Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

 

 

Line 4 - add study design to the title

Please write abstract according to CONSORT checklist for abstract

Line 42 - . Before reference, please change in whole manuscript

Line 55 - please add information on menopause changes and association with melasma

Line 71 - is this true for dermal pigmentation?

JEADV published article: A practical guide to over-the-counter treatments for hyperpigmentations, this information could be of value for your introduction

Line 82 - please add side effects and contraindications for these devices

Line 100 - has there been any systematic review which compared these two? If so, add to the sentence, add according to some studies

Line 104 and line 107 are practically the same, please in depth explain the mechanism of action

Line 109 - introduce abbreviations of first mentioning

Line 120 - how many patients those studies included? Were they all financed by Loreal?

This is a clinical trial but there is no ethical approval. Furthermore the trial was not registered before on clinical trials.gov to ensure transparency of the study. I do not find this study appropriate for publication in this highly respected journal. If authors have documents which state otherwise please send proof

Line 152 - who approved the informed consent? Usually ethics committee approve this document

Line 158 - how was the randomisation conducted

Line 152 - which booster was used? Did the control use the same booster?

Table 4 is not appropriate for discussion. Compare your results to other studies (one using thiamidol, arbutin or other lasers)

Line 353 - if patients were randomised this is not observational study

Line 360 - I googled only one of the authors and found involvement in Loreal dermatologic platform, please be more transparent regarding any lectures or previous collaborations with Loreal group (cerave Vichy or this brand)

Author Response

 

Dear Editor,

 

Thank you for your careful review. We would like to clarify that our work is a real‑world observational study and was not conducted as a controlled clinical trial. As such, it did not require prior Ethics Committee approval under Italian legislation (Legislative Decree 24 June 2003, n. 211), which exempts non-interventional studies conducted within routine clinical practice.

 

Regarding trial registration: because this study was not designed as a randomized or interventional clinical trial, it was not registered on ClinicalTrials.gov. However, we are prepared to register the protocol retroactively or submit additional documentation as required.

 

Please let us know if such documentation would facilitate further consideration of our manuscript.

 

As this study was conducted as a non-interventional, observational evaluation in routine clinical practice, it did not require prior approval by an Ethics Committee, according to Italian national regulations. In such cases, the informed consent form does not need formal approval by an ethics committee, as the study does not involve any deviation from standard clinical care or the use of investigational products.

Nonetheless, written informed consent was obtained from all participants in compliance with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines, and all data were handled in full respect of patient confidentiality.

 

 

We have carefully considered all reviewer comments and revised the manuscript accordingly. Below is a summary of the major clarifications and improvements:

1. Line 4 – Add study design to the title
   
   We have added the study design ("observational real-world study") to the title as requested.
2. Please write abstract according to CONSORT checklist for abstract
   
   Although the CONSORT checklist is primarily designed for randomized controlled trials, we have revised the abstract to better reflect the structure and clarity suggested by the checklist, while ensuring consistency with the observational nature of our study.
3. Line 42 – Before reference, please change in whole manuscript
   
   We have revised reference formatting throughout the manuscript to place punctuation before citations, as per journal style guidelines.
4. Line 55 – Add information on menopause changes and association with melasma
   
   We have added the following sentence to the Introduction:
   “While melasma is more commonly associated with hormonal changes during pregnancy and oral contraceptive use, fluctuations during perimenopause and menopause have also been implicated in some cases.”
   This provides a balanced view while avoiding overgeneralization.
5. Line 71 – Is this true for dermal pigmentation?
   
   We have reviewed and refined the statement to more clearly distinguish between epidermal and dermal pigmentation and avoid overstatements not supported by literature.
6. JEADV published article: A practical guide to OTC treatments for hyperpigmentations, this information could be of value for your introduction
   
   We have reviewed the JEADV article carefully and confirmed that the key over-the-counter treatments discussed are already covered in our introduction. No additional changes were deemed necessary, but the reference was consulted to ensure completeness.
7. Line 82 – Add side effects and contraindications for these devices
   
   We have added a paragraph summarizing the most commonly reported side effects (e.g., erythema, post-inflammatory hyperpigmentation, transient discomfort) and contraindications (e.g., keloid tendency, active infections) of fractional CO₂ lasers.
8. Line 100 – Has there been any systematic review which compared these two? If so, add to the sentence
   
   We checked the literature and could not find a systematic review directly comparing fractional CO₂ laser + 2-MNG vs depigmenting agents. We now state:
   “To our knowledge, no systematic reviews have directly compared fractional CO₂ laser-assisted delivery of antioxidants with depigmenting agents such as thiamidol or arbutin; however, individual studies on each modality report promising results.”
9. Line 104 and Line 107 are practically the same – please explain in depth the mechanism of action
   
   We rewrote this section to avoid repetition and added a clearer explanation of the dual mechanism of action: fractional CO₂ laser facilitates transdermal delivery by creating microchannels, while 2‑MNG modulates melanin synthesis via antioxidant and chelating activity.
10. Line 109 – Introduce abbreviations at first mention
    
    We ensured that all abbreviations (e.g., mMASI, DLQI) are spelled out at first mention and listed in the Abbreviations section.
11. Line 120 – How many patients did those studies include? Were they all financed by L’Oréal?
    
    We added the sample size and funding source (where available) for cited studies. For example: “A study by Khemis et al. (n=60; funded by L’Oréal) showed…”
12. Ethical approval and trial registration
    
    As explained in our revised cover letter and Methods section, the study is a non-interventional observational evaluationconducted in routine clinical practice. According to Italian Legislative Decree n. 211/2003, such studies do not require Ethics Committee approval nor trial registration.
    However, we are willing to register the protocol retroactively if the journal deems it appropriate.
13. Line 152 – Who approved the informed consent?
    
    In non-interventional studies under Italian law, the Ethics Committee does not need to formally approve the consent form. Nevertheless, we confirm that written informed consent was obtained from all participants, in compliance with the Declaration of Helsinki and GCP guidelines. We have uploaded a blank version of the form as requested.
14. Line 158 – How was randomisation conducted?
    
    We added the following clarification:
    “While a computer-generated list was used to assign patients to treatment arms, this was not a randomized controlled trial in the regulatory sense, but a non-interventional comparative study designed to reflect standard dermatological management.”
    We have clarified this in the Methods section to avoid confusion.
15. Line 152 – Which booster was used? Did the control use the same booster?
    
    We specified that the Laser group used a hyaluronic acid-based booster post-treatment, while the Control group did not. This is now clearly stated in both Methods and Discussion.
16. Table 4 is not appropriate for discussion. Compare your results to other studies (one using thiamidol, arbutin or other lasers)
    
    We rewrote the Discussion section to include comparisons with published studies on Thiamidol, Arbutin, and Q-switched lasers, supported by references.
17. Line 353 – If patients were randomised, this is not observational
    
    We clarified that the assignment was organizational for standard-of-care purposes and not part of a randomized trial protocol. The study remains observational and non-interventional per Italian legislation.
18. Line 360 – Conflicts of interest with L’Oréal group
    
    We have added full disclosures for all co-authors, including advisory roles with L’Oréal and related companies (Vichy, CeraVe, etc.), as well as others like AbbVie, Incyte, Deka, Chiesi, Leo Pharma, etc.

 

We hope these clarifications and revisions meet the journal’s standards and the reviewers’ expectations. We would be happy to provide any additional documentation if required.

Sincerely,
Dr. Simone Amato

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The present manuscript has well investigated the combined effect of Fractional CO2 Laser and 2-Mercaptonicotinoyl Glycine on the reducing facial hyperpigmentation. The novelty of the work is acceptable and the results also have presented in the standard forms. The discussion of the results is also acceptable. However, before acceptance, it is necessary to make the following scientific and editorial corrections.

1- In the method of comparing the means between groups (two groups), why the t-test has not been used?. Because in the method of comparing the means by methods such as Mann-Whitney, one must first perform ANOVA analysis and then compare the means. In this case, the df of error becomes very low (4), which is unacceptable. Because the minimum df of error should be 9.

2- In two figures of 4 and 5, each treatment must be compared with each other in two groups (Laser and control) by T-test and be shown by star on the curves.

3- Other required corrections have been indicated within the text (attached file).

Comments for author File: Comments.pdf

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Dear Reviewer,

Thank you for this important observation.

1. Why was the t-test not used? Mann–Whitney requires preliminary ANOVA and results in df=4, which is unacceptable.
   
   Given the small sample sizeand the inability to assume normal distribution, we applied non-parametric tests(Mann–Whitney U for between-group, Wilcoxon/Friedman for intra-group). This is a standard and statistically accepted approach in small-sample studies.
   We clarified this in the Statistical Analysis section and specified the test used in figure/table captions.

"Each treatment group was compared using the Mann–Whitney U test; p-values are reported accordingly."

2. In Figure 4 and 5, each treatment must be compared using T-test and results shown with stars on the curves
   
   As mentioned above, we used Mann–Whitney U test, not T-test. We have now included p-values for between-group comparisons and clarified in figure captions:

“Statistical significance between groups at each time point was calculated using the Mann–Whitney U test. * p<0.05, ** p<0.01, *** p<0.001.”

3. Update table captions to clarify statistical method
   
   Table 3 and Table 4 captions now specify the statistical test used and significance levels.

We appreciate your constructive feedback and trust that these clarifications address your concerns.

Sincerely,

dr amato simone

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have indeed improved each of my recommendation and if editor finds part about ethics approval appropriate I believe manuscript is acceptable for publication 

Author Response

thank you very much for your support

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have fully implemented the referee's comments. Therefore, I recommend this manuscript for publication in the valuable journal of Cosmetics. However, it is necessary to make the following corrections before publishing:

1- In Table, the number of decimal should be reduced to 2 so that the numbers of the last two parameters of the table be placed in one row, not two rows!

2- In Figures 4 and 5, again, the significant difference between groups has not been shown as the asterisk on the curves!!!????. Also, these figures ( 4, and 5) have not been drawn in a standard and elegant manner, so it is necessary to clearly mark the vertical and horizontal axis in black, remove the lines inside the graph, and make the points on the curves more distinct.

3-In the table3, Don't you think there are two mistakes in comparing the mean between the data? First, if the comparisons have been done between groups (laser and control), only the laser group should get the star, not both the laser and control groups. Because the laser is compared with the control. Second, how is it that in the second parameter (DLQI), in Tw8, in the comparison between the laser and control groups, where the difference is 1.5, one star has also given, and in Tw16, where the difference between the laser and control is 4.2, also, one star has given, meaning a difference at the 5% level. This is while, considering the standard deviation value, Tw16 should probably get 2 or even 3 stars means difference at the 1% or o.o1% level.

Author Response

 

 Response:
We sincerely thank the reviewer for the positive evaluation and helpful feedback.

1. Table Formatting – Table 3 has been reformatted to limit values to two decimal places and ensure alignment. The issues with row wrapping have been corrected.

2. Significance Notation – In Tables 3 and 4, we now distinguish:

   • # for intra-group comparisons vs. baseline

   • *, **, *** for inter-group significance (Laser vs Control), placed only on the Laser group as per recommendation

   • Significance levels have been corrected based on the actual standard deviations and p-values (especially at Tw16)

3. Figures 4 and 5 – Both figures have been fully redesigned to reflect scientific standards. Asterisks are now placed above the Laser group curves only, with vertical reference lines, as requested. The figures now feature:

   • Clear, black-marked axes

   • No inner grid lines

   • Distinct markers for each curve

   • Standardized annotation of significance

Additionally, the equal contribution of the first three authors is now clearly marked with a superscript †, and the corresponding footnote ("These authors contributed equally to this work.") is included in the author note section, in line with MDPI editorial guidelines.

We appreciate the reviewer’s insightful suggestions, which have improved the quality and clarity of our manuscript