Unusual metastases from differentiated thyroid cancers: A multicenter study in Korea

Jee Hee Yoon; Min Ji Jeon; Mijin Kim; A. Ram Hong; Hee Kyung Kim; Dong Yeob Shin; Bo Hyun Kim; Won Bae Kim; Young Kee Shong; Ho-Cheol Kang

doi:10.1371/journal.pone.0238207

Peer Review History

Original SubmissionMay 8, 2020
15 Jun 2020 Decision Letter - Domenico Albano, Editor PONE-D-20-13614 Unusual metastases from differentiated thyroid cancers: A multicenter study in Korea PLOS ONE Dear Dr. Kang, 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 1 July. 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. 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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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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: Yes Reviewer #2: 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 ****** 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: Congratulations for presenting a very interesting paper concerning unusual metastases of differentiated thyroid cancers in Korea. The authors presented adequate methodology. The results were analyzed in details. I have one notice. Though the authors used many abbreviations in Abstract (DTC,FDG, PET, CT, PTC, TKI, WBS, Tg) not necessarily obvious for all readers, however the use of an unknown shortcut “UMs” is unacceptable. All the more, descriptions for abbreviations should not be included here in Abstract. Explanations of abbreviations cannot be duplicated both in Abstract and Introduction section. Reviewer #2: The present study highlights an important yet less reported and understood area of differentiated thyroid malignancies. This is in part due to rarity of such findings. There are however, few area on which the authors can improve on their manuscript. Methods: Study design should be explicitly mentioned. Similarly, study duration can be mentioned to enhance readers understanding on the data gathered. Results: Total number of thyroid patients screened can be added. This can further lead to computation of the rate of UMs in their cohort. Table 3 needs revision: Mortality was assessed in months/years? Discussion: There are a number of case series looking into unusual presentation of differentiated thyroid metastasis, they are basically, synchronous metastasis. Comparison with these studies could be helpful to improve on discussion. This was a large multi-center study, addition of a comparison arm (usual distant metastasis to lung and bone) such as a case control study could add to the strength of the study. ****** 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: 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/. 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Revision 1
4 Aug 2020 Author Response Response to Reviewer 1’s comment Reviewer #1: Congratulations for presenting a very interesting paper concerning unusual metastases of differentiated thyroid cancers in Korea. The authors presented adequate methodology. The results were analyzed in details. I have one notice. Though the authors used many abbreviations in Abstract (DTC,FDG, PET, CT, PTC, TKI, WBS, Tg) not necessarily obvious for all readers, however the use of an unknown shortcut “UMs” is unacceptable. All the more, descriptions for abbreviations should not be included here in Abstract. Explanations of abbreviations cannot be duplicated both in Abstract and Introduction section. ANSWER: Thank for your generous review and good comment. We agree with you that acronyms in the abstract detract from the readability of the paper, so we have deleted all abbreviations in the abstract to improve readability and to avoid duplication.(line 21,23,25,26,28,29,31,32,33,34,35,38,39,40,41,42,43,45,46,50,52). Response to Reviewer 2’s comment Reviewer #2: The present study highlights an important yet less reported and understood area of differentiated thyroid malignancies. This is in part due to rarity of such findings. There are however, few area on which the authors can improve on their manuscript. 1. Methods: Study design should be explicitly mentioned. Similarly, study duration can be mentioned to enhance readers understanding on the data gathered. ANSWER: Thank for your meticulous review. We added more details of study design including the study duration. We screened medical records of DTC patients who had been treated between January 2000 and August 2016 from four tertiary hospitals in Korea and searched DTC patients with distant metastasis including usual (lung, bone, and brain) and unusual metastasis (UM). (line 78-82: We screened DTC patients who had been treated between January 2000 and August 2016 from four tertiary hospitals in Korea (Chonnam National University Hwasun Hospital, Asan Medical Center, Busan National University Hospital, Severance Hospital) and retrospectively reviewed the medical records of DTC patients with distant metastasis. Distant metastases were divided to two groups; usual metastasis and UM.) 2. Results: (1) Total number of thyroid patients screened can be added. This can further lead to computation of the rate of UMs in their cohort. ANSWER: According to your recommendation, we have added the total number of DTC patient screened (n=38,772) and calculated the rate of UMs in our cohort. (line 117-119: Among investigated total of 38,772 DTC patients, 442 usual distant metastases (1.1%) in 392 patients (321 cases of lung metastases, 105 cases of bone metastases, and 16 cases of brain metastases) and 25 UMs (0.06%) in 19 patients were observed.) Compared to other researcher’s reports, our data on distant metastasis seems to be rarer, so we added sentences to explain why distant metastasis is rarer in our cohort by citing Korea Central Cancer Registry data. (line 231-236: The National Epidemiologic Survey of Thyroid cancer (NEST) study based on the Korea Central Cancer Registry demonstrated 34 distant metastases (0.6%) among total 5,796 thyroid cancer patients during 10.6 years of follow-up (16). So, our data is in accordance with Korean nationwide data. The low incidence of distant metastases might by due to early surgery and high incidence of small papillary microcarcinoma in Korea.) (2) Table 3 needs revision: Mortality was assessed in months/years? ANSWER: We presented the median follow-up duration from UM diagnosis (months)(IQR), however it is not easy to recognize. So, we changed it to Median follow-up months from UM diagnosis (IQR) (Table 3). 3. Discussion: (1) There are a number of case series looking into unusual presentation of differentiated thyroid metastasis, they are basically, synchronous metastasis. Comparison with these studies could be helpful to improve on discussion. ANSWER: As you mentioned, there have been several case reports and series of UM in DTC patients which occurred synchronously. Even though direct comparison of synchronous and metachronous UMs in DTC patients is impossible due to the lack of basic data in previous studies, some of synchronous metastasis have been published as case reports showing the difficulty in finding the primary cancer focus. We added this point in line 237-239: Some case reports and series have shown that synchronous UM in DTC patients presenting initially with UM-related symptoms, but they have difficulty in finding the primary cancer origin due to unusual metastatic sites (17). In previous studies (Zunino et al and Madani et al), the incidence of metachronous UMs were higher than those of synchronous UMs. This is the same point of view as our study. Long term follow-up due to relatively lower mortality of DTC patients give us more chance to find UMs from DTC. Additionally, high quality of imaging studies used in follow-up period recently increased the probability to discover UMs. Only 4 patients (21.1%) in our study had synchronous UM, indicating a higher incidence of UMs in advanced thyroid cancer during long-term follow-up with diverse imaging modalities such as PET-CT, 131I WBS, and CT scans due to a metachronous pattern. (2) This was a large multi-center study, addition of a comparison arm (usual distant metastasis to lung and bone) such as a case control study could add to the strength of the study. ANSWER: We appreciate your kind and meaningful suggestion; however we are not able to do such a case-control study due to the limitations in the data set. https://doi.org/10.1371/journal.pone.0238207.r002
12 Aug 2020 Decision Letter - Domenico Albano, Editor Unusual metastases from differentiated thyroid cancers: A multicenter study in Korea PONE-D-20-13614R1 Dear Dr. Kang, 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, Domenico Albano Academic Editor PLOS ONE 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: 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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: Thank you for carefully analyzing all comments and making appropriate corrections to the manuscript. Indeed, ther is a clear flow reading your manuscript. ****** 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: No https://doi.org/10.1371/journal.pone.0238207.r003
Formally Accepted
14 Aug 2020 Acceptance Letter - Domenico Albano, Editor PONE-D-20-13614R1 Unusual metastases from differentiated thyroid cancers: A multicenter study in Korea Dear Dr. Kang: 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. Domenico Albano Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0238207.r004

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