Long-term outcome evaluation of medium/high risk acute lymphoblastic leukaemia children treated with or without cranial radiotherapy in the EORTC 58832 randomized study.

We investigated the long-term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high-risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non-inferiority EORTC 58832 study (1983-1989). Median follow-up was 20 years (range 4-32 years). The 25-year disease-free survival rate (±SE) was 67·4 ± 4·9% without CRT and 70·2 ± 5·0% with CRT. The 25-year incidence of isolated (6·5 ± 2·6% vs. 4·8 ± 2·3%) and any CNS relapse {8·7 ± 2·9% vs. 11·9 ± 3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28-1·79]; test of non-inferiority: P = 0·01} was not increased without CRT. The 25-year SN incidence in CR1 was 7·9 ± 4·6% vs. 11·0 ± 4·2%. The 25-year event-free and overall survival rates were quite similar in both arms [59·5 ± 6·3% vs. 60·5 ± 5·9%, HR 0·94 (95% CI 0·57-1·52), and 78·1 ± 4·3% vs. 78·5 ± 4·5%, HR 1·00 (95% CI 0·53-1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL.

Methotrexate-induced Acute Myelopathy in a Teenager With High-risk Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is one of the most frequent malignancies in childhood whose long-term survival has increased up to 80% thanks to modern therapy enhancements. Nevertheless, methotrexate (MTX) remains a mainstay of ALL therapy, but also represents one of the major causes of neurotoxicity in patients with ALL. MTX-induced toxicity occurs in about 9% of patients treated for ALL. It usually affects deep white matter region leading to leukoencephalopathy, which has varying clinical manifestations ranging from acute neurologic disturbances to seizures or chronic permanent encephalopathy. Here we describe a 13-year-old girl affected with ALL who developed lower limbs hypesthesia and static ataxia due to transverse myelopathy after intrathec administration of MTX therapy. A high-dose corticotherapy combined to vitamin supplementation and rehabilitation was tested. Neurological evolution was characterized by slow and partial recovery.

Prolonged versus standard native E. coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951.

Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of non-very high-risk patients by comparing prolonged (long-asparaginase) versus standard (short-asparaginase) native E. coli asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children's Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native E. coli asparaginase were switched to equivalent doses of Erwinia or pegylated E. coli asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87; P=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89; P=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70; P=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3-4 infection during consolidation (25.2% versus 14.4%) and late intensification (22.6% versus 15.9%) and the incidence of grade 2-4 allergy were higher in the long-asparaginase arm (30% versus 21%). Prolonged native E. coli asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy. This trial was registered at www.clinicaltrials.gov as #NCT00003728.

Concomitant nodal involvement by Langerhans cell histiocytosis and Hodgkin's lymphoma.

A 10-year-old girl with a family history of Hodgkin's lymphoma presented with a 2 month history of cervical lymphadenopathy and weight loss. Biopsy indicated concomitant nodal involvement by Langerhans cell histiocytosis and Hodgkin's lymphoma. Such an association is rare, especially so in children, but is not an isolated phenomenon, thereby prompting the question of whether Langerhans cell histiocytosis is a reactive or a neoplastic process.

Osteopetrosis mimicking juvenile myelomonocytic leukemia.

A 5-month-old boy developed splenomegaly, anemia, thrombocytopenia with elevated white cells, monocytosis and immature granulocytes in the peripheral blood. Bone marrow showed dysplasia without blastosis. Increased colony-forming unit-granulocyte-macrophage was found in the peripheral blood, mimicking granulocyte-macrophage colony-stimulating factor hypersensitivity. These findings fulfilled the diagnosis criteria for juvenile myelomonocytic leukemia (JMML), but no mutations in the CBL, NRAS, KRAS, or PTPN11 genes were detected. In addition to these findings severe hypogammaglobulinemia and elevated alkaline phosphatase were present. Bone X-ray showed dense and radiopaque bones with a bone-in-bone appearance characteristic of infantile malignant osteopetrosis (IMO). Genetic mutation in T-cell, immune regulator 1 (TCIRG1) was identified, confirming the diagnosis of IMO. Careful differential diagnosis including osteopetrosis, is therefore recommended in patients with clinical features and hematologic findings consistent with JMML.

A case of osteosarcoma in a patient with pycnodysostosis.

Pycnodysostosis is a rare sclerosing bone dystrophy. The main clinical features are short stature and oral and maxillofacial abnormalities such as a large head, a small and underdeveloped face with prominent nose and eyes, irregular dentition, small hands and feet with dystrophic nails, and trunk deformities such as scoliosis. The differential diagnosis is established with other skeletal dysplasias such as osteopetrosis, cleidocranial dysplasia, and idiopathic acro-osteolysis. Since its first description in 1962 by Maroteaux and Lamy, about 100 cases have been published, some of these with uncommon features. We describe the case of a 22-year-old European man with pycnodysostosis who developed a chondroblastic osteosarcoma of the right femur. No case of bone cancer in this sclerosing bone disease had been described so far.

Endocrine consequences of neuroblastoma treatment in children: 20 years' experience of a single center.

Background Neuroblastoma (NBL) is a child neoplasia affecting extracranial tissue of neuroectodermal origin. It accounts for 10% of solid malignancies in children and is characterized by a survival rate approaching 70%, confronting physicians with the emergence of an adult survivor population who have been previously exposed to surgery, cytotoxic drugs, radiation therapy or metaiodobenzylguanidine (MIBG) therapy. All these treatments potentially affect the endocrine system. Our study consists in a retrospective review of late endocrine effects arising in survivors treated for NBL during childhood. Methods The medical files of 47 patients (M/F = 26/21) treated for NBL were reviewed. Collected data consisted of age, height, weight and biological hormonal values at diagnosis and at the last follow-up consultation. The incidence of late effects in our sample was compared to the data from the literature. Results Patients were between 0 and 15.8 years of age at diagnosis (median: 1.16 years) and between 1 and 25 years of age at last follow-up (median: 16 years). Twenty-six patients were treated with chemotherapy (CT), 11 underwent CT and radiation therapy and five were treated with CT and MIBG therapy. Ten percent of the patients died before reaching the end of therapy. Late effects occurred in 54% of the patients. Thirty-six percent of patients had non-endocrine complications (musculoskeletal, neurological, hematological or hepatic chronic conditions). Endocrine complications (28%) affected mainly patients treated with CT and consisted of gonadal dysfunction (up to 42% patients of over 12 years of age at follow-up) and hypothyroidism (21%). Our analysis revealed that CT had a significant impact on final height (p < 0.05). Conclusions Treatment for childhood malignancies exposes children to late effects affecting the endocrine system. In children treated for NBL, hypothyroidism, gonadal failure and impaired growth appear to be the main endocrine complications. Close follow-up of survivors is thus appropriate.

Pediatric gastric lymphoma: a rare entity.

Primary gastric lymphoma is a rare event in childhood. We describe a 13-year-old boy with gastric Burkitt-like lymphoma localized in the fundus. Symptoms mimicking gastritis-epigastric pain, hypochromic anemia, anorexia, and weight loss had been present for a few months before diagnosis. No Helicobacter pylori infection was shown at diagnosis. Biopsies obtained by ultrasound gastroscopy proved the diagnosis; F-fluorodeoxyglucose-positron emission tomography detected an isolated large gastric hypermetabolic mass. According to the international FAB/LMB 96 trial, the patient was treated with chemotherapy alone and is in first complete remission 2(1/2) years after diagnosis.

Management of diffuse glioma in children: a retrospective study of 27 cases and review of literature.

Gliomas are the most common CNS tumours in children and present either as circumscribed tumours or diffusely infiltrative neoplasms. Diffuse gliomas develop both in the cerebral hemispheres and the brainstem and have a poor prognosis. Guidelines for the therapy of these tumours are still debated. In this study, we reviewed the clinical features of 27 consecutive patients with diffuse gliomas admitted to the Department of Paediatrics of CHR Citadelle, University of Liège, between 1985 and 2005. We review their clinical presentation, diagnosis, treatment and outcome with reference to the published literature.

Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study.

BACKGROUND: Extensive and complex vascular malformations often cause chronic pain and severe functional restraint. Conventional treatments, such as surgery and/or sclerotherapy, are rarely curative, underscoring the great need for new therapeutic modalities. Recent preclinical and clinical data demonstrated that sirolimus could offset the progression of vascular malformations and significantly improve quality of life of patients through inhibition of the Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathway. The purpose of this prospective study was to assess the efficacy and safety of this treatment in patients with extensive or complex slow-flow vascular malformations. METHODS: Sirolimus was administered orally on a continuous dosing schedule with pharmacokinetic-guided target serum concentration level of 10 to 15 ng/ml. Patients were seen every month for the first three months and subsequently every three months. The primary endpoints were safety and efficacy, based on clinical, biological and radiological evaluations, as well as a quality of life questionnaire. RESULTS: Nineteen patients, from 3 to 64 years old, with lymphatic (LM), venous (VM) or complex slow-flow malformations, refractory to standard care, were enrolled and received sirolimus continuously. After 12 months of follow-up, 16 patients were available for assessment of efficacy and safety: all had a significant and rapid improvement of their symptoms and quality of life. In two patients, sirolimus treatment permitted sclerotherapy and surgery, initially evaluated unfeasible. Sirolimus was well tolerated, with mucositis as the most common (10% of patients) grade 3 adverse event. CONCLUSIONS: Sirolimus was efficient in extensive LM, VM and/or complex malformations that were refractory to conventional treatments and was well tolerated.

Malignancy-Induced Hypercalcemia-Diagnostic Challenges.

Hypercalcemia in children is a rare metabolic finding. The clinical picture is usually non-specific, and the etiology includes several entities (metabolic, nutritional, drug-induced, inflammatory, cancer-associated, or genetic) depending on the age at presentation, but severe hypercalcemia is associated mainly with malignancy in childhood and sepsis in neonates. Severe parathyroid hormone (PTH)-suppressed hypercalcemia is challenging and requires multidisciplinary diagnostic and therapeutic approaches to (i) confirm or rule out a malignant cause, (ii) treat it and its potentially dangerous complications. We report a case of severe and complicated PTH-independent hypercalcemia in a symptomatic 3-year-old boy. His age, severity of hypercalcemia and its complicated course, and the first imaging reports were suggestive of malignancy. The first bone and kidney biopsies and bone marrow aspiration were normal. The definitive diagnosis was a malignant-induced hypercalcemia, and we needed 4 weeks to assess other differential diagnoses and to confirm, on histopathological and immunochemical base, the malignant origin of hypercalcemia. Using this case as an illustrative example, we suggest a diagnostic approach that underlines the importance of repeated histology if the clinical suspicion is malignancy-induced hypercalcemia. Effective treatment is required acutely to restore calcium levels and to avoid complications.

Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma.

Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non-coding regions. In total, 5 individual MSP assays (located in CCDC177, NXPH1, lnc-MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) also predict overall survival. Furthermore, a robust 58-marker methylation signature predicting overall and event-free survival was established. In conclusion, this study encompasses the largest DNA methylation biomarker study in neuroblastoma so far. We identified and independently validated several novel prognostic biomarkers, as well as a prognostic 58-marker methylation signature.

Aberrant methylation of candidate tumor suppressor genes in neuroblastoma.

CpG island hypermethylation has been recognized as an alternative mechanism for tumor suppressor gene inactivation. In this study, we performed methylation-specific PCR (MSP) to investigate the methylation status of 10 selected tumor suppressor genes in neuroblastoma. Seven of the investigated genes (CD44, RASSF1A, CASP8, PTEN, ZMYND10, CDH1, PRDM2) showed high frequencies (> or =30%) of methylation in 33 neuroblastoma cell lines. In 42 primary neuroblastoma tumors, the frequencies of methylation were 69%, CD44; 71%, RASSF1A; 56%, CASP8; 25%, PTEN; 15%, ZMYND10; 8%, CDH1; and 0%, PRDM2. Furthermore, CASP8 and CDH1 hypermethylation was significantly associated with poor event-free survival. Meta-analysis of 115 neuroblastoma tumors demonstrated a significant correlation between CASP8 methylation and MYCN amplification. In addition, there was a correlation between ZMYND10 methylation and MYCN amplification. The MSP data, together with optimized mRNA re-expression experiments (in terms of concentration and time of treatment and use of proper reference genes) further strengthen the notion that epigenetic alterations could play a significant role in NB oncogenesis. This study thus warrants the need for a global profiling of gene promoter hypermethylation to identify genome-wide aberrantly methylated genes in order to further understand neuroblastoma pathogenesis and to identify prognostic methylation markers.

Potential application of ELAVL4 real-time quantitative reverse transcription-PCR for detection of disseminated neuroblastoma cells.

BACKGROUND: Reliable detection of neuroblastoma cells in bone marrow (BM) is critical because BM involvement influences staging, risk assessment, and evaluation of therapeutic response in neuroblastoma patients. Standard cytomorphologic examination of BM aspirates is sensitive enough to detect single tumor cells. Consequently, more sensitive and specific detection methods are indispensable. METHODS: We used real-time quantitative reverse transcription-PCR (QPCR) of the tyrosine hydroxylase (TH), GD2 synthetase (GALGT), and embryonic lethal, abnormal vision, Drosophila-like 4 (ELAVL4) genes to detect disseminated neuroblastoma cells. We assessed assay sensitivity by addition experiments and then analyzed 97 neuroblastic tumor, BM, peripheral blood (PB), or peripheral blood stem cell (PBSC) samples from 30 patients. The QPCR results were compared with those of a standardized immunocytochemical assay. RESULTS: The molecular markers were highly expressed in all evaluated tumor samples. In addition, 32%, 11%, and 38% of all BM, PB, and PBSC samples scored positive for TH, GALGT, or ELAVL4, respectively. The TH and ELAVL4 assays could detect 1 neuroblastoma cell in 10(6) mononuclear cells. By contrast, the GALGT QPCR assay could detect 1 neuroblastoma cell in 10(4) mononuclear cells. We assessed the potential prognostic value of TH, GALGT, and ELAVL4 QPCR by analyzing subsequent samples from 3 patients with stage 4 disease. Preliminary results indicated that persistence of high ELAVL4 expression has prognostic value. CONCLUSIONS: ELAVL4 QPCR can be used to detect residual neuroblastoma cells in clinical samples. However, combination of several molecular markers and screening techniques should be considered to ensure reliable detection of rare neuroblastoma cells.

18F-FDG PET in children with lymphomas.

PURPOSE: The aim of this study was to retrospectively evaluate the performance of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) in children with lymphomas, at various stages of their disease. METHODS: Twenty-eight children (mean age 12.5 years, 14 girls, 14 boys) with Hodgkin's disease (HD, n=17) or non-Hodgkin's lymphoma (NHL, n=11) were evaluated. Patients were investigated at initial staging (n=19), early in the course of treatment (n=19), at the end of treatment (n=16) and during long-term follow-up (n=19). A total of 113 whole-body PET studies were performed on dedicated scanners. PET results were compared with the results of conventional methods (CMs) such as physical examination, laboratory studies, chest X-rays, computed tomography, magnetic resonance imaging, ultrasonography and bone scan when available. RESULTS: At initial evaluation (group 1), PET changed the disease stage and treatment in 10.5% of the cases. In early evaluation of the response to treatment (group 2), PET failed to predict two relapses and one incomplete response to treatment. In this group, however, PET did not show any false positive results. There were only 4/75 false positive results for PET among patients studied at the end of treatment (group 3, specificity 94%) or during the systematic follow-up (group 4, specificity 95%), as compared with 27/75 for CMs (specificity 54% and 66%, respectively). CONCLUSION: 18F-FDG-PET is a useful tool for evaluating children with lymphomas. Large prospective studies are needed to appreciate its real impact on patient management.

Acute arrhythmogenicity of first-dose chemotherapeutic agents in children.

BACKGROUND: Chemotherapeutic agents have been reported to cause severe arrhythmias and sudden death in the first 24 hr after administration. In this prospective study, we determined the magnitude of acute arrhythmogenicity of those agents in children. PROCEDURE: Thirty-three patients with diverse malignancies (leukemia n = 16, Wilms tumor n = 3, brain tumor n = 3, lymphoma n = 3, others n = 8) were studied with Holter monitors 24 hr before, during, and in the first 24 hr following the first-dose therapy. RESULTS: Two patients experienced conduction disturbances (phases of 2nd degree sinuatrial and atrioventricular blocks) during a 4-hr period corresponding to a 30 mg/m(2) daunorubicin infusion. Eight patients experienced supraventricular extrasystole (SE), ventricular extrasystole (VE), and/or short salvos of supraventricular (SVT) and/or ventricular tachycardia (VT). Six had leukemia (therapy: daunorubicin + vincristine), one had a lymphoma (therapy: vincristine + cyclophosphamide), and the last one a brain tumor (therapy: carboplatin + procarbazine). Three patients with leukemia had pretreatment arrhythmias (1 VT, 2 SVT). One of them and the five other patients had arrhythmias during and after the first-dose therapy (2 VE, 2 SVT, 1 SVT + VE, 1 VE + SE + SVT). No patient had life-threatening arrhythmias and no prognostic value of those disturbances could be demonstrated. CONCLUSIONS: Conduction disturbances and arrhythmias are common in cancer children at the beginning of the therapy, but no acute or long-term adverse consequences are related to their appearance.