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The value of 68Ga-Pentixafor PET/CT targeting CXCR4 in the diagnosis of ACTH-independent Cushing syndrome

Hypertension Research (2026)Cite this article

Abstract

ACTH-independent Cushing syndrome (CS), a form of endogenous CS and an adrenal cause of hypertension, presents specific challenges in localizing cortisol-producing lesions. This study compared the diagnostic utility of 68Ga-Pentixafor PET/CT for lesion localization between ACTH-independent CS and non-functioning adrenal adenomas (NFAA). We retrospectively analyzed 73 subjects (52 with ACTH-independent CS; 21 with NFAA) undergoing 68Ga-Pentixafor PET/CT. Visual analysis demonstrated high diagnostic accuracy, with a sensitivity of 91.95%, a specificity of 95.24%, and a Youden index of 0.87. In semi-quantitative analysis, the lesion-to-adrenal ratio (LAR) showed superior performance compared to SUVmax and lesion-to-liver ratio (LLR). Using a diagnostic cutoff of SUVmax > 1.30, the sensitivity and specificity were 100% and 76.20%, respectively, supported by an AUC of 0.935 (P < 0.001) and a Youden index of 0.762. 68Ga-Pentixafor PET/CT effectively localizes functional adrenal lesions in ACTH-independent CS with high accuracy, supporting its role in guiding targeted management and surgical planning.

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Data availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

References

  1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015;386:913–27.

    Article  CAS  PubMed  Google Scholar 

  2. Laugesen K, Jørgensen JOL, Petersen I, Sørensen HT. Fifteen-year nationwide trends in systemic glucocorticoid drug use in Denmark. Eur J Endocrinol. 2019;181:267–73.

    Article  CAS  PubMed  Google Scholar 

  3. Hakami OA, Ahmed S, Karavitaki N. Epidemiology and mortality of Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab. 2021;35:101521.

    Article  CAS  PubMed  Google Scholar 

  4. Sconfienza E, Tetti M, Forestiero V, Veglio F, Mulatero P, Monticone S. Prevalence of functioning adrenal incidentalomas: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2023;108:1813–23.

    Article  CAS  PubMed  Google Scholar 

  5. Taillefer R, Soucy JP, Eybalin MC, Levasseur A. 131I-iodocholesterol (NP-59) scintigraphy in adrenocortical diseases. J Can Assoc Radio. 1983;34:120–4.

    CAS  Google Scholar 

  6. Minn H, Salonen A, Friberg J, Roivainen A, Viljanen T, Långsjö J, et al. Imaging of adrenal incidentalomas with PET using (11)C-metomidate and (18)F-FDG[J]. J Nucl Med. 2004;45:972–9.

    CAS  PubMed  Google Scholar 

  7. Berkmann S, Roethlisberger M, Mueller B, Christ-Crain M, Mariani L, Nitzsche E, et al. Selective resection of cushing microadenoma guided by preoperative hybrid 18-fluoroethyl-L-tyrosine and 11-C-methionine PET/MRI. Pituitary. 2021;24:878–86.

    Article  CAS  PubMed  Google Scholar 

  8. Bashari WA, Gillett D, MacFarlane J, Powlson AS, Kolias AG, Mannion R, et al. Modern imaging in Cushing’s disease. Pituitary. 2022;25:709–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Senanayake R, Gillett D, MacFarlane J, Van de Meulen M, Powlson A, Koulouri O, et al. New types of localization methods for adrenocorticotropic hormone-dependent Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab. 2021;35:101513.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang N, Ma Q, You Y, Xia X, Xie C, Huang Y, et al. CXCR4-dependent macrophage-to-fibroblast signaling contributes to cardiac diastolic dysfunction in heart failure with preserved ejection fraction. Int J Biol Sci. 2022;18:1271–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ding J, Tong A, Zhang Y, Wen J, Zhang H, Hacker M, et al. Functional characterization of adrenocortical masses in nononcologic patients using 68Ga-Pentixafor. J Nucl Med. 2022;63:368–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J, Hamet P. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol. 2010;73:1–15.

    Article  CAS  Google Scholar 

  13. Barbieri F, Thellung S, Würth R, Gatto F, Corsaro A, Villa V, et al. Emerging targets in pituitary adenomas: role of the CXCL12/CXCR4-R7 system. Int J Endocrinol. 2014;2014:753524.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ding J, Tong A, Hacker M, Feng M, Huo L, Li X. Usefulness of 68Ga-Pentixafor PET/CT on diagnosis and management of cushing syndrome. Clin Nucl Med. 2022;47:669–76.

    Article  PubMed  Google Scholar 

  15. Ferriere A, Tabarin A. Cushing’s syndrome: treatment and new therapeutic approaches. Best Pr Res Clin Endocrinol Metab. 2020;34:101381.

    Article  Google Scholar 

  16. Heinze B, Fuss CT, Mulatero P, Beuschlein F, Reincke M, Mustafa M, et al. Targeting CXCR4 (CXC chemokine receptor type 4) for molecular imaging of aldosterone-producing adenoma. Hypertension. 2018;71:317–25.

    Article  CAS  PubMed  Google Scholar 

  17. Gao Y, Ding J, Cui Y, Li T, Sun H, Zhao D, et al. Functional nodules in primary aldosteronism: identification of CXCR4 expression with 68Ga-pentixafor PET/CT. Eur Radiol. 2023;33:996–1003.

    Article  CAS  PubMed  Google Scholar 

  18. Zheng Y, Long T, Peng N, Zhen M, Ye Q, Zhang Z, et al. The value of targeting CXCR4 with 68Ga-Pentixafor PET/CT for subtyping primary aldosteronism. J Clin Endocrinol Metab. 2023;109:171–82.

    Article  PubMed  Google Scholar 

  19. Su HC, Dai J, Huang X, Zhou WL, Huang BX, Cao WL, et al. Classification, diagnosis and treatment of ACTH- independent macronodular adrenal hyperplasia. Can Urol Assoc J. 2013;7:E594–7.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lowery AJ, Seeliger B, Alesina PF, Walz MK. Posterior retroperitoneoscopic adrenal surgery for clinical and subclinical Cushing’s syndrome in patients with bilateral adrenal disease. Langenbecks Arch Surg. 2017;402:775–85.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank the participants in this study. The authors specifically thank Shuo Hu (Departments of Nuclear Medicine, Xiangya Hospital, Central South University), Tingting Long (Departments of Nuclear Medicine, Xiangya Hospital, Central South University) and Jing Wang (Departments of Pathology, Xiangya Hospital, Central South University).

Funding

This research was supported by 2023 Hunan Province National Clinical Key Specialized Major Scientific Research Project, China(Z2023056) and 2022 National Clinical Research Center for Geriatric Disease (Xiangya Hospital), China(2022LNJJ18).

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  1. These authors contributed equally: Zhen Zhang, Chun Li

Authors and Affiliations

  1. Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Zhen Zhang, Chun Li, Yao Xiao, Ning Peng, Geru Liu, Huizhu Chen, Qianwen Ye, Mengling Zhen & Tiejian Jiang

  2. Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Yao He

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Zhang, Z., Li, C., Xiao, Y. et al. The value of 68Ga-Pentixafor PET/CT targeting CXCR4 in the diagnosis of ACTH-independent Cushing syndrome. Hypertens Res (2026). https://doi.org/10.1038/s41440-026-02557-0

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