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by
  • Jan Musiałkiewicz *,
  • Bartłomiej Budny and
  • Marek Ruchała
  • et al.

Reviewer 1: Anonymous Reviewer 2: Anonymous Reviewer 3: Anonymous Reviewer 4: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article presented by Musiałkiewicz et al. is a narrative review discussing the clinical relevance of both sporadic and familial forms of pancreatic and intestinal neuroendocrine tumors, along with their implications for future research and personalized management strategies.

The review clearly and orderly discusses, without ignoring the limitations inherent in this type of work, the implications of some relevant genes in these pathological conditions.

Finally, it is suggested to review the bold text at the beginning of line 10.

Author Response

Thank you very much for reviewing the article and for your comments aimed at improving it.

1. Finally, it is suggested to review the bold text at the beginning of line 10.

In response, I would like to convey that the bold text at the beginning of line 10 was corrected.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript presents a narrative review focused on the prognostic and predictive significance of recurrent gene mutations in gastroenteropancreatic neuroendocrine tumors, with an emphasis on pancreatic and intestinal sites. The topic is clinically relevant, and the structured literature search with clear inclusion criteria strengthens the transparency. The overall organization is logical. However, several issues need to be addressed before the manuscript can be considered for publication.

The manuscript is presented as a narrative review, yet it includes a Materials and Methods section. It is recommended that the authors restructure the manuscript into a conventional review format.

The Discussion sections are organized gene by gene and largely summarize literature findings. There is limited critical synthesis or exploration of conflicting evidence.

Throughout the review, the terms prognostic and predictive are sometimes used interchangeably or without a clear distinction.

The evidence for some genes is derived from small cohorts, single case reports, or extrapolation from other tumor types. The text should acknowledge these limitations more explicitly to avoid overstating clinical applicability.

Author Response

Thank you very much for reviewing the article and for your comments aimed at improving it. In response, I would like to provide answers below:

1. The manuscript is presented as a narrative review, yet it includes a Materials and Methods section. It is recommended that the authors restructure the manuscript into a conventional review format.

We restructured the manuscript by removing the slightly misleading “Materials and Methods” heading (which is normally in original papers) and replacing it with “Literature Search Strategy” to better align with the conventional review format and Instructions for Authors in IJMS website.

2. The Discussion sections are organized gene by gene and largely summarize literature findings. There is limited critical synthesis or exploration of conflicting evidence.

We agree with the comment regarding summary of the literature and gene by gene organization. In this review we adopted this structure due to the applied literature search methodology and the number of genes included. In our opinion this approach improves the readability and accessibility of the manuscript for readers seeking information on the significance of a specific gene. A synthesis of the main findings was partially provided in the “Conclusions and Future Directions” section along with Table 2. Nevertheless, in accordance with the reviewer’s suggestion, we have further expanded this section in “Conclusions and Future Directions” paragraph.

3. Throughout the review, the terms prognostic and predictive are sometimes used interchangeably or without a clear distinction.

We reviewed the entire manuscript for the indicated issues and corrected them where necessary.

4. The evidence for some genes is derived from small cohorts, single case reports, or extrapolation from other tumor types. The text should acknowledge these limitations more explicitly to avoid overstating clinical applicability.

We decided to emphasize these limitations more in the summary by adding a separate “Review limitations” section at the end of the article and including the information suggested above.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript is a narrative review with semi-systematic elements that evaluates the prognostic and predictive relevance of selected gene mutations in pancreatic and intestinal neuroendocrine tumors (NETs). The authors focused on a predefined panel of genes (e.g., MEN1, ATRX, DAXX, TP53, PTEN, MTOR, CDKN1B) selected partly from the COSMIC database and summarized their biological roles and clinical implications. The review synthesized findings from approximately 70+ studies, discussed mutation-driven pathways such as chromatin remodeling, mTOR signaling, and telomere maintenance, and concluded that genetic profiling may improve diagnosis, prognostication, and personalized therapy in NETs. The manuscript addresses a relevant topic and compiles useful information; however, in its current form it is predominantly descriptive, methodologically weak, and lacks the critical depth and novelty expected. The following are the major concerns:

  • The manuscript largely reiterates well-established associations between common NET mutations (e.g., MEN1, DAXX/ATRX, TP53) and clinical outcomes without offering new synthesis, critical reinterpretation, or a unifying framework. The review reads as a descriptive catalog rather than an analytical or hypothesis-driven piece.
  • The methodological rigor of the literature review is insufficient. Although described as a “structured narrative review”, it lacks key elements of systematic reviews: no PRISMA compliance, no risk-of-bias assessment, no quality grading of included studies, and no reproducibility of search strategy beyond a single database (PubMed only). This introduces strong selection bias.
  • Genes were preselected based on COSMIC and “recent literature”, meaning the review cannot capture emerging or less-studied biomarkers. This creates a self-confirming narrative rather than an unbiased overview of the field.
  • Despite discussing prognostic relevance (DFS, OS, PFS), the manuscript does not attempt to compare effect sizes, hazard ratios, or consistency across studies. Conclusions such as “negative prognostic marker” are repeatedly asserted without quantitative backing.
  • The manuscript demonstrated systematic overinterpretation of heterogeneous and sometimes contradictory literature. For example, DAXX/ATRX mutations are described as negative prognostic markers, yet opposing findings (better prognosis in metastatic disease) are acknowledged but not critically reconciled (page 7). This reflects a lack of critical synthesis.
  • There is a significant conflation between prognostic and predictive biomarkers. Many genes (e.g., MTOR, RB1) are labeled as both without sufficient distinction between correlation with outcome and prediction of therapeutic response. This is a conceptual flaw that undermines translational relevance.
  • While the authors repeatedly emphasize “personalized medicine” and “clinical decision-making” (page 14), most biomarkers discussed are not validated for routine clinical use. The gap between research findings and clinical implementation is not critically addressed.
  • Pancreatic and intestinal NETs are treated as parallel but largely disconnected sections, despite clear biological differences (e.g., mutation burden vs chromosomal instability). The manuscript misses an opportunity to compare and mechanistically contrast these entities.
  • There is insufficient discussion of epigenetics, transcriptomics, and multi-omics approaches, despite their growing importance in NET biology. The review remains narrowly mutation-centric, which is outdated given current research trends.
  • Case reports and small cohort studies are included without weighting their evidentiary value relative to large genomic studies, leading to potential distortion of conclusions.
  • The manuscript lacks critical evaluation of diagnostic tools mentioned, such as NETest (page 2). It is presented as highly sensitive/specific without discussing controversies, reproducibility, or regulatory status.
  • Despite reviewing many biomarkers, the manuscript does not synthesize them into a usable framework (e.g., risk stratification model, diagnostic workflow).
  • A key conceptual weakness is that the manuscript confuses frequency of mutation with clinical importance. Highly frequent mutations (e.g., MEN1) are emphasized, but rarity does not necessarily equate to lack of clinical relevance, nor does frequency imply utility.
  • The “future directions” section is generic and does not identify specific research gaps, methodological needs, or promising technologies.

Minor issues:

  • Language is generally clear but contains awkward phrasing and grammatical inconsistencies throughout
  • Several sentences are overly long and reduce readability
  • Minor typographical inconsistencies (e.g., spacing in units, gene naming conventions)
  • Redundancy across sections (e.g., repeated explanations of gene functions)
  • Figure 1 (flowchart, page 4) lacks sufficient methodological transparency (e.g., unclear exclusion criteria details)
  • Tables (especially Table 2, pages 12–13) are descriptive but not critically interpreted
  • Inconsistent use of abbreviations (e.g., NETs/NENs interchangeability)
  • Some claims are insufficiently referenced or rely on limited studies
  • Lack of graphical synthesis (e.g., pathway integration figure or biomarker hierarchy)
  • The introduction is broad and not sharply focused on the review’s unique contribution

 

Author Response

Thank you very much for reviewing the article and for your comments aimed at improving it. In response, I would like to provide answers below:

 

  1. The manuscript largely reiterates well-established associations between common NET mutations (e.g., MEN1, DAXX/ATRX, TP53) and clinical outcomes without offering new synthesis, critical reinterpretation, or a unifying framework. The review reads as a descriptive catalog rather than an analytical or hypothesis-driven piece.

We revised the manuscript to strengthen its analytical aspect and improve the overall conceptual coherence of the review. We expanded the synthesis and critical reinterpretation in the “Conclusions and Future Directions” section and added “Review Limitations” section.

  1. The methodological rigor of the literature review is insufficient. Although described as a “structured narrative review”, it lacks key elements of systematic reviews: no PRISMA compliance, no risk-of-bias assessment, no quality grading of included studies, and no reproducibility of search strategy beyond a single database (PubMed only). This introduces strong selection bias.

We have added information regarding the use of a single database (PubMed only) and the potential for selection bias in the “Review Limitations” section. In response to the first part of the comment, we would like to emphasize that our work is a narrative review so it does not require the inclusion of elements specific to systematic reviews, such as PRISMA compliance, risk-of-bias assessment, or formal quality grading of included studies. Nevertheless, we incorporated selected systematic approaches within the literature search strategy to enhance the methodological rigor of the review. This approach was also positively evaluated by the other reviewers.

  1. Genes were preselected based on COSMIC and “recent literature”, meaning the review cannot capture emerging or less-studied biomarkers. This creates a self-confirming narrative rather than an unbiased overview of the field.

The aim of our review was to discuss the relevance of the most frequently reported mutations according to the COSMIC database. Priority was given to recurrent genetic alterations identified in pancreatic and intestinal NETs. This clarification has been added to the “Gene Selection” section. In response to the reviewer’s comment, we also included a statement in the “Conclusions and Future Directions” section highlighting the need for further investigation of emerging and less-studied biomarkers.

  1. Despite discussing prognostic relevance (DFS, OS, PFS), the manuscript does not attempt to compare effect sizes, hazard ratios, or consistency across studies. Conclusions such as “negative prognostic marker” are repeatedly asserted without quantitative backing.

Comparing effect sizes, hazard ratios, or consistency across studies is not required in a narrative review. We have taken note of the comment regarding the use of the term “negative prognostic marker” and have accordingly revised the manuscript where necessary to ensure more cautious and appropriate wording.

  1. The manuscript demonstrated systematic overinterpretation of heterogeneous and sometimes contradictory literature. For example, DAXX/ATRX mutations are described as negative prognostic markers, yet opposing findings (better prognosis in metastatic disease) are acknowledged but not critically reconciled (page 7). This reflects a lack of critical synthesis.

We have added clarification indicating that the statement refers to the identification of loss of DAXX/ATRX in metastases (not in metastatic disease) in order to resolve this inconsistency.

  1. There is a significant conflation between prognostic and predictive biomarkers. Many genes (e.g., MTOR, RB1) are labeled as both without sufficient distinction between correlation with outcome and prediction of therapeutic response. This is a conceptual flaw that undermines translational relevance.

We ensured that, within each discussed gene, the prognostic and predictive roles are described in separate paragraphs to distinct between correlation with outcome and prediction of therapeutic response.

  1. While the authors repeatedly emphasize “personalized medicine” and “clinical decision-making” (page 14), most biomarkers discussed are not validated for routine clinical use. The gap between research findings and clinical implementation is not critically addressed.

We addressed this gap in the “Conclusions and Future Directions” section in accordance with the reviewer’s comment.

  1. Pancreatic and intestinal NETs are treated as parallel but largely disconnected sections, despite clear biological differences (e.g., mutation burden vs chromosomal instability). The manuscript misses an opportunity to compare and mechanistically contrast these entities.

Biological differences (e.g., mutation burden, chromosomal instability) are addressed in the introductory sections of the respective tumor locations (pancreatic NETs and intestinal NETs).

  1. There is insufficient discussion of epigenetics, transcriptomics, and multi-omics approaches, despite their growing importance in NET biology. The review remains narrowly mutation-centric, which is outdated given current research trends.

We agree that the mentioned research directions are highly relevant and important in light of recent scientific advances but were not the interest of our review. However we decided to incorporate this comment into the “Review Limitations” sections. However, we do not fully agree with the statement that this represents an outdated approach. Our review covers publications from the last 15 years (2010–2025), the majority of which originate from the past 6–7 years, indicating that this field remains active and extensively investigated.

  1. Case reports and small cohort studies are included without weighting their evidentiary value relative to large genomic studies, leading to potential distortion of conclusions.

This issue has been addressed in the newly added “Review Limitations” section.

  1. The manuscript lacks critical evaluation of diagnostic tools mentioned, such as NETest (page 2). It is presented as highly sensitive/specific without discussing controversies, reproducibility, or regulatory status.

Informations about controversies and regulatory status of NETest were added in “Introduction” section.

  1. Despite reviewing many biomarkers, the manuscript does not synthesize them into a usable framework (e.g., risk stratification model, diagnostic workflow).

We have incorporated this comment above into the “Conclusions and Future Directions” section.

  1. A key conceptual weakness is that the manuscript confuses frequency of mutation with clinical importance. Highly frequent mutations (e.g., MEN1) are emphasized, but rarity does not necessarily equate to lack of clinical relevance, nor does frequency imply utility.

We do not fully agree with this statement. In our review, we avoid suggesting that mutation frequency directly translates into greater clinical significance or utility. The discussion of highly frequent mutations results from the adopted literature search strategy and selection criteria.

  1. The “future directions” section is generic and does not identify specific research gaps, methodological needs, or promising technologies.

We have expanded the “Conclusions and Future Directions” section in accordance with the reviewer’s comment.

  1. Language is generally clear but contains awkward phrasing and grammatical inconsistencies throughout

We have reviewed the manuscript for language quality and revised it to improve clarity and coherence.

  1. Several sentences are overly long and reduce readability

Where appropriate, we have broken up overly long sentences to improve readability.

  1. Minor typographical inconsistencies (e.g., spacing in units, gene naming conventions)

We have reviewed the manuscript and made corrections.

  1. Redundancy across sections (e.g., repeated explanations of gene functions)

We have removed some of the redundancies in accordance with the reviewer’s comment.

  1. Figure 1 (flowchart, page 4) lacks sufficient methodological transparency (e.g., unclear exclusion criteria details)

We have included information regarding the study inclusion criteria in the “Study Selection” paragraph and therefore were not repeated in the figure description which lays very close to it. Titles and abstracts were independently screened by two reviewers (AA and JS) for adherence to the inclusion criteria and relevance to the study topic. Articles which not met it were excluded. In situations of uncertainty between AA and JS, final decisions were made with input from PK and JM.

  1. Tables (especially Table 2, pages 12–13) are descriptive but not critically interpreted

We intended this table to serve as a summary of the significance of the evaluated genes. Their interpretation is provided in the „Discussion” section.

  1. Inconsistent use of abbreviations (e.g., NETs/NENs interchangeability)

We reviewed the manuscript in response to the comment and made corrections where necessary.

  1. Some claims are insufficiently referenced or rely on limited studies.

We have added this point to the “Review Limitations” section.

  1. Lack of graphical synthesis (e.g., pathway integration figure or biomarker hierarchy)

The number of tables and figures in the manuscript exceeds the typical requirements for a review article in IJMS. Ultimately, we decided not to include a pathway integration figure, and instead to present a summary of the genes related pathways in tabular form. However, if this will be considered a critical factor for acceptance of the manuscript, we would be willing to include such a figure. The hierarchy of biomarkers is not established and would be highly subjective so we did not put them.

  1. The introduction is broad and not sharply focused on the review’s unique contribution

We agree that the introduction is broad. We chose this approach due to the nature of NETs, which are rare tumors and are not frequently encountered by many clinicians. We considered that providing a broader context would help increase awareness of this group of malignancies.

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript presents a narrative review with systematic elements addressing the prognostic and predictive relevance of selected gene mutations in pancreatic and intestinal neuroendocrine tumors (NETs). The topic is timely and clinically relevant, particularly given the increasing interest in molecular stratification and personalized approaches in NET management. The manuscript is generally well-structured, and the authors provide a comprehensive overview of key genetic alterations and their potential clinical implications.

However, while the review is informative, several methodological, structural, and interpretative issues should be addressed to improve clarity, scientific rigor, and overall impact. In its current form, the manuscript requires major revision before it can be considered for publication.

My suggestions are:

The authors should provide a clear rationale for the selection of the included genes.

The intestinal NET section should be expanded to provide as detailed a description as for pancreatic cancers.

Expand discussion on how the biomarkers could be implemented clinically and emphasize the barriers to translation (e.g., availability, validation).

Comments on the Quality of English Language

Language check is required for conciseness and clarity.

Author Response

Thank you very much for reviewing the article and for your comments aimed at improving it. In response, I would like to provide answers below:

1. The authors should provide a clear rationale for the selection of the included genes.

We have added rationale for gene selection in the “Gene Selection” paragraph in accordance with the reviewer’s suggestion

2. The intestinal NET section should be expanded to provide as detailed a description as for pancreatic cancers.

We are unable to expand the intestinal NETs section to the same level of detail as the pancreatic NETs section. This limitation arises from the fact that the molecular landscape of intestinal NETs is characterized predominantly by chromosomal alterations and epigenetic changes, including DNA methylation, rather than by recurrent single somatic mutations. This information has been included at the beginning of the paragraph dedicated to this subgroup of NETs. In addition, in the pancreatic NETs section we have introduced a statement emphasizing that their genetic landscape regarding somatic mutations is much more diverse and more frequently altered compared with NETs of the small or large intestine.

3. Expand discussion on how the biomarkers could be implemented clinically and emphasize the barriers to translation (e.g., availability, validation).

We expanded the discussion in accordance with the recommendations provided in the reviewer’s comment.

4. Language check is required for conciseness and clarity.

We have performed a language check in accordance with the reviewer’s suggestion.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscrit has been improved.

Author Response

Thank you for your comment and for appreciating our improvements. Once again, I would like to express my gratitude for the review, which contributed to improving the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have not fully addressed the major concerns raised by the reviewer, and most of these concerns the authors decided to address by adding to the research limitations, which reduces the volubility of this article. 

Author Response

  1. The authors have not fully addressed the major concerns raised by the reviewer, and most of these concerns the authors decided to address by adding to the research limitations, which reduces the volubility of this article.

Thank you once again for the time devoted to reviewing the article and for the suggestions that made it possible to introduce improvements. We addressed all of the comments raised, while placing only three remarks in the “Review Limitations” section. We believe they should remain there, and that highlighting these limitations and drawing attention to them does not diminish the substantive value of the article.

Reviewer 4 Report

Comments and Suggestions for Authors

I accept the modifications of the authors. The authors made meaningful efforts to strengthen the methodological section, clarify biomarker interpretation, expand the intestinal NET discussion, and improve the clinical perspective.

Author Response

Thank you for the acceptance and for appreciating the modifications. Once again, I would like to express my gratitude for the review, which contributed to improving the manuscript.