The Complexity of the Pancreatic Lymphatic System and the Key Role of Para-Aortic Lymph Node Metastasis in Pancreatic Cancer Prognosis Prediction: A Comprehensive Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I am grateful for the opportunity to review the paper “The Complexity of Pancreatic Lymphatic System and The Key Role of Para-Aortic Lymph Node Metastasis in Pancreatic Cancer Prognosis Prediction: A Comprehensive Review." This review is well-written, and relevant to clinical needs. The authors describe the basic anatomy regarding pancreatic cancer lymph node metastases, and its significance in the clinical setting. However, I do have a few suggestions and concerns.

# The authors mentioned the subtypes of pancreatic cancer in the section 2.2. However, I feel that this is a little bit irrelevant to the current topic and seems too long for me. Please consider making it short.

# The authors should cite the reference for JPS classification.

# It would be great if the authors could provide readers a table depicting the previous studies regarding the association of PALN with patients’ prognosis in the ”7. Para-Aortic Lymph Node Metastasis in Patients Prognosis.”

# The authors should mention that what subsets of patients are needed for intraoperative frozen section of PALN.

# The authors noted that the importance of novel markers in the treatment strategies for pancreatic cancer. It would be appreciated if they mentioned the clinical relevance of novel markers with PALN. For example, we could selectively harvest PALN as a sample from resectable PDAC patients with increased such markers for better diagnosis.

Author Response

I am grateful for the opportunity to review the paper “The Complexity of Pancreatic Lymphatic System and The Key Role of Para-Aortic Lymph Node Metastasis in Pancreatic Cancer Prognosis Prediction: A Comprehensive Review." This review is well-written, and relevant to clinical needs. The authors describe the basic anatomy regarding pancreatic cancer lymph node metastases, and its significance in the clinical setting. However, I do have a few suggestions and concerns.

- We thank you for carefully reading our study, providing feedback and helping us improve the quality of our article.

# The authors mentioned the subtypes of pancreatic cancer in the section 2.2. However, I feel that this is a little bit irrelevant to the current topic and seems too long for me. Please consider making it short.

- We agree with the suggestion, and for this reason, we rewrote the topic more succinctly and directly.

# The authors should cite the reference for JPS classification.

- We appreciate your attention in the references, and for this reason, we add the reference that supports the JPS classification information.

# It would be great if the authors could provide readers a table depicting the previous studies regarding the association of PALN with patients’ prognosis in the ”7. Para-Aortic Lymph Node Metastasis in Patients Prognosis.”

- At this time, we received an invitation to carry out just one review, but we agreed that a systematic review would provide more accurate information about the prognostic value, we believe that a table, which excludes some authors would generate an important bias, therefore, it would be appropriate in a systematic review which we hope to achieve in the near future.

# The authors should mention that what subsets of patients are needed for intraoperative frozen section of PALN.

- Thanks for the suggestion. We added the information.

# The authors noted that the importance of novel markers in the treatment strategies for pancreatic cancer. It would be appreciated if they mentioned the clinical relevance of novel markers with PALN. For example, we could selectively harvest PALN as a sample from resectable PDAC patients with increased such markers for better diagnosis.Primeiramente, gostaríamos de agradecer por sua revisão e por seu cuidado em ajudarnos a realizar melhoras em nosso estudo e por sugerir mudanças que considera importantes para uma maior coesão do artigo. 

- Thanks for the suggestion. We agree that it adds value to the article, for this reason, we added a paragraph just dissecting this information.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors analyzed the pancreatic lymphatic system and the important role of para-aortic lymph nodes in patients with cancer metastasis. This narrative review explores the pancreas anatomy and pancreatic cancer. The authors reviewed the pancreatic lymphatic system and its role in pancreatic cancer. They explained clearly the involvement of PALN in pancreatic cancer diagnosis and prognosis. 

The manuscript is well written in correct English, following logical steps to present the lymphatic system's anatomy, function, and role in pancreatic cancer. The authors may include some images to explain better the involvement and the metastasis of pancreatic cancer, as well as some figures of imaging of lymph nodes.

Author Response

We are grateful for the favorable feedback regarding our study. It is our aspiration that this review will contribute to future research endeavors exploring the key role of para-aortic lymph node in the metastatic progression of pancreatic cancer. In response to your suggestion, we intend to incorporate a figure to elucidate the lymphatic system of the pancreas outlined in textual form.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The issue of investigating the intricacies of the pancreatic lymphatic system and the crucial significance of para-aortic lymph node metastases in predicting the prognosis of pancreatic cancer is of utmost importance in both oncological research and clinical practice for several reasons:

The metastatic spread of pancreatic cancer is significantly influenced by the lymphatic system. Studying the complex system of lymphatic veins in the pancreas and how cancer cells spread to nearby lymph nodes called para-aortic lymph nodes might provide important information about the progression of the illness and its ability to spread to other parts of the body.

The presence of metastases in the para-aortic lymph nodes is a strong predictor of prognosis in pancreatic cancer. Gaining insight into the processes that cause lymphatic metastasis to these nodes may enhance the accuracy of predicting patient outcomes and inform treatment choices, such as selecting suitable therapeutic approaches and determining the level of follow-up care required.

Treatment customisation: Understanding the role of para-aortic lymph nodes in the spread of pancreatic cancer enables more precise and individualised treatment strategies. It could encourage medical professionals to contemplate more assertive measures like neoadjuvant chemotherapy or radiation treatment to specifically address the spread of the illness and enhance the chances of patient survival.

Para-aortic lymph node metastasis has a significant role in determining the prognosis of pancreatic cancer. Understanding this involvement provides valuable insights that may be used to design more precise therapeutic treatment methods. This encompasses the execution of improved surveillance methods for patients with a greater likelihood of lymphatic spread, as well as the incorporation of innovative imaging techniques or biomarkers for the early identification and tracking of metastatic illness.

Research Focus: Exploring the intricacy of the pancreatic lymphatic system and its connection to the spread of cancer to the lymph nodes around the aorta provides opportunities for more investigation. This involves investigating the molecular processes that underlie the spread of cancer cells via the lymphatic system, finding possible targets for therapy to prevent this spread, and creating new diagnostic and prognostic tools to enhance patient outcomes.

Improving our knowledge of the biology of pancreatic cancer and characteristics that predict the spread of cancer cells to lymph nodes helps us provide better treatment and support for patients. It enables healthcare practitioners to provide customised treatment regimens, enhance supportive care measures, and give patients and their families with more precise prognostic information, thereby enhancing the overall quality of life.

Ultimately, it is crucial to study the intricacies of the pancreatic lymphatic system and understand the significant impact of para-aortic lymph node metastasis on predicting the prognosis of pancreatic cancer. This research is essential for advancing our understanding of the disease, optimising treatment approaches, and ultimately enhancing patient outcomes.

Regarding this study, I would like a comparison with several cases described in the literature with pancreatic tumors and surgical treatment performed. This part of your study is too brief. A more detailed analysis of the studies must be done and a PRISMA diagram can be applied to see how these judges were chosen. The interest that the theme develops is great, but we must insist on this part of the study. The English language also needs adjustments. The bibliography needs additions. The conclusions part requires a more precise detail. At the moment this is very vague. The study requires re-evaluation after the corrections made.

Comments on the Quality of English Language

Moderate English adjustments is needed.

Author Response

We deeply appreciate your thorough analysis of our study, and we recognize the immense value of your suggestions in enhancing its quality. In response to your feedback, we have augmented the content to ensure a more comprehensive discussion of the topics, as per your request.

Concerning the PRISMA guidelines, we acknowledge that our study was not intended to be a systematic review but rather an invitation for a review. We regret the absence of a PRISMA study selection flowchart in the article. The subject matter, characterized by its heterogeneity in therapeutic approaches, sample sizes, and follow-up periods, presents a significant challenge in achieving a bias-free selection process. Consequently, we opted to include studies from reputable high-impact journals.

Furthermore, we have refined the language, added a figure, and appropriate references, and enhanced the conclusion section.

We are grateful for each suggestion provided for improvement, and we have endeavored to incorporate them to the best of our ability. Thank you for your invaluable guidance in refining our study to meet the requested standards.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The article is fine. Thank you for the changes.