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.     

RAS and the myelodysplastic syndromes

RAS genes have been implicated in several different malignancies. The mechanism of activation in most cases has been due to point mutations at critical domains responsible for guanine nucleotide binding. These changes alter the conformation of the protein resulting in insensitivity of the protein to the GTPase activating protein which normally hydrolyses the active p21RAS GTP-bound form to the inactive GDP-bound form. RAS genes have potent effects on the differentiation and proliferation program of cells. The mechanism induced depends on the context in which RAS is found as well as its mutational status and indeed which RAS gene family member is involved. RAS mutations have been described early in the disease process in haematologically normal individuals at risk of mutations induced by either occupational hazard exposure, such as benzene, or of secondary disease after chemotherapy for a previous malignancy. It also been associated with disease progression from myelodysplasia (MDS) to acute myelogenous leukaemia (AML), but it has also been described to be lost upon disease progression, thus showing that RAS mutations are unlikely to be initiating events or at least not required for maintenance of disease. As RAS appears to be involved in primary and secondary myeloid leukaemias, it is a good candidate for gene targeted therapeutic intervention. Studies to target RAS either directly or indirectly by interfering in the RAS pathway are underway. Clinical trials with a peptide RAS vaccine are also ongoing in solid tumours. This report seeks to review the evidence for RAS involvement as oncogenes, focusing on MDS, the reasons as to why the hot spots of codons 12/13 and 61 are particularly potent in activating the transformation potential of RAS and the different approaches being undertaken to translate laboratory findings into therapeutic reality.     

The molecular basis of myelodysplastic syndromes

Rabbit lenses expressing spontaneous oscillations in translens short-circuit current (Isc) are obtained somewhat frequently, with this phenomenon observed in approximately 30% of isolated lenses as described earlier (Exp. Eye Res. 61, 129-140, 1995). Since pharmacological protocols to consistently elicit Isc oscillations were not found, characterizations of the underlying transport processes have been limited to the application of various inhibitors on the spontaneous phenomenon. The present report extends the initial observations by confirming that oscillations are immediately inhibited upon the anterior addition of the Ca2+ channel blocker nifedipine (10 microM), and by demonstrating that other treatments which should affect epithelial Ca2+ homeostasis are also inhibitory (e.g., Bay K 8644 (10 microM), diltiazem (10 microM), EGTA (2 mm), and Ca2+-free media). Furthermore, Isc oscillations are immediately inhibited by the K+ channel blocker, Ba2+, but not by the Na+-K+ pump inhibitor, ouabain. The intracellular Ca2+ mobilizing agents thapsigargin (0.1 microM) or acetylcholine (1 microM) modified but did not permanently inhibit the oscillations, confirming earlier observations. At 50 microM, however, acetylcholine addition was inhibitory, but reversible, for oscillations restarted upon its subsequent removal. In addition, lens oscillations were also characterized under open-circuit conditions with microelectrodes inserted in the superficial cells near the equator of lenses isolated in a divided chamber. The potential difference (PD) across each lens face was recorded, as was the translens PD (PDt), which equals the difference between the PDs across each lens surface. Oscillations in PDt were obtained in 7 of 26 lenses. The oscillations arose only from an oscillation in the PD across the anterior face (PDa). While PDa and PDt oscillated with the same amplitude (approximately 12 mV) and period (approximately 70 sec), the PD across the posterior surface remained stable. During these oscillations the conductance of the anterior surface was maximal at the most positive voltage of the anterior bath with respect to the lens interior (46 mV), whereas, minimal conductance occurred at the least positive PDa (34 mV). Overall, these observations are consistent with the likely presence of voltage-operated Ca2+ channels in parallel with various Ca2+-sensitive K+ channels in the epithelial basolateral membrane. A model to explain the oscillatory pattern across the anterior face while the PD across the posterior face remains unaltered is presented.     

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.     

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.     

Treatment with growth factors in myelodysplastic syndromes

In myelodysplastic syndromes (MDS), pancytopenia leads to a high risk of infectious and hemorrhagic complications. The progression to acute myeloid leukemia adds to morbidity and mortality. While transfusions of red blood cells and platelets are still a cornerstone of the therapy, the clinical use of recombinant hematopoietic growth factors has enlarged the range of therapeutic applications in patients with MDS. It is possible to reverse neutropenia by administration of G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte-monocyte colony stimulating factor). In the case of a severe infection, therapeutic administration of G-CSF together with antibiotics might be justified in otherwise neutropenic MDS patients. Since especially patients with only slight impairment of erythropoiesis and no transfusion dependency have the highest response rates but need erythropoietin (EPO) the least, pharmacoeconomic analyses are urgently needed. Controlled randomized trials will have to ascertain wether combinations of EPO with G-CSF or GM-CSF are of benefit. Clinical studies with thrombopoietin (megakaryocyte growth and differentiation factor) have to be initiated to find out whether thrombocytopenia in MDS can be reversed.     

A feature of hematological findings in myelodysplastic syndromes

Ovine FSH (40: g per bird daily for 10 days) increased ovarian weight, follicular size, phosphatase activities, and RNA and protein levels in tree pie (Dendrocitta vagabunda), but exogenous ovine LH (40 micrograms per bird daily for 10 days) with the same dose and duration caused depletion of ovarian cholesterol and ascorbic acid concentrations with a rise in sialic acid and glycogen levels of the ovary. In contrast, prolactin (LTH: 5 I.U. per bird daily for 10 days) administration showed reverse biochemical changes to those of FSH. The findings suggest that FSH induces mainly ovarian follicular growth and LH stimulates ovarian steroidogenesis, but LTH is antigonadal in this wild avian species.     

Changes of the complement system in myelodysplastic syndromes

A retrospective chart review identified patients who had surgery through Henry's standard anterior and anterolateral approaches to the humerus. Of the patients contacted, 62% had problems with the skin incision with reports of pain, numbness, and tingling around the scar. The frequency of cutaneous problems including neuroma prompted an anatomic study; the lower lateral cutaneous nerve branches to the arm were dissected in seven cadaver arms to determine their course. Henry's incision was then compared with a midline anterior incision. The cutaneous nerves were noticeably less numerous and smaller in diameter in the midline incision, probably related to the internervous, or watershed zone of cutaneous nerves in the anterior midline of the arm. Henry's standard intermuscular humeral exposure was no more difficult with the anterior midline incision. This study supports the notion that an anterior midline incision to approach the shaft of the humerus would minimize scar discomfort from cutaneous nerve injury.     

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.     

Histopathologic features of bone marrow in myelodysplastic syndromes

The findings of this pilot study provide some support that there is a significant positive relationship between the level of achievement rating of critical case (basic psychomotor skills) and the level of barmentoring (encouragement) of novice nurses in clinical nursing practice. The leadership gained from the developmental refinement of the mentor/protégé relationship is a key to acting and thinking as a professional in nursing practice. Although the mentor/protégé relationship may contribute to personal and professional goal attainment, mentoring should not be regarded as a panacea, but as one modality for enhancing professional development (Messner, 1991; Yoder, 1990). The limitations of the study include a fairly homogenous sample, self-reported data, and lack of knowledge of the sample's preceptors. The sample size notably affects the generalizability of the findings as well as the statistical findings in the study.     

A patient-oriented approach to treatment of myelodysplastic syndromes

BACKGROUND AND OBJECTIVE: There are several therapeutic options for patients with myeiodysplastic syndrome (MDS) but most of them are poorly effective and the potentially curative ones are available only for a minority of individuals. The aim of this article is to define a rational basis for a patient-oriented approach to treatment of MDS. EVIDENCE AND INFORMATION SOURCES: All four authors have done clinical studies of treatment of MDS, including stem cell transplantation, intensive and low-dose chemotherapy, and use of hematopoietic growth factors. They also participated in the Fourth international Symposium on MDS (Barcelona, 24-27 April 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: At present, the only two treatments that can prolong survival are allogeneic stem cell transplantation (SCT) and intensive chemotherapy, but only a minority of MDS patients can really benefit from them. The heterogeneity of MDS patients, the wide variety of patient inclusion criteria and transplant procedures used, and relatively small numbers of patients in the individual reports of allogeneic SCT make it difficult to draw many definitive conclusions. However, approximately 40% of patients with MDS who are eligible for allogeneic SCT are likely to be cured by this treatment. Intensive chemotherapy with a combination of cytosine arabinoside and an anthracycline should be offered to all patients with an increase in bone marrow blasts who are not eligible for allogeneic SCT, especially those patients up to 65 years of age. Complete remission rates are similar to those obtained in patients with acute myelogenous leukemia, but probability of long-term survival is low. The remaining treatments validated in clinical trials (erythropoietin and/or granulocyte colony-stimulating factor, low-dose cytosine arabinoside) can improve the efficiency of hematopoiesis in subsets of patients. Responsive individuals might experience an improvement in quality of life but very few studies have addressed this question so far. The majority of MDS patients still rely upon supportive therapy. A clinical decision path based on findings of clinical trials and the patient's expectations can help physicians in decision making. Because of the inadequacies of all current treatment modalities, participation in clinical trials should always be encouraged.     

Prognostic factors and scoring systems in myelodysplastic syndromes

The treatment of peptic ulcers has been revolutionized by the discovery that Helicobacter pylori (H. pylori) bacteria is a causative agent for ulcer formation. However, when patients present with dyspepsia or epigastric discomfort, more than 80% of patients will not have ulcer disease and empiric treatment of H. pylori is not recommended for these patients. Eradication of H. pylori has not been demonstrated to improve the symptoms of non-ulcer dyspepsia compared with non-ulcer dyspepsia patients treated with placebo. Therefore, we recommend that patients should first be evaluated for peptic ulcers with endoscopy or upper gastrointestinal series before the diagnosis and treatment of H. pylori. Generally, the treatment of H. pylori should be limited to patients with peptic ulcers, mucosal-associated lymphoid tissue lymphomas, and gastric cancers. Most diagnostic tests for H. pylori, including quantitative IgG antibody, urea breath tests, rapid urease tests (CLO), tests of gastric mucosal biopsies, and staining of gastric mucosal biopsies, have equivalent diagnostic characteristics. Therefore, the choice of diagnostic test for H. pylori should be based on cost, ease of use, and lack of complications. Multiple antibiotic regimens are available for the treatment of H. pylori. Triple antibiotic therapy is the least expensive but has the highest rate of side effects and the least compliance. Combining a proton pump inhibitor with clarithromycin and another antibiotic will eradicate H. pylori with fewer side effects and better compliance but this is the most expensive antibiotic regimen.     

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.     

Hematopoietic growth factors for the treatment of myelodysplastic syndromes

Administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF), rh granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or rh interleukin-3 (rhIL-3) effectively stimulate and expand marrow myelopoiesis resulting in a dose-dependent increment of peripheral blood neutrophils in most patients with myelodysplasias (MDS). Clinical outcome with fewer infections have been reported in a few studies using rhG-CSF or rhGM-CSF, including a large randomized, controlled trial with rhGM-CSF. Clinical effective stimulation of megakaryopoiesis and erythropoiesis are however infrequent. Recently, rh erythropoietin (rhEpo) has been used to overcome the ineffective erythropoiesis in MDS to reduce transfusions needed. However, the efficiency has been low in most studies with marked differences in response rates. The most impressive clinical results were obtained in patients with milder forms of MDS combined with low prestudy endogenous S-Epo levels. The possible synergistic effect of combining rhEpo with rhG-CSF or rhGM-CSF has been studied with erythropoietic response rates of about 40%. The safety of the cytokine administration seems acceptable with no significant stimulation of leukemic myelopoiesis and subsequent progression into overt acute myeloid leukemia. In conclusion, combinations of hematopoietic growth factors may be of clinical benefit in some patients with MDS. However, due to the cost and unpredictable clinical outcome there is a need for extended laboratory research to understand the functional defects of MDS stem cells and progenitors.     

Telomere, telomerase and cytogenetic changes in myelodysplastic syndromes

Myelodysplastic syndrome (MDS) is a heterogenous but clonal disorder characterized by cytopenia and dysplastic features. Telomere length in MDS vary but some of them show shortened telomeres. Telomerase activity in MDS also vary but about 60% of them show slightly elevated telomerase activity. According to the disease progression of MDS, MDS patients categorize into 3 groups, i.e., (1) normal telomere length before and after disease progression, (2) short telomere length before and after progression, and (3) shortened telomere with disease progression. Telomerase change with disease progression is not obscure, indicating impairment of telomere dynamics in MDS. These observations may indicate that some MDS show telomerase upregulation possible due to telomere shortening, while the another pathway without telomerase upregulation associated with complex chromosome changes may link to the pathogenesis of MDS.     

Hypothesis: myelodysplastic syndromes may have a viral etiology

The autonomic nervous system plays a significant role in liver physiology and pathology. The aim of the present study was to investigate peptidergic nerve fibres in the liver of patients with malignant gastrointestinal tumors that are not metastasizing in this organ. Using light and electron microscopic immunohistochemistry, somatostatin (SOM)-, neuropeptide Y (NPY)-, substance P (SP)- and calcitonin gene-related peptide (CGRP)-immunoreactive (IR) nerve fibres (NF) were detected in the portal tract and perisinusoidally. Histologically, the liver showed dilated sinusoids, filled with lymphoid cells, and scarcely marked perisinusoidal fibrosis. Neuropeptide-IR NF were found in close contact with hepatic sinusoids. Numerous IR varicosities were detected in the sinusoidal wall. We discuss the origin and role of these NF in the liver. Probable quantitative changes in peptidergic NF ensue the inflammatory reaction in sinusoids in malignant gastrointestinal tumors. This could also reflect the increased exposure of the liver to toxic substances in the portal blood flow.