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PubMed2002

Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461).

We analyzed prospectively 1213 adults with de novo acute myeloid leukemia (AML) to ascertain the prognostic impact of cytogenetic abnormalities on complete remission (CR) rate, 5-year cumulative incidence of relapse (CIR), and 5-year overall survival (OS). All patients received similar induction therapy. Median follow-up for surviving patients was 8.3 years. Nonprioritized cytogenetics distinguished t(8;21) and inv(16)/t(16;16) as conferring a significantly better prognosis than normal karyotype. Prognostic impact of many abnormalities could not be determined independently because of their association with complex karyotype. Neither complex karyotype nor secondary aberrations affected outcome of patients with t(8;21), inv(16)/t(16;16), or t(9;11). Among other patients, those with complex karyotypes had significantly worse outcomes than cytogenetically normal patients. Based on outcome for specific cytogenetic abnormalities and karyotype complexity, patients were divided into 3 risk groups: favorable (CR 88%, CIR 54%, OS 55%), intermediate (CR 67%, CIR 67%, OS 24%), and adverse (CR 32%, CIR 92%, OS 5%). Multivariate analyses confirmed the major contribution of cytogenetics to the probability of attaining CR, CIR, and OS. For the adverse-risk group, the probability of achieving CR was 4.0 and 11.9 times lower, the probability of relapse 3.0 and 4.4 times higher, and the risk of death 2.1 and 4.3 times higher than those for the intermediate and favorable groups, respectively. We conclude that although the prognostic impact of many recurring abnormalities has not been ascertained independently of complex karyotype, cytogenetics is among the most useful factors predicting attainment of CR, CIR, and long-term survival in adult AML.

Acute Disease↗
PubMed1998

Conversion of interferon-induced, long-term cytogenetic remissions in chronic myelogenous leukemia to polymerase chain reaction negativity.

PURPOSE: Interferon alfa (IFN-alpha) induces complete cytogenetic remission in a significant minority of patients with chronic myelogenous leukemia (CML). To date, use of the polymerase chain reaction (PCR) has suggested that residual disease is present in virtually all these individuals at median follow-up intervals of approximately 1 year after initial achievement of cytogenetic remission. We sought to determine the PCR status of CML patients with very long continuous complete cytogenetic remissions on IFN-alpha. PATIENTS AND METHODS: Blood and/or bone marrow samples from 18 CML patients maintained in continuous cytogenetic remission by IFN-alpha for at least 1 year were studied for residual BCR-ABL mRNA by single-step reverse-transcriptase (RT)-PCR methodology, followed by detection of the amplification product by the hybridization protection assay (HPA). RESULTS: Ten of 18 patients showed RT-PCR negativity for BCR-ABL. The median duration of continuous complete cytogenetic remission at the time of sample collection for the negative patients was 42 months versus 21 months for the patients whose tests remained positive (P = .05). CONCLUSION: Very long-term follow-up of IFN-alpha-treated CML patients in continuous complete cytogenetic remission is associated with a decrease in the number of BCR-ABL transcripts to a level below that detectable by the RT-PCR assay used in this study.

Adult↗
PubMed2006

Comparison between patients with Philadelphia-positive chronic phase chronic myeloid leukemia who obtained a complete cytogenetic response within 1 year of imatinib therapy and those who achieved such a response after 12 months of treatment.

PURPOSE: Imatinib mesylate is a potent inhibitor of BCR-ABL, the constitutively active tyrosine kinase protein critical for the pathogenesis of chronic myeloid leukemia. PATIENTS AND METHODS: We reviewed 284 patients with late chronic-phase Philadelphia chromosome (Ph) -positive chronic myeloid leukemia treated with imatinib 400 mg daily after interferon-alpha failure. In a retrospective study, we evaluated the pattern and rapidity of the response to imatinib, comparing the cytogenetic and molecular responses, progression-free and overall survival rates in patients who obtained a complete cytogenetic response within 1 year of treatment (early responders), and in patients where a complete cytogenetic response was detected after 12 months (late responders). RESULTS: After 3 or 4 years of treatment, the molecular response of the late cytogenetic responders was similar to that of the early cytogenetic responders. At 36 months of treatment the amount of residual disease measured by standardized quantitative reverse-transcriptase polymerase chain reaction was 0.00047 in late responders versus 0.00022 in early responders, and at 48 months it was 0.00019 versus 0.00026 (median values, P value = nonsignificant). The estimated 4-year progression-free survival rate was 88% for early responders and 100% for late responders, while the estimated 4-year overall survival rates were 92% and 100% for early and late responders, respectively. CONCLUSION: The sensitivity and the response (cytogenic and molecular) to imatinib may require 1 year or more. Long-term follow-up results continue to improve in terms of rates and durability of the complete cytogenetic response, major or complete molecular response, and progression-free and overall survival.

Adult↗
PubMedDate not supplied

Cytogenetic analysis in the examination of solid tumors in children.

Although pediatric solid tumors are cytogenetically less well characterized than childhood leukemias, an understanding of the role of chromosomal changes in the development of these neoplasms is emerging. The major clinical importance of chromosome analysis today is diagnostic. Especially in small cell round cell tumors of childhood, the unique karyotypic patterns that characterize some of the differential diagnostic entities make it possible to determine with a high degree of certainty which type of cancer the child has. Molecular studies have revealed that almost all retinoblastomas show homozygous loss of function of the RB1 gene in 13q14. At the cytogenetic level, however, aberrations of 13q are seen in less than 25% of retinoblastomas; instead, the presumably progression-related i(6p) and aberrations leading to gain of 1q predominate, each being present in one-third of the tumors. Twenty percent of cytogenetically aberrant Wilms' tumors show structural rearrangements, often deletions, of 11p13 and 11p15, where the WT1 and WT2 genes map. Other frequent changes are trisomy 12 and duplication of 1q. The most common (80%) cytogenetic abnormality in neuroblastoma is loss of distal 1p, a chromosome segment thought to harbor at least two tumor-suppressor genes of importance in tumorigenesis. Double minute chromosomes or homogeneously staining regions are present in one-third of all neuroblastomas and are associated with MYCN amplification. Loss of 1p material or MYCN amplification predicts a poor outcome. The most common (30%) chromosomal aberration in primitive neuroectodermal tumors of the central nervous system is i(17q). The formation of this isochromosome may help inactivate a tumor-suppressor gene located distal to the TP53 locus on 17p. No specific chromosome abnormality has been detected in gliomas, but monosomy 22 and rearrangements leading to loss of 1p and gain of 1q are recurrent. Few hepatoblastomas with chromosomal changes have been reported, but several potential primary aberrations have been described, including +2, +20, and duplication 8q. In Ewing's sarcoma, t(11;22)(q24;q12) is the primary aberration, with trisomy 8 and gain of 1q being frequent secondary changes. Fibrosarcomas in children often carry only numeric aberrations, especially trisomy for chromosomes 11, 20, 17, and 8. Most osteosarcomas are cytogenetically complex, and no specific abnormality has been detected; the single most common change is loss of chromosome 13, which is observed in half the tumors. In contrast, the low-malignancy parosteal osteosarcomas often display supernumerary ring chromosomes as the sole karyotypic deviation. The cytogenetic profiles of rhabdomyosarcomas differ among the various morphologic subtypes.(ABSTRACT TRUNCATED AT 400 WORDS)

Child↗
PubMed1999

Genomic instability and recurrent breakpoints are main cytogenetic findings in Hodgkin's disease.

BACKGROUND AND OBJECTIVE: Successful cytogenetic studies in Hodgkin's disease (HD) are rare, and, except for hyperdiploidy, no chromosome changes typical for this disorder have been described. The purpose of this study was to collect cytogenetic information from a new series of lymphoid neoplasms diagnosed either as classical HD or as Hodgkin's-like anaplastic large cell lymphoma (HD-like ALCL), according to the REAL Classification. DESIGN AND METHODS: We studied 27 cases of HD and 10 cases of HD-like ALCL. Cytogenetic investigations were performed on lymph nodes (35 cases), bone marrow or pleural effusion. A large screening of slides was performed to detect abnormal metaphases despite the low mitotic index of Reed-Sternberg cells. In addition to ours, available published data were analyzed in detail to identify recurring cytogenetic events. RESULTS: Metaphases which could be analyzed were obtained in 86.5% of cases, with 59.4% showing abnormal clones. We found a peculiar kind of cytogenetic instability in which, despite variations in the type of structural rearrangements, chromosome breakpoints were non-randomly distributed. Moreover, from our data plus those collected from literature on HD (total 177 cases), the number of breakpoints was higher in patients in a more advanced clinical stage. INTERPRETATION AND CONCLUSIONS: Cytogenetic studies in HD are highly informative regarding clonality, provided large numbers of metaphases are examined. Based on karyotype, genetic changes in HD and HD-like ALCL are similar. Results are consistent with a high degree of chromosomal instability and predominance of hyperdiploid complex karyotypes. Chromosome breakpoints are non-randomly distributed and more numerous in advanced clinical stages.

Adolescent↗
PubMed1999

Systematic characterisation of disease associated balanced chromosome rearrangements by FISH: cytogenetically and genetically anchored YACs identify microdeletions and candidate regions for mental retardation genes.

Disease associated balanced chromosome rearrangements (DBCRs) have been instrumental in the isolation of many disease genes. To facilitate the molecular cytogenetic characterisation of DBCRs, we have generated a set of >1200 non-chimeric, cytogenetically and genetically anchored CEPH YACs, on average one per 3 cM, spaced over the entire human genome. By fluorescence in situ hybridisation (FISH), we have performed a systematic search for YACs spanning translocation breakpoints. Patients with DBCRs and either syndromic or non-syndromic mental retardation (MR) were ascertained through the Mendelian Cytogenetics Network (MCN), a collaborative effort of, at present, 270 cytogenetic laboratories throughout the world. In this pilot study, we have characterised 10 different MR associated chromosome regions delineating candidate regions for MR. Five of these regions are narrowed to breakpoint spanning YACs, three of which are located on chromosomes 13q21, 13q22, and 13q32, respectively, one on chromosome 4p14, and one on 6q25. In two out of six DBCRs, we found cytogenetically cryptic deletions of 3-5 Mb on one or both translocation chromosomes. Thus, cryptic deletions may be an important cause of disease in seemingly balanced chromosome rearrangements that are associated with a disease phenotype. Our region specific FISH probes, which are available to MCN members, can be a powerful tool in clinical cytogenetics and positional cloning.

Adolescent↗
PubMed1999

Cytogenetic analysis of 363 consecutively ascertained diffuse large B-cell lymphomas.

Cytogenetic analysis was performed on 363 biopsy specimens with histologically confirmed diffuse large B-cell lymphoma (DLBCL), consecutively ascertained at the Memorial Sloan-Kettering Cancer Center, New York, between 1984 and 1994. Among 248 samples successfully karyotyped, clonal chromosomal abnormalities were noted in 215 (87%). The salient cytogenetic features of DLBCL from this analysis comprised the following. Breakpoints clustered, in decreasing frequency, at 10 recurring sites: 14q32, 18q21, 1q21, 3q27, 1p36, 8q24, 3p21, 6q21, 1p22, and 22q11. Of these, deletion breaks affecting bands 3p2 and 1p22 and translocation breaks affecting bands 14q32, 3q27, and 1q2 were frequent and distinctive for this subset of lymphomas. Translocations affecting band 14q32 were noted in 110 cases (51%) of which 42 (20%) had t(14;18)(q32;q21), 21 (10%) had t(8;14)(q24;q32) or t(8;22)(q24;q11), 14 (6.5%) had t(3;14)(q27;q32) or t(3;22)(q27;q11), and 33 (15%) had other rearrangements of 14q32. Among 144 new translocations detected in the entire group, the breakpoints in 19 were recurrent and clustered at three sites: 1q21, 3q27, and 14q32. Regions of common cytogenetic deletions were identified at 11 sites, 1p36, 1p33-34, 1p31, 1q32, 3p25-26, 3p21, 3q21, 6q15, 6q21, 6q23-24, and 7q32, suggesting possible loss of candidate tumor suppressor genes associated with DLBCL development. Of these, only those at 6q21, 6q23, and 7q32 have previously been described in lymphoid neoplasms. The group of DLBCL with translocations affecting band 14q32 showed a significantly different pattern of additional cytogenetic changes compared to the group lacking such translocation. This new comprehensive cytogenetic characterization provides the basis for investigations aimed at identifying molecular mechanisms as well as the clinical impact of cytogenetic changes in DLBCL.

Chromosome Aberrations↗
PubMed2000

Molecular analysis of lineage-specific chimerism and minimal residual disease by RT-PCR of p210(BCR-ABL) and p190(BCR-ABL) after allogeneic bone marrow transplantation for chronic myeloid leukemia: increasing mixed myeloid chimerism and p190(BCR-ABL) detection precede cytogenetic relapse.

We studied lineage-specific chimerism and minimal residual disease (MRD) in sequential posttransplant samples from 55 patients who underwent unmanipulated (n = 44) or partially T-cell-depleted (n = 11) allogeneic bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Chimerism was assessed by polymerase chain reaction (VNTR [variable number of tandem repeats]-PCR) analysis in highly purified CD19+, CD3+, CD15+, and CD56+ cell fractions, whereas MRD was investigated in whole blood by reverse transcriptase-PCR (RT-PCR) of both p210(BCR-ABL) and p190(BCR-ABL) hybrid transcripts. Of 55 patients, 14 (including 6 T-cell-depleted patients) had cytogenetic relapse at 5-80 months and progressed to hematologic relapse, while 41 patients remained in prolonged cytogenetic remission 12-107 months post-BMT. Before leukemia recurrence, patients in the relapse group showed a consistent evolution pattern sequentially featured by persistent p210(BCR-ABL) positivity, increasing mixed chimerism (MC) in myeloid cells, p190(BCR-ABL) positivity, and, finally, cytogenetic relapse. Myeloid MC preceded cytogenetic relapse by 2-12 months, whereas p190(BCR/ABL) was detected 1-6 months prior to cytogenetic relapse in 11 patients and concomitant with cytogenetic relapse in 3 patients. In the remission group, all patients invariably tested negative for p190(BCR-ABL); 10 patients tested positive for p210(BCR-ABL) at variable time-points but showed persistent full donor chimerism (DC), whereas 31 patients tested p210(BCR-ABL) negative and displayed full DC or transient MC due to the persistence of recipient T cells. Two patients in the relapse group were successfully reinduced into molecular remission with donor lymphocyte infusion. Sequential molecular analysis after such treatment showed the inverse pattern to that observed prior to relapse, ie, progressive disappearance of p190(BCR-ABL) transcripts, conversion of myeloid chimerism to donor type, and, finally, p210(BCR-ABL) negativity. We conclude that lineage-specific chimerism and p190(BCR-ABL) messenger RNA (mRNA) analyses contribute a better characterization of CML evolution after BMT and enable early identification of patients at the highest risk of relapse. (Blood. 2000;95:2659-2665)

Adolescent↗
PubMed2001

CT-guided biopsy of focal lesions in patients with multiple myeloma may reveal new and more aggressive cytogenetic abnormalities.

BACKGROUND AND PURPOSE: Cytogenetic abnormalities, especially chromosome 13 deletion, are high-risk factors for multiple myeloma. Attaining the highest detection rates of cytogenetic abnormalities is important to provide accurate prognostic information to the referring oncologist. The purpose of this study was to use CT-guided percutaneous fine-needle aspiration bone biopsy (CT-guided FNA) of MR-detected focal lesions in patients with multiple myeloma to increase identification of abnormal cytogenetics. METHODS: Patients enrolled in two clinical trials for myeloma therapy underwent MR imaging of the entire spine and pelvis. CT-guided FNA biopsy samples obtained from MR-detected focal lesions in these patients were sent for cytogenetic analysis. FNA results were then compared with random bone marrow sampling of the iliac crest done at or near the same time as the FNA to provide the data revealed in this study. RESULTS: Forty-one patients (47 lesions) in one of the trials and 37 patients (38 lesions) in the other trial had biopsies performed. CT-guided FNA revealed cytogenetic abnormalities in 21% of the total patient population and new information in nearly 10% of the patients in one trial and in 20% of those in the other trial. CONCLUSION: CT-guided biopsy of MR-detected focal lesions is a safe technique that can provide important cytogenetic information in a significant number of patients with multiple myeloma not identified during random marrow sampling.

Biopsy, Needle↗
PubMed2001

[Effect of retinoic acid on the cytogenetic remission in the first chronic phase of chronic myeloid leukemia treated with interferon].

Cytogenetic responses of 11 chronic myeloid leukemic (CML) patients during the first chronic phase, treated with the combination of all-trans retinoic acid (ATRA) + interferon (IFN) were compared to 9 other CML patients of phase one, treated with interferon monotherapy. Metaphase and interphase cytogenetics and a semiquantitative polymerase chain reaction (PCR) were used to evaluate the cytogenetic responses. Two of the 11 patients in the ATRA + interferon treated group were withdrawn, one of them because of interferon intolerance, and the other because of compliance failure. Among the 9 ATRA + interferon treated patients 6 major cytogenetic responses could be detected and 3 of them were complete. Of the 9 patients treated with IFN monotherapy only 2 major cytogenetic responses could be registered. No severe adverse effects were observed. The first results suggest that the ATRA + interferon combination may be superior in achieving cytogenetic remission in the first chronic phase of CML.

Adult↗
PubMed2003

[Cytogenetic risk categories in acute myeloid leukemia: a comparison between MRC (Medical Research Council) and SWOG (Southwest Oncology Group) models)].

BACKGROUND AND OBJECTIVE: Classification of acute myeloid leukemia (AML) based on karyotype provides an important tool for therapy selection. There are two standardized criteria for the classification of patients into groups of cytogenetic risk. One of them was established by the UK Medical Research Council (MRC) and the other by the US Southwest Oncology Group (SWOG). They define three and four cytogenetic categories, respectively. The aim of this study was to define the frequency of chromosomal abnormalities and to compare the groups of cytogenetic risk in patients with AML who received intensive chemotherapy, as a guide for future investigations. PATIENTS AND METHOD: Chromosomal analysis was performed using standard techniques on bone marrow samples from 146 adult patients between January 1995 and December 2001. Kaplan-Meier and Cox's regression models were used for statistical analysis. RESULTS: Cytogenetic results were obtained in 142 patients. The incidence of a complex karyotype and del(5q) was higher in patients with secondary AML. Classification by cytogenetic risk was performed in 105 treated patients. The classification using both models was identical in 82 patients and different in 23. Results in univariate analysis were significant for EFS (p < 0.000 for MRC and p < 0.02 for SWOG). Nevertheless, only the MRC model was significant for OS (p < 0.001). In multivariate analysis, age and cytogenetics were the only variables having prognostic value. CONCLUSIONS: There was some relation between secondary AML, advanced age and adverse karyotype. Both classification models have a great prognostic value. In our experience, codification according to MRC criteria appears to be more effective to detect patients at high risk of relapse.

Acute Disease↗
PubMed2004

The influence of age on prognosis of de novo acute myeloid leukemia differs according to cytogenetic subgroups.

BACKGROUND AND OBJECTIVES: In the presented study the effect of age and cytogenetics on clinical outcome in acute myeloid leukemia (AML) was evaluated. The 1225 patients with de novo AML were separated according to age as follows: A1: 16 to 49 years (n=442), A2: 50 to 59 years (n=246), A3: 60-69 years (n=333), A4: 70 years and older (n=204). DESIGN AND METHODS: Patients were categorized with respect to cytogenetics into 5 groups: C1: t(15;17) (n=107), C2: CBF-AML/inv(16)/t(8;21) (n=171), C3: 11q23/MLL (n=42), C4: complex aberrant karyotype (n=130), C5: other: normal, other abnormalities, 5q-/-5, 7q-/-7, inv(3)/t(3;3), other 3q abnormalities (n=746). For each age category univariate cox regression analysis was performed using age as a continuous variable and C1 to C5 as dichotomous variables. RESULTS: In cohort A1 all parameters were significantly associated with overall survival (OS). However, in multivariate analysis all cytogenetic parameters were independently correlated with OS, while age was not. In cohort A2 only CBF and complex aberrant karyotype were significantly correlated with OS. In A3 t(15;17), complex karyotype and age, and in A4 only complex karyotype and age were significantly associated with OS in univariate and multivariate analyses. Within all cytogenetic subgroups except AML 11q23/MLL there were significant associations between age and OS. INTERPRETATION AND CONCLUSIONS: (i) Both age and cytogenetics are independent prognostic parameters in AML;(ii) up to the age of 49 years age has no major impact on prognosis while the karyotype has; (iii) in patients 50 years and older the influence of age on outcome increases, and (iv) cytogenetics show an independent effect on survival also in patients over 60 years old.

Acute Disease↗
PubMed2005

In chronic myeloid leukemia white cells from cytogenetic responders and non-responders to imatinib have very similar gene expression signatures.

BACKGROUND AND OBJECTIVES: Imatinib induces complete cytogenetic responses (CCR) in the majority of patients with chronic myeloid leukemia (CML) in chronic phase (CP). However, a subgroup of patients is refractory at the cytogenetic level. Clinically, it would be advantageous to identify such patients a priori, since they may benefit from more aggressive therapy. DESIGN AND METHODS: To elucidate mechanisms underlying cytogenetic refractoriness, we used Affymetrix oligonucleotide arrays to determine the transcriptional signature associated with cytogenetic refractoriness in unselected white blood or bone marrow cells from 29 patients with CML in first CP prior to treatment with imatinib. Patients with CCR within 9 months were defined as responders (n = 16) and patients lacking a major cytogenetic response (> 35% Philadelphia-positive metaphases) after 1 year were defined as non-responders (n = 13). RESULTS: Differences in gene expression between responders and non-responders were subtle. Stringent statistical analysis with multiple comparison adjustments revealed very few differentially expressed genes. Differentially expressed genes could not be confirmed in an independent test set. INTERPRETATION AND CONCLUSIONS: We conclude that transcriptional profiling of unselected white cells is of limited value for identifying genes consistently associated with cytogenetic refractoriness to imatinib.

Adult↗
PubMed1991

Interphase cytogenetic analysis in the diagnosis and study of neoplastic disorders.

Cytogenetic information usually is obtained through the direct analysis of chromosomes from cells arrested in metaphase. Recently, advances in molecular genetics have made it possible to acquire cytogenetic information through the study of interphase and terminally differentiated cells. By using chromosome-specific DNA probes or probes that are specific for certain chromosomal regions, and by employing techniques of in situ hybridization along with nonradioactive detection methods, it is now possible to detect numerical and structural chromosomal abnormalities from nonmetaphase cells. When used as an adjunct to conventional cytogenetic analysis or when used together with knowledge of established cytogenetic findings for a particular malignancy, this new technology can serve to broaden the scope and utility of cytogenetic analysis beyond the limits of the present metaphase-based technology. Interphase cytogenetic analysis has application to the diagnosis and study of neoplastic disorders and, thus, has particular importance in pathology.

Chromosome Aberrations↗
PubMed1987

Clonal cytogenetic abnormalities in patients with otherwise typical aplastic anemia.

Between June 1981 and August 1986, 183 patients with the referring diagnosis of aplastic anemia were evaluated with cytogenetic studies and marrow biopsies. Seven patients (4%) on biopsy were found to have myelodysplasia. Seven of the 176 patients (4%) with marrow biopsies that confirmed the pathologic diagnosis of severe aplastic anemia were found to have clonal cytogenetic abnormalities in unstimulated marrow samples. Among the 169 patients with typical aplastic anemia and no cytogenetic abnormalities, 5 (3%) subsequently developed either myelodysplasia or leukemia. Two of three patients with pathologically confirmed aplastic anemia and clonal cytogenetic abnormalities, who were not transplanted, developed myelodysplasia. These results demonstrate that approximately 4% of patients with aplastic anemia have clonal cytogenetic abnormalities of marrow cells, and that while all patients with aplastic anemia may have some risk of developing leukemia, those with a cytogenetic abnormality have an especially high risk.

Adolescent↗
PubMed1987

Cytogenetic and cytochemical studies on progenitor cells of primary acquired sideroblastic anemia (PASA): involvement of multipotent myeloid stem cells in PASA clone and mosaicism with normal clone.

By cytogenetic and cytochemical analyses of individual hematopoietic colonies, we investigated clonality in progenitor compartments of primary acquired sideroblastic anemia (PASA). Two of our four subjects had reduced but countable numbers of CFU-E, BFU-E, and GFU-GM in methylcellulose culture. In one patient with cytogenetic abnormality of 47, XX, +8 in 67% of the bone marrow cells, cytogenetic analysis of individual erythroid bursts and granulocyte/macrophage colonies demonstrated two populations with and without 8 trisomy, the trisomy clone being 38% in BFU-E and 50% in CFU-GM. These findings indicate involvement of multipotent stem cells in PASA clone and mosaicism of two distinct populations in erythroid as well as granulocyte/macrophage progenitor compartments, the abnormal PASA clone and probably the normal clones. In another case with no cytogenetic abnormality, repeated iron staining showed that 31% to 40% of CFU-E and 25% to 54% of BFU-E had erythroblasts with heavy iron deposits. An ultrastructural analysis of 25 individual erythroid bursts revealed that 32% had highly dysplastic erythroblasts with marked ferruginous iron accumulation in the mitochondria. The other 68% and 15 normal bursts from a healthy control did not have noticeable dysplastic changes and iron deposits in the mitochondria. This cytochemical/ultrastructural mosaicism seems to be compatible with the cytogenetic mosaicism. However, whether the BFU-E derived from abnormal PASA clone selectively manifest iron accumulation in the mitochondria or whether the PASA clone itself shows variable degrees of abnormal iron metabolism remains to be determined by simultaneous performance of ultrastructural and cytogenetic analysis for single bursts.

Adult↗
PubMed1984

Correlation of asbestos-induced cytogenetic effects with cell transformation of Syrian hamster embryo cells in culture.

The cytogenetic effects of chrysotile asbestos on Syrian hamster embryo cells in vitro were investigated at doses which induced morphological and neoplastic transformation but which failed to induce measurable gene mutations in the cells at two genetic loci. Chrysotile asbestos treatment of the cells significantly induced chromosome changes in a dose-dependent manner. Up to 50% of the cells had chromosome abnormalities in number or structure following treatment with asbestos (2.0 micrograms/sq cm) for 48 hr. Numerical chromosome changes were the most pronounced abnormalities although significant increases in metaphases with other chromosome aberrations (breaks, fragments, exchanges, and/or dicentrics) and cells with binuclei or micronuclei were also observed. A linear relationship was observed between the incidences of cells with tetraploid metaphases and binucleated cells, suggesting that binucleation and tetraploidy are related. Cytogenetic effects of other mineral dusts were also tested 48 hr following treatment at a concentration of 2.0 micrograms/sq cm. Crocidolite asbestos was less potent than chrysotile asbestos in its ability to induce cell transformation and cytogenetic damage. Treatment of the cells with thin glass fibers (Code 100) was also able to induce cell transformation and cytogenetic effects, but thick glass fibers (Code 110) were much less potent for both endpoints. Milling of the thin glass fibers decreased the length of the fibers and abolished their ability to induce cell transformation and cytogenetic effects. Nonfibrous alpha-quartz induced neither cell transformation nor cytogenetic effects at the dose of 2.0 micrograms/sq cm. The results indicate that the physical characteristics of the fibers determine their ability to induce cell transformation and their ability to induce chromosome mutations, suggesting a possible mechanistic relationship.

Animals↗
PubMed1995

Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis.

Between December 1990 and January 1994, bone marrow (BM) samples from 151 patients with multiple myeloma (MM), including 117 patients evaluated at diagnosis, were collected for cytogenetic analysis. A total of 129 patients had assessable metaphases (100 patients at diagnosis). Cytogenetic studies were performed on BM cells after longterm cultures (6 days) with stimulation of cultures by granulocyte-macrophage colony-stimulating factor (GM-CSF), GM-CSF plus interleukin (IL)-6, IL-3 plus IL-6, or GM-CSF plus IL-3 plus IL-6 to improve myeloma cell growth, and 91 patients had an additional unstimulated culture. Sixty-six patients (51%) had cytogenetic abnormalities, including 47 of 100 patients at diagnosis (47%) and 17 of 24 patients at relapse (71%; P = .04). The aberration rate increased with stage (P = .007), BM plasmacytosis (P = .003), beta 2 microglobulin level (P = .001), C-reactive protein (CRP) level (P = .001), and Ki-67 (P = .007). The abnormality detection rate was higher in stimulated than unstimulated cultures, and the difference was statistically significant (P < .01). Hyperdiploidy was observed in 39 patients (30% of patients with an assessable karyotype) and hypodiploidy in 19 patients (15%). Among numeric changes, gains predominantly involved chromosomes 3, 5, 7, 9, 11, 15, 19 and losses, chromosomes 8, 13, 14, and X. The most frequent loss was loss of chromosome 13, observed in 22 patients (15%), including 18 patients at diagnosis (12%). We observed frequent structural changes of chromosomes 1 (15%) and 14 (10%) but also a 5% incidence of 19q13 abnormality and two patients with translocation t(1;16)(p11;p11). By using the proportional hazard univariate model, patients with abnormal karyotypes were demonstrated to have 2.5-fold greater chance of death than patients with normal karyotypes (P < .014). Despite a multivariate approach with the same model, the respective roles of karyotype abnormality, age, stage, and beta 2 microglobulin level could not be clearly ascertained. From these results we conclude that cytogenetic analysis using stimulation of cultures by cytokine(s) may be a promising method to identify about 50% of cytogenetic abnormalities in patients with newly diagnosed MM. Cytogenetic analysis may help to define a high-risk population that would benefit from intensive therapeutic approaches.

Adult↗