Faculty Bibliography

Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multi-disciplinary NF1 experts.

BACKGROUND:Among adolescents with extremity fractures, individuals with obesity have greater representation compared with individuals of normal-weight, despite having higher areal and volumetric bone mineral density (aBMD, vBMD) than their normal-weight counterparts. The relative increase in BMD in individuals with obesity may thus be insufficient to support the greater force generated upon falling. The load-to-strength ratio is a biomechanical approach for assessing the risk of fracture by comparing applied force to bone strength, with higher load-to-strength ratios indicating higher fracture risk. OBJECTIVE:To assess the load-to-strength ratio at the distal radius in adolescent and young adult females with severe obesity (OB) compared with normal-weight healthy controls (HC). We hypothesized that OB have a higher load-to-strength ratio compared to HC. METHODS:We examined bone parameters in 65 girls 14-21 years old: 33 OB and 32 HC. We used dual-energy X-ray absorptiometry (DXA) to assess body composition, high resolution peripheral quantitative CT (HR-pQCT) to estimate vBMD, and microfinite element analysis (μFEA) to assess bone strength at the distal radius. To quantify fracture risk, we computed the load-to-strength ratio, where the numerator is defined as the load applied to the outstretched hand during a forward fall and the denominator is the bone strength, as estimated by μFEA. RESULTS:, p = 0.002), load-to-strength ratio at the radius was greater in OB than HC after controlling for age and race (0.66 vs. 0.54, p < 0.0001). In OB, impact force and load-to-strength ratio were associated negatively with % lean mass (r = -0.49; p = 0.003 and r = -0.65; p < 0.0001 respectively) and positively with visceral fat (r = 0.65; p < 0.0001 and r = 0.36; p = 0.04 respectively). CONCLUSIONS:Adolescent and young adult females with obesity have higher load-to-strength ratio at the distal radius due to higher forces applied to bone in a fall combined with incomplete adaptation of bone to increasing body weight. This is differentially affected by lean mass, fat mass, and visceral fat mass.

BACKGROUND:Obesity affects more than one-third of adults in the U.S., and effective treatment options are urgently needed. Oxytocin administration induces weight loss in animal models of obesity via effects on caloric intake, energy expenditure, and fat metabolism. We study intranasal oxytocin, an investigational drug shown to reduce caloric intake in humans, as a potential novel treatment for obesity. METHODS:). We investigate the efficacy, safety, and mechanisms of oxytocin administration in reducing body weight. Secondary endpoints include changes in resting energy expenditure, body composition, caloric intake, metabolic profile, and brain activation via functional magnetic resonance imaging in response to food images and during an impulse control task. Safety and tolerability (e.g., review of adverse events, vital signs, electrocardiogram, comprehensive metabolic panel) are assessed throughout the study and six weeks after treatment completion. RESULTS:). The study sample is diverse with 38% identifying as non-White and 20% Hispanic. CONCLUSION:Investigating intranasal oxytocin's efficacy, safety, and mechanisms as an anti-obesity medication will advance the search for optimal treatment strategies for obesity and its associated severe sequelae.

In addition to restrictions on conducting research, COVID-19-related travel bans and scientific meeting cancellations have negatively affected scholars in the Clinical and Translational Science Award (CTSA) Mentored Career Development Award (KL2) program. In response, a national virtual visiting scholar program was developed to provide opportunity for KL2 scholars to be virtual visiting professors at another CTSA hub, meet faculty and scholars, and expand networks and build collaborations. This article describes the design and short-term outcomes of the virtual CTSA Visiting Scholar Program. In 2020, a working group designed core program elements and developed an application and selection process. Anonymized surveys were sent to scholars post visit and to scholars and program directors 6 months post visit to evaluate their experience and solicit suggestions for improvements. Between November 2020 and May 2021, 56 KL2 scholars and 27 hubs participated. Forty-five (80.4%) participating scholars responded to the initial survey. Nearly all scholars (44, 97.7%) agreed their experience was valuable. All respondents indicated they would recommend the program to other KL2 scholars. For the 6-month survey, the response rate was 87.5% (49/56). Within 6 months of their visit, 36 (73.5%) respondents had contacted at least one person at the host hub and for 17 (34.7%) respondents, new collaborations with the host hub ensued. Twenty-five of 27 (92.6%) host hubs responded to the survey. Most (21, 84.0%) agreed that hearing visiting scholar talks was valuable to their own scholars and 23 (92%) indicated likelihood of their hub participating in future round of the program. The virtual Visiting Scholar Program provided KL2 scholars an opportunity to virtually visit another CTSA hub, present their research, and meet with faculty and other scholars to expand their networks. Although geared to KL2 scholars, this model is potentially generalizable to other nationally coordinated career development programs.

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.