Myelodysplastic syndrome with bone marrow eosinophilia: clinical and cytogenetic features

We investigated the hematological and clinical status of 145 patients with de novo myelodysplastic syndrome (MDS), 14 of whom (10%) had eosinophilia in the bone marrow (MDS-Eo). Most of these 14 patients had severe anemia. Their bone marrow cells exhibited trilineage dysplasia and some morphological abnormalities in the eosinophils, including disproportion of eosinophilic granules, basophilic granules, a ring-shaped nucleus, and vacuolation in the cytoplasm. However, these abnormalities were less prominent than those of acute myelomonocytic leukemia with eosinophilia (FAB: M4Eo). Three of the 14 MDS-Eo patients had refractory anemia (RA), seven had RA with excess of blasts (RAEB), and four had RAEB in transformation. Cytogenetic analysis revealed chromosomal abnormalities in 12 of 13 MDS-Eo patients (92%), in particular, there were major karyotypic abnormalities (MAKA) in eight patients (62%). Cytotoxic agents were not effective in the treatment of four patients after leukemic transformation occurred. These four patients died of the leukemic transformation while seven died of bone marrow failure. The other three MDS-Eo patients are still alive; two of them have already transformed to a leukemic phase. The duration of survival of these patients was significantly shorter than that of the other MDS patients. These findings suggest that bone marrow eosinophilia in MDS may be a poor prognostic factor that is strongly related to the existence of MAKA.     

Prognostic classification in myelodysplastic syndromes

Factors for predicting the prognosis of myelodysplastic syndromes (MDS) have been widely used over the last few years. The proportion of bone marrow blasts, number and severity of cytopenias, and cytogenetic abnormalities are the main prognostic factors and can be used in combination to determine prognostic scores capable of predicting the outcome with fairly high accuracy. Molecular biology parameters, such as RAS and p53 mutations, can also be of assistance in establishing a prognosis. Factors that predict responsiveness to therapy are usually the same as those that predict survival. Current prognostic scores are unable to identify the minority of patients who will have very long survivals and therefore require no treatment.     

Surface marker abnormalities in myelodysplastic syndromes

BACKGROUND AND OBJECTIVE: The myelodysplastic syndromes (MDS) are clonal stem cell disorders associated with a variety of abnormalities of mature and maturing cells, including surface antigen abnormalities. Granulocytes and monocytes function as members of the immune system. Surface antigens serve as biological sensors allowing various cells to interact with different stimuli. Abnormalities of surface antigens may be associated with defective cell function and may indicate a more severe or more advanced stage of the disease. INFORMATION SOURCES: The author has a great interest in bone marrow changes in MDS and has several previous publications in this field. In addition, relevant articles published since 1966 were retrieved using Medline of English literature and were included. STATE OF THE ART AND PERSPECTIVES: Several surface antigens in MDS have shown abnormal expression either in the intensity of fluorescence or the percentage of positive cells. These abnormalities include increased, decreased or lineage-aberrant expression. Abnormalities of several surface markers have prognostic significance. MDS patients with a low percentage of bone marrow cells expressing CD11b had a higher risk of evolution to acute myeloid leukemia and shorter survival compared to patients with more than 53% of marrow cells expressing CD11b (29 weeks versus 160 weeks). On the other hand, an increased percentage of bone marrow cells expressing early or immature markers, such as CD 13, CD33, CD34 and HLA-DR, has been associated with a worse outcome and with progression to a higher risk MDS or to acute myeloid leukemia. However, there are numerous discrepancies and inconsistencies in the literature when reviewing surface marker changes in MDS. These discrepancies may be related, at least in part, to the presence of an intracellular storage compartment of numerous surface antigens in the granulocytes and monocytes. Because of these storage pools, the techniques of preparing more mature granulocytes and monocytes, such as density gradient separation, and the interpretation of results must be carefully evaluated. Furthermore, various methods have been used to express abnormal results including percentage of positive or negative cells, fluorescent intensity (FI) of individual patients or a group of patients using a mean fluorescent channel (256 or 1024 channel mode), and finally the expression of FI as molecules of equivalent soluble fluorochromes or antibody binding capacities. Several mechanisms may be involved in the abnormal expression of surface antigens in MDS including defective granulopoiesis, defective intracellular storage pool, abnormal membrane of cytoplasmic granules, and the effect of high levels of marrow cytokines such as tumor necrosis factor alpha and transforming growth factor-beta. Standardization of the methods of preparing and studying mature and maturing granulocytes and monocytes in MDS has to be achieved in order to produce comparable results, thus allowing surface marker studies to be utilized as diagnostic and prognostic tools in MDS.     

Acute myeloid leukemia-type chemotherapy for newly diagnosed patients without antecedent cytopenias having myelodysplastic syndrome as defined by French-American-British criteria: a Cancer and Leukemia Group B Study

PURPOSE: To determine the treatment outcome of standard acute myeloid leukemia (AML)-type chemotherapy in a subset of patients with newly diagnosed myelodysplastic syndromes (MDS) compared with that of patients with de novo AML as defined using French-American-British (FAB) criteria. In addition, to determine the pretreatment variables having prognostic significance for treatment outcome in patients with MDS. PATIENTS AND METHODS: Nine hundred seven newly diagnosed patients with no history of cytopenias having a local institutional de novo AML successfully karyotyped and treated on Cancer and Leukemia Group B (CALGB) protocols for AML from 1984 to 1992. Thirty-three of the 907 patients were reclassified as having MDS on central pathology review using FAB criteria and form the basis of this analysis. RESULTS: The treatment outcomes for patients with MDS and AML were similar; the complete remission (CR) rate was 79% and 68%, respectively (P = .37); median CR duration was 11 and 15 months, respectively (P = .28); and median survival was 13 and 16 months, respectively (P = .72). For the MDS patients, there were no prognostic variables for CR rate identified. For CR duration, only the Sanz classification had prognostic value. The prognostic factors for survival in a univariate analysis included age, WBC count, Sanz classification, and percent blood blasts. In a proportional hazards analysis of survival, age greater than 60 years and WBC less than 2.6 x 10(9)/L were adverse prognostic factors. CONCLUSION: In patients with no known history of cytopenias who are treated intensively at diagnosis, the FAB distinctions between MDS (refractory anemia with excess blasts and refractory anemia with excess blasts in transformation) and AML appear to have little therapeutic relevance.     

Molecular abnormalities and clonality in myelodysplastic syndromes

Few genes have a proven role in the pathogenesis of myelodysplastic syndromes (MDS). The most common abnormalities involve the RAS genes, most notably the N-RAS gene, and are present in 10% of cases at diagnosis and in 30% to 40% during the course of the disease. Mutations of the p53 are found in 5% to 10% of cases. Mutations of the cFMS genes are less common, abnormalities of the NF1 genes seem to occur only in children, and abnormalities of the RB genes are exceedingly rare. A few instances of t(5;12) or t(3;21) translocation have been demonstrated, and their study has provided evidence that the TEL, EVI1, MDS1, and AML1 genes are involved in some cases of MDS. The presence in MDS of recurrent chromosome 7, 5q, and 20q deletions suggests that these chromosomal segments may bear tumor suppressor genes involved in MDS. The gene(s) involved remain(s) to be identified. Clonality studies have shown that stem cell involvement usually occurs at the myeloid level and that normal multipotent stem cells persist in many patients with MDS. This opens up the promising possibility that transplantation of autologous multipotent stem cells may be an effective therapeutic approach.     

Etiopathogeny, prognosis and therapy of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous and common group of clonal hematological disorders characterized by cytopenias, dysplastic changes of hematopoietic cells, and a high rate of transformation into acute myeloblastic leukemia (AML). MDS provide a clinical model for studying the emergency and progression of malignancy. The initiating events leading to MDS remain almost unknown. Imbalance of proliferative and differentiating capabilities of progenitor hematopoietic cells along with abnormalities in the normal process of apoptosis are involved in both the pathogenesis of MDS and transformation into AML. Multiple genomic lesions, comprising oncogene activation and tumor-suppressor gene inactivation, are probably required. Alkylating agents, cytotoxic drugs targeting topoisomerase II and benzene are the only clear etiological factors identified. Advanced age and great prognostic variability, not explained by the FAB subtype, complicates the design and analysis of clinical trials and therapy-planning. The use of recently developed prognostic scores for selecting the best treatment according to the expected risk is encouraged. In most patients therapy is unsatisfactory. At present, bone marrow transplantation is considered as the only curative approach. A better knowledge of the pathobiology of MDS should be valuable to develop new, more rationale and effective therapies.     

Diagnosis, classification, and cytogenetics of myelodysplastic syndromes

BACKGROUND AND OBJECTIVE: The diagnosis of myelodysplastic syndromes (MDS) is essentially morphological and based on the presence of dysplastic features in the peripheral blood and bone marrow. The French-American-British (FAB) Cooperative Group proposed a classification based on easily obtainable laboratory information. In spite of some limitations, the FAB criteria have been useful for a long time. Currently, the recognition of other distinct morphological MDS subgroups such as hypocellular MDS and MDS with myelofibrosis, the increasing incidence of MDS in children as well as that of therapy-related MDS, and the finding of specific chromosomal alterations associated with different morphological features, reveal the insufficiency of this classification. The aim of the present review is to examine some new aspects of the diagnosis, classification, and cytogenetics of MDS. EVIDENCE AND INFORMATION SOURCES: The authors of this review have been actively working and contributing original papers on MDS for the last 15 years. They also organized or participated in the Fourth International Symposium on MDS (Barcelona, April 24-27, 1997). In addition, the present review critically examines relevant articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF THE ART AND PERSPECTIVES: Most of investigators working on MDS tend to integrate morphology and cytogenetics in the diagnosis and classification of these disorders. FAB criteria remain useful particularly for patients with not available cytogenetic study. Refractory cytopenia with multilineage dysplasia should be considered as a new MDS subtype. Some authors propose considering all patients with more than 20% of blast cells in peripheral blood or bone marrow as having acute leukemia. Chronic myelomonocytic leukemia with myeloproliferative features may be included among chronic myeloproliferative disorders. MDS with myelofibrosis is recognized as a new MDS subtype. Therapy-related MDS (t-MDS) should be classified according to the involved agents. Finally, besides including chromosomal abnormalities in the diagnosis (e.g., RAEB with trisomy 8), several cytogenetic abnormalities such as deletion 5q and deletion 17q, associated to specific clinical-morphological features, should be of help to identify new MDS syndromes.     

Results of topotecan single-agent therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia

The activity of topotecan was evaluated in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Sixty patients with a diagnosis of MDS (n = 30) or CMML (n = 30) were treated. Their median age was 66 years, with 50 patients (83%) being over 60 years of age at time of study entry. Chromosomal abnormalities were present in 50% of patients and thrombocytopenia of less than 50 x 10(9)/L in 50%. Topotecan was administered as 2 mg/m2 by continuous infusion over 24 hours daily for five days (10 mg/m2 per course) every 4 to 6 weeks for two courses, then at maximum tolerated dose level (1-2 mg/m2 by continuous infusion over 24 hours daily for five days) once every 4-8 weeks for a maximum of 12 courses. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Nineteen patients (31%) achieved a complete response (CR). A CR was achieved in 11 of 30 patients with MDS (37%) and in eight of 30 with CMML (27%). A CR was achieved in 10 of 23 patients with previously untreated MDS (43%). Eight of 11 patients who presented with cytogenetic abnormalities (five of which involved chromosome 5 and/or 7 abnormalities) and achieved CR, were evaluated cytogenetically in CR: all were cytogenetically normal in CR. Characteristics associated with a higher CR rate were lack of previous chemotherapy, absence of ras oncogene mutations, and presence of less than 10% monocytes in either peripheral blood or bone marrow. In contrast, CR rates were similar by different agent groups, by different karyotype abnormalities, and by other pre-therapy peripheral blood counts. Non-myelosuppressive side effects were mucositis in 67% of patients (severe [grade 3-4] 23%), diarrhea in 38% (severe 17%), and nausea and vomiting in 28% (severe 5%). Febrile episodes during neutropenia occurred in 85% of patients and documented infections in 47 %. Mortality in the first four weeks was 20%. With a median follow-up duration of 31 months, the 12 month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. In summary, topotecan has significant single-agent activity in MDS and CMML. Complete responses associated with topotecan therapy often involve the disappearance of abnormal, poor-prognosis karyotypes, which is particularly encouraging. Future strategies to optimize topotecan's role include combination regimens with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).     

Studies on therapeutic activity of benzoxazinorifamycin KRM-1648 in combination with other antimicrobial agents and biological response modifiers interferon-gamma and granulocyte-macrophage colony-stimulating factor against M. leprae infection in athymic nude mice

Immunological abnormalities (IA) are frequently observed in patients with myelodysplastic syndromes (MDS). Although there have been a number of analyses of the prognostic factors, there have been few studies, if any, to determine whether IA affects prognosis. We investigated the prognosis of 153 MDS patients with or without IA who were treated at a single Japanese institute for 10 years. Nineteen of 153 patients (12%) developed autoimmune disorders. One hundred of 153 patients (63%) had an abnormality in at least one immunological laboratory test. Hypergammaglobulinemia was found in 50 of 128 (39%) patients tested, hypogammaglobulinemia was observed in 10 of 128 (8%), positivities of antinuclear antibody, RA factor. DNA antibody, and direct antiglobulin test were observed in 30%, 14%, 7% and 12%, respectively, and a CD4/CD8 ratio < 1 was observed in 20%. There was no significance in the distribution of age, MDS subtype, or sex between patients with and without IA. The survival of MDS patients without IA was significantly better than that of patients with IA, and the survival of patients with a CD4/CD8 ratio > 1 was also significantly superior to the survival of those with an inverted CD4/CD8 ratio. Patients with IA tended to die of infection or leukemic progression in comparison with those without IA, suggesting that IA may be associated with susceptibility to opportunistic infection and disease progression.     

Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan

It is well known that cytogenetic analysis in patients with myelodysplastic syndrome (MDS) provides information useful in determining their prognosis. Based on the chromosomal results obtained from 401 MDS patients by a multicentric study in Japan, we studied correlations between chromosomal findings and prognosis or leukemic transformation in MDS patients. Patients with complex aberrations (cytogenetic abnormalities at more than three chromosomes), of any subtype, had a poor prognosis; for example, > 60% of patients with refractory anemia (RA) showing complex aberrations died within one year, but only 11% of them developed leukemia. In patients with RA with ringed sideroblasts (RARS), > 70% of those with complex aberrations evolved into the leukemic phase and survived for less than one year, suggesting a biologic heterogeneity in RARS patients. By contrast, about 5% of patients with RA or RARS exhibiting chromosomal findings other than -7/7q-, +8, two aberrations, and complex aberrations, developed leukemia and had a favorable prognosis. Therefore, the presence of chromosome abnormalities alone in patients with RA or RARS is not a factor in predicting leukemic transformation or poor prognosis. In patients with refractory anemia with an excess of blasts (RAEB), the presence of chromosome aberrations at MDS diagnosis affected the occurrence of leukemic transformation (24% versus 43%), however, no particular difference was noted in patients with RAEB in transformation with regard to whether they had chromosome changes or not, and about 60% of them evolved into leukemia. The poor prognosis related to complex aberrations was consistently noted in all MDS subtypes or age-matched groups, indicating that this cytogenetic anomaly is an independent risk factor for a poor prognosis in MDS patients. The duration between MDS diagnosis and development of the leukemic phase and that between the latter and death were significantly shorter in patients with complex aberrations than those without this change. Although the clinical significance of certain chromosomal abnormalities differs among subtypes of MDS, a new scoring system for predicting prognosis by cytogenetic changes, in combination with hematologic parameters, was proposed.     

Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) is the only curative therapy available for patients with myelodysplastic syndrome (MDS). In an attempt to identify prognostic factors influencing outcome, we collected data retrospectively on 60 consecutive adult patients who had undergone BMT at our center for primary MDS or acute myelogenous leukemia evolving from preexisting primary MDS (sAML). Patients were divided into subgroups according to cytogenetic abnormalities based on a recently described International MDS Workshop categorization system. The 7-year actuarial event-free survival (EFS), relapse rate, and nonrelapse mortality (NRM) for all patients were 29% (95% confidence interval [CI], 16% to 43%), 42% (CI, 24% to 67%), and 50% (CI, 37% to 64%), respectively. The EFS for the good-, intermediate-, and poor-risk cytogenetic subgroups were 51% (CI, 30% to 69%), 40% (CI, 16% to 63%), and 6% (CI, 0% to 24%), respectively (P = .003). The corresponding actuarial relapse rates were 19% (CI, 6% to 49%), 12% (CI, 2% to 61%), and 82% (CI, 48% to 99%), respectively (P = . 002) with no difference in NRM between the subgroups. Univariate analysis showed cytogenetic category, French-American-British (FAB) subtype, and graft-versus-host disease (GVHD) prophylaxis used to be predictive of relapse and EFS. In multivariate analysis, only the cytogenetic category was predictive of EFS, with the relative risk of treatment failure for the good-, intermediate-, and poor-risk cytogenetic subgroups being 1.0, 1.5, and 3.5, respectively (P = . 004). For adults with primary MDS and sAML, even after BMT, poor-risk cytogenetics are predictive of an unfavorable outcome; novel treatment strategies will be required to improve results with allogeneic BMT in this patient population.     

Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant

PURPOSE: To determine the incidence of myelodysplasia (MDS) and/or acute leukemia (AL) in breast cancer patients after high-dose chemotherapy (HDC) with a single conditioning regimen and autologous bone marrow transplant (ABMT), and analyze the cytogenetic abnormalities that arise after HDC. PATIENTS AND METHODS: We retrospectively reviewed the records of 864 breast cancer patients who underwent ABMT at Duke University Medical Center, Durham, NC, from 1985 through 1996 who received the same preparative regimen of cyclophosphamide 1,875 mg/m2 for 3 days, cisplatin 55 mg/m2 for 3 days, and BCNU 600 mg/m2 for 1 day (CPB). Pretransplant cytogenetics were analyzed in all patients and posttransplant cytogenetics were evaluated in four of five patients who developed MDS/AL. RESULTS: Five of 864 patients developed MDS/AL after HDC with CPB and ABMT. The crude cumulative incidence of MDS/AL was 0.58%. The Kaplan-Meier curve shows a 4-year probability of developing MDS/AL of 1.6%. Pretransplant cytogenetics performed on these five patients were all normal. Posttransplant cytogenetics were performed on four of five patients and they were abnormal in all four, although only one patient had the most common cytogenetic abnormality associated with secondary MDS/AL (chromosome 5 and/or 7 abnormality). CONCLUSION: Whereas MDS/AL is a potential complication of HDC with CPB and ABMT, the incidence in this series of patients with breast cancer was relatively low compared with that reported in patients with non-Hodgkin's lymphoma who underwent ABMT. The cytogenetic abnormalities reported in this group of breast cancer patients were not typical of those seen in prior reports of secondary MDS/AL and appear to have occurred after HDC.     

Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression

p15(INK4b) gene is an inhibitor of cyclin-dependent kinase (CDK) 4 and CDK6 whose expression is induced by transforming growth factor (TGF)beta. Recent reports suggest frequent methylation of the p15(INK4b) gene promoter in leukemias, and it has been proposed that this methylation could be necessary for leukemic cells to escape TGF beta regulation. We investigated the methylation status of p15(INK4b) gene in 53 myelodysplastic syndromes (MDS) cases, including nine that had progressed to acute myeloid leukemia (AML), using a recently described sensitive method where polymerase chain reaction (PCR) is preceded by bisulfite modification of DNA (methylation specific PCR). p15(INK4b) methylation was observed in 20 of 53 (38%) of the cases. Twenty of the 24 patients with greater than 10% bone marrow blasts had p15(INK4b) methylation (including all nine patients who had progressed to AML) as compared with none of MDS patients with <10% bone marrow blasts. No correlation between karyotypic abnormalities and methylation status was found. Patients with p15(INK4b) methylation had a worse prognosis, but the prognostic significance of p15(INK4b) methylation was no more found by multivariate analysis, due to its strong correlation to the percentage of marrow blasts. In 10 MDS cases, sequential DNA samples were available. In five of them, methylation of the p15(INK4b) gene was detected at leukemic transformation, but not at diagnosis. Our results showed that methylation of the p15(INK4b) gene in MDS is correlated with blastic bone marrow involvement and increases with disease evolution toward AML. It suggests that proliferation of leukemic cells might require an escape of regulation of the G1 phase of the cell cycle, and possibly of TGF beta inhibitory effect.     

Extramedullary myeloid cell tumors in myelodysplastic-syndromes: not a true indication of impending acute myeloid leukemia

The purpose of this report is to record a patient with myelodysplastic syndrome (MDS) associated acute myelogenous leukemia (AML) and leukemia cutis who had blast expression of the neural cell adhesion molecule (NCAM) and to review the world literature on prognostic implications of extramedullary myeloid cell tumors (granulocytic sarcoma, myeloblastoma, chloroma and leukemia cutis) in MDS and MDS associated AML. Case report and world literature from January 1965-January 1994 for all cases of MDS-associated extramedullary myeloid cell tumors (EMT) is reviewed, and the first patient with EMT, MDS associated AML and blast expression of NCAM is described. There have been 46 cases of MDS associated EMT previously reported. 32 cases occurred in the absence of AML. AML developed in 47% of these patients at a mean of 38 weeks from initial EMT. Of the patients not developing AML, median survival from initial EMT was 11 weeks. Nine patients received chemotherapy at the time of EMT and had a median survival of 36 weeks. The median survival for patients receiving conservative therapy for EMT was 48 weeks. Patients (n = 15) with EMT and MDS associated AML had a poor outcome regardless of therapy with a median survival of 11 weeks. Unlike other forms of isolated EMT, MDS associated EMT is not always a forerunner of AML. Premature induction therapy for MDS associated EMT does not appear to prolong survival. EMT in the setting of MDS associated AML is associated with a poor prognosis despite aggressive chemotherapy. Blast expression of NCAM may prove to be a risk factor for EMT in MDS associated AML.     

Granulocyte dysplasia and dysfunction, and CD11/CD18 defects in myelodysplastic syndromes

In myelodysplastic syndromes (MDS), dysplastic changes in neutrophils are a common feature reflecting the total degree of bone marrow dysplasia. Furthermore, granulocyte function is abnormal, so that a high risk of life-threatening infections has been documented. In this review we shall focus on the defects of both granulocytes and their CD11b/CD18 glycoprotein complex, which regulate granulocyte adherence, locomotion, diapedesis and migration into inflammatory sites, in patients suffering from primary MDS. The defective surface membrane glycoprotein expression of myelodysplastic phagocytes is not only a useful diagnostic tool, but also a powerful prognostic one, since MDS patients with such defects present both an increased susceptibility to infections and a decreased survival. Moreover, the administration of colony-stimulating factors is known to be able to elicit long-lasting improvement in neutrophil count, CD11b/CD18 expression and function, marrow myeloid maturation, and possibly to decrease bacterial infections in MDS patients.     

Surgical release for intubation purposes in postburn contractures of the neck

One hundred and twenty-four patients over the age of 75 years were assessed for the cause of their macrocytosis (MCV > 95 fl). A definitive diagnosis was reached in 75/124 (60%) by non-invasive techniques. The remainder underwent a bone marrow biopsy yielding a definitive diagnosis in a further six patients who had an identifiable myelodysplastic syndrome (MDS). A high proportion of the remainder had morphological abnormalities which fitted with no recognized pathological entity. It is suggested that these may represent MDS in evolution.     

Postoperative stability after sagittal split ramus osteotomy with condylar-positioning appliance and screw fixation: asymmetric versus symmetric cases

BACKGROUND AND OBJECTIVE: Myelodysplastic syndrome progenitor cells can be grown and expanded in long term bone marrow liquid cultures in the presence of multiple cytokines. In this study we investigated the pattern of differentiation and response to growth factors in six cases of myelodysplastic syndrome (MDS) with well-defined cytogenetic abnormalities by means of conventional cytogenetics and fluorescence in situ hybridization (FISH). METHODS: Bone marrow cells were grown in stroma-free liquid cultures in the presence of SCF, IL-3, IL-6 and GM-CSF. RESULTS: IN three cases a CFU-GM expansion comparable to normal controls was observed, together with a decrease or increase of cells with abnormal karyotype. Two cases showed no response to growth factor stimulation, morphological signs of terminal myeloid differentiation and increase (one case) or decrease (one case) in the percentage of abnormal FISH signals along the cultures. In one additional case, while CFU-C expansion was present, clearcut leukemic transformation was observed in the culture, together with a sharp decrease in the percentage of abnormal FISH signals, indicating a leukemic transformation of MDS progenitor cells with a normal karyotype. INTERPRETATION AND CONCLUSIONS: Our data indicate that FISH analysis is generally a poor indicator of clonality in MDS; nevertheless, determining the kinetics of cytogenetically abnormal clones in liquid bone marrow cultures may provide insight as to the growth abnormalities of MDS progenitor cells and may be useful prior to in vivo growth factor administration.     

骨髓增生异常综合征T淋巴细胞异常与克隆造血

目的 了解T淋巴细胞异常在骨髓增生异常综合征(MDS)克隆造血中的作用.方法 对76例MDS患者的染色体核型、T淋巴细胞亚群及激活状态进行分析.结果 正常核型36例,异常核型40例,异常发生率52.6%.40例异常核型中,三体8(+8)24例,占异常核型的60.0%.与健康对照组比较,MDS患者CD+3 CD-19、CD+3 CD-4 CD+8以及CD+3 HLA-DR+细胞百分率显著升高,CD-3(CD16 CD56)+细胞的百分率明显降低.将MDS患者进行核型分组,异常核型组CD+3(CD16 CD56)+细胞的百分率显著高于正常对照组.将+8核型从MDS异常核型中独立出来进行分析,CD+3 CD+4 CD-8细胞的百分率明显低于正常核型以及其他异常组,CD4/CD8的比值明显低于健康对照组.结论 MDS存在T淋巴细胞异常,异常核型MDS可能恶性克隆增殖更为优势,预后更差.+8核型MDS存在更为严重的免疫监视功能下降,导致恶性克隆过度增殖与残存造血过度受抑.     

A patient with myelodysplastic syndrome studied by GTG-banding and fluorescent in situ hybridization (FISH)

Molecular cytogenetics using fluorescent in situ hybridization (FISH) is an extremely useful adjunct technique to conventional cytogenetics via GTG-banding. The present paper illustrates the utility of FISH by describing a patient with myelodysplastic syndrome (MDS) who was initially studied using GTG-banding and whose bone marrow was found to be populated with hyperdiploid cells. FISH was used to delineate the numerical and structural chromosomal abnormalities. It revealed the presence of trisomy 8 and determined that the previously unidentifiable marker chromosome was of chromosome 10 origin. Although trisomy 8 is a frequent finding in MDS, the structural chromosomal abnormality of chromosome 10 as reported here is not a common finding.