Nf1 deficiency modulates the stromal environment in the pretumorigenic rat mammary gland.

Background: Neurofibromin, coded by the NF1 tumor suppressor gene, is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1)-a tumor predisposition syndrome caused by a germline NF1 mutation-have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by which NF1 mutations lead to breast cancer tumorigenesis is not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer. Approach: To accurately model the germline monoallelic NF1 mutations in NF1 patients, we utilized an Nf1-deficient rat model with accelerated mammary development before presenting with highly penetrant breast cancer. Results: We identified increased collagen content in Nf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that Nf1-deficient mature adipocytes in the rat mammary gland have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with in vitro differentiation, however, flow cytometry analysis did not show a change in mammary adipose-derived mesenchymal stem cell abundance. Conclusion: Collectively, this study uncovered the previously undescribed role of Nf1 in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary glands will create a foundation for developing early detection strategies of breast cancer among NF1 patients.

Association Between MR Elastography Liver Stiffness and Histologic Liver Fibrosis in Children and Young Adults With Autoimmune Liver Disease.

Background: Liver fibrosis is an important clinical endpoint of progression of autoimmune liver disease (AILD); its monitoring would benefit from noninvasive imaging tools. Objective: To assess the relationship between MR elastography (MRE) liver stiffness measurements and histologic liver fibrosis, as well as to evaluate the performance of MRE and biochemical-based clinical markers for stratifying histologic liver fibrosis severity, in children and young adults with AILD. Methods: This retrospective study used an existing institutional registry of children and young adults diagnosed with AILD [primary sclerosing cholangitis (PSC), ASC (autoimmune sclerosing cholangitis), or AIH (autoimmune hepatitis)]. The registry was searched to identify patients who underwent both a research abdominal 1.5-T MRI that included liver MRE (performed for registry enrollment) and a clinically indicated liver biopsy within a 6-month interval. MRE used a 2D gradient-recalled echo sequence. One analyst measured mean liver shear stiffness (kPa) for each examination. Laboratory markers of liver fibrosis [aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 score (FIB-4)] were recorded. For investigational purposes, one pathologist determined histologic METAVIR liver fibrosis stage, blinded to clinical and MRI data. Spearman rank-order correlation was calculated between MRE liver stiffness and METAVIR liver fibrosis stage. ROC analysis was used to evaluate diagnostic performance for identifying advanced fibrosis (i.e., differentiating METAVIR F0-F1 from F2-F4 fibrosis), calculating sensitivity and specificity at the Youden's index. Results: The study included 46 patients (median [IQR] age, 16.6 [13.7-17.8] years; 20 female, 26 male); 12 had PSC, 10 had ASC, and 24 had AIH. Median MRE liver stiffness was 2.9 kPa (IQR: 2.2-4.0 kPa). MRE liver stiffness and METAVIR fibrosis stage showed strong positive correlation (rho=0.68). For identifying advanced liver fibrosis, MRE liver stiffness had AUC of 0.81, with sensitivity of 65.4% and specificity of 90.0%; APRI had AUC of 0.72, with sensitivity of 60.0% and specificity of 85.0%; and FIB-4 had AUC of 0.71, with sensitivity of 64.0% and 85.0%. Conclusion: MRE liver stiffness measurements were associated with histologic liver fibrosis severity. Clinical Impact: The findings support a role for MRE in noninvasive monitoring of liver stiffness, a surrogate for fibrosis, in children and young adults with AILD.

Spatial predictions of tree density and tree height across Mexico forests using ensemble learning and forest inventory data.

The National Forestry Commission of Mexico continuously monitors forest structure within the country's continental territory by the implementation of the National Forest and Soils Inventory (INFyS). Due to the challenges involved in collecting data exclusively from field surveys, there are spatial information gaps for important forest attributes. This can produce bias or increase uncertainty when generating estimates required to support forest management decisions. Our objective is to predict the spatial distribution of tree height and tree density in all Mexican forests. We performed wall-to-wall spatial predictions of both attributes in 1-km grids, using ensemble machine learning across each forest type in Mexico. Predictor variables include remote sensing imagery and other geospatial data (e.g., mean precipitation, surface temperature, canopy cover). Training data is from the 2009 to 2014 cycle (n > 26,000 sampling plots). Spatial cross validation suggested that the model had a better performance when predicting tree height r 2 = .35 [.12, .51] (mean [min, max]) than for tree density r 2 = .23 [.05, .42]. The best predictive performance when mapping tree height was for broadleaf and coniferous-broadleaf forests (model explained ~50% of variance). The best predictive performance when mapping tree density was for tropical forest (model explained ~40% of variance). Although most forests had relatively low uncertainty for tree height predictions, e.g., values <60%, arid and semiarid ecosystems had high uncertainty, e.g., values >80%. Uncertainty values for tree density predictions were >80% in most forests. The applied open science approach we present is easily replicable and scalable, thus it is helpful to assist in the decision-making and future of the National Forest and Soils Inventory. This work highlights the need for analytical tools that help us exploit the full potential of the Mexican forest inventory datasets.

Urinary tract infections trigger synucleinopathy via the innate immune response.

Symptoms in the urogenital organs are common in multiple system atrophy (MSA), also in the years preceding the MSA diagnosis. It is unknown how MSA is triggered and these observations in prodromal MSA led us to hypothesize that synucleinopathy could be triggered by infection of the genitourinary tract causing ɑ-synuclein (ɑSyn) to aggregate in peripheral nerves innervating these organs. As a first proof that peripheral infections could act as a trigger in MSA, this study focused on lower urinary tract infections (UTIs), given the relevance and high frequency of UTIs in prodromal MSA, although other types of infection might also be important triggers of MSA. We performed an epidemiological nested-case control study in the Danish population showing that UTIs are associated with future diagnosis of MSA several years after infection and that it impacts risk in both men and women. Bacterial infection of the urinary bladder triggers synucleinopathy in mice and we propose a novel role of ɑSyn in the innate immune system response to bacteria. Urinary tract infection with uropathogenic E. coli results in the de novo aggregation of ɑSyn during neutrophil infiltration. During the infection, ɑSyn is released extracellularly from neutrophils as part of their extracellular traps. Injection of MSA aggregates into the urinary bladder leads to motor deficits and propagation of ɑSyn pathology to the central nervous system in mice overexpressing oligodendroglial ɑSyn. Repeated UTIs lead to progressive development of synucleinopathy with oligodendroglial involvement in vivo. Our results link bacterial infections with synucleinopathy and show that a host response to environmental triggers can result in ɑSyn pathology that bears semblance to MSA.

Histologic Severity of Nonalcoholic Fatty Liver Disease Associates with Reduced Bone Mineral Density in Children.

BACKGROUND: Lower whole body bone mineral density (BMD) has been reported in children with nonalcoholic fatty liver disease (NAFLD), but potential mediators remain uncertain. AIMS: To assess BMD at multiple skeletal sites in children with confirmed NAFLD and controls with obesity, adjusting for known determinants of BMD, and examine potential mediators. METHODS: We assessed age-, sex-, and race-specific, and height-adjusted BMD z-scores of whole body, lumbar spine, hip, femoral neck and forearm by dual-energy-x-ray absorptiometry in 79 children, 8-19 years old: 46 with biopsy-confirmed NAFLD [29 steatohepatitis (NASH)/17 fatty liver (NAFL)] and 33 controls without liver disease. We compared BMD z-scores by multivariable regression, adjusting for known BMD determinants and potential mediators (inflammatory and insulin resistance measures). RESULTS: Unadjusted mean BMD z-scores in NAFLD were similar to controls, but significantly lower in NASH vs. NAFL at all sites. After covariate adjustment, mean forearm BMD z-score was higher in NAFL (ß 0.60 ± SE 0.30, p < 0.05) and lower in NASH (ß - 0.49 ± SE 0.26, p = 0.06) vs. controls (p = 0.002 for group), with similar trends at whole body and total hip; hs-CRP negatively associated with whole body and forearm BMD z-scores (p < 0.05), while visceral fat area negatively associated with femoral neck (p < 0.05). Only three children had clinically low whole body BMD z-scores (< - 2), one per group (control, NAFL and NASH). CONCLUSIONS: NASH, but not NAFL, may be associated with increased risk of reduced BMD in children. Systemic inflammation, independent of body composition and load bearing, may mediate reduction in BMD in NASH.

Customized Postoperative Therapy Improves Bile Drainage in Biliary Atresia: A Single Center Preliminary Report.

BACKGROUND: Controversies in management of biliary atresia (BA) after hepatoportoenterostomy (HPE) lead to variable treatment protocols. We implemented standardized medical management after HPE, customizing the use of antibiotics and corticosteroids based on patient-specific factors. METHODS: In this retrospective analysis, 20 consecutive infants underwent HPE for BA and were compared to a historical cohort. Analysis of successful biliary drainage 3 months after HPE (defined as serum total bilirubin <2 mg/dL) was the primary endpoint; survival with native liver at 2 years was the secondary endpoint. RESULTS: Sixteen of 20 (80%) infants had successful bile drainage, compared to 8 of 20 (40%) infants in the historical cohort (P = 0.0225). Sixteen of 20 patients in the new protocol have reached 2 years of age or required liver transplantation. Among the sixteen, 11 (68.8%) are alive with native livers versus 10 of 20 (50%) in the historical cohort (P = 0.0970). CONCLUSION: This preliminary report suggests the potential benefit of tailored use of postoperative antibiotics and corticosteroids in improving biliary drainage after HPE. LEVEL OF EVIDENCE: III.

PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease.

Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3+Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cell accrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically, the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility, glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulation of glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics, CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved in human NAFLD. Together, our data show that the steatotic liver microenvironment regulates Th17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation of these pathways holds potential for development of novel therapeutic strategies for NAFLD.

Serum Matrix Metalloproteinase 7 Is a Diagnostic Biomarker of Biliary Injury and Fibrosis in Pediatric Autoimmune Liver Disease.

In autoimmune liver disease (AILD), including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and overlap syndrome of AIH and PSC (ASC), the presence of biliary injury portends a worse prognosis. We studied serum matrix metalloproteinase 7 (sMMP7) as a biomarker for pediatric sclerosing cholangitis (SC). We prospectively enrolled 54 children (median age, 16 years) with AILD (AIH, n = 26; ASC, n = 16; and PSC, n = 12) at our center. The sMMP7 concentrations were higher in patients with SC compared to those without cholangiopathy (P < 0.001). An sMMP7 concentration >23.7 ng/mL had a sensitivity and specificity of 79% and 96%, respectively, and outperformed alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) in segregating patients with SC. Serum concentrations correlated with liver gene expression levels for MMP7 (r = 0.70; P < 0.001). Using immunofluorescence, MMP7 was localized primarily to the cholangiocytes of patients with SC. In 46 subjects with liver biopsy available for blinded review, elevation in sMMP7 concentrations segregated with the presence of lymphocytic and neutrophilic cholangitis and periductal fibrosis and correlated with Ishak, Ludwig, and Nakanuma scoring systems. Liver stiffness measured by magnetic resonance elastography also correlated with sMMP7 concentrations (r = 0.56; P < 0.01). Using magnetic resonance cholangiopancreatography plus (MRCP+), sMMP7 in 34 patients correlated with the number of biliary dilatations (r = 0.54; P < 0.01) and strictures (r = 0.56; P < 0.01). MMP7 as a marker of biliary injury was validated in an independent cohort of children with ulcerative colitis. Higher sMMP7 concentrations also correlated with a history of SC-related complication. Conclusion: MMP7 is a promising biomarker for pediatric SC that diagnostically outperforms ALP and GGT. sMMP7 may directly reflect biliary injury and fibrosis, the main drivers of disease progression in SC.

Poorly differentiated thyroid carcinoma of childhood and adolescence: a distinct entity characterized by DICER1 mutations.

Poorly differentiated thyroid carcinomas (PDTC) in young individuals are rare and their clinical and histopathologic features, genetic mechanisms, and outcomes remain largely unknown. Here, we report a detailed characterization of a series of six PDTC in patients ≤21 years old defined by Turin diagnostic criteria studied for mutations and gene fusions characteristic of thyroid cancer using targeted next-generation sequencing (NGS) and whole-exome sequencing (WES). All tumors had solid, insular, or trabecular growth pattern and high mitotic rate, and five out of six tumors showed tumor necrosis. Targeted NGS assay identified somatic mutations in the DICER1 gene in five of six (83%) tumors, all of which were "hotspot" mutations encoding the metal-ion binding sites of the RNase IIIb domain of DICER1. WES was performed in five cases which confirmed all hotspot mutations and detected two tumors with additional inactivating DICER1 alterations. Of these two, one was a germline pathogenic DICER1 variant and the other had loss of heterozygosity for DICER1. No other mutations or gene fusions characteristic of adult well-differentiated thyroid cancer and PDTC (BRAF, RAS, TERT, RET/PTC, and other) were detected. On follow-up, available for five patients, three patients died of disease 8-24 months after diagnosis, whereas two were alive with no disease. The results of our study demonstrate that childhood- and adolescent-onset PDTC are genetically distinct from adult-onset PDTC in that they are strongly associated with DICER1 mutations and may herald DICER1 syndrome in a minority. As such, all young persons with PDTC may benefit from genetic counseling. Furthermore, their clinically aggressive behavior contrasts sharply with the indolent nature of the great majority of thyroid tumors with DICER1 mutations reported to date.

Congenital Portosystemic Shunts in Children: Associations, Complications, and Outcomes.

BACKGROUND: Congenital portosystemic shunt (CPSS) is a rare malformation in which splanchnic venous flow bypasses the liver. CPSS is associated with other congenital anomalies and syndromes and can be associated with life-threatening complications. CPSS and their management remain underreported in the literature. Here, we review the clinical characteristics, management, and outcomes of a cohort of children and young adults with CPSS from two pediatric centers. METHODS: Cases of CPSS from Cincinnati Children's Hospital Medical Center and C.S. Mott Children's Hospital were reviewed to define CPSS anatomy, associated anomalies, complications, interventions, and outcomes. The imaging features and histopathology of liver lesions were characterized in detail. RESULTS: A total of 11 cases were identified. Median age was 10 years (range 0-26); 8 (73%) cases were female. Associated anomalies included six patients with heterotaxy (55%), five patients with congenital heart disease (45%), three patients with Turner syndrome (27%), and two patients with omphalocele, exstrophy, imperforate anus, spinal defects (OEIS) complex (18%). Eight (73%) cases had hyperammonemia ± encephalopathy. A 4-month-old presented with hepatopulmonary syndrome, and 12-year-old presented with pulmonary hypertension. Eight patients (73%) had liver lesions including five with premalignant adenomas and three with well-differentiated hepatocellular carcinoma (HCC). Four children underwent successful CPSS occlusion/ligation. Three children underwent liver transplant (2) or resection (1) for HCC without recurrence at extended follow-up. CONCLUSIONS: CPSS is associated with multiple anomalies (heterotaxy, congenital heart disease) and syndromes (Turner syndrome). CPSS liver lesions should be very carefully evaluated due to risk of premalignant adenomas and HCC. Serious complications of CPSS can occur at a young age but can be managed endovascularly or with open surgery.

Rotavirus Reassortant-Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia.

BACKGROUND AND AIMS: Biliary atresia (BA) is a devastating neonatal cholangiopathy that progresses to fibrosis and end-stage liver disease by 2 years of age. Portoenterostomy may reestablish biliary drainage, but, despite drainage, virtually all afflicted patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. APPROACH AND RESULTS: In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling human BA and has been used to study mechanistic aspects of the disease. Unfortunately, nearly all RRV-infected pups succumb by day of life 14. Thus, in this study we generated an RRV-TUCH rotavirus reassortant (designated as TR(VP2,VP4) ) that when injected into newborn mice causes an obstructive jaundice phenotype with lower mortality rates. Of the mice that survived, 63% developed Ishak stage 3-5 fibrosis with histopathological signs of inflammation/fibrosis and bile duct obstruction. CONCLUSIONS: This model of rotavirus-induced neonatal fibrosis will provide an opportunity to study disease pathogenesis and has potential to be used in preclinical studies with an objective to identify therapeutic targets that may alter the course of BA.

Community Socioeconomic Deprivation and Nonalcoholic Fatty Liver Disease Severity.

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity. Obesity is associated with lower socioeconomic status (SES). An independent link between pediatric NAFLD and SES has not been elucidated. The objective of this study was to evaluate the distribution of socioeconomic deprivation, measured using an area-level proxy, in pediatric patients with known NAFLD and to determine whether deprivation is associated with liver disease severity. METHODS: Retrospective study of patients <21 years with NAFLD, followed from 2009 to 2018. The patients' addresses were mapped to census tracts, which were then linked to the community deprivation index (CDI; range 0--1, higher values indicating higher deprivation, calculated from six SES-related variables available publicly in US Census databases). RESULTS: Two cohorts were evaluated; 1 with MRI (magnetic resonance imaging) and/or MRE (magnetic resonance elastography) findings indicative of NAFLD (n = 334), and another with biopsy-confirmed NAFLD (n = 245). In the MRI and histology cohorts, the majority were boys (66%), non-Hispanic (77%-78%), severely obese (79%-80%), and publicly insured (55%-56%, respectively). The median CDI for both groups was 0.36 (range 0.15-0.85). In both cohorts, patients living above the median CDI were more likely to be younger at initial presentation, time of MRI, and time of liver biopsy. MRI-measured fat fraction and liver stiffness, as well as histologic characteristics were not different between the high- and low-deprivation groups. CONCLUSIONS: Children with NAFLD were found across the spectrum of deprivation. Although children from more deprived neighborhoods present at a younger age, they exhibit the same degree of NAFLD severity as their peers from less deprived areas.

Molecular, endoscopic, histologic, and circulating biomarker-based diagnosis of eosinophilic gastritis: Multi-site study.

BACKGROUND: Eosinophilic gastritis (EG) is a clinicopathologic disorder with marked gastric eosinophilia and clinical symptoms. There is an unmet need among patients with EG for more precise diagnostic tools. OBJECTIVE: We aimed to develop tissue- and blood-based diagnostic platforms for EG. METHODS: Patients with EG and control subjects without EG were enrolled across 9 Consortium of Eosinophilic Gastrointestinal Disease Researchers-associated sites. An EG Diagnostic Panel (EGDP; gastric transcript subset) and EG blood biomarker panel (protein multiplex array) were analyzed. EGDP18 scores were derived from the expression of 18 highly dysregulated genes, and blood EG scores were derived from dysregulated cytokine/chemokine levels. RESULTS: Gastric biopsy specimens and blood samples from 185 subjects (patients with EG, n = 74; control subjects without EG, n = 111) were analyzed. The EGDP (1) identified patients with active EG (P < .0001, area under the curve ≥ 0.95), (2) effectively monitored disease activity in longitudinal samples (P = .0078), (3) highly correlated in same-patient samples (antrum vs body, r = 0.85, P < .0001), and (4) inversely correlated with gastric peak eosinophil levels (r = -0.83, P < .0001), periglandular circumferential collars (r = -0.73, P < .0001), and endoscopic nodularity (r = -0.45, P < .0001). For blood-based platforms, eotaxin-3, thymus and activation-regulated chemokine, IL-5, and thymic stromal lymphopoietin levels were significantly increased. Blood EG scores (1) distinguished patients with EG from control subjects without EG (P < .0001, area under the curve ≥ 0.91), (2) correlated with gastric eosinophil levels (plasma: r = 0.72, P = .0002; serum: r = 0.54, P = .0015), and (3) inversely correlated with EGDP18 scores (plasma: r = -0.64, P = .0015; serum: r = -0.46, P = .0084). Plasma eotaxin-3 levels strongly associated with gastric CCL26 expression (r = 0.81, P < .0001). CONCLUSION: We developed tissue- and blood-based platforms for assessment of EG and uncovered robust associations between specific gastric molecular profiles and histologic and endoscopic features, providing insight and clinical readiness tools for this emerging rare disease.

Focal liver lesions following Fontan palliation of single ventricle physiology: A radiology-pathology case series.

PURPOSE: Patients who have undergone Fontan palliation of single ventricle physiology congenital heart disease are prone to developing focal liver lesions. In our experience, the variety of lesions occurring in this population is greater than that described in the literature. The purpose of this study was to describe the breadth of biopsy-proven liver lesions in patients post-Fontan palliation of single ventricle physiology cared for at our institution. METHODS: We retrospectively identified patients who had previously undergone the Fontan operation and had a focal liver lesion biopsied between January 2000 and June 2018. Medical records were reviewed for lesion pathology, background liver findings, pertinent laboratory data, and demographic data. CT and MRI images were reviewed to describe imaging findings of the reported lesions. RESULTS: Twelve patients met inclusion criteria; 58% (7/12) of which were female. Fifteen lesions were biopsied including four macroregenerative/benign hepatocellular hyperplastic nodules, two hepatocellular adenomas, two hepatocellular carcinomas, two intrahepatic cholangiocarcinoma (in the same patient), one venous malformation, and one focus of vascularized scar tissue. Two additional lesions in patients postcardiac transplant were posttransplant lymphoproliferative disorder. CONCLUSION: Patients who have undergone Fontan palliation of single ventricle physiology are prone to develop a variety of liver lesions, both benign and malignant.

Pan-Trk Immunohistochemistry Identifies NTRK Rearrangements in Pediatric Mesenchymal Tumors.

Activating neurotrophic receptor kinase (NTRK) fusions define certain pediatric mesenchymal tumors, including infantile fibrosarcoma and cellular mesoblastic nephroma. Traditionally, molecular confirmation of these fusions has included either fluorescent in situ hybridization for ETV6 rearrangements or reverse-transcriptase polymerase chain reaction for the classic ETV6-NTRK3 fusion. However, these methods overlook variant NTRK rearrangements, which are increasingly appreciated as recurrent events in a subset of pediatric mesenchymal tumors. New therapeutic agents successfully target these fusions and may prevent morbid surgeries in very young children, making recognition of tumors harboring NTRK rearrangements of increasing importance. We evaluated the performance of immunohistochemical (IHC) staining using pan-Trk and TrkA antibodies in 79 pediatric mesenchymal tumors. Negative controls included pediatric mesenchymal tumors not harboring (n=28) or not expected to harbor (n=22) NTRK fusions. NTRK rearrangements were detected predominantly by DNA-based next-generation sequencing assays, specifically UW OncoPlex and UCSF500 Cancer Gene Panel. Pan-Trk IHC (EPR17341) was 97% sensitive and 98% specific for the presence of an NTRK rearrangement, and TrkA IHC (EP1058Y) was 100% sensitive and 63% specific for the presence of an NTRK rearrangement. Tumors with NTRK1 or NTRK2 rearrangements showed cytoplasmic staining, whereas tumors with NTRK3 rearrangements showed nuclear +/- cytoplasmic staining. We conclude that pan-Trk IHC is a highly sensitive and specific marker for NTRK rearrangements in pediatric mesenchymal tumors.

Peroxisomal ß-oxidation regulates whole body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), a metabolic predisposition for development of hepatocellular carcinoma (HCC), represents a disease spectrum ranging from steatosis to steatohepatitis to cirrhosis. Acox1, a rate-limiting enzyme in peroxisomal fatty acid ß-oxidation, regulates metabolism, spontaneous hepatic steatosis, and hepatocellular damage over time. However, it is unknown whether Acox1 modulates inflammation relevant to NAFLD pathogenesis or if Acox1-associated metabolic and inflammatory derangements uncover and accelerate potential for NAFLD progression. Here, we show that mice with a point mutation in Acox1 (Acox1Lampe1) exhibited altered cellular metabolism, modified T cell polarization, and exacerbated immune cell inflammatory potential. Further, in context of a brief obesogenic diet stress, NAFLD progression associated with Acox1 mutation resulted in significantly accelerated and exacerbated hepatocellular damage via induction of profound histological changes in hepatocytes, hepatic inflammation, and robust upregulation of gene expression associated with HCC development. Collectively, these data demonstrate that ß-oxidation links metabolism and immune responsiveness and that a better understanding of peroxisomal ß-oxidation may allow for discovery of mechanisms central for NAFLD progression.

Diagnostic Performance of MR Elastography for Liver Fibrosis in Children and Young Adults with a Spectrum of Liver Diseases.

Purpose To assess the diagnostic performance of magnetic resonance (MR) elastography-derived liver stiffness to detect liver fibrosis in a pediatric and young adult population with a spectrum of liver diseases. Materials and Methods This retrospective study included patients younger than 21 years of age who underwent MR elastography and liver biopsy within 3 months of one another between January 2012 and September 2016 for indications other than liver transplantation or Fontan palliation of congenital heart disease. MR elastography examinations were reprocessed by a single observer, blinded to pathologic findings. Pathology specimens were reviewed by a single pathologist who scored steatosis (lipid in ≥ 5% of hepatocytes) and staged fibrosis. Receiver operating characteristic (ROC) curves were used to assess diagnostic performance. Results A total of 86 patients, 49 (57%) male with a median age of 14.2 years (range, 0.3-20.6 years), were included. Fifty-one patients (59.3%) had Ludwig stage 2 or higher fibrosis; 44 patients (51.2%) had hepatic steatosis. The area under the ROC curve for Ludwig stage 0-1 versus stage 2 or higher fibrosis was 0.70 (95% confidence interval [CI]: 0.59, 0.81) for the whole population and was significantly lower for patients with steatosis versus those without (0.53 [95% CI: 0.35, 0.71] vs 0.82 [95% CI: 0.67, 0.96], P = .014). Optimal stiffness cut-offs for the entire population were 2.27 kPa with 68.6% sensitivity (95% CI: 57.2%, 80.1%) and 74.3% specificity (95% CI: 63.5%, 85.1%) or 1.67 kPa with 35.3% sensitivity (95% CI: 23.5%, 47.1%) and 91.4% specificity (95% CI: 84.5%, 98.3%). Conclusion In children and young adults, MR elastography performs significantly better for distinguishing stage 0-1 versus stage 2 or higher fibrosis in patients without steatosis than in those with steatosis. This suggests a confounding effect of steatosis or inflammation in the population with nonalcoholic fatty liver disease. © RSNA, 2018.

The Effect of Implant-Induced Artifacts on Interpreting Adjacent Bone Structures on Cone-Beam Computed Tomography Scans.

INTRODUCTION: Cone-beam computed tomography (CBCT) imaging can be used to visualize anatomical structures before implant placement. The aim of this study is to evaluate the impact of implant artifacts on the accuracy of measuring periimplant bone dimensions. MATERIALS AND METHODS: Nineteen implants were placed into 9 fresh, frozen cadavers. A CBCT scan was taken, the implants were removed, and a second scan was taken. Implant dimensions and periimplant bone measurements were calculated. The mean differences were compared with paired t tests. Pearson's correlation coefficients were calculated for bone thickness measurements. DISCUSSION: No significant differences were found between the implant dimension or bone thickness measurements on each scan. Bone thickness at the implant platform and apex were significantly correlated (P < 0.001). CONCLUSION: The presence of dental implants did not impact the accuracy of cone-beam computed tomography (CBCT) measurements of bone thickness by metallic artifacts.

Erratum: Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling.

This corrects the article DOI: 10.1038/nm.4346.

Evaluation of Single Tooth Loss to Maxillary Sinus and Surrounding Bone Anatomy With Cone-Beam Computed Tomography: A Multicenter Study.

BACKGROUND: Posterior maxillary tooth loss may complicate the implant treatment due to the alterations in alveolar anatomy and maxillary sinus pneumatization. This study aimed to comprehensively examine the anatomical structure of this region from cone-beam computed tomography (CBCT) images. MATERIALS AND METHODS: The posterior maxilla regions with single tooth loss were analyzed by dividing the variables into 3 subgroups from images of 597 patients chosen from 1160 CBCTs. Variables associated with sinus membrane (SM), sinus dimensions, ostium, septa, sinus neighborhood, alveolar bone height (ABH) and width (RW), posterior superior alveolar artery (PSAA), and adjacent roots were evaluated. RESULTS: The majority of the patients demonstrated 0 to 5 mm membrane thickness. Irregular SM thickening was lower for female patients. While females showed higher number of narrow sinus, males had higher RW than females. Sinus augmentation classification showed negative correlation with ABH, root-tip sinus floor and edentulous site classification. Posterior septa height was correlated with number of septa and ABH. PSAA diameter and location were also correlated between each other. CONCLUSION: The present results define formation of a sinus space with 11 mm coronal and 16 mm apical width after single tooth loss. A flat or semispherical thickening around 4 mm is usual in most cases with 51% possibility of anterior septum existence. A ridge anatomy, around 7.5 mm ABH and 7.2 to 9.3 RW from coronal to apical, complements this anatomy. Further studies are needed to clarify the reasons behind the SM and crestal anatomy variations between genders.