Acquired haemophilia A: A 15-year population-based review of incidence rate, patient demographics and treatment outcomes.

INTRODUCTION: Acquired haemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies against coagulation factor VIII (FVIII). Estimates of AHA incidence are largely based on registry data, which may be prone to referral bias. Population-based studies can enhance our understanding of the epidemiology, presentation and outcomes of AHA. METHODS: We conducted a retrospective, population-based cohort study of all AHA diagnosed and treated in Manitoba, Canada over a 15-year period. Using records from the sole provincial reference laboratory, we identified all patients with FVIII inhibitors who did not have congenital haemophilia.  Using a piloted case report form, patient data was ascertained from hospital and bleeding disorder clinic records. RESULTS: From 2006 to 2021, we identified 34 patients with AHA, corresponding to a population-based incidence rate of AHA of 1.78 cases per million per year. The median age at presentation was 76 years and most cases were idiopathic (79%). Almost all patients (97%) presented with bleeding, of which 58% were considered major bleeds and required haemostatic agents in 67%. Longstanding unexplained bleeding symptoms were commonly reported, suggesting delayed diagnosis. Immunosuppressive therapy (IST) was administered in 88% of patients. Remission was achieved in 79% of patients; median time to remission was 2.1 months. There were two deaths due to bleeding. No deaths due to IST were reported. CONCLUSION: The population-based incidence of AHA in Manitoba is 1.78 cases/million/year. Bleeding is common and can be life-threatening. AHA outcomes are encouraging with the use of haemostatic agents and IST. Serious treatment-associated morbidity and mortality is uncommon.

Skin Lesions as a Presenting Feature of Dimorphic T-Lymphoblastic Leukemia in an Adolescent Male.

Cutaneous involvement is rare in acute lymphoblastic leukemia/lymphoma, particularly within the T-cell lineage. Review of the literature for cutaneous involvement in T-cell lymphoblastic lymphoma/leukemia identifies mostly case reports, with the majority of cases involving adults. We describe an adolescent male presenting with cervical lymphadenopathy and skin lesions leading to a diagnosis of early T-cell precursor lymphoblastic leukemia. Unique to this case is the age of the patient, presence of a dimorphic blast population, and the skin lesions preceding other signs of disease by at least 1 month.

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.

Acute Myeloid Leukemia Presenting as a Posterior Fossa Tumor.

Extramedullary leukemia in pediatric acute myeloid leukemia can manifest as a myeloid sarcoma (MS), also known as granulocytic sarcoma or chloroma, in a variety of sites, or as leukemic blasts in the cerebrospinal fluid. Isolated MS of the central nervous system is rare. We report a case of acute myeloid leukemia with central nervous system-MS presenting as a posterior fossa mass mimicking a primary intracranial tumor.

Precursor B-Cell Acute Lymphoblastic Leukemia With MYC and BCL2 Rearrangements Presenting as Extensive Extranodal Disease in an Adolescent.

Combined rearrangements of MYC and BCL2 are rare in precursor B-cell acute lymphoblastic leukemia (B-ALL). A 14-year-old boy presented with swelling of the knee and face. Imaging revealed diffuse infiltration of lacrimal glands, parotid glands along with the extensive epidural disease. Morphology and immunophenotype of knee joint aspirate were consistent with precursor B-ALL. Fluorescent in situ hybridization identified rearrangements of MYC and BCL2 genes. The disease was refractory to intensive treatment. The patient died of progressive disease. Precursor B-ALL with combined MYC and BCL2 rearrangements is rare, characterized by an aggressive clinical course, and has an inadequate response to standard therapeutic approaches.

Clinical characterization and hematopoietic stem cell transplant outcomes for congenital sideroblastic anemia caused by a novel pathogenic variant in SLC25A38.

BACKGROUND: Congenital sideroblastic anemia (CSA) constitutes an uncommon category of inherited anemia often associated with pathologic iron accumulation. Pathogenic variants in several genes have been identified as causative for CSA. Autosomal recessive pathogenic variants in the mitochondrial glycine transporter SLC25A38 have been implicated in a subset of patients with CSA. PROCEDURE: We describe seven individuals of Canadian Cree descent with a known or inferred homozygous novel founder missense variant in SLC25A38 (c.560G>A, p.Arg187Gln). RESULTS: All individuals presented as young children (median age 6 months) with severe microcytic, hypochromic anemia associated with pretransfusion iron overload, requiring red cell transfusion support and iron chelation. Six individuals received pyridoxine supplementation; two demonstrating transient partial responses. Three individuals underwent allogeneic hematopoietic stem cell transplantation (HSCT). One individual with significant iron loading died in the posttransplant period due to complications of sepsis. The other two individuals remain transfusion-free following HSCT. CONCLUSIONS: Despite a common genetic etiology, phenotypic variability was noted in this cohort. A transient response to pyridoxine was noted in two individuals but should not be considered a long-term therapeutic strategy. HSCT was curative when performed before significant iron loading occurred. Early identification of CSA and timely HSCT can result in excellent long-term outcomes.

Epidural Spinal Mass as the Presenting Feature of B-Acute Lymphoblastic Leukemia in a Young Child.

An isolated epidural mass is a rare presentation of childhood B-acute lymphoblastic leukemia with an estimated incidence of 0.4%. Of the cases reported in the literature, the majority involve adults presenting with spinal cord compression and/or systemic evidence of disease. We describe a young child presenting with pain leading to a refusal to weight-bear secondary to a sacral epidural mass. A biopsy of the sacral lesion confirmed the diagnosis of B-acute lymphoblastic leukemia. Unique to this case is the young age of the child and the lack of spinal cord compression.

Laboratory diagnosis of inherited platelet function disorders.

Platelets respond to vessel wall injury by forming a primary hemostatic plug to arrest blood loss. Hemostatic plug formation is complex, and involves platelet adhesion to the subendothelium that results in platelet activation and ultimately, aggregation. If any of these processes are deficient, primary hemostasis is impaired. Inherited platelet function disorders (IPFDs) are a heterogeneous group of defects in these processes, with patients experiencing mainly mucocutaneous bleeding symptoms that can range from very mild to life threatening, depending on the specific disorder. Here, we review the approach to an initial patient assessment required to inform laboratory testing, and the frequently used clinical laboratory assays for diagnostic evaluation of IPFDs. Newer testing approaches that may improve laboratory diagnosis in the near future are described.

Geographical variation in the incidence of childhood leukaemia in Manitoba.

BACKGROUND: Identification of geographical areas and ecological factors associated with higher incidence of childhood leukaemias can direct further study for preventable factors and location of health services to manage such individuals. AIM: The aim of this study was to describe the geographical variation and the socio-demographic factors associated with childhood leukaemia in Manitoba. METHODS: Information on childhood leukaemia incidence between 1992 and 2008 was obtained from the Canadian Cancer Registry and the socio-demographic characteristics for the area of residence from the 2006 Canadian Census. Bayesian spatial Poisson mixed models were used to describe the geographical variation of childhood leukaemia and to determine the association between childhood leukaemia and socio-demographic factors. RESULTS: The south-eastern part of the province had a higher incidence of childhood leukaemia than other parts of the province. In the age and sex-adjusted Poisson regression models, areas with higher proportions of visible minorities and immigrant residents had higher childhood leukaemia incidence rate ratios. In the saturated Poisson regression model, the childhood leukaemia rates were higher in areas with higher proportions of immigrant residents. Unemployment rates were not a significant factor in leukaemia incidence. CONCLUSION: In Manitoba, areas with higher proportions of immigrants experience higher incidence rates of childhood leukaemia. We have identified geographical areas with higher incidence, which require further study and attention.

Cancer incidence, morbidity, and survival in Canadian first nation children: a Manitoba population-based study from the cancer in young people in Canada (CYP-C) registry.

BACKGROUND: Health disparities between Canadian First Nation (FN) people and the rest of the national population exist. No studies have specifically documented cancer-related health outcomes in Canadian FN children. The purpose of this study was to describe the incidence of pediatric malignancies in Manitoba FN children, and to compare morbidity patterns and survival between FN and non-FN children with cancer in the Canadian province of Manitoba. PROCEDURE: A retrospective, population-based review of all children (0-14.99 years) diagnosed with malignancy (2001-2008) in Manitoba, Canada was undertaken using the Cancer in Young People in Canada registry. FN children were compared to the non-FN population for markers of morbidity and survival. RESULTS: The average annual age-standardized incidence rate for all childhood cancers in FN children was 132 per 1,000,000 per year. 240 children were included in the morbidity and survival analyses (38 FN; 202 non-FN). No differences were found between FN and non-FN children in time from first presentation of symptoms to consultation with an oncology specialist or diagnosis, or number of hospital admissions / total days of admission for treatment complications. Overall survival was inferior for FN children in univariable analysis (P = 0.048) but not when risk group was included in a multivariable analysis (P = 0.15). No difference in event free survival or cumulative incidence of relapse was identified. CONCLUSION: The estimated incidence of childhood cancers in the Manitoba FN population is similar to provincial incidence rates. No differences in morbidity patterns or survival were found between Manitoba FN and non-FN children with cancer.

Mental Disorders Among Adolescents and Young Adults With Cancer: A Canadian Population-Based and Sibling Cohort Study.

PURPOSE: To compare the cumulative incidence of mental disorders among adolescents and young adults (AYAs) diagnosed with cancer with the general population and their unaffected siblings. METHODS: A retrospective, population-based, matched cohort design was used to investigate the impact of cancer diagnosis on mental disorders among individuals age 15-39 diagnosed between 1989 and 2019. Two cancer-free cohorts were identified: matched population-based and sibling cohorts. Outcomes included incidence of mood and anxiety disorders, substance use disorders, suicide outcomes, psychotic disorders, and any of the preceding four categories within 5 years of cancer diagnosis. Competing risk regression was used to estimate adjusted subhazard ratios (aSHR) and 95% CIs. RESULTS: Among 3,818 AYAs with cancer matched to the population-based cancer-free cohort, individuals with cancer were more likely to be diagnosed with incident mental disorders than those without cancer; the risk was highest immediately after a cancer diagnosis and decreased over time with aSHR [95% CI] for mood and anxiety disorders at 0-6 months (11.27 [95% CI, 6.69 to 18.97]), 6-12 months (2.35 [95% CI, 1.54 to 3.58]), and 12-24 months (2.06 [95% CI, 1.55 to 2.75]); for substance use disorders at 0-6 months (2.73 [95% CI, 1.90 to 3.92]); for psychotic disorders at 0-6 months (4.69 [95% CI, 2.07 to 10.65]); and for any mental disorder at 0-6 months (4.46 [95% CI, 3.41 to 5.85]), 6-12 months (1.56 [95% CI, 1.14 to 2.14]), and 12-24 months (1.7 [95% CI, 1.36 to 2.13]) postcancer diagnosis. In sibling comparison, cancer diagnosis was associated with a higher incidence of mood and anxiety and any mental disorder during first 6 months of cancer diagnosis. CONCLUSION: AYAs with cancer experience a greater incidence of mental disorders after cancer diagnosis relative to population-based and sibling cohorts without cancer, primarily within first 2 years, underscoring the need to address mental health concerns during this period.

Corrigendum: Second malignant neoplasms within 5 years from first primary diagnosis in pediatric oncology patients in Canada: a population-based retrospective cohort study.

[This corrects the article DOI: 10.3389/fonc.2024.1376652.].

Second malignant neoplasms within 5 years from first primary diagnosis in pediatric oncology patients in Canada: a population-based retrospective cohort study.

Introduction: From the advancement of treatment of pediatric cancer diagnosis, the five-year survival rate has increased significantly. However, the adverse consequence of improved survival rate is the second malignant neoplasm. Although previous studies provided information on the incidence and risk of SMN in long term survivors of childhood cancer, there is still scarce information known for short term (< 5 years) prognosis. This study aims to assess the incidence, characteristics, management, and outcome of children who develop SMN malignancies within 5 years of diagnosis of their initial cancer. Method: This is a retrospective cohort study of early Second Malignant Neoplasms (SMN) in pediatric oncology patients. The Cancer in Young People - Canada (CYP-C) national pediatric cancer registry was used and reviewed pediatric patients diagnosed with their first cancer from 2000-2015. Results: A total of 20,272 pediatric patients with a diagnosis of a first malignancy were analyzed. Of them, 0.7% were diagnosed with a SMN within the first 5 years following their first cancer diagnosis. Development of a SMN impacted survival, shown by an inferior survival rate in the SMN cohort (79.1%) after three years compared to that of the non-SMN cohort (89.7%). Several possible risk factors have been identified in the study including the use of epipodophyllotoxins, exposure to radiation, and hematopoietic stem cell 169 transplant. Discussion: This is the first national study assessing the incidence, 170 characteristics, risk factors and outcome of early SMN in Canadian children 171 from age 0-15 from 2000-2015.

Vertebral Body Reshaping after Fractures: An Important Index of Recovery in Glucocorticoid-Treated Children.

PURPOSE: In this 6-year study we identified factors associated with spontaneous vertebral body reshaping in glucocorticoid (GC)-treated children with leukemia, rheumatic disorders, and nephrotic syndrome. METHODS: Subjects were 79 children (mean age 7.4 years) who had vertebral fracture (VF) evaluation on lateral spine radiographs at least 1 year after VF detection. VF were graded using the modified Genant semiquantitative method and fracture burden for individuals was quantified using the spinal deformity index (SDI; sum of grades from T4 to L4). RESULTS: Sixty-five children (82.3%) underwent complete vertebral body reshaping (median time from VF detection to complete reshaping 1.3 years by Cox proportional hazard modeling). Of 237 VF, the majority (83.1%) ultimately reshaped, with 87.2% reshaping in the thoracic region vs 70.7% in the lumbar region (P = .004). Cox models showed that (1) every g/m2 increase in GC exposure in the first year after VF detection was associated with a 19% decline in the probability of reshaping; (2) each unit increase in the SDI at the time of VF detection was associated with a 19% decline in the probability of reshaping [hazard ratio (HR) = 0.81; 95% confidence interval (CI) = 0.71, 0.92; P = .001]; (3) each additional VF present at the time of VF detection reduced reshaping by 25% (HR = 0.75; 95% CI = 0.62, 0.90; P = .002); and (4) each higher grade of VF severity decreased reshaping by 65% (HR = 0.35; 95% CI = 0.21, 0.57; P < .001). CONCLUSION: After experiencing a VF, children with higher GC exposure, higher SDI, more severe fractures, or lumbar VF were at increased risk for persistent vertebral deformity.

What we have learned from inherited platelet disorders.

Identifying the molecular basis of inherited platelet disorders has contributed to our understanding of normal platelet physiology. Many of these conditions are rare, but close observation of clinical and laboratory phenotype, and subsequent identification of the abnormal protein and mutated gene, have provided us with unique opportunities to examine specific aspects of platelet biogenesis and function. Phenotype-genotype association studies are providing a detailed understanding of the structure and function of platelet membrane receptors, the biogenesis and release of platelet granules, and the assembly of the cytoskeleton. Genetic polymorphisms contributing to decreased or increased platelet adhesion and activation may translate into increased clinical risks for bleeding or thrombosis. More recently, genome wide association studies have identified new genes contributing to the variation in normal platelet function.

Reductions in Bone Mineral Density Are Apparent Early in Children With Prevalent Osteonecrosis Lesions Following Leukemia Therapy.

Osteonecrosis (ON) is a serious complication of childhood acute lymphoblastic leukemia. We determined the prevalence of osteonecrotic lesions in our patient population by a one-time multisite magnetic resonance imaging (MRI) more than 1 year following leukemia therapy. MRI findings were evaluated in relationship to clinical factors (including longitudinal changes in bone mineral density [BMD]). Eighty-six children enrolled in the Steroid Associated Osteoporosis in the Pediatric Population (STOPP) study were evaluated for ON at 3.1 ± 1.3 years following therapy. Thirty children had a total of 150 confirmed ON lesions (35%). Lumbar spine (LS) BMD Z-scores (mean ± SD) were low at diagnosis and similar between patients with and without ON (-1.09 ± 1.53 versus -1.27 ± 1.25, p = 0.549). LS BMD Z-scores declined from baseline to 12 months in children with ON (-0.31 ± 1.02) but not in those without (0.13 ± 0.82, p = 0.035); the hip BMD Z-scores from baseline to 24 months declined in both groups, but to a greater extent in those with ON (-1.77 ± 1.22) compared to those without (-1.03 ± 1.07, p = 0.045). At the time of the MRI, mean total hip and total body (TB) BMD Z-scores were lower in children with ON (hip -0.98 ± 0.95 versus -0.28 ± 1.06, p = 0.010; TB -1.36 ± 1.10 versus -0.48 ± 1.50, p = 0.018). Pain occurred in 11/30 (37%) with ON versus 20/56 (36%) without, p = 0.841. In multivariable models, older age at diagnosis (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.15-2.13; p = 0.004), and hip BMD Z-score at MRI (OR 2.23; 95% CI, 1.02-4.87; p = 0.046) were independently associated with ON. Overall, one-third of children demonstrated ON after leukemia therapy. Those with ON had greater reductions in spine and hip BMD Z-scores in the first 1 and 2 years of therapy, respectively. Older age and lower hip BMD Z-scores at MRI were significantly associated with prevalent, off-therapy ON. These data assist in identifying children at risk of ON. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

A pharmacogenomic investigation of the cardiac safety profile of ondansetron in children and pregnant women.

BACKGROUND: Ondansetron is a highly effective antiemetic for the treatment of nausea and vomiting. However, this medication has also been associated with QT prolongation. Pharmacogenomic information on therapeutic response to ondansetron exists, but no investigation has been performed on genetic factors that influence the cardiac safety of this medication. METHODS: Three patient groups receiving ondansetron were recruited and followed prospectively (pediatric post-surgical patients n = 101; pediatric oncology patients n = 98; pregnant women n = 62). Electrocardiograms were conducted at baseline, and 5- and 30-min post-ondansetron administration, to determine the effect of ondansetron treatment on QT interval. Pharmacogenomic associations were assessed via analyses of comprehensive CYP2D6 genotyping and genome-wide association study data. RESULTS: In the entire cohort, 62 patients (24.1%) met the criteria for prolonged QT, with 1.2% of the cohort exhibiting unsafe QT prolongation. The most significant shift from baseline occurred at five minutes post-ondansetron administration (P = 9.8 × 10-4). CYP2D6 activity score was not associated with prolonged QT. Genome-wide analyses identified novel associations with a missense variant in TLR3 (rs3775291; P = 2.00 × 10-7) and a variant linked to the expression of SLC36A1 (rs34124313; P = 1.97 × 10-7). CONCLUSIONS: This study has provided insight into the genomic basis of ondansetron-induced cardiac changes and has emphasized the importance of genes that have been implicated in serotonin-related traits. These biologically-relevant findings represent the first step towards understanding this adverse event with the overall goal to improve the safety of this commonly used antiemetic medication.

Platelet disorders in children: A diagnostic approach.

The investigation of children with suspected inherited platelet disorders is challenging. The causes of mucocutaneous bleeding are many, and specialized testing for platelet disorders can be difficult to access or interpret. An algorithm developed for the investigation of suspected platelet disorders provides a sequential approach to evaluating both platelet function abnormalities and thrombocytopenia. Investigation begins with a clinical evaluation and laboratory testing that is generally available, including platelet counting, peripheral blood cell morphology, and aggregometry. Based on results of initial investigations, the algorithm recommends specialized testing for specific diagnoses, including flow cytometry, immunofluorescence microscopy, electron microscopy, and mutational analysis.

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.

Mechanisms of oral bacteria-induced platelet activation.

The oral cavity is inhabited by over 500 different bacterial species that normally exist in ecological balance both with each other and with the host. When this equilibrium is disturbed, an overgrowth of individual organisms can occur, which, in turn, can lead to the onset of pathological processes, notably dental caries and periodontitis. Generally, bacteraemias occur more frequently in individuals with periodontal disease, and these bacteraemias have been implicated in the development of a range of systemic diseases, including atherothrombotic disorders. The mechanism underlying this relationship remains to be precisely defined, although studies have shown a link between bacteria of oral origin and platelet activation. Several orally derived species of bacteria interact with platelets, including those of the Streptococcus (Streptococcus sanguinis, Streptococcus mutans, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus gordonii, Streptococcus pneumoniae, Streptococcus mitis) and Staphylococcus (Staphylococcus epidermidis, Staphylococcus capitis) genera, as well as Pseudomonas aeruginosa and Porphyromonas gingivalis. In addition, some members of both the Streptococcus and the Staphylococcus genera, as well as Porphyromonas gingivalis, can activate platelets in vitro. The current review describes the heterogeneous mechanisms of platelet activation employed by individual bacterial species. The pathological and clinical implications of platelet activation by orally derived bacteria are discussed.