Recent Advances in Photodynamic Imaging and Therapy in Hepatobiliary Malignancies: Clinical and Experimental Aspects

Round 1

Reviewer 1 Report

The authors reviewed development history and current applications of photodynamic diagnosis (PDD) and photodynamic therapy (PDT) for hepatobiliary malignancies. The reviewer would recommend following revisions to make this manuscript more readable and informative for researchers/surgeons in this field.

 

1. “Photodynamic Eye Imaging” in the title and essential parts in the manuscript should be replaced to “Photodynamic Diagnosis”. A term “Photodynamic Eye” may suggest a particular product of intraoperative imaging systems.
2. It seems to be effective to discuss PDD and PDT dividing the target lesions into primary liver cancers (or intrahepatic lesions) and biliary tract malignancies. In addition, please introduce previous publications clarifying which reports are on preclinical studies and which techniques have already been applied to the clinical settings.
3. Especially in the treatment of hilar/distal bile duct cancer, we still have a significant need for new techniques enabling accurate pre-/intra-operative diagnosis of cancer extension and postoperative therapy for residual cancerous tissues on the biliary stumps/anastomosis. This point should be emphasized in the introduction and/or discussion.
4. Regarding preclinical studies of PDT using ICG for primary liver cancer, previous works (PMID: 23595610, 29066756) rather than Ref. 37 should be cited.
5. Recently, consensus guidelines for a use of PDD in hepatobiliary surgery have been reported in Ann Surg (PMID: 33351457).
6. Please consider using color figures (and schema, if possible) to demonstrate clinical applications of PDD and PDT more clearly.

 

Author Response

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Reviewer 2 Report

In this work, the authors had summarized the clinical and experimental aspects of photodynamic diagnosis and photodynamic therapy in hepatobiliary malignancies, which was timing to spread the application of PDT in malignant tumor treatment. Some specific comments were listed as bellow:

1. The advantages and disadvantages of photodynamic diagnosis and photodynamic therapy in hepatobiliary malignancies should be summarized.
2. There was no clinical application PDD and PDT for primary liver malignancies, but the experimental studies should be strengthened.
3. Hiporfin was approved and widely accepted for the treatment of extrahepatic cholangiocarcinoma. The authors were suggested to further summarize the applications of PDT in extrahepatic cholangiocarcinoma.
4. The combination therapy by using PDT as neoadjuvant should be further summarized. Moreover, the combination therapy of PDT with immune checkpoint blockade should be summarized.
5. Come typo errors should be corrected. (lines 168, 198, 199, et al.)

Author Response

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Reviewer 3 Report

The title is a trifle confusing since what is meant by ‘eye imaging’ is unclear. The eye is not involved in the studies reported which relate to the bile duct. This report needs to be examined by someone with more proficiency in English although the content can usually be discerned. Patrick Barron had initiated a very effective editing service at Tokyo Medical College and although he is no longer alive, there must be some service that can help.   

There are some incorrect statements. PDT as currently practiced is totally dependent on the conversion of oxygen to reactive species. Not that this is critical, but PDT was identified as an antitumor approach long before the early 1990s (line 74). Use of eximer lasers is not necessary: any light source will do. Persistent photosensitization of normal skin is mainly encountered with Photofrin or HPD, early photosensitizing agents. More recent agents, e.g., mTHPC and BPD are relatively free from this problem. An examination by someone with more familiarity with PDT might be useful. 

The text needs editing. For example, lines 198-199 discusses irradiation at 375-4445 nm which is clearly wrong. Excitation of porphyrin fluorescence can occur but the wavelength of excitation is a narrow band centered at 400 nm and the emission is not from ‘intracellular ALA’ but from protoporphyrin. This occurs at 630 and 700 nm, not 600-7740 nm. Other statements are confusing, e.g., ‘NIR light cannot be seen with white light’ (line 223). It is not clear what is meant by (lines 206-207) ‘residual tumors at the cut surface of the remnant liver were improved by PDD with 5-ALA’. Does this mean that the resulting tumor detection facilitated treatment? So while the content is in there waiting to be found, someone needs to check the text more carefully. This appears to be a comprehensive and potentially useful discussion of the potential role for PDT in a clinical setting, once these problems are dealt with.

Author Response

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Author Response File: Author Response.doc