Marie-France Vachon

Influence of GST gene polymorphisms on busulfan pharmacokinetics in children.

Busulfan (BU) is a key compound in conditioning myeloablative regimens for children undergoing hematopoietic stem cell transplantation (HSCT). There are wide interindividual differences in BU pharmacokinetics, which increase the risk of veno-occlusive disease, graft rejection and disease relapse. As BU is mainly metabolized by glutathione S-transferase (GST), it is hypothesized that functional polymorphisms in GST genes may explain in part the variability in BU pharmacokinetics. We analyzed polymorphisms in GSTA1 (C-69T, A-513G, G-631T, C-1142G), GSTM1 (deletion) and GSTP1 (A1578G, C2293T) genes in 28 children undergoing HSCT. All patients had individualized dosing based on pharmacokinetics after the first dose of intravenous BU. GSTM1-null individuals had higher drug exposure (PCmax=0.008; PAUC=0.003; PCss=0.02) and lower clearance (PCL=0.001). Multivariate regression models showed that, other than the drug dose and age, the GSTM1 genotype was the best predictor of first-dose pharmacokinetic variability. GSTM1-null patients also received lower cumulative BU doses (P=0.02). No association was found between BU exposure and major GSTA1 or GSTP1 gene variants. In children, GSTM1 polymorphism seems to modify BU pharmacokinetics after intravenous drug administration.

Systemic aspects of conjugal resilience in couples with a child facing cancer and marrow transplantation

Introduction The negative impact of paediatric cancer on parents is well known and is even greater when intensive treatments are used. This study aimed to describe how couples whose child has received a transplant for the treatment of leukaemia view conjugal resilience and to evaluate the role of we-ness as a precursor of conjugal adjustment. Methods Four parental couples were interviewed. Interviews were analysed in two ways: inductive thematic analysis and rating of verbal content with the We-ness Coding Scale. Results Participants report that conjugal resilience involves the identification of the couple as a team and cohesion in the couple. Being a team generates certain collaborative interactions that lead to conjugal resilience. A sense of we-ness in parents is associated with fluctuation in the frequency of themes. Discussion Participants’ vision of conjugal resilience introduced novel themes. The sense of we-ness facilitates cohesion and the process of conjugal resilience.

Risk of Cytomegalovirus Infection and Disease after Umbilical Cord Blood Transplantation in Children

BACKGROUND Pediatric data regarding cytomegalovirus (CMV) infections in pediatric patients receiving umbilical cord blood (UCB) transplantation are sparse. OBJECTIVE To determine whether UCB transplantation increases the risk of CMV infection and disease compared with other graft sources. METHODS The medical files of patients who underwent allogeneic hematopoietic stem cell transplantation at CHU Ste-Justine (Montreal, Quebec) from April 2000 to December 2006 were retrospectively reviewed. A Cox proportional hazard model was used to assess the effect of potential predictors of outcomes. RESULTS A total of 176 patients with a median age of nine years (range 0.1 to 18 years) underwent hematopoietic stem cell transplantation. The source of stem cells were UCB, bone marrow and peripheral blood stem cells in 86, 86 and four of the cases, respectively. CMV infection occurred in 29 patients (16%). At day 100 post-transplantation, the rate of CMV infection was 13% in UCB transplant recipients (11 of 86) versus 20% in those with other sources of graft (18 of 90) (P=0.19). Positive CMV serology of the recipient and leukocyte depletion were two independent variables associated with an increased risk of CMV infection. Among infected patients, six developed CMV disease (20.7%). The rate of CMV disease one year after infection was 49% in patients who received UCB (five of 11) and 6% in others (one of 18). This difference was significant by univariate (P=0.01) but not by multivariate analysis. CONCLUSION In the setting of the current study, with a moderate CMV infection rate (16.5%), UCB transplantation did not appear to increase the risk of CMV infection and disease.

Pharmacokinetics-adapted Busulfan-based myeloablative conditioning before unrelated umbilical cord blood transplantation for myeloid malignancies in children

Unrelated umbilical cord blood transplantation (UCBT) is an alternative to provide transplants in children with acute leukemia or myelodysplastic syndrome who lack a related donor. Intravenous Busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used, with more predictable bioavailability and better outcomes comparing to oral Bu. There is still an important variation in Bu pharmacokinetic between patients that is associated with an increased risk of toxicity and graft failure. The objective of the study was to analyze the impact of first-dose pharmacokinetic adapted myeloablative conditioning regimen of intravenous Bu on the different outcomes after transplantation. Data of 36 children who underwent allogeneic HSCT with Bu plus a second alkylating agent at Sainte Justine Hospital in Montreal, Canada, between December 2000 and April 2012 were analyzed. For children with high risk myeloid malignancies receiving an UCBT, first dose Bu pharmacokinetic seems to be a significant prognostic factor, influencing neutrophil (100% vs 67.9%) and platelet recovery (95.5% vs 70.5%), non-relapse mortality (0% vs 18.6%), EFS (64% vs 28.6%) and OS (81.3% vs 37.5%) for a first-dose steady-state concentration (Css) <600ng/mL vs >600ng/mL, respectively. These data reinforce the importance of Busulfan therapeutic drug monitoring-guided dosing in pediatric HSCT patients, particularly in the context of UCBT.

A comparison of attitudes toward HSCT and survival estimations post HSCT across two pediatric Hematology–Oncology and Intensive Care departments in Canada

Dear Editor, A proportion of 10–20% of children undergoing haemopoietic stem cell transplantation (HSCT) need to be hospitalized in an intensive care unit (ICU) as a result of life-threatening complications (e.g., pulmonary), infections, or graft-vs-host disease. It has been reported that patients surviving after an ICU admission during the transplantation process have a low survival rate in the long run, particularly if they received prolonged mechanical ventilation (e.g., 36% following ICU discharge) [1]. As a result of this low survival rate and the frailty of many hematology–oncology (HO) patients, ICU teams may consider HSCT with mixed feelings with regards to its necessity and associated concerns. Historically, HSCT patients are considered as complex, demanding, and particularly fragile [2]. These perceptions may lead ICU teams to question the benefit of HSCT itself, contrasting with the views of HO teams that the care plan should be followed through as long as there remains some hope for cure. These different outlooks may have pervasive consequences on how ethics dilemmas are approached and how professionals from different departments coordinate, an aspect that is of paramount importance when professionals and families have difficult decisions to make. Communication difficulties between ICU and HO teams may be exacerbated by the intense and dramatic experience of families who are directly confronted with the threat posed to their children’s life when these must be treated in ICUs. In these cases, families must deal with an unknown team and experience a complete lack of control [3, 4]. It is notable that how these different teams consider HSCT has not been studied quantitatively [5]. Although from the existing literature, we could speculate differences in perceptions, there is no data on to what extent teams hold different views. Positive and negative attitudes toward HSCT may result from different sets of factors, including education, regular exposition to scientific data, age, or seniority. The present study aimed to compare attitudes toward HSCT and individual estimations of 5-year survival post HSCT in staff of HO and ICU departments of a pediatric hospital. In addition, we wished to identify explanatory factors of these attitudes. This study was approved by the institution’s Human Research Ethics Committee. Between September and December 2015 we surveyed members of the ICU and the HO departments from the CHU SainteJustine, a major tertiary hospital from the Québec province (Canada) and a labeled excellence center for pediatric HSCT in Canada. The paper–pencil survey was proposed during staff meetings and an e-mail prompt was sent to all eligible staff members, i.e., all members having direct experience with HSCT. Participants had to respond individually to an ad hoc questionnaire and hand it back in a sealed envelope. The survey was fully anonymous. Among the 152 eligible, 63 professionals accepted and handed their questionnaire back (participation: 41%, similar in both departments). Since 4 questionnaires had important missing data, the final sample is composed of 59 professionals (Table 1). To assess attitudes toward HSCT the research team framed two positive and three negative statements [6] for which respondents should provide their degree of agreement on a 7-point scale from 1 “Totally disagree” to * Serge Sultan serge.sultan@umontreal.ca