新しい診断技術が高血圧治療につながる(New diagnostic technique leads to high blood pressure treatment)

2025-02-24 英国研究イノベーション機構(UKRI)

<関連情報>

• https://www.ukri.org/news/new-diagnostic-technique-leads-to-high-blood-pressure-treatment/
• https://jnm.snmjournals.org/content/early/2025/01/30/jnumed.124.268425.long
• https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02755-7/fulltext

健康なボランティアと原発性アルドステロン症患者におけるパラクロロ-2-[18F]フルオロエチルトミデートの安全性と副腎取り込みを評価する第I/IIa相臨床試験 A Phase I/IIa Clinical Trial to Evaluate Safety and Adrenal Uptake of Para-Chloro-2-[18F]Fluoroethyletomidate in Healthy Volunteers and Patients with Primary Aldosteronism

Daniel Gillett, Russell Senanayake, James MacFarlane, Waiel Bashari, August Palma, Lihua Hu, Ines Harper, Iosif A. Mendichovszky, Gunnar Antoni, Per Hellman, Anders Sundin, Matthew Hird, István Boros, Morris J. Brown, Heok Cheow, Luigi Aloj, Franklin Aigbirhio and Mark Gurnell
Journal of Nuclear Medicine  Published: January 2025
DOI: https://doi.org/10.2967/jnumed.124.268425

Visual Abstract

Abstract

Primary aldosteronism (PA) is a common, potentially reversible, cause of hypertension. Distinguishing unilateral from bilateral PA is critical when deciding who should be offered surgery (unilateral adrenalectomy). Recent studies have shown that PET/CT with [¹¹C]metomidate can accurately identify unilateral PA, with localization of the causative aldosterone-producing adenoma (APA). However, the availability of [¹¹C]metomidate is limited to centers with an on-site cyclotron. Here, we report an early-phase human study with the ¹⁸F-labeled analog, para-chloro-2-[¹⁸F]fluoroethyletomidate ([¹⁸F]CETO). Methods: We conducted a phase I/IIa, single-center, open-label, microdosing study. The primary objective was to evaluate the safety of up to 2 administrations of [¹⁸F]CETO in 6 patients with PA (3 unilateral disease, 3 bilateral disease) and 5 healthy volunteers. Safety evaluation included assessment of adrenal function after the first [¹⁸F]CETO administration. The biodistribution of [¹⁸F]CETO was assessed in a 90-min dynamic PET acquisition. In patients with PA, the effect of pretreatment with oral dexamethasone on [¹⁸F]CETO uptake by normal adrenal tissue and APAs was also assessed. Results: Eleven participants were recruited to the trial, including 6 patients and 5 healthy volunteers. No subjects experienced serious adverse events or reactions, and all participants had normal adrenal function after [¹⁸F]CETO administration. [¹⁸F]CETO demonstrated high selectivity for the adrenal glands with low uptake in other tissues. Visualization of APAs was enhanced after dexamethasone pretreatment, which suppressed [¹⁸F]CETO uptake by normal adrenal tissue. Conclusion: [¹⁸F]CETO is a safe radiopharmaceutical for PET imaging of the adrenal glands, with no observed adverse reactions or impairment of adrenal function in this study. [¹⁸F]CETO demonstrates selective high affinity for adrenal tissue, particularly APAs. Distinction between APAs and normal adrenal tissue is enhanced by dexamethasone pretreatment to suppress [¹⁸F]CETO uptake by normal glands. This positions [¹⁸F]CETO as a promising imaging tool for evaluation in the context of PA.

アルドステロン産生腺腫に対する内視鏡的超音波ガイド下ラジオ波焼灼療法(FABULAS):英国、多施設、前向き、概念実証試験 Endoscopic, ultrasound-guided, radiofrequency ablation of aldosterone-producing adenomas (FABULAS): a UK, multicentre, prospective, proof-of-concept trial

Giulia Argentesi, MRCP∙ Xilin Wu, MRCP∙ Alexander Ney, PhD∙ Emily Goodchild, MRCP∙ Kate Laycock, MRCP∙ Yun-Ni Lee, MRCP∙ et al.
The Lancet  Published: February 7, 2025
DOI:https://doi.org/10.1016/S0140-6736(24)02755-7

Summary

Background
Unilateral aldosterone-producing adrenal adenomas (APAs) are the potentially curable cause of 5% of all cases of hypertension. Their localisation (via adrenal vein sampling [AVS]) and removal (by laparoscopic adrenalectomy) require invasive procedures that are unattractive to patients. Molecular imaging-located, endoscopic ultrasound-guided trans-gastric radiofrequency ablation (EUS-RFA) is a potential novel, minimally invasive alternative to AVS and total adrenalectomy for the treatment of APAs in the left adrenal gland, which is very close to the stomach. We aimed to determine whether EUS-RFA can safely target a heterogeneous set of such tumours without damaging the rest of the adrenal gland or adjacent organs.

Methods
We conducted a three-centre feasibility study in the UK of EUS-RFA as a non-surgical, adrenal-sparing treatment for left-sided APAs. Eligible participants were men and women aged 18 years or older, with a diagnosis of primary aldosteronism under the Endocrine Society’s criteria, and with evidence of a left-sided APA, diagnosed by AVS or PET-CT. Recruitment was done in three groups, with data from the first four patients in the previously recruited group being reviewed by an independent Safety Committee before proceeding. We performed molecular imaging on two occasions, first to diagnose and locate the APA, and later to quantify the degree of ablation. Following a fine-needle biopsy for later confirmation of APA diagnosis, ablation was performed using a 19G ablation catheter. Its manipulation under continuous ultrasound guidance permitted an incremental number of 10–20 s treatments (also known as burns) as the study progressed. The primary endpoint was safety, judged by the occurrence of prespecified major hazards (gastric and adrenal puncture: perforation, haemorrhage, or infarction of major organs) 24 h or 48 h post-ablation. Secondary endpoints were reductions in the proportion of radiotracer uptake by the ablated APA compared with the contralateral adrenal on molecular imaging at 3 months, and international consensus criteria for biochemical and clinical success (reductions in plasma aldosterone to renin ratio and blood pressure 6 months post-RFA).

Findings
Between Feb 21, 2018, and Feb 10, 2023, 44 patients were screened and 28 participants were recruited (21 [75%] male and seven [25%] female, mean age 57·7 years [SD 10·3]; 16 [57%] White, 11 [39%] Black, and one [4%] Asian). The 28 participants underwent 35 ablations on one (21 [75%]) or two (seven [25%]) occasions. All PET-CT-positive nodules were identified by the endoscopic ultrasound probe and successfully penetrated by biopsy and ablation catheters. None of the prespecified major hazards occurred in any patient. Localised reduction of radiotracer uptake by the PET-CT-positive APAs at 3 months was associated with complete or partial biochemical cure in 21 participants (75% [95% CI 55–91]), and with complete or partial cure of hypertension (clinical cure) in 12 participants (43% [24–61]). In four participants, disappearance of the APA on molecular imaging was associated with a systolic blood pressure under 135 mm Hg and diastolic blood pressure under 85 mm Hg off all antihypertensive treatment.

Interpretation
EUS-RFA appears a safe alternative to total adrenalectomy for the treatment of left-sided APAs and has the potential to completely cure primary aldosteronism and hypertension when most of the APA is ablated. These findings have informed the design of a pivotal study of thermal ablation versus surgery, which will determine the full benefits of EUS-RFA.

Funding
National Institute for Health and Care Research Biomedical Research Centres at Barts, University College Hospitals, and Cambridge University Hospitals, Barts Charity, and British Heart Foundation.