The role of filtration in the provision of leukocyte poor red cells to multitransfused patients.

Five techniques for the preparation of leukocyte poor red cells were investigated to compare their efficiency in preventing febrile transfusion reactions with their cost of production, in order to establish a cost-effective transfusion programme for chronically anemic patients. Leukocyte depletion and preparation costs per unit for the products were:--microaggregate filtered red cells (MF): 25% leucocyte removal at a cost of $A2; buffy coat poor red cells (BCP): 70% at $A2; washed buffy coat poor red cells (WBCP): 88% at $A28; cotton wool filtered red cells (CWF): 93% at $A23; reconstituted frozen red cells (FC): 97% at $A80. The 5 products were transfused into 103 thalassemia patients with a documented history of febrile transfusion reactions. Reaction rates, expressed as a percentage of units transfused over a 12 mth period (MF 7%, BCP 0.3%, WBCP 0.1%, CWF 0.1%, FC 0.2%) correlated well with the degree of leukocyte depletion. The cost of CWF was reduced by a further 10% using the filter in line during the transfusion. Serum from these patients was screened for leukocyte and platelet antibodies using microlymphocytotoxic, granulocyte immunofluorescence and platelet immunofluorescence assays. There was no correlation between the antibodies present and the type of leukocyte poor product required by a patient to prevent a febrile reaction. A progressive regimen of transfusion (BCP to CWF to FC as the patient reacts) has now been adopted, with considerable cost saving.

Infantile megaloblastosis secondary to maternal vitamin B12 deficiency.

We reviewed six cases of infantile megaloblastosis secondary to maternal vitamin B12 deficiency, the most common cause of infantile megaloblastosis in our institution. Two patients had long-term neurological sequelae, with a further patient remaining abnormal but at short follow-up. In 50% of cases the mother was asymptomatic, with subtle or no peripheral blood abnormalities, having early pernicious anaemia. Any infant which fails to thrive, with progressive neurological deterioration and haematological cytopenias should have their vitamin B12 and folate status rapidly assessed. This is one of the few potentially reversible causes of failure to thrive and neurological deterioration. Early diagnosis and treatment may prevent significant long-term sequelae.

Long-term follow up of patients with transcobalamin II deficiency.

Five cases of transcobalamin II deficiency presenting to our institution were reviewed. A delay in diagnosis often led to acute deterioration. Two patients have long term neurological sequelae. Minimal treatment in these patients may be dangerous. While haematological normality may be maintained, the adequate therapeutic dose of vitamin B-12 to allow normal neurological development and function is not easily determined and damage sustained early in life may be irreversible.

Acute lymphocytic leukemia in children presenting with bone marrow necrosis.

Bone marrow necrosis has been regarded as an indicator of very poor prognosis in malignant disease. The cause and incidence are unknown, and reports of treatment response are few. We describe four children with marrow necrosis at presentation with acute lymphocytic leukemia (ALL), all of whom entered remission with standard treatment showing complete marrow healing. The bleak outlook for patients with marrow necrosis based on early experience in adults with disseminated malignancy does not appear to apply to children with ALL. The incidence of marrow necrosis at diagnosis of childhood ALL is 1%.

Normalization of vitamin B12 absorption after ileal resection in children.

Impaired Vitamin B12 absorption after significant ileal resection has been reported to be permanent, although partial recovery after ileal bypass can occur. Three children are presented in whom Vitamin B12 malabsorption returned to normal 6-8 years after ileal resection. This was due probably to adaptation of the remaining small bowel, although spontaneous resolution of bacterial overgrowth is a possible explanation. An abnormal Schilling test after ileal resection does not automatically imply the need for life-long Vitamin B12 injections.

Fetal brain disruption sequence in sisters.

We report two female siblings with the fetal brain disruption sequence. Extensive investigation of both children failed to define a definitive aetiology but clinical and laboratory findings are consistent with a hitherto unknown storage disease. We postulate that the accumulation of a neurotoxic metabolite may be responsible for the disease phenotype observed. This is the first report of recurrence of the fetal brain disruption sequence and supports the existence of a genetic form of this condition. Previous reports have emphasized possible environmental aetiologies. Infants with fetal brain disruption sequence should be investigated exhaustively and, in the absence of definitive evidence of an environmental cause, the possibility of a genetic aetiology should be considered. In some families the recurrence risk may be as high as one in four.

Hemophagocytic reticulosis. A case report with investigations of immune and white cell function.

A 5-month-old child with hemophagocytic reticulosis is described. Investigations revealed a grossly defective PHA response of the patient's lymphocytes which improved with chemotherapy. Defective glucose oxidation by phagocytosing cells and low IgA levels were demonstrated at diagnosis and have persisted despite chemotherapy. HL-A typing and chromosome studies did not reveal maternal lymphocytes in the child's circulation. The patient was treated with vinblastine and prednisolone and remains well after 11 months of treatment.

Left shift in the peripheral blood count at diagnosis in acute lymphocytic leukemia is significantly correlated with duration of complete remission.

The prognostic significance of a left shift in the peripheral blood at the time of diagnosis of acute lymphocytic leukemia was investigated by a retrospective analysis of 109 patients treated on the same protocol in a single institution. Left shift was defined as the presence of 1% or more of metamyelocytes, myelocytes, or promyelocytes. All peripheral blood films were checked at the time of diagnosis by one of the authors. It was found that the duration of complete remission at 92 mo was 74% in patients with left shift and 42% in those without left shift (p less than 0.05, log-rank test). By Cox regression analysis, only the total white cell count (p less than 0.001) and the presence or absence of left shift (p less than 0.01) were independently significant in determining the proportion of patients in complete remission. Patients with a left shift had a significantly higher granulocyte count at diagnosis (p less than 0.05). We postulate that left shift in the peripheral blood count at the time of diagnosis may be an indirect measure of the total leukemia cell load. It is a new prognostic factor of significance in determining the likely outcome of the disease.

Results of intensive therapy in childhood acute myeloid leukemia, incorporating high-dose melphalan and autologous bone marrow transplantation in first complete remission.

Childhood acute myeloid leukemia (AML) has a poor prognosis with standard chemotherapy. Allogeneic bone marrow transplantation (BMT) in remission improves the outlook only for the one third of patients with sibling donors. Autologous BMT with a lower morbidity and mortality is available to all. In this study, maximum cytoreduction was achieved by intensive early chemotherapy. Final intensification, with autologous BMT was offered to all those remaining in first complete remission (CR). Patients received two induction and two consolidation courses of intensively scheduled chemotherapy. Cytoreduction was assessed on day 14 and remission was assessed after courses 2 and 4. Bone marrow was harvested after recovery from the second consolidation course or after the first maintenance course and separated on a discontinuous percoll gradient before cryopreservation. Twenty-eight of 31 consecutively enrolled patients achieved CR. Three relapsed early and, of the 25 eligible, 24 underwent autologous BMT. Twenty-three patients received high-dose melphalan and 1 received busulphan and cyclophosphamide before autologous BMT at a median of 113 days (range, 86 to 301) after initial CR. Trilineage engraftment occurred in all. Neutrophil recovery to greater than 0.5 x 10(9)/L occurred at a median of 46 days (range, 13 to 92) after autologous BMT. Platelet recovery was delayed, with a median time to achieve greater than 20 x 10(9)/L of 42 days (range, 18 to 215). With a minimum follow up of 25 months following autologous BMT only 3 children have relapsed. The 5-year event-free survival rate (EFS) from diagnosis is 68% (95% confidence interval, 46% to 90%). Five-year EFS following autologous BMT is 87% (95% confidence interval, 67% to 100%). Autologous BMT with high-dose melphalan administration after intensive chemotherapy has produced EFS equivalent to allogeneic BMT and is associated with a strikingly low relapse rate. High-dose melphalan appears to be a valuable agent for conditioning therapy in AML.

Isolation of malignant cells from human bone marrow using a discontinuous Percoll gradient.

A technique for examining relatively large volumes of bone marrow for involvement by malignancy is described. The use of discontinuous Percoll gradients offers no advantage over conventional methods in the diagnosis of hematological malignancy. Its usefulness in detecting infiltration by solid tumor is uncertain. Complete exclusion of malignancy from the fraction containing hematologic stem cells in three patients raises the possibility that this technique is a useful adjunct to other methods of marrow purging before autologous marrow rescue in malignant disease.

Deficiency of immunological and phagocytic function in aboriginal children with protein-calorie malnutrition.

Infection, associated with protein-calorie malnutrition (PCM), is a widespread and important health problem in young Aboriginal children. Clinical obervations have suggested these children to have impaired immune resistance to infection. Children were fivided by anthropometric criteria into three groups: moderately malnourished; showing effects of previous PCM; normally nourished. Numbers and function of T and B lymphocytes and neutrophils were measured in these groups to give an assessment of systemic immune resistance. Primary antigen recognition and blastogenic response of T-lymphocytes were significantly impaired in the malnourished groups. Normal or increased numbers of B and T lymphocytes, and normal secondary antibody response to tetanus toxoid inoculations were found in all groups. Serum opsonin levels, C3 concentrations, immunoglobulin levels, neutrophil numbers and phagocytic activity were normal or increased in all groups. The malnourished children showed relative impairment of neutrophil chemotaxis, metabolic response to phagocytosis and intraphagocytic bactericidal activity. The findings suggested that children with moderate or lasting effects of PCM had multiple dificiencies in the funnction of their immune defence mechanism which may profoundly influence the prevalence, chronicity and mortality of infections diseases in Aboriginal communities.

Autologous bone marrow rescue in the treatment of advanced tumors of childhood.

High-dose multiagent chemotherapy followed by autologous marrow rescue was used in the treatment of 13 patients with Stage III or IV childhood tumors. Encouraging results are being obtained in abdominal lymphoma (1/3 complete remissions (CR); rhabdomyosarcoma (2/4 CR); and retinoblastoma (1/2 CR). In neuroblastoma, the results are disappointing, with only one of four patients in CR; this patient developed a lymphoma associated with Epstein-Barr virus infection. Marrow reconstitution was obtained in 11 patients, with recovery of neutrophils to greater than 0.5 x 10(9)/liter between six and 30 days and platelet recovery to greater than 50 x 10(9)/liter between seven and 38 days. Investigations on the numbers of cells or committed granulocyte precursors ()CFU-c's) infused and parameters of hematologic recovery show poor correlation and suggest that a more accurate and reliable assay for the predictability of cryopreserved marrow to reconstitute marrow function within a reasonable time is necessary. Nonhematologic toxicities of high-dose multiagent chemotherapy are the principal dose-limiting factors.

Dihydrofolate reductase deficiency causing megaloblastic anemia in two families.

To determine the cause of severe megaloblastosis detected at birth and at four weeks in two unrelated infants their bone marrow and liver cells were studied. Both patients had abnormal deoxyuridine suppression tests, corrected to normal by 5-formyl tetrahydrofolic acid. Liver-cell homogenate from one patient had a previously undetectable level of dihydrofolate reductase restored to normal by high cation concentration in the assay. Activity of the liver-cell homogenate from the other patient, which was one quarter of the normal level, was restored to only half normal activity by high cation concentration. Dihydrofolic acid reductase deficiency prevents this conversion of folic acid to tetrahydrofolic acid; the enzyme activity appears to differ in each patient. A satisfactory clinical response in both patients followed parenteral therapy with 5-formyl tetrahydrofolic acid. One sibling in each family died of a similar illness. Autosomal recessive inheritance is probable.