheochromocytoma and paraganglioma.

OBJECTIVE: To compare the diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body CT and MRI for the detection of pheochromocytoma/paraganglioma (PPGL)-related spinal bone metastases. MATERIALS AND METHODS: Between 2014 and 2020, PPGL participants with spinal bone metastases prospectively underwent [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the cervical-thoracolumbar spine (MRIspine), contrast-enhanced MRI of the neck and thoraco-abdominopelvic regions (MRIWB), and contrast-enhanced CT of the neck and thoraco-abdominopelvic regions (CTWB). Per-patient and per-lesion detection rates were calculated. Counting of spinal bone metastases was limited to a maximum of one lesion per vertebrae. A composite of all functional and anatomic imaging served as an imaging comparator. The McNemar test compared detection rates between the scans. Two-sided p values were reported. RESULTS: Forty-three consecutive participants (mean age, 41.7 ± 15.7 years; females, 22) with MRIspine were included who also underwent [68Ga]DOTATATE PET/CT (n = 43), [18F]FDG PET/CT (n = 43), MRIWB (n = 24), and CTWB (n = 33). Forty-one of 43 participants were positive for spinal bone metastases, with 382 lesions on the imaging comparator. [68Ga]DOTATATE PET/CT demonstrated a per-lesion detection rate of 377/382 (98.7%) which was superior compared to [18F]FDG (72.0%, 275/382, p < 0.001), MRIspine (80.6%, 308/382, p < 0.001), MRIWB (55.3%, 136/246, p < 0.001), and CTWB (44.8%, 132/295, p < 0.001). The per-patient detection rate of [68Ga]DOTATATE PET/CT was 41/41 (100%) which was higher compared to [18F]FDG PET/CT (90.2%, 37/41, p = 0.13), MRIspine (97.6%, 40/41, p = 1.00), MRIWB (95.7%, 22/23, p = 1.00), and CTWB (81.8%, 27/33, p = 0.03). CONCLUSIONS: [68Ga]DOTATATE PET/CT should be the modality of choice in PPGL-related spinal bone metastases due to its superior detection rate. CLINICAL RELEVANCE STATEMENT: In a prospective study of 43 pheochromocytoma/paraganglioma participants with spinal bone metastases, [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% (377/382), compared to [18F]FDG PET/CT (p < 0.001), MRI of the spine (p < 0.001), whole-body CT (p < 0.001), and whole-body MRI (p < 0.001). KEY POINTS: • Data regarding head-to-head comparison between functional and anatomic imaging modalities to detect spinal bone metastases in pheochromocytoma/paraganglioma are limited. • [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% in the detection of spinal bone metastases associated with pheochromocytoma/paraganglioma compared to other imaging modalities: [18]F-FDG PET/CT, MRI of the spine, whole-body CT, and whole-body MRI. • [68Ga]DOTATATE PET/CT should be the modality of choice in the evaluation of spinal bone metastases associated with pheochromocytoma/paraganglioma.

Radiopharmaceutical transport in solid tumors via a 3-dimensional image-based spatiotemporal model.

Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA)-targeted radiopharmaceutical therapy is a clinically approved treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Even though common practice reluctantly follows "one size fits all" approach, medical community believes there is significant room for deeper understanding and personalization of radiopharmaceutical therapies. To pursue this aim, we present a 3-dimensional spatiotemporal radiopharmaceutical delivery model based on clinical imaging data to simulate pharmacokinetic of 177Lu-PSMA within the prostate tumors. The model includes interstitial flow, radiopharmaceutical transport in tissues, receptor cycles, association/dissociation with ligands, synthesis of PSMA receptors, receptor recycling, internalization of radiopharmaceuticals, and degradation of receptors and drugs. The model was studied for a range of values for injection amount (100-1000 nmol), receptor density (10-500 nmol•l-1), and recycling rate of receptors (10-4 to 10-1 min-1). Furthermore, injection type, different convection-diffusion-reaction mechanisms, characteristic time scales, and length scales are discussed. The study found that increasing receptor density, ligand amount, and labeled ligands improved radiopharmaceutical uptake in the tumor. A high receptor recycling rate (0.1 min-1) increased radiopharmaceutical concentration by promoting repeated binding to tumor cell receptors. Continuous infusion results in higher radiopharmaceutical concentrations within tumors compared to bolus administration. These insights are crucial for advancing targeted therapy for prostate cancer by understanding the mechanism of radiopharmaceutical distribution in tumors. Furthermore, measures of characteristic length and advection time scale were computed. The presented spatiotemporal tumor transport model can analyze different physiological parameters affecting 177Lu-PSMA delivery.

Spatial Atlas for Mapping Vascular Microcalcification Using 18F-NaF PET/CT: Application in Hyperphosphatemic Familial Tumoral Calcinosis.

BACKGROUND: Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals. METHODS: To develop this technique, 4 patients with hyperphosphatemic familial tumoral calcinosis, a monogenic disorder of FGF23 (fibroblast growth factor-23) deficiency with a high prevalence of vascular calcification, underwent radiolabeled sodium fluoride positron emission tomography/computed tomography imaging. One patient received serial imaging 1 year after treatment with an IL-1 (interleukin-1) antagonist. A radiolabeled sodium fluoride-based microcalcification score, as well as calcification volume, was computed at all perpendicular slices, which were then mapped onto a standardized vascular atlas. Segment-wise mCSmean and mCSmax were computed to compare microcalcification score levels at predefined vascular segments within subjects. RESULTS: Patients with hyperphosphatemic familial tumoral calcinosis had notable peaks in microcalcification score near the aortic bifurcation and distal femoral arteries, compared with a control subject who had uniform distribution of vascular radiolabeled sodium fluoride uptake. This technique also identified microcalcification in a 17-year-old patient, who had no computed tomography-defined calcification. This technique could not only detect a decrease in microcalcification score throughout the patient treated with an IL-1 antagonist but it also identified anatomic areas that had increased responsiveness while there was no change in computed tomography-defined macrocalcification after treatment. CONCLUSIONS: This technique affords the ability to visualize spatial patterns of the active microcalcification process in the peripheral vasculature. Further, this technique affords the ability to track microcalcifications at precise locations not only across time but also across subjects. This technique is readily adaptable to other diseases of vascular calcification and may represent a significant advance in the field of vascular biology.

Physiologically based radiopharmacokinetic (PBRPK) modeling to simulate and analyze radiopharmaceutical therapies: studies of non-linearities, multi-bolus injections, and albumin binding.

BACKGROUND: We aimed to develop a publicly shared computational physiologically based pharmacokinetic (PBPK) model to reliably simulate and analyze radiopharmaceutical therapies (RPTs), including probing of hot-cold ligand competitions as well as alternative injection scenarios and drug designs, towards optimal therapies. RESULTS: To handle the complexity of PBPK models (over 150 differential equations), a scalable modeling notation called the "reaction graph" is introduced, enabling easy inclusion of various interactions. We refer to this as physiologically based radiopharmacokinetic (PBRPK) modeling, fine-tuned specifically for radiopharmaceuticals. As three important applications, we used our PBRPK model to (1) study the effect of competition between hot and cold species on delivered doses to tumors and organs at risk. In addition, (2) we evaluated an alternative paradigm of utilizing multi-bolus injections in RPTs instead of prevalent single injections. Finally, (3) we used PBRPK modeling to study the impact of varying albumin-binding affinities by ligands, and the implications for RPTs. We found that competition between labeled and unlabeled ligands can lead to non-linear relations between injected activity and the delivered dose to a particular organ, in the sense that doubling the injected activity does not necessarily result in a doubled dose delivered to a particular organ (a false intuition from external beam radiotherapy). In addition, we observed that fractionating injections can lead to a higher payload of dose delivery to organs, though not a differential dose delivery to the tumor. By contrast, we found out that increased albumin-binding affinities of the injected ligands can lead to such a differential effect in delivering more doses to tumors, and this can be attributed to several factors that PBRPK modeling allows us to probe. CONCLUSIONS: Advanced computational PBRPK modeling enables simulation and analysis of a variety of intervention and drug design scenarios, towards more optimal delivery of RPTs.

Metabolic tumour volume in Hodgkin lymphoma-A comparison between manual and AI-based analysis.

AIM: To compare total metabolic tumour volume (tMTV), calculated using two artificial intelligence (AI)-based tools, with manual segmentation by specialists as the reference. METHODS: Forty-eight consecutive Hodgkin lymphoma (HL) patients staged with [18F] fluorodeoxyglucose positron emission tomography/computed tomography were included. The median age was 35 years (range: 7-75), 46% female. The tMTV was automatically measured using the AI-based tools positron emission tomography assisted reporting system (PARS) (from Siemens) and RECOMIA (recomia.org) without any manual adjustments. A group of eight nuclear medicine specialists manually segmented lesions for tMTV calculations; each patient was independently segmented by two specialists. RESULTS: The median of the manual tMTV was 146 cm3 (interquartile range [IQR]: 79-568 cm3) and the median difference between two tMTV values segmented by different specialists for the same patient was 26 cm3 (IQR: 10-86 cm3). In 22 of the 48 patients, the manual tMTV value was closer to the RECOMIA tMTV value than to the manual tMTV value segmented by the second specialist. In 11 of the remaining 26 patients, the difference between the RECOMIA tMTV and the manual tMTV was small (<26 cm3, which was the median difference between two manual tMTV values from the same patient). The corresponding numbers for PARS were 18 and 10 patients, respectively. CONCLUSION: The results of this study indicate that RECOMIA and Siemens PARS AI tools could be used without any major manual adjustments in 69% (33/48) and 58% (28/48) of HL patients, respectively. This demonstrates the feasibility of using AI tools to support physicians measuring tMTV for assessment of prognosis in clinical practice.

Skeletal involvement in Erdheim-Chester disease: Multimodality imaging features and association with the BRAFV600E mutation.

OBJECTIVE: The aim of this study was to characterize the distribution of skeletal involvement in Erdheim-Chester disease (ECD) by using radiography, computed tomography (CT), 18F-FDG positron emission tomography/computed tomography (PET/CT), and bone scans, as well as looking for associations with the BRAFV600E mutation. MATERIAL AND METHODS: Prospective study of 50 consecutive patients with biopsy-confirmed ECD who had radiographs, CT, 18F-FDG PET/CT, and Tc-99m MDP bone scans. At least two experienced radiologists with expertise in the relevant imaging studies analyzed the images. Summary statistics were expressed as the frequency with percentages for categorical data. Fisher's exact test, as well as odds ratios (OR) with 95 % confidence intervals (CI), were used to link imaging findings to BRAFV600E mutation. The probability for co-occurrence of bone involvement at different locations was calculated and graphed as a heat map. RESULTS: All 50 cases revealed skeletal involvement at different regions of the skeleton. The BRAFV600E mutation, which was found in 24 patients, was correlated with femoral and tibial involvement on 18F-FDG PET/CT and bone scan. The appearance of changes on the femoral, tibial, fibular, and humeral involvement showed correlation with each other based on heat maps of skeletal involvement on CT. CONCLUSION: This study reports the distribution of skeletal involvement in a cohort of patients with ECD. CT is able to detect the majority of ECD skeletal involvement. Considering the complementary nature of information from different modalities, imaging of ECD skeletal involvement is optimized by using a multi-modality strategy.

Ethical Considerations for Artificial Intelligence in Medical Imaging: Data Collection, Development, and Evaluation.

The development of artificial intelligence (AI) within nuclear imaging involves several ethically fraught components at different stages of the machine learning pipeline, including during data collection, model training and validation, and clinical use. Drawing on the traditional principles of medical and research ethics, and highlighting the need to ensure health justice, the AI task force of the Society of Nuclear Medicine and Molecular Imaging has identified 4 major ethical risks: privacy of data subjects, data quality and model efficacy, fairness toward marginalized populations, and transparency of clinical performance. We provide preliminary recommendations to developers of AI-driven medical devices for mitigating the impact of these risks on patients and populations.

Virtual monoenergetic imaging in photon-counting CT of the head and neck.

PURPOSE: Advantages of virtual monoenergetic images (VMI) have been reported for dual energy CT of the head and neck, and more recently VMIs derived from photon-counting (PCCT) angiography of the head and neck. We report image quality metrics of VMI in a PCCT angiography dataset, expanding the anatomical regions evaluated and extending observer-based qualitative methods further than previously reported. METHODS: In a prospective study, asymptomatic subjects underwent contrast enhanced PCCT of the head and neck using an investigational scanner. Image sets of low, high, and full spectrum (Threshold-1) energies; linear mix of low and high energies (Mix); and 23 VMIs (40-150 keV, 5 keV increments) were generated. In 8 anatomical locations, SNR and radiologists' preferences for VMI energy levels were measured using a forced-choice rank method (4 observers) and ratings of image quality using visual grading characteristic (VGC) analysis (2 observers) comparing VMI to Mix and Threshold-1 images. RESULTS: Fifteen subjects were included (7 men, 8 women, mean 57 years, range 46-75). Among all VMIs, SNRs varied by anatomic location. The highest SNRs were observed in VMIs. Radiologists preferred 50-60 keV VMIs for vascular structures and 75-85 keV for all other structures. Cumulative ratings of image quality averaged across all locations were higher for VMIs with areas under the curve of VMI vs Mix and VMI vs Threshold-1 of 0.67 and 0.68 for the first reader and 0.72 and 0.76 for the second, respectively. CONCLUSION: Preferred keV level and quality ratings of VMI compared to mixed and Threshold-1 images varied by anatomical location.

Update on Positron Emission Tomography/Magnetic Resonance Imaging: Cancer and Inflammation Imaging in the Clinic.

Hybrid PET/MRI is highly valuable, having made significant strides in overcoming technical challenges and offering unique advantages such as reduced radiation, precise data coregistration, and motion correction. Growing evidence highlights the value of PET/MRI in broad clinical aspects, including inflammatory and oncological imaging in adults, pregnant women, and pediatrics, potentially surpassing PET/CT. This newly integrated solution may be preferred over PET/CT in many clinical conditions. However, further technological advancements are required to facilitate its broader adoption as a routine diagnostic modality.

Impact of the confluence of cardiac motion and high spatial resolution on performance of ECG-gated imaging with an investigational photon-counting CT system: A phantom study.

PURPOSE: Photon-counting CT (PCCT) has higher spatial resolution that conventional EID CT which improves imaging of stationary coronary plaques and stents.. In this work, we evaluated the relationship between higher spatial resolution and motion acquisition on an investigational PCCT system. METHODS: An investigational photon-counting CT scanner (Siemens CounT) with ECG gating was used to image a coronary tree phantom with models of healthy, stenotic, and stented arteries using a motion simulator. Images were acquired with matched clinical parameters at rest and 60 beats per minute. An additional set of high dose stationary images were averaged to generate a motion-free, reduced noise reference. Scans were completed at standard (0.5 mm2) and high-resolution (0.25 mm2). Motion images were reconstructed at multiple phases. Regions of interest were drawn around vessels and segmented. Percentage difference from the reference standard was evaluated for vessel diameter and circularity. Mutual information between the reference and stationary and motion datasets was used as a measure of volumetric similarity. RESULTS: The stenotic vessel showed the most variation from the reference when compared to healthy or stented vessels. Compared to standard resolution, high-resolution images had lower bias for diameter (-0.012 ± 0.19% vs -0.052 ± 0.14%) and lower variability for circularity (-0.13 ± 0.138% vs -0.12 ± 0.144%). Both differences were found to be statistically significant. High-resolution images had a slightly lower mutual information (1.28) than standard resolution (1.31). CONCLUSION: The higher spatial resolution enabled by photon-counting CT can be harnessed for cardiac imaging as the benefits of high spatial resolution acquisitions remain relevant in the presence of motion.

Ethical Considerations for Artificial Intelligence in Medical Imaging: Deployment and Governance.

The deployment of artificial intelligence (AI) has the potential to make nuclear medicine and medical imaging faster, cheaper, and both more effective and more accessible. This is possible, however, only if clinicians and patients feel that these AI medical devices (AIMDs) are trustworthy. Highlighting the need to ensure health justice by fairly distributing benefits and burdens while respecting individual patients' rights, the AI Task Force of the Society of Nuclear Medicine and Molecular Imaging has identified 4 major ethical risks that arise during the deployment of AIMD: autonomy of patients and clinicians, transparency of clinical performance and limitations, fairness toward marginalized populations, and accountability of physicians and developers. We provide preliminary recommendations for governing these ethical risks to realize the promise of AIMD for patients and populations.

Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results.

The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent (n = 3) or after lymphodepletion (LD, n = 29). Dose-limiting toxicities of grade 3 pneumonitis and grade 5 bronchioalveolar hemorrhage were noted. The RP2D was determined as 1 × 108 cells per m2 after LD. Grade 3 or higher pneumonitis was seen in 16% of all patients and in none at the RP2D; grade 3 or higher cytokine release syndrome occurred in 25% of all patients and in 15% at the RP2D. In 30 evaluable patients, the overall response rate and disease control rate were 20% (13% confirmed) and 77%, respectively, and the 6-month overall survival rate was 70%. Gavo-cel warrants further study in patients with mesothelin-expressing cancers given its encouraging anti-tumor activity, but it may have a narrow therapeutic window. ClinicalTrials.gov identifier: NCT03907852 .

CCS-GAN: COVID-19 CT Scan Generation and Classification with Very Few Positive Training Images.

We present a novel algorithm that is able to generate deep synthetic COVID-19 pneumonia CT scan slices using a very small sample of positive training images in tandem with a larger number of normal images. This generative algorithm produces images of sufficient accuracy to enable a DNN classifier to achieve high classification accuracy using as few as 10 positive training slices (from 10 positive cases), which to the best of our knowledge is one order of magnitude fewer than the next closest published work at the time of writing. Deep learning with extremely small positive training volumes is a very difficult problem and has been an important topic during the COVID-19 pandemic, because for quite some time it was difficult to obtain large volumes of COVID-19-positive images for training. Algorithms that can learn to screen for diseases using few examples are an important area of research. Furthermore, algorithms to produce deep synthetic images with smaller data volumes have the added benefit of reducing the barriers of data sharing between healthcare institutions. We present the cycle-consistent segmentation-generative adversarial network (CCS-GAN). CCS-GAN combines style transfer with pulmonary segmentation and relevant transfer learning from negative images in order to create a larger volume of synthetic positive images for the purposes of improving diagnostic classification performance. The performance of a VGG-19 classifier plus CCS-GAN was trained using a small sample of positive image slices ranging from at most 50 down to as few as 10 COVID-19-positive CT scan images. CCS-GAN achieves high accuracy with few positive images and thereby greatly reduces the barrier of acquiring large training volumes in order to train a diagnostic classifier for COVID-19.

Role of Artificial Intelligence in PET/CT Imaging for Management of Lymphoma.

Our review shows that AI-based analysis of lymphoma whole-body FDG-PET/CT can inform all phases of clinical management including staging, prognostication, treatment planning, and treatment response evaluation. We highlight advancements in the role of neural networks for performing automated image segmentation to calculate PET-based imaging biomarkers such as the total metabolic tumor volume (TMTV). AI-based image segmentation methods are at levels where they can be semi-automatically implemented with minimal human inputs and nearing the level of a second-opinion radiologist. Advances in automated segmentation methods are particularly apparent in the discrimination of lymphomatous vs non-lymphomatous FDG-avid regions, which carries through to automated staging. Automated TMTV calculators, in addition to automated calculation of measures such as Dmax are informing robust models of progression-free survival which can then feed into improved treatment planning.