Publications by authors named "Paola Francalanci"

81 Publications

Pattern-based Histologic Approach in Very Early Onset IBD: Main Features and Differential Diagnosis.

Adv Anat Pathol 2021 Oct 7. Epub 2021 Oct 7.

Units of Pathology Pediatrics Gastroenterology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia Unit of Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova Ospedale Policlinico San Martino, IRCCS, Genova Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia Surgical Pathology Unit, Department of Medicine (DIMED), University of Padova Veneto Institute of Oncology (IOV-IRCCS), Padova Pathology Unit, Children's Hospital Bambino Gesù, IRCCS, Roma, Italy.

Very early onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella classification composed of IBD-like diseases encompassing both classic IBD (Crohn's disease and ulcerative colitis) and monogenic disorder, both arising before 6 years of age. VEO-IBD patients present significant clinical differences from IBD occurring in older children and in adults, including more severe disease, often unresponsive to conventional IBD therapy and a greater proportion of cases featuring an underlying genetic alteration. Histologic findings of gastrointestinal biopsies can show an IBD-like pattern (both Crohn's disease-like and ulcerative colitis-like pattern), an apoptotic-like and enterocolitis-like pattern. Findings of specific morphologic alterations, such as villous blunting, apoptosis, dense eosinophilic infiltrates, lack of plasma cells and severe glandular atrophy, can suggest a monogenic disorder. Moreover, individuals with monogenic disorders may develop significant problems such as primary immunodeficiency, impacting treatment options. Finally, IBD histology in childhood can differ from that in older patients and adults. This complexity makes a differential diagnosis between IBD and other pediatric diseases involving the gastrointestinal tract difficult, especially considering that histologic features can be similar between different diseases. Without an appropriate diagnosis, the clinical course of VEO-IBD has greater potential for escalated treatment regimens involving extensive surgery and more intensive medical therapies rather than specific therapy directed toward the underlying defect. For these reasons, a pattern-based histologic approach correlated with clinical and laboratory findings with a multidisciplinary approach is fundamental to reach a correct diagnosis in an adequate clinical context.
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http://dx.doi.org/10.1097/PAP.0000000000000323DOI Listing
October 2021

Changes in Total Homocysteine and Glutathione Levels After Laparoscopic Sleeve Gastrectomy in Children with Metabolic-Associated Fatty Liver Disease.

Obes Surg 2021 Sep 21. Epub 2021 Sep 21.

Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, Viale San Paolo 15, 00146, Rome, Italy.

Purpose: Paediatric obesity is a well-known risk factor for metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate the effects of laparoscopic sleeve gastrectomy (LSG) on the levels of total homocysteine (tHcy) and total glutathione (tGSH) plasma levels in children with MAFLD.

Material And Methods: Twenty-four children with severe obesity who underwent LSG were included in the study. The metabolic parameters, systemic inflammatory markers, one-carbon metabolism products, ultrasound and histological improvement were evaluated at baseline (T0M) and after 12 months from LSG (T12M).

Results: The patients exhibited a significant amelioration of several metabolic parameters at T12M. A significant reduction of steatosis was observed at ultrasound (from 72.7% of moderate-severe grade to 0% severe steatosis), accompanied by a statistically significant improvement of ballooning, portal and lobular inflammation and fibrosis. A statistically significant decrease of tumour necrosis factor circulating levels was also observed (T0M median = 290.3, IQR = 281.0-317.0 pg/mL; T12M median = 260.4, IQR = 240.0-279.0 pg/mL; p < 0.0001). After 12 months from LSG, a significant increase of mean plasma levels of tHcy(T0M mean = 15.7 ± 4.1 μmol/L; T12M mean = 21.1 ± 9.3 μmol/L; p = 0.0146) was also observed. The increase of tHcy showed no causal link with the improvement of MAFLD-related inflammatory, metabolic and histological pattern.

Conclusion: LSG in children with obesity induces an improvement of MAFLD-related metabolic derangement and liver damage, but also a mild hyperhomocysteinemia that should be avoided to prevent cardiovascular risk.
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http://dx.doi.org/10.1007/s11695-021-05701-6DOI Listing
September 2021

AIRE mutation triggering acute liver failure: between genetic testing and treatment options.

Pediatr Transplant 2021 Aug 16:e14118. Epub 2021 Aug 16.

Hepatology Gastroenterology and Nutrition, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization, and Health Care, Rome, Italy.

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http://dx.doi.org/10.1111/petr.14118DOI Listing
August 2021

Allograft Fibrosis After Pediatric Liver Transplantation: Incidence, Risk Factors, and Evolution.

Liver Transpl 2021 Jun 23. Epub 2021 Jun 23.

Department of Pathology, Bambino Gesù Children's Hospital Istituto di Ricerca e di Cura a Carattere Scientifico, Rome, Italy.

Allograft fibrosis (AF) after pediatric liver transplantation (pLT) is frequent, but its dynamics are unclear. Our aim was to assess the evolution and risk factors of AF after pLT. A retrospective single-center analysis of pLT patients with a follow-up of ≥5 years who underwent protocol liver biopsies at 6 months, 1 year, 2 years, 5 years, and 10 years was performed. Fibrosis was assessed using the METAVIR and Ishak systems and the liver allograft fibrosis score (LAFs). Of 219 pLTs performed from 2008 to 2018, 80 (36.5%) pLTs were included, and 320 biopsies were reviewed. At 6 months after pLT, fibrosis was found in 54 (67.5%) patients by the METAVIR/Ishak systems and in 59 (73.8%) by the LAFs (P = 0.65). By 5 years, AF was detected in 67 (83.8%), 69 (86.3%), and 72 (90%) specimens using the METAVIR, Ishak, and LAFs systems, respectively (P = 0.54); mild (METAVIR, 51 [63.8%]; Ishak, 60 [75%]; LAFs, 65 [81.2%]) and moderate (METAVIR, 16 [20%]; Ishak, 9 [11.9%]; LAFs, 7 [8.8%]) stages were detected, but severe fibrosis was not found (P = 0.09). In the LAFs, fibrosis involved the portal (85%), sinusoidal (15%), and centrolobular (12%) areas. Of 18 patients with 10-year protocol biopsies, AF was present in 16 (90%), including 1 (5.5%) with severe fibrosis. In all systems, 36.3% of patients showed fibrosis progression from 2 years to 5 years after LT, but they remained stable at the 10-year biopsies without clinical implications. In multivariate analysis, only donor age >40 years was a risk factor for moderate AF at 5 years after LT (odds ratio, 8.3; 95% confidence interval, 1.6-42.1, P = 0.01). Cold ischemia time (CIT) >8 hours was associated with portal (P < 0.001)/sinusoidal fibrosis (P = 0.04), donor age >40 years was associated with sinusoidal (P = 0.01)/centrilobular (P = 0.04) fibrosis, and low tacrolimus trough level within 1 year after LT was associated with centrilobular fibrosis (P = 0.02). AF has a high incidence after pLT, occurring early after transplantation. In most cases, AF is mild or moderate and remains stable in the long run without clinical implications. Donor selection, short CIT, and immunosuppression adherence are crucial to reducing the risk of advanced AF.
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http://dx.doi.org/10.1002/lt.26218DOI Listing
June 2021

Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases.

Int J Mol Sci 2021 May 28;22(11). Epub 2021 May 28.

Department of Pathology, Childrens' Hospital Bambino Gesù IRCCS, 00165 Rome, Italy.

Alpha-1-antitrypsin (AAT) and fibrinogen are secretory acute phase reactant proteins. Circulating AAT and fibrinogen are synthesized exclusively in the liver. Mutations in the encoding genes result in conformational abnormalities of the two molecules that aggregate within the rough endoplasmic reticulum (RER) instead of being regularly exported. That results in AAT-deficiency (AATD) and in hereditary hypofibrinogenemia with hepatic storage (HHHS). The association of plasma deficiency and liver storage identifies a new group of pathologies: endoplasmic reticulum storage disease (ERSD).
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http://dx.doi.org/10.3390/ijms22115778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198767PMC
May 2021

Gastric cancer, inflammatory bowel disease and polyautoimmunity in a 17-year-old boy: CTLA-4 deficiency successfully treated with Abatacept.

Eur J Gastroenterol Hepatol 2021 May 21. Epub 2021 May 21.

Unit of Digestive Endoscopy and Surgery Unit of Immune and Infectious Diseases, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare Department of Systems Medicine, University of Rome Tor Vergata Department of Pathology and Molecular Histopathology Unit of General and Thoracic Surgery, Department of Pediatric Surgery Department of Pediatric Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children's Hospital - Scientific Institute for Research and Healthcare, Rome Unit of Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood 'G. Barresi,' University of Messina, Messina Unit of Pediatric Oncology and Hematology, Department of Pediatrics, Vittorio Emanuele University Hospital, University of Catania, Catania Translational Cytogenomics Research Unit, Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, Scientific Institute for Research and Healthcare, Rome, Italy.

Gut involvement is frequent in immunologic disorders, especially with inflammatory manifestations but also with cancer. In the last years, advances in functional and genetic testing have improved the diagnostic and therapeutic approach to immune dysregulation syndromes. CTLA-4 deficiency is a rare disease with variable phenotype, ranging from absence of symptoms to severe multisystem manifestations and complications. We describe a rare case of CTLA-4 deficiency in a boy with gastric cancer, very early onset inflammatory bowel disease and polyautoimmunity, the second-ever reported in the literature with the same characteristics. A 17-year-old boy was referred to Bambino Gesù Children's Hospital of Rome, a tertiary care center, for a gastric mass and a long-term history of very early onset inflammatory bowel disease, diabetes mellitus type 1, polyarthritis and psoriasis. Histology of gastric biopsies revealed the presence of neoplastic signet ring cells. Imaging staging showed localized cancer; therefore, the patient underwent subtotal gastrectomy with termino-lateral gastro-jejunal anastomosis. Immunological work up and genetic testing by next-generation sequencing panels for primary immunodeficiencies led to the diagnosis of CTLA-4 deficiency. Good disease control was obtained with the administration of Abatacept. The patient experienced an asymptomatic SARS-CoV-2 infection without any concern. Eighteen months after treatment initiation, the patient is alive and well. Immunologic and genetic testing, such as next-generation sequencing, should always be part of the diagnostic approach to patients with complex immune dysregulation syndrome, severe clinical course, poor response to treatments or cancer. The early recognition of the monogenic disease is the key for disease management and targeted therapy.
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http://dx.doi.org/10.1097/MEG.0000000000002185DOI Listing
May 2021

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness.

Brain 2021 May 8. Epub 2021 May 8.

Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.

Leukodystrophies are a heterogeneous group of rare inherited disorders that involve preferentially the white matter of the central nervous system (CNS). These conditions are characterized by a primary glial cell and myelin sheath pathology of variable etiology, which causes secondary axonal degeneration, generally emerging with disease progression. Whole exome sequencing performed in 5 large consanguineous nuclear families allowed to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying a novel form of leukodystrophy with ataxia and sensorineural deafness. We report on two homozygous missense variants (p.R363Q and p.R365Q) in the ubiquitin E3 ligase RNF220 as the cause underlying a novel form of leukodystrophy with ataxia and sensorineural deafness having fibrotic cardiomyopathy and hepatopathy as associated features, in seven consanguineous families. Mass spectrometry analysis identified lamin B1 as RNF220 binding protein and co-immunoprecipitation experiments demonstrated reduced binding of both RNF220 mutants to lamin B1. We demonstrate that RNF220 silencing in Drosophila melanogaster specifically affects proper localization of lamin Dm0, the fly lamin B1 orthologue, promotes its aggregation, and causes a neurodegenerative phenotype, strongly supporting the functional link between RNF220 and lamin B1. Finally, we demonstrate that RNF220 plays a crucial role in the maintenance of nuclear morphology: mutations primary skin fibroblasts determine nuclear abnormalities such as blebs, herniations and invaginations, which are typically observed in cells of patients affected by laminopathies. Overall, our data identify RNF220 as a gene implicated in leukodystrophy with ataxia and sensorineural deafness, and document a critical role of RNF220 in the regulation of nuclear lamina. Our findings provide further evidence on the direct link between nuclear lamina dysfunction and neurodegeneration.
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http://dx.doi.org/10.1093/brain/awab185DOI Listing
May 2021

A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant.

Orphanet J Rare Dis 2021 04 14;16(1):179. Epub 2021 Apr 14.

Postgraduate School of Pediatrics Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via Allende, 84081, Baronissi, (SA), Italy.

Background: ZFYVE19 (Zinc Finger FYVE-Type Containing 19) mutations have most recently been associated to a novel type of high gamma-glutamyl transpeptidase (GGT), non-syndromic, neonatal-onset intrahepatic chronic cholestasis possibly associated to cilia dysfunction. Herein, we report a new case with further studies of whole exome sequencing (WES) and immunofluorescence in primary cilia of her cultured fibroblasts which confirm the observation.

Results: A now 5-year-old girl born to clinically healthy consanguineous Moroccan parents was assessed at 59 days of life due to severe cholestatic jaundice with increased serum bile acids and GGT, and preserved hepatocellular synthetic function. Despite fibrosis/cirrhosis and biliary ducts proliferation on liver biopsy suggested an extrahepatic biliary obstacle, normal intra-operatory cholangiography excluded biliary atresia. Under choleretic treatment, she maintained a clinically stable anicteric cholestasis but developped hyperlipidemia. After exclusion of the main causes of cholestasis by multiple tests, abnormal concentrations of sterols and WES led to a diagnosis of hereditary sitosterolemia (OMIM #618666), likely unrelated to her cholestasis. Further sequencing investigation revealed a homozygous non-sense mutation (p.Arg223Ter) in ZFYVE19 leading to a 222 aa truncated protein and present in both heterozygous parents. Immunofluorescence analysis of primary cilia on cultured skin fibroblasts showed a ciliary phenotype mainly defined by fragmented cilia and centrioles abnormalities.

Conclusions: Our findings are consistent with and expands the recent evidence linking ZFYVE19 to a novel, likely non-syndromic, high GGT-PFIC phenotype with neonatal onset. Due to the possible role of ZFYVE19 in cilia function and the unprecedented coexistence of a coincidental hereditary sterol disorder in our case, continuous monitoring will be necessary to substantiate type of liver disease progression and/or possible emergence of a multisystemic involvement. What mentioned above confirms that the application of WES in children with undiagnosed cholestasis may lead to the identification of new causative genes, widening the knowledge on the pathophysiology.
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http://dx.doi.org/10.1186/s13023-021-01775-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048179PMC
April 2021

Remember friedreich ataxia even in a toddler with apparently isolated dilated (not hypertrophic!) cardiomyopathy: revisited.

Minerva Pediatr (Torino) 2021 Apr 2. Epub 2021 Apr 2.

European Reference Network for rare, low prevalence and complex diseases of the heart - ERN GUARD-Heart HCP, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, Rome, Italy -

Background: Friedreich Ataxia (FRDA) is the most common form of ataxia in late childhood. Neurological manifestations often precede cardiac involvement, presenting mainly as hypertrophic cardiomyopathy.

Methods: We describe a toddler with apparently isolated severe heart failure, successfully managed with heart transplant (HT). Although well described in adolescents and adults, onset of FRDA is very uncommon in toddlers and neurological ataxic features are predominant. The presenting symptom of cardiomyopathy is very rare. Similar history is rarely reported in literature, that we described, including an aggressive cardiomyopathy in children younger than 5years-old.

Results: Our patient was diagnosed with FRDA at a postoperative stage due to minimal neurological manifestations. Moreover, the novelty of this study lies in demonstrating a major DNA triplet repeat expansion in skeletal muscle compared to DNA from peripheral blood leukocytes. These results support the concept that triplet repeat expansion is variable among different tissues in FRDA, and in our case it was more expanded in the post mitotic muscular tissue than in blood cells.

Conclusions: We believe on the importance of taking in consideration this rare condition even in a toddler with apparently isolated cardiomyopathy and especially when conventional investigations give negative results. We discuss potential trigger effect of heart transplant as a precipitating factor in manifesting neurological symptoms. This observation corresponds to our experience and relates to three patients described so far (the third patient died suddenly). Early onset cardiomyopathy with FRDA should increase awareness of this rare condition and we highlight HT successful outcome. Further reports are needed to delineate this rare condition in youngsters.
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http://dx.doi.org/10.23736/S2724-5276.21.05969-3DOI Listing
April 2021

Evaluation of Gastroesophageal Reflux Disease 1 Year after Esophageal Atresia Repair: Paradigms Lost from a Single Snapshot?

J Pediatr 2021 01 9;228:155-163.e1. Epub 2020 Sep 9.

Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy.

Objective: To analyze the findings of both multichannel intraluminal impedance with pH (MII-pH) and endoscopy/histopathology in children with esophageal atresia at age 1 year, according to current recommendations for the evaluation of gastroesophageal reflux disease (GERD) in esophageal atresia.

Study Design: We retrospectively reviewed both MII-pH and endoscopy/histopathology performed in 1-year-old children with esophageal atresia who were followed up in accordance with international recommendations. Demographic data and clinical characteristics were also reviewed to investigate factors associated with abnormal GERD investigations.

Results: In our study cohort of 48 children with esophageal atresia, microscopic esophagitis was found in 33 (69%) and pathological esophageal acid exposure on MII-pH was detected in 12 (25%). Among baseline variables, only the presence of long-gap esophageal atresia was associated with abnormal MII-pH. Distal baseline impedance was significantly lower in patients with microscopic esophagitis, and it showed a very good diagnostic performance in predicting histological changes.

Conclusions: Histological esophagitis is highly prevalent at 1 year after esophageal atresia repair, but our results do not support a definitive causative role of acid-induced GERD. Instead, they support the hypothesis that chronic stasis in the dysmotile esophagus might lead to histological changes. MII-pH may be a helpful tool in selecting patients who need closer endoscopic surveillance and/or benefit from acid suppression.
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http://dx.doi.org/10.1016/j.jpeds.2020.09.015DOI Listing
January 2021

Diagnosis of Acute Rejection of Liver Grafts in Young Children Using Acoustic Radiation Force Impulse Imaging.

AJR Am J Roentgenol 2020 11 2;215(5):1229-1237. Epub 2020 Sep 2.

Department of Radiology, Bambino Gesù Children's Hospital, Rome, Italy.

Frequency of acute rejection (AR) after pediatric liver transplant remains high despite progress in immunosuppression. Liver biopsy (LB) is the reference standard for the diagnosis of AR despite its potential for morbidity. The purpose of our study was to evaluate the ability of acoustic radiation force impulse (ARFI) imaging to distinguish AR from other causes of short- and medium-term liver dysfunction and to identify liver transplant cases with normal liver function. ARFI imaging was used to evaluate shear wave velocity (SWV) after liver transplant in young children. All pediatric liver grafts that had LB and ARFI examination between January 2014 and December 2017 were included in this retrospective study. Results of LB were compared with those of SWV. Collected data included age at biopsy and transplant, sex, weight, height, body mass index, interval between liver transplant and shear wave elastography and LB, kind of graft, type of donor, and diagnosis at transplant. ROC curve analysis was performed to assess the diagnostic performance of SWV. Optimal cutoff of SWV using ARFI imaging in predicting AR was identified using the Youden index. Statistical analysis was performed on 54 children; six of the original 60 were excluded because of confounding alterations or changes in outcome. Median SWV was higher in patients with AR (2.03 m/s; interquartile range [IQR], 1.80-2.45 m/s) compared with those with idiopathic hepatitis (1.33 m/s; IQR, 1.12-1.53 m/s), portal hypertension (1.42 m/s; IQR, 1.32-1.72 m/s), cholangitis (1.56 m/s; IQR, 1.07-1.62 m/s) or normal liver function (1.23 m/s; IQR 1.12-1.29 m/s) at protocol biopsies (all comparisons, < 0.01). SWV higher than 1.73 m/s was predictive for AR (AUC, 0.966). SWV also showed good diagnostic accuracy in normal liver function (AUC, 0.791). ARFI imaging was not predictive for hepatitis (AUC, 0.402), portal hypertension (AUC, 0.556), or cholangitis (AUC, 0.420). ARFI imaging could be routinely used in place of LB in pediatric patients with liver dysfunction after liver transplant, restricting indication and risks of biopsy to selected cases.
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http://dx.doi.org/10.2214/AJR.19.22057DOI Listing
November 2020

Focal Adhesion Kinase (FAK) Over-Expression and Prognostic Implication in Pediatric Hepatocellular Carcinoma.

Int J Mol Sci 2020 Aug 12;21(16). Epub 2020 Aug 12.

Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital and IRCCS, 00165 Rome, Italy.

Focal adhesion kinase (FAK) is over-expressed and is correlated with aggressiveness in adult hepatocellular carcinoma (HCC). Inhibition of FAK decreases HCC invasiveness by down-regulating Enhancer of Zeste homolog 2 (EZH2), an epigenetic controller, that acts in transcriptional repression of a large number of genes via histone 3 methylation of lysine 27 (H3K27me3). Here, we investigated the hepatic expression of total FAK, EZH2, H3K27me3, and proliferating cell nuclear antigen (PCNA) in 17 pediatric HCCs and 8 healthy livers (CTRL). Quantitative imaging analysis showed that FAK gene/protein expression is up-regulated in HCCs compared to CTRL and, among tumor samples the levels of this gene/protein are significantly higher in cirrhotic HCCs than in a healthy milieu. Accordingly, the protein levels of EZH2 were also significantly increased in HCCs from a cirrhotic background. Intriguingly, the protein expression of FAK, EZH2, and PCNA significantly inversely correlated with tumor size. Finally, in HCC samples, mainly in cirrhotic background, the up-regulation of FAK gene positively correlated with that observed in β-Catenin gene. Conclusion: FAK gene/protein is over-expressed in pediatric HCCs concomitantly to EZH2 protein and β-Catenin gene, with a more significant up-regulation in a cirrhotic background. This triad of interactors deserves further investigations for translational application.
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http://dx.doi.org/10.3390/ijms21165795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460809PMC
August 2020

The New Horizon of Split-Liver Transplantation: Ex Situ Liver Splitting During Hypothermic Oxygenated Machine Perfusion.

Liver Transpl 2020 10;26(10):1363-1367

Division of Hepatology and Gastroenterology, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization, and Health Care, Rome, Italy.

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http://dx.doi.org/10.1002/lt.25843DOI Listing
October 2020

ERNICA guidelines for the management of rectosigmoid Hirschsprung's disease.

Orphanet J Rare Dis 2020 06 25;15(1):164. Epub 2020 Jun 25.

Department of Pediatric Surgery, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: Hirschsprung's disease (HSCR) is a serious congenital bowel disorder with a prevalence of 1/5000. Currently, there is a lack of systematically developed guidelines to assist clinical decision-making regarding diagnostics and management.

Aims: This guideline aims to cover the diagnostics and management of rectosigmoid HSCR up to adulthood. It aims to describe the preferred approach of ERNICA, the European Reference Network for rare inherited and congenital digestive disorders.

Methods: Recommendations within key topics covering the care pathway for rectosigmoid HSCR were developed by an international workgroup of experts from 8 European countries within ERNICA European Reference Network from the disciplines of surgery, medicine, histopathology, microbiology, genetics, and patient organization representatives. Recommendation statements were based on a comprehensive review of the available literature and expert consensus. AGREE II and GRADE approaches were used during development. Evidence levels and levels of agreement are noted.

Results: Thirty-three statements within 9 key areas were generated. Most recommendations were based on expert opinion.

Conclusion: In rare or low-prevalence diseases such as HSCR, there remains limited availability of high-quality clinical evidence. Consensus-based guidelines for care are presented.
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http://dx.doi.org/10.1186/s13023-020-01362-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318734PMC
June 2020

Successful muscle regeneration by a homologous microperforated scaffold seeded with autologous mesenchymal stromal cells in a porcine esophageal substitution model.

Therap Adv Gastroenterol 2020 26;13:1756284820923220. Epub 2020 May 26.

Digestive Endoscopy and Surgical Unit, Ospedale Pediatrico Bambino Gesù, Roma, Italy.

Background: Since the esophagus has no redundancy, congenital and acquired esophageal diseases often require esophageal substitution, with complicated surgery and intestinal or gastric transposition. Peri-and-post-operative complications are frequent, with major problems related to the food transit and reflux. During the last years tissue engineering products became an interesting therapeutic alternative for esophageal replacement, since they could mimic the organ structure and potentially help to restore the native functions and physiology. The use of acellular matrices pre-seeded with cells showed promising results for esophageal replacement approaches, but cell homing and adhesion to the scaffold remain an important issue and were investigated.

Methods: A porcine esophageal substitute constituted of a decellularized scaffold seeded with autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs) was developed. In order to improve cell seeding and distribution throughout the scaffolds, they were micro-perforated by Quantum Molecular Resonance (QMR) technology (Telea Electronic Engineering).

Results: The treatment created a microporous network and cells were able to colonize both outer and inner layers of the scaffolds. Non seeded (NSS) and BM-MSCs seeded scaffolds (SS) were implanted on the thoracic esophagus of 4 and 8 pigs respectively, substituting only the muscle layer in a mucosal sparing technique. After 3 months from surgery, we observed an esophageal substenosis in 2/4 NSS pigs and in 6/8 SS pigs and a non-practicable stricture in 1/4 NSS pigs and 2/8 SS pigs. All the animals exhibited a normal weight increase, except one case in the SS group. Actin and desmin staining of the post-implant scaffolds evidenced the regeneration of a muscular layer from one anastomosis to another in the SS group but not in the NSS one.

Conclusions: A muscle esophageal substitute starting from a porcine scaffold was developed and it was fully repopulated by BM-MSCs after seeding. The substitute was able to recapitulate in shape and function the original esophageal muscle layer.
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http://dx.doi.org/10.1177/1756284820923220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257852PMC
May 2020

Terminal Ileum Thickening and Mucosal Ulcers in a Boy With Neurofibromatosis Type 1.

Gastroenterology 2020 12 23;159(6):e9-e11. Epub 2020 Apr 23.

Digestive Endoscopy and Surgery Unit, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

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http://dx.doi.org/10.1053/j.gastro.2020.04.041DOI Listing
December 2020

Recurrent Wheezing in Pre-school Age: Not Only Airway Reactivity!

Front Pediatr 2020 17;8:101. Epub 2020 Mar 17.

Paediatric Pulmonology and Respiratory Intermediate Care Unit, Sleep and Long-Term Ventilation Unit, Academic Department of Paediatrics, Research Institute, Bambino Gesù Children's Hospital, Rome, Italy.

About a fifth of all mediastinal masses are primary cysts arising in the absence of other underlying pathology. Bronchogenic cysts, although rare, are the most frequent type responsible for lower airways compression as they often develop in the peripheral branches of the tracheobronchial tree. We report the case of a 6-months-old child admitted for acute respiratory distress and wheezing not responsive to asthma treatment. Digestive and airway endoscopy proved a mild and a marked reduction of the esophageal and tracheal lumen, respectively. The nocturnal polygraphy showed an underlying obstructive disorder and the chest CT scan confirmed the presence of a wide mediastinal cyst compressing the trachea. The mass, later identified as a bronchogenic cyst, was surgically removed with complete resolution of the patient's respiratory symptoms. Our case shows that differential diagnosis of wheezing in pre-school aged children should encompass causes others than airway reactivity, thus prompting further evaluation and management.
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http://dx.doi.org/10.3389/fped.2020.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090094PMC
March 2020

Targeting Epidermal Growth Factor Receptor (EGFR) in Pediatric Colorectal Cancer.

Cancers (Basel) 2020 Feb 11;12(2). Epub 2020 Feb 11.

Department of Pediatric Onco-Hematology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, 00165 Rome, Italy.

: Colorectal carcinoma (CRC) is very rare in the pediatric and adolescent age range and clinical management is performed according to adult protocols. We report, for the first time in the literature, a case of a child with metastatic CRC successfully treated with panitumumab associated to chemotherapy. : A twelve-year-old male was diagnosed with CRC with nodal metastasis and peritoneal neoplastic effusion. After performing a genetic evaluation, in light of the absence of mutations in family genes, anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody, panitumumab, was added to chemotherapy FOLFOXIRI. : The child successfully responded to therapy with normalization of the Carbohydrate Antigen (CA) 19.9 value after the third cycle of treatment. After the sixth cycle, he underwent surgery that consisted in sigmoid resection with complete D3 lymphadenectomy. At histological evaluation, no residual neoplastic cells were detectable in the surgical specimen. He completed 12 cycles of chemotherapy plus panitumomab and he is alive without disease 14 months from diagnosis. : Our results suggest performing mutational screening for colorectal cancer also in the pediatric setting, in order to orient treatment that should include targeted therapies.
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http://dx.doi.org/10.3390/cancers12020414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072611PMC
February 2020

The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis.

PLoS One 2019 17;14(12):e0226043. Epub 2019 Dec 17.

Division of Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Aim of this study was to investigate the activation of the IFNγ pathway in the affected liver and in the blood of patients with secondary hemophagocytic lymphohistiocytosis (sHLH). To this purpose, the mRNA expression levels of IFNG and IFNγ-inducible genes as well as Tyrosine (701)-phosphorylated signal transducer and activator of transcription 1 (STAT1) protein levels were evaluated in the liver and in peripheral blood mononuclear cells (PBMCs) of three patients with sHLH with predominant liver involvement. The mRNA expression levels of IFNG and IFNγ-inducible genes were markedly higher in patient livers compared to control livers and to one disease control liver. Conversely, slight differences in the expression levels of Type I IFN-inducible genes and other classical inflammatory cytokine genes were found. Further supporting the activation of the IFNγ pathway, higher protein levels of phosphorylated and total STAT1 were detected in patient livers compared to control livers. When the expression of the same genes analysed in liver tissues was evaluated in PBMCs collected from 2 out of 3 patients before the liver biopsy, we found that mRNA levels of IFNγ-inducible genes were markedly increased. Accordingly, high circulating levels of IFNγ-inducible CXCL9 were observed in patients. Altogether, these data demonstrate the selective and marked up-regulation of the IFNγ pathway in the liver tissue and blood of patients with active sHLH. Finally, we show that measurement of circulating CXCL9 levels and evaluation of IFNγ-inducible gene expression levels in PBMCs may represent a new valid tool to better identify patients with suspected HLH with predominant liver involvement.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226043PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917341PMC
April 2020

Establishment of a Seronegative Occult Infection With an Active Hepatitis B Virus Reservoir Enriched of Vaccine Escape Mutations in a Vaccinated Infant After Liver Transplantation.

J Infect Dis 2019 11;220(12):1935-1939

Department of Experimental Medicine, University of Rome "Tor Vergata,", Rome, Italy.

We describe the establishment of a seronegative occult hepatitis B virus (HBV) infection (OBI) in a successfully vaccinated infant who underwent liver transplantation from an donor positive for antibody to hepatitis B core antigen (anti-HBc). The use of highly sensitive droplet digital polymerase chain reaction assays revealed a not negligible and transcriptionally active intrahepatic HBV reservoir (circular covalently closed DNA, relaxed circular DNA, and pregenomic RNA: 5.6, 2.4, and 1.1 copies/1000 cells, respectively), capable to sustain ongoing viral production and initial liver damage. Next-generation sequencing revealed a peculiar enrichment of hepatitis B surface antigen vaccine-escape mutations that could have played a crucial role in OBI transmission. This clinical case highlights the pathobiological complexity and the diagnostic challenges underlying OBI.
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http://dx.doi.org/10.1093/infdis/jiz411DOI Listing
November 2019

Chronic liver involvement in urea cycle disorders.

J Inherit Metab Dis 2019 11 25;42(6):1118-1127. Epub 2019 Aug 25.

Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

The increased survival of urea cycle disorders (UCDs) patients has led the attention to clinical manifestations that characterize the long-term disease course. Acute and chronic liver disease have been anecdotally reported since the very first description of UCDs. However, a detailed analysis of long-term liver involvement in large patient cohorts is still needed. Chronic liver damage in UCDs has probably a multifactorial origin, but the specific underlying mechanisms of liver disease have not yet been well elucidated. In this study, we report on chronic liver involvement and on associated metabolic abnormalities in a large cohort of 102 UCD patients, followed by two reference centers in Italy. Chronic liver involvement was observed in over 60% of UCDs patients, and comparison between individual diseases showed a significant higher frequency in argininosuccinate lyase deficiency (ASLD) and in hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome with elevation of transaminases and of gamma-GT in ASLD, and of alpha-fetoprotein in HHH syndrome. Also, consistent with a chronic hepatic dysfunction, ultrasound examination revealed more pronounced abnormalities in ASLD and in HHH syndrome, when compared to other UCDs. Our study highlights in a large UCDs patients' cohort that chronic liver disease is a common finding in UCDs, often with a distinct phenotype between different diseases. Furthers studies are needed to elucidate the specific involvement of different metabolic pathways in the pathogenesis of liver dysfunction in UCDs.
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http://dx.doi.org/10.1002/jimd.12144DOI Listing
November 2019

Mineralization of alpha-1-antitrypsin inclusion bodies in Mmalton alpha-1-antitrypsin deficiency.

Orphanet J Rare Dis 2018 05 16;13(1):79. Epub 2018 May 16.

Genetic and Rare Diseases, Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Alpha-1-antitrypsin (AAT) deficiency (AATD) of Z, Mmalton, Siiyama type is associated with liver storage of the mutant proteins and liver disease. The Z variant can be diagnosed on isoelectric focusing (IEF) while Mmalton and Siiyama may be missed or misdiagnosed with this technique. Therefore, molecular analysis is mandatory for their characterization. In particular, that holds true for the Mmalton variant as on IEF profile it resembles the wild M2 subtype.

Methods: This is a retrospective analysis involving review of medical records and of liver biopsy specimens from a series of Mmalton, Z and Siiyama Alpha-1-antitrypsin deficiency patients. The review has been implemented by additional histological stains, electron microscopic observations and 3-D modeling studies of the sites of the mutations.

Results: Z, Mmalton and Siiyama liver specimen contained characteristic intrahepatocytic PAS-D globules. The globules differed in the three variants as only Mmalton cases showed dark basophilic precipitates within the AAT inclusions. The precipitates were visualized in haematoxylin-eosin (H.E.) stained preparations and corresponded to calcium precipitates as demonstrated by von Kossa staining. On immunohistochemistry, ZAAT inclusions were stained by polyclonal as well as monoclonal noncommercial anti-AAT antibody (AZT11), whilst Mmalton and Siiyama inclusion bodies remained negative with the monoclonal anti-Z antibody. 3-D protein analysis allowed to predict more severe misfolding of the Mmalton molecule as compared to Z and Siiyama that could trigger anomalous interaction with endoplasmic reticulum chaperon proteins, namely calcium binding proteins.

Conclusions: Mmalton AAT inclusion bodies contain calcium precipitates inside them that allow the differential diagnosis with Siiyama and ZAAT inclusions in routine histological sections. The study has confirmed the specificity of the monoclonal AZT11 for the Z mutant. Thus, the combination of these two features is crucial for the distinction between the three variants and for predicting the genotype, whose confirmation would definitely require molecular analysis. Our study provides new data on the pathomorphogenesis of Mmalton inclusion bodies whose mineralization could play a central role in disease pathogenesis of Mmalton that is distinct from the Z and Siiyama variants. Calcium is known to be a major effector of cell death either via the increased intracellular concentration or the alteration of homeostasis.
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http://dx.doi.org/10.1186/s13023-018-0821-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956786PMC
May 2018

Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis.

EMBO Mol Med 2018 04;10(4)

INSERM, UMR1163, Laboratory of Intestinal Immunity and Institut Imagine, Paris, France

Herein, we report the first identification of biallelic-inherited mutations in as a Mendelian cause of inflammatory bowel disease in two unrelated patients. encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all mutations were loss of function. mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate that mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.
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http://dx.doi.org/10.15252/emmm.201708483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887907PMC
April 2018

Fibrinogen Gamma Chain Mutations Provoke Fibrinogen and Apolipoprotein B Plasma Deficiency and Liver Storage.

Int J Mol Sci 2017 Dec 15;18(12). Epub 2017 Dec 15.

Genetics and Rare Diseases, Research Division, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen γ. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three and genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the and genes. and genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the "end-to-end" interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon.
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http://dx.doi.org/10.3390/ijms18122717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751318PMC
December 2017

Inflammatory bowel disease in chronic granulomatous disease: An emerging problem over a twenty years' experience.

Pediatr Allergy Immunol 2017 Dec;28(8):801-809

University Department of Pediatrics, Unit of Immune and Infectious Diseases, Bambino Gesù Children's Hospital IRCCS, University of Rome Tor Vergata, Rome, Italy.

Background: Chronic granulomatous disease (CGD) is a primary immunodeficiency of phagocytes, characterized by life-threatening infections and hyperinflammation. Due to survival improvement, inflammatory bowel disease (IBD) is becoming increasingly relevant. Here, we report our 20 year experience.

Methods: We retrospectively analyzed clinic, endoscopic, and histologic features, as well as the management of CGD-IBD patients referred to the Bambino Gesù Children's Hospital in Rome, Italy.

Results: Of 20 patients with CGD, 9 presented with CGD-IBD at diagnosis and/or during follow-up. Symptoms occurred at a median age of 16 years (range 3.2-42), with a median delay of 6 months for endoscopic confirmation. Patients mainly complained of nonspecific diarrhea (55%), with discrepancy between symptom paucity and severe endoscopic appearance, mainly represented by extensive colonic involvement (44%). Histology revealed at least 2 characteristic features (epithelioid granulomas, pigmented macrophages, and increased eosinophils) in 78% of patients. Eight of 9 patients received oral mesalamine, and 5 required systemic steroids. One patient received azathioprine due to steroid dependence. No patient required biological therapy or surgery. Clinical remission was obtained in all patients, but the majority complained of mild relapses. Two episodes of severe infection occurred early after steroid therapy.

Conclusions: Penetrance of CGD-IBD increases with age. Clinical manifestations may be subtle, and clinicians should have a low threshold to recommend endoscopy. Treatment with NSAIDs and/or steroids achieves a good response, but relapses usually occur. Infection surveillance is mandatory during treatment, to prevent opportunistic infections. A close collaboration between pediatric immunologists and gastroenterologists is pivotal, including combined follow-up.
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http://dx.doi.org/10.1111/pai.12814DOI Listing
December 2017

Anastomotic ulcers in short bowel syndrome: New suggestions from a multidisciplinary approach.

J Pediatr Surg 2018 Mar 3;53(3):483-488. Epub 2017 Jun 3.

Intestinal Failure Rehabilitation Group, Bambino Gesù Children's Hospital, Rome, Italy.

Background And Aims: Anastomotic ulceration (AU) is a rare potential life-threatening complication that may occur after intestinal resection. The diagnosis is often delayed after a long-lasting history of refractory anemia. The pathogenesis remains unknown and there are no established therapies. The aim of the study was to analyze the medical history of children with short bowel syndrome (SBS) who were experiencing AU.

Methods: Records of SBS children were retrospectively reviewed. Demographics, baseline characteristics, presentation, diagnosis and treatment of AU cases were analyzed.

Results: Eight out of 114 children with SBS were identified as having AU. Mean gestational age was 32.5weeks. Underlying diseases were: 5 necrotising enterocolitis, 2 gastroschisis and 1 multiple intestinal atresia. The mean age at AU diagnosis was 6.5years (diagnosis delay of 35months). All but 2 patients had AU persistency after medical treatment. Endoscopic treatment (2 argon plasma coagulation; 1 platelet-rich fibrin instillation; 2 endoscopic hydrostatic dilations) was effective in 3 out of 5 children. Surgery was required in 3 patients.

Conclusions: Severe bowel ischemic injury, especially in preterm infant, could predispose to AU development. Medical treatment showed discouraging results. We firstly described that different endoscopic treatment could be attempted before resorting to further surgery.

Level Of Evidence: IV.
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http://dx.doi.org/10.1016/j.jpedsurg.2017.05.030DOI Listing
March 2018

Pediatric adrenocortical neoplasms: immunohistochemical expression of p57 identifies loss of heterozygosity and abnormal imprinting of the 11p15.5.

Pediatr Res 2017 03 14;81(3):468-472. Epub 2016 Nov 14.

Department of Pathology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Diagnosis of adrenocortical neoplasms (ACN), in pediatric age, is based on Wieneke criteria. The p57, a cyclin-dependent kinase inhibitor, acts to negatively regulate cell proliferation and is frequently found dysregulated in cancer. The identification of loss of heterozygosity (LOH) of 11p15, containing the p57 gene, could be a tool for differential diagnosis of benign and malignant ACN.

Methods: Immunohistochemistry with anti-p57 and microsatellite markers analysis of 11p15 region to value LOH were made in both ACN and surrounded normal adrenal cortex.

Results: Nine ACN, two clinically benign, two uncertain, and five malignant, were diagnosed. Positive p57 cells were evident in normal adrenal cortex and in one histologically benign ACN. A low/absent expression of p57 was documented in eight ACN independently from the classification on the basis of pathological and clinical criteria. Microsatellite marker analysis confirmed the LOH of 11p15 region in the same ACN.

Conclusion: LOH of 11p15 has a high prognostic value suggesting the p57 gene is important in ACN pathogenesis. Immunohistochemistry for p57 is a simple and cheap tool that can be used to quickly identify LOH of 11p15 in ACN.
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http://dx.doi.org/10.1038/pr.2016.239DOI Listing
March 2017
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