Clinical significance of the del(20q) chromosome in hematologic disorders.

Patients with hematologic neoplasias often have chromosomal aberrations in the cells of their bone marrow or unstimulated blood. One recurrent abnormality is a deletion of the long arm of chromosome 20, primarily described in polycythemia vera, but later seen in a range of hematologic disorders. We have studied 32 patients with del(20q) as the sole chromosomal aberration, investigating significance of this aberration for the clinical diagnoses, hematologic parameters, and prognoses within this patient group. According to our results, del(20q) is primarily associated with myeloid disorders, but it is not specific for any certain disease, nor does the proportion of cells with del(20q) correlate with prognosis.

Familial pericentric inversion (3)(p12q24).

A large kindred with a familial pericentric inversion of chromosome 3, (p12q24), was found after an investigation initiated by a young female with three spontaneous first-trimester abortions. Altogether 22 (33%) inversion carriers were discovered, 9 females and 13 males. 6 women and 9 men were included in the fertility and segregation analyses because they were all either sexually mature or past maturity. The abortion frequency was below the average European rate in both the inversion carrier group and the cytogenetically normal relative group; 6%:3%, respectively. The mean numbers of pregnancies and live births (1.8-3.1) did not vary significantly in the two comparison groups. The segregation analysis among the inversion carriers showed a good correspondence to the theoretical 1:1 ratio (16:13). Males and females contributed equally. No duplication/deletion syndromes have been found in the kindred; all family members are phenotypically normal. We report a balanced familial pericentric inversion with no adverse effects. This chromosome aberration could be an example of a harmless chromosome polymorphism.

[Chromosomes and chromosome disorders]. / Kromosomer och kromosomrubbningar.

The risk of bearing a child with chromosomal defects increases once the mother reaches the age of 35; the principal indication for chromosomal examination of the fetus is that the pregnant woman is "older". Chromosomal examination of new-born babies is indicated if it is suspected that dysmorphic features may depend on cytogenetic deviation. Other indications include suspicion of so-called fragile X syndrome or rare congenital disorders such as Fanconi's anemia, Xeroderma pigmentosum etc. Chromosomal examination is routine today in investigation of suspected or verified hematological diseases. Nevertheless the possibilities of cytogenetic techniques have not yet been used to the full in diagnostics, assessment of prognoses, choice of therapy and follow-up of disease.

Clodronate for osteolytic metastases due to breast cancer.

Breast-cancer patients with multiple osteolytic bone metastases were treated with clodronate (Cl2MDP) 1.6 g/day (17 patients) or placebo (17 patients) for 12 months. Bone pain, extension of bone metastases and formation of new osteolytic foci were reduced by Cl2MDP, and development of severe hypercalcaemia was prevented. After withdrawal of treatment, the patients were followed up for at least 12 months. New bone metastases developed in both groups. There were, however, less fractures and less hypercalcaemia in the Cl2MDP than in the placebo group. The survival rate was higher in the Cl2MDP group than in the placebo group. No side-effects were observed in the Cl2MDP group.

Cytogenetic investigations of patients on clodronate therapy for Paget's disease of bone.

In order to judge whether or not clodronate used for treatment of patients with Paget's disease of bone had an effect on the haematopoetic tissue, the frequency of chromosome/chromatid breaks in bone marrows and blood cells was evaluated. Seven patients were studied before treatment, after a few days of treatment and after greater than or equal to 2 months of treatment. Three additional patients were studied after exposure to clodronate for greater than or equal to 6 months. There was no significant increase in the occurrence of chromosomal aberrations induced by treatment. Thus no negative effect of clodronate on the haematopoetic tissue could be noted.

Treatment of skeletal disease in breast cancer: a controlled clodronate trial.

Normocalcaemic breast cancer patients with progressive osteolytic bone metastases were treated with clodronate 1.6 g/day (17) or placebo (17) for 12 months. Bone pain, extension of bone metastases and formation of new osteolytic foci were reduced by clodronate, and development of severe hypercalcaemia was prevented. After withdrawal of treatment the patients were followed-up for at at least 12 months. New bone metastases developed in both groups. There were, however, less fractures and less hypercalcaemia in the clodronate than in the placebo group. The survival rate was higher in the clodronate group than in the placebo group. No haematological toxicity was observed in the clodronate group.

Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia.

The importance of banded chromosome analyses in predicting long-term outcome in acute lymphoblastic leukemia (ALL) was evaluated in this follow-up study of 329 patients from the Third International Workshop on Chromosomes in Leukemia. Patients were divided into ten groups according to pretreatment karyotype: no abnormalities, one of the following structural abnormalities [the Philadelphia chromosome, translocations involving 8q24,t(4;11), 14q+, 6q-] or, in the remaining cases, modal number [less than 46, 46, 47 to 50, greater than 50]. Achievement and duration of complete remission (CR) and survival differed among chromosome groups (P less than .0001). Karyotype was an independent prognostic factor for duration of first CR and survival, even when age, initial leukocyte count (WBC), French-American-British (FAB) type, and immunologic phenotype were considered. Among adults, prolonged remission and survival were uncommon in all chromosome groups. Only in the normal karyotype group was median survival even two years. Among children, striking differences in long-term remission and survival were seen depending upon karyotype. Children in the greater than 50 group did best, with 70% remaining in first CR for a median duration in excess of five years. Children in the 47-50, 6q-, and normal karyotype groups also had prolonged survivals. In contrast, certain translocations [t(9;22)(q34;q11), t(4;11)(q21;q14-23), t(8;14)(q24;q32)] identified children who had short survivals, even in the presence of favorable prognostic factors including a low WBC, L1 morphology, and non-T, non-B immunologic phenotype. We conclude that chromosome analysis is required at diagnosis in patients with ALL, and that children with these specific translocations should be managed as having high-risk ALL.

A method for simultaneous study of the karyotype, morphology, and immunologic phenotype of mitotic cells in hematologic malignancies.

A major problem in the cytogenetic analysis of hematologic neoplasms has been an inability to identify the cell from which the chromosomes were obtained. We describe a procedure that allows simultaneous analysis of karyotype and cell cytology in mitotic cells. The method differs from conventional cytogenetic analysis in that after mild hypotonic treatment, the cells are cytocentrifuged onto glass slides. In mitotic cells, this procedure often results in adequate spread of the chromosomes within the intact cell membrane. The cytoplasmic structure also remains intact, so that cytologic preparations are of good quality. Morphologic and immunologic identification of mitotic cells can be done using routine hematologic stains, such as Giemsa or Sudan black B, and various antisera using immunofluorescence techniques. The chromosomes can be simultaneously analyzed either without banding on slides stained with Giemsa or with Q-banding on slides stained with immunofluorescence techniques. Identification of numerical and structural karyotype aberrations thus is possible in morphologically identified cells.

Chromosome abnormalities in 16 Finnish patients with Burkitt's lymphoma or L3 acute lymphocytic leukemia.

Eleven patients with Burkitt's lymphoma (BL), i.e., small noncleaved non-Hodgkin's lymphoma, and 5 patients with Burkitt-type acute lymphocytic leukemia (ALL-L3) were selected for chromosome study. Two of the 16 patients had no B-cell markers, but the erythrocyte marker--glycophorin A--was present on the surface of the leukemic blasts. The critical breakpoint at 8q24 was detected in 14 of the 16 patients, whereas this aberration was not detected in any of the 134 patients belonging to other subgroups of non-Hodgkin's lymphoma or ALL that we studied during the same period. In addition to the t(8;14)(q24;q32), the following translocations with the breakpoint at 8q24 were seen: t(2;8)(p11;q24), t(8;11)(q24;q13) in BL, and t(2;8;14)(p11 or p12;q24;q32) in ALL. Additional aberrations seen more than once were trisomy #7 and abnormalities in chromosomes #1, #11, and #13.

Abnormalities of chromosome 13 in myelofibrosis.

19 patients with myelofibrosis, primary or following polycythaemia vera were studied cytogenetically. Bone marrow cells, unstimulated and stimulated cells from peripheral blood were investigated. 7 patients were found to have clonal aberrations, 3 of whom had a structural rearrangement of chromosome 13. In 2 additional cases single mitoses with 13q- were found. Reviewing the files on patients previously studied in our laboratory, 2 more patients with 13q- markers were noted. Both had had haematologic disorders in which fibrosis of the bone marrow can be found, but this feature could not be evaluated retrospectively, because no biopsies had been taken. Our data and those found in the literature suggest that rearrangements of 13q12----q22 are often associated with myelofibrosis, both in its primary form or following polycythaemia vera.

Peripheral blood cells in the study of chromosome aberrations of patients with chronic myeloid leukaemia or myelofibrosis.

Chromosome studies were performed on peripheral blood (PB) cells with and without stimulation, and/or on bone marrow (BM) cells from 21 patients with chronic myeloid leukaemia (CML), and 18 patients with myelofibrosis (MF). Our results show that almost all the patients with immature granulocyte precursors in PB also had mitotic cells in their unstimulated PB. In CML all unstimulated mitoses had the Philadelphia chromosome. In each patient the abnormal karyotype in the PB was the same as in the BM. Because of the high frequency of dry taps in myelofibrosis, the tissue of choice for chromosome study is peripheral blood.

Abnormalities of chromosome No. 17 in myeloproliferative disorders.

In routine analyses, abnormalities of chromosome No. 17 were found in the bone marrow cells of 28 patients with Ph1-positive and three patients with Ph1-negative chronic myeloid leukemia (CML), 4 patients with acute nonlymphocytic leukemia (ANLL), and 4 patients with preleukemia. With three exceptions, all patients were in the blastic (CML) or the terminal phase. In 28 patients, the aberrant chromosome No. 17 arose by clonal evolution from the karyotype found at diagnosis or before the terminal phase. The abnormalities encountered were an isochromosome for the long arm, i(17q), (26 cases), translocations involving No. 17 (12 cases), trisomy 17 (three cases), and ring 17 (one case). In 35 patients, there was an unbalanced structural aberration of at least one of the No. 17 chromosomes. In every case (35/35), detailed analysis of the structurally abnormal No. 17 revealed loss of the distal part of the short arm (or possibly most of the short arm). Gain of the long arm (or at least its proximal part) was also common, but not invariably present (26/35). It is suggested that loss of 17p is a highly nonrandom event related to blastic crisis in CML and the terminal phase in other myeloid leukemias.

The 5q- chromosome in preleukaemia and acute leukaemia.

13 patients with the 5q- chromosome are described. In 6 patients the 5q- chromosome was the sole aberration. 10 patients had preleukaemia, 1 a preleukaemia-like syndrome after treatment of polycythaemia vera, a 2 acute myeloid leukaemia. The prognosis was especially poor in terms of survival in preleukaemic patients with 3 or more affected chromosomes: none of these 6 patients survived for more than 6 months. In 4 patients the haematological picture resembled 'the 5q- syndrome'. In the long arm of chromosome No 5 deletions of 3 different kinds were detected. They were named according to the size of the 5q- marker: the short type (10 patients), the intermediate type (1 patient) and the long type (2 patients). There was no clear correlation between the clinical picture and the type of deletion. While the break points cannot always be exactly defined, our data and those reviewed from the literature suggest that the loss of a segment of regions 5q2 or 5q3 is common to all or most deletions.

Haem biosynthesis in refractory sideroblastic anaemia associated with the preleukaemic syndrome.

The activities of 5 enzymes of the haem biosynthetic pathway and the protoporphyrin concentrations have been measured in peripheral red blood cells of 23 patients having a preleukaemic syndrome with refractory sideroblastic anaemia. A decreased delta-aminolaevulinic acid synthase (ALA-S) activity, an increased uroporphyrinogen I synthase activity and an increased red cell protoporphyrin concentration were consistent findings. Patients with abnormal leucocyte and/or platelet counts in the peripheral blood as well as patients with an excess of blast cells in the bone marrow had the lowest ALA-S activities. A further decrease in ALA-S activity was observed in 3 patients after leukaemic change in the disease. Patients having cytogenetic abnormalities showed no unique enzyme abnormalities. These results indicate that enzymatic disturbances of haem synthesis cannot be used as prognostic indicator of leukaemic transformation in refractory sideroblastic anaemia, but a very low ALA-S activity appears to accompany the development of a leukaemia in such patients.