Edwin L. Palmer

Identification and importance of brown adipose tissue in adult humans.

BACKGROUND Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. METHODS We analyzed 3640 consecutive (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomographic and computed tomographic (PET-CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of (18)F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from the neck and supraclavicular regions in patients undergoing surgery. RESULTS Substantial depots of brown adipose tissue were identified by PET-CT in a region extending from the anterior neck to the thorax. Tissue from this region had UCP1-immunopositive, multilocular adipocytes indicating brown adipose tissue. Positive scans were seen in 76 of 1013 women (7.5%) and 30 of 959 men (3.1%), corresponding to a female:male ratio greater than 2:1 (P<0.001). Women also had a greater mass of brown adipose tissue and higher (18)F-FDG uptake activity. The probability of the detection of brown adipose tissue was inversely correlated with years of age (P<0.001), outdoor temperature at the time of the scan (P=0.02), beta-blocker use (P<0.001), and among older patients, body-mass index (P=0.007). CONCLUSIONS Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism.

Redifferentiation of Iodine-Refractory BRAF V600E-Mutant Metastatic Papillary Thyroid Cancer with Dabrafenib

Purpose: To determine whether the selective BRAF inhibitor, dabrafenib, can stimulate radioiodine uptake in BRAF V600E-mutated unresectable or metastatic iodine-refractory papillary thyroid cancer (PTC). Experimental Design: Ten patients with BRAF V600E-mutant iodine-refractory PTC were enrolled. Absence of radioiodine uptake on iodine-131 whole body scan obtained within 14 months of study entry was required. Each patient received dabrafenib (150 mg twice daily) for 25 days before thyrotropin α-stimulated iodine-131 whole body scan (4 mCi/148 MBq). Patients whose scan showed new sites of radioiodine uptake remained on dabrafenib for 17 more days, and then were treated with 150 mCi (5.5 GBq) iodine-131. The primary endpoint of the study was the percentage of patients with new radioiodine uptake after treatment with dabrafenib. Results: Six of 10 patients (60%) demonstrated new radioiodine uptake on whole body scan after treatment with dabrafenib. All 6 were treated with 5.5 GBq iodine-131. Two patients had partial responses and 4 patients had stable disease on standard radiographic restaging at 3 months. Thyroglobulin decreased in 4 of 6 treated patients. One patient developed squamous cell carcinoma of the skin. There were no other significant adverse events attributed to dabrafenib. Conclusions: Dabrafenib can stimulate radioiodine uptake in patients with metastatic BRAF V600E-mutant iodine-refractory PTC, representing a potential new therapeutic approach for these patients. Clin Cancer Res; 21(5); 1028–35. ©2014 AACR.

Pediatric Brown Adipose Tissue: Detection, Epidemiology, and Differences from Adults

OBJECTIVES To evaluate the prevalence and factors affecting the detection of active brown adipose tissue (BAT) in children and adolescents using (18)F-fluorodeoxyglucose positron emission tomography. STUDY DESIGN A total of 385 positron emission tomography scans performed for various oncologic indications in 172 patients aged 5-21 years were reviewed. BAT activity was detected by visual inspection as present or absent in the neck, thorax, and abdomen based on its well-characterized and typical appearance and then quantified by comparing the (18)F-fluorodeoxyglucose activity in the cervical-supraclavicular depots with that measured in the liver. Clinical indices were recorded. RESULTS The BAT detection rate was not significantly different between boys and girls (43.3% vs 45.3%). BAT activity was found most often in the cervical-supraclavicular depots. The highest percentage of patients with detectable BAT and the highest BAT/liver activity were in the 13- to 14.99-year age group in both males and females (P = .005). Body mass index percentile correlated inversely with BAT activity (P = .012). BAT activity did not correlate with outdoor temperature or clinical diagnosis. CONCLUSION Under typical clinical imaging conditions, BAT is detected more frequently in children than in adults. BAT activity increases from childhood into adolescence, when it is detected in almost half of patients, and it correlates inversely with obesity, suggesting that BAT may play a prominent role in pediatric metabolism.

Complications of exercise and pharmacologic stress tests: differences in younger and elderly patients.

BackgroundAge characteristics of patients undergoing various types of stress tests are important because of differences in clinical background and exercise performance between the young and elderly. Adverse effects of pharmacologic agents are known to be more common in the elderly, who are less able to perform vigorous exercise stress testing. We investigated the clinical background, performance characteristics, and complication rate of various stress tests in younger (≤75 years old) and elderly (>75 years old) patient populations.MethodsA total of 3412 patients (2796 younger, 616 elderly) underwent 5 types of stress tests with (1) technetium-99m sestamibi (MIBI) single photon emission computed tomography: symptom-limited exercise (Ex, 1598 younger, 173 elderly), (2) dipyridamole infusion (0.14 mg/kg/min, 4 minutes) without exercise (D, 260 younger, 114 elderly), (3) with exercise (DEx, 339 younger, 112 elderly), (4) adenosine infusion (0.14 mg/kg/min, 5 minutes) without exercise (A, 253 younger, 101 elderly), and (5) with exercise (AEx, 346 younger, 116 elderly).ResultsSixty-seven percent of patients in the younger population were able to achieve 85% of the maximum predicted heart rate, whereas 54% of the elderly reached this level of exercise. No patient had life-threatening complications. In both the younger and elderly groups, chest discomfort, feelings of impending syncope, flushing, and fall in blood pressure occurred less frequently in DEx than D and in AEx than A. Sinus bradycardia occurred less frequently in AEx than A in the younger (1.2% vs 4.3%, P<.05) and elderly groups (0.9% vs 6.9%, P<.05). Atrioventricular block was less frequent in AEx than A in the younger group (3.2% vs 7.9%, P<.05) but not so in the elderly group (13.0% vs 17.8%, not significant). The frequency of ischemic electrocardiographic changes in DEx and AEx was very similar to that of Ex in both the younger and elderly groups, although ischemic electrocardiographic changes in D and A are known to be less frequent.ConclusionOf the elderly group who were judged to be fit to exercise to 85% of maximum predicted heart rate, nearly half failed to reach this level. In contrast, the younger patients were able to achieve this level in 67% of tests. Supplementation with modest exercise reduced most of the pharmacologically related adverse effects. The elderly group was not protected from atrioventricular block as effectively as the younger group by additional exercise in the adenosine stress test. Ischemic electrocardiographic changes in the pharmacologic stress test were as frequent as in the exercise stress test when modest supplementary exercise was added to the pharmacologic protocol. There were no deaths, myocardial infarction, or other major complications. These observations suggest that exercise and pharmacologic stress tests are safe in the elderly, including those patients more than 75 years old.

Brown Fat at PET/CT: Correlation with Patient Characteristics

PURPOSES To assess the prevalence of brown fat in patients with cancer, compare demographic characteristics of those with and those without brown fat, and correlate these characteristics with the mean and maximum standardized uptake values of brown fat. MATERIALS AND METHODS This case-control study was institutional review board approved and HIPAA compliant. Informed consent was waived. Reports of 12 195 consecutive positron emission tomography/computed tomography examinations performed in 6867 patients between January 2004 and November 2008 were reviewed for documented fluorodeoxyglucose (FDG) uptake in brown fat (n = 298). Control patients (n = 298) without brown fat were chosen and matched for age, sex, and month and year of examination. Age, sex, weight, body mass index, ethnicity, and examination stage (initial vs restaging) were compared between groups. Paired Student t test, χ(2) test, Pearson correlation coefficient, and analysis of variance were used for statistical analysis. RESULTS Uptake of FDG in brown fat was demonstrated in 298 of 6867 (4.33%) patients. Prevalence of brown fat was significantly higher in female (5.9% [211 of 3587]) than in male patients (2.65% [87 of 3280]; P < .001). Those with brown fat had significantly lower body weight (147.5 lb ± 3.8 vs 168.61 lb ± 5.0; P < .001) and body mass index (24.3 ± 0.54 vs 27.6 ± 0.77; P < .001) than control patients. There was no significant difference in the prevalence of brown fat among ethnic groups. The maximum standardized uptake value of brown fat had a significant inverse correlation with age (r = -0.3, P < .001). CONCLUSION Patients with brown fat were more likely to be female and thinner than those without brown fat. Younger patients were more likely to have higher maximum standardized uptake values of brown fat.

Quantification of Human and Rodent Brown Adipose Tissue Function Using 99mTc-Methoxyisobutylisonitrile SPECT/CT and 18F-FDG PET/CT

For brown adipose tissue (BAT) to be effective at consuming calories, its blood flow must increase enough to provide sufficient fuel to sustain energy expenditure and also transfer the heat created to avoid thermal injury. Here we used a combination of human and rodent models to assess changes in BAT blood flow and glucose utilization. Methods: 99mTc-methoxyisobutylisonitrile (MIBI) SPECT (n = 7) and SPECT/CT (n = 74) scans done in adult humans for parathyroid imaging were reviewed for uptake in regions consistent with human BAT. Site-directed biopsies of subcutaneous and deep neck fat were obtained for electron microscopy and gene expression profiling. In mice, tissue perfusion was measured with 99mTc-MIBI (n = 16) and glucose uptake with 18F-FDG (n = 16). Animals were kept fasting overnight, anesthetized with pentobarbital, and given intraperitoneally either the β3-adrenergic receptor agonist CL-316,243, 1 mg/kg (n = 8), or saline (n = 8) followed by radiotracer injection 5 min later. After 120 min, the mice were imaged using SPECT/CT or PET/CT. Vital signs were recorded over 30 min during the imaging. BAT, white adipose tissue (WAT), muscle, liver, and heart were resected, and tissue uptake of both 99mTc-MIBI and 18F-FDG was quantified by percentage injected dose per gram of tissue and normalized to total body weight. Results: In 5.4% of patients (4/74), 99mTc-MIBI SPECT/CT showed increased retention in cervical and supraclavicular fat that displayed multilocular lipid droplets, dense capillary investment, and a high concentration of ovoid mitochondria. Expression levels of the tissue-specific uncoupling protein-1 were 180 times higher in BAT than in subcutaneous WAT (P < 0.001). In mice, BAT tissue perfusion increased by 61% (P < 0.01), with no significant changes in blood flow to WAT, muscle, heart, or liver. CL-316,243 increased glucose uptake in BAT even more, by 440% (P < 0.01). Conclusion: Pharmacologic activation of BAT requires increased blood flow to deliver glucose and oxygen for thermogenesis. However, the glucose consumption far exceeds the vascular response. These findings demonstrate that activated BAT increases glucose uptake beyond what might occur by increased blood flow alone and suggest that activated BAT likely uses glucose for nonthermogenic purposes.

Skeletal Scintigraphy With 18F-NaF PET for the Evaluation of Bone Pain in Children

OBJECTIVE Although not commonly used in current clinical practice, the PET agent (18)F-NaF provides an excellent alternative to the standard tracers used for radionuclide bone scintigraphy. This article illustrates the use and appearance of (18)F-NaF PET and shows examples of its utility in the assessment of bone pain in children. CONCLUSION Skeletal imaging with (18)F-NaF harnesses both the superior imaging characteristics of PET and the improved biodistribution of the fluoride tracer in comparison with standard nuclear techniques, resulting in excellent-quality images that can effectively be used to investigate the cause of bone pain in children.

Impact of fluorodeoxyglucose positron emission tomography on the clinical management of patients with glioma.

The past decade has seen the identification of many clinical settings in the treatment of primary brain tumors in which information from fluorodeoxyglucose positron emission tomography (FDG-PET) might be useful, if not essential, to therapeutic formulation. FDG-PET is currently used at referral centers in the management of primary brain tumors. The clinical pattern of FDG-PET use was assessed and its value compared to other information sources in clinical decision making. The clinical records of 75 glioma patients who were evaluated by FDG-PET were reviewed. The range of circumstances in which FDG-PET was employed included: pretherapeutic baseline studies for monitoring the effect of a therapy (1% of all cases), mapping of hypermetabolic regions before surgery or biopsy (2%), mapping of hypermetabolic regions before radiotherapy (2%), postsurgical evaluation for residual tumor (2%), assessment of the malignancy of a mass as a substitute for biopsy (11%), and distinguishing between radiation necrosis and recurrent tumor (87%). Other sources of information that contributed to the therapeutic management of patients included: gadolinium-enhanced MRI, contrast-CT, and clinical findings.

Anti-CD19 CAR T Cells in CNS Diffuse Large-B-Cell Lymphoma

In this case, a woman with refractory diffuse large-B-cell lymphoma had a CNS recurrence that responded completely to anti-CD19 CAR T-cell therapy. After biopsy of a subsequent skin recurrence, the lesions cleared in association with an expansion of the CAR T cells in the blood.

Lymphomatoid Granulomatosis: CT and FDG-PET Findings

Objective Lymphomatoid granulomatosis (LG) is a rare, aggressive extranodal Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disease. The purpose of our study was to analyze the CT and fluorodeoxyglucose positron emission tomography (FDG-PET) findings of pulmonary LG. Materials and Methods Between 2000 and 2009, four patients with pathologically proven pulmonary LG and chest CT were identified. Two of these patients also had FDG-PET. Imaging features of LG on CT and PET were reviewed. Results Pulmonary nodules or masses with peribronchovascular, subpleural, and lower lung zonal preponderance were present in all patients. Central low attenuation (4 of 4 patients), ground-glass halo (3 of 4 patients), and peripheral enhancement (4 of 4 patients) were observed in these nodules and masses. An air-bronchogram and cavitation were seen in three of four patients. FDG-PET scans demonstrated avid FDG uptake in the pulmonary nodules and masses. Conclusion Pulmonary LG presents with nodules and masses with a lymphatic distribution, as would be expected for a lymphoproliferative disease. However, central low attenuation, ground-glass halo and peripheral enhancement of the nodules/masses are likely related to the angioinvasive nature of this disease. Peripheral enhancement and ground-glass halo, in particular, are valuable characteristic not previously reported that can help radiologists suggest the diagnosis of pulmonary LG.