The hematology journal : the official journal of the European Haematology Association最新文献

Introduction: In this report, we propose the application of the p-iodophenol-enhanced luminol chemiluminescent technique to the determination of peroxidase (myeloperoxidase and/or platelet peroxidase) activity in blasts of minimally differentiated acute myeloblastic leukemia (AML-M0) and acute megakaryoblastic leukemia (AML-M7).

Methods: The frozen blast cells from 29 patients were thawed and submitted to the optimized protocol.

Results: All cases of AML-M7 and AML-M I exhibited integrated light emission greater than 73(10(2) mV x s), which was the arbitrary cutoff point set for the discrimination between AML and acute lymphoblastic leukemia (ALL) (mean + 3 x s.d. of ALL samples, n = 10). In addition, five out of seven cases of AML-MO showed results above the cutoff point.

Conclusion: This highly sensitive enhanced chemiluminescent technique may be applied to discriminate between ALL and AML-M7 or AML-MI cases, and most AML-M0 cases. It is very simple, cheap and easy to perform compared to other procedures used to measure MPO activity in AML-leukemias including AML-M7 and AML-M0.

Glutathione sulfur transferases (GSTs) is a group of enzymes involved in the detoxification process of carcinogens and other substances. The genes encoding isoenzymes M1 and T1 are polymorphic in humans and the phenotypic absence of enzyme activity (null genotype) may have an effect on the risk of chronic lymphoblastic leukemia (CLL). Our purpose was to examine whether the GSTM1 and GSTT1 homozygous null genotypes altered the risk of CLL. DNA was extracted from the peripheral blood of 27 patients with CLL and 147 cancer-free controls; both groups originated from a defined population (residents of the Ioannina region, northwestern Greece) and were similar with regard to mean age, race and sex; GSTM1 and GSTT1 were simultaneously analyzed by a multiplex polymerase chain reaction (PCR) method and Fisher's exact test was used for comparisons between the two groups. A significantly increased incidence of the GSTM1 null genotype was found in the group of patients compared to the controls (74.07 versus 34.69%, P = 0.0002). Additionally, the incidence of the GSTT1 null genotype was comparable in patients and controls (25.92 versus 10.20%, P = 0.05). The frequency of the combined GSTM1 null/T1 null genotype was significantly different between patients and controls (14.81 versus 2.04%, P = 0.012). However, there was no relationship between the advanced stage of the disease and the GSTs status. Individuals with the GSTM1 and GSTT1 null genotypes may have enhanced susceptibility to CLL.

Background/objective: Fulminant, potentially life-threatening infection represents a major long-term risk after splenectomy. This study examines the impact of patient's knowledge and compliance on the prevention of overwhelming postsplenectomy infection (OPSI).

Methods: A Total of 318 splenectomized patients (median age: 18 years (10-26 years); M : F, 187 : 131) were enrolled in this study. A questionnaire was administered to assess the degree of knowledge and patient compliance and their role in the prevention of postsplenectomy risks; while identifying the group of health-care providers most successful in conveying information.

Results: The 318 patients had been splenectomized and followed up through a 17-year period. OPSI occurred among 5.7% (n=18) of patients. Of these, 56% occurred within the first 6 months and 44% in the following 10 years post splenectomy. Three patients died of OPSI, two during the first 6 months and one 2 years later. Of the followed up patients, 44.8% (n=142) had good knowledge of the risks of splenectomy and their prevention, 30.4% (n=96) had fair knowledge and 24.8% (n=79) had poor knowledge. Patients displaying greatest knowledge had a prevalence of OPSI of 1.4% compared to 16.5% among those with poor knowledge (P<0.001). In all, 60% of patients with good knowledge got their information principally from their tending hematologist. Among patients on regular and irregular prophylactic oral penicillin, OPSI occurred in 2.7 and 10% respectively (P<0.01). The incidence of OPSI also decreased from 7.3 to 3.2% after routine administration of pneumococcal vaccine (P<0.05).

Conclusion: Although good knowledge, prophylactic penicillin and pneumococcal vaccination have remarkably reduced OPSI, it was not enough for complete prevention. The use of lifelong antibiotic prophylaxis remains of disputed value since no OPSI was recorded more than 10 years post splenectomy.

Chronic DIC is a rare complication of aortic aneurysm. Surgical correction is the treatment of choice but for inoperable patients or those with continued DIC after surgery heparin can be used to control the coagulopathy. A case with inoperable multiple aortic aneurysm and chronic DIC managed successfully with dalteparin over a long period is discussed in this report.

In B-cell chronic lymphocytic leukemia (CLL), accumulation of neoplastic B cells may be the result of dysregulated apoptosis. One of the major molecules triggering apoptosis, CD95 (FAS), is not expressed on CLL B cells at resting conditions. However, CD40 triggering of CLL B cells upregulates receptors belonging to the tumor necrosis factor (TNF) superfamily, like CD95. In the present study, we analyzed in B cells from 20 CLL patients the effect of CD40/CD40L interaction on: (i) CD95 modulation; (ii) CD95-mediated apoptosis and (iii) mRNA and protein expression of the death-inducing signaling complex (DISC) molecules.CD40 activation of CLL B cells was carried out by coculture with CD40L-transfected cells and cytofluorimetric analyses were performed to study CD95 modulation and apoptosis induction by an anti-CD95 moAb. Despite strong CD95 upregulation on the membrane of all the cases studied, only a minority of cases analyzed (3/20) proved weakly responsive to CD95-mediated apoptosis. Multiplex RT-PCR was used to analyze FLICE, FAS, FADD and TRADD mRNAs before and after CD40 triggering. In agreement with the cytofluorimetric data, FAS mRNA appeared significantly increased after CD40 triggering; the other molecules involved in DISC formation and in CD95-mediated apoptosis were also expressed without relevant differences between resting and activated conditions. Western blot analyses further confirmed FLICE and FADD protein expression by resting and activated CLL cells. Our findings demonstrate that, following CD40 triggering, CLL B cells are resistant to CD95-mediated apoptosis despite a strong CD95 upregulation on the membrane and a normal mRNA or protein expression of the DISC components.

STI571 is the most innovative drug for the cure of Chronic Myeloid Leukemia. It inhibits, in fact, the disease causative event, the p210 bcr-abl tyrosine kinase, and addresses clonal myeloid progenitors to apoptotic death. Here, we demonstrated that STI571 also induces growth arrest by activating the Chk2-Cdc25A-Cdk2 axis, a pathway complementary to p53 in the activation of G(1)/S cell cycle checkpoint. In vitro exposure to STI571 of 32D murine myeloid progenitor cell clones transducing a temperature-sensitive p210 bcr-abl construct was associated with Chk2 phosphorylation and activation, Cdc25A degradation and persistent Cdk2 inhibitory phosphorylation, preventing, in turn, cell transition to and progression throughout the S phase of cell cycle. Chk2 and Cdc25A are both components of a complex network that integrates signals involved in regulated cell cycle progression, DNA repair and cell decision between life or death. Chk2 gene mutations or decreased expression, leading to its protein loss of function on Cdc25A target, and Cdc25A overexpression have been linked to poor prognosis of human cancers. In CML, they might further enhance the proliferative advantage and genomic instability of clonal myeloid progenitors featuring a class of poor prognosis patients eventually resistant to STI571.

Developments in the understanding of disease biology and in therapeutic approaches during the last decade have failed to alter the natural history of many human hematological malignancies, including chronic lymphocytic leukemia (CLL). Despite better appreciation of the molecular foundations and phenotypic characteristics of these cancers, improvements to disease classification and prognosis, and the discovery of more effective cytotoxic and biological agents, these disorders remain largely incurable. The development of a new class of cytotoxic agents in the 1980 s, namely the purine analogs, heralded a period of renewed optimism in the treatment of indolent lymphoid leukemias and lymphomas. More recently, monoclonal antibodies that selectively target cell-surface proteins, and agents that target cell-cycle or apoptotic pathways, have been developed and their use alone or in combination promise to have a major impact on the treatment of these conditions. Of these, the anti-CD52 antibody alemtuzumab and the anti-CD20 antibody rituximab have demonstrated the most potential for the treatment of CLL. Further, because of their different mode of action in comparison to conventional cytotoxic agents, combination regimens involving fludarabine and these antibodies are showing particular promise in early trials. The encouraging findings with these combination therapies are moving the intent of therapy from palliation towards cure. This paper reviews the therapeutic application of present and future fludarabine-containing approaches. The strategies that are discussed include fludarabine given with alemtuzumab, rituximab, or other monoclonal antibodies, and the potential benefits of combining fludarabine with more experimental agents such as antisense oligonucleotides, immunotoxins, or radioimmunoconjugates. The successful application of fludarabine plus alemtuzumab, or fludarabine in combination with other cytotoxic agents, as preparative regimens for stem cell transplantation techniques is also covered.

Well-established clinical staging systems continue to form a basis for deciding when to initiate treatment and assigning prognosis in chronic lymphocytic leukaemia. However, these staging systems do not identify those patients with early-stage disease who will progress to require treatment. Recent developments have provided a variety of prognostic markers, which can determine those patients with poor prognosis disease. For example, serum markers (soluble CD23), cell surface (CD38) and cytoplasmic (ZAP70) proteins, cytogenetics and immunoglobulin gene mutational status have all been utilised for this purpose. In order for patients to benefit fully from these discoveries they need to be translated into rapid, standardised and cost-effective clinical laboratory tests. The current range of prognostic markers, and techniques for measuring them are discussed.

In an effort to minimise induction therapy-related toxicity, avoid unnecessary hospitalisation and facilitate early ASCT, we have prospectively evaluated an outpatient-based oral chemotherapeutic regimen, cyclophosphamide, idarubicin, dexamethasone (CID) in patients with previously untreated multiple myeloma (mm). Patients subsequently underwent ASCT conditioned with melphalan 200 g/m(2). A total of 36 newly diagnosed MM patients were enrolled between February 1997 and March 2000. In all 136 cycles of CID were administered requiring only four unplanned hospital admissions. Grade 3 or 4 haematological toxicities were documented following 14 cycles (10%). There were no treatment-related deaths. Response rates (PR + CR) based on an intention-to-treat basis were 66% (23 of 35, 9% CR) post-CID and 80% (28 of 35, 34% CR) post-ASCT. In all, 28 of the 35 patients remain alive with a median follow-up for surviving patients of 40 months (range, 30-67 months). Progression-free survival from the time of diagnosis was 32 months (range, 3-55+ months). Median overall survival from diagnosis has not been reached with an estimated overall survival at 4 years of 77%. CID in combination with early ASCT is an effective and well-tolerated antimyelomatous regimen and is a practical alternative to more toxic and invasive therapeutic approaches.