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Carbonic anhydrase IX stratifies patient prognosis and identifies nodal status in animal models of nasopharyngeal carcinoma using a targeted imaging strategy

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

An Editorial to this article was published on 22 August 2022

Abstract

Purpose

Accurate identification of nodal status enables adequate neck irradiation for nasopharyngeal carcinoma (NPC). However, most conventional techniques are unable to pick up occult metastases, leading to underestimation of tumor extensions. Here we investigate the clinical significance of carbonic anhydrase IX (CAIX) in human NPC samples, and develop a CAIX-targeted imaging strategy to identify occult lymph node metastases (LNMs) and extranodal extension (ENE) in animal studies.

Methods

A total of 211 NPC samples are performed CAIX staining, and clinical outcomes are analyzed. The metastatic murine models are generated by foot pad injection of NPC cells, and a CAIX-targeted imaging agent (CAIX-800) is intravenously administered. We adopt fluorescence molecular tomography and ultrasonography (US)-guided spectroscopic photoacoustic (sPA) imaging to perform in vivo studies. Histological and immunohistochemical characterization are carried out via node-by-node analysis.

Results

For clinical samples, 90.1% (91/101) primary tumors, 73.3% (66/90) metastases, and 100% (20/20) local recurrences are CAIX positive. In metastases group, 84.7% (61/72) nodal metastases and 22.2% (4/18) organ metastases are CAIX positive. CAIX expression in primary tumors is significantly associated with NPC stage and prognosis. For animal studies, CAIX-800-based fluorescence imaging achieves 81.3% sensitivity and 93.8% specificity in detecting occult LNMs in vivo, with a minimum detectable diameter of 1.7 mm. Coupled with CAIX-800, US-guided sPA imaging could not only detect subcapsular deposits of metastatic cancer cells 2 weeks earlier than conventional techniques, but also successfully track pathological ENE.

Conclusion

CAIX remarkably expresses in human NPCs and stratifies patient prognosis. In preclinical studies, CAIX-800-based imaging successfully identifies occult LNMs and tracks early stage of pathological ENE. This attractive method shows potential in clinic, allowing medical workers to longitudinally monitor nodal status and helping to reduce unnecessary nodal biopsy for patients with NPC.

Graphical abstract

The schematic diagram for the study. CAIX, carbonic anhydrase IX; NPC, nasopharyngeal carcinoma; US, ultrasonography; sPA, spectroscopic photoacoustic.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study received financial support from the National Natural Science Foundation of China (Grants Nos. 82027803, 62027901, 81930053, 81227901, 81871346, 81871323, 92059101, 21877004), the Chinese Academy of Sciences (Grants Nos. YJKYYQ20180048 and QYZDJ-SSW-JSC005), the Excellent Member Project of Youth Innovation Promotion Association CAS (Grants No.2016124), and the Project of High-Level Talents Team Introduction in Zhuhai City, the instrumental and technical support of Multimodal Biomedical Imaging Experimental Platform, Institute of Automation, Chinese Academy of Sciences.

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Authors and Affiliations

  1. College of Medicine and Biological Information Engineering, Northeastern University, 110057, Shenyang, China

    Wenhui Huang & Jie Tian

  2. CAS Key Laboratory of Molecular Imaging, the State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, No. 95 Zhongguancun East Road, Haidian District, Beijing, 100190, China

    Wenhui Huang, Kun Wang & Jie Tian

  3. Medical Imaging Center, the First Affiliated Hospital, Jinan University, No. 613, Huangpu West Road, Tianhe District, 510632, Guangzhou, China

    Wenhui Huang, Zicong He, Bin Zhang & Shuixing Zhang

  4. Department of Radiology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), 570311, Haikou, China

    Weiyuan Huang & Feng Chen

  5. Department of Nuclear Medicine, Peking University First Hospital, No. 8, Xishiku Road, Xicheng District, Beijing, 100034, China

    Jingming Zhang & Xing Yang

  6. Department of Chemical and Bio-Molecular Engineering, The University of Melbourne, Victoria 3010, Melbourne, Australia

    Zhiyuan Xiong

  7. Department of Radiology, Weill Medical College of Cornell University, 407 E 61st Street, New York, NY, USA

    Kelly McCabe Gillen

  8. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 100191, Beijing, China

    Wenzhe Li

  9. Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, 100191, Beijing, China

    Jie Tian

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  1. Wenhui Huang
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis: Wenhui Huang, Kun Wang, Weiyuan Huang, Feng Chen, Zicong He, Jingming Zhang, Bin Zhang, Zhiyuan Xiong, Wenzhe Li. Writing the first draft: Wenhui Huang, Kun Wang, Weiyuan Huang. Revising the manuscript: Jie Tian, Shuixing Zhang, Xing Yang, Kelly McCabe Gillen. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xing Yang, Shuixing Zhang or Jie Tian.

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Ethics approval

In human subjects, the study was approved by the Institutional Review Board at the Hainan General Hospital (Permit Number: 2018–0928-26). In animal subjects, all experiments were performed according to the guidelines of the Institutional Animal Care and Use Committee of Beijing Municipal Science & Technology Commission (Permit Number: 2020–0049).

Consent to participate

Written informed consent was obtained from the patients before starting the study.

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The authors declare no competing interests.

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Wenhui Huang, Kun Wang, and Weiyuan Huang are the co-first authors.

This article is part of the Topical Collection on Oncology—Head and Neck

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Huang, W., Wang, K., Huang, W. et al. Carbonic anhydrase IX stratifies patient prognosis and identifies nodal status in animal models of nasopharyngeal carcinoma using a targeted imaging strategy. Eur J Nucl Med Mol Imaging 49, 4427–4439 (2022). https://doi.org/10.1007/s00259-022-05922-6

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