Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion.

Infant acute leukemia (IAL) frequently involves breakage and recombination of the MLL gene with one of several potential partner genes. These gene fusions arise in utero and are similar to those found in leukemias secondary to chemotherapy with inhibitors of topoisomerase II (topo-II). This has led to the hypothesis that in utero exposures to chemicals may cause IAL via an effect on topo-II. We report a pilot case-control study of IAL across different countries and ethnic groups. Cases (n = 136) were population-based in most centers. Controls (n = 266) were selected from inpatients and outpatients at hospitals serving the same populations. MLL rearrangement status was derived by Southern blot analysis, and maternal exposure data were obtained by interviews using a structured questionnaire. Apart from the use of cigarettes and alcohol, very few mothers reported exposure to known topo-II inhibitors. Significant case-control differences were apparent for ingestion of several groups of drugs, including herbal medicines and drugs classified as "DNA-damaging," and for exposure to pesticides with the last two being largely attributable, respectively, to one nonsteroidal anti-inflammatory drug, dipyrone, and mosquitocidals (including Baygon). Elevated odds ratios were observed for MLL+ve (but not MLL-ve) leukemias (2.31 for DNA-damaging drugs, P = 0.03; 5.84 for dipyrone, P = 0.001; and 9.68 for mosquitocidals, P = 0.003). Although it is unclear at present whether these particular exposures operate via an effect on topo-II, the data suggest that specific chemical exposures of the fetus during pregnancy may cause MLL gene fusions. Given the widespread use of dipyrone, Baygon, and other carbamate-based insecticides in certain settings, confirmation of these apparent associations is urgently required.

HTLV-I induced intestinal lymphoma.

We document an unusual case of HTLV-I positive adult T-cell leukaemia lymphoma (ATLL) in a 25 year old Chilean patient who presented with primary small intestinal involvement and during evolution developed a leukaemic phase. Duodenal biopsy showed infiltration by pleomorphic lymphoid cells with a CD45RO+ CD20- phenotype. Circulating lymphocytes had a convoluted nucleus and displayed a mature T-cell phenotype: CD2+, CD3+, CD4+, CD8-, CD25+, HLA-Dr+. HTLV-I serology was positive and HTLV-I retroviral sequences were demonstrated by PCR in the tissue. The patient was treated with chlorambucil and is well, disease free five years from diagnosis. Intestinal lymphoma as initial manifestation of ATLL is extremely uncommon, but when a T-cell lymphoma is detected in this localisation, in patients from a HTLV-I endemic area, retroviral studies are recommended in order to exclude an association with this retrovirus.

Análisis no-lineal de la dinámica de enfermedades infecciosas en Chile / Non linear analysis of the infectious disease dynamics in Chile

Background: The incidence of infectious diseases generally has large fluctuations, probably due to interactions between seasonal fluctuations and those secondary to case-susceptible host interactions. Aim: To analyze the complexity and attractant topological resemblance of seven infectious diseases in Chile. Material and methods: The annual incidence of measles, whooping cough, scarlet fever, meningococcal meningitis, diphtheria, typhoid fever and poliomyelitis was obtained from the annual reports of diseases. Correlation dimensions and the largest Lyapunov series exponents were estimated. The resemblance among their attractants was assessed by Hausdorff distance. The measures were performed both before and after seasonal filtering. Results: All series showed a dynamics near low dimensional chaos. The correlation dimensions ranged between 2.12 and 2.76. The correlation dimensions did not change after seasonal differentiation. Apart from one, all disease dynamics had large Lyapunov exponents, near 0.6 Bits/year. These decreased if series were differentiated. Before differentiation, the topological resemblance was mainly caused by the seasonal component of the dynamics but thereafter, the resemblance increased. In spite of different transmission mechanisms and etiologies, all analyzed infectious diseases conformed a truly single group, during cluster analyses. Conclusions: These results suggest that beneath the dynamics of infectious diseases, obscured by seasonal environmental factors, lays a very consistent nonlinear agent-susceptible host dynamics

[Adult T cell leukemia lymphoma in Chile. A clinical pathologic and molecular study of 26 patients]. / Leucemia linfoma T del adulto en Chile. Estudio clínico-patológico y molecular de 26 pacientes.

BACKGROUND: Adult T cell leukemia lymphoma is a lymphoproliferative syndrome etiologically associated to human T cell lymphotropic virus type I. AIM: To describe the clinical and laboratory features of 26 Caucasian Chilean patients, with HTLV-I positive adult T-cell leukemia lymphoma (ATLL). MATERIAL AND METHODS: Diagnostic criteria included clinical features, cell morphology, immunophenotype, HTLV-I serology and/or DNA analysis by Southern blot or PCR. RESULTS: According to the clinical presentation, 12 cases had the acute ATLL form, 6 had a lymphoma, 4 the chronic form and 4 had smoldering ATLL. The median presentation age was 50 years, younger than the Japanese patients, but significantly older than patients from other South American countries (e.g. Brasil, Jamaica, Colombia). The main clinical features: lymphadenopathy, skin lesions and hepatosplenomegaly, were similar in frequency to those of patients from other countries, except for the high incidence of associated neurological disease. Tropical Spastic Paraparesis (TSP) in our series of ATLL, was seen in one third of the patients (8/26). A T-cell immunophenotype was shown in all 26 cases and HTLV-I serology was positive in 25/26 patients. Molecular analysis on the seronegative patient showed clonal integration of proviral HTLV-I DNA into the lymphocytes DNA, and thus he may have been a poor responder to the retroviral infection. Proviral DNA integration was also demonstrated in 15/16 patients being clonal in 10, polyclonal in 3 (all smoldering cases) and oligoclonal in one. CONCLUSIONS: ATLL in Chile has similar clinical and laboratory features than the disease in other parts of the world, except for a younger age than Japanese patients but older than those from other Latin American countries and a high incidence of patients with associated TSP. Detailed morphological and immunophenotypic analysis of the abnormal circulating lymphocytes, together with the documentation of HTLV-I by serology and/or DNA analysis are key tests for the identification of this disease.

[Acute myeloid leukemia MO: clinical and laboratory characteristics]. / Leucemia mieloide aguda Mo: características clínicas y de laboratorio.

BACKGROUND: A recent update of FAB classification has included a myeloid leukemia subtype with a minimal degree of differentiation, that has been denominated LMA-MO. AIM: To report the clinical, morphological and immunophenotypic features of patients with LMA-MO. PATIENTS AND METHODS: Eight patients, out of 368, with acute myeloid leukemia that were studied in the Hematology Laboratory of a public hospital in Santiago, were classified as LMA-MO. RESULTS: Blast cell morphology was undifferentiated or of subtype FAB-L2 lymphoblastic leukemia with medium sized blasts, agranular basophilic cytoplasm, reticular nuclear chromatin and a prominent nucleolus. Cytochemical staining was negative for peroxidase and esterases, immunophenotyping showed the expression of one or more myeloid antigens (CD13, CD33) and was negative for lymphoid antigens. Immunocytochemical expression of myeloperoxidase was positive in the three cases where it was performed. Only one patient achieved complete remission and is free of disease after 36 months of follow up. All other patients died without obtaining remission, six shortly after the onset and one 12 months after. CONCLUSIONS: The diagnosis of LMA-MO is essential considering its dismal prognosis.

[Immunophenotype. Clinical and laboratory features of acute lymphoblastic leukemia in Chile. Study of 500 children and 131 adults]. / Inmunofenotipo. características clínicas y laboratorio de la leucemia linfoblástica aguda en chile. Estudio de 500 niños y 131 adultos.

We describe the clinical features and immunophenotype of 500 children and 131 adults with acute lymphoblastic leukemia (ALL), diagnosed between 1984 and 1993. Cases were classified, according to immunophenotype in B-cell ALL with three subtypes (pro-B or null, common and B) and T-cell ALL. Among children, common ALL accounted for 74% of cases and pro-B all was more common in children of less than one year (14%). B ALL was observed in 2% of children. Ten percent of children, mostly males, had T-cell ALL. The third part of these children had high leukocyte counts and a mediastinal mass. Children from Mapuche origin, compared with Caucasian children had a lower proportion of common ALL (36 and 74% respectively) and a higher proportions of T-cell ALL (41 and 10% respectively). Among adults common ALL was the most common phenotype (72%) followed by T-cell ALL (15%), pro-B ALL (11%) and B-cell ALL (2%). There was a lower incidence of children with common ALL with positive cytoplasmic immunoglobulin compared to North American or European studies (2 and 15-33% respectively) and a higher proportion of adults with common ALL compared with pro-B cell ALL, in contrast to European studies that show a higher proportion of patients with pro-B cell ALL. No other immunophenotypic, clinical or laboratory differences were observed with ALL from developed countries. It is concluded that the immunophenotyping of ALL allows a more precise diagnosis of this disease.

Rapid intraclonal switch of lineage dominance in congenital leukaemia with a MLL gene rearrangement.

We describe a case of neonatal mixed lineage leukaemia which presented with a dominant B progenitor lymphoblast population plus a minor monocytic component. Treatment of the patient with corticosteroid and Ara-C resulted in loss of lymphoblasts and a rapid (within 7 days) increase and dominance of the monocytic component. The common clonal origin of the two cell types was evident from the identical rearrangement in the MLL gene and a shared rearrangement of one IGH allele. In common with other neonatal or infant ALL with MLL gene rearrangements, this leukaemia may have originated in a common B-monocytic lineage stem cell during foetal haemopoiesis. The observations further suggest that the therapeutic impact of the MLL gene rearrangement is to some extent dependent on the cellular context in which it is expressed.

HTLV-I positive adult T-cell leukaemia/lymphoma (ATLL) in Chile.

We describe the clinical and laboratory features of nine patients born in Chile with HTLV-I-positive adult T-cell leukemia/lymphoma (ATLL). All were adults (median age 51 years) of Caucasian origin without evidence of Indian or foreign extraction and none had been out of the country. The main disease features were organomegaly, cutaneous lesions, hypercalcemia and leukemia with atypical polylobed lymphocytes displaying a CD2+, CD3+, CD4+, CD8-, CD7- T-cell phenotype. Eight patients presented with acute type ATLL and one had a chronic form lasting for 16 months prior to the development of the acute phase. Lymph node histology (three cases) was consistent with a T-cell non-Hodgkin's lymphoma (large and small cells). Antibodies to HTLV-I were detected by ELISA and particle agglutination in the serum from eight of nine patients. DNA analysis showed HTLV-I proviral DNA in all seven cases investigated, including the single serologically negative patient. In five cases, HTLV-I was monoclonally integrated and in one case oligoclonal. In the seventh case viral DNA clonal status was ambiguous. Response to therapy was poor and median survival was 3 months (range 2-20 months). This study provides further evidence that HTLV-I is endemic in Chile, a non-tropical country where the two main diseases associated with HTLV-I, ATLL and TSP, are found.

[Prolymphocytic leukemia, description of 2 cases]. / Leucemia prolinfoctica, descripción de dos casos.

We present the clinical and laboratory features of 2 patients with B prolymphocytic leukemia. Both are females of the fifth and seventh decade of life. One had the classical clinical picture of massive splenomegaly and a high white cell count, with characteristic prolymphocytes, and the other was asymptomatic, with a low white cell count. The cells were positive to B cell lineage reagents with strong surface immunoglobuline (Ig) and unreactive to T cell antibodies. Analysis of Ig genes at the DNA level demonstrated that both cases had heavy-chain gene rearrangements, confirming the B-cell origin. These are the first patients of prolymphocytic leukemia described in Chile.

[Immunologic study of lymphoproliferative diseases]. / Estudio inmunológico de enfermedades linfoproliferativas.

Thirty six patients with stage IV lymphoproliferative diseases, were studied with a panel of monoclonal antibodies. There were 26 B-Lymphoproliferative Diseases (BLD): 11 B-chronic lymphocytic leukemia, 15 B-cell non Hodgkin lymphoma and 10 T-Lymphoproliferative Diseases (TLD): 4 T-cell non Hodgkin lymphoma, 4 adult T-cell leukemia/lymphoma, 1 T-chronic lymphocytic leukemia and 1 Sezary Syndrome. HLA-DR and CD 19 (B4) were the most common antigens found in BLD. CD4 + CD8 was the most common phenotype in TLD. 13 out of 26 BLD and 1 out of 10 TLD, patient were alive at the end of a 4 year observation period. Our study shows that immunophenotyping is a very useful diagnostic test in lymphoproliferative diseases. Along with cytology and histopathology, it can better define different pathologic groups and lead more specific treatments.