The Role of TARE for Bridging and Downstaging of HCC Before Resection or Liver Transplant

Round 1

Reviewer 1 Report (Previous Reviewer 1)

Comments and Suggestions for Authors

I would like to thank the authors for their thorough and constructive point-by-point responses to all my comments. The manuscript has been carefully revised, and the changes implemented have adequately addressed the issues previously raised.

In its current form, the study is clearer, more focused, and methodologically sound, with conclusions appropriately aligned with the presented data and the acknowledged limitations.

I therefore consider the manuscript suitable for acceptance.

Reviewer 2 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

I appreciated your comments and explanations.

Reviewer 3 Report (Previous Reviewer 3)

Comments and Suggestions for Authors

The authors have adequately addressed all the concerns.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Please find attached my detailed review. I hope the comments will be helpful to the authors in revising the manuscript.

Comments for author File: Comments.pdf

Author Response

Response Letter

• Reviewer 1

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.

Abstract

Comment 1: Remove “25 patients…” from the Methods, as this number belongs to the Results.

Response 1: Agreed. We have accordingly revised the Abstract section. To address this point, we have removed 25 patients from methods, and added in results. These changes can be found in the manuscript file on page 1, line 23.

Comment 2: Reduce background details and avoid interpretative phrasing in the Results.

Response 2: Agreed. We have accordingly revised the Abstract section. To address this point, we have reduced background details and also rephrased results section. These changes can be found in the manuscript file on page 1, lines 17-19 for background and page 1, lines 23-28 for results.

 

Introduction

Comment 1: Condense the literature review and improve focus on the specific aim of the study.

Response 1: Thank you for pointing this out. We agree with this comment. Therefore, we have shortened the introduction and kept only the important studies to make the focus clearer. These changes can be found in the manuscript file on page 1-2 (introduction section), lines 37-72.

Comment 2: Replace all occurrences of “liver lobe,” which is outdated; use “right liver,” “left liver,” or “right/left hemiliver” according to Brisbane 2000 terminology.

Response 2: Thank you for pointing this out. We agree with this comment. Therefore, we have replaced all “liver lobe” terms with terminology such as right liver, left liver, or hemiliver. These changes can be found in the manuscript file on page 1, line 42 and page 2, line 46.

Comment 3: Clarify the novelty of reporting outcomes after TARE for both resection and LDLT.

Response 3: Thank you for pointing this out. We agree with this comment. Therefore, we have added a clear statement in the introduction section. These changes can be found in the manuscript file on page 2 (introduction section), lines 52-56.

 

 Methods

Comment 1: Define bridging vs downstaging explicitly.

Response 1: Thank you for pointing this out. We have accordingly revised the Methodology section. Therefore, we have defined bridging and downstaging, and these changes can be found in the manuscript file on page 3, lines 118-122.

Comment 2: Harmonize inclusion/exclusion criteria with what is later shown in the Results.

Response 2: Thank you for pointing this out. We agree with this comment. Therefore, we clarified the inclusion and exclusion criteria in methodology (patients subsection). These changes can be found in the manuscript file on page 2, lines 78-83.

Comment 3: A patient flow diagram would increase transparency.

Response 3: We acknowledge this concern. But we have not added a patient flow diagram because all included patients underwent TARE and proceeded directly to either surgical resection or LDLT, with no intermediate exclusion steps. (Patient numbers and treatment pathways are already described in the Methods and Results sections.)

Comment 4: Provide justification for analyzing a heterogeneous set of surgical procedures together.

Response 4: Thank you for pointing this out. We agree with this comment. Therefore, we have explained that all surgical procedures were analyzed together, in the methodology (statistical analysis subsection). These changes can be found in the manuscript file on page 3-4, lines 136-141.

 

Results

Comment 1: Report complications using a standardized classification such as Clavien–Dindo.

Response 1: We agree with this comment. Therefore, we reported postoperative complications using the Clavien–Dindo classification. These changes can be found in the manuscript file on page 8, lines 246-251.

Comment 2: Reformulate the sentence comparing TACE alone vs TACE+TARE, as it reads as discussion rather than results.

Response 2: Thank you for pointing this out. We agree with this comment. Therefore, we have revised the sentence. These changes can be found in the manuscript file on page 6, lines 212-214.

Comment 3: Clarify the DFS sentence, since comparing DFS between recurrent and non-recurrent patients is tautological; specify the intended analysis.

Response 3: Thank you for pointing this out. We agree with this comment. Therefore, we have clarified the DFS description in the outcomes section of Results. These changes can be found in the manuscript file on page 7, lines 227-230.

 

Tables and Figures

Comment 1: Table 1: the p-value for the ASA classification is missing and should be added for completeness.

Response 1: P- value added for this statistical part

 

Discussion

Comment 1: The Discussion is long and occasionally repetitive; consider reorganizing it into thematic subsections (e.g., TARE response, conversion to curative surgery, comparison of resection vs LDLT).

Response 1: We agree with this comment. Therefore, we have reorganized the Discussion into thematic subsections. These changes can be found in the manuscript file on pages 9-11, in the discussion section.

Comment 2: Moderate interpretations where the dataset is limited by sample size and heterogeneity.

Response 2: Thank you for pointing this out. We agree with this comment. Therefore, we moderated interpretative language. These changes can be found in the manuscript file on pages 9-11, in the discussion section.

Comment 3: In my opinion, the sentence describing right hemihepatectomy as a “cornerstone” option should be removed, as it is out of context and does not add meaningful value to the Discussion.

Response 3: Thank you for pointing this out. We agree with this comment. Therefore, we rephrased the sentence, and removed the term “cornerstone”. These changes can be found in the manuscript file on page 9, lines 278-280.

Comment 4: The Discussion would benefit from integrating recent evidence on the use of TARE both as a downstaging tool toward liver transplantation and as a strategy preceding right or right extended hepatectomy.

Response 4: Thank you for pointing this out. We agree with this comment. Therefore, we have added TARE’s role in downstaging to liver transplantation in discussion section, also added supporting studies using citations. These changes can be found in the manuscript file on page 9-10, lines 314-320.

Comment 5: You may also consider discussing your findings in the context of emerging frameworks defining ‘borderline resectable HCC’. In particular, two recent classifications may be relevant for interpreting your cohort: (1) the international validation and refinement of borderline resectability criteria using Tumor Burden Score proposed by Pawlik et al. (Ann Surg, 2025), and (2) the BR1–BR3 categorization recently introduced by the Japanese Liver Cancer Association/JSHBPS (Liver Cancer, 2024). Positioning your patients within these systems — for example, identifying which cases would correspond to BR1, the group most likely to benefit from neoadjuvant or bridging strategies — could substantially strengthen the clinical interpretation of your results and increase the overall impact of the manuscript.

Response 5:  We agree with this comment. Therefore, we have added discussion about studies defining borderline resectable HCC. These additions can be found in the manuscript file on page 10, lines 333-341.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

I appreciated your paper even if I have some minor considerations:
“T/N ratio, corresponding tumor-to-normal liver (T/N) ratios”,  line 138, in which way this ratio was assessed? 

Table 3.   First column Tumor Necrosis (T/N) ,  3rd column Mean T/N Ratio it should be Tumor to Normal liver ratio (as reported in line 138).  Has the acronym T/N the same meaning?
   Tumour Radiation Dose (Gy)  in which way has been estimated?, 
in table 4 dosimetry  was not assessed in 7/25, it is more than a quarter, is  there an explanation why dosimetry was not assessed?
In table 4 the dosimetry (Gy) in many cases is expressed with 2 numbers separated by underscore, does it represent the range in different areas?

Table 4 Pt 1: reason for TARE is AAA, what does it mean?
    pt 8: “glass type”, unlikely it is different from the other pts (except 2 resin type of course)

The discussion is well articulated by focusing on the aspects of TARE in bridging and downstaging HCC.  The authors correctly highlighted the limitations of their study  (pts number, follow-up time) in lines 340-348 , however it would be preferable to more specifically highlight the differences and/or analogies of this study with the cited studies

Author Response

Response Letter

• Reviewer 2

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.

Comment 1: “T/N ratio, corresponding tumor-to-normal liver (T/N) ratios”, line 138, in which way this ratio was assessed? 

Response 1: Thank you for pointing this out. We agree with this comment. Therefore, we clarified how the T/N ratio was assessed, and added detail in TARE procedure subsection of methodology. These changes can be found in the manuscript file on page 3, lines 107-112.

Comment 2: Table 3. First column Tumor Necrosis (T/N) ,  3rd column Mean T/N Ratio it should be Tumor to Normal liver ratio (as reported in line 138).  Has the acronym T/N the same meaning?

Response 2: Thank you for pointing this out. Yes, the acronym T/N refers to the tumor-to-normal liver ratio. We have revised the 1^st column heading. These changes can be found in the manuscript file on pages 6-7 (Table 3).

Comment 3: Tumour Radiation Dose (Gy) in which way has been estimated? 

Response 3: Thank you for pointing this out. Therefore, we clarified how tumor radiation dose was estimated. These changes can be found in the manuscript file (in the TARE procedure subsection of methodology) on page 3, lines 113-117.

Comment 4: In table 4 dosimetry was not assessed in 7/25, it is more than a quarter, is there an explanation why dosimetry was not assessed?

Response 4: Thank you for pointing this out. Therefore, we have explained that dosimetry was not assessed in some patients, in the TARE procedure subsection of methodology. These changes can be found in the manuscript file on page 3, lines 123-127.

Comment 5: In table 4 the dosimetry (Gy) in many cases is expressed with 2 numbers separated by underscore, does it represent the range in different areas?

Response 5: Agreed. Thank you for pointing this out. Therefore, we have clarified that in the results section. These changes can be found in the manuscript file on page 6, lines 219-221.

Comment 6: Table 4 Pt 1: reason for TARE is AAA, what does it mean? pt 8: “glass type”, unlikely it is different from the other pts (except 2 resin type of course).

Response 6:  Thank you for pointing this out. To address these concerns, we have clarified the meaning of “AAA” by writing its full form, and confirmed that “glass type” as glass Y-90 microspheres. These changes can be found in the manuscript file on pages 6-7, in Table 4.

Comment 7: The discussion is well articulated by focusing on the aspects of TARE in bridging and downstaging HCC.  The authors correctly highlighted the limitations of their study  (pts number, follow-up time) in lines 340-348 , however it would be preferable to more specifically highlight the differences and/or analogies of this study with the cited studies.

Response 7: Agreed. Thank you for pointing this out. Therefore, we have added a limitation noting differences between our cohort and previously published studies, in the limitations section. These changes can be found in the manuscript file on page 11, lines 389-392.

 

 

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The present study investigated the role of TARE for bridging and downstaging in patients with HCC prior to liver resection or liver transplantation. However, several limitations should be noted.

1. the role of TARE in this clinical setting has already been reported in prior studies, and the novelty of the current work is therefore limited.
2. The sample size was relatively small. And substantial heterogeneity among patients was observed, as shown in Table 4, which may compromise the internal validity of the conclusions.
3. The median follow-up time was only 10.8 months, with a high proportion of censored cases in the K–M analysis, which may introduce significant bias and limit the reliability of the survival outcomes.

Author Response

Response Letter

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.

• Reviewer 3

The present study investigated the role of TARE for bridging and downstaging in patients with HCC prior to liver resection or liver transplantation. However, several limitations should be noted.

Comment 1: The role of TARE in this clinical setting has already been reported in prior studies, and the novelty of the current work is therefore limited.

Response 1: Agreed. Thank you for pointing this out. Therefore, we have added a limitation noting differences between our cohort and previously published studies, in the limitations section. These changes can be found in the manuscript file on page 11, lines 389-392.

Comment 2: The sample size was relatively small. And substantial heterogeneity among patients was observed, as shown in Table 4, which may compromise the internal validity of the conclusions.

Response 2: We appreciate your concerns. But these limitations were already described in the limitation section. These limitations can be found in the manuscript file, on page 11, lines 381-385.

Comment 3: The median follow-up time was only 10.8 months, with a high proportion of censored cases in the K–M analysis, which may introduce significant bias and limit the reliability of the survival outcomes.

Response 3: We appreciate your concerns. But these limitations were already described in the limitation section. These limitations can be found in the manuscript file, on page 11, lines 385-387.

 

 

 

 

Author Response File: Author Response.docx