Skip to main content

Advertisement

SpringerLink
Log in

Clinical application of photodynamic medicine technology using light-emitting fluorescence imaging based on a specialized luminous source

  • Review
  • Published:
Medical Molecular Morphology Aims and scope Submit manuscript

Abstract

The natural amino acid 5-aminolevulinic acid (ALA) is a protoporphyrin IX (PpIX) precursor and a new-generation photosensitive substance that accumulates specifically in cancer cells. When indocyanine green (ICG) is irradiated with near-infrared (NIR) light, it shifts to a higher energy state and emits infrared light with a longer wavelength than the irradiated NIR light. Photodynamic diagnosis (PDD) using ALA and ICG-based NIR fluorescence imaging has emerged as a new diagnostic technique. Specifically, in laparoscopic examinations for serosa-invading advanced gastric cancer, peritoneal metastases could be detected by ALA-PDD, but not by conventional visible-light imaging. The HyperEye Medical System (HEMS) can visualize ICG fluorescence as color images simultaneously projected with visible light in real time. This ICG fluorescence method is widely applicable, including for intraoperative identification of sentinel lymph nodes, visualization of blood vessels in organ resection, and blood flow evaluation during surgery. Fluorescence navigation by ALA-PDD and NIR using ICG imaging provides good visualization and detection of the target lesions that is not possible with the naked eye. We propose that this technique should be used in fundamental research on the relationship among cellular dynamics, metabolic enzymes, and tumor tissues, and to evaluate clinical efficacy and safety in multicenter cooperative clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Namikawa T, Sato T, Hanazaki K (2015) Recent advances in near-infrared fluorescence-guided imaging surgery using indocyanine green. Surg Today 45:1467–1474

    Article  CAS  Google Scholar 

  2. Namikawa T, Yatabe T, Inoue K, Shuin T, Hanazaki K (2015) Clinical applications of 5-aminolevulinic acid-mediated fluorescence for gastric cancer. World J Gastroenterol 21:8769–8775

    Article  CAS  Google Scholar 

  3. Inoue K, Fukuhara H, Shimamoto T, Kamada M, Iiyama T, Miyamura M, Kurabayashi A, Furihata M, Tanimura M, Watanabe H, Shuin T (2012) Comparison between intravesical and oral administration of 5-aminolevulinic acid in the clinical benefit of photodynamic diagnosis for nonmuscle invasive bladder cancer. Cancer 118:1062–1074

    Article  CAS  Google Scholar 

  4. Namikawa T, Inoue K, Uemura S, Shiga M, Maeda H, Kitagawa H, Fukuhara H, Kobayashi M, Shuin T, Hanazaki K (2014) Photodynamic diagnosis using 5-aminolevulinic acid during gastrectomy for gastric cancer. J Surg Oncol 109:213–217

    Article  CAS  Google Scholar 

  5. Hagiya Y, Endo Y, Yonemura Y, Takahashi K, Ishizuka M, Abe F, Tanaka T, Okura I, Nakajima M, Ishikawa T, Ogura S (2012) Pivotal roles of peptide transporter PEPT1 and ATP-binding cassette (ABC) transporter ABCG2 in 5-aminolevulinic acid (ALA)-based photocytotoxicity of gastric cancer cells in vitro. Photodiagnosis Photodyn Ther 9:204–214

    Article  CAS  Google Scholar 

  6. Inoue K, Karashima T, Kamada M, Shuin T, Kurabayashi A, Furihata M, Fujita H, Utsumi K, Sasaki J (2009) Regulation of 5-aminolevulinic acid-mediated protoporphyrin IX accumulation in human urothelial carcinomas. Pathobiology 76:303–314

    Article  CAS  Google Scholar 

  7. Fukuhara H, Kureishi M, Khoda T, Inoue K, Tanaka T, Iketani K, Orita M, Inoue K, Shuin T (2015) The utility of a flexible fluorescence-cystoscope with a twin mode monitor for the 5-aminolevulinic acid-mediated photodynamic diagnosis of bladder cancer. PLoS One 10:e0136416

    Article  Google Scholar 

  8. Fisher CJ, Niu C, Foltz W, Chen Y, Sidorova-Darmos E, Eubanks JH, Lilge L (2017) ALA-PpIX mediated photodynamic therapy of malignant gliomas augmented by hypothermia. PLoS One 12:e0181654

    Article  Google Scholar 

  9. Teng L, Nakada M, Zhao SG, Endo Y, Furuyama N, Nambu E, Pyko IV, Hayashi Y, Hamada JI (2011) Silencing of ferrochelatase enhances 5-aminolevulinic acid-based fluorescence and photodynamic therapy efficacy. Br J Cancer 104:798–807

    Article  CAS  Google Scholar 

  10. Fukuhara H, Inoue K, Satake H, Tamura K, Karashima T, Yamasaki I, Tatsuo I, Kurabayashi A, Furihata M, Shuin T (2011) Photodynamic diagnosis of positive margin during radical prostatectomy: preliminary experience with 5-aminolevulinic acid. Int J Urol 18:585–591

    Article  CAS  Google Scholar 

  11. Inoue K, Fukuhara H, Kurabayashi A, Furihata M, Tsuda M, Nagakawa K, Fujita H, Utsumi K, Shuin T (2013) Photodynamic therapy involves an antiangiogenic mechanism and is enhanced by ferrochelatase inhibitor in urothelial carcinoma. Cancer Sci 104:765–772

    Article  CAS  Google Scholar 

  12. Kishi K, Fujiwara Y, Yano M, Motoori M, Sugimura K, Takahashi H, Ohue M, Sakon M (2016) Usefulness of diagnostic laparoscopy with 5-aminolevulinic acid (ALA)-mediated photodynamic diagnosis for the detection of peritoneal micrometastasis in advanced gastric cancer after chemotherapy. Surg Today 46:1427–1434

    Article  CAS  Google Scholar 

  13. Motoori M, Yano M, Tanaka K, Kishi K, Takahashi H, Inoue M, Saito T, Sugimura K, Fujiwara Y, Ishikawa O, Sakon M (2015) Intraoperative photodynamic diagnosis of lymph node metastasis in esophageal cancer patients using 5-aminolevulinic acid. Oncol Lett 10:3035–3039

    Article  CAS  Google Scholar 

  14. Ushimaru Y, Fujiwara Y, Kishi K, Sugimura K, Omori T, Moon JH, Yanagimoto Y, Ohue M, Yasui M, Takahashi H, Kobayashi S, Akita H, Miyoshi N, Tomokuni A, Sakon M, Yano M (2017) Prognostic significance of basing treatment strategy on the results of photodynamic diagnosis in advanced gastric cancer. Ann Surg Oncol 24:983–989

    Article  Google Scholar 

  15. Kishi K, Fujiwara Y, Yano M, Motoori M, Sugimura K, Ohue M, Noura S, Marubashi S, Takahashi H, Sakon M (2014) Diagnostic laparoscopy with 5-aminolevulinic-acid-mediated photodynamic diagnosis enhances the detection of peritoneal micrometastases in advanced gastric cancer. Oncology 87:257–265

    Article  CAS  Google Scholar 

  16. Kishi K, Fujiwara Y, Yano M, Inoue M, Miyashiro I, Motoori M, Shingai T, Gotoh K, Takahashi H, Noura S, Yamada T, Ohue M, Ohigashi H, Ishikawa O (2012) Staging laparoscopy using ALA-mediated photodynamic diagnosis improves the detection of peritoneal metastases in advanced gastric cancer. J Surg Oncol 106:294–298

    Article  CAS  Google Scholar 

  17. Murayama Y, Ichikawa D, Koizumi N, Komatsu S, Shiozaki A, Kuriu Y, Ikoma H, Kubota T, Nakanishi M, Harada Y, Fujiwara H, Okamoto K, Ochiai T, Kokuba Y, Takamatsu T, Otsuji E (2012) Staging fluorescence laparoscopy for gastric cancer by using 5-aminolevulinic acid. Anticancer Res 32:5421–5427

    CAS  PubMed  Google Scholar 

  18. Kobuchi H, Moriya K, Ogino T, Fujita H, Inoue K, Shuin T, Yasuda T, Utsumi K, Utsumi T (2012) Mitochondrial localization of ABC transporter ABCG2 and its function in 5-aminolevulinic acid-mediated protoporphyrin IX accumulation. PLoS One 7:e50082

    Article  CAS  Google Scholar 

  19. Susanto J, Lin YH, Chen YN, Shen CR, Yan YT, Tsai ST, Chen CH, Shen CN (2008) Porphyrin homeostasis maintained by ABCG2 regulates self-renewal of embryonic stem cells. PLoS One 3:e4023

    Article  Google Scholar 

  20. Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT (2017) Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390:2461–2471

    Article  CAS  Google Scholar 

  21. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J, REGARD Trial Investigators (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383:31–39

    Article  CAS  Google Scholar 

  22. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A (2014) RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15:1224–1235

    Article  CAS  Google Scholar 

  23. Handa T, Katare RG, Nishimori H, Wariishi S, Fukutomi T, Yamamoto M, Sasaguri S, Sato T (2010) New device for intraoperative graft assessment: HyperEye charge-coupled device camera system. Gen Thorac Cardiovasc Surg 58:68–77

    Article  Google Scholar 

  24. Handa T, Katare RG, Sasaguri S, Sato T (2009) Preliminary experience for the evaluation of the intraoperative graft patency with real color charge-coupled device camera system: an advanced device for simultaneous capturing of color and near-infrared images during coronary artery bypass graft. Interact Cardiovasc Thorac Surg 9:150–154

    Article  Google Scholar 

  25. Kitagawa H, Namikawa T, Iwabu J, Fujisawa K, Uemura S, Tsuda S, Hanazaki K (2018) Assessment of the blood supply using the indocyanine green fluorescence method and postoperative endoscopic evaluation of anastomosis of the gastric tube during esophagectomy. Surg Endosc 32:1749–1754

    Article  Google Scholar 

  26. Namikawa T, Uemura S, Kondo N, Yamamoto M, Maeda H, Nishimori H, Sato T, Orihashi K, Kobayashi M, Hanazaki K (2014) Successful preservation of the mesenteric and bowel circulation with treatment for a ruptured superior mesenteric artery aneurysm using the HyperEye Medical System. Am Surg 80:E359–E361

    PubMed  Google Scholar 

  27. Kitagawa H, Namikawa T, Munekage M, Akimori T, Kobayashi M, Hanazaki K (2015) Visualization of the stomach’s arterial networks during esophageal surgery using the hypereye medical system. Anticancer Res 35:6201–6205

    CAS  PubMed  Google Scholar 

  28. Hokimoto N, Sugimoto T, Namikawa T, Funakoshi T, Oki T, Ogawa M, Fukuhara H, Inoue K, Sato T, Hanazaki K (2018) A novel color fluorescence navigation system for intraoperative transcutaneous lymphatic mapping and resection of sentinel lymph nodes in breast cancer: comparison with the combination of gamma probe scanning and visible dye methods. Oncology 94:99–106

    Article  CAS  Google Scholar 

  29. Yamamoto M, Orihashi K, Nishimori H, Handa T, Kondo N, Fukutomi T, Sato T (2015) Efficacy of intraoperative HyperEye Medical System angiography for coronary artery bypass grafting. Surg Today 45:966–972

    Article  Google Scholar 

  30. Yamamoto M, Sasaguri S, Sato T (2011) Assessing intraoperative blood flow in cardiovascular surgery. Surg Today 41:1467–1474

    Article  Google Scholar 

  31. Yamamoto M, Orihashi K, Nishimori H, Wariishi S, Fukutomi T, Kondo N, Kihara K, Sato T, Sasaguri S (2012) Indocyanine green angiography for intra-operative assessment in vascular surgery. Eur J Vasc Endovasc Surg 43:426–432

    Article  CAS  Google Scholar 

  32. Wada T, Kawada K, Takahashi R, Yoshitomi M, Hida K, Hasegawa S, Sakai Y (2017) ICG fluorescence imaging for quantitative evaluation of colonic perfusion in laparoscopic colorectal surgery. Surg Endosc 31:4184–4193

    Article  Google Scholar 

  33. Liberale G, Vankerckhove S, Caldon MG, Ahmed B, Moreau M, Nakadi IE, Larsimont D,Donckier V, Bourgeois P (2016) Group R&D for the clinical application of fluorescence imaging of the Jules Bordetʼs Institute. Fluorescence imaging after indocyanine green injection for detection of peritoneal metastases in patients undergoing cytoreductive surgery for peritoneal carcinomatosis from colorectal cancer: a pilot study. Ann Surg 264:1110–1115

    Article  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan

    Tsutomu Namikawa, Kazune Fujisawa, Eri Munekage, Jun Iwabu, Sunao Uemura, Shigehiro Tsujii, Hiroyuki Kitagawa & Kazuhiro Hanazaki

  2. Center for Photodynamic Medicine, Kochi Medical School Hospital, Kochi, Japan

    Tsutomu Namikawa, Hideo Fukuhara, Keiji Inoue, Takayuki Sato & Kazuhiro Hanazaki

  3. Cancer Treatment Center, Kochi Medical School Hospital, Kochi, Japan

    Hiromichi Maeda & Michiya Kobayashi

  4. Department of Urology, Kochi Medical School, Kochi, Japan

    Hideo Fukuhara & Keiji Inoue

  5. Department of Cardiovascular Control, Kochi Medical School, Kochi, Japan

    Takayuki Sato

  6. Department of Human Health and Medical Sciences, Kochi Medical School, Kochi, Japan

    Michiya Kobayashi

Authors
  1. Tsutomu Namikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazune Fujisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eri Munekage
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun Iwabu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sunao Uemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shigehiro Tsujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiromichi Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroyuki Kitagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hideo Fukuhara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Keiji Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takayuki Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michiya Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kazuhiro Hanazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsutomu Namikawa.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Namikawa, T., Fujisawa, K., Munekage, E. et al. Clinical application of photodynamic medicine technology using light-emitting fluorescence imaging based on a specialized luminous source. Med Mol Morphol 51, 187–193 (2018). https://doi.org/10.1007/s00795-018-0190-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00795-018-0190-2

Keywords

Search

Navigation