Management of Epstein-Barr virus reactivation following allogeneic stem cell transplantation

BackgroundEpstein-Barr virus (EBV) reactivation is a frequent event (5–20%) following allogeneic stem cell transplantation (allo-SCT) that may progress to life-threatening EBV-lymphoproliferative disease (EBV-LPD).AimTo present data relevant to incidence, diagnosis and contemporary management of Epstein-Barr virus (EBV) reactivation in children undergoing allogeneic haematopoietic stem cell transplantation.Materials/MethodsA review of PubMed references based on evidence-based recommendations and own experienceResultsEpstein-Barr virus (EBV) reactivation is a frequent event (5–20%) following allogeneic stem cell transplantation that may progress to life-threatening EBV-lympho-proliferative disease (EBV-LPD), especially after T-cell depletion in vitro and/or in vivo. Clinical symptoms are frequently lacking in the early stages of EBV reactivation. The introduction of real-time polymerase chain reaction (RQ-PCR) several years ago has provided a powerful tool to monitor EBV reactivation in still asymptomatic allo-SCT recipients and to predict increased risk of developing EBV-LPD. Recently, evidence has been provided that EBV-DNA load guided preemptive treatment with B cell depleting CD20 monoclonal antibodies (Rituximab®) is effective in preventing EBV-LPD in allo-SCT recipients at high risk.ConclusionsWe propose that simultaneous and on-line analysis of both EBV-DNA load and T cell recovery will improve the identification of patients at high risk for EBV-LPD. These patients will probably benefit most from pre-emptive interventions

Immunotherapy: Is it different for sarcomas?

The Janus-faced roles of macrophages in cancer imply both tumor-suppressive and -stimulating actions of these innate immune cells. Whereas the balance is toward tumor promotion in most epithelial cancers, we have recently shown that osteosarcoma metastasis seems to be inhibited by macrophages. Here we discuss the possible mechanism of this observation

Long-term parental distress after pediatric hematopoietic stem cell transplantation for nonmalignant diseases

Background: Survival rates have continued to increase for pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. Despite the crucial role of caregivers in this high-intensity treatment, knowledge about long-term parental impact is lacking. Procedure: This cross-sectional study assessed parental distress and everyday problems in parents of patients 2 years and older after pediatric HSCT for a nonmalignant disease using Distress Thermometer for Parents (DT-P), and compared outcomes to matched Dutch parents of healthy children and Dutch parents of children with a chronic condition (CC). Results: Median follow-up was 5.3 years (interquartile range [IQR]: 2.9–8.6). Underlying diseases were inborn errors of immunity (N = 30), hemoglobinopathies (N = 13), and bone marrow failure (N = 27). Mothers of pediatric HSCT recipients (N = 70) reported comparable overall distress levels to mothers of healthy children, but experienced more distress related to parenting problems, specifically managing their child's emotions, discussing disease consequences, and fostering independence. Fathers of HSCT recipients (N = 45) reported higher overall distress levels and had more emotional distress compared to fathers of healthy children. Conclusions: Overall, parental distress and everyday problems of parents of HSCT recipients are comparable to those of parents of children with CC. However, there is ongoing parental burden, both emotional and in parenting, long-term after HSCT compared to parents of healthy children, and the type of burden differs between mothers and fathers. These results indicate that individualized parental supportive care should not remain restricted to the acute hospitalization phase, but also be actively offered during long-term follow-up after pediatric HSCT.</p

Effects of salt water on the ballistic protective performance of bullet-resistant body armour

Bullet-resistant body armour is used by law enforcement agencies and military personnel worldwide, often in inclement weather. Some fibre types used in body armour perform poorly when wet, resulting in a reduced level of protection; this is why most body armour protective elements are water-repellent treated and/or protected by a water-resistant cover. Some of the users operate in the maritime environment. The effect of salt water on body armour performance has not been previously reported. In this work the effect of soaking body armour in salt water and exposing body armour for up to 10 soaking and drying cycles in salt water was investigated. The effectiveness of the water-resistant cover was investigated by considering three cover conditions: (i) intact, (ii) cut and (iii) removed. Wet armour was heavier and provided significantly less protection from 9 mm Luger FMJ ammunition when compared to not-exposed armour irrespective of cover condition. A degradation in performance of armours exposed to soaking and drying cycles was noted, but this was similar across all regimes considered (one, three, five and ten cycles) and not as great as for wet armours

Population pharmacokinetics of treosulfan in paediatric patients undergoing hematopoietic stem cell transplantation

Aims: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. Methods: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42&nbsp;g/m2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. Results: A 2-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650&nbsp;mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7&nbsp;hours after start of infusion resulted in the best limited sampling strategy. Conclusions: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure

The value of using patient-reported outcomes for health screening during long-term follow-up after paediatric stem cell transplantation for nonmalignant diseases

Introduction: The assessment of using patient-reported outcomes (PROs) within comprehensive care follow-up programmes, specifically focused on health screening, remains largely unexplored. PROs were implemented in our late effects and comprehensive care programme after paediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. The programme focuses solely on screening of physical and mental health and on discussing PROs during the consultation. Methods: The primary method of this study was semistructured interviews to explore the perspective of both patients and healthcare providers' (HCP) on the use of PROs, which were thematically analyzed. Additionally, an explorative quantitative approach with patient-reported experience measures (PREMS) was used, with a pretest–posttest design, to assess whether the use of PROs was accompanied by more patient-centred care. Results: From the patient-interviews (N = 15) four themes were extracted: use of PROs (1) help to discuss topics; (2) make the patients feel understood; (3) create a moment of self-reflection; and (4) make consultations more efficient. Pre- and postimplementation analysis of PREMs (N = 40) did not show significant differences in terms of patient-centeredness. Conclusion: Our results demonstrate the added value of integrating PROs for health screening purposes within the long-term follow-up programme after paediatric HSCT, as perceived by both patient and HCP. With the active use of PROs, patients are stimulated to consciously assess their health status. Patient Contribution: This study included patients as participants. Caregivers were approached if patients were below a certain age. Additionally, preliminary results were shared with all patients (including nonparticipants) during a patient conference day.</p

Histone deacetylase inhibitors enhance expression of NKG2D ligands in Ewing sarcoma and sensitize for natural killer cell-mediated cytolysis

Background: Ewing sarcoma patients have a poor prognosis despite multimodal therapy. Integration of combination immunotherapeutic strategies into first-/second-line regimens represents promising treatment options, particularly for patients with intrinsic or acquired resistance to conventional therapies. We evaluated the susceptibility of Ewing sarcoma to natural killer cell-based combination immunotherapy, by assessing the capacity of histone deacetylase inhibitors to improve immune recognition and sensitize for natural killer cell cytotoxicity. Methods: Using flow cytometry, ELISA and immunohistochemistry, expression of natural killer cell receptor ligands was assessed in chemotherapy-sensitive/-resistant Ewing sarcoma cell lines, plasma and tumours. Natural killer cell cytotoxicity was evaluated in Chromium release assays. Using ATM/ATR inhibitor caffeine, the contribution of the DNA damage response pathway to histone deacetylase inhibitor-induced ligand expression was assessed. Results: Despite comparable expression of natural killer cell receptor ligands, chemotherapy-resistant Ewing sarcoma exhibited reduced susceptibility to resting natural killer cells. Interleukin-15-activation of natural killer cells overcame this reduced sensitivity. Histone deacetylase inhibitor-pretreatment induced NKG2D-ligand expression in an ATM/ATR-dependent manner and sensitized for NKG2D-dependent cytotoxicity (2/4 cell lines). NKG2D-ligands were expressed in vivo, regardless of chemotherapy-response and disease stage. Soluble NKG2D-ligand plasma concentrations did not differ between patients and controls. Conclusion: Our data provide a rationale for combination immunotherapy involving immune effector and target cell manipulation in first-/second-line treatment regimens for Ewing sarcoma

Preferences about Future Alzheimer’s Disease Treatments Elicited through an Online Survey Using the Threshold Technique

Background: Treatments aiming at slowing down the progression of Alzheimer’s disease (AD) may soon become available. However, information about the risks that people are willing to accept in order to delay the progression of the disease is limited.Objective: To determine the trade-offs that individuals are willing to make between the benefits and risks of hypothetical treatments for AD, and the extent to which these trade-offs depend on individuals’ characteristics and beliefs about medicines.Design: Online, cross-sectional survey study.Setting: Population in the UK. Public link to the survey available at the websites of Alzheimer’s Research UK and Join Dementia Research.Participants: Everyone self-reported ≥18 years old was eligible to participate. A total of 4384 people entered the survey and 3658 completed it.Measurements: The maximum acceptable risks (MARs) of participants for moderate and severe adverse events in exchange for a 2-year delay in disease progression. The risks were expressed on ordinal scales, from &lt;10% to ≥50%, above a pre-existing risk of 30% for moderate adverse events and 10% for severe adverse events. We obtained the population median MARs using log-normal survival models and quantified the effects of individuals’ characteristics and beliefs about medicines in terms of acceleration factors.Results: For the moderate adverse events, 26% of the participants had a MAR ≥50%, followed by 25% of the participants with a MAR of 10 to &lt;20%, giving an estimated median MAR of 25.4% (95% confidence interval [CI] 24.5 to 26.3). For the severe adverse events, 43% of the participants had a MAR &lt;10%, followed by 25% of the participants with a MAR of 10 to &lt;20%, resulting in an estimated median MAR of 12.1% (95%CI 11.6 to 12.5). Factors that were associated with the individuals’ MARs for one or both adverse events were age, gender, educational level, living alone, and beliefs about medicines. Whether or not individuals were living with memory problems or had experience as a caregiver had no effect on the MARs for any of the adverse events.Conclusion: Trade-offs between benefits and risks of AD treatments are heterogeneous and influenced by individuals’ characteristics and beliefs about medicines. This heterogeneity should be acknowledged during the medicinal product decision-making in order to fulfil the needs of the various subpopulations.</p

High interpatient variability of treosulfan exposure is associated with early toxicity in paediatric HSCT: a prospective multicentre study

Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30&nbsp;g/m2, administered over 3 consecutive days in infants &lt;1&nbsp;year old (n&nbsp;=&nbsp;12) and 42&nbsp;g/m2 in children ≥1&nbsp;year old (n&nbsp;=&nbsp;65). Mean day 1 treosulfan exposure was 1744&nbsp;±&nbsp;795&nbsp;mg*h/l (10&nbsp;g/m2) and 1561&nbsp;±&nbsp;511&nbsp;mg*h/l (14&nbsp;g/m2), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (&gt;1650&nbsp;mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19–16·28, P&nbsp;=&nbsp;0·026] and skin toxicity (OR 4·51; 95% CI 1·07–18·93, P&nbsp;=&nbsp;0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity