Person:

Bredella, Miriam

Background: Obesity is associated with a relative deficiency of growth hormone, which is predictive of greater visceral fat and markers of cardiovascular risk. The study’s purpose was to use recombinant human growth hormone (rhGH) as a physiologic probe to assess the effects of reversing obesity-related GH deficiency on body composition, cardiovascular risk markers, and insulin resistance. Methods: 22 obese girls 13–21 years old were followed for a randomized 6-month trial of rhGH vs. placebo/no treatment. At baseline and 6-months, DXA was performed for body composition, MRI to measure visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT), and fasting blood drawn for IGF-1, inflammatory cardiovascular risk markers [soluble intercellular adhesion molecule (sICAM), high sensitivity CRP], lipids and HbA1C. An oral glucose tolerance test (OGTT) was performed. Twelve girls completed the 6-month visit. Baseline and mean 6-month change were compared between the groups using the Student t-test and the relationship between variables was determined through multiple regression analysis. Results: After 6-months, the rhGH group maintained IGF-1 levels, and had decreases in total cholesterol (p = 0.03), sICAM-1 (p = 0.04) and HbA1C (p = 0.03) compared to placebo/no treatment. The rhGH group trended towards greater decreases in LDL and 2-hour OGTT glucose. Glucose tolerance did not worsen with rhGH administration. Conclusions: Administering rhGH in small doses is able to stabilize IGF-1 levels in obesity. We have also shown that rhGH administration leads to an improvement in some markers of cardiovacular risk with without adversely affecting glucose tolerance. Trial registration Clinical Trial Registration Number: NCT01169103.

Context: The elbow is a complex joint and commonly injured in athletes. Evaluation of the elbow by magnetic resonance imaging (MRI) is an important adjunct to the physical examination. To facilitate accurate diagnosis, a concise structured approach to evaluation of the elbow by MRI is presented. Evidence Acquisition: A PubMed search was performed using the terms elbow and MR imaging. No limits were set on the range of years searched. Articles were reviewed for relevance with an emphasis of the MRI appearance of normal anatomy and common pathology of the elbow. Results: The spectrum of common elbow disorders varies from obvious acute fractures to chronic overuse injuries whose imaging manifestations can be subtle. MRI evaluation should include bones; lateral, medial, anterior, and posterior muscle groups; the ulnar and radial collateral ligaments; as well as nerves, synovium, and bursae. Special attention should be paid to the valgus extension overload syndrome and the MRI appearance of associated injuries when evaluating throwing athletes. Conclusion: MRI evaluation of the elbow should follow a structured approach to facilitate thoroughness, accuracy, and speed. Such an approach should cover bone, cartilage, muscle, tendons, ligaments, synovium, bursae, and nerves.

Objective: The purpose of this study was to test a newly developed DXA method for abdominal fat depot quantification in subjects with AN, normal weight, and obesity using CT as a gold standard. Design and Methods 135 premenopausal women (overweight/obese: n=89, normal-weight: n=27, AN: n=19); abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT) areas determined on CT and DXA. Results: There were strong correlations between DXA and CT measurements of abdominal fat compartments in all groups with the strongest correlation coefficients in the normal-weight and overweight/obese groups. Correlations of DXA and CT VAT measurements were strongest in the obese group and weakest in the AN group. DXA abdominal fat depots were higher in all groups compared to CT, with the largest % mean difference in the AN group and smallest in the obese group. Conclusions: A new DXA technique is able to assess abdominal fat compartments including VAT in premenopausal women across a large weight spectrum However, DXA measurements of abdominal fat were higher than CT, and this percent bias was most pronounced in the AN subjects and decreased with increasing weight, suggesting that this technique may be more useful in obese individuals.

Objectives: The mechanisms responsible for the development of nonalcoholic fatty liver disease (NAFLD) and progression to nonalcoholic steatohepatitis (NASH) are incompletely understood. Growing evidence suggests that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may have roles in the development and progression of NAFLD. We hypothesized that lower serum IGF-1 levels would be associated with increased liver fat accumulation, inflammation, and fibrosis in a group of meticulously phenotyped obese subjects with liver biopsies. Methods: A retrospective, cross-sectional study was performed at Massachusetts General Hospital, Boston, MA, USA and St. Mary's Hospital, Richmond, VA, USA. Liver biopsies were performed in 142 subjects during NAFLD work-up or bariatric surgery and were graded by a single, blinded pathologist. Main outcome measures included liver histology and serum IGF-1. Results: Mean age was 52±10 years and body mass index (BMI) was 43±9 kg/m2. Mean serum IGF-1 was lower in subjects with lobular inflammation (112±47 vs. 136±57 ng/ml, P=0.01), hepatocyte ballooning (115±48 vs. 135±57 ng/ml, P=0.05), higher fibrosis stage (stage 2–4 vs. 0–1; 96±40 vs. 125±51 ng/ml, P=0.005), and NASH (109±45 vs. 136±57 ng/ml, P=0.002). All results remained significant after controlling for age, BMI, and a diagnosis of diabetes, and all but hepatocyte ballooning (trend, P=0.06) remained significant after excluding individuals with cirrhosis. Steatosis was not significantly associated with mean serum IGF-1 levels. Conclusions: Low serum IGF-1 levels are associated with increased histologic severity of NAFLD when rigorously controlled for age, BMI, the presence of diabetes, and after the exclusion of subjects with cirrhosis. Further investigation is warranted to determine the differential effects of GH and IGF-1 on the development and progression of NAFLD, which could further elucidate pathophysiology and identify therapeutic targets.

Purpose

Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease.

Methods

We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors.

Results

WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10).

Conclusion

WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations.

Purpose: To develop a three-dimensional (3D) segmentation and computerized volumetry technique for use in the assessment of neurofibromatosis and to assess the ability of this technique to aid in the calculation of tumor burden in patients with neurofibromatosis types 1 and 2 (NF1 and NF2, respectively) and schwannomatosis detected with whole-body magnetic resonance (MR) imaging.

Materials and Methods: Institutional review board approval and written informed consent were obtained for this prospective HIPAA-compliant study. Fifty-two subjects (27 women, 25 men; mean age, 42 years ± 15 [standard deviation]; age range, 24–86 years) underwent whole-body MR imaging performed with coronal short inversion time inversion-recovery (STIR) sequences. Whole-body tumor burden was estimated with a 3D segmentation method (the dynamic-threshold [DT] level set method) in 29 subjects (16 with NF1, six with NF2, and seven with schwannomatosis) in whom at least one nerve sheath tumor was reliably identified on MR images. Fifty tumors (25 plexiform and 25 discrete tumors) were randomly selected and subjected to manual and computerized volumetry to assess reliability. Ten plexiform tumors 5 cm or larger in diameter were retrospectively selected and segmented with three initialization methods for computerized volumetry and manually contoured by three radiologists to assess repeatability. Bland-Altman analysis was performed, and intraclass correlation coefficients (ICCs) were calculated.

Results: A total of 398 nerve sheath tumors (185 plexiform and 213 discrete tumors) were identified in 29 subjects. Volumetric measurements obtained with the computerized method and manual contouring were highly correlated (rICC = 0.99). Bland-Altman analysis showed that computerized volumetry had a mean difference of −2.6% compared with manual volumetry. The repeatability coefficient of the computerized scheme was ±5% compared with ±30% for manual contouring.

Conclusion: This 3D segmentation and computerized volumetry technique is reliable relative to manual segmentation and has the advantage of being less labor intensive and more repeatable. This technique can be paired with whole-body MR imaging to determine tumor burden in patients with neurofibromatosis.

Purpose: To determine if CT density thresholds of osteoblastic bone lesions can be used to distinguish untreated osteoblastic metastases from enostoses. Materials and Methods: The study group comprised 62 patients (37 enostoses, 25 untreated osteoblastic metastases) with sclerotic bone lesions found on CT. Etiology of sclerotic lesions was assessed histologically or by clinical and imaging follow-up. None of the patients had prior treatment for metastases. The average and maximum densities in Hounsfield Units (HU) were measured. Receiver operating curve (ROC) analysis was performed to determine sensitivity, specificity, area under the ROC curve (AUC), confidence intervals (CI), and cutoff values of CT densities to differentiate metastases from enostoses. Interreader reproducibility was assessed using intraclass correlation coefficient (ICC) with 95% CI. Results: Mean and maximum CT densities of enostoses were 1190 ± 239 and 1323 ± 234 HU and of osteoblastic metastases were 654 ± 176 and 787 ± 194 HU, respectively. Using a cut-off of 885 HU for average density, AUC was 0.982, sensitivity was 95%, and specificity was 96%. Using a cut-off of 1058 HU for maximum CT density, AUC was 0.976, sensitivity was 95%, and specificity was 96%. Mean density ICC was 0.987 for enostoses and 0.81 for metastases. Maximum density ICC was 0.814 for enostoses and 0.980 for metastases. Conclusion: CT density measurements can be used to distinguish untreated osteoblastic metastases from enostoses. An average density of 885 HU and a maximum density of 1058 HU provide reliable thresholds below which a metastatic lesion is the favored diagnosis.

Purpose: Osseous metastases often undergo an osteoblastic response following chemotherapy also known as the “flare” phenomenon. The purpose of our study was to demonstrate the quantitative CT changes in density of osseous metastases before and after chemotherapy. Materials and Methods: Our study was IRB approved and HIPAA compliant. Our cohort consisted of 48 consecutive cancer patients with studies both before chemotherapy/at the time of diagnosis of osseous metastases and 14 ± 3 (12-20) months after the initiation of treatment 60 ±10 (range: 37-80) years, 26 F, 22 M). CT density of all lesions was measured by two fellowship trained MSK radiologists. The largest possible region of interest was selected to measure the average and maximum densities in Hounsfield Units (HU). If multiple lesions were present, the largest lesion was evaluated. Treatment effects were assessed using paired t-tests, using P < 0.05 as statistically significant. Intraclass correlation coefficient (ICC) was calculated for the two readers. Results: The distribution of primary tumors was as follows: breast (20/48, 42%), lung (10/48, 21%), prostate (5/48, 10%), pancreatic (5/48, 10%), renal (2/48, 4%), and other (6/48, 13%). The measured lesions were in the following locations: spine/sacrum (35/48, 73%), pelvis (10/48, 21%), sternum (3/48, 6%). The distribution of lesion types were as follows: lytic (14/48, 29%), blastic (25/48, 52%), and mixed lytic-blastic (9/48, 19%). Mean and maximum CT densities (Reader 1) of all metastases before chemotherapy treatment were 328 ± 206 HU and 580 ± 391 HU, respectively and after chemotherapy treatment were 511 ± 263 HU and 789 ± 439 HU, respectively. There was a significant increase in mean and maximum CT densities of metastases following chemotherapy for all lesions collectively but also when separated into lytic, blastic, and mixed lytic-blastic lesions (P < 0.05). ICC was almost perfect for average density and moderate to substantial for maximum density. Conclusion: Quantitative assessment of osseous metastatic disease using CT density measurements confirms a statistically significant increase in density 12-20 months after initiation of chemotherapy. Clinical Application: Measuring changes in CT density of osseous metastases may have a significant role in evaluating chemotherapy effect.

Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation in MAT adipocyte development, regulation, size, lipid composition, gene expression, and genetic determinants. Early MAT formation in mice is conserved, while later development is strain dependent. Proximal, but not distal, MAT is lost with 21-day cold exposure. Rat MAT adipocytes from distal sites have an increased proportion of monounsaturated fatty acids and expression of Scd1/Scd2, Cebpa and Cebpb. Humans also have increased distal marrow fat unsaturation. We define proximal ‘regulated’ MAT (rMAT) as single adipocytes interspersed with active hematopoiesis, whereas distal ‘constitutive’ MAT (cMAT) has low hematopoiesis, contains larger adipocytes, develops earlier, and remains preserved upon systemic challenges. Loss of rMAT occurs in mice with congenital generalized lipodystrophy type 4, whereas both rMAT and cMAT are preserved in mice with congenital generalized lipodystrophy type 3. Consideration of these MAT subpopulations may be important for future studies linking MAT to bone biology, hematopoiesis and whole-body metabolism.

Background: Obesity is prevalent among adolescents and is associated with serious health consequences. Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) are bariatric procedures that cause significant weight loss in adults and are increasingly being performed in adolescents with morbid obesity. Data comparing outcomes of RYGB vs. SG in this age-group are scarce. This study aims to compare short-term (1–6 months) and longer-term (7–18 months) body mass index (BMI) and biochemical outcomes following RYGB and SG in adolescents/young adults. Methods: A retrospective study using data extracted from medical records of patients 16–21 years who underwent RYGB or SG between 2012 and 2014 at a tertiary care academic medical center. Results: Forty-six patients were included in this study: 24 underwent RYGB and 22 underwent SG. Groups did not differ for baseline age, sex, race, or BMI. BMI reductions were significant at 1–6 months and 7–18 months within groups (p < 0.0001), but did not differ by surgery type (p = 0.65 and 0.09, for 1–6 months and 7–18 months, respectively). Over 7–18 months, within-group improvement in low-density lipoprotein (LDL) (−24 ± 6 in RYGB, p = 0.003, vs. −7 ± 9 mg/dl in SG, p = 0.50) and non-high-density lipoprotein (non-HDL) cholesterol (−23 ± 8 in RYGB, p = 0.02, vs. −12 ± 7 in SG, p = 0.18) appeared to be of greater magnitude following RYGB. However, differences between groups did not reach statistical significance. When divided by non-alcoholic steatohepatitis stages (NASH), patients with Stage II–III NASH had greater reductions in alanine aminotransferase levels vs. those with Stage 0–I NASH (−45 ± 18 vs. −9 ± 3, p = 0.01) after 7–18 months. RYGB and SG groups did not differ for the magnitude of post-surgical changes in liver enzymes. Conclusion: RYGB and SG did not differ for the magnitude of BMI reduction across groups, though changes trended higher following RYGB. Further prospective studies are needed to confirm these findings.