Presenting features and prognosis of B-cell chronic lymphocytic leukemia patients less than 50 years old.
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Biomedical subjects
Publications and source records attributed to F Morabito.
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We report a case of Ph1-positive, bcr-positive chronic myeloid leukemia blast crisis (CML-BC) which at presentation showed a mixed myeloid/B-lymphoid immunophenotype along with TdT positivity and, at the molecular level, an oligoclonal rearrangement of the immunoglobulin heavy chain (IgH) gene region. After obtaining a successful remission, at the time of relapse the patient underwent a phenotypic and genotypic switch from mixed to myeloid phenotype, characterized by the loss of the lymphoid markers and TdT expression and by a germline configuration of the IgH gene region. The same bcr rearrangement was, however, found in both phases of the disease, supporting the suggestion of a true phenotypic and genotypic conversion. This report confirms that the neoplastic event in CML may take place at an early multipotent stem-cell level, prior to a well-defined phenotypic and genotypic lineage expression. Moreover, it is suggested that different factors (chemotherapy? growth factors?) may have either eradicated the bcr+/IgH+ clone and promoted the growth of bcr+/IgH- leukemic cells or, alternatively, supported the lymphoid differentiation program and induced a myeloid lineage shift.
The immunophenotype of 72 cases with acute myelocytic leukemia was investigated with a panel of monoclonal antibodies. When the morphologic criteria of the FAB classification was compared with the normal myeloid and erythroid pathway of differentiation identified by MoAbs, a relationship was found with FAB M5 and M6. Moreover, a constant negativity to HLA-DR and CD15 antigens in M3 and the contemporaneous expression of HLA-DR and CD11b antigens on the M4 and M5 leukemic cells were observed. We identified phenotypically distinct groups of patients with different responses to therapy. In fact, patients whose leukemic cells did not express the HLA-DR antigen showed, in a univariate analysis, a significantly higher percentage of complete remissions than did HLA-DR-positive patients. Multivariate discriminant analysis, in line with this result, showed that the parameters of discriminant capacity were, in order of statistical significance, young age, low WBC count and the lack of DR expression, respectively. A trend for a better response to therapy, without any statistical relevance, was also observed in CD11b-negative and CD33-positive cases. Similar results were detected in patients who expressed either DR or CD11b, or none of these markers. These findings indicate that immunophenotype may identify some FAB subtypes. Moreover, in some cases the phenotypic profile can provide useful information about the clinical outcome.
The study aimed to assess the effect of juvenile simple adiposity on growth. The height (measured using a Hapenden stadiometer) of 1443 subjects (799 boys and 644 girls) aged from 6 to 16 was measured. The Quetelet index (QI) of adiposity was used; all subjects examined exceeded the 95th centile of the standard Cronk and Roche scale. Heights are expressed as standard deviation scores (SDS) and are compared to the British Standard. Adipose boys are taller than British boys up to the age of 12, then the difference lessens and the average heights of 15-year-old adipose boys are below the 50th centile of British growth charts. Female subjects showed a higher SDS from 6 to 8 years, after which the difference lessens gradually, and after 13 years the average height is below the 50th centile of British standards. Adipose boys are taller than normal boys during childhood; in prepuberty and puberty this difference lessens and during puberty they are shorter than British boys. This growth model is probably due to advanced skeletal maturity in adipose subjects with the result that at puberty growth lessens because it is exhausted. The wide epidemiological cross-sectional study confirms that growth is favourable in juvenile adiposity but does not alter adult height.
The well know fact that high blood pressure and impaired glucose tolerance are frequently associated with obesity has suggested that hyperinsulinemia could represent one of the possible pathogenetic connections between obesity and systodiastolic hypertension. With the aim of verifying this hypothesis 67 obese subjects (36 hypertensive and 31 normotensive), males, were admitted to our study. All of the subjects underwent standard OGTT in order to measure their glycemic and insulinemic levels. No differences were found between two groups, as regard age and the degree of obesity; blood pressure values were significantly different (p less than 0.01). No significative differences were detected for glycemic and insulinemic levels between normotensive and hypertensive subjects; basal hyperinsulinemia was detected in a similar percentage (16.6 vs 19.3%) in the two groups. Under these circumstances it is not possible to confirm that hyperinsulinemia is the prominent link between obesity and high blood pressure, as previously observed by others.
A case of Ph1+ chronic myeloid leukemia in blast crisis (CML-BC) is reported, in which the periodic acid Schiff and myeloperoxidase negative blasts displayed high terminal deoxynucleotidyl activity and coexpressed both B- (CD19, CD10, and CD24) and T- (CD7) lymphoid markers. In line with the immunophenotype, DNA analysis revealed a rearranged configuration of both the immunoglobulin and T-cell receptor (beta, gamma, and delta) genes. In spite of this dual B/T phenotype and genotype, the negativity of CyCD3 favors the suggestion that the target of the neoplastic event is an early B cell, with a cross lineage involvement of the putative common recombinase. However, taking into account that a normal counterpart of a biphenotypic B/T ALL has been recognized, it could be hypothesized that the leukemic transformation may have involved an oligopotent B/T lymphoid precursor. This case confirms the lineage heterogeneity of CML-BC and suggests that DNA analyses coupled to extensive immunophenotyping may allow further insight for a more precise recognition of both normal and leukemic ontogenesis.
Lipid plasma levels were measured in a group of 519 obese subjects, aged 7-66 years, divided according to age, sex and BMI. Lipidemia and total cholesterolemia increased both with age and BMI, irrespective of sex; LDL and VLDL increased in relation to age and, with less evident differences, to BMI. Triglycerides increased in the age bracket from adolescent to adult, especially in males, whereas their increase in relation to BMI showed no difference between the sexes. Chylomicron plasma levels remained steady both in relation to age and BMI.
The incidence of impaired glucose tolerance (IGT) in obese juvenile has not yet been well defined. Glycemic and insulin responses to OGTT were evaluated in 398 obese juveniles (and 70 healthy control subjects) to investigate possible correlations with age, body mass index (BMI) and obesity duration. Subjects were subdivided into two groups according to OGTT results: obese with normal glucose tolerance (OB-NGT) and obese with impaired glucose tolerance (OB-IGT). IGT was found in 11% of subjects but no correlations were observed in relation to age, BMI and obesity duration. There was no difference in the glycemic response to OGTT in terms of the biological parameters examined. Insulin plasma levels were twice as high in OB-NGT in comparison to control subjects and OB-NGT. Basal insulinemia increased with BMI in OB-IGT but not in OB-NGT.
It has been suggested that children with constitutional growth delay might have a transient immaturity of the neurotransmitter pathways necessary for the control of growth hormone releasing hormone (GHRH) secretion. In this study we evaluated the effects of two consecutive GHRH boluses (1 microgram/kg, i.v.) in nine prepubertal boys with constitutional growth delay. Growth hormone (GH) responses to GHRH administration were similar to that observed in normal children (first GHRH bolus, GH net incremental area under the curve (nAUC) +/- SE: 788 +/- 244 vs 984 +/- 242 ng/ml per hour; second bolus, GHnAUC: 657 +/- 122 vs 541 +/- 129 ng/ml per hour, respectively). These data suggest that no relevant abnormalities in the mechanisms determining the somatotroph sensitivity to GHRH are present in children with constitutional growth delay.
Osteocalcin (OC) concentration, a specific index of bone formation, was measured in 29 female patients with microprolactinoma (serum prolactin, PRL: 105 +/- 10.9 ng/ml; mean +/- SE). Mean OC levels were significantly lower than in controls (1.7 +/- 0.2 vs 5.1 +/- 0.3 ng/ml; p less than 0.001), being below the normal range in 28 out of 29 patients. All patients were treated with dopaminergic agents (dihydroergocriptine, bromocriptine or cabergoline). After treatment mean serum PRL levels were significantly reduced (12 +/- 3.1 ng/ml; p less than 0.001), a full normalization being obtained in 26 patients. There were no significant differences in both basal and after treatment PRL levels among patients treated with different drugs, although a greater PRL decrease was induced by cabergoline. Serum OC levels significantly increased after 12 month therapy (4.7 +/- 0.6 ng/ml, p less than 0.001), a normal concentration being reached in 14 of 29 cases. During treatment there were no significant differences in serum estradiol and PRL concentrations between patients who normalized or not their OC levels, while the reduction in PRL levels with respect to baseline was more pronounced in the former group. The absolute increase in OC levels positively correlated with serum PRL decrements (p less than 0.01). It is noteworthy that serum OC normalized in 1/10 patients during dihydroergocriptine, 3/8 during bromocriptine and 10/11 during cabergoline. Four patients, previously treated with dihydroergocriptine and bromocriptine without normalizing OC and PRL levels, underwent a second course of therapy with cabergoline and then normalized OC concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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Recent observations have demonstrated that the pineal hormone melatonin (MLT) plays a role in the neuroendocrine control of the cardiovascular system. On the other hand, it has been observed that the cardiac hormone alpha-atrial natriuretic peptide (ANP) may regulate the neuroendocrine functions. The present study was carried out to investigate the possible relationship between cardiac and pineal endocrine functions. Six healthy volunteers were treated on two different occasions with placebo or ANP at a dose of 0.1 mg i.v. as a bolus. An increase of greater than 100% in MLT serum levels was seen in 2/6 subjects. These preliminary results would suggest that ANP may play a role in the regulation of MLT secretion. Further studies will be needed to define better the cardiac-pineal interactions.
It is known that the pineal hormone melatonin plays a role in the regulation of several biological functions. In an attempt to investigate interactions between the pineal and the cardiac endocrine activity, in this preliminary study we have evaluated the effect of melatonin on the secretion of the cardiac hormone, atrial natriuretic peptide (ANP). The study included five healthy volunteers, and melatonin was given orally at a dose of 30 mg at 17:00. The results of the study show that the administration of melatonin does not influence ANP plasma concentrations. Further studies will be required to better define the cardiac-pineal interaction.
Essential adiposity positively influences growth during childhood, but little is known about its effects on final height. A study was performed in 39 subjects (20 males and 19 females, mean age 10.7 for males, and 8.2 years for females) affected by essential adiposity to assess height during and at the end of the developmental age. During childhood the height of adipose subjects included in the study exceeded the mean values for matched chronological ages from the British reference sample (0.716 SDS for males, 0.587 for females). In adulthood, this advantage was completely reversed: the height of males in the study was in line with mean values (0.069 SDS), whereas the females were slightly under the mean height of the reference group (0.165 SDS). Since height is known to be heavily influenced by genetic factors, the results have been corrected for genetic bias. Improved results are obtained following correction for genetic influence: males (0.890 SDS), females (0.584 SDS). In conclusion, childhood adiposity has a positive influence on growth during the developmental age, and also appears to have a positive influence on genetic potential, as may be deduced from the height of the parents, thus improving final height.
To evaluate the possible interest of the dosage of glycated plasma proteins in the diagnosis of glucidic intolerance, OGTT with determination of glycaemia and insulinaemia, HbA1c and fructosamine was determined in 6 normal and 35 obese subjects. On the basis of OGTT the subjects were subdivided into 20 obese with normal glucose tolerance, 7 with IGT and 8 with DM. In the comparison between all the subjects there was a significantly higher plasma fructosamine concentration in the obese with DM (p less than 0.001). No difference was noticed between the normal subjects and the other two classes of obese patients. This suggests that the evaluation of glycated plasma proteins is scarcely sure in a screening plan.
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This study evaluates residual disease in 28 B-cell chronic lymphocytic leukemia (B-CLL) patients who obtained a clinicohematologic remission after intensive chemotherapy. Sixteen of 28 patients (57%) showed a normal number of circulating B-lymphocytes, as demonstrated by the low percentage of mouse rosette-forming cells (M-RFC), surface immunoglobulins (SIg), and CD24-positive cells. Clinically, a lower number of relapses occurred in this group of patients compared to those with a persistent expansion of peripheral B-cells (P less than 0.05). In order to assess monoclonality of the residual peripheral B-cell population, the distribution of SIg light chains was investigated on the B-cell-enriched fraction of 15 of these 16 cases. Only six of them had a kappa/lambda ratio which ranged between 1.7:1 and 3:1, whereas the remaining patients still displayed a clearly imbalanced kappa/lambda Ig light chain distribution. On the other hand, the analysis of the configuration of the Ig heavy chain gene region, performed in nine cases (including five of the above six cases), showed the persistence of a rearranged pattern in all cases tested but one. Therefore, residual monoclonal B-cells were found also in the majority of cases which displayed the lowest kappa/lambda ratio, a normal bone marrow lymphocytosis and a long-lasting clinical remission. Studies at the DNA level confirm that a remission is rarely achieved in this disease in spite of intensive and prolonged chemotherapy. Nonetheless, the follow-up of B-CLL patients by conventional immunologic markers may be helpful to better define response to therapy and to predict the occurrence of clinical relapse.