Dear Dr. Murtola,

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.

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PLOS ONE

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"Teuvo LJ Tammela: consultant fees from Astellas, Bayer and Roche.

Teemu J Murtola: consultant fees from Novartis, Astellas, Janssen Cilag, Amgen and Recordati. Lecture fees from Ferring, Novartis, Sanofi, Bayer, Roche, Pfizer, Ipsen, Astellas, Amgen and Janssen Cilag. Research funding from Bayer.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: Yes

Reviewer #4: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

**********

Reviewer #1: The authors investigate the potential association between diabetes and BCa prognosis, but there are several questions that need to be answered before considering the publication.

1) The use of nationwide registries is commendable, but the specific criteria for inclusion and exclusion of data need to be detailed.

2) The limitations section is brief; a more thorough discussion of potential biases and their impact on the results is needed.

3) The study mentions the lack of smoking data but does not discuss how this might affect the results.

4) The study should discuss whether there are significant differences in the results between men and women.

5) More detailed information on drug resistance, including specific mechanisms, should be provided.

6) The generalisability of the results to other populations should be discussed.

7) The manuscript should highlight the novel aspects of this study compared to previous research.

8) The clinical implications of the study findings should be discussed in detail.

9) The limitations of the study, such as potential sources of bias and the generalisability of the results, should be clearly stated.

10) The manuscript should be carefully checked for grammatical errors, spelling mistakes, or unclear presentation.

Reviewer #2: In the submitted article, "Diabetes and Bladder Cancer Prognosis in a Finnish Population-based Cohort," Vuoristo et al. investigate the association between diabetes and bladder cancer prognosis in a Finnish cohort. They find that diabetic hyperglycemia post-diagnosis is linked to increased mortality, although the analysis is limited by insufficient smoking data and incomplete information on glycemic control. However, the study has several other limitations, with comments, suggestions, and concerns that need addressing, and the text in the manuscript requires significant modifications.

Main Concerns:

1. Variable Availability of Comorbidity Data: While diabetes and other comorbidities such as hypertension and obesity were accounted for, the methods section does not specify how consistently these were recorded across the study period. Variations in recording these data can affect the study's ability to accurately assess the impact of these comorbid conditions on bladder cancer outcomes.

2. Suboptimal Control of Confounders: The study utilized multivariable Cox regression models which adjusted for several factors. However, it's unclear if all potential confounders were adequately controlled. For instance, treatment modalities and tumor characteristics could also influence survival outcomes but were not extensively detailed in the context of their influence on the diabetes-cancer link. The author should include detailed analyses of how different treatments and tumor characteristics influence the diabetes-bladder cancer mortality link to provide deeper insights. This would help in understanding whether the observed associations are directly due to diabetes or mediated by other factors.

3. Statistical Significance in Subgroups: Some of the subgroup analyses, such as those involving pre-diagnostic glycemic levels, did not reach statistical significance. This raises questions about the robustness of these associations and whether they could be due to chance. The author should employ advanced statistical techniques that can handle missing data effectively, such as multiple imputation, which might mitigate some of the biases arising from incomplete data. Additionally, using stratified models or propensity score matching could better control for unmeasured confounders.

Text Problems:

1. Original: "Diabetic post-diagnostic blood glucose level was associated with worse BCa-specific HR 1.58 (1.10–2.28) and overall survival HR 1.50 (1.20–1.89)."

Suggestion: "The post-diagnostic blood glucose levels in diabetics were associated with a worse BCa-specific hazard ratio (HR) of 1.58 (1.10–2.28) and an overall survival HR of 1.50 (1.20–1.89)."

2. Original: "The risk increase was slightly lower among hyperglycemic DM medication users (HR 1.43 (0,68–3.02) than non-users HR 1.80 (1.13–2.85)."

Suggestion: "The increase in risk was slightly lower among hyperglycemic DM medication users, with an HR of 1.43 (0.68–3.02), compared to non-users, who had an HR of 1.80 (1.13–2.85)."

3. Original: "We assessed the risk of comorbidity by using Charlson comorbidity index (CCI)."

Suggestion: "We assessed the risk of comorbidity using the Charlson Comorbidity Index (CCI)."

4. Original: "Information was collected on fasting glucose and glycated haemoglobins (HbA1c) levels during 1995-2012 for a subset of study population living in the Pirkanmaa region in Finland."

Suggestion: "Information was collected on fasting glucose and glycated hemoglobin (HbA1c) levels from 1995-2012 for a subset of the study population living in the Pirkanmaa region of Finland."

5. Original: "Diagnoses made in 1995 were recorded as ICD-9 codes: 250 participants had diagnosis for diabetes, 272 for hypercholesterolemia, 401 for hypertension and 278 for obesity."

Suggestion: "Diagnoses made in 1995 were recorded using ICD-9 codes: 250 participants were diagnosed with diabetes, 272 with hypercholesterolemia, 401 with hypertension, and 278 with obesity."

Reviewer #3: The study includes a large cohort of 14,638 BCa patients diagnosed in Finland between 1995 and 2012. Utilizing data from three national databases, the study evaluates the impact of diabetes, measured through blood glucose levels and HbA1c, on BCa-specific and overall mortality using multivariable Cox regression models. The findings indicate that diabetic blood glucose levels are associated with worse BCa-specific and overall survival, with the increased risk being slightly mitigated among those using antidiabetic medication. The study highlights the need for further research to understand the mechanisms behind these associations and the potential implications for clinical management of BCa patients with diabetes.

Here are my questions based on the article:

1. How did the researchers ensure the completeness and accuracy of the data obtained from the three national databases, and what measures were taken to address any potential data gaps or inconsistencies?

2. What criteria were used to classify participants' glycemic status, and how did the study account for variations in blood glucose levels and HbA1c measurements over time?

3. How did the use of antidiabetic medication influence the survival outcomes of BCa patients, and what potential mechanisms might explain the observed differences in mortality risk between medication users and non-users?

4. What confounding factors were considered in the multivariable Cox regression models, and how did the study address potential confounders such as smoking and comorbidities?

5. How did the associations between diabetic glycemic status and BCa-specific mortality differ by gender and cancer stage, and what implications do these findings have for personalized treatment strategies in BCa patients with diabetes?

Here are the grammatical and phrasing errors found in the provided document along with corrections:

1. Location: Abstract (Lines 21-22)

- Original: "Diabetes might increase a risk of bladder cancer (BCa) incidence and bladder cancer specific death."

- Correction: "Diabetes might increase the risk of bladder cancer (BCa) incidence and bladder cancer-specific death."

2. Location: Abstract (Lines 27-28)

- Original: "Three databases were used to obtain information on BCa, diabetes and comorbidities."

- Correction: "Three databases were used to obtain information on BCa, diabetes, and comorbidities."

3. Location: Abstract (Lines 30-31)

- Original: "During median follow-up of 4.3 years after BCa diagnosis 3,582 (24.5 %) participants died of BCa."

- Correction: "During a median follow-up of 4.3 years after BCa diagnosis, 3,582 (24.5%) participants died of BCa."

4. Location: Abstract (Line 33)

- Original: "The risk increase was slightly lower among hyperglycemic DM medication users (HR 1.43 (0,68–3.02) than non-users HR 1.80 (1.13–2.85)."

- Correction: "The risk increase was slightly lower among hyperglycemic DM medication users (HR 1.43 (0.68–3.02)) than non-users (HR 1.80 (1.13–2.85))."

5. Location: Abstract (Line 37)

- Original: "This was observed in both genders."

- Correction: "This was observed in both men and women."

6. Location: Introduction (Line 43)

- Original: "Bladder cancer (BCa) is the ninth most common cancer worldwide [1]. Well-known risk factors are smoking, male gender, living in developed countries and chemical exposure [1,2]."

- Correction: "Bladder cancer (BCa) is the ninth most common cancer worldwide [1]. Well-known risk factors include smoking, being male, living in developed countries, and chemical exposure [1,2]."

7. Location: Introduction (Line 50)

- Original: "These presumably support growth of cancer cells by offering energy and growth factors for rapid cell growth."

- Correction: "These presumably support the growth of cancer cells by providing energy and growth factors for rapid cell growth."

8. Location: Results (Line 156)

- Original: "No clear differences in Charlson co-morbidity score or prevalence of COPD were observed by medication use or blood glucose level."

- Correction: "No clear differences in Charlson comorbidity score or prevalence of COPD were observed by medication use or blood glucose level."

9. Location: Results (Line 160)

- Original: "DM medication users had similar overall mortality than non-users, while hyperglycemic participants had higher overall mortality than normoglycemic participants."

- Correction: "DM medication users had similar overall mortality to non-users, while hyperglycemic participants had higher overall mortality than normoglycemic participants."

10. Location: Results (Line 174)

- Original: "The risk increase was slightly lower among hyperglycemic DM medication users HR 1.43 (0,68–3.02) than non-users HR 1.80 (1.13–2.85) but remained elevated compared to normoglycemia in both groups."

- Correction: "The risk increase was slightly lower among hyperglycemic DM medication users (HR 1.43 (0.68–3.02)) than non-users (HR 1.80 (1.13–2.85)) but remained elevated compared to normoglycemia in both groups."

11. Location: Discussion (Line 219)

- Original: "Expectedly, also overall mortality was higher in diabetics compared to non-diabetics."

- Correction: "As expected, overall mortality was also higher in diabetics compared to non-diabetics."

12. Location: Discussion (Line 240)

- Original: "Therefore, they might be treated in less aggressive manner."

- Correction: "Therefore, they might be treated in a less aggressive manner."

13. Location: Discussion (Line 258)

- Original: "For our knowledge only one study has previously reported increased risk of BCa-specific death among women with diabetes."

- Correction: "To our knowledge, only one study has previously reported an increased risk of BCa-specific death among women with diabetes."

14. Location: Discussion (Line 265)

- Original: "To decrease this limitation, we adjusted the analysis for records of COPD and smoking from the HILMO database, but the information especially on smoking was severely limited."

- Correction: "To mitigate this limitation, we adjusted the analysis for records of COPD and smoking from the HILMO database, but the information on smoking was particularly limited."

15. Location: Conclusions (Line 281)

- Original: "whereas antidiabetic medication use may mitigate the risk increase to small degree."

- Correction: "whereas antidiabetic medication use may mitigate the risk increase to a small degree."

Reviewer #4: Although this study is a large-scale investigation, encompassing almost all bladder cancer cases in Finland from 1995 to 2012, and explores the relationship between diabetes and bladder cancer prognosis through the analysis of blood glucose levels and antidiabetic medication history, it has two major limitations that significantly impact its clinical relevance.

Firstly, the data is outdated. The study covers diabetic patients from 1995 to 2012, but many new antidiabetic drugs have been introduced since 2012, such as SGLT-2 inhibitors and GLP-1 receptor agonists. These newer medications can significantly affect patients' weight, blood glucose levels, and even urine glucose, potentially influencing the final risk assessment. Therefore, I recommend the authors use more recent data for their analysis.

Secondly, there is a conceptual confusion. Not using antidiabetic drugs does not equate to not having diabetes. In fact, many patients can control their blood glucose levels solely through diet and exercise without needing medication, but this does not change the fact that they have diabetes or that they may have hyperinsulinemia. Thus, relying solely on the use of antidiabetic drugs to classify individuals as diabetic or non-diabetic is clearly inappropriate. Additionally, categorizing groups based on blood glucose levels is also flawed. When patients manage their blood glucose to normal levels through medication, they are still diabetic, their insulin levels have not improved, and insulin resistance remains. They may still be using antidiabetic drugs.

Minor issues

The study does not differentiate between type 1 and type 2 diabetes. As the authors mentioned from Line49-51, elevated blood glucose and high insulin levels are risk factors, and the fundamental difference between type 1 and type 2 diabetes is insulin levels. If the two types cannot be distinguished, using blood glucose alone to assess the risk of diabetes for cancer is inappropriate. Although this was explained in the limitations section, I suggest focusing the analysis on only one type of diabetes.

Additionally, the authors did not assess the impact of smoking, which is a significant risk factor for bladder cancer. The proportion of smokers is high among diabetic patients, which affects the accuracy of the conclusions. This should be further explained in the limitations section.

The study concludes that antidiabetic medications may have a protective effect in reducing the risk of bladder cancer. However, since the specific medication regimens of the patients are unclear, this conclusion is not accurate. In particular, the potential risk of bladder cancer associated with pioglitazone has garnered attention from various organizations, including the FDA, in recent years.

Why was acarbose excluded?

There are some grammatical and spelling errors in the articles, such as

Line 53-55, I suggest using “According to a meta-analysis of 36 studies, diabetes was associated with an increased risk of bladder cancer (BCa) in men【6】. A prospective population-based cohort study also found an increased risk of BCa death, but only in men【7】. Conversely, another study with 1,000 patients found no association between diabetes (type 1 or 2) and BCa risk or mortality【8】.”

Line67-69, I suggest using “The most common tumor morphologies were transitional cell carcinoma(12,027 cases, 82.0%), papillary transitional cell carcinoma( 1,626 cases ,11.1%), and unspecified malignant neoplasm( 533 cases ,3.6%).

**********

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Reviewer #1: Yes:  Xiaodong Zou

Reviewer #2: No

Reviewer #3: Yes:  Peng Wang

Reviewer #4: Yes:  YUAN LIU

**********

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Attachments

Attachment

Submitted filename: Review Comments.pdf

Dear Dr. Murtola,

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 21 2025 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.

• 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'.
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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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH, ChFC®, EA, CLU

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: 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??>

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #3: Yes

**********

Reviewer #1: (No Response)

Reviewer #3: The authors have thoroughly addressed all of my concerns. I have no further questions and recommend proceeding with the acceptance process according to the journal's guidelines.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes:  Xiaodong Zou

Reviewer #3: Yes:  peng wang

**********

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Dear Dr. Murtola,

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 May 08 2025 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.

• 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 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH, ChFC®, EA, CLU

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #3: Yes

Reviewer #5: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #3: Yes

Reviewer #5: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #3: Yes

Reviewer #5: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #3: Yes

Reviewer #5: (No Response)

**********

Reviewer #3: The authors have thoroughly addressed all of my concerns. I have no further questions and recommend proceeding with the acceptance process according to the journal's guidelines.

Reviewer #5: In this study, the authors investigate the potential association between diabetes and bladder cancer prognosis.

I think the revisions made by the authors in line with the referee suggestions are sufficient. I have no additional questions about the study. However, while correcting the grammar of the article, I think some words were forgotten to be deleted in the 3rd paragraph of the introduction.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #3: Yes:  peng wang

Reviewer #5: No

**********

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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

Dear Dr. Murtola,

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 May 29 2025 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.

• 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 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH, ChFC®, EA, CLU

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #3: Yes

Reviewer #5: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #3: Yes

Reviewer #5: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #3: Yes

Reviewer #5: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #3: Yes

Reviewer #5: (No Response)

**********

Reviewer #3: ALL COMMENTS HAVE BEEN ADDRESSED. The authors have thoroughly addressed all of my concerns. I have no further questions and recommend proceeding with the acceptance process according to the journal's guidelines.

Reviewer #5: (No Response)

**********

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 #3: Yes:  peng wang

Reviewer #5: 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

Dear Dr. Murtola,

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 Jun 06 2025 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.

• 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 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH, ChFC®, EA

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

Reviewer #5: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #3: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #3: Yes

Reviewer #5: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #3: Yes

Reviewer #5: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #3: Yes

Reviewer #5: Yes

**********

Reviewer #3: The authors have thoroughly addressed all of my concerns. I have no further questions and recommend proceeding with the acceptance process according to the journal's guidelines.

Reviewer #5: I want to thank the authors for the revisions made to the article. (Location: Materials and methods, Lines 98-99 ) The authors removed the 14th reference (‘’14. The Anatomical Therapeutic Chemical (ATC) classification system. https://www.whocc.no/atc_ddd_index/ ‘’) from the article, but the referenced text was not removed, and no reference was provided. I recommend that this situation be explained, or that the appropriate reference be added.

**********

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 #3: Yes:  peng wang

Reviewer #5: 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

Dear Dr. Murtola,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 20 2025 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.

• 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 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH, ChFC®, EA

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #3: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #3: Yes

Reviewer #5: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #3: Yes

Reviewer #5: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #3: Yes

Reviewer #5: Yes

**********

Reviewer #3: The authors have thoroughly addressed all of my concerns. I have no further questions and recommend proceeding with the acceptance process according to the journal's guidelines.

Reviewer #5: I want to thank the authors for their thorough consideration and revision of all my concerns. The reference numbers have been updated following the revisions to the article. I believe some of the previously changed reference numbers were not removed from the text, so I recommend checking. (Example: Materials and methods, Lines 100, ‘’We assessed the risk of comorbidity by using Charlson comorbidity index (CCI) [1213].’’) I have no additional questions or suggestions, and I recommend proceeding with the acceptance process according to the journal's guidelines.

**********

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 #3: Yes:  peng wang

Reviewer #5: 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

Dear Dr. Murtola,

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 Sep 18 2025 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.

• 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 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH, ChFC®, EA

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #5: All comments have been addressed

Reviewer #6: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #5: Yes

Reviewer #6: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #5: I Don't Know

Reviewer #6: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #5: No

Reviewer #6: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #5: Yes

Reviewer #6: Yes

**********

Reviewer #5: I want to thank the authors for their thorough consideration and revision of all my concerns. I have no additional questions or suggestions, and I recommend proceeding with the acceptance process according to the journal's guidelines.

Reviewer #6: The manuscript is technically sound. The research question is clear and well-defined, the study design (a large, population-based cohort) is appropriate, and the conclusions are well-supported by the data. The statistical methodology, including the use of multivariable Cox regression and time-varying covariates, is appropriate for the research question and data structure.

Strengths:

Large, nationally representative cohort (n=14,638).

Linkage of multiple reliable registries enhances data validity.

Sensitivity and subgroup analyses (including competing risks) strengthen the robustness of findings.

Thoughtful discussion of limitations and contextualization within existing literature.

The statistical analysis is largely rigorous and appropriate. The use of multivariable Cox regression and time-dependent covariates is commendable. The authors correctly adjusted for relevant covariates and provided person-time denominators when reporting mortality rates.

Missing data on tumor stage and primary treatment (available for only 74% and 80%, respectively) were not imputed. Although a complete-case sensitivity analysis was conducted, use of multiple imputation would strengthen the conclusions.

Dichotomization of continuous glycemic variables (e.g., glucose, HbA1c) may reduce statistical power. Consider exploring dose-response relationships or using categories aligned with clinical thresholds in future work.

I recommend the manuscript be accepted after minor revisions or clarifications, particularly regarding the impact of missing data and the potential use of multiple imputation for future studies.

**********

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 #5: No

Reviewer #6: 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

Hyperglycemia and bladder cancer prognosis in a Finnish population-based cohort

PONE-D-24-16036R7

Dear Dr. Murtola

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. For questions related to billing, please contact billing support .

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,

Filomena de Nigris, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #5: All comments have been addressed

Reviewer #7: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #5: Yes

Reviewer #7: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #5: I Don't Know

Reviewer #7: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #5: No

Reviewer #7: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #5: Yes

Reviewer #7: Yes

**********

Reviewer #5: I want to thank the authors for their thorough review and revisions. I have no further questions or suggestions, and I recommend moving forward with the acceptance process following the journal's guidelines.

Reviewer #7: Dear Authors,

Thank you for the thorough revisions and the clear and comprehensive responses provided.The changes you have made satisfactorily address all the points raised and further enhance the clarity and methodological rigor of the manuscript.

We have no additional comments and confirm the recommendation to proceed with acceptance of the manuscript in accordance with the journal’s guidelines.

**********

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 #5: No

Reviewer #7: No

**********