Faculty Bibliography

CONTEXT:Areal bone mineral density (BMD) is lower, particularly at the spine, in low-weight women with anorexia nervosa (AN). However, little is known about vertebral integral volumetric BMD (Int.vBMD) or vertebral strength across the AN weight spectrum, including "atypical" AN [body mass index (BMI) ≥18.5 kg/m2]. OBJECTIVE:To investigate Int.vBMD and vertebral strength, and their determinants, across the AN weight spectrum. DESIGN:Cross-sectional observational study. SETTING:Clinical research center. PARTICIPANTS:153 women (age 18 to 45): 64 with low-weight AN (BMI <18.5 kg/m2; 58% amenorrheic), 44 with atypical AN (18.5≤BMI<23 kg/m2; 30% amenorrheic), 45 eumenorrheic controls (19.2≤BMI<25 kg/m2). MEASURES:Int.vBMD and cross-sectional area (CSA) by quantitative computed tomography of L4; estimated vertebral strength (derived from Int.vBMD and CSA). RESULTS:Int.vBMD and estimated vertebral strength were lowest in low-weight AN, intermediate in atypical AN, and highest in controls. CSA did not differ between groups; thus, vertebral strength (calculated using Int.vBMD and CSA) was driven by Int.vBMD. In AN, Int.vBMD and vertebral strength were associated positively with current BMI and nadir lifetime BMI (independent of current BMI). Int.vBMD and vertebral strength were lower in AN with current amenorrhea and longer lifetime amenorrhea duration. Among amenorrheic AN, Int.vBMD and vertebral strength were associated positively with testosterone. CONCLUSIONS:Int.vBMD and estimated vertebral strength (driven by Int.vBMD) are impaired across the AN weight spectrum and are associated with low BMI and endocrine dysfunction, both current and previous. Women with atypical AN experience diminished vertebral strength, partially due to prior low-weight and/or amenorrhea. Lack of current low-weight or amenorrhea in atypical AN does not preclude compromise of vertebral strength.

PURPOSE/OBJECTIVE:To describe the imaging and clinical characteristics of chordoma osseous metastases (COM). MATERIALS AND METHODS/METHODS:Our study was IRB approved and HIPAA compliant. A retrospective search of our pathology database for pathology-proven COM yielded 15 patients who had undergone MRI, CT, bone scan, and/or FDG-PET/CT. The imaging and clinical features of the COMs were recorded. A control group of age and gender matched chordoma patients without osseous metastasis was evaluated. RESULTS:The COM mean maximal dimension was 6.4 ± 4.0 cm. The majority (60%) of patients had one lesion. Extra-osseous soft tissue component was present in 85% and was larger than intra-osseous component in 76%. On MRI the lesions were heterogeneous but predominantly T2 hyperintense with hypointense septae, and with variable enhancement. On CT the lesions were typically destructive or permeative; calcifications were rare. The extent of the soft tissue component was isodense to muscle on CT and therefore better evaluated on MRI. COM was in a body part contiguous to the site of the primary tumor. Compared to the controls, COM patients were more likely to have local recurrence (P = 0.0009) and positive resection margins (P = 0.002). At 1 year, 33% of COM patients were deceased and 13% had progressive metastases. CONCLUSION/CONCLUSIONS:COM are associated with large extra-osseous soft tissue components, which are better visualized by MRI. They are often located in a body part contiguous to the site of the primary tumor, portend poor prognosis, and are associated with positive resection margins and local recurrence.

BACKGROUND:Previous studies have demonstrated that an individual's race and ethnicity are important determinants of their areal bone mineral density (aBMD), assessed by dual-energy X-ray absorptiometry. However, there are few data assessing the impact of race on bone microarchitecture and strength estimates, particularly in older adolescent girls and young adults. We hypothesized that bone microarchitecture and strength estimates would be superior in Blacks compared to White and Asian American adolescent girls and young adults of similar age based on reports of higher aBMD in Blacks. METHODS:We assessed BMD using dual-energy X-ray absoptiometry (DXA), bone microarchitecture at the distal radius and distal tibia using high-resolution peripheral quantitative computed tomography (HRpQCT) and estimated measures of bone strength using micro-finite element analysis (FEA) in 35 White, 15 Asian American, and 10 Black girls 14-21 years. RESULTS:After controlling for height, most DXA measures of aBMD and aBMD Z scores were higher in Black girls compared with Whites and Asian Americans. HRpQCT and FEA showed that at the distal radius, Blacks had greater cortical perimeter, cortical area, trabecular thickness, trabecular BMD, estimated failure load, and stiffness than the other two groups. For the distal tibia, trabecular number and BMD were higher in Blacks than Asian Americans. CONCLUSIONS:Particularly at the distal radius, adolescent and young adult White and Asian American girls have less favorable bone microarchitecture and lower bone strength than Blacks, possibly explaining the lower risk of fracture seen in Blacks. LEVEL OF EVIDENCE:Level II.

Neurofibromatosis type 1 (NF1) is associated with neurocognitive deficits that can impact everyday functioning of children, adolescents, and adults with this disease. However, there is little agreement regarding measures to use as cognitive endpoints in clinical trials. This article describes the work of the Neurocognitive Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration. The goal of this committee is to identify standardized and specific cognitive assessment tools for use in NF clinical trials. The committee first identified cognitive domains relevant to NF1 and prioritized attention as the first domain of focus given prior and current trends in NF1 cognitive clinical trials. Performance measures and behavioral rating questionnaires of attention were reviewed by the group using established criteria to assess patient characteristics, psychometric properties, and feasibility. The highest rated tests underwent side-by-side comparison. The Digit Span subtest from the Wechsler scales was given the highest ratings of the performance measures due to its good psychometrics, feasibility, utility across a wide age range, and extensive use in previous research. The Conners scales achieved the highest ratings of the behavioral questionnaires for similar reasons. Future articles will focus on other cognitive domains, with the ultimate goal of achieving agreement for cognitive endpoints that can be used across NF clinical trials.

OBJECTIVE:Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working group's goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs). METHODS:The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings. RESULTS:We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in decentralized biobanks. CONCLUSIONS:These recommendations are intended to provide clinicians and researchers with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for NF1, NF2, and SWN.

OBJECTIVE:Tumors and other disease complications of neurofibromatosis (NF) can cause pain and negatively affect physical functioning. To document the clinical benefit of treatment in NF trials targeting these manifestations, patient-reported outcomes (PROs) assessing pain and physical functioning should be included as study endpoints. Currently, there is no consensus on the selection and use of such measures in the NF population. This article presents the recommendations of the PRO group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration for assessing the domains of pain and physical functioning for NF clinical trials. METHODS:The REiNS PRO group reviewed and rated existing PRO measures assessing pain intensity, pain interference, and physical functioning using their systematic method. Final recommendations are based primarily on 4 main criteria: patient characteristics, item content, psychometric properties, and feasibility for clinical trials. RESULTS:The REiNS PRO group chose the Numeric Rating Scale-11 (≥8 years) to assess pain intensity, the Pain Interference Index (6-24 years) and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Scale (≥18 years) to evaluate pain interference, and the PROMIS Physical Functioning Scale to measure upper extremity function and mobility (≥5 years) for NF clinical trials. CONCLUSIONS:The REiNS Collaboration currently recommends these PRO measures to assess the domains of pain and physical functioning for NF clinical trials; however, further research is needed to evaluate their use in individuals with NF. A final consensus recommendation for the pain interference measure will be disseminated in a future publication based on findings from additional published research.

OBJECTIVE:Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. METHODS:The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. RESULTS:For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. CONCLUSIONS:These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs.

OBJECTIVE:To examine associations between tongue adiposity with upper airway measures, whole-body adiposity and gender. We hypothesized that increased tongue adiposity is higher in males and positively associated with abnormal upper airway measures and whole-body adiposity. METHODS:We studied subjects who underwent whole-body positron emission tomography/computed tomography to obtain tongue attenuation (TA) values and cross-sectional area, pharyngeal length (PL) and mandibular plane to hyoid distance (MPH), as well as abdominal circumference, abdominal subcutaneous and visceral (VAT) adipose tissue areas, neck circumference (NC) and neck adipose tissue area. Metabolic syndrome was determined from available clinical and laboratory data. RESULTS:). Males had lower TA values (P=0.0002) and higher upper airway measures (P<0.0001) independent of age and BMI (P<0.001). In all subjects, TA was negatively associated with upper airway measures (P<0.001). TA was negatively associated with body composition parameters (all P<0.0001), most notably with VAT (r=-0.53) and NC (r=-0.47). TA values were lower in subjects with metabolic syndrome (P<0.0001). CONCLUSION/CONCLUSIONS:Increased tongue adiposity is influenced by gender and is associated with abnormal upper airway patency and body composition parameters.

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/CONCLUSIONS: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.