[Cytogenetic monitoring acute myeloid leucosis in children].

Preliminary results of cytogenetic monitoring acute myeloid leukosis (AML) in children are presented. Repeated chromosomal analyses were accomplished in 23 patients that presented with cell clones showing various karyotype abnormalities prior to the onset of therapy. All the patients were treated following identical protocols. Complete hematological remission was achieved in 20 cases. The majority of patients did not have cells with chromosomal abnormalities changes after a 2-4 month follow up. Anomalous metaphases persisted in 6 patients although their occurrence decreased. Five of them poorly responded to therapy whereas simultaneous achievement of morphological and cytogenetic remission ensured more beneficial outcome of the treatment. Results of the study agree with recent reports of delayed reversion to normal karyotype under effect of AML therapy that as a rule predicts an unfavourable prognosis Repeated analysis during stable hematological remission did not reveal cells with karyotype abnormalities in bone marrow with the exception of a single patient who had marrow cells with chromosomal translocation (16:16) up to the 8th month of complete hematological remission. This patient remains under observation (duration of remission is now 15 months). It was shown that the relative amount of cells with abnormal karyotype in bone marrow frequently exceeds that of blast cells (usually before the onset of therapy and sometimes in the beginning of morphological remission). During stable remission, such an excess is an antecedent of relapse. It is concluded that cytogenetic analysis for monitoring AML extends the possibility of detecting leukemia cells.

[Chromosomal translocation t(8,21) in acute myeloid leukemia of children: prognostic value of additional karyotype abnormalities].

Prognostic significance of additional karyotype abnormalities was studied in 73 children with t(8,21) acute myeloid leukemia (AML). Additional chromosomal aberrations were documented in 61 cases (83.6%). The loss of sex chromosomes and/or deletion of the long arm of chromosome 9 (9q-) were predominant abnormalities, in agreement with the literature data. Other additional abnormalities detected in 14 cases were tentatively designated as "atypical". Comparison of pretreatment cytogenetic data and those obtained during relapses revealed the previously unknown rise in the frequency of atypical abnormalities in AML relapses (to 63.6% vs 19.2% at the first presentation, p < 0.005). It is supposed that atypical additional abnormalities reflect relatively late stages of leukemia, and their presence before therapy predicts poor prognosis. In fact, general, relapse-free, and uneventful survival rates in patients with atypical abnormalities were significantly lower that in the remaining patients with t(8;21) AML. Poor survival was associated not only with early relapses but also with high mortality from fatal infections soon after onset of treatment. The incidence of fatal infections in this group was significantly higher than in patients without atypical abnormalities (p = 0.027). Atypical additional abnormalities are rather variable and each variant should to be specifically characterized to estimate its prognostic significance. Our results need to be verified in a larger-scale multicentre study.

[Complex karyotype abnormalities in pediatric acute myeloid leukemia].

A majority of the data on the prognostic significance of distinct chromosome changes and combinations of them in pediatric acute myeloid leukemia (AML) has been derived from adult studies, with not numerous published data in pediatric patients. One of points needed to be clarified is prognostic significance of complex karyotype (at least 3 unrelated abnormalities). We investigated characteristic features of complex karyotype in newly diagnosed pediatric AML de novo. Cell clones with complex karyotype were found in 35 of 254 (13.8%) patients at the age from 0 to 15 years studied prior to therapy. The group was divided into 2 subgroups depending on presence of favorable chromosome abnormalities, i.e. (see symbols)(8;21), t(15;17) and inv(16). The abnormalities were absent in 20 cases (1st subgroup), in 15 remaining patients they were identified (2nd subgroup). In 2nd subgroup karyotypes were not so considerably changed and no adverse risk markers were detected as distinct from 1st subgroup. New data were obtained for complex karyotype differences of adult and pediatric AML. In the great majority (76%) of complex karyotypes in our adult patients chromosome abnormalities associated with adverse risk were found but in pediatric patients their frequency was significantly less (30%). The highest rate of complex karyotype we observed in children at the age from 0 to 3 years. Similar data were not published earlier. Complex karyotype is considered to be characteristic of older AML patients and in the majority of the patients the karyotype contains markers of adverse risk. Possibly, worse outcome in older AML patients is connected with the markers but not with multiple chromosome changes. New data of frequency and the peculiarities of complex karyotype in pediatric AML are important for understanding of AML pathogenesis and for development a more effective AML treatment.

Increased karyotype precision using fluorescence in situ hybridization and spectral karyotyping in patients with myeloid malignancies.

We studied seven patients with various malignant hematologic disorders using fluorescence in situ hybridization (FISH) and one of these patients with spectral karyotyping (SKY). With appropriate probes, the t(8;21) and inv(16) were confirmed in two patients and the karyotypic precision was increased in five others using FISH and SKY. Two of three patients with 12p rearrangements had a deletion of one TEL allele. Thus, these newer techniques are an important adjunct to accurate chromosome analysis in malignancy.

MLL is involved in a t(2;11)(p21;q23) in a patient with acute myeloblastic leukemia.

We describe a patient with acute myeloblastic leukemia (AML-M0) whose cells had a t(2;11)(p21;q23). Fluorescence in situ hybridization analysis with a probe for MLL showed that it was split, hybridizing to both the derivative 2 and 11 chromosomes. Nineteen other patients with 2p;11q translocations have been described; breakpoints in 14 of these are the same as in the case we describe. The phenotype of these patients is quite variable, with 14 patients having myelodysplastic syndrome which evolved to AML in six. Four patients had AML and two had acute lymphoblastic leukemia. MLL status has been studied in two other patients; one had MLL rearranged and one did not.

[Karyotypic anomalies and chromosomal sites of increased fragility in colorectal cancer]. / Anomalii kariotipa i saity povyshennoi lomskiti khromosom pri kolorektal'nykh rakakh.

Karyotypic structural aberrations in tumor cells and chromosome constitutive fragile sites (cFSs) in peripheral blood lymphocytes were studied in ten patients with colorectal adenocarcinoma Most chromosome breakpoints (38 out of 40, i.e., 95.0%) were shown to be located within cFSs in tumor cells. Expression of 24 out of 137 cFSs in patients was higher than that in healthy donors. Four of these cFSs (6q26, 7q36, 16q23, and 17q21), were involved in the formation of nonrandom tumor cell chromosome markers most characteristic of colorectal neoplasms. The frequency of damages induced within these sites was analyzed in each patient. Expression of 7q36, 16q23, and 17q21 was increased in blood cells of patients carrying specific chromosome rearrangements with the breakpoints within these sites. The association between nonrandom chromosome aberrations in tumor cells and cFSs in normal cells is discussed.

[Metachronous cancer of the gastro-intestinal tract with signs of endocrine-cell differentiation]. / Metakhronnyi rak zheludochno-kishechnogo trakta s priznakami éndokrinnokletochnoi differentsirovki.

A case of metachronous cancer of gastrointestinal tract is reported. Three poorly differentiated malignant epithelial tumours developed in a 27-year-old patient within three years. They located in the stomach, small and large intestine. Light-microscopically, the tumours were formed mainly of non-differentiated rounded cells with occasional signet ring cells. At electron microscopic examination the presence of mucin granules was confirmed. Moreover, a variable amount of electron-dense endocrine-like granules was found in tumour cells. According to some publications, endocrine differentiation of gastrointestinal cancers is considered to be a poor prognostic feature, hence electron microscopy or special staining when possible can be important in the evaluation of prognosis.

[Geographic differences in the frequency of chromosome alterations characteristic of cancer of the large intestine]. / Geograficheskie razlichiia v chastote khromosomnykh izmenenii kharakternykh dlia raka tolstoi kishki.

The authors' material (33 tumours) and that from foreign literature (18 to 100 tumours from every country) was used. The following chromosome aberrations were compared: the deletion of a part of chromosome 1 short arm, deletion of chromosome 5 and a part of its long arm, additional chromosomes 7, complete or partial deletion of chromosome 17 short arm, deletion of chromosome 18 and appearance of additional chromosomes 20. Clear-cut differences were revealed between the following three groups of regions: 1) countries of the Eastern and Western Europe (Russia, France, Germany); 2) Northern Europe countries (Denmark, SWeden); 3) USA and China. Geographical differences in chromosome anomalies in hemoblastosis were found in 1970s, the difference in colon carcinoma are presented for the first time. The experimental results suggest that non-homogeneous distribution of the karyotype alterations typical for certain morphological types of malignant tumours are due to different environmental influences.

Translocation (2;3)(p13;q26) in two cases of myeloid malignancies. Acute myeloblastic leukemia (M2) and blastic phase of chronic myeloid leukemia.

Two cases of myeloid leukemias (acute [AML M2] and chronic [CMC]), blastic crisis, with identical t(2;3)(p13;q26) are described. These cases had some peculiarities: no significant decrease of blood thrombocyte count in the AML patient and high increase of blood thrombocyte count during blastic phase in the CML patient; dysplastic megakaryocytes in bone marrow and unfavorable course of the disease; and short remission (3 months) in AML and short chronic phase (8 months) in CML. Clinical and morphologic findings in patients with t(2;3)(p13;q26) resembled those in cases with 3q21q26 syndrome or with other chromosome rearrangements involving 3q21 or 3q26.

[A comparative clinico-morphological analysis of acute myelo- and myelomonoblastic leukemias in children and adults]. / Sravnitel'nyi kliniko-morfologicheskii analiz ostrogo mielo- i mielomonoblastnogo leikozov u detei i vzroslykh.

Previous morphocytochemical, immunological and cytogenetic analyses of blast cells in 174 children and 188 adults admitted to Cancer Research Center have shown that compared to adults in children leukemic precursors belong to earlier stage of differentiation similar to polypotent cell. The analysis covered 2 FAB-variants of ANLL comparable by the number of patients and intensity of the given chemotherapy (M2 and M4 ANLL FAB variants). The study included 65 children (50 with M2 and 15 with M4 FAB variants) and 43 adults (26 with M2 and 17 with M4 FAB variants) given therapy of standard intensity in the regimen 3+7 and 2+5. The children more frequently demonstrated involvement of the liver, spleen and peripheral lymph nodes. The percentage of complete remissions in both groups was not significantly different. 2- and 3-year recurrence-free survival was similar in two age groups with M2 FAB variants of ANLL. However, in M4 variant in adults this survival made up 18% against 0% in children. The differences may arise from lower peroxidase activity in children than in adults. It is suggested that M4 FAB variant in adults may indicate better prognosis than in children. Therefore, therapy in children with M4 FAB ANLL variant should be intensified.

Blast cells in child and adult AML: comparative study of morphocytochemical, immunological and cytogenetic characteristics.

Bone marrow blast cells of 174 child and 188 adult patients with AML were examined and characterized in terms of their FAB type, immunological phenotype (102 children, 123 adults) and karyotype (69 children, 95 adults). The incidence of FAB variants of AML proved similar in children and adults. In patients under 15 and over 60, peroxidase activity in myeloblasts was lower than in middle-aged patients. Similar rates of HLA-Dr. Thy-1, CD11a, T-cell antigens, CD19, Gly-A and Eb antigens were found in cells of child and adult patients. The frequency of CD11b, CD38 and CD10 antigen expression on blast cells was higher in children than in adults. Abnormal blast karyotype was noted in 81.8% of children and 73.7% of adults. Translocation (8;21) was usually found in cases of M2 type (82%), significantly more frequently in children. predominantly in the group aged 6-10. t(15;17) was detected in all age groups only in M3 type of cells (86%). t(9;22) occurred more frequently in adults than in children; t(11q23) incidence rates were somewhat higher in children than in adults. Three cases of AML in children are described with deletion of chromosome 5 in their leukaemic cells. The data obtained indicate different biological characteristics of blast cells in children and adults. It is likely that haemopoietic cell involvement in children under 2 years and adult patients over 60 occurs at earlier stages than in middle-aged patients.

11q deletions in human colorectal carcinomas: cytogenetics and restriction fragment length polymorphism analysis.

Deletions and/or allelic losses of a portion of the long arm of chromosome 11 were discovered by cytogenetic and restriction fragment length polymorphism analyses in 23 of 39 (59%) informative cases of colorectal carcinoma. By comparing the patterns of loss of heterozygosity and chromosome rearrangements in different patients, we could map a common target region to 11q22-23. This region may contain a tumor suppressor gene, the inactivation of which may be involved in the development of tumors of the large intestine. The subgroup of malignancies with 11q alterations seemed to be enriched by tumors that were located in the rectum, that were Dukes' stage A, and that were well differentiated and mucin producing.

Translocations (17;20) in colorectal adenocarcinomas.

We describe new recurrent chromosome translocations (17;20) observed in 3 of 19 colorectal tumors. Two of them were identical: der(20)t(17;20)(q21;p12), resulting in the loss of 17(pter-->q21) and the third was a dicentric dic(17;20)(p11;p12). A similar dicentric was described previously in one tumor [1], but we report der(20)t(17;20)(q21;p12) for the first time.

Karyotype peculiarities of human colorectal adenocarcinomas.

The data of the chromosome abnormalities in 15 colorectal tumors are presented. Rearrangements of the short arm of chromosome 17, leading to deletions of this arm or its part were noted in 12 tumors; in 2 other cases, one of the homologs of pair 17 was lost. The losses of at least one homolog of other chromosomal pairs were also found: chromosome 18, in 12 out of 13 cases with fully identified numerical abnormalities; chromosome 5, in 6 tumors; chromosome 21, in 5 cases; chromosomes 4, 15, and 22, in 4 cases each. Additional homologs of pair 20 were observed in 6 tumors, extra 8q was found in 5 tumors, and extra 13q in 6 cases. Rearrangements of the short arm of chromosome 1 and the long arm of chromosome 11 characterized 6 tumors each. The data recorded in our series differ from the data of other authors in two respects: the high incidence of the loss of sex chromosomes and the rearrangements of the long arm of chromosome 9. X chromosomes were missing in 4 out of 7 tumors in females, and Y chromosomes were absent in 5 out of 8 tumors in males. The long arm of chromosome 9 was rearranged in 8 cases, in 5 of them the breakpoint being at 9q22. Cytological manifestations of gene amplification (double minutes or multiple microchromosomes) were noted in 6 tumors.

Chromosomal characteristics of malignant lymphoma.

Results of a cytogenetic and morphological study of 60 malignant lymphomas (ML) are presented. The most often observed chromosome abnormalities were rearrangements involving 14q32, 11q13, 11q21-23, 6q15, 6q21, 12p11-12, 17p11-12, and extra chromosomes 18, 3, 21 and 7. Translocations involving 14q32, leading to the appearance of marker 14q+, were noted in 41% of the tumors. Strict correlations between karyotype and morphology of ML were not seen. However, rearrangements of 11q were mostly found in low-grade tumors and markers 6q- in high-grade tumors. The absence of t(14;18), which is regarded to be the most common abnormality in ML, and an unusually high incidence of t(11;14) in our series confirm the uneven geographical distribution of ML with these translocations. Chromosome abnormalities in ML and acute lymphoblastic leukemia are compared.

Chromosomal rearrangements with a common breakpoint at 6p23 in five cases of myeloid leukemia.

Rearrangement of the short arm of chromosome 6 with a breakpoint at 6p23 was found in five patients with myeloid leukemia. Three of them had different morphological variants of AML (M2, M3, M4) and two blastic crisis of Ph1 negative and Ph1 positive CML. Identical translocation, t(6;9)(p23;q34), was revealed in two patients. One of them had AML (M2), the other blastic crisis of Ph1 negative CML. The blast cells of the last patient were morphologically similar to those in the M2 variant of AML. Translocation (6;9)(p23;q34) was also detected in two AML patients of Rowley and Potter (1976). The role of the breakpoint at 6p23 in myeloid malignancies needs further investigation.

Correlations between the clinical course, characteristics of blast cells, and karyotype patterns in chronic myeloid leukemia.

Results of chromosome studies of blood and bone marrow cells from 101 patients with Ph1 positive chronic myeloid leukemia (CML) confirm the assumptions that clinical and morphologic manifestations of the disease correlate with karyotype peculiarities of leukemia cells. Several variants of the clinical course of CML may be distinguished. One is the variant with a short chronic phase and a comparatively long terminal phase. In blastic crisis the blast cells are peroxidase negative and do not possess cytoplasmic inclusions. Acute transformation occurs without any additional chromosome damage. The second, more common form is less severe because of longer chronic phase but it has a short and grave acute stage. The blast cells present definite signs of myeloid differentiation, they have basophilic or neutrophilic cytoplasmic granules and are peroxidase positive. Marker i(17q) often combined with trisomy 8 is a characteristic chromosome abnormality in the terminal stage of this variant. The third type has an extremely long chronic phase but ends in a rapidly progressing severe and resistant to therapy "lymphoid" blastic crisis. Blast cells have typical "lymphoid" morphology, they are peroxidase negative and contain granular PAS positive substance. Various additional chromosome changes appear in the terminal stage. Future studies of a larger series of patients may possibly reveal more CML variants.