Supportive care including growth factors in myelodysplastic syndromes

In spite of recent advances in the treatment of myelodysplastic syndromes (MDS), supportive care remains a very important part of the therapy. Red blood cells transfusions are the most important component of this supportive care. They transiently relieve anemia symptoms and alleviate their effects on quality of life and daily functioning. Platelet transfusion therapy is less frequently needed, at least in low-risk MDS. Dealing with an increased risk of infections linked to neutropenia, mainly by broad spectrum antibiotics, is also needed, more often in advanced stages of [dict: MDS] or when the MDS evolves to acute myeloid leukemia. Chronic red blood cell transfusions expose patients to various side-effects, including blood components intolerance reactions and alloimmunization risks, but also increased frequency of iron overload, a more significant problem in low-risk heavily transfused MDS patients, who have prolonged life expectancy. The use of growth factors is becoming a more and more important part of current supportive care. High-dose erythropoietin is able to reduce or suppress red blood cell transfusions needs in selected subgroups of MDS. The short-term use of granulocyte colony-stimulating factor is also often proposed in infections, although not formally established by prospective trials. Although trials of growth factors with thrombopoeitic activity have been performed with interleukin 11 and are underway with thrombopoeitin, none of them are available for routine use.     

Advances in the treatment of acute myeloid leukemia: from chromosomal aberrations to biologically targeted therapy

We describe several recent advances in our understanding and treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) including the use of cytogenetics to classify these diseases and to identify therapies that are specific for the abnormalities. Cell lines have provided readily available and very relevant models to understand these diseases. The two clear successes include the use of retinoic acid for acute promyelocytic leukemia and tyrosine kinase inhibitors (e.g., imatinib) for chronic myelogenous leukemia. Very recent results suggest a particular activity of lenalidomide, an analogue of thalidomide, in MDS patients with deletions of the long arm of chromosome 5 (so-called 5q minus syndrome), and notable activity of azanucleoside DNA demethylating agents in MDS with loss of chromosome 7. However, for the vast majority of cytogenetic abnormalities found in AML/MDS, no specific therapies have been identified. The use of a variety of molecular biology techniques have identified a large number of genomic abnormalities; the challenge of the next several decades is to identify specific therapies for these molecular defects.     

Comparing Bona Fide Psychotherapies of Depression in Adults with Two Meta-Analytical Approaches

Objective

Despite numerous investigations, the question whether all bona fide treatments of depression are equally efficacious in adults has not been sufficiently answered.

Method

We applied two different meta-analytical techniques (conventional meta-analysis and mixed treatment comparisons). Overall, 53 studies with 3,965 patients, which directly compared two or more bona fide psychotherapies in a randomized trial, were included. Meta-analyses were conducted regarding five different types of outcome measures. Additionally, the influence of possible moderators was examined.

Results

Direct comparisons of cognitive behavior therapy, behavior activation therapy, psychodynamic therapy, interpersonal therapy, and supportive therapies versus all other respective treatments indicated that at the end of treatment all treatments but supportive therapies were equally efficacious whereas there was some evidence that supportive therapies were somewhat less efficacious than all other treatments according to patient self-ratings and clinical significance. At follow-up no significant differences were present. Age, gender, comorbid mental disorders, and length of therapy session were found to moderate efficacy. Cognitive behavior therapy was superior in studies where therapy sessions lasted 90 minutes or longer, behavior activation therapy was more efficacious when therapy sessions lasted less than 90 minutes. Mixed treatment comparisons indicated no statistically significant differences in treatment efficacy but some interesting trends.

Conclusions

This study suggests that there might be differential effects of bona fide psychotherapies which should be examined in detail.     

Translational research in myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are receiving unusual attention recently as great strides have been made in understanding the biology. Recognition that excessive cytokine-induced apoptosis plays a significant role in the cytopenias of the majority of patients opened the doors to anti-cytokine therapy, with thalidomide being used with success in approximately 20% patients. Other therapies that have emerged include the thalidomide analog lenalidomide which is particularly beneficial for 5q- patients as well as a subset of non-5q- patients with low or intermediate-1 risk MDS. Other targeted therapies include vitamins, agents that are cytoprotective, differentiation inducers, anti-angiogenic, or immune modulatory. In addition, inhibitors of proteasome, methylation, histone deacetylation, farnesylation, receptor tyrosine kinases, topoisomerase, and matrix mettaloproteinases have yielded encouraging responses in subsets of patients. Specific therapies have also been developed for genetic abnormalities that lead to fusion genes (TEL-PDGFR-beta, or FIP1L1-PDGFR-alpha), or abnormal proteins due to mutations/functional inactivation (FLT3), dysregulated expression (EVI-1). In a short span of ten years, the field has evolved from having no effective therapy to offer the majority of MDS patients save chemotherapy, to having one FDA approved drug, several on the way to approval, and a number of novel agents producing exciting clinical results. This chapter summarizes the novel targets and targeted therapies in the rapidly evolving therapeutic landscape of MDS.     

Getting the right stuff： controlling neural stem cell state and fate in vivo and in vitro with biomaterials

Stem cell therapy holds great promises in medical treatment by, e.g., replacing lost cells, re-constitute healthy cell populations and also in the use of stem cells as vehicles for factor and gene delivery. Embryonic stem cells have rightfully attracted a large interest due to their proven capacity of differentiating into any cell type in the embryo in vivo. Tissue-specific stem ceils are however already in use in medical practice, and recently the first systematic medical trials involving human neural stem cell （NSC） therapy have been launched. There are yet many obstacles to overcome and procedures to improve. To ensure progress in the medical use of stem cells increased basic knowledge of the molecular mechanisms that govern stem cell characteristics is necessary. Here we provide a review of the literature on NSCs in various aspects of cell therapy, with the main focus on the potential of using biomaterials to control NSC characteristics, differentiation, and delivery. We summarize results from studies on the characteristics of endogenous and transplanted NSCs in rodent models of neurological and cancer diseases, and highlight recent advancements in polymer compatibility and applicability in regulating NSC state and fate. We suggest that the development of specially designed polymers, such as hydrogels, is a crucial issue to improve the outcome of stem cell therapy in the central nervous system.     

The Nonsteroidal Anti-Inflammatory Drug Exisulind Selectively Induces Apoptosis via JNK in Secondary Acute Myeloid Leukemia after Myelodysplastic Syndrome

Treatment of patients suffering from myelodysplastic syndromes and secondary acutemyeloid leukemia after MDS is often unsuccessful. Pro-apoptosis with arsenic trioxide hasrecently been proposed as a novel therapeutic approach. Exisulind is another potentially proapoptoticagent, and therefore, we investigated its influence on proliferation, differentiation,cell cycle and apoptosis in two sAML/MDS cell lines, one de-novo AML cell line and healthyCD34+ bone marrow cells. Treatment of sAML/MDS cells with Exisulind clearly inhibitedcolony formation in the CFU-assays. Interestingly, Exisulind did not alter the percentages ofsAML/MDS cells in G1-, G2-, M- or S-phase, but reduced proliferation and inducedapoptosis in this cell type. Exisulind had no effect on de-novo AML or normal CD34+ cells.We detected increased c-Jun NH2-terminal kinase activity in sAML/MDS cells treated withExisulind. Adding a specific JNK-inhibitor to Exisulind-treated sAML/MDS cells partiallyabrogated apoptosis, thus proving that Exisulind-mediated apoptosis in sAML/MDS cells isdependent on JNK activation. We conclude that JNK is one mediator of apoptosis insAML/MDS cells treated with Exisulind. Moreover, our data strongly suggests to explore thepotential use of Exisulind as a novel, pro-apoptotic therapy for patients with MDS andsAML/MDS.     

Methods for the identification of vascular markers in health and disease: From the bench to the clinic

Several diseases are characterized by changes in the molecular composition of vascular structures, thus offering the opportunity to use specific ligands (e.g., monoclonal antibodies) for imaging and therapy application. This novel pharmaceutical strategy, often referred to as “vascular targeting”, promises to facilitate the discovery and development of selective biopharmaceuticals for the management of angiogenesis-related diseases. This article reviews novel biomedical applications based on vascular targeting strategies, as well as methodologies which have been used for the discovery of vascular markers of pathology.     

Supportive therapy of lung cancer patients

The effectiveness of cancer treatment given to lung cancer patients is indicated by the asymptomatic and non-toxic survival time. The goal is not to prolong the patients' suffering, but to lengthen the duration of the best quality of life lived (Time Without Symptoms and Toxicity-TWIST). Supportive care is the prevention and management of side effects which occur during therapy (chemotherapy, radiotherapy, surgery) given to patients suffering from cancer. Supportive care is the widespread activity of doctors, nurses and social workers, including psychosocial assistance and rehabilitation through the various stages of illness till death. Though palliative therapy is understood to be the high level and professional treatment of terminally ill patients in those cases where curative measures are not possible anymore, supportive and palliative treatment often overlap (e.g. pain control, cachexia, obstructive syndromes). Palliative care is part of supportive therapy. The goal of supportive care is to reduce the patients' subjective symptoms to the minimum ("well being") during therapy, follow up and consequently until death. The essence of supportive care is to keep the patients' quality of life on the highest possible level. This article summarizes the pathophysiology, prevention and therapy of the most frequently occuring side effects observed during the management of lung cancer patients.     

Regression of established liver tumor induced by monoepitopic peptide-based immunotherapy

Most types of cancer are difficult to eradicate, and some, like hepatocellular carcinoma, are almost always fatal. Among various interventions to improve the survival of patients with cancer, immunotherapy seems to hold some promises. However, it requires relevant animal models for preclinical development. In this study we report a new and relevant experimental model where liver tumors grow inside a nontumoral parenchyma of adult mice. This model is based on the intrasplenic injection in syngeneic recipient mice of hepatocytes from transgenic mice expressing SV40 large T oncogene specifically in the liver. Using this model where no apparent spontaneous cellular immune response was observed, immunization using a single injection of monoepitopic SV40 T Ag short peptide was sufficient to provoke liver tumor destruction, leading rapidly to complete remission. Tumor regression was associated with the induction of a long-lasting CD8+ T cell response, observed not only in the spleen but also, more importantly, in the tumoral liver. These results show the efficacy of peptide immunotherapy in the treatment of liver cancer.     

An in vitro assessment for evaluating the efficiency of β-d-mannuronic acid (M2000) in myelodysplastic syndrome

β-d -Mannuronic acid (M2000), a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive properties, has been previously shown to exhibit potential therapeutic effects on autoimmune diseases. Immunosuppression therapy has been a standard approach for myelodysplastic syndrome (MDS) for many years. We evaluated the effect of M2000 on isolated peripheral blood mononuclear cells (PBMCs) from patients with MDS. The PBMCs were isolated from 13 patients with MDS and 13 normal donors. The cells were then treated with low, moderate, and high doses of M2000 and diclofenac as a control group. The level of interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL-3, granulocyte colony-stimulating factor (G-CSF) gene expression and the serum level of IL-6 and TNF-α production were evaluated by real-time polymerase chain reaction and enzyme-linked immunosorbent assay methods, respectively. Our findings indicated a significant reduction in the production of IL-6 and TNF-α as inflammatory cytokines. Furthermore, the level of G-CSF gene expression was significantly increased. In conclusion, M2000, a newly designed NSAID, has a remarkable effect on isolated PBMC in patients with MDS, which might bring a potential hope for its oral administrations in these patients.     

New therapeutic options for lysosomal storage disorders: enzyme replacement,small molecules and gene therapy

During the last few years, much progress has been made in the treatment of lysosomal storage disorders. In the past, no specific therapy was available for the affected patients, and management consisted solely of supportive care and treatment of complications. Since enzyme replacement therapy has been successfully introduced for patients with Gaucher disease, this principle of treatment has been taken into consideration for other lysosomal storage disorders as well. Clinical trials could demonstrate the clinical benefit of this therapeutic principle in Fabry disease, mucopolysaccharidoses type I, II and VI and in Pompe disease. However, the usefulness of enzyme replacement therapy is limited due to the fact that a given enzyme preparation does not have beneficial effects on all aspects of a disorder in the same degree. Additionally, clinical studies have shown that many symptoms of a lysosomal storage disorder even after long-term treatment are no more reversible. A further novel therapeutic option for lysosomal storage disorders consists of the application of small molecules that either inhibit a key enzyme which is responsible for substrate synthesis (substrate deprivation) or act as a chaperone to increase the residual activity of the lysosomal enzyme (enzyme enhancing therapy). Various gene therapeutic techniques (in vivo and ex vivo technique) have been developed in order to administer the gene that is defective in a patient to the bloodstream or directly to the brain in order to overcome the blood–brain barrier. This review will give an insight into these newly developed therapeutic strategies and will discuss their advantages and limitations.     

Antisense oligonucleotides as therapeutic agents.

Antisense oligonucleotides can block the expression of specific target genes involved in the development of human diseases. Therapeutic applications of antisense techniques are currently under investigation in many different fields. The use of antisense molecules to modify gene expression is variable in its efficacy and reliability, raising objections about their use as therapeutic agents. However, preliminary results of several clinical studies demonstrated the safety and to some extent the efficacy of antisense oligodeoxynucleotides (ODNs) in patients with malignant diseases. Clinical response was observed in some patients suffering from ovarian cancer who were treated with antisense targeted against the gene encoding for the protein kinase C-alpha. Some hematological diseases treated with antisense oligos targeted against the bcr/abl and the bcl2 mRNAs have shown promising clinical response. Antisense therapy has been useful in the treatment of cardiovascular disorders such as restenosis after angioplasty, vascular bypass graft occlusion, and transplant coronary vasculopathy. Antisense oligonucleotides also have shown promise as antiviral agents. Several investigators are performing trials with oligonucleotides targeted against the human immunodeficiency virus-1 (HIV-1) and hepatitis viruses. Phosphorothioate ODNs now have reached phase I and II in clinical trials for the treatment of cancer and viral infections, so far demonstrating an acceptable safety and pharmacokinetic profile for continuing their development. The new drug Vitravene, based on a phosphorothioate oligonucleotide designed to inhibit the human cytomegalovirus (CMV), promises that some substantial successes can be reached with the antisense technique.     

Molecular mechanisms that produce secondary MDS/AML by RUNX1/AML1 point mutations

RUNX1/AML1 point mutations have been identified in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. A heterozygous germline mutation of the RUNX1 gene causes a familial platelet disorder with a predisposition to AML. RUNX1 mutations have also been detected with high frequency in minimally differentiated AML M0 subtypes and myelodysplastic/myeloproliferative neoplasms. Here we propose a new disease category of myelodysplastic neoplasms (MDN) consisting of MDS refractory anemia with excess blasts and AML with myelodysplasia-related changes, including therapy-related cases. RUNX1 mutations have been detected in about 20% of patients with "MDN". Among the MDN cases, histories of radiation exposure, therapy-related myeloid neoplasms after successful treatment for acute promyelocytic leukemia, and leukemic transformation of myeloproliferative neoplasms have been reported to have a strong association with RUNX1 mutations. The mutations occur in a normal, a receptive, or a disease-committed hematopoietic stem cell. It is suspected that the "MDN" phenotypes are defined by the RUNX1 mutations in addition to some other abnormalities.     

Stem cell transplantation for a myelodysplastic syndrome in children

The myelodysplastic syndrome (MDS) is a rare, clonal disorder of pluripotent stem cells in children and is characterized by ineffective haematopoiesis, morphologic abnormalities in one or more cell lines in a usually cellular bone marrow, and by predilection for the acute leukaemia. A large proportion of children with MDS present associated clinical abnormalities. Allogeneic stem cell transplantation (SCT) is the only definitive cure for this heterogeneous group of lethal disorders. Results with SCT have been difficult to interpret due to the variability of conditioning regimens, types of donors, and pretransplant therapy. In many series, the outcome with donors other than matched siblings has been extremely poor. The optimal pre-transplant therapy and conditioning regimen for SCT in MDS have not yet been defined. The establishment of several international working groups will eventually help to elucidate the pathogenesis of childhood MDS and will evaluate new treatment strategies to improve their clinical outcome.     

Long-term Control of Bacteriuria with Trimethoprim-Sulphonamide

Long-term antibacterial therapy with the drug combination trimethoprim-sulphonamide has been used for the treatment of 52 patients with persistent or recurrent bacteriuria. Hypersensitivity or gastrointestinal intolerance was observed in six. Bacteriuria was controlled in 36 out of 38 patients with organisms sensitive to trimethoprim-sulphonamide, 28 having received treatment for periods ranging from 6 to 49 months. Treatment was in some cases curative and in others suppressive or prophylactic. The importance of supportive measures is re-emphasized.     

Aggressive chemotherapy in adult primary myelodysplastic syndromes. A report on 29 cases

Twenty-nine adult patients with primary myelodysplastic syndromes (MDS) and an excess of marrow blasts were treated by aggressive chemotherapy while still in MDS phase (20 cases) or after progression to ANLL (9 cases). Median age was 47.5 (range 18-68). Twenty-eight patients received a combination of Rubidazone and Ara C and 1 received High dose Ara C. Fourteen patients (48%) achieved complete remission (CR), 5 (17%) were treatment failures (F) and 10 (35%) died during therapy induced aplasia (DA). Median disease free survival was 8.5 months. Median survival of the whole population was 6 months from the onset of treatment, and 17 months in patients achieving CR. These results were significantly less favorable than those obtained at our institution in de novo ANLL with the same chemotherapy regimens. No statistically significant prognostic factors of treatment outcome emerged but patients with normal cytogenetic findings seemed to have both a higher CR rate and longer remissions than patients with abnormal karyotypes. Patients under 50 did not have higher CR rates than older patients, although they had longer remissions (with 3 out of 6 CRs exceeding 2 years). Finally, treatment outcome and survival were identical in patients treated in the MDS phase and in those treated after progression to ANLL. Combination chemotherapy is a highly toxic approach in MDS and essentially seems to benefit younger patients with a normal karyotype, in whom some long remissions can be obtained.     

Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid

5-azacytidine (AZA) has become standard treatment for patients with higher-risk myelodysplastic syndrome (MDS). Response rate is about 50% and response duration is limited. Histone deactylase (HDAC) inhibitors are attractive partners for epigenetic combination therapy. We treated 24 patients with AZA (100?mg/m(2), 5?days) plus valproate (VPA; continuous dosing, trough serum level 80-110?μg/ml). According to WHO classification, 5 patients had MDS, 2 had MDS/MPD, and 17 had acute myeloid leukemia (AML). Seven patients (29%) had previously received intensive chemotherapy, and five had previous HDAC inhibitor treatment. The overall response rate was 37% in the entire cohort but significantly higher (57%) in previously untreated patients, especially those with MDS (64%). Seven (29%) patients achieved CR (29%) and two PR (8%), respectively. Hematological CR was accompanied by complete cytogenetic remission according to conventional cytogenetics in all evaluable cases. Some patients also showed complete remission according to FISH on bone marrow mononuclear cells and CD34(+) peripheral blood cells, as well as by follow-up of somatic mitochondrial DNA mutations. Four additional patients achieved at least marrow remissions. Factors influencing response were AML (vs. MDS), marrow blast count, pretreatment, transfusion dependency, concomitant medication with hydroxyurea, and valproic acid (VPA) serum level. This trial is the first to assess the combination of AZA plus VPA without additional ATRA. A comparatively good CR rate, relatively short time to response, and the influence of VPA serum levels on response suggest that VPA provided substantial additional benefit. However, the importance of HDAC inhibitors in epigenetic combination therapy can only be proven by randomized trials.     

Improvement of anemia by recombinant erythropoietin in patients with myelodysplastic syndromes and aplastic anemia

Eight patients with myelodysplastic syndromes (MDS) and four patients with aplastic anemia (AA) were treated with recombinant erythropoietin (rEpo) to investigate its effect on the anemia of these patients. rEpo was administered by i.v. injection three times a week for at least four weeks. The doses were 3,000, 6,000, or 12,000 U/day. Despite an elevated "endogenous" Epo level, a greater than 1.5 g/dl increase in hemoglobin (Hb) concentration was observed in one patient with refractory anemia (RA), one patient with refractory anemia with excess of blasts (RAEB), and one patient with AA. A greater than 50% decrease in red cell transfusion requirement was observed in one patient with RA and one patient with AA. One RA patient and one AA patient have received rEpo as maintenance therapy for more than 64 and 100 weeks, respectively. They no longer need red cell transfusions and have had a normal Hb concentration and normal ferrokinetics. No side effect was seen. These results indicate that rEpo may benefit some patients with MDS and AA who are dependent on red cell transfusions while further studies will be necessary to elucidate the mechanism by which rEpo stimulates erythropoiesis and improves anemia in patients with these diseases.     

Anti-TNF therapies in the management of acute and chronic uveitis

Patients with anterior uveitis may be treated with topical therapy alone but patients with posterior uveitis and those with sight threatening complications of anterior uveitis usually require systemic treatment especially if the disease is bilateral. The mainstay of treatment is corticosteroids and additional immunosuppressive agents such as cyclosporin and mycophenolate are used when necessary. There remains a significant cohort of patients in whom this therapy is either not tolerated or is ineffective. The use of the anti-tumour necrosis factor (TNF) antibodies has been very successful in controlling other immune-mediated disorders such as rheumatoid arthritis and has subsequently been extended to use in other arthritidies and other disorders such as psoriasis and Crohn's disease. TNF is known to play a key role in ocular inflammation as shown by animal studies and its detection in the ocular fluids of inflamed eyes in man. In some disorders all types of anti-TNF antibodies have similar efficacy but that does not appear to be the case with uveitis where infliximab is at present looking to be more effective than etanercept. The data on the use of anti-TNF drugs in uveitis is presented together with new data on its role as a steroid sparing agent.     

Lessons for the stem cell discourse from the gene therapy experience

The discovery of human embryonic stem cells has pointed to the potential use of these cells in developing new approaches to therapy for many major human diseases. While there is general agreement that such applications are possible and will require a great deal of additional basic and preclinical research, some discussions of the therapeutic applications of human embryonic stem cells have been characterized by the kinds of exaggerations and elevated expectations that characterized the field of human gene therapy a decade ago. In the case of gene therapy, public perception of and confidence in the field were damaged by the hype. Most unfortunate of all, the hopes of patients and their advocates were disappointed. The eventual success of a gene therapy approach, albeit one still plagued by serious adverse events, has come through scientific advance and careful clinical application. The probable eventual use of human embryonic stem cells for therapy of human disease will also require thorough basic and clinical research, but that goal is endangered by the current level of inaccurate representations and undeliverable promises.