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Quattrocchi C.C.,IRCCS Ospedale Pediatrico Bambino Gesu | Alexandre A.M.,IRCCS Ospedale Pediatrico Bambino Gesu | Pepa G.M.D.,Catholic University of Rome | Altavilla R.,Biomedical University of Rome | Zobel B.B.,IRCCS Ospedale Pediatrico Bambino Gesu
Acta Neurochirurgica, Supplementum | Year: 2011

Studying discovertebral complex anatomy is extremely important for the understanding of the pathophysiology of disc degeneration which leads to vertebral endplates signal changes, also known as Modic changes. The sequelae of disc degeneration are among the leading causes of functional incapacity in both sexes and are one of the most common sources of chronic disability in the working years. Even if the presence of degenerative changes in MRI of the spine is by no means an indicator of symptoms, we are concordant in a positive association between Modic changes and low back pain, above all as a relatively specific but insensitive sign of discogenic low back pain. © 2011 Springer-Verlag/Wien.


PubMed | University of Genoa, Monash University, IRCCS Instituto Giannina Gaslini, University of Cardiff and 4 more.
Type: Journal Article | Journal: The Journal of experimental medicine | Year: 2016

Natural killer (NK) cells play a key role in immunity, but how HLA class I (HLA-I) and killer cell immunoglobulin-like receptor 3DL1 (KIR3DL1) polymorphism impacts disease outcome remains unclear. KIR3DL1 (*001/*005/*015) tetramers were screened for reactivity against a panel of HLA-I molecules. This revealed different and distinct hierarchies of specificity for each KIR3DL1 allotype, with KIR3DL1*005 recognizing the widest array of HLA-I ligands. These differences were further reflected in functional studies using NK clones expressing these specific KIR3DL1 allotypes. Unexpectedly, the Ile/Thr80 dimorphism in the Bw4-motif did not categorically define strong/weak KIR3DL1 recognition. Although the KIR3DL1*001, *005, and *015 polymorphisms are remote from the KIR3DL1-HLA-I interface, the structures of these three KIR3DL1-HLA-I complexes showed that the broader HLA-I specificity of KIR3DL1*005 correlated with an altered KIR3DL1*005 interdomain positioning and increased mobility within its ligand-binding site. Collectively, we provide a generic framework for understanding the impact of KIR3DL1 polymorphism on the recognition of HLA-I allomorphs.


Tomai F.,European Hospital | Adorisio R.,IRCCS Ospedale Pediatrico Bambino Gesu | De Luca L.,European Hospital | Pilati M.,IRCCS Ospedale Pediatrico Bambino Gesu | And 5 more authors.
Catheterization and Cardiovascular Interventions | Year: 2014

Objectives To assess coronary plaque composition by virtual histology intravascular ultrasound (VH-IVUS) analysis in young adult recipients and to correlate these findings with time from heart transplant (HTx) and long-term outcomes. Background Rapid progression of coronary allograft vasculopathy after heart transplantation is a powerful predictor of mortality and clinical events at long-term. Methods Forty consecutive young adult recipients transplanted during childhood undergoing VH-IVUS during coronary surveillance have been prospectively included in this study. According to the time interval from HTx to VH-IVUS assessment, our cohort was divided into two groups (group A: ≤5 years, n = 13; group B: >5 years, n = 27). Results Group B showed an higher percentage of necrotic core and dense calcium (12 ± 2 vs. 5 ± 1%, P = 0.04; 8.2 vs. 2.1%, P = 0.03; respectively). An "inflammatory plaque" (necrotic core and dense calcium ≥30%) was detected in 34.8% of patients in group B and in none among group A patients (P = 0.03). Patients in group B had a number of adverse clinical events significantly higher than group A patients (53.8 vs. 14.3%; HR 4.45; 95% CI 1.62-12.16; P = 0.029) at long-term follow-up (4.2 years). The multivariate regression analysis showed that age (HR 1.5; 95% CI 1.1-2.0; P = 0.007), time from HTx (HR 1.8; 95% CI 1.6-4.8; P = 0.02), and inflammatory plaque (HR 2.4; 95% CI 1.1-5.3; P = 0.03) were independent predictors of adverse clinical events. Conclusions This study supports the hypothesis that time-dependent differences in plaque composition, as assessed by VH-IVUS, occur after HTx in young adult recipients, probably determining an increased risk of long-term clinical events. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.


Della Chiesa M.,University of Genoa | Moretta L.,IRCCS Instituto Giannina Gaslini | Muccio L.,University of Genoa | Bertaina A.,IRCCS Ospedale Pediatrico Bambino Gesu | And 4 more authors.
Current Topics in Microbiology and Immunology | Year: 2016

Natural killer cells play an important role in the immune responses against cancer and viral infections. In addition, NK cells have been shown to exert a key role in haploidentical hematopoietic stem cell (HSC) transplantation for the therapy of high-risk leukemias. The anti-leukemia effect is mostly related to the presence of “alloreactive” NK cells, i.e., mature KIR+ NK cells that express inhibitory KIR mismatched with HLA class I (KIR-L) of the patient. In addition, an important role is played by certain activating KIR (primarily, but not only, KIR2DS1) upon interaction with their HLA class I ligand (C2 alleles). In general, the presence of activating KIR correlates with a better prognosis. Beside the infusion of “pure” CD34+ cells, a novel protocol has been recently developed in which depletion of αβ T cells and CD19+ B cells makes it possible to infuse into the patient, together with donor CD34+ HSCs, important effector cells including mature PB NK cells and γδ T cells. Recent studies revealed that cytomegalovirus (CMV) infection/reactivation may induce rapid NK cell maturation and greatly influence the NK receptor repertoire. The remarkable expansion of a subset expressing the activating receptor NKG2C, together with a more efficient virus-specific effector response after rechallenge with CMV (i.e., antigen specificity), and the longevity of the expanded population are all features consistent with an adaptive type of response and support the notion of a memory-like activity of NK cells. © Springer International Publishing Switzerland 2015.


Carretto E.,University of Padua | Inserra A.,IRCCS Ospedale Pediatrico Bambino Gesu | Ferrari A.,Fondazione IRCCS Instituto Nazionale Tumori | Conte M.,Giannina Gaslini Childrens Hospital | And 4 more authors.
Orphanet Journal of Rare Diseases | Year: 2011

Background: Thymic epithelial tumours (thymoma and carcinoma) are exceptionally rare in children. We describe a national multicentre series with a view to illustrating their clinical behaviour and the results of treatment. Methods. From January 2000 all patients under 18 years of age diagnosed with "rare paediatric tumours" were centrally registered by the Italian centres participating in the TREP project (Tumori Rari in Et Pediatrica [Rare Tumours in Paediatric Age]). The clinical data of children with a thymic epithelial tumour registered as at December 2009 were analyzed for the purposes of the present study. Results: Our series comprised 4 patients with thymoma and 5 with carcinoma (4 males, 5 females; median age 12.4 years). The tumour masses were mainly large, exceeding 5 cm in largest diameter. Based on the Masaoka staging system, 3 patients were stage I, 1 was stage III, 1 was stage IVa and 4 were stage IVb. All 3 patients with stage I thymoma underwent complete tumour resection at diagnosis and were alive 22, 35 and 93 months after surgery. One patient with a thymoma metastasizing to the kidneys died rapidly due to respiratory failure. Thymic carcinomas were much more aggressive, infiltrating nearby organs (in 4 cases) and regional nodes (in 5), and spreading to the bone (in 3) and liver (in 1). All patients received multidrug chemotherapy (platinum derivatives + etoposide or other drugs) with evidence of tumour reduction in 3 cases. Two patients underwent partial tumour resection (after chemo-radiotherapy in one case) and 4 patients were given radiotherapy (45-54 Gy). All patients died of their disease. Conclusions: Children with thymomas completely resected at diagnosis have an excellent prognosis while thymic carcinomas behave aggressively and carry a poor prognosis despite multimodal treatment. © 2011 Carretto et al; licensee BioMed Central Ltd.


Locatelli F.,IRCCS Ospedale Pediatrico Bambino Gesu | Locatelli F.,University of Pavia | Lucarelli B.,IRCCS Ospedale Pediatrico Bambino Gesu | Merli P.,IRCCS Ospedale Pediatrico Bambino Gesu
Expert Opinion on Pharmacotherapy | Year: 2014

Introduction: One significant obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT) is represented by graft failure, defined as either lack of initial engraftment of donor cells (primary graft failure) or loss of donor cells after initial engraftment (secondary graft failure). Graft failure mediated by host immune cells attacking donor stem cells is named graft rejection. Factors associated with graft failure include HLA disparity in the donor/recipient pair, underlying disease, viral infections, type of conditioning regimen and stem cell source employed. Areas covered: In this article, the experts summarize current approaches to treat graft failure/rejection after HSCT, and they discuss new strategies of graft manipulation and immune therapy of particular interest for preventing/treating this complication. Expert opinion: A limited array of options is available to treat graft failure. The experts believe that re-transplantation from another donor or the same donor (if there is no evidence of immunologically mediated graft failure) is the treatment of choice for patients with primary graft failure or acute graft rejection. The experts think that strategies based on innovative approaches of graft manipulation, new agents or cellular therapies could render in the future graft failure a much less relevant problem for HSCT recipients. © 2014 Informa UK, Ltd.


Strippoli R.,IRCCS Ospedale Pediatrico Bambino Gesu | Caiello I.,IRCCS Ospedale Pediatrico Bambino Gesu | De Benedetti F.,IRCCS Ospedale Pediatrico Bambino Gesu
Journal of Rheumatology | Year: 2013

Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic diseases. The condition is considered part of secondary hemophagocytic lymphohistiocytoses (HLH). There are similarities in genetic background, pathogenesis, and clinical and laboratory features with primary HLH (p-HLH). We describe findings in mouse models of secondary HLH, comparing them with models of p-HLH and the cellular and molecular mechanisms involved, and relate them to recent findings in patients with secondary HLH. A multilayer model is presented in which background inflammation, infections, and genetics all contribute in different proportions and in several ways. Once the "threshold" has been reached, inflammatory cytokines are the final effectors, independent of the interplay between different upstream pathogenic factors. Copyright © 2013. All rights reserved.


Franzini A.,Fondazione Irccs Instituto Neurologico C Besta | Cordella R.,Fondazione Irccs Instituto Neurologico C Besta | Rizzi M.,Fondazione Irccs Instituto Neurologico C Besta | Rizzi M.,University of Milan | And 4 more authors.
Journal of Neural Transmission | Year: 2014

Some neurological conditions require admission to an intensive care unit (ICU) where deep sedation and mechanical ventilation are administered to improve the patient's condition. Nevertheless, these treatments are not always helpful in disease control. At this stage, deep brain stimulation (DBS) could become a viable alternative in the treatment of critical neurological conditions with long-lasting clinical benefit. The value of deep brain stimulation has been investigated in the treatment of patients who had undergone surgical electrode implants as an emergency procedure to treat acute life-threatening conditions requiring admission to neurological ICU (NICU). A before-and-after perspective study was examined of seven patients who were treated with DBS for status dystonicus (SD) and post-stroke severe hemiballismus. Bilateral globus pallidus internus (GPi) DBS was performed in five SD patients and unilateral ventralis oralis anterior and posterior (Voa/Vop) nucleus of the thalamus DBS in two post-stroke hemiballismus patients. Bilateral GPi-DBS allowed SD resolution in a time lapse varying from 1 week to 3 months. No clear improvements compared to the baseline clinical condition were observed. Unilateral Voa/Vop-DBS intervention controlled hemiballismus after 10 h, and the patient was discharged in 2 days. The other patient was transferred from the NICU to the neurosurgery ward after 13 days. No surgical complications were observed in any of the above procedures. Neurostimulation procedures could represent a valuable choice in critical care conditions, when involuntary movements are continuous, life-threatening and refractory to intensive care procedures. DBS is feasible, safe and effective in selected cases. © 2013 Springer-Verlag Wien.


PubMed | A.O.R.N.A. Cardarelli, CNR Institute of Neuroscience, IRCCS Fondazione Stella Maris, The Second University of Naples and 4 more.
Type: Case Reports | Journal: Neuromuscular disorders : NMD | Year: 2016

Mutations in the MTM1 gene cause X-linked myotubular myopathy (XLMTM), characterized by neonatal hypotonia and respiratory failure, and are responsible for a premature mortality in affected males. Female carriers are usually asymptomatic but they may present with muscular weakness because of a hypothesized skewed pattern of X-chromosome inactivation. By combining next generation sequencing (NGS) and CGH array approaches, we have investigated the role of MTM1 variants in a large cohort of undiagnosed patients with a wide spectrum of myopathies. Seven novel XLMTM patients have been identified, including two girls with an unremarkable family history for myotubular myopathy. Moreover, we have detected and finely mapped a large deletion causing a myotubular myopathy with abnormal genital development. Our data confirm that the severe neonatal onset of the disease in male infants is sufficient to address the direct molecular testing toward the MTM1 gene and, above all, suggest that the number of undiagnosed symptomatic female carriers is probably underestimated.


PubMed | IRCCS Ospedale Pediatrico Bambino Gesu
Type: | Journal: British journal of haematology | Year: 2017

Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has invitro activity against ALL blasts. A phase I-II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2-3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively. Bortezomib (13mg/m

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