The Establishment and Verification of a Nomogram Model for Predicting the Overall Survival of Medullary Thyroid Carcinoma: An Analysis Based on the SEER Database
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors constructed a nomogram model for prognostic stratification of medullary thyroid carcinoma patients. The hypothesis of the manuscript is sound but not novel, and the statistical analysis seems to be in place. However, I find that the manuscript has major flaws and cannot be accepted in present form.
Major concerns:
1. The title of the manuscript needs to be modified because “predicting the prognosis” is not an acceptable term. Prognosis is already a prediction. This can be seen throughout the manuscript.
2. The term “prognosis” is not uniformly used throughout the manuscript. The authors should state which prognostic factor is taken to consideration in each analysis.
3. In the introduction section, line 35, the authors state that “It has been reported that about 15-20% of MTC patients exhibit distant metastatic disease at the time of diagnosis, and the 10-year overall survival after the first distant metastasis is about 10-40%” (Pacini et al, 2010).
In contrast, in line 44, they state that “Nevertheless, studies have shown that MTC has a 15-year survival rate of around 85%” (Rendl et al, 2008). These two statements seem to be in colision. The authors should decide which cited publication is more trustworthy.
4. The Material and Methods section does not provide sufficient information on how the study was performed. There should be an explanation on how the data from the Modeling group, Internal validation group and External validation group were compared and analysed. A short overview of the method could also be incorporated in the Introduction section.
5. The first part of discussion is merely a repetition of the beginning of the Introduction section
6. The Conclusion section should reflect more on the factual results of the manuscript
Minor concerns:
1. Lines 89 and 93-94 contain incomplete sentences
2. Line 151 contains a typo. Please change “Compares” to “Compared”
3. Lines 161-163 are unclear
Comments on the Quality of English Language
There are typos and incomplete sentences in the manuscript. Some sentences also need rephrasing as their meaning is unclear.
Author Response
Dear reviewers:
Thank you for your comments concerning our manuscript entitled “Establishment and Verification of A Nomogram Model for Predicting the Overall Survival of Medullary Thyroid Carcinomas: An Analysis Based on the SEER Database” (manuscript ID: curroncol-2733635). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portion are marked in red in the paper. The main corrections in the paper and the responds to the reviewers’ are as following:
Responds to the reviewer’s comments:
Reviewer #1:
Major concerns:
Comment 1: “Predicting the prognosis” is not an acceptable term, the title of the manuscript needs to be modified.
Response 1: We have made correction according to the Reviewer’s comment. In the title, we have substituted “overall survival” for “prognosis ”.
Comment 2: The term “prognosis” is not uniformly used throughout the manuscript.
Response 2: We have carefully noted your observation regarding the inconsistent use of the term "prognosis" throughout the manuscript.. In this study, we evaluated patients’ prognosis primarily by overall survival. Therefore, we have changed the necessary part to “overall survival” in the paper.
Comment 3: The contradiction between survival rate of metastatic MTC and survival rate of MTC.
Response 3: In the introduction section, line 40, we found in the literature that MTC patients who first found distant metastasis had a 10-year survival rate of 10-40%. But in line 53, we looked in the literature at an average 15-year survival rate of 85% for all patients diagnosed with MTC. Thus, we think maybe the two sentences are not contradictory. In order to make the description of the object more accurate, we also made the corresponding changes in line 53.
Comment 4: Improve the section of “materials and methods”, analyze and compare the data of each group, and introduce it in introduction briefly.
Response 4: We have made correction according to the Reviewer’s comments. In lines 75-78 of introduction, we described the study methods briefly. In the Materials and Methods section, we described the process and method of data analysis in detail in the Statistical Analyses section. For example, K-M curves and grouping principles, methods for verifying prediction effects, etc. Please see lines 103-116 for details.
Comment 5: The first part of discussion is merely a repetition of the beginning of the Introduction section.
Response 5: Thank you for your insightful review of our manuscript. We have carefully considered your comment regarding the repetition of the Introduction section in the first part of the Discussion. To address this concern, we have revised the Discussion section to eliminate redundancy and ensure a more seamless flow of ideas. Specifically, in the first part of discussion, we added related contents about hereditary MTC and MEN II to facilitate further research progress of MTC in the following sections. Please see lines 294-295.
Comment 6: The Conclusion section should reflect more on the factual results of the manuscript.
Response 6: Considering the Reviewer’s suggestion, we have included the actual results of the manuscript in the conclusion. Please see lines 387-388.
Minor concerns:
Comment 7: Lines 89 and 93-94 contain incomplete sentences.
Response 7: We are sorry for our wrong sentences, we have revised them into correct sentences. Please see lines 110-111 and 115-116.
Comment 8: Line 151 contains a typo. Please change “Compares” to “Compared”.
Response 8: We are very sorry for our incorrect writing, we have changed “Compares” to “Compared” in line 174.
Comment 9: Lines 161-163 are unclear.
Response 9: We are sorry for our unclear sentences, we have removed them.
As for some wrong words and incorrect sentences, we have conducted english editing in MDPI. The proof of english editing is shown in the attachment.
Special thanks to you for your good comments.
You can also view the response by downloading the attachment.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe article presents a study establishing a nomogram model to predict the prognosis of Medullary Thyroid Carcinoma (MTC) patients. The model uses four factors: age, tumor size, N stage, and M stage. The model's predictive power was evaluated using the C-index, ROC, and AUC, with the C-indexes of the modeling group, internal validation group, and external validation group being 0.792, 0.793, and 0.871, respectively. The study concludes that the model can accurately predict the clinical prognosis of MTC patients.
The article in question has several limitations, as outlined in the search results:
1. Missing Laboratory Test Results: Some laboratory test results, such as CT and CEA, must be included in the SEER database. This could potentially affect the accuracy and completeness of the study's findings.
2. Single-Center Data: The data used in the study are from a single center, limiting the sample size and reducing the findings' applicability. Single-center studies often need more generalizability because they may not represent the diversity of the larger population.
3. Small Sample Size: The study has a small sample size, which can limit the statistical power and the ability to detect significant effects. Small studies may also be more prone to sampling error, leading to inaccurate conclusions.
4. SEER Database Limitations: The SEER database, which the study relies on for its data, has its limitations. These include the completeness of the variables, biases associated with unmeasured reasons for receiving or not receiving certain treatments, and the interpretation of sequence data variables.
5. Need for Multicenter, Large-sample Prospective Studies: The study's authors acknowledge the need for multicenter, large-sample prospective studies to confirm their findings. Multicenter studies can offer larger sample sizes and greater generalizability, but they also come with their own set of challenges, such as potential variation in results due to differences in techniques and inclusion criteria across centers.
6. Lack of External Funding: The research received no external funding for the SEER database. This could potentially limit the resources available for the study, affecting aspects such as the sample size, the extent of data collection, and the depth of analysis.
7. Retrospective Study Design: The retrospective study relies on existing data and records. While this approach can provide valuable insights, it also has limitations. For instance, the researchers have no control over what data were originally collected, which can lead to gaps in the data. Additionally, retrospective studies can be subject to various biases, such as selection bias and information bias.
8. Potential for Publication Bias in Single-Center Studies: Single-center studies may be more prone to publication bias and may have lower methodological quality than multicenter trials. This could potentially affect the reliability and validity of the study's findings.
9. Lack of Workflow Standardization in Multicenter Studies: If the study were to be expanded to a multicenter format, it could face challenges such as a lack of workflow standardization. This could lead to consistency in data collection and analysis across different centers, potentially affecting the reliability and validity of the results.
10. Potential Conflicts of Interest in Multicenter Studies: Multicenter studies can also face potential conflicts of interest, which could affect the integrity of the research. For instance, different centers might have different interests or priorities, which could influence the conduct and outcomes of the study.
In conclusion, while the study provides valuable insights, these limitations should be considered when interpreting its findings. Future research that addresses these limitations would be beneficial in confirming and expanding upon these results.
Author Response
Dear reviewers:
Thank you for your comments concerning our manuscript entitled “Establishment and Verification of A Nomogram Model for Predicting the Overall Survival of Medullary Thyroid Carcinomas: An Analysis Based on the SEER Database” (manuscript ID: curroncol-2733635). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portion are marked in red in the paper. The main corrections in the paper and the responds to the reviewers’ are as following:
Responds to the reviewer’s comments:
Reviewer #2:
Comment 1: Missing Laboratory Test Results.
Response 1: As the reviewer said, our study lacked laboratory data, such as calcitonin and CEA. For this part, we have further explained in the discussion section in lines 240-249.
Comment 2-3: Single-Center Data and Small Sample Size.
Response 2-3: It is really true as Reviewer suggested that it’s a single-center and small sample size study. This affected the accuracy and generalizability of our analysis, and we have discussed this issue in detail in the discussion section, see lines 258-261.
Comment 4: SEER Database Limitations.
Response 4: As the reviewers have commented, the SEER database has certain limitations. Due to the difference of data update time, some data cannot be obtained completely. As a result, we also lack some laboratory test results and cannot do a more comprehensive analysis. We have further explained in the discussion section in lines 240-249.
Comment 5: Need for Multi-center, Large-sample Prospective Studies.
Response 5: Due to the poor generalizability of single-center, small sample data analysis, and the data obtained by retrospective analysis is relatively limited. We need multi-center prospective studies with large-sample size. We’ve already talked about this in discussion section, in lines 262-266.
Comment 6: Lack of External Funding.
Response 6: The lack of external funding also limits our ability to conduct a multi-center study with a large sample size, which is discussed in lines 264-265 of the discussion section.
Comment 7: Retrospective Study Design.
Response 7: As suggested by the reviewer, the retrospective study design cannot fully capture the data we need. Therefore, we need prospective studies to compensate for this shortcoming, which we have explained in the discussion section in lines 250-254.
Comment 8: Potential for Publication Bias in Single-Center Studies.
Response 8: Single-center studies do have many drawbacks, and their potential publication bias has been explained in lines 254-257 of the discussion section.
Comment 9: Lack of Workflow Standardization in Multicenter Studies.
Response 9: The reviewer’s suggestion of standardizing the workflow of multi-center studies is also quite correct. The discussion of workflow standardization is also covered in the discussion section in lines 267-270.
Comment 10: Potential Conflicts of Interest in Multicenter Studies.
Response 10: Many thanks to the reviewer for his/her comments on potential conflicts of interest in multi-center research. We have added the relevant instruction in the discussion section in lines 270-272.
Special thanks to you for your valuable comments.
You can also download an attachment to view response.
Reviewer 3 Report
Comments and Suggestions for AuthorsThis manuscript reports on the development of a nomogram to predict prognosis in medullary thyroid cancer, using data from the SEER database for initial modelling and internal validation, and then data from a single centre for external validation.
As a general comment, the English throughout the paper would benefit from review- for example there are multiple instances of incorrect word order which render understanding difficult.
The abstract provides a generally clear and concise summary of the work undertaken and of the main findings of the study.
The introduction gives generally helpful background information. Whilst it is true that overall thyroid cancer incidence is increasing, it would probably be worth noting that this is driven mainly by an increase in diagnosis of low risk papillary cancers, and that actually incidence of MTC has been relatively stable.
It would also be worth commenting in greater detail in the introduction on recent developments in the understanding of molecular genetic drivers of MTC (ie RET mutations) and their prognostic significance, and also on other more recent prognostic factors such as calcitonin doubling time.
The methods are clearly set out and statistical methodology appears appropriate.
The results are again clearly set out and tables 1 and 2 well presented. It would appear that the nomogram that has been developed does fairly reliably predict prognosis based on 4 simple prognostic factors, as confirmed by testing an external validation set. The finding that these 4 factors have independent prognostic significance is not novel, but the development of a nomogram is potentially helpful.
Whilst some limitations of the study are acknowledged, this section could be significantly expanded. In particular, it would be appropriate to comment on developments in understanding of the relevant of RET mutations in this disease, both as a prognostic factor, but also more recently in presenting novel treatment options. With the advent of specific RET inhibitors, the outcomes of patients with advanced disease are likely to significantly improve and this will affect prognosis and likely render the survival data from this historical cohort less relevant.
Comments on the Quality of English LanguageThroughout the manuscript the English requires review- in several places for example word order is incorrect, making the manuscript difficult to read and understand.
Author Response
Dear reviewers:
Thank you for your comments concerning our manuscript entitled “Establishment and Verification of A Nomogram Model for Predicting the Overall Survival of Medullary Thyroid Carcinomas: An Analysis Based on the SEER Database” (manuscript ID: curroncol-2733635). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. Revised portion are marked in red in the paper. The main corrections in the paper and the responds to the reviewers’ are as following:
Responds to the reviewer’s comments:
Reviewer #3:
Comment 1: The English throughout the paper would benefit from review.
Response 1: We are very sorry for our unprofessional English writing. Following the suggestions of reviewers, we have polished the article in the English editor‘s office of MDPI. Our English editing certificate is shown in the attachment.
Comment 2: The increase in the incidence of thyroid cancer is mainly due to the increase in the diagnosis of low-risk papillary carcinoma, while the incidence of medullary carcinoma is relatively stable.
Response 2: Thank you very much for your supplement on the incidence of thyroid cancer. We have consulted relevant literature and added it in lines 34-36 of introduction section.
Comment 3: The latest progress of MTC molecular driver genes and prognostic factors can be introduced in introduction briefly.
Response 3: Thank you very much for your comments on the introduction section, which can make our manuscript more complete. Recent advances in MTC molecular driver genes and prognostic factors have been described in lines 41-47 and lines 57-63. In addition, we have added relevant content in the discussion section on lines 206-212.
Comment 4: The study of RET gene mutation in the diagnosis, treatment and prognosis of this disease can be added to the discussion.
Response 4: We think the reviewer’s suggestion are very valuable, so we have consulted relevant literature and added relevant contents into the discussion. RET targeted therapy has effectively improved the prognosis of MTC patients in recent years, as explained in lines 183-204 of the discussion section.
Special thanks to you for your valuable comments.
You can also download an attachment to view response.
We tried our best to improve the manuscript and made some changes in the manuscript. We appreciate for Reviewers’ warm work earnestly, and hope that the correction will meet with approval.
Once again, thank you very much for your comments and suggestions.
Your Sincerely,
Jian Liu
Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China.
liujianzy@zju.edu.cn
Author Response File: 
Author Response.docx
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript has been sufficiently improved to be published
Author Response
Dear reviewers:
Thank you for your opinions concerning our manuscript entitled “Establishment and Verification of A Nomogram Model for Predicting the Overall Survival of Medullary Thyroid Carcinomas: An Analysis Based on the SEER Database” (manuscript ID: curroncol-2733635). Those opinions are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied these comments carefully and have made correction which we hope meet with approval. Revised portion are marked in red in the paper. The main corrections in the paper and the responds to the reviewers’ are as following:
Responds to the reviewer’s comments:
Reviewer #1:
Comment 1: The manuscript has been sufficiently improved to be published.
Response 1: Thanks very much for your kind work and consideration on publication of our paper. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
We tried our best to improve the manuscript and made some changes in the manuscript. We appreciate for editors’ and reviewers’ warm work earnestly, and hope that the correction will meet with approval.
You can also find our response in the attachment.
Once again, thank you very much for your comments and suggestions.
Your Sincerely,
Jian Liu
Author Response File: Author Response.docx
Reviewer 3 Report
Comments and Suggestions for AuthorsThank you for addressing my earlier comments. The standard of English in the manuscript is much improved and I think the paper now reads well.
Just a couple of minor comments remain-
1. Line 36- Many would argue that the increase in diagnosis of papillary thyroid cancer is not an 'improvement' but rather a problem of overdiagnosis of disease that is clinically irrelevant.
2. Line 560 'surgery used to be the primary treatment for MTC'- I would argue that surgery remains the primary treatment, the change is that we now have novel therapies that can be beneficial where surgery is not immediately feasible.
Author Response
Dear reviewers:
Thank you for your opinions concerning our manuscript entitled “Establishment and Verification of A Nomogram Model for Predicting the Overall Survival of Medullary Thyroid Carcinomas: An Analysis Based on the SEER Database” (manuscript ID: curroncol-2733635). Those opinions are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied these comments carefully and have made correction which we hope meet with approval. Revised portion are marked in red in the paper. The main corrections in the paper and the responds to the reviewers’ are as following:
Responds to the reviewer’s comments:
Reviewer #3:
Comment 1: Line 36- Many would argue that the increase in diagnosis of papillary thyroid cancer is not an 'improvement' but rather a problem of overdiagnosis of disease that is clinically irrelevant.
Response 1: Thank you very much for reviewing our manuscript again. We strongly agree with your suggestion about overdiagnosis of PTC. We have revised the relevant content in line 36, stating that the incidence of thyroid cancer is increasing mainly because of overdiagnosis of PTC.
Comment 2: Line 560 'surgery used to be the primary treatment for MTC'- I would argue that surgery remains the primary treatment, the change is that we now have novel therapies that can be beneficial where surgery is not immediately feasible.
Response 2: We think the reviewer’s suggestion are very valuable, we recognize that surgery has always been the primary treatment for MTC. We have revised the relevant content in lines 195-197.
We tried our best to improve the manuscript and made some changes in the manuscript. We appreciate for editors’ and reviewers’ warm work earnestly, and hope that the correction will meet with approval.
You can also find our response in the attachment.
Once again, thank you very much for your comments and suggestions.
Your Sincerely,
Jian Liu
Author Response File: Author Response.docx
