Prognostic impact of the distance from the anterior surface to tumor cells in pancreatoduodenectomy with neoadjuvant chemoradiotherapy for pancreatic ductal adenocarcinoma

Miki Usui; Katsunori Uchida; Aoi Hayasaki; Masashi Kishiwada; Shugo Mizuno; Masatoshi Watanabe

doi:10.1371/journal.pone.0307876

Peer Review History

Original SubmissionMarch 16, 2024
16 Jun 2024 Decision Letter - Paolo Aurello, Editor PONE-D-24-08272Prognostic impact of the distance from the anterior surface to tumor cells in pancreatoduodenectomy with neoadjuvant chemoradiotherapy for pancreatic ductal adenocarcinomaPLOS ONE Dear Dr. UCHIDA, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== ============================== Please submit your revised manuscript by Jul 31 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Pancreatic ductal adenocarcinoma has a 5-year survival rate of 12% for all stages of disease, it is therefore important to assess the efficacy of neoadjuvant therapy for such tumors, very carefully. Whilst the distance between tumor cells and pancreatoduodenectomy (PD) resection margin is an accepted prognostic factor, the significance of distance from the anterior or posterior surface is currently debated. This study aims to assess the prognostic impact of the distance from the anterior surface in PD specimens that underwent neoadjuvant therapy, and to provide insights for future reporting guidelines to include the distance of tumor cells from the anterior surface. The researchers gathered data from 134 individuals who had undergone pancreatectomy surgery following chemoradiotherapy at Mie University Hospital between 2012 and 2019. Of those, 98 eligible patients, were included in the analysis. The authors performed multi variate analysis and and rank-sum tests that produced a significant p-value that may indicate an association with poor OS and DFS, when tumor cells are found within 5mm of the anterior surface, they also acknowledged the limitations of the study, being a retrospective study that was performed in a single center. while the study informs the need for further investigation, however, it does not seem sufficient to inform standards for reporting guidelines. The authors do not provide a clear explanation of the biological reasoning behind their conclusions, and the challenges of assessing post-NAT specimens, however, they do mention that "In our study, the distance from the anterior surface to the tumor cells for better DFS and OS was longer than that in previous reports. This could have been caused by neoadjuvant therapy; however, this could not be clarified" [1] The authors should cite and consider recent publications on the prognostic value of margin clearance [2] References Verbeke, C., Löhr, M., Karlsson, J. S., & Del Chiaro, M. (2015). Pathology reporting of pancreatic cancer following neoadjuvant therapy: challenges and uncertainties. Cancer treatment reviews, 41(1), 17-26. Aaquist, T., Fristrup, C. W., Hasselby, J. P., Hamilton-Dutoit, S., Eld, M., Pfeiffer, P., ... & Detlefsen, S. (2024). Prognostic value of margin clearance in total and distal pancreatectomy specimens with pancreatic ductal adenocarcinoma in a Danish population-based nationwide study. Pathology-Research and Practice, 254, 155077. Reviewer #2: A patient data is missing is very important for the practice of general surgery. The manuscript is well written. The data used are secondary and the institutional ethical approval is appropriate. Exclusion criteria are well stated. There is a patient data missing in the CA-19-9 result. Please cross-check. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: PROF. LUKMAN OLAJIDE ABDUR-RAHMAN ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: PONE-D-24-08272_reviewed copy.pdf https://doi.org/10.1371/journal.pone.0307876.r001
Revision 1
12 Jul 2024 Author Response July 7th 2024 Paolo Aurello Academic Editor PLOS ONE Response to Reviewer #1: Thank you very much for reviewing our manuscript and offering valuable suggestions. We have addressed your comments with point-by-point responses and revised the manuscript accordingly. Comments 1 and 2: The authors do not provide a clear explanation of the biological reasoning behind their conclusions, and the challenges of assessing post-NAT specimens, however, they do mention that "In our study, the distance from the anterior surface to the tumor cells for better DFS and OS was longer than that in previous reports. This could have been caused by neoadjuvant therapy; however, this could not be clarified" [1] The authors should cite and consider recent publications on the prognostic value of margin clearance [2] Response: We appreciate the helpful suggestion. Following the reviewer's comment, we have compared our conclusions with those of recent reports on the prognostic value of margin clearance. Many of these reports did not clearly describe the procedure for sampling, and, likely, the search was not adequate. We have added the following to the Discussion (p.13, lines 144-151 and p13, lines 157-p14, lines 170): Regarding the longer distance from the anterior surface to tumor cells required to improve DFS and OS than previously reported, we have highlighted the method of tissue sampling (p.13, lines 144-151) and discrepancies in diagnosis between pathologists (p13, lines 157-p14, lines 170). “This discrepancy may be due to neither of these reports providing a detailed description of their tissue sampling methods and potentially sampling less tissue compared to our method, which sampled all pancreatic tissue. In pancreatectomy specimens post-preoperative adjuvant therapy, validated studies with extensively sampled specimens showed a pathological complete response rate of 2.5% [22], whereas validated studies with fewer sampled specimens tended to report higher rates [23–24]. This suggests that a greater number of samples increases the detection rate of tumor cells, which may also impact the assessment of the distance from margins to the tumor cells.” “A report analyzing the prognostic significance of tumor cell distance from margins in total and distal pancreatectomy following neoadjuvant therapy revealed that in total pancreatectomy, the proximity of tumor cells to the SMA margin impacts OS, whereas the distance from other margins does not influence survival. In contrast, for distal pancreatectomy, the proximity of tumor cells to both the anterior and posterior surfaces does not affect survival [25]. Extensive tissue sampling was conducted for pathological examinations in this study. Patients undergoing either total or distal pancreatectomy generally present with fewer symptoms of biliary stenosis and typically have more advanced tumors at diagnosis compared to those undergoing pancreatoduodenectomy; therefore, our findings are not directly comparable. Moreover, in PDAC, the closeness of tumor cells to the anterior surface is not the sole determinant of OS. Furthermore, distinguishing between non-neoplastic ductal cells and intraepithelial and invasive carcinoma in pancreatectomy specimens after preoperative adjuvant therapy can be challenging. Accurate pathological assessment is essential, as diagnostic discrepancies among pathologists may influence study outcomes [26].” Response to Reviewer #2: Thank you very much for reviewing our manuscript and offering valuable suggestions. We have addressed your comments with point-by-point responses and revised the manuscript accordingly. Comment: A patient data is missing is very important for the practice of general surgery. The manuscript is well written. The data used are secondary and the institutional ethical approval is appropriate. Exclusion criteria are well stated. There is a patient data missing in the CA-19-9 result. Please cross-check. Response: We appreciate the helpful suggestion. Following the reviewer's comment, we can confirm that preoperative serum CA19-9 levels had not been measured in one patient; we have changed the following text in the Result (p.5, lines 103-105) Histological evaluation of extra-pancreatic nerve plexus invasion was impossible in two patients. In one patient, preoperative serum CA19-9 levels were not measured, and in two patients, histological evaluation of extra-pancreatic nerve plexus invasion was impossible. Thank you again for your comments on our manuscript. I trust that the revised manuscript now meets the standards for publication in PLOS ONE. Sincerely, Katsunori Uchida Department of Pathology, Kansai Medical University, Osaka, Japan 2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan Phone number: +81-72-804-0101 Fax number: +81-72-804-2960 Email address: uchidkat@hirakata.kmu.ac.jp Attachments Attachment Submitted filename: Response to Reviewes.docx https://doi.org/10.1371/journal.pone.0307876.r002
15 Jul 2024 Decision Letter - Paolo Aurello, Editor Prognostic impact of the distance from the anterior surface to tumor cells in pancreatoduodenectomy with neoadjuvant chemoradiotherapy for pancreatic ductal adenocarcinoma PONE-D-24-08272R1 Dear Dr. KATSUNORI UCHIDA We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Paolo Aurello Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0307876.r003
Formally Accepted
17 Jul 2024 Acceptance Letter - Paolo Aurello, Editor PONE-D-24-08272R1 PLOS ONE Dear Dr. Uchida, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Paolo Aurello Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0307876.r004

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