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Vincenzo Arena, Ilaria Pennacchia, Fabio Maria Vecchio, Arnaldo CarboneInstitute of Pathology, Catholic University of Sacred Heart, Rome, ItalyAbstract: Chondroma is the most common neoplasia of the hand. Histologically, it consists of lobules of normal-appearing hyaline cartilage showing a lobular arrangement. To the best of our knowledge, this is the first reported case of chondroma of the hand in which, interestingly, osteoid production was observed.Keywords: chondroma, hand, osteoid

Context.-Gastrointestinal stromal tumors (GISTs) are Kit/CD117-expressing mesenchymal neoplasms of uncertain malignant potential. The lack of a reliable method of prognostication hampers the selection of patients eligible for STI571 therapy. 10q22-q23 is a region involved in chromosomal losses found in a fraction of malignant primary and metastatic GISTs harboring PTEN (phosphatase and tensin homologue deleted on chromosome 10), a tumor suppressor gene often altered in human neoplasms. Objective.-To investigate the role of PTEN in GISTs, an issue that to our knowledge has not been addressed previously. Design.-PTEN status was determined in a series of 21 GISTs, with follow-up ranging between 6 and 198 months, using immunohistochemistry correlated with clinical data. Results.-A greater than 25% fraction of cells with low or absent PTEN immunostaining was detected in 9 GISTs, including all those showing malignancy. By the log-rank test, a fraction of PTEN-deficient cells greater than 25% was associated with malignancy ( P < .001). Percentage of cells under expressing PTEN, size, cellularity, MIB-1 immunoreactivity, and coagulative necrosis proved to be associated with malignancy by Cox proportional hazards univariate analysis; low or absent expression of PTEN was the only factor selected by multivariate analysis ( P = .03).Conclusions.-PTEN downregulation is implied in GIST progression. The immunohistochemical assessment of PTEN status appears to be a promising method of GIST prognostication. [ABSTRACT FROM AUTHOR]

Background: Observational studies suggest that bariatric-metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial., Methods: We did a multicentre, open-label, randomised trial at three major hospitals in Rome, Italy. We included participants aged 25-70 years with obesity (BMI 30-55 kg/m 2 ), with or without type 2 diabetes, with histologically confirmed NASH. We randomly assigned (1:1:1) participants to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. The primary endpoint of the study was histological resolution of NASH without worsening of fibrosis at 1-year follow-up. This study is registered at ClinicalTrials.gov, NCT03524365., Findings: Between April 15, 2019, and June 21, 2021, we biopsy screened 431 participants; of these, 103 (24%) did not have histological NASH and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n=96 [33%]), Roux-en-Y gastric bypass (n=96 [33%]), or sleeve gastrectomy (n=96 [33%]). In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in the Roux-en-Y gastric bypass group (54 [56%]) and sleeve gastrectomy group (55 [57%]) compared with lifestyle modification (15 [16%]; p<0·0001). The calculated probability of NASH resolution was 3·60 times greater (95% CI 2·19-5·92; p<0·0001) in the Roux-en-Y gastric bypass group and 3·67 times greater (2·23-6·02; p<0·0001) in the sleeve gastrectomy group compared with in the lifestyle modification group. In the per protocol analysis (236 [82%] participants who completed the trial), the primary endpoint was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (p<0·0001). No deaths or life-threatening complications were reported in this study. Severe adverse events occurred in ten (6%) participants who had bariatric-metabolic surgery, but these participants did not require re-operations and severe adverse events were resolved with medical or endoscopic management., Interpretation: Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH., Funding: Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy., Competing Interests: Declaration of interests GM reports consulting fees from Novo Nordisk, Fractyl, and Recor. She is also scientific adviser for Metadeq, Keyron, GHP Scientific, and Jemyll, these all being unpaid positions. FR reports receiving research grants from Ethicon and Medtronic; receiving consulting fees from Novo Nordisk, Ethicon, and Medtronic; serving on the scientific advisory board of and receiving consultancy fees from GI Dynamics; and is a former director and current scientific advisor of Metadeq, Keyron, and GHP Scientific, these all being unpaid positions. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Conflict of interest None declared.

Aim: To investigate the prevalence of biopsy-proven non-alcoholic steatohepatitis (NASH) in a cohort of patients with morbid obesity and with or without type 2 diabetes (T2D) and to find non-invasive predictors of NASH severity., Methods: We evaluated a cohort of 412 subjects (age 19-67 years, body mass index-BMI: 44.98 kg/m 2 ), who underwent fine-needle liver biopsy during bariatric surgery. Thirty-six percent of the subjects were affected by T2D. Liver biopsies were classified according to the Kleiner's NAFLD Activity Score (NAS). NAFLD Fibrosis Score (NFS), AST/ALT ratio, AST to Platelet ratio (APRI), fibrosis-4 score (FIB4) were calculated. A neural network analysis (NNA) was run to predict NASH severity., Results: The prevalence of biopsy-proven NASH was 63% and 78% in subjects with obesity and without or with T2D, respectively. T2D doubled the risk of NASH [OR 2.079 (95% IC=1.31-3.29)]. The prevalence of NAFL increased with the increase of BMI, while there was an inverse correlation between BMI and NASH (r=-0.145 p=0.003). Only mild liver fibrosis was observed. HOMA-IR was positively associated with hepatocyte ballooning (r=0.208, p<0.0001) and fibrosis (r=0.159, p=0.008). The NNA highlighted a specificity of 77.3% using HDL-cholesterol, BMI, and HOMA-IR as main determinants of NASH., Conclusions: Our data show a higher prevalence of NASH in patients with morbid obesity than reported in the literature and the pivotal role of T2D among the risk factors for NASH development. However, the inverse correlation observed between BMI and biopsy-proven NASH suggests that over a certain threshold adiposity can be somewhat protective against liver damage. Our model predicts NASH presence with high specificity, thus helping identifying subjects who should promptly undergo liver biopsy., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objectives: Intersystem variability in liver stiffness (LS) quantification with ultrasound shear wave elastography (SWE) precludes direct comparison of results obtained with different equipment. The aim of this study was to investigate the agreement between point-SWE and 2-dimensional-SWE with Esaote-MyLab 9 (p-QElaXto and 2D-QElaXto, respectively) and 2D-SWE with SuperSonic Imagine (SSI) in order to assess specific LS thresholds for fibrosis staging with QElaXto techniques, using SSI as a reference standard., Methods: A total of 235 compensated chronic liver disease (CLD) patients without comorbidities potentially affecting LS were enrolled in the study. Among them, 101 patients underwent also liver biopsy. Agreement between the equipment was assessed with Pearson coefficient and Bland-Altman analysis, while cut-off values were calculated with receiver operating characteristics analysis., Results: Correlation between 2D-QElaXto and p-QElaXto with SSI resulted very good (r = 0.898 and r = 0.866), especially in precirrhotic stages, with a mean difference between LS values of -1.3 kPa for 2D-QElaXto and -0.6 kPa for p-QElaXto compared with SSI. Cut-off thresholds for diagnosing fibrosis ≥F2, ≥F3, and F4 in non-HBV-related CLD were, respectively, 5.5, 8.0, and 10.6 kPa for 2D-QElaXto and 6.1, 8.1, and 11.7 kPa for p-QElaXto. All three SWE techniques were effective in differentiating significant fibrosis ≥F2 from mild or absent fibrosis in the subgroup of patients submitted to biopsy and showed good feasibility., Conclusions: Correlation between QElaXto techniques and SSI in LS measurements is very good. Our study identifies for the first time cut-off thresholds for fibrosis staging in non-HBV-related CLD using two QElaXto techniques., (© 2021 American Institute of Ultrasound in Medicine.)

Objective: The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD., Design: The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI) 2 ). Liver/non-liver-related events and survival free of transplantation were recorded during the follow-up, compared by log-rank testing and reported by adjusted HR., Results: Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p<0.001; advanced fibrosis 10.1% vs 25.2% p<0.001), lower prevalence of diabetes (9.2% vs 31.4%, p<0.001), but no significant differences in the prevalence of the PNPLA3 I148M variant (p=0.57). During a median follow-up of 94 months (>10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069)., Conclusions: Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds., Lay Summary: NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain., Methods: The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell's c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available., Results: Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices <0.7) for extrahepatic events., Conclusions: Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death., Lay Summary: Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty liver disease to identify those at risk of advanced fibrosis and hence clinical complications. Herein, we compared various non-invasive scoring systems and identified those that were best at identifying risk, as well as those that were best for the prediction of long-term outcomes, such as liver-related events, liver cancer and death., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease and ranges from simple steatosis to nonalcoholic steatohepatitis. Recently, a platelet role in NAFLD pathogenesis and progression has been reported in mouse models and in patients. We investigated whether platelets are involved in liver and systemic inflammation processes in NAFLD. In this exploratory study we recruited 24 consecutive patients with biopsy-proven diagnosis of NAFLD and 17 healthy volunteers. We measured plasma levels of inflammatory markers by ELISA. We investigated hemostatic and inflammatory transcripts in circulating platelets and leukocytes from NAFLD patients. We analyzed platelet and neutrophil extracellular traps (NET) accumulations in liver sinusoids using CD42 and H3 citrullinated histones immunohistochemical staining on liver biopsies. NAFLD patients had increased inflammation markers and lipolysaccharides plasma levels. We found significant increase of inflammatory transcripts in circulating platelets and not in leukocytes of NAFLD subjects compared with healthy controls. We demonstrated increased intrahepatic platelet accumulation that correlated with NAFLD activity score (NAS) score and intrahepatic neutrophil extracellular traps (NET) formation in liver biopsies of NAFLD patients. NET formation was higher in livers with higher NAS and inflammation scores. The presence of low-grade systemic inflammation and proinflammatory changes of circulating platelets indicate that platelets participate on systemic inflammatory changes associated with NAFLD. Liver platelet accumulation and liver NET formation, together with low-grade endotoxemia, suggest that platelets may act to protect the liver from invading microorganisms by favoring local NET formation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Context: Nonalcoholic steatohepatitis (NASH) is considered the hepatic counterpart of metabolic syndrome., Objective: This work aimed to investigate the determinants of NASH reversal in patients undergoing biliopancreatic diversion (BPD) in a 5-year follow-up study., Methods: This prospective study was conducted at Policlinico Universitario Agostino Gemelli. A total of 37 patients underwent fine-needle liver biopsy during BPD. Ultrasonography-guided percutaneous liver biopsy was obtained 5 years after the operation. The primary outcome of our study was histologic NASH reversal at 5-year follow-up. To better characterize the clinical variables involved in the resolution of NASH, we also compared patients without histologic NASH resolution at 5 years with those in whom NASH had disappeared., Results: At follow-up, NASH had reversed in 56.5% of the patients. The NAFLD activity score (NAS) improved from 3.7 ± 0.93 to 2 ± 1.11 (P < .001). Fibrosis reversed in 16% patients (P = .022), and 32% improved (95% CI, 0.05-0.54). No significant differences in body mass index or clinical parameters changes explained the effect of surgery on NASH, apart from the measure of insulin sensitivity post surgery. The Homeostasis Model Assessment of Insulin Resistance decreased from 3.31 ± 1.72 at baseline to 1.73 ± 1.08 (P < .001) after BPD, and the Matsuda index improved from 2.66 ± 1.79 to 4.73 ± 3.05 (P < .001). The lipid profile normalized (total cholesterol from 4.75 ± 1.18 to 3.32 ± 0.77 mmol/L, P < .001; low-density lipoprotein cholesterol from 2.92 ± 0.91 to 1.60 ± 0.51 mmol/L, P = .0001; high-density lipoprotein cholesterol from 0.97 ± 0.33 to 1.10 ± 0.35 mmol/L, P = .023; triglycerides from 2.52 ± 1.6 to 1.47 ± 0.67 mmol/L, P = .003). Neural network analysis showed that the end-study Matsuda index discriminated between responders and nonresponders with high accuracy (receiver operating characteristic area under the curve = 0.98%)., Conclusion: Remission of NASH is driven by reversal of whole-body insulin resistance post intervention., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: We investigated the longitudinal impact of antinuclear antibody (ANA) on clinical outcomes and survival in nonalcoholic fatty liver disease (NAFLD)., Methods: ANA were found in 16.9% of 923 biopsy-proven NAFLD patients, but none of them had histologic autoimmune hepatitis (AIH) or developed AIH after a mean follow-up of 106±50 months., Results: Although ANA-positive cases had a higher prevalence of nonalcoholic steatohepatitis at baseline, the occurrence of liver-related events, hepatocellula carcinoma, cardiovascular events, extrahepatic malignancy, and overall survival were similar to ANA-negative., Discussion: Once AIH has been ruled out, the long-term outcomes and survival are unaffected by the presence of ANA in patients with NAFLD.

Objective: Hepatocellular carcinoma (HCC) is one of the most common fatal cancer in the world and androgens are among the possible etiological factors. Congenital adrenal hyperplasia (CAH) is a group of inherited diseases caused by enzyme failure in the steroid biosynthesis of the adrenal cortex, resulting in an augmented 17-hydroxyprogesterone, androstenedione and testosterone production. While the occurrence of testicular adrenal rest tumors and adrenocortical tumors in congenital adrenal hyperplasia is well described in the literature, no data on HCC occurrence are available., Case Presentation: A 35-years-old Italian man of Caucasian origin, affected by non-classic CAH due to partial 21-hydroxylase deficiency came to observation for revaluation of his adrenal picture. Besides common hormonal and biochemical analysis, an abdomen Magnetic Resonance Imaging was performed, resulting in an 18 mm large nodular lesion between liver segments VII and VIII. Radiological reports matched with an increased serum α-fetoprotein level. A surgical removal of the lesion was performed. After that, several recurrences of the lesion, which was consequently treated by radiofrequency ablation, occurred. Every recurrence was accompanied by an increase in testosterone and steroid hormone binding globulin serum levels., Conclusions: Our report suggests the need for screening of liver lesions in males affected by this syndrome.