New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Synovial sarcoma of bone: Sarcoma typically of soft tissues presenting as a primary bone tumor

Synovial sarcoma typically presents as periarticular soft tissue mass in adolescent and young adult patients. Very rarely, soft tissue sarcomas may arise primarily within bone posing a significant diagnostic challenge as primary osseous malignancies such as osteosarcoma and metastatic disease are much more common. While tissue sampling with immunohistochemical and genetic testing are required for definitive diagnosis, radiologists and orthopedic oncologists should consider alternate etiologies when typical imaging features of more common bone tumors are not identified. As an example, we present a 33-year-old male referred with a pathologic hip fracture proven to represent primary synovial sarcoma of bone. Keywords: Primary bone tumor, Synovial sarcom

Identification of a novel MTAP-RAF1 fusion in a soft tissue sarcoma

Abstract Background RAF family activating fusions have been described as a potentially targetable molecular finding in a subset of soft tissue sarcomas. To further expand upon the landscape of this genetic feature, we describe a novel MTAP-RAF1 activating fusion identified in a S100 positive soft tissue sarcoma. Case presentation A 51 year old man underwent excision of a soft tissue mass in his foot. Pathology revealed a spindle cell neoplasm with S100 positivity, ultimately classified as a soft tissue sarcoma, not otherwise specified. Comprehensive molecular profiling was performed to help establish the diagnosis and revealed a novel MTAP-RAF1 fusion that includes the tyrosine kinase domain of RAF1. Conclusions Our report adds to the spectrum of fusion-driven RAF activation observed in soft tissue sarcomas and lends additional evidence that RAF activation plays an important role in some soft tissue sarcomas. Identification of novel fusions involving the MAPK/ERK pathway in sarcomas may provide new avenues for precision medicine strategies involving targeted kinase inhibitors

Myopericytoma/myopericytomatosis of the lower extremity in two young patients: a recently designated rare soft tissue neoplasm

Myopericytomas are rare, slow-growing benign perivascular tumors most commonly arising within the superficial subcutaneous soft tissues of the lower extremity. They represent one of several related perivascular tumors of myoid lineage with similar morphology and shared immunohistochemical profile including positive staining for smooth muscle actin. Histologically, myopericytoma exhibit concentric, perivascular proliferation of spindled myoid cells with bland elongated nuclei and associated blood vessels. A solitary well-demarcated nodule or mass is typically referred to as myopericytoma, whereas an infiltrative multinodular lesion has more recently been termed myopericytomatosis. At magnetic resonance imaging, tumors are most commonly superficial, may be well-defined (myopericytoma) or ill-defined (myopericytomatosis), and demonstrate highly vascularized, avidly enhancing soft tissue often with areas of internal hemorrhage. We report 2 cases involving the lower extremity (1 myopericytoma and 1 myopericytomatosis) occurring in young patients, focusing on the clinical, histopathologic, and radiologic characteristics of this relatively new distinct entity

Langerhans cell histiocytosis of bone in an adult: A case report

Langerhans cell histiocytosis (LCH) may clinically manifest in a variety of ways due to its ability to involve nearly every organ system. LCH may present as a single bone lesion, skin rash, or as invasive disseminated disease and occurs typically in the pediatric and adolescent population, affecting both males and females. Independent of its clinical presentation and severity, LCH lesions share the common histology of CD1a+/CD207+ dendritic cells along with an inflammatory infiltrate, and, based upon improved scientific understanding, is now classified as a myeloproliferative neoplasm. We present a case report of an adult diagnosed with LCH of the pelvis. Keywords: Langerhans cell histiocytosis, Adults, Pelvi