Management of Small Bowel Neuroendocrine Tumours: 10 Years' Experience at a Tertiary Referral Centre.

BACKGROUND: Neuroendocrine tumours (NET) arising from the small bowel are clinically challenging and are often diagnosed at advanced stages. Disease control with surgery alone can be demanding. Multimodal treatment concepts integrating surgery and non-surgical modalities could be of benefit. METHOD: Retrospective review of consecutive adult patients with SB NET treated at Imperial College Healthcare NHS Trust between 1 January 2010 and 31 December 2019. Data regarding clinicopathological characteristics, treatments, and disease trajectory were extracted and summarised. Overall and progression/recurrence-free survival were estimated at 5 and 10 years. RESULTS: 154 patients were identified, with a median age of 64 years (range 33-87); 135/154 (87.7%) had stage III/IV disease at diagnosis. Surgery was used in 125 individuals (81.2%), typically with either segmental small bowel resection (60.8%) or right hemicolectomy (33.6%) and mesenteric lymphadenectomy for the primary tumour. Systemic and/or liver-directed therapies were used in 126 (81.8%); 60 (47.6%) had more than one line of non-surgical treatment. Median follow-up was 67.2 months (range 3.1-310.4); overall survival at 5 and 10 years was 91.0% (95% CI: 84.9-94.7%) and 82.5% (95% CI: 72.9-88.9%), respectively. Imaging-based median progression-free survival was 42.7 months (95% CI: 24.7 to 72.4); 5-year progression-free survival was 63.4% (95% CI: 55.0-70.6%); 10-year progression-free survival was 18.7% (95% CI: 12.4-26.1). Nineteen patients (12.3%) reached 10 years follow-up without disease recurrence and therefore were considered cured. CONCLUSIONS: Most patients with SB NET present in a metastasised stage. Multimodal treatment concepts may be associated with excellent clinical outcomes. Future work should explore optimal approaches to treatment sequencing and patient selection.

Reprogramming cellular identity in vivo.

Cellular identity is established through complex layers of genetic regulation, forged over a developmental lifetime. An expanding molecular toolbox is allowing us to manipulate these gene regulatory networks in specific cell types in vivo. In principle, if we found the right molecular tricks, we could rewrite cell identity and harness the rich repertoire of possible cellular functions and attributes. Recent work suggests that this rewriting of cell identity is not only possible, but that newly induced cells can mitigate disease phenotypes in animal models of major human diseases. So, is the sky the limit, or do we need to keep our feet on the ground? This Spotlight synthesises key concepts emerging from recent efforts to reprogramme cellular identity in vivo. We provide our perspectives on recent controversies in the field of glia-to-neuron reprogramming and identify important gaps in our understanding that present barriers to progress.

Developmental delay during eye morphogenesis underlies optic cup and neurogenesis defects in mab21l2u517 zebrafish mutants.

Shaping the vertebrate eye requires evagination of the optic vesicles. These vesicles subsequently fold into optic cups prior to undergoing neurogenesis and allocating a population of late progenitors at the margin of the eye. mab21l2 encodes a protein of unknown biological function expressed in the developing optic vesicles, and loss of mab21l2 function results in malformed eyes. The bases of these defects are, however, poorly understood. To further study mab21l2 we used CRISPR/Cas9 to generate a new zebrafish mutant allele (mab21l2u517). We characterized eye morphogenesis and neurogenesis upon loss of mab21l2 function using tissue/cell-type-specific transgenes and immunostaining, in situ hybridization and bromodeoxyuridine incorporation. mab21l2u517 eyes fail to grow properly and display an excess of progenitors in the ciliary marginal zone. The expression of a transgene reporter for the vsx2 gene -a conserved marker for retinal progenitors- was delayed in mutant eyes and accompanied by disruptions in the epithelial folding that fuels optic cup morphogenesis. Mutants also displayed nasal-temporal malformations suggesting asynchronous development along that axis. Consistently, nasal retinal neurogenesis initiated but did not propagate in a timely fashion to the temporal retina. Later in development, mutant retinas did laminate and differentiate. Thus, mab21l2u517 mutants present a complex eye morphogenesis phenotype characterized by an organ-specific developmental delay. We propose that mab21l2 facilitates optic cup development with consequences both for timely neurogenesis and allocation of progenitors to the zebrafish ciliary marginal zone. These results confirm and extend previous analyses supporting the role of mab21l2 in coordinating morphogenesis and differentiation in developing eyes.