Review Reports - Vitamin D Deficiency and Replacement Challenges in Type 1 Gastric Neuroendocrine Tumors: A Comparative Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I have read with interest the manuscript "Vitamin D Deficiency and Replacement Challenges in Type 1 Gastric Neuroendocrine Tumors: A Comparative Study, by Benevento et al. The authors analyzed the issues related to vitamin D deficiency in this special group of patients.

The study is well-designed, but it includes a limited number of patients. But given that the study is based on a single center and the rarity of this tumor, it would not be easy to obtain larger numbers.

The manuscript needs some improvements regarding the writing, presentation of results, and discussions.

The authors must imporved all these sections. The text must be divided into paragraphs by different ideas. They must emphasize in the introduction the relevance of the study idea more.

Also, the Methods should be presented in separate paragraphs, emphasising the inclusion and exclusion criteria, methods used, and statistics analysis.

The results should follow the main objective presented by the authors. The Table include data that were also presented in figures. It is better to avoid repeating the presentation of results. Also, the Table must present data grouped by population characteristics, vitamin D deficiency, bone diseases, treatment, and adherence. Osteoporosis and osteopenia are presented in the table, after the data on the daily dose of vitamin D needed.

Moreover, the Discussions section is presented as a single paragraph, beginning with a repetition of the results and a brief discussion of the autoimmune background and issues with vitamin D treatment. I consider that the authors must rearrange this section into separate paragraphs and improve the discussion of all aspects studied. Also, they must enhance the presentation of their study's strengths and its relevance to the management of these cases. The limitations of the study should be presented in a different paragraph.

Author Response

Reviewer 1

Comment 1: I have read with interest the manuscript "Vitamin D Deficiency and Replacement Challenges in Type 1 Gastric Neuroendocrine Tumors: A Comparative Study, by Benevento et al. The authors analyzed the issues related to vitamin D deficiency in this special group of patients. The study is well-designed, but it includes a limited number of patients. But given that the study is based on a single center and the rarity of this tumor, it would not be easy to obtain larger numbers. The manuscript needs some improvements regarding the writing, presentation of results, and discussions.

The authors must imporved all these sections. The text must be divided into paragraphs by different ideas. They must emphasize in the introduction the relevance of the study idea more.

Response 1: We thank the Reviewer for this constructive and insightful comment. In response, the manuscript has been carefully revised to improve overall clarity, structure, and readability. The text has been reorganized into well-defined paragraphs, each focused on a single concept. In addition to the Introduction, which has been thoroughly revised to better emphasize the clinical relevance and novelty of the study, the Results and Discussion sections have also been revised in accordance with the Reviewer’s suggestions, with improved presentation of the findings and a more focused and coherent discussion.

Comment 2: Also, the Methods should be presented in separate paragraphs, emphasising the inclusion and exclusion criteria, methods used, and statistics analysis.

Response 2: We thank the Reviewer for this valuable suggestion. The Materials and Methods section has been revised and reorganized into distinct paragraphs, clearly separating (2.1) study population, (2.2) inclusion/exclusion criteria, (2.3) data collection, (2.4) dietary assessment, and (2.5) statistical analysis. This restructuring improves clarity and readability and better aligns the manuscript with the journal’s format requirements.

Comment 3: The results should follow the main objective presented by the authors. The Table include data that were also presented in figures. It is better to avoid repeating the presentation of results. Also, the Table must present data grouped by population characteristics, vitamin D deficiency, bone diseases, treatment, and adherence. Osteoporosis and osteopenia are presented in the table, after the data on the daily dose of vitamin D needed.

Response 3: We thank the Reviewer for this helpful comment. The Results section has been revised to more closely follow the main study objective and to improve clarity and coherence. To minimize redundancy, the presentation of results has been streamlined so that numerical data are reported once and then referenced consistently to the corresponding table or figure. Regarding data presentation, Table 1 has been reorganized to group variables in a more logical and clinically meaningful order, specifically: population characteristics, vitamin D deficiency, treatment-related variables, and bone outcomes. In particular, the positioning of osteoporosis and osteopenia variables has been revised to ensure better consistency with the overall structure of the table and the flow of the Results section. Figures have been retained to visually emphasize key comparisons directly related to the study objectives, while tables provide a comprehensive overview of the collected data. We believe that this revised structure improves readability and avoids unnecessary repetition while enhancing the interpretation of the results.

Comment 4: Moreover, the Discussions section is presented as a single paragraph, beginning with a repetition of the results and a brief discussion of the autoimmune background and issues with vitamin D treatment. I consider that the authors must rearrange this section into separate paragraphs and improve the discussion of all aspects studied. Also, they must enhance the presentation of their study's strengths and its relevance to the management of these cases. The limitations of the study should be presented in a different paragraph.

Response 4: We thank the Reviewer for this important and constructive suggestion. The Discussion has been fully reorganized into distinct thematic paragraphs. The relevance of the findings for clinical management of type 1 gNET patients has been substantially emphasized. In addition, a dedicated paragraph has been added to clearly outline the strengths of the study and its clinical relevance. The limitations of the study, including the single-center design and limited sample size, are now explicitly addressed in a separate paragraph.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript addresses a significant and clinically relevant topic: vitamin D deficiency and supplementation challenges in patients with type 1 gastric neuroendocrine tumors compared to entero-pancreatic NETs. The study's aim is precise, and the results are interesting; however, several issues require improvement

1. Inclusion/Exclusion Criteria
Please state whether patients with prior vitamin D supplementation or recent high-dose therapy were excluded, as this could significantly influence baseline 25(OH)D levels and response to treatment. Additionally, consider reporting BMI and metabolic comorbidities, since obesity affects vitamin D distribution and absorption. Renal function was mentioned in the exclusion criteria, but detailed eGFR values should be reported to confirm comparability between groups.

2. The Discussion
The discussion should be expanded to explain why gNET patients required higher doses and multiple formulations. Please include the role of autoimmune chronic atrophic gastritis, gastric hypochlorhydria, bile acids, pancreatic exocrine function, and chronic inflammation in vitamin D malabsorption. These mechanisms are well-documented and would provide a stronger physiological rationale for your findings.

3. Inflammatory State
Consider adding information on whether systemic inflammatory markers (e.g., CRP) or other autoimmune conditions were assessed. Chronic inflammation can influence vitamin D metabolism and bone health, and acknowledging this would strengthen the interpretation of results.

4. Statistical analyses
Currently, only p-values are presented. Please, if possible, add effect sizes and confidence intervals for key comparisons (e.g., daily dose differences, prevalence of bone impairment). A short note on power limitations due to the small sample size would improve transparency.

5. Figures and tables
Figures are precise but should include sample sizes and statistical tests in the legends. Adding confidence intervals or effect sizes to graphical elements would improve interpretability. Tables should include complete footnotes that explain abbreviations (e.g., BMI, VDD, MD).

6. Reference list
The current bibliography is very limited. Please consider recent and authoritative sources, such as:

1. Demay MB, et al., doi: 10.1210/clinem/dgae290.
This guideline is the most authoritative and up-to-date source on vitamin D dosing, monitoring, and clinical management. It provides:

Evidence-based recommendations for daily vs. intermittent dosing strategies. Guidance on target serum 25(OH)D levels and testing indications. Context for interpreting your findings on higher dose requirements in gNET patients. Including this reference will align your discussion with international standards and demonstrate how your results align with current clinical practice.

2. Giustina A, , et al., doi: 10.1007/s11154-023-09792-7.
This review explains the mechanisms of impaired vitamin D absorption in gastrointestinal disorders, including:
The impact of gastric atrophy, hypochlorhydria, and autoimmune gastritis on fat-soluble vitamin absorption.
The role of bile acids and pancreatic enzymes in micelle formation.
Clinical parallels with conditions like celiac disease and bariatric surgery. Adding this source will strengthen your discussion and justify why gNET patients may require higher doses and alternative formulations.

These references will strengthen your discussion by linking your findings to current guidelines, mechanistic insights, and patient-centered outcomes.

7. Limitations of the study section

Please include a dedicated paragraph acknowledging the retrospective design, small sample size, lack of detailed renal and inflammatory data, and absence of gastric pH or bile acid assessment. It will improve the scientific reliability.

Author Response

Comment 1: The manuscript addresses a significant and clinically relevant topic: vitamin D deficiency and supplementation challenges in patients with type 1 gastric neuroendocrine tumors compared to entero-pancreatic NETs. The study's aim is precise, and the results are interesting; however, several issues require improvement

Inclusion/Exclusion Criteria

Please state whether patients with prior vitamin D supplementation or recent high-dose therapy were excluded, as this could significantly influence baseline 25(OH)D levels and response to treatment. Additionally, consider reporting BMI and metabolic comorbidities, since obesity affects vitamin D distribution and absorption. Renal function was mentioned in the exclusion criteria, but detailed eGFR values should be reported to confirm comparability between groups.

Response 1: We thank the Reviewer for these insightful comments. Patients receiving chronic high-dose vitamin D supplementation before the diagnosis of hypovitaminosis D were not included in the study. Occasional low-dose supplementation before diagnosis was not considered an exclusion criterion, reflecting real-life clinical practice; however, baseline 25(OH)-vitamin D levels were consistently measured at the time of documented deficiency. This clarification has now been added to the Methods section. Body mass index (BMI) was systematically collected for all patients and is now explicitly reported and analyzed, given its known influence on vitamin D metabolism. In addition, the prevalence of obesity and other metabolic comorbidities is now detailed in the Results section, and BMI was included as a covariate in the multivariable analyses. Regarding renal function, patients with chronic kidney disease stage ≥IIIb were excluded. Estimated glomerular filtration rate (eGFR) values were comparable between groups and are now reported to confirm homogeneity of renal function across the study population. All corresponding clarifications have been added to the revised manuscript.

Comment 2: The Discussion

The discussion should be expanded to explain why gNET patients required higher doses and multiple formulations. Please include the role of autoimmune chronic atrophic gastritis, gastric hypochlorhydria, bile acids, pancreatic exocrine function, and chronic inflammation in vitamin D malabsorption. These mechanisms are well-documented and would provide a stronger physiological rationale for your findings.

Response 2: We thank the Reviewer for this important suggestion. We have expanded the Discussion to include detailed pathophysiological mechanisms linking autoimmune chronic atrophic gastritis, hypochlorhydria, bile acid alterations, pancreatic exocrine function, and chronic inflammation to impaired vitamin D absorption, citing recent authoritative literature (Giustina et al., 2023).

Comment 3: Inflammatory State

Consider adding information on whether systemic inflammatory markers (e.g., CRP) or other autoimmune conditions were assessed. Chronic inflammation can influence vitamin D metabolism and bone health, and acknowledging this would strengthen the interpretation of results.

Response 3: We thank the Reviewer for this insightful comment. Systemic inflammatory markers were not consistently available due to the retrospective design. This limitation is now explicitly acknowledged, and the potential role of chronic inflammation in vitamin D metabolism and bone health is discussed.

Comment 4: Statistical analyses

Currently, only p-values are presented. Please, if possible, add effect sizes and confidence intervals for key comparisons (e.g., daily dose differences, prevalence of bone impairment). A short note on power limitations due to the small sample size would improve transparency.

Response 4: We thank the Reviewer for this valuable suggestion. In response, we have expanded the statistical reporting by adding effect size estimates and 95% confidence intervals for key outcomes. Specifically, odds ratios (ORs) with 95% confidence intervals were calculated for categorical variables using 2 × 2 contingency tables. For vitamin D deficiency prevalence, patients with type 1 gNET (12/13) were compared with EP-NET patients (6/13), yielding an OR of 14.0 (95% CI: 1.4–141), indicating a strong association between gastric primitivity and hypovitaminosis D. Similarly, bone impairment (defined as osteoporosis or osteopenia) was significantly more prevalent in the gNET group (8/13) compared with the EP-NET group (2/13), yielding an OR of 8.8 (95% CI: 1.3–60). For continuous outcomes, effect sizes were quantified using linear regression models. In multivariable linear regression analysis restricted to patients with vitamin D deficiency, type 1 gNET status was independently associated with higher daily cholecalciferol dose requirements (β = +1463 IU/day, p = 0.037), whereas BMI and autoimmune comorbidities were not significant predictors. We have also added a specific statement in the Discussion addressing the limited statistical power due to the small sample size and the resulting width of confidence intervals, to enhance transparency and appropriate interpretation of the findings.

Comment 5: Figures and tables

Figures are precise but should include sample sizes and statistical tests in the legends. Adding confidence intervals or effect sizes to graphical elements would improve interpretability. Tables should include complete footnotes that explain abbreviations (e.g., BMI, VDD, MD).

Response 5: We thank the reviewer for these helpful suggestions. In response, all figure legends have been revised to explicitly report sample sizes and the statistical tests applied. In addition, all tables now include complete footnotes explaining all abbreviations used (e.g., BMI, VDD, MD), thereby improving clarity and readability. Regarding the inclusion of effect sizes or confidence intervals within the graphical elements, we considered this suggestion carefully. However, we decided not to display them directly in the figures, as this would have compromised visual clarity given the limited sample size and the layout of the graphs. Importantly, all effect size estimates and confidence intervals are fully reported in the Results section and in the corresponding tables, ensuring transparent and comprehensive statistical reporting.

Comment 6: Reference list

The current bibliography is very limited. Please consider recent and authoritative sources, such as:

Demay MB, et al., doi: 10.1210/clinem/dgae290.

This guideline is the most authoritative and up-to-date source on vitamin D dosing, monitoring, and clinical management. It provides:

Giustina A, , et al., doi: 10.1007/s11154-023-09792-7.

This review explains the mechanisms of impaired vitamin D absorption in gastrointestinal disorders, including:

The impact of gastric atrophy, hypochlorhydria, and autoimmune gastritis on fat-soluble vitamin absorption.

The role of bile acids and pancreatic enzymes in micelle formation.

Clinical parallels with conditions like celiac disease and bariatric surgery. Adding this source will strengthen your discussion and justify why gNET patients may require higher doses and alternative formulations.

These references will strengthen your discussion by linking your findings to current guidelines, mechanistic insights, and patient-centered outcomes.

Response 6: We thank the Reviewer for this valuable suggestion. The reference list has been substantially expanded to include recent international guidelines (Demay, 2024) and mechanistic reviews (Giustina, 2023), aligning our findings with current standards of vitamin D management.

Comment 7: Limitations of the study section

Response 7: We thank the Reviewer for this insightful comment. A dedicated limitations paragraph has been added, addressing study design, sample size, lack of inflammatory and gastric functional data, and supplementation adherence.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript entitled Vitamin D Deficiency and Replacement Challenges in Type 1 Gastric Neuroendocrine Tumors: A Comparative Study is an original article. The authors assessed the vitamin D status, supplementation requirements, and bone involvement in patients with type 1 gastric Neuroendocrine Tumors (gNET) compared with those with enteropancreatic NET (EP-NET). It is a retrospective study which show that type 1 gNET is associated with higher burden of Vitamin D Deficiency, increased vitamin D supplementation requirements, and a higher prevalence of bone impairment compared with EP-NET, irrespective of dietary habits.

The topic of the article is interesting but currently there is still no clear pathophysiological support in the literature, only an association. Therefore, authors should clearly emphasize this in the manuscript.

I recommend introducing into the discussions a scheme suggesting the association of vitamin D deficiency with this type of tumors (even if the authors have a review on this topic). This scheme could also include suggestions for research topics.

The manuscris is very poor as discussions and references.

The article has only 13 references and 3 of them belong to the authors of this manuscript. Only 2 bibliographic references are used in the discussions because the remaining 11 are mentioned in the first part of the manuscript. Therefore, the discussions are very limited and are based very much on the 3 articles of the authors (a review and 2 retrospective clinical studies).

It seems that there are a few more articles on this topic in Pubmed, some even in Nutrients. Please add all references with the associated theme precisely because there are very few of them.

Author Response

Comment 1: The manuscript entitled Vitamin D Deficiency and Replacement Challenges in Type 1 Gastric Neuroendocrine Tumors: A Comparative Study is an original article. The authors assessed the vitamin D status, supplementation requirements, and bone involvement in patients with type 1 gastric Neuroendocrine Tumors (gNET) compared with those with enteropancreatic NET (EP-NET). It is a retrospective study which show that type 1 gNET is associated with higher burden of Vitamin D Deficiency, increased vitamin D supplementation requirements, and a higher prevalence of bone impairment compared with EP-NET, irrespective of dietary habits.

Response 1: We thank the reviewer for this important comment. We agree that current literature primarily reports associations rather than well-established pathophysiological mechanisms. We have revised the manuscript to explicitly acknowledge this limitation and to clearly state that the observed findings are associative. We also discuss the need for further studies to elucidate the underlying pathophysiological pathways.

Comment 2: I recommend introducing into the discussions a scheme suggesting the association of vitamin D deficiency with this type of tumors (even if the authors have a review on this topic). This scheme could also include suggestions for research topics.

Response 2: We thank the Reviewer for this valuable suggestion. To better illustrate the proposed association between type 1 gastric neuroendocrine tumors and vitamin D deficiency, we have added a new conceptual figure to the Discussion section. This scheme summarizes the pathophysiological mechanisms linking autoimmune atrophic gastritis, impaired vitamin D absorption and metabolism, increased supplementation requirements, and bone impairment. In addition, the figure highlights potential future research directions, including prospective studies on vitamin D pharmacokinetics and alternative supplementation strategies in this specific population.

Comment 3: The manuscris is very poor as discussions and references. The article has only 13 references and 3 of them belong to the authors of this manuscript. Only 2 bibliographic references are used in the discussions because the remaining 11 are mentioned in the first part of the manuscript. Therefore, the discussions are very limited and are based very much on the 3 articles of the authors (a review and 2 retrospective clinical studies). It seems that there are a few more articles on this topic in Pubmed, some even in Nutrients. Please add all references with the associated theme precisely because there are very few of them.

Response 3: We thank the Reviewer for this constructive comment. In response, the Discussion section has been substantially expanded and thoroughly revised to provide a more comprehensive and balanced interpretation of the results. The Discussion has been reframed within the broader and most recent literature on vitamin D metabolism, bone health, and neuroendocrine tumors, integrating relevant mechanistic, clinical, and guideline-based evidence. The reference list has been significantly updated by adding several relevant and recent publications, including mechanistic studies, clinical investigations, and guideline-based references, with particular attention to the limited but emerging literature available on this topic. Each reference has been integrated into the Discussion with a specific thematic purpose, thereby strengthening the scientific context and clinical relevance of the manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors addressed the reviewers' comments appropriately and improved the manuscript's structure. I consider this version publishable, as it addresses an interesting idea regarding type 1 gNET and vitamin D metabolism.

Author Response

Comment 1: The authors addressed the reviewers' comments appropriately and improved the manuscript's structure. I consider this version publishable, as it addresses an interesting idea regarding type 1 gNET and vitamin D metabolism.

Response 1: We sincerely thank the reviewer for positive evaluation and constructive feedback. We are pleased that the revisions and clarifications improved the manuscript and that the topic was found interesting and suitable for publication.

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you to the authors for the revisions and for the effort invested in improving the manuscript. The structure, clarity, and consistency have clearly improved, and the expanded discussion and refined results are appreciated.
However, several issues remain that were not previously addressed but now require particular attention and either correction or clarification to meet the journal’s standards:

Incomplete Ethics Approval Information
The “Ethics approval” section only states that there is no ethical conflict and that informed consent was obtained for publication, but it does not provide the name of the ethics committee, approval number, or date. Please add these details or clearly explain whether a formal waiver was granted for this retrospective study.

Vitamin D Assay Methodology Over a Long Timeframe (2010–2025)
The manuscript does not specify which assay types were used (e.g., LC-MS/MS, immunoassay), whether the methods changed over the 15-year period, or if harmonization was performed. This is critical for comparability—please provide these details.

Confounding Factors and Missing Clinical Data
The analysis does not account for important variables that may influence vitamin D status and bone health, such as:

season of sampling, sun exposure,
medication use (PPIs, H2-blockers, steroids, metformin),
biochemical markers (PTH, calcium, ALP), menopausal status, antiresorptive therapy.
Please provide available data or explicitly acknowledge these limitations in the discussion.

Definition and Calculation of “Daily Cholecalciferol Dose”
It is unclear how daily doses were calculated for intermittent regimens (e.g., monthly dosing). Please describe the conversion method to IU/day and consider reporting the median and IQR to reduce the influence of outliers.

Statistical Details

Logistic models showed quasi-complete separation; consider using Firth’s penalized logistic regression or provide exact 95% CIs for ORs.
Clarify how normality was assessed and which tests were applied for each variable (t-test vs. Mann–Whitney).

Terminology Consistency and Editorial Corrections

EP-NET vs GEP-NET terminology should be standardized.
Correct units (m² instead of “mq”), typographic issues, and title artifacts (“Type 1 2 Gastric…”).
Add axis labels, units, exact p-values, and confidence intervals to tables and figures.

Data Availability and Transparency
The current statement indicates that data are available upon request; however, for reproducibility, please consider providing an anonymized dataset (with dates removed or grouped by season) and a codebook, or explain why this cannot be done due to ethical restrictions.

Author Response

Comment 1: Thank you to the authors for the revisions and for the effort invested in improving the manuscript. The structure, clarity, and consistency have clearly improved, and the expanded discussion and refined results are appreciated.

However, several issues remain that were not previously addressed but now require particular attention and either correction or clarification to meet the journal’s standards:

Incomplete Ethics Approval Information

The “Ethics approval” section only states that there is no ethical conflict and that informed consent was obtained for publication, but it does not provide the name of the ethics committee, approval number, or date. Please add these details or clearly explain whether a formal waiver was granted for this retrospective study.

Response 1: We thank the reviewer for the comment. We have now revised details of ethics approval to make them more clearly and formally expressed: the study was approved by the Ethics Committee of “Università Federico II and AORN A. Cardarelli” (protocol no. 259/2023, report no. 15, 5 June 2023), and written informed consent was obtained from all patients for publication.

Comment 2: Vitamin D Assay Methodology Over a Long Timeframe (2010–2025)

The manuscript does not specify which assay types were used (e.g., LC-MS/MS, immunoassay), whether the methods changed over the 15-year period, or if harmonization was performed. This is critical for comparability—please provide these details.

Response 2: We thank the reviewer for this important comment. All vitamin D assessments were performed in accredited laboratories affiliated with the Italian National Health System, always using chemiluminescent immunoassay (CLIA) throughout the study period (2010–2025). No changes in methodology were made, ensuring comparability of the results. This information has now been explicitly included in the Methods section of the manuscript.

Comment 3: Confounding Factors and Missing Clinical Data

The analysis does not account for important variables that may influence vitamin D status and bone health, such as:

season of sampling, sun exposure, medication use (PPIs, H2-blockers, steroids, metformin), biochemical markers (PTH, calcium, ALP), menopausal status, antiresorptive therapy.

Please provide available data or explicitly acknowledge these limitations in the discussion.

Response 3: We thank the reviewer for this important comment. Data on season of sampling, sun exposure, and use of medications such as PPIs, H2-blockers, steroids, or metformin were not available in the medical records, and given the retrospective nature of the study, these factors would likely provide limited additional information (e.g., patients may have travelled, altering sun exposure and compliance to therapies). To minimize potential confounding, the comparison group was matched for age and sex, which also helps control for factors such as menopausal status and chronic therapies or comorbidities. No patient received antiresorptive therapy, as in 6/26 osteoporotic patients the diagnosis occurred after identification of vitamin D deficiency, as already specified in the Methods. Mean values of PTH and calcium are now reported, while data on ALP were not available. These limitations have been explicitly acknowledged in the revised Discussion.

Comment 4: Definition and Calculation of “Daily Cholecalciferol Dose”
It is unclear how daily doses were calculated for intermittent regimens (e.g., monthly dosing). Please describe the conversion method to IU/day and consider reporting the median and IQR to reduce the influence of outliers.

Response 4: We thank the reviewer for this comment. Daily cholecalciferol doses were calculated by dividing the total administered dose over the treatment period by the number of days of supplementation, including for intermittent regimens (e.g., monthly doses were divided by 30 to obtain IU/day). We reported mean doses to allow comparability across patients; given the relatively small sample size, the influence of outliers is limited. This calculation method has now been explicitly clarified in the Methods section of the manuscript.

Comment 5: Statistical Details

Logistic models showed quasi-complete separation; consider using Firth’s penalized logistic regression or provide exact 95% CIs for ORs.

Clarify how normality was assessed and which tests were applied for each variable (t-test vs. Mann–Whitney).

Response 5: We thank the Reviewer for the constructive and valuable comments, which helped us to improve the methodological clarity and statistical robustness of the manuscript. Regarding the concern about quasi-complete separation in logistic models, we acknowledge that this issue may arise due to the small sample size and the presence of zero cells in some categorical variables. Therefore, instead of applying standard logistic regression, we calculated exact odds ratios (ORs) with exact 95% confidence intervals, derived from Fisher’s exact test, which is more appropriate under these conditions. To avoid overinterpretation of unstable estimates, effect sizes with confidence intervals are reported only for statistically significant associations in the revised table, while non-significant comparisons are presented with p-values alone. This choice has been explicitly justified in the Statistical Analysis section. Normality of continuous variables was assessed using the Shapiro–Wilk test, supported by visual inspection of distribution plots. Accordingly, Student’s t-test was used for normally distributed variables, while the Mann–Whitney U test was applied for non-normally distributed data. This information has now been clearly stated in the Methods section. Finally, all tables and figures have been revised to include clear axis labels, measurement units, exact p-values, and 95% confidence intervals, where applicable. Figure captions and table footnotes were expanded to improve transparency and interpretability of the results. We believe that these revisions have substantially strengthened the manuscript and addressed the Reviewer’s concerns.

Comment 6: Terminology Consistency and Editorial Corrections

EP-NET vs GEP-NET terminology should be standardized.

Correct units (m² instead of “mq”), typographic issues, and title artifacts (“Type 1 2 Gastric…”).

Add axis labels, units, exact p-values, and confidence intervals to tables and figures.

Response 6: We thank the Reviewer for this helpful comment and for drawing attention to issues of terminology consistency and editorial clarity. The acronyms EP-NET and GEP-NET refer respectively to Entero-Pancreatic Neuroendocrine Tumors and Gastro-Entero-Pancreatic Neuroendocrine Tumors; these terms are defined in the Introduction and listed in the abbreviations section, as they describe related but distinct groups of neoplasms. To further improve clarity, we have carefully rechecked the manuscript to ensure consistent and appropriate use of this terminology throughout. All measurement units have been revised and aligned with the journal standards. With regard to the title, we have verified that no typographical artifacts are present; the numbering noted by the Reviewer refers to line numbering and not to the manuscript title. Regarding figures and tables, axis labels, measurement units, and exact p-values were already provided in the original version. In response to the Reviewer’s suggestion, we have further improved the figures by explicitly reporting confidence intervals, adding the corresponding 95% CI information within each panel and clarifying the meaning of the error bars in the figure legend. These revisions enhance the clarity and transparency of the graphical presentation without affecting the underlying analyses.

Comment 7: Data Availability and Transparency

The current statement indicates that data are available upon request; however, for reproducibility, please consider providing an anonymized dataset (with dates removed or grouped by season) and a codebook, or explain why this cannot be done due to ethical restrictions.

Response 7: We thank the Reviewer for this important comment regarding data availability and transparency. The dataset used in this study includes sensitive clinical information from oncological patients and, even after anonymization, cannot be made publicly available due to ethical and privacy regulations approved by the local Ethics Committee. Nevertheless, in order to support transparency and reproducibility, anonymized data underlying the main findings can be shared upon reasonable request, subject to approval by the Ethics Committee and in compliance with institutional and regulatory requirements. This data-sharing approach balances the need for scientific reproducibility with the obligation to ensure full protection of patient confidentiality.