Autoimmune complications after hematopoietic stem cell transplantation in children with nonmalignant disorders.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for many nonmalignant disorders, such as autoimmune disorders, inborn metabolic disorders, hemoglobinopathies, and immunodeficiency disorders. Autoimmune complications (AICs) after HSCT, such as autoimmune cytopenias, autoimmune hepatitis, primary biliary cirrhosis, and autoimmune cutaneous manifestations, are still neither well defined nor characterized. PATIENTS: Between 2000 and 2012, 92 patients (47 males, 45 females) were treated with HSCT in our hospital, 51 with congenital hemoglobinopathies, 19 with primary immunodeficiency disease, 10 with metabolic disorders, five with Fanconi anemia, three with aplastic anemia, and four with familial hemophagocytic lymphohistiocytosis. RESULTS: Mean age at HSCT was 6.4 years (range, 0.2-32 years) and mean duration of followup after HSCT was 6.81 years (range, 1-11 years). Sixteen (17.4%) patients developed chronic GVHD and five (5.4%) showed sclerodermatous features. Five (5.4%) patients were diagnosed with scleroderma manifestations, six (6.5%) with vitiligo, six (6.5%) with autoimmune hemolytic anemia (AIHA), six (6.5%) with idiopathic thrombocytopenia, three (3.3%) with mild leucopenia, two (2.2%) with aplastic anemia, two (2.2%) (one boy, one girl) with autoimmune thyroid disease, and one (1.1%) with autoimmune hepatitis. CONCLUSIONS: It was concluded that AICs are clinically significant complications after HSCT that contribute to morbidity but not to mortality. AICs are more frequent after HSCT for metabolic disorders, and sclerodermatous GVHD is more significant in children who underwent allogeneic HSCT for hemoglobinopathies. The potential to identify risk factors for AICs could lead to less morbidity and mortality and to maintain the patient's quality of life.

Alkaline phosphatase level change in patients with osteosarcoma: its role as a predictive factor of tumor necrosis and clinical outcome.

BACKGROUND: In osteosarcoma the histological response, measured by the percentage of tumor necrosis, constitutes one of the most significant predictive factors, with better survival in patients whose tumor necrosis is > or = 90%. OBJECTIVES: To determine if the decrease rate of serum alkaline phosphatase (SAP) levels during the first month of neoadjuvant chemotherapy could serve as a predictive indicator of tumor necrosis and clinical outcome. METHODS: We analyzed the medical files of 53 osteosarcoma patients (19 females, 34 males) (median age 16 years, range 8-24); the disease was metastatic in 12 and localized in the other 41. RESULTS: The histological responses were good in 38 patients (71.7%) and poor in 15 (28.3%). At a median follow-up of 50 months, 34 patients (64.2%) had no evidence of disease and 19 (35.8%) had died from the disease. High levels of SAP at diagnosis correlated with worse survival (P = 0.002). There was no difference in overall survival between patients whose SAP decrease rate was > 25% and those with a rate < 25% (P = 0.14). Among female patients, "rapid" SAP responders had better survival than "slow" responders (P= 0.026). In patients with metastases the SAP decrease rate was positively correlated with survival (P = 0.042). CONCLUSIONS: There was no evidence that "rapid" SAP responders had a higher percentage of tumor necrosis than "slow" responders, although female "rapid" SAP responders had a better prognosis than "slow" responders. Patients with metastases at presentation and "rapid" SAP response had better prognoses.

Cancer incidence and survival among infants in Israel, 1998-2007.

Cancer during the first year of life is relatively rare and often has clinical and biological properties different from those of the same histologic type of cancer occurring in older children. The aim of this study was to find differences in epidemiology and survival between infants and older children and to compare the percentage of distribution of infant cancer types in Israel with that reported in the United States. We collected infant <1 year of age cases diagnosed between 1998 and 2007 as having cancer from the database of the Israel National Cancer Registry, a total of 309 cases with an incidence rate of 228.5 cases per million. The largest group was diagnosed with neuroblastoma (35%) with an incident rate of 80 per million, followed by leukemia (15.9%), with acute lymphoid leukemia and acute myeloid leukemia accounting for most of this group and central nervous system malignancies comprised 10.7% of infant cancer. One hundred and fifty four new cases of infant girls was diagnosed compared to 155 infant boys with an incidence rates of 234 cases per million for girls and 224.7 for boys, not statistically significant (F:M rate ratio of 1.04). The 5-year survival rates seen in the different groups were leukemia: 55.3%, lymphoma: 71%, CNS tumors: 53.3%, neuroblastoma: 93.4%, retinoblastoma: 94.7% renal tumors: 90.9%, hepatic tumors: 63.3%, soft tissue sarcoma: 76.2%, germ cell neoplasms: 83.3%, and other epithelial neoplasms: 100%. Our study did not find survival differences with statistical significance upon comparing survival rates between different genders and ethnic groups.

Pre-clinical and clinical significance of heparanase in Ewing's sarcoma.

Heparanase is an endoglycosidase that specifically cleaves heparan sulphate side chains of heparan sulphate proteoglycans, activity that is strongly implicated in cell migration and invasion associated with tumour metastasis, angiogenesis and inflammation. Heparanase up-regulation was documented in an increasing number of human carcinomas, correlating with reduced post-operative survival rate and enhanced tumour angiogenesis. Expression and significance of heparanase in human sarcomas has not been so far reported. Here, we applied the Ewing's sarcoma cell line TC71 and demonstrated a potent inhibition of cell invasion in vitro and tumour xenograft growth in vivo upon treatment with a specific inhibitor of heparanase enzymatic activity (compound SST0001, non-anticoagulant N-acetylated, glycol split heparin). Next, we examined heparanase expression and cellular localization by immunostaining of a cohort of 69 patients diagnosed with Ewing's sarcoma. Heparanase staining was noted in all patients. Notably, heparanase staining intensity correlated with increased tumour size (P = 0.04) and with patients' age (P = 0.03), two prognostic factors associated with a worse outcome. Our study indicates that heparanase expression is induced in Ewing's sarcoma and associates with poor prognosis. Moreover, it encourages the inclusion of heparanase inhibitors (i.e. SST0001) in newly developed therapeutic modalities directed against Ewing's sarcoma and likely other malignancies.

Current status of palliative care in Israel: a pediatric oncologist's perspective.

Pediatric cancer palliative care is characterized by diversity of care delivery models; effect of cancer on the family as the central focus of care and consideration of culture, spirituality, communication, and ethical standards. In Israel, children who are in palliative care are treated by the staff of the centers and about 70 to 80 % of the children are dying in the pediatric Hematology Oncology departments and units. Special efforts are also made in the pediatric departments in order to better treat adolescents in terminal phases. Palliative care education program in Israel was started several years ago together with adult palliative care specialists, the Israeli pediatric oncologists still witness many barriers for treatment amongst parents as well as in medical pediatric teams especially in pain management. During the last years, the Israeli pediatric palliative care teams improved the management of all symptoms in a dying child with special attention to existential, emotional and social demands of the child and the whole family. Education of the medical and nursing team is imperative, training in pharmacology and metabolism of antalgic drugs is also mandatory in order to better manage symptom control of the children at the end of life.

Value of routine bone scans in patients with bone sarcomas before local treatment.

During modern treatment of children with bone sarcomas, the children undergo multiple diagnostic imaging procedures, including bone scan (BS) with Tc99m. The aim of the BS is to establish the metastatic status of the skeletal system at the time of initial diagnosis and thereafter. We retrospectively reviewed 85 medical charts of patients with osteosarcoma (n = 40) and Ewing sarcoma (n = 45) who had been treated in our department between 01.01.1995 and 01.11.2009. Every patient underwent routine imaging studies including BS at the time of initial diagnosis and before local treatment. Median age of all patients was 15.5 years (range, 8 to 29). Fifteen patients had metastases at diagnosis. All patients were treated with neoadjuvant chemotherapy. No patient with localized disease developed metastatic disease to the skeletal system before local treatment; those with localized disease who developed metastases did so some time after completion of the treatment plan. As the probability of developing bone metastatic disease while receiving therapy is very low, routine BS in asymptomatic patients before local treatment may safely be omitted.

Treatment of T cell lymphoblastic lymphoma in children and adolescents: Israel Society of Pediatric Hematology Oncology retrospective study.

BACKGROUND: 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. OBJECTIVES: To assess the outcome of the NHL-BFM-95 protocol in children and adolescents hospitalized during the period 1999-2006. METHODS: 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. RESULTS: 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). CONCLUSIONS: Our study shows that OS and EFS for all patients was 86.5% and 83.8%, respectively.

Undifferentiated sarcoma of the thyroid in a child.

The most common malignant tumor of the thyroid is papillary carcinoma. Sarcoma of the thyroid is encountered very rarely; its therapy is complex and poses significant problems due to the problematic location of the tumor. A 14-year-old female was diagnosed with undifferentiated sarcoma of the thyroid and received combined therapy comprising surgery, chemo- and radiotherapy without significant side effects. This case underlines the fact that undifferentiated thyroid sarcoma may be a diagnostic possibility in children with malignant masses of the neck and may be successfully treated with modern therapeutic strategies.

Delayed spontaneous remission in a child with primary acquired chronic pure red cell aplasia.

The acquired form of pure red cell aplasia (PRCA) presents either as an acute self-limited disease, predominantly seen in children, or as a chronic illness more frequently seen in adults with rare spontaneous remissions. A 14-year-old boy presented with pallor, without hepatosplenomegaly, jaundice, lymphadenopathy, petechiae, or any other apparent abnormalities. Isolated anemia in the presence of normal white cell and platelet counts with a marrow of normal cellularity and absence of erythroblasts but normal myeloid cells and megakaryocytes revealed the diagnosis of PRCA. All possible investigations excluded secondary causes of PRCA. The patient required packed red cell transfusions every 2 to 3 weeks. He failed therapy with intravenous immunoglobulin, corticosteroids, cyclosporine A plus corticosteroids, antithymocyte globulin, anti-CD 20 (rituximab), and erythropoietin (EPO). He showed a severe, resistant, and transfusion-dependent PRCA. Spontaneous remission with normal hemoglobin and reticulocyte levels was dramatic 6.5 years after the diagnosis of PRCA and 3.6 years after his last treatment.

Insulin-related metabolism following hematopoietic stem cell transplantation in childhood.

OBJECTIVES: To assess insulin-related metabolism following hematopoietic stem cell transplantation (HSCT) in childhood. STUDY DESIGN: Thirty-four patients who underwent HSCT were compared with 21 patients with similar diseases who were not transplanted. Median follow-up was 3.6 yr after HSCT. Anthropometric parameters, fasting plasma glucose and insulin levels, hemoglobin A(1c) (HbA(1c)) and lipid profile were measured and compared. RESULTS: HbA(1c) was significantly higher (p = 0.001) in the study group. Two (5.8%) patients in the study group developed type 2 diabetes mellitus. Among thalassemic patients, significantly lower insulin resistance indices (p = 0.05) and fasting plasma insulin levels (p = 0.033) were found in the study group compared with the control group. CONCLUSIONS: Attentive follow-up of insulin-related metabolism following HSCT in children is needed. The significance of the higher HbA1c values in the study group remains to be evaluated in a larger cohort of patients.

Optimal care for the child with cancer: A summary statement from the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology.

Since its foundation in 1991, the SIOP Working Committee on Psychosocial Issues in Paediatric Oncology1 has developed and published 12 sets of Guidelines for health-care professionals treating children with cancer and their families. Those elements considered essential in the process of cure and care of children with cancer are summarized in this document as a formal statement, developed at the 2007 SIOP annual meeting in Mumbai. Elaboration of the concepts with detailed strategies for practice can be found in the referenced guidelines [1-12] and in a companion publication [13]. This article is a summary of what practitioners considered critical elements in the optimal care of the child with cancer, with the goal of stimulating a broader application of these elements throughout the SIOP membership.

Plasma heparanase as a significant marker of treatment response in children with Hodgkin lymphoma: pilot study.

INTRODUCTION: The aim of this pilot study was to determine heparanase plasma levels (HP) at diagnosis and at restaging in children diagnosed with Hodgkin lymphoma and to investigate whether this parameter provides prognostic information for response to treatment after induction therapy. PATIENTS AND METHODS: HP levels of 19 pediatric patients (mean age: 10.3 years (y) (range, 4-18 y), 9 girls, 10 boys) with Hodgkin lymphoma were assayed at diagnosis and at restaging. HP levels were determined using an ELISA anti-human heparanase immunoassay kit. According to diagnosis, CAT scan and/or FDG/ PET-CT fusion were performed to assess response to treatment after 2-3 courses of chemotherapy. Two patients received VAMP protocol (1 stage IA, 1 stage IIA), 1 received AV-PC (nonbulky stage IIA), 4 received COPP/ABV (3 stage IIA bulky, 1 stage IIIA nonbulky), 4 received ABVE-PC (2 stage IIB, 1 stage IIA bulky, 1 stage IIIA bulky), 2 received ABVD (1 stage IIA bulky, 1 stage IIIA), and 6 received escalated BEACOPP (1 stage IIIB, 3 stage IVA, 2 stage IVB). RESULTS: Changes in HP levels were found to correlate with response to treatment for most of the children. At diagnosis, average HP level was 1019 pg/mL (range, 141-5733 pg/mL), decreasing at restaging to 588 pg/mL (range, 62-3267 pg/mL) (p = .034). At diagnosis, the average HP of the 16 patients in CR or VGPR was 1104 pg/mL; it had decreased at restaging to 586 pg/mL (p = .032). At diagnosis, the average HP level for the 3 patients with TP or PR was 1704 pg/mL; it had increased to 1938 pg/mL at restaging (p = .166). Due to the small number of patients, no correlation was observed between HP levels at diagnosis, staging, or any other clinical prognostic factor. CONCLUSIONS: Changes in plasma HP levels correlated with response to treatment for children diagnosed with Hodgkin lymphoma. This provides a rationale for exploring clinical interest in plasma heparanase measurements of a larger group, using the test for clinical trials of antiangiogenic therapies.

Effects of radiotherapy on the growth of children with leukemia.

The five-year over all survival rates of childhood lymphoblastic leukemia (ALL) have recently increased to more than 80%. During recent years, CNS radiation doses delivered to all children with ALL according to international guideline protocols have decreased. In the 1980s, the prophylactic radiation dose to the CNS decreased from 2400 cGy to 1800 cGy; in the 1990s chemotherapy alone with intrathecal chemotherapy demonstrated that there was no need for prophylactic CNS radiation in standard risk ALL, except in CNS relapse and high risk patients. Late effects on pituitary function and growth were reported by most endocrinologists involved in the follow-up of the cancer survivors. The long-term effects of cranial irradiation on growth in children treated for ALL are reviewed, specifically addressing the deficit in final height, contributing factors for height deficits, growth catch-up after stopping therapy, and growth hormone replacement therapy.

Practice of palliative sedation in children with brain tumors and sarcomas at the end of life.

Despite progress in the treatment of pediatric cancer, approximately 25% of these children will die of the disease. The last period of life is characterized by profound physical and psychological suffering, both of the children and their loved ones. Adequate alleviation of this suffering becomes the priority in the management of these patients. The authors retrospectively evaluated the indications, incidence, and characteristics of palliative sedation (PS) in 19 children with brain tumors (BT) and 18 with sarcomas (S) at the end of life. Twelve of the 18 S patients received PS, as did 13 of the 19 BT patients. Indications for initiation of PS for those with BT were seizures and/or pain, for those with S were pain and/or respiratory insufficiency. It was concluded that PS may be the only efficacious and safe treatment for the alleviation of suffering in these children at the end of life, despite differing indications.

Primary intraspinal primitive neuroectodermal tumor treated with autologous stem cell transplantation: case report and review of the literature.

The authors describe the case of a 19-year-old female patient with a primary primitive neuroectodermal tumor (PNET) of the thoraco-lumbar spinal cord, who presented with acute urinary retention and back pain for 2 months. Magnetic resonance imaging revealed an intradural extramedullary tumor, 6.5 cm long, in the region of the conus medullaris. Histological examination disclosed a small round cell tumor with immunohistochemical characteristics of a peripheral PNET. Metastatic workup showed no evidence of an intracranial tumor or metastases outside the neuroaxis. The patient received multidisciplinary treatment, including surgical excision, irradiation of the entire cranio-spinal axis, and high-dose chemotherapy with autologous stem cell rescue. Presently, 24 months after diagnosis, the patient remains in complete remission.

Infant anaplastic lymphoma: case report and review of the literature.

Anaplastic large cell lymphoma (ALCL) is a well-known entity, but there are no data on prognosis according to the age of the patient, especially in infants. A 2-month-old girl was admitted with a 2-week history of coughing, fever, and lymphadenopathy. Physical examination revealed mild respiratory distress, an erythematous macular rash on her trunk, massive cervical lymphadenopathy, splenomegaly, and very mild ascites. Chest radiograph showed bilateral pulmonary infiltrates, pleural effusion, and a mediastinal mass. CBC count showed WBC: 172,000/microL (PMN 40%, lymphocytes 47%, monocytes 3%); hemoglobin concentration: 8.7 g/dL; platelets: 390,000/microL. Cervical lymph node biopsy revealed anaplastic lymphoma with positive staining to ALK 1 and TIA 1. Immunophenotypic analysis of peripheral and bone marrow lymphoid cells showed an aberrant T-cell immunophenotype, including expression of CD3, CD45R0+, CD43+, and CD30+. Cytogenetic analysis performed on blood and bone marrow samples demonstrated the translocation t(2;5) (p23;q35), and trisomy 47. After leucophoresis, the child received chemotherapy according to the ALCL-99-EICNHL protocol, and was started on corticosteroids and cyclophosphamide, which resulted in marked improvement. After the second course, WBC decreased to 6000/microL without tumor lysis syndrome, but the child developed bacterial and fungal disseminated infections and died of septic shock with multiorgan failure. This report is of a rare case of infant anaplastic lymphoma and excellent response to treatment. Unfortunately, she did succumb to overwhelming infection. More reports of similar cases may determine the cause and prognosis of such children, helping to tailor therapy according to the age of the child and other prognostic factors, especially bone marrow involvement.

Local therapy is critical in localised pelvic rhabdomyosarcoma: experience of the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP-MMT) committee.

BACKGROUND: Localised pelvic rhabdomyosarcomas (pRMS) are rare tumours with a poorer prognosis than the majority of RMS. This study analysed patient outcome according to the type of local therapy delivered and the effect of disease-related factors on prognosis. PATIENTS AND METHODS: 97 children with localised pRMS were enrolled in the SIOP-MMT84, 89 and 95 studies. After primary surgery or biopsy, all children received ifosfamide/actinomycin/vincristine-based chemotherapy. Radiotherapy and surgery were planned in patients failing to achieve complete remission. RESULTS: Median age at diagnosis was 52 months [5 months-18 years]. IRS staging was I for five patients, II for 15 and III for 77. Patients had embryonal RMS (N = 41), alveolar RMS (N = 29), botryoid RMS (N = 3), or not otherwise specified RMS (N = 24). OUTCOME: 87 patients achieved local control (90%), 37 relapsed (43%), mainly locally (84%). With a median follow-up of more than 10 years [4-22 years], 5-year OS was 66% (95% CI: 56-75%) and EFS was 52% (95% CI: 42-61%). Among the 18 IRS-I/II patients treated without radiotherapy, 15 survived. Seven out of the 20 IRS-III patients treated without local therapy died. In multivariate analysis, IRS staging, age greater than 10 years and lymph node involvement had a negative impact on OS. Perineal/perianal locations had a trend towards a worse prognosis. CONCLUSION: pRMS still have a relatively poor prognosis. Radiotherapy or brachytherapy is necessary for all IRS-III patients including those with radiological complete remission after neoadjuvant chemotherapy with or without surgery. Radiotherapy may be withheld in IRS-I patients and children under 3 years with IRS-II pRMS.

The role of the doctor and the medical system in the diagnostic delay in pediatric malignancies.

AIM: We evaluated the roles of the doctor and the medical system in Israel in the diagnostic delay of childhood malignancies. METHODS: We investigated the factors affecting the delay in the diagnosis of childhood malignancies in 315 children with solid malignancies, diagnosed and treated in Rambam Medical Center (RMC), between 1993 and 2001. Those factors were divided into two groups: 'Healthcare-system-related parameters', (factors directly related to the medical system), and 'Patient-related parameters' (factors that are not part of the medical system, but directly affect medical judgment and decisions, including factors related to the tumor). We also took into consideration epidemiological, social, and medical issues. RESULTS: The main 'Healthcare-system-related parameters', which were found to influence the delay in diagnosis, were the type of medical authority that was initially consulted; the specialty of the first doctor; the number of additional doctors whom the child had visited, and the number of times the child had visited the first doctor. The main 'Patient-related parameters' found to have an impact on the delay in diagnosis were the age of the child, the tumor type, and the presenting symptom. CONCLUSIONS: The education and awareness of doctors at the primary healthcare clinics must be improved. We suggest ways of improving the approach of doctors and managing a child with a suspected malignancy.

Prophylactic therapy with enoxaparin in children with acute lymphoblastic leukemia and inherited thrombophilia during L-asparaginase treatment.

INTRODUCTION: Thrombotic events (TE) are well documented in patients with acute lymphoblastic leukemia (ALL). They occur due to a combination of disease, host and treatment-related risk factors. Low molecular weight heparin (LMWH) has been found to be effective and safe in children with ALL during L-asparaginase treatment. At present, whether or not to give primary anticoagulant prophylaxis for TE during induction or reinduction courses to children with ALL is controversial. Our group investigated the use of LMWH as a prophylactic treatment for ALL children with a genetic prothrombotic predisposition. METHODS: Eighty consecutive children with ALL treated between the years 1999 and 2008 were studied. Genetic analysis of factor V Leiden (G1691A) and prothrombin (G20210A) gene mutations were done at diagnosis. LMWH was given once daily subcutaneously at a dose of 1mg/kg, starting with the first dose of L-asparaginase (day 12 of induction, day 8 of consolidation) until one week after the last dose (day 40 of induction, day 25 of consolidation), to patients with inherited thrombophilia stemming from either factor V Leiden or prothrombin gene mutation. RESULTS: Eighteen patients were found to have a genetic predisposition for TE, all of them received prophylactic LMWH. Six of the 80 (7.5%) patients developed thromboembolic events. Three of these six had a prothrombin (PT) gene mutation and received prophylactic LMWH. No TE event occurred in patients with factor V Leiden mutation receiving prophylactic LMWH. CONCLUSION: It is suggested that patients with ALL and PT gene mutation may have a higher risk of clotting complications in comparison to patients with factor V Leiden mutation. A randomized trial of LMWH should be performed to assess its safety and efficacy in preventing venous TE.