Total plaque score helps to determine follow-up strategy for carotid artery stenosis progression in head and neck cancer patients after radiation therapy

Chi-Hung Liu; Joseph Tung-Chieh Chang; Tsong-Hai Lee; Pi-Yueh Chang; Chien-Hung Chang; Hsiu-Chuan Wu; Ting-Yu Chang; Kuo-Lun Huang; Chien-Yu Lin; Kang-Hsing Fan; Chan-Lin Chu; Yeu-Jhy Chang

doi:10.1371/journal.pone.0246684

Peer Review History

Original SubmissionOctober 30, 2020
9 Dec 2020 Decision Letter - Paula Boaventura, Editor PONE-D-20-34151 Total Plaque Score Helps Determining Follow-up Strategy for Carotid Artery Stenosis Progression in Head and Neck Cancer Patients after Radiation therapy PLOS ONE Dear Dr. Chang, 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. The manuscript will need extensive English editing. Please submit your revised manuscript by Jan 23 2021 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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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”). For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly Reviewer #3: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: Yes Reviewer #3: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? 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 Reviewer #3: 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: The authors sought to investigate if carotid duplex ultrasound (CDU) predicts the development of ischemic stroke (IS) in patients with mild carotid artery stenosis after radiation therapy (RT) for head and neck cancer (HNC). They prospectively studied all patients treated with RT at their hospital so the population is equivalent to a random sample. They utilized a total plaque score (TPS) to categorize participants as low plaque (LP) and high plaque (HP). Utilizing multivariate logistic regression the authors determined that TPS was the main predictor of carotid arterial disease (CAD) progression. They noted that in contrast to the LP group, membership in the HP group was associated with older age, male sex, hypertension, smoking, impaired renal functioning, antiplatelet use, and increased uric acid The authors conclude CDU may be a valuable tool to assess patients with HNC immediately after RT and to follow those with HP regularly to consider for intervention if there is progression of CAD. The study was well-conducted with a reasonable analysis. The manuscript will likely merit publication with revisions. Page 4 The authors state that all data are fully available without restriction. Please publish the full dataset without identifying items to accompany the manuscript. If the datasets are too large to be supplementary files, then please publish in a separate repository, such as Zenodo or Mendeley. Page 7 Keywords Since some search engine list only the title and keywords, choose terms that are not included in the title. Page 17 Second paragraph First line The authors note that HNC is common in Chinese populations. How many of their participants had Han ancestry? Does Han ancestry play a role in the outcomes if introduced to their models? Please identify the Han Chinese heritage of each participant to include in the multivariate logistic regression models. Figure 3. Legend Define "cum" ordinate. Reviewer #2: thank you to the authors for their submission. This is a cogent, nicely composed, well rationalized, and potentially informative study intending to assess the predictive value of readily available ultrasonographic evaluation of patients with radiation induced carotid injury following HnN cancer. I would applaud the authors for attempting to study a widely available, easily repeatable, and, generally speaking, affordable methodology for this purpose. I do see very strong potential for its applications, but a few criticisms come to mind which I do believe are likely addressable. In all I believe the study would be of interest of the readership. I would emphasize the following: 1. I do believe some ground truth comparison to cross-sectional angiographic methods that offer a more legitimate structural assessment would have been a complement. I do understand that this may not be possible in the entirety of the cohort, but even if a subset has such imaging, whether CTA, cath, or MRI , it would greatly contribute 2. I believe the longitudinal follow up is still Somewhat short term, and truly disambiguating in the arc of disease in different patients would require more regular and longer-term evaluation. I understand that this may be considered hypothesis building data for know and I hope the authors can emphasize that. Completely shifting practice paradigms based on what our somewhat preliminary results should be done only with immense circumspection Lastly, imaging examples are completely lacking. Keep in mind that this is a highly operator dependent technique, and if anything I would suggest a large number of imaging examples including those that might highlight pitfalls or limitations. Reviewer #3: The authors present methodology to predict progression of carotid arterial stenosis in head and neck cancer patients who have undergone radiation therapy. The authors report the results of 217 such patients who have undergone carotid doppler ultrasound. The studies were reviewed by blinded trained radiologists. The inter-rater reliability was > 90% agreement. (HOW WERE THE REMAINING DISAGREEMENTS HANDLED). The authors report that high initial plaque score of >/= to 7 is very important in determining likelihood of progression in carotid stenosis following radiation therapy. (PLEASE REPORT THE TRANSDUCER ANGLE AT WHICH THE VELOCITIES WERE ACQUIRED FOR THE INTIIAL WORK UP AND FOR THE FOLLOW-UP SESSION. DIFFERENCES IN THE ANGLE COULD ARTIFICIALLY ELEVATE THE MEASURED ENDOVASCULAR FLOW VELOCITIES AND ERRONEOUSLY LEAD ONE TO INTERPRET INCREASING STENOSIS. PLEASE PROVIDE THIS INFORMATION. ****** 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: Yes:** James Robert Brasic Reviewer #2: No Reviewer #3: No [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. https://doi.org/10.1371/journal.pone.0246684.r001
Revision 1
25 Dec 2020 Author Response Dear Paula Boaventura Academic Editor, PLOS ONE Thank you for your nice and detailed review. We’ve provided a point-by-point revision and our responses to all of your comments. The reasons and revisions are provided in the following contents. In the revised manuscript, all the changes are highlighted. We deeply appreciate your valuable review, which stimulated a more thorough consideration of the essay. Thank you very much. Sincerely Yours, Yeu-Jhy Chang, MD Stroke Center and Department of Neurology Chang Gung Memorial Hospital, Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan No. 5, Fu-Hsing ST. Kueishan, Taoyuan, 33333 Taiwan Tel: 886-3-3281200 ext 8340 Fax: 886-3-3288849 Editor’s comment 1. The manuscript will need extensive English editing. Answer: Thank you, we’ve tried our best to improve the English editing, including the English revision by the native speaker. 2. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Answer: Thank you, we’ve revised the manuscript according to PLOS ONE's style requirements. 3. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”). Answer: Thank you for your reminding. We’ve added this in the manuscript. Materials and Methods, page 4, line 12-14 The study was approved by the Ethics Institutional Review Board of Chang Gung Memorial Hospital (IRB No. 100-4153B). All of the included patients signed written informed consent forms. Reviewers' comments: Reviewer #1: The study was well-conducted with a reasonable analysis. The manuscript will likely merit publication with revisions. 1. The authors state that all data are fully available without restriction. Please publish the full dataset without identifying items to accompany the manuscript. If the datasets are too large to be supplementary files, then please publish in a separate repository, such as Zenodo or Mendeley. Answer: Thank you for your comment. After discussing with the Ethics Institutional Review Board of out hospital, we’ve provided the data those could be accessible in the supplementary file. 2. Keywords Since some search engine list only the title and keywords, choose terms that are not included in the title. Answer: Thank you for your wonderful suggestion. We’ve added one keyword. Keywords: Carotid artery stenosis, carotid duplex ultrasound, head and neck cancer, plaque scores, radiation therapy, radiation vasculopathy. 3. The authors note that HNC is common in Chinese populations. How many of their participants had Han ancestry? Does Han ancestry play a role in the outcomes if introduced to their models? Please identify the Han Chinese heritage of each participant to include in the multivariate logistic regression models. Answer: Thank you for your expert opinion. In Taiwan, more than 95 percent of the population claiming Han ancestry (https://www.taiwan.gov.tw/content_2.php). In our study, all recruited patients were Han Chinese. It would be difficult to discuss the role of Han Chinese heritage in clinical outcomes. We revised the manuscript accordingly. Results, page 7, line 23-24 Between 2013 and 2014, we prospectively screened 361 Han Chinese patients with HNC who received RT at our hospital. Discussion, page 12, line 12-14 We stated this in the limitation paragraph. Fourth, the single-center nature of this study could have led to patient selection bias. Fifth, the generalizability of our conclusions to other ethnicities remains uncertain. 4. Figure 3. Legend Define "cum" ordinate. Answer: Thank you for your suggestion. We’ve revised the ordinate of this figure. Besides, due to one figure was suggested to be added by another reviewer, figure 3 was renamed as figure 4. New ordinate of this figure is “Cumulative CAS progression-free rate”. Figure 4. Multivariate-adjusted survival curves estimating the time to CAS progression. The incidence rate of CAS progression was significantly higher in the HP group than in the LP group. CAS, carotid artery stenosis; HP, high plaque score; LP, low plaque score; TPS, total plaque score. Reviewer #2: This is a cogent, nicely composed, well rationalized, and potentially informative study intending to assess the predictive value of readily available ultrasonographic evaluation of patients with radiation induced carotid injury following HnN cancer. I would applaud the authors for attempting to study a widely available, easily repeatable, and, generally speaking, affordable methodology for this purpose. I do see very strong potential for its applications, but a few criticisms come to mind which I do believe are likely addressable. In all I believe the study would be of interest of the readership. Answer: Thank you for your suggestion. We will keep working hard. 1. I do believe some ground truth comparison to cross-sectional angiographic methods that offer a more legitimate structural assessment would have been a complement. I do understand that this may not be possible in the entirety of the cohort, but even if a subset has such imaging, whether CTA, cath, or MRI , it would greatly contribute Answer: Thank you for your suggestion. These are indeed important issues. However, due to the limitation of this study, we could only address this in the limitation paragraph. In the future study, we will endorse this suggestion into study protocol. Discussion, page 11, line 26- page 12, line 9 First, CDU studies may not be a precise method to evaluate the degree of stenosis and plaque features. Confounding factors caused by the technique may have influenced the study results, and thus limited the interpretation of CAS progression. In addition, advanced cerebrovascular images including computerized tomography angiography, magnetic resonance angiography, or conventional angiography were not routinely arranged as a confirmatory study when CAS progression was detected by CDU. This may also have limited the interpretation of the study results. Second, baseline vascular status may have confounded the conclusions drawn from our results. A higher TPS or CAS before RT may have further worsened the clinical progression and may have led to bias in this study. However, in real-world practice, primary physicians may not know the vascular status of the carotid arteries prior to RT. Further cohort studies with more strict follow-up protocols and confirmatory vascular imaging studies are still needed to validate our suggested follow-up strategy. 2. I believe the longitudinal follow up is still Somewhat short term, and truly disambiguating in the arc of disease in different patients would require more regular and longer-term evaluation. I understand that this may be considered hypothesis building data for know and I hope the authors can emphasize that. Completely shifting practice paradigms based on what our somewhat preliminary results should be done only with immense circumspection Answer: Thank you for your suggestion. These are quite important. We’ve added this into the limitation paragraph. Discussion, page 12, line 14-16 Lastly, a longer follow-up duration may provide more conclusive answers. Completely shifting practice paradigms based on what our preliminary results should be done only with immense circumspection. 3.Lastly, imaging examples are completely lacking. Keep in mind that this is a highly operator dependent technique, and if anything I would suggest a large number of imaging examples including those that might highlight pitfalls or limitations. Answer: Thank you for your suggestion. These are quite important. We’ve added one figure (figure 2) showing imaging examples. Results, page 8, line 3-5 Of these 217 patients, 209 (96.3%) received CDU follow-up for more than 18 months after enrolment. We first recorded the presence and evaluated the predictors of CAS progression (Figure 2). Figure 2. An illustrated case with carotid artery stenosis progression. This figure shows typical carotid duplex ultrasound findings in a patient after radiation therapy. Prominent segmental changes were noted in bilateral common carotid arteries at the time of enrolment (A-C). Follow-up carotid duplex ultrasonography of the same patient 2 years later (D-F) demonstrated significant progression of stenosis (>50%) in the left common carotid artery (D) with hemodynamic changes (E). Reviewer #3: The authors report the results of 217 such patients who have undergone carotid doppler ultrasound. The studies were reviewed by blinded trained radiologists. The inter-rater reliability was > 90% agreement. 1. (HOW WERE THE REMAINING DISAGREEMENTS HANDLED). Answer: thank you for your comment. The results of the CDU were read by single blind neurologist (CLC) when performing this retrospective analysis. Dr. CLC did not know the status of each enrolled patient. We compared Dr. CLC’s CDU results to the official reports of the CDU documented at the time of examination (between January 1, 2013 and December 31, 2014). There was no discordance between the official reports and Dr. CLC’s documentation. We stated this in the revised manuscript. Besides, “> 90%” was not the “inter-rater reliability” of CDU reporting. Instead, “> 90%” was the accuracy data comparing CDU results and conventional angiography when we set-up our CDU laboratory in 1992. We added the reference (Ref. 16) for this accuracy data. Materials and Methods, page 5, line 19-23 The investigators who performed and read (CLC et al.) the baseline and follow-up CDU were blinded to the patients’ clinical conditions. Agreement was achieved in all CDU results between the investigators. Our CDU laboratory has an overall diagnostic accuracy rate of >90% for carotid stenosis [15, 16]. Newly added reference: 16. Tseng KY, Lee TH, Ryu SJ, Chen ST. Correlation between sonographic and angiographic findings of extracranial carotid artery disease. Zhonghua yi xue za zhi = Chinese medical journal; Free China ed. 1992;50(4):302-6. Epub 1992/10/01. PubMed PMID: 1334789. 2. The authors report that high initial plaque score of >/= to 7 is very important in determining likelihood of progression in carotid stenosis following radiation therapy. (PLEASE REPORT THE TRANSDUCER ANGLE AT WHICH THE VELOCITIES WERE ACQUIRED FOR THE INTIIAL WORK UP AND FOR THE FOLLOW-UP SESSION. DIFFERENCES IN THE ANGLE COULD ARTIFICIALLY ELEVATE THE MEASURED ENDOVASCULAR FLOW VELOCITIES AND ERRONEOUSLY LEAD ONE TO INTERPRET INCREASING STENOSIS. PLEASE PROVIDE THIS INFORMATION. Answer: Thank you for your reminding, we’ve revised the manuscript accordingly. Materials and Methods, page 5, line 17-18 The degree of CAS was examined in the CDU study according to standard ultrasound criteria. The percentage of maximum stenosis in longitudinal views was determined using computer-assisted measurements of the 1-residual lumen diameter/vessel diameter × 100. The angle of insonation was set at 60 degrees during the flow velocity examination. Peak systolic velocities ≥120 cm/s were used to identify ≥50% CAS [14]. Thank you for the reviewers’ constructive and valuable advice and comments. We hope the revised version could be more readable and can meet the requirements of PLOS ONE. Best regards Yeu-Jhy Chang, MD Stroke Center and Department of Neurology Chang Gung Memorial Hospital, Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan Attachments Attachment Submitted filename: letter to the reviewer_1224.docx https://doi.org/10.1371/journal.pone.0246684.r002
20 Jan 2021 Decision Letter - Paula Boaventura, Editor PONE-D-20-34151R1 Total Plaque Score Helps to Determine Follow-up Strategy for Carotid Artery Stenosis Progression in Head and Neck Cancer Patients after Radiation Therapy PLOS ONE Dear Dr. Chang, 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 Mar 06 2021 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. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Paula Boaventura, PhD Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) Reviewer #2: All comments have been addressed Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? 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 Reviewer #3: Yes ****** 6. 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: The authors assessed the utility of a total plaque score to predict carotid artery stenosis progression in patients with head and neck cancer after radiation. The study was well-conducted with a reasonable analysis. The manuscript will likely merit publication with revision to facilitate interpretation by clinicians. Page 28 Figure 2 Legend Please state the age and sex of the participant. Reviewer #2: Thank you for making the requested additions and clarifications. and its current form of this manuscript, while in park comprising preliminary or hypothesis building data is likely to offer some valuable insights regarding the intersection of credit disease and radiation – treated head and neck cancer patients. The largest areas for future clarification are cross reference with advanced structural cross-sectional angiographic imaging, the presence of longitudinal data to assess true progression over a longer period of time, and a better understanding of baseline variables in these patients. Reviewer #3: My concerns about potentially suboptimal transducer angles contributing to elevated endovascular velocities was satisfactorily addressed. ****** 7. 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: Yes:** James Robert Brasic Reviewer #2: No Reviewer #3: No [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. https://doi.org/10.1371/journal.pone.0246684.r003
Revision 2
20 Jan 2021 Author Response Reviewers' comments: Reviewer #1: The authors assessed the utility of a total plaque score to predict carotid artery stenosis progression in patients with head and neck cancer after radiation. The study was well-conducted with a reasonable analysis. The manuscript will likely merit publication with revision to facilitate interpretation by clinicians. Page 28 Figure 2 Legend Please state the age and sex of the participant. Answer: Thank you for your suggestion. We’ve added the age and sex of the illustrated case. Figure legends, figure 2 This figure shows typical carotid duplex ultrasound findings in a 69-year-old male patient after radiation therapy. Reviewer #2: Thank you for making the requested additions and clarifications. and its current form of this manuscript, while in park comprising preliminary or hypothesis building data is likely to offer some valuable insights regarding the intersection of credit disease and radiation – treated head and neck cancer patients. The largest areas for future clarification are cross reference with advanced structural cross-sectional angiographic imaging, the presence of longitudinal data to assess true progression over a longer period of time, and a better understanding of baseline variables in these patients. Answer: Thank you for your kind comment, which indeed help us to design a better study to answer this question. We’ve revised the last paragraph of our discussion accordingly. Discussion, page 12, line 17-20 Completely shifting practice paradigms based on what our preliminary results should be done only with immense circumspection. In the future, we may need a cross reference with advanced structural cross-sectional angiographic imaging, a longitudinal data to assess true progression over a longer period of time, and more comprehensive baseline variables in these patients for further clarification of our conclusions. Reviewer #3: My concerns about potentially suboptimal transducer angles contributing to elevated endovascular velocities was satisfactorily addressed. Answer: Thank you for your wonderful help. Your excellent comments indeed make our manuscript more readable. Attachments Attachment Submitted filename: letter to the editor_minor revision.docx https://doi.org/10.1371/journal.pone.0246684.r004
25 Jan 2021 Decision Letter - Paula Boaventura, Editor Total Plaque Score Helps to Determine Follow-up Strategy for Carotid Artery Stenosis Progression in Head and Neck Cancer Patients after Radiation Therapy PONE-D-20-34151R2 Dear Dr. Chang, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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, Paula Boaventura, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0246684.r005
Formally Accepted
2 Feb 2021 Acceptance Letter - Paula Boaventura, Editor PONE-D-20-34151R2 Total Plaque Score Helps to Determine Follow-up Strategy for Carotid Artery Stenosis Progression in Head and Neck Cancer Patients after Radiation Therapy Dear Dr. Chang: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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 plosone@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. Paula Boaventura Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0246684.r006

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