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The correlation length ξ, a key quantity in glassy dynamics, can now be precisely measured for spin glasses both in experiments and in simulations. However, known analysis methods lead to discrepancies either for large external fields or close to the glass temperature. We solve this problem by introducing a scaling law that takes into account both the magnetic field and the time-dependent spin-glass correlation length. The scaling law is successfully tested against experimental measurements in a CuMn single crystal and against large-scale simulations on the Janus II dedicated computer.

Objectives: We present here data on Gram-negative rods bacteremia (GNRB) rates, risk factors and associated mortality., Methods: Data on GNRB episodes were prospectively collected in 65 allo-/67 auto-HSCT centers in 24 countries (Europe, Asia, Australia). In patients with and without GNRB, we compared: demography, underlying disease, HSCT-related data, center` fluoroquinolone prophylaxis (FQP) policy and accreditation status, and involvement of infection control team (ICT)., Results: The GNRB cumulative incidence among 2818 allo-HSCT was: pre-engraftment (pre-eng-allo-HSCT), 8.4 (95% CI 7-9%), post-engraftment (post-eng-allo-HSCT), 5.8% (95%CI: 5-7%); among 3152 auto-HSCT, pre-eng-auto-HSCT, 6.6% (95%CI: 6-7%), post-eng-auto-HSCT, 0.7% (95%CI: 0.4-1.1%). GNRB, especially MDR, was associated with increased mortality. Multivariate analysis revealed the following GNRB risk factors: (a) pre-eng-allo-HSCT: south-eastern Europe center location, underlying diseases not at complete remission, and cord blood source; (b) post-eng-allo-HSCT: center location not in northwestern Europe; underlying non-malignant disease, not providing FQP and never accredited. (c) pre-eng-auto-HSCT: older age, autoimmune and malignant (vs. plasma cell) disease, and ICT absence., Conclusions: Benefit of FQP should be explored in prospective studies. Increased GNRB risk in auto-HSCT patients transplanted for autoimmune diseases is worrying. Infection control and being accredited are possibly protective against bacteremia. GNRB are associated with increased mortality., Competing Interests: Declarations of Competing Interest HA declares receiving a research grant from MSD; speaker grant from Gilead, MSD, Pfizer. Other co-authors have no conflicts of interest to declare relevant to this study., (Copyright © 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: Few studies have detected qualitative and quantitative aspects of patients who underwent HSCT during childhood. The aims of this study are to explore the most recurrent narrative themes of HSCT experience in families five years after the procedure, and to observe statistical correlations between meaning attributed to the experience and defined variables., Methods: Thirty-five families of pediatric HSCT survivors participated in the research. Both survivors and their families were asked to write a brief composition about their disease experiences. Qualitative analysis of the texts was performed using the T-LAB software. Information about medical aspects and psychological problems in HSCT survivors were collected with interviews and administering the Child Behavior Checklist 6-18., Results: HSCT survivor families that reported the presence of externalizing and internalizing symptoms focused on thematic areas concerning broken families with separation between parents and the affected child versus healthy children., Conclusions: Long term psychological problems seem to be connected to the perception of family disruption. Specifically, family relationships seem to be the factor that protects from or enhances the risk of psychopathology in HSCT survivors. Moreover, the use of metaphoric terms to refer to HSCT presents higher associations with psychopathology. On the contrary, the possibility of referring directly to the transplantation is associated with psychological well-being. It is important to consider the family as a group in order to improve care.

We report the results of an analysis of unrelated allogeneic hematopoietic stem cell transplantations (HSCT) in 71 patients with sickle cell disease (SCD) transplanted in EBMT centers between 2005 and 2017. Median age was 9.3 years; graft type was bone marrow in 79% and peripheral blood in 21%. Recipient-donor HLA match at high resolution typing was 10/10 in 31, 9/10 in 20, and 8/10 in 4 patients; the other patients had intermediate resolution typing. The most frequent conditioning regimens were fludarabine-thiotepa-treosulfan (64%) or busulfan-cyclophosphamide (12%). Cumulative incidence of neutrophil engraftment was 92%; platelet engraftment was 90%. Eleven patients (15%) experienced graft failure. Grade II-IV acute graft-vs.-host disease (GvHD) was 23%; 3-year chronic GvHD was 23%. Three-year overall survival (OS) was 88 ± 4%. GRFS was 62 ± 6%. HLA matching was the most significant risk factor for OS: 3-year OS was 96 ± 4% in 10/10 group vs. 75 ± 10% in 9-8/10 (p = 0.042); GRFS was 69 ± 9% vs. 50 ± 12% (p = 0.114), respectively. In conclusion, unrelated donor HSCT is a valid option for SCD patients who lack an HLA-identical sibling donor, preferably in the context of clinical trials. Using a 10/10 HLA-matched unrelated donor yields better survival indicating that HLA matching is an important donor selection factor in this nonmalignant disease.

Patients given allogeneic hematopoietic stem cell transplantation (alloHSCT) present an increased incidence of long-term toxicities that can be attributed to the preparative regimen. We retrospectively analyzed in a population of 670 children receiving allo-HSCT for acute leukemia the occurrence of different late effects in function of the choice made between total body irradiation (TBI) and busulfan, as part of the preparative regimen. In univariable analysis, we found that patients treated with TBI developed cataract in 24% of the cases compared with 4% in patients treated with BU (p = 0.0001) and that the incidence of secondary malignant neoplasia (SMN) was higher in patients treated with TBI (18%) as compared with those prepared to the allograft with a Bu-based regimen (0%) (p = 0.019). Conditioning regimen did not show a statistically significant correlation with the occurrence of all the other investigated late effects. In multivariable analysis, TBI remained associated with the occurrence of cataracts (Relative Risk: 0.33 p = 0.012) and secondary malignancies (Relative Risk 3.96 × 10e-6 p < 0.001); however, other variables, as GvHD and disease type, were also correlated with these long-term sequels, indicating that in our study population the preparative regimen is not the only factor influencing the incidence of these complications.

The current pandemic SARS-CoV-2 has required an unusual allocation of resources that can negatively impact chronically ill patients and high-complexity procedures. Across the European Reference Network on Pediatric Transplantation (ERN TransplantChild), we conducted a survey to investigate the impact of the COVID-19 outbreak on pediatric transplant activity and healthcare practices in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The replies of 30 professionals from 18 centers in Europe were collected. Twelve of 18 centers (67%) showed a reduction in their usual transplant activity. Additionally, outpatient visits have been modified and restricted to selected ones, and the use of telemedicine tools has increased. Additionally, a total of 14 COVID-19 pediatric transplanted patients were identified at the time of the survey, including eight transplant recipients and six candidates for transplantation. Only two moderate-severe cases were reported, both in HSCT setting. These survey results demonstrate the limitations in healthcare resources for pediatric transplantation patients during early stages of this pandemic. COVID-19 disease is a major worldwide challenge for the field of pediatric transplantation, where there will be a need for systematic data collection, encouraging regular discussions to address the long-term consequences for pediatric transplantation candidates, recipients, and their families., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Diffuse large B-cell Lymphoma (DLBCL) secondary to a chronic severe Epstein-Barr virus (EBV) infection has not been previously described in a patient with trisomy 21. Here we report the case of a 14-year-old girl with trisomy 21 with impaired control of EBV and DLBCL. She was cured with dose-adapted chemotherapy and hematopoietic stem cell transplantation without severe treatment-related toxicity. We describe the first case of EBV-positive DLBCL in a patient with trisomy 21 and we propose a treatment modality for this rare entity.

Background: To date, there are few studies that describe pharmacokinetics, safety and efficacy of posaconazole delayed-release tablet (DRT) formulation in the paediatric population., Objectives: We evaluated retrospectively posaconazole plasma concentrations and safety of posaconazole DRT in paediatric haematology-oncology patients., Patients and Methods: Posaconazole DRT was assessed in 28 haematological paediatric patients with a median age 15 of years (range 5-18) and a median body weight of 50 kg (range 22-83 kg). Twenty-one patients received posaconazole DRT as prophylaxis and 7 patients as therapy., Results: As prophylaxis, the median daily dose was 5.5 mg/kg/day (range 2.2-22.2) with posaconazole trough level ≥ 0.7 μg/mL in 80% by first week, 62.5% by second week and 87.5% by fourth week. As therapy, the median daily dose was 4 mg/kg/day (range 3.3-4.5) with trough level ≥ 1 μg/mL 100% by first week, 80% by second week and 33.4% by fourth week., Conclusions: Posaconazole DRT is feasible in paediatric patients capable to swallow tablets. Specific pharmacokinetic studies are needed., (© 2020 Blackwell Verlag GmbH.)

We analyzed the use of isavuconazole (ISA) as treatment or prophylaxis for invasive fungal disease (IFD) in children with hemato-oncologic diseases. A multicentric retrospective analysis was performed among centers belonging to the Italian Association for Pediatric Hematology and Oncology (AIEOP). Pharmacokinetic (PK) monitoring was applied by a high-performance liquid chromatography-tandem mass spectrometry (HLPC-MS/MS) assay. Twenty-nine patients were studied: 10 during chemotherapy and 19 after allogeneic hematopoietic stem cell transplantation (HSCT). The patients consisted of 20 males and 9 females with a median age of 14.5 years (age range, 3 to 18 years) and a median body weight of 47 kg (body weight range, 15 to 80 kg). ISA was used as prophylaxis in 5 patients and as treatment in 24 cases (20 after therapeutic failure, 4 as first-line therapy). According to European Organization for Research and Treatment of Cancer (EORTC) criteria, we registered 5 patients with proven IFD, 9 patients with probable IFD, and 10 patients with possible IFD. Patients with a body weight of <30 kg received half the ISA dose; the others received ISA on the adult schedule (a 200-mg loading dose every 8 h on days 1 and 2 and a 200-mg/day maintenance dose); for all but 10 patients, the route of administration switched from the intravenous route to the oral route during treatment. ISA was administered for a median of 75.5 days (range, 6 to 523 days). The overall response rate was 70.8%; 12 patients with IFD achieved complete remission, 5 achieved partial remission, 5 achieved progression, and 3 achieved stable IFD. No breakthrough infections were registered. PK monitoring of 17 patients revealed a median ISA steady-state trough concentration of 4.91 mg/liter (range, 2.15 to 8.54 mg/liter) and a concentration/dose (in kilograms) ratio of 1.13 (range, 0.47 to 3.42). Determination of the 12-h PK profile was performed in 6 cases. The median area under the concentration-time curve from 0 to 12 h was 153.16 mg·h/liter (range, 86.31 to 169.45 mg·h/liter). Common Terminology Criteria for Adverse Events grade 1 to 3 toxicity (increased transaminase and/or creatinine levels) was observed in 6 patients, with no drug-drug interactions being seen in patients receiving immunosuppressants. Isavuconazole may be useful and safe in children with hemato-oncologic diseases, even in the HSCT setting. Prospective studies are warranted., (Copyright © 2020 American Society for Microbiology.)

The Mpemba effect occurs when a hot system cools faster than an initially colder one, when both are refrigerated in the same thermal reservoir. Using the custom-built supercomputer Janus II, we study the Mpemba effect in spin glasses and show that it is a nonequilibrium process, governed by the coherence length ξ of the system. The effect occurs when the bath temperature lies in the glassy phase, but it is not necessary for the thermal protocol to cross the critical temperature. In fact, the Mpemba effect follows from a strong relationship between the internal energy and ξ that turns out to be a sure-tell sign of being in the glassy phase. Thus, the Mpemba effect presents itself as an intriguing avenue for the experimental study of the coherence length in supercooled liquids and other glass formers.

Invasive fungal infections (IFI) of the Central Nervous System (IFI-CNS) and Paranasal Sinuses (IFI-PS) are rare, life-threatening infections in haematologic patients, and their management remains a challenge despite the availability of new diagnostic techniques and novel antifungal agents. In addition, analyses of large cohorts of patients focusing on these rare IFI are still lacking. Between January 2010 and December 2016, 89 consecutive cases of Proven (53) or Probable (36) IFI-CNS (71/89) and IFI-PS (18/89) were collected in 34 haematological centres. The median age was 40 years (range 5-79); acute leukaemia was the most common underlying disease (69%) and 29% of cases received a previous allogeneic stem cell transplant. Aspergillus spp. were the most common pathogens (69%), followed by mucormycetes (22%), Cryptococcus spp. (4%) and Fusarium spp. (2%). The lung was the primary focus of fungal infection (48% of cases). The nervous system biopsy was performed in 10% of IFI-CNS, and a sinus biopsy was performed in 56% of IFI-PS (P = 0.03). The Galactomannan test on cerebrospinal fluid has been performed in 42% of IFI-CNS (30/71), and it was positive in 67%. Eighty-four pts received a first-line antifungal therapy with Amphotericine B in 58% of cases, Voriconazole in 31% and both in 11%. Moreover, 58% of patients received 2 or more lines of therapy and 38% were treated with a combination of 2 or more antifungal drugs. The median duration of antifungal therapy was 60 days (range 5-835). A surgical intervention was performed in 26% of cases but only 10% of IFI-CNS underwent neurosurgical intervention. The overall response rate to antifungal therapy (complete or partial response) was 57%, and 1-year overall survival was 32% without significant differences between IFI-CNS and IFI-PS. The overall mortality was 69% but the IFI attributable mortality was 33%. Mortality of IFI-CNS/PS remains high but, compared to previous historical data, it seems to be reduced probably due to the availability of newer antifungal drugs. The results arising from this large contemporary cohort of cases may allow a more effective diagnostic and therapeutic management of these very rare IFI complications in haematologic patients., (© 2018 Blackwell Verlag GmbH.)

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially life-threatening complication that may develop after hematopoietic stem cell transplantation (HSCT). The aims of this retrospective multicenter study were to evaluate the incidence of SOS/VOD in a large cohort of children transplanted in centers across Italy by applying the new European Society for Blood and Marrow Transplantation (EBMT) criteria and to analyze the risk factors underlying this complication. We retrospectively reviewed data of pediatric HSCTs performed in 13 AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica)-affiliated centers between January 2000 and April 2016. The new pediatric EBMT criteria were retrospectively applied for diagnoses of SOS/VOD and severity grading. Among 5072 transplants considered at risk for SOS/VOD during the study period, 103 children (2%) developed SOS/VOD, and the grade was severe or very severe in all patients. The median time of SOS/VOD occurrence was 17 days after HSCT (range, 1 to 104). Sixty-nine patients (67%) were treated with defibrotide for a median time of 16 days (range, 4 to 104). In multivariable analysis age < 2 years, use of busulfan during the conditioning regimen, female gender, and hemophagocytic lymphohistiocytosis were risk factors statistically associated with the development of SOS/VOD. The overall mortality directly related to SOS/VOD was 15.5%. Overall survival at 1 year was worse in patients with SOS/VOD (P = .0033), and this difference disappeared 5 years after HSCT. Nonrelapse mortality was significantly higher 1 and 5 years after transplantation in patients who developed SOS/VOD (P < .001). Based on the application of new EBMT criteria, the overall incidence of SOS/VOD recorded in this large Italian pediatric retrospective study was 2%. Nonrelapse mortality was significantly higher in patients who developed SOS/VOD. Identifying the risk factors associated with SOS/VOD can lead to more effective early treatment strategies of this potentially fatal HSCT complication in childhood., (Copyright © 2018. Published by Elsevier Inc.)

Background: Invasive mucormycosis is a rare but frequently fatal fungal disease. The acute and rapidly progressive evolution causes unfavourable outcome in 22%-59% of patients and its treatment represents a clinical challenge, especially in immunocompromised patients. Current data in paediatric oncological patients are limited., Objectives: The infection Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) analysed the episodes of invasive mucormycosis occurred between 2009 and 2016., Patients: Fifteen cases of proven mucormycosis (male/female 8/7; median age 14.1 years, range 7.7-18.6) were reported after chemotherapy for acute leukaemia and lymphoma (12) and allogeneic stem cell transplantation (3). The aetiology was Rhizopus oryzae 4, Lichtheimia corymbifera 3 and Mucor spp. 8., Results: Paranasal sinus was the primary site of infection in 14/15 patients combined with orbital involvement (9), central nervous system (8), lung (4), thyroid gland and kidney (1). All patients received liposomal Amphotericin B (L-AmB) (3-10 mg/kg), with surgical debridement in 14/15 cases. Eleven patients received maintenance treatment with posaconazole (9) or isavuconazole (2). Eight out of fifteen patients (53.3%) died, after 3-6 months., Conclusions: Mucormycosis involved mainly the sinu-orbital site and affected children >10 years. Despite aggressive treatment with high-dose L-AmB and timely surgical debridement, the mortality rate remains still high., (© 2018 Blackwell Verlag GmbH.)

Experiments on spin glasses can now make precise measurements of the exponent z(T) governing the growth of glassy domains, while our computational capabilities allow us to make quantitative predictions for experimental scales. However, experimental and numerical values for z(T) have differed. We use new simulations on the Janus II computer to resolve this discrepancy, finding a time-dependent z(T,t&#95;{w}), which leads to the experimental value through mild extrapolations. Furthermore, theoretical insight is gained by studying a crossover between the T=T&#95;{c} and T=0 fixed points.

Background: Posaconazole is a triazole with limited pharmacokinetic information in children. This study assessed the correlation between posaconazole oral solution daily dosage/kg/body weight and trough plasma level., Methods: A total of 97 hematology-oncology pediatric patients with ≥1 posaconazole plasma concentration level (PPC) assessment in the first 6 weeks after the start of posaconazole treatment were included., Results: Posaconazole was used as prophylaxis in 84 of 97 (87%) patients and as therapy in 13 of 97 (13%). The median daily dose/kg/bw ranged from 10 to 12 mg in the prophylaxis group and 12.5 to 16.5 mg in the therapy group. The median value of PPC for the prophylaxis group was 0.9 and 0.8 μg/mL at the first and second/third determinations, respectively. Posaconazole prophylaxis failed in 4 of 84 patients (5%). The median value of PPC for the therapy group was 1.5 and 1.4 μg/mL at the first/second and the third determination, respectively. Posaconazole-related side effects were reported in 6 patients and all regressed with the suspension of the drug. In the prophylaxis group, the use of proton-pump inhibitors was significantly associated with a lower PPC, P = 0.04., Conclusions: Posaconazole may be a valuable antifungal agent in children despite the incomplete knowledge of its pharmacokinetic characteristics., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.

Background: Invasive fungal infection (IFI) is a cause of morbidity, mortality and increased health costs in children undergoing chemotherapy or hematopoietic stem cell transplant (HSCT)., Methods: Multicenter, retrospective study to assess the incidence, outcome of proven and probable IFI (PP-IFI) in children treated for acute leukemia, non-Hodgkin lymphoma or who underwent HSCT from 2006 to 2012., Results: Over the 7-year period, 127 PP-IFI were diagnosed in 123 patients, median age of 9.7 years. The 1-year cumulative incidence was 2.5% (CI 1.8-3.7) after frontline chemotherapy, 9.4% (CI 5.8-15.0) after relapse, and 5.3% (CI 3.9-7.1) after HSCT. Severe neutropenia was present in 98 (77%) patients. Culture-proven agents were Candida spp., mostly non-albicans, 28, mold 23, whereas three proven IFI were identified by histopathology. Favorable response to treatment within 3 months from diagnosis was observed in 77 (89%). The overall ninety-day probability of survival was 68% (CI 59-76)., Conclusions: About two-thirds of pediatric patients with PP-IFI survived, regardless of whether the infection occurred after frontline chemotherapy, reinduction chemotherapy for disease relapse, or after HSCT. Further prospective studies are needed to define the impact of antifungal prophylaxis and early combination therapy on short-term overall survival., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients who undergo pediatric Hematopoietic Stem Cell Transplantation (HSCT) may experience long-term psychological sequelae and poor Quality of Life (QoL) in adulthood. This study aimed to investigate subjective illness experience, QoL, and psychopathology in young adults who have survived pediatric HSCT. Method: The study involved patients treated with HSCT in the Hematology-Oncology Department between 1984 and 2007. Psychopathology and QoL were investigated using the SCL-90-R and SF-36. Socio-demographic and medical information was also collected. Finally, participants were asked to write a brief composition about their experiences of illness and care. Qualitative analysis of the texts was performed using T-LAB, an instrument for text analysis that allows the user to highlight the occurrences and co-occurrences of lemma. Quantitative analyses were performed using non-parametric tests (Spearman correlations, Kruskal-Wallis and Mann-Whitney tests). Results: Twenty-one patients (9 males) participated in the study. No significant distress was found on the SCL-90 Global Severity Index, but it was found on specific scales. On the SF-36, lower scores were reported on scales referring to bodily pain, general health, and physical and social functioning. All the measures were significantly ( p < 0.05) associated with specific socio-demographic and medical variables (gender, type of pathology, type of HSCT, time elapsed between communication of the need to transplant and effective transplantation, and days of hospitalization). With regard to the narrative analyses, males focused on expressions related to the body and medical therapies, while females focused on people they met during treatment, family members, and donors. Low general health and treatment with autologous HSCT were associated with memories about chemotherapy, radiotherapy, and the body parts involved, while high general health was associated with expressions focused on gratitude ( V -Test ± 1.96). Conclusion: Pediatric HSCT survivors are more likely to experience psychological distress and low QoL in adulthood compared with the general population. These aspects, along with survivors' subjective illness experience, show differences according to specific medical and socio-demographic variables. Studies are needed in order to improve the care and long-term follow-up of these families.

To describe incidence, causes, and outcomes related to pediatric intensive care unit (PICU) admission for patients undergoing hematopoietic stem cell transplantation (HSCT), we investigated the risk factors predisposing to PICU admission and prognostic factors in terms of patient survival. From October 1998 to April 2015, 496 children and young adults (0 to 23 years) underwent transplantation in the HSCT unit. Among them, 70 (14.1%) were admitted to PICU. The 3-year cumulative incidence of PICU admission was 14.3%. The main causes of PICU admission were respiratory failure (36%), multiple organ failure (16%), and septic shock (13%). The overall 90-day cumulative probability of survival after PICU admission was 34.3% (95% confidence interval, 24.8% to 47.4%). In multivariate analysis, risk factors predisposing to PICU admission were allogeneic HSCT (versus autologous HSCT, P = .030) and second or third HSCT (P = .018). Characteristics significantly associated with mortality were mismatched HSCT (P = .011), relapse of underlying disease before PICU admission (P < .001), acute respiratory distress syndrome at admission (P = .012), hepatic failure at admission (P = .021), and need for invasive ventilation during PICU course (P < .001). Our data indicate which patients have a high risk for PICU admission after HSCT and for dismal outcomes after PICU stay. These findings may provide support for the clinical decision-making process on the opportunity of PICU admission for severely compromised patients after HSCT., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We first reproduce on the Janus and Janus II computers a milestone experiment that measures the spin-glass coherence length through the lowering of free-energy barriers induced by the Zeeman effect. Secondly, we determine the scaling behavior that allows a quantitative analysis of a new experiment reported in the companion Letter [S. Guchhait and R. Orbach, Phys. Rev. Lett. 118, 157203 (2017)].PRLTAO0031-900710.1103/PhysRevLett.118.157203 The value of the coherence length estimated through the analysis of microscopic correlation functions turns out to be quantitatively consistent with its measurement through macroscopic response functions. Further, nonlinear susceptibilities, recently measured in glass-forming liquids, scale as powers of the same microscopic length.

We have performed a very accurate computation of the nonequilibrium fluctuation-dissipation ratio for the 3D Edwards-Anderson Ising spin glass, by means of large-scale simulations on the special-purpose computers Janus and Janus II. This ratio (computed for finite times on very large, effectively infinite, systems) is compared with the equilibrium probability distribution of the spin overlap for finite sizes. Our main result is a quantitative statics-dynamics dictionary, which could allow the experimental exploration of important features of the spin-glass phase without requiring uncontrollable extrapolations to infinite times or system sizes.

Background and Objectives: Lack of suitable donors and regimen related toxicity are major barriers for hematopoietic stem cell transplantation (HSCT) in patients with sickle cell disease (SCD). The aim of the study is the assessment of efficacy and toxicity of Treosulfan-based conditioning regimen for SCD also when alternative donors such as mismatched unrelated donor and haploidentical donor are employed., Methods: We report our single-center experience: 11 patients with SCD received HSCT with a Treosulfan/Thiotepa/Fludarabine/Anti-thymoglobulin conditioning regimen between 2010 and 2015. The donor was a matched sibling donor (n= 7), a haploidentical parent (n= 2), a matched unrelated donor (n= 1) or a mismatched unrelated donor (n=1). The haploidentical and mismatched unrelated donor grafts were manipulated by removing TCRαβ and CD19 positive cells., Results: All patients survived the procedure and achieved stable engraftment. Stable mixed chimerism was observed in 5/11 patients. Grade III-IV regimen related toxicity was limited to mucositis and no grade III-IV graft-versus-host disease (GvHD) occurred. No SCD manifestation was observed post transplant and cerebral vasculopathy improved in 3/5 evaluable patients. Organ function evaluation showed no pulmonary, cardiac or renal toxicity but gonadal failure occurred in 1/4 evaluable patients., Conclusion: Our data suggest that Treosulfan is associated with low toxicity and may be employed also for unrelated and haploidentical donor HSCT.

Whereas overt visuospatial attention is customarily measured with eye tracking, covert attention is assessed by various methods. Here we exploited Steady-State Visual Evoked Potentials (SSVEPs) - the oscillatory responses of the visual cortex to incoming flickering stimuli - to record the movements of covert visuospatial attention in a way operatively similar to eye tracking (attention tracking), which allowed us to compare motion observation and motion extrapolation with and without eye movements. Observers fixated a central dot and covertly tracked a target oscillating horizontally and sinusoidally. In the background, the left and the right halves of the screen flickered at two different frequencies, generating two SSVEPs in occipital regions whose size varied reciprocally as observers attended to the moving target. The two signals were combined into a single quantity that was modulated at the target frequency in a quasi-sinusoidal way, often clearly visible in single trials. The modulation continued almost unchanged when the target was switched off and observers mentally extrapolated its motion in imagery, and also when observers pointed their finger at the moving target during covert tracking, or imagined doing so. The amplitude of modulation during covert tracking was ∼25-30% of that measured when observers followed the target with their eyes. We used 4 electrodes in parieto-occipital areas, but similar results were achieved with a single electrode in Oz. In a second experiment we tested ramp and step motion. During overt tracking, SSVEPs were remarkably accurate, showing both saccadic-like and smooth pursuit-like modulations of cortical responsiveness, although during covert tracking the modulation deteriorated. Covert tracking was better with sinusoidal motion than ramp motion, and better with moving targets than stationary ones. The clear modulation of cortical responsiveness recorded during both overt and covert tracking, identical for motion observation and motion extrapolation, suggests to include covert attention movements in enactive theories of mental imagery., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Acute graft-versus-host disease (aGVHD) is the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Systemic steroid treatment represents the first-line therapy for aGVHD and is associated with a response rate of 30% to 60%. Steroid-resistant patients have a poor prognosis with high transplantation-related mortality (TRM). Several second-line therapies have been proposed for the management of unresponsive aGVHD, without proven beneficial effects on patients' outcome or overall long-term survival. For these reasons, extracorporeal photochemotherapy/photopheresis (ECP), a cell-based approach to control GVHD that spares generalized immunosuppression, seems to be promising. In this study, we report the outcome of 72 consecutive pediatric patients treated with ECP between 1997 and 2013 for aGVHD. Among them, 21 patients had steroid-resistant aGVHD, 42 had steroid-dependent aGVHD, and 9 did not receive steroid as first-line therapy because of clinical contraindications. A complete response was obtained in 72% of patients, a partial response was observed in 11%, and there was no response in 17% of patients. At day +180, TRM was 4% in the whole cohort; TRM was 3% and 20% among responders and nonresponders to ECP, respectively (P < .0001). The 5-year overall survival was 71%, showing a difference between responders and nonresponders of 78% and 30%, respectively (P = .0004). The 5-year time to progression of primary disease was 81%, without any significant difference between the 2 groups. Moreover, the 5-year progression-free survival of primary disease was 72%, with a significant difference (P = .0007) between responders (79%) and nonresponders (30%) to ECP. In conclusion, this study demonstrates that ECP is highly effective in aGVHD without a negative impact on primary disease., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: In hematopoietic stem cell transplantation (HSCT), late hemorrhagic cystitis (HC) has been associated with BK virus (BKV) infection. We assessed the value of plasma BKV load in predicting HC., Methods: Plasma and urine BKV-DNA load were assessed prospectively in 107 pediatric patients., Results: Twenty patients developed grade II and III HC, with 100-day cumulative incidence of 18.8%. At diagnosis of HC, the median load of BKV DNA was 2.3 × 10(3) copies/mL. A plasma BKV-DNA load of 10(3) copies/mL had a sensitivity of 100% and a specificity of 86% with a negative predictive value (NPV) of 100% and a positive predictive value (PPV) of 39% for HC. A urine BKV-DNA load of >10(7) copies/mL had a sensitivity of 86% and a specificity of 60% with a NPV of 98% and a PPV of 14% for HC. A BKV load of 10(3) copies/mL on plasma was significantly associated with HC in multivariate analysis (hazard ratio [HR], 6.1; P = .0006). Patients with HC had a significantly higher risk of mortality than patients who did not have HC (HR, 2.6; P = .018)., Conclusions: The above values were used to monitor plasma BKV-DNA load, and they provided a better prediction of patients at risk of HC than urine BKV-DNA load., (© The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

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.

The properties of pygmy dipole states in 208Pb were investigated using the 208Pb(17O, 17O'γ) reaction at 340 MeV and measuring the γ decay with high resolution with the AGATA demonstrator array. Cross sections and angular distributions of the emitted γ rays and of the scattered particles were measured. The results are compared with (γ, γ') and (p, p') data. The data analysis with the distorted wave Born approximation approach gives a good description of the elastic scattering and of the inelastic excitation of the 2+ and 3- states. For the dipole transitions a form factor obtained by folding a microscopically calculated transition density was used for the first time. This has allowed us to extract the isoscalar component of the 1- excited states from 4 to 8 MeV.

Background: Peripheral blood stem cells (PBSCs) are the preferred source in autologous transplantation. We assessed prospectively the efficacy of mobilization in pediatric patients and risk factors associated with its failure., Study Design and Methods: Patients, aged 0 to 17 years, needing a first collection of PBSCs for autologous stem cell transplantation were eligible. The study period was from July 2008 to September 2010. A blood peak of fewer than 20 × 10(6) CD34+ cells/L was used as the cutoff to define a poor mobilizer., Results: A total of 145 patients, 57% male (82) and 43% female (63), with a median age of 7 years, affected by solid tumor, 79% (114), and acute leukemia or lymphoma, 21% (31), were enrolled. Granulocyte-colony-stimulating factor used was filgrastim in 69%, lenograstim in 26%, and pegfilgrastim in 5% of patients. A total of 83% (121) of patients mobilized successfully, the median CD34+ count being 120 × 10(6) /L (range, 23 × 10(6) -1840 × 10(6) /L). A single leukapheresis procedure was sufficient to achieve the target CD34+ cell dose in 82% (99/121) of patients. Among 24 poor mobilizer patients, 15 underwent a second mobilizing course and nine required a marrow harvest. Factors associated with poor mobilization were metastatic disease and relapse. Among 99 patients who underwent autologous stem cell transplantation, the median times to neutrophil and platelet engraftment and of hospitalization were longer by 2, 12, and 6 days in poor versus good mobilizer group., Conclusions: In pediatric patients undergoing a first mobilization, the incidence of poor mobilization was 17%. Failure of mobilization resulted in an increase in health costs and a longer hospitalization for those who underwent autologous stem cell transplantation., (© 2012 American Association of Blood Banks.)

Purpose: 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)., Methods: 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., Results: 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., Conclusions: We conclude that pegfilgrastim was not inferior to daily filgrastim in pediatric patients who underwent PBSCT. EU CLINICAL TRIAL REGISTER NUMBER: 2007-001430-14.

Background: Veno-occlusive disease (VOD) is a major complication following hematopoietic stem cell transplantation (HSCT). Its diagnosis is based on clinical criteria, which have a limited sensitivity. Increased plasminogen activator inhibitor-1 (PAI-1) levels have been suggested as a marker of VOD. We aimed to prospectively evaluate how the fibrinolytic parameters behaved to discriminate VOD from other liver disorders occurring after HSCT in a pediatric population., Procedures: A total of 195 HSCT were performed on 161 children and VOD complicated 11 cases (6.8%). Alanine aminotransferase, total bilirubin, PAI-1 antigen (PAI-1:Ag) and activity, t-PA antigen, D-dimer, prothrombin time, activated partial thromboplastin time, antithrombin, fibrinogen, and platelet counts were measured in 105 HSCT before and then weekly for 1 month after HSCT., Results: An early, significant increase in the fibrinolytic parameters was seen in patients who developed VOD, even before VOD was diagnosed clinically, by comparison with patients without complications or those with non-VOD liver disorders. The combined increase in bilirubin, D-dimer, and PAI-1:Ag levels beyond the normal range distinguished VOD cases from other liver complications with a high sensitivity and specificity., Conclusions: Our study demonstrates that fibrinolytic tests can help diagnose VOD after HSCT in the pediatric population., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Several studies proved that virus-specific T-cells play a pivotal role in controlling cytomegalovirus (CMV) infection in adult allogeneic hematopoietic stem-cell transplant (HSCT) patients. Fewer data are available in pediatric HSCT settings, when immature and inexperienced immune system may affect antiviral immune reconstitution., Methods: We analyzed prospectively the CMV-specific T-cell reconstitution in a cohort of 31 pediatric allogeneic HSCT recipients at 30, 60, 90, 120, 180, and 360 days after HSCT., Results: Depending on donor-recipient CMV serostatus, we observed distinct patterns and kinetics of CMV-specific T-cell immune reconstitution: during the early time-points, patients displayed a severe reduction in CMV-specific T-cell recovery in both CMV seropositive donor (D+) group and CMV seronegative donor (D-) on CMV seropositive recipients (R+). From day 90 onward, statistical significant differences in the profile of T-cell immune reconstitution emerged between D+ and D-. The pattern of immune reconstitution was characterized by heterogeneous kinetics and efficiencies: we report cases of: (1) spontaneous antiviral T-cell recovery with no previous viremia, (2) immune T-cell recovery anticipated by CMV viremia, and (3) no T-cell immune reconstitution despite previous viremia episodes., Conclusions: Given the heterogeneous scenarios of antiviral T-cell immune recovery in pediatric allogeneic HSCT, we conclude that the evaluation of the antiviral immune reconstitution is a promising and appealing system for identifying patients at higher risk of CMV infection. The use of interferon-γ ELISPOT test is a valid tool for immunological monitoring and predicting CMV viremia in pediatric HSCT.

A number of apoptotic stimuli produce a different response by CD4(+) regulatory and effector lymphocytes. So far, little is known concerning the sensitivity of CD4(+) regulatory T cells (Treg) to genotoxic agents. Observations from a mouse model suggest that Treg are more resistant to DNA damage compared to CD4(+) T effector cells (Teff). By flow cytometry we analysed the apoptotic response to genotoxic stimuli in culture, comparing Treg and Teff. CD4(+) regulatory lymphocytes appeared to be more resistant than CD4(+) effector lymphocytes. Results of costaining experiments for CD45RA suggest that this dissimilarity is not related to the differentiation to a CD45RA negative phenotype. Further, neither the antiapoptotic protein Bcl-2 nor Bcl-xL were found to be expressed in greater amounts by Treg compared to Teff. The differential sensitivity of Treg and Teff to DNA-damage inducing agents may be of clinical relevance in cancer therapy. © 2011 International Society for Advancement of Cytometry., (Copyright © 2011 International Society for Advancement of Cytometry.)

In HSCT setting, KIR-driven alloreactivity might be better predicted if the donor KIR genotype is considered in addition to the recipient HLA genotype. The prediction of NK cell alloreactivity relies on the missing ligand in the recipient, a scenario that can be found in HLA-identical and non-identical allotransplants. The aim of this study was to investigate at genetic level the prognostic impact of recipient HLA-I lacking for donor KIR on allotransplanted patients outcome. We analysed donors KIR genotype and HLA genotype of 60 paediatric patients who received related (n=15) or unrelated (n=45) transplantation. When patients were grouped based on the KIR gene type involved in the KIR/HLA-I mismatch, we did not observe any relapse in the group of patients characterized by mismatches involving only inhibitory KIR. On the contrary, all relapses were observed in patients showing at least one activating gene involved in the mismatch (p<0.05). Although the biological mechanism accounting for this putative genetic rule is still to be clarified, we suggest that a careful survey of KIR/HLA-I mismatching should be taken into account in the selection of donor in related and unrelated HSCT., (© 2010 John Wiley & Sons A/S.)

Background: Posttransplant lymphoproliferative disease caused by Epstein-Barr virus (EBV-PTLD) is a severe complication after allogeneic hematopoietic stem-cell transplantation (HSCT). We evaluated whether the modulation of immunosuppression (IS) guided by quantitative polymerase chain reaction for EBV (EBV-PCR) was effective as a first-line therapeutic approach for EBV reactivation., Methods: Eighty-nine pediatric patients who received an HSCT from an unrelated donor were prospectively assessed by quantitative EBV-PCR. The EBV-PCR threshold to modulate IS was set to more than 300 genomic copies (gc)/10 peripheral blood mononuclear cells., Results: EBV-PCR positivity was observed in 56 (63%) of 89 patients at a median time of 44 days after HSCT. The variables associated with EBV-PCR positivity were bone marrow stem cells (P=0.047) and a lower total dose of nuclear cells reinfused (P=0.03). Thirty-one patients (35%) had more than or equal to 300 gc. IS was withdrawn or reduced in 18 (58%) and 13 (42%) of the 31 patients, respectively. EBV viral load (EBV-VL) less than 300 gc was achieved in 30 of these 31 patients at a median of 25 days. Only 1 (1%) of the 89 patients progressed to EBV-PTLD. The patients with EBV-VL more than 300 gc had a lower incidence of acute graft versus host disease III-IV than patients with EBV-VL less than 300 gc: 13% vs. 36%, P=0.02. No differences in terms of chronic graft versus host disease, overall survival, event-free survival and transplant-related mortality were observed between the two groups., Conclusions: We conclude that PCR-guided modulation of IS may play a role in early intervention for EBV-PTLD and a prospective, randomized study is needed.

A reliable diagnosis of invasive aspergillosis (IA) is hampered by the difficulty in obtaining suitable tissue samples. To evaluate the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the LightCycler PCR for the diagnosis of IA, 536 blood samples were collected over a 22-month period from 62 paediatric patients (median age 10 years, range 1-18) considered at risk of IA. The galactomannan antigen (GM) and fungal DNA were assessed on serial blood samples. IA was diagnosed in eight of 62 patients (13%): proven, five, probable, three. Sensitivity, specificity, PPV and NPV of LightCycler PCR varied according to the number of positive samples used to define positivity: 88%; 37%; 17% and 95% for single sample positivity; and 63%, 81%, 33% and 94% for serial sample positivity respectively. The concordance between positivity of LightCycler PCR assay and the diagnosis of IA was 79%. The single positivity of LightCycler PCR assay showed a good sensitivity for the diagnosis of IA in paediatric patients. The high NPV makes LightCycler PCR a promising tool in addition to GM testing to design a strategy of pre-emptive antifungal therapy, although further validation studies are needed.

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.

We describe two episodes of CMV retinitis in a pediatric patient who underwent a CD34+ selected graft from his haploidentical father. Both recipient and donor were cytomegalovirus (CMV) seropositive. Both episodes occurred late post-grafting during a phase of complete immunological recovery with sufficient numbers of circulating CMV-specific clones. Antiviral treatment with foscarnet and ganciclovir was successful but prolonged treatment was required to prevent relapses. We hypothesize that this complication was more related to an immune reconstitution process than to an immune-deficient state post-grafting. We conclude that CMV retinitis is a late complication of HSCT that can occur despite satisfactory immune reconstitution. Usually, it is responsive to antiviral therapy. Dilated fundoscopic examination is essential both for examining patients with reduced visual acuity and for screening asymptomatic patients.

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.

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 > or =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 x 10(6) genomic copies/ml had a sensitivity of 95% and specificity of 90%; while a blood BK load >1 x 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.

Background and Objectives: Veno-occlusive disease (VOD) is one of the most frequent complications after stem cell transplantation. We conducted a prospective survey of 244 hematopoietic stem cell transplants in children to determine the incidence of VOD, its main risk factors, treatment and effect on the transplant., Design and Methods: Two hundred and forty-four hematopoietic stem cell transplants (HSCT) performed in 220 pediatric patients from 1993 to 2003 were evaluated. The series included 127 males and 93 females with a median age of 6.7 years at the time of transplantation., Results: VOD was diagnosed following 26 of the 244 transplants (cumulative incidence 11%), but a higher incidence was found in patients with at least one known risk factor for VOD (cumulative incidence 20%). In multivariate analysis, risk factors for VOD were age < 6.7 years; type of VOD prophylaxis, and busulphan-containing conditioning regimens. Routine treatment of VOD was based on supportive care and, starting from 1999, defibrotide was used. All patients were monitored with daily Doppler ultrasound-(US) for early diagnosis of inversion of portal blood flow. Twelve patients developed inversion of portal flow (9 had severe VOD; 3 had moderate VOD) and were promptly started on fibrinolytic and anticoagulant therapy with heparin and recombinant tissue plasminogen activator (rt-PA). Hepatic flow reverted to normal in all 12 patients; only 4 patients ultimately developed multiorgan failure and died. The transplant-related-mortality (TRM) rate in patients with or without inversion of portal flow was 33% vs 7%, (p=0.1). The TRM in patients with or without VOD was 19% vs 8% (p=0.001)., Interpretation and Conclusions: This study showed that younger age, type of VOD prophylaxis, and busulphan-based conditioning regimens are independent risk factors for VOD. Inversion of portal flow was found in 9 of 10 patients with severe VOD. Doppler US monitoring may be helpful in early identification of the patients with VOD-induced inversion of portal flow who might benefit from therapy with heparin and rt-PA.

To assess a real-time polymerase chain reaction-based modulation of immunosuppression in patients with an increasing Epstein-Barr virus (EBV) viral load, we studied 79 paediatric allogeneic stem cell transplantations (allo-SCT) performed between January 1998 and December 2003. EBV reactivation was observed in 42 of 79 patients (53%) after a median time of 45 d from allo-SCT: 37 (88%) and five (12%) patients had received the graft from an unrelated and a related donor respectively (P = 0.001). Twenty-eight patients (67%) had a viral load > or =300 genomic copies x10(5) peripheral blood mononuclear cells (PBMC) and antithymocyte globulin was the only factor significantly associated with EBV reactivation (P = 0.001, RR 7.1). Among these 28 patients, immunosuppression was suspended and reduced in 17 and 11 patients respectively. Overall, post-transplant lymphoproliferative disease was diagnosed in one of 79 patients (1%). The pre-emptive modulation of immunosuppression in patients with EBV reactivation and a viral load > or =300 genomic copies x10(5) PBMC did not negatively influence transplant-related mortality, overall survival or event-free survival. In conclusion, EBV reactivation is frequent even in 'low risk' patients and the pre-emptive modulation of immunosuppression enables it to be managed safely, with no significant flare in graft-versus-host disease status.

Objective: Data on the use of combination of liposomal amphotericin B and caspofungin followed by voriconazole, as maintenance or further rescue treatment, in 10 patients with invasive mycosis are reported., Material and Methods: The diagnoses were acute leukemia (7), myelodysplastic syndrome (1) and Hodgkin's lymphoma (1). All patients developed an invasive mycosis (proven, 3; probable, 6; and possible, 1) refractory to first-line antifungal treatment (liposomal amphotericin B in all patients except one who received fluconazole)., Results: Rescue therapy with a combination of caspofungin and liposomal amphotericin B was well tolerated, hypokalemia, and thrombophlebitis being the most common side-effects. Combination therapy was administered for a median of 17 d, range 6-40. Among the nine patients with proven or probable mycosis, one was not evaluated because of early death caused by massive hemoptysis whilst in the remaining eight patients, the response was classified as complete, stable and failure in four, three, and one patients, respectively. Complete response was also observed in patient with possible mycosis. Eight of nine patients received voriconazole for a median of 75 d, range 42-194. Voriconazole was well tolerated although some drug interactions were observed during treatment with methotrexate and digoxin. After a median follow-up of 125 d, nine of 10 patients are alive. Overall, a favorable response to antifungal treatment (including the case of possible mycosis) was obtained in eight of 10 patients., Conclusion: These data suggest that medical antifungal treatment may be intensified in severely ill patients without significantly compromising patient safety. The combination of synergistic antifungal drugs as well as their sequential use warrants further investigation by a larger randomized controlled study.

This study aimed to ascertain whether extracorporeal photochemotherapy (ECP) is an effective treatment for paediatric patients with refractory graft-versus-host disease (GVHD). From January 1992 to December 2000, 77 children (median age 8.6 years) with either acute (n = 33) or chronic (n = 44) GVHD, resistant to conventional immunosuppressive therapy, were treated with ECP in four Italian paediatric hospitals. After ECP, acute GVHD involving skin, liver and gut responded completely in 76%, 60% and 75% of patients respectively. The 5-year overall survival was 69% for responding patients vs 12% for non-responders (P = 0.001). Among the 44 children with chronic GVHD, 15 (44%) showed a complete response and 10 (29%) a significant improvement after ECP. The 5-year overall survival was 96% for responders vs 58% for non-responders (P = 0.04). Our results suggest that ECP is an effective treatment that may be useful in paediatric patients with either acute or chronic GVHD who have failed to respond to standard immunosuppressive therapy.

Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative option for primary hemophagocytic lymphohistiocytosis (HLH), a rare disease of infants and young children, characterized by recurrent fever, hepatosplenomegaly, and cytopenia. We report a case of successful engraftment and stable full-donor chimerism in a patient with HLH who underwent peripheral allogeneic CD34-selected HSCT. The donor was his 1-antigen-HLA-mismatched grandmother. After a conditioning regimen based on the combination of thiotepa, fludarabine, melphalan, and rabbit antilymphocyte serum, the patient received a megadose of 26.3 x 10(6)/kg of CD34(+) peripheral blood cells. Neutrophil (>0.5 x 10(9)/L) and platelet (>50 x 10(9)/L) engraftment was observed on days +16 and +12, respectively, and the patient was discharged home on day +24. No acute or chronic GVHD was observed. Infectious complications were the main causes of re-hospitalization in the first year after transplantation, but no significant morbidity was observed thereafter. Thirty-two months after HSCT, the patient is alive and well, still in complete clinical remission of his underlying disease with a durable engraftment, normal NK activity and full donor chimerism. This case suggests that a fludarabine-based conditioning regimen and CD34-selected peripheral allogeneic HSCT may be a feasible option in case of unavailability of a fully HLA-matched related or unrelated donor., (Copyright 2003 Wiley-Liss, Inc.)

Treatment of healthy donors with recombinant human granulocyte colony-stimulating factor (rhG-CSF) allows the mobilization and peripheralization into circulating blood of an adequate number of CD34+ cells that can then be collected by leukapheresis (PBSC). This procedure avoids the invasiveness of bone marrow harvest and the risks related to general anesthesia. The main adverse effects of rhG-CSF are: bone pain, 84%, headache, 54%, fatigue, 31%, and nausea, 13%, which are usually scored by the donors as moderate to severe, resolving within 2-3 days after discontinuation of the cytokine. Analgesics, mainly acetaminophen, are sufficient to control the pain. Less than 5% of the donors experience non-cardiac chest pain, a local reaction at the injection site, insomnia, dizziness or a low-grade fever. Discontinuation of the PBSC procedure because of adverse effects of rhG-CSF or leukapheresis is rarely necessary (0.5%) but this good tolerability can be hampered by the need, in 5-20% of cases, for an adequate venous access that requires insertion of a central or venous catheter. There are no absolute contraindications to the stimulation of healthy donors with rhG-CSF but the description of cases of non-traumatic splenic rupture, iritis, cardiac ischemia, and gouty arthritis suggests that further precautionary restrictions are advisable when deciding eligibility for PBSC collection. The main advantages for patients receiving an allogeneic PBSC transplant are the faster hematologic and immunologic recovery and the potential for a greater efficacy in advanced disease by lowering the transplant-related mortality. One of the major concerns regarding the use of rhG-CSF in unrelated healthy donors is the uncertainty about its possible role in triggering malignancy, in particular myelodysplastic syndrome and acute myeloid leukemia. There are no studies with an adequate sample size and follow-up that can answer this question but two recent retrospective studies reported that in the medium term rhG-CSF is not associated with an excess of lymphoproliferative disorders. Currently, caution on the long-term safety of the use of rhG-CSF in healthy donor is still warranted but the data so far accumulated on allogeneic PBSC transplants are encouraging both as far as concerns the good short-medium tolerability profile of G-CSF-stimulation of the donor and the potential major efficacy in leukemia patients.