Scott Persohn

Metabolic and anthropometric evaluation of insulin resistance in nondiabetic patients with nonalcoholic steatohepatitis

OBJECTIVES:Insulin resistance is nearly universal in patients with nonalcoholic steatohepatitis (NASH) when tested by glucose tolerance tests or clamp methods. However, the pattern of insulin resistance in these patients after a physiological challenge is unknown. We conducted a study to characterize the metabolic response to a mixed meal in nondiabetic patients with NASH (NDN) and to identify anthropometric determinants of insulin resistance in these patients.METHODS:Serum insulin, C-peptide, glucose, and free fatty acid (FFA) levels were measured at 0, 30, 60, 90, and 120 min after a 500-kcal standard meal in 18 NDN and 18 age-, gender-, and body mass index (BMI)-matched controls. Correlations were made between insulin resistance and various anthropometric, calorimetric, and serological variables.RESULTS:Compared with controls, NDN had significantly higher levels of insulin and C-peptide at baseline and after the mixed meal. However, glucose levels were not different either at baseline or after the meal. NDN had higher fasting levels of FFA than the controls (459 ± 190 vs 339 ± 144 μmol/L, respectively, p = 0.03); however, meal-induced suppression in lipolysis was similar between the two groups (39 ± 113% vs 46 ± 60%, p = 0.8). Insulin resistance was significantly correlated with BMI (r = 0.39, p = 0.02) and visceral fat (r = 0.50, p = 0.004). Whereas BMI, percent total body fat, and subcutaneous abdominal fat were similar between the groups, the NASH group had significantly higher percent visceral fat compared with controls (28 ± 10% vs 22 ± 14%, p = 0.02).CONCLUSION:NDN are significantly hyperinsulinemic, both at fasting and after the mixed meal; however, their glucose homeostasis and suppression in lipolysis after a meal challenge are maintained. Insulin resistance in these patients is likely related to their higher visceral fat mass.

Race and sex differences in bone mineral density and geometry at the femur.

INTRODUCTION Differences in osteoporotic hip fracture incidence between American whites and blacks and between women and men are considered to result, in part, from differences in bone mineral density and geometry at the femur. The aim of this study was to quantify differences in femoral bone density and geometry between a large sample of healthy American white and black women and men. SUBJECTS AND METHODS Healthy American white (n=612) and black (n=164) premenopausal women, aged 23 to 57 years, and healthy American white (n=492) and black (n=169) men, aged 20 to 63 years, had volumetric bone mineral density (vBMD) and geometry variables measured at the femur by computerized tomography (CT), and areal bone mineral density (aBMD) at femoral neck measured by dual X-ray absorptiometry (DXA). RESULTS American blacks had higher vBMD at the femoral neck and femoral shaft cortex than American whites whereas femoral axis length and femoral neck area were not different. Men had lower vBMD at the femoral neck and femoral cortex than women but had greater femoral axis length and femoral neck area than women. The higher aBMD in American blacks than whites persisted after correction for measured area whereas the higher aBMD in men than women disappeared. CONCLUSIONS At the femoral neck, American whites have lower bone density than American blacks but similar geometry. Women have higher bone density than men in both races but have smaller geometry variables. The differences in bone density may account in part for the differences in hip fracture incidence between American blacks and whites, whereas the differences in femur size may account for the differences in hip fracture rates between men and women.

Stent grafting of abdominal aortic aneurysms: pre-and postoperative evaluation with multislice helical CT.

Endovascular stent grafting of abdominal aortic aneurysms is a new technique that may replace open surgery in selected cases. Pre-and postoperative angiography can be replaced by helical CT. This pictorial essay describes and illustrates the use of multislice helical CT where maximum intensity projection and multiplanar reformats play a central role in the evaluation.

18F-NaF PET Imaging of Early Coronary Artery Calcification

Studies to date have focused on 18F-sodium fluoride (18F-NaF) uptake in advanced lesions of coronary artery disease (CAD) patients [(1)][1]. However, others suggest that 18F-NaF soft-tissue uptake imaged by positron-emission tomography (PET) may occur in coronary arteries before the advanced stages

In Vivo UTE‐MRI Reveals Positive Effects of Raloxifene on Skeletal‐Bound Water in Skeletally Mature Beagle Dogs

Raloxifene positively affects mechanical properties of the bone matrix in part through modification of skeletal‐bound water. The goal of this study was to determine if raloxifene‐induced alterations in skeletal hydration could be measured in vivo using ultra‐short echotime magnetic resonance imaging (UTE‐MRI). Twelve skeletally mature female beagle dogs (n = 6/group) were treated for 6 months with oral doses of saline vehicle (VEH, 1 mL/kg/d) or raloxifene (RAL, 0.5 mg/kg/d). After 6 months of treatment, all animals underwent in vivo UTE‐MRI of the proximal tibial cortical bone. UTE‐MRI signal intensity versus echotime curves were analyzed by fitting a double exponential to determine the short and long relaxation times of water with the bone (dependent estimations of bound and free water, respectively). Raloxifene‐treated animals had significantly higher bound water (+14%; p = 0.05) and lower free water (–20%) compared with vehicle‐treated animals. These data provide the first evidence that drug‐induced changes in skeletal hydration can be noninvasively assessed using UTE‐MRI.

Feasibility of Mapping T2 Relaxation Time in the Pediatric Metacarpal Head With a 3-T MRI System

OBJECTIVE T2 relaxation time is sensitive in detecting early cartilage damage. There are few reports of T2 mapping for smaller joints because of technical challenges. The purpose of this study is to evaluate the feasibility of T2 mapping of the metacarpal head cartilage in children. CONCLUSION T2 mapping of the metacarpal head cartilage is feasible in children on a 3-T scanner with commercially available coils. An increase in the T2 values near the osteochondral junction likely reflects the secondary physis.

Correlation of Technetium-99m Macroaggregated Albumin and Yttrium-90 Glass Microsphere Biodistribution in Hepatocellular Carcinoma: A Retrospective Review of Pretreatment Single Photon Emission CT and Posttreatment Positron Emission Tomography/CT

PURPOSE To evaluate whether technetium-99 (99mTc)-labeled macroaggregated albumin (MAA) can predict subsequent yttrium-90 (90Y) distribution and imaging response in patients with hepatocellular carcinoma (HCC). MATERIALS Retrospective review was performed of records of 83 patients with HCC who underwent 90Y glass microsphere radioembolization with 99mTc-MAA single photon emission computed tomography (SPECT) and 90Y positron emission tomography (PET)/CT between January 2013 and December 2014. Images were fused to segment the whole liver normal tissue (WLNT) and the largest tumors. Fused images were reviewed and analyzed for comparison of absorbed dose (AD) to tumors and WLNT as calculated from 99mTc-MAA SPECT and from 90Y PET/CT, subjective imaging comparison of 99mTc-MAA SPECT and 90Y PET for tumors and WLNT, and correlation of tumoral AD with response on follow-up CT. RESULTS Final analysis included 73 and 63 patients for WLNT and tumor 99mTc-MAA/90Y correlation, respectively, and 62 patients for AD vs response. 99mTc-MAA/90Y limit of agreement for each reviewer was viewed as clinically acceptable only for WLNT (-15 to 15 Gy). AD interreviewer variability was clinically acceptable for WLNT but was too broad for tumor. Mean tumor AD for objective response (78%) was 313 Gy vs 234 Gy for nonresponders. No threshold was found between tumor AD and response (P > .1). Catheter mismatch between 99mTc-MAA and 90Y had a direct impact on AD mismatch between the 2 image sets. CONCLUSIONS 99mTc-MAA was found to be a poor surrogate to quantitatively predict subsequent 90Y AD to hepatocellular tumors. 99mTc-MAA distribution correlated with 90Y distribution in the normal hepatic parenchyma.

EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represents a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers, including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft model that is intrinsically resistant to the RTKi sunitinib, but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its antiangiogenic and antimetastatic activity but lost its direct antitumor effects due to kinome reprogramming, which resulted in suppression of proapoptotic and cell-cycle-regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTKs, restoring the antitumor effects of sunitinib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease. Cancer Res; 77(23); 6651-66. ©2017 AACR.

Effects of combination treatment with alendronate and raloxifene on skeletal properties in a beagle dog model.

A growing number of studies have investigated combination treatment as an approach to treat bone disease. The goal of this study was to investigate the combination of alendronate and raloxifene with a particular focus on mechanical properties. To achieve this goal we utilized a large animal model, the beagle dog, used previously by our laboratory to study both alendronate and raloxifene monotherapies. Forty-eight skeletally mature female beagles (1–2 years old) received daily oral treatment: saline vehicle (VEH), alendronate (ALN), raloxifene (RAL) or both ALN and RAL. After 6 and 12 months of treatment, all animals underwent assessment of bone material properties using in vivo reference point indentation (RPI) and skeletal hydration using ultra-short echo magnetic resonance imaging (UTE-MRI). End point measures include imaging, histomorphometry, and mechanical properties. Bone formation rate was significantly lower in iliac crest trabecular bone of animals treated with ALN (-71%) and ALN+RAL (-81%) compared to VEH. In vivo assessment of properties by RPI yielded minimal differences between groups while UTE-MRI showed a RAL and RAL+ALN treatment regimens resulted in significantly higher bound water compared to VEH (+23 and +18%, respectively). There was no significant difference among groups for DXA- or CT-based measures lumbar vertebra, or femoral diaphysis. Ribs of RAL-treated animals were smaller and less dense compared to VEH and although mechanical properties were lower the material-level properties were equivalent to normal. In conclusion, we present a suite of data in a beagle dog model treated for one year with clinically-relevant doses of alendronate and raloxifene monotherapies or combination treatment with both agents. Despite the expected effects on bone remodeling, our study did not find the expected benefit of ALN to BMD or structural mechanical properties, and thus the viability of the combination therapy remains unclear.