Fani Athanassiadou

Metabolic syndrome in children and adolescents with acute lymphoblastic leukemia after the completion of chemotherapy.

The metabolic syndrome is a cluster of potent risk factors for cardiovascular diseases. To provide information on the late complications of chemotherapy for acute lymphoblastic leukemia (ALL), the authors prospectively studied the frequency of overweight, obesity, and metabolic syndrome in survivors of ALL in the initial years after the completion of therapy. Children and adolescents were classified as having the metabolic syndrome if they met three or more of the following criteria: hypertriglyceridemia, low levels of high-density lipoprotein (HDL), high fasting glucose, obesity, and hypertension. Obesity was defined on the basis of Body Mass Index (BMI) (kg/m2) standard deviation scores or z-scores. Cutoff points for triglycerides and HDL were taken from equivalent pediatric percentiles with the cutoff points proposed by the Adult Treatment Panel III (ATPIII). Hyperglycemia was defined using the ATPIII cutoff points. Elevated systolic or diastolic blood pressure was defined as a value greater than the 95th percentile for age, gender, and height. Fifty-two subjects (29 male and 23 female) with a median age of 15.2 years (range 6.1-22.6 years) were evaluated. Median interval since completion of therapy was 37 months (range 13-121 months). All of them had been treated according to the ALL-BFM 90 chemotherapy protocol and none had received cranial radiotherapy. Of the 52 subjects, 25 (48%) were overweight (BMI z-score >1.5) and 3 (5.76%) were obese (BMI z-score >2); among them, 1 was severely obese (BMI z-score >2.5). Three criteria for the metabolic syndrome (high triglyceride levels, glucose intolerance, and obesity) were fulfilled by three subjects (5.76%). Twenty-nine subjects (55.7%) had at least one risk factor for metabolic syndrome. Hyperglycemia and hypertension were infrequent. Prompt recognition of the risk factors for metabolic syndrome and intervention seem mandatory to ensure early prevention of cardiovascular disease in survivors of ALL.

Expression of Multidrug Resistance 1 (MDR1), Multidrug Resistance-Related Protein 1 (MRP1), Lung Resistance Protein (LRP), and Breast Cancer Resistance Protein (BCRP) Genes and Clinical Outcome in Childhood Acute Lymphoblastic Leukemia

The aim of this prospective study was to analyze the expression of messenger RNA of genes, such as MDR1, MRP1, BCRP, and LRP, implicated in the mechanism of multidrug resistance (MDR) in relation to the response to induction chemotherapy and relapse and these genes’ correlation with each other and with pretreatment laboratory and clinical characteristics. We prospectively studied 49 children (26 boys and 23 girls) with acute lymphoblastic leukemia (ALL) (median age, 5.5 years; range, 15 months to 12.5 years) who were treated with the BFM95 chemotherapy protocol. We used bone marrow mononuclear cells from 7 healthy children as controls. The expression of MDR genes and the β-actin housekeeping gene was detected by the reverse transcription-polymerase chain reaction with the appropriate primers. The mean expression of each MDR gene was significantly higher in the patients than in the control group (P <.01). We found statistically significant correlations between MRP1 and LRP expression and between MRP1 or LRP expression and MDR1 expression (P <.05). High expression for the MDR1 gene was found in 18 patients (36.7%), and their prognoses were significantly worse than those with low expression (event-free survival, 55.56% versus 86.67%;P =.03, log-rank test). Expression of each of the MDR genes was independent of the initial white blood cell count, immunophenotype, National Cancer Institute risk classification, and prednisone response. Interestingly, MDR1 expression was significantly higher at relapse than at diagnosis for 4 sample pairs. Evaluation of MDR1 expression at diagnosis of childhood ALL may contribute to the early identification of patients at risk of treatment failure.

In vitro fertilization and risk of childhood leukemia in Greece and Sweden.

Cancer risk in children born after in vitro fertilization (IVF) remains largely unknown. We aimed to investigate risk of leukemia and lymphoma following IVF using two nationwide datasets.

Haemostatic profile of full-term, healthy, small for gestational age neonates

BACKGROUND Small for Gestational Age (SGA) neonates often appear with haemostatic alterations, principally due to hepatic dysfunction that results from chronic intrauterine hypoxia. Polycythaemia and thrombocytopenia are common findings in this neonatal population. STUDY DESIGN We performed a comparison of coagulation, natural inhibitors and fibrinolysis between SGA and Appropriate for Gestational Age (AGA) infants born full term [gestational age (G.A.) >37 weeks]. Study population consisted of 188 healthy newborns, 90 of whom were SGA (62 females and 28 males), while the rest were the control group (44 females and 54 males). Blood samples were obtained within 30 minutes following birth and before the administration of vitamin K. Investigation included: PT, INR, APTT, fibrinogen, coagulation factors II, V, VII, VIII, IX, X, XI, XII, vWillebrand factor, protein C and free protein S, antithrombin (AT), APCR, tPA and PAI-1. The independent t-test was used to compare the differences between the values of haemostatic parameters. RESULTS Statistical analysis revealed a significant prolongation in PT, INR, elevated levels of tPA (p<0.015, 0.01 and 0.002 respectively) and a decrease in the values of XII and free protein S (p<0.045 and 0.007 respectively) in SGA full term neonates. The two groups had similar demographic characteristics (except birth weight), without significant differences in the values of other haemostatic parameters. CONCLUSIONS Despite of statistically significant differences in PT, INR, values of tPA, XII and free protein S, levels of haemostatic factors range within laboratory references for healthy full term newborns. These findings were not accompanied with clinical manifestations of altered haemostasis.

SPINAL EPIDURAL EXTRASKELETAL EWING SARCOMA IN AN ADOLESCENT BOY: A Case Report

Extraskeletal Ewing sarcoma (EES) represents a rare soft tissue malignant neoplasm histologically similar to skeletal Ewing sarcoma. It occurs mainly in adolescents and young adults and commonly affects the paravertebral regions. The differential diagnosis includes other small, blue round cells tumors. The authors report a case of an EES involving the spinal epidural and paravertebral spaces in an adolescent boy. EES diagnosis was confirmed by features of histologic analysis and immunohistochemistry and by the presence of the t(11;22)(q24;q12) chromosomal translocation by reverse transcriptase–polymerase chain reaction.

Socioeconomic status, area remoteness, and survival from childhood leukemia: results from the Nationwide Registry for Childhood Hematological Malignancies in Greece

The aim of the present nationwide Greek study is to assess whether survival from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is modified by socioeconomic status (SES) and area remoteness. Detailed precoded information derived from a personal interview conducted by specially trained health personnel with the child guardians was available for 883 ALL and 111 AML incident childhood cases registered in the Nationwide Registry for Childhood Hematological Malignancies during the period 1996–2010. Parental socioprofessional category was recorded on the basis of ISCO68 and ISCO88 codes; the exact traveling distance between residence and the treating hospital was ad hoc calculated. Multivariate Cox’s proportional hazards models were applied to examine the mutually adjusted associations between survival and potential predictors. Children from a lower parental socioprofessional category experienced 40% worse survival (P=0.02) independent of age, sex, and ALL subtype, whereas those whose parents were married had better outcomes (rate ratio: 0.47, P=0.01). Urbanization of residence at diagnosis or ‘residence to treating hospital’ distance was not nominally associated with survival from ALL. By contrast, no noteworthy associations implicating SES were found for AML survival, probably because of the burden of the disease and small numbers. Lower SES indicators and a single-parenthood family milieu seem to be independently associated with unfavorable outcomes from childhood ALL. Area remoteness might not be a significant outcome predictor during recent years, following considerable improvements in the motorway infrastructures and care delivery patterns. This study may provide a valuable snapshot capturing the impact of socioeconomic covariates before the burst of the Greek financial crisis.

EVALUATION OF BONE METABOLISM IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA AFTER INDUCTION CHEMOTHERAPY TREATMENT

Osteopenia and osteoporosis are currently receiving particular attention as late effects of therapy in survivors of childhood acute lymphoblastic leukemia (ALL). The aim of this study was to evaluate abnormalities in bone mass and mineral homeostasis in children with ALL after induction therapy (during consolidation treatment). Lumbar spine (L2–L4) bone mineral density (BMD, g/cm2) was measured by dual energy X-ray absorptiometry in 20 children with ALL, a median of 25.9 months postdiagnosis and results were expressed as z-scores relative to healthy Caucasian children (controls). Serum levels of intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), calcium, phosphate, and magnesium were also analyzed. In addition, the body mass indexes (kg/cm2) of patients and controls were calculated. Results were compared with those of 40 healthy controls. Among the 20 children with ALL (12 boys and 8 girls), 12 presented z-scores < 1 SD (normal) and 8 were osteopenic (z-score between 1 and 2.5 SD). In addition, children with ALL had reduced lumbar BMDs (z-score −0.817) in comparison to healthy controls (z-score −0.353) (p =. 04). Moreover, alkaline phosphatase and intact parathyroid hormone values were significantly increased compared to controls values. The data demonstrate that bone metabolism in children with ALL during consolidation therapy is disturbed, resulting in a reduced BMD and z-score with respect to healthy controls. Since a reduced BMD predisposes to osteopenia and osteoporosis, specific attention and therapeutic interventions should be considered.

Severe hyperlipidemia in a child with acute lymphoblastic leukemia treated with L‐asparaginase and prednisone

The current cure rate for children with acute lymphoblastic leukemia (ALL) in developed countries is about 80%. 1 A very important advancement in treatment responsible for this accomplishment was the combination of multiple agents in chemotherepy which was introduced in 1960. Current investigations are focused on the development of more efficient and less toxic treatment regimens. Asparaginase has been an effective drug in the treatment of childhood ALL for more than 30 years, and has become an important component of most childhood ALL regimens during the remission induction or intensification phases of treatment. Asparaginase is a bacteria-derived enzyme that catalyzes the hydrolysis of L-asparagine to L-aspartic acid and depletes the blood of this amino acid. In most tissues, asparagine is synthesized from aspartic acid and glutamine by the enzyme asparagine synthase and can respond to asparagine depletion by up-regulation of this enzyme. In contrast, sensitive lymphoid malignancies do not up-regulate asparagine synthase and, therefore, depend on exogenous circulating asparagine for protein synthesis. 2

INCREASED EXPRESSION OF MULTIDRUG RESISTANCE GENE (MDR1) AT RELAPSE IN A CHILD WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Modern treatment protocols lead to complete remission in a high proportion of patients with childhood acute lymphoblastic leukemia (ALL). However, a large number of them show a relapse of the disease. Treatment failure in these patients is mainly attributable to de novo or acquired resistance to a wide variety of cytotoxic drugs, which is called multi drug resistance (MDR). Expression of multi drug resistance 1 gene (MDR1) is implicated in the drug-resistance mechanism. In order to contribute further information we present a rare case of a 15-month old girl with newly diagnosed CALLA positive pre-B acute lymphoblastic leukemia with favourable prognostic factors at diagnosis who experienced a relapse of the disease. Using reverse transcriptase polymerase chain reaction method, m-RNA expression of the MDR1 gene upon relapse, was five-fold compared with that at diagnosis. This is the first report on increased mRNA expression at relapse in a paired sample of a child with ALL in our region.

Invasive fungal infections in children with hematological malignancies: a 5-year study.

Invasive fungal infections (IFI) are life-threatening infections and represent an important cause of morbidity and mortality in immunocompromised children, particularly those with hematological malignancies and stem cell transplantation [1]. Although in the last decades there has been an improvement in event-free survival (EFS) in children with cancer secondary to advances in current treatment and successful management of bacterial and viral infections, IFI remain a devastating problem [2, 3]. Many factors contribute to developing of fungal infections. More than 90% of patients who develop an IFI have at least one of the following factors: cytotoxic chemotherapy, corticosteroid therapy, mucositis, bone marrow transplantation, long-term parenteral nutrition, and prolonged and/or severe neutropenia [4, 5]. The purpose of this study, therefore, was to evaluate the frequency of IFI in a major pediatric oncology center in Greece and to report our results regarding patient characteristics, diagnosis, efficacy of treatment, and outcome of IFI. A retrospective analysis for documented or suspected fungal infection was performed in the Pediatric Oncology Unit of the 2nd Pediatric Department