Assessment of Nutritional Status in Sri Lankan Children: Validity of Current Anthropometry Cutoffs?

Despite socioeconomic improvement, undernutrition rates stagnate in Sri Lanka, while a slow rise in obesity and noncommunicable diseases (NCD) is seen. Inability to improve undernutrition and detection of NCD could be due to overdiagnosing stunting/wasting and underdiagnosing overweight/obesity. Obesity, being a risk factor for NCDs, needs correct tools for early diagnosis. Although body mass index (BMI) is a commonly used surrogate index, the validity of universal cutoffs is questioned. Evidence shows that body composition varies with ethnic origin and cutoff value reflecting fat mass (FM) varies in different ethnic groups. This study was conducted in 12 788, 5- to 15-year-old children from 8 schools in Negombo, Sri Lanka, to identify the validity of current anthropometric cutoffs. Obesity prevalence identified by body fat content was high. International BMI cutoffs had high specificity but varied sensitivity. Locally developed BMI cutoffs had high sensitivity and specificity. Validity of internationally developed anthropometric cutoffs in South Asian children is unsatisfactory; hence, locally/regionally developed anthropometric tools should be used for screening of obesity.

Evidence-based malaria control in Timor Leste from 2006 to 2012.

BACKGROUND: Malaria has been a major public health problem in the newly established Democratic Republic of Timor Leste with over 200,000 cases being reported in 2006 and 2007. The National Malaria Control Programme (NMCP) was established in 2003. The progress made in malaria control in Timor Leste is reported. METHODS: Records maintained at the NMCP, the district health services, the Health Information and Management System, the National Laboratory on malaria diagnosis and entomological data of the NMCP were reviewed. RESULTS: There has been a 97% decrease in the reported malaria incidence from 2006 (223,002 cases) to 2012 (6,202 cases). 185,106 clinical cases reported in 2006 decreased to 2,016 in 2012 with introduction and expansion of malaria microscopy services and introduction of monovalent RDTs in 2008 and bivalent RDTs in 2010 in all parts of the country. The National Treatment Guidelines using ACT as the first-line treatment for Plasmodium falciparum infections and introduction of monovalent RDTs, led to a 42% and a 33% decrease from 2007 to 2008 in reported clinical and total malaria cases, respectively. LLINs were distributed initially to pregnant females and children under five and later per every two persons living in high-risk areas (based on microstratification at sub-district level). IRS was carried out in three districts in 2010 and extended to six districts in 2012. Anopheles barbirostris and Anopheles subpictus have been incriminated as malaria vectors. A National Laboratory, which routinely cross checks blood smears for quality assurance of microscopy was established. Malaria focal points at regional, district and sub district level, entomology surveillance staff, monitoring and evaluation officers, and quality control technicians were appointed to strengthen malaria control activities at all levels in the country. CONCLUSION: The 97% decrease in the incidence of malaria in Timor Leste is due to application of evidence-based malaria control methods that included enhancing improved quality surveillance, early diagnosis and prompt treatment of cases with effective anti-malarials, targeted vector control, human resource development and deployment, commitment of staff, GFATM funding and technical assistance from WHO.

Antileukemic and long-term effects of two regimens with or without TBI in allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia.

Between September 1986 and June 1997, 24 children with high-risk ALL in CR1 were allografted after TAM (fractionated TBI, high-dose Ara-C, and melphalan; n = 10) or BAM protocol (busulfan, high-dose Ara-C, and melphalan; n = 14). The EFS for transplants from sibling donors was 33% with TAM and 62% with BAM (P = 0.148). The probability of acute GvHD was 70% with TAM and 15% with BAM (P = 0.003). Four of 17 evaluable patients relapsed: one after TAM and three after BAM. In all, 46 other children transplanted in CR beyond CR1 were studied for sequelae. Long-term side effects were more frequent in TAM vs BAM. In children with ALL, busulfan may be a good alternative to TBI to improve the quality of life.

Renal enlargement as presentation of isolated renal relapse in childhood leukemia.

Extramedullary relapses in children with acute lymphoblastic leukemia occur most frequently in the central nervous system and in the testis. In this report, the authors describe a 16-year-old girl with an isolated renal relapse of acute lymphoblastic leukemia after a disease-free interval of 2 years and 8 months. This clinically inconspicuous renal relapse was suggested by a routine follow-up renal sonography. No evidence of disease was found in bone marrow or peripheral blood. Renal biopsy was required to establish the diagnosis. Treatment consisted of intensive chemotherapy and autologous bone marrow transplantation. The patient has been in second complete continuous remission for 7 years. The authors recommend the use of an intensive multidrug salvage regimen.

Outcome of unrelated bone marrow donor searches in 174 children resulting in 45 patients transplanted in the HLA-matched and -mismatched situation.

The aim of the study was to evaluate the outcome of unrelated bone marrow donor (UBMD) searches initiated for 174 children between 1986 and 1997. Seven patients were registered twice so that a total of 181 UBMD searches took place. At the time of registration, patients suffered from hematological malignancies (n = 121), non-malignant hemopathies (n = 26) and inborn errors (n = 34). Forty-five of the patients (26%) were given transplants from unrelated donors of whom 26 (58%) were HLA-mismatched transplants. Our strategy accepted HLA mismatches at the time of donor selection, using Thymoglobuline as part of the conditioning regimen. Of the 45 patients given unrelated donor transplants, overall survival was 60% at 3 years and concerned 27 patients of whom 14 were from HLA-mismatched donors. Disease-free survival for hematological malignancies was 65% in HLA-matched transplants and 50% in HLA-mismatched transplants. For some patients (16%) urgency led us to use alternative options: non-identical related donor (n = 14), autograft (n = 10), related cord blood transplant (n = 4). For others, UBMD searches were stopped because of favorable evolution (n = 29), death (n = 24), disease progression (n = 22) or other reasons (n = 21). By the end of the follow-up period, 88 patients had died (50%), 75 (43%) are currently alive with or without being transplanted of whom eight are still having active searches and 11 are no longer contactable. In conclusion, in severe disease in children, an immediate transplant from a partially matched donor might be preferable to a prolonged search for a full match. Consequently, this strategy increases the number of patients for whom a suitable donor can be found. We have chosen this option in order not to delay BMT; in so doing we have obtained encouraging results which include high overall survival, low incidence of acute GVHD grade III-IV and low percentage of relapse even in mismatched pairs.

Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children Leukemia Cooperative Group.

We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (+/- s.e.) at 6 and 10 years were 66% +/- 1.8% and 65% +/- 1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6% +/- 1% and 7% +/- 1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium- and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study 58881 (1989-1998) the overall EFS rate at 8 years was 68.4% +/- 1.2% and the risk of isolated CNS relapse was 4.2%+/-0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of 6-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts >100 x 10(9)/l, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the 58881 trial.

[Aseptic femur head osteonecrosis during treatment of acute lymphoblastic leukemia in the child]. / Ostéonécrose aseptique de la tête fémorale au cours du traitement des leucémies aiguës lymphoblastiques de l'enfant.

UNLABELLED: Avascular femoral head necrosis (AFN) is an uncommon complication of acute lymphoblastic leukemia (ALL) occurring in association with serious functional late effects. One of the many risk factors is high-dose corticosteroid therapy. CASE REPORT: Three children belonging to a series of 266 patients developed AFN. The diagnosis was not made immediately when X-rays were normal. In spite of the fact that treatment was begun as soon as possible, the three children had a difference in the length of their legs, with reduction of their walking perimeter and, in one case, an arthroplasty was necessary. CONCLUSION: If some patients treated for ALL limp or suffer when walking or when practising sports, the diagnosis of AFN is to be evoked. The diagnosis is not only based on simple X-rays but also on magnetic resonance imaging, which is more sensitive and reveals lesions earlier. The treatment consists of immobilization of the hip, whether or not associated with surgical procedures.

Leukaemic presentation of small cell variant anaplastic large cell lymphoma: report of four cases.

We report four cases of a rare subtype of CD30-positive anaplastic large cell lymphoma (ALCL) with a predominant small cell component (small cell variant of ALCL) presenting with a leukaemic feature. Lymph node biopsy showed malignant cells of varying size with a predominant population of small to medium-sized malignant cells associated with large anaplastic cells strongly positive for CD30 and epithelial membrane antigen (EMA). Both large and small cells were reactive with antibody ALK1, which recognizes the chimaeric NPM-ALK protein associated with the t(2;5)(p23;q35). All patients presented with hyperleucocytosis with atypical small lymphocytes. Bone marrow involvement was detected on both aspirate and bone marrow trephine where scattered malignant cells were only demonstrated by immunostaining for CD30 and ALK protein. Atypical cells in peripheral blood, lymph node and skin biopsies showed a T or null cell phenotype. Cytogenetic analysis of blood, bone marrow and/or lymph node revealed the t(2:5)(p23;q35) characteristic of ALCL. The patients responded to chemotherapy but showed early relapse without abnormal cells in peripheral blood. This report shows that the small cell variant of ALCL may have a leukaemic presentation with peripheral blood involvement by atypical lymphocytes and provides evidence that, in the small cell variant of ALCL, the small cell component is a part of the malignant clone.

Enhanced expression of p16ink4a is associated with a poor prognosis in childhood acute lymphoblastic leukemia.

The tumor suppressor gene p16ink4a is homozygously deleted in numerous T as well as in some B lineage acute lymphoblastic leukemia (ALL). We therefore analyzed the clinical and biological implications of this feature by studying p16ink4a expression in 58 cases of childhood ALL. mRNA and protein were significantly correlated and both appeared more highly expressed in B than in T lineage ALLs: 13 out of the 15 T cell ALLs did not show any p16ink4a expression. The main result of this study is the strong prognostic value of p16ink4a expression. When stratifying the patients in three groups according to p16ink4a expression, we observed in univariate analysis: (1) the shortest disease-free survival for patients presenting a high p16ink4a level; (2) contrasting with the good prognosis in the group of patients expressing p16ink4a at low level; (3) while cases without any expression of the inhibitor were associated with a medium course of the disease (P=0.0165). This prognostic value was confirmed by the multivariate analysis showing therapeutic regimen and p16ink4a protein expression as the only variables retained in the model. A specific metabolic profile related to cellular survival and proliferation was observed in each of the three p16ink4a expression groups. Among the cell cycle-related proteins we analyzed, only p21waf1 bcl-2 and CDK4 were significantly and positively correlated to p16ink4a. Furthermore, CDK6 was also strongly expressed in the group of cases with high p16ink4a level. An enhancement of p16ink4a, p21waf1 and bcl-2 was previously described in prolonged cellular survival, while aging cells showed a decrease in CDK4 expression. The concomitant high expression of the oncogenic protein CDK4 (and of CDK6), we observed, may amplify the leukemic advantage of prolonged lifespan blast cells by favoring cell progression through G1 phase. These data suggest that at least two mechanisms may be associated in the oncogenesis of very aggressive ALLs, ie deregulation of cell multiplication and prolonged blast lifespan.

Myelodysplastic syndromes in childhood: is the FAB classification relevant? Report of 81 children from a French multicentre study. French Group of Cellular Hematology.

We reviewed the peripheral blood and bone marrow smears of 81 children with myelodysplastic syndrome (MDS). The morphological FAB classification was applicable in 59 children (72.8%): RAEB and RAEBt were the most frequent, 32 cases (39.5%). CMML was observed in 15 cases (18.5%) and in 25% of them, serological evidence for a recent EBV infection was demonstrated. In 22 cases (27.2%), the FAB classification was not convenient. In some of these children, dysmyelopoiesis was associated with constitutional disorders. Among these various inherited conditions, Down syndrome in which myelodysplasia is the expression of an abnormal clonal hematopoiesis, and mitochondrial cytopathies in which MDS is the hematological expression of a polyclonal multi-organ disease. The FAB classification does not appear to be satisfactory for all the disorders included in the group of childhood MDS and should be modified for specific use in children.

Differential expression of cell proliferation regulatory proteins in B- and T-lineage acute lymphoblastic leukaemias.

In order to better understand the molecular background of differences between the clinical picture of T- and B-lineage ALLs, we studied the expression of several proteins involved in the regulation of cell proliferation in bone marrow blast cells from 30 cases of previously untreated acute lymphoblastic leukaemia (ALL); 14 cases were T- and 16 B-cell lineage ALLs. We studied several cyclin-dependent kinases (cdk1, cdk2, cdk4, cdk6) and cyclins (cyclin A, cyclin B1, cyclin D3 and cyclin E). We also studied proliferating cell nuclear antigen (PCNA) and Bcl-2 expression, the latter protein known to be involved in the prolonged survival of B-lineage ALL blasts. Proteins obtained from cell lysates were resolved on polyacrylamide gel followed by immunodetection and densitometry of specific bands. Expression of cdk1 and PCNA, markers of proliferative activity, was significantly higher in T- than in B-lineage ALL. Cdk6, which was highly correlated to PCNA, was also higher in T-cell ALL. In contrast, B-lineage ALL displayed a higher expression of anti-apoptotic protein Bcl-2. We hypothesize that those particularities may reflect differential roles of cell multiplication and apoptosis in the neoplastic proliferation of B- and T-lineage ALL.

Mitoxantrone-containing regimen for treatment of childhood acute leukemia (AML) and analysis of prognostic factors: results of the EORTC Children Leukemia Cooperative Study 58872.

The objective of this study was to evaluate the feasibility, the toxicity and the efficiency of a BFM-like treatment protocol for acute nonlymphoblastic leukemia (ANLL) of children in which mitoxantrone was substituted for conventional anthracycline. The chemotherapy called for induction (mitoxantrone, cytosine arabinoside, etoposide), consolidation (mitoxantrone, cytosine arabinoside, 6 thioguanine), followed by two intensification courses with cytosine arabinoside plus, respectively, mitoxantrone during the first and etoposide during the second courses. Maintenance therapy consisted of daily 6 thioguanine, four-weekly courses of cytosine arabinoside (s.c. daily during 4 days) and eight-weekly courses of mitoxantrone. The latter drug was pursued up to a total cumulative dose of 150 mg/sqm. Maintenance therapy was stopped at 2 years of diagnosis. Out of 108 patients, 84 (77%) achieved a complete remission, 10 died during induction of hemorrhage, sepsis or pulmonary infiltration by leukemic cells. A total of 32 relapses occurred. The median follow-up was 3.5 years. Actuarial event-free survival, disease-free survival and overall survival at 3 years as 41%, 52%, 56%, respectively. These results compare favorably with most reported data, and cytogenetic findings appear to be the most important prognostic factor.

Myelodysplastic syndromes in childhood: report of 49 patients from a French multicentre study. French Society of Paediatric Haematology and Immunology.

We describe the clinical, cytological and cytogenetic features of 49 cases of myelodysplastic syndromes (MDS) in childhood. Three children had received prior cytotoxic treatment (group 1); all of these had cytogenetic abnormalities and died shortly after diagnosis. 22 children had constitutional anomalies (group 2). The remaining 24 MDS were considered as 'primary' (group 3). Hypoplastic marrow was found in nine cases, and only 53% of the MDS fitted the adult FAB classification. Transformation to AML occurred in 11 cases, development of aplastic anaemia in three cases, and spontaneous remission in one case each of RA and RAEB. Differences were observed between groups 2 and 3 in terms of mean age at diagnosis (11.1 months v 5 years), rate of cytogenetic anomalies (15% v 38%) and rate of progression towards acute leukaemia (13% v 29%). In group 2, all the fur girls studied exhibited a polyclonal pattern of X-inactivation, which suggests that MDS may be only the haematological expression of an embryological defect with different target tissues. This study suggests that some MDS in childhood can exhibit particular features such as congenital anomalies associated with MDS, bone marrow hypoplasia, polyclonality, and spontaneous remission. It emphasizes that the FAB classification is not adequate for children and addresses the question of whether these MDS are always malignant diseases.

Proliferation of MIELIKI a novel t(7;9) early pre-B acute lymphoblastic leukemia cell line is inhibited concomitantly by IL-4 and IL-7.

The present study describes a novel cell line, MIELIKI, established from bone marrow of a pediatric patient with B lineage acute lymphoblastic leukemia (ALL) at diagnosis. The MIELIKI cell line displays an early pre-B cell phenotype (CD10+, CD19+, CD20+, CD34-, Cmu-, sIg-) with rearrangements on both Ig heavy chain and k light chain alleles, and carries an unfrequent t(7;9) chromosomal translocation identical to the freshly isolated leukemic blasts. The proliferation of MIELIKI cells was abrogated by IL-4 and by IL-7, as measured by DNA replication and viable cell recovery. The effects of IL-4 and IL-7 were mediated, respectively, through the CDw124 and CDw127 IL-4 and IL-7 receptor components. Growth inhibition by IL-4 was not mediated by soluble factors released by MIELIKI cells in response to IL-4, suggesting the existence of an intrinsic negative signaling pathway. Finally, neither IL-4 nor IL-7 were found to induce maturation of MIELIKI into cells expressing cytoplasmic or surface membrane mu chain. The present cell line should constitute a useful model of t(7;9) early pre-B ALL and allow investigation of the relationship between IL-4 and IL-7 negative signaling in leukemic B cell ontogeny.

Heterogeneity of t(1;19)(q23;p13) acute leukaemias. French Haematological Cytology Group.

The t(1;19)(q23;p13) translocation occurs commonly in B-lineage ALL. Previous reports have demonstrated a predominance of cases with expression of cytoplasmic Ig mu (C mu+), and FAB L1/L2 phenotype, a poor prognosis and expression of a fusion transcript involving the E2A and PBX1 genes in C mu+ but not in C mu- cases. Of 38 patients with karyotypically proven t(1;19) (q23;p13) leukaemias, we extensively analysed 18 patients with acute leukaemia including 16 B-lineage ALLs, one T-ALL and one AML M4. The AML was associated with a classic E2A-PBX1 fusion transcript and may represent the human counterpart of the AMLs induced by E2A-PBX1 retroviral infection of murine marrow progenitors. The T-ALL was E2A-PBX1 negative and neither the E2A nor the LYL-1 genes, both situated at chromosome 19 p13, were rearranged. Of the 16 B-lineage ALLs, four had cytological features resembling an 'L3-like' phenotype classically associated with Burkitt's lymphoma, two at diagnosis and relapse and two exclusively at relapse. E2A-PBX1 fusion transcripts were detected by RT-PCR in all 13 C mu+ patients and in 2/3 C mu- cases. The 'L3-like' phenotype did not correlate with a particular stage of maturation arrest (one sIg+, one C mu+, one C mu-) or type of E2A-PBX1 transcript, but was associated in all cases with a trisomy 8. Translocation, rearrangement, amplification or over-expression of the c-myc gene was not observed in these cases, demonstrating that the apparent association with trisomy 8 is not due to deregulation of this gene. We therefore show that the E2A-PBX1 transcript, although occurring predominantly in C mu+ pre-B ALL, also occurs in C mu- early pre-B ALL, sIg+ B-ALL and even in AML. These results suggest that the stage of maturation arrest, and indirectly the prognosis, are not solely due to the type of fusion transcript associated with the t(1;19).

[Transient erythroblastopenia in early childhood]. / L'érythroblastopénie transitoire de la petite enfance.

BACKGROUND: Transient erythroblastopenia is rare in young children although its frequency is increasing. POPULATION AND RESULTS: Six infants (four boys, two girls), aged 29-41 months (mean: 33) were admitted for polar and asthenia. Only one displayed infectious episode two months earlier. Hemoglobin ranged from 40 to 67 g/l and reticulocyte number from 1 to 10 G/l. Mean corpuscular volume was normal as was Coombs' test. There was a profound erythroblastopenia in the bone marrow in five of the six patients. Parvovirus B19 infection was excluded in all. The white cell and platelet counts were normal. All patients were given an unique blood transfusion. Reticulocytosis spontaneously appeared within a few weeks in three patients. Another patient had normal number of erythroid precursors in the bone marrow 1 month after admission. CONCLUSION: Diagnosis of transient erythroblastopenia can only be made after exclusion of known causes such as drugs, virus, immune deficiency, leukemia and of Blackfan-Diamond disease. Its persistence must lead to search for another cause.

Nuclear texture during the cell cycle in acute lymphoid leukemia.

Description of morphological and textural changes during cell cycle were studied in 31 diploid Acute Lymphoid Leukemia ALL cases. Feulgen stained nuclei were measured by image analysis. Cells with 2C, 3C and 4C content of DNA were considered as being in G1, S and G2 phase of cell cycle respectively. The main observed transformations associated with cell cycle were continuous increases in nuclear size and in quantities of black/white chromatin clumps and points. An overall correct classification of 92.5% was achieved by multivariate data analysis. However, significant differences between A L L cases were noticed.

Characterization of a t(1;19) pre-B acute lymphoblastic leukemia (ALL) cell line which proliferates in response to IL-7.

The present study describes the establishment of the cell line Pre-Alp from the bone marrow of a pediatric patient with a t(1;19) pre-B acute lymphoblastic leukemia (ALL) at diagnosis. Proliferation of leukemic blasts was found to be initially dependent on the presence of autologous stromal cells. However, after five weeks of culture, the stromal cells were no longer necessary and cells began to grow autonomously, with a doubling time of approximately 24 hours. The established Pre-Alp cell line displays a pre-B cell phenotype (CD19+, CD10+, CD34-, c mu+, s mu-), with immunoglobulin (Ig) light chain DNA in germline configuration, and carries a (1;19)(p23;q13.3) chromosomal translocation identical to the freshly-isolated leukemic blasts. A unique feature of this cell line is represented by its ability to respond to interleukin 7 (IL-7). Thus, IL-7 enhances 3H-thymidine uptake by Pre-Alp cells in a dose-dependent manner, under conditions of low cell density and serum concentration, and increases cell recovery. Finally, Pre-Alp cells were found to remain at a pre-B stage even upon addition of various cytokines, which failed to induce a transition to surface Ig+ cells. The presently described cell line should constitute a useful model of t(1;19) pre-B ALL and permit the study of IL-7 dependent signal transduction in human pre-B cells.