Challenges and opportunities of microRNAs in lymphomas.

MicroRNAs (miRNAs) are small non-coding RNAs that control the expression of many target messenger RNAs (mRNAs) involved in normal cell functions (differentiation, proliferation and apoptosis). Consequently their aberrant expression and/or functions are related to pathogenesis of many human diseases including cancers. Haematopoiesis is a highly regulated process controlled by a complex network of molecular mechanisms that simultaneously regulate commitment, differentiation, proliferation, and apoptosis of hematopoietic stem cells (HSC). Alterations on this network could affect the normal haematopoiesis, leading to the development of haematological malignancies such as lymphomas. The incidence of lymphomas is rising and a significant proportion of patients are refractory to standard therapies. Accurate diagnosis, prognosis and therapy still require additional markers to be used for diagnostic and prognostic purpose and evaluation of clinical outcome. The dysregulated expression or function of miRNAs in various types of lymphomas has been associated with lymphoma pathogenesis. Indeed, many recent findings suggest that almost all lymphomas seem to have a distinct and specific miRNA profile and some miRNAs are related to therapy resistance or have a distinct kinetics during therapy. MiRNAs are easily detectable in fresh or paraffin-embedded diagnostic tissue and serum where they are highly stable and quantifiable within the diagnostic laboratory at each consultation. Accordingly they could be specific biomarkers for lymphoma diagnosis, as well as useful for evaluating prognosis or disease response to the therapy, especially for evaluation of early relapse detection and for greatly assisting clinical decisions making. Here we summarize the current knowledge on the role of miRNAs in normal and aberrant lymphopoiesis in order to highlight their clinical value as specific diagnosis and prognosis markers of lymphoid malignancies or for prediction of therapy response. Finally, we discuss their controversial therapeutic role and future applications in therapy by modulating miRNA.

Changes in angiogenesis and hypoxia-inducible factor-1α protein expression in relapsed/refractory indolent non-Hodgkin lymphomas.

Angiogenesis is involved in the pathogenesis and progression of non-Hodgkin lymphomas (NHL), and hypoxia-inducible factor-1α (HIF-1α, also termed HIF1A) might contribute to this process. Currently, there is no direct evidence that the clinical progression of indolent NHL is associated with angiogenesis, and the expression of HIF-1α at recurrence is unknown. Matched lymph node biopsies at diagnosis and recurrence of relapsed/refractory indolent NHL patients were analysed by immunohistochemical and morphometric analysis. We observed an increased vascular network and HIF-1α protein expression in the second biopsy, providing direct evidence that angiogenesis is an essential process for disease progression.

The costs of mobilisation and collection of peripheral blood stem cells in multiple myeloma and lymphoma in an European country: results from The Gruppo Italiano Trapianto Midollo Osseo (GITMO) and Società Italiana di Emaferesi e Manipolazione Cellulare (SIdEM) survey.

Scarce information is available about the cost of mobilisation/collection of peripheral blood stem cells for patients undergoing autologous transplant for relapsed Lymphoma or Multiple Myeloma. This paper reports the consumption of resources and costs collected through a survey among Italian Centres who adhere to the GITMO and SIdEM scientific societies. General transplant information was extracted from the European Promise database. Resources used alongside the phases of mobilisation/collection were retrieved. Resources for each of the process phases were quantified and averaged across centres and a unit cost value was attributed, based on administrative data from 3 centres, tariffs and market values. 25/89 Centres (34% of 2009 Promise transplants) provided data according to their standard practice. The mean cost/patient of the process of cell mobilisation/collection was € 6830 ± 1802 for Multiple Myeloma and € 7304 ± 1542 for Lymphoma. The organisational path for PBSC mobilisation/collection appears complex and cumbersome, spread amongst different treatment settings, with many different healthcare professionals being involved and considerable amounts of time and resources being currently dedicated to the management of patients requiring autologous transplantation.

Plerixafor added to chemotherapy plus G-CSF is safe and allows adequate PBSC collection in predicted poor mobilizer patients with multiple myeloma or lymphoma.

We evaluated the safety and efficacy of plerixafor, subsequent to disease-specific chemotherapy followed by granulocyte-colony stimulating factor (G-CSF), in 37 multiple myeloma (MM) or lymphoma patients, who were candidates for autologous stem cell transplantation (ASCT) predicted as poor mobilizers (PMs). Patients were identified as predicted PMs according to the history of a previously failed mobilization attempt or the presence of ≥1 factors predicting an unsuccessful harvest, such as advanced disease, prior extensive radiotherapy, or prolonged treatment, with stem cell poisons, advanced age, or extensive bone marrow involvement. Plerixafor (0.24 mg/kg) was administered subcutaneously for up to 3 consecutive days while continuing G-CSF for 9 to 11 hours before the planned apheresis. Plerixafor administration was safe and no significant adverse events were recorded. We observed a median 4-fold increase (range: 1.4-32) in the number of circulating CD34(+) cells following plerixafor compared with baseline CD34(+) cell concentration (from a median of 5 cells/µL, range: 1-32, to a median of 32 cells/µL, range: 6-201). Twenty-seven of the 37 patients (14 of 17 with MM and 13 of 20 with lymphoma) had ≥2×10(6) CD34(+) cells/kg collected in 1-3 apheretic procedures. Of the 27 patients rescued with plerixafor, 24 (13 MM, 11 lymphoma) have been transplanted with plerixafor-mobilized peripheral blood stem cells, showing a rapid and durable hematologic recovery. Our results suggest that the addition of plerixafor to G-CSF after disease-oriented chemotherapy is safe and allows for a satisfactory harvest in order to perform a safe ASCT, in a relevant proportion of lymphoma and MM patients considered to be PMs.

Type 2 diabetes mellitus impairs the maturation of endothelial progenitor cells and increases the number of circulating endothelial cells in peripheral blood.

Type 2 diabetes mellitus (T2DM) is associated with endothelial dysfunction, which leads to vascular complications. Endothelial progenitor cells (EPCs) are thought to be a subset of cells derived from the bone marrow that play a crucial role in the neovascularization of ischemic tissue and in the maintenance of endothelial cell integrity. In contrast, circulating endothelial cells (CECs) are of endothelial origin and become detached from the intima of blood vessels in response to pathological stimuli. The study investigated the effects of T2DM on subpopulations of EPCs and CECs in peripheral blood, as compared with the effects on unacylated (UAG) and acylated (AG) ghrelin levels, which have been shown recently to play an important role in endothelial dysfunction associated with diabetes. Using the high-performance flow cytometer FACSCanto, and UAG/AG ghrelin enzyme immunoassay kits, we analyzed whole peripheral blood samples from: (i) diabetic patients with a history of disease of less than 1 year and no clinical evidence of angiopathy, (ii) diabetic patients with long-standing disease with vascular complications, and (iii) healthy donors. We found that T2DM did not affect bone-marrow mobilization, but it altered the UAG/AG profile and decreased the number of highly differentiated EPCs (late EPCs) greatly. In addition, T2DM increased the number of CECs, together with the number of activated CECs. Our results suggest that: (i) the endothelial damage could be due mainly to altered maturation/commitment of EPCs, rather than a simple decrease in their production in the bone marrow; and (ii) EPC subpopulations and ghrelin levels could be useful markers to assess endothelial damage in diabetes.

A molecular and computational diagnostic approach identifies FOXP3, ICOS, CD52 and CASP1 as the most informative biomarkers in acute graft-versus-host disease.

BACKGROUND: Acute graft-versus-host disease is a severe complication of allogeneic stem cell transplantation in which the functional immune cells of the donor recognize the recipient as foreign and mount an immunological attack. There is an urgent need for better diagnostic instruments for the assessment of acute graft-versus-host disease. In the present study, a novel bioinformatics framework was used to identify gene expression patterns associated with acute graft-versushost disease in patients undergoing allogeneic hematopoietic stem cell transplantation. DESIGN AND METHODS: Peripheral blood cells were collected prospectively from patients who did develop acute graftversus-host disease (YES) and from those who did not (NO). Gene expression profiling was performed using a panel of 47 candidate genes potentially involved in alloreactive responses. The entire population of YES/NO acute graft-versus-host disease patients formed the experimental validation set. Personalized modeling based on a gene selection technique was applied to identify the most significant mRNA transcripts, which were then used to profile individual data samples for training and testing the classification/prediction framework. RESULTS: A leave-one-out cross-validation procedure was performed to investigate the robustness of the classification framework producing the following results: 100% on the training dataset and 97% on the testing dataset. According to our integrated methodology, transcripts for FOXP3, ICOS, CD52 and CASP1, genes involved in immune alloreactive responses and participating in immune cell interactions, were identified as the most informative biomarkers in allogeneic stem cell transplant recipients experiencing acute graft-versus-host disease. CONCLUSIONS: This study demonstrates that the integrated methodology proposed is useful for the selection of valid gene targets for the diagnosis of acute graft-versus-host disease, producing satisfactory accuracy over independent clinical features of the allogeneic transplanted population.

Allogeneic hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma relapsed after autologous stem cell transplantation: a GITMO study.

Patients who relapse after an autologous hematopoietic stem cell transplantation (SCT) have a very poor prognosis. We have retrospectively analyzed diffuse large B cell lymphoma patients who underwent an allo-SCT after an auto-SCT relapse reported in the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) database. From 1995 to 2008, 3449 autologous transplants were reported in the GITMO database. Eight hundred eighty-four patients relapsed or progressed after transplant; 165 patients, 19% of the relapsed patients, were treated with allo-transplant. The stem cell donor was related to the patient in 108 cases. A reduced intensity conditioning regimen was used in 116. After allo-SCT, 72 patients (43%) obtained a complete response and 9 obtained a partial response with an overall response rate of 49%; 84 patients (51%) experienced rapid progression of disease. Ninety-one patients died, 45 due to disease and 46 due to treatment-related mortality. Acute graft-versus-host disease was recorded in 57 patients and a chronic GvHD in 38 patients. With a median follow-up of 24 months (2-144) after allo, overall survival (OS) was 39%, and after a median of 21 months (2-138) after allo, progression-free survival (PFS) was 32%. Multivariate analysis indicated that the only factors affecting OS were status at allo-SCT, and those affecting PFS were status at allo-SCT and stem cell donor. This retrospective analysis shows that about one-fifth of patients with diffuse large B cell lymphoma who experience relapse after autologous transplantation may be treated with allogeneic transplantation. Moreover, the only parameter affecting either OS or PFS was the response status at the time of allo-SCT.

Changes in RPS14 expression levels during lenalidomide treatment in Low- and Intermediate-1-risk myelodysplastic syndromes with chromosome 5q deletion.

BACKGROUND: Haploinsufficiency of the ribosomal protein S14 RPS14 gene, located in the common deleted region of chromosome 5q, is a potential causal factor of 5q- syndrome. Lenalidomide elicits high response rates and morphological improvements in myelodysplastic syndrome (MDS) patients with chromosome 5q deletion [del(5q)]. METHODS: To further evaluate the role of RPS14, its transcription was tested in bone marrow cells from 17 patients with International Prognostic Scoring System defined Low- or Intermediate-1-risk MDS with del(5q) as a single or additional cytogenetic abnormality receiving treatment with lenalidomide. RESULTS: After 12 wk of lenalidomide treatment, erythroid responses were observed in all cases with an increase in hemoglobin levels of 2.7 +/- 2.5 g/dL (up to a mean 11.8 +/- 1.9 g/dL; P = 0.001). Before treatment, RPS14 expression levels were under-expressed in 15 patients with respect to normal controls. After 12 wk of lenalidomide treatment, all patients had an erythroid response. There was a significant increase in median RPS14 expression from baseline 0.01 (IQR 0.05-0.31) to 12 wk 204.71-fold (2.86-446.32; P < 0.0001). CONCLUSIONS: These observations in the patient setting support the importance of RPS14 in the pathogenesis of MDS with del(5q).

Absence of the V617F JAK2 mutation in the lymphoid compartment in a patient with essential thrombocythemia and B-chronic lymphocytic leukemia and in two relatives with lymphoproliferative disorders.

BACKGROUND: Myeloproliferative neoplasms likely involve both myeloid and lymphoid lineages. Nevertheless, the coincidence of chronic myeloproliferative and lymphoproliferative diseases in the same patient is a rare phenomenon. METHODS: We report a case of a patient having essential thrombocythemia (ET) and B-chronic lymphocytic leukemia (B-CLL). In this patient and in 2 relatives with lymphoproliferative disorders, we searched for JAK2(V617F) mutation in lymphocytes. RESULTS: In the patient with ET and B-CLL, we identified homozygous JAK2(V617F) mutation in the granulocytic compartment. Both relatives were heterozygous for JAK2(V617F) mutation, whereas no mutation signal could be detected in the lymphoid compartment of all 3 patients. CONCLUSION: Our results seem to confirm that CLL cases are negative for JAK2(V617F) mutation in B- and T-lymphocyte populations.Presence of JAK2(V617F) mutation in subjects without myeloproliferative diseases could indicate an increased risk of a future myeloproliferative neoplasm development.

Response to chemotherapy and tandem autologous transplantation of multiple myeloma patients and GSTP1 and TYMS polymorphisms.

This study examines the response to dexamethasone-doxorubicin-vincristine (DAV) therapy, followed by conditioning regimen and autologous stem cells transplantation (ASCT) in patients with multiple myeloma in relation with the presence of polymorphisms in genes involved in drug metabolism (GSTP1) and DNA synthesis (TYMS). GSTP1 G313G genotype (OR=5.49; 95% CI, 1.3-22.5, p=0.02) and TYMS A227A genotype (OR=3.41; 95% CI, 1.3-8.9, p=0.01) resulted significantly associated with a poor response following chemotherapy and the risk increased for the combined genotype (OR=13.54; 95% CI, 2.0-91.3, p=0.01). TYMS T157T genotype was significantly associated with a poor response after ASCT (OR=4.60; 95% CI, 1.2-16.9, p=0.02). Pre-therapeutic individual determination of the GSTP1 and TYMS polymorphisms could help in choosing the most appropriate protocol.

Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).

BACKGROUND: Allogeneic stem cell transplantation is a potentially curative treatment for myelofibrosis, although its use is limited by a high rate of transplant-related mortality. In this study, we evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors. DESIGN AND METHODS: One hundred patients were transplanted in 26 Italian centers between 1986 and 2006. We analyzed the influence of the patients' characteristics and the clinical features of their disease before stem cell transplantation and of transplant procedures on transplant-related mortality, overall survival, and relapse-free survival by means of univariate and multivariate analyses. RESULTS: The median age of the patients at the time of stem cell transplantation was 49 years (range, 21-68) and 90% of them had an intermediate or high Dupriez score. Forty-eight percent received a myeloablative conditioning regimen and 78% received stem cells from matched sibling donors. The cumulative incidence of engraftment at day 90 after transplant was 87% (95% CI, 0.87-0.97). The cumulative 1-year and 3-year incidences of transplant-related mortality were 35% and 43%, respectively. The estimated 3-year overall and relapse-free survival rates after stem cell transplantation were 42% and 35%, respectively. In multivariate analysis, negative predictors of transplant-related mortality were year of stem cell transplantation before 1995, unrelated donor, and a long interval between diagnosis and transplantation. There was a trend towards longer overall and relapse-free survival in patients receiving peripheral blood stem cells rather than bone marrow as the source of their graft (p=0.070 and p=0.077, respectively). The intensity of the conditioning regimen (myeloablative versus reduced intensity regimens) did not significantly influence the outcome. CONCLUSIONS: We conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after 1996 due to the reduction in transplant-related mortality. We observed that a reduction in transplant-related mortality was associated with the choice of a matched sibling donor, whereas longer overall survival was associated with the use of peripheral blood as the source of stem cells.

Peg-filgrastim versus filgrastim after autologous stem cell tranplantation: case-control study in patients with multiple myeloma and review of the literature.

We investigated the effects of a single s.c. injection of peg-filgrastim in 32 patients with multiple myeloma who underwent autologous stem cell transplantation (AuSCT) as first line treatment. For comparison, 32 myeloma patients with similar characteristics and receiving standard daily administration of filgrastim were matched. Overall, there were no statistically significant differences between peg-filgrastim and filgrastim in terms of tolerability, marrow recovery, severity of neutropenia, incidence and duration of febrile neutropenia, documented infections and transfusions. However, some favourable trends or effects in favour of peg-filgrastim were observed. This was confirmed by a review of the published papers about this topic.

Utility of the clinical practice of administering thrombophilic screening and antithrombotic prophylaxis with low-molecular-weight heparin to healthy donors treated with G-CSF for mobilization of peripheral blood stem cells.

The aim of the study was to verify the utility of the clinical practice of administering thrombophilic screening and antithrombotic prophylaxis with low-molecular-weight heparin to healthy donors receiving granulocyte colony-stimulating factor to mobilize peripheral blood stem cells. Thrombophilia screening comprised of testing for factor V Leiden G1691A, prothrombin G20210A, the thermolabile variant (C677T) of the methylene tetrahydrofolate reductase gene, protein C, protein S, factor VIII and homocysteine plasmatic levels, antithrombin III activity, and acquired activated protein C resistance. We investigated prospectively 72 white Italian healthy donors, 39 men and 33 women, with a median age of 42 years (range, 18-65). Five donors (6.9%) were heterozygous carriers of Factor V Leiden G1691A; two healthy donors had the heterozygous prothrombin G20210A gene mutation; C677T mutation in the methylene tetrahydrofolate reductase gene was present in 34 (47.2%) donors in heterozygous and in 7 donors (9.7%) in homozygous. Acquired activated protein C resistance was revealed in 8 donors of the study (11.1%). The protein C plasmatic level was decreased in 3 donors (4.2%); the protein S level was decreased in 7 donors (9.7%). An elevated factor VIII dosage was shown in 10 donors (13.9%) and hyperhomocysteinemia in 9 donors (12.5%). Concentration of antithrombin III was in the normal range for all study group donors. The factor V Leiden mutation was combined with the heterozygous prothrombin G20210A in 2 cases and with protein S deficiency in one case; 2 healthy donors presented an associated deficiency of protein C and protein S. Although none of these healthy subjects had a previous history of thrombosis, low-molecular-weight heparin was administered to all donors during granulocyte colony-stimulating factor administration to prevent thrombotic events. No donor experienced short or long-term thrombotic diseases after a median follow-up of 29.2 months. Our data do not support this clinical practice because there is no evidence that the combination of granulocyte colony-stimulating factor to previous hypercoagulable conditions results in thrombotic events.

Wernicke's encephalopathy after allogeneic stem cell transplantation.

Wernicke's encephalopathy is an acute neuropsychiatric condition due to thiamine deficiency frequently associated with chronic alcohol abuse. We describe 2 cases of patients who experienced acute Wernicke's encephalopathy after allogeneic stem cell transplantation associated with the use of commercial total parental nutrition. Early diagnosis with magnetic resonance imaging and timely treatment with thiamine resulted in rapid resolution of clinical and radiological signs. In conclusion, the prolonged use of commercial total parental nutrition formulas must be supplemented with thiamine in the form of intramuscularly administered multivitamins.

Different gamma/delta T clones sustain GVM and GVH effects in multiple myeloma patients after non-myeloablative transplantation.

TCR gamma/delta profiles were analyzed in 13 multiple myeloma patients after allogeneic non-myeloablative transplantation. Results show that both aGVHD and minimal residual disease (MRD) eradication did significantly affect TCR gamma/delta profile. During follow-up, six patients developed an aGVHD episode; in five of them, this event fitted with a modification of the TCR profile. Eleven patients achieved PCR-negativity during follow-up. In the 90% of them, the appearance of a new predominant TCR peak was concomitant to the disappearance of the IgH clone. These results suggest that different T gamma/delta populations would sustain GVM and GVH effects after non-myeloablative allogeneic transplant.

Eosinophilic fasciitis associated with autoimmune phenomena after bone marrow transplantation: report of two cases.

Between January 1992 and May 2004, 189 patients underwent allogeneic bone marrow transplantation (BMT) for haematological malignancies from HLA-identical sibling donors in our transplantation unit. Of the 189 patients, 2 developed eosinophilic fasciitis (EF). The first patient developed Hashimoto's thyroiditis and EF 11 and 21 months after BMT, respectively. In the second patient EF occurred 9 months after BMT, accompanied by antinuclear antibodies, antiextractable nuclear antigens and antigliadin antibodies. Both patients were treated with extracorporeal photochemotherapy (ECP), resulting in improvement of fasciitis in both and normalization of antithyroid antibodies in the first patient. Our data confirm the rarity of fasciitis after BMT and the efficacy of ECP, recently applied experimentally in one patient for the treatment of fasciitis after BMT. Moreover, we report for the first time the association of fasciitis with autoimmune phenomena after BMT. The correlation between the two entities is supported by remission of Hashimoto's thyroiditis after ECP treatment for fasciitis.

Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation.

This study evaluates the prognostic value of molecular monitoring of minimal residual disease (MRD) in 20 patients with multiple myeloma (MM) following autologous (peripheral blood stem cell transplantation, PBSCT) and non-myeloablative allogeneic (NMT) transplant. All patients completed their program, with a treatment-related mortality (TRM) of 20% and a 2-year progression-free survival (PFS) of 51%. After PBSCT, only 3 patients (15%) achieved PCR-negativity, versus 12 (60%) after NMT. The eradication of MRD had a favorable impact on 2-year OS. In fact, 76% of patients with no detectable MRD was still alive versus 34% of persistently IgH-positive cases (p=0.03). PCR status did not correlate with chimerism percentage: Seventy-five percent of patients achieved full donor chimerism, which was more frequently observed in cases presenting cGHVD (p=0.01). These data sustain the relevant role of molecular monitoring in MM patients undergoing NMT. MRD monitoring would assist physicians in making additional therapeutic decisions to better control this hematological malignancy.

Chimerism does not influence graft-versus-myeloma and graft-versus-host disease in reduced intensity setting.

In this study we serially evaluated the chimerism status in 20 multiple myeloma patients allotransplanted with a reduced intensity regimen. All patients engrafted, with total 75% overall responses and 35% of CRs. After a median follow-up of 35 months, seven patients (35%) died, three of them due to disease progression. Four patients died before day +100, with a TRM of 20%. Nine patients (45%) developed aGVHD and six (40%) had cGVHD. Twenty-five percent of patients achieved full donor chimerism (FDC) before day +100, 42% before day +200 and 75% 24 months after graft. In our series, level of chimerism did not correlate with either the quality of response or aGVHD. No significant differences were found between bone marrow and peripheral blood samples. Analogously, even if donor DNA percentage often resulted higher in the PMN fraction than in the mononuclear one, these differences were not significant after statistical analysis. On the other hand, cGVHD was associated with increased rates of FDC, with 6/6 cases showing a full donor pattern in concomitance of the cGVHD versus 5/9 cases presenting a FDC in the group of patients without cGVHD (p=0.057). The Kaplan-Meier estimates of OS and PFS at 2 years were 59% and 58%, respectively; chimerism pattern did not impact in the predicting clinical outcome. In summary, our study shows that a stable engraftment and high frequency of donor chimerism are achievable after a reduced intensity conditioning regimen. Moreover, even as result of a single center experience, we suggest that chimerism, graft-versus-myeloma and GVHD would represent distinct entities that require larger immunological studies for further clarification.

Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial.

OBJECTIVE: To assess in multiple sclerosis (MS) the effect of intense immunosuppression followed by autologous hematopoietic stem cells transplantation (AHSCT) vs mitoxantrone (MTX) on disease activity measured by MRI. METHODS: We conducted a multicenter, phase II, randomized trial including patients with secondary progressive or relapsing-remitting MS, with a documented increase in the last year on the Expanded Disability Status Scale, in spite of conventional therapy, and presence of one or more gadolinium-enhancing (Gd+) areas. Patients were randomized to receive intense immunosuppression (mobilization with cyclophosphamide and filgrastim, conditioning with carmustine, cytosine-arabinoside, etoposide, melphalan, and anti-thymocyte globulin) followed by AHSCT or MTX 20 mg every month for 6 months. The primary endpoint was the cumulative number of new T2 lesions in the 4 years following randomization. Secondary endpoints were the cumulative number of Gd+ lesions, relapse rate, and disability progression. Safety and tolerability were also assessed. Twenty-one patients were randomized and 17 had postbaseline evaluable MRI scans. RESULTS: AHSCT reduced by 79% the number of new T2 lesions as compared to MTX (rate ratio 0.21, p = 0.00016). It also reduced Gd+ lesions as well as the annualized relapse rate. No difference was found in the progression of disability. CONCLUSION: Intense immunosuppression followed by AHSCT is significantly superior to MTX in reducing MRI activity in severe cases of MS. These results strongly support further phase III studies with primary clinical endpoints. The study was registered as EUDRACT No. 2007-000064-24.

Bone marrow failure associated with herpesvirus 8 infection in a patient undergoing autologous peripheral blood stem cell transplantation.

We describe a fatal case of human herpesvirus 8-associated bone marrow failure in a patient who had received intense treatment for Hodgkin lymphoma and was undergoing bone marrow transplantation. Bone marrow failure was resistant to antiviral treatment and a second infusion of autologous stem cells. Human herpesvirus 8 infection continues to be a major concern in transplant recipients in critical condition.