Bonnie G. Massing

A population-based study of childhood myelodysplastic syndrome in British Columbia, Canada

Myelodysplastic syndrome (MDS) is considered to be very rare in children. However, the only two published population‐based studies reported widely divergent incidence figures. To further explore the epidemiology of childhood MDS and to evaluate the accuracy of cancer registry and treatment trial data, we conducted a population‐based study of children aged 0–14 years in British Columbia (BC), Canada, between 1982 and 1996. MDS was diagnosed in 31 cases corresponding to an annual incidence of 3.2 per million children or 6% of all leukaemias, compared with an incidence of 6.0/million for acute myeloid leukaemia (AML), and of 0.5/million for chronic myeloid leukaemia. There was a non‐significant (P = 0.19) trend toward an increase in MDS incidence with time, the increase was partly explained by an increasing number of patients with Down syndrome. Associated abnormalities were found in 48% of the MDS cases with Down syndrome as the most common (seven cases). Only one third of the MDS cases were correctly registered in the Cancer Registry and less than half of the eligible MDS patients were enrolled on a cooperative group study. Data on MDS from treatment‐based studies and cancer registries were inaccurate and seemed to significantly underestimate the incidence of MDS in children.

Two Distinct Receptors Mediate Nonopsonic Phagocytosis of Different Strains of Pseudomonas aeruginosa

Complement receptor 3 (CR3) mediates both opsonic and nonopsonic phagocytosis of bacteria. Leukocyte adhesion deficiency (LAD) allows for the study of CR3-dependent phagocyte-bacterial ingestion, since LAD phagocytes do not express this receptor. Phagocytes from an infant with LAD were unable to ingest 50% of the Pseudomonas aeruginosa strains studied, which indicates a requirement for CR3. However, the remaining strains were phagocytosed in the absence of CR3, and ingestion was blocked by monoclonal antibodies directed at CD14. This CR3/CD14 receptor bias was further confirmed by using thioglycollate-elicited murine peritoneal macrophages, which have nonfunctional CR3 before activation. Results indicate that either CR3 or CD14 is involved independently in nonopsonic phagocytosis of different P. aeruginosa strains. Clearance of P. aeruginosa from the endobronchial space may be facilitated by nonopsonic phagocytosis, since low levels of opsonins are present. The impact of lung infection with P. aeruginosa may be determined, in part, by the phagocytic receptor that mediates ingestion.

ETV6 (TEL)-AML1 pre-B acute lymphoblastic leukaemia cells are associated with a distinct antigen-presenting phenotype.

Summary. The recently recognized translocation t(12;21)(p13;q22), which results in the ETV6‐AML1 fusion product, is the most common genetic rearrangement found in childhood pre‐B acute lymphoblastic leukaemia (ALL). It has been associated with a more favourable prognosis and a distinct immunophenotype in terms of myeloid and B cell‐associated antigen expression. Using flow cytometry, we investigated whether the unique ETV6‐AML1 phenotype extended to molecules associated with antigen presentation by analysing 50 diagnostic bone marrow samples from paediatric pre‐B ALL patients. Reverse transcription polymerase chain reaction for the ETV6‐AML1 fusion transcript was positive in 14 patients. ETV6‐AML1‐positive samples were characterized by a significantly higher expression of the co‐stimulatory molecule CD40 (P < 0·0001), as well as a significantly higher class II HLA‐DR mean channel fluorescence (P = 0·001). In contrast, CD86 expression was significantly lower on fusion‐positive samples (P = 0·010) while there was no difference in expression of CD80 or major histocompatibility complex class I between ETV6‐AML1‐positive and ‐negative samples. This is the first observation in acute leukaemia that the distinct immunophenotype associated with specific translocations includes the expression of molecules associated with antigen presentation. In the case of ETV6‐AML1 pre‐B ALL, this characteristic immunophenotype may have implications for the immunogenicity of the leukaemic cells.

L-selectin expression on polymorphonuclear leukocytes and monocytes in premature infants: Reduced expression after dexamethasone treatment for bronchopulmonary dysplasia

We examined the effect of dexamethasone on the expression of the adhesion molecule L-selectin on circulating polymorphonuclear leukocytes (PMLs) and monocytes from premature infants with bronchopulmonary dysplasia (BPD). Nineteen infants who received dexamethasone (Dex group) and 28 who did not receive dexamethasone (no Dex group) were studied. L-selectin expression, measured as mean fluorescence intensity, was lower on circulating PMLs (5.7 +/- 0.6 vs 10.6 +/- 0.7, p < 0.001) and monocytes (7.9 +/- 0.9 vs 12.5 +/- 0.9, p < 0.02) isolated from those who had received dexamethasone. Because L-selectin is important for the recruitment of PMLs to inflammatory foci in the lungs, we speculate that one of the mechanisms by which dexamethasone reduces inflammation in BPD is by impairing the ability of leukocytes to migrate into the BPD lesions.

Importance of the day 7 bone marrow biopsy as a prognostic measure of the outcome in children with acute lymphoblastic leukemia.

The presence of > or = 25% blasts in a marrow aspirate obtained on day 7 of induction followed by a remission at day 28 has been associated with a poor prognosis in children with acute lymphoblastic leukemia (ALL). We evaluated whether a day 7 marrow biopsy may be used to more accurately assess therapeutic reduction of leukemia tumor burden. Studied were 76 children with ALL enrolled on CCG protocols at B.Cs Childrens Hospital who received both a day 7 aspirate and biopsy and were in remission by day 28. Evaluation for the correlation of the percentage aspirate blasts on day 7 with the biopsy demonstrated a moderate correlation with the percentage biopsy blasts (R = 61), but not correlation with the biopsy cellularity. We saw a similar prediction of outcome by the percentage blasts on day 7 marrow aspirate in the study as reported previously although it was not significant. Outcome analysis was done using leukemia burden as measured by the day 7 absolute blast index-aspirate (ABI-aspirate) calculated as the product of the biopsy cellularity with the percentage blasts on the aspirate. The ABI-aspirate significantly predicted patient outcome with 83% survival in those with an ABI-aspirate of < .06 compared to 51% in those > or = .06 (P = .01) and was highly significant when analyzed as a continuous predictor (P = .004). This is the first study to demonstrate that information gained from the day 7 marrow biopsy can improve prediction of outcome in children with ALL. Based on this preliminary study, we recommend that large population ALL therapy trials evaluate the role of the day 7 marrow biopsy for outcome prediction in children with ALL.

Nonopsonic phagocytosis of Pseudomonas aeruginoas: insights from an infant with leukocyte adhesion deficiency.

Children with leukocyte adhesion deficiency type I are at risk for overwhelming infection because their neutrophils lack surface beta 2 integrins (CD18/CD11) that normally interact with endothelial cell adhesion molecules and mediate migration to sites of bacterial invasion. In vitro studies of phagocytic cells from an infant with leukocyte adhesion deficiency type I demonstrated that complement receptor 3 (CD18/CD11b) mediates nonopsonic phagocytosis of some Pseudomonas aeruginosa strains and might play a control role in the control of Pseudomonas infections at sites where there are low levels of opsonins.