Antonio Marzollo

Interleukin‐22 in the diagnosis of active chronic graft‐versus‐host disease in paediatric patients

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Eltrombopag use in a patient with Wiskott-Aldrich syndrome

Wiskott–Aldrich syndrome (WAS) is an inherited X‐linked disorder characterized by microthrombocytopenia, immunodeficiency, and eczema. Hematopoietic stem cell transplantation (HSCT) is the treatment of choice. Eltrombopag, a thrombopoietin receptor agonist, may be useful to prevent bleeding while awaiting HSCT. We present a case of a male with WAS, profound thrombocytopenia, and bleeding diathesis successfully managed with eltrombopag before HSCT. Eltrombopag was given for 32 weeks obtaining a stable platelet count without any platelet transfusion. The patient did not experience any bleeding symptom. Eltrombopag may be a suitable therapeutic option for patients with WAS and severe thrombocytopenia as “bridge” to definitive cure.

Psychopathological Aspects in Childhood Hematopoietic Stem Cell Transplantation (HSCT): The Perception of Parents and Adolescents

Background: Data about psychosocial sequelae of childhood Hematopoietic Stem Cell Transplantation (HSCT) are limited and the association with a specific donor type or other medical factors is largely unknown (Chang et al., 2012). The aim of the present study was to compare the psychological aspects of pediatric HSCT survivors with healthy peers. A secondary aim was to detect whether parents and children differed in the perception of mental health status. The influence of medical factors on psychological status was also examined. Method: Thirty seven HSCT survivors (23 males) with a mean age of 14.4 years (SD = 3.03; range 8.16–18.33) were recruited. Twenty-six patients underwent an allogenic HSCT (matched unrelated donor, n = 20; matched sibling donor, n = 6) and 11 patients received an autologous HSCT. The children psychological aspects were assessed using the Youth Self Report (YSR) (Achenbach and Rescorla, 2001) and compared to a group of matched healthy peers. At the same time, parents were requested to complete the Child Behavior Checklist 6–18 (Achenbach and Rescorla, 2001). Medical and socio-demographic data were also collected. Results: HSCT survivors reported significantly higher levels of somatic complains (t27 = 3.14; p = 0.004; mean = 3.1) when compared to healthy peers (mean = 1.5). The parent CBCL scores on “child total competence” exceeded the normative clinical cutoff in 48.6% cases. Inter-rater agreement between parent and patient reports was present only in three scales: total competence score (K = 0.06, p = 0.002), somatic complaints (K = 0.21, p = 0.003) and attention problems (k = 0.13; p = 0.02). According to Ancova models, internalizing problems were more frequent in HSCT from family donors (F2 = 3.13; p = 0.06) or in the presence of acute complications (F1 = 11.95; p = 0.003). Conclusion: In contrast to the perception of parents, pediatric HSCT survivors reported good psychological health. However, they complained about more somatic problems as compared with healthy peers. Medical aspects such as donor source and the presence of acute complications should be taken into consideration for the psychological approach in order to improve pediatric HSCT survivor care.

Can high dose methotrexate be continued after severe hypersensitivity reaction

To the Editor: We read with great interest the report [1] describing a case of successful readministration of high-dose methotrexate (HD MTX) after a hypersensitivity reaction. We would like to support the conclusions with our own recent experience. A 16-year-old female was diagnosed with a localized osteoblastic osteosarcoma of the right humerus. She had no associated comorbidities and began treatment according to the Italian Sarcoma Group OS-2 (ISG/OS-2) protocol. She received a first course of HD MTX (12 g/m in 4 hours) with normal drug clearance and good tolerance. The second course was complicated by moderately elevated transaminases and emesis. The patient underwent surgery and good histological response to neoadjuvant chemotherapy was documented. Fifteen minutes after completing the infusion of the third course of HD MTX the patient developed abdominal pain, emesis, emission of loose stools, and persistent hypotension. She received fluid resuscitation, two doses of hydrocortisone and two doses of im. adrenaline. After 1 hour, her blood pressure normalized and her clinical symptoms faded. Four hours after completing the infusion, the concentration of MTX in blood was 350mmol/L; at the same time blood tests revealed altered coagulation and elevated liver enzymes (AST 2,905U/L, ALT 2,594U/L). Due to signs of rapid and severe organ damage, the patient was given high-dose calcium levofolinate and glucarpidase; 1 hour after such treatment her MTX level was 9.95mmol/L and reached 0.43mmol/L 32 hours later. Given the importance of HD MTX in the treatment of osteosarcoma, we decided to continue with its administration. The next course was given after premedication with methylprednisolone and chlorphenamine, and the timing of MTX infusion was extended to 6 hours, starting with 400mg of MTX/m/h and gradually increasing the infusion rate. The total dose was unchanged (12 g/m). The patient reported no symptoms or signs during or after the next two MTX infusions, apart from a moderate elevation in liver enzymes. The MTX levels measured in the blood 24 and 48 hours after starting the infusion did not differ substantially from those measured after the first two cycles. Compared with the case reported [1], our patient suffered more severe cardiovascular impairment and liver toxicity. Our experience supports the conclusion that it is not necessary to exclude methotrexate from the treatment plan after an even severe hypersensitivity reaction. This may be a crucial issue for osteosarcoma patients because methotrexate is essential to their treatment. Giving adequate premedication, prolonging the infusion time from 4 to 6 hours and increasing the infusion rate gradually seem to allow safe re-administration of HD MTX.

Cerebral Lymphoproliferation in a Patient with Kabuki Syndrome

To the Editor Kabuki syndrome (KS) is a multi-systemic inherited disorder characterized by distinctive facial features, cardiac and skeletal abnormalities, developmental delay, growth retardation, and neurosensorial hearing loss. Facial features include long palpebral fissures, everted lower eyelids, arched eyebrows, short columella with depressed nasal tip and prominent or cupped ears. Immune deficiency has been reported in patients with KS and results in a predisposition to upper and lower respiratory tract infections, recurrent or chronic otitis media, autoimmune cytopenia and vitiligo. Two thirds of patients have IgA deficiency and half of patients have low IgG levels [1]. Most patients have reduced CD4+ T cells, low memory B cells, and impaired antibody response to vaccination [2]. Tcell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) levels and T cell proliferation after stimulus with mitogens are normal [2]. Autosomal dominant mutations in the KMT2D gene, resulting in impaired histone methylation and acetylation, are the most frequent cause of KS [1]. In order to expand the knowledge concerning the immunological phenotype of KS, we here report a KS patient with immune deficiency and autoimmunity, complicated by cerebral lymphocytic infiltrates. The patient was born from non-consanguineous parents of Northern Italian origin after in vitro fertilization. Her twin brother is healthy and the remaining family history is unremarkable. At birth, single umbilical artery, narrow bifrontal diameter, relative hypertelorism, posteriorly rotated ears, broad nose, and high arched palate were noted. The patient underwent cardiac surgery at the age of 45 days for the repair of a large interventricular defect. From the second year of life, the patient showed developmental delay and attention deficit without hyperactivity. Concomitantly, she was diagnosed with immune thrombocytopenia (ITP) and treated with high-dose intravenous immunoglobulin (IgIV) with a rapid and complete recovery. During the following 3 years, four relapses of ITP occurred and were treated with high-dose IgIV and a short course of steroid therapy. From the age of 4 years, the patient experienced three episodes of pneumonia requiring intravenous antibiotic treatment and more than ten episodes per year of otitis media with perforation despite adenoidectomy and antibiotic prophylaxis. At the age of 5 years, partial IgA deficiency, IgG2 deficiency, and poor antibody response to vaccines were noted. IgG levels were initially normal but progressively declined, reaching 4.21 g/L at the age of 9 when immunoglobulin substitution was initiated. Lymphocyte counts were normal, but lymphocyte subset analysis revealed mild CD4+ lymphopenia (570/μL, normal value 650–1520), reduced CD3+CD4+CD25brCD45RA-Treg cells (0.1%, n.v. 0.5– 1%), reduced CD4+ naïve cells (28%, n.v. 54–74%), modestly elevated CD4−CD8−TCRαβ+ Tcells (4% of the CD3+ cells), and reduced CD27+IgD−memory B cells (1.6%, n.v. 3–18%). The detailed immunological phenotype is shown in Online Resource 1. Direct antiglobulin test was repeatedly positive while all other tested autoantibodies were negative. Fas-mediated apoptosis assay and DEB test were normal. At the age of 9 years, the patient presented with refractory status epilepticus and required admission to intensive care unit. Brain magnetic resonance imaging (MRI) showed contrast-enhanced lesions in the cortical-subcortical left frontal region and bulbar region, and a leptomeningeal enhancement in the right posterior parietal region (Fig. 1a). Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-018-0516-9) contains supplementary material, which is available to authorized users.

Haploidentical stem cell transplantation cures autoimmune hepatitis and cerebrovascular disease in a patient with sickle cell disease

Sickle Cell Disease (SCD) may lead to several acute and chronic complications and the end-organ damage may be aggravated by co-existing conditions. [1] Among SCD patients, autoimmune disorders, such as autoimmune hepatitis (AIH) or systemic lupus erythematosus, are not infrequent and are difficult to treat due to the high risk of adverse events associated with steroids or other immunosuppressive treatments. [2–4] Hematopoietic Stem Cell Transplantation (HSCT) is the most consolidated curative therapy for patients with SCD, but benefits and risks in both the short and long term must be carefully considered, taking into consideration disease variability and the recent appearance of new drugs. Despite the progressive broadening of indications for HSCT, [5] the majority of pediatric haematologists still offers it only to patients with a severe phenotype: cerebrovascular disease, recurrent vasoocclusive crises (VOC) or acute chest syndrome not responsive to Hydroxycarbamide, or sickle nephropathy. [6, 7] HSCT is also an option for the management of severe autoimmune disorders such as multiple sclerosis, systemic sclerosis and rheumatoid arthritis, but it has not been previously reported for autoimmune hepatitis. [8] We report a patient with SCD and AIH, both cured after HSCT. Our patient was diagnosed with HbSS SCD at the age of 4 years when she was hospitalized for severe haemolytic anaemia. At the age of 7 years, Trans-Cranial Doppler (TCD) showed a velocity >200 cm/s in both the middle cerebral arteries and the basilar artery with a normal brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). The patient began a regular blood transfusion program for stroke prevention, which was changed to monthly red cell exchange transfusions (ECA) at the age of 8 years when adequate venous lines could be placed. At the age of 11 years, severe stenosis of the carotid syphon and middle cerebral arteries and moderate stenosis of the anterior cerebral arteries seen on MRA (Fig. 1a) prompted ECA to be scheduled every three weeks to maintain HbS under 30%. At the age of 13 years, MRI/ MRA showed a minimal reduction of arterial stenosis with a concomitant normalization of TCD, which was confirmed two years later. No clinical or subclinical stroke occurred. At the age of 13 years the patient was hospitalised for cholestatic jaundice (total bilirubin 277.1 μmol/L, conjugated bilirubin 171.2 μmol/L) and elevation of liver enzymes (AST 1188 U/L, ALT 74 U/L and GGT 188 U/L). Liver infection, liver sequestration and disorders of the biliary tree were excluded by appropriate investigations including magnetic resonance cholangio-pancreatography. Anti-nuclear and anti-smooth muscle antibodies resulted positive at a titer of 1:320 and >1:80 respectively, and hypergammaglobulinemia was noticed (IgG 25 g/L). The diagnosis of type I AIH was confirmed by liver histology, which showed portal and peri-portal fibrosis, portal inflammatory infiltrates (mostly constituted of lymphocytes and plasma cells) and focal areas of necrosis (Fig. 2). Treatment with prednisolone was initiated with prompt normalization of liver enzymes and resolution of cholestasis, and one month later azathioprine was added after having excluded TPMT variants. Steroid treatment was Raffaella Colombatti and Laura Sainati contributed equally to the work.

Outcomes of Children with Hemophagocytic Lymphohistiocytosis Given Allogeneic Hematopoietic Stem Cell Transplantation in Italy

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34+ cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft.

Risk Factors and Outcomes Related to Pediatric Intensive Care Unit Admission after Hematopoietic Stem Cell Transplantation: A Single-Center Experience

To describe incidence, causes, and outcomes related to pediatric intensive care unit (PICU) admission for patients undergoing hematopoietic stem cell transplantation (HSCT), we investigated the risk factors predisposing to PICU admission and prognostic factors in terms of patient survival. From October 1998 to April 2015, 496 children and young adults (0 to 23 years) underwent transplantation in the HSCT unit. Among them, 70 (14.1%) were admitted to PICU. The 3-year cumulative incidence of PICU admission was 14.3%. The main causes of PICU admission were respiratory failure (36%), multiple organ failure (16%), and septic shock (13%). The overall 90-day cumulative probability of survival after PICU admission was 34.3% (95% confidence interval, 24.8% to 47.4%). In multivariate analysis, risk factors predisposing to PICU admission were allogeneic HSCT (versus autologous HSCT, P = .030) and second or third HSCT (P = .018). Characteristics significantly associated with mortality were mismatched HSCT (P = .011), relapse of underlying disease before PICU admission (P < .001), acute respiratory distress syndrome at admission (P = .012), hepatic failure at admission (P = .021), and need for invasive ventilation during PICU course (P < .001). Our data indicate which patients have a high risk for PICU admission after HSCT and for dismal outcomes after PICU stay. These findings may provide support for the clinical decision-making process on the opportunity of PICU admission for severely compromised patients after HSCT.

Automated peritoneal dialysis-related peritonitis due to Salmonella enteritidis in a pediatric patient

Peritoneal dialysis (PD) represents the preferred renal replacement therapy in pediatric patients; however, the younger the age at PD initiation, the greater the risk of PD-related infections. We present here the first case report of a 14-year-old girl with automated peritoneal dialysis-related Salmonella enteritidis peritonitis. The child responded only partially to an appropriate course of antibiotic therapy;the PD catheter was therefore removed and the patient shifted to hemodialysis. Along with the clinical course description, we review the mechanisms by which this group of Salmonella could infect the peritoneal cavity in patients on PD. Pediatric nephrologists should be aware that peritoneal catheter removal is often required for the complete resolution of this type of bacterial peritonitis.