Review Reports - New Insights into Surgical Management of Intrahepatic Cholangiocarcinoma in the Era of “Transplant Oncology”

Round 1

Reviewer 1 Report

The following work offers a review on the surgical management of intrahepatic cholangiocarcinoma. The review is complete, well structured, and offers a comprehensive and up-to-date vision of the current management of cholangiocarcinoma. However, some issues should be taken into account:

Major revisions:
- In the inadequate future liver remnat section, although you mention the PVE and LVD, they are not developed in the text or at least they should be compared with the ALPPS procedure.
- A current fundamental point in the treatment of intrahepatic cholangiocarcinoma are tumor markers and genetics. Emerging molecularly-directed therapies should be mentioned in the text.
- In the conclusions, the sentence "Artificial intelligence algorithms have shown promise in aiding iCCA early detection, diagnosis, treatment planning, and patient outcome prediction", must be removed. This conclusion cannot be reached by reading the text.

Minor revisions:
- Figure 1 looks very blurry. A new neat figure should be attached according to the journal's instructions.
- They should unify the writing style in English style or american style (e.g. tumor vs tumour).
- The text is a little bit rough. It should be improved, including fewer full stops and removing some repeated sentences.
- The following sentence from the introduction: “biliary obstruction is often related to lymph-nodal compression of the hilum” should be modified. Although it is true that jaundice can be secondary to lymph-nodal compression, most cases of jaundice are secondary to tumor growth and infiltration of the biliary tree.

Author Response

Reviewer 1 comments:

A. We thank the Reviewer for the fine revision and the constructive comments. We entirely agree with the limitation highlighted. For this reason, we modified the article accordingly with the suggestions.

Major revisions:

- In the inadequate future liver remnat section, although you mention the PVE and LVD, they are not developed in the text or at least they should be compared with the ALPPS procedure.

A. Thank you for these valuable suggestions. We improved the text as follows:

“PVE, a gold standard hypertrophy strategy in CCA patients, is an easy and safe procedure with a low morbidity and mortality. Despite this, the success of this technique is limited by slow growth of FRL, high rate of inadequate liver regeneration and tumor progression ⁽⁵²⁾.

To obviate this issue, ALPPS was described as surgical strategy to quickly induce liver hypertrophy. The main limitation of ALPPS is the high rate of 90- day mortality and morbidity.”

“LVD is an emerging strategy including simultaneous PVE and hepatic vein embolization in the same hemiliver. LVD showed a higher degree of hypertrophy compared to PVE, and a better safety profile compared to ALPPS. This technique showed advantageous functional and volumetric results in HCC and CRLM patients and emerging advantages also in the field of CCA (56-57).”

- A current fundamental point in the treatment of intrahepatic cholangiocarcinoma are tumor markers and genetics. Emerging molecularly-directed therapies should be mentioned in the text.

A. Thank you for pointing this out. We apologize for the lack of information. We provided an additional paragraph about genetic markes and molecularly-directed therapies:

New tumor biomarkers emerged in the diagnostic assessment and in the choice of tailored therapies⁽⁷⁾. Introduction of liquid biopsy in the diagnostic panel, allowed to better define the disease genetic profile making us of new sequencies technologies as next-generation sequencing ⁽⁸⁾.

Isocitrate dehydrogenase (IDH1/IDH2) are two genetic markers characterized by high rate of mutations in iCCA. The prognostic role of IDH is still unclear but a recent trial based on an IDH inhibitor (Ivosidenib) showed improved progression free survival ⁽⁹⁾.

Fibroblast growth factor receptor 2 (FGFR2) fusions is another genomic mutation emerged as marker for target therapies with promising result in phase 2-studies involving FGFR2 inhibitors as infigratinib, pemigatinib, andTAS-120 ⁽⁷⁾.

The potential of other genetic targets, already well studied in other malignancies, as KRAS, B-RAF, HeR2/neu, showed significant interest and optimism in the last years, but further investigations are needed to determine the effective role in iCCA ⁽⁷⁾.”

- In the conclusions, the sentence "Artificial intelligence algorithms have shown promise in aiding iCCA early detection, diagnosis, treatment planning, and patient outcome prediction", must be removed. This conclusion cannot be reached by reading the text.

A. Thank you for this suggestion. We deleted this sentence from the text.

Minor revisions:

- Figure 1 looks very blurry. A new neat figure should be attached according to the journal's instructions.

A. We apologize for the mistake. We modified the figure according to guidelines.

- They should unify the writing style in English style or american style (e.g. tumor vs tumour).

A. Thank you. We unified the text in American style.

- The text is a little bit rough. It should be improved, including fewer full stops and removing some repeated sentences.

A. Thank you. We checked the entire text and We modified according to the suggestions.

- The following sentence from the introduction: “biliary obstruction is often related to lymph-nodal compression of the hilum” should be modified. Although it is true that jaundice can be secondary to lymph-nodal compression, most cases of jaundice are secondary to tumor growth and infiltration of the biliary tree.

A. Thank you for the suggestion. We sorry for the mistake and emended the text as follows:

“Biliary obstruction is often related to tumor growth in the biliary tree or lymph-nodal compression of the hilum”.

We thank the reviewers for their thorough analysis and appreciate the opportunity to enhance the manuscript. We hope that the manuscript is now acceptable for publication. If you have any questions, please do not hesitate to contact us.

Sincerely,

Fabio Melandro

-----------------------------------

Reviewer 2 Report

In this manuscript, Melandro et al. summarize the latest treatment strategies for patients with resectable ICC. In light of the dismal prognosis of ICC patients, there is growing interest in alternative approaches, including liver transplantation. Overall, the summarized treatment strategies are reasonable, and the manuscript covers most of the hot topics in ICC treatment.

Major comments

1. The prognosis of ICC patients is mentioned on page 2, line 55-73. Since "2. Diagnosis and staging" are discussed as a section, the prognosis should be also mentioned separately from the introduction probably after "Diagnosis and staging".

2. As for "Figure 1", some of the characters are difficult to see especially the red zone describing "FRL not sufficient". Please change the resolution of the Figure. Additionally, in the center rectangle in Figure 1, locally advanced diseases including multifocal and vascular invasion are suggested to receive NT. But under the square, surgeries are mentioned to be considered, which is confusing.

3. Table 1 should include another key paper with the DOI of https://doi.org/10.1002/lt.25052.

Minor comments

1. The 5-year OS of 30-40% might be overestimated compared with previous papers (page 2, line 55). Please check several major studies and add the references.

2. The words "to date" are repeatedly used in the Abstract (page 1, line 12 and 14). Please correct it.

Overall, the manuscript is adequate and covers most of the hot topics in ICC treatment.

Author Response

Reviewer 2

Major comments

A. We thank the reviewer for this suggestion. We now created a new section named “Prognosis” after “Diagnosis and staging”

A. Thank you for the suggestion. We apologize for the mistake. We updated the figure according with your valuable comment and journal guidelines.

3. Table 1 should include another key paper with the DOI of https://doi.org/10.1002/lt.25052.

A. Thank you for this suggestion. We improved the text and the table with the paper of Lee et al.

Minor comments

1. The 5-year OS of 30-40% might be overestimated compared with previous papers (page 2, line 55). Please check several major studies and add the references.

A. We completely agree with the reviewer and We apologize for the mistake: as reported in the reference cited (6), the 5-years OS is 20-35. We emended the text.

2. The words "to date" are repeatedly used in the Abstract (page 1, line 12 and 14). Please correct it.

A. We apologize for the mistake. We emended the text as follow: Despite a considerable improvement in the outcome, recurrence after surgery remains unfortunately still common.

Sincerely,

Fabio Melandro

=======================================

Round 2

Reviewer 1 Report

The authors amended the manuscript in accordance with the reviewer's suggestions.

-----------------------------------

Reviewer 2 Report

The revised paper has been updated appropriately according to the reviewers' comments. We thank the authors for their contributions to the field of cholangiocarcinoma.