Frequency and clinical impact of ETV6/RUNX1, AF4-MLL, and BCR/ABL fusion genes on features of acute lymphoblastic leukemia at presentation.

BACKGROUND: Variations in disease presentation and outcome of leukemia treatment has been associated with the presence of certain mutant genes. Three major translocations (ETV6-RUNX1, BCR-ABL, and AF4-MLL) in acute lymphoblastic leukemia (ALL) have been shown to affect treatment outcome. This study is aimed at assessing the relationship between these translocations and the presence of other indicators of disease severity (white cell count, hemoglobin concentration, platelet count, and hematocrit) in ALL. PATIENTS AND METHODS: Forty chemotherapy naïve patients aged between 9 months and 54 years had their marrow samples analyzed for the prevalent mutations. Their clinical and laboratory details on presentation were also obtained. RESULTS: Abnormal genes detected were BCR/ABL1 major transcript in 5 (12.5%), ETV6/RUNX1 in 2 (5.0%), MLL/AF4 none and none of the patients had more than one fusion gene. There was no relationship between the presence of these fusion genes and the clinical and laboratory features of ALL. An association exists between the fusion genes and ethnic origin of the patients (P = 0.005). There is no significant association between the abnormal fusion genes detected and some laboratory features of prognostic importance, which include total white blood cell count (P = 0.416) and FAB subtype (P = 0.576). CONCLUSION: Presence of fusion the genes BCR/ABL1, ETV6/RUNX1, and MLL/AF4 does not have any impact on the clinical and laboratory features of ALL at presentation.

Platelet count as a predictor of the severity of sickle cell disease during pregnancy.

Recent evidence implicates the immune system and the clotting mechanisms in the pathophysiology of sickle cell disease (SCD). This study investigates the association of steady state platelet count with the severity of SCD in pregnancy. A total of 40 SCD women who were asymptomatic early in pregnancy were studied retrospectively: 14 remained asymptomatic throughout pregnancy and 26 developed at least one SCD-related complication. The early pregnancy platelet count was compared between the two groups using t-test and its ability to predict SCD-related complications in pregnancy was investigated using Receiver-Operator Characteristics (ROC) curve. Compared with asymptomatic patients, women who developed SCD-related complications had significantly higher early-pregnancy platelet count [328x10(9)/l (95% CI: 268-389) vs 210x10(9)/l (146-275), p < 0.01]. The area under the ROC curve was 76.4% (95% CI 59.7-93.2). These indicate that the platelet count in early pregnancy is significantly higher in SCD patients who subsequently develop SCD-related complications and may be used for screening.

l-selectin gene polymorphisms and complications of sickle cell disease.

We had found high expression of L-selectin and alphaMbeta2 integrin on leukocytes in patients with complications of sickle cell disease (SCD). In non-SCD patients, L-selectin polymorphisms are associated with vasculopathy and nephropathy. Our objective was to determine if L-selectin gene polymorphisms affect leukocyte expression of the protein, or the development of complications in SCD. By polymerase chain reaction with sequence-specific primers incorporating mismatches at the 3'-end, we analysed DNA from 142 HbSS patients and 102 healthy, racially matched, HbAA controls; to detect the F206L, T49S, and P213S L-selectin gene polymorphisms. All patients were assessed for complications of SCD. Steady-state expression of L-selectin on leukocytes was measured by flow cytometry in 44 patients. We excluded HbSS patients on hydroxyurea, with any other disease, pregnancy, or HbF > or = 10%. There were no significant differences in distribution of F206L, T49S or P213S l-selectin gene polymorphisms between patients and controls (chi(2) = 0.1, P > 0.05). There was no association between any of these gene polymorphisms and high expression of L-selectin by leukocytes, or the development of complications in SCD (chi(2) = 2.37, P > 0.05). The findings suggest that these three gene polymorphisms do not predispose to high leukocyte expression of L-selectin, or development of complications in SCD.

Complement haemolytic activity, circulating immune complexes and the morbidity of sickle cell anaemia.

The aim of this study was to find out if the number of crises and complications of sickle cell anaemia (SCA) relate to complement function, or the levels of circulating immune complexes (CIC), complement factor B (Bf), C3 and C4. In 73 steady-state HbSS patients and 50 HbAA control subjects, we determined the haemolytic activity of the alternative pathway of complement (AP50), of the classical pathway (CH50); and the serum concentrations of Bf, C3, C4 and CIC. By clinical examination of each patient and review of the medical records, we determined the number of complications of SCA which had occurred and the mean number of crises per year over a minimum period of 3 years. The mean+/-SD AP50 for the patients (14+/-2 U/ml) was significantly lower than the control value of 16+/-3 U/ml (p<0.001). AP50 had a significant inverse correlation with the number of crises (r=-0.30, p<0.02). Mean+/-SD CIC in patients (0.45+/-0.38 g/l) was significantly higher than in controls: 0.24+/-0.15 g/l (p<0.002). CIC showed a significant direct correlation with the number of complications of SCA (r=+/-0.28, p<0.02). Mean+/-SD Bf in SCA patients (0.19+/-0.09) was higher than in controls (0.17+/-0.05). The difference reached marginal statistical significance (p=0.049). SCA patients and controls had no significant differences in CH50, C3 and C4. These parameters and Bf did not correlate with either the number of crises or complications. The mechanisms underlying the correlations observed in this study are yet to be fully elucidated.

The management of crisis in sickle cell disease.

The symptoms and signs of sickle cell disease are exacerbated in times of crisis, characterized by tissue infarction or worsening anaemia. Prompt medical intervention is required in these distressing situations to provide relief and comfort to the patient. Effective analgesia is crucial in treating the painful crisis of sickle cell disease. The haemoglobinopathy may cause hyposthenuria with reduced ability to excrete the sodium load in normal saline. A 5% dextrose solution or 5% dextrose in 25% normal saline is therefore recommended for intravenous hydration. As the leading cause of morbidity and mortality in sickle cell disease, infections call for vigorous antibiotic therapy. Oxygen administration should be reserved for hypoxic patients, and blood transfusion given only when really indicated. Acute chest syndrome and cerebrovascular accidents are life-threatening complications of sickle cell disease whereas priapism can cause important long-term sequelae; all deserve urgent attention. In the long term, comprehensive care is cost-effective in reducing the frequency and adverse effects of sickle cell crisis.

Effect of Plasmodium falciparum malaria on plasma fibrinopeptide-A (FpA) concentration.

Plasma Fibrinopeptide-A (FpA) concentrations were determined using Enzyme-linked Immunosorbent Assay (ELISA) in patients with acute Plasmodium falciparum malaria infection and in 30 healthy controls. The mean FpA levels of the malaria patients were significantly raised (p < 0.001). The patients' FpA level correlated positively with malaria parasitaemia, but negatively with plasma fibrinogen concentration. A week after commencement of chloroquine therapy and subsequent disappearance of malaria parasites from the thick blood films, the patients' FpA levels decreased significantly from pre-treatment values. It is suggested that the elevated FpA and reduced plasma fibrinogen levels in the patients probably indicate a more widespread existence of overt coagulation defect in acute malaria infection.

A review of cephalhaematoma in adult sickle cell disease patients.

Twelve patients with sickle cell disease (SCD), eleven males within the age range 21 to 24 years and one female, fourteen years old presenting with cephalhaematoma at the Haematology Day Care Unit (H.D.C.U.) of the University College Hospital, Ibadan during a three year period were reviewed. Only one patient was sickle cell haemoglobin SC (HbSC) while others were homozygous (HbSS). They all presented with a triad of symptoms consisting of fever, headaches and scalp swelling. Significant findings include the exclusive male preponderance and the almost exclusive presentation in HbSS patients. Treatment include analgesic and intravenous fluids.

Immunoglobulin and immune complex levels in Nigerians with acute lymphoblastic leukaemia.

Twenty-five patients with acute lymphoblastic leukaemia (ALL) aged 10 months to 43 years and twenty-five age and sex matched healthy control subjects were investigated in this study. Serum immunoglobulins A, G and M levels were measured by single radial immunodiffusion method and immune complex levels estimated by polyethylene glycol precipitation technique. Significant increase in immune complexes and decrease in immunoglobulin G were observed in the patients. Although not statistically significant, the patients had a lower mean level of immunoglobulin A, and a higher mean immunoglobulin M concentration than the controls. Hypoimmunoglubulinaemia observed in this study may contribute to the aetiology of ALL or be an effect of the disease. Raised immune complexes could result from specific antibodies combining with tumour associated or microbial antigens. Immunoglobulin G levels showed a significant positive correlation with survival in the patients. The adverse effect of reduced immunoglobulin G on the prognosis of ALL is probably due to compromised immunity in the patients.

HIV seropositivity in Nigerians with lymphoproliferative malignancies.

One hundred and four Nigerians with lymphoproliferative malignancies were tested for antibodies to human immunodeficiency virus types 1 and 2 (HIV-1 and 2). All the patients with high grade lymphomas in this series were seronegative for HIV-1 and 2. Only 1 of the 104 patients had antibody to HIV-1 and none had antibody to HIV-2. Although the single positive result would suggest a higher HIV-1 seropositivity rate among the patients compared with the general Nigerian population, it should be interpreted with caution. This preliminary data emphasizes the need for an urgent countrywide study of the problem among this category of patients in Nigeria in view of the low prevalence rate of HIV-1 and 2 in the country.

PIP: Several workers have reported an association between lymphoproliferative malignancies and HIV infection. The revised diagnostic criteria for AIDS which include HIV-seropositivity in patients with Non-Hodgkin's lymphoma of the small, noncleaved, immunoblastic and large cell types are consistent with the observed relationship between HIV infection and lymphoproliferative malignancies. Following this revised definition, it was deemed necessary to determine the prevalence of HIV infection among the patients with lymphoproliferative malignancies seen in the University College Hospital, Ibadan, Nigeria. 104 newly-diagnosed Nigerian patients with lymphoproliferative malignancies seen at the hospital between December 1986 to May 1990 were tested for antibodies to HIV-1 and HIV-2. One patient was HIV-1-seropositive and none were HIV-2-seropositive. All patients with high-grade lymphomas were seronegative for both viruses. These preliminary data indicate the urgent need for a countrywide study designed to learn more about the relationship between HIV infection and lymphoid malignancies in Nigeria. The authors stress that while Burkitt's lymphoma coexisting with HIV-seropositivity is currently taken as diagnostic of AIDS, it is important to establish that the viral infection was acquired before the tumor developed in each patient. This observation is important due to the commonality of Burkitt's lymphoma in Nigeria where some hospitals are still unable to screen blood for HIV before transfusion.

Acute phase reactants and severity of homozygous sickle cell disease.

Serum concentrations of seven acute-phase reactants: albumin, transferrin (Tf), alpha-1-antitrypsin (AIAT), caeruloplasmin (Cp), alpha 2-macroglobulin (alpha 2-MG), haptoglobin (hp) and C-reactive protein (CRP) were determined in 73 subjects with varying severities of homozygous sickle cell (HbSS) disease. Fifty healthy subjects of comparable sex, age and socio-economic class distributions as the HbSS subjects served as controls. Albumin and alpha 2-MG were comparable in all the subject groups. Tf and hp levels were significantly reduced in the HbSS groups relative to the control group. Conversely, AIAT, CRP and CP were significantly elevated. However only Tf and CRP manifested significant correlations with any of the indices of disease severity employed. Transferrin and CRP are suggested as plasma proteins worthy of further evaluation as indicators of severity in homozygous sickle cell disease.

Serum immunoglobulin (G, A and M) classes and IgG subclasses in sickle cell anaemia.

Serum concentrations of immunoglobulins G, A, M and IgG subclasses were determined by single radial immunodiffusion assay in a population of sickle cell anaemia patients resident in the tropics. Fifty apparently healthy subjects of haemoglobin genotype AA, of comparable age, sex and socioeconomic status (SES), and in the same environment as the patients, were included as controls. Three indices of morbidity in SCA, namely frequency of crisis, degree of anaemia and the number of organ complications, were used to derive a severity score for each patient; and thus categorize the subjects into severity groups. Immunoglobulin levels were then correlated with the indices of morbidity as well as the derived severity score. IgG, IgA, IgM, IgG1 and IgG3 levels were significantly raised in the SCA subjects when they were compared as a group with the controls. When separated into disease severity groups, the mildly affected patients were found to have virtually normal levels of immunoglobulins. Total IgG concentration and level of the IgG3 subclass showed significant positive correlation with frequency of crisis and derived severity score. Markedly raised levels of IgG and IgG3 may be predictive of severity in sickle cell anaemia.

Foetal haemoglobin levels in Nigerians with sickle cell anaemia. A revisitation.

Foetal haemoglobin (HbF) levels were estimated by the alkali denaturation method in 73 Nigerians with sickle cell anaemia (SCA). Subjects were studied during their asymptomatic periods and were divided into three groups based on HbF levels. Group I: HbF levels < 10%; group II: HbF levels > or = 10% but < 15%; group III: HbF levels > or = 15%. Mean crises per year, number of organ (system) complications, degree of anaemia, as well as total severity scores derived from these three parameters did not vary significantly in the three groups. Similarly, HbF levels failed to manifest significant correlation between either frequency of crises, occurrence of complications, degree of anaemia or the derived total severity scores. It is probable that in Nigerian SCA subjects whose HbF concentrations are mostly < 20%, other variables apart from HbF may influence the severity of their disease.

Socio-economic class distribution of the prognostic variants of lymphoproliferative cancers in Nigerians.

One hundred and twenty Nigerians with various lymphoproliferative cancers were grouped according to socio-economic class and the prognosis of their disease. The best prognostic variant of acute lymphoblastic leukaemia occurred mainly in the highest socio-economic class and the worst variant mostly in the low socio-economic class. Chronic lymphocytic leukaemia, a low grade malignancy, and the high grade Burkitt's type of Non-Hodgkin's lymphoma occurred predominantly in the low class. The relationship between prognosis and socio-economic class was not so remarkable in patients with Hodgkin's disease and multiple myeloma. The precise mechanisms by which socio-economic strata influence development of the different prognostic variants of individual lymphoproliferative cancers are not certain.

Lecithin cholesterol acyltransferase activity in acute lymphoblastic leukemia.

Lecithin cholesterol acyltransferase (LCAT) activity and free cholesterol and cholesterol ester concentrations were determined in serum samples from 28 patients with acute lymphoblastic leukemia (ALL) and in an equal number of healthy controls. No significant alterations in LCAT activity, free cholesterol, or esterified cholesterol levels were observed in the ALL patients compared with the controls.

Hepatitis B surface antigenaemia in patients with malignant lymphoproliferative disorders.

One hundred and four patients with malignant lymphoproliferative disorders and 5,690 control subjects were screened for the presence of Hepatitis B surface antigen (HBsAg) in their sera. Lymphoproliferative disorders included in the study were acute lymphoblastic leukaemia (ALL), non Hodgkin's Lymphoma (NHL), chronic lymphocytic leukaemia (CLL), Hodgkin's disease (HD), Burkitt's lymphoma (BL) and multiple myeloma (MM). Screening was done by the Reverse Passive Haemagglutination method using the Welcome kit. The percentage antigenaemia in the patients and control subjects were 35.6 and 7.7% respectively (p less than 0.0001). Using the Odds ratio the relative risk was found to be 6.75. The Odds ratio for individual disorders ranged from 2.8 to 9.17. The results suggest an association between Hepatitis B surface antigenaemia and malignant lymphoproliferative disorders and highlights the risk involved in handling specimens from the patients.

Lymphomas in University College Hospital, Ibadan, Nigeria.

The authors reviewed 508 cases of lymphoma seen during a 16-year period in University College Hospital, Ibadan, Nigeria. Hodgkin's disease was diagnosed in 95 (18.6%) patients, of which 45% had mixed cellularity type; 19%, lymphocyte predominance; 18%, nodular sclerosis; and 18%, lymphocyte depletion. The age distribution showed a single mode in the 11 to 25-year-old group. Male preponderance was more marked in children who made up 32% of the Hodgkin's disease patients. Non-Hodgkin's lymphoma occurred in 413 cases, of which 296 (71.7%) were high-grade malignancies. Burkitt's tumor occurred in 211 (41.5%) patients, 95% of whom were children, and showed a male to female ratio of 1.7:1. Compared with previous findings in this hospital, Hodgkin's disease showed increased proportions of the lymphocyte predominant and nodular sclerosing types. However, the characteristics of Burkitt's lymphoma did not change appreciably in the last three decades.

The prognostic value of serum immunoglobulin G and immune complex levels in acute lymphoblastic leukaemia.

Twenty-five newly diagnosed patients with acute lymphablastic leukaemia and an equal number of controls matched for age and sex were admitted to this study. Serum immunoglobulin G concentration was determined by single radial immunodiffusion and immune complex level by polyethylene glycol precipitation. The patients had significantly higher immune complex and lower immunoglobulin G levels than the controls. No significant correlation was observed between length of survival and serum concentrations of immunoglobulin G or immune complexes in patients who died during the period of study. Decreased immunoglobulin G and raised immune complex levels reduce the ability to mount an immune response and imply bad prognosis. However, their practical value for estimating the length of survival in acute lymphoblastic leukaemia is limited.