Rochelle Yanofsky

Impact of Caring for a Child With Cancer on Parents’ Health-Related Quality of Life

PURPOSE To compare the health-related quality of life (QOL) of parents of children who are undergoing treatment for cancer with that of Canadian population norms and to identify important parent and child predictors of parental QOL. PATIENTS AND METHODS A total of 411 respondents of 513 eligible parents were recruited from five pediatric oncology centers in Canada between November 2004 and February 2007. Parents were asked to complete a questionnaire booklet that included a measure of adult QOL (SF-36), a measure of child health status (functional status IIR), and questions to assess health-promoting self-care actions (eg, sleep, diet, and exercise habits) and characteristics of the child with cancer (eg, relapse status, time since diagnosis, prognosis, treatment intensity). RESULTS Compared with population norms, parents of children with cancer reported poorer physical and psychosocial QOL in all psychosocial domains (effect sizes range, -0.71 to -1.58) and in most physical health domains (effect sizes range, -0.08 to -0.63). Parent characteristics associated with better parental QOL included better eating, exercise and sleep habits, younger age, and higher income. Child characteristics associated with better parental QOL included better child health status (functional status IIR scores), lower treatment intensity, and longer time since diagnosis. CONCLUSION Parents of children with cancer report poorer QOL compared with population norms. Interventions directed at parents should be included as part of the treatment plan for a child with cancer. Modifiable variables associated with poorer parental QOL, such as sleep quality and diet and exercise habits, indicate those parents most likely to experience poor QOL and may be potential areas for intervention.

Quality of life during active treatment for pediatric acute lymphoblastic leukemia

The objectives of the study were to describe quality of life (QoL), identify predictors of worse QoL and examine QoL during different phases of active therapy for acute lymphoblastic leukemia (ALL). A multiinstitutional cross‐sectional study was performed in children with ALL. We included children at least 2 months from diagnosis who were receiving treatment in first remission. Parents described QoL using the PedsQL 4.0 Generic Core Scales and the PedsQL 3.0 Acute Cancer Module. The 206 children on treatment for ALL had overall [median 62.5, 95% confidence interval (CI) 34.8–94.4], physical (median 62.5, 95% CI 18.8–100.0) and psychosocial (median 65.4, 95% CI 38.3–94.2) summary scores that were one to two standard deviations lower than population norms. In high‐risk ALL, girls and older children had worse QoL. In standard‐risk ALL, those with lower household incomes and unmarried parents had worse QoL. QoL scores were generally constant across phases of ALL therapy. Children on therapy for ALL have lower QoL compared to healthy children. Age and gender predicted QoL in high‐risk ALL, whereas socioeconomics predicted QoL in standard‐risk ALL. Future efforts should focus on longitudinal studies that describe QoL over time within individual patients.

Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial

The Childrens Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (+/- 1.8%) and to MP was 79.0% (+/- 2.1%; P = .004 log rank), although overall survival was 91.9% (+/- 1.4%) and 91.2% (+/- 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m(2) per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m(2) (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at http://clinicaltrials.gov as NCT00002744.

Parents of children with cancer: Which factors explain differences in health-related quality of life

Research with parents of children with cancer has identified factors related to their adjustment and coping, but it is not fully understood why some parents do well and others do not. Guided by a stress process model, we examined the interrelationships among a comprehensive set of factors to identify the most important determinants of health‐related quality of life (HRQoL) in parents of children in active treatment for cancer. A cross‐sectional survey of 411 parents (80% response rate) of children receiving cancer treatment in Canada was conducted between November 2004 and February 2007. The following constructs were measured: background and context factors, child characteristics, family‐centered service delivery, caregiver strain, intrapsychic factors, coping/supportive factors and parental HRQoL. The model was evaluated using structural equation modeling. Analysis was stratified by time since diagnosis (i.e., <12 months and ≥12 months). For those within 12 months of their childs diagnosis, family‐centred service provision, caregiver strain, and self‐perception accounted for 58% of the variation in psychosocial health, whereas caregiver strain and social support explained 50% of the variation in physical health. For parents in the >12 month group, caregiving strain was the only factor with a direct relationship with parental psychosocial and physical health, accounting for 66% and 55% of the variance in these constructs, respectively. Our findings reinforce the need for health professionals to be particularly attuned to family caregivers in the early stages of treatment and identify potential areas for interventions to promote parental health.

Clinical and genetic analysis of unclassifiable inherited bone marrow failure syndromes.

OBJECTIVE. Unclassified inherited bone marrow failure syndromes are a heterogeneous group of genetic disorders that represent either new syndromes or atypical clinical courses of known inherited bone marrow failure syndromes. The relative prevalence of the unclassified inherited bone marrow failure syndromes and their characteristics and the clinical and economic challenges that they create have never been studied. METHODS. We analyzed cases of inherited bone marrow failure syndrome in the Canadian Inherited Marrow Failure Registry that were deemed unclassifiable at study entry. RESULTS. From October 2001 to March 2006, 39 of the 162 patients enrolled in the Canadian Inherited Marrow Failure Registry were registered as having unclassified inherited bone marrow failure syndromes. These patients presented at a significantly older age (median: 9 months) than the patients with classified inherited bone marrow failure syndrome (median: 1 month) and had substantial variation in the clinical presentations. The hematologic phenotype, however, was similar to the classified inherited bone marrow failure syndromes and included single- or multiple-lineage cytopenia, severe aplastic anemia, myelodysplasia, and malignancy. Grouping patients according to the affected blood cell lineage(s) and to the presence of associated physical malformations was not always sufficient to characterize a condition, because affected members from several families fit into different phenotypic groups. Compared with the classified inherited bone marrow failure syndromes, the patients with unclassified inherited bone marrow failure syndromes had 3.2 more specific diagnostic tests at 4.5 times higher cost per evaluated patient to attempt to categorize their syndrome. At last follow-up, only 20% of the unclassified inherited bone marrow failure syndromes were ultimately diagnosed with a specific syndrome on the basis of the development of new clinical findings or positive genetic tests. CONCLUSIONS. Unclassified inherited bone marrow failure syndromes are relatively common among the inherited bone marrow failure syndromes and present a major diagnostic and therapeutic dilemma.

Association Between Corticosteroids and Infection, Sepsis, and Infectious Death in Pediatric Acute Myeloid Leukemia (AML): Results From the Canadian Infections in AML Research Group

BACKGROUND Infection continues to be a major problem for children with acute myeloid leukemia (AML). Objectives were to identify factors associated with infection, sepsis, and infectious deaths in children with newly diagnosed AML. METHODS We conducted a retrospective, population-based cohort study that included children ≤ 18 years of age with de novo, non-M3 AML diagnosed between January 1995 and December 2004, treated at 15 Canadian centers. Patients were monitored for infection from initiation of AML treatment until recovery from the last cycle of chemotherapy, conditioning for hematopoietic stem cell transplantation, relapse, persistent disease, or death (whichever occurred first). Consistent trained research associates abstracted all information from each site. RESULTS 341 patients were included. Median age was 7.1 years (interquartile range [IQR], 2.0-13.5) and 29 (8.5%) had Down syndrome. In sum, 26 (7.6%) experienced death as a first event. There were 1277 courses of chemotherapy administered in which sterile site microbiologically documented infection occurred in 313 courses (24.5%). Sepsis and infectious death occurred in 97 (7.6%) and 16 (1.3%) courses, respectively. The median days of corticosteroid administration was 2 per course (IQR, 0-6). In multiple regression analysis, duration of corticosteroid exposure was significantly associated with more microbiologically documented sterile site infection, bacteremia, fungal infection, and sepsis. The only factor significantly associated with infectious death was days of corticosteroid exposure (odds ratio, 1.05; 95% confidence interval, 1.02-1.08; P = .001). CONCLUSIONS In pediatric AML, infection, sepsis, and infectious death were associated with duration of corticosteroid exposure. Corticosteroids should be avoided when possible for this population.

Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes

Background Phenotypic overlap among the inherited bone marrow failure syndromes (IBMFSs) frequently limits the ability to establish a diagnosis based solely on clinical features. >70 IBMFS genes have been identified, which often renders genetic testing prolonged and costly. Since correct diagnosis, treatment and cancer surveillance often depend on identifying the mutated gene, strategies that enable timely genotyping are essential. Methods To overcome these challenges, we developed a next-generation sequencing assay to analyse a panel of 72 known IBMFS genes. Cases fulfilling the clinical diagnostic criteria of an IBMFS but without identified causal genotypes were included. Results The assay was validated by detecting 52 variants previously found by Sanger sequencing. A total of 158 patients with unknown mutations were studied. Of 75 patients with known IBMFS categories (eg, Fanconi anaemia), 59% had causal mutations. Among 83 patients with unclassified IBMFSs, we found causal mutations and established the diagnosis in 18% of the patients. The assay detected mutant genes that had not previously been reported to be associated with the patient phenotypes. In other cases, the assay led to amendments of diagnoses. In 20% of genotype cases, the results indicated a cancer surveillance programme. Conclusions The novel assay is efficient, accurate and has a major impact on patient care.

Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations

Introduction Inherited bone marrow failure syndromes (IBMFSs) often have substantial phenotypic overlap, thus genotyping is often critical for establishing a diagnosis. Objectives and methods To determine the genetic characteristics and mutation profiles of IBMFSs, a comprehensive population-based study that prospectively enrols all typical and atypical cases without bias is required. The Canadian Inherited Marrow Failure Study is such a study, and was used to extract clinical and genetic information for patients enrolled up to May 2010. Results Among the 259 primary patients with IBMFS enrolled in the study, the most prevalent categories were Diamond–Blackfan anaemia (44 patients), Fanconi anaemia (39) and Shwachman–Diamond syndrome (35). The estimated incidence of the primary IBMFSs was 64.5 per 106 births, with Fanconi anaemia having the highest incidence (11.4 cases per 106 births). A large number of patients (70) had haematological and non-haematological features that did not fulfil the diagnostic criteria of any specific IBMFS category. Disease-causing mutations were identified in 53.5% of the 142 patients tested, and in 16 different genes. Ten novel mutations in SBDS, RPL5, FANCA, FANCG, MPL and G6PT were identified. The most common mutations were nonsense (31 alleles) and splice site (28). Genetic heterogeneity of most IBMFSs was evident; however, the most commonly mutated gene was SBDS, followed by FANCA and RPS19. Conclusion From this the largest published comprehensive cohort of IBMFSs, it can be concluded that recent advances have led to successful genotyping of about half of the patients. Establishing a genetic diagnosis is still challenging and there is a critical need to develop novel diagnostic tools.

Primary Antiphospholipid Syndrome with Moyamoya-Like Vascular Changes

We describe a young girl with antiphospholipid syndrome (APS) and moyamoya-like cerebrovascular changes which reversed after anticoagulation. Although there was a risk of hemorrhage from collateral vessels, we speculate that this treatment may have prevented progression of the vascular abnormalities, while resolution of the thrombus resulted in improved cerebrovascular circulation.

Predictors and outcomes of viridans group streptococcal infections in pediatric acute myeloid leukemia: from the Canadian infections in AML research group.

Background: Viridans group streptococci (VGS) cause significant morbidity in children treated for acute myeloid leukemia (AML). Our goals were to determine the occurrence and impact of these infections in children treated for AML and to understand the factors that increase the risk of VGS infections and viridans streptococcal shock syndrome (VSSS) in this population. Methods: We conducted a retrospective, population-based cohort study that included children ⩽18 years of age with de novo AML treated at 15 Canadian centers. We evaluated factors related to VGS infection and VSSS. Results: Among 341 children with AML, VGS occurred in 78 (22.9%) children over the entire course of therapy and 16 had recurrent episodes. VGS infection occurred in 97 of 1277 courses of chemotherapy (7.6%). VSSS occurred in 19.6% of these episodes and included 11 patients who required intensive care services with 2 VGS infections resulting in death. In multiple regression analysis, factors independently related to VGS included treatment on a Medical Research Council-based protocol (odds ratio (OR) 2.87, 95% confidence interval (CI) 1.53–5.39; P = 0.001), cytarabine dose per gram/m2 (OR 1.04, 95% CI 1.01–1.07; P = 0.002) and prolonged neutropenia (OR 1.58, 95% CI: 0.97–2.56; P = 0.06). None of the evaluated factors were predictive of VSSS. Conclusions: VGS infections occur in 7.6% of chemotherapy courses and remain an important cause of morbidity and even mortality in children being treated for AML. Interventions to reduce VGS need to be identified.