Theranostics: Leveraging Molecular Imaging and Therapy to Impact Patient Management and Secure the Future of Nuclear Medicine.

Nuclear medicine is experiencing a renaissance, with U.S. Food and Drug Administration approval recently being obtained for theranostic agents and a wide variety of such agents soon to impact patient care significantly in the era of precision medicine. The NETTER-1 trial demonstrated the therapeutic effect of a theranostic agent in markedly improving progression-free survival in patients with metastatic gastroenteropancreatic neuroendocrine tumors. Predominantly retrospective studies have demonstrated a significant response to 177Lu-labeled agents targeting prostate-specific membrane antigen (PSMA) in patients with prostate cancer. At least 2 prospective clinical trials involving 177Lu-PSMA agents are under way that will likely pave the way for Food and Drug Administration approval in the United States. A significant upside to theranostics is that patients tend to tolerate these agents better than chemotherapy. Theranostic compounds are likely to impact many cancers in the near future, not only through improvements in quality of life but also in terms of survival. This article provides an overview of already approved agents as well as those on the horizon. It is important that as these agents are clinically onboarded, nuclear medicine physicians have the expertise to deploy theranostics safely and efficiently, ensuring that these agents attain and maintain their position as leading lines of therapy in managing patients with cancer as well as becoming an important aspect of nuclear medicine practice in the future.

18F-NaF-PET/CT for the detection of bone metastasis in prostate cancer: a meta-analysis of diagnostic accuracy studies.

PURPOSE: This meta-analysis aims to establish the diagnostic performance of 18F-NaF-PET/CT for the detection of bone metastases in prostate cancer patients. The performance of 18F-NaF-PET/CT was compared with other imaging techniques in the same cohort of patients. METHODS: A systematic search was performed in PubMed/Medline and EMBASE (last Updated, September 28, 2018). Studies with histopathology confirmation and/or clinical/imaging follow-up as reference standard were eligible for inclusion. RESULTS: A total of 14 studies were included. Twelve studies including 507 patients provided per-patient basis information. The pooled sensitivity, specificity, diagnostic odds ratio (DOR) and the area under the summary receiver operating characteristics curve (AUC) of 18F-NaF-PET/CT for the detection of bone metastases were 0.98 (95% CI 0.95-0.99), 0.90 (95% CI 0.86-0.93), 123.2 and 0.97, respectively. Seven studies provided the lesion-based accuracy information of 1812 lesions identified on 18F-NaF-PET/CT with the pooled sensitivity, specificity, DOR and AUC of 0.97 (95% CI 0.95-0.98), 0.84 (95% CI 0.81-0.87), 206.8 and 0.97, respectively. The overall diagnostic performance of 18F-NaF-PET/CT is superior to 99mTc-bone scintigraphy (AUC 0.842; P < 0.001; four studies) and 99mTc-SPECT (AUC 0.896; P < 0.001, four studies). Compared to 18F NaF-PET/CT, whole-body MRI with diffusion-weighted imaging (DWI) was shown to have lower sensitivity (0.83, 95% CI 0.68-0.93), with no significant difference in the overall performance (AUC 0.947; P = 0.18, four studies). CONCLUSION: 18F-NaF-PET/CT has excellent diagnostic performance in the detection of bone metastases in staging and restaging of high-risk prostate cancer patients. The performance of 18F-NaF-PET/CT is superior to 99mTc bone scintigraphy and SPECT, and comparable to DWI-MRI.

Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker.

OBJECTIVE: To compare brain metabolism patterns on fluorodeoxyglucose (FDG)-PET/CT in anti-NMDA receptor and other definite autoimmune encephalitis (AE) and to assess how these patterns differ between anti-NMDA receptor neurologic disability groups. METHODS: Retrospective review of clinical data and initial dedicated brain FDG-PET/CT studies for neurology inpatients with definite AE, per published consensus criteria, treated at a single academic medical center over a 10-year period. Z-score maps of FDG-PET/CT were made using 3-dimensional stereotactic surface projections in comparison to age group-matched controls. Brain region mean Z scores with magnitudes ≥2.00 were interpreted as significant. Comparisons were made between anti-NMDA receptor and other definite AE patients as well as among patients with anti-NMDA receptor based on modified Rankin Scale (mRS) scores at the time of FDG-PET/CT. RESULTS: The medial occipital lobes were markedly hypometabolic in 6 of 8 patients with anti-NMDA receptor encephalitis and as a group (Z = -4.02, interquartile range [IQR] 2.14) relative to those with definite AE (Z = -2.32, 1.46; p = 0.004). Among patients with anti-NMDA receptor encephalitis, the lateral and medial occipital lobes were markedly hypometabolic for patients with mRS 4-5 (lateral occipital lobe Z = -3.69, IQR 1; medial occipital lobe Z = -4.08, 1) compared with those with mRS 0-3 (lateral occipital lobe Z = -0.83, 2; p < 0.0005; medial occipital lobe Z = -1.07, 2; p = 0.001). CONCLUSIONS: Marked medial occipital lobe hypometabolism by dedicated brain FDG-PET/CT may serve as an early biomarker for discriminating anti-NMDA receptor encephalitis from other AE. Resolution of lateral and medial occipital hypometabolism may correlate with improved neurologic status in anti-NMDA receptor encephalitis.

Use of quantitative SPECT/CT reconstruction in 99mTc-sestamibi imaging of patients with renal masses.

OBJECTIVE: Technetium-99m (99mTc)-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) has previously been shown to allow for the accurate differentiation of benign renal oncocytomas and hybrid oncocytic/chromophobe tumors (HOCTs) apart from other malignant renal tumor histologies, with oncocytomas/HOCTs showing high uptake and renal cell carcinoma (RCC) showing low uptake based on uptake ratios from non-quantitative single-photon emission computed tomography (SPECT) reconstructions. However, in this study, several tumors fell close to the uptake ratio cutoff, likely due to limitations in conventional SPECT/CT reconstruction methods. We hypothesized that application of quantitative SPECT/CT (QSPECT) reconstruction methods developed by our group would provide more robust separation of hot and cold lesions, serving as an imaging framework on which quantitative biomarkers can be validated for evaluation of renal masses with 99mTc-sestamibi. METHODS: Single-photon emission computed tomography data were reconstructed using the clinical Flash 3D reconstruction and QSPECT methods. Two blinded readers then characterized each tumor as hot or cold. Semi-quantitative uptake ratios were calculated by dividing lesion activity by background renal activity for both Flash 3D and QSPECT reconstructions. RESULTS: The difference between median (mean) hot and cold tumor uptake ratios measured 0.655 (0.73) with the QSPECT method and 0.624 (0.67) with the conventional method, resulting in increased separation between hot and cold tumors. Sub-analysis of 7 lesions near the separation point showed a higher absolute difference (0.16) between QPSECT and Flash 3D mean uptake ratios compared to the remaining lesions. CONCLUSIONS: Our finding of improved separation between uptake ratios of hot and cold lesions using QSPECT reconstruction lays the foundation for additional quantitative SPECT techniques such as SPECT-UV in the setting of renal 99mTc-sestamibi and other SPECT/CT exams. With robust quantitative image reconstruction and biomarker analysis, there may be an expanded role for SPECT/CT imaging in renal masses and other pathologic conditions.

Patterns of uptake of prostate-specific membrane antigen (PSMA)-targeted 18F-DCFPyL in peripheral ganglia.

OBJECTIVE: Radiotracers targeting prostate-specific membrane antigen (PSMA) have increasingly been recognized as showing uptake in a number of normal structures, anatomic variants, and non-prostate-cancer pathologies. We aimed to explore the frequency and degree of uptake in peripheral ganglia in patients undergoing PET with the PSMA-targeted agent 18F-DCFPyL. METHODS: A total of 98 patients who underwent 18F-DCFPyL PET/CT imaging were retrospectively analyzed. This included 76 men with prostate cancer (PCa) and 22 patients with renal cell carcinoma (RCC; 13 men, 9 women). Scans were evaluated for uptake in the cervical, stellate, celiac, lumbar and sacral ganglia. Maximum standardized uptake value corrected to body weight (SUVmax), and maximum standardized uptake value corrected to lean body mass (SULmax) were recorded for all ganglia with visible uptake above background. Ganglia-to-background ratios were calculated by dividing the SUVmax and SULmax values by the mean uptake in the ascending aorta (Aortamean) and the right gluteus muscle (Gluteusmean). RESULTS: Overall, 95 of 98 (96.9%) patients demonstrated uptake in at least one of the evaluated peripheral ganglia. With regard to the PCa cohort, the most frequent sites of radiotracer accumulation were lumbar ganglia (55/76, 72.4%), followed by the cervical ganglia (51/76, 67.1%). Bilateral uptake was found in the majority of cases [lumbar 44/55 (80%) and cervical 30/51 (58.8%)]. Additionally, discernible radiotracer uptake was recorded in 50/76 (65.8%) of the analyzed stellate ganglia and in 45/76 (59.2%) of the celiac ganglia, whereas only 5/76 (6.6%) of the sacral ganglia demonstrated 18F-DCFPyL accumulation. Similar findings were observed for patients with RCC, with the most frequent locations of radiotracer uptake in both the lumbar (20/22, 90.9%) and cervical ganglia (19/22, 86.4%). No laterality preference was found in mean PSMA-ligand uptake for either the PCa or RCC cohorts. CONCLUSION: As PSMA-targeted agents become more widely disseminated, the patterns of uptake in structures that are not directly relevant to patients' cancers must be understood. This is the first systematic evaluation of the uptake of 18F-DCFPyL in ganglia demonstrating a general trend with a descending frequency of radiotracer accumulation in lumbar, cervical, stellate, celiac, and sacral ganglia. The underlying biology that leads to variability of PSMA-targeted radiotracers in peripheral ganglia is not currently understood, but may provide opportunities for future research.

Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis.

OBJECTIVE: To compare the rate of abnormal brain metabolism by FDG-PET/CT to other paraclinical findings and to describe brain metabolism patterns in autoimmune encephalitis (AE). METHODS: A retrospective review of clinical data and initial dedicated brain FDG-PET/CT studies for neurology inpatients with AE, per consensus criteria, treated at a single tertiary center over 123 months. Z-score maps of FDG-PET/CT were made using 3-dimensional stereotactic surface projections with comparison to age group-matched controls. Brain region mean Z-scores with magnitudes ≥2.00 were interpreted as significant. Comparisons were made to rates of abnormal initial brain MRI, abnormal initial EEG, and presence of intrathecal inflammation. RESULTS: Sixty-one patients with AE (32 seropositive) underwent brain FDG-PET/CT at median 4 weeks of symptoms (interquartile range [IQR] 9 weeks) and median 4 days from MRI (IQR 8.5 days). FDG-PET/CT was abnormal in 52 (85%) patients, with 42 (69%) demonstrating only hypometabolism. Isolated hypermetabolism was demonstrated in 2 (3%) patients. Both hypermetabolic and hypometabolic brain regions were noted in 8 (13%) patients. Nine (15%) patients had normal FDG-PET/CT studies. CSF inflammation was evident in 34/55 (62%) patients, whereas initial EEG (17/56, 30%) and MRI (23/57, 40%) were abnormal in fewer. Detection of 2 or more of these paraclinical findings was in weak agreement with abnormal brain FDG-PET/CT (κ = 0.16, p = 0.02). CONCLUSIONS: FDG-PET/CT was more often abnormal than initial EEG, MRI, and CSF studies in neurology inpatients with AE, with brain region hypometabolism the most frequently observed.

Diagnostic Value of 18F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis.

Diagnosis of autoimmune encephalitis presents some challenges in the clinical setting because of varied clinical presentations and delay in obtaining antibody panel results. We examined the role of neuroimaging in the setting of autoimmune encephalitides, comparing the utility of 18F-FDG PET/CT versus conventional brain imaging with MRI. Methods: A retrospective study was performed assessing the positivity rate of MRI versus 18F-FDG PET/CT during the initial workup of 23 patients proven to have antibody-positive autoimmune encephalitis. 18F-FDG PET/CT studies were analyzed both qualitatively and semiquantitatively. Areas of cortical lobar hypo (hyper)-metabolism in the cerebrum that were 2 SDx from the mean were recorded as abnormal. Results: On visual inspection, all patients were identified as having an abnormal pattern of 18F-FDG uptake. In semiquantitative analysis, at least 1 region of interest with metabolic change was identified in 22 of 23 (95.6%) patients using a discriminating z score of 2. Overall, 18F-FDG PET/CT was more often abnormal during the diagnostic period than MRI (10/23, 43% of patients). The predominant finding on brain 18F-FDG PET/CT imaging was lobar hypometabolism, being observed in 21 of 23 (91.3%) patients. Hypometabolism was most commonly observed in the parietal lobe followed by the occipital lobe. An entire subset of antibody-positive patients, anti-N-methyl-d-aspartate receptor (5 patients), had normal MRI results and abnormal 18F-FDG PET/CT findings whereas the other subsets demonstrated a greater heterogeneity. Conclusion: Brain 18F-FDG PET/CT may play a significant role in the initial evaluation of patients with clinically suspected antibody-mediated autoimmune encephalitis. Given that it is more often abnormal when compared with MRI in the acute setting, this molecular imaging technique may be better positioned as an early biomarker of disease so that treatment may be initiated earlier, resulting in improved patient outcomes.