Scission-Enhanced Molecular Imaging (SEMI).

Positron emission tomography (PET) imaging methods have advanced our understanding of human biology, while targeted radiotherapeutic drug treatments are now routinely used clinically. The field is expected to grow considerably based on an expanding repertoire of available affinity ligands, radionuclides, conjugation chemistries, and their FDA approvals. With this increasing use, strategies for dose reduction have become of high interest to protect patients from unnecessary and off-target toxicity. Here, we describe a simple and powerful method, scission-enhanced molecular imaging (SEMI). The technique allows for rapid corporeal elimination of radionuclides once imaging or theranostic treatment is completed and relies on "click-to-release" bioorthogonal linkers.

Evaluating the added value of concurrent contrast-enhanced diagnostic CT for PSMA-PET/CT Interpretation.

RATIONALE AND OBJECTIVES: To determine whether concurrent contrast-enhanced diagnostic CT (DxCT) confers added diagnostic certainty compared to PSMA-PET/CT alone. MATERIALS AND METHODS: This retrospective multi-reader study analyzed imaging comprising combined F-18-piflufolastat PSMA-PET/CT with diagnostic chest/abdominopelvic CT from prostate cancer patients within the first 6 months of FDA-approval of the PET agent. Six nuclear radiology readers were randomly presented with PSMA-PET/CT studies with or without DxCT and asked to report their diagnostic certainty for PSMA-avid lesions found on PET. Subsequently, readers re-reviewed the same study after an interlude (with the CT if not previously presented and vice-versa) to determine if DxCT altered their diagnostic assessment. Inter-rater concordance was assessed on a subset of images read by all readers. Diagnostic certainties for PSMA-PET/CT with and without DxCT were compared, and the variables for which DxCT may add value were examined. RESULTS: Good inter-rater concordance across readers was noted for both PET/CT (Finn's coefficient of reliability for overall scan certainty: 0.85,p < 0.01) and combined DxCT-PET/CT (0.59,p < 0.01). Overall certainty and concordance between PET/CT and combined DxCT-PET/CT datasets were similar (overall scan certainty: 92% ± 16 vs. 92% ± 17,p = 0.43), with no significant advantage for adding DxCT across different anatomic locations or clinical parameters. A slight predilection for combined DxCT-PET/CT was noted when interpreting images acquired for the initial staging of prostate cancer (89% ± 16 vs. 93% ± 17,p = 0.08). CONCLUSION: Good inter-reader concordance can be achieved across different training levels with PSMA-PET/CT. Furthermore, using DxCT concurrent with PSMA-PET/CT does not significantly improve diagnostic certainty for most indications but may be useful for initial staging.

Extended Pharmacokinetics Improve Site-Specific Prodrug Activation Using Radiation.

Radiotherapy is commonly used to treat cancer, and localized energy deposited by radiotherapy has the potential to chemically uncage prodrugs; however, it has been challenging to demonstrate prodrug activation that is both sustained in vivo and truly localized to tumors without affecting off-target tissues. To address this, we developed a series of novel phenyl-azide-caged, radiation-activated chemotherapy drug-conjugates alongside a computational framework for understanding corresponding pharmacokinetic and pharmacodynamic (PK/PD) behaviors. We especially focused on an albumin-bound prodrug of monomethyl auristatin E (MMAE) and found it blocked tumor growth in mice, delivered a 130-fold greater amount of activated drug to irradiated tumor versus unirradiated tissue, was 7.5-fold more efficient than a non albumin-bound prodrug, and showed no appreciable toxicity compared to free or cathepsin-activatable drugs. These data guided computational modeling of drug action, which indicated that extended pharmacokinetics can improve localized and cumulative drug activation, especially for payloads with low vascular permeability and diffusivity and particularly in patients receiving daily treatments of conventional radiotherapy for weeks. This work thus offers a quantitative PK/PD framework and proof-of-principle experimental demonstration of how extending prodrug circulation can improve its localized activity in vivo.

Tau propagation in the brain olfactory circuits is associated with smell perception changes in aging.

The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer's disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system.

Creating the freedom to thrive: Honoring the legacy of RSNA gold medalist, Deborah Levine, MD.

Awarded the Radiological Society of North America (RSNA) Gold Medal in 2018, Dr. Deborah Levine's research, journalism, and mentorship have left an indelible mark on the radiology field. Her work in ultrasound led to its use as the standard for monitoring benign adnexal cysts. She helped popularize obstetric magnetic resonance imaging (MRI) through her research on its use in placental accreta and fetal abnormalities, which led to the development of the 'Compendium of Fetal MRI' website. This work in research led naturally to a career in journalism, where she eventually became Senior Deputy Editor of Radiology and founded Radiology Select. Concurrently with her personal achievements, Dr. Levine has dedicated herself to the mentorship of her female trainees. She sought various leadership positions to learn more about and advocate for the promotion and support of female leadership in radiology departments. In many ways, Dr. Levine's career and work have transformed radiology as we know it today for both patients and physicians.

Deep learning based automated delineation of the intraprostatic gross tumour volume in PSMA-PET for patients with primary prostate cancer.

PURPOSE: With the increased use of focal radiation dose escalation for primary prostate cancer (PCa), accurate delineation of gross tumor volume (GTV) in prostate-specific membrane antigen PET (PSMA-PET) becomes crucial. Manual approaches are time-consuming and observer dependent. The purpose of this study was to create a deep learning model for the accurate delineation of the intraprostatic GTV in PSMA-PET. METHODS: A 3D U-Net was trained on 128 different 18F-PSMA-1007 PET images from three different institutions. Testing was done on 52 patients including one independent internal cohort (Freiburg: n = 19) and three independent external cohorts (Dresden: n = 14 18F-PSMA-1007, Boston: Massachusetts General Hospital (MGH): n = 9 18F-DCFPyL-PSMA and Dana-Farber Cancer Institute (DFCI): n = 10 68Ga-PSMA-11). Expert contours were generated in consensus using a validated technique. CNN predictions were compared to expert contours using Dice similarity coefficient (DSC). Co-registered whole-mount histology was used for the internal testing cohort to assess sensitivity/specificity. RESULTS: Median DSCs were Freiburg: 0.82 (IQR: 0.73-0.88), Dresden: 0.71 (IQR: 0.53-0.75), MGH: 0.80 (IQR: 0.64-0.83) and DFCI: 0.80 (IQR: 0.67-0.84), respectively. Median sensitivity for CNN and expert contours were 0.88 (IQR: 0.68-0.97) and 0.85 (IQR: 0.75-0.88) (p = 0.40), respectively. GTV volumes did not differ significantly (p > 0.1 for all comparisons). Median specificity of 0.83 (IQR: 0.57-0.97) and 0.88 (IQR: 0.69-0.98) were observed for CNN and expert contours (p = 0.014), respectively. CNN prediction took 3.81 seconds on average per patient. CONCLUSION: The CNN was trained and tested on internal and external datasets as well as histopathology reference, achieving a fast GTV segmentation for three PSMA-PET tracers with high diagnostic accuracy comparable to manual experts.

Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin-Drug Conjugate Response.

PURPOSE: Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK-ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies. EXPERIMENTAL DESIGN: Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin. The impacts of ectopic BRAFV600E and mutant RAS, genetic PTEN silencing, and inhibitors targeting RET, BRAF, and MEK kinases were quantified. BrafV600E p53-/- ATC tumors in immunocompetent mice were used to measure efficacy of an albumin-drug conjugate comprising microtubule-destabilizing monomethyl auristatin E (MMAE) linked to serum albumin via a cathepsin-cleavable peptide (Alb-vc-MMAE). RESULTS: FTC and ATC cells showed greater macropinocytosis than non-malignant and PTC cells. ATC tumors accumulated albumin at 8.8% injected dose per gram tissue. Alb-vc-MMAE, but not MMAE alone, reduced tumor size by >90% (P < 0.01). ATC macropinocytosis depended on MAPK/ERK activity and nutrient signaling, and increased by up to 230% with metformin, phenformin, or inhibition of IGF1Ri in monoculture but not in vivo. Macrophages also accumulated albumin and express the cognate IGF1R ligand, IGF1, which reduced ATC responsiveness to IGF1Ri. CONCLUSIONS: These findings identify regulated oncogene-driven macropinocytosis in thyroid cancers and demonstrate the potential of designing albumin-bound drugs to efficiently treat them.

A Practical Guide for Paid Family and Medical Leave in Radiology, From the AJR Special Series on DEI.

Paid family and medical leave (FML) has significant benefits to organizations, including improvements in employee recruitment and retention, workplace culture, and employee morale and productivity, and is supported by evidence for overall cost savings. Furthermore, paid FML related to childbirth has significant benefits to individuals and families, including but not limited to improved maternal and infant health outcomes and improved breastfeeding initiation and duration. In the case of nonchildbearing parental leave, paid FML is associated with more equitable long-term division of household labor and childcare. Paid FML is increasingly being recognized as an important issue in medicine, as evidenced by the recent passage of policies by national societies and governing bodies, including the American Board of Medical Specialties, American Board of Radiology, Accreditation Council for Graduate Medical Education (ACGME), American College of Radiology, and American Medical Association. Implementation of paid FML requires adherence to federal, state, and local laws as well as institutional requirements. Specific requirements pertain to trainees from national governing bodies, such as the ACGME and medical specialty boards. Flexibility, work coverage, culture, and finances are additional considerations for ensuring an optimal paid FML policy that accounts for concerns of all impacted individuals.

COVID-19: Findings in nuclear medicine from head to toe.

COVID-19 is a multisystemic disease, and hence its potential manifestations on nuclear medicine imaging can extend beyond the lung. Therefore, it is important for the nuclear medicine physician to recognize these manifestations in the clinic. While FDG-PET/CT is not indicated routinely in COVID-19 evaluation, its unique capability to provide a functional and anatomical assessment of the entire body means that it can be a powerful tool to monitor acute, subacute, and long-term effects of COVID-19. Single-photon scintigraphy is routinely used to assess conditions such as pulmonary embolism, cardiac ischemia, and thyroiditis, and COVID-19 may present in these studies. The most common nuclear imaging finding of COVID-19 vaccination to date is hypermetabolic axillary lymphadenopathy. This may pose important diagnostic and management dilemmas in oncologic patients, particularly those with malignancies where the axilla constitutes a lymphatic drainage area. This article aims to summarize the relevant literature published since the beginning of the pandemic on the intersection between COVID-19 and nuclear medicine.

Neurolymphomatosis in Recrudescent Diffuse Large B-cell Lymphoma.

Neurolymphomatosis is an uncommon manifestation of lymphoma, often presenting with painful polyneuropathy or polyradiculopathy and concomitant distal extremity weakness. Differentiation from other etiologies resulting in similar neuropathic symptoms such as compressive or inflammatory pathologies can be difficult and often results in delayed diagnosis. Here we describe a case of neurolymphomatosis affecting a 64-year-old man with a history of diffuse large B-cell lymphoma (DLBCL) in remission presenting with a right-sided foot drop following a gunshot wound. MRI at that time demonstrated thickening and enhancement of the cauda equina nerve roots. Over the course of the subsequent eight months, he developed left lower extremity sensory symptoms, left-sided foot drop and signs of upper motor neuron involvement, including left facial weakness, dysphonia, and dysphagia. 18F-FDG PET/CT revealed intensely avid left lumbosacral nerve roots, bilateral lower extremity and left upper extremity neurovascular bundles. Left sural nerve biopsies showed infiltration of DLBCL and confirmed neurolymphomatosis. We highlight the role of 18F-FDG PET/CT, with histological verification, for the diagnosis of an extended course of neurolymphomatosis occurring in the absence of typical painful neuropathy but with cranial and peripheral neuropathies.

Standard Adult Gastric Emptying Scintigraphy Criteria Is Applicable for Partial Meal Ingestion.

BACKGROUND/AIMS: Gastric emptying scintigraphy is commonly performed to assess for dysmotility. A standardized meal with associated threshold criteria was established in 2000 to enable robust interpretation. However, no guidance is available to interpret results when patients do not ingest the entire meal. The purpose of this study is to determine the continued appropriateness of the threshold criteria in contemporary clinical practice and its relevance for partially ingested meals. METHODS: This retrospective study analyzed patients (n = 1365 total) who underwent solid-phase gastric emptying scintigraphy at an academic medical center. Patients were stratified based on their completion of the standard meal. Patients were further stratified into normal and delayed gastric emptying cohorts based on the current criteria. Percent gastric retention values at 1, 2, 3, and 4 h were compared. RESULTS: Median (95% upper reference) normal gastric retention values for the complete standard meal were 64% (87%) at 1 h, 25% (60%) at 2 h, 13% (54%) at 3 h and 4% (9%) at 4 h. Consumption of at least 50% of the standard meal yielded similar retention; 53% (86%) at 1 h, 19% (58%) at 2 h, 6% (29%) at 3 h and 3% (10%) at 4 h. There was no significant age- or gender-specific differences using the current criteria, and no differences were observed based on diabetic status. Retention values matched well with the current criteria and validated with data-driven clustering. CONCLUSION: Adult normative standards for gastric emptying scintigraphy are appropriate for differentiating normal and delayed populations and can be applied to partial meals with at least 50% completion.

Key Factors to Attract More U.S. Diagnostic Radiology Residents into the Field of Nuclear Medicine and Molecular Imaging: A National Survey.

RATIONALE AND OBJECTIVES: To understand the current state of radiology residents' exposure to nuclear medicine and molecular imaging (NM/MI), determine key factors that may attract more trainees into the field, and identify differentiating aspects between those specializing in NM/MI and those who are not. MATERIALS AND METHODS: An anonymous web-based survey was sent to contacts at all diagnostic radiology residency programs in the United States for dissemination to their residents, collecting information about trainees' NM/MI exposure during residency and factors that may attract them to NM/MI. RESULTS: A total of 198 trainees responded to the survey, 34 of whom plan on pursuing a career in NM/MI. Most trainees reported early exposure to NM/MI during residency; most (97.4%) reported ample exposure to general NM/MI and oncologic studies. Less than 3% of trainees reported adequate exposure to therapies, neurological applications, molecular imaging/research advances, and physics. Respondents reported a need for better quality education (38.9%) and exposure to mentors (28.8%) as ways to attract trainees to NM/MI. Routinely encountered clinical pathology was the most interesting for those specializing in NM/MI (29.4%), whereas lifestyle was the most attractive aspect of NM/MI for those not pursuing a career in the field (27.4%). NM/MI-associated research was the least attractive for those specializing in NM/MI (35.3%), while job market concerns was the least attractive aspect for those not specializing in NM/MI (37.2%). Trainees planning to specialize in NM/MI reported higher satisfaction with their orientation to NM/MI during their first clinical rotation compared to those who do not plan to specialize in the field (3.03/5.00 and 2.67/5.00, respectively, p = 0.04). CONCLUSION: This survey highlights several factors that training programs and national societies can target to improve interest in NM/MI among radiology residents. We found that optimized education initiatives, including improved orientation to the field, increased mentoring, and career opportunities are essential levers for recruiting radiology trainees into the NM/MI workforce.

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy.

BRAF-targeted kinase inhibitors (KIs) are used to treat malignancies including BRAF-mutant non-small cell lung cancer, colorectal cancer, anaplastic thyroid cancer, and, most prominently, melanoma. However, KI selection criteria in patients remain unclear, as are pharmacokinetic/pharmacodynamic (PK/PD) mechanisms that may limit context-dependent efficacy and differentiate related drugs. To address this issue, we imaged mouse models of BRAF-mutant cancers, fluorescent KI tracers, and unlabeled drug to calibrate in silico spatial PK/PD models. Results indicated that drug lipophilicity, plasma clearance, faster target dissociation, and, in particular, high albumin binding could limit dabrafenib action in visceral metastases compared to other KIs. This correlated with retrospective clinical observations. Computational modeling identified a timed strategy for combining dabrafenib and encorafenib to better sustain BRAF inhibition, which showed enhanced efficacy in mice. This study thus offers principles of spatial drug action that may help guide drug development, KI selection, and combination.

Probing immune infiltration dynamics in cancer by in vivo imaging.

Cancer immunotherapies typically aim to stimulate the accumulation and activity of cytotoxic T-cells or pro-inflammatory antigen-presenting cells, reduce immunosuppressive myeloid cells or regulatory T-cells, or elicit some combination of effects thereof. Notwithstanding the encouraging results, immunotherapies such as PD-1/PD-L1-targeted immune checkpoint blockade act heterogeneously across individual patients. It remains challenging to predict and monitor individual responses, especially across multiple sites of metastasis or sites of potential toxicity. To address this need, in vivo imaging of both adaptive and innate immune cell populations has emerged as a tool to quantify spatial leukocyte accumulation in tumors non-invasively. Here we review recent progress in the translational development of probes for in vivo leukocyte imaging, focusing on complementary perspectives provided by imaging of T-cells, phagocytic macrophages, and their responses to therapy.

Confocal Imaging of Single-Cell Signaling in Orthotopic Models of Ovarian Cancer.

Ovarian cancer (OVCA) is frequently detected at late stages of disease, often with dissemination throughout the peritoneal cavity surface, abdomen, and ascites fluid. Tumor signaling via mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways can promote OVCA progression and depend on local microenvironmental cues. To better study OVCA in situ within native tissue contexts, here we describe confocal microscopy techniques to image mouse models of intraperitoneal disease at a single-cell resolution. As a proof of principle demonstration, examples are highlighted for simultaneously imaging tumor vascularization, infiltrating and often immunosuppressive immune cells (tumor-associated macrophages), and OVCA kinase activity.

Evaluation of Deep Learning-Based Approaches to Segment Bowel Air Pockets and Generate Pelvic Attenuation Maps from CAIPIRINHA-Accelerated Dixon MR Images.

Attenuation correction remains a challenge in pelvic PET/MRI. In addition to the segmentation/model-based approaches, deep learning methods have shown promise in synthesizing accurate pelvic attenuation maps (µ-maps). However, these methods often misclassify air pockets in the digestive tract, potentially introducing bias in the reconstructed PET images. The aims of this work were to develop deep learning-based methods to automatically segment air pockets and generate pseudo-CT images from CAIPIRINHA-accelerated MR Dixon images. Methods: A convolutional neural network (CNN) was trained to segment air pockets using 3-dimensional CAIPIRINHA-accelerated MR Dixon datasets from 35 subjects and was evaluated against semiautomated segmentations. A separate CNN was trained to synthesize pseudo-CT µ-maps from the Dixon images. Its accuracy was evaluated by comparing the deep learning-, model-, and CT-based µ-maps using data from 30 of the subjects. Finally, the impact of different µ-maps and air pocket segmentation methods on the PET quantification was investigated. Results: Air pockets segmented using the CNN agreed well with semiautomated segmentations, with a mean Dice similarity coefficient of 0.75. The volumetric similarity score between 2 segmentations was 0.85 ± 0.14. The mean absolute relative changes with respect to the CT-based µ-maps were 2.6% and 5.1% in the whole pelvis for the deep learning-based and model-based µ-maps, respectively. The average relative change between PET images reconstructed with deep learning-based and CT-based µ-maps was 2.6%. Conclusion: We developed a deep learning-based method to automatically segment air pockets from CAIPIRINHA-accelerated Dixon images, with accuracy comparable to that of semiautomatic segmentations. The µ-maps synthesized using a deep learning-based method from CAIPIRINHA-accelerated Dixon images were more accurate than those generated with the model-based approach available on integrated PET/MRI scanners.

Incorporating PSMA-Targeting Theranostics Into Personalized Prostate Cancer Treatment: a Multidisciplinary Perspective.

Recent developments in prostate-specific membrane antigen (PSMA) targeted diagnostic imaging and therapeutics (theranostics) promise to advance the management of primary, biochemically recurrent, and metastatic prostate cancer. In order to maximize the clinical impact of PSMA-targeted theranostics, a coordinated approach between the clinical stakeholders involved in prostate cancer management is required. Here, we present a vision for multidisciplinary use of PSMA theranostics from the viewpoints of nuclear radiology, medical oncology, urology, and radiation oncology. We review the currently available and forthcoming PSMA-based imaging and therapeutics and examine current and potential impacts on prostate cancer management from early localized disease to advanced treatment-refractory disease. Finally, we highlight the clinical and research opportunities related to PSMA-targeted theranostics and describe the importance of multidisciplinary collaboration in this space.