Faculty Bibliography

Clinical and Translational Science Award (CTSA) TL1 trainees and KL2 scholars were surveyed to determine the immediate impact of the COVID-19 pandemic on training and career development. The most negative impact was lack of access to research facilities, clinics, and human subjects, plus for KL2 scholars lack of access to team members and need for homeschooling. TL1 trainees reported having more time to think and write. Common strategies to maintain research productivity involved time management, virtual connections with colleagues, and shifting to research activities not requiring laboratory/clinic settings. Strategies for mitigating the impact of the COVID-19 pandemic on training and career development are described.

OBJECTIVE:The aim of the study was to determine abdominal and breast adipose tissue parameters on 18-fluorodeoxyglucose positron emission tomography/computed tomography (CT) that may serve as outcome predictors in breast angiosarcoma patients. MATERIALS/METHODS:Women with breast angiosarcoma (n = 13) who underwent 18-fluorodeoxyglucose positron emission tomography/CT were identified. A control group was selected (n = 25). Abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) were assessed on unenhanced computed tomographies. Breast adipose tissue (BAT) volumes of the uninvolved breast were quantified. Metabolic activity of VAT, SAT, and BAT was calculated (standardized uptake value [SUV]). RESULTS:Breast angiosarcoma patients had higher metabolic activity of VAT compared with controls (SUV 0.93 ± 0.39 vs 0.64 ± 0.11, P = 0.044). Within the patient group, there were 6 deaths (46.2%). Patients who died had higher SAT activity (SUV 0.52 ± 0.24 vs 0.29 ± 0.06, P = 0.027) and higher BAT metabolic activity (SUV 0.48 ± 0.20 vs 0.27 ± 0.11, P = 0.045) compared with nondeceased patients. CONCLUSIONS:Patients with breast angiosarcoma have higher metabolic activity of VAT. Higher abdominal SAT and higher BAT metabolic activity of the uninvolved breast might predict mortality.

BACKGROUND:Sleeve gastrectomy (SG), the most commonly performed metabolic and bariatric surgery, is associated with reductions in areal bone mineral density at multiple sites, and changes in bone structure at the distal radius and tibia without reductions in strength estimates at these peripheral sites. Data are lacking regarding effects on hip strength estimates. OBJECTIVE:To evaluate effects of SG on measures of hip structural analysis in adolescents and young adults over 12 months using dual-energy x-ray absorptiometry. SETTINGS/METHODS:Translational and Clinical Research Center. METHODS:We enrolled 48 youth 14- to 22-years old with moderate-to-severe obesity; 24 underwent SG and 24 controls were followed without surgery (18 females, 6 males in each group). Hip structure was assessed using dual-energy x-ray absorptiometry at baseline and 12 months. Analyses are adjusted for age, sex, race, and the baseline bone measure. RESULTS:The SG group lost 25.9% weight versus .3% in controls. Compared with controls, SG had reductions in narrow neck, intertrochanteric and femoral shaft bone mineral density Z-scores (P ≤ .012). Furthermore, SG had greater reductions in narrow neck and intertrochanteric region (but not femoral shaft) cross-sectional area, cortical thickness, cross-sectional moment of inertia and section modulus, and increases in buckling ratio (P ≤ .039). Differences were attenuated after adjusting for 12-month body mass index change. At 12 months, differences were minimal after adjusting for age, sex, race, and weight. CONCLUSIONS:Over 12 months, SG had negative effects at the narrow neck and intertrochanteric regions of the hip, but not the femoral shaft. Reduced body mass index may compensate for these deleterious effects on bone.

BACKGROUND:Areal bone mineral density (BMD) of the lumbar spine by DXA is greater in Black compared to White adolescents. Bone strength is determined not only by BMD but also its microenvironment, and marrow adipose tissue (MAT) has been shown to be an important determinant of skeletal integrity, independent of BMD. Racial differences in volumetric BMD (vBMD) and MAT in adolescents and young adults with obesity are unknown. OBJECTIVE:To assess racial differences in lumbar vBMD and MAT in Black and White adolescents and young adults with obesity and to assess body composition determinants of bone parameters. We hypothesized that Blacks will have higher vBMD and lower MAT of the lumbar spine compared to Whites. METHODS:-test or Wilcoxon test. Correlation analysis was performed to assess associations between bone parameters and body composition. RESULTS:Black adolescents/young adults with obesity had higher vBMD compared to Whites (p < 0.0001), while there was no significant difference in lumbar MAT (p = 0.64). There were also no significant differences in body composition measures between groups (p ≥ 0.28). An inverse association between MAT and vBMD was observed in Whites (r = -0.47, P = 0.001) but not in Blacks (p = 0.6). There were no significant associations between body composition measures and bone parameters (p > 0.1). CONCLUSION/CONCLUSIONS:There are racial differences in lumbar vBMD in adolescents and young adults with moderate to severe obesity, with Blacks having higher vBMD than Whites, while there were no differences in MAT content. The known inverse association between BMD and MAT was only observed in Whites but not in Blacks, suggesting possible racial differences in stem cell differentiation into the bone and fat lineages.

CONTEXT:Sleeve gastrectomy (SG), the most common metabolic and bariatric surgery in adolescents, is associated with bone loss. Marrow adipose tissue (MAT) is a dynamic endocrine organ that responds to changes in nutrition and might serve as a novel biomarker for bone health. Two types of MAT have been described, which differ in anatomic location-proximal regulated MAT vs distal constitutive MAT. OBJECTIVE:To determine the effects of SG on volumetric bone mineral density (vBMD) and MAT in adolescents with obesity. We hypothesized that SG would lead to a decrease in vBMD and differential changes in MAT. DESIGN:12-month prospective study in 52 adolescents with moderate-to-severe obesity (38 female; mean age:17.5 ± 2.2 years; mean BMI 45.2 ± 7.0 kg/m2), comprising 26 subjects before and after SG and 26 nonsurgical controls. MAIN OUTCOME MEASURES:Lumbar vBMD by quantitative computed tomography; MAT of the lumbar spine, femur and tibia by proton magnetic resonance spectroscopy; abdominal fat and thigh muscle by magnetic resonance imaging. RESULTS:Adolescents lost 34.1 ± 13.1 kg after SG vs 0.3 ± 8.4 kg in the control group (P < 0.001). Lumbar vBMD decreased in the SG group (P = 0.04) and this change was associated with a reduction in weight and muscle area (P < 0.05) and an increase in lumbar MAT (P = 0.0002). MAT of the femur and tibia decreased after SG vs controls (P < 0.05); however, the differences were no longer significant after controlling for change in weight. CONCLUSION:SG in adolescents decreased lumbar vBMD associated with an increase in lumbar MAT and decrease in extremity MAT. This demonstrates differential changes of regulated MAT in the lumbar spine and constitutive MAT in the distal skeleton in adolescents in response to SG.

BACKGROUND/OBJECTIVE:Less muscle mass has been associated with greater insulin resistance, but whether the association is independent of deleterious adipose depots in young adults with overweight/obesity who are at high risk for type 2 diabetes (T2DM) but are otherwise metabolically healthy is not known. The objective of this study was to determine whether muscle mass is independently associated with insulin sensitivity (IS) in young adults with overweight/obesity. SUBJECTS/METHODS:and metabolically healthy without T2DM. Primary independent variable: percent ideal appendicular lean mass (ALM) calculated as measured ALM divided by predicted ALM for age, weight, and height, calculated using validated NHANES data-based equation. Primary dependent variable: IS by Matsuda index. RESULTS:(mean ± SD). Individuals in the highest % ideal ALM tertile had mean IS 45% higher than the lowest tertile [6.94 ± 0.85 vs 4.80 ± 0.56 (mean ± SEM), p = 0.008] (sex interaction p = 0.003). Men in the highest % ideal ALM tertile had mean IS twice the lowest tertile (5.47 ± 0.68 vs 2.68 ± 0.34, p = 0.001), which remained significant controlling for visceral/subcutaneous and intermuscular adipose tissue, and intramyocellular and intrahepatic lipids (p = 0.03). The association was not significant in women. CONCLUSIONS:Muscle mass is associated with IS independent of detrimental adipose depots in young men with overweight/obesity, at risk for T2DM but currently metabolically healthy. Muscle mass relative to sex, age, weight, and height-specific norms may be used to ascertain individual T2DM risk associated with low muscle mass.

Dedifferentiated chordoma is a rare chordoma subtype characterized by a high-grade sarcoma juxtaposed to conventional chordoma. We identified a series of dedifferentiated chordomas, reviewed clinicopathologic features, performed next-generation sequencing in select cases, and analyzed all related English-language publications. Our series included 7 men and 3 women (age 15 to 80 y [median: 54 y]; <1% of >1000 chordomas surveyed). The tumor (2.8 to 24.5 cm [median: 5.8 cm] in size) presented de novo or as recurrence (including postradiotherapy) in sacrum (n=5), skull base (n=2), lumbar spine (n=1), thoracic/mediastinum (n=1), and lung (n=1; as metastasis). Histologically, the dedifferentiated component (3% to 95% [median: 60%]) was pleomorphic-to-fibrosarcomatous, juxtaposed to conventional (n=8) or chondroid (n=2) component. By immunohistochemistry, the conventional/chondroid component consistently expressed cytokeratin and brachyury, whereas the dedifferentiated component showed loss of both. We identified a sacral conventional chordoma with INI1 loss, with one of the lung metastases showing biphasic histology with loss of cytokeratin and brachyury in the dedifferentiated component. Sequencing identified tumor suppressor mutations in 4 tumors, including TP53 mutations in the dedifferentiated component in 3 tumors. Of 7 patients with follow-up, 6 developed metastases; 4 died at 15 to 99 months (median: 24 mo) after dedifferentiated chordoma diagnosis. Collectively, of 87 dedifferentiated chordoma patients described in 1913-2020 (including 10 herein), the median overall survival was 20 months. In summary, dedifferentiated chordoma involves diverse sites and presents de novo, postradiotherapy, or as recurrence/metastasis months-to-years after initial diagnosis. The dedifferentiated component shows loss of brachyury and cytokeratin staining and harbors recurrent TP53 mutations, implicating tumor suppressor dysregulation in chordoma dedifferentiation.

BACKGROUND:African Americans (AA) have more favorable bone density and microarchitecture compared to Whites (W), which may explain their observed lower fracture rates. Obesity has deleterious effects on bone microarchitecture and strength estimates and is associated with an increase in fracture risk. Adolescence and young adulthood are periods of active bone accrual and also periods characterized by an increasing prevalence of obesity. The effect of obesity on the relationship between race and bone parameters remains unclear, particularly in youth. OBJECTIVE:To assess differences in BMD, bone microarchitecture and strength estimates in AA and W adolescents and young adults with moderate to severe obesity. We hypothesized that racial differences in bone endpoints in lean youth would also be noted in youth with moderate to severe obesity. METHODS:who underwent dual energy X-ray absorptiometry (DXA), high resolution peripheral quantitative computed tomography (HRpQCT), extended cortical analysis (ECA) and micro-finite element analysis (FEA) to obtain measures of volumetric bone mineral density (vBMD), bone geometry, microarchitecture, and strength estimates at the distal radius and tibia. RESULTS:We found no differences between AA and W for total fat and lean mass, and areal BMD Z-scores (p > 0.05 for all). At the distal radius, no significant differences were detected in vBMD, bone geometry or microarchitecture (p > 0.05 for all); however, stiffness and failure load were higher in the AA group (p = 0.031 and 0.047 respectively). At the distal tibia, cortical vBMD was higher in AA vs. W (p = 0.012), while trabecular number was higher and trabecular separation lower in W vs. AA (p ≤ 0.028). Stiffness and failure load trended higher in AA vs. W (p = 0.052 and p = 0.048, respectively). Groups did not differ for any other bone parameter (p > 0.05). CONCLUSION:Racial differences in bone endpoints appear to be less marked in those with moderate to severe obesity, suggesting that effects of obesity may blunt the effect of race on bone endpoints.

PURPOSE/OBJECTIVE:Ischiofemoral impingement (IFI) is associated with abnormalities of the quadratus femoris muscle and narrowing of the ischiofemoral (IF) and quadratus femoris (QF) spaces. The hip abductors play an important role in pelvic stability and abductor tears might play a role in the pathophysiology of IFI. The purpose of our study was to assess the association between hip abductor tears and IFI on MRI. MATERIALS AND METHODS/METHODS:The study was IRB approved and HIPAA compliant. Inclusion criteria were MRI findings of IFI (narrowing of the IF space ≤ 15 mm or QF space ≤ 10 mm with associated ipsilateral quadratus femoris edema or fatty infiltration/atrophy). Two MSK radiologists assessed hip/pelvic MRIs and integrity of the tensor fascia lata, gluteus medius, and minimus tendons. IFI and control groups were compared with a two-tailed Student t test or chi-squared test. RESULTS:We identified 140 patients with MRI findings of IFI (mean age 56 ± 13 years, 130 f, 10 m) and 140 controls of similar age and sex. Patients with IFI had a higher prevalence of gluteus medius/minimus partial tears (37 vs 21, p = 0.02) and full-thickness tears (24 vs 21, p = 0.03). Patients with IFI had a higher prevalence and higher grade of gluteal muscle atrophy compared with controls (p < 0.03). There were no tears of the tensor fascia lata in either group. CONCLUSION/CONCLUSIONS:Patients with IFI had a higher prevalence of abductor tears and abductor muscle atrophy compared with matched controls. This suggests that abductor tears might play a role in the pathophysiology of IFI.

Bone marrow adipose tissue (BMAT) resides within the bone marrow microenvironment where its function remains poorly understood. BMAT is elevated in anorexia nervosa, a disease model of chronic starvation, despite depletion of other fat depots. In addition to BMAT, the marrow microenvironment also consists of osteoblast and hematopoietic progenitors. BMAT is inversely associated with bone mineral density (BMD) in multiple populations including women with anorexia nervosa, and regulates hematopoiesis in animal models. We hypothesized that BMAT would be associated with circulating populations of hematopoietic cells (red and white blood cells) in humans and performed a post hoc analysis of two studies-a cross-sectional study and a longitudinal study-to investigate this hypothesis. We studied 89 premenopausal women cross-sectionally (median age [interquartile range], 27 [24.5, 31.7] years), including 35 with anorexia nervosa. We investigated associations between red blood cell (RBC) and white blood cell (WBC) counts and BMAT assessed by ¹ H-magnetic resonance spectroscopy, BMD assessed by DXA, and bone microarchitecture assessed by HR-pQCT. In addition, we analyzed longitudinal data in six premenopausal women with anorexia nervosa treated with transdermal estrogen for 6 months and measured changes in BMAT and blood cell counts during treatment. Cross-sectionally, BMAT was inversely associated with WBC and RBC counts. In contrast, BMD and parameters of bone microarchitecture were positively associated with WBC and RBC. In women with anorexia nervosa treated with transdermal estrogen for 6 months, decreases in BMAT were significantly associated with increases in both RBC and hematocrit (rho = -0.83, p = 0.04 for both). In conclusion, we show that BMAT is inversely associated with WBC and RBC in premenopausal women, and there is a potential association between longitudinal changes in BMAT and changes in RBC. These associations warrant further study and may provide further insight into the role and function of this understudied adipose depot. © 2020 American Society for Bone and Mineral Research.