Robert R. Chilcote

Childhood non-Hodgkin's lymphoma. The results of a randomized therapeutic trial comparing a 4-drug regimen (COMP) with a 10-drug regimen (LSA2-L2).

Members of the Childrens Cancer Study Group treated 234 eligible patients in a randomized trial designed to study the relative effectiveness of two therapy programs for the treatment of childhood and adolescent non-Hodgkins lymphoma. Two chemotherapeutic strategies were compared: a 4-drug regimen (COMP) and a 10-drug regimen (modified LSA2-L2). Failure-free survival for all patients was 60 per cent at 24 months. In patients with disseminated disease treatment success was influenced by both the histologic subtype of disease and the therapeutic regimen followed. The 10-drug program was more effective than the 4-drug program in patients with disseminated lymphoblastic disease (two-year failure-free survival rate, 76 vs. 26 per cent, respectively; P = 0.0002), whereas the 4-drug program was more effective than the 10-drug program in those with nonlymphoblastic disease (57 vs. 28 per cent, respectively, P = 0.008). The less toxic, more easily administered 4-drug regimen was as effective as the 10-drug regimen in patients with localized disease (89 vs. 84 per cent, respectively).

Septicemia and meningitis in children splenectomized for hodgkin's disease.

Retrospective evaluation of the occurrence of septicemia and meningitis in 200 children who had staging laparotomy iwth splenectomy for Hodgkins disease revealed 20 episodes occurring in 18 children. Symptoms were usually fulminant; only 10 of these patients survived their episode. Infections occurred eight days to three years after splenectomy. Adolescents, as well as younger children, were affected; half were older than 10 years of age. Leukopenia was not a major factor in onset or survival since the average white-cell count was 12,000 in both survivors and children who died. Pneumonococcus accounted for 50 per cent, and streptococcus for 15 per cent of infections; there was one episode each of Haemophilus influenzae and meningococcus; in 25 per cent, no organism was isolated. Predominance of penicillin-sensitive organisms and high mortality suggest that penicillin prophylaxis and the protection offered by bacterial vaccines should be evaluated in children with Hodgkins disease whose staging laparotomy includes splenectomy.

Glucose phosphate isomerase deficiency with hereditary nonspherocytic hemolytic anemia

Eight children (5 living, 3 deceased) with severe hereditary nonspherocytic hemolytic anemia caused by glucose phosphate isomerase deficiency have been observed in two Kentucky and Indiana families. All affected children were severely anemic in early life. Three deaths occurred in young patients who did not receive adequate transfusions of blood or whose parents refused to permit splenectomy. Splenectomy generally abolishes the requirement for blood transfusion. No patient has required regular transfusion of blood after puberty. Growth and development have been surprisingly normal and no patient has died of infection. The anemia is expressed as an autosomal recessive trait, but the enzyme variant can be detected in hematologically normal heterozygotes. The abnormal isomerase molecule is heat labile and is contained in neutrophils and lymphocytes as well as in erythrocytes.

Atypical bleeding in hemophilia: application of the conversion model to the case study of a child.

&NA; Although it has been suggested that psychosocial events may trigger bleeding in patients with hemophilia, few specific instances have been described. In this report we interpret a series of atypical bleeding episodes in a child with a factor VIII deficiency. Although the specific pathophysiologic events that led to bleeding into the elbow are unknown in this child, they are probably similar to those of “psychogenic purpura.” It is likely that these episodes of atypical bleeding can be interpreted in terms of conversion model and that conversion reactions in children required involvement by at least one parent.

Acute Non-Lymphoid Leukemia

Acute non-lymphoid leukemia is a group of hematologic neoplasms which have been the subject of intensive basic and clinical research. These studies have led to a better understanding of the genetic basis of leukemia and may ultimately help establish the molecular mechanisms of malignant transformation. They also have increased our understanding of myeloid differentiation. As a result of clinical trials, we can now induce a clinical remission in a large majority of patients with acute non-lymphoid leukemia. Future studies will attempt to lessen toxicity and to maximize the response rate. Many of these advances will come from improvements in supportive care given during the periods of therapy-related marrow aplasia. The role of intensive chemotherapy to prolong remission duration and to increase the usefulness of allogenic bone marrow transplantation will be clarified during the next several years.

5|[prime]|-DEOXY|[ndash]|5|[prime]|-METHYLTHIOADENOSINE (MTA) PHOSPHORYLASE DEFICIENCY IN LEUKEMIA: GENETICS AND BIOCHEMICAL ASPECTS: 28

MTA is produced in eukaryotic cells during the synthesis of polyamines from decarboxylated S-adenosylmethlonine. The nucleoside is rapidly cleaved to adenine and methylthioribose-1-P by MTA phosphoryiase (MTAse). We have assigned the gene MTAP to chromosome 9pter->9q12 by enzymatic and electrophoretic analysis of somatic cell hybrids.All normal tissues and non-malginant cell lines contain MTAse. However, several human leukemic cell lines are deficient in the enzyme, and 5 patients with acute lymphoblastic leukemia (ALL) have been shown thus far to lack MTAse in their malignant cells. Karyotypic abnormalities involving fragile site 9p21 occur in ALL with lymphomatous clinical features. One of 5 such patients studied prospectively lacked MTAse in her leukemic cells but not in normal blood cells at remission. No inactive enzyme protein has been detected by immunoadsorption among 7 leukemic lines tested. The MTAse deficient cell lines excrete MTA up to 0.32 nmol/hr/mg protein. In mice, the growth of MTAse deficient mutant lymphoma cells (but not MTAse positive wild type cells) causes plasma MTA to rise from undetectable levels to > 800 nM pre-terminally. Assay of plasma or urine MTA may thus prove useful to screen leukemic patients for MTAse deficient malignant cell clones.

REVERSIBLY SICKLED CELLS: A CORRELATE OF THE FREQUENCY OF PAINFUL CRISES IN HbSS SICKLE CELL ANEMIA

Despite intensive investigation, no prognostic factor has yet been identified for predicting the frequency of painful crises in HbSS. Direct microscopic observation of a transfused animal model suggested that reversibly sickling cells (RSC), rahter than ISC, were more likely to obstruct vessels (Lacelle, Blood Cells, 1977). We examined the significance of this observation by following 65 children with HbSS for the frequency of painful crises. Without knowledge of the clinical course, hematologic parameters and proportion of ISC (morphologic criteria) were used to estimate the absolute number of cells capable of being RSC (100% -%ISC -%F) × RBC. The patients were followed for a mean of 27 months (144 prospective patient-years). A median of I event occurred per 12 months (range 0-10). The frequency of painful events was correlated with RSC (r=0.32, p <0.01), those patients with the highest red cell levels and fewest ISC having higher RSC levels and more frequent crises. RSC was for any given patient stable over time and inversely correlated to MCH (r= -0.64, p <0.01). These results indicate that the proportion of RSC is a prognostic factor and imply that strategies which decrease the number of ISC or increase the hemoglobin level without decreasing the number of cells capable of reversible sickling may increase the frequency of painful crises.