Endoscopic, ultrasound guided, radiofrequency ablation of aldosterone producing adenomas: A prospective, proof-of-concept trial

Endoscopic, ultrasound guided, radiofrequency ablation of aldosterone producing adenomas: A prospective, proof-of-concept trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Endoscopic, ultrasound guided, radiofrequency ablation of aldosterone producing adenomas: A prospective, proof-of-concept trial Morris Brown, Giulia Argentesi, Xilin Wu, Alexander Ney, Emily Goodchild, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4365782/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Unilateral aldosterone-producing adrenal adenomas (APAs) are the potentially curable cause of 5% of all cases of hypertension. At present surgical removal of a whole gland is the only approved option for achieving cure, with uncertain long-term outcomes. Endoscopic ultrasound-guided trans-gastric radiofrequency ablation (EUS-RFA) offers a less invasive alternative to total adrenalectomy for the treatment of left-sided APAs. We aimed to determine whether EUS-RFA of APAs is safe and evaluate its likelihood of success in curing primary aldosteronism. We conducted a multi-centre feasibility study of EUS-RFA as a nonsurgical, adrenal-sparing treatment for left-sided APAs. The primary endpoint was safety, judged by the occurrence of pre-specified major hazards (intestinal haemorrhage, infarction or viscus perforation); and the secondary endpoints were biochemical and clinical efficacy (Primary Aldosterone Surgical Outcome (PASO) criteria). 28 participants (21 male, 7 female, mean age 57.7 +/- 10.3 years; 16 White, 11 Black, 1 Asian), underwent 35 ablations on one (n=21) or two (n=7) occasions. None of the pre-specified major hazards occurred. There were 21 biochemical and 12 clinical successes. These were complete in 16 and 4 participants, respectively, associated with >75% eradication of the APA, judged by molecular imaging. EUS-guided trans-gastric RFA is a safe alternative to total adrenalectomy for the treatment of left-sided APAs and can lead to complete PASO success when most of the APA is ablated. Health sciences/Endocrinology/Endocrine system and metabolic diseases/Adrenal gland diseases Health sciences/Medical research Figures Figure 1 Figure 2 INTRODUCTION Primary aldosteronism (PA) is a common, high-risk form of hypertension and frequently leads to treatment-resistant hypertension. 1–3 The risk of cardiometabolic complications is at least twice that of age- and gender- matched people with essential hypertension. 4,5 Approximately 50% of patients with PA have a unilateral sub-type, usually due to an aldosterone-producing adenoma (APA) whose removal by adrenalectomy can cure PA, reverse the enhanced cardiovascular risk, and sometimes cure hypertension altogether. 6,7 However, the lack of prospective data proving long-term superiority of adrenalectomy over non-surgical approaches, understandable when PA was considered a rarity, is a problem for a condition with a prevalence exceeding 5% of hypertension. 8 Availability of surgery is also unlikely to meet demand as diagnosis of PA increases above 1% of cases; and the small size of most APAs discovered by modern imaging is a further incentive to find minimally-invasive, adrenal-sparing approaches that permit rapid resumption of normal activities. 9,10 An alternative to surgery has been percutaneous radiofrequency ablation (RFA) of the culprit nodule, with several (mainly retrospective) reports of comparable efficacy to surgery 11–15 . However, the benefit is offset by pressor crises due to adrenomedullary excitation, and by the challenge of identifying the culprit APA(s) in a gland with more than one macroscopic nodule. 16–19 In one prospective study, intraprocedural hypertension > 180 mmHg was observed in 43% of cases, serious adverse events in 26%, of which 8% were life-threatening. 20 These hazards, we hypothesized, could be avoided for left-sided APAs by a transgastric endoscopic ultrasound (EUS)-guided approach, which enables continuous catheter manipulation and real-time monitoring. 21,22 Our concepts were that molecular imaging would enable EUS-RFA to target aldosterone-secreting nodules, and that multiple short treatments (i.e. RFA burns) would avoid risk of damage to either the adjacent adrenal or nearby organs. The aim of this study, which we have termed FABULAS (Feasibility study of radiofrequency endoscopic Ablation, with Ultrasound guidance, as a non-surgical, Adrenal Sparing treatment for aldosterone-producing adenomas), was to determine whether EUS-RFA of left-sided APAs is a safe method of achieving sustained reduction in plasma aldosterone levels. Recruitment of three sequential, overlapping groups of 10 participants each was planned, allowing initial assessment to be performed in those whose potential favourable benefit:risk derived from their unsuitability for surgery, progressing to a final group for whom RFA was a personal preference, with a benefit:risk derived in part from initial experience in FABULAS. All participants had PA as defined by the Endocrine Society Guidelines 6 , and left-sided APAs diagnosed by Adrenal Vein Sampling (AVS) or molecular imaging. The close proximity of the left adrenal and the stomach, and the transgastric route of access to the left APA using EUS is demonstrated in Supplementary Fig. 1. EUS-RFA was performed, initially under general anaesthesia, subsequently under deep sedation. Safety was assessed by an independent Safety Committee who reviewed the reporting of any of the three pre-specified major hazards (perforation, haemorrhage or infarction of major organs) and all serious adverse event (SAEs); in addition to analysis of changes in intra- and post-procedure biochemistry and BP. The secondary objectives were to evaluate the efficacy of EUS-RFA, by biochemical and clinical success as defined by the PASO Consensus 23 (Supplementary Table 1); and by pre- and post-ablation radiological measurements on molecular imaging ([ 11 C]metomidate PET-CT, MTO, or para-chloro-2-[ 18 F]fluoroethyletomidate PET-CT, [ 18 F]CETO). Immunohistochemistry (IHC) and molecular analyses were also performed on fine needle biopsy (FNBs) taken at the time of the procedure to confirm diagnosis of APA (that the treated nodule stained positive for CYP11B2/aldosterone synthase) and for genotyping. Full details of the inclusion and exclusion criteria, procedures and endpoints are presented in the Online Methods. RESULTS Participant Characteristics A total of 44 participants were screened, 31 were recruited, and 28 (21 male, seven female, mean age 57.7 +/- 10.3 years) proceeded to RFA (Fig. 1a and Table 1). By self-identification, 16 (57%) participants were White, and 11 (39%) were Black (the latter approximately three times their proportionate representation in the local population). Seven participants had a second procedure, and all 35 RFAs were included in the primary safety assessment. The demographic and clinical details are shown in Table 1 and Supplementary Table 2. Unilateral PA was diagnosed with high or medium probability in 19 and 7 participants, respectively, with [ 11 C]metomidate- or [ 18 F]CETO-positive nodules in 25 and 1, respectively (Supplementary Table 3). The remaining two participants had bilateral focal [ 11 C]metomidate uptake, and were included because of poor BP control on maximal tolerated doses of mineralocorticoid receptor antagonists. The first participant underwent screening on 21 st February 2018. After a pandemic-related interruption to the trial, the last participant visit occurred on 10 th February 2023. The study outline is shown in Figure 1b. All 28 participants had primary safety measurements (at 48 hours post-RFA in the first ten participants, or after 24 hours in the remaining 18), and proceeded to efficacy assessments at six months after RFA. Primary endpoint: safety No participant experienced any of the pre-specified major hazards of perforation, haemorrhage or infarction of major organs (Table 2a). At 24 or 48 hours post-RFA, only one participant had an elevated plasma amylase (baseline 87 iu/L, 24h 195 iu/L) without any clinical or radiological evidence of acute pancreatitis; no participant had a reduction in haemoglobin (Supplementary Table 4), or abnormal liver function tests. Secondary endpoint: efficacy Six months after sole (n=21) or final (n=7) RFA, 16 and 5 participants achieved complete or partial biochemical success, respectively; 4 and 8 participants achieved complete or partial clinical success (Supplementary Table 5). Except for complete clinical success (home BP <135 and <85 mmHg off treatment), the other PASO criteria are susceptible to interfering drug effects. Since efficacy was a secondary endpoint, these were not discontinued, and are shown alongside outcomes for each participant in Supplementary Table 3. Aldosterone-renin ratio (ARR) fell by median 2286 (95% CI, 902,4081), p<0.001 (Table 3, Supplementary Figure 2). Average BP was unchanged, but the median defined daily dose of antihypertensive medications fell by 1.4 (95% CI, 0.5,3.0). Radiological success was estimated as the change in maximum standardized uptake value (SUVmax) ratio, comparing maximum [ 11 C]metomidate or [ 18 F]CETO uptake in left versus right adrenal (Figure 2a-b and Supplementary Figure 3). The SUVmax ratio fell by median 0.26 (95% CI, 0.06,0.49), associated with a fall in median nodule diameter of 2.0 mm (95% CI, 1.0,4.0) (Table 3). Exploratory analyses [ 11 C]metomidate / [ 18 F]CETO uptake was qualitatively preserved in the adrenal adjacent to the APA. IHC and/or quantitative polymerase chain reaction (qPCR) confirmed CYP11B2 positivity in 22 nodules, whereas six were positive for CYP11B1 but not CYP11B2 (Figure 2e and Supplementary Table 6) and comprised all but one of the seven absent biochemical successes. Conversely, of nine participants with a qualitatively complete ‘radiological’ ablation (defined as 75-100% reduction in [ 11 C]metomidate/[ 18 F]CETO uptake over the ablated PET-positive nodule), only two failed to achieve complete biochemical success (Supplementary Table 7). One participant with absent success was noted to have increased SUVmax over a contralateral nodule (Figure 2). RNAseq identified mutations in 13/19 (68%) tumour FNB samples sent for sequencing (Supplementary Table 8). The two most common somatic mutations, KCNJ5 and CACNA1D, were the least abundant in our cohort (found in two tumours each). 3/19 tumours harboured ATP2B3 mutations while the ATP1A1 was the most prevalent genotype (6/19). Serious Adverse Events All study-related and non-study related SAEs are listed in Table 2b and Supplementary Table 9 respectively. All resolved spontaneously. Four were judged by the Safety Committee to be procedure-related, including three (pneumonia, arrhythmia and myocardial ischaemia) more likely related to general anaesthesia (GA) than RFA itself, since these complications are also reported after laparoscopic adrenalectomies. 24-27 One SAE, an episode of intra-procedural hypertension associated with increase in plasma metanephrine, was graded as serious and procedure-related, but was considered to be due to the intravenous drugs used during GA (metaraminol and ephedrine), not due to adrenomedullary stimulation. 28,29 This case is described in detail in the Supplementary Appendix. There were no other episodes of increased BP during RFA. The pre- and post-RFA plasma normetanephrine and metanephrine concentrations are shown in Supplementary Figure 4 and Supplementary Table 4. DISCUSSION In this proof-of-concept study of an endoscopic approach to treatment of PA, culprit APAs previously identified by PET-CT could be seen and targeted by EUS-RFA, and the multiple, small ablation fields avoided damage to adjacent tissues. Exclusion of rare complications of EUS-RFA will require larger studies, but the incidence excluded by the sample-size calculation for FABULAS has permitted progression to a pivotal comparison of nodular ablation with surgery (NCT05405101). Complete biochemical and/or clinical success – namely cure of PA and/or hypertension itself – were the exception, but were observed in 7/9 particiapnts whose APA was completely eradicated, as judged by the post-procedure PET-CT. The strategy of ablating culprit nodules, rather than removing a whole organ, is clearly attractive. Despite this, and the number of studies of APA ablation, the procedure has not been widely adopted for PA, and was not mentioned in Endocrine Society guidelines. 6 Clinician hesitancy in adopting RFA into routine practice may relate to both safety and efficacy, and the limited ability of retrospective trials to evaluate these. Concerns about adrenomedullary excitation during RFA emerged with reports of florid phaeochromocytoma-like crises during long treatments of adrenal or peri-adrenal tumours. 16–18 Contributing to the recognition that safety is paramount is the growing realisation that the traditional binary monikers of unilateral APAs and bilateral idiopathic hyperplasia refer to ends of a continuous spectrum. 30,31 If the majority of unilateral PA is actually ‘asymmetric’, and intervention in such patients is debulking rather than curing, then anticipated average benefits of unilateral interventions are reduced, and risks need to be comparably lower. Low-risk RFA may indeed be considered as an alternative to medical treatment of PA, or at least as a non-surgical strategy to reduce the overall tablet burden. 32 Against this background, EUS-RFA of APAs was considered appropriate to evaluate, given reported safety of a comparable approach in patients with pancreatic neuroendocrine tumours. 33 The gastric ultrasound probe provides clear images of the APA and adjacent adrenal (Supplementary Fig. 1), with cortex and medulla often distinguishable from each other. The proximity also allows continual repositioning of the catheter. Because APAs are benign, the penalty of incomplete ablation is biochemical not oncological, and can be viewed in the contexts of lower morbidity and potentially greater availability of intertentional endoscopists than endocrine surgeons. In FABULAS, we did not anticipate either biochemical or clinical efficacy to approach that seen post-adrenalectomy for several reasons. First, the primary endpoint of safety mandated operator caution in the judgement of the appropriate ablation zone to target. Second, eligibility in two of the three groups included individuals with relative contra-indications to surgery, such as ambiguous evidence of unilateral PA. Third, the demographics of the FABULAS cohort were closer to those who, in our MATCH trial, were likely to have partial/absent rather than complete success. Retrospective analyses of the FNB samples confirmed paucity or absence of tumour genotypes ( KCNJ5 or CTNNB1&GNAQ mutations) associated with complete clinical successes in MATCH. 9 Of most relevance to the future success of EUS-RFA in a typical unilateral PA population, was the informal titration of number of treatments (burns), and analysis of ablation completeness by molecular imaging. Exploratory analysis demonstrated only 9/28 APAs were > 75% ablated (as judged independently by two groups of observers). In these participants, FABULAS proved the concept that hypertension due to PA can be cured by an endoscopic procedure. There was no technical bar to achieving near 100% ablation. The phase I study-equivalent design of FABULAS prioritised safety, and the number of treatments (burns) during each ablation procedure was slowly increased once safety had been demonstrated in previous participants. Since many APAs are not spherical, multiple treatments monitored in real-time offer an advantage (compared to CT-guided RFA) of limiting ablation to the APA. Our development of RFA for APAs has been driven, in part, by patient involvement in decision-making, facilitated by the evident mis-match on molecular imaging between size of a typical focal area of tracer uptake and that of the whole organ removed by surgery. Until now, the potential attractions of RFA have been offset by concerns about ablating the wrong nodule, or that in some patients with unilateral PA this is due wholly or partly to microscopic clusters of aldosterone-producing cells, not visible radiologically. The FNB analyses show that, at worst, EUS-RFA of a non-culprit nodule is unusual. Although some were negative for CYP11B2, discrepancies between the IHC and RNA samples (e.g. in participant 20 who was completely cured by the procedure) illustrate the known heterogeneity of CYP11B2 expression in APAs. Other PET ligands in evaluation may increase accuracy, with the aldosterone-synthase inhibitor ligand in principle quantifying relative contribution to aldosterone excess from the target nodule. 34 Unlike surgery, where an adrenal cannot be replaced after unsuccessful adrenalectomy, all treatment options remain open after nodular RFA. Three of the participants with absent biochemical success have undergone adrenalectomy since conclusion of the study without any technical difficulty. We encountered four spontaneously resolving, procedure-related SAEs, which were reviewed by the Safety Committee. Three were scenarios that also occur in patients with longstanding PA who undergo laparoscopic adrenalectomy, and were deemed a consequence of GA rather than the ablation itself. 24 The episode of severe hypertension initially appeared different, and a possible instance of adrenomedullary excitation during adrenal RFA. 16–18 However, independent scrutiny of the anaesthetic record concluded this episode too was a probable consequence of GA, and the drugs deployed (see Supplementary Appendix for full discussion of the hypertensive episode and changes in plasma metanephrine). The 2–4 fold rises in plasma metanephrine in some participants (Supplementary Fig. 4, Supplementary Table 4) are similar to the fold-change reported for catecholamines during laparoscopic surgery, and much lower than the fold-increases in plasma epinephrine which cause substantial haemodynamic changes. 35–38 Evidently these cases cannot yet completely exclude adrenomedullary excitation, and have influenced us, in our current ‘WAVE’ trial, to obtain serial peri-procedure samples for plasma metanephrines that separate the effects of GA (or sedation) from subsequent instrumentation, in both the ablation and surgical groups. FABULAS has limitations. First, the study is small, and initial participants had lower ‘doses’ (fewer treatments/burns) of RFA. The results focused on safety, to enable efficacy of ablation to be compared to surgery in our pivotal trial WAVE (NCT05405101). Unlike pharmacotherapy, device-based interventions need not wait for phase 2/3 studies before entering practice, and EUS-RFA is already used for non-adrenal indications. 39 While our findings may permit risk-assessed early application to PA patients ineligible or unwilling to contemplate surgery, operator training and experience will be important. Second, clinical safety dictated that many participants could not discontinue interfering medications to facilitate ‘clean’ measurement of ARR. Proof-of-concept for efficacy derives principally from participants able to discontinue all drugs. Indeed the acronym of the study, meaning ‘stories’, anticipated that the best evidence of potential efficacy might arise from individual cases, rather than the pooled results. Third, FABULAS was a study of left adrenal APAs. In WAVE, surgery is being compared to nodular ablation of left- and right-sided APAs by endoscopic and percutaneous routes, respectively. Lastly, efficacy was evidently lower than after surgery, similar to that in a recent prospective study of percutaneous RFA. 32 Superior efficacy of nodular ablation vs total adrenalectomy is inconceivable. FABULAS has provided preliminary experience of a minimally-invasive alternative to surgery for APAs that can start the debate amongst clinicians as to what level of biochemical and clinical efficacy would be appropriate to accept in the context of the obvious advantages of a day-case procedure performed under sedation. It is 70 years since the discovery of primary aldosteronism. 40 For much of this period, management of PA has been substantially unchanged. Molecular imaging-located, EUS-guided RFA is a potentially curative treatment for PA, when this is due to an APA, and FABULAS has provided sufficient safety data to inform a pivotal comparison with surgery. Declarations DATA AVAILABILITY Clinical trial data may be granted to qualified academic researchers upon approval by the study management committee and subject to appropriate data sharing and transfer agreements. Requests for data should include rationale and the relevance of the proposed research, hypothesis, research methodology, statistical analysis plan and publication plan. Genotyping and transcriptome data will be made available from Sequence Read Archive. ACKNOWLEDGEMENTS We thank Professor Sir Christopher Edwards, Chair of the Trial Steering Committee; Mr Satya Bhattacharya, Dr Scott Akker and Professor Anju Sahdev, Safety Committee; Cambridge Bio-bank for FNA analyses; Giorgia Ala for assistance with EUS-FNA procedures, and STARmed for provision of RFA catheters and generators. The expertise of anaesthetists Dr's Elizabeth Cervi, Raz Mahroof and Jose Bastos was also gratefully acknowledged. FUNDING The study was funded by the British Heart Foundation (PG/16/40/3213) and Barts Charity (MGU0360). G.A., K.L. and J.K. are British Heart Foundation Research Fellows; X.W. and E.G. are National Institute of Health Research (NIHR) Academic Clinical Lecturers; Y-N.L. is a Barts Charity Research Fellow. M.G., S.P. and M.J.B. are supported by NIHR Biomedical Research Centres, at Cambridge (NIHR203312), University College Hospitals and Barts NHS Trusts. AUTHOR CONTRIBUTIONS M.J.B., M.G., W.M.D. and S.P. conceived of and designed the study. X.W., G.A., A.N, E.G., K.L., Y-N.L., R.S., J.M, S.M.O. A.P., U.M., E.D., P.E. ran the study and collected the data under the supervision of M.J.B., M.G., S.P. and W.M.D. J.S. was trial coordinator. [11C]metomidate and [18F]CETO PET-CT grading was performed by H.C., with input on further analysis by D.G., E.N. and J.K. EUS-RFA was performed by S.P., N.C., P.W., E.M.G., and G.G. IHC grading was performed by A.M. and J.T. Adrenal tissue collection was performed by X.W., E.G., G.A., S.M.O. and K.L. X.W. prepared the adrenal samples for RNA-seq and preformed the quantitative PCR experiments, with help from Y-N.L. and K.L. RNA-seq was analysed by M.J.B. Statistical analysis was performed by J.B. The manuscript was prepared by X.W., G.A., M.J.B., W.M.D. and M.G. with substantial input on revisions from E.G., S.M.O., M.G. and S.P. References Monticone, S. , et al. Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice. J Am Coll Cardiol 69 , 1811-1820 (2017). Rossi, G.P. , et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 48 , 2293-2300 (2006). Williams, B. , et al. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. The Lancet Diabetes & Endocrinology 6 , 464-475 (2018). 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[11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial. Nature Medicine 29 , 190-202 (2023). Drake, W.M. & Brown, M.J. Management of Primary Aldosteronism, Chapter 5.6.2 Oxford Textbook of Endocrinology and Diabetes 3e, John Wass, Wiebke Arlt, Robert Semple , 871-884 (2022). Yang, M.H., Tyan, Y.S., Huang, Y.H., Wang, S.C. & Chen, S.L. Comparison of radiofrequency ablation versus laparoscopic adrenalectomy for benign aldosterone-producing adenoma. Radiol Med 121 , 811-819 (2016). Sacks, B.A., Sacks, A.C. & Faintuch, S. Radiofrequency ablation treatment for aldosterone-producing adenomas. Current Opinion in Endocrinology, Diabetes and Obesity 24 , 169-173 (2017). Guo, R.Q., Li, Y.M. & Li, X.G. Comparison of the radiofrequency ablation versus laparoscopic adrenalectomy for aldosterone-producing adenoma: a meta-analysis of perioperative outcomes and safety. Updates Surg 73 , 1477-1485 (2021). 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Young and Barry A. Sacks. https://pro.endocrineweb.com/conference-news/functional-adrenal-tumor-should-we-whip-it-whack-it-or-zap-it (2022). Oguro, S. , et al. Safety and feasibility of radiofrequency ablation using bipolar electrodes for aldosterone-producing adenoma: a multicentric prospective clinical study. Scientific Reports 12 , 14090 (2022). Pai, M. , et al. Endoscopic ultrasound guided radiofrequency ablation, for pancreatic cystic neoplasms and neuroendocrine tumors. World journal of gastrointestinal surgery 7 , 52-59 (2015). Waung, J.A., Todd, J.F., Keane, M.G. & Pereira, S.P. Successful management of a sporadic pancreatic insulinoma by endoscopic ultrasound-guided radiofrequency ablation. Endoscopy 48 Suppl 1 , E144-145 (2016). Williams, T.A. , et al. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. The Lancet Diabetes & Endocrinology 5 , 689-699 (2017). Henry, J.F., Defechereux, T., Raffaelli, M., Lubrano, D. & Gramatica, L. Complications of laparoscopic adrenalectomy: results of 169 consecutive procedures. World journal of surgery 24 , 1342-1346 (2000). Meria, P., Kempf, B.F., Hermieu, J.F., Plouin, P.F. & Duclos, J.M. Laparoscopic management of primary hyperaldosteronism: clinical experience with 212 cases. The Journal of urology 169 , 32-35 (2003). Lev-Chelouche, D., Sagie, B., Keidar, A., Klausner, J.M. & Szold, A. Laparoscopic adrenalectomy: indications, technique, complications and follow-up. Isr Med Assoc J 5 , 101-104 (2003). Bergamini, C., Martellucci, J., Tozzi, F. & Valeri, A. Complications in laparoscopic adrenalectomy: the value of experience. Surg Endosc 25 , 3845-3851 (2011). McDonnell, N.J., Paech, M.J., Muchatuta, N.A., Hillyard, S. & Nathan, E.A. A randomised double-blind trial of phenylephrine and metaraminol infusions for prevention of hypotension during spinal and combined spinal-epidural anaesthesia for elective caesarean section. Anaesthesia 72 , 609-617 (2017). Burgen, A.S.V. & Iversen, L.L. The inhibition of noradrenaline uptake by sympathomimetic amines in the rat isolated heart. Br J Pharmacol Chemother. 25 , 35-49 (1967). Gomez-Sanchez, C.E., Kuppusamy, M., Reincke, M. & Williams, T.A. Disordered CYP11B2 Expression in Primary Aldosteronism. Horm Metab Res 49 , 957-962 (2017). Azizan, E.A., Drake, W.M. & Brown, M.J. Primary Aldosteronism: Molecular Medicine Meets Public Health. Nat Rev Neph in press (2023). Zhao, Z. , et al. Catheter-Based Adrenal Ablation Remits Primary Aldosteronism: A Randomized Medication-Controlled Trial. Circulation 144 , 580-582 (2021). Barthet, M. , et al. Long-term outcome after EUS-guided radiofrequency ablation: Prospective results in pancreatic neuroendocrine tumors and pancreatic cystic neoplasms. Endosc Int Open 9 , E1178-E1185 (2021). Sander, K. , et al. Development of [(18)F]AldoView as the First Highly Selective Aldosterone Synthase PET Tracer for Imaging of Primary Hyperaldosteronism. J Med Chem 64 , 9321-9329 (2021). Donald, R.A. , et al. The plasma ACTH, AVP, CRH and catecholamine responses to conventional and laparoscopic cholecystectomy. Clinical endocrinology 38 , 609-615 (1993). Mikami, O. , et al. High intra-abdominal pressure increases plasma catecholamine concentrations during pneumoperitoneum for laparoscopic procedures. Arch Surg 133 , 39-43 (1998). Brown, M.J., Brown, D.C. & Murphy, M.B. Hypokalemia from beta-2 receptor stimulation by circulating epinephrine. N Engl J Med 309 , 1414-1419 (1983). Struthers, A.D., Whitesmith, R. & Reid, J.L. Metabolic and haemodynamic effects of increased circulating adrenaline in man. Effect of labetalol, an alpha and beta blocker. Br Heart J 50 , 277-281 (1983). Oleinikov, K. , et al. Endoscopic Ultrasound-Guided Radiofrequency Ablation: A New Therapeutic Approach for Pancreatic Neuroendocrine Tumors. J Clin Endocrinol Metab 104 , 2637-2647 (2019). Conn, J.W. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 45 , 3-17 (1955). Tables Table 1. Demographics and Clinical Characteristics at Baseline Characteristic Mean Age +/- SD – yrs Range 57.7 +/- 10.3 39.2-77.6 Sex – no. (%): Male Female 21 (75) 7 (25) Median BMI – kg/m 2 Median (IQR) 28.4 (23.9-31.6) Ancestry – no. (%): White Black Asian 16 (57.1) 11 (39.3) 1 (3.6) Study Group – no. (%)* Group 1 Group 2 Group 3 8 (28.6) 12 (42.8) 8 (28.6) Comorbidities – no. Ischaemic heart disease Heart failure Type II diabetes Stroke Chronic kidney disease Obstructive sleep apnea Peripheral vascular disease Obesity (BMI >30 kg/m 2 ) Arrhythmias 1 0 4 1 2 5 0 10 4 Comorbidities – no. (%) 0 1 2 3 4 5 13 (46.4%) 9 (32.1%) 2 (7.1%) 2 (7.1%) 1 (3.6%) 1 (3.6%) *Study group classification is defined in the Supplementary Methods SD denotes standard deviation, BMI: Body Mass Index, IQR: interquartile range. Table 2. Primary Outcomes – Safety Data Table 2a. Number of Pre-Specified Major Hazards Findings No. of events Radiological: Perforation Haemorrhage Infarction of Major Organs 0 0 0 Biochemical/haematological: Rise in Amylase Fall in Haemoglobin 1 0 Table 2b. Study Related Serious Adverse Events (SAE)s SAE Event Severity* Related to Procedure? SAE reason Outcome 1 Hospital acquired pneumonia and atrial fibrillation with fast ventricular rate developing two days post-procedure 3 Yes Prolonged in-patient stay (by two days) Resolved 2 Hypokalaemia induced atrial fibrillation occurring during the procedure 3 Yes Prolonged in-patient stay (by two days) Resolved 3 Post-procedural non-ST elevation myocardial infarction (NSTEMI) 3 Yes Prolonged in-patient stay (by eight days) Resolved 4 Hypertensive episode during the procedure with raised post- procedure metanephrines 3 Yes Life threatening Resolved a. Table showing the number of pre-specified major hazards occurring within the study. These are grouped into radiological finding on the CT abdomen performed 24/48 hours post-ablation and abnormality on blood tests performed for safety at 24 hours post-ablation. The only pre-specified adverse event was a rise in Amlyase in one individual, from 87 iu/L at baseline to 195 iu/L at 24 hours. b. Table showing study-related SAEs. Severity and relation to procedure was determined by the independent Safety Committee, upon review of the individual cases. * Severity was graded 1: low, asymptomatic or mild symptoms, minimal or no clinical intervention indicated. 2: medium, symptomatic, minimal invasive intervention indicated e.g. intravenous fluids and 3: high, severe to life-threatening medically significant event; requiring urgent intervention, hospitalization or prolongation of hospitalisation. SAEs not related to the study are listed in Supplementary Table 9 (n= 5). Table 3. Clinical and Biochemical Outcomes Baseline Post-Ablation Difference Median ARR (95% CI) 3748 (2669, 6081) 853 (445, 1294) -2286 (-4080, -902) (pmol/L) per (nmol/L/h) Mean Aldosterone (95% CI) 1301 (856, 1746) 810 (385, 1235) -491 (-912, -70) pmol/L Mean Plasma Renin Activity (95% CI) 0.8 (-0.3, 1.9) 1.3 (0.4, 2.2) 0.5 (-0.8, 1.8) nmol/L/h Mean Potassium (95% CI) 3.9 (3.7, 4.1) 4.3 (4.1, 4.4) 0.3 (0.1, 0.6) mmol/L Median Defined Daily Dose (95% CI) 4.0 (2.8, 6.5) 2.3 (1.1, 4.7) -1.4 (-3.0, -0.5) Median no. of Antihypertensives (95% CI) 3.0 (2.0, 3.0) 1.5 (1.0, 2.0) -1 (-1.7, 0.0) Mean Home Systolic BP (95% CI) 136.3 (126.2, 146.3) 138.8 (130.6, 147.0) 5.9 (-7.5, 19.3) mmHg Mean Home Diastolic BP (95% CI) 80.3 (74.7, 85.8) 86.9 (81.6, 92.3) 8.0 (1.5, 14.5) mmHg Mean Clinic Systolic BP (95% CI) 144 (134.8, 153.2) 146.8 (140.1, 153.5) 3.2 (-5.7, 12.1) mmHg Mean Clinic Diastolic BP (95% CI) 84.8 (78.2, 91.4) 90.3 (85.1, 95.6) 5.8 (-0.5, 12.1) mmHg Median SUV max ratio (95% CI) 1.38 (1.18, 1.65) 1.17 (1.04, 1.29) -0.26 (-0.49, -0.06) (ratio shown as left : right) Median Tumor Size (95% CI) 13.0 (12.0, 15.0) 12.0 (10.7, 13.6) -2 (-4, -1) mm Baseline and 6-month post-ablation biochemical and clinical data. For the 7 participants who underwent two ablations, 3-month data is shown. PET-CT data was collected at 3-months post-ablation in all participants. ARR: aldosterone renin ratio (reference range <1000 (pmol/L)per(nmol/L/h)); CI: confidence interval; BP: blood pressure; SUV max : maximum standard uptake value using time of flight sequences. ONLINE METHODS Study Design FABULAS was a three-centre study (Barts Health NHS Trust, Queen Mary University of London; Addenbrooke’s Hospital, University of Cambridge; and University College London Hospitals NHS Foundation Trust, University College London). It was modelled on phase 1b/2a trials of novel drugs. The primary aim was to assess the safety of EUS-RFA, while the secondary objective was to determine the feasibility and efficacy of the procedure. The trial was performed in accordance with the ethical principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The protocol was approved by the London - Bloomsbury Research Ethics Committee (United Kingdom, REC ref: 17/LO/0948, IRAS ID 222446) and by the local research and development department at each participating centre. The trial registration was submitted to ClinicalTrials.gov on 20th January 2018 (NCT03405025). Informed, written consent was obtained from all study participants before any trial-related activity. Participants The trial enrolled participants > 18 years of age with a diagnosis of PA meeting the Endocrine Society’s criteria, 1 and evidence of a probable or definite left-sided APA. This was determined by adrenal vein sampling (AVS) or molecular imaging ([ 11 C]-metomidate PET-CT, MTO, or para-chloro-2-[ 18 F]fluoroethyletomidate PET-CT, [ 18 F]CETO). 2,3 The inclusion criteria for each of the three sequential, overlapping groups of 10 participants is detailed below. Group 1: Left-sided APA proven on either AVS or PET-CT. Participants wishing to take fewer drugs for their hypertension. Participants meeting Endocrine Society criteria for considering curative treatment of unilateral disease, but who were often not referred for surgery because the benefit: risk was considered too low. Participants aged ≥60 whose BP was at or near target (BP140/90 mmHg for most participants, or BP 130/80 mmHg in those with co-morbidities listed in the Hypertension guidelines) on treatment with tolerated antihypertensive medication. Participants with identified macroadenomas (APAs > 1 cm in diameter), who had probably at least 1 cm of peri-adrenal fat on axial and coronal projections. Group 2: Participants with either: (i) a definite unilateral left-sided APA, but did not want surgery; or (ii) probable but not unequivocal evidence of a unilateral left adrenal APA. Group 3: Participants > 18 years of age meeting criteria for surgery but consented to undergo endoscopic ablation instead. Individuals were excluded from the study if they were unable to give informed consent, were unable to discontinue beta blockers or direct renin blockers, were pregnant or unable/unwilling to take secure contraceptive precautions, or had any illness, condition or drug regimen considered a contraindication by the Principal Investigator or Chief Investigator. AVS Adrenal Vein Sampling (AVS) was performed under cosyntropin stimulation. An infusion of 50 ug/h of intravenous cosyntropin was commenced one hour prior to the procedure and continued throughout. Cannulation was considered successful if the cortisol level in each adrenal vein was ≥3× greater than that in the iliac and/or infrarenal inferior vena cava. A high probability of unilateral left sided PA was diagnosed if the aldosterone/cortisol ratio in left adrenal vein was ≥4 times that in the right adrenal vein. 4,5 A 'probable’ left sided PA was diagnosed if the aldosterone/cortisol ratio was three to four. [ 11 C]metomidate and [ 18 F]CETO PET-CT [ 11 C]metomidate/ [ 18 F]CETO PET-CT was performed to confirm the presence of a focal, left sided-APA which could be targeted for ablation. All participants were pre-treated with 0.5 mg dexamethasone orally four times a day for 72 h before scanning. PET-CT imaging was performed on a GE Discovery PET-CT 690 scanner (GE Medical Systems). Non-contrast CT images were acquired over the adrenals (140 kV; 30 mA; slice thickness = 3.75 mm). Following an intravenous injection of [ 11 C]metomidate or [ 18 F]CETO (mean: 215 mBq; range: 86–289 MBq), dynamic PET images were acquired for 30 minutes at 30 minutes after administration. The images were reconstructed with iterative reconstruction (ordered subset expectation maximization) using two iterations, 24 subsets and a Gaussian filter of 6.4 mm. The reconstruction included time-of-flight, attenuation, scatter and decay corrections. The images were converted to standardized uptake values (SUVs; g ml−1) by dividing the activity concentration in the image voxels (Bq ml−1) by the injected activity per patient weight (Bq g−1). A left-sided APA was diagnosed if it fulfilled the following three criteria: a focal adrenal nodule with Hounsfield Units in keeping with a benign adrenocortical adenoma, evidence of high [ 11 C]metomidate or [ 18 F]CETO uptake into the identified nodule, and a calculated left/right maximum SUV (SUVmax) ratio of >1.25 6 . A ‘probable’ left-sided APA was diagnosed if 2/3 of the above criteria were fulfilled. Pre- and post-ablation PET-CTs were performed to allow comparison of the tracer-avid nodule(s) and determine whether ablation was successful from a radiological perspective. EUS-RFA technique and protocol As a preventive measure against the consequences of possible adrenomedullary stimulation during RFA, all participants received combined alpha and beta-blockade for two weeks prior to ablation. If required, other drugs were reduced in dose to maintain stable BP. The protocol allowed for RFA to be performed under general anaesthesia (GA) or deep sedation, and the latter was adopted by the last of the three sites to undertake EUS-RFA. On the day of the procedure participants were examined and clinic BPs and blood tests (full blood count, urea and electrolytes, liver function tests, amylase/lipase and c-reactive protein) were taken as a baseline. Baseline home BP readings taken over the 4 days prior to ablation (three readings taken twice daily, 24 in total) were also recorded. After induction of GA or deep sedation, a linear-array EUS endoscope (Olympus, Keymed UK Ltd.; Pentax, Hitachi Medical Systems UK Ltd.) was advanced into the stomach, and the left adrenal gland identified using EUS. The nodule, presumed APA, can be identified as an echo-poor region (Supplementary Figure 1). The pre-ablation PET-CT was also used to help confirm the target lesion. Prior to advancement of the RFA needle into the targeted lesion, surrounding vascular structures were carefully visualized, aided by colour Doppler, in order to avoid inadvertent thermal injury during ablation of the APA. A 25-gauge needle was then passed transgastrically into the nodule enabling a fine needle biopsy (FNB) to be drawn into formalin or RNAlater© (Thermofisher, USA) and stored for subsequent immunohistochemistry (IHC) and molecular analyses respectively. A 19-gauge monopolar needle electrode with a non-insulated 5mm/10mm tip (EUSRATM, STARmed, Taewoong, Korea) and Viva Combo RF Generator System was used to deliver the radiofrequency (RF) current. The tip of the RFA catheter was positioned at the distal margin of the targeted lesion under sonographic guidance. The RF current was delivered with the tip of the electrode maintained within the target mass and controlled by the endo-sonographer. Short bursts of treatment/burtns up to 25 seconds at 15-30W were applied, and stopped when hyperechoic bubbles were observed at the site of ablation, or impedance exceeded 100 Ohms. The acoustic scattering from formed gas bubbles was used as an estimate of the induced area of tissue necrosis. Depending on size, repeated treatments were performed by catheter withdrawal and repositioning in different planes in a fanned movement. Each treatment lasted 5-20 seconds before the catheter was repositioned within the nodule. The number of treatments during each ablation procedure increased during the study, as operators modified their approach based on the findings from post-RFA PET-CTs from the initial cases. For participants who underwent a second procedure, the extent of viable adenoma was assessed intra-procedurally with or without the administration of contrast medium (SonoVue, Bracco UK Ltd) to areas of untreated tissue, and repeated treatment cycles applied as deemed appropriate by the operator in order to attempt complete ablation of the targeted lesion. Post-procedure Monitoring All participants had clinical examination and blood tests (full blood count, urea and electrolytes, liver function tests, amylase/lipase and c-reactive protein) at baseline (morning of procedure) and at 24-48 hours post-procedure, to identify any procedure-related complications. In addition, an abdominal CT was also performed at 24-48 hours to look for radiological evidence of any of the pre-specified major hazards. Follow-up Visits Participants were followed up at one, three and six months post-EUS-RFA. Home BP readings (taken during the 4 days prior to each visit) were recorded. Clinic BPs and blood tests (full blood count, urea and electrolytes, creatinine, bicarbonate, liver function tests, amylase/lipase, c-reactive protein, renin and aldosterone) were also collected to allow for assessment of efficacy (biochemical and clinical cure). A repeat PET-CT scan was performed at three months post-ablation to assess evidence of successful ablation of APA, or ‘radiological cure’. MDT Decision Regarding a Second Ablation Procedure The protocol allowed a second ablation procedure to be offered to participants who did not achieve complete biochemical success and who also had a residual radiological target on molecular imaging. It was considered that this would be necessary in individuals with large APAs. The post-ablation PET-CT scan was reviewed, along with biochemical and clinical data, at a monthly multidisciplinary team (MDT) meeting. A decision for offering a second ablation was based on a number of factors, including reductions in isotope uptake, change in SUVmax ratio between PET-CT scans before and after the first ablation, changes in clinic and home blood pressures, as well as participant wishes for a second procedure. The ablation procedure and follow-up visits in those who underwent a second ablation were the same as per the first ablation. Safety Committee The independent Safety Committee comprised of an expert adrenal radiologist (Anju Sahdev, FRCR), an endocrinologist (Scott Akker, PhD MRCP), and a hepatobiliary-pancreatic surgeon with experience of RFA (Satyajit Bhattacharya, FRCS). Their role was to independently assess the safety of EUS-RFA. They initially convened after the first two participants had undergone EUS-RFA, and then once again following the subsequent two participants. Recruitment into each subsequent group could only commence if the Safety Committee deemed the procedure to be safe in the first four participants of each prior group. Primary Outcomes The primary endpoint was safety, defined as occurrence of any of the three pre-specified major hazards: perforation, haemorrhage and infarction of major visceral organs. These were sought radiologically on the 24/48-hour post-procedure CT and supported by clinical examination, and comparison of serum amylase (and/or lipase) and full blood count pre- and 24/48 hours post-RFA. This assessment was made by the independent Safety Committee, who also reviewed the severity of all documented serious adverse events (SAEs) and their likelihood in relation to EUS-RFA. Reporting of Events We recorded all SAEs. A SAE is officially defined as any untoward medical occurrence that results in: • Death • A life-threatening event • Inpatient hospitalisation or prolongation of hospitalisation. • Severe or permanent disability • Cancer (other than cancers diagnosed prior to enrolment in studies involving patients with cancer) • Congenital anomaly • Any grade four toxicity We also recorded events related to GA or sedation (e,g: drowsiness, confusion and respiratory depression). Events related to the gastric puncture and delivery of the RFA (e.g: bowel perforation, haemorrhage and infarction of major organs) and finally events related to complications of accidental adrenomedullary stimulation (e.g: severe hypertension and rise in plasma metanephrines). Serious Adverse Events (SAEs) were reported to and independently reviewed by the Sponsor. Decisions on further reporting to the regulatory body (Medicines and Healthcare products Regulatory Agency) were made by the Sponsor, according to local protocol. Extended Safety Meeting At the end of the study an extended safety meeting was held at which all unexpected events / SAEs were discussed and scored by the Safety Committee. The below scoring system was drawn up and applied. Safety committee scoring system: Level of significant event: a. Low: asymptomatic or mild symptoms, minimal or no clinical intervention indicated. b. Medium: symptomatic, minimal invasive intervention indicated e.g. intravenous fluids. c. High: severe to life-threatening medically significant event requiring urgent intervention, hospitalisation, or prolongation of hospitalisation. Likelihood of significant event being associated with intervention: 1. Low: no association. 2. Medium: minimum to moderate association. 3. High: as a direct consequence of. Statistical Analysis The sample size of 30 was estimated on the basis of a 95% probability of at least one serious complication occurring, whose true risk was greater than one-in-ten ((1-p)^30=0.05), and 80% probability of at least one serious complication occurring if risk-per-participant was >one-in-twenty ((1- p)^30=0.2). The study was not powered for efficacy. No hypothesis testing was planned for the primary endpoint (safety), or for the categorical secondary biochemical and/or clinical success endpoints. In order to avoid adjustment for multiplicity, and so maximise the likelihood of detecting a significant efficacy endpoint in 30 patients, there was a single pre-specified hypothesis, for the comparison of pre- and post-ablation aldosterone/renin ratios. A Wilcoxon signed rank test was used. For other continuous variables, descriptive statistics with 95% confidence intervals were reported. Efficacy was estimated after all ablations in each participant, and then only after first ablations. Secondary Outcomes The secondary outcomes were evidence of clinical and biochemical success at six months post-RFA (as defined by the international PASO Consensus, Supplementary Table 1), 7 . Successful ablation of the APA, or ‘radiological success’ was quantified by comparing PET-CT images from before and after EUS-RFA. Visual assessment of the PET-positive nodule(s) in all planes was reviewed by a radiologist (H.C.) without prior knowledge of the biochemical and clinical outcomes for each participant. For quantification, the reduction in isotope activity was graded by as a percentage of the original PET-positive nodule, and grouped into quartiles of reduction (<25%, 25-50%, 50-75% or 75-100% reduction). Exploratory Analysis Exploratory outcomes included immunohistochemistry (IHC) and quantitative polymerase chain reaction (qPCR) for CYP11B2(aldosterone synthase) expression were performed on the FNB samples to confirm whether the targeted nodule was an APA. Immunohistochemistry (IHC) IHC was performed on 3-μm sections cut from paraffin blocks using a fully automated system (BOND III IHC and ISH stainer from Leica Biosystems). The CYP11B1 primary antibody clone RAT-87 (MABS502, Merck) was used at a dilution of 1:100 after heat-induced epitope retrieval at pH 9.0 (BOND Epitope Retrieval Solution 2, AR9640, Leica) for 20 minutes; and the CYP11B2 primary antibody clone EPR10494 (ab168388, Abcam) was used at a dilution of 1:200 after proteolytic-induced epitope retrieval with Proteinase K (BOND Enzyme Pre-treatment kit, AR9551, Leica) for 10 min. The primary antibody binding to tissue sections was visualized using BOND Polymer Refine Detection system (DS9800, Leica). Semi quantitative analysis of IHC was performed by two experienced board certified endocrine pathologists, blinded to clinical, biochemical and radiological outcome information. Quantitative Polymerase Chain Reaction (qPCR) qPCR was used to quantify the level of mRNA expression of the genes of interest. FNB samples of adrenal tissue were homogenised in lysis buffer for 20s using FastPrep-24 5G Sample Preparation System (MP-Biomedicals.) Total RNA was extracted using PureLink RNA minikit as per protocol (#12183018A, Invitrogen) and reverse transcribed to cDNA using High Capacity RNA-to-cDNA Kit (#4387406, Applied Biosystem). Quantification of mRNA expression was performed using TaqMan Fast Gene Expression Master Mix (#4444557, Applied Biosystems) and commercially available probes from Life Technology: CYP11B2 (Hs01597732_m1), CYP11B1 (Hs01596404_m1) and 18S rRNA (Hs99999901_s1) as a housekeeping gene. Results were analysed using the 2-ΔΔCT method 8 . Where sufficient RNA was available, RNAseq was performed by the Barts and The London Genome Centre, United Kingdom; for analysis of somatic genotype and full transcriptome as previously described 9 . Biochemistry Methods All blood tests were analysed at United Kingdom Accreditation Service-accredited clinical laboratories. Serum aldosterone was measured by either an automated chemiluminescence immunoassay (LIAISON; DiaSorin) or by tandem mass spectrometry (in-house method adapted from 10 ). The direct renin mass was measured at two centres by automated chemiluminescence immunoassay (LIAISON; DiaSorin). Plasma renin activity was measured in the final centre by liquid chromatography tandem mass spectrometry (North West London Pathology). Conversion between activity (nmol/L/h) to renin mass (mU/L) was performed using a conversion factor of 10.989. 2 REFERENCES 1. Funder, J.W. , et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 101 , 1889-1916 (2016). 2. Wu, X. , et al. [11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial. Nature Medicine 29 , 190-202 (2023). 3. Goodchild, E. , et al. Novel radiolabeled ligand, Para-chloro-2-[ 18 F]fluoroethyletomidate (CETO) compared to [ 11 C]metomidate-PET (MTO) for the lateralisation of primary aldosteronism (PA). Endocrine Abstracts (2022). 4. Rossi, G.P. , et al. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension 63 , 151-160 (2014). 5. Young, W.F. & Stanson, A.W. What are the keys to successful adrenal venous sampling (AVS) in patients with primary aldosteronism? Clinical endocrinology 70 , 14-17 (2009). 6. Burton, T.J. , et al. Evaluation of the sensitivity and specificity of (11)C-metomidate positron emission tomography (PET)-CT for lateralizing aldosterone secretion by Conn's adenomas. J Clin Endocrinol Metab 97 , 100-109 (2012). 7. Williams, T.A. , et al. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. The Lancet Diabetes & Endocrinology 5 , 689-699 (2017). 8. Livak, K.J. & Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25 , 402-408 (2001). 9. Wu, X. , et al. Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production. Nature Genetics 55 , 1009-1021 (2023). 10. Hinchliffe, E., Carter, S., Owen, L.J. & Keevil, B.G. Quantitation of aldosterone in human plasma by ultra high performance liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 913-914 , 19-23 (2013). Supplementary Figures Supplementary Figures are not available with this version Supplementary Tables Supplementary Tables are not available with this version Additional Declarations There is NO Competing Interest. Supplementary Files FABULASProtocolV5final.pdf FABULASSAPV128022023.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4365782","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":299413447,"identity":"9689efed-2f34-430a-aebf-70fc3d2972ad","order_by":0,"name":"Morris 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London","correspondingAuthor":false,"prefix":"","firstName":"Iulia","middleName":"","lastName":"Munteanu","suffix":""},{"id":299413486,"identity":"96af7af4-e3fe-4717-ae91-cb39e97d6e29","order_by":14,"name":"Jackie Salsbury","email":"","orcid":"","institution":"Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London","correspondingAuthor":false,"prefix":"","firstName":"Jackie","middleName":"","lastName":"Salsbury","suffix":""},{"id":299413487,"identity":"c78ae236-a266-4b08-8305-888a32d95955","order_by":15,"name":"Elena Benu","email":"","orcid":"","institution":"Queen Mary University of London","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Benu","suffix":""},{"id":299413488,"identity":"b52a238e-2e36-457c-8645-9130ad62f038","order_by":16,"name":"Patrizia Ebano","email":"","orcid":"","institution":"Queen Mary University of London","correspondingAuthor":false,"prefix":"","firstName":"Patrizia","middleName":"","lastName":"Ebano","suffix":""},{"id":299413489,"identity":"c8d7be77-5e4d-48b4-8e01-6fc7546c48d4","order_by":17,"name":"Nick Carroll","email":"","orcid":"","institution":"Cambridge University Hospitals NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Nick","middleName":"","lastName":"Carroll","suffix":""},{"id":299413490,"identity":"64611ad5-971b-46be-9ca4-09add91584da","order_by":18,"name":"Daniel Gillett","email":"","orcid":"","institution":"University of Cambridge","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Gillett","suffix":""},{"id":299413491,"identity":"aae8c0b3-c033-440e-9c1d-aa5d6228aff0","order_by":19,"name":"John Tadross","email":"","orcid":"","institution":"Cambridge University Hospitals NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"","lastName":"Tadross","suffix":""},{"id":299413492,"identity":"c1495c24-da29-450e-a0b1-6cd36488367a","order_by":20,"name":"Alison Marker","email":"","orcid":"","institution":"Cambridge University Hospitals NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Alison","middleName":"","lastName":"Marker","suffix":""},{"id":299413493,"identity":"18988562-538a-4986-ac56-e27463f31365","order_by":21,"name":"Patrick Wilson","email":"","orcid":"","institution":"Cambridge University Hospitals NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Patrick","middleName":"","lastName":"Wilson","suffix":""},{"id":299413494,"identity":"ea54d3dd-5ba9-4db9-a8c7-7952a6fc84c3","order_by":22,"name":"Edmund Godfrey","email":"","orcid":"","institution":"Cambridge University Hospitals NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Edmund","middleName":"","lastName":"Godfrey","suffix":""},{"id":299413495,"identity":"a3a36b5d-d191-46ca-8cfd-7e0c629550dc","order_by":23,"name":"George Goodchild","email":"","orcid":"","institution":"Barts Health NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"George","middleName":"","lastName":"Goodchild","suffix":""},{"id":299413501,"identity":"75dc867d-00f3-48cd-b3cb-a219c6a9484b","order_by":24,"name":"Jonathan Bestwick","email":"","orcid":"","institution":"Queen Mary University of London","correspondingAuthor":false,"prefix":"","firstName":"Jonathan","middleName":"","lastName":"Bestwick","suffix":""},{"id":299413502,"identity":"9f7c52a0-773d-4e50-8ea6-d367db33b6f1","order_by":25,"name":"Mark Gurnell","email":"","orcid":"","institution":"Metabolic Research Laboratories, Welcome Trust-MRC Institute of Metabolic Science, and NIHR Cambridge Biomedical Research Centre","correspondingAuthor":false,"prefix":"","firstName":"Mark","middleName":"","lastName":"Gurnell","suffix":""},{"id":299413503,"identity":"201cace7-4809-4a70-9097-f1d5234969f6","order_by":26,"name":"Heok Cheow","email":"","orcid":"","institution":"Department of Radiology, Addenbrooke’s Hospital, Cambridge Universities NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Heok","middleName":"","lastName":"Cheow","suffix":""},{"id":299413504,"identity":"6784baba-f5ba-46e9-90a4-a7e7bb9fc345","order_by":27,"name":"Stephen Pereira","email":"","orcid":"https://orcid.org/0000-0003-0821-1809","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"","lastName":"Pereira","suffix":""},{"id":299413505,"identity":"664bdf08-5d6d-4f25-85d2-13041372f41b","order_by":28,"name":"William Drake","email":"","orcid":"","institution":"Endocrinology","correspondingAuthor":false,"prefix":"","firstName":"William","middleName":"","lastName":"Drake","suffix":""}],"badges":[],"createdAt":"2024-05-03 19:55:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4365782/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4365782/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56204832,"identity":"29295834-fa36-41c5-ad6e-dbfaf9457e5e","added_by":"auto","created_at":"2024-05-09 20:51:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":86315,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCONSORT Diagram and Study Outline\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e CONSORT diagram showing the disposition of study participants. 28 participants completed endoscopic ultrasound radiofrequency ablation, of which seven had two ablation procedures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb.\u003c/strong\u003e Schematic showing the study outline and the stages at which safety and efficacy were assessed. Participants with confirmed Primary Aldosteronism (PA), as per Endocrine Society consensus guidelines, and a probable or definite unilateral left aldosterone producing adenoma (APA) were eligible for the study. Two participants who did not fulfil the latter criteria underwent left-sided ablation for de-bulking purposes. The first 10 participants were monitored as an inpatient for 48 hours, reducing to 24 hours in the subsequent 18 participants. The main assessment of efficacy (home blood pressures and measurements of ARR) were performed at six months post-ablation, except in seven participants where assessment of efficacy was done at three months after the second ablation procedure due to time constraints.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4365782/v1/f93358ff98a9f2557418db56.png"},{"id":56205338,"identity":"a16c383c-a208-48e0-9b44-e27cdb144e8a","added_by":"auto","created_at":"2024-05-09 21:07:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":740238,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePre- and post-ablation [\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e11\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eC]metomidate PET-CT images and measurements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea. \u003c/strong\u003ePre-\u003cstrong\u003e \u003c/strong\u003eand \u003cstrong\u003eb. \u003c/strong\u003epost-ablation axial PET-CT overlay images for selected participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ec. \u003c/strong\u003eTable showing pre-and post-ablation maximum standardized uptake value (SUV\u003csub\u003emax\u003c/sub\u003e) measurements over each adrenal and adenoma. SUV\u003csub\u003emax \u003c/sub\u003eover the liver is included for reference. The SUV\u003csub\u003emax \u003c/sub\u003eratio is the SUV\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;over the left adenoma divided by SUV\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;over the right adrenal (or adenoma if present). Note participant 5 had bilateral adenoma, of which the right appeared non-functioning. However the SUV\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;over the right adenoma increased post-ablation (while the SUV\u003csub\u003emax \u003c/sub\u003eratio left:right reduced post-ablation, the SUV\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;ratio right : left increased to 1.27). All SUV\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;values show time of flight (TOF), except when indicated by asterisks*, where SUV\u003csub\u003emax\u003c/sub\u003e\u0026nbsp;SharpIR is shown. SUV\u003csub\u003emax \u003c/sub\u003eratio \u0026gt;1.25 is indicative of unilateral disease. ‘Low’ indicates below the limit of detection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ed. \u003c/strong\u003eTable showing clinical and biochemical outcomes at 6 months for each participant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ee.\u003c/strong\u003e Fine needle biopsy (FNB) from representative participants obtained endoscopically, immediately prior to ablation of the adenoma (prior to first ablation only in participant 2). Top panels show hematoxylin and eosin (H\u0026amp;E) staining. Adrenocortical cells with either eosinophilic, lipid-poor or lipid-rich cytoplasm are seen in all three participants. Middle panels show immunohistochemistry (IHC) staining with anti-CYP11B2 while bottom panels show IHC staining for anti-CYP11B1 antibodies. Strong uniform staining for CYP11B2 in the lipid-poor cells with reciprocal staining of CYP11B1 in the lipid-rich cells is seen in participant 2 and 4. This confirms presence of an aldosterone producing adenoma. For participant 5, IHC shows weak to strong positivity in most cells for CYP11B1. Staining for CYP11B2 is negative, apart from a small group of cells in one of the fragments. It was not possible to confirm a diagnosis of an aldosterone producing adenoma from this FNA sample. However, RNA extracted from a second FNA sample from the adenoma demonstrated increased CYP11B2 expression on qPCR (Supplementary Table 7). Further details on these three participants can be found in Supplementary Tables 2 and 3.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4365782/v1/39996fa29b69a79b34289ca2.png"},{"id":58377732,"identity":"ea48aaab-9831-4854-b2bf-9be0d28c2ceb","added_by":"auto","created_at":"2024-06-14 15:43:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1920043,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4365782/v1/abfc3299-d8de-40b9-9a89-13c8e1438032.pdf"},{"id":56205179,"identity":"24918c8b-effa-44ab-be00-2d49f68eb55d","added_by":"auto","created_at":"2024-05-09 20:59:42","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1091869,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"FABULASProtocolV5final.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4365782/v1/0af7f84cebc6eeb1e7d99b9c.pdf"},{"id":56204836,"identity":"521745b7-d173-4126-9454-e1ceb1b69dcf","added_by":"auto","created_at":"2024-05-09 20:51:44","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":727317,"visible":true,"origin":"","legend":"","description":"","filename":"FABULASSAPV128022023.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4365782/v1/a0f9f0297294c5524500629f.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Endoscopic, ultrasound guided, radiofrequency ablation of aldosterone producing adenomas: A prospective, proof-of-concept trial","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePrimary aldosteronism (PA) is a common, high-risk form of hypertension and frequently leads to treatment-resistant hypertension.\u003csup\u003e1\u0026ndash;3\u003c/sup\u003e The risk of cardiometabolic complications is at least twice that of age- and gender- matched people with essential hypertension.\u003csup\u003e4,5\u003c/sup\u003e Approximately 50% of patients with PA have a unilateral sub-type, usually due to an aldosterone-producing adenoma (APA) whose removal by adrenalectomy can cure PA, reverse the enhanced cardiovascular risk, and sometimes cure hypertension altogether.\u003csup\u003e6,7\u003c/sup\u003e However, the lack of prospective data proving long-term superiority of adrenalectomy over non-surgical approaches, understandable when PA was considered a rarity, is a problem for a condition with a prevalence exceeding 5% of hypertension.\u003csup\u003e8\u003c/sup\u003e Availability of surgery is also unlikely to meet demand as diagnosis of PA increases above 1% of cases; and the small size of most APAs discovered by modern imaging is a further incentive to find minimally-invasive, adrenal-sparing approaches that permit rapid resumption of normal activities.\u003csup\u003e9,10\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAn alternative to surgery has been percutaneous radiofrequency ablation (RFA) of the culprit nodule, with several (mainly retrospective) reports of comparable efficacy to surgery\u003csup\u003e11\u0026ndash;15\u003c/sup\u003e. However, the benefit is offset by pressor crises due to adrenomedullary excitation, and by the challenge of identifying the culprit APA(s) in a gland with more than one macroscopic nodule.\u003csup\u003e16\u0026ndash;19\u003c/sup\u003e In one prospective study, intraprocedural hypertension\u0026thinsp;\u0026gt;\u0026thinsp;180 mmHg was observed in 43% of cases, serious adverse events in 26%, of which 8% were life-threatening.\u003csup\u003e20\u003c/sup\u003e These hazards, we hypothesized, could be avoided for left-sided APAs by a transgastric endoscopic ultrasound (EUS)-guided approach, which enables continuous catheter manipulation and real-time monitoring.\u003csup\u003e21,22\u003c/sup\u003e Our concepts were that molecular imaging would enable EUS-RFA to target aldosterone-secreting nodules, and that multiple short treatments (i.e. RFA burns) would avoid risk of damage to either the adjacent adrenal or nearby organs.\u003c/p\u003e \u003cp\u003eThe aim of this study, which we have termed FABULAS (Feasibility study of radiofrequency endoscopic Ablation, with Ultrasound guidance, as a non-surgical, Adrenal Sparing treatment for aldosterone-producing adenomas), was to determine whether EUS-RFA of left-sided APAs is a safe method of achieving sustained reduction in plasma aldosterone levels. Recruitment of three sequential, overlapping groups of 10 participants each was planned, allowing initial assessment to be performed in those whose potential favourable benefit:risk derived from their unsuitability for surgery, progressing to a final group for whom RFA was a personal preference, with a benefit:risk derived in part from initial experience in FABULAS. All participants had PA as defined by the Endocrine Society Guidelines\u003csup\u003e6\u003c/sup\u003e, and left-sided APAs diagnosed by Adrenal Vein Sampling (AVS) or molecular imaging. The close proximity of the left adrenal and the stomach, and the transgastric route of access to the left APA using EUS is demonstrated in Supplementary Fig.\u0026nbsp;1. EUS-RFA was performed, initially under general anaesthesia, subsequently under deep sedation. Safety was assessed by an independent Safety Committee who reviewed the reporting of any of the three pre-specified major hazards (perforation, haemorrhage or infarction of major organs) and all serious adverse event (SAEs); in addition to analysis of changes in intra- and post-procedure biochemistry and BP. The secondary objectives were to evaluate the efficacy of EUS-RFA, by biochemical and clinical success as defined by the PASO Consensus\u003csup\u003e23\u003c/sup\u003e (Supplementary Table\u0026nbsp;1); and by pre- and post-ablation radiological measurements on molecular imaging ([\u003csup\u003e11\u003c/sup\u003eC]metomidate PET-CT, MTO, or para-chloro-2-[\u003csup\u003e18\u003c/sup\u003eF]fluoroethyletomidate PET-CT, [\u003csup\u003e18\u003c/sup\u003eF]CETO). Immunohistochemistry (IHC) and molecular analyses were also performed on fine needle biopsy (FNBs) taken at the time of the procedure to confirm diagnosis of APA (that the treated nodule stained positive for CYP11B2/aldosterone synthase) and for genotyping. Full details of the inclusion and exclusion criteria, procedures and endpoints are presented in the Online Methods.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eParticipant Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 44 participants were screened, 31 were recruited, and 28 (21 male, seven female, mean age 57.7 +/- 10.3 years) proceeded to RFA (Fig. 1a and Table 1). By self-identification, 16 (57%) participants were White, and 11 (39%) were Black (the latter approximately three times their proportionate representation in the local population). Seven participants had a second procedure, and all 35 RFAs were included in the primary safety assessment. The demographic and clinical details are shown in Table 1 and Supplementary Table 2. Unilateral PA was diagnosed with high or medium probability in 19 and 7 participants, respectively, with [\u003csup\u003e11\u003c/sup\u003eC]metomidate- or [\u003csup\u003e18\u003c/sup\u003eF]CETO-positive nodules in 25 and 1, respectively (Supplementary Table 3). The remaining two participants had bilateral focal [\u003csup\u003e11\u003c/sup\u003eC]metomidate uptake, and were included because of poor BP control on maximal tolerated doses of mineralocorticoid receptor antagonists.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe first participant underwent screening on 21\u003csup\u003est\u003c/sup\u003e February 2018. After a pandemic-related interruption to the trial, the last participant visit occurred on 10\u003csup\u003eth\u003c/sup\u003e February 2023. The study outline is shown in Figure 1b. All 28 participants had primary safety measurements (at 48 hours post-RFA in the first ten participants, or after 24 hours in the remaining 18), and proceeded to efficacy assessments at six months after RFA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary endpoint: safety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo participant experienced any of the pre-specified major hazards of perforation, haemorrhage or infarction of major organs (Table 2a). At 24 or 48 hours post-RFA, only one participant had an elevated plasma amylase (baseline 87 iu/L, 24h 195 iu/L) without any clinical or radiological evidence of acute pancreatitis; no participant had a reduction in haemoglobin (Supplementary Table 4), or abnormal liver function tests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary endpoint: efficacy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSix months after sole (n=21) or final (n=7) RFA, 16 and 5 participants achieved complete or partial biochemical success, respectively; 4 and 8 participants achieved complete or partial clinical success (Supplementary Table 5). Except for complete clinical success (home BP \u0026lt;135 and \u0026lt;85 mmHg off treatment), the other PASO criteria are susceptible to interfering drug effects. Since efficacy was a secondary endpoint, these were not discontinued, and are shown alongside outcomes for each participant in Supplementary Table 3. Aldosterone-renin ratio (ARR) fell by median 2286 (95% CI, 902,4081), p\u0026lt;0.001 (Table 3, Supplementary Figure 2). Average BP was unchanged, but the median defined daily dose of antihypertensive medications fell by 1.4 (95% CI, 0.5,3.0). Radiological success was estimated as the change in maximum standardized uptake value (SUVmax) ratio, comparing maximum [\u003csup\u003e11\u003c/sup\u003eC]metomidate or [\u003csup\u003e18\u003c/sup\u003eF]CETO uptake in left versus right adrenal (Figure 2a-b and Supplementary Figure 3). The SUVmax ratio fell by median 0.26 (95% CI, 0.06,0.49), associated with a fall in median nodule diameter of 2.0 mm (95% CI, 1.0,4.0) (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExploratory analyses\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e[\u003csup\u003e11\u003c/sup\u003eC]metomidate / [\u003csup\u003e18\u003c/sup\u003eF]CETO uptake was qualitatively preserved in the adrenal adjacent to the APA.\u0026nbsp;IHC and/or quantitative polymerase chain reaction (qPCR) confirmed CYP11B2 positivity in 22 nodules, whereas six were positive for CYP11B1 but not CYP11B2 (Figure 2e and Supplementary Table 6) and comprised all but one of the seven absent biochemical successes. Conversely, of nine participants with a qualitatively complete ‘radiological’ ablation (defined as 75-100% reduction in [\u003csup\u003e11\u003c/sup\u003eC]metomidate/[\u003csup\u003e18\u003c/sup\u003eF]CETO uptake over the ablated PET-positive nodule), only two failed to achieve complete biochemical success (Supplementary Table 7). One participant with absent success was noted to have increased SUVmax over a contralateral nodule (Figure 2). RNAseq identified mutations in 13/19 (68%) tumour FNB samples sent for sequencing (Supplementary Table 8). The two most common somatic mutations, \u003cem\u003eKCNJ5\u0026nbsp;\u003c/em\u003eand \u003cem\u003eCACNA1D,\u003c/em\u003e were the least abundant in our cohort (found in two tumours each). 3/19 tumours harboured \u003cem\u003eATP2B3\u003c/em\u003e mutations while the \u003cem\u003eATP1A1\u003c/em\u003e was the most prevalent genotype (6/19).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSerious Adverse Events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll study-related and non-study related SAEs are listed in Table 2b and Supplementary Table 9 respectively. All resolved spontaneously. Four were judged by the Safety Committee to be procedure-related, including three (pneumonia, arrhythmia and myocardial ischaemia) more likely related to general anaesthesia (GA) than RFA itself, since these complications are also reported after laparoscopic adrenalectomies.\u003csup\u003e24-27\u003c/sup\u003e One SAE, an episode of intra-procedural hypertension associated with increase in plasma metanephrine, was graded as serious and procedure-related, but was considered to be due to the intravenous drugs used during GA (metaraminol and ephedrine), not due to adrenomedullary stimulation.\u003csup\u003e28,29\u003c/sup\u003e This case is described in detail in the Supplementary Appendix. There were no other episodes of increased BP during RFA. The pre- and post-RFA plasma normetanephrine and metanephrine concentrations are shown in Supplementary Figure 4 and Supplementary Table 4.\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this proof-of-concept study of an endoscopic approach to treatment of PA, culprit APAs previously identified by PET-CT could be seen and targeted by EUS-RFA, and the multiple, small ablation fields avoided damage to adjacent tissues. Exclusion of rare complications of EUS-RFA will require larger studies, but the incidence excluded by the sample-size calculation for FABULAS has permitted progression to a pivotal comparison of nodular ablation with surgery (NCT05405101). Complete biochemical and/or clinical success \u0026ndash; namely cure of PA and/or hypertension itself \u0026ndash; were the exception, but were observed in 7/9 particiapnts whose APA was completely eradicated, as judged by the post-procedure PET-CT.\u003c/p\u003e \u003cp\u003eThe strategy of ablating culprit nodules, rather than removing a whole organ, is clearly attractive. Despite this, and the number of studies of APA ablation, the procedure has not been widely adopted for PA, and was not mentioned in Endocrine Society guidelines.\u003csup\u003e6\u003c/sup\u003e Clinician hesitancy in adopting RFA into routine practice may relate to both safety and efficacy, and the limited ability of retrospective trials to evaluate these. Concerns about adrenomedullary excitation during RFA emerged with reports of florid phaeochromocytoma-like crises during long treatments of adrenal or peri-adrenal tumours.\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e Contributing to the recognition that safety is paramount is the growing realisation that the traditional binary monikers of unilateral APAs and bilateral idiopathic hyperplasia refer to ends of a continuous spectrum.\u003csup\u003e30,31\u003c/sup\u003e If the majority of unilateral PA is actually \u0026lsquo;asymmetric\u0026rsquo;, and intervention in such patients is debulking rather than curing, then anticipated average benefits of unilateral interventions are reduced, and risks need to be comparably lower. Low-risk RFA may indeed be considered as an alternative to medical treatment of PA, or at least as a non-surgical strategy to reduce the overall tablet burden.\u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAgainst this background, EUS-RFA of APAs was considered appropriate to evaluate, given reported safety of a comparable approach in patients with pancreatic neuroendocrine tumours.\u003csup\u003e33\u003c/sup\u003e The gastric ultrasound probe provides clear images of the APA and adjacent adrenal (Supplementary Fig.\u0026nbsp;1), with cortex and medulla often distinguishable from each other. The proximity also allows continual repositioning of the catheter.\u003c/p\u003e \u003cp\u003eBecause APAs are benign, the penalty of incomplete ablation is biochemical not oncological, and can be viewed in the contexts of lower morbidity and potentially greater availability of intertentional endoscopists than endocrine surgeons. In FABULAS, we did not anticipate either biochemical or clinical efficacy to approach that seen post-adrenalectomy for several reasons. First, the primary endpoint of safety mandated operator caution in the judgement of the appropriate ablation zone to target. Second, eligibility in two of the three groups included individuals with relative contra-indications to surgery, such as ambiguous evidence of unilateral PA. Third, the demographics of the FABULAS cohort were closer to those who, in our MATCH trial, were likely to have partial/absent rather than complete success. Retrospective analyses of the FNB samples confirmed paucity or absence of tumour genotypes (\u003cem\u003eKCNJ5\u003c/em\u003e or \u003cem\u003eCTNNB1\u0026amp;GNAQ\u003c/em\u003e mutations) associated with complete clinical successes in MATCH.\u003csup\u003e9\u003c/sup\u003e Of most relevance to the future success of EUS-RFA in a typical unilateral PA population, was the informal titration of number of treatments (burns), and analysis of ablation completeness by molecular imaging. Exploratory analysis demonstrated only 9/28 APAs were \u0026gt;\u0026thinsp;75% ablated (as judged independently by two groups of observers). In these participants, FABULAS proved the concept that hypertension due to PA can be cured by an endoscopic procedure. There was no technical bar to achieving near 100% ablation. The phase I study-equivalent design of FABULAS prioritised safety, and the number of treatments (burns) during each ablation procedure was slowly increased once safety had been demonstrated in previous participants. Since many APAs are not spherical, multiple treatments monitored in real-time offer an advantage (compared to CT-guided RFA) of limiting ablation to the APA.\u003c/p\u003e \u003cp\u003eOur development of RFA for APAs has been driven, in part, by patient involvement in decision-making, facilitated by the evident mis-match on molecular imaging between size of a typical focal area of tracer uptake and that of the whole organ removed by surgery. Until now, the potential attractions of RFA have been offset by concerns about ablating the wrong nodule, or that in some patients with unilateral PA this is due wholly or partly to microscopic clusters of aldosterone-producing cells, not visible radiologically. The FNB analyses show that, at worst, EUS-RFA of a non-culprit nodule is unusual. Although some were negative for CYP11B2, discrepancies between the IHC and RNA samples (e.g. in participant 20 who was completely cured by the procedure) illustrate the known heterogeneity of CYP11B2 expression in APAs. Other PET ligands in evaluation may increase accuracy, with the aldosterone-synthase inhibitor ligand in principle quantifying relative contribution to aldosterone excess from the target nodule.\u003csup\u003e34\u003c/sup\u003e Unlike surgery, where an adrenal cannot be replaced after unsuccessful adrenalectomy, all treatment options remain open after nodular RFA. Three of the participants with absent biochemical success have undergone adrenalectomy since conclusion of the study without any technical difficulty.\u003c/p\u003e \u003cp\u003eWe encountered four spontaneously resolving, procedure-related SAEs, which were reviewed by the Safety Committee. Three were scenarios that also occur in patients with longstanding PA who undergo laparoscopic adrenalectomy, and were deemed a consequence of GA rather than the ablation itself.\u003csup\u003e24\u003c/sup\u003e The episode of severe hypertension initially appeared different, and a possible instance of adrenomedullary excitation during adrenal RFA.\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e However, independent scrutiny of the anaesthetic record concluded this episode too was a probable consequence of GA, and the drugs deployed (see Supplementary Appendix for full discussion of the hypertensive episode and changes in plasma metanephrine). The 2\u0026ndash;4 fold rises in plasma metanephrine in some participants (Supplementary Fig.\u0026nbsp;4, Supplementary Table\u0026nbsp;4) are similar to the fold-change reported for catecholamines during laparoscopic surgery, and much lower than the fold-increases in plasma epinephrine which cause substantial haemodynamic changes.\u003csup\u003e35\u0026ndash;38\u003c/sup\u003e Evidently these cases cannot yet completely exclude adrenomedullary excitation, and have influenced us, in our current \u0026lsquo;WAVE\u0026rsquo; trial, to obtain serial peri-procedure samples for plasma metanephrines that separate the effects of GA (or sedation) from subsequent instrumentation, in both the ablation and surgical groups.\u003c/p\u003e \u003cp\u003eFABULAS has limitations. First, the study is small, and initial participants had lower \u0026lsquo;doses\u0026rsquo; (fewer treatments/burns) of RFA. The results focused on safety, to enable efficacy of ablation to be compared to surgery in our pivotal trial WAVE (NCT05405101). Unlike pharmacotherapy, device-based interventions need not wait for phase 2/3 studies before entering practice, and EUS-RFA is already used for non-adrenal indications.\u003csup\u003e39\u003c/sup\u003e While our findings may permit risk-assessed early application to PA patients ineligible or unwilling to contemplate surgery, operator training and experience will be important. Second, clinical safety dictated that many participants could not discontinue interfering medications to facilitate \u0026lsquo;clean\u0026rsquo; measurement of ARR. Proof-of-concept for efficacy derives principally from participants able to discontinue all drugs. Indeed the acronym of the study, meaning \u0026lsquo;stories\u0026rsquo;, anticipated that the best evidence of potential efficacy might arise from individual cases, rather than the pooled results. Third, FABULAS was a study of left adrenal APAs. In WAVE, surgery is being compared to nodular ablation of left- and right-sided APAs by endoscopic and percutaneous routes, respectively. Lastly, efficacy was evidently lower than after surgery, similar to that in a recent prospective study of percutaneous RFA.\u003csup\u003e32\u003c/sup\u003e Superior efficacy of nodular ablation vs total adrenalectomy is inconceivable. FABULAS has provided preliminary experience of a minimally-invasive alternative to surgery for APAs that can start the debate amongst clinicians as to what level of biochemical and clinical efficacy would be appropriate to accept in the context of the obvious advantages of a day-case procedure performed under sedation.\u003c/p\u003e \u003cp\u003eIt is 70 years since the discovery of primary aldosteronism.\u003csup\u003e40\u003c/sup\u003e For much of this period, management of PA has been substantially unchanged. Molecular imaging-located, EUS-guided RFA is a potentially curative treatment for PA, when this is due to an APA, and FABULAS has provided sufficient safety data to inform a pivotal comparison with surgery.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical trial data may be granted to qualified academic researchers upon approval by the study management committee and subject to appropriate data sharing and transfer agreements. Requests for data should include rationale and the relevance of the proposed research, hypothesis, research methodology, statistical analysis plan and publication plan. Genotyping and transcriptome data will be made available from Sequence Read Archive.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Professor Sir Christopher Edwards, Chair of the Trial Steering Committee; Mr Satya Bhattacharya, Dr Scott Akker and Professor Anju Sahdev, Safety Committee; Cambridge Bio-bank for FNA analyses; Giorgia Ala for assistance with EUS-FNA procedures, and STARmed for provision of RFA catheters and generators. The expertise of anaesthetists Dr's Elizabeth Cervi, Raz Mahroof and Jose Bastos was also gratefully acknowledged.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by the British Heart Foundation (PG/16/40/3213)\u0026nbsp;and Barts Charity (MGU0360). G.A., K.L. and J.K. are British Heart Foundation Research Fellows; X.W. and E.G. are National Institute of Health Research (NIHR) Academic Clinical Lecturers; Y-N.L. is a Barts Charity Research Fellow. \u0026nbsp;M.G., S.P. and M.J.B. are supported by NIHR Biomedical Research Centres, at Cambridge (NIHR203312), University College Hospitals and Barts NHS Trusts.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM.J.B., M.G., W.M.D. and S.P. conceived of and designed the study. X.W., G.A., A.N, E.G., K.L., Y-N.L., R.S., J.M, S.M.O. A.P., U.M., E.D., P.E. ran the study and collected the data under the supervision of M.J.B., M.G., S.P. and W.M.D. J.S. was trial coordinator. [11C]metomidate and [18F]CETO PET-CT grading was performed by H.C., with input on further analysis by D.G., E.N. and J.K. EUS-RFA was performed by S.P., N.C., P.W., E.M.G., and G.G. IHC grading was performed by A.M. and J.T. Adrenal tissue collection was performed by X.W., E.G., G.A., S.M.O. and K.L. X.W. prepared the adrenal samples for RNA-seq and preformed the quantitative PCR experiments, with help from Y-N.L. and K.L. RNA-seq was analysed by M.J.B. Statistical analysis was performed by J.B. The manuscript was prepared by X.W., G.A., M.J.B., W.M.D. and M.G. with substantial input on revisions from E.G., S.M.O., M.G. and S.P.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMonticone, S.\u003cem\u003e, et al.\u003c/em\u003e Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice. \u003cem\u003eJ Am Coll Cardiol\u003c/em\u003e \u003cstrong\u003e69\u003c/strong\u003e, 1811-1820 (2017).\u003c/li\u003e\n \u003cli\u003eRossi, G.P.\u003cem\u003e, et al.\u003c/em\u003e A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. \u003cem\u003eJ Am Coll Cardiol\u003c/em\u003e \u003cstrong\u003e48\u003c/strong\u003e, 2293-2300 (2006).\u003c/li\u003e\n \u003cli\u003eWilliams, B.\u003cem\u003e, et al.\u003c/em\u003e Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. \u003cem\u003eThe Lancet Diabetes \u0026amp; Endocrinology\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, 464-475 (2018).\u003c/li\u003e\n \u003cli\u003eHundemer, G.L., Curhan, G.C., Yozamp, N., Wang, M. \u0026amp; Vaidya, A. 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Hypokalemia from beta-2 receptor stimulation by circulating epinephrine. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e309\u003c/strong\u003e, 1414-1419 (1983).\u003c/li\u003e\n \u003cli\u003eStruthers, A.D., Whitesmith, R. \u0026amp; Reid, J.L. Metabolic and haemodynamic effects of increased circulating adrenaline in man. Effect of labetalol, an alpha and beta blocker. \u003cem\u003eBr Heart J\u003c/em\u003e \u003cstrong\u003e50\u003c/strong\u003e, 277-281 (1983).\u003c/li\u003e\n \u003cli\u003eOleinikov, K.\u003cem\u003e, et al.\u003c/em\u003e Endoscopic Ultrasound-Guided Radiofrequency Ablation: A New Therapeutic Approach for Pancreatic Neuroendocrine Tumors. \u003cem\u003eJ Clin Endocrinol Metab\u003c/em\u003e \u003cstrong\u003e104\u003c/strong\u003e, 2637-2647 (2019).\u003c/li\u003e\n \u003cli\u003eConn, J.W. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. \u003cem\u003eJ Lab Clin Med\u003c/em\u003e \u003cstrong\u003e45\u003c/strong\u003e, 3-17 (1955).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Demographics and Clinical Characteristics at Baseline\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"529\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.45283018867924%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.54716981132076%\"\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.45283018867924%\"\u003e\n \u003cp\u003eMean Age +/- SD \u0026ndash; yrs\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.54716981132076%\"\u003e\n \u003cp\u003e\u0026nbsp;57.7 +/- 10.3\u003c/p\u003e\n \u003cp\u003e39.2-77.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.45283018867924%\"\u003e\n \u003cp\u003eSex \u0026ndash; no. (%):\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Male\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.54716981132076%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e21 (75)\u003c/p\u003e\n \u003cp\u003e7 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.45283018867924%\"\u003e\n \u003cp\u003eMedian BMI \u0026ndash; kg/m\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.54716981132076%\"\u003e\n \u003cp\u003e28.4 (23.9-31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.45283018867924%\"\u003e\n \u003cp\u003eAncestry \u0026ndash; no. (%):\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;White\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Black\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Asian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.54716981132076%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 (57.1)\u003c/p\u003e\n \u003cp\u003e11 (39.3)\u003c/p\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.45283018867924%\"\u003e\n \u003cp\u003eStudy Group \u0026ndash; no. (%)*\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Group 1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Group 2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Group 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.54716981132076%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (28.6)\u003c/p\u003e\n \u003cp\u003e12 (42.8)\u003c/p\u003e\n \u003cp\u003e8 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.45283018867924%\"\u003e\n \u003cp\u003eComorbidities \u0026ndash; no.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Ischaemic heart disease\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Heart failure\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Type II diabetes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Stroke\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Chronic kidney disease\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Obstructive sleep apnea\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Peripheral vascular disease\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Obesity (BMI \u0026gt;30 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Arrhythmias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.54716981132076%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.45283018867924%\"\u003e\n \u003cp\u003eComorbidities \u0026ndash; no. (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;4\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.54716981132076%\"\u003e\n \u003cp\u003e13 (46.4%)\u003c/p\u003e\n \u003cp\u003e9 (32.1%)\u003c/p\u003e\n \u003cp\u003e2 (7.1%)\u003c/p\u003e\n \u003cp\u003e2 (7.1%)\u003c/p\u003e\n \u003cp\u003e1 (3.6%)\u003c/p\u003e\n \u003cp\u003e1 (3.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e*Study group classification is defined in the Supplementary Methods\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSD denotes standard deviation, BMI: Body Mass Index, IQR: interquartile range.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Primary Outcomes \u0026ndash; Safety Data\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"487\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2a. Number of Pre-Specified Major Hazards\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.57494866529774%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFindings\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.42505133470226%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.57494866529774%\"\u003e\n \u003cp\u003eRadiological:\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Perforation\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Haemorrhage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Infarction of Major Organs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.42505133470226%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.57494866529774%\"\u003e\n \u003cp\u003eBiochemical/haematological:\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Rise in Amylase\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Fall in Haemoglobin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.42505133470226%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"680\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"6\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2b. Study Related Serious Adverse Events (SAE)s\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.3097345132743365%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSAE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.9882005899705%\"\u003e\n \u003cp\u003e\u003cstrong\u003eEvent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.176991150442477%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeverity*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.24188790560472%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelated to\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eProcedure?\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.336283185840706%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSAE reason\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.946902654867257%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.3097345132743365%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.9882005899705%\"\u003e\n \u003cp\u003eHospital acquired pneumonia and atrial fibrillation with fast ventricular rate developing two days post-procedure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.176991150442477%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.24188790560472%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.336283185840706%\"\u003e\n \u003cp\u003eProlonged in-patient stay\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(by two days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.946902654867257%\"\u003e\n \u003cp\u003eResolved\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.3097345132743365%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.9882005899705%\"\u003e\n \u003cp\u003eHypokalaemia induced atrial fibrillation occurring during the procedure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.176991150442477%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.24188790560472%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.336283185840706%\"\u003e\n \u003cp\u003eProlonged in-patient stay\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(by two days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.946902654867257%\"\u003e\n \u003cp\u003eResolved\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.3097345132743365%\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.9882005899705%\"\u003e\n \u003cp\u003ePost-procedural non-ST elevation myocardial infarction (NSTEMI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.176991150442477%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.24188790560472%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.336283185840706%\"\u003e\n \u003cp\u003eProlonged in-patient stay\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(by eight days)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.946902654867257%\"\u003e\n \u003cp\u003eResolved\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.3097345132743365%\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.9882005899705%\"\u003e\n \u003cp\u003eHypertensive episode during the procedure with raised post- procedure metanephrines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.176991150442477%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.24188790560472%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.336283185840706%\"\u003e\n \u003cp\u003eLife threatening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.946902654867257%\"\u003e\n \u003cp\u003eResolved\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003ea.\u003c/strong\u003e Table showing the number of pre-specified major hazards occurring within the study. These are grouped into radiological finding on the CT abdomen performed 24/48 hours post-ablation and abnormality on blood tests performed for safety at 24 hours post-ablation. The only pre-specified adverse event was a rise in Amlyase in one individual, from 87 iu/L at baseline to 195 iu/L at 24 hours.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb.\u0026nbsp;\u003c/strong\u003eTable showing study-related SAEs. Severity and relation to procedure was determined by the independent Safety Committee, upon review of the individual cases. \u003cstrong\u003e*\u003c/strong\u003eSeverity was graded 1: low, asymptomatic or mild symptoms, minimal or no clinical intervention indicated. 2: medium, symptomatic, minimal invasive intervention indicated e.g. intravenous fluids and 3: high, severe to life-threatening medically significant event; requiring urgent intervention, hospitalization or prolongation of hospitalisation. SAEs not related to the study are listed in Supplementary Table 9 (n= 5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Clinical and Biochemical Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-Ablation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDifference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian ARR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e3748 (2669, 6081)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e853 (445, 1294)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;-2286 (-4080, -902)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003e(pmol/L) per (nmol/L/h)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Aldosterone (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e1301 (856, 1746)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e810 (385, 1235)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-491 (-912, -70)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003epmol/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Plasma Renin Activity (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e0.8 (-0.3, 1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e1.3 (0.4, 2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" rowspan=\"2\"\u003e\n \u003cp\u003e0.5 (-0.8, 1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003enmol/L/h\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Potassium (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e3.9 (3.7, 4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e4.3 (4.1, 4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" rowspan=\"2\"\u003e\n \u003cp\u003e0.3 (0.1, 0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003emmol/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian Defined Daily Dose (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\"\u003e\n \u003cp\u003e4.0 (2.8, 6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\"\u003e\n \u003cp\u003e2.3 (1.1, 4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\"\u003e\n \u003cp\u003e-1.4 (-3.0, -0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian no. of Antihypertensives (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\"\u003e\n \u003cp\u003e3.0 (2.0, 3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\"\u003e\n \u003cp\u003e1.5 (1.0, 2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\"\u003e\n \u003cp\u003e-1 (-1.7, 0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Home Systolic BP (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e136.3 (126.2, 146.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e138.8 (130.6, 147.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" rowspan=\"2\"\u003e\n \u003cp\u003e5.9 (-7.5, 19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003emmHg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Home Diastolic BP (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e80.3 (74.7, 85.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e86.9 (81.6, 92.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" rowspan=\"2\"\u003e\n \u003cp\u003e8.0 (1.5, 14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003emmHg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Clinic Systolic BP (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e144 (134.8, 153.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e146.8 (140.1, 153.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" rowspan=\"2\"\u003e\n \u003cp\u003e3.2 (-5.7, 12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003emmHg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Clinic Diastolic BP (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e84.8 (78.2, 91.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e90.3 (85.1, 95.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" rowspan=\"2\"\u003e\n \u003cp\u003e5.8 (-0.5, 12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003emmHg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian SUV\u003csub\u003emax\u003c/sub\u003e ratio (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e1.38 (1.18, 1.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e1.17 (1.04, 1.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;-0.26 (-0.49, -0.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e(ratio shown as left : right)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.598694942903755%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian Tumor Size (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e13.0 (12.0, 15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" rowspan=\"2\"\u003e\n \u003cp\u003e12.0 (10.7, 13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;-2 (-4, -1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003emm\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBaseline and 6-month post-ablation biochemical and clinical data. For the 7 participants who underwent two ablations, 3-month data is shown. PET-CT data was collected at 3-months post-ablation in all participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eARR: aldosterone renin ratio (reference range \u0026lt;1000 (pmol/L)per(nmol/L/h)); CI: confidence interval; BP: blood pressure; SUV\u003csub\u003emax\u003c/sub\u003e: maximum standard uptake value using time of flight sequences.\u0026nbsp;\u003c/p\u003e"},{"header":"ONLINE METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy Design\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFABULAS was a three-centre study (Barts Health NHS Trust, Queen Mary University of London; Addenbrooke\u0026rsquo;s Hospital, University of Cambridge; and University College London Hospitals NHS Foundation Trust, University College London). It was modelled on phase 1b/2a trials of novel drugs. The primary aim was to assess the safety of EUS-RFA, while the secondary objective was to determine the feasibility and efficacy of the procedure. The trial was performed in accordance with the ethical principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The protocol was approved by the London - Bloomsbury Research Ethics Committee (United Kingdom, REC ref: 17/LO/0948, IRAS ID 222446) and by the local research and development department at each participating centre. The trial registration was submitted to ClinicalTrials.gov on 20th January 2018 (NCT03405025). Informed, written consent was obtained from all study participants before any trial-related activity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial enrolled participants \u003cu\u003e\u0026gt;\u003c/u\u003e18 years of age with a diagnosis of PA meeting the Endocrine Society\u0026rsquo;s criteria,\u003csup\u003e1\u003c/sup\u003e and evidence of a probable or definite left-sided APA. This was determined by adrenal vein sampling (AVS) or molecular imaging ([\u003csup\u003e11\u003c/sup\u003eC]-metomidate PET-CT, MTO, or para-chloro-2-[\u003csup\u003e18\u003c/sup\u003eF]fluoroethyletomidate PET-CT, [\u003csup\u003e18\u003c/sup\u003eF]CETO).\u003csup\u003e2,3\u003c/sup\u003e The inclusion criteria for each of the three sequential, overlapping groups of 10 participants is detailed below.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGroup 1:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eLeft-sided APA proven on either AVS or PET-CT.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eParticipants wishing to take fewer drugs for their hypertension.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eParticipants meeting Endocrine Society criteria for considering curative treatment of unilateral disease, but who were often not referred for surgery because the benefit: risk was considered too low.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eParticipants aged \u0026ge;60 whose BP was at or near target (BP140/90 mmHg for most participants, or BP 130/80 mmHg in those with co-morbidities listed in the Hypertension guidelines) on treatment with tolerated antihypertensive medication.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eParticipants with identified macroadenomas (APAs \u003cu\u003e\u0026gt;\u003c/u\u003e 1 cm in diameter), who had probably at least 1 cm of peri-adrenal fat on axial and coronal projections. \u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGroup 2:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants with either:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(i) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; a definite unilateral left-sided APA, but did not want surgery; or\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(ii) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;probable but not unequivocal evidence of a unilateral left adrenal APA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGroup 3:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants \u003cu\u003e\u0026gt;\u003c/u\u003e18 years of age meeting criteria for surgery but consented to undergo endoscopic ablation instead.\u003c/p\u003e\n\u003cp\u003eIndividuals were excluded from the study if they were unable to give informed consent, were unable to discontinue beta blockers or direct renin blockers, were pregnant or unable/unwilling to take secure contraceptive precautions, or had any illness, condition or drug regimen considered a contraindication by the Principal Investigator or Chief Investigator.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAVS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdrenal Vein Sampling (AVS) was performed under cosyntropin stimulation. An infusion of 50 ug/h of intravenous cosyntropin was commenced one hour prior to the procedure and continued throughout. Cannulation was considered successful if the cortisol level in each adrenal vein was \u0026ge;3\u0026times; greater than that in the iliac and/or infrarenal inferior vena cava. A high probability of unilateral left sided PA was diagnosed if the aldosterone/cortisol ratio in left adrenal vein was \u0026ge;4 times that in the right adrenal vein.\u003csup\u003e4,5\u003c/sup\u003e\u0026nbsp; A \u0026apos;probable\u0026rsquo; left sided PA was diagnosed if the aldosterone/cortisol ratio was three to four.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e[\u003csup\u003e11\u003c/sup\u003eC]metomidate and [\u003csup\u003e18\u003c/sup\u003eF]CETO PET-CT\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e[\u003csup\u003e11\u003c/sup\u003eC]metomidate/ [\u003csup\u003e18\u003c/sup\u003eF]CETO PET-CT was performed to confirm the presence of a focal, left sided-APA which could be targeted for ablation. All participants were pre-treated with 0.5\u0026thinsp;mg dexamethasone orally four times a day for 72\u0026thinsp;h before scanning. PET-CT imaging was performed on a GE Discovery PET-CT 690 scanner (GE Medical Systems). Non-contrast CT images were acquired over the adrenals (140\u0026thinsp;kV; 30\u0026thinsp;mA; slice thickness\u0026thinsp;=\u0026thinsp;3.75\u0026thinsp;mm). Following an intravenous injection of [\u003csup\u003e11\u003c/sup\u003eC]metomidate or [\u003csup\u003e18\u003c/sup\u003eF]CETO (mean: 215\u0026thinsp;mBq; range: 86\u0026ndash;289\u0026thinsp;MBq), dynamic PET images were acquired for 30\u0026thinsp;minutes at 30\u0026thinsp;minutes after administration. The images were reconstructed with iterative reconstruction (ordered subset expectation maximization) using two iterations, 24 subsets and a Gaussian filter of 6.4\u0026thinsp;mm. The reconstruction included time-of-flight, attenuation, scatter and decay corrections. The images were converted to standardized uptake values (SUVs; g\u0026thinsp;ml\u0026minus;1) by dividing the activity concentration in the image voxels (Bq\u0026thinsp;ml\u0026minus;1) by the injected activity per patient weight (Bq\u0026thinsp;g\u0026minus;1).\u003c/p\u003e\n\u003cp\u003eA left-sided APA was diagnosed if it fulfilled the following three criteria: a focal adrenal nodule with Hounsfield Units in keeping with a benign adrenocortical adenoma, evidence of high [\u003csup\u003e11\u003c/sup\u003eC]metomidate or [\u003csup\u003e18\u003c/sup\u003eF]CETO uptake into the identified nodule, and a calculated left/right maximum SUV (SUVmax) ratio of \u0026nbsp;\u0026gt;1.25\u003csup\u003e6\u003c/sup\u003e. A \u0026lsquo;probable\u0026rsquo; left-sided APA was diagnosed if 2/3 of the above criteria were fulfilled. Pre- and post-ablation PET-CTs were performed to allow comparison of the tracer-avid nodule(s) and determine whether ablation was successful from a radiological perspective. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEUS-RFA technique and protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs a preventive measure against the consequences of possible adrenomedullary stimulation during RFA, all participants received combined alpha and beta-blockade for two weeks prior to ablation. If required, other drugs were reduced in dose to maintain stable BP. The protocol allowed for RFA to be performed under general anaesthesia (GA) or deep sedation, and the latter was adopted by the last of the three sites to undertake EUS-RFA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn the day of the procedure participants were examined and clinic BPs and blood tests (full blood count, urea and electrolytes, liver function tests, amylase/lipase and c-reactive protein) were taken as a baseline. Baseline home BP readings taken over the 4 days prior to ablation (three readings taken twice daily, 24 in total) were also recorded. After induction of GA or deep sedation, a linear-array EUS endoscope (Olympus, Keymed UK Ltd.; Pentax, Hitachi Medical Systems UK Ltd.) was advanced into the stomach, and the left adrenal gland identified using EUS. The nodule, presumed APA, can be identified as an echo-poor region (Supplementary Figure 1). The pre-ablation PET-CT was also used to help confirm the target lesion. Prior to advancement of the RFA needle into the targeted lesion, surrounding vascular structures were carefully visualized, aided by colour Doppler, in order to avoid inadvertent thermal injury during ablation of the APA. A 25-gauge needle was then passed transgastrically into the nodule enabling a fine needle biopsy (FNB) to be drawn into formalin or RNAlater\u0026copy; (Thermofisher, USA) and stored for subsequent immunohistochemistry (IHC) and molecular analyses respectively. A 19-gauge monopolar needle electrode with a non-insulated 5mm/10mm tip (EUSRATM, STARmed, Taewoong, Korea) and Viva Combo RF Generator System was used to deliver the radiofrequency (RF) current.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe tip of the RFA catheter was positioned at the distal margin of the targeted lesion under sonographic guidance. The RF current was delivered with the tip of the electrode maintained within the target mass and controlled by the endo-sonographer. Short bursts of treatment/burtns up to 25 seconds at 15-30W were applied, and stopped when hyperechoic bubbles were observed at the site of ablation, or impedance exceeded 100 Ohms. The acoustic scattering from formed gas bubbles was used as an estimate of the induced area of tissue necrosis. Depending on size, repeated treatments were performed by catheter withdrawal and repositioning in different planes in a fanned movement. Each treatment lasted 5-20 seconds before the catheter was repositioned within the nodule. The number of treatments during each ablation procedure increased during the study, as operators modified their approach based on the findings from post-RFA PET-CTs from the initial cases.\u003c/p\u003e\n\u003cp\u003eFor participants who underwent a second procedure, the extent of viable adenoma was assessed intra-procedurally with or without the administration of contrast medium (SonoVue, Bracco UK Ltd) to areas of untreated tissue, and repeated treatment cycles applied as deemed appropriate by the operator in order to attempt complete ablation of the targeted lesion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePost-procedure Monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants had clinical examination and blood tests (full blood count, urea and electrolytes, liver function tests, amylase/lipase and c-reactive protein) at baseline (morning of procedure) and at 24-48 hours post-procedure, to identify any procedure-related complications. In addition, an abdominal CT was also performed at 24-48 hours to look for radiological evidence of any of the pre-specified major hazards.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up Visits\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants were followed up at one, three and six months post-EUS-RFA. Home BP readings (taken during the 4 days prior to each visit) were recorded. Clinic BPs and blood tests (full blood count, urea and electrolytes, creatinine, bicarbonate, liver function tests, amylase/lipase, c-reactive protein, renin and aldosterone) were also collected to allow for assessment of efficacy (biochemical and clinical cure). A repeat PET-CT scan was performed at three months post-ablation to assess evidence of successful ablation of APA, or \u0026lsquo;radiological cure\u0026rsquo;.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMDT Decision Regarding a Second Ablation Procedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe protocol allowed a second ablation procedure to be offered to participants who did not achieve complete biochemical success and who also had a residual radiological target on molecular imaging. It was considered that this would be necessary in individuals with large APAs. The post-ablation PET-CT scan was reviewed, along with biochemical and clinical data, at a monthly multidisciplinary team (MDT) meeting. A decision for offering a second ablation was based on a number of factors, including reductions in isotope uptake, change in SUVmax ratio between PET-CT scans before and after the first ablation, changes in clinic and home blood pressures, as well as participant wishes for a second procedure. The ablation procedure and follow-up visits in those who underwent a second ablation were the same as per the first ablation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety Committee\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe independent Safety Committee comprised of an expert adrenal radiologist (Anju Sahdev, FRCR), an endocrinologist (Scott Akker, PhD MRCP), and a hepatobiliary-pancreatic surgeon with experience of RFA (Satyajit Bhattacharya, FRCS). Their role was to independently assess the safety of EUS-RFA. They initially convened after the first two participants had undergone EUS-RFA, and then once again following the subsequent two participants. Recruitment into each subsequent group could only commence if the Safety Committee deemed the procedure to be safe in the first four participants of each prior group. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint was safety, defined as occurrence of any of the three pre-specified major hazards: perforation, haemorrhage and infarction of major visceral organs. These were sought radiologically on the 24/48-hour post-procedure CT and supported by clinical examination, and comparison of serum amylase (and/or lipase) and full blood count pre- and 24/48 hours post-RFA. This assessment was made by the independent Safety Committee, who also reviewed the severity of all documented serious adverse events (SAEs) and their likelihood in relation to EUS-RFA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eReporting of Events\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe recorded all SAEs. A SAE is officially defined as any untoward medical occurrence that results in:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Death\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; A life-threatening event\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Inpatient hospitalisation or prolongation of hospitalisation.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Severe or permanent disability\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Cancer (other than cancers diagnosed prior to enrolment in studies involving patients with cancer)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Congenital anomaly\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Any grade four toxicity\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe also recorded events related to GA or sedation (e,g: drowsiness, confusion and respiratory depression). Events related to the gastric puncture and delivery of the RFA (e.g: bowel perforation, haemorrhage and infarction of major organs) and finally events related to complications of accidental adrenomedullary stimulation (e.g: severe hypertension and rise in plasma metanephrines).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSerious Adverse Events (SAEs) were reported to and independently reviewed by the Sponsor. Decisions on further reporting to the regulatory body (Medicines and Healthcare products Regulatory Agency) were made by the Sponsor, according to local protocol.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Safety Meeting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the end of the study an extended safety meeting was held at which all unexpected events / SAEs were discussed and scored by the Safety Committee. The below scoring system was drawn up and applied.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSafety committee scoring system: Level of significant event:\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ea. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003cstrong\u003eLow:\u003c/strong\u003e asymptomatic or mild symptoms, minimal or no clinical intervention indicated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eb. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003cstrong\u003eMedium:\u003c/strong\u003e symptomatic, minimal invasive intervention indicated e.g. intravenous fluids.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ec. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003cstrong\u003eHigh:\u003c/strong\u003e severe to life-threatening medically significant event requiring urgent intervention, hospitalisation, or prolongation of hospitalisation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLikelihood of significant event being associated with intervention:\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e1. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003cstrong\u003eLow:\u003c/strong\u003e no association.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003cstrong\u003eMedium:\u003c/strong\u003e minimum to moderate association.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003cstrong\u003eHigh:\u0026nbsp;\u003c/strong\u003eas a direct consequence of.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size of 30 was estimated on the basis of a\u0026nbsp;95% probability of at least one serious complication occurring, whose true risk was greater than one-in-ten ((1-p)^30=0.05), and 80% probability of at least one serious complication occurring if risk-per-participant was \u0026gt;one-in-twenty ((1- p)^30=0.2). The study was not powered for efficacy.\u003c/p\u003e\n\u003cp\u003eNo hypothesis testing was planned for the primary endpoint (safety), or for the categorical secondary biochemical and/or clinical success endpoints. In order to avoid adjustment for multiplicity, and so maximise the likelihood of detecting a significant efficacy endpoint in 30 patients, there was a single pre-specified hypothesis, for the comparison of pre- and post-ablation aldosterone/renin ratios. A Wilcoxon signed rank test was used. For other continuous variables, descriptive statistics with 95% confidence intervals were reported. Efficacy was estimated after all ablations in each participant, and then only after first ablations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe secondary outcomes were evidence of clinical and biochemical success at six months post-RFA (as defined by the international PASO Consensus, Supplementary Table 1),\u003csup\u003e7\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSuccessful ablation of the APA, or \u0026lsquo;radiological success\u0026rsquo; was quantified by comparing PET-CT images from before and after EUS-RFA. Visual assessment of the PET-positive nodule(s) in all planes was reviewed by a radiologist (H.C.) without prior knowledge of the biochemical and clinical outcomes for each participant. For quantification, the reduction in isotope activity was graded by as a percentage of the original PET-positive nodule, and grouped into quartiles of reduction (\u0026lt;25%, 25-50%, 50-75% or 75-100% reduction).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExploratory Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExploratory outcomes included immunohistochemistry (IHC) and quantitative polymerase chain reaction (qPCR) for CYP11B2(aldosterone synthase) expression were performed on the FNB samples to confirm whether the targeted nodule was an APA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eImmunohistochemistry (IHC)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIHC was performed on 3-\u0026mu;m sections cut from paraffin blocks using a fully automated system (BOND III IHC and ISH stainer from Leica Biosystems). The CYP11B1 primary antibody clone RAT-87 (MABS502, Merck) was used at a dilution of 1:100 after heat-induced epitope retrieval at pH 9.0 (BOND Epitope Retrieval Solution 2, AR9640, Leica) for 20 minutes; and the \u0026nbsp;CYP11B2 primary antibody clone EPR10494 (ab168388, Abcam) was used at a dilution of 1:200 after proteolytic-induced epitope retrieval with Proteinase K (BOND Enzyme Pre-treatment kit, AR9551, Leica) for 10 min. The primary antibody binding to tissue sections was visualized using BOND Polymer Refine Detection system (DS9800, Leica). Semi quantitative analysis of IHC was performed by two experienced board certified endocrine pathologists, blinded to clinical, biochemical and radiological outcome information.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eQuantitative Polymerase Chain Reaction (qPCR)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eqPCR was used to quantify the level of mRNA expression of the genes of interest. FNB samples of adrenal tissue were homogenised in lysis buffer for 20s using FastPrep-24 5G Sample Preparation System (MP-Biomedicals.) Total RNA was extracted using PureLink RNA minikit as per protocol (#12183018A, Invitrogen) and reverse transcribed to cDNA using High Capacity RNA-to-cDNA Kit (#4387406, Applied Biosystem). Quantification of mRNA expression was performed using TaqMan Fast Gene Expression Master Mix (#4444557, Applied Biosystems) and commercially available probes from Life Technology: CYP11B2 (Hs01597732_m1), CYP11B1 (Hs01596404_m1) and 18S rRNA (Hs99999901_s1) as a housekeeping gene. Results were analysed using the 2-\u0026Delta;\u0026Delta;CT method\u003csup\u003e8\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eWhere sufficient RNA was available, RNAseq was performed by the Barts and The London Genome Centre, United Kingdom; for analysis of somatic genotype and full transcriptome as previously described\u003csup\u003e9\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiochemistry Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll blood tests were analysed at United Kingdom Accreditation Service-accredited clinical laboratories. Serum aldosterone was measured by either an automated chemiluminescence immunoassay (LIAISON; DiaSorin) or by tandem mass spectrometry (in-house method adapted from\u003csup\u003e10\u003c/sup\u003e). The direct renin mass was measured at two centres by automated chemiluminescence immunoassay (LIAISON; DiaSorin). Plasma renin activity was measured in the final centre by liquid chromatography tandem mass spectrometry (North West London Pathology). Conversion between activity (nmol/L/h) to renin mass (mU/L) was performed using a conversion factor of 10.989.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eREFERENCES\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Funder, J.W.\u003cem\u003e, et al.\u003c/em\u003e The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. \u003cem\u003eJ Clin Endocrinol Metab\u003c/em\u003e \u003cstrong\u003e101\u003c/strong\u003e, 1889-1916 (2016).\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Wu, X.\u003cem\u003e, et al.\u003c/em\u003e [11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial. \u003cem\u003eNature Medicine\u003c/em\u003e \u003cstrong\u003e29\u003c/strong\u003e, 190-202 (2023).\u003c/p\u003e\n\u003cp\u003e3. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Goodchild, E.\u003cem\u003e, et al.\u003c/em\u003e Novel radiolabeled ligand, Para-chloro-2-[ 18 F]fluoroethyletomidate (CETO) compared to [ 11 C]metomidate-PET (MTO) for the lateralisation of primary aldosteronism (PA). \u003cem\u003eEndocrine Abstracts\u003c/em\u003e (2022).\u003c/p\u003e\n\u003cp\u003e4. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Rossi, G.P.\u003cem\u003e, et al.\u003c/em\u003e An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. \u003cem\u003eHypertension\u003c/em\u003e \u003cstrong\u003e63\u003c/strong\u003e, 151-160 (2014).\u003c/p\u003e\n\u003cp\u003e5. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Young, W.F. \u0026amp; Stanson, A.W. What are the keys to successful adrenal venous sampling (AVS) in patients with primary aldosteronism? \u003cem\u003eClinical endocrinology\u003c/em\u003e \u003cstrong\u003e70\u003c/strong\u003e, 14-17 (2009).\u003c/p\u003e\n\u003cp\u003e6. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Burton, T.J.\u003cem\u003e, et al.\u003c/em\u003e Evaluation of the sensitivity and specificity of (11)C-metomidate positron emission tomography (PET)-CT for lateralizing aldosterone secretion by Conn\u0026apos;s adenomas. \u003cem\u003eJ Clin Endocrinol Metab\u003c/em\u003e \u003cstrong\u003e97\u003c/strong\u003e, 100-109 (2012).\u003c/p\u003e\n\u003cp\u003e7. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Williams, T.A.\u003cem\u003e, et al.\u003c/em\u003e Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. \u003cem\u003eThe Lancet Diabetes \u0026amp; Endocrinology\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 689-699 (2017).\u003c/p\u003e\n\u003cp\u003e8. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Livak, K.J. \u0026amp; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. \u003cem\u003eMethods\u003c/em\u003e \u003cstrong\u003e25\u003c/strong\u003e, 402-408 (2001).\u003c/p\u003e\n\u003cp\u003e9. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Wu, X.\u003cem\u003e, et al.\u003c/em\u003e Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production. \u003cem\u003eNature Genetics\u003c/em\u003e \u003cstrong\u003e55\u003c/strong\u003e, 1009-1021 (2023).\u003c/p\u003e\n\u003cp\u003e10. \u0026nbsp; \u0026nbsp; \u0026nbsp; Hinchliffe, E., Carter, S., Owen, L.J. \u0026amp; Keevil, B.G. Quantitation of aldosterone in human plasma by ultra high performance liquid chromatography tandem mass spectrometry. \u003cem\u003eJ Chromatogr B Analyt Technol Biomed Life Sci\u003c/em\u003e \u003cstrong\u003e913-914\u003c/strong\u003e, 19-23 (2013).\u003c/p\u003e"},{"header":"Supplementary Figures","content":"\u003cp\u003eSupplementary Figures are not available with this version\u003c/p\u003e"},{"header":"Supplementary Tables","content":"\u003cp\u003eSupplementary Tables are not available with this version\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4365782/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4365782/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eUnilateral aldosterone-producing adrenal adenomas (APAs) are the potentially curable cause of 5% of all cases of hypertension. At present surgical removal of a whole gland is the only approved option for achieving cure, with uncertain long-term outcomes. Endoscopic ultrasound-guided trans-gastric radiofrequency ablation (EUS-RFA) offers a less invasive alternative to total adrenalectomy for the treatment of left-sided APAs. We aimed to determine whether EUS-RFA of APAs is safe and evaluate its likelihood of success in curing primary aldosteronism.\u003c/p\u003e\n\u003cp\u003eWe conducted a multi-centre feasibility study of EUS-RFA as a nonsurgical, adrenal-sparing treatment for left-sided APAs. The primary endpoint was safety, judged by the occurrence of pre-specified major hazards (intestinal haemorrhage, infarction or viscus perforation); and the secondary endpoints were biochemical and clinical efficacy (Primary Aldosterone Surgical Outcome (PASO) criteria).\u003c/p\u003e\n\u003cp\u003e28 participants (21 male, 7 female, mean age 57.7 +/- 10.3 years; 16 White, 11 Black, 1 Asian), underwent 35 ablations on one (n=21) or two (n=7) occasions. None of the pre-specified major hazards occurred. There were 21 biochemical and 12 clinical successes. These were complete in 16 and 4 participants, respectively, associated with \u0026gt;75% eradication of the APA, judged by molecular imaging.\u003c/p\u003e\n\u003cp\u003eEUS-guided trans-gastric RFA is a safe alternative to total adrenalectomy for the treatment of left-sided APAs and can lead to complete PASO success when most of the APA is ablated.\u003c/p\u003e","manuscriptTitle":"Endoscopic, ultrasound guided, radiofrequency ablation of aldosterone producing adenomas: A prospective, proof-of-concept trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-09 20:51:28","doi":"10.21203/rs.3.rs-4365782/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a535ef69-3896-4eaf-8062-8ba3a03821bd","owner":[],"postedDate":"May 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":31587479,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases/Adrenal gland diseases"},{"id":31587480,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2024-06-14T15:35:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-09 20:51:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4365782","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4365782","identity":"rs-4365782","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}