ALBERT

Description: Background Four key challenges have been identified for the informed consent process in pediatric Bone Marrow Transplantation (BMT): 1. The information disclosed is complex, 2. parents are often under significant emotional duress, 3. life or death circumstances are perceived, and 4. there is often significant time pressure. The purposes of this study were A. to survey parental perceptions of the validity of the informed consent provided for their child’s BMT, B. to determine if the quality of the consent influenced hope, guilt, anxiety or stress. Methods An information package and informed consent document were mailed to 67 English-speaking parents whose children underwent BMT and were prepared for transplant by one physician using a standardized template at the IWK Health Centre (Halifax, Nova Scotia, Canada) between 1998 and 2002. These parents represented the guardians of 36 children who had undergone BMT. Semi-structured interviews were conducted by phone or in person and audiotaped. Transcripts were independently analyzed for common themes by 2 reviewers. Results Twenty parents (12 mothers and 8 fathers) of 12 children consented to participate in the study. Participants did not differ from eligible non-participants in indication for transplant, donor source, major complications, or death rates. Elements of consent: (A) Freedom to Choose. All parents reported feeling personally compelled to consent, but denied external pressure to do so. All participants, including those whose children had died (n=5), would consent to BMT again. No parent reported questioning the validity of the informed consent for BMT. (B) Capacity to Understand. A minority of parents (n=5, 25%) reported diminished ability to understand the process, usually related to emotional duress at the time of consent. (C) Adequacy of Information. Most parents (n=15, 75%) stated directly that they felt fully prepared for the potential side effects of BMT. However, there were four reports of unexpected severity of side effects of therapy [excess hair growth (n=1), bleeding (n=1), and fatigue (n=2)] and 1 of an unexpected side effect (pneumonitis). Emotional impact: 7 parents (35%) reported marked hopelessness during the disclosure process, although all parents expressed that they did not want false hope. 14 parents reported a direct relationship between hope and objective test results (ie daily complete blood count). Parents (n=18) reported peak stress leading up to BMT and the first 6 months post BMT. 18 parents noted ongoing, significant, stress at the time of the study, despite length of time from BMT (median 39 months). One parent reported experiencing guilt. All parents denied experiencing second thoughts with respect to the decision to consent. 8 parents reported heightened health vigilance for their child and increased stress with the appearance of minor health concerns (ie mosquito bites, bruises), or at the time of recheck, despite length of time post BMT. In addition to geographic isolation, all parents reported social isolation, sometimes severe, at the time of, and following BMT. Conclusions Despite significant barriers to informed consent, no parent reported questioning the validity of the consent for BMT for their child. Hopelessness, social isolation and continuing high levels of stress related to the health of their child are frequently reported. Consent conferences and ongoing follow up should proactively address these issues for parents of children undertaking BMT.

Description: Background: Offering research results to study participants is increasingly considered an ethical obligation founded on the principle of respect for persons. This practice acknowledges the importance of the participant’s contribution in the study and, in some instances, enables the participant to benefit directly from the health information derived from the research. Recent studies have established that there is growing support for this practice among investigators and study participants in highly selected populations. The frequency and means of this practice is unknown in the broader national and international research community. Methods: We pilot-tested a questionnaire, which we designed for this study. It had a high content validity. The questionnaire was designed to document the frequency with which researchers offer return of results to research participants, the means by which researchers offer results, the role of Research Ethics Boards (REBs) in the return of research results, and the demographics of the study participants. We classified all 887 abstracts presented at the American Society of Hematology Annual Meeting in December 2003 according to study type. Only those abstracts involving human subjects were included. Of the 478 eligible abstracts, email addresses for 472 (98.7%) first or senior authors were found using public web sites. The investigators were sent the 4–5 minute survey by email. Two reminders were sent to non-respondents. Responses were downloaded to a secure server and analyzed by descriptive and Chi squared techniques. Results: Interim results were obtained 11 days after initiating the survey. Complete responses were received from 84 of the 471 (18%) investigators. Most responders were physicians (n=68; 81%) and almost half (n=40; 47%) received Research Ethics Board (REB) approval for their study in the United States. Only 23 (27%) investigators had a formal plan for the return of results to study participants. No clear preference for any one means of returning research results was indicated. The majority (n=18; 78%) indicated that they would provide the participant with a choice of whether or not to receive research results and most (n=14; 61%) indicated that they would provide an overall summary of results rather than an overall summary plus individual level results. Reasons for not returning research results included: did not consider it (n=25), contact difficulties (n=22), and participant difficulty in understanding results (n=19). Cost and concern for the patient regarding adverse effects of receiving results were infrequently cited. Only 2 (2%) of investigators reported that their REB mandated the offer of return of research results to all participants. 55 researchers (66%) supported or strongly supported the return of results to participants, 27 (32%) were neutral, and only 2 (2%) opposed or strongly opposed this practice. Updated data and further analyses will be reported at the annual meeting. Conclusion: Investigators in the international research community infrequently offer to return results to research participants, and REBs rarely mandate this practice. Our study reaffirms the findings of other studies that indicate a high level of support for this practice among researchers. Further work is needed to assess participant needs and concerns, and how to bridge the gap between the expressed attitudes of researchers and actual practice.

Description: Background. Hurler’s syndrome is a lysosomal storage disease with devastating neurological sequelae if left untreated. The negative correlation between age and IQ is significant (r = −0.82, p〈 0.0003). These children have a normal intelligence at birth but on average decline by 2 standard deviations within the first 2 years of life (represents 30 point decrease in IQ). The underlying abnormality is an absence of the enzyme alpha-L-iduronidase, which is available as a recombinant enzyme but does not cross the blood-brain barrier. Currently, bone marrow transplant (BMT) is the only way to prevent the expected neurological deterioration. It is believed that higher levels of enzyme activity are associated with better neurological outcomes. Case report: We report on a 4 year 6 month old boy who was diagnosed with Hurler’s syndrome at 9 months of age. At 15 months of age, he received a matched related transplant with a preparative regimen of cyclophosphamide, busulfan and low dose total body irradiation (300 cGy). In the post transplant period, he had some minor complications but no neurological insults. He received Cyclosporin A for GVHD prophylaxis, which was discontinued after 5 months. Initially there was complete engraftment and normal enzyme activity but this was temporary (See Table 1). Table 1 Alpha-L-iduronidase Chimerism % * believed to be secondary to assay problems Pretransplant 0 Post transplant Normal 14–41 nmol/h/mg protein Ideal 〉 90% 1 month 28 90 4 months 0 45 6 months 14 30 1 year 3 15 1 year 5 months 2 15 1 year 8 months 3 10 2 year 1 month 73* 15 2 year 6 months 4 10 3 year 2 months 3 10 He had an excellent clinical response to BMT with softening of the characteristic facial features and resolution of airway obstruction. Prior to BMT he was report to be developing normally. He sat at 61/2 months, stood at 7 month, had single words at 10 months, and walked at 13 months. Despite mixed chimerism and sub-optimal enzyme activity, his development since BMT has been impressive. 2 years post-BMT (age 3 yr 3 mo), he underwent a formal neuropsychological evaluation. Full Scale intelligence testing revealed he had average intelligence (45th percentile), with a discrepancy between his verbal and performance intelligence. His language skills were within normal limits. He was reported to have some difficulties with visual spatial testing (in block design). Clinical assessment, at this time, revealed that he was doing well in school and had been fully toilet trained. At his last assessment at age 4 yr 5 mo (3 yr 2 mo post BMT), he had made dramatic improvements on the Peabody Developmental Motor Skills, with an age equivalent of 41 months. This was likely hampered somewhat by flexion contractures of his fingers. He continued to do well in school and was speaking both English and French. He had clinically normal development for age. Formal neuropsychological tests will be presented in poster format. Conclusions : This case is the first in the literature with halting of the characteristic neurological decline in Hurler’s syndrome despite poor engraftment and low enzyme activity following BMT. Full donor chimerism and normal alpha-L-iduronidase expression may not be needed to ameliorate the devastating consequences of Hurler’s syndrome.