Parathyroid near-infrared autofluorescence differently benefits depending on the surgeon’s skill for preventing from hypoparathyroidism after total thyroidectomy: A systematic review and meta-analysis

Takeshi Takahashi; Shalyn J. D. Sa; Ryohei Oya; Shusuke Ohshima; Jo Omata; Yusuke Yokoyama; Ryusuke Shodo; Yushi Ueki; Yukinori Takenaka; Hidenori Inohara; Arata Horii

doi:10.1371/journal.pone.0321310

Peer Review History

Original SubmissionSeptember 21, 2024
21 Sep 2024 Author Response https://doi.org/10.1371/journal.pone.0321310.r001
14 Nov 2024 Decision Letter - Mohamed Khaled Ibrahim, Editor PONE-D-24-42113Parathyroid near-infrared autofluorescence differently benefits depending on the surgeon's skill for preventing from hypoparathyroidism after total thyroidectomy: A systematic review and meta-analysisPLOS ONE Dear Dr. Takahashi, 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. ============================== Dear Authors, Thank you for submitting your manuscript for consideration. Your study investigating the impact of parathyroid near-infrared autofluorescence on hypoparathyroidism after total thyroidectomy is well-conducted, and your analysis highlights important findings in this area. However, to further strengthen the manuscript and address key concerns, the following revisions are necessary: Frozen Section Analysis: The impact of using frozen sections on hypoparathyroidism outcomes requires further clarification. Please address how this variable may influence your results and whether it was explicitly accounted for in the studies analyzed. If applicable, include a sensitivity analysis or a discussion of its limitations. Surgeon Skill and Procedural Variability: It is challenging to attribute the incidence of transient hypocalcemia solely to surgical skill using the current framework. Consider revising the discussion to distinguish between surgical skill and variability in surgical procedures (e.g., lymph node resection techniques or parathyroid autotransplantation). Additional analysis demonstrating the relationship between surgical skill and outcomes would strengthen this aspect. Modeling Autotransplantation and Inadvertent Resection: Since assumptions about the rates of parathyroid autotransplantation and inadvertent resection influence your results, please clarify their impact using sensitivity analysis or modeling. Explicitly state the assumptions and their implications on the overall conclusions. Highlighting Efficacy of Near-Infrared Autofluorescence: Your manuscript effectively discusses the benefits of parathyroid near-infrared autofluorescence. Ensure these findings are emphasized in the results and discussion sections. A summary table or figure may further enhance the clarity and impact of your findings. By addressing these points, the manuscript will provide a more comprehensive and robust contribution to the field. We look forward to your revised submission. ============================== Please submit your revised manuscript by Dec 29 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 . 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'. 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Please also provide details on how you will ensure persistent or long-term data storage and availability. 3. Please include a new copy of Tables1 and 2 in your manuscript; the current table is difficult to read. Please follow the link for more information: https://blogs.plos.org/plos/2019/06/looking-good-tips-for-creating-your-plos-figures-graphics/ " 4. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following: A numbered table of all studies identified in the literature search, including those that were excluded from the analyses. For every excluded study, the table should list the reason(s) for exclusion. If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed. A table of all data extracted from the primary research sources for the systematic review and/or meta-analysis. The table must include the following information for each study: Name of data extractors and date of data extraction Confirmation that the study was eligible to be included in the review. All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses. If data or supporting information were obtained from another source (e.g. correspondence with the author of the original research article), please provide the source of data and dates on which the data/information were obtained by your research group. If applicable for your analysis, a table showing the completed risk of bias and quality/certainty assessments for each study or outcome. Please ensure this is provided for each domain or parameter assessed. For example, if you used the Cochrane risk-of-bias tool for randomized trials, provide answers to each of the signalling questions for each study. If you used GRADE to assess certainty of evidence, provide judgements about each of the quality of evidence factor. This should be provided for each outcome. An explanation of how missing data were handled. This information can be included in the main text, supplementary information, or relevant data repository. Please note that providing these underlying data is a requirement for publication in this journal, and if these data are not provided your manuscript might be rejected. [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: Yes ******** 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: Thank you for allowing me to conduct the following review. The article attempts to summarize information about the use of near-infrared autofluorescence (NIRAF) of parathyroid glands during thyroidectomy from selected literature on this subject. The conclusions supported by a thorough statistical analysis and a discussion of the limitations of the method used will allow the potential reader to learn more about the application and effectiveness of the described method for detecting parathyroid glands. I believe that the article in its current form qualifies for publication. Reviewer Reviewer #2: Thank you for giving me the opprotunity to review this manuscript. This study investigated the impact of the parathyroid near-infrared autofluorescence on the hypoparathyroidism after total thyroidectomy using systematic review and meta analysis. The analysis of this study was conducted well. However, the impact of the frozen section of the parathyorid glands might influecnce the results. It is uncertain to define the surgeons' skill using incidence of T-hypo Ca relying on the N-E, because in the lymph node resection, some surgeons resect all of the parathyroid glands with lymp nodes and autografted. This might depend on the surgical procedures, not the surgical skills. The authors should demonstrate the results that surgeons' skill can cause T-hypo Ca relying on the N-E. The authors should clarify the influence of assumption of numbers of autotransplanted and inadvertently resected on the results using some models because they are only assumptions. However, this manuscript well mentioned the efficacy of parathyroid near-infrared autofluorescence. ****** 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 . 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Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0321310.r002
Revision 1
9 Jan 2025 Author Response Thank you very much for your insightful comments. We have provided point-by-point responses below. Frozen Section Analysis: The impact of using frozen sections on hypoparathyroidism outcomes requires further clarification. Please address how this variable may influence your results and whether it was explicitly accounted for in the studies analyzed. If applicable, include a sensitivity analysis or a discussion of its limitations. Response: Thank you for pointing out this important issue. As you have mentioned, we think it would affect the outcome, especially where a frozen section is performed before autotransplantation. Frozen sections were performed in three studies; however, the results were not described. We added the following sentence to the Results and Limitations sections. In three studies frozen section was performed prior to PGs autotransplantation; however, pathology results were not described [18, 22, 32]. Third, the results of the frozen section analysis might have influenced the decision to perform autotransplantation. However, these results were not described in all studies. Surgeon Skill and Procedural Variability: It is challenging to attribute the incidence of transient hypocalcemia solely to surgical skill using the current framework. Consider revising the discussion to distinguish between surgical skill and variability in surgical procedures (e.g., lymph node resection techniques or parathyroid autotransplantation). Additional analysis demonstrating the relationship between surgical skill and outcomes would strengthen this aspect. Response: As the reviewer has pointed out, we recognized that other factors than surgical skills, such as lymph node dissection and autotransplantation, would affect the transient hypocalcemia (T-hypoCa). Unfortunately, owing to the lack of data, it was not possible to estimate the effect of surgical procedures on T-hypoCa; therefore, we alternatively investigated the association of percentage of malignant diseases, which usually require central neck dissection and autotransplantation of PGs, with T-hypoCa. For this purpose, meta-regression analysis and correlation analysis were newly performed for malignant disease as possible factors which would influence the incidence of T-hypoCa. As a result, however, there was no association between the percentage of malignant disease and either the incidence of T-hypoCa by N-E surgery or the odds ratio (ORs) of T-HypoCa/hypoPT (Fig 8A, 7C, D). These results suggest that the incidence of T-hypoCa by the N-E surgery may be mainly related to the surgeon's skill to preserve the blood supply to the PG. We added following text in the revised manuscript. In Methods section These moderators were: 1) the incidence of T-hypoCa by N-E surgery, which may be affected by a surgeon’s skill; 2) the percentage of malignant disease, which usually requires central neck dissection and autotransplantation of PGs. Moreover, the correlation analysis between the incidence of T-hypoCa by N-E surgery and the percentage of malignant disease or percentage of autotransplantation by N-E surgery was performed using Spearman’s rank correlation coefficient. In the Results section Significant negative correlations were found between the incidence of T-hypoCa by N-E surgery and the ORs for T-hypoCa, T-hypoPT, and PGs autotransplantation (p = 0.0385, 0.00192, and 0.0225, respectively, Fig 7A, B, E). In contrast, other moderators showed no significant associations, including those between the percentage of malignant disease and the ORs for T-hypoCa and T-hypoPT (p = 0.61and p = 0.90,　respectively, Fig 7 C, D). Correlation analysis revealed no correlation between the percentage of malignant diseases and incidence of T-hypoCa by N-E surgery (Fig 8A), whereas moderate correlation was found between the incidence of T-hypoCa by the N-E surgery and percentage of autotransplantation by N-E surgery (Fig 8B, r = 0.624, p = 0.0602) Figure 7 Figure 8 In Discussion The benefits of NIRAF may depend on 1) surgeons’ skills: relatively less beneficial for experienced and skillful surgeons who can identify PGs to preserve parathyroid function even without NIRAF use and 2) pathologies: relatively more beneficial in malignant cases to identify PGs for autotransplantation in excised specimens following central neck lymph node dissection. Therefore, regarding 1), we tested the association between the incidence of T-hypoCa by N-E surgery, which may be affected by surgeons’ skill and ORs of T-hypoCa/hypoPT. Regarding 2), association between the percentage of malignant diseases and ORs of T-hypoCa/hypoPT was also examined. Meta-regression analyses revealed that the higher the incidence of T-hypoCa by N-E surgery, the lower the ORs of T-hypoCa/hypoPT with NIRAF use (Fig 7A, B). Thus, NIRAF may be particularly beneficial for less skilled surgeons with a high incidence of T-hypoCa by N-E surgery in preventing T-hypoCa/hypoPT. In contrast, there was no association between the percentage of malignant disease and ORs of T-hypoCa/hypoPT (Fig 7C, D). Moreover, percentage of malignant diseases did not correlate with incidence of T-hypoCa by N-E surgery (Fig 8A). Further stratified analysis also showed that NIRAF use resulted in a significant improvement in T-hypoCa for surgeons with an incidence of ≥15% of T-hypoCa by N-E surgery (Fig 9). These results suggest that the use of NIRAF may especially benefit less skilled surgeons to prevent T-hypoCa/hypoPT and pathology and its related surgical procedures do not largely affect the usefulness of NIRAF. Modeling Autotransplantation and Inadvertent Resection: Since assumptions about the rates of parathyroid autotransplantation and inadvertent resection influence your results, please clarify their impact using sensitivity analysis or modeling. Explicitly state the assumptions and their implications on the overall conclusions. Response: As shown in Fig 6, although the number of PGs identified either in situ or in resected specimens increased and the inadvertent resection of PGs decreased by the use of NIRAF, the number of autotransplantation of PGs was not affected by the use of NIRAF. We assumed that this is perhaps due to the increase in the number of PGs that can be preserved in situ by NIRAF. For this purpose, correlation analysis was newly performed between the incidence of T-hypoCa and percentage of autotransplanations in N-E surgeries. Correlation analysis revealed a moderate correlation between the percentage of autotransplantation of PGs and incidence of T-hypoCa by N-E surgery (Fig 8B). Therefore, in N-E surgeries, more autotransplantations of PGs were performed in surgeries with T-hypoCa. Nonetheless, the higher the incidence of T-hypoCa by N-E surgery, the lower the ORs of T-hypoCa/hypoPT and autotransplantations of PGs (Fig 7A, B, E), which means more PGs were preserved in situ by the use of NIRAF. We added the following text in each section. In Methods section, These moderators were: 1) the incidence of T-hypoCa by N-E surgery, which may be affected by a surgeon’s skill; 2) the percentage of malignant disease, which usually requires central neck dissection and autotransplantation of PGs. Moreover, the correlation analysis between the incidence of T-hypoCa by N-E surgery and the percentage of malignant disease or percentage of autotransplantation by N-E surgery was performed using Spearman’s rank correlation coefficient. In Results section, Correlation analysis revealed no correlation between the percentage of malignant diseases and incidence of T-hypoCa by N-E surgery, whereas moderate correlation was found between the incidence of T-hypoCa and percentage of autotransplantation in N-E surgeries (r = 0.624, p = 0.0602) (Fig 8B). In Discussion section, Autotransplantation of PGs may be the second-best method following in situ preservation to prevent P-hypoCa/hypoPT. As shown in Fig 6, the pooled data demonstrated a significant increase in the number of PGs identified in situ or in the resected specimens and a significant decrease in inadvertent resections of PGs by the use of NIRAF. However, the OR of autotransplantation of PGs was not significantly high by the use of NIRAF (Fig 6), probably because NIRAF was as useful for in situ preservation of PGs as for detecting PGs eligible for autotransplantation. In N-E surgeries, incidence of T-hypoCa showed moderate positive correlation with the percentage of autotransplantation (Fig 8B). Nonetheless, meta-regression analysis showed that the ORs for T-hypoCa/T-hypoPT and the PGs autotransplantion with NIRAF use were negatively associated with the incidence of T-hypoCa by N-E surgery (Fig 7A, B, E). This implies that the use of NIRAF can be useful to increase the number of PGs that can be preserved in situ and decrease the number of autotransplanted PGs in the high incidence group of T-hypoCa by N-E surgery. At the same time, NIRAF may be useful in the low incidence group of T-hypoCa by N-E surgery because it aids in detecting PGs within excised specimens, thereby increasing the number of autotransplanted PGs (Fig 7E). Therefore, the OR for autotransplanted PGs was non-significant when surgeons with several incidence of T-hypoCa by N-E surgery were mixed (Fig 6). Highlighting Efficacy of Near-Infrared Autofluorescence: Your manuscript effectively discusses the benefits of parathyroid near-infrared autofluorescence. Ensure these findings are emphasized in the results and discussion sections. A summary table or figure may further enhance the clarity and impact of your findings. Response: Thank you very much for your insightful suggestions. As you have pointed out, we thought that our results should emphasize that NIRAF is useful for many surgeons. We added the following sentence to the Conclusions section. From these results, it is evident that the use of NIRAF in total thyroidectomy provides significant benefits for surgeons with different levels of experience, such as novices and experts. 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Response: The general secretary of our department will keep the data independently of the author and respond to external requests. Email: okayoko@med.niigata-u.ac.jp 3. Please include a new copy of Tables1 and 2 in your manuscript; the current table is difficult to read. Please follow the link for more information: "https://blogs.plos.org/plos/2019/06/looking-good-tips-for-creating-your-plos-figures-graphics/" Response: We followed these instructions and modified the Tables accordingly. Table 1 Table 2 4. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following: A numbered table of all studies identified in the literature search, including those that were excluded from the analyses. For every excluded study, the table should list the reason(s) for exclusion. If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed. Response: We followed these instructions and prepared a Table listing all the extracted papers and the reasons for our selections. (Supplemental Table 1) A table of all data extracted from the primary research sources for the systematic review and/or meta-analysis. The table must include the following information for each study: Name of data extractors and date of data extraction Confirmation that the study was eligible to be included in the review. All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses. If data or supporting information were obtained from another source (e.g. correspondence with the author of the original research article), please provide the source of data and dates on which the data/information were obtained by your research group. Response: We have compiled a Table detailing the 14 papers we used for our statistical review. (Supplemental Table 2) If applicable for your analysis, a table showing the completed risk of bias and quality/certainty assessments for each study or outcome. Please ensure this is provided for each domain or parameter assessed. For example, if you used the Cochrane risk-of-bias tool for randomized trials, provide answers to each of the signalling questions for each study. If you used GRADE to assess certainty of evidence, provide judgements about each of the quality of evidence factor. This should be provided for each outcome. Response: These are included in the manuscript as Figure 2 and Table 2. An explanation of how missing data were handled. Response:The following sentence has been added to the Materials and Methods section. Missing data w Attachments Attachment Submitted filename: response_to_reviewers_comments.docx https://doi.org/10.1371/journal.pone.0321310.r003
4 Mar 2025 Decision Letter - Mohamed Khaled Ibrahim, Editor Parathyroid near-infrared autofluorescence differently benefits depending on the surgeon's skill for preventing from hypoparathyroidism after total thyroidectomy: A systematic review and meta-analysis PONE-D-24-42113R1 Dear Dr. Takahashi, 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, Mohamed Khaled Ibrahim, MD Guest Editor PLOS ONE Additional Editor Comments (optional): 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 #2: 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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: 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 #2: 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 #2: 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 #2: This manuscript was well revised according to the reviewers comments. This manuscript is worthwhile publication now. ****** 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 #2: No ******** https://doi.org/10.1371/journal.pone.0321310.r004
Formally Accepted
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