bcr-abl mRNA检测在慢性粒细胞白血病诊治中的意义

目的 探讨bcr-abl mRNA在慢性粒细胞白血病(CML)诊断、治疗及微小残留病变监测中的意义.方法 采用实时定量聚合酶链反应(real-time PCR)方法检测324例CML患者518份标本的bcr-abl mRNA表达情况.结果 CML慢性期、加速期和急变期患者的bcr-abl mRNA定量结果逐渐增高,分别为12.6%、25.4%和57.2%(P<0.05).异基因造血干细胞移植后的bcr-abl mRNA定量结果随时间延长逐渐降低,一般在移植6个月后转阴,服用伊马替尼(商品名:格列卫)与异基因造血干细胞移植病程相似,但融合基因转阴所用时间较长.结论 real-time PCR检测bcr-abl mRNA对于诊断、评价疗效、监测微小残留病变以及预测疾病进展具有重要的临床应用价值.     

Benign intracranial hypertension in chronic myeloid leukemia

Persistent pulmonary hypertension of the newborn (PPHN) is a challenge for the neonatologist and a common indication for treatment with extracorporeal membrane oxygenation (ECMO) when medical management fails. We observed 132 neonates born between January 1985 and December 1988 with the diagnosis of persistent pulmonary hypertension of the newborn: 73 (55%) met the Bartlett criteria for treatment with ECMO with 80% predicted mortality; 21 (29%) deteriorated despite conventional medical treatment, were thought to be dying, and were sent for ECMO. Among the 52 patients who were medically treated 40 (77%) survived, a marked difference compared with a predicted 20% survival. All ECMO-treated neonates survived. Although conventionally treated infants showed a trend toward less dependence on supplemental oxygen at > 28 days of life, this study failed to detect a significant difference between those two groups. We conclude that mortality was lower for ECMO-treated infants than for those who were medically treated (0 of 21 vs 12 of 52, p < 0.05); mortality for infants with persistent pulmonary hypertension of the newborn who met Bartlett's criteria and were medically treated was lower than published data; and there was no significant difference in oxygen dependence at > 28 days between the survivors who received ECMO and those who received medical therapy.     

Basophilic blast crisis in chronic myeloid leukemia

Acute nonoliguric renal failure developed in a 13-year-old girl, 1 month after the institution of isoniazid therapy because of a positive tuberculin test at school screening. A renal biopsy demonstrated severe crescentic glomerulonephritis with focal interstitial changes. Discontinuation of isoniazid and a short course of steroids and cyclophosphamide therapy were followed by complete recovery. Whereas isoniazid has been shown to induce a lupus-like syndrome and antihistone antinuclear antibodies, our patient displayed none of the clinical or immunological features that are characteristic of drug-induced lupus. Furthermore, none of the identifiable causes for crescentic glomerulonephritis was evident in this girl. To the best of our knowledge this is the first report suggesting a possible association of crescentic glomerulonephritis to isoniazid treatment.     

Rationalizing autotransplant strategies for chronic myeloid leukemia

The molecular genetic basis of chronic myeloid leukemia (CML) is well-defined, but until recently therapeutic approaches have been largely empiric. Conventional chemotherapy and interferon offer palliation, but only bone marrow transplantation provides for cure. Because the majority of CML patients are not candidates for allogeneic transplantation, autologous strategies have emerged as an alternative. Data from murine models of CML provide insights into the mechanisms by which autotransplant might be effective in the treatment of CML. Further dissection of the molecular pathways by which the BCR/ABL protein can induce leukemia offers the promise of a more targeted, rationally-designed therapy. When used for remission maintenance therapy following autologous bone marrow transplantation, specific inhibitors of BCR/ABL should provide for long term disease-free survival.     

Interferon-alpha and hydroxyurea in early chronic myeloid leukemia: a comparative analysis of the Italian and German chronic myeloid leukemia trials with interferon-alpha

In 1994, the Italian and the German Chronic myeloid leukemia (CML) trials comparing interferon-alpha (IFN-alpha) with conventional chemotherapy were published. The survival advantage in favor of IFN-alpha compared with hydroxyurea (HU; 72 v 52 months) was significant in the Italian (P < .002), but not in the German trial (66 v 56 months, P < .44). We set up a collaborative study to identify the reasons for the different outcomes. There are major differences in the trial protocols concerning admission criteria, treatment strategy, and definitions. The German patients were older and more seriously sick. Fifty-two of the 327 patients in the German IFN and HU arms did not fulfil Italian admission criteria, and 41 of the 322 Italian patients did not fulfil German admission criteria. Using mutually uniform admission criteria, the median survival times of the IFN patients are 76 (Italian) and 72 (German) months (P = .56). The Italian group administered IFN combined with HU as needed, whereas the German group strictly used IFN as monotherapy with rerandomization to busulfan (BU) or HU after IFN resistance or intolerability. The differences seen between the Italian and the German trial results can be accounted for by objective differences in study design, especially the admission criteria, treatment strategy, and bias due to intention to treat analysis. The detailed analysis of the data suggests that the combination of IFN with HU as needed is more effective than either agent alone.     

The biological therapy of acute and chronic leukemia

With the increasing knowledge of the mechanisms of immune-mediated cytotoxicity, immunotherapeutic strategies are rapidly being incorporated into chemotherapy treatment schemes for acute and chronic leukemias. This includes the use of mAbs, immunotoxins, tumor-specific T cells, and, most recently, vaccines. Much of the new information is derived from bone marrow transplant data, where immune enhancement from IL-2 and donor T-cell infusions are being studied. Trials using humanized mAbs that permit prolonged and repeated dosing will allow better evaluation of the effectiveness of mAb therapy. More sophisticated molecular tests have been developed, allowing the detection of minimal residual disease to a greater degree. It is likely that biological and immunological therapy of leukemia will have its greatest impact here.     

Autografting in chronic myeloid leukemia: an overview

Autografting could become a promising treatment for patients with chronic myeloid leukemia (CML) who cannot undergo allogeneic bone marrow transplantation or failed to respond to recombinant alpha-interferon (IFN). In this review, we analyze the results which have been published for patients transplanted in chronic phase and which suggest that autografting could prolong survival, at least in some patients. We also discuss the different methods of purging whose clinical efficacy remains to be assessed.     

Hematopoietic stem cell transplantation in chronic myeloid leukemia

The expression of three sialylated mucin-associated antigens - sialosyl-Lewisa (SLEA), sialosyl-Lewisx (SLEX) and sialosyl-Tn (STN) - and their correlation with the TNM stage, histopathological growth pattern and prognosis was investigated in a series of 127 gastric carcinomas. Various classification systems (pTNM, WHO and Laurén) did not display any correlation with an expression of the sialomucin antigens under study. SLEA reactivity was strongly associated with an unfavorable outcome of the total population, whereas SLEX and STN did not exert such an impact. However, in the subgroups of pTNM stage I as well as pN0 patients, SLEA and SLEX reactivity of the tumors was associated with a worse prognosis. In the subgroup of diffuse-type cancers as defined according to Laurén's classification, the expression of all three antigens indicated a worsening of the prognosis.     

Clinical significance of cytogenetics in acute myeloid leukemia

The chick/quail chimeric system is now extensively used to study the development of the central nervous system. Here we discuss data obtained by this powerful experimental approach by which to study several issues of the cerebellar ontogenesis. We first discuss experiments which have allowed redefinition of the localization of the cerebellar primordium in the early neural tube and which suggest that the cerebellum could originate from different morphogenetic units. Then, we discuss experiments testing the possible role of the homeobox containing gene En-2 in cerebellar specification and showing that the En-2 expressing cerebellar neuroepithelium can act as an organizer. Finally we discuss data obtained in chimeric embryos with partial cerebellar grafts used to reexamine the origin and settling of several types of cortical cerebellar cells, in particular granule cells, molecular layer interneurons and Purkinje cells.     

Simultaneous occurrence of B-cell chronic lymphocytic leukemia and chronic myeloid leukemia with further evolution to lymphoid blast crisis

The coexistence of chronic myeloid leukemia (CML) and B-cell chronic lymphocytic leukemia (CLL) in the same patient is rare. A 71-year-old woman developed a B-lineage lymphoid blast crisis at 18 months after diagnosis of Ph-positive CML. At this time, a lymphoid cell population with morphologic and immunophenotypic features of CLL was demonstrated. The retrospective review of the tests performed at diagnosis and thereafter disclosed the presence of lymphoid nodules in the initial bone marrow biopsy in the absence of lymphocytosis. Subsequently, there was an appearance of moderate lymphocytosis in the following months. Therefore, diagnosis of CML and coexistent CLL was established. Although a transient remission of blast crisis was achieved, blast cells reappeared two months later and the patient died shortly afterwards. Molecular studies of the immunoglobulin heavy chain gene (IH) rearrangement pattern point to the origin of the diseases in two different cell clones. In addition, previously published cases of simultaneous CLL and CML are reviewed.     

Autologous hematopoietic stem cell transplantation in chronic myeloid leukemia

A circuit that simulates T-type calcium-channel current characteristics of the sinoatrial (SA) node was developed from discrete electronic components and tested at physiologic membrane voltage ranges. The circuit design was based on the T-type calcium-channel current dynamics obtained from a mathematical model of the SA node membrane, which, in turn, is based on physiologic data. The design was held at a resting membrane potential and then stepped to new voltages over the entire operating range of the T-type calcium channel. The circuit was validated by comparing its transient response current with the predicted current from the mathematical model. In addition, the peak currents of the circuit were compared with plots of peak current obtained from the mathematical model and physiologic data. By showing that the electronic circuit mimics the T-type calcium-channel current dynamics found within the SA node, the results may provide a foundation for developing a novel cardiac pacemaker that is based on the ion-channel characteristics of excitable tissue.     

Developments in the treatment of patients with chronic myeloid leukemia

In the treatment of chronic myelocytic leukaemia (CML) allogeneic bone marrow transplantation (BMT) from a sibling donor is the treatment of choice in patients younger than 50 years; the overall 5-year survival is about 60%. Donor lymphocyte infusion without chemotherapy may serve as an efficacious therapy for recurrence of CML after allogeneic BMT. Application of allogeneic BMT from a matched unrelated donor is increasing, but the outcome is still inferior to that of sibling BMT, largely due to more severe and more frequent complications. Treatment with interferon-alpha has been shown to prolong the overall median survival, but especially in a subgroup of patients (about 15%) who achieve a major cytogenic response. Combination of interferon-alpha and low-dose cytarabine leads to increased survival and a better cytogenic response than interferon-alpha alone. Current investigations are aimed at further improving survival and cytogenic response by using more intensive chemotherapy, such as high-dose cytarabine, followed by interferon-alpha maintenance therapy.     

Mobilization of hematopoietic progenitors in patients with chronic myeloid leukemia

Although the mobilization and harvesting of Philadelphia chromosome-negative progenitors has been proven feasible by a number of groups, it is not clear which techniques should be used with regard to the monitoring of purging and evaluation of stem cell yield. Therefore, we isolated CD34-positive cells from leukapheresis samples of seven CML patients after induction therapy. These cells were analyzed using the colony-forming unit granulocyte-macrophage (CFU-GM) and long-term culture-initiating cell (LTCIC) assays. In addition, we analyzed frequency and clonogenicity of single stem cells using the LTCIC assay at limiting dilution. Individual colonies derived from these assays were subsequently analyzed for the presence of the bcr-abl gene with interphase fluorescence in situ hybridization (FISH) and for the presence of bcr-abl mRNA with RT-PCR. We compared these results with the cytogenetic analysis of the leukapheresis material. Molecular analysis of individual colonies correlated well with the results of cytogenetic analysis. However, in nine out of 18 samples, cytogenetic analysis exclusively demonstrated the presence of either Philadelphia chromosome-positive or -negative cells whereas with the molecular analysis of individual colonies tumor contamination or the presence of residual normal cells could be substantiated. We concluded that molecular analysis of individual colonies should be employed to further optimize induction protocols. With regard to stem cell mobilization we demonstrated that about 67 CFU-GM colonies and clusters were generated by one single LTCIC both for the CML samples and the samples obtained from patients with non-hematologic malignancy. This number is important since until now most centres use a number of four colonies and clusters generated by one LTCIC. Dividing the CFU-GM output in the LTCIC assay by four to determine LTCIC frequency could thus lead to an almost 20-fold overestimation of the LTCIC frequency. It is concluded that stem cell frequency analysis is an important tool with regard to the interpretation of mobilization protocols.     

Immunophenotypic characteristics of the blast crisis in chronic myeloid leukemia

The objective of this study was to provide the Tamworth Rural Training Unit with a clear understanding and practical strategic directions for contributing to an equitable distribution of rural general practitioners in the New England Area Health Service. A survey was sent to all 139 general practitioners practising in this region. The best and worst features of rural practice, both professionally and personally, were surveyed, as well as ways to attract more general practitioners to rural areas. It was found that this region required an additional 46 full-time general practitioners in 1995 if equity and social justice principles were to be met. Projecting to the year 2005, the total shortfall of full-time general practitioners in the New England Area Health Service amounts to 90. It is recommended that this critical shortage of rural general practitioners be assessed within two distinct time frames, namely short-term strategies (1996-1998) and medium-term strategies (1999-2005).