Exploring the Epidemiologic Burden, Pathogenetic Features, and Clinical Outcomes of Primary Liver Cancer in Patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Scoping Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an interesting review article with high novelty. However, some points should be addressed

• In title a more formal language should be used concerning "alarming time bomb".
• In Abstract, the databases and the keywords used shiuld be reported in the Methods section. The type of review, e.g. literature, narrative, systematic, etc. should be reported.
• The first two paragraph of the Introduction section should be merged.
• Th 1st sentence in the 3rd paragraph of Introduction should be split into two smaller sentences) lines 49-53.
• The next sentence (lines 53-59) should also be split into two smaller sentence to be more readable.
• Again the 4th, 5th and 6th paragraphs (lines 60-74) should be merged.
• Again the 6th and 7th paragraphs (lines 75-84) should be merged.
• Th 8th, 9th and 10th paragraphs (lines 85-100) should also be merged.
• Before the aim of the study, the authors should report in the Introduction the literature gap that this review aim to cover.
• The last paragrpa pf the Introduction is only one sentence. The authors should split this sentence into at least two sentence in order to be more readable.
• After the Introduction section, a Methods section should be added reporting the type of manuscriptreview, the time of studies included, the databases and keywords used as well as the inclusion and exclusion criteria. A flow char diagram for studies recruitment could be useful for the readers.
• Concerning the section 2.2.1 and the 1st paragraphs, what hapens in adults and not only in young adults?
• The authors report tha "IR and inflammation appear significantly involved in the genesis and progression of PLCs in MASLD patients presenting T2DM" (lines 234-235. This statement is very interesting and needsmore analysis.
• The paragraph in lines 260-261 needs more analysis or should be merged with the following paragraph.
• The paragraphs in lines 282-294 should be merged.
• The paragraphs in lines 302-312 should also be merged.
• The paragraphs in lines 326-333 should also be merged.
• Please, merge all the small paragraphs which include 1-2 small sentence with the above or below relevant paragraphs.
• At the end of the Results-Discussion add a paragraph with the strengths and the limitations fo the reviewing studies.

Author Response

Reviewer 1

This is an interesting review article with high novelty. However, some points should be addressed

• Title

• In the title, a more formal language should be used concerning "alarming time bomb".

Reply: We sincerely thank the Reviewer for this suggestion. In the resubmitted version, the title has been modified as proposed by using a more formal language and properly adapted to the topic(s) and type of the review.

• Abstract

• In the Abstract, the databases and the keywords used should be reported in the Methods section. The type of review, e.g., literature, narrative, systematic, etc., should be reported.

Reply: We sincerely thank the Reviewer for this valuable notification. In the resubmitted version of the manuscript, the abstract has been properly modified by reporting the type of review and including the adopted databases and the used search keywords in the Methods section.

 

• Introduction
• The first two paragraphs of the Introduction section should be merged.
• The 1st sentence in the 3rd paragraph of the Introduction should be split into two smaller sentences (lines 49-53).
• The next sentence (lines 53-59) should also be split into two smaller sentences to be more readable.
• Again, the 4th, 5^th, and 6th paragraphs (lines 60-74) should be merged.
• Again, the 6th and 7th paragraphs (lines 75-84) should be merged.
• The 8th, 9^th, and 10th paragraphs (lines 85-100) should also be merged.
• Before the aim of the study, the authors should report in the Introduction the literature gap that this review aims to cover.
• The last paragraph of the Introduction is only one sentence. The authors should split this sentence into at least two sentences in order to be more readable.

Reply: We sincerely thank the Reviewer for this precious suggestion. As proposed, in the revised version of our manuscript, the first two paragraphs (with the relative sections and subsections) have been merged as suggested, as well as the paragraph was completely reorganized to avoid redundancy and improve the clarity of the paper. Besides, to improve the readability, all the indicated long sentences have been split into at least two sentences. Finally, before the aim of the study, the literature gap that this research aimed to cover was described.

• Concerning section 2.2.1 and the 1st paragraphs, what happens in adults and not only in young adults?

Reply: We thank the Reviewer for this precious comment. In the incipit of the novel paragraph “1.2. Primary liver cancer in MASLD […]”, relevant epidemiological features concerning PLC in the MASLD adult setting have been reported and properly referenced, emphasizing the emerging dramatic burden of hepatic cancer in younger MASLD population in contrast with its already well-known role of epidemiologic “plague” among older patients.

• Methods:

• After the Introduction section, a Methods section should be added reporting the type of manuscript review, the time of studies included, the databases and keywords used, as well as the inclusion and exclusion criteria. A flow chart diagram for studies recruitment could be useful for the readers.

Reply: We sincerely thank the reviewer for this crucial comment. According to this, in the updated version of our manuscript, a Methods section reporting the type of manuscript review (i.e., scoping review), the time of studies included, the databases and keywords used, as well as the inclusion and exclusion criteria, has been properly added. Moreover, as suggested, a flow chart diagram (Figure 1) explaining the evidence selection process was enclosed. Finally, the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) Guidelines checklist was proposed as Supplementary File 1.

• Results
• The authors report that "IR and inflammation appear significantly involved in the genesis and progression of PLCs in MASLD patients presenting T2DM" (lines 234-235. This statement is very interesting and needs more analysis.
• The paragraph in lines 260-261 needs more analysis or should be merged with the following paragraph.
• The paragraphs in lines 282-294 should be merged.
• The paragraphs in lines 302-312 should also be merged.
• The paragraphs in lines 326-333 should also be merged
• Please, merge all the small paragraphs which include 1-2 small sentence with the above or below relevant paragraphs.
• At the end of the Results-Discussion add a paragraph with the strengths and the limitations of the reviewing studies

Reply: We sincerely thank the Reviewer for all these valuable comments. In the resubmitted version of our manuscript, the “Results” section has been completely reorganized, as well as the small paragraphs have been appropriately merged and/or extensively discussed, as suggested. Also, the statement concerning the imbricated role of IR and inflammation in the setting of PLC MASLD-T2DM has been properly analyzed, discussed, and referenced (in the novel paragraph “3.1.2. Insulin resistance-related inflammation influences hepatobiliary cancerogenesis” and the relative figure). Finally, as proposed, the strengths and limitations of the reviewing studies have been added at the end of the results (in the discussion section).

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Certain areas require clarification and refinement to improve scientific rigor, flow, and overall clarity:

1. Overextension and redundancy: The manuscript is very long, with occasional repetitions and excessive detail (especially in pathogenesis sections). Condensing or summarizing certain mechanistic subsections (e.g., repeated references to IGF-1, TLR4, COX-2) would improve readability.

2. Lack of visual summaries: The inclusion of summary tables or graphical abstracts (e.g., for therapeutic strategies, pathogenetic pathways, or microbiota changes) would help consolidate the extensive data.

3. Critical analysis: While the article is rich in citations, there is limited critical appraisal or comparison of conflicting data. The authors should discuss the strength/limitations of existing evidence (e.g., retrospective vs. prospective data on GLP-1 RA and cancer risk).

4. Balance in therapeutics: The potential risks of some antidiabetic agents (e.g., DPP4i or GLP-1 RA in cancer) are only briefly mentioned. A more balanced discussion is needed.

5. Grammar and Style: Some sentences are overly complex or awkwardly constructed (e.g., “represent encouraging therapeutic strategies” should be revised for clarity), or use of passive voice and long clauses detracts from readability. A careful language revision is suggested.

6. Other comments:

• Abstract: Consider simplifying some of the terminology and defining key acronyms upfront.

• Figures: Figure 1 is referenced, but not visible in the PDF excerpt. Ensure all figures are included and appropriately labeled.

• Consistency: Ensure consistent use of terms like “MASLD”, “T2DM”, and abbreviations throughout.

Author Response

Reviewer 2

Certain areas require clarification and refinement to improve scientific rigor, flow, and overall clarity:

• Overextension and redundancy: The manuscript isvery long, with occasional repetitions and excessive detail (especially in pathogenesis sections). Condensing or summarizing certain mechanistic subsections (e.g., repeated references to IGF-1, TLR4, COX-2) would improve readability.

Reply: We sincerely thank the Reviewer for this precious comment. As suggested, in the revised version of our paper, paragraphs (with the relative sections and subsections) have been properly merged, and the entire manuscript was completely reorganized to avoid redundancy and improve the clarity and flow of the paper (particularly in the pathogenesis-dedicated sections).

• Lack of visual summaries: The inclusion of summary tables or graphical abstracts (e.g., for therapeutic strategies, pathogenetic pathways, or microbiota changes) would help consolidate the extensive data.

Reply: We sincerely thank the Reviewer for this precious comment. In the resubmitted version of our manuscript, each section has been enriched with a graphical representation (figures or tables) summarizing the reported topics (i.e., Figure 1 for “Methods”; Figure 2 & Figure 3 for IR-pathogenesis; Table 1 & Table 2 for microbiota changes; Table 3 for antidiabetic-based therapeutic strategies).

• Critical analysis: While the article is rich in citations, there is limited critical appraisal or comparison of conflicting data. The authors should discuss the strength/limitations of existing evidence (e.g., retrospective vs. prospective data on GLP-1 RA and cancer risk).

Reply: We sincerely thank the Reviewer for this relevant observation. According to this, in the updated version, a critical appraisal with a comparison of controversial evidence has been proposed both for the pathogenetic and clinical sections. Moreover, a detailed discussion of the strengths/limitations of existing evidence has been inserted in the novel dedicated section (i.e., “Discussion”).

 

• Balance in therapeutics: The potential risks of some antidiabetic agents (e.g., DPP4i or GLP-1 RA in cancer) are only briefly mentioned. A more balanced discussion is needed.

Reply: We sincerely thank the Reviewer for this precious suggestion. According to this comment, the paragraph dedicated to the antidiabetic agents has been completely reformulated, and the potential risks associated with the administration of reported antidiabetic agents have been properly and critically described for each drug class, ultimately obtaining a more balanced discussion, illustrating the specific risk-benefit-efficacy profiles.

• Grammar and Style: Some sentences are overly complex or awkwardly constructed (e.g., “represent encouraging therapeutic strategies” should be revised for clarity), or the use of passive voice and long clauses detracts from readability. A careful language revision is suggested.

Reply: We thank the Reviewer for this relevant notification. In the resubmitted version of the paper, grammar and style have been deeply revised, all the complex sentences have been reformulated and/or split into at least two sentences to improve the readability, as well as the use of passive voice has been limited to necessary context.

 

 

OTHER COMMENTS

• Abstract: Consider simplifying some of the terminology and defining key acronyms upfront.
• Figures: Figure 1 is referenced, but not visible in the PDF excerpt. Ensure all figures are included and appropriately labeled.
• Consistency: Ensure consistent use of terms like “MASLD”, “T2DM”, and abbreviations throughout.

 

Reply: We sincerely thank the Reviewer for all these precious comments. In the resubmitted version of the manuscript, the abstract has been properly updated by simplifying the terminology, as well as clarifying all the acronyms. Figure 1 (in the updated version “Figure 2”) is now visible in the PDF excerpt.

Finally, as suggested, a consistent use of the terms “MASLD”, “T2DM”, and other abbreviations has been ensured by using the acronyms for the first time and respecting these throughout the manuscript. 

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have significantlly improved their manuscript. From my point of view, the revised version of the manuscript meets the criteria for publication.