Carbonic anhydrase IX stratifies patient prognosis and identifies nodal status in animal models of nasopharyngeal carcinoma using a targeted imaging strategy,European Journal of Nuclear Medicine and Molecular Imaging

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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
European Journal of Nuclear Medicine and Molecular Imaging ( IF 8.6 ) Pub Date : 2022-08-04 , DOI: 10.1007/s00259-022-05922-6
Wenhui Huang _{1,

2,

3} , Kun Wang ₂ , Weiyuan Huang ₄ , Zicong He ₃ , Jingming Zhang ₅ , Bin Zhang ₃ , Zhiyuan Xiong ₆ , Kelly McCabe Gillen ₇ , Wenzhe Li ₈ , Feng Chen ₄ , Xing Yang ₅ , Shuixing Zhang ₃ , Jie Tian _{1,

2,

9}

Affiliation

College of Medicine and Biological Information Engineering, Northeastern University, 110057, Shenyang, China.
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.
Medical Imaging Center, the First Affiliated Hospital, Jinan University, No. 613, Huangpu West Road, Tianhe District, 510632, Guangzhou, China.
Department of Radiology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), 570311, Haikou, China.
Department of Nuclear Medicine, Peking University First Hospital, No. 8, Xishiku Road, Xicheng District, Beijing, 100034, China.
Department of Chemical and Bio-Molecular Engineering, The University of Melbourne, Victoria 3010, Melbourne, Australia.
Department of Radiology, Weill Medical College of Cornell University, 407 E 61st Street, New York, NY, USA.
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 100191, Beijing, China.
Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, 100191, Beijing, China.

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.

中文翻译：

碳酸酐酶 IX 使用靶向成像策略对患者预后进行分层并确定鼻咽癌动物模型中的淋巴结状态

目的

准确识别淋巴结状态可以对鼻咽癌 (NPC) 进行充分的颈部照射。然而，大多数传统技术无法发现隐匿性转移，导致低估肿瘤扩展。在这里，我们研究了碳酸酐酶 IX (CAIX) 在人类 NPC 样本中的临床意义，并开发了一种 CAIX 靶向成像策略，以在动物研究中识别隐匿性淋巴结转移 (LNM) 和结外扩散 (ENE)。

方法

对总共 211 个 NPC 样本进行了 CAIX 染色，并分析了临床结果。转移性小鼠模型是通过脚垫注射 NPC 细胞产生的，并静脉内施用 CAIX 靶向显像剂 (CAIX-800)。我们采用荧光分子断层扫描和超声 (US) 引导的光谱光声 (sPA) 成像来进行体内研究。通过逐节点分析进行组织学和免疫组织化学表征。

结果

对于临床样本，90.1% (91/101) 的原发肿瘤、73.3% (66/90) 的转移瘤和 100% (20/20) 的局部复发肿瘤为 CAIX 阳性。在转移组中，84.7%（61/72）的淋巴结转移和 22.2%（4/18）的器官转移为 CAIX 阳性。CAIX 在原发性肿瘤中的表达与 NPC 分期和预后显着相关。对于动物研究，基于 CAIX-800 的荧光成像在检测体内隐匿性 LNM 方面实现了 81.3% 的灵敏度和 93.8% 的特异性，最小可检测直径为 1.7 mm。与 CAIX-800 相结合，超声引导的 sPA 成像不仅可以比传统技术提前 2 周检测到转移性癌细胞的包膜下沉积物，而且还可以成功追踪病理性 ENE。