@article {10852, title = {Total body irradiation and iron chelation treatment are associated with pancreatic injury following pediatric hematopoietic stem cell transplantation.}, journal = {Oncotarget}, volume = {9}, year = {2018}, month = {2018 Apr 13}, pages = {19543-19554}, abstract = {

Whereas many studies have addressed the risk of organ dysfunction following hematopoietic stem cell transplantation (HSCT), little is known about pancreatic susceptibility in this setting. We aimed to investigate the effect of iron overload (IO) and total body irradiation (TBI) on pancreatic function of children undergoing HSCT. We retrospectively evaluated children admitted between 2012-2016 fulfilling the following criteria: normal pancreatic iron concentration (PIC), regular pancreatic function before HSCT, availability of abdominal magnetic resonance imaging with gradient-recalled-echo sequences and a full set of biochemical markers of IO and pancreatic function performed before HSCT and at discharge. We divided the patients according to the use of TBI or myeloablative chemotherapy (MCHT) in the conditioning regimen. All patients with severe IO or moderate IO with a high risk of engraftment delay or transplantation-related complications underwent chelation therapy with deferoxamine (DFO) from the first day of conditioning to discharge. 63 patients had a HSCT in the study period, 13 did not fulfill the inclusion criteria; 50 (25 in each group) are included in the analysis, and did not show differences at baseline evaluation. At follow up testing the TBI group showed a significantly higher PIC (107,8{\textpm}100,3 μmol/g vs 28,4{\textpm}37,9 in MCHT group, p<0,0001). In the TBI group the patients who had DFO treatment had higher PIC (223,2{\textpm}48,8 μmol/g vs 55,7{\textpm}10,5 without DFO treatment, p<0,0001), and all patients having PIC >100 μmol/g at follow up had DFO-based chelation therapy, versus 26\% of those with lower PIC (p<0,0001). The number of patients presenting exocrine pancreatic dysfunctions one month after transplantation was significantly higher in the TBI group (48\% vs 4\%; p<0.0001). The mean pancreatic volume reduction was significantly greater in the TBI group (39,1\% vs 0,9\% in the MCHT group; p<0,05), and was significantly worse on those who received DFO therapy. Based on our data, we suggest that TBI is detrimental for pancreatic functions, and speculate that DFO may contribute to the rapid pancreatic IO observed in these patients.

}, issn = {1949-2553}, doi = {10.18632/oncotarget.24646}, author = {Maximova, Natalia and Gregori, Massimo and Simeone, Roberto and Sonzogni, Aurelio and Zanon, Davide and Boz, Giulia and D{\textquoteright}Antiga, Lorenzo} } @article {10853, title = {Vanishing Bile Ducts in the Long Term after Pediatric Hematopoietic Stem Cell Transplantation.}, journal = {Biol Blood Marrow Transplant}, volume = {24}, year = {2018}, month = {2018 Nov}, pages = {2250-2258}, abstract = {

There are no structured studies on liver histology after hematopoietic stem cell transplantation (HSCT). We aimed to prospectively describe the clinicopathologic features of liver disease in the long term after HSCT in an observational, longitudinal study of liver histology in a consecutive cohort of children undergoing allogeneic HSCT. First liver biopsy was performed in presence of abnormal liver function tests and repeated per protocol thereafter. A previously reported semiquantitative score evaluating inflammation, cholestasis, and ductopenia (bile ducts-to-portal tracts ratio <= .5) was adopted. Graft-versus-host disease (GVHD) was diagnosed according to standard criteria. We evaluated 131 biopsies taken in 50 HSCTs performed in 47 children (mean age, 9.7 {\textpm} 5.2 years). Pre-HSCT chemotherapy was administered in 36 of 50 (72\%). GVHD was diagnosed in 17 of 50 (34\%). Over time the overall score decreased from a mean of 6 {\textpm} 2.7 to 3.25 {\textpm} .96 (P < .01), inflammation from 1.22 {\textpm} 1.19 to 1 {\textpm} 0 (not significant), and cholestasis from 3.9 {\textpm} 2.08 to 1.5 {\textpm} .58 (P < .01). Ductopenia, found in 113 of 131 biopsies (93\%), worsened from .63 {\textpm} .35 to .16 {\textpm} .14 (P < .01). On multivariate analysis severe ductopenia (ratio <= .2) was associated with previous chemotherapy (P = .04), in particular with thiotepa, but not with history of GVHD. Vanishing bile duct syndrome after HSCT may be due to drug-induced liver disease. Longer follow-up will reveal whether these patients are prone to late liver-related morbidity and mortality.

}, issn = {1523-6536}, doi = {10.1016/j.bbmt.2018.07.009}, author = {Maximova, Natalia and Sonzogni, Aurelio and Matarazzo, Lorenza and Ghirardi, Arianna and D{\textquoteright}Antiga, Lorenzo} } @article {10854, title = {What is known about deferasirox chelation therapy in pediatric HSCT recipients: two case reports of metabolic acidosis.}, journal = {Ther Clin Risk Manag}, volume = {14}, year = {2018}, month = {2018}, pages = {1649-1655}, abstract = {

To date, in pediatric field, various hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Iron overload and systemic siderosis often occur in this particular cohort of patients and are associated with poor prognosis. We describe herein the case of two allo-HSCT patients, on treatment with deferasirox; they showed histopathological elements compatible with venoocclusive disease or vanishing bile duct syndrome in ductopenic evolution before deferasirox started. The first patient developed drug-induced liver damage with metabolic acidosis and the second one a liver impairment with Fanconi syndrome. After withdrawing deferasirox treatment, both patients showed improvement. Measurements of drug plasma concentrations were performed by HPLC assay. The reduction and consequent disappearance of symptoms after the suspension of deferasirox substantiate its role in inducing hepatic damage, probably enabling the diagnosis of drug-induced liver damage. But the difficulties in diagnosing drug-related toxicity must be underlined, especially in compromised subjects. For these reasons, in patients requiring iron-chelating therapy, close and careful drug therapeutic monitoring is strongly recommended.

}, issn = {1176-6336}, doi = {10.2147/TCRM.S170761}, author = {Fucile, Carmen and Mattioli, Francesca and Marini, Valeria and Gregori, Massimo and Sonzogni, Aurelio and Martelli, Antonietta and Maximova, Natalia} } @article {8510, title = {Hepatic Gadolinium Deposition and Reversibility after Contrast Agent-enhanced MR Imaging of Pediatric Hematopoietic Stem Cell Transplant Recipients.}, journal = {Radiology}, year = {2016}, month = {2016 Jun 8}, pages = {152846}, abstract = {

Purpose To determine if hepatic gadolinium deposition occurs in pediatric patients with iron overload but normal renal and hepatic function who undergo gadolinium-based contrast agent (GBCA)-enhanced magnetic resonance (MR) imaging. Materials and Methods Design and execution of this study was approved by the Ethical Committee of Institute for Research in Maternal and Child Health Burlo Garofolo of Trieste (reference no. 1105/2015). Because of the retrospective nature of the study, the requirement to obtain informed consent was waived. Twenty-one recipients of allogeneic hematopoietic stem cell transplants who underwent GBCA-enhanced MR imaging for suspected infection or relapse followed by liver biopsy comprised the study group. The number of GBCA-enhanced MR examinations and cumulative gadolinium dose for each patient was analyzed by comparing liver histologic analysis and iron and gadolinium liver concentration (GLC). Eight patients had siderosis and underwent chelation therapy. The study group was compared with four control patients who were never exposed to GBCA. Statistical analysis was performed with Spearman rank coefficient for correlation. Results All 21 patients had positive correlations between GLC and total GBCA dose (r = 0.4486; P < .05) and between GLC and liver iron concentration (r = 0.56; P < .05). Patients who underwent deferoxamine therapy had a significant reduction of GLC (from 0.64 μg/g {\textpm} 0.29 to 0.20 μg/g {\textpm} 0.17 [standard deviation]; P < .05). Conclusion In the presence of siderosis, a transmetallation mechanism may be set off between ferric ion and gadoterate meglumine. Deferoxamine appears capable of binding to gadolinium ion. Further studies of the safety of GBCAs in severe siderosis are needed. Chelation should be considered in patients with iron overload and a history of GBCA exposure. ({\textcopyright}) RSNA, 2016.

}, issn = {1527-1315}, doi = {10.1148/radiol.2016152846}, author = {Maximova, Natalia and Gregori, Massimo and Zennaro, Floriana and Sonzogni, Aurelio and Simeone, Roberto and Zanon, Davide} } @article {8492, title = {"Safety and utility of percutaneous liver biopsy in hematopoietic stem cell transplant pediatric recipients: a retrospective study".}, journal = {BMC Cancer}, volume = {16}, year = {2016}, month = {2016}, pages = {590}, abstract = {

BACKGROUND: Liver biopsies in pediatric hematopoietic stem cell transplantation (HSCT) patients are as and effective when performed at bedside in the Bone Marrow Transplant Unit (BMTU) than in the Day Surgery Unit (DSU), with better patient compliance and lower emotional distress for these children.

METHODS: The study group consisted of 45 children who underwent allogeneic HSCT. We reviewed 68 liver biopsies performed between April 2006 and September 2015. 12 (17.6~\%) biopsies were performed in the DSU and 56 (82.3~\%) in the BMTU; nine (13.2~\%) prior to HSCT and 59 (86.7~\%) after HSCT. Pre-procedural behavioral status (subjective score) was evaluated by pediatric transplant physicians by filling in a questionnaire employing a three-point scale: "calm and cooperative", "agitated and non-cooperative" or "frightened and suffering". Objective score was obtained measuring patient{\textquoteright}s heart rate before the procedure and comparing it with mean heart rate.

RESULTS: Patients who underwent the procedure at the BMTU experienced less emotional distress than those who underwent it in the DSU: 58.3~\% of patients treated at the DSU were agitated as compared with 16.1~\% of those treated at the BMTU (p < 0.01). Among the 59 biopsies performed after HSCT, 41 (69.5~\%) were taken from symptomatic patients for a diagnostic purpose and 18 (30.5~\%) in asymptomatic ones in order to rule out hepatic GVHD. Among these 18 procedures, GVHD was diagnosed in 16 (88.9~\%) cases. Minor complications occurred in about 17~\% of procedures (12 biopsies), at a rate of 25~\% for the DSU location compared with 16~\% for the BMTU location. Only two major complications were reported, one in the DSU and one in the BMTU.

CONCLUSION: Liver biopsy performed at bedside in HSCT patients does not carry a higher risk of adverse events than the same procedure performed in the DSU and has lower emotional distress associated with better patient compliance, thus contributing significantly to a higher standard of care.

}, issn = {1471-2407}, doi = {10.1186/s12885-016-2603-8}, author = {Maximova, Natalia and Gregori, Massimo and Barbieri, Francesca and Pizzol, Antonio and Sonzogni, Aurelio} } @article {7706, title = {Metal accumulation in the renal cortex of a pediatric patient with sickle cell disease: a case report and review of the literature.}, journal = {J Pediatr Hematol Oncol}, volume = {37}, year = {2015}, month = {2015 May}, pages = {311-4}, abstract = {

BACKGROUND: Sickle cell disease (SCD) is a well-known multisystem illness characterized by vascular injury due to vasoocclusion and hemolysis, as well as infectious complications and iron overload, all of which contribute to high morbidity and mortality rates among children. In these patients, some authors have previously described iron cortical deposition in the kidney. We here report the first case in the literature of a girl affected by SCD showing an anomalous metal and rare element retention in the renal cortex.

CASE PRESENTATION: A 10-year-old white girl affected by SCD underwent a routine magnetic resonance imaging investigation that evidenced a reduced signal intensity in the renal cortex, compatible with hemosiderin precipitation. Histologic and elemental analyses of the hepatic and the renal biotic samples, performed with inductively coupled plasma mass spectrometry, revealed that concomitant with the high iron deposition, toxic and potentially carcinogenic elements such as nickel, magnesium, rubidium, and gadolinuim were anomalously retained particularly in the kidney.

CONCLUSIONS: The finding of rare and toxic elements in the kidney of SCD patients might be linked to the development of specific neoplastic transformations already described in this patient cohort. To be confirmed, our speculations need to be demonstrated in large sampling of patients.

}, keywords = {Anemia, Sickle Cell, Child, Female, Humans, Kidney Cortex, Metals, Spectrophotometry, Atomic}, issn = {1536-3678}, doi = {10.1097/MPH.0000000000000322}, author = {Maximova, Natalia and Zanon, Davide and Pascolo, Lorella and Zennaro, Floriana and Gregori, Massimo and Grosso, Daniele and Sonzogni, Aurelio} } @article {7704, title = {Polyclonal gammopathy after BKV infection in HSCT recipient: a novel trigger for plasma cells replication?}, journal = {Virol J}, volume = {12}, year = {2015}, month = {2015}, pages = {23}, abstract = {

BACKGROUND: BK polyomavirus infects most of the general population. However, its clinical manifestations are almost exclusively seen in immunocompromised patients, particularly in kidney and hematopoietic stem cell transplantation recipients.

CASE PRESENTATION: A 15-y-old female suffering from common B-cell acute lymphoblastic leukaemia underwent hematopoietic stem cell transplantation. The patient had reactivation of BKPyV infection and developed an haemorrhagic cystitis. Three months after transplant, BKPyV viremia and viruria increased and she developed a severe nephropathy associated to a polyclonal gammopathy with high levels of isolated IgM.

CONCLUSION: This case report describes a rare and unexpected polyclonal gammopathy developed during a polyomavirus-associated nephropathy confirmed by immunohistochemical and laboratory analyses.

}, issn = {1743-422X}, doi = {10.1186/s12985-015-0254-z}, author = {Maximova, Natalia and Pizzol, Antonio and Sonzogni, Aurelio and Gregori, Massimo and Granzotto, Marilena and Tamaro, Paolo} }