Royal Manchester Children's Hospital

IgA vasculitis (IgAV) is an autoimmune disease that affects the small vessels of the skin, joints, gastrointestinal (GI) tract, and kidneys. In the long term, IgAV associated with nephritis (IgAV-N) can progress to kidney failure. Evidence-based clinical studies of IgAV-N are few, leading to huge variations in treatment approaches and suboptimal outcomes. The wealth of emerging efficacious treatments for IgA nephrology brings new opportunities to this disease. The aim of this report is to describe the proceedings of a multiprofessional collaborative workshop convened to identify the barriers to developing high quality evidence for patients with IgAV-N. A multiprofessional group consisting of 53 attendees from 13 countries met. The meeting was represented by a variety of professional backgrounds, including lay attendees, with different levels of expertise (32% professors and 19% midcareer doctors). Using predefined aims, key themes were extracted, and an action plan developed. Consensus was obtained that there is sufficient similarity between adults and children in terms of the organs involved, pathophysiology, histological features, and likely response to treatment. Important differences included the greater spontaneous improvement in children and worse kidney outcomes in some populations. It was agreed that patients at greatest risk of kidney failure should be the primary focus of initial clinical trials. Important considerations included the following: diagnostic classification for adult onset IgAV, observational data, evidence of scientific similarity to IgA nephropathy (IgAN), an age-inclusive approach to trial design, systemic disease secondary end points, and the inclusion of patient-reported outcomes. This manuscript communicates an expert-informed pathway to high-quality evidence for IgAV-N.

Introduction Asymptomatic physiological hypercalcaemia in exclusively breastfed infants is recognised but has not been systematically characterised when breastfeeding is continued.Objective To evaluate the clinical, biochemical and radiological outcomes of breast milk–associated physiological hypercalcaemia.Methods A multi-centre retrospective study over 5 years included infants with hypercalcaemia (serum corrected calcium (cCa) ≥2.8 mmol/L) who were exclusively breastfed and had no other identifiable causes of hypercalcaemia. Clinical, biochemical and radiological data were analysed.Results Twenty-five infants (15 males, 10 females) were studied. The mean peak cCa was 3.08 mmol/L (SD 0.17; normal 2.2–2.8 mmol/L). All infants were asymptomatic and continued exclusive breastfeeding without interventions such as intravenous fluids, diuretics or bisphosphonates. Mean serum parathyroid hormone (PTH) was suppressed at 1.04 pmol/L (SD 0.9; reference 2.0–9.4 pmol/L). Renal ultrasound examinations performed in all infants showed no nephrocalcinosis. Hypercalcaemia resolved spontaneously over a median of 64 (range, 9–329) days, and the median duration of exclusive breastfeeding was 150 (range, 8–540) days.Conclusion Breast milk–associated physiological hypercalcaemia is a benign, PTH-independent condition without clinical symptoms or nephrocalcinosis. Infants can safely continue exclusive breastfeeding, preserving its well-established benefits, without switching to low calcium formulas. Further research is needed to elucidate the underlying mechanisms.

Radiation therapy (RT) is an essential treatment modality for paediatric head and neck (HN) cancer, but irradiation during craniofacial development can cause dentofacial side effects, including facial deformation (FD). This systematic review evaluates the evidence on FD post-RT, including assessment methods, prevalence, and dose-response. A literature search was conducted in PubMed and EMBASE. Studies were included if they reported FD > 2 years post-RT on average across the whole cohort in children treated for HN cancer aged 0-18 years. Studies were assessed using the Cochrane Childhood Cancer Risk of Bias tool. Of 2766 articles identified, 25 met the inclusion criteria, reporting on 1155 children treated between 1965 and 2022 (median cohort size: 24, range: 6 - 192) participants. Median age at treatment/diagnosis was 4.9 years. FD assessment methods were analysed in two categories: objective measures and clinical reporting. Objective measures were further categorised: 1) cephalometric (2D image), 2) external surface (3D), 3) internal anatomy (3D). Clinical reporting included clinician-reported and patient-reported outcomes. Measurement and grading criteria varied considerably. Where it could be calculated, prevalence of FD was between 21% and 97%. In seven of the eight studies which examined dose-response, a range of doses between 24-40 Gy was linked to risk of FD, as was age < 5-7 years at the time of treatment. However, heterogeneity in tumour sites and treatment regimens limited comparability. Additionally, limited data on FD location and severity constrained dose-response study. This review highlights the need for standardised assessment tools and grading criteria that captures both location and severity of FD. Such standardisation would improve clinical reporting and support robust dose-response analysis in future research.

ABSTRACT:We evaluated long-term outcomes of 288 children with refractory-Langerhans cell histiocytosis (R-LCH) from 26 countries, who were prescribed off-label MAPK inhibitors (MAPKis) according to clinical indications. MAPKi indications included 148 R-risk-organ-positive (R-RO+), 67 R-risk-organ-negative (R-RO-), 13 lung destruction (lung), 9 sclerosing cholangitis (SC), 49 neurodegeneration (ND), and 2 diabetes insipidus (DI) cases. Median ages at diagnosis and MAPKi onset were 1.3 and 2.3 years, respectively, with median follow-up of 3.7 years (1166 person-years). Agents mostly prescribed as monotherapies were 184 prescriptions of vemurafenib, 115 of dabrafenib, 3 of encorafenib, 42 of cobimetinib, 45 of trametinib, and/or 1 prescription of binimetinib; followed 51 times by various chemotherapies or hematopoietic stem-cell transplantation, or 28 times by combined anti-BRAF-anti-MEK. Short-term responses (<8 weeks) ranged from 98% (R-RO+ and R-RO-), to 30% (lung) to none (ND, DI, and SC); although long-term lung and ND responses could be observed. Skin rash was the most frequent adverse event (∼55%), and 7 others included 1 case of cardiomyopathy and 6 of retinitis. Five developed MAPKi-unrelated tumors and 9 patients died. Five-year survival was 98%. After 113 patients with R-LCH discontinued MAPKi, 69 experienced disease reactivation. None of the various empirical maintenance therapies were able to prevent secondary reactivation. Among the 143 assessable patients without ND-LCH at MAPKi onset, 60 developed ND (45%, 5-year risk). MAPKis appeared to be safe and effective in children with R-RO+/RO-LCH, whereas other indications' responses were less frequent or occurred later. Further studies are needed to find effective maintenance-therapy approaches, particularly to prevent frequently observed secondary ND.

Aims: This retrospective multicentre study, involving 38 UK hospital trusts, aimed to characterise the demographic features, inpatient management, and referral patterns of patients with prosthetic hip dislocations. The primary focus was to identify factors influencing a definitive management plan following acute total hip arthroplasty (THA) dislocation, and to assess differences in the management of primary versus revision THA dislocations. Methods: Data from 645 patients who sustained acute prosthetic hip dislocations between 01 January 2019 and 31 July 2019, were collected from electronic medical records. Patients were divided into Primary and Revision THA groups. Statistical analyses were used to explore demographic patterns, comparative analyses, and factors influencing referral decisions, with significance set at p < 0.05. Results: The mean age of patients was 76.2 years, with a predominance of females (65.7%) and posterior dislocations (72.7%). Of the patients, 37.8% underwent reduction in the Emergency Department (ED), with a success rate of 69.7%, while 72.9% required reduction in theatre, achieving a success rate of 90.6%. Inpatient mortality was 1.2%. Only 32.5% of patients had a definitive management plan following their dislocation. Primary THA patients (n = 504) were predominantly female (69.6%) compared to Revision THA patients (n = 141, 48.9%, p < 0.001). Anterior dislocations were more common in the Revision THA group (26.2% vs. 17.3%, p = 0.017). The primary THA group had a higher success rate in closed reduction (92.9% vs. 82.9%, p = 0.002). Revision THA patients were more likely to have a definitive management plan (52.9% vs. 26.9%, p < 0.001). Conclusions: This study highlights significant variability in the management of THA dislocations, particularly in the lack of standardised protocols for inpatient management and onward referral to revision arthroplasty surgeons. Standardisation of care pathways is needed to optimise outcomes for patients with prosthetic hip dislocations.