Abstract
Von Hippel–Lindau (VHL) disease is a rare genetic syndrome caused by a germline pathogenic variant in one VHL allele. Any somatic event disrupting the other allele induces VHL protein (pVHL) loss of function, ultimately leading to patients developing multiple tumours in multiple organs at multiple timepoints, and reducing life expectancy. Treatment of this complex, rare disease is often fragmented, as patients visit specialist clinicians in isolation at different medical centres. Consequently, patients can receive sub-optimal treatment that results in decreased quality of life and a poor experience of health care systems. In 2021, we established a comprehensive clinical centre at San Raffaele Hospital, Milan, devoted to VHL disease. The centre provides a structured programme for the diagnosis, surveillance and treatment of patients alongside research into VHL disease and involves a multidisciplinary team of dedicated physicians. This programme demonstrates the benefits of care centralization, including concentration of knowledge and services, synergy and multidisciplinary management, improved networking and patient resources, reducing health care costs, and fostering research and innovation. VHL disease provides an ideal model to assess the advantages of centralizing care for rare disease and represents an unparalleled opportunity to broaden our understanding of cancer biology in general.
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References
Orphanet An online rare disease and orphan drug data base. © INSERM 1999. Available on http://www.orpha.net. (2023). Accessed on 27 December 2023.
Ferreira, C. R. The burden of rare diseases. Am. J. Med. Genet. A 179, 885–892 (2019).
100,000 Genomes Project Pilot Investigators. et al. 100,000 genomes pilot on rare-disease diagnosis in health care — preliminary report. N. Engl. J. Med. 385, 1868–1880 (2021).
Ball, M. W. et al. Growth rates of genetically defined renal tumors: implications for active surveillance and intervention. J. Clin. Oncol. 38, 1146–1153 (2020).
Ljungberg, B. et al. European Association of Urology guidelines on renal cell carcinoma: the 2022 update. Eur. Urol. 82, 399–410 (2022).
Cho, H. et al. On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models. Nature 539, 107–111 (2016).
Mitchell, T. J. et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell 173, 611–614.e17 (2018).
von Hippel, E. Über eine sehr seltene Erkrankung der Netzhant. Graefes Arch. Clin. Exp. Ophthalmol. 59, 83–106 (1904).
LINDAU, A. Zur Frage der Angiomatosis retinæ und ihrer Hirnkomplikationen. Acta Ophthalmol. 4, 193–226 (1926).
Lonser, R. R. et al. Von Hippel-Lindau disease. Lancet 361, 2059–2067 (2003).
Larcher, A. et al. Von Hippel-Lindau disease-associated renal cell carcinoma: a call to action. Curr. Opin. Urol. 32, 31–39 (2022).
Binderup, M. L. M. et al. Von Hippel-Lindau disease: updated guideline for diagnosis and surveillance. Eur. J. Med. Genet. 65, 104538 (2022).
Jonasch, E. et al. Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial. Lancet Oncol. 19, 1351–1359 (2018).
Jonasch, E. et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N. Engl. J. Med. 385, 2036–2046 (2021).
Larcher, A. et al. The ERUS curriculum for robot-assisted partial nephrectomy: structure definition and pilot clinical validation. Eur. Urol. 75, 1023–1031 (2019).
Larcher, A. et al. Prediction of complications following partial nephrectomy: implications for ablative techniques candidates. Eur. Urol. 69, 676–682 (2016).
Larcher, A. et al. Comparison of renal function detriments after local tumor ablation or partial nephrectomy for renal cell carcinoma. World J. Urol. 34, 383–389 (2015).
Binderup, M. L. M., Jensen, A. M., Budtz-Jørgensen, E. & Bisgaard, M. L. Survival and causes of death in patients with von Hippel-Lindau disease. J. Med. Genet. 54, 11–18 (2017).
Larcher A. et al. Removing barriers to the use of systemic agents for patients with von Hippel-Lindau disease. Eur. Urol. Oncol. https://doi.org/10.1016/j.euo.2024.01.003 (2024).
Larcher, A. et al. Is robot-assisted surgery contraindicated in the case of partial nephrectomy for complex tumours or relevant comorbidities? A comparative analysis of morbidity, renal function, and oncologic outcomes. Eur. Urol. Oncol. 1, 61–68 (2018).
Cei, F. et al. Pre-operative risk calculator for the probability of completing nephron sparing for kidney cancer. Eur. Urol. Open Sci. 19, e137–e138 (2012).
Kutikov, A. et al. Academic ranking score: a publication-based reproducible metric of thought leadership in urology. Eur. Urol. 61, 435–439 (2012).
Go, R. S. et al. Association between treatment facility volume and mortality of patients with multiple myeloma. J. Clin. Oncol. 35, 598–604 (2017).
Arora, S., Keeley, J., Pucheril, D., Menon, M. & Rogers, C. G. What is the hospital volume threshold to optimize inpatient complication rate after partial nephrectomy? Urol. Oncol. 36, 339.e17–339.e23 (2018).
Larcher, A. et al. The learning curve for robot-assisted partial nephrectomy: impact of surgical experience on perioperative outcomes. Eur. Urol. 75, 253–256 (2019).
Pockros, B. M., Finch, D. J. & Weiner, D. E. Dialysis and total health care costs in the united states and worldwide: the financial impact of a single-payer dominant system in the US. J. Am. Soc. Nephrol. 32, 2137–2139 (2021).
Kim, W. Y. & Kaelin, W. G. Role of VHL gene mutation in human cancer. J. Clin. Oncol. 22, 4991–5004 (2004).
Jiménez, C., Cote, G., Arnold, A. & Gagel, R. F. Review: should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J. Clin. Endocrinol. Metab. 91, 2851–2858 (2006).
Chatani, P. D., Agarwal, S. K. & Sadowski, S. M. Molecular signatures and their clinical utility in pancreatic neuroendocrine tumors. Front. Endocrinol. 11, 575620 (2021).
Acknowledgements
The authors would like to thank the many clinicians and researchers who work as part of the San Raffaele VHL programme, whose efforts and collaboration are vital to the success of the programme, including M. Ponzoni, R. Lucianò, M. Santangelo, N. Tenace, A. Giustina, L. Castellino, R. Galli, M. Falconi, S. Partelli, S. Crippa, F. Muffatti, G. Guarneri, D. Di Napoli, P. Carrera, M. Grazia Patricelli, G. B. Pipitone, A. Russo Raucci, M. Locatelli, L. Soldini, A. Naclerio, G. Pizzagalli, P. Mortini, J. F. Capitanio, M. Bailo, A. Falini, S. Calloni, M. Barbera, F. Bandello, R. Lattanzio, E. Bruschi, L. Cancellieri, A. Necchi, V. Di Mattei, S. Clerici, F. De Cobelli, R. Mellone, G. Brembilla, G. Guazzarotti, A. Chiti, M. Sollini, L. Antunovic, F. Gelardi, R. Bertini, G. Musso, L. Salerno, F. Corea, C. Carenzi, D. Canibus, A. M. Ferrara, I. Franco, A. R. Battista, L. Piccioni, F. Beltrando, E. Papaleo, V. S. Vanni, M. T. Sciarrone Alibrandi, M. Catania, K. Kola and L. De Rosa.
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All authors made a substantial contribution to discussion of content. A.L., F.B., F.C. and C.R. wrote the manuscript, and I.R., F.M., U.C. and A.S. reviewed and/or edited the manuscript before submission.
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The authors declare a restricted research grant from VHL Alliance to support the project “Investigation of treatment targets and tumour heterogeneity in Von Hippel–Lindau (VHL)-related renal cancer”, a restricted research grant from the Italian Ministry of Health and the European Union for the project “Overtaking Intra and Inter Tumoral Heterogeneity In Von Hippel–Lindau related Renal Cancer” (PNRR-MR1-2022-12375818), a restricted research grant from the Italian Ministry of Health and the European Union for the project “CAT-VHL - Exploring the role of Carbonic Anhydrase IX as diagnostic and Theranostic target in Von-Hippel Lindau disease” (PNRR-POC-2023-12377493), a restricted research grant from Intuitive Foundation for the project “Does robotics allow for shorter surgical learning than laparoscopy? A comparison analysis from a large, multi-institutional series of patients treated with partial nephrectomy”. In addition, A.L. declares consulting activity for Telix Pharmaceuticals and Merck Sharp & Dohme.
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Nature Reviews Urology thanks Kan Gong, who co-reviewed with Jingcheng Zhou; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Clinical Care Centers: https://www.vhl.org/care-treatment/clinical-care-centers/
European reference networks: https://health.ec.europa.eu/european-reference-networks/overview_en
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Larcher, A., Belladelli, F., Cei, F. et al. Centralization of care for rare genetic syndromes associated with cancer: improving outcomes and advancing research on VHL disease. Nat Rev Urol 21, 565–571 (2024). https://doi.org/10.1038/s41585-024-00874-y
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DOI: https://doi.org/10.1038/s41585-024-00874-y
