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Background: Respiratory viral infections may be associated with high morbidity and mortality among immunosuppressed children. Our aim was to characterize clinical course and epidemiology of respiratory infections suspected as viral among children treated in a single hematology-oncology department in a tertiary hospital. Methods: Prospective, observational study during 1.10.2014–1.10.2015. All children with respiratory infection event in the Pediatric Hematology-oncology department at the Ruth Rappaport Children Hospital, Haifa, who were tested for respiratory viruses, were included. Collected data included signs and symptoms, pathogens, background disease, epidemiological characteristics, complications and duration of illness. Viruses were detected by molecular methods. Results: 159 events were observed among 102 children (55 males). Age range: 3 months-19 years. Single event was observed in 62%. In 79 events (50%) a respiratory virus was detected. Children who underwent allogeneic bone marrow transplantation had more events compared with those with other diseases (58% vs. 32%, p = 0.018). Viral detection was positively associated with symptoms of cough and rhinitis (p

Fanconi anemia (FA), an inherited bone marrow failure (BMF) syndrome, caused by mutations in DNA repair genes, is characterized by congenital anomalies, aplastic anemia, high risk of malignancies and extreme sensitivity to alkylating agents. We aimed to study the clinical presentation, molecular diagnosis and genotype-phenotype correlation among patients with FA from the Israeli inherited BMF registry. Overall, 111 patients of Arab (57%) and Jewish (43%) descent were followed for a median of 15 years (range: 0.1-49); 63% were offspring of consanguineous parents. One-hundred patients (90%) had at least one congenital anomaly; over 80% of the patients developed bone marrow failure; 53% underwent hematopoietic stem-cell transplantation; 33% of the patients developed cancer; no significant association was found between hematopoietic stem-cell transplant and solid tumor development. Nearly 95% of the patients tested had confirmed mutations in the Fanconi genes FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%), including twenty novel mutations. Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001); however, the overall survival did not depend on the causative gene. We hereby describe a large national cohort of patients with FA, the vast majority genetically diagnosed. Our results suggest an older age for cancer development in patients with FANCA mutations and no increased incidence of solid tumors following hematopoietic stem-cell transplant. Further studies are needed to guide individual treatment and follow-up programs.

Neuroblastoma is the most common non-central nervous system (CNS) solid malignant tumor in children. The surgical treatment of high-risk neuroblastoma presents a challenge, and the benefits of aggressive surgical resection have been called into question.To examine our experience with surgical resection of neuroblastoma.We report on a retrospective chart review of our preliminary surgical experience in 25 patients with neuroblastoma who underwent surgery performed by a single surgeon at two institutions over a 3 year period. Demographic data, including stage of tumor and risk stratification, were recorded. Primary outcome was total gross resection. Patients were followed for 3 years after surgery.We found that 80% of the patients, including those with high-risk neuroblastoma tumors, had total gross resection of their tumor with minimal operative morbidity and no mortality; 88% had greater than 90% resection of their tumor. Overall, 3 year survival was 84% (21/25).Resection of neuroblastoma, even large, high-risk, bilateral tumors, was possible when performed by surgical teams with considerable experience.

Although the role of MYCN amplification in neuroblastoma is well established, the biological and clinical characteristics of the 2p gain region harboring the MYCN gene remain unclear. The aim of this study was to compare the biological and clinical characteristics of these tumors with MYCN amplified and nonamplified neuroblastoma and to determine their impact on disease outcome. Samples from 177 patients were analyzed by fluorescence in situ hybridization, including MYCN, 1p, 17q, and 11q regions; 2p gain was identified in 25 patients, MYCN amplification in 31, and no amplification in 121 patients. Patients with 2p gain had a significantly worse 5-year event-free survival rate than patients with no MYCN amplified (P < 0.001), and an intermediate 5-year overall survival rate difference existed between the MYCN amplified tumors (P = 0.025) and nonamplified (P = 0.003) groups. All of the 2p gain samples were associated with segmental and/or numerical alterations in the other tested regions. The presence of segmental alterations with or without MYCN amplification was recently found to be the strongest predictor of relapse in a multivariate analysis. The results of the present study suggest that the determination of MYCN gene copy number relative to chromosome 2, when evaluating MYCN status at diagnosis, may help to reveal the underlying genetic pattern of these tumors and better understand their clinical behavior.

Background Inherited bone marrow failure syndromes are rare genetic disorders characterized by bone marrow failure, congenital anomalies, and cancer predisposition. Available single disease registries provide reliable information regarding natural history, efficacy and side effects of treatments, and contribute to the discovery of the causative genes. However, these registries could not shed light on the true incidence of the various syndromes. We, therefore, established an Israeli national registry in order to investigate the relative frequency of each of these syndromes and their complications. Design and methods Patients were registered by their hematologists in all 16 medical centers in Israel. We included patients with Fanconi anemia, severe congenital neutropenia, Diamond-Blackfan anemia, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, Shwachman-Diamond syndrome, and thrombocytopenia with absent radii. Results One hundred and twenty-seven patients diagnosed between 1966 and 2007 were registered. Fifty-two percent were found to have Fanconi anemia, 17% severe congenital neutropenia, 14% Diamond-Blackfan anemia, 6% congenital amegakaryocytic thrombocytopenia, 5% dyskeratosis congenita, 2% Shwachman-Diamond syndrome, and 2% thrombocytopenia with absent radii. No specific diagnosis was made in only 2 patients. Of the thirty patients (24%) developing severe bone marrow failure, 80% had Fanconi anemia. Seven of 9 patients with leukemia had Fanconi anemia, as did all 6 with solid tumors. Thirty-four patients died from their disease; 25 (74%) had Fanconi anemia and 6 (17%) had severe congenital neutropenia. Conclusions This is the first comprehensive population-based study evaluating the incidence and complications of the different inherited bone marrow failure syndromes. By far the most common disease was Fanconi anemia, followed by severe congenital neutropenia and Diamond-Blackfan anemia. Fanconi anemia carried the worst prognosis, with severe bone marrow failure and cancer susceptibility. Diamond-Blackfan anemia had the best prognosis. The data presented provide a rational basis for prevention programs and longitudinal surveillance of the complications of inherited bone marrow failure syndromes.

PET/CT with 18F-FDG is an important noninvasive diagnostic tool for management of patients with lymphoma, and its use may surpass current guideline recommendations. The aim of the present study is to enlarge the growing body of evidence concerning 18F-FDG avidity of lymphoma to provide a basis for future guidelines. Methods: The reports from 18F-FDG PET/CT studies performed in a single center for staging of 1,093 patients with newly diagnosed Hodgkin disease and non-Hodgkin lymphoma between 2001 and 2008 were reviewed for the presence of 18F-FDG avidity. Of these patients, 766 patients with a histopathologic diagnosis verified according to the World Health Organization classification were included in the final analysis. 18F-FDG avidity was defined as the presence of at least 1 focus of 18F-FDG uptake reported as a disease site. Nonavidity was defined as disease proven by clinical examination, conventional imaging modalities, and histopathology with no 18F-FDG uptake in any of the involved sites. Results: At least one 18F-FDG–avid lymphoma site was reported for 718 patient studies (94%). Forty-eight patients (6%) had lymphoma not avid for 18F-FDG. 18F-FDG avidity was found in all patients (100%) with Hodgkin disease (n = 233), Burkitt lymphoma (n = 18), mantle cell lymphoma (n = 14), nodal marginal zone lymphoma (n = 8), and lymphoblastic lymphoma (n = 6). An 18F-FDG avidity of 97% was found in patients with diffuse large B-cell lymphoma (216/222), 95% for follicular lymphoma (133/140), 85% for T-cell lymphoma (34/40), 83% for small lymphocytic lymphoma (24/29), and 55% for extranodal marginal zone lymphoma (29/53). Conclusion: The present study indicated that with the exception of extranodal marginal zone lymphoma and small lymphocytic lymphoma, most lymphoma subtypes have high 18F-FDG avidity. The cumulating evidence consistently showing high 18F-FDG avidity in the potentially curable Burkitt, natural killer/T-cell, and anaplastic large T-cell lymphoma subtypes justifies further investigations of the utility of 18F-FDG PET in these diseases at presentation.

Heparanase is an endoglycosidase that specifically cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans, the major proteoglycan in the extracellular matrix (ECM) and cell surfaces. Heparanase upregulation was documented in an increasing number of primary human tumors, correlating with reduced postoperative survival rate and enhanced tumor angiogenesis. The purpose of the current study was to determine heparanase levels in blood samples collected from pediatric cancer patients using an ELISA method. Heparanase levels were elevated four-fold in the plasma of cancer patients compared with healthy controls (664 ± 143 vs 163 ± 18 pg/ml, respectively). Evaluating plasma samples following anticancer therapy revealed reduced heparanase levels (664 ± 143 vs 429 ± 82 pg/ml), differences that are statistically highly significant (P = .0048). Of the 55 patients with complete remission (CR) or very good partial remission (VGPR) at restaging, 41 (74.5%) had lower heparanase amounts, whereas 14 patients (25.5%) had similar or higher amounts of plasma heparanase. All nine patients with stable or advancing disease had similar or elevated levels of heparanase on restaging. The results show that heparanase levels are elevated in the plasma of pediatric cancer patients and closely correlate with treatment responsiveness, indicating that heparanase levels can be used to diagnose and monitor patient's response to anticancer treatment.

In an attempt to abrogate the deleterious effects of graft-versus-host disease (GVHD), allogeneic transplantation for nonmalignant diseases was performed using high-dose CD34-cell infusion, partial T cell depletion, and no posttransplantation GVHD prophylaxis. Between 1998 and 2004, 16 patients with matched related donors were treated. Median age was 1.5 years (range, 5 months-18 years). The conditioning regimen consisted of busulphan 16 mg/kg, cyclophosphamide 200 mg/kg, antithymocyte globulin (ATG) 25 mg/kg, and fludarabine 200 mg/m 2 . No GVHD prophylaxis was given. High doses of CD34 cells, positively selected by immunomagnetic beads, were infused at a median dose of 10.7 × 10 6 CD34/kg (range, 7.4-50 × 10 6 ). A total of 1 × 10 5 /kg T cells were given. All patients engrafted, with no graft rejections. All were alive and well at a median of 37 months posttransplantation (range, 18-89 months). Only 1 patient developed chronic GVHD. No episodes of severe infection occurred during or after transplantation. Immunologic reconstitution with CD3/CD4 T cells > 200/μL was observed at a median of 117 days and that with naive T cells (CD4/CD45RA) at a median of 188 days posttransplantation. Our findings suggest that allogeneic transplantation from a matched family donor for nonmalignant disorders can be successfully performed using high doses of CD34 cells, moderate T cell depletion, and no posttransplantation immunosuppression.

Palliative treatment ore remains a significant clinical problem.To retrospectively determine the clinical response to 131I-MIBG therapy at low doses in patients with refractory neuroblastoma.We performed a retrospective chart review of 10 patients with neuroblastoma treated with 1311-MIBG at Rambam Health Care Campus from 1994 to 2012. Clinical data, number of 131I-MIBG courses delivered, toxicities, and clinical responses were reviewed. MIBG scan was performed after each course.Twenty-one courses of 131I-MIBG were delivered to 10 patients (3 girls, 7 boys). Their mean age was 3.8 years (range 1.5-6 years). All patients received several protocols of chemotherapy including the high dose form. Three patients received three courses of 131I-MIBG with a minimum of 6 weeks between each course, five patients received two courses, and two patients received only one course. An objective response to the first course was obtained in nine patients and to the second course in six of eight, and in three children who underwent the third course the pain decreased. One patient has no evidence of disease, four are alive with disease, and five died of the disease. No unanticipated toxicities were observed.Low dose 131I-MIBG is an effective and relatively non-toxic treatment in neuroblastoma disease palliation. Rapid and reproducible pain relief with 131I-MIBG was obtained in most of the children. Treatment with systemic radiotherapy in the form of low dose 131I-MIBG was easy to perform and effective in cases of disseminated neuroblastoma, demonstrating that this primary therapy can be used for palliative purposes.

Survival in T cell lymphoblastic lymphoma has improved over the past 30 years, largely due to treatment protocols derived from regimens designed for children with acute lymphoblastic leukemia.To assess the outcome of the NHL-BFM-95 protocol in children and adolescents hospitalized during the period 1999-2006.We conducted a retrospective multi-institutional, non-randomized study of children and adolescents up to age 21 with T cell lymphoma admitted to pediatric departments in six hospitals in Israel, with regard to prevalence, clinical characteristics, pathological characteristics, prognostic factors, overall survival (OS) and event-free survival (EFS). All patients had a minimal follow-up of one year after diagnosis. The study was based on the NHL-BFM-95 protocol.At a median follow-up of 4 years (range 1-9 years), OS and EFS for all patients was 86.5% and 83.8%, respectively. OS was 86.7% and 83.3% for patients with stage III and stage IV, respectively, and EFS was 83.3% and 83.3%, respectively. EFS was 62.5% for Arab patients and 89.7% for Jewish patients (P = 0.014). Patients who did not express CD45 antigen showed superior survival (P = 0.028). Five patients (13.5%) relapsed, four of whom died of their disease. Death as a consequence of therapy toxicity was documented in one patient while on the re-induction protocol (protocol IIA).Our study shows that OS and EFS for all patients was 86.5% and 83.8%, respectively.

Although the role of MYCN amplification in neuroblastoma is well established, the biological and clinical characteristics of the 2p gain region harboring the MYCN gene remain unclear. The aim of this study was to compare the biological and clinical characteristics of these tumors with MYCN amplified and nonamplified neuroblastoma and to determine their impact on disease outcome. Samples from 177 patients were analyzed by fluorescence in situ hybridization, including MYCN, 1p, 17q, and 11q regions; 2p gain was identified in 25 patients, MYCN amplification in 31, and no amplification in 121 patients. Patients with 2p gain had a significantly worse 5-year event-free survival rate than patients with no MYCN amplified (P < 0.001), and an intermediate 5-year overall survival rate difference existed between the MYCN amplified tumors (P = 0.025) and nonamplified (P = 0.003) groups. All of the 2p gain samples were associated with segmental and/or numerical alterations in the other tested regions. The presence of segmental alterations with or without MYCN amplification was recently found to be the strongest predictor of relapse in a multivariate analysis. The results of the present study suggest that the determination of MYCN gene copy number relative to chromosome 2, when evaluating MYCN status at diagnosis, may help to reveal the underlying genetic pattern of these tumors and better understand their clinical behavior.

Febrile neutropenia (FN) is a common complication among children undergoing chemotherapy for hematologic malignancies. A microbial agent is identified in 15–30% of these episodes. Recently, several studies reported a high incidence (25% -60%) of respiratory viral infections (RVI) in children with FN, using RT- PCR analysis. Implementation of routine RVI workup in children with FN was suggested, in order to minimize the overuse of antibiotics. However, data on the incidence of RVI in children with persistent FN (PFN) is meager. In the setting of PFN, invasive fungal infection (IFI) is a major concern. The incidence of IFI among children with hematologic malignancies varies with clinical settings, although most children who present with PFN do not have IFI eventually. Yet, most international guidelines indicate empiric initiation of antifungal therapy after 4-7 days of FN. Alternatively, a “preemptive” approach using currently available diagnostic modalities (CT and serum specific biomarkers) was suggested in adult patients. In children with PFN, however, this workup resulted only in a modest decline in the antifungal treatment rate. Therefore, there is a growing need to enhance diagnostic resolution, in order to stratify pediatric patients according to their risk for IFI, and minimize the overuse of antifungal drugs, imaging, and invasive procedures. To the best of our knowledge, there are no studies comparing the incidence of RVI to that of IFI in the setting of PFN. Based on previous published data, we hypothesized that RV infection is a significant cause of PFN in children with hematologic malignancies, and that IFI is the cause in a minority of cases. We further aimed to investigate whether detection of RVI, as the cause of PFN in these children, would affect their risk of IFI. For that purpose, we analyzed the clinical charts of children (38oc, for >96 hours and ≤500ANC/µl) and documented PCR results of RV. Patients were considered positive for IFI if they had ‘possible’, ‘probable’ or ‘proven’ infection according to the revised EORTC definition (2008). RVI were detected in nasopharyngeal aspirates using RT-PCR and included: RSV, Influenza A/B, H1N1, Parainfluenza 1/2/3, HMPV, Adenovirus and HHV-6. Additional data included age and gender, specific hematologic malignancy, total number of neutropenia ( A total number of 75 PFN episodes were evaluable, representing 54 patients with ALL (HR n=18; SR n=23), AML (n=6), NHL (n=5) or Hodgkin’s (n=2). Of these, there were 31 episodes with RV-positive infections (41.3%). The most prevalent virus was RSV (29%), followed by Parainfluenza (26%) and Adenovirus (19%).There were 16 possible (21%), 2 probable (2.6%), and 2 proven (2.6%) episodes of IFI. Only in 3 episodes we detected co-infection of IFI (2 possible and 1 probable) and RVI. Multivariate analysis revealed that the total days of neutropenia and antibiotic therapy were independent risk-factors for IFI (p Children with PFN and RVI have a significantly lower risk for IFI. This observation may reduce unnecessary imaging and invasive procedures, antifungal treatment, and hospital expanses. Further studies are needed in order to establish whether RV-status can be implemented in the routine workup algorithm of PFN in children with hematologic malignancies. Disclosures No relevant conflicts of interest to declare.

Inherited bone marrow failures syndromes (IBMFS) are rare genetic disorders usually characterized by congenital anomalies, development of bone marrow failure and a tendency to develop malignant diseases. Although single disease registries for Fanconi anemia (FA), Diamond-Blackfan Anemia (DBA), Severe Congenital Neutropenia (SCN) and Dyskeratois Congenita (DC) have been established the true incidence of many of the IBMFS is still unknown. To investigate the prevalence of each of the IBMFS and to the types and frequencies of complications we set up a retrospective national registry of these disorders in Israel. We reviewed charts of 127 patients with IBMFS diagnosed between 1964 and 2005. This represents the majority of such patients in the country. Consanguinity was recorded in 50 (40%) patients. Median time since diagnosis was 6 years (range: 1 month-39 years). Genetic analysis was available in 60 (47%) patients. The number of patients within each disease category is presented in the Table. The majority of patients who succumbed to their disease had FA. Of the 29 patients who developed malignancies (hematological and solid) the majority 23 (79%) had FA. All of the 6 patients who developed solid tumors had FA. The solid tumors were squamous cell carcinoma of head and neck, esophagus, cervix and vulva. Table: Israeli Inherited Bone Marrow Failure Cohort - Diagnosis, Complications and Survival No. of pts. FA DBA SCN CAMT DC SDS TAR NOS All Total (%) 66 (52) 18 (14) 21 (16.5) 8 (6) 6 (5) 3 (2) 3 (2) 2 (1.5) 127 (100) Per 106 people 5.3 2.6 2.1 1.1 0.86 0.43 0.29 Deceased (%) 24 (36) - 6 (29) - 2 (33) 1 (33) - - 33 (26) Molecular diagnosis (%) 34 (51) 6 (33) 7 (33) 8 (100) 4 (67) 1 (33) - - 60 (47) MDS/AML/ALL (%) 19 (29) - 4 (19) 2 (25) - - - - 25 (20) Solid tumor (%) 6 (9) - - - - - - - 6 (5) CAMT, Congenital Amegakaryocytic Thrombocytopenia; SDS-Shwachman-Diamond Syndrome; TAR, Thrombocytopenia Absent Radii; NOS-not otherwise specified. This is the largest population-based study which has examined the relative frequency of each of the IBMFS. In this cohort, FA was by far the most common form of an IBMFS (52% of pts), followed by DBA (16.5%) and SCN (14%), while CAMT, DC, SDS and TAR were far less common. These findings agree with the frequencies of FA, DBA and SCN reported by individual disease registries, and contrast with the results from the Canadian inherited marrow failure registry (Pediatr Blood Cancer47:918, 2006), where among a smaller number (39) of patients with an IBMFS the frequencies of FA, SDS, DBA and SCN were similar (12% each). One caveat is that the Israeli cohort has a large proportion of consanguineous families, which differs from most cohorts in other countries. The number of undiagnosed patients with IBMFS in our study was very small. SDS and DC are either rare in our region or under-diagnosed. The implementation of new diagnostic tests will help to resolve this issue. These data provide a rational basis for longitudinal surveillance and prevention of complications in the severe forms of IBMFS.

Although deletional α-thalassemia is the most common form of the disease worldwide, in Israel, point mutations leading to α-thalassemia are relatively common. We routinely sequence the α-globin genes when we fail to find deletions which can account for the hematological phenotype. Our PCR is specific for sequencing either the α1 or α2 globin gene. We here report two novel mutations, one in α1 and the other in α2, which lead to a thalassemia phenotype. Case 1. A 5 yr old Druze girl from northern Israel was referred due to microcytic anemia. Her hematological values were: RBC 5x109/L, Hb 8.8 gr%, MCV 55 fl, MCH 17.6 pg, MCHC 31.7gr/dl, RDW 16.2. HbA 2: 2.2%, HbF: 1%. Iron deficiency was excluded (serum iron: 58 mg/dl, transferrin: 247mg%, and ferritin: 46.2 ng/ml) The patient’s physical examination and mental development were normal, without splenomegaly or jaundice. No therapy was required, and transfusion was unnecessary. The parents had very mild microcytic anemia (mother Hb 11 gr% MCV 75.5, father Hb 13.8, MCV 78.6) with normal Hb electrophoresis. DNA of the parents and propositus was sequenced. The child was found to be homozygous (and the parents, heterozygous) for a deletion of a single cytosine (within a stretch of four) at codons 118/119 of the α2 globin gene, leading to a frameshift at codon 119. Case 2. This family is of mixed ancestry, the mother is from Bukhara. The hematological data is presented in the table below. Sequencing of the α-globin genes of the mother revealed an A to G change at the acceptor site of IVS1 at nt 116 in the α1 gene in compound heterozygosity with the well known 5 nt deletion in IVS1 of α2 (HphI). The same IVS1 nt 116 mutation at this exact nucleotide was previously reported by Harteveld (1996) to be found in the α2 globin gene, causing Hb H inclusion bodies when found in combination with 3.7 kb deletional α-thalassemia. We conclude that rare point mutations can still be identified in the α-globin genes which can be the cause of otherwise unexplained α-thalassemia phenotypes. Family 2 hematological data and alpha globin genotype Family member RBC Hb MCV MCH RDW chromosome 1 chromosome 2 del=deletion Mother 5.68 10.7 63.2 18.8 16.4 α2 HphI α1 IVS1-116 Father 6.15 13.4 70.7 21.8 13.9 del 3.7kb del 3.7 kb Son (9 yrs) 5.59 11.1 64.4 19.9 13.7 α2 HphI del 3.7 kb Daughter (7 yrs) 5.44 10.9 64.3 20.0 13.5 del 3.7 kb α1 IVS1-116 Son (2 yrs) 5.55 10.5 61.6 18.9 14.3 del 3.7 kb α1 IVS1-116

Background The three-year pre-medical programme ‘Becoming a Physician’ focuses on different aspects of medical professionalism. Objectives are to increase awareness and sensitivity to disadvantaged populations, and practise sensitive effective communication skills. Methods The curriculum includes: (1) Visits to treatment centres for people with special needs, mental illnesses, substance abuse issues, physically or sexually abused, and prisoners. Students tour the facility, hold discussions with residents, and discuss ethical professional interrelations to the medical world. Students then write ‘reflective diaries’ summarizing their thoughts and emotions. (2) Participation in a communication course that focuses on learning by practising patient-oriented communication. Qualitative data were collected from three sources: reflective diaries, studentsʼ course evaluations, and interviews with the studentsʼ tutors. Results Data indicated that the students were very satisfied with the programme. They indicated an increase in awareness of the special needs of diverse populations, and in the sense of efficacy for conducting interviews tailored to patients' needs. Tutors reported a sense of ‘personal growth’ following their role as mentors. Reflections Interactions of medical students with diverse populations, when accompanied by appropriate feedback mechanisms and strengthening of communication skills, can improve awareness and sensitivity to patients' special needs. This could help students become more sensitive and thoughtful physicians.