Targeted Treatment Approaches for Gastrointestinal Metastases of Malignant Melanoma: Clinical Insights and Overcoming Drug Resistance

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

the article manuscript adequately adheres to the mission and scope of the journal

 

Author Response

the article manuscript adequately adheres to the mission and scope of the journal

Authors’ Response: Thank you for your positive feedback. We are pleased that our work aligns with the journal's mission and scope.

Reviewer 2 Report

Comments and Suggestions for Authors

In their manuscript entitled "Targeted Treatment Approaches for Gastrointestinal Metastases of Malignant Melanoma: Clinical Insights and Overcoming Drug Resistance" the authors present an overview of targeted treatment strategies for gastrointestinal melanoma metastases, focusing on current therapeutic options and the mechanisms underlying drug resistance and advances in immune checkpoint inhibitors (ICIs) and 1targeted therapies, such as BRAF and MEK inhibitors.

In general, this is an very important and interesting topic.

The review is well structered and mentiones the important facts, however (to be a "good" review (and not a a "summary by words) it nees some additional infprmation for the readership.
As this topic it very complex, for understanding it is important to present more graphical sketches in each sub-chapter. 
e. g. How do the inhibitors act on celluar level ? 
So, the review needs an workup on grafical visalization.

 

Author Response

In their manuscript entitled "Targeted Treatment Approaches for Gastrointestinal Metastases of Malignant Melanoma: Clinical Insights and Overcoming Drug Resistance" the authors present an overview of targeted treatment strategies for gastrointestinal melanoma metastases, focusing on current therapeutic options and the mechanisms underlying drug resistance and advances in immune checkpoint inhibitors (ICIs) and 1targeted therapies, such as BRAF and MEK inhibitors.

In general, this is an very important and interesting topic.

The review is well structered and mentiones the important facts, however (to be a "good" review (and not a a "summary by words) it nees some additional infprmation for the readership.
As this topic it very complex, for understanding it is important to present more graphical sketches in each sub-chapter. 
e. g. How do the inhibitors act on celluar level ? 
So, the review needs an workup on grafical visalization.

Authors’ Response: We appreciate your positive assessment and valuable recommendation. We have revised the manuscript to include additional visual aids and schematic illustrations in key sub-chapters to support understanding. Specifically, we added a new figure depicting mechanisms of action of targeted therapies and immune checkpoint inhibitors at the cellular level.

Reviewer 3 Report

Comments and Suggestions for Authors

The format of this article is good.

Specific comments are below

 

1. What is CSD, SSM, LMM? Never defined these abbreviations for full names. Please check the entire manuscript (MS). If only use 1-2 times, you should not use abbreviations but full name.

 

2. These authors may consider whether it is possible to add a figure for some sections’ information description, which have no figure. This is only a possibility. If can, this may further increase the article readability.

 

3. For the section of “4. Strategies for Overcoming Immunotherapy Resistance”, relevant references should be inserted, especially in each points listed.

 

4. “4. Conclusion” should be “5. Conclusion”.

Author Response

The format of this article is good.

Specific comments are below

 Authors’ Response: We appreciate your positive assessment and valuable recommendation.

1. What is CSD, SSM, LMM? Never defined these abbreviations for full names. Please check the entire manuscript (MS). If only use 1-2 times, you should not use abbreviations but full name.

 

 Authors’ Response: Thank you for pointing this out. We have now defined all abbreviations at their first mention and removed abbreviations used only once or twice, replacing them with their full terms.

1. These authors may consider whether it is possible to add a figure for some sections’ information description, which have no figure. This is only a possibility. If can, this may further increase the article readability.

 

Authors’ Response: Additional figure has been added to improve clarity and complement the text, especially in the more concept-heavy sections.

 

1. For the section of “4. Strategies for Overcoming Immunotherapy Resistance”, relevant references should be inserted, especially in each points listed.

 

Authors’ Response: Relevant and up-to-date references have now been added to each subsection within this section to support the points made.

 

1. “4. Conclusion” should be “5. Conclusion”.

 

Authors’ Response: Corrected. The Conclusion section has been renumbered accordingly.

Reviewer 4 Report

Comments and Suggestions for Authors

The figures and tables require significant improvement, and the logical flow and clarity of the textual descriptions also need strengthening.

Author Response

The figures and tables require significant improvement, and the logical flow and clarity of the textual descriptions also need strengthening.

Authors’ Response: Thank you for this helpful comment. We have revised all figures and tables for clarity, resolution, and coherence. Additionally, we reorganized certain paragraphs to improve the logical flow and enhance readability.

Reviewer 5 Report

Comments and Suggestions for Authors

I   agree with the authors that Melanoma gastrointestinal metastases are frequent and should be addressed in specific ways.

This article covers different general aspects of melanoma, the sequence of discussed points is not linear, sometime confused, I suggest debating the following aspects:

1) incidence of GI mets

2) specific clinical and imaging characteristics: should single lesions be treated as multiple or diffuse mets?

3) the place of surgery in presence of ulceration or intussusception

4) response to the different treatments, primary and secondary resistance, discussing also sequencing.

5) mechanisms to overcome resistance

Specific points

Lines 39-41: the distinct types of melanoma are 10 and they include also nodular melanoma see table 1 in reference 3

 Line 53: sentinel lymph node excision should be performed   with wide excision according to pathology report when there is ulceration or ≥ 0.8 mm Breslow, and without   evidence of macroscopic lymph nodes and/or metastasis.

Cells 2021, 10, 327. https://doi.org/10.3390/cells10020327 comment on clinical symptoms, stressing that new onset of iron-deficiency anemia is a common and sometime early finding in presence of GI mets.

Lines79-80: should be better explained

Lines 83-90, not necessary; you can only say   that patients with melanoma metastases according to the current TNM staging system AJCC 8th Edition guidelines are classified as stage IV M1c.

Lines 91-92: “At the initial presentation, clinical diagnoses often included gastrointestinal bleeding of unknown origin, small bowel obstruction, rectal carcinoma, gastric ulcer, lymphoma, and cholelithiasis”. Not clearly do you mean clinical differential diagnosis?

The superiority pf PET/CT scan imaging respect to CT scan in the diagnosis of GI involvement should be discussed Tatlidil R., Mandelkern M. FDG-PET in the detection of gastrointestinal metastases in melanoma. Melanoma Res. 2001; 11:297–301. doi: 10.1097; Othman A.E., Eigentler T.K., Bier G., Pfannenberg C., Bösmüller H., Thiel C., Garbe C., Nikolaou K., Klumpp B. Imaging of gastrointestinal melanoma metastases: Correlation with surgery and histopathology of resected specimen. Eur. Radiol. 2017; 27:2538–2545. doi: 10.1007, besides the cited reference 17

Line 123:  I would say that chemotherapy  is not the first option perhaps the last  with very low  activity and an increased risk of anemia

Line 124: As above dacarbazine, IL-2, vemurafenib are not the first choice, or even a choice

Lines 125-127: should be rephrased:  the actual treatments are monoclonal antibodies that block the PD-1 pathway, alone or combined with  anti CTLA4 or anti -lag3 monoclonal antibodies, target therapy  with anti Braf inhibitors  combined with anti MEK inhibitors for melanomas harboring BRAF v600 mutations, and anti ckit inhibitors for melanomas with cKIT mutations  on exon 11-and 13, very uncommon finding however possible in mucosal melanomas arising in the GI or metastasizing  to the GI.

Lines 143-160: out of contest.  Since the title is “immunotherapy for melanoma – current state” the authors should debate the efficacy of immunotherapy in gastrointestinal metastases from melanoma, the relative risks, the resistance.

3.2. Melanoma cell plasticity: a key component of therapy resistance, also this chapter is out of contest at this point and

Lines 179-219   seem to debate the use of targeted therapies

Table 3   summarizes the resistance to immunotherapy

Lines 306-328 are not related to gastrointestinal metastases, but to melanoma itself

 Figure 3 and 4   too generic for this specific topic

Author Response

I   agree with the authors that Melanoma gastrointestinal metastases are frequent and should be addressed in specific ways.

This article covers different general aspects of melanoma, the sequence of discussed points is not linear, sometime confused, I suggest debating the following aspects:

Authors’ Response: Thank you for your detailed and thoughtful suggestions. We have extensively revised the manuscript for better structure and focus. The discussion has been reorganized to follow a logical sequence:

• incidence of GI mets

Authors’ Response: We have now included epidemiological data indicating that gastrointestinal metastases occur in up to 60% of patients with advanced melanoma, though often asymptomatic and only detected at autopsy.

 

2) specific clinical and imaging characteristics: should single lesions be treated as multiple or diffuse mets?

Authors’ Response: We have clarified that clinical presentations vary depending on the site of GI involvement, and we have included a discussion on whether solitary lesions should be managed differently from diffuse involvement. PET/CT has been emphasized as the preferred modality for identifying multifocal or occult lesions.

 

3) the place of surgery in presence of ulceration or intussusception

Authors’ Response: We have elaborated on the role of surgery, highlighting that it may be curative or palliative. Indications such as symptomatic bleeding, perforation, obstruction, or intussusception have been clearly outlined. Ulcerated and isolated lesions may benefit from resection prior to systemic treatment.

 

4) response to the different treatments, primary and secondary resistance, discussing also sequencing.

Authors’ Response: We have revised the treatment section to provide a structured overview of responses to immunotherapy, targeted therapies, and their sequencing. We now distinguish between primary and acquired resistance and have cited studies discussing optimal sequencing strategies.

 

5) mechanisms to overcome resistance

Authors’ Response: This section has been revised.

 

Specific points

 

Lines 39-41: the distinct types of melanoma are 10 and they include also nodular melanoma see table 1 in reference 3

Authors’ Response: We have updated this section to include all recognized subtypes, including nodular melanoma.

 

 Line 53: sentinel lymph node excision should be performed   with wide excision according to pathology report when there is ulceration or ≥ 0.8 mm Breslow, and without   evidence of macroscopic lymph nodes and/or metastasis.

Authors’ Response: The explanation for sentinel lymph node excision has been revised in accordance with current guidelines and the referenced article.

 

Cells 2021, 10, 327. https://doi.org/10.3390/cells10020327 comment on clinical symptoms, stressing that new onset of iron-deficiency anemia is a common and sometime early finding in presence of GI mets.

Authors’ Response: This has been incorporated into the clinical presentation section.

Lines79-80: should be better explained

Lines 83-90, not necessary; you can only say   that patients with melanoma metastases according to the current TNM staging system AJCC 8th Edition guidelines are classified as stage IV M1c.

Lines 91-92: “At the initial presentation, clinical diagnoses often included gastrointestinal bleeding of unknown origin, small bowel obstruction, rectal carcinoma, gastric ulcer, lymphoma, and cholelithiasis”. Not clearly do you mean clinical differential diagnosis?

Authors’ Response: These sections have been clarified, condensed, or removed as suggested.

The superiority pf PET/CT scan imaging respect to CT scan in the diagnosis of GI involvement should be discussed Tatlidil R., Mandelkern M. FDG-PET in the detection of gastrointestinal metastases in melanoma. Melanoma Res. 2001; 11:297–301. doi: 10.1097; Othman A.E., Eigentler T.K., Bier G., Pfannenberg C., Bösmüller H., Thiel C., Garbe C., Nikolaou K., Klumpp B. Imaging of gastrointestinal melanoma metastases: Correlation with surgery and histopathology of resected specimen. Eur. Radiol. 2017; 27:2538–2545. doi: 10.1007, besides the cited reference 17

Authors’ Response: The suggested articles by Tatlidil et al. and Othman et al. have been added, with corresponding discussion on the advantages of PET/CT.

Line 123:  I would say that chemotherapy  is not the first option perhaps the last  with very low  activity and an increased risk of anemia

Line 124: As above dacarbazine, IL-2, vemurafenib are not the first choice, or even a choice

Lines 125-127: should be rephrased:  the actual treatments are monoclonal antibodies that block the PD-1 pathway, alone or combined with  anti CTLA4 or anti -lag3 monoclonal antibodies, target therapy  with anti Braf inhibitors  combined with anti MEK inhibitors for melanomas harboring BRAF v600 mutations, and anti ckit inhibitors for melanomas with cKIT mutations  on exon 11-and 13, very uncommon finding however possible in mucosal melanomas arising in the GI or metastasizing  to the GI.

Authors’ Response: All these sections have been rewritten to reflect current clinical practice, with prioritization of ICIs and targeted therapies over older options like chemotherapy.

Lines 143-160: out of contest.  Since the title is “immunotherapy for melanoma – current state” the authors should debate the efficacy of immunotherapy in gastrointestinal metastases from melanoma, the relative risks, the resistance.

Authors’ Response: We agree with the referee, we put this explanation for the readers that are not so familiar with the topic.

3.2. Melanoma cell plasticity: a key component of therapy resistance, also this chapter is out of contest at this point and

Authors’ Response: We agree that it seems a bit out of the context, however, this cell plasticity play a role in the drug resistance.

Lines 179-219   seem to debate the use of targeted therapies

Authors’ Response: we tried to make it more assertive.

Table 3  summarizes the resistance to immunotherapy

Lines 306-328 are not related to gastrointestinal metastases, but to melanoma itself

Authors’ Response: These lines have been included in the topic to clarify the mechanisms related to melanoma.

Figure 3 and 4   too generic for this specific topic

Authors’ Response: We agree that these figures have been incorporated to focus specifically on melanomas and their possible GI metastases and are now directly aligned with the manuscript’s objectives.

We believe that the revised manuscript now addresses all the reviewers’ concerns and has been significantly improved. We thank the editorial board and reviewers for the opportunity to revise and resubmit our work.

 

Round 2

Reviewer 5 Report

Comments and Suggestions for Authors

Page 12, Fig 4: The combination of targeted therapy with immunotherapy is not more effective than IO combinations and it is a bit more toxic.  The combination of atezo- cobimetinib and vemutafenib the only one approved, did not show an improved survival at a longer follow-up.So, I would not put this sentence  in the first step.

Author Response

Authors` reply: Thank you for your valuable observation. We agree that the combination of targeted therapy with immunotherapy, particularly the triple combination of atezolizumab, cobimetinib, and vemurafenib, has shown increased toxicity and has not demonstrated an improvement in overall survival in longer follow-up data.
In response, we have revised the text and adjusted Figure 4 to reflect this. The combination is no longer listed as a preferred first-line step but is now placed as an option in later lines of therapy or under specific clinical circumstances.