Faculty Bibliography

Approaches to manage nonalcoholic fatty liver disease (NAFLD) are limited by an incomplete understanding of disease pathogenesis. The aim of this study was to identify hepatic gene-expression patterns associated with different patterns of liver injury in a high-risk cohort of adults with obesity. Using the NanoString Technologies (Seattle, WA) nCounter assay, we quantified expression of 795 genes, hypothesized to be involved in hepatic fibrosis, inflammation, and steatosis, in liver tissue from 318 adults with obesity. Liver specimens were categorized into four distinct NAFLD phenotypes: normal liver histology (NLH), steatosis only (steatosis), nonalcoholic steatohepatitis without fibrosis (NASH F0), and NASH with fibrosis stage 1-4 (NASH F1-F4). One hundred twenty-five genes were significantly increasing or decreasing as NAFLD pathology progressed. Compared with NLH, NASH F0 was characterized by increased inflammatory gene expression, such as gamma-interferon-inducible lysosomal thiol reductase (IFI30) and chemokine (C-X-C motif) ligand 9 (CXCL9), while complement and coagulation related genes, such as C9 and complement component 4 binding protein beta (C4BPB), were reduced. In the presence of NASH F1-F4, extracellular matrix degrading proteinases and profibrotic/scar deposition genes, such as collagens and transforming growth factor beta 1 (TGFB1), were simultaneously increased, suggesting a dynamic state of tissue remodeling. Conclusion: In adults with obesity, distinct states of NAFLD are associated with intrahepatic perturbations in genes related to inflammation, complement and coagulation pathways, and tissue remodeling. These data provide insights into the dynamic pathogenesis of NAFLD in high-risk individuals.

The Harvard Catalyst KL2/CMeRIT program is a 2-year mentored institutional career award that includes KL2 grants funded by National Institutes of Health (NIH) and CMeRIT grants funded by Harvard Catalyst nonfederal funds. The purpose of this study was to compare outcomes for early-stage investigators funded by the KL2/CMeRIT program to a group of applicants who were not chosen for support to assess the potential impact of the program on early career outcomes. Career data, including academic promotions, subsequent grant funding, and publication rates, from both successful and unsuccessful 2008-2018 KL2/CMeRIT applicants were compiled throughout the year 2020. Data were obtained directly through outreach to both groups and through assessment of online resources. The cohort comprised 487 individuals, 109 awardees, and 378 nonawardees. Awardees were more likely to be subsequently involved in clinical and translational research than nonawardees (92% vs 75%, p < 0.001). A higher proportion of awardees also had achieved academic promotion (81% vs 69%, p = 0.016) and subsequent NIH funding (72% vs 58%, p = 0.047), while there was no difference in publication rates (p = 0.555). Participants in the Harvard Catalyst KL2/CMeRIT program demonstrate greater early career success than nonparticipants though the nonparticipants also fared relatively well.

BACKGROUND:States of chronic overnutrition and undernutrition are both associated with impaired bone health and increased fracture risk but there are no data on bone microarchitecture following short-term controlled nutritional challenges. OBJECTIVE:The purpose of our study was to evaluate the impact of short-term high-caloric feeding and fasting on bone microarchitecture. We hypothesized that both high-caloric feeding and fasting would have negative effects on microarchitecture. MATERIALS AND METHODS:). Subjects underwent an in-patient 10-day high-caloric visit (caloric intake with goal to achieve 7% weight gain), after which they went home to resume a normal diet for 13-18 days (stabilization period), and were then readmitted for a 10-day in-patient fasting stay (no caloric intake). All subjects underwent HRpQCT (XtremeCT, Scanco Medical AG, Brüttisellen, Switzerland) of the distal tibia and distal radius after each visit to assess volumetric bone mineral density (vBMD), trabecular and cortical microarchitecture, and strength estimates. The Wilcoxon signed rank test was used to perform within group comparisons. RESULTS:During the high-caloric period, there was a mean increase in weight by 6.3 + 1.7% (p < 0.0001). There were no significant changes in bone parameters in the distal tibia or distal radius (p > 0.05). During the stabilization period there was a significant reduction in weight by -2.7 + 1.9% (p < 0.0001) but no change in bone parameters (p > 0.05). During the fasting period there was a further reduction in weight by -8.8 + 1.2% (p < 0.0001). In the distal tibia, there was a significant increase in total and cortical vBMD, trabecular and cortical parameters as well as strength estimates (p < 0.05). In the distal radius there was an increase in total and trabecular vBMD (p < 0.05), while there were no changes in other microarchitecture parameters or strengths estimates. CONCLUSION:Short-term fasting after high-caloric feeding improves vBMD, bone microarchitecture and strength estimates of the distal tibia, while short-term high-caloric feeding does not change vBMD or microarchitecture. These results suggest that short-term fasting after high-caloric feeding in healthy individuals improves bone health and that these changes can be detected using HRpQCT in-vivo.

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.

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.

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.

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.

UNLABELLED:In a population-based study, we found that computed tomography (CT)-based bone density and strength measures from the thoracic spine predicted new vertebral fracture as well as measures from the lumbar spine, suggesting that CT scans at either the thorax or abdominal regions are useful to assess vertebral fracture risk. INTRODUCTION/BACKGROUND:Prior studies have shown that computed tomography (CT)-based lumbar bone density and strength measurements predict incident vertebral fracture. This study investigated whether CT-based bone density and strength measurements from the thoracic spine predict incident vertebral fracture and compared the performance of thoracic and lumbar bone measurements to predict incident vertebral fracture. METHODS:This case-control study of community-based men and women (age 74.6 ± 6.6) included 135 cases with incident vertebral fracture at any level and 266 age- and sex-matched controls. We used baseline CT scans to measure integral and trabecular volumetric bone mineral density (vBMD) and vertebral strength (via finite element analysis, FEA) at the T8 and L2 levels. Association between these measurements and vertebral fracture was determined by using conditional logistic regression. Sensitivity and specificity for predicting incident vertebral fracture were determined for lumbar spine and thoracic bone measurements. RESULTS:Bone measurements from T8 and L2 predicted incident vertebral fracture equally well, regardless of fracture location. Specifically, for predicting vertebral fracture at any level, the odds ratio (per 1-SD decrease) for the vBMD and strength measurements at L2 and T8 ranged from 2.0 to 2.7 (p < 0.0001) and 1.8 to 2.8 (p < 0.0001), respectively. Results were similar when predicting fracture only in the thoracic versus the thoracolumbar spine. Lumbar and thoracic spine bone measurements had similar sensitivity and specificity for predicting incident vertebral fracture. CONCLUSION/CONCLUSIONS:These findings indicated that like those from the lumbar spine, CT-based bone density and strength measurements from the thoracic spine may be useful for identifying individuals at high risk for vertebral fracture.

Aneurysmal bone cyst is a benign bone neoplasm that most commonly arises from the metaphyses of long bones in the first and second decades of life. Here, we describe a case of an aneurysmal bone cyst that occurred in the distal tibial diaphysis of a 72-year-old female that was concerning for malignancy on imaging, demonstrating cortical breakthrough and soft tissue extension. Histologically, the tumor showed the characteristic morphologic features of aneurysmal bone cyst. Fluorescence in situ hybridization was positive for USP6 rearrangement, and RNA sequencing revealed a USP6 gene fusion with VDR, a novel partner that encodes the vitamin D receptor and that has not been implicated previously in human neoplasia. This case highlights the diagnostic challenges presented by aneurysmal bone cyst in elderly adults, and it expands the genetic spectrum of USP6 rearrangements.

BACKGROUND:Bone stress injuries (BSIs) occur in up to 20% of runners and military personnel. Typically, after a period of unloading and gradual return to weightbearing activities, athletes return to unrestricted sports participation or military duty approximately 4 to 14 weeks after a BSI diagnosis, depending on the injury location and severity. However, the time course of the recovery of the bone's mechanical competence is not well-characterized, and reinjury rates are high. PURPOSE:To assess the bone microarchitecture and volumetric bone mineral density (vBMD) over 12 months after a tibial BSI diagnosis. STUDY DESIGN:Case-control study; Level of evidence, 3. METHODS:We enrolled 30 female athletes from the local community (aged 18-35 years) with a tibial BSI (grade ≥2 of 4 on magnetic resonance imaging) for this prospective observational study. Participants completed a baseline visit within 3 weeks of the diagnosis. At baseline and 6, 12, 24, and 52 weeks after the BSI diagnosis, we collected high-resolution peripheral quantitative computed tomography scans of the ultradistal tibia (4% of tibial length) of the injured and uninjured legs as well as pain and physical activity assessment findings. RESULTS:< .05 for all). CONCLUSION:Bone density declined in both the injured and the uninjured legs and, on average, did not return to baseline for 3 to 6 months after a tibial BSI diagnosis. The observed time to the recovery of baseline vBMD, coupled with the high rate of recurrent BSIs, suggests that improved return-to-sports and military duty guidelines may be in order.