Ticlopidine-induced aplastic anemia: development of chromosomal abnormalities and response to immunosuppressive therapy.

Severe aplastic anemia is a well-recognized complication of ticlopidine therapy that carries a high mortality. Therapy with colony-stimulating factors or corticosteroids has been largely ineffective in this disorder. We report a case of ticlopidine-induced aplastic anemia that was successfully treated with cyclosporine and high-dose dexamethasone. The patient rapidly responded to immunosuppressive therapy and had a normal hemogram after cessation of immunosuppression. On long-term follow-up, the patient developed a progressive macrocytic anemia. Repeat bone marrow evaluation demonstrated myelodysplasia with erythroid hypoplasia. An associated chromosomal abnormality consisting of a t(3;16) (q21; p13.3) translocation was detected. This is the first report of a chromosomal abnormality associated with ticlopidine induced marrow aplastic anemia.

Estudio citogenético en pacientes con leucemia mieloblástica aguda: Caracterización de grupos de riesgo por estudios cromosómicos / Cytogenetic study in patients with acute myeloblastic leukemia: Characterization of high risk groups by cytogenetic studies

Presentamos el estudio citogenético en 30 pacientes adultos en los que se diagnosticó leucemia mieloblástica aguda de novo, para caracterizar grupos de mayor riesgo en nuestra población. Los pacientes fueron tratados con esquemas conocidos "7 + 3" de daunorrubicina y arabinósido de citosina; así como ácido retinoico en los casos de M3. El cariotipo se realizó al momento del diagnóstico y en el seguimiento cada seis a ocho meses. Se observaron alteraciones cromosómicas en 90 por ciento de los casos, una incidencia mayor a la registrada en la literatura. Una respuesta clínica efectiva con periodos más largos de remisión y supervivencia se observó en los pacientes que tenían M2 con t(8;21), M4 con rearreglos de (16g) o cariotipo normal. En cambio, los pacientes con M3 y t(15;17) o los que presentan t(9;22), +8, o -7 tuvieron las peores respuestas, con menor tiempo de remisión y los más altos índices de mortalidad, por lo que deben considerarse de alto riesgo en nuestra población

[Growth hormone therapy in dysmorphic syndromes and chronic disease]. / Groeihormoontherapie bij dysmorfe syndromen en chronische ziekten.

Many clinical syndromes are associated with short stature, which can be proportionate or disproportionate. In the first group of syndromes, such as Turner syndrome and its variants, Down syndrome, Prader-Willi-Labhart syndrome, Noonan syndrome, and Silver-Russell syndrome growth hormone therapy can lead to increased growth velocity, but so far only short-term results have been reported. Growth hormone is contraindicated in syndromes with an increased risk of chromosomal breakage, e.g. Bloom syndrome. In disproportionate syndromes, such as hypochondroplasia, pseudopseudohypoparathyroidism, spina bifida, and hypophosphataemic rickets, the results of growth hormone therapy are not encouraging. Growth hormone therapy in children with rheumatoid arthritis and thalassaemia appears little effective. Long-term clinical trials of reasonable size are needed before reliable conclusions can be drawn about the value of growth hormone therapy in these conditions.

Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia.

Detailed cytogenetic analyses were performed on specimens from 198 patients with de novo acute nonlymphocytic leukemia (ANLL), including high-resolution banding studies in 79 patients. One hundred ninety-two patients received induction therapy with daunorubicin and cytosine arabinoside (Ara-C) with an overall complete response rate (CR) of 63%. Responding patients received repetitive cycles of Ara-C-based intensification therapy. Clonal abnormalities were detected in 69% of the patients with specimens adequate for cytogenetic analysis. Certain cytogenetic changes were closely associated with French-American-British (FAB) morphology, age, and outcome: t(8;21) (closely associated with FAB M2), t(15;17) (associated with FAB M3), and abn 16q22 (associated with FAB M4EOS) tended to occur in younger patients and were associated with favorable outcomes in terms of both CR rate and long-term disease-free survival. In contrast, 19% of patients who had -5/5q- and or -7/7q- and seven patients with trisomy 8 were older, had a poor prognosis, and usually failed to achieve remission (CR) because of chemotherapy-resistant leukemia. The adverse effect on CR rate and duration in this group of patients was independent of age, and there was no association with particular morphologic subtypes. These data suggest that cytogenetic findings should influence future therapeutic choices. In particular, patients with abnormalities associated with poor responses may be considered for investigational approaches and may also provide insights into mechanisms of drug resistance.

Short remission durations in therapy-related leukemia despite cytogenetic complete responses to high-dose cytarabine.

Seventeen patients with therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute nonlymphocytic leukemia (t-ANLL) were treated with single-agent high-dose cytarabine (HDAC; 1 to 3 g/m2 every 12 hours for 12 doses). The initial neoplasm was still present in eight patients when t-MDS/t-ANLL developed. Fifteen of the 16 patients with chromosomal abnormalities in bone marrow cells had loss or rearrangement of chromosomes 5 and/or 7. One patient had a t(15;17), and one had inadequate material for cytogenetic analysis. Twelve patients had normal metaphase cells (3% to 71%). Indications for HDAC therapy were progressive pancytopenia in 13 patients or rising blast count in four. Five patients died of marrow hypoplasia following therapy. Four others had refractory t-ANLL and died within the subsequent 5 months. Only one of ten patients with a poor performance status (PS greater than or equal to 2 using the ECOG scale) achieved a complete remission, but all seven patients with a good performance status (PS less than or equal to 1) had a complete remission. Hematologic remissions were achieved in 8 patients (47%) after one (6 patients) or two (2 patients) induction courses and were confirmed by recovery of a 100% normal marrow karyotype in six of the seven patients who were retested. Patients in remission received one to four consolidation courses with HDAC alternating with cytarabine/doxorubicin, but seven relapsed within 8 months (median remission duration, 5 months). In every case, the original chromosomal abnormality reappeared at relapse. HDAC has a high response rate for good-performance patients with t-MDS/t-ANLL, but complete remissions are short even when confirmed cytogenetically and consolidated intensively.

[Clinical polymorphism in amenorrhea of chromosomal and nonchromosomal etiologies]. / Izuchenie klinicheskogo polimorfizma amenorei khromosomnoi i nekhromosomnoi étiologii.

In search of the basis of distinguishing amenorrhea, due to chromosomal mosaicism and other causes, 179 females affected by primary or secondary amenorrhea were examined, 83 of them being 45,X/46,XX mosaics. 119 traits characterizing the morphological status of the musculoskeletal and reproductive systems, as well as skin, hair and nails were scored. By means of statistical approaches, a group of 21 traits were specified, which makes it possible to diagnose the amenorrhea of chromosomal origin. Statistically significant association between the clinical manifestations and the rate of mosaicism was shown.

Specific chromosomal abnormalities in acute nonlymphocytic leukemia correlate with drug susceptibility in vivo.

Specific chromosomal abnormalities are independent predictors of response to therapy in acute nonlymphocytic leukemia (ANLL) de novo. In a series of 149 patients with ANLL, we sought to determine whether the t(8;21), t(15;17), t(9;11) or other abnormalities of the long arm of chromosome 11, inv(16) or t(16;16), inv(3) or t(3;3), trisomy 8, and abnormalities of chromosome 5 (-5/5q-) or of chromosome 7 (-7/7q-) identify differences in susceptibility to chemotherapy drugs in vivo. The immediate outcome of the first cycle of remission induction chemotherapy was analyzed for patients in each cytogenetic subgroup as an index of the drug susceptibility of the leukemia cells in vivo. Patients with t(8;21), inv(16), t(16;16), or 11q abnormalities had high rates of complete remission after initial therapy (60-100%), whereas patients with -7/7q- or -5/5q- had low initial response rates (0-36%), suggestive of drug resistance in vivo. In general, cytogenetic groups with high initial complete remission rates ("drug sensitive") also had long disease-free survivals; those groups with low initial remission rates ("drug resistant") had short remission durations even if these patients eventually achieved complete remission with further therapy. Patients with acute promyelocytic leukemia (APL), all of whom had the t(15;17), were the exception; despite low initial remission rates, they had long disease-free survivals, possibly due to a more rapid cytotoxic effect of chemotherapy on the clonogenic APL cells than on the more numerous malignant promyelocytes. We conclude that the prognostic importance of specific chromosomal abnormalities in ANLL resides in part in differing susceptibilities to chemotherapy.

Chromosomal abnormalities in B-CLL.

Amongst 141 patients with B-CLL, 53% had an abnormal karyotype. Treatment free survival was shorter in those with karyotypic abnormalities, and especially in those with multiple abnormalities. Multiple abnormalities tended to be associated with progressive disease. Trisomy 12 alone carried no worse a prognosis than a normal karyotype. 49% of patients with stage AO disease had an abnormal karyotype.

Cytogenetic studies of early myeloid progenitor compartments in Ph1-positive chronic myeloid leukemia. II. Long-term culture reveals the persistence of Ph1-negative progenitors in treated as well as newly diagnosed patients.

We recently showed that long-term marrow cultures can be used to demonstrate the presence of Philadelphia (Ph1) negative progenitors in patients with newly diagnosed Ph1-positive chronic myeloid leukemia (CML). We now report results for 6 chronic phase patients studied 5-83 mo postdiagnosis and an additional 3 newly diagnosed patients. Marrow metaphases were exclusively Ph1-positive. Clonogenic assays revealed a minor population of Ph1-negative progenitors in 3 cases (1 treated, 2 untreated). Long-term marrow culture adherent layers contained Ph1-negative progenitors in 6 cases (3 treated, 3 untreated). Whenever this occurred, the Ph1-negative population had become the only one detectable within 3-4 wk, and this was always associated with a rapid decline of the Ph1-positive population. For 2 of the 3 cases where Ph1-negative progenitors were not detected, there was a similar rapid decline in the Ph1-positive population in culture. In the other case, Ph1-positive progenitors were maintained at levels typically seen in normal long-term marrow cultures. These results suggest that chromosomally normal stem cells may persist for a considerable period in the marrow of some, but perhaps not all, patients with CML, even in the face of maintenance chemotherapy. In addition, they provide new evidence of heterogeneity in this disease, as shown by the variable ability of Ph1-positive progenitor populations to be maintained in vitro.

[Antimutagenic effectiveness of pyrimidine derivatives in lesions of the bone marrow cell chromosome apparatus in mice infected with measles or poliomyelitis viruses]. / Amtimutagennaia éffektivnost' pirimidinovykh proizvodnykh pri porazheniiakh khromosomnogo apparata kletok kostnogo mozga myshei, zarazhennykh virusami kori i poliomielita.

It is determined that the number of marrow cells with cytogenetic disturbances grows in mice infected with measles or polymyelitis viruses. The level of marrow cells with disturbances is much lower in the mice fed with methyluracilum or pentoxylum before infection. The level of deteriorated cells also decreases when the mice were fed with the mentioned drug after infection. In an analogous experiment with polymyelitis viruses the antimutagenic effect was not determined.