Hepatocellular Carcinoma, Alpha Fetoprotein, and Liver Allocation for Transplantation: Past, Present and Future

Round 1

Reviewer 1 Report

Ruch et al. provide a strong historical and retrospective review of transplant allocation for HCC, with a focus on the value of AFP measurements as selection criteria.  They consider pragmatic, medical, and ethical (equitable allocation criteria).  This is a valuable submission that I recommend for publication with only one minor change.

1.  The abstract completely lacks the final recommendation.  The statements made in likes 430-433 are the critical take-home message of this treatise, and these need to be clearly stated in the abstract.

Author Response

 Dear Reviewer,

 Thank you for your review of our paper. We have edited the abstract to include the key message of our review in response to your response. This correction was made in lines 21 – 24 of the paper.

Reviewer comment:  The abstract completely lacks the final recommendation.  The statements made in likes 430-433 are the critical take-home message of this treatise, and these need to be clearly stated in the abstract.

 Edit made: “We aim to review the history of liver allocation for HCC in the US, the utility of AFP in liver transplantation, the implications of weaving AFP as a biomarker into policy. Based on this review, we encourage the US transplant community to revisit its HCC organ allocation model, to incorporate more precise oncologic principles for patient selection, and to adopt AFP dynamics to better stratify waitlist dropout risk.”

Thank  you,

Brianna Ruch

Reviewer 2 Report

Title: Hepatocellular Carcinoma, Alpha Fetoprotein, and Liver Allocation for Transplantation: Past, Present and Future 

This paper summarize the history of liver allocation for Hepatocellular Carcinoma (HCC) in the US, the utility of AFP in liver transplantation, the implications of AFP as a biomarker into policy, and potential future directions. This article adds additional interpretation that would advance our understanding of the potential role of AFP in HCC. Overall, the manuscript is well-written and well-organized. 

Minor comments:

1.     There have been several published article on this same topic, including Int J Biol Sci. 2022; 18(2): 536–55, Viruses. 2022 Apr 8;14(4):775, J Clin Transl Hepatol. 2022 Feb 28;10(1):159-163, World J Gastroenterol. 2022 Jan 14;28(2):216-229. Ann Hepatol. 2022 Jan-Feb;27(1):100654, and etc. The authors should explain why their findings were promising as compared to previous studies.

2.     Figure 1: Please describe the structure analysis of Alpha Fetoprotein in detailed.

3.     Table 1 should be adjusted.

4.     Figure 3: The image resolution should be improved.

Author Response

Dear Editors,

 Thank you for your review of our paper. We have edited the paper as best to address your responses. These corrections and responses are summarized below.

1. There have been several published articles on this same topic, including Int J Biol Sci. 2022; 18(2): 536–55, Viruses. 2022 Apr 8;14(4):775, J Clin Transl Hepatol. 2022 Feb 28;10(1):159-163, World J Gastroenterol. 2022 Jan 14;28(2):216-229. Ann Hepatol. 2022 Jan-Feb;27(1):100654, and etc. The authors should explain why their findings were promising as compared to previous studies.

Absolutely. Many of the current articles address the role of AFP in HCC alone,  not specifically how AFP is becoming instrumental in transplantation prognostication and allocation for patients with HCC. There are a few reviews looking at AFP and HCC for transplantation specifically (Trevisani, Semin Liver Dis. 2019 May;39(2):163-177) and (Ozdemir Journal of Gastrointestinal Cancer (2020) 51:1127-1132). These articles, although hitting on the importance of AFP in transplantation, do not include how the current allocation model has been shaped, the discussion of waitlist dropout as it pertains to AFP, or the most recent information regarding AFP dynamics. Our article strives to address these topics in a single review.

To address this we made the following addition through lines 52-58.

Although the role of AFP in liver transplantation has been reviewed [4,16], there is not a centralized discussion of how AFP has been incorporated into allocation, or the new potential roles of AFP dynamics and waitlist stratification. The aim of this review was to provide an evolutionary perspective of liver transplantation and allocation for HCC, focusing on the increasingly central role of AFP as an HCC biomarker, and future directions.

2. Figure 1: Please describe the structure analysis of Alpha Fetoprotein in detailed.

• The structural analysis is relatively limited. We included the main discussion of the structure as described in the Zhu article the figure was derived. The alteration was made in lines 46-48:
  • It has a V-shaped structure comprised of three major domains, with the active binding sites in domain I and III, Figure 1[11].

3. Table 1 should be adjusted.

• Attempted to better adjust Table 1. Added summary of abbreviations used into the table description. Aligned table type to the left and altered the bullet points for better clarity. If these are not the adjustments intended, please let us know. We are happy to make any further edits as requested.

4. Figure 3: The image resolution should be improved.

• Thank you, Figure was redone, and resolution improved. Line 376.

Thank you,

Brianna Ruch