Maria Kourti

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.

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.

Lipid Profile of Children with a Family History of Coronary Heart Disease or Hyperlipidemia: 9-Year Experience of an Outpatient Clinic for the Prevention of Cardiovascular Diseases

The authors evaluated the lipid profile of children with a positive family history of coronary heart disease (CHD), cerebrovascular disease (CVD), or hyperlipidemia and compared them with controls in order to identify risk indicators for atherosclerosis. A group of 315 children (group A) aged more than 2 years old with a positive family history were evaluated for serum concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), highdensity lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein B100 (ApoB100), apolipoprotein A1 (Apo A1), and lipoprotein (a) (Lp[a]). These values were compared with the levels of a control group of 214 children of comparable age (group B). The median age of children in groups A and B was 10.6 (range 2.3-16) and 9.8 (range 3-13.7) years of age, respectively. Among these children, 196 (52%), 47 (12.5%), and 72 (19.1%) had a positive family history of CHD (group A1), cerebrovascular disease (CVD) (group A2), and hypercholesterolemia (group A3), respectively. We identified 8 children with genetically determined dyslipidemia: 2 children with homozygous and 6 with heterozygous familial hypercholesterolemia. Children in group A3 had significantly higher concentrations of TC, TG, LDL-C, and ApoB100 and lower concentrations of Apo A1 compared with controls, while no significant differences were found in concentrations of lipid variables among children of group A1, A2, and A3. Significant differences were also noted in the concentrations of TC, LDL-C, and Lp(a) between children of group A1 and controls. Screening the progeny of young patients with CHD or familial hypercholesterolemia can identify children at excessive risk for future vascular disease.

Prelabor cesarean delivery and early-onset acute childhood leukemia risk.

The long-term impact of cesarean delivery (CD) on the health of the offspring is being explored methodically. We sought to investigate the effect of birth by (a) prelabor and (b) during-labor CD on the risk of early-onset (⩽3 years) acute lymphoblastic leukemia (ALL), specifically of its prevailing precursor B (B-ALL) subtype. A total of 1099 incident cases of ALL (957 B-ALL), 131 of acute myeloid leukemia (AML), and their 1 : 1 age-matched and sex-matched controls, derived from the Nationwide Registry for Childhood Hematological Malignancies (1996–2013), were analyzed using multivariate regression models. A null association was found between prelabor and/or during labor CD and either ALL (B-ALL) or AML in the 0–14 age range. By contrast, birth by CD increased significantly the risk of early-onset ALL [odds ratioCD (ORCD)=1.57, 95% confidence interval (CI): 1.10–2.24] mainly on account of prelabor CD (ORprelaborCD=1.66, 95% CI: 1.13–2.43). The respective figures were even higher for the early-onset precursor B-ALL (ORCD=1.66, 95% CI: 1.15–2.40 and ORprelaborCD=1.79, 95% CI: 1.21–2.66), whereas no association emerged for early-onset AML. Prelabor CD, which deprives exposure of the fetus/infant to the presumably beneficial effect of stress hormones released in both vaginal labor and during labor CD, was associated exclusively with an increased risk of early-onset ALL, particularly the precursor B-ALL subtype. If confirmed, these adverse long-term outcomes of CD may point to re-evaluation of prelabor CD practices and prompt scientific discussion on the best ways to simulate the effects of vaginal delivery, such as a precesarean induction of labor.

Central precocious puberty due to hypothalamic hamartoma in a 7-month-old infant girl

Hypothalamic hamartomas (HH) are rare congenital lesions of the tuber cinereum presenting with the classic triad of gelastic epilepsy, central precocious puberty (CPP) and developmental delay. In light of the important and diverse consequences of precocious puberty for affected children and their families, a correct diagnosis without delay is imperative. We present here a rare case of a 7-month-old infant girl with CPP and HH who was successfully treated with depot gonadotropin-releasing hormone (GnRH) analogue.

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

Childhood essential thrombocytosis

To the Editor: We report a 5-year-old female who was incidentally found to have thrombocytosis (platelet count 1,783 10/L) on routine laboratory investigations before tonsillectomy. Reactive thrombocytosis was excluded by multiple serological and immunological tests. On clinical and ultrasonography investigation she had splenomegaly. Therewas no family history of thrombocytosis. Cytogenetics showed normal 46XX karyotype with absence of the Philadelphia chromosome. Bone marrow aspirate was markedly hypercellular with numerous clusters of megakaryocytes and platelet clumps. (Fig. 1). In agreement with the Polycythemia Vera Study Group (PVSG) criteria (platelet count >600 10/L, absence of conditions associated with reactive thrombocytosis, normal iron stores, normal red cell mass, and absence of Philadelphia chromosome) our patient was diagnosed with essential thrombocytosis (ET) [1]. Hydroxyurea, 15 mg/kg daily, was administered for 15 days until normalization of platelet count. One year later, she remains in good health and tonsillectomy was successfully performed without any haemorrhagic complications. ET is amyeloproliferative disorder of unknown origin that has usually been considered a disease of the middle-aged [1]. It is extremely rare in childhood with an annual incidence about 1 per 10 million, 60 times lower than in adults [2,3]. Forty eight other children have been reported in the literature [2–4]. Their age ranged from 6 weeks to 18 years with median age at diagnosis of 11 years. Splenomegaly is a common clinical feature, in agreement with thrombocytosis of clonal disorder. Patients with clonal thrombocytosis have functionally abnormal platelets that are associated with a variety of thrombohemorrhagic complications and may require cytoreductive therapy. About 30% of the reported children experienced thromboembolic or haemorrhagic complications at the time of diagnosis or later [3,4]. Indications for treatment included thrombotic events, bleeding, or a high platelet count. Hydroxyurea has been the mainstay of therapy due to its predictable control of the platelet count and rapid reversal of its effects on hematopoiesis once it is stopped. It is the only drug known to effectively decrease the incidence of thrombotic events in patients with clonal thrombocytosis [5]. The risk of leukemic transformation after long-term treatment with hydroxyurea in children remains a concern [6]. This risk may be higher when hydroxyurea is combined with other agents such as 32P, busulfan or pipobroman, or in the 10% of patients who have chromosomal abnormalities at the time of diagnosis [7]. Anagrelide, an oral imidazo-quinazoline derivative with a specific effect on megakaryopoiesis, may also prove to be useful as an alternative agent to treat primary thrombocytosis in young patients [8].