Multicentre study of patient-reported and clinical outcomes following immediate and delayed Autologous Breast Reconstruction And Radiotherapy (ABRAR study).

BACKGROUND: Timing of autologous breast reconstruction in patients requiring adjuvant radiotherapy remains contentious. The primary objective of this study was to assess clinical and patient reported outcomes in immediate reconstruction with radiotherapy compared to delayed reconstruction after radiotherapy, the two relevant clinical pathways for patients who need radiotherapy. METHODS: This retrospective UK multi-centre study grouped patients into three categories: immediate reconstruction with post-operative radiotherapy (IBR); delayed reconstruction after radiotherapy (DBR); control group of immediate reconstruction without radiotherapy (noRT). Data collection utilised clinician questionnaire, patient questionnaire (BreastQ) and medical examination. Examination assessed fat necrosis, texture, symmetry and overall result. RESULTS: 412 patients were recruited (IBR 104; DBR 119; noRT 189) with median follow-up time of 57 months. Post-operative complications were higher in IBR & noRT (p <0.001). Total number of operations for completion of reconstruction was similar in all groups. Completion of reconstruction after mastectomy was three years longer in DBR versus IBR. BreastQ domain scores were lower in IBR versus DBR and noRT (p <0.01) but all scores were within acceptable range (satisfaction with outcome: IBR 71; DBR 85; noRT 81). Examination scores were similar for IBR and DBR but lower than noRT (p <0.01). Correlation between BreastQ and examination scores was poor. CONCLUSIONS: Acceptable results are observed with either IBR or DBR, with high rates of patient and clinician satisfaction, low rates of complications, and a similar number of operations to complete reconstruction in all groups suggesting all options should be considered for patients.

Directed evolution of an angiopoietin-2 ligand trap by somatic hypermutation and cell surface display.

Tie2 is a receptor tyrosine kinase that is essential for the development and maintenance of blood vessels through binding the soluble ligands angiopoietin 1 (Ang1) and 2 (Ang2). Ang1 is constitutively produced by perivascular cells and is protective of the adult vasculature. Ang2 plays an important role in blood vessel formation and is normally expressed during development. However, its re-expression in disease states, including cancer and sepsis, results in destabilization of blood vessels contributing to the pathology of these conditions. Ang2 is thus an attractive therapeutic target. Here we report the directed evolution of a ligand trap for Ang2 by harnessing the B cell somatic hypermutation machinery and coupling this to selectable cell surface display of a Tie2 ectodomain. Directed evolution produced an unexpected combination of mutations resulting in loss of Ang1 binding but maintenance of Ang2 binding. A soluble form of the evolved ectodomain binds Ang2 but not Ang1. Furthermore, the soluble evolved ectodomain blocks Ang2 effects on endothelial cells without interfering with Ang1 activity. Our study has created a novel Ang2 ligand trap and provided proof of concept for combining surface display and exogenous gene diversification in B cells for evolution of a non-immunoglobulin target.