Lenka M. Pereira Arias-Bouda

Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study

BACKGROUND Individuals of south Asian origin have a very high risk of developing type 2 diabetes compared with white Caucasians. We aimed to assess volume and activity of brown adipose tissue (BAT), which is thought to have a role in energy metabolism by combusting fatty acids and glucose to produce heat and might contribute to the difference in incidence of type 2 diabetes between ethnic groups. METHODS We enrolled Dutch nationals with south Asian ancestry and matched Caucasian participants at The Rijnland Hospital (Leiderdorp, Netherlands). Eligible participants were healthy lean men aged 18-28 years, and we matched groups for BMI. We measured BAT volume and activity with cold-induced (18)F-fluorodeoxyglucose ((18)F-FDG) PET CT scans, and assessed resting energy expenditure, non-shivering thermogenesis, and serum parameters. This study is registered with the Netherlands Trial Register, number 2473. FINDINGS Between March 1, 2013, and June 1, 2013, we enrolled 12 participants in each group; one Caucasian participant developed hyperventilation after (18)F-FDG administration, and was excluded from all cold-induced and BAT measurements. Compared with Caucasian participants, south Asian participants did not differ in age (mean 23.6 years [SD 2.8] for south Asians vs 24.6 years [2.8] for Caucasians) or BMI (21.5 kg/m(2) [2.0] vs 22.0 kg/m(2) [1.6]), but were shorter (1.74 m [0.06] vs 1.85 m [0.04]) and lighter (65.0 kg [8.5] vs 75.1 kg [7.2]). Thermoneutral resting energy expenditure was 1297 kcal per day (SD 123) in south Asian participants compared with 1689 kcal per day (193) in white Caucasian participants (difference -32%, p=0.0008). On cold exposure, shiver temperature of south Asians was 2.0°C higher than Caucasians (p=0.0067) and non-shivering thermogenesis was increased by 20% in white Caucasians (p<0.0001) but was not increased in south Asians. Although the maximum and mean standardised uptake values of (18)F-FDG in BAT did not differ between groups, total BAT volume was lower in south Asians (188 mL [SD 81]) than it was in Caucasians (287 mL [169]; difference -34%, p=0.04). Overall, BAT volume correlated positively with basal resting energy expenditure in all assessable individuals (β=0.44, p=0.04). INTERPRETATION Lower resting energy expenditure, non-shivering thermogenesis, and BAT volumes in south Asian populations might underlie their high susceptibility to metabolic disturbances, such as obesity and type 2 diabetes. Development of strategies to increase BAT volume and activity might help prevent and treat such disorders, particularly in south Asian individuals. FUNDING Dutch Heart Foundation (2009T038) and Dutch Diabetes Research Foundation (2012.11.1500).

Supraclavicular skin temperature as a measure of 18F-FDG uptake by BAT in human subjects.

Background Brown adipose tissue (BAT) has emerged as a novel player in energy homeostasis in humans and is considered a potential new target for combating obesity and related diseases. The current ‘gold standard’ for quantification of BAT volume and activity is cold-induced 18F-FDG uptake in BAT. However, use of this technique is limited by cost and radiation exposure. Given the fact that BAT is a thermogenic tissue, mainly located in the supraclavicular region, the aim of the current study was to investigate whether cold-induced supraclavicular skin temperature and core body temperature may be alternative markers of BAT activation in humans. Subjects/Methods BAT volume and activity were measured in 24 healthy lean adolescent males (mean age 24.1±0.8 years), using cold-induced 18F-FDG uptake with PET-CT. Core body temperature was measured continuously in the small intestine with use of an ingestible telemetric capsule and skin temperature was measured by eighteen wireless iButtons attached to the skin following ISO-defined locations. Results Proximal and distal (hand/feet) skin temperatures markedly decreased upon cold exposure, while supraclavicular skin temperature significantly increased (35.2±0.1 vs. 35.5±0.1°C, p = 0.001). Furthermore, cold-induced supraclavicular skin temperature positively correlated with both total (R2 = 0.28, P = 0.010) and clavicular BAT volume (R2 = 0.20, P = 0.030) and clavicular SUVmax (R2 = 0.27, P = 0.010), while core body temperature did not. Conclusions Supraclavicular skin temperature as measured by iButtons may have predictive value for BAT detection in adult humans. This is highly desirable considering the increasing interest in pharmacological interventions to stimulate BAT in human subjects. Trial Registration NTR 2473

Is Technetium-99m Sestamibi Imaging Able to Predict Pathologic Nonresponse to Neoadjuvant Chemotherapy in Breast Cancer? A Meta-analysis Evaluating Current Use and Shortcomings

Micro‐Abstract In breast cancer, interest in technetium‐99m (99mTc) sestamibi‐based therapy monitoring is increasing owing to the growing use of 99mTc‐sestamibi‐based molecular breast imaging. In the present meta‐analysis of 529 patients, 99mTc‐sestamibi planar imaging showed low sensitivity for predicting a pathologic nonresponse to neoadjuvant chemotherapy. In contrast, 99mTc‐sestamibi imaging performed during treatment seemed highly sensitive for the prediction of nonresponse. New tools incorporating quantitative single photon emission computed tomography/computed tomography need to be explored. Background: Interest in technetium‐99m (99mTc)‐sestamibi imaging for neoadjuvant chemotherapy (NAC) response monitoring in locally advanced breast cancer (LABC) is increasing but remains matter of discussion. The present study conducted a meta‐analysis of the diagnostic performance of 99mTc‐sestamibi to predict pathologic nonresponse to NAC for primary LABC. Materials and Methods: A systematic data search was performed. Studies with a minimum of 10 LABC patients that had evaluated 99mTc‐sestamibi imaging for NAC nonresponse using conventional planar scintimammography, breast‐specific &ggr;‐imaging, and/or single photon emission computed tomography/computed tomography (SPECT/CT) were included. The histopathologic findings were the reference standard. The meta‐analysis was performed using a mixed logistic regression model. Results: The search revealed 14 eligible studies with 529 patients. Of the 14 studies, 11 had evaluated scintimammography and 3 breast‐specific &ggr;‐imaging. No studies examining SPECT or SPECT/CT were found. The overall estimated pooled sensitivity, specificity, and positive and negative likelihood ratios of 99mTc‐sestamibi imaging to predict nonresponsiveness to NAC were 70.3% (95% confidence interval [CI], 56.5%‐81.3%%), 90.1% (95% CI, 77.5%‐96.0%), 7.13 (95% CI, 3.08‐16.53), and 0.33 (95% CI, 0.22‐0.49), respectively. Only 3 studies (107 patients) evaluated 99mTc‐sestamibi imaging during NAC, reported an estimated pooled sensitivity of 87% (95% CI, 72%‐100%) and specificity of 93% (95% CI, 85%‐100%). Conclusion: Only planar 99mTc‐sestamibi imaging has been investigated for NAC nonresponse in LABC but showed low sensitivity to predict pathologic nonresponse. However, most studies focused on the prediction of pathologic complete response after NAC. Although experience is limited, 99mTc‐sestamibi uptake during NAC seems highly sensitivity for the prediction of nonresponsiveness. Features such as SPECT/CT imaging, standardized quantification, relation to tumor subtypes, and proper timing have been insufficiently evaluated and require further investigation.

The impact of using BARCIST 1.0 criteria on quantification of BAT volume and activity in three independent cohorts of adults

Human brown adipose tissue (BAT) is commonly assessed by cold-induced 18F-fluorodeoxyglucose (FDG) PET-CT using several quantification criteria. Uniform criteria for data analysis became available recently (BARCIST 1.0). We compared BAT volume and activity following BARCIST 1.0 criteria against the most commonly used criteria [Hounsfield Units (HU):-250, -50, standardized uptake value (SUV):2.0; HU: Not applied, SUV:2.0 and HU:-180, -10, SUV:1.5] in a prospective study using three independent cohorts of men including young lean adults, young overweight/obese adults and middle-aged overweight/obese adults. BAT volume was the most variable outcome between criteria. While BAT volume calculated using the HU: NA; SUV: 2.0 criteria was up to 207% higher than the BAT volume calculated based on BARCIST 1.0 criteria, it was up to 57% lower using the HU: -250, -50; SUV: 2.0 criteria compared to the BARCIST 1.0. Similarly, BAT activity (expressed as SUVmean) also differed between different thresholds mainly because SUVmean depends on BAT volume. SUVpeak was the most consistent BAT outcome across the four study criteria. Of note, we replicated these findings in three independent cohorts. In conclusion, BAT volume and activity as determined by 18F-FDG-PET/CT highly depend on the quantification criteria used. Future human BAT studies should conduct sensitivity analysis with different thresholds in order to understand whether results are driven by the selected HU and/or SUV thresholds. The design of the present study precludes providing any conclusive threshold, but before more definitive thresholds for HU and SUV are available, we support the use of BARCIST 1.0 criteria to facilitate interpretation of BAT characteristics between research groups.

LysoPC-acyl C16 : 0 is associated with brown adipose tissue activity in men

IntroductionBrown adipose tissue (BAT) recently emerged as a potential therapeutic target in the treatment of obesity and associated disorders due to its fat-burning capacity. The current gold standard in assessing BAT activity is [18F]FDG PET-CT scan, which has severe limitations including radiation exposure, being expensive, and being labor-intensive. Therefore, indirect markers are needed of human BAT activity and volume.ObjectiveWe aimed to identify metabolites in serum that are associated with BAT volume and activity in men.MethodsWe assessed 163 metabolites in fasted serum of a cohort of twenty-two healthy lean men (age 24.1 (21.7–26.6) years, BMI 22.1 (20.5–23.4) kg/m2) who subsequently underwent a cold-induced [18F]FDG PET-CT scan to assess BAT volume and activity. In addition, we included three replication cohorts consisting of in total thirty-seven healthy lean men that were similar with respect to age and BMI compared to the discovery cohort.ResultsAfter correction for multiple testing, fasting concentrations of lysophosphatidylcholine-acyl (LysoPC-acyl) C16:1, LysoPC-acyl C16:0 and phosphatidylcholine-diacyl C32:1 showed strong positive correlations with BAT volume (β= 116 (85–148) mL, R2 = 0.81, p = 4.6 × 10−7; β = 79 (93–119) mL, R2 = 0.57, p = 5.9 × 10−4 and β= 91 (40–141) mL, R2 = 0.52, p = 1.0 × 10−3, respectively) as well as with BAT activity (β= 0.20 (0.11–0.29) g/mL, R2 = 0.59, p = 1.9 × 10−4; β = 0.15 (0.06–0.23) g/mL, R2 = 0.47, p = 2.0 × 10−3 and β= 0.13 (0.01–0.25) g/mL, R2 = 0.28, p = 0.04, respectively). When tested in three independent replication cohorts (total n = 37), the association remained significant between LysoPC-acyl C16:0 and BAT activity in a pooled analysis (β= 0.15 (0.07–0.23) g/mL, R2 = 0.08, p = 4.2 × 10−4).ConclusionsLysoPC-acyl C16:0 is associated with BAT activity in men. Since BAT is regarded as a promising tool in the battle against obesity and related disorders, the identification of such a noninvasive marker is highly relevant.

First Clinical Experience Using Stereotactic Breast Biopsy Guided by 99mTc-Sestamibi

OBJECTIVE The purpose of this study is to evaluate a new device using molecular breast imaging (MBI) for 99mTc-sestamibi-guided stereotactic lesion localization as a complementary biopsy tool. MATERIALS AND METHODS From December 2012 to May 2016, a total of 38 consecutive women (mean age, 59 years; range, 41-77 years) underwent 99mTc-sestamibi-guided biopsy using a new MBI-based device and were retrospectively reviewed. The biopsy modality used five steps: stereotactic localization of the 99mTc-sestamibi-avid lesion, calculation of coordinates of the lesion location using dedicated software, placement of the needle, verification of the correct needle position, and tissue sampling with a vacuum-assisted device followed by placement of a radiologic marker at the biopsy site and ex vivo measurement of the biopsy specimens. RESULTS The procedure was technically successful in all 38 lesions. In all cases, biopsy samples were radioactive and adequate for histopathologic analysis. Nineteen lesions (50%) were found to be malignant, and the remaining lesions were found to be benign. The mean procedure time was 71 minutes (range, 44-112 minutes). The radiologic marker was successfully deployed in 37 lesions (97%). Two hematomas and three vasovagal reactions were observed. CONCLUSION Technetium-99m sestamibi-guided biopsy performed using a dedicated MBI-based device is technically feasible and represents a valuable complementary biopsy tool in breast lesion diagnosis.

Nuclear Medicine Imaging of Foot Injuries

In sports medicine, foot disorders present a significant clinical challenge due to the complex anatomy and function of the foot. Injuries are complex involving soft tissue as well as bony structures. Bone scintigraphy is a sensitive technique, which provides essential functional information which correlates better with clinical symptoms and treatment response than anatomical abnormalities. It is a useful tool to detect conditions affecting the bony structures of the foot in an early phase, but can also be helpful in the initial evaluation of soft tissue injuries. MRI though remains better in delineating most soft tissue injuries. The emergence of SPECT-CT has increased the accuracy of bone scintigraphy. This is particularly true for the recently developed hybrid systems, which are capable of acquiring high-resolution multislice CT images. Bone SPECT-CT has shown to have incremental value in orthopedic conditions and sports injuries. However, one should be aware of the fact that available evidence concerning the clinical value of bone SPECT-CT in sports injuries in the foot is scarce; especially the specificity of the technique needs to be further elucidated.

Radiomics in vulvar cancer: first clinical experience using18F-FDG PET/CT images

This study investigated whether radiomic features derived from preoperative PET images could predict both tumor biology and prognosis in women with invasive squamous cell carcinoma of the vulva. Methods: Patients were retrospectively included if they had a unifocal primary cancer at least 2.6 cm in diameter, received a preoperative 18F-FDG PET/CT scan followed by surgery, and had at least 6 mo of follow-up data. 18F-FDG PET images were analyzed by semiautomatically drawing a volume of interest on the primary tumor in each PET image, followed by extraction of 83 radiomic features. Unique radiomic features were identified by principal-component analysis (PCA), after which they were compared with histopathology using nonpairwise group comparison and linear regression. Univariate and multivariate Cox regression analyses were used to correlate the identified features with progression-free survival (PFS) and overall survival (OS). Survival curves were estimated using the Kaplan–Meier method. Results: Forty women were included. PCA revealed 4 unique radiomic features, which were not associated with histopathologic characteristics such as grade, depth of invasion, lymph-vascular space invasion, and metastatic lymph nodes. No statistically significant correlation was found between the identified features and PFS. However, Moran’s I, a feature that identifies global spatial autocorrelation, correlated with OS (P = 0.03). Multivariate Cox regression analysis showed that extracapsular invasion of the metastatic lymph nodes and Moran’s I were independent prognostic factors for PFS and OS. Conclusion: Our data show that PCA is usable to identify specific radiomic features. Although the identified features did not correlate strongly with tumor biology, Moran’s I was found to predict patient prognosis. Larger studies are required to establish the clinical relevance of the observed findings.

Experimental validation of absolute SPECT/CT quantification for response monitoring in breast cancer

PURPOSE Recent developments in iterative image reconstruction enable absolute quantification of SPECT/CT studies by incorporating compensation for collimator-detector response, attenuation, and scatter as well as resolution recovery into the reconstruction process (Evolution; Q.Metrix package; GE Healthcare, Little Chalfont, UK). The aim of this experimental study is to assess its quantitative accuracy for potential clinical 99m Tc-sestamibi (MIBI)-related SPECT/CT application in neoadjuvant chemotherapy response studies in breast cancer. METHODS Two phantoms were filled with MIBI and acquired on a SPECT/CT gamma camera (Discovery 670 Pro; GE Healthcare), that is, a water cylinder and a NEMA body phantom containing six spheres that were filled with an activity concentration reflecting clinical MIBI uptake. Subsequently, volumes-of-interest (VOI) of each sphere were drawn (semi)automatically on SPECT using various isocontour methods or manually on CT. Finally, prone MIBI SPECT/CT scans were acquired 5 and 90 min p.i. in a locally advanced breast cancer patient. RESULTS Activity concentration in the four largest spheres converged after nine iterations of evolution. Depending on the count statistics, the accuracy of the reconstructed activity concentration varied between -4.7 and -0.16% (VOI covering the entire phantom) and from 6.9% to 10% (8.8 cm ⌀ cylinder VOI placed in the center of the phantom). Recovery coefficients of SUVmax were 1.89 ± 0.18, 1.76 ± 0.17, 2.00 ± 0.38, 1.89 ± 0.35, and 0.90 ± 0.26 for spheres with 37, 28, 22, 17, and 13 mm ⌀, respectively. Recovery coefficients of SUVmean were 1.07 ± 0.06, 1.03 ± 0.09, 1.17 ± 0.21, 1.10 ± 0.20, and 0.52 ± 0.14 (42% isocontour); 1.10 ± 0.07, 1.02 ± 0.09, 1.13 ± 0.19, 1.06 ± 0.19, and 0.51 ± 0.13 (36% isocontour with local background correction); and 0.96, 1.09, 1.03, 1.03, and 0.29 (CT). Patient study results were concordant with the phantom validation. CONCLUSIONS Absolute SPECT/CT quantification of breast studies using MIBI seems feasible (<17% deviation) when a 42% isocontour is used for delineation for tumors of at least 17 mm diameter. However, with tumor shrinkage, response evaluation should be handled with caution, especially when using SUVmax .