[Large granular lymphocytic leukemia. Case report with scarce expression in peripheral blood]. / Leucemia de linfocitos grandes granulares. Presentación de un caso con escasa expresión en sangre periférica.

The case of a 33 year old woman with a large granular lymphocytic leukemia is presented. The main symptoms were neutropenia and recurrent respiratory bacterial infections. No enlargement of the liver, spleen or lymph nodes was noted. Circulating lymphocytes averaged 3000/microliter with 35% of large granular cells. The bone marrow biopsy showed lymphatic infiltration with both nodular and interstitial pattern. Lymphocytes bore the T suppressor phenotype (CD8+, CD45 RO+, CD20-, kappa-, lambda-). Cytogenetic studies revealed a low expression clone with 7q-: del (7)(q36). Gene rearrangements for immunoglobulins or T-cell receptors could not be demonstrated by Southern Blot. Bone marrow cultures grew normally while both normal and patient bone marrow showed marked inhibition when incubated with patients serum. Normalization of the peripheral granulocytic count was obtained with prednisone, while granulocytic-stimulating factors, chlorambucil, and cyclosporine A were partially active or inactive. We suggest that this case represents a form of the lymphoproliferative disease of granular lymphocytes. To our knowledge, the deletion of the long arm of chromosome 7 has not been described in this disease.

[Enzyme replacement therapy in type 1 Gaucher's disease]. / Terapia de reemplazo enzimático en la enfermedad de Gaucher Tipo 1.

Gaucher disease is a sphingolipid storage disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase (GC) and the consequent deposition of glucocerebrosides into the cells of the macrophagic system. Among the three types of clinical disease, type 1 leads to hepatosplenomegaly, hypersplenism and skeletal abnormalities including bone pain, osteopenia and fractures. Two pediatric female patients with moderately severe type 1 Gaucher disease were treated with commercially available GC, mannose terminated to be macrophage-targeted. GC was given by intravenous infusion (30 to 60 units per kilogram of body weight every two weeks) for 8 and 18 months. The hemoglobin concentration increased and the serum acid phosphatase decreased in both patients. In the most affected child, hepatic volume decreased significantly and bony symptoms disappeared. Infusions were uneventful except for an episode of anaphylaxis that subsided rapidly, allowed resumption and did not affect efficacy. These observations are in agreement with the international experience in approximately 800 cases, with good tolerance in all type 1 patients who show objective clinical improvement; patterns of response are variable from patient to patient, independent from previous splenectomy, and dose-dependent; the dose can be tapered after a period of time. Antibodies anti-GC are seen in 13% of the patients, but their presence does not have clinical consequences. The cost of the enzyme makes it crucial to define precise indications, optimal dosing schedules, duration of treatment and cost-benefit ratio.

[Incidence and probable etiology of toxic agranulocytosis in a definite population in the province of Buenos Aires (1963-1976)]. / Incidencia y etiología probable de agranulocitosis tóxica en una población definida de la provincia de Buenos Aires (1963-1976).

The medical records of 55 patients with toxic agranulocytosis (unrelated to radiation, anticancer drugs or known industrial toxics) were reviewed in a well defined population of the Province of Buenos Aires during 1963-1976. There were 65 episodes in 30 women and 25 men, age average 49 years. Nine patients repeated the episode by reexposure to the same drug. The annual incidence rate was 8.4 cases per million/year. Nineteen (35.5%) of the patients died. Forty-three episodes (64.3%) were associated with analgesic-antipyretics, mainly dipyrone (34 cases). In most situations, drugs were prescribed for mild complaints such as pharyngitis, arthralgias or abdominal pain. Although toxic agranulocytosis is an infrequent disease, its relationship with drugs is well known and its mortality remains high.

Incidencia y etiología probable de agranulocitosis tóxica en una población definida de la provincia de Buenos Aires (1963-1976) / Incidence and probable etiology of toxic agranulocytosis in a definite population of the Buenos Aires province (1963-1976

Se revisaron las historias clínicas de 55 enfermos com agranulocitosis tóxica (no relacionada con antineoplásicos, irradiación o tóxicos industriales conocidos), procedentes de la zona de influencia sanitaria de la ciudad de Bahía Blanca, entre 1963 y 1976. Hubieron 65 episodios en 30 mujeres y 25 hombres, con una edad promedio de 49 años. Nueve enfermos repitieron el episodio por reexposición al mismo fármaco. La incidencia anual media fue de 8,4 casos por millón de habitantes por año. Diecinueve pacientes (34,5 por ciento) murieron. Cuarenta y tres episodios (64,3 por ciento se asociaron con analgésicos-antipiréticos, en especial dipirona (34 episodios). En la mayoría de los casos, los fármacos se indicaron por problemas banales tales como faringitis, artralgias o dolor abdominal. Aunque la agrunulocitosis tóxica es una enfermedad infrecuente, su relación con fármacos es bien conocida y su mortalidad es relativamente alta

Terapia de reemplazo enzimático en la enfermedad de Gaucher Tipo 1 / Enzyme replacement therapy in type 1 Gaucher's disease

La enfermedad de Gaucher es una deficiencia de glucocerebrosidasa (GC) con acumulación de glucocerebrósidos en el sistema macrofágico, y da lugar a tres formas clínicas diferentes. De ellas, el tipo 1 se caracteriza por infiltración del bazo, hígado y médula ósea e incluye además alteraciones esqueléticas, evidenciadas por dolor óseo, osteopenia y fracturas. Se trataron dos niñas con GC disponible comercialmente, usando dosis bimensuales entre 30 y 60 U/Kg. En ambas pudo observarse tendencia a la normalización de la hemoglobina y fosfatasa ácida sérica, y en la más afectada menor hepatomegalia y desaparición de los síntomas esquelético. Un episódio de anafilaxia observado en esta misma enferma cedió rápidamente, y pudo continuar el tratamiento sin que ocurriera disminución de la respuesta. Los resultados coincidentes con la experiencia mundial, confirman que el tratamiento con GC es racional y efectivo en la enfermedad de Gaucher tipo I. La tolerancia es buena y no se describen fenómenos de resistencia. La modalidad de respuesta es variable, pero todos los enfermos responden y al cabo de un tiempo se puede disminuir lentamente la dosis. Aun así, el precio de la enzima impone una precisa definición de las indicaciones en función de una óptima relación conto-beneficio

[Dacie syndrome and other splenomegalies without apparent cause]. / El síndrome de Dacie y otras esplenomegalias sin causa aparente.

Some enlarged spleens do not seem to be related with known pathogenetic mechanisms (passive congestion, functional workload, malignant infiltration and inflammatory or storage disorders). Non-tropical idiopathic splenomegaly (Dacie's syndrome) is a form of hypersplenism of unknown origin that evolves into a non-Hodgkin lymphoma, after a variable interval, in 20% of the patients. Tropical idiopathic splenomegaly (or hyperreactive malarial splenomegaly) develops when a chronic malarial challenge triggers an abnormal immunological response consisting in decreased suppressor T lymphocytes and increased amounts of circulating immunoglobulin M and immunocomplexes, which are cleared by the splenic macrophages. This peculiar response to malaria seems to be linked to particular HLA antigens. Other confusing splenomegalies are seen in Felty's syndrome, in populations subjected to recurrent infections, and in some families. Overlapping findings and diseases suggest chronic antigenic stimulation as a common feature, with diverse responses depending on the host. A small percentage (probably less than 3%) of normal individuals has minimal splenomegaly without any clinical significance.

Incidence and etiology of aplastic anemia in a defined population of Argentina 1966-1977

Se estudió la incidencia y etiología de la anemia aplástica en una población estable y bien definida del salud de la provincia de Buenos Aires, entre los años 1966 y 1977. Se diagnosticaron 35 casos entre 450.000 habitantes, (incidencia promedio 6 por millón/año). Este valor es parecido al encontrado en la mayoría de los apíses del hemisferio occidental, lo mismo que la edad promedio (49,6 años) y la distribución etaria. Se encontró además, una relación hombre/mujer alta, una mayor frecuencia en la población urbana comparada con la rural, y una incidencia decreciente en función del tiempo. El significado de estos hallazgos es, sin embargo, especulativo, dado el relativamente escaso número de pacientes. La etiología fue desconocida en el 65,7% de los casos. Los agentes causales encontrados fueron mielotóxicos conocidos (cloramfenicol, hepatitis viral). El 54,2% delos enfermos presentó la forma severa de la enfermedad; este grupo no mostró ninguna característica definida. Estos datos se estiman útiles para estudios comparativos y prospectivos

Correlation if circulating immune complexes and disease status in patients with leukaemia.

The occurrence of soluble immune complexes (IC) was investigated in 177 serum samples from 92 patients with various leukaemias using the Raji cell immunoassay. In general, patients with myeloproliferative diseases had a higher incidence and higher quantities of IC than did patients with lymphoproliferative disorders. Elevated levels of IC were found in the sera of patients as follows: 17% with chronic lymphocytic leukaemia (mean value of 13.1 microgram/ml), 67% with acute lymphocytic leukaemia (54.1 microgram/ml), 65% with chronic myelocytic leukaemia (86.7 microgram/ml), 70% with acute myelocytic leukaemia (202.5 microgram/ml) and 56% with acute myelomonocytic leukaemia (41.9 microgram/ml). Patients in terminal blastic crisis of chronic myelocytic leukaemia had the highest levels, with a mean level of 1,364.1 microgram/ml. Serial samples were obtained, as available, from individual patients during the course of the disease in an attempt to relate severity with the incidence and quantity of IC. No significant correlation could be made between the occurrence or levels of IC and the presence of absence of systemic symptoms. Similarly, no correlations could be made between levels of IC and haematological parameters, infection, or therapy. However, the data does indicate a positive relationship between the levels of IC and the progressive state of the leukaemia, especially, the myelocytic leukaemias.

Evaluation of drug-antibody conjugates in the treatment of human myelosarcomas transplanted in nude mice.

Methotrexate, daunomycin, and chlorambucil were independently conjugated to immune goat gamma-globulins specifically raised to the Ph1 + chronic myelogenous leukemia cell line K-562. The drug-antibody conjugates were then tested against myelosarcomas made up of K-562 cells growing in nude mice and their efficacy was compared with that of the drug alone, gamma-globulins, a mixture of the two, or conjugates of drugs with normal goat gamma-globulin. Conjugation methods for methotrexate and daunomycin abrogate the antibody activity as indicated by the absence of complement-mediated cytotoxicity of the conjugates in vitro and the lack of effect on myelosarcomas in vivo. Simultaneous administration of either of these drugs and antibody partially abrogated the development of myelosarcomas. Chlorambucil-antibody conjugates, however, retained their cytotoxicity in vitro and were found effective in vivo. It is the first successful attempt to covalently bind chlorambucil to gamma-globulins without the loss of drug or antibody biological activity. Although the simultaneous administration of chlorambucil and gamma-globulins and conjugated drug gamma-globulins reduced the growth of myelosarcomas considerably, the immune gamma-globulins alone either reduced their weight to a larger degree or eliminated their growth completely. Results of this study indicate that myelosarcomas made up of K-562 cells grown in nude mice are good and reproducible models for testing various therapeutic agents. The advantage of using human cells proliferating in an in vivo environment brings experimental therapy one step closer to clinical trials.

Hematopoiesis of hereditarily asplenic-athymic (lasat) mice.

The hematopoiesis of athymic-asplenic (lasat) mice was compared with that of normal, asplenic, and athymic littermates with the same strain background. Erythrocyte blood volume, number and survival time were normal when related to the body weight of the animals. Peripheral blood showed leukopenia with absolute and relative lymphopenia, resembling the athymic rather than the asplenic pattern. The bone marrow was hypocellular as a consequence of a decrease in both lymphocytes and erythroid precursors, while thrombocytopoiesis and granulcytopoiesis-monocytopoiesis were essentially normal. Although the percentile value of femoral stem cells was high, their absolute number was, in fact, reduced by 35% as a result of the bone marrow hypocellularity. When lasat bone marrow cells were injected into normal, lethally irradiated mice, a rapid erythropoietic recovery was observed, whereas the restoration of the granlocytic compartment was impaired. It was concluded that: 1) lasat mice depict a normal hematopoiesis in spite of the congenital absence of the thymus and the spleen; 2) bone marrow stem cells may be defective when administered to lethally irradiated hosts; and 3) the athymic status predominates over the asplenic one.

Postirradiation erythropoietic recovery in splenectomized mice.

The influence of splenectomy on erythropoietic recovery of lethally X-irradiated mice injected with different doses of syngeneic bone marrow was studied. Splenectomized animals showed less activation than unoperated controls in the lower dose range; however, by increasing the number of injected cells the response obtained was similar in both groups. Providing an adequate number of stem cells is administered to the splenectomized recipients, an enhanced erythropoietic activity of the graft may compensate for the absence of the spleen, which is an important organ in postirradiation recovery. Suggested explanations for this observation are lack of an haematopoietic inhibitory effect of the irradiated spleen, or changes in the environment provided by the spleenless host.

Some aspects of iron metabolism during erythropoietic depression in the mouse.

Spleen and bone marrow patterns of response differ in mice subjected to erythropoietic depressors. Radioiron injected a few hours after a high dose of cyclophosphamide or x-irradiation is retained in the bone marrow. The magnitude of medullary retention is closely related to the number of cells able to synthesize hemoglobin at the moment of iron administration, and to the rate of cell death provoked by the cytotoxic agent. Depressors such as Actinomycin and transfusion, that block the differentiation of stem cells while allowing normal maturation of the erythroid cohort, do not induce marrow entrapment of iron. By contrast, retention is never observed in the spleen, where the 59-Fe turnover is not influenced by the mechanism and magnitude of aplasia. A functional lack of homogeneity of splenic and bone marrow erythropoiesis, hemoglobin metabolism and/or handling of iron stores is proposed. These results would be in agreement with other data from the literature reporting physiological differences among the various sectors of the reticuloendothelial system.