Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1.The total sample size is 178 cases, with only 57 cases in the LI-positive group. The relatively limited sample size may affect the statistical power, especially in subgroup analysis (the number of LI-positive patients not receiving locoregional treatment is further reduced), and the extrapolation of conclusions may be limited. In addition, the patients included in the study are all from three hospitals in Turkey, which may have selection bias in region, ethnicity, and diagnosis and treatment models, making it difficult to represent HCC patients in different regions and with different diagnosis and treatment levels.

2.The study mainly focuses on the correlation between LI and clinical prognosis, and there is little discussion on the potential mechanism of LI affecting recurrence and survival of HCC after LT. Only the relationship between the lymphatic system and the immune system and tumor metastasis is briefly mentioned, without in-depth analysis of the specific pathways of LI promoting tumor recurrence (such as the expression of lymphangiogenesis-related factors VEGF-C/VEGF-D, the molecular mechanism of tumor cell spread through the lymphatic system, etc.) combined with the study data or existing basic research results.

3.The study found that LI is related to preoperatively available indicators such as AFP level, tumor size, and number of lesions, but did not further construct a preoperative prediction model of LI based on these indicators, which cannot provide a practical tool for preoperative assessment of LI status, limiting the clinical transformation efficiency of the study results.

Comments on the Quality of English Language

Conduct a comprehensive proofreading of the spelling of terms in the full text to unify the expression standards; standardize the data format in the table, supplement missing values, correct incorrect symbols, and ensure the accuracy and readability of the data.

Author Response

1 The total sample size is 178 cases, with only 57 cases in the LI-positive group. The relatively limited sample size may affect the statistical power, especially in subgroup analysis (the number of LI-positive patients not receiving locoregional treatment is further reduced), and the extrapolation of conclusions may be limited. In addition, the patients included in the study are all from three hospitals in Turkey, which may have selection bias in region, ethnicity, and diagnosis and treatment models, making it difficult to represent HCC patients in different regions and with different diagnosis and treatment levels.

Reply 1.We agree that the relatively limited sample size (n=178) and the specific number of LI-positive cases (n=57) are limitations that may affect the statistical power of subgroup analyses. To address this, we have now explicitly stated this as a limitation in the "Discussion" section. Regarding the geographical focus, while our study is limited to two centers in Turkey, these centers are major referral hospitals that treat a diverse patient population. However Both centers serve  patient populations in the immediate area.We believe our findings provide a crucial baseline for Mediterranean and Middle Eastern cohorts, which are often underrepresented in global HCC literature.

316-318 added ‘Furthermore, due to the limited number of patients within the subgroups, analyses regarding LI might be especially underpowered to reach significant results. Larger sample sizes could provide more robust conclusions ‘

300-311 added ‘Our view, the clinical significance of lymphovascular invasion may stem from the fact that HCC tends to recur primarily within the liver rather than metastasizing to intra and extrahepatic .In the context of adjuvant  therapy, we focused on the evaluation of recurrence. we also aimed to identify patient groups that could potentially benefit from adjuvant therapy. Patients with adverse findings, especially lymphatic  invasion, appear to be strong candidates for adjuvant treatment. The potential role of adjuvant locoregional treatments such as TACE, radiofrequency ablation, and radiotherapy may be crucial for patients with high risk of intra and extrahepatic metastasis and poor survival outcome However, survival analysis based on adjuvant treatment was not conducted in this study, primarily due to potential selection bias and the limited number of patients who received adjuvant treatment.

Despite its findings, this study has certain limitations. The sample size of 178 patients, particularly the LI-positive subgroup (n=57), may limit the statistical power for complex subgroup analyses and the generalizability of the results. Furthermore, the single-country, two-center design may introduce regional or ethnic selection biases. Lastly, while we identified significant preoperative indicators for LI, a formal predictive model was not constructed. Future studies with larger, international cohorts are necessary to validate these findings and translate them into a practical preoperative assessment tool.

2.The study mainly focuses on the correlation between LI and clinical prognosis, and there is little discussion on the potential mechanism of LI affecting recurrence and survival of HCC after LT. Only the relationship between the lymphatic system and the immune system and tumor metastasis is briefly mentioned, without in-depth analysis of the specific pathways of LI promoting tumor recurrence (such as the expression of lymphangiogenesis-related factors VEGF-C/VEGF-D, the molecular mechanism of tumor cell spread through the lymphatic system, etc.) combined with the study data or existing basic research results

2 reply. I have added the detailed explanations you mentioned in pages 69-91, along with updated references.

 

 

3 The study found that LI is related to preoperatively available indicators such as AFP level, tumor size, and number of lesions, but did not further construct a preoperative prediction model of LI based on these indicators, which cannot provide a practical tool for preoperative assessment of LI status, limiting the clinical transformation efficiency of the study results.

Reply 3 This is an excellent point. Our study aimed to identify and confirm the correlation between preoperative indicators (AFP, tumor size, etc.) and LI status. We agree that a scoring system or a nomogram would significantly increase the clinical utility of the results. However, we intentionally refrained from constructing a model in this study to avoid "overfitting" due to the current sample size. We believe that identifying these key indicators is a mandatory first step, and we plan to develop and validate a formal prediction model in a larger, multi-center prospective study in the near future.

3 The study mainly focuses on the correlation between LI and clinical prognosis, and there is little discussion on the potential mechanism of LI affecting recurrence and survival of HCC after LT. Only the relationship between the lymphatic system and the immune system and tumor metastasis is briefly mentioned, without in-depth analysis of the specific pathways of LI promoting tumor recurrence (such as the expression of lymphangiogenesis-related factors VEGF-C/VEGF-D, the molecular mechanism of tumor cell spread through the lymphatic system, etc.) combined with the study data or existing basic research results.

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript describing impact of lymphovascular invasion as a prognostic factor following liver transplant for HCC.

Major points

1. The authors need to describe their accpetance criteria for transplant for HCC
2. The details of LDLT/ DDLT in LI vs no LI group should be included.
3. The description of LRT modality is required as is the time from LRT to transplant as that may have implications in excluding patients who progress while waiting after LRT

Minor point

The result section in lines 138 to 141 the text does not match the graphs and shows superior outcome for Lymphatic invasion group.

Comments on the Quality of English Language

The discussion section needs to be re organized with clarity regarding impact of LI in HCC and other malignancies and then talk about LN spread.

Author Response

1.The authors need to describe their acceptance criteria for transplant for HCC

 

Repyl1 I added in to lines 104 to 107 ‘Milan criteria were used for deceased donor liver transplantation(DDLT), while Expanded criteria, along with downstaging modalities such as ablation and TACE, were used for living donor liver transplantation(LDLT) as acceptance criteria for transplant for HCC.’

2.The details of LDLT/ DDLT in LI vs no LI group should be included.

Reply2 ı added in to 107-109 lines ‘In the LI group, 14 patients underwent DDLT and 43 patients underwent LDLT, while in the non-LI group, 48 patients underwent DDLT and 73 patients underwent LDLT.’

3.reply.ı added into 119-121 lines ‘The patient, who received downstaging treatment, underwent a living donor transplant after a one-month waiting period if there was no progression.’

4) The result section in lines 138 to 141 the text does not match the graphs and shows superior outcome for Lymphatic invasion group.

Reply. We noted that poor prognostic criteria such as high AFP values, tumor diameter, and tumor lesion number were higher in the LI patient group. This was reflected in the graphs, where overall and disease-free survival were inversely proportional and lower in the LI group.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

1.The introduction section should be modified to reflect the clinical nature of the manuscript. The description of lymphatic spread should be moved to the discussion section.

Minor: Use full text instead of abbreviation in the conclusion section of the abstract.

2. The conclusion is replicating the abstract. The conclusion/ conclusions need to be concise and clear. All other aspects are already discussed and need not be repeated in the conclusion.

 

3. Lines 168 to 171- Text and graphs do not match; text needs to be corrected

"In  the patient subgroup who did not receive LRT, median DFS was significantly higher in the LI group than the non-LI group (89.9 and 119.3 months, respectively). Likewise, Median OS was significantly higher in the LI group compared to the non-LI group in the non LRT subgroup.(86.4 and 111.2 months, respectively).(figure 2b)"

Author Response

Round 2.

1. The introduction section should be modified to reflect the clinical nature of the manuscript. The description of lymphatic spread should be moved to the discussion section.

Reply 1. I brought the section on spread via the lmphatic system to the beginning of the discussion. The part was included into 150 to 185 lines

I used full text instead of abbreviation in the conclusion section of the abstract.

2. The conclusion is replicating the abstract. The conclusion/ conclusions need to be concise and clear. All other aspects are already discussed and need not be repeated in the conclusion.

Reply 2. I made the conclusion section clear  and concise

3. Lines 168 to 171- Text and graphs do not match; text needs to be corrected

"In  the patient subgroup who did not receive LRT, median DFS was significantly higher in the LI group than the non-LI group (89.9 and 119.3 months, respectively). Likewise, Median OS was significantly higher in the LI group compared to the non-LI group in the non LRT subgroup.(86.4 and 111.2 months, respectively).(figure 2b)"

Reply 3.Thank you for pointing out a very important point. The overlooked discrepancy between the text and graph 2 has been corrected. The corrected version is available on lines 133-137.