MTHFR, TS and XRCC1 genetic variants may affect survival in patients with myelodysplastic syndromes treated with supportive care or azacitidine.

We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P<0.001; P=0.026; P=0.058; P=0.024). MTHFR 677T/T, TS 3'-UTR -6 bp/-6 bp and XRCC1 399G/G genotypes were associated with short survival in patients receiving azacitidine by multivariate analysis (P<0.001; P=0.004; P=0.002). We then performed an exploratory analysis to evaluate the effect of the simultaneous presence of multiple adverse variant genotypes. Interestingly, patients with ⩾1 adverse genetic variants had a short survival, independently from their International Prognostic Scoring System (IPSS) and therapy received. To our knowledge, this is the first study showing that polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair genes could influence survival of MDS patients.

Low dose interferon-alpha2b combined with PUVA is an effective treatment of early stage mycosis fungoides: results of a multicenter study. Cutaneous-T Cell Lymphoma Multicenter Study Group.

BACKGROUND AND OBJECTIVE: The early stages of mycosis fungoides (MF) can be treated but not cured by photochemotherapy (PUVA) alone; some recent studies of the effect of a combination of human interferon-alpha (IFN(alpha)) and PUVA reported a high degree of response. The aim of our study was to evaluate the activity of a low dose of IFN-alpha2b combined with PUVA. DESIGN AND METHODS: Twenty-five patients were included: 16 men and 9 women aged between 23-80 years; 19 patients ahd stage I and 6 stage II disease. In the induction phase, the dose of IFNalpha was gradually raised over 6-8 weeks to the target dose of 18 MU/week; in the maintenance phase, the combination with PUVA allowed IFNalpha to be reduced to a maximum dose of 6 MU/week; in this way the cumulative administration of IFNalpha and PUVA was considerably lower than in similar combination protocols. Treatment success was analyzed in terms of freedom from treatment failure (FFTF). RESULTS: After the induction phase 9/25 patients (36%) achieved complete remission (CR) and 15/25 (56%) achieved partial remission (PR). One to five months from the beginning of the maintenance phase, a CR was recorded in 19/25 patients (76%) and a PR in 5/25 patients (20%) accounting for an overall response rate of 96%. The median of FFTF was not reached; probability of FFTF was 82% at 12 months and 62% at 24 months. Disease free survival projected to 48 months was 75%. INTERPRETATION AND CONCLUSIONS: Even with low doses of IFNalpha plus PUVA it is possible to achieve excellent clinical responses,many of which are long-lasting, in patients with early MF.

[Biologic aspects and clinical use of granulocyte growth factor]. / Aspetti biologici e impiego clinico del fattore di crescita granulocitario.

Granulocyte colony stimulating factors (G-CSF) has a wide spectrum of action: it stimulates proliferation and differentiation of granulocyte-macrophage progenitors, it promotes the chemotactic activity of monocytes and granulocytes and it develops the antibody-dependent cytotoxicity of neutrophils. In vivo G-CSF induces leucocytosis and it hastens the granulocyte recovery after chemio-radiotherapy. So it has been used in many pathologies: aplastic anaemia, AIDS in treatment with antiviral drugs, myelodysplastic syndromes, acute leukemias and solid tumors. If G-CSF is administered after chemotherapy, both in acute leukemias and in solid tumors, it reduces the duration of neutropenia and the number of febrile episodes so that it is possible to give the whole therapy at the planned dosage with no delay. However G-CSF does not modify the incidence of complete remissions and the overall survival. G-CSF allowed the increase of dose-intensity in chemoresistent neoplasms even if this therapy is always complicated by a heavy extrahaematological toxicity. Moreover G-CSF shortens the total duration of neutropenia after autologous or allogenic bone marrow and peripheral stem cell transplantation even if the appearance of the first neutrophil is not accelerated.

[Idiopathic myelofibrosis. Main pathogenetic, prognostic and therapeutic aspects]. / Mielofibrosi idiopatica. Principali aspetti patogenetici, prognostici e terapeutici.

Primary myelofibrosis is a complex disorder characterized by bone marrow fibrosis with no apparent cause. It is known in literature under a wide number of terms, reflecting the variety of clinical features and the different pathogenetic hypotheses. In most cases it is plain that marrow fibrosis is secondary to a clonal myeloproliferative disorder and, in particular, to the presence of abnormal megakaryocytes secreting (MKDGF/PDGF); but probably some other growth factors synthesized by megakaryocytes and contained in platelet alpha-granules are involved. The molecular event that determines the advantage of the clonal growth is, at present, unknown, and the pathogenetic importance of some chromosome anomalies is still under discussion. Over the last years, besides megakaryocyte dysplasia, several fibrogenetic mechanisms such as a bone marrow immune damage have been taken into consideration. Studies on prognostic factors regarding the main clinical, hematological and histological parameters have given conflicting results, because of low incidence of the disease, different criteria used for the diagnosis, and different terms of the clinic presentation of the pathology. Although a great deal of progress has been made in terms of pathogenetic mechanisms, a lot of questions must be still definitively settled, further in depth studies still have to go into many matters.