E. Lanino

Treatment of advanced neuroblastoma with I-131 meta-iodobenzylguanidine.

From February 1986 to December 1988, 31 children with advanced pretreated neuroblastoma were treated with 131‐I meta‐Iodobenzylguanidine (131‐MIBG). Thirteen children had been resistant to first‐line therapy, three had suffered a local relapse, and fourteen had suffered a disseminated relapse without overt bone marrow infiltration. One child was treated initially because of resistance to first‐line therapy, and subsequently for a local relapse. A total of 72 courses of 131‐MIBG was administered, with doses ranging from 2.8 to 6.0 GBq (median, 3.7 GBq). One child received five courses, two four courses, 13 three courses, four two courses, and 12 one course of 131‐MIBG. The most common toxic effect was thrombocytopenia, with a platelet level of less than 50,000/cmm occurring after 19 of 60 evaluable courses. A leukocyte count less than 1000/cmm was seen only once. There were six major responses (two complete) lasting 4 to 9 months, and two minor responses lasting longer than 38 and 44 months. Responses were seen more commonly in children whose only lesion was a residual primary tumor and in children who had not been pretreated who experienced disseminated relapse. Further studies of the role of 131‐I meta‐Iodobenzylguanidine in treatment of neuroblastoma are needed.

Cytogenetic and molecular study of two human neuroblastoma cell lines

Long-term cell cultures (GI-LA-N and GI-ME-N) were established from the metastases of two disseminated neuroblastomas (NB). The first was obtained from a lymph node biopsy of a stage III NB after 7 months of chemotherapy, and the second from a bone marrow specimen of a stage IV NB after 6 months of chemotherapy. Cytogenetic investigation revealed several structural and numerical alterations in both cell cultures, but the only common chromosomal aberration was partial monosomy of 1p. Moreover, at the 5th in vitro passage, GI-LA-N displayed a high number of double minutes, not seen in GI-ME-N even after 33 subcultures. Molecular analysis revealed N-myc oncogene amplification in GI-LA-N cells, whereas, only one copy was found in GI-ME-N. No structural N-myc rearrangement was detected in either cell culture.

Osteochondroma after Hematopoietic Stem Cell Transplantation in Childhood. An Italian Study on Behalf of the AIEOP-HSCT Group

A retrospective study was conducted among Italian children treated with hematopoietic stem cell transplant (HSCT) to evaluate the incidence and risk factors in the development of osteochondroma (OC). OC occurred in 27 patients who received autologous or allogeneic HSCT. The estimated 5-, 10-, and 15-year cumulative risk of developing OC was 0.5%, 3.2%, and 6.1%, respectively. Analysis of cumulative risk stratified by the various risk factors revealed that male sex (P=.026), autologous HSCT (P=.001), age at HSCT (< or =3 years) (P < .0001), and total body irradiation (TBI) (P <.0001) significantly affected the risk of OC. Multivariate analysis, restricted only to tumor types with at least 1 case of OC, showed that earlier age at HSCT (P =.0004) and TBI (P < .0001) were the only factors that were significantly associated with OC.

Open issues in Mucopolysaccharidosis type I-Hurler

Mucopolysaccharidosis I-Hurler (MPS I-H) is the most severe form of a metabolic genetic disease caused by mutations of IDUA gene encoding the lysosomal α-L-iduronidase enzyme. MPS I-H is a rare, life-threatening disease, evolving in multisystem morbidity including progressive neurological disease, upper airway obstruction, skeletal deformity and cardiomyopathy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the gold standard for the treatment of MPS I-H in patients diagnosed and treated before 2–2.5xa0years of age, having a high rate of success. Beyond the child’s age, other factors influence the probability of treatment success, including the selection of patients, of graft source and the donor type employed. Enzyme replacement therapy (ERT) with human recombinant laronidase has also been demonstrated to be effective in ameliorating the clinical conditions of pre-transplant MPS I-H patients and in improving HSCT outcome, by peri-transplant co-administration. Nevertheless the long-term clinical outcome even after successful HSCT varies considerably, with a persisting residual disease burden. Other strategies must then be considered to improve the outcome of these patients: one is to pursue early pre-symptomatic diagnosis through newborn screening and another one is the identification of novel treatments. In this perspective, even though newborn screening can be envisaged as a future attractive perspective, presently the best path to be pursued embraces an improved awareness of signs and symptoms of the disorder by primary care providers and pediatricians, in order for the patients’ timely referral to a qualified reference center. Furthermore, sensitive new biochemical markers must be identified to better define the clinical severity of the disease at birth, to support clinical judgement during the follow-up and to compare the effects of the different therapies. A prolonged neuropsychological follow-up of post-transplant cognitive development of children and residual disease burden is needed. In this perspective, the reference center must guarantee a multidisciplinary follow-up with an expert team. Diagnostic and interventional protocols of reference centers should be standardized whenever possible to allow comparison of clinical data and evaluation of results. This review will focus on all these critical issues related to the management of MPS I-H.

Nitazoxanide or CD3+/CD4+ lymphocytes for recovery from severe Cryptosporidium infection after allogeneic bone marrow transplant?

Abstract:u2002 We describe a case of Cryptosporidium infection occurring in a child after allogeneic SCT for acute non‐lymphoblastic leukemia. This patient presented an intestinal, biliar, and pancreatic Cryptosporidium disease associated with an intestinal aGvHD. The increase in CD3+/CD4+ cells secondary to the reduction of steroid therapy associated with the improvement of aGvHD and the use of antiparasitic treatments (especially nitazoxanide) improved the infection‐related symptoms and led to a complete clearance of the Cryptosporidium.

Hepatitis B reactivation in allogeneic hemopoietic stem cell transplantation setting: A pediatric experience

Abstract:u2002 Reactivation of HBV is a well known complication in patients undergoing HSCT. Lamivudine treatment appears to prevent hepatitis B virus reactivation and to decrease the mortality in at risk HSCT patients. We describe HBV reactivation occurred in three allogeneic HSCT pediatric patients coming from Eastern Europe, one of whom was successfully treated with lamivudine. Our experience confirms that HBV‐DNA may persist as intra‐hepatic infection or in extra‐hepatic sites and that HBV reactivation may appear during immunodepression. Careful and complete screening for HBV markers is mandatory before HSCT, especially in children coming from countries at risk for HBV. Furthermore, a treatment with lamivudine could also represent an efficacious prophylaxis in pediatric patients to avoid HBV reactivation and to decrease the development of severe hepatic disease.

Prophylaxis of streptococcal bacteraemia with oral penicillin V in children undergoing bone marrow transplantation.

The work described aimed to evaluate the incidence of streptococcal bacteraemia in children undergoing bone marrow transplantation and receiving prophylaxis with penicillin V. From January 1991 to December 1993 oral penicillin V was administered as prophylaxis for streptococcal bacteraemia to patients undergoing bone marrow transplantation at G. Gaslini Childrens Hospital, Genoa, Italy. The data were compared with those from a similar population receiving bone marrow transplantation from September 1984 to July 1990 and not receiving this kind of prophylaxis. Streptococcal bacteraemia was diagnosed in 7/17 (41%) episodes of bacteraemia observed in the period January 1991 to December 1993, while it accounted for 71% of all bacteraemias in the period from September 1984 to July 1990 and was especially frequent from January 1988 to July 1990, comprising 13/15 (87%) of observed bacteremias. The decrease of this complication observed after the beginning of the prophylaxis programme was statistically significant. Oral penicillin V is effective as prophylaxis of streptococcal bacteraemias in children receiving bone marrow transplantation in a centre with a high incidence of this complication.

Helicobacter pylori as cause of gastrointestinal disease in children with hemato-oncologic diseases

After documentation of a case of life threatening Helicobacter pylori (H. pylori) gastric ulcer in an adolescent girl on treatment for acute lymphoblastic leukaemia, we started to systematically look for gastro‐intestinal symptoms due to H. pylori infection in our cancer patients at G. Gaslini Childrens Hospital. During a period of 46 months, we observed 13 further cases of severe dyspepsia syndrome or gastro intestinal bleeding associated with presence of H. pylori faecal antigen. All patients recovered with appropriate therapy. H. pylori may represent a cause of severe gastrointestinal complications in children with cancer or following bone marrow transplant.

Treatment of Poor-Risk Neuroblastoma with Intensive Chemotherapy and Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor

Advanced neuroblastoma is one of the most lethal pediatric malignancies. Several antitumor compounds are able to induce tumor regression, and a dose-response relationship has been demonstrated for some of them. A significant improvement in both response rate and duration of survival has thus been obtained by treatment intensification [1–4]. In the Italian experience, the median survival time of children treated with aggressive chemotherapy has been doubled compared with historical controls [5]. However, the higher initial response rate and the prolonged remission time has resulted in only a marginal improvement in cure rate, presently not exceeding 25% [6, 7]. Hematopoietic growth factors (colony-stimulating factors, CSFs), by mitigating the myelotoxic effect of chemotherapy, may reduce the treatment-related morbidity and thus permit the delivery of higher dosages and the shortening of intervals between chemotherapy courses [8, 9].

Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease after Autologous or Allogeneic Hematopoietic Stem Cell Transplantation in Children: A Retrospective Study of the Italian Hematology-Oncology Association–Hematopoietic Stem Cell Transplantation Group

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially life-threatening complication that may develop after hematopoietic stem cell transplantation (HSCT). The aims of this retrospective multicenter study were to evaluate the incidence of SOS/VOD in a large cohort of children transplanted in centers across Italy by applying the new European Society for Blood and Marrow Transplantation (EBMT) criteria and to analyze the risk factors underlying this complication. We retrospectively reviewed data of pediatric HSCTs performed in 13 AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica)-affiliated centers between January 2000 and April 2016. The new pediatric EBMT criteria were retrospectively applied for diagnoses of SOS/VOD and severity grading. Among 5072 transplants considered at risk for SOS/VOD during the study period, 103 children (2%) developed SOS/VOD, and the grade was severe or very severe in all patients. The median time of SOS/VOD occurrence was 17 days after HSCT (range, 1 to 104). Sixty-nine patients (67%) were treated with defibrotide for a median time of 16 days (range, 4 to 104). In multivariable analysis age < 2 years, use of busulfan during the conditioning regimen, female gender, and hemophagocytic lymphohistiocytosis were risk factors statistically associated with the development of SOS/VOD. The overall mortality directly related to SOS/VOD was 15.5%. Overall survival at 1 year was worse in patients with SOS/VOD (Pu202f=u202f.0033), and this difference disappeared 5 years after HSCT. Nonrelapse mortality was significantly higher 1 and 5 years after transplantation in patients who developed SOS/VOD (P < .001). Based on the application of new EBMT criteria, the overall incidence of SOS/VOD recorded in this large Italian pediatric retrospective study was 2%. Nonrelapse mortality was significantly higher in patients who developed SOS/VOD. Identifying the risk factors associated with SOS/VOD can lead to more effective early treatment strategies of this potentially fatal HSCT complication in childhood.