Poor outcome after hematopoietic stem cell transplantation of patients with unclassified inherited bone marrow failure syndromes.

Classification of inherited bone marrow failure syndromes (IBMFSs) according to clinical and genetic diagnoses enables proper adjustment of treatment. Unfortunately, 30% of patients enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) with features suggesting hereditability could not be classified with a specific syndromic diagnosis. We analyzed the outcome of hematopoietic stem cell transplantation (HSCT) in unclassified IBMFSs (uIBMFSs) and the factors associated with outcome. Twenty-two patients with uIBMFSs and 70 patients with classified IBMFSs underwent HSCT. Five-year overall survival of uIBMFS patients after HSCT was inferior to that of patients with classified IBMFSs (56% vs 76.5%). The outcome of patients with uIBMFS who received cord blood was significantly lower than that of patients who received other stem cell sources (14.8% vs 90.9%). Engraftment failure was higher among patients with uIBMFS who received cord blood than those who received bone marrow. None of the following factors were significantly associated with poor survival: transfusion load, transplant indication, the intensity of conditioning regimen, human leukocyte antigen-identical sibling/alternative donor. We suggest that identifying the genetic diagnosis is essential to modulate the transplant procedure including conditioning agents and stem cell sources for better outcome and the standard cord blood transplantation (CBT) should be avoided in uIBMFS.

Patterns of joint damage in severe haemophilia A treated with prophylaxis.

OBJECTIVE: The primary objective of this study was to assess whether there are different patterns (classes) of joint health in young boys with severe haemophilia A (SHA) prescribed primary tailored prophylaxis. We also assessed whether age at first index joint bleed, blood group, FVIII gene abnormality variant, factor VIII trough level, first-year bleeding rate and adherence to the prescribed prophylaxis regimen significantly predicted joint damage trajectory, and thus class membership. METHODS: Using data collected prospectively as part of the Canadian Hemophilia Primary Prophylaxis Study (CHPS), we implemented a latent class growth mixture model technique to determine how many joint damage classes existed within the cohort. We used a multinomial logistic regression to predict the odds of class membership based on the above predictors. We fitted a survival model to assess whether there were differences in the rate of dose escalation across the groups. RESULTS: We identified three distinct classes of trajectory: persistently low, moderately increasing and rapidly increasing joint scores. By multinomial regression, we found that only age at first index joint bleed predicted rapidly increasing joint scores. The rapidly increasing joint score class group moved through dose escalation significantly faster than the other two groups. CONCLUSIONS: Using tailored prophylaxis, boys with SHA follow one of three joint health trajectories. By using knowledge of disease trajectories, clinicians may be able to adjust treatment according to a subject's predicted long-term joint health and institute cost-effective programmes of prophylaxis targeted at the individual subject level.

Androgen therapy in inherited bone marrow failure syndromes: analysis from the Canadian Inherited Marrow Failure Registry.

Progressive cytopenia is a serious complication among paediatric patients with inherited bone marrow failure syndromes (IBMFS). Androgens have been used to improve blood counts in different bone marrow failure conditions. Little is known about efficacy and toxicity with new androgens (i.e., danazol) in different types of IBMFS. We identified 29 patients from the Canadian Inherited Marrow Failure Registry, who received oxymetholone or danazol. Sixteen (55%) had haematological response including patients with unclassified IBMFS (45%). Danazol showed a better toxicity profile and similar efficacy compared to oxymetholone. Androgens are an effective and safe option to ameliorate bone marrow failure in IBMFS.

An international study of trainee-trained transitions: Introducing the transition-to-trained-doctor (T3D) model.

Background: Throughout their careers, doctors and other healthcare professionals experience numerous transitions. When supporting transitions, opportunities for development and learning should be maximized, while stressors having negative impacts on well-being should be minimized. Building on our international data, this study aimed to develop a conceptual model of the trainee-trained transition (i.e. the significant transitions experienced by doctors as they complete postgraduate training moving from trainee/resident status to medical specialist roles).Methods: Employing Multiple and Multidimensional Transitions (MMT) theory and current conceptualizations of clinical context, this study undertook secondary analysis of 55 interviews with doctors from three countries (Netherlands, Cananda and the UK) undergoing trainee-trained transitions.Results: Through this analysis, the Transition-To-Trained-Doctor (T3D) conceptual model has been developed. This model takes into consideration the multiple contexts and multiple domains in which transitions take place.Discussion: This model is significant in that it has several uses and is applicable across countries: to remind doctors, managers and medical educators of the complexity of transitions; to frame and facilitate supportive conversations; and as a basis to teach about transitions.

Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency.

IKBKB immune deficiency is a rare but life-threatening primary immunodeficiency disorder, involving activation defects in adaptive and innate immunity. We present sixteen cases of a homozygous IKBKB mutation (c.1292dupG) in infants characterized by early-onset bacterial, viral, fungal and Mycobacterial infections. In most cases, T- and B-cells were quantitatively normal, but phenotypically naïve, with severe hypogammaglobulinemia. T-cell receptor excision circles were normal, meaning newborn screening by TREC analysis would miss IKBKB cases. Although IKBKB immune deficiency does not meet traditional laboratory based definitions for SCID, this combined immune deficiency appears to be at least as profound. Urgent HSCT, performed in eight patients, remains the only known curative therapy, although only three patients are survivors. Ongoing infections after transplant remain a concern, and may be due to combinations of poor social determinants of health, secondary graft failure, and failure of HSCT to replace non-hematopoietic cells important in immune function and dependent upon IKK/NF-κB pathways.

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.

The impact of category, cytopathology and cytogenetics on development and progression of clonal and malignant myeloid transformation in inherited bone marrow failure syndromes.

Inherited bone marrow failure syndromes are a group of rare, heterogeneous genetic disorders with a risk of clonal and malignant myeloid transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome and acute myeloid leukemia. The clinical characteristics, risk classification, prognostic factors and outcome of clonal and malignant myeloid transformation associated with inherited bone marrow failure syndromes are largely unknown. The aims of this study were to determine the impact of category, cytopathology and cytogenetics, the three components of the "Category Cytology Cytogenetics" classification of pediatric myelodysplastic syndrome, on the outcome of clonal and malignant myeloid transformation associated with inherited bone marrow failure. We used data from the Canadian Inherited Marrow Failure Registry. Among 327 patients with inherited bone marrow failure syndrome enrolled in the registry, the estimated risk of clonal and malignant myeloid transformation by the age of 18 years was 37%. The risk of clonal and malignant myeloid transformation varied according to the type of inherited bone marrow failure syndrome but was highest in Fanconi anemia. The development of clonal and malignant myeloid transformation significantly affected overall survival. Mortality varied based on cytopathological group. The largest group of patients had refractory cytopenia. Clonal marrow cytogenetic abnormalities were identified in 87% of patients with clonal and malignant myeloid transformation, and different cytogenetic groups had different impacts on disease progression. We conclude that category, cytopathology and cytogenetics in cases of clonal and malignant myeloid transformation associated with inherited bone marrow failure syndromes have an important impact on outcome and that the classification of such cases should incorporate these factors.

Is the Give Youth a Voice questionnaire an appropriate measure of teen-centred care in paediatric oncology: a Rasch measurement theory analysis.

BACKGROUND: Adolescents have their own views about the cancer care they receive and how they feel they are treated, but their opinions are rarely solicited. OBJECTIVE: To determine whether the 56-item Give Youth a Voice (GYV-56), its subscales and its 20-item short-form, are clinically meaningful and psychometrically sound instruments that can be used to measure teen-centred care (TCC) in paediatric oncology. DESIGN: Qualitative interviews and a questionnaire survey. SETTING AND PARTICIPANTS: Qualitative interviews with 38 childhood cancer survivors. GYV-56 data collected from 200 paediatric cancer patients and survivors. MAIN OUTCOME MEASURE: The GYV-56, which measures the following four aspects of service delivery: Supportive and respectful relationships; Information sharing and communication; Supporting independence; and Teen-centred services. RESULTS: Qualitative data provided broad support for the TCC conceptual framework and GYV-56 items. After post-hoc reduction of the response options from 7 to 3 (to correct for disordered thresholds), fit to the Rasch model was good, most items showed acceptable fit residuals and chi-square P-values, scale reliability were supported and item locations defined a continuum for TCC that was well-targeted to the sample. By calibrating the items for each subscale and the short-form to the full scale, the scores obtained on each measure are directly comparable. CONCLUSION: Our study found initial support for use of the GYV with a reduced response option format for examining TCC in the adolescent oncology patients. in this paediatric population. Further research using the GYV is needed to elaborate upon our findings.

Empowering patients with sickle cell anemia and their families through innovative educational methods.

Sickle cell disease (SCD) is a group of inherited blood disorders caused by a mutation in the beta subunit of hemoglobin (HbS). SCD will hereafter be referred to as sickle cell anemia (SCA) as this is the term our patients and their families prefer. There are approximately 5000 Canadians living with SCA including children. Pediatric SCA patient education can: improve knowledge, decrease hospitalization, improve medication possession ratio, lead to better SCA-related functioning, and lower pain impact. Innovative educational materials were developed to improve knowledge and self-efficacy regarding the illness management of patients and parents/guardians. Patients (n = 5; aged 8-18) with SCA and parents (n = 5) of patients (aged 0-18) were recruited via flyers sent directly to patients and distributed through partner patient organization Sickle Cell Awareness Network of Saskatchewan. Patient and parent focus groups were held separately over Zoom to receive feedback for the video. An additional interview was held for a participant that required a translation of the video. Audio recordings were transcribed using Zoom and Otter.ai. The coding of transcripts was facilitated by NVivo (QSR International Pty Ltd, 2022, release 1.6.2). The thematic analysis centered around SCA management concepts relevant to the research aims. Important themes that emerged included 'Age Appropriateness', 'Empowerment', 'Knowledge Gaps', 'Linguistic Accessibility', 'Medication Adherence', 'Strength in Community', and 'Transition to Adult Care'. The video was well received, and "brought peace of mind". Patient feedback was incorporated into the final version of the educational materials.

Keeping Hope Possible Toolkit: The Development and Evaluation of a Psychosocial Intervention for Parents of Infants, Children and Adolescents with Life Limiting and Life Threatening Illnesses.

BACKGROUND: Globally, many infants and children are diagnosed with illnesses that impose limitations on their well-being and life course trajectory. Children's care becomes the central focus of family life. Inadequate support for parents is detrimental to their well-being and management of their child's care and support needs. METHODS: The second phase of this evaluation study followed a quasi-experimental crossover design to test a theory-based psychosocial intervention, the Keeping Hope Possible Toolkit. Fifty-nine participants were randomly assigned to one of two sequence groups, with measures of hope, feelings of control, distress, and uncertainty completed pre- and post-intervention, and at a three-month follow-up. Qualitative interviews sought to assess participant experiences with the intervention, along with acceptability and feasibility. RESULTS: Significant influence on parental distress was found, and the qualitative findings reveal benefits of the intervention for parental wellbeing. The intervention effectively offered practical and emotional support to diverse family caregivers. CONCLUSIONS: The evidence-informed KHP intervention can be used by healthcare providers to intervene with family caregivers to support their dynamic emotions including hope, need to live in the moment and remember self, and social preferences. In doing so, parents' critical caregiving activities can be sustained and their child's health and wellbeing optimized.

Magnetic resonance imaging in boys with severe hemophilia A: Serial and end-of-study findings from the Canadian Hemophilia Primary Prophylaxis Study.

BACKGROUND: This study examined the structural outcomes for joints of boys with severe hemophilia A receiving frequency/dose-escalated primary prophylaxis using magnetic resonance imaging (MRI), and the importance of interval MRI changes. METHODS: Forty-six subjects (27 with interval studies) were evaluated by radiographs (X-rays) and mid- and end-of-study MRIs (using the International Prophylaxis Study Group scale), as part of the Canadian Hemophilia Prophylaxis Study. The primary outcome was the presence of MRI osteochondral findings. RESULTS: The median (range) time on study at the end-of-study MRI examination was 9.6 (4.8-16.0) years, during which 18 of 46 subjects (39%) had osteochondral changes in at least one joint. An interval change in MRI score of at least 1 point was observed in 44% of joints (43 ankles, 21 elbows, 4 knees); at least one joint showed this change in all 27 subjects. Self-reported interval hemarthrosis was associated with a higher likelihood of interval osteochondral change (odds ratio [OR], 1.49; 95% confidence interval [CI] = 1.08-2.06). Presence of synovial hypertrophy or hemosiderin on interval MRIs was associated with an OR of 4.71 (95% CI, 1.92-11.57) and 5.25 (95% CI, 2.05-13.40) of later osteochondral changes on MRI. DISCUSSION: MRI changes were seen in 39% of subjects. Interval index joint bleeding was associated with an increased risk of later MRI changes, and earlier soft-tissue changes were associated with subsequent osteochondral changes.

Hemophilia prophylaxis adherence and bleeding using a tailored, frequency-escalated approach: The Canadian Hemophilia Primary Prophylaxis Study.

BACKGROUND: Standard of care for persons with severe hemophilia A includes regular replacement of factor VIII (FVIII). Prophylaxis regimens using standard half-life (SHL) FVIII concentrates, while effective, are costly and require frequent intravenous infusions. AIM: This study evaluated the adherence of 56 boys with severe hemophilia A to tailored, frequency-escalated prophylaxis with an SHL recombinant FVIII concentrate. METHODS: We reviewed the factor infusion and bleeding logs of study subjects. Adherence to the prescribed regimen was calculated on a weekly basis, and bleeding rates were determined from self/proxy-reported bleeding logs. The primary outcome was adherence to the prescribed prophylaxis regimen. RESULTS: The median (range of values [ROV]) weekly adherence to prophylaxis was 85.7% (37.4%-99.8%). The median (ROV) adherent weeks on steps 1 (weekly), 2 (twice weekly), and 3 (alternate-day) were 92.9% (50%-100%), 80.3 (32%-96%), and 72.6% (14%-98%); relative to step 1, subjects were less likely to be adherent on steps 2 and 3 (P < 0.00). On step 1, our cohort had higher adherence than previously reported rates. The median (ROV) adherence to the breakthrough bleeding protocol was 47.1% (0%-100%). At any given time, bleeding risk was reduced by 15% for each 10% increase in adherence during the preceding 12 weeks (hazard ratio, 0.85; 95% confidence interval, 0.81-0.90). CONCLUSION: This cohort had high rates of adherence to the prescribed prophylaxis regimen. Initiating prophylaxis with once-weekly infusions facilitated adherence to the prophylaxis regimen in this cohort of boys with severe hemophilia A started on primary prophylaxis at a very young age.

Canadian Pediatric Neuro-Oncology Standards of Practice.

Primary CNS tumors are the leading cause of cancer-related death in pediatrics. It is essential to understand treatment trends to interpret national survival data. In Canada, children with CNS tumors are treated at one of 16 tertiary care centers. We surveyed pediatric neuro-oncologists to create a national standard of practice to be used in the absence of a clinical trial for seven of the most prevalent brain tumors in children. This allowed description of practice across the country, along with a consensus. This had a multitude of benefits, including understanding practice patterns, allowing for a basis to compare in future research and informing Health Canada of the current management of patients. This also allows all children in Canada to receive equivalent care, regardless of location.

Reanalysing genomic data by normalized coverage values uncovers CNVs in bone marrow failure gene panels.

Inherited bone marrow failure syndromes (IBMFSs) are genetically heterogeneous disorders with cytopenia. Many IBMFSs also feature physical malformations and an increased risk of cancer. Point mutations can be identified in about half of patients. Copy number variation (CNVs) have been reported; however, the frequency and spectrum of CNVs are unknown. Unfortunately, current genome-wide methods have major limitations since they may miss small CNVs or may have low sensitivity due to low read depths. Herein, we aimed to determine whether reanalysis of NGS panel data by normalized coverage value could identify CNVs and characterize them. To address this aim, DNA from IBMFS patients was analyzed by a NGS panel assay of known IBMFS genes. After analysis for point mutations, heterozygous and homozygous CNVs were searched by normalized read coverage ratios and specific thresholds. Of the 258 tested patients, 91 were found to have pathogenic point variants. NGS sample data from 165 patients without pathogenic point mutations were re-analyzed for CNVs; 10 patients were found to have deletions. Diamond Blackfan anemia genes most commonly exhibited heterozygous deletions, and included RPS19, RPL11, and RPL5. A diagnosis of GATA2-related disorder was made in a patient with myelodysplastic syndrome who was found to have a heterozygous GATA2 deletion. Importantly, homozygous FANCA deletion were detected in a patient who could not be previously assigned a specific syndromic diagnosis. Lastly, we identified compound heterozygousity for deletions and pathogenic point variants in RBM8A and PARN genes. All deletions were validated by orthogonal methods. We conclude that careful analysis of normalized coverage values can detect CNVs in NGS panels and should be considered as a standard practice prior to do further investigations.

Application of a Simulation Model to Estimate Treatment Error and Clinical Risk Derived from Point-of-Care International Normalized Ratio Device Analytic Performance.

BACKGROUND: In 2016, the Food and Drug Administration (FDA) proposed to enhance performance expectations for point-of-care testing (POCT) international normalized ratio (INR) devices relative to International Organization for Standardization (ISO) 17593:2007. The objective of the study was to estimate the frequency of warfarin dosing errors associated with a central laboratory INR method, a POCT INR method, and the proposed FDA performance goals. METHODS: A data set of INR results (n = 51912) from adult patients with INR ≤4 was used to assess the influence of adding assay imprecision and bias on warfarin dose decisions. The frequency of error in warfarin dose and size of error (≥1 or ≥2 dose categories) was compared using published assay specifications for the Instrumentation Laboratory ACL TOP® and the Roche Diagnostics CoaguChek® XS relative to the proposed FDA guidelines. RESULTS: The frequency of warfarin dose misclassification was largely influenced by bias and was not sensitive to assay imprecision. The central laboratory and POCT INR methods met the FDA performance specifications, had equal rates of ≥2 warfarin dose category error, and had statistically different rates of ≥1 warfarin dose category error in large samples (n >250). CONCLUSIONS: Simulation models are useful tools for evaluating POCT INR assay performance criteria required to achieve the proposed FDA guidelines. This simulation depicted how the Roche Diagnostics CoaguChek XS instrument meets the guideline.

The clinical impact of copy number variants in inherited bone marrow failure syndromes.

Inherited bone marrow failure syndromes (IBMFSs) comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants (CNVs) were reported in some IBMFSs. It is unclear what impact CNVs play in patients evaluated for a suspected diagnosis of IBMFS. Clinical and genetic data of 323 patients from the Canadian Inherited Marrow Failure Registry from 2001 to 2014, who had a documented genetic work-up, were analyzed. Cases with pathogenic CNVs (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of CNVs. Pathogenic nucleotide-level mutations were found in 157 of 303 tested patients (51.8%). Genome-wide CNV analysis by single nucleotide polymorphism arrays or comparative genomic hybridization arrays revealed pathogenic CNVs in 11 of 67 patients tested (16.4%). In four of these patients, identification of CNV was crucial for establishing the correct diagnosis as their clinical presentation was ambiguous. Eight additional patients were identified to harbor pathogenic CNVs by other methods. Of the 19 patients with pathogenic CNVs, four had compound-heterozygosity of a CNV with a nucleotide-level mutation. Pathogenic CNVs were associated with more extensive non-hematological organ system involvement (p=0.0006), developmental delay (p=0.006) and short stature (p=0.04) compared to nucleotide-level mutations. In conclusion, a significant proportion of patients with IBMFSs harbor pathogenic CNVs which were associated with a more extensive non-hematological phenotype in this cohort. Patients with a phenotype suggestive of IBMFSs but without identification of pathogenic nucleotide-level mutations should undergo specific testing for CNVs.

The happy docs study: a Canadian Association of Internes and Residents well-being survey examining resident physician health and satisfaction within and outside of residency training in Canada.

BACKGROUND: Few Canadian studies have examined stress in residency and none have included a large sample of resident physicians. Previous studies have also not examined well-being resources nor found significant concerns with perceived stress levels in residency. The goal of "The Happy Docs Study" was to increase knowledge of current stressors affecting the health of residents and to gather information regarding the well-being resources available to them. FINDINGS: A questionnaire was distributed to all residents attending all medical schools in Canada outside of Quebec through the Canadian Association of Internes and Residents (CAIR) during the 2004-2005 academic years.In total 1999 resident physicians responded to the survey (35%, N = 5784 residents). One third of residents reported their life as "quite a bit" to "extremely" stressful (33%, N = 656). Time pressure was the most significant factor associated with stress (49%, N = 978). Intimidation and harassment was experienced by more than half of all residents (52%, N = 1050) with training status (30%, N = 599) and gender (18%, N = 364) being the main perceived sources. Eighteen percent of residents (N = 356) reported their mental health as either "fair" or "poor". The top two resources that residents wished to have available were career counseling (39%, N = 777) and financial counseling (37%, N = 741). CONCLUSION: Although many Canadian resident physicians have a positive outlook on their well-being, residents experience significant stressors during their training and a significant portion are at risk for emotional and mental health problems. This study can serve as a basis for future research, advocacy and resource application for overall improvements to well-being during residency.