Biliary Tract and Pancreatic Cancer (BTPC) in Adult Patients: The Role of the Biliary Microbiota in Cancer and Therapeutic Strategies—A Scoping Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Carlo et al presented scoping review manuscript titled, “Biliary Tract and Pancreatic Cancer (BTPC) in Adult Patients: The Role of the Biliary Microbiota in Cancer and Therapeutic Strategies”. The authors aimed to investigate whether the microbiome associated with tumors of the biliary-pancreatic system for the early diagnosis of pancreatic tract neoplasms. The authors addressed resistance mechanisms, cutting-edge new platforms of current innovations and future directions in relation with the pharmacological perspectives. The literature covered a period of the past decade including the areas of bioinformatics and machine learning approaches employed in the identification of microbial biomarkers associated with pancreaticobiliary diseases. The introduction section provided with recent literature reports followed by detailed information related to biomarkers associated with cancers. The methodology part composed of the essential components of inclusion/exclusion criteria, research question, data extractions. The obtained results are discussed, systematically. The authors concluded that microbial and functional biomarkers could enable personalized diagnosis and therapy of cancer. However, a revision is required before acceptance.

1. In simple summary, delete (150 words).
2. The authors need to provide/address novelty of this review over the currently available literature, besides the data covering a past decade.
3. In the introduction section, the global mortality due to PDAC and BTC needs to be incorporated.
4. Wherever applicable, authors need to provide the names of microorganisms in italic.
5. At the end of conclusion, future perspectives to be incorporated.
6. Abbreviation is short. Hence, they can be mentioned in the text, followed by deleting Abbreviation section.

Author Response

Reviewer 1

Di Carlo et al presented scoping review manuscript titled, “Biliary Tract and Pancreatic Cancer (BTPC) in Adult Patients: The Role of the Biliary Microbiota in Cancer and Therapeutic Strategies”. The authors aimed to investigate whether the microbiome associated with tumors of the biliary-pancreatic system for the early diagnosis of pancreatic tract neoplasms. The authors addressed resistance mechanisms, cutting-edge new platforms of current innovations and future directions in relation with the pharmacological perspectives. The literature covered a period of the past decade including the areas of bioinformatics and machine learning approaches employed in the identification of microbial biomarkers associated with pancreaticobiliary diseases. The introduction section provided with recent literature reports followed by detailed information related to biomarkers associated with cancers. The methodology part composed of the essential components of inclusion/exclusion criteria, research question, data extractions. The obtained results are discussed, systematically. The authors concluded that microbial and functional biomarkers could enable personalized diagnosis and therapy of cancer. However, a revision is required before acceptance.

1) In simple summary, delete (150 words).

[Reply]: Thank you for your suggestion. We have removed “(150 words)” from the Simple Summary section accordingly.

 

2) The authors need to provide/address novelty of this review over the currently available literature, besides the data covering a past decade.

[Reply]: Thank you for this important comment. We agree that clearly highlighting the novelty of this scoping review is essential.

Compared with the existing literature, our review offers several innovative features. First, it focuses specifically on the biliary microbiota in pancreaticobiliary cancers, whereas most prior reviews address the gut microbiome or provide more general overviews of microbiota–cancer interactions. Second, we integrate microbiological, clinical, and therapeutic perspectives, including the impact of biliary interventions (such as stenting), chemoprophylaxis, and antibiotic resistance patterns, which are often underrepresented in previous reviews.

Furthermore, this scoping review incorporates recent advances in bioinformatics and machine learning applied to microbiome analysis, highlighting their potential to identify diagnostic and prognostic biomarkers. Finally, by systematically mapping the available evidence from the last decade following a PRISMA-ScR framework, we identify current knowledge gaps and future research priorities, particularly regarding functional microbiome analysis and its translation into clinical practice.

We have added these aspects in the Introduction section (lines: 135-143) to better emphasize the novelty of our work.

 

3) In the introduction section, the global mortality due to PDAC and BTC needs to be incorporated.

[Reply]: Thank you for this important suggestion. We have incorporated information on the global mortality burden of pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancers (BTC) in the Introduction section, including appropriate references, to better contextualize the clinical relevance of these malignancies. Lines: 73-78

 

4) Wherever applicable, authors need to provide the names of microorganisms in italic.

[Reply]: Thank you for your suggestion. We have provided the names of microorganisms in Italic.

 

5) At the end of conclusion, future perspectives to be incorporated.

[Reply]: Thank you for this valuable suggestion. We have revised the Conclusion section to better highlight future perspectives, streamline the text, and incorporate a concise statement on future research directions and potential clinical applications.

 

6) Abbreviation is short. Hence, they can be mentioned in the text, followed by deleting Abbreviation section.

 [Reply]: Thank you for your suggestion. We agree that the number of abbreviations used in the manuscript is relatively limited; however, we have retained the Abbreviations section in accordance with the journal’s formatting guidelines and to ensure clarity and consistency for the readers.

Reviewer 2 Report

Comments and Suggestions for Authors

This scoping review appears to be well-written and outlines the methodology to be followed in the study, as well as the current evidence and existing gaps regarding the role of the biliary microbiota in pancreaticobiliary carcinogenesis. However, the section regarding therapeutic strategies could be more emphasized, as would be expected from the review title.
Additionally, some details:

The meaning of the acronym OTUs in Table 2 or in the caption is missing, since all the acronyms have been explained.

Also in Table 2, the space between the words "Gallstones and hepatobiliary disease" is missing. 

In the text, the names of some bacteria are not in italics.

In line 329, there is probably a typo regarding the superscript number 1 in "IPMN1".

In line 386, the reference relating to Sidiropoulos et al. is not 27, but number 31, and then the sentence between lines 386-387 needs to be corrected.

Author Response

Reviewer 2

This scoping review appears to be well-written and outlines the methodology to be followed in the study, as well as the current evidence and existing gaps regarding the role of the biliary microbiota in pancreaticobiliary carcinogenesis. However, the section regarding therapeutic strategies could be more emphasized, as would be expected from the review title.
Additionally, some details:

1) The meaning of the acronym OTUs in Table 2 or in the caption is missing, since all the acronyms have been explained.

 [Reply]: Thank you for your comment. We have defined the acronym “OTUs” (operational taxonomic units) in the caption of Table 2 to ensure consistency with the other abbreviations.

 

2) Also in Table 2, the space between the words "Gallstones and hepatobiliary disease" is missing. 

[Reply]: Thank you for your suggestion. We have corrected the spacing error in Table 2, ensuring proper separation between the words as suggested.

 

3) In the text, the names of some bacteria are not in italics.

[Reply]: Thank you for this important comment. We have carefully revised the manuscript to ensure that all bacterial names are formatted in italics in accordance with standard scientific conventions throughout the text and tables.

 

4) In line 329, there is probably a typo regarding the superscript number 1 in "IPMN1".

[Reply]: Thank you for your suggestion. We have corrected the typographical error in the indicated sentence by removing the unintended superscript and ensuring that the comparison between IPMN and IPMC is clearly presented.

 

5) In line 386, the reference relating to Sidiropoulos et al. is not 27, but number 31, and then the sentence between lines 386-387 needs to be corrected.

[Reply]: Thank you for your suggestion. We have corrected according to the new references (NOW Sideropoulos et al is 35)

 

Reviewer 3 Report

Comments and Suggestions for Authors

This study addresses the contribution of biliary dysbiosis to carcinogenesis in pancreatic and biliary neoplasias and outcomes related to targeted therapy. It is suggested, according to the data gathered in the review process, that microbial alterations may reflect biological pathways relatedto inflammation, antimicrobial resistance and prognosis.

The methodology of the study presents as strong and convincing, given the conformity to PRISMA-ScR guidelines, the definition of criteria according to a PICo structure, and due to an independent screening process performed by a third party, all of which increase transparency. The final cluster includes 17 studies drawn from heterogeneous designs; despite that, heterogeneity can be itself descriptive because it reflects the current state of the body of data for this specific topic.

The results are crearly presented. Across studies, recurrent findings include factors such as biliary dysbiosis in cholangiocarcinoma and pancreatic cancer, associations with resistant bacterial species after biliary decompression procedures or neoadjuvant therapy regimens. Prognostic correlations are presented for some selected cohorts and despite presenting interesting restuls, remain limited in terms of validity. These findings are backed by a consistent body of data in the field of oncology already linking tumor-associated microbiota with inflammatory and immune response and treatment outcomes.

Overall, the article offers a plausible and clinically relevant analysis of datas that, once brough together, should trigger interests for a broad variety of clinical specialties including clinical oncology, gastroenterology, surgical oncology as well as microbiology.

 

Author Response

Reviewer 3

This study addresses the contribution of biliary dysbiosis to carcinogenesis in pancreatic and biliary neoplasias and outcomes related to targeted therapy. It is suggested, according to the data gathered in the review process, that microbial alterations may reflect biological pathways relatedto inflammation, antimicrobial resistance and prognosis.

The methodology of the study presents as strong and convincing, given the conformity to PRISMA-ScR guidelines, the definition of criteria according to a PICo structure, and due to an independent screening process performed by a third party, all of which increase transparency. The final cluster includes 17 studies drawn from heterogeneous designs; despite that, heterogeneity can be itself descriptive because it reflects the current state of the body of data for this specific topic.

The results are crearly presented. Across studies, recurrent findings include factors such as biliary dysbiosis in cholangiocarcinoma and pancreatic cancer, associations with resistant bacterial species after biliary decompression procedures or neoadjuvant therapy regimens. Prognostic correlations are presented for some selected cohorts and despite presenting interesting restuls, remain limited in terms of validity. These findings are backed by a consistent body of data in the field of oncology already linking tumor-associated microbiota with inflammatory and immune response and treatment outcomes.

Overall, the article offers a plausible and clinically relevant analysis of datas that, once brough together, should trigger interests for a broad variety of clinical specialties including clinical oncology, gastroenterology, surgical oncology as well as microbiology.

 

[Reply]: We thank the Reviewer for the positive and insightful assessment of our manuscript and for highlighting its interdisciplinary relevance. In line with the Reviewer’s comments, the Conclusions section has been further strengthened.