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Memory and rejuvenation effects in the magnetic response of off-equilibrium spin glasses have been widely regarded as the doorway into the experimental exploration of ultrametricity and temperature chaos. Unfortunately, despite more than twenty years of theoretical efforts following the experimental discovery of memory and rejuvenation, these effects have, thus far, been impossible to reliably simulate. Yet, three recent developments convinced us to accept this challenge: first, the custom-built Janus II supercomputer makes it possible to carry out simulations in which the very same quantities that can be measured in single crystals of CuMn are computed from the simulation, allowing for a parallel analysis of the simulation and experimental data. Second, Janus II simulations have taught us how numerical and experimental length scales should be compared. Third, we have recently understood how temperature chaos materializes in aging dynamics. All these three aspects have proved crucial for reliably reproducing rejuvenation and memory effects on the computer. Our analysis shows that at least three different length scales play a key role in aging dynamics, whereas essentially all the theoretical analyses of the aging dynamics emphasize the presence and crucial role of a single glassy correlation length.Reliably probing rejuvenation and memory effects in spin glasses by means of simulations is difficult. Now, a state-of-the-art numerical study shows that at least three different length scales play a crucial role in aging dynamics of spin glasses.

Hepatic focal nodular hyperplasia (FNH) is a nonmalignant condition rarely affecting children previously treated for cancer, especially those who received hematopoietic SCT (HSCT). Some aspects of its pathogenesis still remain unclear and a strong association with specific risk factors has not yet been identified. We report here a single institution's case series of 17 patients who underwent HSCT and were diagnosed with FNH, analyzing retrospectively their clinical features and the radiological appearance of their hepatic lesions. We aimed to compare the diagnostic accuracy of ultrasound (US) and magnetic resonance imaging (MRI) and to explore the role of transient elastography (FibroScan) to evaluate the degree of hepatic fibrosis in FNH patients. Our analysis showed an association of FNH with age at transplant ⩽12 years (hazard ratio (HR) 9.10); chronic GVHD (HR 2.99); hormone-replacement therapy (HR 4.02) and abdominal radiotherapy (HR 4.37). MRI proved to be a more accurate diagnostic tool compared with US. Nine out of 12 patients who underwent FibroScan showed hepatic fibrosis. Our study points out that FNH is an emerging complication of HSCT, which requires a lifelong surveillance to follow its course in cancer patients.

We investigated the incidence, risk factors and outcome of haemorrhagic cystitis (HC) in paediatric patients undergoing HSCT and the predictive value of BK viruria and viraemia for developing HC. Over a period of 54 months, 74 patients were recruited. The cumulative incidence of HC was 22%. Among 15 patients prospectively monitored for BK viruria and viraemia, four patients developed HC of grade ⩾II. This group, which had two consecutive BK positive samples, showed a sensitivity of 100%, a specificity of 82%, a positive predictive value of 67%, and negative predictive value of 100% for developing HC. Analysed by a receiver–operator characteristic curve (ROC), a urine BK load >9 × 10 6 genomic copies/ml had a sensitivity of 95% and specificity of 90%; while a blood BK load >1 × 10 3 genomic copies/ml had a sensitivity of 40% and a specificity of 93% for HC, respectively. In univariate analysis, BK positivity was the only factor significantly associated with HC. After a median follow-up of 1.8 years, patients with HC showed a lower overall survival, 40 vs 65%, P 0.01, and a lower event-free survival, 42 vs 62%, P 0.03, compared to patients without HC. We conclude that BK detection in urine and/or plasma is a specific predictor for developing HC.

Several guidelines have been published about management of chronic GvHD (cGvHD), but the clinical practice still remains demanding. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has planned a prospective observational study on cGvHD, supported by a dedicated software, including the updated recommendations. In view of this study, two surveys have been conducted, focusing the management of cGvHD and ancillary therapy in cGvHD, to address the current ‘ real life ’ situation. The two surveys were sent to all 57 GITMO centers, performing allografting in Italy; the response rate was 57% and 66% of the interviewed centers, respectively. The first survey showed a great disparity especially regarding steroid-refractory cGvHD, although extracorporeal photo-apheresis resulted as the most indicated treatment in this setting. Another challenging issue was the strategy for tapering steroid: our survey showed a great variance, and this disagreement could be a real bias in evaluating outcomes in prospective studies. As for the second survey, the results suggest that the ancillary treatments are not standardized in many centers. All responding centers reported a strong need to standardize management of cGvHD and to participate in prospective trials. Before starting observational and/or interventional studies, a detailed knowledge of current practice should be encouraged.

Acute GVHD (aGVHD) is a major cause of morbidity and mortality after unrelated BMT (UBMT). Our purpose was to analyze the role of extracorporeal photochemotherapy (ECP) in controlling grade II–IV aGVHD in children given UBMT. Of 41 consecutive children, 31 developed grade II–IV aGVHD after UBMT: 16 had a good response to steroids (GR group), whereas 15 underwent ECP (ECP group) within 100 days of UBMT. Eligibility criteria for starting ECP were steroid resistance, dependence or viral reactivations. Criteria for judging response to aGVHD treatment were that the resolution of all signs were considered a complete response (CR), at least a 50% improvement was classified as a partial response (PR) and stable or progressive disease was judged as no response (NR). On completing ECP, the CR rate was 73%, whereas the GR group had a CR rate of 56% by day 100. The 2-year overall survival and progression-free survival rates were 57 and 67% in the GR group vs 85 and 87% in the ECP group. Our data seem to suggest that ECP may improve outcome in patients after UBMT. These findings need to be confirmed in a larger population.

GvHD remains a source of significant morbidity and mortality in the setting of allogeneic haematopoietic SCT. Improving outcomes in stem cell transplant recipients requires additional therapeutic modalities for GvHD, especially for patients who fail to respond to initial therapy with steroids. Moreover, while the absence of acute GvHD (aGvHD) is associated with a higher risk of relapse of the underlying malignant disease, severe aGvHD usually induces the occurrence of life-threatening complications such as severe infections. This article summarizes the current state of aGvHD prophylaxis and treatment.

Osteonecrosis (ON) is a critical complication in the treatment of childhood leukemia and lymphoma. It particularly affects survivors of acute lymphoblastic leukemia and non-Hodgkin lymphoma reflecting the cumulative exposure to glucocorticosteroid therapy. ON is often multiarticular and bilateral, specially affecting weight-bearing joints. A conventional approach suggests a surgical intervention even if pharmacological options have also recently been investigated. We reported two cases of long time steroid-treated patients who underwent Bone Marrow Transplantation (BMT) for hematological disease. Both patients developed femoral head osteonecrosis (ON) that was diagnosed by magnetic resonance imaging (MRI) and the ON was also accompanied with pain and a limp. Despite of the conventional strategies of therapy, we successfully started a short-term treatment with bisphosphonates in order to decrease the pain and the risk of fracture.

Background: Graft-versus host disease (GvHD) is mediated by donor effector T lymphocytes. Regulatory T cells mediate peripheral tolerance and protect from GvHD. Polychromatic flow cytometry allows to examine manifold antigens displayed by a single cell and to identify fine lymphocyte subsets without the need of multiple tubes and a huge number of cells. Unwanted spectral overlaps increase with the number of dyes employed and require to optimize instrument settings and to select staining combinations carefully. Objective: to develop an 8-color flow cytomety protocol to distinguish T cell subsets including naive, effector memory, central memory, effector memory RA+ and regulatory T cells. To evaluate this approach for clinical use in paediatrics early after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Antigen groups were created according to the expression modality. Selected dyes were assigned to each group and different combinations of conjugates were tested. Analysis were performed with a digital eight colour flow cytometer. The accuracy of the determination of individual subpopulations was estimated for different sample sizes with normal white blood cells. Clinical use was tested with ten specimens drawn for routine blood counts on day 14 and day 20 after allo-HSCT. Results: An 8-color panel was identified for optimal resolution of T cell subsets by staining with monoclonal antibody conjugates to CD3, CD4, CD8, CD25, CD127, CD45RA, CD62L and CCR7. Sample sizes of CD4 T and CD8 T cells available for analysis of subpopulations were < 10000 on day 14 for most recipients, while on day 20, > 10000 events could be collected generally for both subpopulations. Regulatory CD4 T cells could be identified as a CD25high/CD127 low subpopulation in most patients starting from day 20. Similar to CD4 and CD8 effector T lymphocytes, regulatory T cells with a memory phenotype were prevalent. Conclusions: We have found that 8-color flow cytometry allows to define multiple T lymphocyte subsets starting from day 20 after transplantation in most recipients despite low lymphocyte counts and the small size of clinical specimens available in paediatrics. The estimation of T cell subsets including regulatory T cells early after HSCT may be useful to correlate phenotypic profiles with (1) the risk to develop severe GvHD or (2) with the responsiveness to therapeutic efforts undertaken to prevent or to cure GvHD.

To assess the non-inferiority of pegfilgrastim versus filgrastim in speeding the recovery of polymorphonuclear cells (PMN) in pediatric patients who underwent autologous peripheral blood stem cell transplant (PBSCT). The sample size of this randomized, multicenter, phase III study, was calculated assuming that a single dose of pegfilgrastim of 100 ug/kg was not inferior to 9 doses of filgrastim of 5 ug/kg/day. Randomization was performed by a computer-generated list and stored by sequentially numbered sealed envelopes. Sixty-one patients, with a median age of 11.5 years, were recruited: 29 in the filgrastim arm and 32 in the pegfilgrastim arm. Twenty percent were affected by lymphoma/leukaemia and eighty percent by solid tumors. The mean time to PMN engraftment was 10.48 days (standard deviation [SD] 1.57) and 10.44 days (SD 2.44) in the filgrastim and pegfilgrastim arms, respectively. Having fixed a non-inferiority margin Delta of 3, the primary endpoint of non-inferiority was reached. No differences were observed for other secondary endpoints: platelet engraftment, mean time to platelet recovery (28 days vs. 33 days), fever of unknown origin (79% vs. 78%), proven infection (34% vs. 28%), mucositis (76% vs. 59%). After a median follow-up of 2.3 years (95% C.I.: 1.5, 3.3), 20 deaths were observed due to disease progression. We conclude that pegfilgrastim was not inferior to daily filgrastim in pediatric patients who underwent PBSCT. EU CLINICAL TRIAL REGISTER NUMBER: 2007-001430-14.