Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity.

BACKGROUNDMirabegron is a ß3-adrenergic receptor (ß3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that ß3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of ß3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).

Eruption of Metastatic Paraganglioma After Successful Therapy with 177Lu/90Y-DOTATOC and 177Lu-DOTATATE.

ABSTRACT: Metastatic paraganglioma treatment options are limited. Peptide receptor radionuclide therapy (PRRT) has been introduced as a novel management option for metastatic neuroendocrine tumors demonstrating safety, efficacy, and increased quality of life. We present two cases of marked progression of metastatic paraganglioma following initial partial response to PRRT. Given their positivity on 68Ga-DOTATATE PET/CT and 111In-octreotide SPECT, they underwent PRRT. Imaging following treatment revealed significant improvement in size and intensity, with some foci nearly completely resolved in one patient, and disease regression with a decrease in the number and size of bone and liver lesions in the second patient. Within months, repeat imaging in both patients revealed extensive metastatic disease with new lesions, which eventually lead to their deaths. The mechanism for rapid disease progression after partial response is not well understood, although it could be related to initially high Ki-67 levels or 18F-FDG PET/CT SUVmax values. However, naturally rapid disease progression despite PRRT response cannot be excluded. This finding warrants the importance of proper patient counseling along with early and accurate pre-PRRT assessment, taking into consideration the above potential risk factors for therapy response in order to personalize treatment regimens and achieve maximum patient benefit. CLINICALTRIALSGOV IDENTIFIER: NCT00004847.

Regulation of Human Adipose Tissue Activation, Gallbladder Size, and Bile Acid Metabolism by a ß3-Adrenergic Receptor Agonist.

ß3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We performed tissue receptor profiling and showed that the human ß3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in 12 healthy men given one-time randomized doses of placebo, the approved dose of 50 mg, and 200 mg of the ß3-AR agonist mirabegron. There was a more-than-dose-proportional increase in BAT metabolic activity as measured by [18F]-2-fluoro-D-2-deoxy-d-glucose positron emission tomography/computed tomography (medians 0.0 vs. 18.2 vs. 305.6 mL ⋅ mean standardized uptake value [SUVmean] ⋅ g/mL). Only the 200-mg dose elevated both nonesterified fatty acids (68%) and resting energy expenditure (5.8%). Previously undescribed increases in gallbladder size (35%) and reductions in conjugated bile acids were also discovered. Therefore, besides urinary bladder relaxation, the human ß3-AR contributes to white adipose tissue lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective ß3-AR agonists to treat obesity-related complications.

Anatomy, Functionality, and Neuronal Connectivity with Manganese Radiotracers for Positron Emission Tomography.

PURPOSE: Manganese ion has been extensively used as a magnetic resonance imaging (MRI) contrast agent in preclinical studies to assess tissue anatomy, function, and neuronal connectivity. Unfortunately, its use in human studies has been limited by cellular toxicity and the need to use a very low dose. The much higher sensitivity of positron emission tomography (PET) over MRI enables the use of lower concentrations of manganese, potentially expanding the methodology to humans. PROCEDURES: PET tracers manganese-51 (Mn-51, t1/2 = 46 min) and manganese-52 (Mn-52, t1/2 = 5.6 days) were used in this study. The biodistribution of manganese in animals in the brain and other tissues was studied as well as the uptake in the pancreas after glucose stimulation as a functional assay. Finally, neuronal connectivity in the olfactory pathway following nasal administration of the divalent radioactive Mn-52 ([52Mn]Mn2+) was imaged. RESULTS: PET imaging with the divalent radioactive Mn-51 ([51Mn]Mn2+) and [52Mn]Mn2+ in both rodents and monkeys demonstrates that the accumulation of activity in different organs is similar to that observed in rodent MRI studies following systemic administration. Furthermore, we demonstrated the ability of manganese to enter excitable cells. We followed activity-induced [51Mn]Mn2+ accumulation in the pancreas after glucose stimulation and showed that [52Mn]Mn2+ can be used to trace neuronal connections analogous to manganese-enhanced MRI neuronal tracing studies. CONCLUSIONS: The results were consistent with manganese-enhanced MRI studies, despite the much lower manganese concentration used for PET (100 mM Mn2+ for MRI compared to ~ 0.05 mM for PET). This indicates that uptake and transport mechanisms are comparable even at low PET doses. This helps establish the use of manganese-based radiotracers in both preclinical and clinical studies to assess anatomy, function, and connectivity.

Congenital Adrenal Hyperplasia Presenting as an Adrenal Mass With Increased 18F-FDG Positron Emission Tomography Uptake.

This article describes congenital adrenal hyperplasia presenting as an adrenal mass with increased 18F-FDG positron emission tomography uptake.

Functional Imaging Signature of Patients Presenting with Polycythemia/Paraganglioma Syndromes.

Pheochromocytoma/paraganglioma (PPGL) syndromes associated with polycythemia have previously been described in association with mutations in the von Hippel-Lindau gene. Recently, mutations in the prolyl hydroxylase gene (PHD) 1 and 2 and in the hypoxia-inducible factor 2 α (HIF2A) were also found to be associated with multiple and recurrent PPGL. Such patients also presented with PPGL and polycythemia, and later on, some presented with duodenal somatostatinoma. In additional patients presenting with PPGL and polycythemia, no further mutations have been discovered. Because the functional imaging signature of patients with PPGL-polycythemia syndromes is still unknown, and because these tumors (in most patients) are multiple, recurrent, and metastatic, the goal of our study was to assess the optimal imaging approach using 4 different PET radiopharmaceuticals and CT/MRI in these patients. Methods: Fourteen patients (10 women, 4 men) with confirmed PPGL and polycythemia prospectively underwent 68Ga-DOTATATE (13 patients), 18F-FDG (13 patients), 18F-fluorodihydroxyphenylalanine (18F-FDOPA) (14 patients), 18F-fluorodopamine (18F-FDA) (11 patients), and CT/MRI (14 patients). Detection rates of PPGL lesions were compared between all imaging studies and stratified between the underlying mutations. Results:18F-FDOPA and 18F-FDA PET/CT showed similar combined lesion-based detection rates of 98.7% (95% confidence interval [CI], 92.7%-99.8%) and 98.3% (95% CI, 90.9%-99.7%), respectively. The detection rates for 68Ga-DOTATATE (35.3%; 95% CI, 25.0%-47.2%), 18F-FDG (42.3; 95% CI, 29.9%-55.8%), and CT/MRI (60.3%; 95% CI, 48.8%-70.7%) were significantly lower (P < 0.01), irrespective of the mutation status. Conclusion:18F-FDOPA and 18F-FDA are superior to 18F-FDG, 68Ga-DOTATATE, and CT/MRI and should be the radiopharmaceuticals of choice in this rare group of patients.

Lymph Node Activation by PET/CT Following Vaccination With Licensed Vaccines for Human Papillomaviruses.

BACKGROUND: While PET using F-FDG is most commonly used for imaging malignant tumors, vaccination is known to cause transient inflammation of lymph nodes inducing positive findings on F-FDG PET scans. The pattern, magnitude, and duration of lymph node activation following vaccination have not been clearly defined. Furthermore, the addition of adjuvants to vaccines can further enhance the immune response. The presented study was designed to define lymph node activation following administration of the Food and Drug Administration-licensed human papillomavirus vaccines, Cervarix and Gardasil, which contain similar antigens with different adjuvants. METHODS: Twenty-seven women aged 18 to 25 years were randomized to receive either Cervarix or Gardasil in the clinical trial VRC 900. Fifteen subjects participated in the PET/CT portion of the trial and received scans of lymph node activation at prevaccination and "1 week" (8-14 days) and "1 month" (23-36 days) after the first or third vaccination. RESULTS: PET/CT scans revealed that all vaccine recipients had ipsilateral axillary lymph node activity. Three of 4 Cervarix recipients also showed contralateral lymph node activity 1 month after the first vaccination. For both Cervarix and Gardasil, the SUV activity resolved over time, with activity extended up to day 37 after the first and third vaccinations. CONCLUSIONS: Following intramuscular vaccination, there were no major differences between duration of uptake and intensity of SUV between Cervarix and Gardasil recipients in ipsilateral axillary lymph nodes. Contralateral node activation was detected up to 1 month after the first vaccination in Cervarix recipients only, possibly reflecting differences in vaccine adjuvant formulation.

Relevant Discordance Between 68Ga-DOTATATE and 68Ga-DOTANOC in SDHB-Related Metastatic Paraganglioma: Is Affinity to Somatostatin Receptor 2 the Key?

Pheochromocytomas/paragangliomas are somatostatin receptor 2-overexpressing tumors. Ga-DOTA-peptide imaging has recently shown excellent results in the detection of metastatic lesions in these tumors. However, currently used Ga-DOTA peptides show different somatostatin receptor affinities. Here, we report the remarkable differences in a patient who was imaged with Ga-DOTANOC and Ga-DOTATATE PET/CT within a 7-month period. The patient presented with a nearly negative Ga-DOTANOC PET/CT scan, whereas on Ga-DOTATATE PET/CT, multiple highly positive lesions were identified.

PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma.

PURPOSE: Pheochromocytomas/paragangliomas (PPGLs) and their metastases are tumors that predominantly express somatostatin receptor 2 (SSR2). (68)Ga-DOTA(0)-Tyr(3)-octreotate ((68)Ga-DOTATATE) is a PET radiopharmaceutical with both high and selective affinity for SSRs. The purpose of this study was to evaluate the utility of (68)Ga-DOTATATE in comparison with other specific and nonspecific radiopharmaceuticals recommended in the current guidelines for the localization of metastatic sporadic PPGL by PET/CT. METHODS: This prospective study included 22 patients (15 men, 7 women; aged 50.0 ± 13.9 years) with confirmed metastatic PPGL, a negative family history for PPGL, and negative genetic testing, who underwent (68)Ga-DOTATATE, (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/CT, and CT/MRI. Only 12 patients underwent an additional (18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) PET/CT scan and only 11 patients underwent an additional (18)F-fluorodopamine ((18)F-FDA) PET/CT scan. The rates of detection of metastatic lesions were compared among all the imaging studies. A composite of all functional and anatomical imaging studies served as the imaging comparator. RESULTS: (68)Ga-DOTATATE PET/CT showed a lesion-based detection rate of 97.6 % (95 % confidence interval, CI, 95.8 - 98.7 %). (18)F-FDG PET/CT, (18)F-FDOPA PET/CT, (18)F-FDA PET/CT, and CT/MRI showed detection rates of 49.2 % (CI 44.5 - 53.6 %; p < 0.01), 74.8 % (CI 69.0 - 79.9 %); p < 0.01), 77.7 % (CI 71.5 - 82.8 %; p < 0.01), and 81.6 % (CI 77.8 - 84.8 %; p < 0.01), respectively. CONCLUSION: The results of this study demonstrate the superiority of (68)Ga-DOTATATE PET/CT in the localization of sporadic metastatic PPGLs compared to all other functional and anatomical imaging modalities, and suggest modification of future guidelines towards this new imaging modality.

Rapidly Growing Chest Wall Mass in a Case of Sporadic Metastatic Paraganglioma: Imaging With 4 Different PET Radiopharmaceuticals.

Pheochromocytomas/paragangliomas (PGLs) are rare tumors and mostly benign. We report on a 32-year-old woman with metastatic PGL who was first diagnosed with an abdominal PGL at the age of 12 years. She soon developed metastatic disease and received several treatments including external beam radiation and chemotherapy. When she was referred to our institution in 2014, her major complaint was a rapidly growing chest wall mass on the left side. The patient was imaged at our institution with 4 different PET radiopharmaceuticals.

68Ga-DOTATATE PET/CT in the Localization of Head and Neck Paragangliomas Compared with Other Functional Imaging Modalities and CT/MRI.

UNLABELLED: Pheochromocytomas/paragangliomas overexpress somatostatin receptors, and recent studies have already shown excellent results in the localization of sympathetic succinate dehydrogenase complex, subunit B, mutation-related metastatic pheochromocytomas/paragangliomas using (68)Ga-DOTATATE PET/CT. Therefore, the goal of our study was to assess the clinical utility of this functional imaging modality in parasympathetic head and neck paragangliomas (HNPGLs) compared with anatomic imaging with CT/MRI and other functional imaging modalities, including (18)F-fluorohydroyphenylalanine ((18)F-FDOPA) PET/CT, currently the gold standard in the functional imaging of HNPGLs. METHODS: (68)Ga-DOTATATE PET/CT was prospectively performed in 20 patients with HNPGLs. All patients also underwent (18)F-FDOPA PET/CT, (18)F-FDG PET/CT, and CT/MRI, with 18 patients also undergoing (18)F-fluorodopamine ((18)F-FDA) PET/CT. (18)F-FDOPA PET/CT and CT/MRI served as the imaging comparators. RESULTS: Thirty-eight lesions in 20 patients were detected, with (18)F-FDOPA PET/CT identifying 37 of 38 and CT/MRI identifying 23 of 38 lesions (P < 0.01). All 38 and an additional 7 lesions (P = 0.016) were detected on (68)Ga-DOTATATE PET/CT. Significantly fewer lesions were identified by (18)F-FDG PET/CT (24/38, P < 0.01) and (18)F-FDA PET/CT (10/34, P < 0.01). CONCLUSION: (68)Ga-DOTATATE PET/CT identified more lesions than other imaging modalities. With the results of the present study, and the increasing availability and use of DOTA analogs in the therapy of neuroendocrine tumors, we expect that (68)Ga-DOTATATE PET/CT will become the preferred functional imaging modality for HNPGLs in the near future.

Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of SDHB-Associated Metastatic Pheochromocytoma and Paraganglioma.

PURPOSE: Patients with succinate dehydrogenase subunit B(SDHB) mutation-related pheochromocytoma/paraganglioma (PHEO/PGL) are at a higher risk for metastatic disease than other hereditary PHEOs/PGLs. Current therapeutic approaches are limited, but the best outcomes are based on the early and proper detection of as many lesions as possible. Because PHEOs/PGLs overexpress somatostatin receptor 2 (SSTR2), the goal of our study was to assess the clinical utility of [(68)Ga]-DOTA(0)-Tyr(3)-octreotate ([(68)Ga]-DOTATATE) positron emission tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison with the currently recommended functional imaging modalities [(18)F]-fluorodopamine ([(18)F]-FDA), [(18)F]-fluorodihydroxyphenylalanine ([(18)F]-FDOPA), [(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]- FDG) PET/CT as well as CT/MRI. EXPERIMENTAL DESIGN: [(68)Ga]-DOTATATE PET/CT was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent [(18)F]-FDG PET/CT and CT/MRI, with 16 of the 17 patients also receiving [(18)F]-FDOPA and [(18)F]-FDA PET/CT scans. Detection rates of metastatic lesions were compared between all these functional imaging studies. A composite synthesis of all used functional and anatomical imaging studies served as the imaging comparator. RESULTS: [(68)Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% [95% confidence interval (CI), 96.5%-99.5%], [(18)F]-FDG, [(18)F]-FDOPA, [(18)F]-FDA PET/CT, and CT/MRI showed detection rates of 85.8% (CI, 81.3%-89.4%; P < 0.01), 61.4% (CI, 55.6%-66.9%; P < 0.01), 51.9% (CI, 46.1%-57.7%; P < 0.01), and 84.8% (CI, 80.0%-88.5%; P < 0.01), respectively. CONCLUSIONS: [(68)Ga]-DOTATATE PET/CT showed a significantly superior detection rate to all other functional and anatomical imaging modalities and may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL.

Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature.

CONTEXT: The contribution of brown adipose tissue (BAT) to the energy balance in humans exposed to sustainable cold has not been completely established, partially because of measurement limitations of both BAT activity and energy expenditure (EE). OBJECTIVE: The objective of the study was to characterize the role of BAT activation in cold-induced thermogenesis (CIT). DESIGN: This study was a single-blind, randomized crossover intervention. SETTING: The study was conducted at the National Institutes of Health Clinical Center. STUDY PARTICIPANTS: Thirty-one healthy volunteers participated in the study. INTERVENTIONS: The intervention included mild cold exposure. MAIN OUTCOMES: CIT and BAT activation were the main outcomes in this study. METHODS: Overnight EE measurement by whole-room indirect calorimeter at 24 °C or 19 °C was followed by 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (PET) scan. After 36 hours, volunteers crossed over to the alternate study temperature under identical conditions. BAT activity was measured in a 3-dimensional region of interest in the upper torso by comparing the uptake at the two temperatures. RESULTS: Twenty-four volunteers (14 males, 10 females) had a complete data set. When compared with 24 °C, exposure at 19 °C resulted in increased EE (5.3 ± 5.9%, P < .001), indicating CIT response and mean BAT activity (10.5 ± 11.1%, P < .001). Multiple regression analysis indicated that a difference in BAT activity (P < .001), age (P = .01), and gender (P = .037) were independent contributors to individual variability of CIT. CONCLUSIONS: A small reduction in ambient temperature, within the range of climate-controlled buildings, is sufficient to increase human BAT activity, which correlates with individual CIT response. This study uncovers for the first time a spectrum of BAT activation among healthy adults during mild cold exposure not previously recognized by conventional PET and PET-computed tomography methods. The enhancement of cold-induced BAT stimulation may represent a novel environmental strategy in obesity treatment.

Use of PET/CT with cosyntropin stimulation to identify and localize adrenal rest tissue following adrenalectomy in a woman with congenital adrenal hyperplasia.

CONTEXT: Adrenalectomy is an experimental treatment option for select patients with congenital adrenal hyperplasia who have failed medical therapy. After adrenalectomy, adrenal rest tissue can remain in extraadrenal locations, cause recurrent hyperandrogenism, and be difficult to localize. OBJECTIVE: The aim of the study was to investigate the usefulness of positron emission tomography/computerized tomography (PET/CT) in identifying adrenal rest tissue. SUBJECT: A female with salt-wasting 21-hydroxylase deficiency who had bilateral adrenalectomy at age 17 yr presented with hyperandrogenism at age 32 yr. Pelvic magnetic resonance imaging and ultrasound imaging were nondiagnostic for the source of androgen production. METHODS AND RESULTS: A baseline F-18 labeled fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT scan showed no active uptake; however, a second scan preceded by a 250-µg cosyntropin injection identified three areas of active uptake near both ovaries. Subsequent ovarian venous sampling showed elevations in 17-hydroxyprogesterone, androstenedione, and 21-deoxycortisol in both ovarian veins compared to a peripheral vein at baseline and more so after cosyntropin administration. At laparoscopy, three well-circumscribed nodules (2.4 × 0.9 × 1.3 cm, 1.2 × 1.5 × 1.5 cm, and 2 × 1.5 × 1 cm) lying lateral to the fallopian tubes adjacent to the broad ligaments were removed. The paraovarian nodules and previously removed adrenal glands had similar histology and immunohistochemistry. Postoperatively, androgen concentrations were undetectable, with no response to cosyntropin stimulation. CONCLUSIONS: Patients with CAH after an adrenalectomy may experience recurrent hyperandrogenism due to adrenal rest tissue. 18F-FDG PET/CT with cosyntropin stimulation accurately identified adrenal rest tissue not visualized with conventional imaging, allowing for successful surgical resection.