• Duplication of referral, a tsunami of paper: how much does it cost the Irish health services?

      Walsh, Nicola; Malone, Lisa; Lynch, Sally Ann (2022-01-10)
      Background: Prolonged waiting lists increase costs as medical problems may become more expensive to fix. There are also hidden financial costs. Irish Clinical Genetic services have long out-patient waiting times. We noticed duplicate referrals (patients on the waiting list) being re-referred because the patient still had not been seen. These re-referrals waste consultant and administrative time, pose a clinical risk by distracting clinician time, and are costly to our health service. Methods: We prospectively collected duplicate referral data over a 3-month period (1 October 2020-31 January 2021) in order to estimate costs. We costed (1) referring consultant and administrative time; (2) stationary, postage, and storage cost; and (3) receiving consultant and administrative time processing these referrals. Results: We noted 82/986 (8%) referrals to our service over the trial period were duplicate. The mean length of time between first and duplicate referral was 306 days. In 35/82 (42.68%), a duplicate referral had already been received (e.g. 3rd or more referral for same patient). In total, we received 132 re-referral letters for 82 patients. Duplicate referrals changed triage outcome in 7/82 (8.54%) cases. Conclusion: National Treatment Purchase Fund data suggests that 271,560 patients are waiting > 12 months for both in- and out-patient public appointments on 1 January 2021. Assuming duplicate referrals are occurring across the Irish health system with equal frequency after 12 months of waiting (8% of total appointments), then we estimate a conservative cost of 757,392 € per quarter to the health service and an annual cost to the HSE of 3,029,568 €.
    • COVID-19 related occupational stress in teachers in Ireland.

      Minihan, Elisha; Adamis, Dimitrios; Dunleavy, Michele; Martin, Angela; Gavin, Blanaid; mcnicholas, fiona (2021-12-21)
      Moderate or high levels of personal burnout was reported by 82% (n = 202) of the sample and 79% (n = 193) reported work burnout. COVID-19 related adverse effects were reported by teachers on physical (43%) and mental health (67%), with deterioration in eating (34%), sleeping (70%) and alcohol use (33%). 100 (42%) participants felt unable to keep safe at work. Low levels of job satisfaction were present (66%), negatively correlating with burnout scores (rs=-0.405, p<.01). 142 (58%) teachers had seriously considered changing jobs in the previous 6-12 months.
    • Exploring carer burden amongst those caring for a child or adolescent with an eating disorder during COVID-19.

      Maunder, Kristen; mcnicholas, fiona (2021-10-03)
      Background: Carer burden amongst carers of youth with an eating disorder is substantial and if not addressed can lead to negative outcomes for the patient, carer and family. The Coronavirus Disease 2019 (COVID-19) pandemic has made caring for youth with an ED even more onerous and preliminary research is beginning to emerge demonstrating the profound negative impact the pandemic is having upon individuals with EDs and their carers. MAIN: In this review, we briefly summarize what is known about carer burden in families where a young person has an ED, consider the additional impact consequent to COVID-19 and highlight the need for interventions aimed at alleviating this. Pre-COVID-19 research identifies high levels of psychological and physical strain amongst those caring for a child with an ED. Themes are beginning to emerge as to why COVID-19 may further exacerbate carer burden: (1) reduced access to ED services; (2) increased physical vulnerability and exacerbation of psychiatric co-morbidity amongst youth with EDs; (3) increased practical demands placed on carers; and (4) social isolation and decreased social support. Conclusion: The COVID-19 pandemic poses a specific threat to the mental health of youth with EDs and their carers. Given the salient role families play in caring for youth with an ED, attending to carer burden is imperative. Supporting carers through all phases of their child's ED journey by offering adaptive and flexible supportive services which accommodate time constraints, geographic barriers and possible COVID-19 spread is essential.
    • One and done? Outcomes from 3961 patients managed via a virtual fracture clinic pathway for paediatric fractures.

      Kennedy, Jim; Blackburn, Carol; Barrett, Michael; O'Toole, Patrick; Moore, David (2021-06-01)
      Purpose: The aim of this paper is to describe our experience with a virtual fracture management pathway in the setting of a paediatric trauma service. Methods: All patients referred to the virtual fracture clinic service from the Paediatric Emergency Department (PED) were prospectively collected. Outcome data of interest (patients discharged, referred for urgent operative treatment, referred back to emergency department for further evaluation, referred for face-to-face clinical assessment and all patients who re-presented on an unplanned basis for further management of the index injury) were compiled and collated. Cost analysis was performed using established costing for a virtual fracture clinic within the Irish Healthcare System. Results: There were a total of 3961 patients referred to the virtual fracture clinic from the PED. Of these, 70% (n = 2776) were discharged. In all, 26% (n = 1033) were referred to a face-to-face appointment. Of discharged patients, 7.5% (n = 207) required an unplanned face-to-face evaluation. A total of 0.1% (n = 3) subsequently required operative treatment relating to their index injury. Implementation of the virtual fracture clinic model generated calculated savings of €254 120. Conclusion: This prospective evaluation has demonstrated that a virtual fracture clinic pathway for minor paediatric trauma is safe, effective and brings significant cost savings.
    • Smartphone Usage Among Doctors in the Clinical Setting in Two Culturally Distinct Countries: Cross-sectional Comparative Study.

      Nair, Anjali Ajay; Afroz, Samreen; Ahmed, Bushra Urooj; Ahmed, Uzma Urooj; Foo, Chi Chung; Zaidan, Hind; Corbally, Martin (2021-05-10)
      Background: Smartphones and mobile applications have seen a surge in popularity in recent years, a pattern that has also been reflected in the health care system. Despite increased reliance among clinicians however, limited research has been conducted on the uptake and impact of smartphone usage in medical practice, especially outside the Western world. Objective: This study aimed to identify the usage of smartphones and medical apps by doctors in the clinical setting in 2 culturally distinct countries: King Hamad University Hospital (KHUH), Bahrain and Queen Mary Hospital (QMH), Hong Kong. Methods: A cross-sectional, comparative study was conducted where doctors in both hospitals were asked to take part in a 15-item online survey. The questions were categorized into the following groups: demographics of the study population, ownership and main use of smartphones, number and names of medical apps currently owned, rating usage of smartphones for medical purposes, time spent on a smartphone related to clinical use, clinical reliance on smartphones, and views on further integration of smartphones. The results were then tabulated and analyzed using SPSS Statistics 25 for Mac (IBM Corp Inc, Armonk, NY). Results: A total of 200 doctors were surveyed, with a total of 99.0% (99/100) of the doctors owning a smartphone in both KHUH and QMH; 58% (57/99) and 55% (54/99) of the doctors from KHUH and QMH, respectively, identified communication as their main use of smartphones in the clinical setting (P=.004). Doctors from KHUH were likely to spend more time on medical apps than doctors from QMH (P=.002). According to the overall results of both hospitals, 48% (32/67) of the junior doctors claimed high reliance on smartphones, whereas only 32.3% (41/127) of the senior doctors said the same (P=.03). Of doctors in KHUH and QMH, 78.0% (78/100) and 69.0% (69/100), respectively, either strongly agreed or agreed that smartphones need to be integrated into the clinical setting. In terms of preferences for future apps, 48% (48/100) and 56% (56/100) of the doctors in KHUH and QMH, respectively, agreed that more medical applications need to be created in order to support smartphone use in the clinical setting. Conclusions: These results suggest a substantial acceptance of smartphones by doctors in the clinical setting. It also elicits the need to establish policies to officially integrate smartphone technology into health care in accordance with ethical guidelines. More emphasis should be placed on creating medical applications that aid health care professionals in attaining their information from accurate sources and also regulate a system to monitor the usage of mobile devices within hospitals to prevent a breach of patient privacy and confidentiality.
    • Medical education and training within congenital cardiology: current global status and future directions in a post COVID-19 world.

      McMahon, Colin J; Tretter, Justin T; Redington, Andrew N; Bu'Lock, Frances; Zühlke, Liesl; Heying, Ruth; Mattos, Sandra; Krishna Kumar, R; Jacobs, Jeffrey P; Windram, Jonathan D (2021-04-12)
      Despite enormous strides in our field with respect to patient care, there has been surprisingly limited dialogue on how to train and educate the next generation of congenital cardiologists. This paper reviews the current status of training and evolving developments in medical education pertinent to congenital cardiology. The adoption of competency-based medical education has been lauded as a robust framework for contemporary medical education over the last two decades. However, inconsistencies in frameworks across different jurisdictions remain, and bridging gaps between competency frameworks and clinical practice has proved challenging. Entrustable professional activities have been proposed as a solution, but integration of such activities into busy clinical cardiology practices will present its own challenges. Consequently, this pivot towards a more structured approach to medical education necessitates the widespread availability of appropriately trained medical educationalists, a development that will better inform curriculum development, instructional design, and assessment. Differentiation between superficial and deep learning, the vital role of rich formative feedback and coaching, should guide our trainees to become self-regulated learners, capable of critical reasoning yet retaining an awareness of uncertainty and ambiguity. Furthermore, disruptive innovations such as "technology enhanced learning" may be leveraged to improve education, especially for trainees from low- and middle-income countries. Each of these initiatives will require resources, widespread advocacy and raised awareness, and publication of supporting data, and so it is especially gratifying that Cardiology in the Young has fostered a progressive approach, agreeing to publish one or two articles in each journal issue in this domain.
    • Recombinant factor VIII Fc for the treatment of haemophilia A.

      Hermans, Cedric; Mancuso, Maria Elisa; Nolan, Beatrice; Pasi, K John (2021-03-31)
      Prophylaxis with factor VIII (FVIII) is the current therapeutic approach for people with haemophilia A. However, standard half-life (SHL) FVIII products must be injected frequently, imposing a substantial burden on the individual and making it difficult to tailor therapy according to patient need and lifestyle, which could impact adherence. Recombinant FVIII Fc fusion protein (rFVIIIFc; Elocta® , Sobi; Eloctate® , Sanofi) is a recombinant fusion protein that undergoes slower clearance from the body than SHL FVIII products. This pharmacokinetic property of rFVIIIFc allows prophylactic administration every 3-5 days, or once weekly in selected patients, with doses adjusted to patient needs and clinical outcomes. Higher FVIII levels can be achieved maintaining dosing frequency similar to that usually applied with SHL FVIII. This review provides a summary of recent data from the A-LONG, Kids A-LONG, ASPIRE and PUPs A-LONG studies and recently published real-world experience relevant to rFVIIIFc use in individualised regimens. The review also introduces ongoing studies of rFVIIIFc, including its use for induction of immune tolerance, and discusses some aspects to consider when switching patients to rFVIIIFc and managing ongoing treatment. In summary, rFVIIIFc is suitable for individualised prophylaxis regimens that can be tailored according to patient clinical needs and lifestyle.
    • Opportunities to Target T Cell Trafficking in Pediatric Inflammatory Bowel Disease.

      Giannoudaki, Eirini; Gargan, Siobhan; Hussey, Seamus; Long, Aideen; Walsh, Patrick T (2021-03-18)
      T cell subsets are considered central orchestrators of inflammation and homeostasis in the intestine and are established targets for the treatment of inflammatory bowel disease. While approaches aimed at the neutralization of T cell effector cytokines have provided significant benefits for pediatric and adult patients, more recent strategies aimed at inhibiting the infiltration of pathogenic T cell subsets have also emerged. In this review, we describe current knowledge surrounding the function of T cell subsets in pediatric inflammatory bowel disease and outline approaches aimed at targeting T cell trafficking to the intestine which may represent a new treatment option for pediatric inflammatory bowel disease.
    • Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome.

      Forde, Karina; Resta, Nicoletta; Ranieri, Carlotta; Rea, David; Kubassova, Olga; Hinton, Mark; Andrews, Katrina A; Semple, Robert; Irvine, Alan D; Dvorakova, Veronika (2021-02-27)
      Background: PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods. Results: Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22-28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported. Conclusion: We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).
    • A model for occupational stress amongst paediatric and adult critical care staff during COVID-19 pandemic.

      Feeley, T; Ffrench-O'Carroll, R; Tan, M H; Magner, C; L'Estrange, K; O'Rathallaigh, E; Whelan, S; Lyons, B; O'Connor, E (2021-02-25)
      Purpose: The coronavirus 2019 pandemic has placed all intensive care unit (ICU) staff at increased risk of psychological distress. To date, measurement of this distress has largely been by means of validated assessment tools. We believe that qualitative data may provide a richer view of staff experiences during this pandemic. Methods: We conducted a cross-sectional, observational study using online and written questionnaires to all ICU staff which consisted of validated tools to measure psychological distress (quantitative findings) and open-ended questions with free-text boxes (qualitative findings). Here, we report our qualitative findings. We asked four questions to explore causes of stress, need for supports and barriers to accessing supports. A conventional content analysis was undertaken. Results: In total, 269 of the 408 respondents (65.9%) gave at least one response to a free-text question. Seven overarching themes were found, which contribute to our proposed model for occupational stress amongst critical care staff. The work environment played an important role in influencing the perceived psychological impact on healthcare workers. Extra-organisational factors, which we termed the "home-work interface" and uncertainty about the future, manifested as anticipatory anxiety, had a proportionally larger influence on worker well-being than would be expected in non-pandemic conditions. Conclusion: Our findings have important implications for appropriate allocation of resources and ensuring well-being of the ICU multidisciplinary team for this and future pandemics. Keywords: Anticipatory anxiety; COVID-19; Critical care staff; Home-work interface; Occupational stress; Pandemic; Work intensification.
    • Dendritic Cell-Based Therapy Using LY6E Peptide with a Putative Role Against Colorectal Cancer.

      Tokhanbigli, Samaneh; Asadirad, Ali; Baghaei, Kaveh; Piccin, Andrea; Yarian, Fatemeh; Parsamanesh, Gilda; Hashemi, Seyed Mahmoud; Asadzadeh Aghdaei, Hamid; Zali, Mohammad Reza (2020-05-22)
      Introduction: Albeit early stage gastrointestinal (GI) carcinomas have a good prognosis if treated with surgery, diagnosis is often confirmed at a late stage and efficacious drugs are lacking. Recent progress in immune-based therapies has focused on dendritic cells (DCs), aiming to elicit tumor-specific responses by inducing immunological memory. Our previous microarray study indicated that a biomarker, termed lymphocyte antigen-6E (LY6E), is commonly overexpressed in two potentially lethal GI cancers: those of colon and stomach. In this study, we examined the antigenic potency of LY6E in stimulating DCs. Methods: Following isolation, differentiation, and maturation of mononuclear cells, DCs were pulsed with LY6E peptide, a protein related to major histocompatibility complex (MHC) class I/II. Subsequently, DCs were co-cultured with mouse splenocytes to assess antigen-specific T-cell proliferation. Elucidated cytotoxic T-lymphocyte responses were assessed using subcutaneous colorectal murine tumor models. Results: Our in vitro results suggest that DCs loaded with LY6E peptide antigen are capable of stimulating and inducing proliferation of murine T-cells. Furthermore, our in vivo results demonstrate that LY6E peptide has a substantial impact on provoking immune responses against induced colon cancer in mice. Discussion: In conclusion, based on the overexpression of LY6E in colorectal, gastric, and pancreatic cancers, the role of this peptide should be further investigated with a goal of developing new therapies for these challenging diseases.
    • Global Retinoblastoma Presentation and Analysis by National Income Level.

      Fabian, Ido Didi; Abdallah, Elhassan; Abdullahi, Shehu U; Abdulqader, Rula A; Adamou Boubacar, Sahadatou; Ademola-Popoola, Dupe S; Adio, Adedayo; Afshar, Armin R; Aggarwal, Priyanka; Aghaji, Ada E; et al. (2020-05)
      Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, setting, and participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main outcomes and measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.
    • Heart University: a new online educational forum in paediatric and adult congenital cardiac care. The future of virtual learning in a post-pandemic world?

      Tretter, Justin T; Windram, Jonathan; Faulkner, Theresa; Hudgens, Michelle; Sendzikaite, Skaiste; Blom, Nico A; Hanseus, Katarina; Loomba, Rohit S; McMahon, Colin J; Zheleva, Bistra; et al. (2020-04-13)
      Online learning has become an increasingly expected and popular component for education of the modern-day adult learner, including the medical provider. In light of the recent coronavirus pandemic, there has never been more urgency to establish opportunities for supplemental online learning. Heart University aims to be "the go-to online resource" for e-learning in CHD and paediatric-acquired heart disease. It is a carefully curated open access library of paedagogical material for all providers of care to children and adults with CHD or children with acquired heart disease, whether a trainee or a practising provider. In this manuscript, we review the aims, development, current offerings and standing, and future goals of Heart University.
    • Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: Final results from the ASPIRE extension study.

      Nolan, Beatrice; Mahlangu, Johnny; Pabinger, Ingrid; Young, Guy; Konkle, Barbara A; Barnes, Chris; Nogami, Keiji; Santagostino, Elena; Pasi, K John; Khoo, Liane; et al. (2020-03-30)
      Introduction: The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half-life treatment for severe haemophilia A were demonstrated in the Phase 3 A-LONG and Kids A-LONG studies. Eligible subjects who completed A-LONG and Kids A-LONG could enrol in ASPIRE (NCT01454739), an open-label extension study. Aim: To report the long-term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. Methods: Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. Results: A total of 150 subjects from A-LONG and 61 subjects from Kids A-LONG enrolled in ASPIRE. Most subjects received the IP regimen (A-LONG: n = 110; Kids A-LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A-LONG and Kids A-LONG was 3.9 (0.1-5.3) years and 3.2 (0.3-3.9) years, respectively. No inhibitors were observed (0 per 1000 subject-years; 95% confidence interval, 0-5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was <1.0) and extended-dosing intervals were maintained (median of 3.5 days) for the majority of subjects in ASPIRE. Conclusion: ASPIRE results, which include up to 5 years of follow-up data, confirm earlier reports on the consistent and well-characterized safety and efficacy of rFVIIIFc treatment for severe haemophilia A.
    • Protocol for a prospective, observational, longitudinal study in paediatric patients with moderate-to-severe atopic dermatitis (PEDISTAD): study objectives, design and methodology.

      Paller, Amy S; Guttman-Yassky, Emma; Irvine, Alan D; Baselga, Eulalia; de Bruin-Weller, Marjolein; Jayawardena, Shyamalie; Zhang, Annie; Mina-Osorio, Paola; Rizova, Elena; Ozturk, Zafer E (2020-03-24)
      Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease often associated with atopic comorbidities and has significant impact on children and their families. There is a lack of robust and longitudinal long-term data on disease characteristics and typical clinical practice with currently available treatments in children with moderate-to-severe AD. Hence, an observational study is needed to evaluate AD characteristics and progression in paediatric patients with moderate-to-severe AD. Methods and analysis: Pediatric Study in Atopic Dermatitis (PEDISTAD) is a prospective, observational, longitudinal study in paediatric patients with moderate-to-severe AD who are currently receiving systemic or topical treatment and whose disease is not adequately controlled by topical prescription therapies or for whom those therapies are not medically advisable. 1300 children at 100-150 sites in approximately 20 countries worldwide will be enrolled and followed for 5 years. AD therapy is at the discretion of the investigator. Data collected will include: AD disease characteristics and comorbidities; current therapy for AD and initiation of new treatments/changes in current treatment; patient-reported/caregiver-reported outcomes; days missed from school/work for the patient/caregiver; healthcare professional visits; safety and biomarkers. Ethics and dissemination: This study is conducted in accordance with the principles established by the 18th World Medical Assembly and all subsequent amendments and the guidelines for Good Epidemiology Practice. Each individual country assures that ethics approval has been received and local regulatory requirements are met. Ethics approval has been obtained in all countries currently participating in PEDISTAD. Study data will be disseminated in manuscripts submitted to peer-reviewed medical journals as well as in abstracts submitted to congresses and in the resulting posters and presentations.
    • The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants.

      Rio-Machin, Ana; Vulliamy, Tom; Hug, Nele; Walne, Amanda; Tawana, Kiran; Cardoso, Shirleny; Ellison, Alicia; Pontikos, Nikolas; Wang, Jun; Tummala, Hemanth; et al. (2020-02-25)
      he inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.
    • Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1).

      Ladenstein, Ruth; Pötschger, Ulrike; Valteau-Couanet, Dominique; Luksch, Roberto; Castel, Victoria; Ash, Shifra; Laureys, Genevieve; Brock, Penelope; Michon, Jean Marie; Owens, Cormac; et al. (2020-01-28)
      To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR); the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients' eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2-8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38-47%) and 50% (46-55%) but was 57% (51-62%) and 64% (59-69%) for 378 patients receiving immunotherapy (p < 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573); type of HDT (p = 0.0029, HR 1.431); less than complete response prior to maintenance therapy (p = 0.0043, HR 1.494) and >1 metastatic compartment at diagnosis (p < 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.
    • International randomised controlled trial for the treatment of newly diagnosed EWING sarcoma family of tumours - EURO EWING 2012 Protocol.

      Anderton, Jennifer; Moroz, Veronica; Marec-Bérard, Perrine; Gaspar, Nathalie; Laurence, Valerie; Martín-Broto, Javier; Sastre, Ana; Gelderblom, Hans; Owens, Cormac; Kaiser, Sophie; et al. (2020-01-17)
      Background: Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or busulfan and mephalan (IE/VC/VAI/BuMel) consolidation (randomisation 1, or R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome. Methods: EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomly assigned at two different time points: at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes or metastases (or both), and achievement of local control at the end of treatment. Discussion: This study will establish which is the "standard regimen" of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and consider that international cooperation is needed to provide answers in a timely manner.
    • Risk Factors for Respiratory Syncytial Virus Bronchiolitis Admissions.

      Meenaghan, S; Breatnach, C; Smith, H (2020-01-16)
      Aim Determine the seasonal incidence of hospital Respiratory Syncytial Virus (RSV) bronchiolitis and explore the variables associated with admission to ward versus the Paediatric Intensive Care Unit (PICU). Method Retrospective case-control study. Children, aged ≤2 years, between November and March, over a 3 year period with a positive RSV nasopharyngeal aspirate test. Results A total of 557 children were included; 19% (n=106) required PICU admission. Children admitted to the PICU were younger in age, median (IQR) 6.93 (3.96, 11.89) weeks compared to children who remained on the wards 11.00 (5.86, 24.14) weeks. Being underweight at the point of admission (adjusted odds ratio 3.15, 95% 1.46, 6.70, p=0.003) was associated with a PICU admission. Conclusion Number of RSV bronchiolitis hospitalisations are increasing each year. Age, weight and the use of HFNC were independent predictors for PICU admission.