Intraoperative near-infrared fluorescence imaging can identify pelvic nerves in patients with cervical cancer in real time during radical hysterectomy

Kunshan He, Pengfei Li, Zeyu Zhang, Jiaqi Liu, Pan Liu, Shipeng Gong, Chongwei Chi, Ping Liu, Chunlin Chen, Jie Tian, Kunshan He, Pengfei Li, Zeyu Zhang, Jiaqi Liu, Pan Liu, Shipeng Gong, Chongwei Chi, Ping Liu, Chunlin Chen, Jie Tian

Abstract

Purpose: Radical hysterectomy combined with pelvic lymphadenectomy is the standard treatment for early-stage cervical cancer, but unrecognized pelvic nerves are vulnerable to irreversible damage during surgery. This early clinical trial investigated the feasibility and safety of intraoperative near-infrared (NIR) fluorescence imaging (NIR-FI) with indocyanine green (ICG) for identifying pelvic nerves during radical hysterectomy for cervical cancer.

Methods: Sixty-six adults with cervical cancer were enrolled in this prospective, open-label, single-arm, single-center clinical trial. NIR-FI was performed in vivo to identify genitofemoral (GN), obturator (ON), and hypogastric (HN) nerves intraoperatively. The primary endpoint was the presence of fluorescence in pelvic nerves. Secondary endpoints were the ICG distribution in a nerve specimen and potential underlying causes of fluorescence emission in pelvic nerves.

Results: In total, 63 patients were analyzed. The ON was visualized bilaterally in 100% (63/63) of patients, with a mean fluorescence signal-to-background ratio (SBR) of 5.3±2.1. The GN was identified bilaterally in 93.7% (59/63) of patients and unilaterally in the remaining 4 patients, with a mean SBR of 4.1±1.9. The HN was identified bilaterally in 81.0% (51/63) of patients and unilaterally in 7.9% (5/63) of patients, with a mean SBR of 3.5±1.3. ICG fluorescence was detected in frozen sections of a nerve specimen, and was mainly distributed in axons. No ICG-related complications were observed.

Conclusion: This early clinical trial demonstrated the feasibility and safety of NIR-FI to visualize pelvic nerves intraoperatively. Thus, NIR-FI may help surgeons adjust surgical decision-making, avoid nerve damage, and improve surgical outcomes.

Trial registration: ClinicalTrials.gov NCT04224467.

Keywords: Cervical cancer; Indocyanine green; Near-infrared fluorescence imaging; Pelvic nerves; Radical hysterectomy.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Representative images of the a–c obturator, d–f genitofemoral, and e–h hypogastric nerves
Fig. 2
Fig. 2
Fluorescent microscopy confirmed that ICG was mainly distributed in the axon of the hypogastric nerve. a–b The transverse and c–d longitudinal sections of the hypogastric nerve; e–f ICG fluorescent signal distributed in axons labeled with anti-NF 200 antibody; and g–h less ICG fluorescence signal in myelin sheath labeled with anti-MBP antibody
Fig. 3
Fig. 3
ICG uptake and secretion cell test. a–d ICG can be taken up by neuronal cells. e The internalized ICG of different cells is similar after 5 min of incubation with an ICG-containing medium. f Neuronal cells secreted ICG significantly slower than other cells after incubation with 0.5 mg/ml ICG for 5 min and DMEM medium for 12h

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249. doi: 10.3322/caac.21660.
    1. Berek JS, Kehoe ST, Kumar L, Friedlander M. Cancer of the ovary, fallopian tube, and peritoneum. Int J Gynecol Obstet. 2018;143(Suppl 2):59–78. doi: 10.1002/ijgo.12614.
    1. Koh WJ, Abu-Rustum NR, Bean S, Bradley K, Campos SM, Cho KR, et al. Cervical cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2019;17:64–84. doi: 10.6004/jnccn.2019.0001.
    1. van Gent MDJM, Romijn LM, van Santen KE, Trimbos JBMZ, de Kroon CD. Nerve-sparing radical hysterectomy versus conventional radical hysterectomy in early-stage cervical cancer. A systematic review and meta-analysis of survival and quality of life. Maturitas. 2016;94:30–38. doi: 10.1016/j.maturitas.2016.08.005.
    1. Moawad GN, Wu C, Klebanoff JS, Urbina P, Alkatout I. Pelvic neuroanatomy: an overview of commonly encountered pelvic nerves in gynecologic surgery. J Minim Invasive Gynecol. 2021;28:178. doi: 10.1016/j.jmig.2020.06.005.
    1. Wang XQ, Chen CL, Liu P, Li WL, Wang LL, Liu YL. The morbidity of sexual dysfunction of 125 Chinese women following different types of radical hysterectomy for gynaecological malignancies. Arch Gynecol Obstet. 2018;297:459–466. doi: 10.1007/s00404-017-4625-0.
    1. Walsh EM, Cole D, Tipirneni KE, Bland KI, Udayakumar N, Kasten BB, et al. Fluorescence imaging of nerves during surgery. Ann Surg. 2019;270:69–76. doi: 10.1097/SLA.0000000000003130.
    1. Diaz-Feijoo B, Bradbury M, Perez-Benavente A, Franco-Camps S, Gil-Moreno A. Nerve-sparing technique during laparoscopic radical hysterectomy: critical steps. J Minim Invasive Gynecol. 2018;25:1144–1145. doi: 10.1016/j.jmig.2018.01.034.
    1. Lauwerends LJ. van Driel PBAA, Jong RJBd, Hardillo JAU, Koljenovic S, Puppels G, et al. Real-time fluorescence imaging in intraoperative decision making for cancer surgery. Lancet Oncol. 2021;22:E186–EE95. doi: 10.1016/S1470-2045(20)30600-8.
    1. You HJ, Shang WT, Min XD, Weinreb J, Li QB, Leapman M, et al. Sight and switch off: nerve density visualization for interventions targeting nerves in prostate cancer. Sci Adv. 2020;6:eaax6040. doi: 10.1126/sciadv.aax6040.
    1. Mieog JSD, Achterberg FB, Zlitni A, Hutteman M, Burggraaf J, Swijnenburg RJ, et al. Fundamentals and developments in fluorescence-guided cancer surgery. Nat Rev Clin Oncol. 2022;19:9–22. doi: 10.1038/s41571-021-00548-3.
    1. Lee JYK, Cho SS, Stummer W, Tanyi JL, Vahrmeijer AL, Rosenthal E, et al. Review of clinical trials in intraoperative molecular imaging during cancer surgery. J Biomed Opt. 2019;24:1–8.
    1. Chen QY, Xie JW, Zhong Q, Wang JB, Lin JX, Lu J, et al. Safety and efficacy of indocyanine green tracer-guided lymph node dissection during laparoscopic radical gastrectomy in patients with gastric cancer a randomized clinical trial. Jama Surg. 2020;155:300–311. doi: 10.1001/jamasurg.2019.6033.
    1. Dousse D, Vibert E, Nicolas Q, Terasawa M, Cano L, Allard MA, et al. Indocyanine green fluorescence imaging to predict graft survival after orthotopic liver transplantation: a pilot study. Liver Transpl. 2020;26:1263–1274. doi: 10.1002/lt.25796.
    1. He KS, Hong XP, Chi CW, Cai CN, Wang K, Li PP, et al. A new method of near-infrared fluorescence image-guided hepatectomy for patients with hepatolithiasis: a randomized controlled trial. Surg Endosc. 2020;34:4975–4982. doi: 10.1007/s00464-019-07290-z.
    1. Shang WT, Peng L, He KS, Guo PY, Deng H, Liu Y, et al. A clinical study of a CD44v6-targeted fluorescent agent for the detection of non-muscle invasive bladder cancer. Eur J Nucl Med Mol Imaging. 2022 doi: 10.1007/s00259-022-05701-3.
    1. He KS, Zhou J, Yang F, Chi CW, Li H, Mao YM, et al. Near-infrared intraoperative imaging of thoracic sympathetic nerves: from preclinical study to clinical trial. Theranostics. 2018;8:304–313. doi: 10.7150/thno.22369.
    1. Wang CB, Tong FZ, Cao YM, Liu P, Zhou B, Liu HJ, et al. Long-term follow-up results of fluorescence and blue dye guided sentinel lymph node biopsy in early breast cancer. Breast Cancer Res Treatment. 2021;188:361–368. doi: 10.1007/s10549-021-06196-6.
    1. He KS, Chi CW, Li DL, Zhang JJ, Niu G, Lv FQ, et al. Resection and survival data from a clinical trial of glioblastoma multiforme-specificIRDye800-BBNfluorescence-guided surgery. Bioeng Transl Med. 2021;6:e10182. doi: 10.1002/btm2.10182.
    1. An Y, Wang K, Tian J. Recent methodology advances in fluorescence molecular tomography. Vis Comput Ind Biomed Art. 2018;1:1–11. doi: 10.1186/s42492-018-0001-6.
    1. Wen JK, Qian CH, Pan MJ, Wang XH, Li YY, Lu YM, et al. Lentivirus-mediated RNA interference targeting RhoA slacks the migration, proliferation, and myelin formation of schwann cells. Mol Neurobiol. 2017;54:1229–1239. doi: 10.1007/s12035-016-9733-5.
    1. Nguyen QT, Tsien RY. Fluorescence-guided surgery with live molecular navigation - a new cutting edge. Nat Rev Cancer. 2013;13:653–662. doi: 10.1038/nrc3566.
    1. Shi RX, Wei WW, Jiang PC. Laparoscopic nerve-sparing radical hysterectomy for cervical carcinoma emphasis on nerve content in removed cardinal ligaments. Int J Gynecol Cancer. 2016;26:192–198. doi: 10.1097/IGC.0000000000000577.
    1. Wang LG, Barth CW, Kitts CH, Mebrat MD, Montaño AR, House BJ, et al. Near-infrared nerve-binding fluorophores for buried nerve tissue imaging. Sci Transl Med. 2020;12:eaay0712. doi: 10.1126/scitranslmed.aay0712.
    1. Muallem MZ, Diab Y, Sehouli J, Fujii S. Nerve-sparing radical hysterectomy: steps to standardize surgical technique. Int J Gynecol Cancer. 2019;29:1203–1208. doi: 10.1136/ijgc-2019-000410.
    1. Glasgow HL, Whitney MA, Gross LA, Friedman B, Adams SR, Crisp JL, et al. Laminin targeting of a peripheral nerve-highlighting peptide enables degenerated nerve visualization. P Natl Acad Sci USA. 2016;113:12774–12779. doi: 10.1073/pnas.1611642113.
    1. Samarasena JB, Ahluwalia A, Shinoura S, Choi KD, Lee JG, Chang KJ, et al. In vivo imaging of porcine gastric enteric nervous system using confocal laser endomicroscopy &molecular neuronal probe. J Gastroenterol Hepatol. 2016;31:802–807. doi: 10.1111/jgh.13194.
    1. Hingorani DV, Whitney MA, Friedman B, Kwon JK, Crisp JL, Xiong Q, et al. Nerve-targeted probes for fluorescence-guided intraoperative imaging. Theranostics. 2018;8:4226–4237. doi: 10.7150/thno.23084.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit