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PubMedDate not supplied

[Molecular cytogenetic techniques and their application in clinical diagnosis].

Cytogenetics analysis is at present the basic element of the diagnostic process of genetic disorders which are caused by chromosomal abnormalities. Since the chromosome banding technique has been introduced in the 1970s, it has been available as a diagnostic tool of a number of clinical syndromes. It enabled to prove the causal association between specific chromosomal abnormalities and clinical features observed in patients. However, since banding resolution is not always sufficient for the identification of chromosomal abnormalities, additional techniques for solving diagnostic dilemma of classical cytogenetics are needed. A new field of cytogenetics -- molecular cytogenetics, the product of a combination of cytogenetics and molecular biology, has increased the resolution and diagnostic utility of cytogenetic analysis. The basic method of molecular cytogenetics is fluorescence in situ hybridization (FISH). It enables a specific detection of unique sequences, chromosomal regions or entire chromosomes in metaphase, interphase cells or in tissue sections. In this article FISH technique and its modifications such as multicolor FISH (M-FISH, SKY, CCK), Primed In Situ Labelling (PRINS) and Comparative Genomic Hybridization (CGH) are presented. The range of applications and the use of these techniques for the identification of chromosomal abnormalities in relation to diagnostic possibilities of the classical methods of karyotyping is also discussed.

Chromosome Aberrations↗
PubMedDate not supplied

Cytogenetics and their prognostic value in childhood and adult acute lymphoblastic leukemia (ALL) excluding L3.

Cytogenetic analysis was made at diagnosis in 174 cases of ALL (101 children less than 20 years and 73 adults), excluding Burkitt's ALL (L3). In 11 children (11 per cent) insufficient material was obtained. In the remaining 90, 50 (56 per cent) had a normal karyotype, 20 (22 per cent) a hyperdiploid karyotype, five (6 per cent) a hypodiploid karyotype, 12 (13 per cent) had a translocation (including seven cases of t(1;19] and three had a pseudodiploid karyotype without translocation. Ninety-eight per cent of patients reached complete remission (CR). Median actuarial CR duration was not attained, was 50 months, 13 months, and 11 months respectively in patients with hyperdiploid, normal, hypodiploid karyotype and in patients with a translocation, the difference between subgroups being significant. In a Cox model, cytogenetics were the strongest factor predicting CR duration (p = 0.03) followed by leukocytes (p = 0.04), whereas the presence of 'bulky disease' had a borderline value (p = 0.077). Of note was that 9/17 (53 per cent) patients with a hypodiploid karyotype or a translocation had no 'risk factors' before cytogenetic analysis. In adults, cytogenetic analysis was unsuccessful in 15 (20 per cent) of patients. In the remaining 58 cases, 19 (33 per cent) had a normal karyotype, 15 (26 per cent) had a hyperdiploid, one (2 per cent) had a hypodiploid karyotype, 19 (33 per cent) had a translocation (including 12 t(9;22], and four (7 per cent) had a pseudodiploid without translocation. 73 per cent patients reached CR. Median actuarial DFS was 12.5 months. No significant differences in CR rate and CR duration were seen between cytogenetic groups, but median CR duration was slightly longer in patients with a normal karyotype (17 months) and shorter in patients with t(9;22) (8.5 months). Only 3/12 of the latter had major risk factors before cytogenetic analysis. Cytogenetic analysis is important in ALL, especially in patients with otherwise standard risk factors, as it may reveal unexpected translocations or hypodiploidy, which may require a therapeutic reinforcement.

Adolescent↗
PubMed1978

Cytogenetics in malignant lymphoma.

There appear to be four primary areas of interest in the application of cytogenetic techniques to the study of malignant lymphomas: (1) the role of cytogenetics in the diagnosis of lymphoma in problem cases, (2) as an aid to the classification of malignant lymphomas, (3) whether specific chromosomal patterns will have prognostic significance for response to therapy or survival, and (4) the role of cytogenetics in staging of malignant lymphomas. A case of reactive lymphoid hyperplasia is reported in which cytogenetic studies demonstrated an aneuploid clone suggesting that cytogenetic abnormalities of lymphoma may precede the diagnostic histopathologic picture. The occurrence of 14q+ marker chromosomes in plasmacytic myeloma, plasma cell leukemia, malignant lymphomas, Burkitt's lymphoma, and ataxia-telangiectasia suggest that a common etiologic or pathogenetic mechanism may be present in some of these disorders. A preliminary pilot study of spleens removed at staging laparotomy for Hdgkin's disease suggests that cytogenetic studies may be able to detect Hodgkin's disease that is not apparent histologically. Further studies are required to provide answers to these areas of interest in cytogenetics in malignant lymphoma.

Chromosome Aberrations↗
PubMed1997

The role of cytogenetics in the classification of soft tissue tumours.

Soft tissue tumours represent a heterogeneous group of mesenchymal lesions, and their classification is the subject of continuous debate. Chromosome analysis, molecular cytogenetics and molecular assays may become increasingly useful in diagnosis, and this review summarises advances in the cytogenetic characterisation and classification of soft tissue tumours. Among the group of fibrous lesions, superficial fibromatosis exhibits trisomy 8. This genomic change is also observed in desmoid fibromatosis in association with trisomy 20. Trisomy 11 is the most frequently observed chromosomal aberration in congenital fibrosarcoma. Dermatofibrosarcoma protuberans and giant cell fibroblastoma share a translocation t(17;22), which supports the concept of the existence of a common differentiation pathway. Adipose tissue tumours is the group in which integration of genetics and pathology has been most fruitful. Ordinary lipomas cytogenetically show an abnormal karyotype in about half the cases. Genomic changes of the 11q13 region are observed in hibernoma. Lipoblastoma exhibits a specific 8q rearrangement in 8q11-q13. Loss of material from the region 16q13-qter and 13q deletions are observed in spindle cell/pleomorphic lipomas. The well-differentiated liposarcoma/atypical lipoma group is characterised karyotypically by the presence of one extra ring and/or extra giant chromosome marker. Myxoid and round cell liposarcoma share the same characteristic chromosome change: t(12;16)(q13;p11) in most cases. In the group of smooth muscle lesions most data are derived from uterine leiomyomas, which can be subclassified cytogenetically into seven different types. Half of all leiomyomas are chromosomally normal; the other half have one of six possible consistent chromosome changes. Alveolar rhabdomyosarcoma is characterised cytogenetically by two variant translocations t(2;13)(q35;q14) and t(1;13)(p36;q14). Among tenosynovial tumours, the localised type of giant cell tumour of tendon sheath exhibits two different karyotypic changes. One involves 1p11 in a translocation with chromosome 2 or with another chromosome. A second type involves 16q24. Synovial sarcoma is characterised cytogenetically by a translocation occurring between chromosome 18 and presumably two adjacent loci on the X chromosome. In neural tumours, abnormalities of chromosome 22 have been reported in benign schwannomas and perineuriomas. Malignant peripheral nerve sheath tumours exist in two main forms: sporadic and associated with the NF-1 syndrome. Karyotypes are very complex, but chromosomes 17q and 22q are very often involved. Clear cell sarcoma is characterised cytogenetically and molecularly by a translocation t(12;22)(q13;q12). The Ewing's sarcoma/peripheral neuroectodermal tumour category shows a central karyotypic anomaly represented by the translocation t(11;22). The two variants t(21;22) and t(7;22) are found in some cases. Among cartilaginous lesion, the most frequently described anomaly is the t(9;22)(q22;q12) in extraskeletal myxoid chondrosarcoma. Intra-abdominal desmoplastic small round cell tumour is characterised by a t(11;22)(p13;q12).

Chromosomes, Human↗
PubMed1989

Cytogenetic follow-up after bone marrow transplantation for Philadelphia-positive chronic myeloid leukemia.

Forty-eight consecutive patients affected by chronic myelogenous leukemia (CML) Philadelphia (Ph) chromosome positive during the chronic phase of the disease underwent allogeneic bone marrow transplantation (BMT). Thirty-five patients had a follow-up over 12 months and were included in a cytogenetic study in order to evaluate the Ph clone eradication. In 25 cases, the Ph chromosome disappeared in all cytogenetic studies, and their hematologic picture is at present apparently normal. Ten patients showed cytogenetic relapse. In one case, the cytogenetic relapse was transitory without any clinical sign of the disease; in three cases, after a transitory cytogenetic relapse, a persistent relapse with clinical picture of progression of the disease occurred; in six cases cytogenetic and a clinical relapse were coincident. Structural chromosomal abnormalities other than Ph were temporarily seen in three cases. The so-called "nonrandom" chromosomal changes typical of the blastic phase were never detected. The reappearing Ph-positive clone spontaneously disappeared in three patients, and their hematologic picture reverted to complete chimerism. The present study confirms that the eradication of the Ph clone is often defective with BMT, and cytogenetic analysis can detect the competition between donor and residual host marrow. Furthermore, the karyotype evolution is different from that found in CML patients treated with conventional chemotherapy.

Bone Marrow↗
PubMed1995

Comparison of DNA content in non-Hodgkin's lymphoma as measured by flow cytometry and cytogenetics.

Specific cytogenetic changes such as t(14;18) and t(8;14) are associated with specific histologic subtypes of non-Hodgkin's lymphoma (NHL) and may predict disease outcome. Nonspecific cytogenetic changes include other structural rearrangements or numerical changes such as monosomies and trisomies, which may cause changes in total cellular DNA content. In many solid tumors, the presence of abnormal DNA content may be predictive of clinical behavior. NHL biopsies, however, contain normal (diploid) as well as abnormal cells, and DNA changes in the peridiploid range are detectable by cytogenetic analysis, but not consistently by flow cytometry. In the present study, we performed flow cytometric and cytogenetic analysis of DNA on biopsies from 129 patients with non-Hodgkin's lymphoma (NHL). Cytogenetic studies were successful on 88 (68%) of the samples. There was 55% concordance between flow cytometric and cytogenetic techniques in detecting aneuploid DNA content, with the majority of discrepancies occurring in the peridiploid range. We also detected six samples which were aneuploid by flow cytometry, but diploid by cytogenetics. We suggest that a reasonable approach to determine DNA content, as it relates to prediction of outcome in NHL, would be to combine data from both of these techniques and analyze the results in terms of ranges of DNA rather than by categorizing as diploid versus aneuploid.

Aneuploidy↗
PubMed1995

Cytogenetic analysis is non-informative for assessing the remission rate in chronic myeloid leukemia (CML) patients on interferon-alpha (IFN-alpha) therapy.

Cytogenetic analysis is considered pivotal for assessing the remission rate in CML patients on IFN therapy. On the basis of general agreement, at least 25 metaphases should be analyzed in each case. The main limitations to this approach are: 1) the small number of analyzable metaphases generally found in cytogenetic preparations from IFN-alpha-treated patients; and 2) the inability of this technique for scoring interphase cells. We compared the results of cytogenetic analysis and double-color FISH detection of bcr/abl genes fusion in 13 CML patients on IFN-alpha therapy (marrow sampling for cytogenetic and FISH analysis was carried out after 12 months in all patients and repeated after 18 months of IFN therapy in patients 4, 6, and 8). In five specimens, 20 to 25 cells were evaluable for cytogenetic examination, in another five no analyzable metaphases were scored, and in the remaining six samples two to 14 cells could be analyzed. With FISH detection at least 100 cells were easily scored in each specimen (mean number, 175). Comparing the results carried out with the two methods in different samples it emerged that cytogenetic analysis led to improper conclusions as regards the rate of Ph positivity, even in those patients where 20-25 metaphases were analyzed. Although many more cases have to be studied to establish the role of FISH analysis in Ph-positive patients, we are of the opinion that cytogenetic analysis is unfit for easily and accurately assessing the actual quality of remission in IFN-treated subjects.

Chromosome Aberrations↗
PubMed1997

Regional cancer cytogenetics: a report on 1,143 diagnostic cases.

The results of studies from a regional cancer cytogenetics diagnostic service are reported. In a 10-year period, 1,143 marrow samples from patients with newly diagnosed leukemia and myelodysplastic syndrome were referred. Successful studies were completed on 992 cases (87%). Among all referred cases, the rates of detection of cytogenetically abnormal clones were 95% for chronic myelogenous leukemia (CML), 54% for acute lymphoblastic leukemia (ALL), 51% for acute myeloid leukemia (ANLL), and 43% for myelodysplastic syndrome (MDS). Of 169 cases of CML studied, 90.5% bore the standard Philadelphia chromosome (Ph), 3.55% had an unusual Ph, and 5.33% were Ph-negative. Among the 59 cases of cytogenetically abnormal MDS, common abnormalities observed were trisomy 8 and changes resulting in loss of material from the long arm of chromosomes 5 and 7, and 20q-. Of the 168 abnormal ANLL, there was a strikingly non-random pattern of aneuploidy, with monosomy 7 and trisomy 8 predominating. Common structural changes observed were changes resulting in loss of material from the long arm of chromosomes 5 and 7, trisomy 8, rearrangements of 11q23, t(15;17), t(8;21), rearrangements of 12q13 and 3q, inversion 16, trisomy 11, Ph, trisomy 21, t(6;9) and t(1;22). The differences between adult and pediatric findings were minor, with the exception of chromosome 5 abnormalities, which were common among adults with ANLL but rare in the pediatric cases. There were 273 ALLs with abnormal cytogenetic findings. There was preferential gain of chromosomes 21, X, 14, 6, 4, 18, 17, and 10 (in decreasing order of frequency) in leukemic clones. Of the 193 ALLs with structural changes, many fell into-well-defined categories with established correlations to FAB subtypes. Common changes in ALL were rearrangements of 9p, 12p, 6q, TCR loci, 11q23, Ig loci, and 8q24, and duplication of 1q, Ph, i(17q), t(1;19), i(9q) and dic(9;12). The detailed documentation of the cytogenetic findings in this relatively large, single-institution study will likely facilitate the further characterization of rare, primary cytogenetic changes associated with leukemias and MDS. From a managed health care perspective, regional cancer cytogenetic services may be cost-effective alternatives to single-institution laboratories.

Adult↗
PubMed1999

Clinical significance of cytogenetic findings at diagnosis and in remission in childhood and adult acute lymphoblastic leukemia: experience from India.

We report cytogenetic findings in 114 patients of acute lymphoblastic leukemia (ALL), which includes 78 children (< or = 15 years) and 36 adults (16-60 years). Chromosome aberrations were detected in 109 (95%) cases. A lower frequency of hyperdiploidy (15%) in children and a higher frequency of hypodiploidy both in children (38.4%) and adults (44.4%) were found, in contrast to literature. Translocations were detected in one third of adult and pediatric cases. The incidence of t(9;22) was comparatively low in adults (7.7%). Frequency of t(1:19) was also low in overall ALL cases. Various other recurrent abnormalities such as del(6q), abn(11q23), i(9p), abn(12q13), del(7q), and i(17q) were seen in our cases; a striking difference in the incidence of del(6q) (41%) and abn(11q23) (30%) was found in our series versus reported literature. Ploidy distribution indicated association of pseudo- and hypodiploidy with B-lineage, and hypodiploidy with T-lineage in children. The occurrence of del(6q) was more frequent in pediatric ALL with highly aberrant pattern and also with lymphadenopathy. Abn(11q23) was found to be early-B and pre-B specific. Kaplan-Meier analysis of overall survival revealed prognostic value of sex, FAB, immunophenotype, and cytogenetic findings. Females and T-ALL patients had a better prognosis, whereas males and B-ALL patients had poor outcome in overall and pediatric age groups. Prognostic evaluation of cytogenetics indicated translocations as an independent high-risk predictor in childhood (P < 0.008) and adult ALL (P < 0.01). Childhood ALL with t(8;14) and t(4;11) and adults with t(9;22) had poor survival. Cytogenetics of remission marrows demonstrated disappearance of abnormal clones in 31.4%, and expansion in normal clones in 50% of patients. Persistence of original clones and development of new clones were observed in 20% and 33% of patients, respectively; whereas karyotype evolution was identified in 10% of patients. The prognostic significance of cytogenetic findings at diagnosis, and differential cytogenetic response in so-called clinical remission in our study indicated the utmost need for more intensive therapy for eradication of resistant clones, and necessity of sequential cytogenetic follow-up in these patients for identification of minimal residual disease.

Adolescent↗
PubMed1999

Retroactive DNA analysis for sex determination and dystrophin gene by polymerase chain reaction with archived cytogenetic slides.

We describe a rapid and efficient diagnostic method for sex determination and the dystrophin gene by the polymerase chain reaction (PCR) using archived cytogenetic slides. Archived cytogenetic slides stored for about 4 years at room temperature were used. To confirm whether DNA analysis is possible using the archived cytogenetic slides, we extracted the DNA from the slides and amplified the Y centromeric region (DYZ3), the X centromeric region (DXZ1) and the exon 46 of the dystrophin gene. Of the 50 cases, 24 were peripheral bloods, 13 were amniotic fluid cells, 5 were chorionic villus samplings and 8 were cord bloods. The PCR related sex determination in 22 females and 28 males, showed 100% concordance with the results of chromosome analysis, and all cases showed positive band for the exon 46 of the dystrophin gene. Of the 50 cases of the archived cytogenetic slides, we were fortunate enough to obtain the fresh blood sample from one fetus whose karyotype showed 45,X[34]/46,X,+mar[145] to compare the results of the gDNA with that from archived cytogenetic slide. To confirm whether the marker chromosome was derived from Y chromosome, we studied the six loci (PABY, SRY, RPS4Y (SY16, 17), ZFY, DYS14) on the short arm, one locus (DYZ3) on the centromere and one locus (DYZ1) on the long arm. Of the 8 loci studies, all PCR related Y chromosome showed positive band from both gDNA obtained from cord blood and archived cytogenetic slides. We could conclude from the above results that the marker chromosome was derived from the Y chromosome. We believe our experiment is rapid and efficient for studies of over 10 independent loci from a single slide which has been kept in storage for up to 4 years and that archival Giemsa-stained cytogenetic slide repositories represent valuable DNA resources for clinical and forensic studies.

DNA↗
PubMed1997

What happens subsequently in AML when cytogenetic abnormalities persist at bone marrow harvest? Results of the 10th UK MRC AML trial. Medical Research Council Leukaemia Working Parties.

Cytogenetic analysis performed at diagnosis is widely recognised to provide one of the most valuable prognostic indicators in AML. Yet any role for this technique in residual disease assessment, particularly in the context of subsequent transplantation procedures has been incompletely explored. The present study considers the outcome of 190 patients drawn from the UK MRC AML 10 trial in whom cytogenetics were assessed whilst in morphological CR at the time of bone marrow harvest. Cytogenetics at this stage were abnormal in 19 patients (10%). In 11/19 patients, the abnormalities detected reflected the acquisition of new clonal (3/11) or nonclonal changes (8/11) that were not identified at diagnosis; comparison of this group to patients with normal cytogenetics at harvest provided no evidence that such acquired changes are of prognostic significance. In 8/19 patients, abnormalities detected were indicative of persistence of the disease-related clone in harvested marrow. Two of these patients died of sepsis during consolidation therapy. Two received ABMT in first morphological CR: one patient with AML associated with a favourable karyotype (+8,inv(16)) remains in CR, 5.5 years post-transplant, whereas the other with cytogenetic abnormalities considered to confer a poor prognosis (inv(3q),-7), relapsed within 5 months of ABMT. All four of the remaining patients with cytogenetic evidence of persistent disease who were not transplanted in first CR, relapsed within 6.5 months of harvest. Therefore, among 101 of 190 patients with AML characterised by abnormal karyotype at diagnosis, persistence of the disease-related clone in eight patients (8%), revealed by conventional cytogenetic assessment at bone marrow harvest whilst in morphological remission, was found to predict a poor prognosis. Nevertheless, transplantation procedures using marrow which is obviously contaminated with the original leukaemic clone may occasionally still be associated with long-term survival.

Adolescent↗
PubMed2002

Serial monitoring of BCR-ABL by peripheral blood real-time polymerase chain reaction predicts the marrow cytogenetic response to imatinib mesylate in chronic myeloid leukaemia.

Imatinib mesylate (trade name Glivec or Gleevec) is emerging as an important therapy in the management of chronic myeloid leukaemia (CML). It is clinically useful to monitor the cytogenetic response to imatinib, although frequent marrow examinations are inconvenient. We have used serial real-time reverse transcription-polymerase chain reaction (RT-PCR) to monitor the ratio of peripheral blood BCR-ABL to normal ABL transcripts in 43 patients receiving imatinib, and compared the results to concurrent conventional bone marrow (BM) cytogenetics. After 6 months of treatment, 13 cases were complete cytogenetic responders, defined as all BM metaphases negative for the Philadelphia (Ph) chromosome. In these patients, the BCR-ABL/ABL ratio was less than 0.08%. Six cases achieved a partial cytogenetic response (1-35% Ph-positive BM metaphases) and their BCR-ABL/ABL ratio was between 0.08 and 10%. In total, 24 cases were cytogenetic non-responders, and their BCR-ABL/ABL ratio exceeded 11%. The data suggested that the 6-month BCR-ABL/ABL ratio may reliably predict the contemporary marrow cytogenetic response. It was concluded that serial real-time RT-PCR may offer a convenient surrogate assessment of the marrow cytogenetic response to imatinib therapy in CML.

Adult↗
PubMed2006

Achieving a major molecular response at the time of a complete cytogenetic response (CCgR) predicts a better duration of CCgR in imatinib-treated chronic myeloid leukemia patients.

PURPOSE: Most patients with chronic-phase chronic myeloid leukemia (CML) who receive imatinib achieve a complete cytogenetic remission (CCgR) and low levels of BCR-ABL transcripts. CCgR is durable in the majority of patients but relapse occurs in a subset. EXPERIMENTAL DESIGN: To determine the potential of quantitative reverse transcription-PCR of BCR-ABL to predict cytogenetic relapse, we serially monitored residual disease in 97 CML patients with an imatinib-induced CCgR. Patients with late chronic phase CML after IFN-alpha failure were treated with imatinib (400 mg daily). RESULTS: During the imatinib median follow-up time of 36 months (range, 12-54 months), disease monitoring occurred by cytogenetics and quantitative PCR. Twenty percent of patients experienced cytogenetic relapse at a median of 18 months after CCgR and a median of 24 months after starting imatinib. None of the possible prognostic factors studied in univariate and multivariate analyses seemed to predict for loss of cytogenetic response but the reduction of BCR-ABL transcript levels at the time of CCgR is an important prognostic factor. CONCLUSIONS: In our study, we showed not only that achieving a major molecular remission at 12 months is predictive of a durable cytogenetic remission but also that patients who achieved a major molecular remission (expressed both as the BCR-ABL/beta2 microglobulin ratio % <0.0005 and as a 3-log reduction from median baseline value) already at the time of first achieving a CCgR have significantly longer cytogenetic remission durations than those without this magnitude of molecular response (P < 0.05).

Adult↗
PubMed2002

Identification of frequent cytogenetic aberrations in hepatocellular carcinoma using gene-expression microarray data.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Frequent cytogenetic abnormalities that occur in HCC suggest that tumor-modifying genes (oncogenes or tumor suppressors) may be driving selection for amplification or deletion of these particular genetic regions. In many cases, however, the gene(s) that drive the selection are unknown. Although techniques such as comparative genomic hybridization (CGH) have traditionally been used to identify cytogenetic aberrations, it might also be possible to identify them indirectly from gene-expression studies. A technique we have called comparative genomic microarray analysis (CGMA) predicts regions of cytogenetic change by searching for regional gene-expression biases. CGMA was applied to HCC gene-expression profiles to identify regions of frequent cytogenetic change and to identify genes whose expression is misregulated within these regions. RESULTS: Using CGMA, 104 HCC gene-expression microarray profiles were analyzed. CGMA identified 13 regions of frequent cytogenetic change in the HCC samples. Ten of these regions have been detected in previous CGH studies (+lq, -4q, +6p, -8p, +8q, -13q, -16q, -17p, +17q, +20q). CGMA identified three additional regions that have not been previously identified by CGH (+5q, +12q, +19p). Genes located in regions of frequent cytogenetic change were examined for changed expression in the HCC samples. CONCLUSIONS: Our results suggest that CGMA predictions using gene-expression microarray datasets are a practical alternative to CGH profiling. In addition, CGMA might be useful for identifying candidate genes within cytogenetically abnormal regions.

Carcinoma, Hepatocellular↗
PubMed1997

Secondary cytogenetic changes in acute promyelocytic leukemia--prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: a Cancer and Leukemia Group B study.

PURPOSE: To examine, in newly diagnosed patients with acute promyelocytic leukemia (APL), the prognostic significance of secondary cytogenetic changes and the relationship between such changes and the two major promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) mRNA types. PATIENTS AND METHODS: One hundred sixty-one patients with t(15;17)(q22;q11-12) enrolled onto Cancer and Leukemia Group B (CALGB) protocol 8461, a prospective study of cytogenetics in acute myeloid leukemia (AML), were studied. Eighty of these 161 patients were treated solely with chemotherapy and evaluated for response to treatment and survival. PML-RAR alpha mRNA type was determined using reverse transcriptase polymerase chain reaction (RT-PCR) in 56 patients. RESULTS: The incidence of secondary cytogenetic abnormalities was 32%. Among 80 patients treated with chemotherapy, the presence of a secondary chromosome abnormality was associated with longer complete remission (CR) duration (median, 29.9 v 15.7 months; P = .03) and longer event-free survival (EFS) duration (median, 17.0 v 12.2 months; P = .03). There was no difference in overall survival (P = .28). In a separate group of 56 patients with both cytogenetic and molecular data, 32 had the type L PML-RAR alpha transcript (intron 6 PML breakpoint). Of these 32 patients, four (12.5%) had chromosome changes in addition to t(15;17), whereas 12 of 20 patients (60%) with the type 5 PML-RAR alpha transcript (intron 3 PML breakpoint) had secondary cytogenetic changes (P < .001). CONCLUSION: (1) Secondary cytogenetic changes do not confer a poor prognosis in APL patients treated with anthracycline/cytarabine (Ara-C)-based chemotherapy; and (2) A highly significant relationship exists between the PML-RAR alpha 5 isoform (intron 3 PML genomic breakpoint) and secondary cytogenetic changes in APL.

Adolescent↗
PubMed2004

Abnormal cytogenetics at date of morphologic complete remission predicts short overall and disease-free survival, and higher relapse rate in adult acute myeloid leukemia: results from cancer and leukemia group B study 8461.

PURPOSE: As most patients with acute myeloid leukemia (AML) with morphologic complete remission (CR) ultimately relapse, better predictors for outcome are needed. Recently, Cheson et al suggested using cytogenetic remission (CRc) as part of the criteria for CR. To our knowledge, ours is the first relatively large study evaluating the usefulness of CRc attained immediately following induction chemotherapy. PATIENTS AND METHODS: We included AML patients treated on Cancer and Leukemia Group B front-line studies with cytogenetic samples obtained at diagnosis and at the first day of documented CR following induction. Patients with abnormal cytogenetics at diagnosis, and normal cytogenetics at CR (NCR; n = 103) were compared with those with abnormal cytogenetics both at diagnosis and at CR (ACR; n = 15) for overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR). Cox proportional hazards models determined the prognostic significance of cytogenetics at CR, adjusting for other covariates. RESULTS: Clinical features were similar for both groups, with the exception of favorable cytogenetics [t(8;21), inv(16)/t(16;16), t(15;17)] at diagnosis, which was more frequent (P =.03) in the NCR group. Median follow-up was 3.1 years (range, 1.0 to 11.4 years). ACR patients had significantly shorter OS (P =.006) and DFS (P =.0001), and higher CIR (P =.0001). In multivariable models, the NCR and ACR groups were predictors for OS (P =.03), DFS (P =.02), and CIR (P =.05). The relative risk of relapse or death was 2.1 times higher for ACR patients than for NCR patients (95% CI, 1.1 to 3.9). CONCLUSION: Our data suggest that converting to normal karyotype at the time of first CR is an important prognostic indicator and support the use of CRc as a criterion of CR in AML.

Acute Disease↗
PubMed1995

Good predictive value of combined cytogenetic and molecular follow up in chronic myelogenous leukemia after non T-cell depleted allogeneic bone marrow transplantation: a report on 38 consecutive cases.

We prospectively performed repeated cytogenetic and PCR monitoring of residual disease in all cases Ph positive of chronic myeloid leukemia (CML) allografted with non T cell depleted marrow at our institution over a period of 8 years. Thirty eight patients who survived the immediate post transplant period could be analyzed (median of 3 cytogenetic analyses/patient, examining 100 mitoses, and 4 PCR analyses/patient). Seven of the 38 patients had a hematological relapse (which was extramedullary in one case) and one a purely cytogenetic relapse, possibly stabilised by interferon treatment. Within 6 months of transplant, Ph positive mitoses were seen in 2 patients, and positive PCR in most cases, without implying subsequent relapse. Six of the 32 patients analyzed cytogenetically more than 6 months post transplant had Ph positive mitoses on at least one occasion: 5 had a hematological relapse within 7 months of positive cytogenetic analysis, and the remaining patient, treated by interferon remained in purely cytogenetic relapse. (The extramedullary relapse was not preceded by a positive marrow karyotype). Eight of the 38 patients had positive PCR findings on at least one occasion more than 6 months post transplant. Seven relapsed (6 hematological relapses including the extramedullary relapse, and 1 cytogenetic relapse) after 3 to 20 months, but the remaining patient remained in CR 36 months later, with negative PCR. The 30 patients who never had positive PCR findings remained in CR. In this relatively large series of patients, we found a good correlation between PCR findings more than 6 months post transplant and remission or relapse status.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1996

Diagnostic and prognostic significance of cytogenetics in adult primary myelodysplastic syndromes.

Cytogenetic analysis has proven to be a mandatory part of the diagnosis of myelodysplastic syndromes (MDS) as well as a major indicator for predicting clinical course and outcome. This review concentrates on the cytogenetic classifications, the incidence and types of chromosome defects and the prognostic significance of the karyotype in adult primary MDS. Two cytogenetic classifications are currently used: one is based on the karyotype complexity (normal, single, double or complex defects), the other on clonal status (all metaphases normal, abnormal or admixture of normal and abnormal clones). Chromosome abnormalities are of both numerical and structural types. Aside from the 5q-syndrome, no specific clinico-cytogenetic entity has been reported. However, several distinct clinical and cellular features have been identified that correlate with the presence of specific chromosome defects such as inv(3)/t(3;3), +6, t(5;12), del(17p) and del(20q). The presence of complex defects is associated with reduced survival and a high risk of leukemic transformation. Among single defects, specific abnormalities may define distinct prognostic groups. Patients with del(5q) as a sole chromosome defect and a refractory anemia without excess of blasts have a favourable prognosis. For patients with trisomy 8 or monosomy 7 there may be distinct types of clinical evolution. Most patients with the 3q21q26 syndrome have a short survival. The presence of two chromosome defects may constitute an independent cytogenetic entity probably associated with relative poor prognosis. Karyotypic evolution generally represents a poor risk factor. The combination of cytogenetics with clinical and hematological features has proven to provide for a better prediction of patients' survival, leukemic transformation and response to treatment. Several scoring systems have been developed. They have to be improved by the study of new patients according to strict clinical and cytogenetic criteria and by the addition of newly recognized prognostic indicators such as histopathological features and molecular genetic mutations.

Adult↗