Oncologic Outcomes of Interventions to Decrease Allograft Ischemia-Reperfusion Injury within Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma: A Systematic Review
, Zuhaib M. Mir 2, Yara Azizieh 3, Stephanie E. Hiebert 2, Scott M. Livingstone 2, Mark J. Walsh 2 and Boris L. Gala-Lopez 2,3,4,*
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
This systematic review assessed interventions aimed at reducing ischemia-reperfusion injury during liver transplantation for hepatocellular carcinoma and their effects on oncologic outcomes. Four retrospective studies involving 938 HCC patients were analyzed, which utilized interventions such as post-operative prostaglandin administration, hypothermic machine perfusion, and normothermic machine perfusion. Treated patients showed reduced post-operative hepatocellular injury and inflammation, along with significantly improved recurrence-free survival. However, the impact of these interventions on overall survival remains unclear, indicating the need for further prospective research. Despite the inclusion of only four studies, this analysis adds useful information to the limited research available on intervention strategies against HCC recurrence after liver transplantation. Some revisions are suggested.
1. It is interesting to note that the intervention group in the included studies reported significantly higher RFS compared to their control groups. However, there was no significant improvement in overall survival. Does that suggest that the cause of death may not be tumor-related. Providing this information of cause of death would be beneficial in understanding the distinction between RFS and OS.
2. In the two studies utilizing HMP, both DCD and DBD donors were included. Were the beneficial effects of the intervention different between these two types of donors? Any difference in RFS and OS?
3. In addition to PGE, it would be ideal to discuss other pharmacological strategies aimed at reducing IRI after LT.
Comments on the Quality of English Language
Minor
Author Response
Reviewer #1:
- It is interesting to note that the intervention group in the included studies reported significantly higher RFS compared to their control groups. However, there was no significant improvement in overall survival. Does that suggest that the cause of death may not be tumor-related? Providing this information of cause of death would be beneficial in understanding the distinction between RFS and OS.
Answer: This is a good point. It would be very informative to dissect the actual effect of these strategies to decrease IRI on oncological outcomes after transplant. However, given the review nature of this work, we can only rely on the information provided by others. This would be a good premise for a randomized clinical trial. We acknowledge this limitation in the manuscript.
- In the two studies utilizing HMP, both DCD and DBD donors were included. Were the beneficial effects of the intervention different between these two types of donors? Any difference in RFS and OS?
Answer: This is an essential question as DCD livers sustain, by concept, a more intense IRI-related injury. Unfortunately, we are severely limited by the number of available valid studies and the information provided on them. We acknowledge this limitation in the manuscript.
- In addition to PGE, it would be ideal to discuss other pharmacological strategies aimed at reducing IRI after LT.
Answer: Indeed, many strategies are under evaluation in pre-clinical and clinical studies to ameliorate IRI during liver transplantation. Unfortunately, using ex-vivo liver machine preservation and infusion with prostaglandins were the only strategies found on the papers included in this systematic review. We acknowledge this limitation in the manuscript. Hopefully, more papers will be available soon as MP becomes more utilized worldwide.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for Authors
The authors reviewed the literature on the methodologies adopted to reduce the risk of ischemia-reperfusion injury (IRI) in liver transplants (LTx) performed for hepatocellular carcinoma (HCC).
The quality of the research is outstanding and reflects the PRISMA criteria.
However, the PICO specification adopted determines the choice of 4 very heterogeneous jobs.
The heterogeneity results in uninformative work that does not effectively respond to the background behind the choice of the specific "Interventions" adopted in the works.
Furthermore, the small number of manuscripts enrolled does not change readers' opinions on clinical practice.
The element that weighs the most is the small amount of data on overall survival.
Comments on the Quality of English Language
The quality of the English language is excellent. It is only necessary to review some spelling errors.
Author Response
Reviewer #2:
The authors reviewed the literature on the methodologies adopted to reduce the risk of ischemia-reperfusion injury (IRI) in liver transplants (LTx) performed for hepatocellular carcinoma (HCC). The quality of the research is outstanding and reflects the PRISMA criteria. However, the PICO specification adopted determines the choice of 4 very heterogeneous jobs. The heterogeneity results in uninformative work that does not effectively respond to the background behind the choice of the specific "Interventions" adopted in the works. Furthermore, the small number of manuscripts enrolled does not change readers' opinions on clinical practice. The element that weighs the most is the small amount of data on overall survival.
Answer: Thank you for diving further into the relevance of this study and the potential value for the transplant community. We totally agree that with the few available papers, it's difficult to draw meaningful conclusions. Still, we hope the scenario changes as many more centers embrace machine perfusion as the standard of care. This will facilitate clinical trials to answer questions such as ours more appropriately. We acknowledge this limitation in the manuscript.
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for Authors
The answers of the authors clarified many of the doubts about the manuscript. The formal aspect of the construction of the review was clarified, thanks to the notice about the PROSPERO guidelines
