florio® HAEMO: A Longitudinal Survey of Patient Preference, Adherence and Wearable Functionality in Central Europe.

INTRODUCTION: florio® HAEMO is a hemophilia treatment monitoring application (app) offering activity tracking and wearable device connectivity. Its use might support everyday activities for people with hemophilia. The aim of this study was to evaluate user satisfaction, long-term usage and the impact on data entry when pairing a wearable with a hemophilia monitoring app. METHODS: This is a follow-up of a two-part user survey conducted in Central Europe. People with hemophilia and parents/caregivers of children with hemophilia using florio HAEMO and who completed part one were invited to complete a second online questionnaire at least 4 months later. RESULTS: Fifty participants (83.3%) who completed part one of the survey continued to use the florio HAEMO app and completed part two. Of 14 participants who chose to use the app with a wearable, more than half (57.1%) were aged between 13 and 25 years. Overall, the results demonstrated that florio HAEMO is very easy or rather easy to use, especially for individuals pairing the app with a wearable. Most people using a wearable indicated that florio HAEMO was very or rather important in bringing certainty to daily activities (85.7%). Notably, 14 of 36 (38.9%) non-wearable users indicated that they would prefer to pair the app with a wearable in the future. CONCLUSIONS: Adherence to the florio HAEMO app is maintained over an extended period of use. Pairing the app with a wearable might enable easier access to app features, increase data entry motivation and provide more certainty about daily activities for people with hemophilia.

Case Report: A Child With Hemophilia A Serves as Donor for Hematopoietic Stem Cell Transplantation to Cure His Brother's Severe Aplastic Anemia.

The first-line treatment of severe aplastic anemia is allogeneic hematopoietic stem cell transplantation with a matched sibling donor. However, co-morbidities of the identical donor can make donation difficult. We present a transplantation where in parallel with the patient's conditioning treatment, the preparation of the donor with severe hemophilia A required a special management with perioperative factor VIII substitution. Donation was successful without complications, and 18 months after transplantation, the patient and his donor are well without any long-term sequelae. To our knowledge, this is the first reported succesfull transplantation with hemophilic child serving as a bone marrow donor. The procedure did not mean a significant risk to donor health, so donors with hemophilia should not be excluded from donation.

First experience of a hemophilia monitoring platform: florio HAEMO.

Background: florio HAEMO is a new hemophilia treatment monitoring application consisting of a patient smartphone application (app) and a web-based dashboard for healthcare professionals, providing several novel features, including activity tracking, wearable connectivity, kids and caregiver mode, and real-time pharmacokinetic factor level estimation. Objectives: To assess intuitiveness, ease-of-use, and patient preference of florio HAEMO in Central Europe using a cross-sectional survey. Methods: This survey was conducted in six Central European countries between 9 December 2020 and 24 May 2021. The online questionnaire included 17 questions about overall satisfaction, ease-of-use, intuitiveness, and patient preference. Adults or children with hemophilia on regular prophylaxis and using the florio HAEMO app for a minimum of 1 week were invited to complete the online questionnaire by their treating physician. Results: Sixty-six participants took part in the survey. The median duration for all respondents using the florio HAEMO app was 3 to 4 weeks. Overall, 89.4% of users reported being very satisfied or rather satisfied after using florio HAEMO. Of the 23 respondents who had switched from another hemophilia app, 87.0% indicated that they strongly preferred or preferred using florio HAEMO. Most florio HAEMO users reported that the app was very easy or rather easy to use (97.0%) and intuitive (94.0%). florio HAEMO had a positive impact on daily living, with 78.8% of users reporting that the app was very important or rather important to them. Conclusions: This survey suggests that florio HAEMO is an easy-to-use and intuitive app to assist self-management of home prophylaxis.

Late mortality in survivors of childhood cancer in Hungary.

The Hungarian Pediatric Oncology Network provides centralized treatment and population-based registration for cases of childhood cancer since 1973. We collected and analized data on late mortality, secondary malignancies and cardiac diseases in survivors (> 5 years) of childhood cancer to evaluate long-term risks. We extracted all solid tumour cases (3,650 followed up for 5-39.3 years, diagnosis: 1973-2008) from the database of the Hungarian Childhood Cancer Registry and checked against the Population Registry. Among the 301 patients who died after 5 years (8.2%) the most common causes of death were progression of primary cancer (52.5%), secondary malignancies (16%) and cardiovascular diseases (8%). Late mortality rates (SMR, total: 35,006 pyrs) showed highly elevated risk of death (SMR: 10.7 95% CI 9-12.4) for the second 5 years of follow up and moderately elevated risk for 10-year survivors (SMR: 3.5 95% CI 3-4.1). Marked differences were detected in the pattern of causes of death between diagnostic groups of primary cancer; with highest risks beyond 10 years for CNS tumours, Hodgkin disease, osteosarcoma and advanced stage neuroblastoma. The longstanding mortality risk for 5-year survivors underlines the need for tailored long-term follow-up and monitoring of late consequences according to the context of different primary diseases of childhood cancer.

MicroRNA-181a as novel liquid biopsy marker of central nervous system involvement in pediatric acute lymphoblastic leukemia.

BACKGROUND: Refractory central nervous system (CNS) involvement is among the major causes of therapy failure in childhood acute leukemia. Applying contemporary diagnostic methods, CNS disease is often underdiagnosed. To explore more sensitive and less invasive CNS status indicators, we examined microRNA (miR) expressions and extracellular vesicle (EV) characteristics. METHODS: In an acute lymphoblastic leukemia (ALL) discovery cohort, 47 miRs were screened using Custom TaqMan Advanced Low-Density Array gene expression cards. As a validation step, a candidate miR family was further scrutinized with TaqMan Advanced miRNA Assays on serial cerebrospinal fluid (CSF), bone marrow (BM) and peripheral blood samples with different acute leukemia subtypes. Furthermore, small EV-rich fractions were isolated from CSF and the samples were processed for immunoelectron microscopy with anti-CD63 and anti-CD81 antibodies, simultaneously. RESULTS: Regarding the discovery study, principal component analysis identified the role of miR-181-family (miR-181a-5p, miR-181b-5p, miR-181c-5p) in clustering CNS-positive (CNS+) and CNS-negative (CNS‒) CSF samples. We were able to validate miR-181a expression differences: it was about 52 times higher in CSF samples of CNS+ ALL patients compared to CNS‒ cases (n = 8 vs. n = 10, ΔFC = 52.30, p = 1.5E-4), and CNS+ precursor B cell subgroup also had ninefold higher miR-181a levels in their BM (p = 0.04). The sensitivity of CSF miR-181a measurement in ALL highly exceeded those of conventional cytospin in the initial diagnosis of CNS leukemia (90% vs. 54.5%). Pellet resulting from ultracentrifugation of CNS+ CSF samples of ALL patients showed atypical CD63-/CD81- small EVs in high density by immunoelectron microscopy. CONCLUSIONS: After validating in extensive cohorts, quantification of miR-181a or a specific EV subtype might provide novel tools to monitor CNS disease course and further adjust CNS-directed therapy in pediatric ALL.

Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree.

Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms. In-depth chromosomal characterization of tumors revealed acquired copy number gains and uniparental disomy amplifying RUNX1, JAK2 and SH2B3 variants, highlighting the significance of co-operation between these disrupted pathways. One sibling, presenting with myelodysplasia at 14 years, had no evidence of clonal or subclonal JAK2 or SH2B3 variants, suggesting the latter were specifically associated with leukemic transformation in her sisters. Collectively, the clinical and molecular homogeneity across these three young siblings provides the first notable example of convergent AML evolution in a RUNX1 pedigree, with the recurrent acquisition of JAK-STAT pathway variants giving rise to high-risk AML, characterized by chemotherapy resistance and relapse.