Dear Dr. Farzat,

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Yudai Ishiyama

Academic Editor

PLOS One

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6. Please amend the manuscript submission data (via Edit Submission) to include authors Sami-Ramzi Leyh-Bannura, Mykyta Kachanov, and Florian M. Wagenlehner.

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[The authors have declared that no competing interests exist.].

We note that one or more of the authors are employed by a commercial company: UKGM.

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Additional Editor Comments:

In addition to the reviewers’ comments, please carefully consider the following points from the Editor and incorporate them into your revision:

1. Scientific soundness and sample size considerations

It is the journal’s policy to consider manuscripts for publication as long as the findings are scientifically sound. I am therefore aiming to make the editorial decision based solely on this criterion. That said, the main finding of the present study—namely, the lack of difference between the two groups—requires careful attention, as underpowered studies often introduce confusion into the scientific literature.

Please review the reviewers’ comments thoroughly, and note that the editorial decision regarding scientific soundness and suitability for publication at this time—especially given the small sample size—will be further considered after your revision.

Additionally, the Introduction requires more context. Many prior studies have evaluated oncological differences between pelvic and ureteral tumors, and this body of evidence should be appropriately summarized.

2. Clarification and standardization of the Methods section

Authors are strongly advised to revise the Methods section using more standardized and conventional descriptions. The current presentation leads to confusion, and clearer methodology will improve the overall readability of the manuscript.

3. Interpretation of non-significant results

As noted by one reviewer, non-significant p-values alone are not valid or clinically meaningful when the sample size is very small. The revised manuscript should avoid overreliance on non-significance and consider alternative approaches to presenting and interpreting the data.

4. Inclusion of figures

Authors are encouraged to provide figures, especially Kaplan–Meier curves. These are essential for adequately presenting survival analyses.

Thank you for your thoughtful revision of the manuscript. I look forward to reviewing your updated submission.

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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: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: No

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Overall Assessment

This manuscript presents a well-structured retrospective analysis evaluating the impact of tumor location (ureter vs renal pelvis) on perioperative and oncological outcomes following robot-assisted radical nephroureterectomy (RANU). The study population is relatively homogeneous, with all procedures performed by a single experienced surgeon, which strengthens internal validity. The paper is clearly written and provides valuable real-world data regarding surgical outcomes and recurrence patterns.

Importantly, the authors challenge the commonly held view that ureteral tumors carry a worse prognosis, reporting no significant differences between locations in this contemporary RANU cohort. Only minor revisions are required before the manuscript can be considered for publication.

Major Comments

1. The Methods section contains several exclusion criteria (prior cystectomy, segmental ureterectomy, NAC, palliative cases) but the flow of how 85 patients were narrowed to 54 could be more clearly summarized.

Suggestion: Add a short CONSORT-style flow diagram or a clear descriptive paragraph stating the exact numbers excluded for each reason.

2. The manuscript uses the term muscle-invasive (e.g., “15% with muscle-invasive disease”). However, UTUC staging does not commonly use this term (unlike bladder cancer).

Suggestion: Replace with “≥pT2 disease” or specify explicitly that muscle-invasive corresponds to ≥pT2.

3. You state that 33% of patients had “locally advanced disease,” but the staging definition is not provided. Suggestion: Add a definition (e.g., locally advanced = pT3–T4 and/or cN+).

4. It is stated that LAD was performed “in high-risk cases,” but high-risk criteria are not clearly defined.

Suggestion: Specify the criteria (e.g., suspicious nodes on imaging, high-grade tumor, large tumor size).

5. The Results section describes recurrence times, but adding a median time to bladder recurrence—even if the sample is small—would improve clarity.

6. There are several p-values written as “p = 0.9” or “p=0.1” without consistent spacing.

Suggestion: Standardize formatting (e.g., p = 0.90). Also specify whether all p-values are two-sided.

7. CSS is reported as 98.1% and OS as 94.4%, but the follow-up period (median 29 months) is relatively short.

Suggestion: Explicitly highlight in the Results or Discussion that survival estimates may be inflated due to limited follow-up.

8. There are several minor grammatical inconsistencies and spacing issues throughout the manuscript (e.g., “64%%”, “5 lymph nodes”, “10 Adjuvant chemotherapy”).

A light language edit would improve readability.

Reviewer #2: 1. The study is described as a “case-control” study. However, the design is more accurately a retrospective single-center cohort study in which patients are divided into two groups based on tumor location (ureter vs renal pelvis). Please revise the description of the study design throughout the manuscript.

2. The definitions of the survival outcomes and the methods used to assess them are not clearly described. Please explicitly define all primary and secondary endpoints (CSS, OS, RFS).

3. The manuscript states that Kaplan–Meier and Cox regression analyses were used to estimate CSS and OS. However, there is only one cancer-related death and two deaths overall (CSS 98.1%, OS 94.4%). With such a low number of events, Cox regression is statistically unstable and unlikely to yield reliable hazard ratios, and hazard ratios and 95% confidence intervals are not reported. Either present the Cox regression results explicitly (variables included, HRs, 95% CIs) or, if the analysis is not robust, remove Cox regression from the Methods and focus on descriptive Kaplan–Meier curves and univariable log-rank tests. Please clearly state in the Discussion and Limitations that, due to the small number of events, the study has limited power to detect clinically relevant differences between locations.

4. The Methods state that lymphadenectomy was performed in high-risk cases and that all consenting patients received immediate intravesical instillation therapy. In the Results, 26 patients with muscle-invasive or locally advanced disease are reported, of whom 13 received adjuvant therapy (10 chemotherapy, 3 immunotherapy). However, important details are missing: Which agents and doses were used for intravesical instillation? How many patients (overall and by tumor location) actually received it? What were the regimens for adjuvant chemotherapy and immunotherapy? Please provide these details.

5. The median follow-up of 29 months is relatively short for UTUC, particularly for detecting late recurrences and deaths. Nonetheless, the Abstract and Conclusion state that tumor location “does not impact postoperative and oncological outcomes.” Given the small sample and limited follow-up, softening the conclusion is recommended to reflect that no statistically significant differences were observed between ureteral and renal pelvis tumors in this single-center cohort, pending confirmation in larger, multicenter series with longer follow-up.

6. The study reports a statistically significant difference in hospital stay (8 days for the ureter group vs. 6.5 days for the renal pelvis group). The Discussion (Page 8, lines 227-230) attributes this generally to local clinical practices and catheter removal. This finding warrants a more specific explanation of why the ureter group specifically required longer stays, rather than a general comment on discharge planning. Was the protocol for catheter removal different between the groups?

7. There appear to be small inconsistencies between the Abstract and the main text regarding the proportions of muscle-invasive vs locally advanced disease (“14% muscle-invasive” vs “15%” in the Results). Please review and harmonize these percentages.

8. In Table 1, the p-value for gender is 0.5; however, in the first sentence of the Results section, it is described as if the p-value for BMI were 0.5 instead of gender, which seems an error.

9. In Table 1, BMI is significantly higher in the ureteral group than in the renal pelvis group (30.5 vs 27.0 kg/m², p = 0.04). Please comment on the observed baseline difference in BMI and its potential relevance.

10. The Methods state that 85 patients underwent UTUC surgery between July 2019 and July 2025, with data assessed on 01.09.2025. The date of data evaluation is written as “01.09.2025.” To ensure it is correctly understood, please revise it, for example, by writing out the month in English.

11. The term “locally advanced disease,” which seems to refer to T3–T4 tumors, is used in the Discussion, but it is not explicitly defined in the Methods or in the Results. Please clearly define “locally advanced” disease in the Methods.

12. In the Discussion, the statement about Colin et al. and positive surgical margins appears to be cited as reference (16). In contrast, the reference list suggests that Colin et al. correspond to reference 5. Please review all in-text citations and reference numbers for accuracy and consistency.

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

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Reviewer #1: Yes: Fumihiko Urabe

Reviewer #2: No

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[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.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

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Impact of Tumor Location on Oncological and Perioperative Outcomes after Robot-Assisted Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

PONE-D-25-54309R1

Dear Dr. Farzat,

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.

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Kind regards,

Yudai Ishiyama

Academic Editor

PLOS One

Additional Editor Comments (optional):

All concerns and comments have been adequately addressed. The authors should be commended for their substantial efforts to improve the manuscript.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

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

Reviewer #2: (No Response)

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

Reviewer #2: (No Response)

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

The PLOS Data policy

Reviewer #2: (No Response)

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

Reviewer #2: (No Response)

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Reviewer #2: (No Response)

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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

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