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PubMed1988

Cytogenetic study of chronic myeloid leukemia.

A total of 122 patients with chronic myeloid leukemia (CML) were cytogenetically examined. At the first cytogenetic examination 68 of them were in chronic phase (CP) and 54 in blastic phase (BP) of the disease. The mean age of the whole group was 44.8 +/- 15.2 years. All patients included in this study were Ph-positive. In two of them constitutional chromosomal aberrations were ascertained. In two patients the standard Ph translocation was accompanied within onset of BP by a clone with complex translocation and in three patients Ph chromosome was found in mosaics with normal karyotype. Standard translocation t(9.22) (q34;q11) as the sole chromosomal abnormality was found in 17 (31%) patients in BP and in 47 (69%) of patients in CP. The most frequent additional abnormalities found were +8, i(17q), +Ph and their combination, and other nonrandom chromosomal changes. Clonal evolution was proved in 11 out of 24 serially examined patients during the progression of the disease. The analysis of relationship between prognosis of the disease and the results of cytogenetic examination revealed significant differences, and a more favorable course of the disease was observed for the group of patients in CP and with Ph chromosome as the sole chromosomal aberration.

Adult↗
PubMed1987

[Immunology of myeloma].

Multiple myeloma (MM) is the most common malignant plasma cell dyscrasia. It is defined as the malignant expression of clonal expansion (in blood and bone marrow) of idiotypic B lymphoid cells (B id+) with proliferation, asynchronic maturation, and abnormal secretion of idiotypic plasma cells, initially maintained in the bone marrow. Malignancy includes: suppression of nonidiotypic (= polyclonal) B cell activation, suppression of normal hematopoiesis, and excessive osteoclastic resorption, via the production of osteoclast activating factors by myeloma cells. In MM, tumor growth is initially very slow in bone marrow (= chronic phase), controlled by chemotherapy or spontaneously controlled (= indolent variant). Terminal disease is marked by uncontrolled and fast tumor growth with extramedullary involvement of tumor cells (= fulminant or acute phase). Clonal evolution with chromosomal changes (chromosomes 1, 11, 14) is generally involved in the growth pattern changes. The nature of the oncogenic event and of the myeloma stem cell remains unknown.

B-Lymphocytes↗
PubMed1988

Frequent nonrandom chromosome abnormalities in 27 patients with untreated large cell lymphoma and immunoblastic lymphoma.

Fresh tumor samples from 27 patients with large cell lymphoma, either previously untreated (26 patients) or minimally treated (one patient), were processed for cytogenetic studies. Cytogenetic abnormalities were observed in all patients, most commonly in chromosomes 1, 3, 7, 12, 14, 17, and 18. Nine chromosomal breakpoints appeared frequently: 14q32 in 14 instances; 18q21 in seven; 9p13-21, 17p11-13, and 3q21-23 in six each; 1p11-21 in five instances; 1p36 in four; and 2p21-23 in three. The most common structural abnormalities were t(14;18)(q32;q21) in seven patients (26%) and 17p- in six (22%). The presence of 17p- was associated with a significantly higher proliferative capacity as manifested by the percentage of S phase = 22% versus 11% for cases without 17p-(P less than 0.05). Trisomy 12, typical of small lymphocytic lymphoma, was seen in five patients in this series, all of whom had diffuse large cell lymphoma; frequently, it appeared simultaneously with t(14;18). The two patients with immunoblastic lymphoma of B-cell type had an abnormality involving chromosome 2p21-23. Deletions in the long arm of chromosome 6, previously described as typical of diffuse large cell lymphoma and B-cell immunoblastic lymphoma were observed infrequently in this series. However, this abnormality has been present in 50% of patients with large cell lymphoma previously exposed to therapy, suggesting that it may be related to effects of chemotherapy or to clonal evolution.

Chromosome Aberrations↗
PubMed1987

Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia.

Leukemic cells from 31 (7.6%) of 409 children with newly diagnosed acute lymphoblastic leukemia (ALL) had a hypodiploid karyotype. The patients' ages ranged from 0.8 to 17 years (median, 5 years) and their initial leukocyte counts from 1.0 to 132 X 10(9)/L (median, 12.7 X 10(9)/L). Modal chromosome numbers for the leukemic stem lines were 45 in 26 cases, 28 in two cases, and 26, 36 and 43 in one case each. Seven cases had one to three additional abnormal lines due to clonal evolution. Chromosome 20 was lost most frequently (nine cases). Structural abnormalities--including chromosomal translocations (21 cases), deletions (ten cases), duplications (two cases), or inversions (one case)--were common findings; the nonrandom translocations consisted of the t(1;19)(q23;p13.3) in two pre-B cases and tdic(9;12)(p1?1;p1?2) in three cases of common ALL. When compared with hyperdiploid cases (greater than 50 chromosomes), ALL with hypodiploidy was found to have a poorer outcome and was more likely to be associated with chromosomal translocations, higher serum lactic dehydrogenase levels, and age less than 2 or greater than or equal to 10 years. Moreover, patients with hypodiploid ALL fared as poorly as those with pseudodiploid karyotypes, even though their leukocyte counts and serum lactic dehydrogenase levels were lower and they had a comparable frequency of leukemic cell translocations. Hypodiploidy is therefore an unfavorable karyotypic feature in childhood ALL.

Acute Disease↗
PubMed1987

Association of a chromosomal 3;21 translocation with the blast phase of chronic myelogenous leukemia.

An identical reciprocal translocation between the long arms of chromosomes 3 and 21 with breakpoints in bands 3q26 and 21q22, t(3;21)(q26;q22), was found in three male patients with the blast phase of chronic myelogenous leukemia (CML). The abnormality was clonal in all three patients and was always accompanied by either a standard or variant 9;22 translocation resulting in a Philadelphia chromosome (Ph1). In two cases, the t(3;21) was the only abnormality other than a t(9;22) in the primary clone. Serial studies of one patient demonstrated that the t(3;21) occurred as a result of clonal evolution near the time of development of the blast phase. We have not observed the t(3;21) in greater than 500 patients with CML in the chronic phase. Thus, the t(3;21) is a new recurring cytogenetic abnormality associated with the blast phase of CML.

Adult↗
PubMed1987

Nonrandom chromosomal changes in human solid tumors: application of an improved culture method.

A cytogenetic study was performed on 48 primary human benign, borderline malignant, and malignant solid tumors from more than 10 different tissues. An improved cell culture method using an extracellular matrix substrate and a polyvalent serum-free medium was applied, which ensured a success rate of about 68%. The results disclosed a nonrandom involvement of chromosomes 1, 3, and 7 (especially duplication of chromosome 7) in numerical changes and a clustering of breakpoints on chromosomes 1, 3, 7, and 11. These data indicate that some chromosomal changes are shared by various types of tumors, suggesting some common genetic clonal evolution pathways.

Chromosome Aberrations↗
PubMed1987

Cytogenetic study of twelve human near-diploid breast cancers with chromosomal changes.

The karyotypes of 12 fresh breast cancers, including two of the male, selected for their near-diploidy and their slight number of anomalies, i.e. less than 10 rearranged chromosomes, are reported. A clonal evolution could be demonstrated in 4 cases. Most of chromosomal imbalances result from structural rearrangement, frequently after breakage in juxtacentromeric heterochromatin. There does not seem to exist a specific breakpoint, but many of the imbalances are recurrent. They are, by decreasing order of frequency: gain of 1q, (7 cases), losses of 11q, 16q and 1p (5 cases), losses of 8p and 13q (4 cases), gain of 8q and losses of 6q and 17p (3 cases). None of these anomalies can be regarded as primary, but they are likely to be selected because they confer a slight selective advantage for the carrier cells during the tumoral progression.

Breast Neoplasms↗
PubMed1987

[A new hypothesis on the natural history of bladder cancer based on the study of tumor DNA levels by flow cytometry].

72 bladder tumors were studied for nuclear DNA content with flow cytometry. A bimodal DNA profile was present in 33 of them (45%). The following findings concerning the aneuploid second peak of these 33 tumors are remarkable. Aneuploid peak DNA index distribution is discontinuous: there is no peak below 1.5 nor between 2.3 and 2.7. Aneuploid peak importance (second peak cell percentage versus all tumor cells in the same sample) increases when its DNA index decreases from 2.0 to 1.5 = this percentage is on average 45% for a DNA index of 2.0 and increases to 75% when DNA index decreases to 1.5. Aneuploid peak mitotic activity increases when DNA index decreases from 2.0 to 1.5 = the percentage of S G2 M cells of the aneuploid peak is in the range of 15% for a DNA index of 2.0 and in the range of 22% for a DNA index of 1.5. These findings are in favor of a dynamics in bladder cancer natural history. Tumors are supposed to share the same clonal evolution, in 3 stages. First stage: transformed tumor cell DNA profile is unimodal with a DNA index in the region of 1; second stage: due to chromosomic non-dysjunction during mitosis, a second peak appears with a DNA index of 2. Third stage: DNA index of this aneuploid second peak progressively decreases from 2 to 1.5 as a consequence of non vital chromosomes loss by tumor cells. It is suggested that DNA index as defined by flow cytometry does not have an absolute prognostic value per se, but in combination with tumors mitotic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Aneuploidy↗
PubMed1986

Analysis of growth fractions and stem cell compartments in transformed rat tracheal epithelial cell colonies.

The purpose of the studies described here was to define the biological behavior of the various clonally transformed colonies observed in cultures of carcinogen-exposed rat tracheal epithelial cells. As described in the preceding paper (H. Kitamura et al., Cancer Res., 46: 4631-4641, 1986), these colonies fall into four morphologically distinct categories. In the studies reported here we found that type I colonies had the smallest growth fraction (7%) and contained the lowest frequency of clonogenic cells (approximately 10(-3)). Colonies of types II to IV had mean growth fractions of 21 to 28%, and the frequency of clonogenic cells was 2 to 5 X 10(-2) when measured under growth-permissive conditions (3T3 feeders). When the clonogenic cell assays were performed under selective conditions to identify cell variants which can grow without feeder support, the average frequency of such clonogenic cells in type I colonies was less than 4 X 10(-5) and in colonies of types II to IV, between 5 X 10(-4) and 10(-2). In type IV colonies, the total number of cells per colony increased 8-fold between 5 and 12 wk postcarcinogen, but the clonogenic cell compartment increased 42-fold; the compartment of variant clonogenic cells, which are able to replicate on plastic, increased 139-fold during the same period of time. This indicated that major changes in the self-renewal capacity of the clonogenic cells were taking place during this early stage of transformation. Examination of the daughter colonies produced by replating colonies of types I to IV revealed that clonogenic cells with different growth potential existed within the same parent colony. Comparison of transformed colonies of the same type showed a marked degree of heterogeneity in the sizes of growth fractions and clonogenic cell fractions. These studies further indicated that, within all colonies, including the most advanced transformants, the majority of the cells were nonreplicating, terminal cells, suggesting that, at least during early stages of transformation, the transformed characteristics were not transferred from parent to daughter cells. With the exception of type I colonies, most of the colonies recognizable at 5 wk after carcinogen exposure progressed with time and acquired the morphological characteristics of type IV colonies, which were the most transformed phenotype. We conclude that transformation of rat tracheal epithelial cells is an asynchronous process and that the morphologically distinct types of rat tracheal epithelial cell colonies represent different stages of the clonal evolution of transformants.

Animals↗
PubMed1985

Cytogenetics and flow cytometry may predict phenotype of CML blast crisis.

Twenty-eight patients with chronic myelocytic leukemia (CML) and the Philadelphia chromosome (Ph1) were monitored using cytofluorometry and cytogenetics. During chronic phase, abnormal populations could be detected using commercially available monoclonal antibodies. These abnormal populations fell into two categories based on the presence or absence of HLA.DR. Patients with HLA.DR+ abnormal cells showed no clonal evolution and progressed to lymphoid blast crisis. Patients with HLA.DR- abnormal cells exhibited chromosomal abnormalities in addition to the Ph1 and progressed to a myeloblastic acute phase.

Adult↗
PubMed1985

Establishment of two new myeloma cell lines from bilateral pleural effusions: evidence for sequential in vivo clonal change.

Two new human myeloma cell lines have been established from a 36-year-old woman with refractory IgG kappa multiple myeloma in whom bilateral malignant pleural effusions developed. The malignant plasma cells from each effusion were set up in a liquid culture using an L-15 medium containing catalase, glutathione, selenous acid, ascorbic acid, insulin, transferrin, additional glutamine hydrocortisone, and 2-mercaptoethanol and designated as M-3 medium. Two IgG kappa cell lines, LB -831 and LB-832, were established and proved to be Epstein-Barr virus negative using the internal repeat sequence DNA probe. Characteristic plasma cell morphology was evident by light and electron microscopy. Immunotyping revealed an IgG kappa , B1+, B2-, Ia (HLA-DR)+, CALLA+ phenotype for each cell line as well as for the original pleural fluid and bone marrow myeloma cells. The supernatants also contained IgG kappa, beta 2 microglobulin, and large amounts of osteoclast-activating factor (indicating bone-resorbing activity). Cytogenetic analysis of the LB-831 cell line revealed a nearly triploid highly abnormal karyotype with numerous clonal chromosomal abnormalities involving chromosomes 1, 3, 5, 7, 13, and 15; several structurally abnormal marker chromosomes; and a putative homogeneously staining region on chromosome 7p at band p22. Analysis of the LB-832 cell line revealed several additional clonal abnormalities. These additional cytogenetic changes suggest that in vivo sequential clonal evolution occurred in this patient. Therefore, two new but related cell lines have been established, which should prove useful for further biological studies.

Adult↗
PubMed1986

Reliability and stability of the thymidine labeling index of breast carcinoma.

We have approached the question of the reliability of the thymidine labeling index (TLI) of breast carcinoma by comparing paired samples. Because the distribution of the TLI is approximately lognormal, comparisons were made after transformation to the natural logarithm. For 38 paired samples from the primary carcinoma (biopsy versus residual tumor in mastectomy specimen), r, 0.89, p less than 0.0001. For 68 primary carcinomas versus their axillary metastases, r, 0.90, p less than 0.0001. Substantial correlation was also observed between the TLIs of 18 primary breast carcinomas and their recurrent or metastatic lesions studied after relapse (r, 0.75, p less than 0.0003), and between 14 pairs of first and second primary carcinomas recovered from the same breast (r, 0.72, p less than 0.003). Good agreement was achieved among three observers in measuring the TLI from a set of breast carcinoma autoradiographs. We conclude that the TLI is sufficiently reliable for semiquantitative use as a means of separating breast carcinomas into groups with slow, moderate, and rapid rates of proliferation. The substantial similarities between the TLIs of breast carcinoma samples from different sites of the primary tumor, between primary tumor and axillary metastases, and between primary tumor and subsequent samples of relapsed tumor suggest that clonal evolution either is infrequent or does not usually affect the cell kinetics of the carcinoma. The similarity of the TLIs of synchronous dual primary carcinomas is an additional interesting finding.

Biopsy↗
PubMed1979

[Chromosome abnormalities in malignant lymphoma].

Analysis of the karyotype from bone marrow tissue and lymphocyte culture of the peripheral blood was performed in 25 children either with Hodgkin's or non-Hodgkins' lymphoma prior to any treatment. numeric aberrations were confirmed in 40% of the patients; in these the hyperdiploid number of chromosomes ranged from 52 to 94, while 24% of the cases had cells with 47 chromosomes of which the surplus chromosome corresponded to those of the group C and, in one case, of the group G. The occurence of cells with abnormal chromosome sets confirmed presence of clonal evolution. This was also a poor prognostic sign. By using cytogenetic of high accuracy and by studying further the chromosome abnormalities, problems concerning the importance of these abnormalities in the etiology and epidemiology of these diseases might be solved.

Chromosome Aberrations↗
PubMed1983

Clonal chromosome abnormalities in patients with Waldenström's and CLL-associated macroglobulinemia: significance of trisomy 12.

We performed cytogenetic analyses by Q- and G-banding techniques of unstimulated or B-mitogen-stimulated spleen, bone marrow, and peripheral blood cells from six patients with malignant macroglobulinemia [two with Waldenström's macroglobulinemia (WM) and four with chronic lymphocytic leukemia associated macroglobulinemia (CLL-M)]. Normal karyotypes were obtained in two of the treated patients (one with WM in remission and the other with CLL-M in relapse). An extra chromosome 12 (trisomy 12) was observed in all four untreated patients. In patient no. 2 (K.R.) and no. 3 (F.G.) with CLL-M, an abnormal karyotype, with trisomy 12 as the only abnormality, was identified. In patient no. 1 (C.C.) with WM, there were two clonal chromosome changes, identified: 47, XX, -9, +12, plus marker chromosome and 48, XX, -9, +12, plus both marker and minute chromosomes. In patient no. 4 (R.M.) with CLL-M, a minute chromosome with or without loss of a G-group chromosome was seen in some metaphases without trisomy 12, in addition to metaphases with trisomy 12 alone. Each of the four untreated patients with WM or CLL-M had clonal chromosome abnormalities, suggesting that chromosome changes may be more frequently associated with WM or CLL-M than with typical CLL without macroglobulinemia. These observations also suggest that trisomy 12 may be the primary karyotypic change in malignant macroglobulinemia, whereas the appearance of the minute or marker chromosome as well as the loss of G-group chromosomes or chromosome no. 9 may be secondary karyotypic changes resulting from clonal evolution in these malignancies.

Aged↗
PubMed1983

Effect of X irradiation on a heterotransplanted human colonic carcinoma before and after a change in the cellular DNA content.

A spontaneous change of cellular DNA content occurred in a hyperdiploid human colonic carcinoma grown in nude mice. After the change to hyperpentaploidy the tumor was exposed to single-dose X irradiation, and the effects on growth curves and on the cell cycle, determined by flow cytometric DNA analysis (FCM), were compared to results obtained with the tumor prior to the evolutionary event. The results showed that the radiation effects on growth rate and on cell kinetics had changed after the change in cellular DNA content. In the hyperpentaploid tumor the irradiation had no effect on the regrowth rate, whereas in the hyperdiploid tumor the postirradiation growth rate had decreased. As a consequence of the different effect on the regrowth rate of the tumors the growth delay was inadequate as a parameter for comparing the radiosensitivity. In the hyperpentaploid tumor the irradiation induced a partial synchronization of accumulated cells, whereas no synchronization effect was found in the hyperdiploid tumor. The redistribution time was 8-10 days for both tumors. The results indicate that clonal evolution may affect radiosensitivity, and that FCM analysis may prove to be a valuable method to provide rapid information on cellular synchronization and on redistribution time.

Animals↗
PubMed1981

Cytogenetic observations in chronic myeloid leukemia (CML) correlations of the cytogenetic findings with morphological cytochemical features of blast cells in various types of blastic phase.

Forty-nine cases of chronic myeloid leukemia have been investigated using cytogenic methods. Twenty-six patients were studied in chronic phase, twenty-three during the transformation of the disease. Out of the second group of the patients, nine were myeloid, five myelomonocytic, two promyelocytic, two megakaryoblastic and five lymphoid in their morphological and cytochemical appearance. Some correlation could be observed between the clinical, morphological, cytological and cytogenetic findings of different subgroups of the blastic phase in CML. The results demonstrate the divergent clonal evolution of transformed blast cells, and emphasize the importance of chromosome investigations -- in addition to the early diagnosis of metamorphosis -- in distinguishing the different subgroups of the terminal stage of CML.

Adult↗
PubMed1982

Flow cytometry of breast carcinoma. III. Possible altered kinetics in axillary lymph node metastases.

The cell cycle distribution of human mammary carcinoma was determined by flow cytometry in 21 cases and compared with that of the same tumor concurrently metastatic in regional lymph nodes. The percentage of S-phase cells in the nodal metastasis as compared to the primary tumor was significantly lower in estrogen-binding-positive tumors than in estrogen-binding-negative tumors. Since we do not have evidence of clonal evolution in the metastases, it is possible that there is a local inhibitory effect of the lymph node on tumor cell proliferation in the case of some estrogen-binding-positive tumors.

Breast Neoplasms↗
PubMed1981

Multicentric nature of vulvar carcinoma in situ.

A detailed histologic and DNA-microspectrophotometric study is presented of 31 lesions selected from 12 of 65 patients with vulvar carcinoma in situ whom the authors have seen. In 6 patients the lesions were multicentric and in 6 they were confluent. The purpose of the study was to determine whether or not there was a measurable biologic difference between these 2 distinctly different clinical lesions that would justify separating them into different categories. A hypothesis as to the clonal evolution of multicentric and confluent vulvar carcinoma is presented based on the authors' findings.

Carcinoma in Situ↗