Fibroblast Growth Factor (FGF) Receptor Mutations: A Pathway to Understanding Multigenic Risk in Disease?

Fibroblast growth factor receptor (FGFR) gain-of-function mutations form the pathogenic basis of multiple congenital pathologies. A pioneering body of work over the past two decades has established that a unique mutation selection process within the testis likely underlies the paternal age effect characteristics of such diseases. This mechanism, analogous to positive selection of mutations promo­ting proliferation in tumorigenesis, sparked interest in mutation profiling of testicular and other cancers. The resulting discovery of FGFR gain-of-function mutations akin to those of congenital syndromes has enabled a novel hypothesis to be born: that mutations represent a spectrum of activation. As such, FGFR gain-of-function mutations could be pathogenic not solely in defined monogenic syndromes but within myriad disease processes with ‘low activation’ conferring increased disease risk. Do such mutations contribute to multigenic risk in multiple pathologies? This review evaluates this hypothesis, alluding to the plausible clinical implications that ensue

Transparency in the International Journal of Medical Students

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Surgical-PEARL protocol:a multicentre prospective cohort study exploring aetiology, management and outcomes for patients with congenital anomalies potentially requiring surgical intervention

INTRODUCTION: Congenital anomalies affect over 2% of pregnancies. Surgical advances have reduced mortality and improved survival for patients with congenital anomalies potentially requiring surgical (CAPRS) intervention. However, our understanding of aetiology, diagnostic methods, optimal management, outcomes and prognostication is limited. Existing birth cohorts have low numbers of individual heterogenous CAPRS. The Surgical Paediatric congEnital Anomalies Registry with Long term follow-up (Surgical-PEARL) study aims to establish a multicentre prospective fetal, child and biological parent cohort of CAPRS. METHODS AND ANALYSIS: From 2022 to 2027, Surgical-PEARL aims to recruit 2500 patients with CAPRS alongside their biological mothers and fathers from up to 15 UK centres. Recruitment will be antenatal or postnatal dependent on diagnosis timing and presentation to a recruitment site. Routine clinical data including antenatal scans and records, neonatal intensive care unit (NICU) records, diagnostic and surgical data and hospital episode statistics will be collected. A detailed biobank of samples will include: parents’ blood and urine samples; amniotic fluid if available; children’s blood and urine samples on admission to NICU, perioperatively or if the child has care withdrawn or is transferred for extracorporeal membrane oxygenation; stool samples; and surplus surgical tissue. Parents will complete questionnaires including sociodemographic and health data. Follow-up outcome and questionnaire data will be collected for 5 years. Once established we will explore the potential of comparing findings in Surgical-PEARL to general population cohorts born in the same years and centres. ETHICS AND DISSEMINATION: Ethical and health research authority approvals have been granted (IRAS Project ID: 302251; REC reference number 22/SS/0004). Surgical-PEARL is adopted onto the National Institute for Health Research Clinical Research Network portfolio. Findings will be disseminated widely through peer-reviewed publication, conference presentations and through patient organisations and newsletters. TRIAL REGISTRATION NUMBER: ISRCTN12557586

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Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease