Faculty Bibliography

CONTEXT:Sleeve gastrectomy (SG) improves metabolic endpoints but is associated with impaired bone outcomes. OBJECTIVE:To determine mechanisms contributing to impaired bone health in youth following SG. METHODS:12-month longitudinal observational study in a multidisciplinary tertiary-care hospital, including 64 youth 13-25 years old with moderate-to-severe obesity (51 females); 30 underwent SG and 34 were nonsurgical (NS) controls. SG was undertaken after a combined decision-making process between treatment team and patient. The main outcome measures were fasting blood for enteric peptides, sex steroids, sclerostin, and bone turnover markers (N-terminal propeptide of type 1 procollagen [P1NP] and C-terminal cross-linking telopeptide [CTX]); dual-energy X-ray absorptiometry measures of areal bone mineral density (aBMD) and body composition; high resolution peripheral quantitative computed tomography; measures of volumetric BMD (vBMD); microfinite element analysis of strength estimates (distal radius and tibia). RESULTS:SG had greater reductions in body mass index (BMI) z-scores, serum estrone, and the free androgen index (FAI) (P ≤ .046), and greater increases in sclerostin, P1NP, and CTX (P ≤ .010) than NS controls. Fasting ghrelin decreased in SG vs NS (P < .0001); fasting peptide YY did not change. Most changes were driven by female SG participants. Among females (the majority of study participants), after controlling for baseline age and race, reductions in total hip aBMD Z-scores were positively associated with changes in BMI, lean mass, estrone, FAI, and ghrelin, and inversely with changes in sclerostin.. Decreases in total vBMD of the radius and tibia were associated positively with decreases in BMI. Increases in CTX were associated with decreases in BMI, lean mass, and ghrelin, and increases in sclerostin. CONCLUSION:Bone loss after SG in youth is associated with changes in body composition, sex steroids, sclerostin, and enteric peptides. These are potential targets for future preventative or therapeutic strategies.

CONTEXT:Obesity is a state of relative growth hormone (GH) deficiency, and GH has been identified as a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) because of its lipolytic and anti-inflammatory properties. However, the GH/IGF-1 axis has not been well characterized in NAFLD. OBJECTIVE:We aimed to investigate serum GH and IGF-1 levels in relation to intrahepatic lipid content (IHL) and markers of hepatocellular damage and fibrosis in NAFLD. METHODS:This cross-sectional study included 102 adults (43% women; age 19-67; BMI ≥ 25 kg/m2) without type 2 diabetes. IHL was measured by magnetic resonance spectroscopy; NAFLD was defined by ≥ 5% IHL. Peak-stimulated GH in response to GH releasing hormone and arginine was assessed as was serum IGF-1 (LC/MS). RESULTS:There was no difference in mean age, BMI, or sex distribution in NAFLD vs controls. Mean (± SD) IHL was higher in NAFLD vs controls (21.8 ± 13.3% vs 2.9 ± 1.1%, P < 0.0001). Mean peak-stimulated GH was lower in NAFLD vs controls (9.0 ± 6.3 vs 15.4 ± 11.2 ng/mL, P = 0.003), including after controlling for age, sex, visceral adipose tissue, and fasting glucose. In a stepwise model, peak-stimulated GH predicted 14.6% of the variability in IHL (P = 0.004). Higher peak-stimulated GH was also associated with lower ALT. Higher serum IGF-1 levels were associated with lower risk of liver fibrosis by Fibrosis-4 scores. CONCLUSION:Individuals with NAFLD have lower peak-stimulated GH levels but similar IGF-1 levels as compared to controls. Higher peak-stimulated GH levels are associated with lower IHL and less hepatocellular damage. Higher IGF-1 levels are associated with more favorable fibrosis risk scores. These data implicate GH and IGF-1 as potential disease modifiers in the development and progression of NAFLD.

OBJECTIVE:The GH and IGF-1 axis is a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) given its lipolytic, anti-inflammatory and anti-fibrotic properties. IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult, human hepatic tissue is not well understood across the spectrum of NAFLD severity. Therefore, we sought to investigate hepatic IGF-1R and GHR expression in subjects with NAFLD utilizing gene expression analysis (GEA) and immunohistochemistry (IHC). DESIGN:GEA (n = 318) and IHC (n = 30) cohorts were identified from the Massachusetts General Hospital NAFLD Tissue Repository. GEA subjects were categorized based on histopathology as normal liver histology (NLH), steatosis only (Steatosis), nonalcoholic steatohepatitis (NASH) without fibrosis (NASH F0), and NASH with fibrosis (NASH F1-4) with GEA by the Nanostring nCounter assay. IHC subjects were matched for age, body mass index (BMI), sex, and diabetic status across three groups (n = 10 each): NLH, Steatosis, and NASH with fibrosis (NASH F1-3). IHC for IGF-1R, IGF-1 and GHR was performed on formalin-fixed, paraffin-embedded hepatic tissue samples. RESULTS:IGF-1R gene expression did not differ across NAFLD severity while IGF-1 gene expression decreased with increasing NAFLD severity, including when controlled for BMI and age. GHR expression did not differ by severity of NAFLD based on GEA or IHC. CONCLUSIONS:IGF-1R and GHR expression levels were not significantly different across NAFLD disease severity. However, expression of IGF-1 was lower with increasing severity of NAFLD. Additional research is needed regarding the contribution of the GH/IGF-1 axis to the pathophysiology of NAFLD and NASH.

BACKGROUND:With the growing prevalence of severe obesity in adolescents, sleeve gastrectomy (SG), a type of metabolic bariatric surgery (MBS), is increasingly being performed at a younger age. Data regarding changes in homeostatic and hedonic appetite following SG are conflicting in adults, with some studies showing no change and others showing a decrease in appetite. Data evaluating the effect of SG on appetite during adolescence, when appetite is more plastic, are currently lacking. OBJECTIVE:To evaluate appetite changes one year after SG in adolescents with obesity vs. in non-surgical controls (NS). METHODS:Thirty-nine subjects 13-21 years old with severe obesity were followed for a year; 19 underwent SG, and 20 were followed without surgery. Subjects had fasting blood tests for appetite-regulating hormones and completed a visual analog scale for appetite assessment (VAS). RESULTS:= 0.011). Appetite changes were not associated with weight loss or final BMI. CONCLUSIONS:There were no changes in appetite measures one-year after SG from pre-surgery levels in adolescents with obesity, and appetite changes were not associated with changes in BMI. It is important to evaluate the impact of long-term appetite changes, if any, on weight loss after SG.

Recent studies have highlighted the role of bone marrow adipose tissue (BMAT) as a regulator of skeletal homeostasis and energy metabolism. While long considered an inert filler, occupying empty spaces from bone loss and reduced hematopoiesis, BMAT is now considered a secretory and metabolic organ that responds to nutritional challenges and secretes cytokines, which indirectly impact energy and bone metabolism. The recent advances in our understanding of the function of BMAT have been enabled by novel noninvasive imaging techniques, which allow longitudinal assessment of BMAT in vivo following interventions. This review will focus on the latest advances in our understanding of BMAT and its role in metabolic health. Imaging techniques to quantify the content and composition of BMAT will be discussed.

PURPOSE/OBJECTIVE:The aim of this study is to evaluate the safety and effectiveness of CT-guided corticosteroid injection for the treatment of osseous Langerhans cell histiocytosis (LCH) in a multi-institutional study. MATERIALS AND METHODS/METHODS:This IRB-approved study included patients from three institutions. We retrospectively reviewed clinical, procedural, and imaging data for corticosteroid injections performed to treat osseous LCH. Location of the lesion, lesion maximum dimension and volume, corticosteroid type and dose, and time interval between injection and change in lesion size/volume and symptoms were recorded. Generalized estimating equations (accounting for multiple lesions per subject) were used to evaluate the association between predictors (dose, maximum lesion dimension, and lesion volume) and outcomes (time to partial and complete radiographic resolution, and time to pain control). This analysis was adjusted by anatomic site. RESULTS:. Imaging and clinical follow-up were available for 22/40 (55%) and 34/40 (85%) of injections, respectively. All lesions responded to corticosteroid injection. Times to partial and complete imaging resolution were 13 ± 9 and 32 ± 13 weeks, respectively, and time to pain resolution was 22 ± 14 weeks. There were no complications. CONCLUSION/CONCLUSIONS:CT-guided corticosteroid injection is a safe and effective treatment for LCH. Pain resolution was achieved in all patients and imaging did not show progressive disease in any of the patients.

OBJECTIVE/UNASSIGNED:Overweight/obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity. DESIGN/UNASSIGNED:An 18-month, randomized, double-blind, placebo-controlled study of GH, followed by 6-month observation. METHODS/UNASSIGNED:In this study, 77 adults (53% men), aged 18-65 years, BMI ≥ 25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized to daily subcutaneous GH or placebo, targeting IGF1 in the upper quartile of the age-appropriate normal range. Forty-nine completed 18 months. DXA, volumetric quantitative CT, and high-resolution peripheral quantitative CT were performed. RESULTS/UNASSIGNED:Pre-treatment mean age (48 ± 12 years), BMI (33.1 ± 5.7 kg/m2), and BMD were similar between groups. P1NP, osteocalcin, and CTX increased (P < 0.005) and visceral adipose tissue decreased (P = 0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased in the GH vs placebo group (P < 0.05). Between 18 and 24 months (post-treatment observation period), radius aBMD and tibia cortical thickness increased in the GH vs placebo group. At 24 months, there were no differences between the GH and placebo groups in bone density, structure, or strength compared to baseline. CONCLUSIONS/UNASSIGNED:GH administration for 18 months increased bone turnover in adults with overweight/obesity. It also decreased some measures of BMD, bone microarchitecture, and bone strength, which all returned to pre-treatment levels 6 months post-therapy. Whether GH administration increases BMD with longer treatment duration, or after mineralization of an expanded remodeling space post-treatment, requires further investigation.

The use of denosumab to treat giant cell tumors of bone (GCT) and other giant cell-containing bone tumors has become more common. While the clinicopathologic features of denosumab-treated giant cell tumors of bone have been well-illustrated, descriptions of other denosumab-treated bone tumors are very limited. Surgical pathology files of two institutions and consultation files from two authors were searched for denosumab-treated aneurysmal bone cysts and denosumab-treated osteoblastomas. Clinicopathologic features were reviewed and analyzed. We identified four patients with denosumab-treated bone tumors other than GCT from our surgical pathology and consultation files, including two aneurysmal bone cysts and two osteoblastomas. All were treated with denosumab for 0.5-7.0 (median 4.5) months. Radiologically, denosumab-treated tumors showed decreased size with increased ossification and mineralization on CT and heterogeneous intermediate to hypointense signal on MRI. Histologically, denosumab-treated aneurysmal bone cyst contained thin, elongated, curvilinear, and anastomosing strands of bone with empty lacunae, while denosumab-treated osteoblastoma showed circumscribed nodules of woven bone lined by small osteoblasts. Denosumab-treated aneurysmal bone cyst and osteoblastoma showed treatment-related morphologic changes that can mimic other bone neoplasms. Their recognition requires correlation with the clinical history of denosumab use and radiologic findings.

BACKGROUND CONTEXT:Although survival of patients with spinal metastases has improved over the last decades due to advances in multi-modal therapy, there are currently no reliable predictors of mortality. Body composition measurements obtained using computed tomography (CT) have been recently proposed as biomarkers for survival in patients with and without cancer. Patients with cancer routinely undergo CT for staging or surveillance of therapy. Body composition assessed using opportunistic CTs might be used to determine survival in patients with spinal metastases. PURPOSE:The purpose of this study was to determine the value of body composition measures obtained on opportunistic abdomen CTs to predict 90-day and 1-year mortality in patients with spinal metastases undergoing surgery. We hypothesized that low muscle and abdominal fat mass were positive predictors of mortality. STUDY DESIGN:Retrospective study at a single tertiary care center in the United States. PATIENT SAMPLE:This retrospective study included 196 patients between 2001 and 2016 that were 18 years of age or older, underwent surgical treatment for spinal metastases, and had a preoperative CT of the abdomen within three months prior to surgery. OUTCOME MEASURES:Ninety-day and 1-year mortality by any cause. METHODS:for women. Bivariate and multivariate Cox proportional-hazard analyses were used to determine the associations between body compositions and 90-day and 1-year mortality. RESULTS:The median age was 62 years (interquartile range=53-70). The mortality rate for 90-day was 24% and 1-year 54%. The presence of sarcopenia was associated with an increased 1-year mortality rate of 66% compared with a 1-year mortality rate of 41% in patients without sarcopenia (hazard ratio, 1.68; 95% confidence interval, 1.08-2.61; p=.02) after adjusting for various clinical factors including primary tumor type, ECOG performance status, additional metastases, neurology status, and systemic therapy. Additional analysis showed an association between sarcopenia and increased 1-year mortality when controlling for the prognostic modified Bauer score (HR, 1.58; 95%CI, 1.04-2.40; p=.03). Abdominal fat CSAs or muscle attenuation were not independently associated with mortality. CONCLUSIONS:The presence of sarcopenia is associated with an increased risk of 1-year mortality for patients surgically treated for spinal metastases. Sarcopenia retained an independent association with mortality when controlling for the prognostic modified Bauer score. This implies that body composition measurements such as sarcopenia could serve as novel biomarkers for prediction of mortality and may supplement other existing prognostic tools to improve shared decision making for patients with spinal metastases that are contemplating surgical treatment.