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Gastroenterol. Insights2025, 16(4), 43;https://doi.org/10.3390/gastroent16040043 
(registering DOI)
by
  • Nabil Ismaili1,2

Reviewer 1: Kaibo Guo Reviewer 2: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors
  1. Clarity of Study Selection and Methodology
    The manuscript provides a comprehensive overview of recent trials but lacks transparency in the criteria for selecting the discussed studies. A systematic approach (e.g., PRISMA guidelines) should be outlined to explain how trials like ATOMIC, NICHE-2, and IMHOTEP were identified and evaluated. This omission limits reproducibility. Suggestion: Include a brief methodology section describing literature search strategies, inclusion/exclusion criteria, and data synthesis processes to enhance rigor.
  2. Data Accuracy and Contextualization
    While the 3-year DFS benefit from ATOMIC (86.4% vs. 76.6%) is highlighted, the manuscript does not address potential confounding factors, such as tumor heterogeneity or Lynch syndrome prevalence in the cohort. Additionally, the reported 100% 3-year DFS in NICHE-2 requires clarification—does this apply to all enrolled patients or only those achieving pCR? Suggestion: Provide subgroup analysis data (if available) and discuss limitations of the cited trials, including sample size biases or follow-up duration.
  3. Critical Comparison of Neoadjuvant vs. Adjuvant Approaches
    The discussion advocates for neoadjuvant immunotherapy but inadequately addresses the absence of a direct comparison with adjuvant strategies in ATOMIC. The manuscript mentions the ongoing AZURE-2 trial but fails to explore interim findings or hypotheses. Suggestion: Expand the discussion to include mechanistic differences (e.g., priming of antitumor immunity in neoadjuvant settings) and cite preclinical/translational studies supporting these hypotheses.
  4. Overstated Clinical Recommendations
    The proposed treatment algorithm (Figure 1) recommends 3 months of chemotherapy plus 1 year of atezolizumab for low-risk stage III disease, extrapolating from IDEA and ATOMIC data. However, IDEA’s 3-month regimen was validated only for low-risk patients receiving CAPOX, not FOLFOX. Combining this with immunotherapy lacks direct evidence. Suggestion: Qualify recommendations with caveats (e.g., “hypothetical” or “awaiting validation”) and emphasize the need for biomarker-driven trials.
  5. Formatting and Referencing Issues
    • Table 1 incorrectly lists “LV5FU2” as the control arm in MOSAIC; the trial compared FOLFOX to LV5FU2 (André et al., NEJM 2004).
    • References 12 and 15 (Xu et al.; Shiu et al.) are incomplete, lacking journal names and page numbers.
    • Critical recent studies, such as the KEYNOTE-564 trial evaluating adjuvant pembrolizumab in dMMR CRC, are omitted. Suggestion: Verify trial details in tables, standardize references per journal guidelines, and incorporate pivotal missing literature.

Author Response

Subject: Revised Manuscript - "Shifting Paradigm in Mismatch Repair Deficient Stage III Resected Colon Cancer: The ATOMIC Trial"

Dear Reviewer,

Thank you for your prompt response and for the important feedback and constructive comments from the reviewers.

We have carefully revised our manuscript, "Shifting Paradigm in Mismatch Repair Deficient Stage III Resected Colon Cancer: The ATOMIC Trial," to address all the points raised. The specific changes made are as follows:

  • The English language has been thoroughly reviewed and improved throughout the manuscript.
  • Both Tables 1 and 2 have been enhanced for greater clarity and data presentation.
  • The figure has been significantly improved to better illustrate the proposed clinical pathway.

All modifications have been highlighted in red in the manuscript file for your convenience.

We believe these revisions have substantially strengthened the paper and we hope it is now suitable for publication in your esteemed journal.

Thank you for considering our work.

Sincerely,

 

 

  • Clarity of Study Selection and Methodology
    The manuscript provides a comprehensive overview of recent trials but lacks transparency in the criteria for selecting the discussed studies. A systematic approach (e.g., PRISMA guidelines) should be outlined to explain how trials like ATOMIC, NICHE-2, and IMHOTEP were identified and evaluated. This omission limits reproducibility. Suggestion:Include a brief methodology section describing literature search strategies, inclusion/exclusion criteria, and data synthesis processes to enhance rigor: The PRISMA guidelines were used to selection pivotal and relevant trials and a methodology section was used to switch to a systematic review article  
  • Data Accuracy and Contextualization
    While the 3-year DFS benefit from ATOMIC (86.4% vs. 76.6%) is highlighted, the manuscript does not address potential confounding factors, such as tumor heterogeneity or Lynch syndrome prevalence in the cohort. Additionally, the reported 100% 3-year DFS in NICHE-2 requires clarification—does this apply to all enrolled patients or only those achieving pCR? Suggestion:Provide subgroup analysis data (if available) and discuss limitations of the cited trials, including sample size biases or follow-up duration: Limitation paragraph was added in a subsection in the discussion
  • Critical Comparison of Neoadjuvant vs. Adjuvant Approaches
    The discussion advocates for neoadjuvant immunotherapy but inadequately addresses the absence of a direct comparison with adjuvant strategies in ATOMIC. The manuscript mentions the ongoing AZURE-2 trial but fails to explore interim findings or hypotheses. Suggestion:Expand the discussion to include mechanistic differences (e.g., priming of antitumor immunity in neoadjuvant settings) and cite preclinical/translational studies supporting these hypotheses: preclinical and translational studies were discussed and more detail from AZURE-2 trials were included

 

  • Overstated Clinical Recommendations
    The proposed treatment algorithm (Figure 1) recommends 3 months of chemotherapy plus 1 year of atezolizumab for low-risk stage III disease, extrapolating from IDEA and ATOMIC data. However, IDEA’s 3-month regimen was validated only for low-risk patients receiving CAPOX, not FOLFOX. Combining this with immunotherapy lacks direct evidence. Suggestion:Qualify recommendations with caveats (e.g., “hypothetical” or “awaiting validation”) and emphasize the need for biomarker-driven trials. We agree with you and we add this note in the figure 2.

 

  • Formatting and Referencing Issues
  • Table 1 incorrectly lists “LV5FU2” as the control arm in MOSAIC; the trial compared FOLFOX to LV5FU2 (André et al., NEJM 2004): correction was made
  • References 12 and 15 (Xu et al.; Shiu et al.) are incomplete, lacking journal names and page numbers: correction was made
  • Critical recent studies, such as the KEYNOTE-564 trial evaluating adjuvant pembrolizumab in dMMR CRC, are omitted. Suggestion: Verify trial details in tables, standardize references per journal guidelines, and incorporate pivotal missing literature. KEYNOTE-564 investigate adjuvant pembrolizumab in renal cell carcinoma. The PRISMA model was used to select relevant trials and to exclude non relevant one.

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Author, 

Thank you for the opportunity to be able to evaluate your work. 

Here are some issues I recommend to be addressed.

  1. Some abbreviations are not defined in the abstract, yet used.
  2. CRC abbreviation is defined, yet not used, and is misleading with CC abbreviation included.
  3. The abstract should include more general sentences instead of: 'In 2004, six months of chemotherapy with FOLFOX resulted in a significant improvement in disease-free survival (DFS) and overall survival (OS).'
  4. Table 1 and 2 adverse events sometimes include exact data, while in some sections, just general ones. Please unify.
  5. It is not clear whether the tables include all studies that examine phase II/III trials.
  6. Please rephrase: 'Who needs treatment?' 
  7. Figure 1 - Stage should be written in capital. 
  8. Figure 1- SoC and IO may not be evident abbreviations to all readers.
Comments on the Quality of English Language

See my comments about rephrasing.

Author Response

Response to Reviewer 2

Dear Reviewer 

All modification were made following your recommendations :

  1. Some abbreviations are not defined in the abstract, yet used: Changes were made
  2. CRC abbreviation is defined, yet not used, and is misleading with CC abbreviation included: Change were made
  3. The abstract should include more general sentences instead of: 'In 2004, six months of chemotherapy with FOLFOX resulted in a significant improvement in disease-free survival (DFS) and overall survival (OS). Abstract was improved as the article type was changed as recommended to a systematic narrative review
  4. Table 1 and 2 adverse events sometimes include exact data, while in some sections, just general ones. Please unify: Data were unifid   
  5. It is not clear whether the tables include all studies that examine phase II/III trials: The PROSMA guidelines were used for trial selection
  6. Please rephrase: 'Who needs treatment?' English was improved
  7. Figure 1 - Stage should be written in capital: Modifications were made
  8. Figure 1- SoC and IO may not be evident abbreviations to all readers: Modifications were made

Your sincerely 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript has been well revised and is recommended for publication.

Author Response

Dear Reviewer,

Thank you for your positive feedback and for recommending our manuscript for acceptance. We are delighted to know that you found the revisions satisfactory and that no further modifications are required.

Your insightful comments and guidance throughout the review process have been invaluable in improving the quality of our work.

Sincerely

Prof Nabil Ismaili

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Author, 

The Response letter to my earlier inquiries was a bit simple and unpolished.

There are many issues regarding left in the manuscript that needs changing. 

  1. The newspaper states that a template shoudl be used for articles.
  2. The title page is too casual, and I advise you to pay attention to the usage of capital letters.
  3. The entire manuscript is not justified.
  4. You use colon cancer in Line 48, yet later initiate CRC abbreviation. Please unify.
  5. The references are not formatted based on the journal's requirements. 
  6. The manuscript does not contain a List of abbreviations. 
  7. You state 'We conducted', yet you are the sole author of the article.
  8. The required statements are not present at the end of the manuscript - Please check journal requirements.
  9. with 14 key studies ultimately included for narrative synthesis - This is a result, not a method.
  10. Please rephrase the first sentence of the abstract's Results section.
  11. Most abbreviations are not defined, yet used in the abstract.
  12. Evolution of Adjuvant Therapy in Stage III Colon Cancer: Key Clinical Trials - It seems like this table aims to demonstrate how things changed in time, yet the reader can only realise the first one is from 1990, when searching for the exact article. I recommend year of publication to be added to the table.
  13. I recommend to unifiy the patient population section in this table.
  14. Table 1 - Moertel et al and ATOMIC trial adverse events are not listed with exact numbers.
  15. Note: The DFS benefit in MOSAIC was significant for stage III but not stage II. The
    ATOMIC trial showed a statistically significant improvement in DFS (HR 0.50; 95% CI
    0.34–0.72). - I would rephrase and add this to the text.
  16. Table 1 is already a result of literature search, therefore, not proper to be present in the Introduction section.
  17. Please rephrase questions between line 126-130 into sentences. Although I have to highlight that these should not be questions, while these are already stated by national and NCCN guidelines...
  18. Capitals are used chaotically in Figure 1, just for random nouns. 
  19. Please rephrase 'wrong' in figure 1. 
  20. Data Synthesis: Please rephrase the '...' part.
  21. By checking the articles, a meta-analysis would be feasible to carry out.
  22. Please do not define abbreviations in a table. Either before in the text, or in the legend.
  23. Talbe 2 does not have a list of abbreviations.
  24. Overview of Included Studies and Synthesized Findings - This section should be rephrased into sentences. This is a list.
  25. Please delete: 'The efficacy and safety data from these key modern trials are summarized in Tables 1, and 3 in the main article.'
  26. The question-answer structure of the Discussion does not comply with scientific articles.
Comments on the Quality of English Language

See my comments about rephrasing. I think the article has worsened since the last time I saw it. 

The article states a metaanalysis was not feasible to carry out, and I disagree with that.

 

Author Response

Dear Reviewer,

We thank you for your thorough review and valuable constructive feedback on our manuscript. We have carefully considered all your comments and have revised the manuscript accordingly. We believe these changes have significantly improved the quality and clarity of our work. Our point-by-point responses are detailed in attached.

Author Response File: Author Response.pdf

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Author, 

Thank you for carrying out the recommended modifications. 

A single issue regarding '...' (Line 115) remains.

Author Response

Subject: Final Revisions: Manuscript for Submission

 

Dear Team,

 

Please find below a summary of the final modifications I have made to the manuscript in preparation for submission. All changes are highlighted in blue in the updated document for easy review.

 

Response to Reviewers Comment:

 

Comment: The reviewer noted that a meta-analysis might be feasible despite the heterogeneity among studies.

Response: We thank the reviewer for this insightful comment. We have revised the manuscript to acknowledge this point. Specifically, in the Data Synthesis section, we have modified the text to state that while a narrative synthesis was performed for the current review, the similarity of endpoints across studies suggests a future meta-analysis is indeed a valuable possibility. The revised text now reads:

 

"A quantitative meta-analysis was not performed due to the significant clinical heterogeneity of interventions (chemotherapy alone, chemoimmunotherapy, neoadjuvant immunotherapy alone) and settings (adjuvant vs. neoadjuvant) among the included studies. Therefore, a narrative synthesis was conducted. The results are presented to chronologically and thematically illustrate the evolution of the treatment paradigm, from the establishment of adjuvant chemotherapy to the current era of immunotherapy. While the present study adopted a narrative approach, the similarity of the endpoints in the studies included suggests that a quantitative meta-analysis could be conducted in the future to present robust pooled estimations."

 

The sentence, "While the present study adopted a narrative approach, the similarity of the endpoints in the studies included suggests that a quantitative meta-analysis could be conducted in the future to present robust pooled estimations," has been moved from the Discussion/Limitations section to the Data Synthesis section in Methods. This change proactively frames our narrative methodology while formally acknowledging the potential for future quantitative synthesis.

 

Additional Revisions:

 

Table 1: Added the Hazard Ratios (HR) and 95% Confidence Intervals (CI) for a more robust presentation of the DFS data.

 

Methods Section: Included the PROSPERO registration number (1174716) in the new "Protocol Registration" subsection.

 

Table 2: Clarified the nature of key trials by adding the term "adjuvant" where appropriate (e.g., ATOMIC, MOSAIC).

 

Abbreviations: Removed all duplicate entries in the abbreviations list to ensure consistency.

 

Text & Tables: Standardized the reporting of survival outcomes by replacing Event-Free Survival (EFS) with Disease-Free Survival (DFS) throughout the text and in all tables.

 

These revisions ensure clarity, consistency, and adherence to reporting standards while adequately addressing reviewer feedback.

 

Please let me know if you have any final comments.

 

Best regards,