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Abstract Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma.

Background: Centralising specialist cancer surgical services is an example of major system change. High-volume centres are recommended to improve specialist cancer surgery care and outcomes. Objective: Our aim was to use a mixed-methods approach to evaluate the centralisation of specialist surgery for prostate, bladder, renal and oesophago-gastric cancers in two areas of England [i.e. London Cancer (London, UK), which covers north-central London, north-east London and west Essex, and Greater Manchester Cancer (Manchester, UK), which covers Greater Manchester]. Design: Stakeholder preferences for centralising specialist cancer surgery were analysed using a discrete choice experiment, surveying cancer patients (n = 206), health-care professionals (n = 111) and the general public (n = 127). Quantitative analysis of impact on care, outcomes and cost-effectiveness used a controlled before-and-after design. Qualitative analysis of implementation and outcomes of change used a multisite case study design, analysing documents (n = 873), interviews (n = 212) and non-participant observations (n = 182). To understand how lessons apply in other contexts, we conducted an online workshop with stakeholders from a range of settings. A theory-based framework was used to synthesise these approaches. Results: Stakeholder preferences – patients, health-care professionals and the public had similar preferences, prioritising reduced risk of complications and death, and better access to specialist teams. Travel time was considered least important. Quantitative analysis (impact of change) – only London Cancer’s centralisations happened soon enough for analysis. These changes were associated with fewer surgeons doing more operations and reduced length of stay [prostate –0.44 (95% confidence interval –0.55 to –0.34) days; bladder –0.563 (95% confidence interval –4.30 to –0.83) days; renal –1.20 (95% confidence interval –1.57 to –0.82) days]. The centralisation meant that renal patients had an increased probability of receiving non-invasive surgery (0.05, 95% confidence interval 0.02 to 0.08). We found no evidence of impact on mortality or re-admissions, possibly because risk was already low pre-centralisation. London Cancer’s prostate, oesophago-gastric and bladder centralisations had medium probabilities (79%, 62% and 49%, respectively) of being cost-effective, and centralising renal services was not cost-effective (12% probability), at the £30,000/quality-adjusted life-year threshold. Qualitative analysis, implementation and outcomes – London Cancer’s provider-led network overcame local resistance by distributing leadership throughout the system. Important facilitators included consistent clinical leadership and transparent governance processes. Greater Manchester Cancer’s change leaders learned from history to deliver the oesophago-gastric centralisation. Greater Manchester Cancer’s urology centralisations were not implemented because of local concerns about the service model and local clinician disengagement. London Cancer’s network continued to develop post implementation. Consistent clinical leadership helped to build shared priorities and collaboration. Information technology difficulties had implications for interorganisational communication and how reliably data follow the patient. London Cancer’s bidding processes and hierarchical service model meant that staff reported feelings of loss and a perceived ‘us and them’ culture. Workshop – our findings resonated with workshop attendees, highlighting issues about change leadership, stakeholder collaboration and implications for future change and evaluation. Limitations: The discrete choice experiment used a convenience sample, limiting generalisability. Greater Manchester Cancer implementation delays meant that we could study the impact of only London Cancer changes. We could not analyse patient experience, quality of life or functional outcomes that were important to patients (e.g. continence). Future research: Future research may focus on impact of change on care options offered, patient experience, functional outcomes and long-term sustainability. Studying other approaches to achieving high-volume services would be valuable. Study registration: National Institute for Health and Care Research (NIHR) Clinical Research Network Portfolio reference 19761. Funding: This project was funded by the NIHR Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 11, No. 2. See the NIHR Journals Library website for further project information.

The Hypoxia-inducible transcription Factor (HIF) represents an important adaptive mechanism under hypoxia, whereas sustained activation may also have deleterious effects. HIF activity is determined by the oxygen regulated α-subunits HIF-1α or HIF-2α. Both are regulated by oxygen dependent degradation, which is controlled by the tumor suppressor "von Hippel-Lindau" (VHL), the gatekeeper of renal tubular growth control. HIF appears to play a particular role for the kidney, where renal EPO production, organ preservation from ischemia-reperfusion injury and renal tumorigenesis are prominent examples. Whereas HIF-1α is inducible in physiological renal mouse, rat and human tubular epithelia, HIF-2α is never detected in these cells, in any species. In contrast, distinct early lesions of biallelic VHL inactivation in kidneys of the hereditary VHL syndrome show strong HIF-2α expression. Furthermore, knockout of VHL in the mouse tubular apparatus enables HIF-2α expression. Continuous transgenic expression of HIF-2α by the Ksp-Cadherin promotor leads to renal fibrosis and insufficiency, next to multiple renal cysts. In conclusion, VHL appears to specifically repress HIF-2α in renal epithelia. Unphysiological expression of HIF-2α in tubular epithelia has deleterious effects. Our data are compatible with dedifferentiation of renal epithelial cells by sustained HIF-2α expression. However, HIF-2α overexpression alone is insufficient to induce tumors. Thus, our data bear implications for renal tumorigenesis, epithelial differentiation and renal repair mechanisms.

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