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.

Primary aldosteronism (PA) causes hypertension and is potentially surgically curable when it is caused by a unilateral aldosterone-producing adrenal adenoma (APA). Adrenal vein sampling (AVS) is required to guide surgery, but it is invasive, is technically difficult, and has limited availability. To determine whether the accuracy of post-dexamethasone [11C]metomidate ([11C]MTO) positron emission tomography-computed tomography, a diagnostic test for APAs, is superior or noninferior to the accuracy of AVS in predicting outcomes from unilateral adrenalectomy, and whether [11C]MTO is interchangeable with its longer-half-life analogue, para-chloro-2-[18F]fluoroethyletomidate ([18F]CETO). Prospective within-patient comparison of diagnostic interventions. (ClinicalTrials.gov: NCT02945904). Three referral centers. 174 patients with PA desiring surgery if a unilateral source of PA was diagnosed. [11C]MTO and AVS in 169 patients, plus [18F]CETO in the final 31. International consensus criteria for biochemical and clinical success at 6 and 24 months after surgery; κ statistic and Bland-Altman analyses comparing predictions of surgical outcomes by [11C]MTO and [18F]CETO. Eighty-nine of 169 (52.7%), 78 of 169 (46.2%), and 43 of 169 (25.4%) patients were predicted to have unilateral PA by [11C]MTO, AVS, or both, respectively. One hundred of 169 (59.1%) were assigned to adrenalectomy by the multidisciplinary team; primary outcome data were available for 156 of 169. Predictions were most accurate for complete or partial biochemical success ([11C]MTO, 71.3% [95% CI, 61.0% to 80.1%]; AVS, 62.8% [CI, 52.2% to 72.6%]) and least accurate for complete clinical success (home blood pressure <135/85 mm Hg off treatment). The 95% CIs around differences between accuracies crossed zero, excluding superiority for [11C]MTO, but not the prespecified lower bound of -17%, allowing [11C]MTO to be declared noninferior to AVS. [18F]CETO and [11C]MTO agreed in 29 of 31 patients (κ = 0.85 [CI, 0.68 to 1.00]). The accuracy of [11C]MTO could be assessed only in the surgical group. Molecular imaging is an accurate, noninvasive alternative to AVS. National Institute for Health and Care Research.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Although the term neuroendocrine is now applied to many different contexts in which the nervous system interacts with the endocrine system to regulate hormone release and bring about important changes in physiology, the hypothalamic–pituitary axis remains the best known and most well-characterised example of a neuroendocrine system. Here, the hypothalamus acts as the major coordinating centre, integrating a diverse array of intrinsic (e.g. higher cortical, autonomic, endocrine) and extrinsic (e.g. environmental) signals to direct the function of multiple different target cells/tissues within the central nervous system, pituitary gland and peripheral sites. Hypothalamic regulation of pituitary function has far-reaching consequences, governing the release of hormones from other key endocrine glands (e.g. adrenal, thyroid, gonad), which, in turn, regulate the function of many physiological pathways with important consequences for energy balance and metabolism, osmo- and thermo-regulation, heart rate and blood pressure control, central nervous system function, growth and reproduction.

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [ 11 C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = −6.5 to 24.1%) and 3.8% (95% confidence interval = −11.9 to 9.4) lay within the pre-specified −17% margin for non-inferiority ( P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA.

Abstract Disclosure: X. Wu: None. E. Goodchild: None. R. Senanayake: None. W. Bashari: None. J. Salsbury: None. C.P. Cabrera: None. G. Argentesi: None. S.M. O’Toole: None. J. McFarlane: None. M. Matson: None. L. Parvanta: None. N. Hilliard: None. V. Kosmoliaptsis: None. A. Marker: None. D.M. Berney: None. W. Tan: None. R. Foo: None. C.A. Mein: None. E. Wozniak: None. A. Sahdev: None. N. Bird: None. K. Laycock: None. E. Adeyeye: None. A. Dawnay: None. D. Gillett: None. A. Prete: None. A.E. Taylor: None. W. Arlt: None. A.N. Bhuva: None. C. Manisty: None. K.J. Cruickshank: None. H. Cheow: None. G. Mark: None. W. Drake: None. M.J. Brown: None. Introduction: A recent prospective, within-patient study (MATCH) demonstrated 11C-metomidate PET-CT is non-inferior to Adrenal Vein Sampling in accurately detecting unilateral Primary Aldosteronism (PA)1. At 6 months post-adrenalectomy 79.5% and 28.2% of patients achieved, respectively, partial/complete or complete clinical success (by PASO consensus). These outcomes reiterate the need for careful selection of patients for surgery, especially when a widely available non-invasive test could increase, by many-fold, the number of patients diagnosed with unilateral PA. In MATCH, age, sex, genotype of tumour and systolic blood pressure (SBP) response (reduction to <135 mmHg) after 4 weeks of Spironolactone therapy all predicted clinical success at 6 month-adrenalectomy. Aims and Methods: To determine whether these short-term clinical outcomes and the above predictors of success are sustained at 2-year follow-up; and establish whether baseline urinary hybrid steroid (18-OH cortisol/cortisol) ratio could assist clinical decision making by providing surrogate evidence of genotype and probability of clinical success. We report outcomes for all patients who had undergone adrenalectomy with ­­>2-year follow-up on 20th December 2022, including all 78/142 surgical patients in the original study, in addition to 18/40 in the study extension. Results: Partial/complete or complete clinical success were achieved in 78/96 (81%) and 24/96 (25%) of patients respectively. The mean defined daily dose of antihypertensives at 2 years was 1.32 (SD 1.76), comparable to 1.34 (1.90) at 6 months, and significantly lower than at baseline: 3.86 (2.47), t = 7.70, p = 0.0001. Younger age and female sex were associated with higher likelihood of complete clinical success (Fisher’s Exact test p = 0.0084 and p = 0.0001 respectively). Pre-operatively, SBP reduction to <135 mmHg after 4 weeks of spironolactone was seen in 10/23 patients and associated with higher likelihood of complete clinical success at 2 years (versus 6/39 complete clinical success in the SBP >135 mmHg group, Fisher’s exact test p = 0.0135). 13/18 (72%) of patients harbouring KCNJ5 mutations achieved complete clinical success at 2 years, compared to 1/20 (5%) with CACNA1D mutations. A baseline hybrid steroid ratio >2 was seen in 13/14 (93%) patients with KCNJ5 mutations. Absence of clinical success in the KCNJ5 cohort was seen in the only patient with a ratio <2. Conclusion: Favorable clinical outcomes seen at 6 months post-adrenalectomy were sustained at 2-year follow-up. SBP response to spironolactone and KCNJ5 genotype are both potential predictors of ongoing clinical success at 2 years. The presence of high urinary hybrid steroid ratios in patients with KCNJ5 mutations could highlight, pre-operatively, those likely to derive the most clinical benefit from surgery. 1. Nature Medicine, in press, https://doi.org/10.1038/s41591-022-02114-5 Presentation: Thursday, June 15, 2023

Image optimization is a key step in clinical nuclear medicine, and phantoms play an essential role in this process. However, most phantoms do not accurately reflect the complexity of human anatomy, and this presents a particular challenge when imaging endocrine glands to detect small (often subcentimeter) tumors. To address this, we developed a novel phantom for optimization of positron emission tomography (PET) imaging of the human pituitary gland. Using radioactive 3D printing, phantoms were created which mimicked the distribution of 11C-methionine in normal pituitary tissue and in a small tumor embedded in the gland (i.e., with no inactive boundary, thereby reproducing the in vivo situation). In addition, an anatomical phantom, replicating key surrounding structures [based on computed tomography (CT) images from an actual patient], was created using material extrusion 3D printing with specialized filaments that approximated the attenuation properties of bone and soft tissue. The phantom enabled us to replicate pituitary glands harboring tumors of varying sizes (2, 4 and 6 mm diameters) and differing radioactive concentrations (2 ×, 5 × and 8 × the normal gland). The anatomical phantom successfully approximated the attenuation properties of surrounding bone and soft tissue. Two iterative reconstruction algorithms [ordered subset expectation maximization (OSEM); Bayesian penalized likelihood (BPL)] with a range of reconstruction parameters (e.g., 3, 5, 7 and 9 OSEM iterations with 24 subsets; BPL regularization parameter (β) from 50 to 1000) were tested. Images were analyzed quantitatively and qualitatively by eight expert readers. Quantitatively, signal was the highest using BPL with β = 50; noise was the lowest using BPL with β = 1000; contrast was the highest using BPL with β = 100. The qualitative review found that accuracy and confidence were the highest when using BPL with β = 400. The development of a bespoke phantom has allowed the identification of optimal parameters for molecular pituitary imaging: BPL reconstruction with TOF, PSF correction and a β value of 400; in addition, for small (< 4 mm) tumors with low contrast (2:1 or 5:1), sensitivity may be improved using a β value of 100. Together, these findings should increase tumor detection and confidence in reporting scans.

Abstract Disclosure: E. Goodchild: None. R. Senanayake: None. X. Wu: None. W. Bashari: None. J. Salsbury: None. G. Argentesi: None. S.M. O'Toole: None. J. McFarlane: None. K. Laycock: None. D. Gillett: None. I. Boros: None. A. Sahdev: None. N. Bird: None. S. Hader: None. V. Warnes: None. K. Cruickshank: None. F. Aigbirhio: None. H. Cheow: None. W. Drake: None. M. Gurnell: None. M.J. Brown: None. Introduction: Our MATCH study demonstrated 11-C ligand MTO was non-inferior to adrenal vein sampling in predicting adrenalectomy outcomes in patients with PA.1 The 20-minute half-life of 11-C imposes major logistic constraints. We investigated an 18-F ligand, CETO; its 2 hour half-life permits use in anywhere with fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan facilities. Objective: To determine whether molecular adrenal imaging, using CETO, is as accurate as MTO in predicting which patients with PA will achieve biochemical and/or clinical remission after unilateral adrenalectomy. Methods: This was an extension to the MATCH study (clinical trial number NCT02945904). All patients had an AVS and MTO scanning,1 and in 31 patients, a second (CETO) scan was performed and interpreted in ignorance of the AVS results. Results: The probability of unilateral APA was in agreement in 27/31 patients (Kappa= 0.76). The number of APAs detected by CETO (18 on the left side, 19 on the right) was similar to MTO (21 left, 19 right) (Wilcoxon P=0.424 and P=0.773). The mean tumour maximum standardised uptake value (SUVmax), by time of flight (TOF), did not differ between CETO (21.9 on the left side, 22.6 on the right) and MTO (22.8 on the left, 24.1 on the right) (Wilcoxon P=0.142). The probability of an adenoma identified by CETO or MTO was very similar: CETO, low 48.4%, medium 22.6%, high 29.0% on the left; low 48.4%, medium 12.9%, high 38.7% on the right; MTO, low 38.7%, medium 19.4% and high 41.9% on left; low 48.4%, medium 16.1%, high 35.5% on the right (Kappa 0.765 for the left and 0.833 for the right). Analysis of scans by SharpIR gave similar probabilities as thee TOF analyses. There was less liver uptake measured by CETO than MTO, (CETO mean 3.7, MTO mean 14.5, Wilcoxon P<0.001). Conclusions: There is no significant difference in the primary outcome of CETO and MTO scans in the investigation of PA. CETO has the potential to be a more favourable ligand, for clinical use, due to its longer half-life, and consequent potential for greater geographical distribution. 18-F CETO PET-CT imaging has the potential to increase lateralisation rates in PA. References: 1)11C-metomidate PET CT versus Adrenal Vein Sampling for diagnosing surgically curable primary aldosteronism. Nature Medicine https://www.nature.com/articles/s41591-022-02114-5. In press. Presentation: Friday, June 16, 2023

OBJECTIVE:Primary hyperparathyroidism is a common endocrine disorder, with 80% of all cases usually caused by one single hyperfunctioning parathyroid adenoma. Conventional imaging modalities for the diagnostic work-up of primary hyperparathyroidism (PHPT) include ultrasound of the neck, 99mTc-sestamibi scintigraphy, and four-dimensional computed tomography (4D-CT). However, the role of other imaging modalities, such as 11C-methionine PET/CT, in the care pathway for PHPT is currently unclear. Here, we report our experience of the diagnostic utility of 11C-methionine PET/CT in a single-center patient cohort (n = 45).DESIGN:Retrospective single-center cohort study.PATIENTS AND MEASUREMENTS:The data of eligible patients that underwent 11C-methionine PET/CT between 2014 and 2022 at Addenbrooke's Hospital (Cambridge, UK) were collected and analyzed. The clinical utility of imaging modalities was determined by comparing the imaging result with histopathological and biochemical outcomes following surgery.RESULTS:In patients with persistent primary hyperparathyroidism following previous surgery, 11C-methionine PET/CT identified a candidate lesion in 6 of 10 patients (60.0%), and histologically confirmed in 5 (50.0%). 11C-methionine PET/CT also correctly identified a parathyroid adenoma in 9 out of 12 patients (75.0%) that failed to be localized on other imaging modalities. 11C-methionine PET/CT had a sensitivity of 70.0% (95% CI 55.8 - 84.2%) for the detection of parathyroid adenomas.CONCLUSIONS:This study highlights a diagnostic role for 11C-methionine PET/CT in patients that have undergone unsuccessful prior surgery or have equivocal or negative prior imaging results, aiding localization and a targeted surgical approach.

Tumors of the pituitary gland, although mostly benign adenomas, are a cause of significant morbidity and even excess mortality due to local compressive effects (eg visual loss, hypopituitarism) and unregulated hormone secretion (eg acromegaly or Cushing Disease). Surgery, radiotherapy, and medical management (sometimes in combination) may be needed to mitigate the effects of tumor expansion and endocrine dysfunction. Magnetic resonance imaging (MRI) plays a central role in treatment planning for most patients. However, it does not always reliably identify the site(s) of primary or recurrent disease, especially where post-treatment remodeling results in indeterminate anatomical appearances. In these contexts, molecular imaging is a potential game-changer, allowing precise localization of sites of active disease and enabling safe and effective targeted intervention when patients would otherwise be consigned to expensive life-long medication. For pituitary and parasellar imaging, PET is the preferred modality due to its superior spatial resolution and sensitivity compared with SPECT, and an array of PET radioligands have been studied in different pituitary adenoma (PA) subtypes. While 18F-fluorodeoxyglucose (18F-FDG) is widely available, significant heterogeneity in tumoral uptake has limited its use. Instead, ligands targeting specific molecular pathways relevant to PA biology (eg somatostatin or dopamine receptor expression, amino acid uptake) are increasingly preferred and are beginning to find application in routine clinical practice. In addition, novel approaches to distinguish adenomatous tissue from normal gland (eg through comparison of images obtained with different radiotracers) and increase confidence that a suspected abnormal focus is indeed pathological (eg through subtraction imaging) have been proposed. It is likely therefore that molecular imaging will continue to find increasing application in the management of pituitary tumors just as it already does in other endocrine disorders.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract Background Pituitary adenomas (PA) affect ~ 1:1200 of the population and can cause a wide range of symptoms due to hormone over-secretion, loss of normal pituitary gland function and/or compression of visual pathways, resulting in significantly impaired quality of life. Surgery is potentially curative if the location of the adenoma can be determined. However, standard structural (anatomical) imaging, in the form of MRI, is unable to locate all tumors, especially microadenomas (< 1 cm diameter). In such cases, functional imaging [11C-methionine PET/CT (Met-PET)] can facilitate tumor detection, although may be inconclusive when the adenoma is less metabolically active. We, therefore, explored whether subtraction imaging, comparing findings between two Met-PET scans with medical therapy-induced suppression of tumor activity in the intervening period, could increase confidence in adenoma localization. In addition, we assessed whether normalization to a reference region improved consistency of pituitary gland signal in healthy volunteers who underwent two Met-PET scans without medical suppression. Results We found that the mean percentage differences in maximum pituitary uptake between two Met-PET scans in healthy volunteers were 2.4% for (SUVr) [cerebellum], 8.8% for SUVr [pons], 5.2% for SUVr [gray matter] and 23.1% for the SUVbw [no region]. Laterality, as measured by contrast–noise ratio (CNR), indicated the correct location of the adenoma in all three image types with mean CNR values of 6.2, 8.1 and 11.1 for SUVbw, SUVbwSub and SUVrSub [cerebellum], respectively. Subtraction imaging improved CNR in 60% and 100% of patients when using images generated from SUVbw [no region] and SUVr [cerebellum] scans compared to standard clinical SUVbw imaging. Conclusions Met-PET scans should be normalized to the cerebellum to minimize the effects of physiological variation in pituitary gland uptake of 11C-methionine, especially when comparing serial imaging. Subtraction imaging following endocrine suppression of tumor function improved lateralization of PA when compared with single time point clinical Met-PET but, importantly, only if the images were normalized to the cerebellum prior to subtraction.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Hyponatraemia is the most common electrolyte abnormality encountered in the inpatient setting and is associated with increased morbidity, mortality, and length of hospital stay. Syndrome of inappropriate anti-diuresis (SIAD) remains the most common cause. Hyponatraemia due to SIAD presents various challenges in treatment approaches, including poor concordance (e.g., to fluid restriction), medication intolerance (e.g., demeclocycline), and risk of rapid sodium shifts (e.g., with vaptan therapy). The use of oral sodium chloride (NaCl) tablets is a recognised treatment approach. However, it is not commonly advocated. We present the cases of two elderly patients in whom the temporary use of NaCl tablets, as an adjunct to fluid restriction, led to safe and effective correction of SIAD-related hyponatraemia with resultant reduced length of hospital admission.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)