PET Imaging of Metabolism, Perfusion, and Hypoxia: FDG and Beyond.

ABSTRACT: Imaging glucose metabolism with [18F]fluorodeoxyglucose positron emission tomography has transformed the diagnostic and treatment algorithms of numerous malignancies in clinical practice. The cancer phenotype, though, extends beyond dysregulation of this single pathway. Reprogramming of other pathways of metabolism, as well as altered perfusion and hypoxia, also typifies malignancy. These features provide other opportunities for imaging that have been developed and advanced into humans. In this review, we discuss imaging metabolism, perfusion, and hypoxia in cancer, focusing on the underlying biology to provide context. We conclude by highlighting the ability to image multiple facets of biology to better characterize cancer and guide targeted treatment.

Total-Body Perfusion Imaging with [11C]-Butanol.

Tissue perfusion can be affected by physiology or disease. With the advent of total-body PET, quantitative measurement of perfusion across the entire body is possible. [11C]-butanol is a perfusion tracer with a superior extraction fraction compared with [15O]-water and [13N]-ammonia. To develop the methodology for total-body perfusion imaging, a pilot study using [11C]-butanol on the uEXPLORER total-body PET/CT scanner was conducted. Methods: Eight participants (6 healthy volunteers and 2 patients with peripheral vascular disease [PVD]) were injected with a bolus of [11C]-butanol and underwent 30-min dynamic acquisitions. Three healthy volunteers underwent repeat studies at rest (baseline) to assess test-retest reproducibility; 1 volunteer underwent paired rest and cold pressor test (CPT) studies. Changes in perfusion were measured in the paired rest-CPT study. For PVD patients, local changes in perfusion were investigated and correlated with patient medical history. Regional and parametric kinetic analysis methods were developed using a 1-tissue compartment model and leading-edge delay correction. Results: Estimated baseline perfusion values ranged from 0.02 to 1.95 mL·min-1·cm-3 across organs. Test-retest analysis showed that repeat baseline perfusion measurements were highly correlated (slope, 0.99; Pearson r = 0.96, P < 0.001). For the CPT subject, the largest regional increases were in skeletal muscle (psoas, 142%) and the myocardium (64%). One of the PVD patients showed increased collateral vessel growth in the calf because of a peripheral stenosis. Comorbidities including myocardial infarction, hypothyroidism, and renal failure were correlated with variations in organ-specific perfusion. Conclusion: This pilot study demonstrates the ability to obtain reproducible measurements of total-body perfusion using [11C]-butanol. The methods are sensitive to local perturbations in flow because of physiologic stressors and disease.

Total-Body Multiparametric PET Quantification of 18F-FDG Delivery and Metabolism in the Study of Coronavirus Disease 2019 Recovery.

Conventional whole-body static 18F-FDG PET imaging provides a semiquantitative evaluation of overall glucose metabolism without insight into the specific transport and metabolic steps. Here we demonstrate the ability of total-body multiparametric 18F-FDG PET to quantitatively evaluate glucose metabolism using macroparametric quantification and assess specific glucose delivery and phosphorylation processes using microparametric quantification for studying recovery from coronavirus disease 2019 (COVID-19). Methods: The study included 13 healthy subjects and 12 recovering COVID-19 subjects within 8 wk of confirmed diagnosis. Each subject had a 1-h dynamic 18F-FDG scan on the uEXPLORER total-body PET/CT system. Semiquantitative SUV and the SUV ratio relative to blood (SUVR) were calculated for different organs to measure glucose utilization. Tracer kinetic modeling was performed to quantify the microparametric blood-to-tissue 18F-FDG delivery rate [Formula: see text] and the phosphorylation rate k 3, as well as the macroparametric 18F-FDG net influx rate ([Formula: see text]). Statistical tests were performed to examine differences between healthy subjects and recovering COVID-19 subjects. The effect of COVID-19 vaccination was also investigated. Results: We detected no significant difference in lung SUV but significantly higher lung SUVR and [Formula: see text] in COVID-19 recovery, indicating improved sensitivity of kinetic quantification for detecting the difference in glucose metabolism. A significant difference was also observed in the lungs with the phosphorylation rate k 3 but not with [Formula: see text], which suggests that glucose phosphorylation, rather than glucose delivery, drives the observed difference of glucose metabolism. Meanwhile, there was no or little difference in bone marrow 18F-FDG metabolism measured with SUV, SUVR, and [Formula: see text] but a significantly higher bone marrow [Formula: see text] in the COVID-19 group, suggesting a difference in glucose delivery. Vaccinated COVID-19 subjects had a lower lung [Formula: see text] and a higher spleen [Formula: see text] than unvaccinated COVID-19 subjects. Conclusion: Higher lung glucose metabolism and bone marrow glucose delivery were observed with total-body multiparametric 18F-FDG PET in recovering COVID-19 subjects than in healthy subjects, implying continued inflammation during recovery. Vaccination demonstrated potential protection effects. Total-body multiparametric PET of 18F-FDG can provide a more sensitive tool and more insights than conventional whole-body static 18F-FDG imaging to evaluate metabolic changes in systemic diseases such as COVID-19.

Total-Body Multiparametric PET Quantification of 18 F-FDG Delivery and Metabolism in the Study of COVID-19 Recovery.

Conventional whole-body 18 F-FDG PET imaging provides a semi-quantitative evaluation of overall glucose metabolism without gaining insight into the specific transport and metabolic steps. Here we demonstrate the ability of total-body multiparametric 18 F-FDG PET to quantitatively evaluate glucose metabolism using macroparametric quantification and assess specific glucose delivery and phosphorylation processes using microparametric quantification for studying recovery from coronavirus disease 2019 (COVID-19). Methods: The study included thirteen healthy subjects and twelve recovering COVID-19 subjects within eight weeks of confirmed diagnosis. Each subject had a dynamic 18 F-FDG scan on the uEXPLORER total-body PET/CT system for one hour. Semiquantitative standardized uptake value (SUV) and SUV ratio relative to blood (SUVR) were calculated for regions of interest (ROIs) in different organs to measure glucose utilization. Tracer kinetic modeling was performed to quantify microparametric rate constants K 1 and k 3 that characterize 18 F-FDG blood-to-tissue delivery and intracellular phosphorylation, respectively, and a macroparameter K i that represents 18 F-FDG net influx rate. Statistical tests were performed to examine differences between the healthy controls and recovering COVID-19 subjects. Impact of COVID-19 vaccination was investigated. We further generated parametric images to confirm the ROI-based analysis. Results: We detected no significant difference in lung SUV but significantly higher lung SUVR and K i in the recovering COVID-19 subjects, indicating an improved sensitivity of kinetic quantification for detecting the difference in glucose metabolism. A significant difference was also observed in the lungs with the phosphorylation rate k 3 , but not with the delivery rate K 1 , which suggests it is glucose phosphorylation, not glucose delivery, that drives the observed difference of glucose metabolism in the lungs. Meanwhile, there was no or little difference in bone marrow metabolism measured with SUV, SUVR and K i , but a significant increase in bone-marrow 18 F-FDG delivery rate K 1 in the COVID-19 group ( p < 0.05), revealing a difference of glucose delivery in this immune-related organ. The observed differences were lower or similar in vaccinated COVID-19 subjects as compared to unvaccinated ones. The organ ROI-based findings were further supported by parametric images. Conclusions: Higher lung glucose metabolism and bone-marrow glucose delivery were observed with total-body multiparametric 18 F-FDG PET in recovering COVID-19 subjects as compared to healthy subjects, which suggests continued inflammation due to COVID-19 during the early stages of recovery. Total-body multiparametric PET of 18 F-FDG delivery and metabolism can provide a more sensitive tool and more insights than conventional static whole-body 18 F-FDG imaging to evaluate metabolic changes in systemic diseases such as COVID-19.

Impact of Online Group Psychoeducation and Support Sessions on Receptivity Towards Digital Mental Health Care During the COVID-19 Pandemic: A Pilot Study.

While social distancing was crucial to slow the COVID-19 virus, it also contributed to social isolation and emotional strain. This pilot study evaluated the impact of stand-alone psychoeducational group sessions designed to build social connectedness and space for people to learn about mental health during the pandemic. The study examined if offering the stand-alone group sessions increased uptake of and receptivity to additional mental health services. People had access to free, online group psychoeducational sessions offered by a digital mental health platform company. Sessions were offered to (1) employees who had mental health benefits offered through their employer, and to (2) members of the general public. Session formats included discussions, didactic lectures, and workshops, were facilitated by a mental health provider, and used live video conference technology. Topics included race and identity, stress management, coping with political events, relationship issues, and self-compassion. First-time session registrations were tracked from June 2020 to July 2021 on 6723 participants (3717 benefits-eligible employees and 3006 from the general public). Among the employee subsample, 49.5% attended a group session as their first use of any available service on the platform; 52.5% of these employees sought additional services after their first session. In anonymous post-session surveys of employees and members of the general public, 86% of respondents endorsed knowledge increases, 79.5% reported improved understanding of their mental health, 80.3% endorsed gaining actionable steps to improve mental health, 76.5% said that they would consider group sessions in addition to therapy, and 43.5% said that they would consider group sessions instead of therapy. These results suggest that scalable, brief group psychoeducational sessions are a useful conduit to mental health care and have potential to reach people who may not otherwise access available mental health services.

Efficient Delay Correction for Total-Body PET Kinetic Modeling Using Pulse Timing Methods.

Quantitative kinetic modeling requires an input function. A noninvasive image-derived input function (IDIF) can be obtained from dynamic PET images. However, a robust IDIF location (e.g., aorta) may be far from a tissue of interest, particularly in total-body PET, introducing a time delay between the IDIF and the tissue. The standard practice of joint estimation (JE) of delay, along with model fitting, is computationally expensive. To improve the efficiency of delay correction for total-body PET parametric imaging, this study investigated the use of pulse timing methods to estimate and correct for delay. Methods: Simulation studies were performed with a range of delay values, frame lengths, and noise levels to test the tolerance of 2 pulse timing methods-leading edge (LE) and constant fraction discrimination and their thresholds. The methods were then applied to data from 21 subjects (14 healthy volunteers, 7 cancer patients) who underwent a 60-min dynamic total-body 18F-FDG PET acquisition. Region-of-interest kinetic analysis was performed and parametric images were generated to compare LE and JE methods of delay correction, as well as no delay correction. Results: Simulations demonstrated that a 10% LE threshold resulted in biases and SDs at tolerable levels for all noise levels tested, with 2-s frames. Pooled region-of-interest-based results (n = 154) showed strong agreement between LE (10% threshold) and JE methods in estimating delay (Pearson r = 0.96, P < 0.001) and the kinetic parameters vb (r = 0.96, P < 0.001), Ki (r = 1.00, P < 0.001), and K1 (r = 0.97, P < 0.001). When tissues with minimal delay were excluded from pooled analyses, there were reductions in vb (69.4%) and K1 (4.8%) when delay correction was not performed. Similar results were obtained for parametric images; additionally, lesion Ki contrast was improved overall with LE and JE delay correction compared with no delay correction and Patlak analysis. Conclusion: This study demonstrated the importance of delay correction in total-body PET. LE delay correction can be an efficient surrogate for JE, requiring a fraction of the computational time and allowing for rapid delay correction across more than 106 voxels in total-body PET datasets.

Understanding Components of Therapeutic Alliance and Well-Being from Use of a Global Digital Mental Health Benefit During the COVID-19 Pandemic: Longitudinal Observational Study.

Digital mental health services leverage technology to increase access to care, yet less is known about the quality of therapeutic relationships in a virtual setting. This study examined components of therapeutic alliance (a mechanism underlying successful treatment) and its association with beneficial treatment outcomes in a real-world, virtual setting. The objective is to examine (1) participant ratings of components of therapeutic alliance with providers in a virtual setting, (2) changes in subjective well-being and depressive symptoms among participants who began care with elevated depressive symptoms, and (3) the association between components of alliance and changes in participants' well-being. Adults (N = 3,087, M age = 36 ± 9 years, 54% female) across the world with access to digital mental health benefits who engaged in videoconference sessions with a licensed therapist (18%, 555/3,087), certified coach (65%, 2,003/3,087), or both (17%, 529/3,087) between Sept. 29, 2020 and Oct. 12, 21. Participants completed 2 adapted items from the Working Alliance Inventory (goals and bonds subscales) after each session, and ratings were averaged across visits (Cronbach's ɑ = .72). Participants' World Health Organization-Five (WHO-5) Well-Being Index scores at the start and end of the study period were used to measure changes in subjective well-being. Descriptive and inferential statistics were conducted to examine average alliance ratings across demographics and utilization types and the association between alliance and well-being. The median adapted therapeutic alliance score was 4.8 (range: 1-5) and did not differ by age, country, or baseline well-being (Ps > .07). Females reported higher components of alliance than males (4.88 vs. 4.67, P = .01). Participants utilizing telecoaching reported higher components of alliance than those utilizing teletherapy or both telecoaching and teletherapy (4.83 v. 4.75, P = .004), though effect sizes were negligible. Among those with elevated baseline depressive symptoms (n = 835), participants reported an average WHO-5 increase of 15.42 points (95% CI 14.19-16.65, P < .001, Cohen d = 1.06) with 58% (485/835) reporting clinical recovery and 57% (481/835) reporting clinical improvement in depressive symptoms. Higher components of therapeutic alliance scores predicted greater well-being at follow-up (b = 2.04, 95% CI 0.09-3.99, P = .04) after controlling for age, sex, baseline WHO-5, and number of days in care (R 2 = .06, P < .001). Exploratory analyses indicated this association did not differ by utilization type, baseline well-being, or session utilization (Ps > .34). People with access to one-on-one videoconferencing care via a digital mental health benefit formed a strong bond and sense of alignment on goals with both coaches and therapists. Higher components of alliance scores were associated with improvements in subjective well-being among participants who began care with elevated depressive symptoms, providing evidence that a positive bond and goal alignment with a provider are two of many factors influencing virtual care outcomes. Continued focus on the quality of therapeutic relationships will ensure digital mental health services are patient-tailored as these platforms expand equitable access to evidence-based care.

Blanching Defects at the Pressure Points: Observations from Dynamic Total-Body PET/CT Studies.

Total-body PET/CT allows simultaneous acquisition of all the body parts in a single bed position during the radiotracer uptake phase. Dynamic imaging protocols employing total-body PET could demonstrate findings that may not have been previously visualized or described using conventional PET/CT scanners. We examined the characteristics of blanching defects, areas of markedly reduced (partial defect) or absent (complete defect) radiotracer uptake seen at the skin/subcutaneous tissues opposite the bony prominences at pressure points. Methods: In this observational study, 77 participants underwent dynamic total-body PET/CT imaging using 18F-FDG (Group 1, N = 47, 60-min dynamic, arms-down, divided into 3 subgroups according to the injected dose) or 18F-fluciclovine (Group 2, N = 30, 25-min dynamic, arms above the head). 40 out of 47 participants in Group 1 were re-imaged at 90 min after being allowed off the scanning table. Blanching defects, partial or complete, were characterized opposite the bony prominences at 7 pressure points (the skull, scapula, and calcaneus bilaterally, as well as the sacrum). Association of the blanching defects with different clinical and technical characteristics were analyzed using uni- and multi-variate analyses. Results: A total of 124 blanching defects were seen in 68 out of 77 (88%) participants at one or more pressure points. Blanching defects were higher, on average, in Group 2 participants (3.5±1.7) compared to Group 1 (2.1±1.4; P <0.001), but it did not vary within Group 1 for different 18F-FDG dose subgroups. All defects resumed normal pattern on delayed static (90-min) images except for 14 partial defects. No complete blanching defects were seen on the 90-min images. By multivariate analysis, arm positioning above the head was associated with skull defects; scapular and sacral defects were significantly more encountered in men and with lower BMI, while calcaneal defects could not be associated to any factor. Conclusion: Blanching defects opposite the bony pressure points are common on dynamic total-body PET/CT images using different radiopharmaceuticals and injection doses. Their appearance should not be immediately interpreted as an abnormality. The current findings warrant further exploration in a prospective setting and may be utilized to study various mechano-pathologic conditions, such as pressure ulcers.