Sixty-four patients < 20 years of age, investigated for a suspicion of Philadelphianegative myeloproliferative disease (MPD), were retrospectively evaluated to characterize the different forms and to examine the treatments used and longterm outcome. JAK2 mutations, endogenous erythroid colony growth, and clonality were investigated in 51 children. After a median follow-up of 124 months, no patient had developed leukemia or myelofibrosis and 5% had thrombosis; the miscarriage rate in thrombocythemic patients was 14%. The low complication rate in our population suggests that children with MPD may be managed by tailored approaches.

Summary. Immune tolerance induction (ITI) iseffective in approximately 70% of haemophilia patients with inhibitors. Poor prognostic factors are age >6 years, ITI started >1 year from inhibitor development, inhibitor peaks >200 BU, inhibitor titre >10 BU when ITI is started and previously failed ITI. The objective of this study was to identify the effectiveness in ITI of a high purity von Willebrand factor/factor VIII (VWF/FVIII) complex concentrate in inhibitor patients at high risk of failure. Patients with severe or moderate haemophilia A and high responding inhibitors who had at least one poor prognostic factor for ITI failure were prospectively followed-up. Success was defined by undetectable inhibitor, recovery and half life >66% of expected values. ITI dose regimens were chosen by each haemophilia centre. Seventeen haemophiliacs (16 severe, one moderate), aged 4-54 years (median 23) were followed-up for 6-71 months. Poor prognostic factors were delayed-onset ITI (n ¼ 16), age >6 years (n ¼ 16), previously failed ITI (n ¼ 4), inhibitor peak >200 BU (n ¼ 2) and inhibitor >10 BU when ITI was started (n ¼ 4). Complete success was obtained in nine patients (53%) after 4-30 months of treatment (median 24), including two of four patients who had previously failed ITI. Seven patients achieved a partial success, with sustained low inhibitor titres (median 1.5 BU, range 1.1-2.8) but abnormal recovery and/or half-life, while the remaining patient withdrew ITI after 12 months when the inhibitor titer was still 70 BU. These findings suggest that high purity VWF/ FVIII complex concentrates are effective in ITI, even in patients at high risk of failure.

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Human TT virus (TTV) recently isolated from the serum of a patient with post-transfusion hepatitis does seem to have only hepatopathic effect. The virus can also infect the serum, peripheral blood mononuclear cells (PBMC) and bone marrow cells (BMC ). Additional evidence has indicated that TTV is also present in the serum of people with hematopoietic malignancies. A significant increase in the incidence of lymphoma has recently been observed worldwide. We have investigated the presence of TTV DNA in lymph node biopsies of Italian patients affected with the most common lymphoma types in Western Countries: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and nodular sclerosis Hodgkin's disease (NS-HD). The possible role of a co-infection with Epstein-Barr virus (EBV) has also been investigated. DNA was extracted from 73 paraffin-embedded and 38 snap-frozen tissue specimens. From these, only 67 samples (29 paraffin-embedded and 38 snap-frozen tissues) from a total of 56 patients, were suitable for PCR analysis. TTV and EBV were detected by PCR using primers from two different conserved region in TTV and EBV genomes respectively. TTV DNA was detected in 30.0-50.0% of FL, 30.8% of DLBCL and 30.0-50.0% of NS-HD cases, depending on the primers used. All cases of non-specific reactive lymphoid hyperplasia (RLH), used as a putative control, were negative. The two major TTV genotypes circulating in Italy (G1 and G2) were detected in the analysed lymphoid neoplasms. EBV DNA was detected in 40.0% of FL, in 72.7%of DLBCL, in 80.0% of SN-HD and in 40.0% of RLH cases. EBV co-infection was found in 90% of TTV positive cases. The in situ hybridization assay was performed in TTV positive frozen samples. The significant prevalence of TTV DNA in lymphocytes circulating in the lymph nodes of both B-cell lymphomas and HD reported herewith suggests an implication of TTV infection in the development of these lymphoproliferative disorders.

We report the immunohistological, molecular and clinical findings in four patients affected by B-cell chronic lymphocytic leukaemia (CLL) who developed "Richter's syndrome with Hodgkin's disease (HD) features" or "CLL with Hodgkin's transformation", all characterised by the presence of typical Hodgkin/Reed-Sternberg (H/RS) cells in lymph node biopsies. In three cases the nodal involvement by CLL was demonstrated both by the presence of a predominant background of CD5/CD19/CD23+ small lymphocytes and an IgH monoclonal rearrangement revealed by PCR analysis. Conversely, in the remaining case there was neither immunohistological nor molecular evidence of lymph node involvement by CLL. In all four cases H/RS cells were Epstein-Barr virus (EBV) latent membrane protein (LMP-1) positive. These findings suggest that the presence of H/RS cells in the first three patients, who had CLL/HD nodal involvement, might be related to transformation or clonal evolution of CLL cells in H/RS cells, which is in keeping with use of the term "CLL with Hodgkin's transformation". In the fourth case a de novo HD may be postulated, representing a second malignancy presumably not clonally related to CLL. In all cases a key pathogenetic role of EBV is suggested by the expression of LMP-1 in H/RS cells. Our findings indicate that the presence of typical H/RS cells in lymph node biopsies in CLL patients may reflect a heterogeneous pathogenetic background. The different clinico-pathologic settings should be taken into consideration because of their possible implications for patients' treatment and prognosis.