Round 1

Reviewer 1 Report

Broad comments

The subject of the article "High incidence and early onset of urinary tract cancers in patients with polyomavirus BK-associated nephropathy" fits the aims and scope of Viruses. The subject of the study is important for clinicians and shows important dependencies.

All sections: Introduction, Material and methods, Results and Discussion are well and interestingly written. The Introduction, although short, is well written and introduces the reader to the topic. Study included 244 kidney transplant recipients in a 20- year cohort - so the research material is representative. Both the description of the patients and the statistical methods used to develop the results seem correct. The Results are clearly described, as are the accompanying graphs and tables.

The discussion is quite short, but this is largely due to the innovation of the research presented and the lack of literature for discussion.

Specific comments

Abstract

Page 1: Line: 16 "Background Over-immunosuppressed kidney transplant recipients are susceptible to..." - delete "Background"

Please standardize the number format (sometimes there is a space, sometimes there is no)

Please standardize the number format - there is a different number of decimal places in different numbers.

Page:2 Line: 88 0 remove red color

Page: 10 Line: 331 - remove red color

 

Author Response

Responding to the opinions of the reviewer 1.

We would like to thank the reviewer for the recommendations to improve this manuscript.

Broad comments

The subject of the article "High incidence and early onset of urinary tract cancers in patients with polyomavirus BK-associated nephropathy" fits the aims and scope of Viruses. The subject of the study is important for clinicians and shows important dependencies. All sections: Introduction, Material and methods, Results and Discussion are well and interestingly written. The Introduction, although short, is well written and introduces the reader to the topic. Study included 244 kidney transplant recipients in a 20- year cohort - so the research material is representative. Both the description of the patients and the statistical methods used to develop the results seem correct. The Results are clearly described, as are the accompanying graphs and tables. The discussion is quite short, but this is largely due to the innovation of the research presented and the lack of literature for discussion.

A: We would like thank the reviewer for the comments and appreciate the reviewer’s understanding of the limitations of this study.

Specific comments

Abstract

1. Page 1: Line: 16 "Background Over-immunosuppressed kidney transplant recipients are susceptible to..." - delete "Background"

A: We thank the reviewer for pointing out our error. We have deleted “Background” in the abstract section.

2. Please standardize the number format (sometimes there is a space, sometimes there is no)

A: We thank the reviewer for pointing out our errors. We have corrected the errors and used the same number format (one space between the numbers) throughout the text.

3. Please standardize the number format - there is a different number of decimal places in different numbers.

A: We thank the reviewer for the recommendation. We have amended our errors as suggested.

4. Page:2 Line: 88 0 remove red color

A: We thank the reviewer to remind us the mistake. We have changed the red-color word to the black-ink word.

5. Page: 10 Line: 331 - remove red color

A: We appreciate the reviewer’s notice. We have changed the word color.

Author Response File: Author Response.docx

Reviewer 2 Report

GENERAL COMMENT

The work "High incidence and early onset of urinary tract cancers in patients with polyomavirus BK-associated nephropathy" by Li et al. reports on the association between BKPyV infection and urinary tract cancers (UTC). Authors demonstrates that BKPyVAN patients have greater allograft losses, higher incidence, a lower cancer-free survival rate, and an earlier onset with a higher relative risk of developing UTC compared to non-BKPyVAN patients. The limit of this observational study is few cases reported.

SUGGESTIONS FOR AUTHORS

1. Since 2016 the taxonomy/nomenclature of polyomaviruses has been updated/changed, including BKV (BK virus), which is now BKPyV (BK polyomavirus). Please see Archives ofVirology volume 161, pages1739–1750(2016). Authors shoud use the new BKPyV in their revised text.
2. In the Introduction section authors state, line 54-55:  Among these polyomaviruses, SV40 seems not to exist in human cancers. This sentence is not correct. A better sentence could be: Among these polyomaviruses, the role of SV40 in the onset of human cancers remains to be clarified. Indeed, many investigations reported the association between SV40 and human cancers, while other studies publhished negative data. A recent review has been published in this field, such as doi.org/10.3389/fonc.2019.00670

3. This sentence "However, the direct causal role of these viruses in tumorigenesis remains inconclusive" should be re-written, such as "However, the direct causal role of these small DNA tumor viruses in human cancers needs to be investigated further with new innovative methods".

4. This sentence "An epidemiologic study demonstrated that 80-100% of the general population was infected by BKV in their childhood [15]" is based on a old reference. More recent articles, which should be cited,  reported a lower prevalence in the general population and children. Similarly, the citation 24 is very old. New additional studies/reviews have been published since 1982!
5. In general, too many old studies have been reported in the text, introduction , discussion, reference sections. More recent investigations should be cited, whereas new references added instead of the old references. Accordingly, the revised text should enclose major revisons.

Author Response

Responding to the opinions of the reviewer 2.

We would like to thank the reviewer for the constructive recommendations. We have amended the manuscript as suggested. The changed text is highlighted in red color.

GENERAL COMMENT

The work "High incidence and early onset of urinary tract cancers in patients with polyomavirus BK-associated nephropathy" by Li et al. reports on the association between BKPyV infection and urinary tract cancers (UTC). Authors demonstrates that BKPyVAN patients have greater allograft losses, higher incidence, a lower cancer-free survival rate, and an earlier onset with a higher relative risk of developing UTC compared to non-BKPyVAN patients. The limit of this observational study is few cases reported.

A: We agree with the reviewer about small case number of BKPyVAN in this study. It would be better to conduct multi-center analysis as BKPyVAN is relatively rare in most transplant centers. This study provides an important observation and multi-center studies will be required to verify the finding of this study. The collaborative project of multi-transplant centers is undergoing.

SUGGESTIONS FOR AUTHORS

1. Since 2016 the taxonomy/nomenclature of polyomaviruses has been updated/changed, including BKV (BK virus), which is now BKPyV (BK polyomavirus). Please see Archives of Virologyvolume 161, pages1739–1750(2016). Authors should use the new BKPyV in their revised text.

A: We would like o thank the reviewer for the recommendation. We have changed “polyomavirus BK (BKV)” to “BK polyomavirus (BKPyV)”, and “polyomavirus BK-associated nephropathy (BKVAN)” to “BK polyomavirus-associated nephropathy (BKPyVAN)” in the revised text.

2. In the Introduction section authors state, line 54-55:  Among these polyomaviruses, SV40 seems not to exist in human cancers. This sentence is not correct. A better sentence could be: Among these polyomaviruses, the role of SV40 in the onset of human cancers remains to be clarified. Indeed, many investigations reported the association between SV40 and human cancers, while other studies published negative data. A recent review has been published in this field, such as doi.org/10.3389/fonc.2019.00670

A: We thank the reviewer for correcting our errors. We have changed our description to the correct sentence as recommended. We have also added the review article in the reference as suggested.

3. This sentence "However, the direct causal role of these viruses in tumorigenesis remains inconclusive" should be re-written, such as "However, the direct causal role of these small DNA tumor viruses in human cancers needs to be investigated further with new innovative methods".

A: We thank the reviewer for the recommendation. We have changed our description as suggested.

4. This sentence "An epidemiologic study demonstrated that 80-100% of the general population was infected by BKV in their childhood [15]" is based on an old reference. More recent articles, which should be cited, reported a lower prevalence in the general population and children. Similarly, the citation 24 is very old. New additional studies/reviews have been published since 1982.

A: We have cited a newer reference that demonstrated 82% of general population having infected with BKPyV (reference 14: Kean, J. M.; Rao, S.; Wang, M.; Garcea, R. L., Seroepidemiology of human polyomaviruses. PLoS pathogens 2009, 5, (3), e1000363). We have rewritten the description as “approximately 80% of the general population was infected with BKPyV in their childhood”. In addition, we have cited more recent studies or reviews to replace the old reference 24 in the section of Introduction.

5. In general, too many old studies have been reported in the text, introduction, discussion, reference sections. More recent investigations should be cited, whereas new references added instead of the old references. Accordingly, the revised text should enclose major revisions.

A: We thank the reviewer for the recommendation. We have deleted the old references and replaced with the recent references. The changed references are highlighted in yellow color.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Please modify JCV with JCPyV