Publications by authors named "Renata Boldrini"

111 Publications

Cellular and gene signatures of tumor-infiltrating dendritic cells and natural-killer cells predict prognosis of neuroblastoma.

Nat Commun 2020 11 25;11(1):5992. Epub 2020 Nov 25.

Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy.

Tumor-infiltrating lymphocytes play an essential role in improving clinical outcome of neuroblastoma (NB) patients, but their relationship with other tumor-infiltrating immune cells in the T cell-inflamed tumors remains poorly investigated. Here we show that dendritic cells (DCs) and natural killer (NK) cells are positively correlated with T-cell infiltration in human NB, both at transcriptional and protein levels, and associate with a favorable prognosis. Multiplex imaging displays DC/NK/T cell conjugates in the tumor microenvironment of low-risk NB. Remarkably, this connection is further strengthened by the identification of gene signatures related to DCs and NK cells able to predict survival of NB patients and strongly correlate with the expression of PD-1 and PD-L1. In summary, our findings unveil a key prognostic role of DCs and NK cells and indicate their related gene signatures as promising tools for the identification of clinical biomarkers to better define risk stratification and survival of NB patients.
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http://dx.doi.org/10.1038/s41467-020-19781-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689423PMC
November 2020

Hoarse cry in a newborn with epidermolysis bullosa simplex, generalized severe.

Pediatr Dermatol 2020 Mar 19;37(2):393-395. Epub 2020 Jan 19.

Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Hoarse cry and respiratory stridor are the signs of potentially life-threatening laryngeal involvement in selected severe and frequently early lethal subtypes of inherited epidermolysis bullosa (EB). We present a newborn with generalized skin blistering and onychodystrophy who developed a hoarse cry and inspiratory stridor. Ultrastructural skin examination revealed tonofilament clumping in basal keratinocytes and genetic testing identified the de novo missense mutation p.Arg125Cys in the KRT14 gene, consistent with EB simplex generalized severe, which is characterized by major morbidity in infancy but a favorable long-term prognosis. The present case underlines the importance to consider EB simplex generalized severe in the differential diagnosis of EB infants presenting hoarseness and stridor.
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http://dx.doi.org/10.1111/pde.14105DOI Listing
March 2020

Salvage treatment for children with relapsed/refractory germ cell tumors: The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience.

Pediatr Blood Cancer 2020 03 18;67(3):e28125. Epub 2019 Dec 18.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.

Background: Malignant germ cell tumors (GCTs) are a heterogeneous group of rare neoplasms in children. Optimal outcome is achieved with multimodal therapies for patients with both localized and advanced disease, especially after the introduction of platinum-based chemotherapy regimens. In this respect, data on salvage treatment for children with relapsed or platinum-refractory disease are still limited.

Methods: Retrospective analysis of data regarding patients affected by malignant GCTs with platinum-refractory or relapsed disease after first-line treatment according to AIEOP TCGM 2004 protocol was conducted.

Results: Twenty-one patients, 15 females and 6 males, were considered for the analysis. All 21 patients received second-line conventional chemotherapy (SLCT), two of these immediately after surgery for local relapse removal. Two patients showed a progression of disease during SLCT and died of disease shortly thereafter, whereas 19 patients were in partial remission (PR) or complete remission (CR) after SLCT. Treatment after SLCT consisted in surgery on residual tumor mass (9/19) followed by high dose of chemotherapy (HDCT) with autologous hematopoietic stem cell support (16/19). The overall survival (OS) and event-free survival of the whole populations are 71% and 66.6%, respectively. Platinum-refractory patients OS is 54.5% compared with 91.5% of the relapsed group. There were no treatment-related deaths.

Conclusion: SLCT followed or not by HDCT is an effective salvage treatment for children with relapsed/refractory GCTs. However, the role of HDCT following SLCT needs to be further investigated, especially regarding the identification of specific patient subgroups, which can benefit from this more intensive treatment.
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http://dx.doi.org/10.1002/pbc.28125DOI Listing
March 2020

Phenotype characterisation of mutation and deletion carriers with neonatal and paediatric pulmonary hypertension.

Eur Respir J 2019 08 22;54(2). Epub 2019 Aug 22.

Division of Neonatology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA

Rare variants in the T-box transcription factor 4 gene () have recently been recognised as an emerging cause of paediatric pulmonary hypertension (PH). Their pathophysiology and contribution to persistent pulmonary hypertension in neonates (PPHN) are unknown. We sought to define the spectrum of clinical manifestations and histopathology associated with variants in neonates and children with PH.We assessed clinical data and lung tissue in 19 children with PH, including PPHN, carrying rare variants identified by next-generation sequencing and copy number variation arrays.Variants included six 17q23 deletions encompassing the entire locus and neighbouring genes, and 12 likely damaging mutations. 10 infants presented with neonatal hypoxic respiratory failure and PPHN, and were subsequently discharged home. PH was diagnosed later in infancy or childhood. Three children died and two required lung transplantation. Associated anomalies included patent ductus arteriosus, septal defects, foot anomalies and developmental disability, the latter with a higher prevalence in deletion carriers. Histology in seven infants showed abnormal distal lung development and pulmonary hypertensive remodelling. mutations and 17q23 deletions underlie a new form of developmental lung disease manifesting with severe, often biphasic PH at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects, neurodevelopmental disability and other anomalies.
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http://dx.doi.org/10.1183/13993003.01965-2018DOI Listing
August 2019

Tumor-infiltrating T cells and PD-L1 expression in childhood malignant extracranial germ-cell tumors.

Oncoimmunology 2019;8(2):e1542245. Epub 2018 Dec 13.

Department of Oncohaematology, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Although pediatric malignant extracranial germ-cell tumors (meGCTs) are among the most chemosensitive solid tumors, a group of patients relapse and die of disease. To identify new markers predicting clinical outcome, we examined the prognostic relevance of tumor-infiltrating T lymphocytes (TILs) and the expression of PD-1 and PD-L1 in a cohort of pediatric meGCTs by immunohistochemistry. MeGCTs were variously infiltrated by T cell-subtypes according to the tumor subtype, tumor location and age at diagnosis. We distinguished three different phenotypes: i) tumors not infiltrated by T cells (immature teratomas and half of the yolk sac tumors), ii) tumors highly infiltrated by CD8 T cells expressing PD-1, which identifies activated tumor-reactive T cells (seminomas and dysgerminomas), iii) tumors highly infiltrated by CD8 T cells within an immunosuppressive tumor microenvironment characterized by CD4FOXP3 Treg cells and PD-L1-expressing tumor cells (embryonal carcinomas, choriocarcinomas and the remaining yolk sac tumors). Tumor subtypes belonging mixed meGCTs were variously infiltrated, suggesting the coexistence of multiple immune microenvironments either facilitating or precluding the entry of T cells. These findings support the hypothesis that TILs influence the development of meGCTs and might be of clinical relevance to improve risk stratification and the treatment of pediatric patients.
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http://dx.doi.org/10.1080/2162402X.2018.1542245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343784PMC
December 2018

Malignant testicular germ cell tumors in children and adolescents: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) protocol.

Urol Oncol 2018 11 21;36(11):502.e7-502.e13. Epub 2018 Sep 21.

Hematology/Oncology Unit, A.R.N.A.S Civico Di Cristina e Benfratelli, Palermo, Italy.

Objectives: We report the results of an Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study on the treatment of testicular germ cell tumors (TGCT) with a pediatric PEB (pPEB) regimen (cisplatin 25 mg/m daily on days 1-4; etoposide 100 mg/m daily on days 1-4; bleomycin 15 mg/m on day 2, once per cycle).

Methods And Materials: Male patients under 18 years old with malignant TGCT were enrolled for a second national prospective protocol. All patients underwent orchiectomy at diagnosis. Those with Stage I received no chemotherapy; those with Stage II-III disease received three cycles of pPEB; and those with Stage IV received four cycles. After chemotherapy, resection of radiologically-evident residual disease was recommended. The main study end-points were overall survival and relapse-free survival.

Results: Ninety-nine boys from 0.5 to 17.8 years old (median 15.4 years) were evaluable, and staged as follows: 58 Stage I (59%), 7 Stage II (7%), 14 Stage III (14%), and 20 Stage IV (20%). With a median follow-up of 59 months (range 4-165 months), 5-year relapse-free survival (95% CI) was 73% (65%-83%) for the whole sample, 65% (53%-79%) for Stage I patients, and 86% (75%-98%) for Stage II-IV patients. Five-year overall survival (95% CI) was 99% (97%-100%).

Conclusions: We confirmed a good prognosis for malignant TGCT in children and adolescents. Reducing the number of chemotherapy cycles for Stage II-III disease does not seem to negatively affect survival outcomes.
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http://dx.doi.org/10.1016/j.urolonc.2018.07.001DOI Listing
November 2018

Phenotypic Features of Epidermolysis Bullosa Simplex due to KLHL24 Mutations in 3 Italian Cases.

Acta Derm Venereol 2019 02;99(2):238-239

Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital-IRCCS, Piazza S. Onofrio 4, IT-00165 Rome, Italy.

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http://dx.doi.org/10.2340/00015555-3046DOI Listing
February 2019

gene acts as a tumor suppressor in human neuroblastoma.

Oncotarget 2018 May 25;9(40):25903-25921. Epub 2018 May 25.

Laboratorio Cellule Staminali Post Natali e Terapie Cellulari, Istituto Giannina Gaslini, Genova, Italy.

Neuroblastoma is an aggressive, relapse-prone childhood tumor of the sympathetic nervous system that accounts for 15% of pediatric cancer deaths. A distal portion of human chromosome 3p is often deleted in neuroblastoma, this region may contain one or more putative tumor suppressor genes. A 2.54 Mb region at 3p26.3 encompassing the smallest region of deletion pinpointed gene, the locus for neuronal cell adhesion molecule close homolog of L1. We found that low expression predicted poor outcome in neuroblastoma patients. Here we have used two inducible cell models to analyze the impact of CHL1 on neuroblastoma biology. Over-expression of induced neurite-like outgrowth and markers of neuronal differentiation in neuroblastoma cells, halted tumor progression, inhibited anchorage-independent colony formation, and suppressed the growth of human tumor xenografts. Conversely, knock-down of CHL1 induced neurite retraction and activation of Rho GTPases, enhanced cell proliferation and migration, triggered colony formation and anchorage-independent growth, accelerated growth in orthotopic xenografts mouse model. Our findings demonstrate unambiguously that CHL1 acts as a regulator of proliferation and differentiation of neuroblastoma cells through inhibition of the MAPKs and Akt pathways. is a novel candidate tumor suppressor in neuroblastoma, and its associated pathways may represent a promising target for future therapeutic interventions.
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http://dx.doi.org/10.18632/oncotarget.25403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995240PMC
May 2018

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

Congenital Rhabdomyosarcoma: a different clinical presentation in two cases.

BMC Pediatr 2018 05 15;18(1):166. Epub 2018 May 15.

Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.

Background: Rhabdomyosarcoma (RMS), one of the most common soft tissue sarcomas of childhood, is very rare in the neonatal period (0.4-2% of cases). In order to gain a deeper understanding of this disease at such age, patient and tumor features, as well as treatment modality and outcome need to be reported.

Case Presentation: We describe two cases with congenital RMS treated at Bambino Gesù Children's Hospital between 2000 and 2016. They represent only 2.24% of all RMS patients diagnosed during that period in our Institution; this data is in agreement with the incidence reported in the literature. They reflect the two different clinical forms in which the disease may manifest itself. One patient, with the alveolar subtype (positive for specific PAX3-FOXO1 fusion transcript) and disseminated disease, had a fatal outcome with central nervous system (CNS) progression despite conventional and high dose chemotherapy. The other child, with the localized embryonal subtype, was treated successfully with conservative surgery and conventional chemotherapy, including prolonged maintenance therapy. He is disease free at 7 years of follow-up.

Conclusions: RMS can also be diagnosed during the neonatal period. Given the young age, disease management is often challenging, and especially for the alveolar subtype, the outcome is dismal despite intensified multimodality therapy. In fact, it characteristically manifests with multiple subcutaneous nodules and progression most commonly occurs in the CNS (Rodriguez-Galindo et al., Cancer 92(6):1613-20, 2001). In this context, CNS prophylaxis could play a role in preventing leptomeningeal dissemination, and molecular studies can allow a deeper tumor characterization, treatment stratification and identification of new potential therapeutic targets.
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http://dx.doi.org/10.1186/s12887-018-1128-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953406PMC
May 2018

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome or Fowler syndrome: Report of a family and insight into the disease's mechanism.

Mol Genet Genomic Med 2018 05 3;6(3):446-451. Epub 2018 Mar 3.

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

Background: Fowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly-hydrocephaly and multiple pterygium due to fetal akinesia. To date, around 45 cases from 27 families have been reported, and the pathogenic bi-allelic mutations in FLVCR2 gene described in 15 families. The pathogenesis of this condition has not been fully elucidated so far.

Methods: We report on an additional family with two affected fetuses carrying a novel homozygous mutation in FLVCR2 gene, and describe the impact of known mutants on the protein structural and functional impairment.

Results: The present report confirms the genetic homogeneity of Fowler syndrome and describes a new FLVCR2 mutation affecting the protein function. The structural analysis of the present and previously published FLVCR2 mutations supports the hypothesis of a reduced heme import as the underlying disease's mechanism due to the stabilization of the occluded conformation or a protein misfolding.

Conclusion: Our data suggest the hypothesis of heme deficiency as the major pathogenic mechanism of Fowler syndrome.
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http://dx.doi.org/10.1002/mgg3.376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014450PMC
May 2018

Evaluation of Endoglin (CD105) expression in pediatric rhabdomyosarcoma.

BMC Cancer 2018 01 5;18(1):31. Epub 2018 Jan 5.

Department of Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4, 00165, Rome, Italy.

Background: The Intratumoral Microvessel Density (IMVD) is commonly used to quantify tumoral vascularization and is usually assessed by pan-endothelial markers, such as CD31. Endoglin (CD105) is a protein predominantly expressed in proliferating endothelium and the IMVD determined by this marker measures specifically the neovascularization. In this study, we investigated the CD105 expression in pediatric rhabdomyosarcoma and assessed the neovascularization by using the angiogenic ratio IMVD-CD105 to IMVD-CD31.

Methods: Paraffin-embedded archival tumor specimens were selected from 65 pediatric patients affected by rhabdomyosarcoma. The expression levels of CD105, CD31 and Vascular Endothelial Growth Factor (VEGF) were investigated in 30 cases (18 embryonal and 12 alveolar) available for this study. The IMVD-CD105 to IMVD-CD31 expression ratio was correlated with clinical and pathologic features of these patients.

Results: We found a specific expression of endoglin (CD105) in endothelial cells of all the rhabdomyosarcoma specimens analyzed. We observed a significant positive correlation between the IMVD individually measured by CD105 and CD31. The CD105/CD31 expression ratio was significantly higher in patients with lower survival and embryonal histology. Indeed, patients with a CD105/CD31 expression ratio < 1.3 had a significantly increased OS (88%, 95%CI, 60%-97%) compared to patients with higher values (40%, 95%CI, 12%-67%). We did not find any statistical correlation among VEGF and EFS, OS and CD105/CD31 expression ratio.

Conclusion: CD105 is expressed on endothelial cells of rhabdomyosarcoma and represent a useful tool to quantify neovascularization in this tumor. If confirmed by further studies, these results will indicate that CD105 is a potential target for combined therapies in rhabdomyosarcoma.
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http://dx.doi.org/10.1186/s12885-017-3947-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755407PMC
January 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

Pediatric Chronic Intestinal Failure in Italy: Report from the 2016 Survey on Behalf of Italian Society for Gastroenterology, Hepatology and Nutrition (SIGENP).

Nutrients 2017 Nov 5;9(11). Epub 2017 Nov 5.

Department of Medical and Surgical Neonatology, Bambino Gesù Children's Hospital, 00165 Rome, Italy.

Background: Intestinal failure (IF) is the reduction in functioning gut mass below the minimal level necessary for adequate digestion and absorption of nutrients and fluids for weight maintenance in adults or for growth in children. There is a paucity of epidemiologic data on pediatric IF. The purpose of this study was to determine the prevalence, incidence, regional distribution and underlying diagnosis of pediatric chronic IF (CIF) requiring home parenteral nutrition (HPN) in Italy.

Methods: Local investigators were selected in 19 Italian centers either of reference for pediatric HPN or having pediatric gastroenterologists or surgeons on staff and already collaborating with the Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition with regard to IF. Data requested in this survey for children at home on Parenteral Nutrition (PN) on 1 December 2016 included patient initials, year of birth, gender, family's place of residence and underlying diagnosis determining IF.

Results: We recorded 145 CIF patients on HPN aged ≤19 years. The overall prevalence was 14.12/million inhabitants (95% CI: 9.20-18.93); the overall incidence was 1.41/million inhabitant years (95% CI: 0.53-2.20).

Conclusion: Our survey provides new epidemiological data on pediatric CIF in Italy; these data may be quantitatively useful in developing IF care strategy plans in all developed countries.
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http://dx.doi.org/10.3390/nu9111217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707689PMC
November 2017

MYCN is an immunosuppressive oncogene dampening the expression of ligands for NK-cell-activating receptors in human high-risk neuroblastoma.

Oncoimmunology 2017;6(6):e1316439. Epub 2017 Apr 20.

Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Neuroblastoma (NB) is the most common extracranial solid tumor occurring in childhood. Amplification of the oncogene is associated with poor prognosis. Downregulation on NB cells of ligands recognized by Natural Killer (NK) cell-activating receptors, involved in tumor cell recognition and lysis, may contribute to tumor progression and relapse. Here, we demonstrate that in human NB cell lines MYCN expression inversely correlates with that of ligands recognized by NKG2D and DNAM1 activating receptors in human NB cell lines. In the MYCN-inducible Tet-21/N cell line, downregulation of MYCN resulted in enhanced expression of the activating ligands MICA, ULBPs and PVR, which rendered tumor cells more susceptible to recognition and lysis mediated by NK cells. Conversely, a MYCN non-amplified NB cell line transfected with MYCN showed an opposite behavior compared with control cells. Consistent with these findings, an inverse correlation was detected between the expression of MYCN and that of ligands for NK-cell-activating receptors in 12 NB patient specimens both at mRNA and protein levels. Taken together, these results provide the first demonstration that MYCN acts as an immunosuppressive oncogene in NB cells that negatively regulates the expression of ligands for NKG2D and DNAM-1 NK-cell-activating receptors. Our study provides a clue to exploit MYCN expression levels as a biomarker to predict the efficacy of NK-cell-based immunotherapy in NB patients.
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http://dx.doi.org/10.1080/2162402X.2017.1316439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486189PMC
April 2017

PD-L1 Is a Therapeutic Target of the Bromodomain Inhibitor JQ1 and, Combined with HLA Class I, a Promising Prognostic Biomarker in Neuroblastoma.

Clin Cancer Res 2017 Aug 7;23(15):4462-4472. Epub 2017 Mar 7.

Immuno-Oncology Laboratory, Oncohaematology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

This study sought to evaluate the expression of programmed cell death-ligand-1 (PD-L1) and HLA class I on neuroblastoma cells and programmed cell death-1 (PD-1) and lymphocyte activation gene 3 (LAG3) on tumor-infiltrating lymphocytes to better define patient risk stratification and understand whether this tumor may benefit from therapies targeting immune checkpoint molecules. IHC staining for PD-L1, HLA class I, PD-1, and LAG3 was assessed in 77 neuroblastoma specimens, previously characterized for tumor-infiltrating T-cell density and correlated with clinical outcome. Surface expression of PD-L1 was evaluated by flow cytometry and IHC in neuroblastoma cell lines and tumors genetically and/or pharmacologically inhibited for MYC and MYCN. A dataset of 477 human primary neuroblastomas from GEO and ArrayExpress databases was explored for PD-L1, MYC, and MYCN correlation. Multivariate Cox regression analysis demonstrated that the combination of PD-L1 and HLA class I tumor cell density is a prognostic biomarker for predicting overall survival in neuroblastoma patients ( = 0.0448). MYC and MYCN control the expression of PD-L1 in neuroblastoma cells both and Consistently, abundance of PD-L1 transcript correlates with MYC expression in primary neuroblastoma. The combination of PD-L1 and HLA class I represents a novel prognostic biomarker for neuroblastoma. Pharmacologic inhibition of MYCN and MYC may be exploited to target PD-L1 and restore an efficient antitumor immunity in high-risk neuroblastoma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2601DOI Listing
August 2017

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

Start codon mutation of GYG1 causing late-onset polyglucosan body myopathy with nemaline rods.

J Neurol 2016 Oct 20;263(10):2133-5. Epub 2016 Aug 20.

Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

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http://dx.doi.org/10.1007/s00415-016-8268-zDOI Listing
October 2016

Anaplastic lymphoma kinase aberrations correlate with metastatic features in pediatric rhabdomyosarcoma.

Oncotarget 2016 09;7(37):58903-58914

Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Rhabdomyosarcoma (RMS) is the most frequent soft tissue tumor in childhood and arises from immature mesenchymal cells committed to skeletal muscle differentiation. Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in several cancers. Moreover, ALK full-length receptor protein has been observed in RMS, although its clinical and functional significance is yet controversial. The role of ALK and its clinical relevance were investigated in a selected cohort of 74 FFPE pediatric RMS and a panel of RMS cell lines, evaluating its gene and protein status, utilizing Fluorescent In Situ Hybridization (FISH), immunohistochemistry (IHC) and Western blot approaches. Moreover, to get insight into its possible therapeutic relevance, effects of ALK silencing on cell proliferation, invasion and apoptosis were studied in RMS cells. ALK IHC positivity was significantly correlated with gene copy number gain, the alveolar subtype, PAX3/7-FOXO1 rearrangements, the presence of metastasis at diagnosis and a worse overall outcome. Furthermore, EML4-ALK fusion gene associated with higher protein expression was identified in an embryonal RMS. ALK silencing in RH30 ALK positive cells strongly inhibited invasion capability. Overall, our data suggest a potential role of ALK in pediatric RMS.
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http://dx.doi.org/10.18632/oncotarget.10368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312284PMC
September 2016

Structural Defects of Laminin β3 N-terminus Underlie Junctional Epidermolysis Bullosa with Altered Granulation Tissue Response.

Acta Derm Venereol 2016 Nov;96(7):954-958

Dermatology Division, Bambino Gesù Children's Hospital-IRCCS, P.zza Sant'Onofrio, 4, IT-00165 Rome, Italy.

Mutations in the laminin-332 (α3Aβ3γ2) genes cause junctional epidermolysis bullosa (JEB), a recessively inherited disease characterized by blistering and altered wound repair. In addition, specific mutations that affect the N-terminus of the α3A chain cause a JEB-related non-blistering condition characterized by chronic production of granulation tissue, suggesting a critical role of this region in epithelial-mesenchymal communication. We report here a 9-year-old patient with JEB with a few long-standing skin ulcers with prominent granulation tissue in the absence of active blistering. He bears a homozygous missense mutation, p.Gly254Asp, within the first laminin epidermal growth factor-like (LE) repeat of the β3 short arm. We show that p.Gly254Asp causes mis-folding of the LE motif, leading to reduced secretion of laminin-332 and structural alterations of the cutaneous basement membrane zone. These findings demonstrate, in a patient in vivo, that the β3 short arm is also involved in the outcome of the granulation tissue response.
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http://dx.doi.org/10.2340/00015555-2439DOI Listing
November 2016

Surfactant Protein C-associated interstitial lung disease; three different phenotypes of the same SFTPC mutation.

Ital J Pediatr 2016 Feb 29;42:23. Epub 2016 Feb 29.

Pneumology Unit - Department of Pediatric Medicine, Bambino Gesù Children's Hospital, IRCCS, Piazza S Onofrio 4, 00165, Rome, Italy.

Background: Monoallelic mutations of the Surfactant Protein C gene (SFTPC) are associated with Interstitial Lung Disease in children. I73T is the most common mutation, accounting for 30 % of all cases reported.

Case Presentation: We describe three patients carrying the same I73T SPC mutation with very different phenotypes, clinical course (ranging from mild respiratory symptoms to death for respiratory failure) and outcome.

Conclusions: The disease mechanisms associated with SP-C mutations suggest that the combination of individual genetic background and environmental factors contribute largely to the wide variability of clinical expression. Infants, children and adults with ILD of unknown etiology should be investigated for SP-C genetic abnormalities.
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http://dx.doi.org/10.1186/s13052-016-0235-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772310PMC
February 2016

Frequent Occurrence of Aplasia Cutis Congenita in Bullous Dermolysis of the Newborn.

Acta Derm Venereol 2016 Aug;96(6):784-7

Dermatology Unit, Bambino Gesù Children's Hospital-IRCCS, P.zza Sant'Onofrio, 4, IT-00165 Rome, Italy.

Bullous dermolysis of the newborn (BDN) is a subtype of dystrophic epidermolysis bullosa characterized by rapid improvement in skin fragility within the first months of life, associated with typical immunofluorescence and ultrastructural features. Inheritance can be autosomal dominant or recessive. We report here 4 cases of BDN, 2 of which presented with aplasia cutis congenita of the lower extremities. All patients improved rapidly and blister formation ceased by the third month of life in 3 cases. In these patients only residual milia, nail dystrophies and atrophic scarring at sites of aplasia cutis were visible by one year. Family history indicated dominant inheritance in 2 cases, confirmed by identification of COL7A1 mutation. Molecular analysis also revealed recessive inheritance in the 2 sporadic cases. A literature search identified several patients with BDN born with skin defects localized to the lower extremities. In conclusion, these findings indicate that aplasia cutis congenita is not an infrequent manifestation of BDN.
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http://dx.doi.org/10.2340/00015555-2364DOI Listing
August 2016

Mediastinal Germ Cell Tumors in Pediatric Patients: A Report From the Italian Association of Pediatric Hematology and Oncology.

Pediatr Blood Cancer 2016 May 14;63(5):808-12. Epub 2016 Jan 14.

Operative Unit of General and Thoracic Surgery, Bambino Gesù Pediatric Hospital IRCCS, Rome, Italy.

Background: Primary mediastinal germ cell tumors (GCTs) are rare in children and still represent a challenge for both adult and pediatric oncologists because of their worse outcome compared to their gonadal counterpart.

Procedure: Prospectively collected data concerning patients enrolled in the Italian Association of Pediatric Haematology and Oncology study on malignant GCTs (AIEOP TCGM 2004) protocol for the treatment of GCTs were analyzed. Patients with malignant mediastinal primary GCTs were included in this study. Data regarding patients with newly diagnosed mediastinal teratoma were also collected.

Results: From 2005 to 2013, 20 children diagnosed with mediastinal GCTs were registered in AIEOP TCGM 2004 protocol. With a median follow-up of 89 months (range 35-123), the overall survival (OS) and event free survival (EFS) rates were 100% for teratoma and 90% for malignant GCTs.

Conclusions: We confirm the favorable outcome of children affected by mediastinal teratoma and malignant GCTs. For malignant tumors, further studies on the clinical characteristics and genetic signatures on tumor samples might be necessary to better understand differences observed in high-risk patients and to assist the development of more effective treatment for this subgroup.
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http://dx.doi.org/10.1002/pbc.25895DOI Listing
May 2016

Role of molecular testing in the multidisciplinary diagnostic approach of ichthyosis.

Orphanet J Rare Dis 2016 Jan 13;11. Epub 2016 Jan 13.

Molecular Genetics Laboratory, Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: The term ichthyosis describes a generalized disorder of cornification characterized by scaling and/or hyperkeratosis of different skin regions. Mutations in a broad group of genes related to keratinocyte differentiation and epidermal barrier function have been demonstrated to play a causative role in disease development. Ichthyosis may be classified in syndromic or non-syndromic forms based on the occurrence or absence of extracutaneous signs. In this setting, the diagnosis of ichthyosis is an integrated multistep process requiring a multidisciplinary approach in order to formulate the appropriate diagnostic hypothesis and to address the genetic testing.

Methods: Due to the complex features of the different ichthyoses and the high number of genes involved we have investigated a group of 64 patients, affected by syndromic and non-syndromic diseases, using Next Generation Sequencing as a new tool for the molecular diagnosis.

Results: Using this innovative molecular approach we were able to find pathogenic mutations in 53 out of 64 patients resulting in 82.8 % total detection rate. An interesting result from the analysis of the data is the high rate of novel sequence variations found compared to known mutations and the relevant rate of homozygous mutations.

Conclusions: The possibility to analyze a large number of genes associated with various diseases allows to study cases with phenotypes not well-determined, giving the opportunity to make new genotype-phenotype correlation. In some cases there were discrepancies between clinical features and histology or electron microscopy and only molecular analysis allowed to definitively resolve the diagnostic dilemma. The genetic diagnosis of ichthyosis leads to a more accurate and effective genetic counseling, allowing correct evaluation of the risk of recurrence, particularly in families with consanguineous background.
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http://dx.doi.org/10.1186/s13023-016-0384-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712481PMC
January 2016

A waterborn zoonotic helminthiase in an Italian diver: a case report of a cutaneous Sparganum infection and a review of European cases.

Pathog Glob Health 2015 9;109(8):383-6. Epub 2016 Jan 9.

1 Unit of Parasitology, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy.

Many waterborne helminthes are opportunistic parasites that can travel directly from animals to man and may contain forms capable of penetrating the skin. Among these, Sparganum is the pseudophyllidean tapeworm that belongs to the genus Spirometra, which is responsible for parasitic zoonosis; it is rarely detected in Europe and is caused by the plerocercoid infective larva. Thus far, only six cases of cutaneous and ocular sparganosis have been reported in Europe; two and four cases have occurred in France and Italy, respectively. Herein, we describe a new case of sparganosis in Italy that affected a male diver who presented to the Bambino Gesù Children's Hospital of Rome. The patient's skin biopsy was submitted to the Parasitology department who, in consultation with Pathology, concluded that the morphologic and microscopic findings were those of Sparganum spp. larvae. The patient recovered following a single dose of 600 mg praziquantel.
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http://dx.doi.org/10.1080/20477724.2015.1123901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809237PMC
October 2016
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