Inflammatory Mesenteric Disease and Sarcoidosis-like Reaction in a Patient with Lung Adenocarcinoma Who Received Pembrolizumab: Paraneoplastic Syndrome, Secondary to Checkpoint Inhibitor or Chance Finding?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

My sincere congratulationg for having compiled such an interesting case report. It is really well-written and -organized. I have only few suggestions to address:

1) Do you think there is a pathogenic link between sarcoidosis-like reaction and mesenteric panniculitis? If so, what would it be? Or, conversely, do you think that these events are two independents phenomena?

2) I agree with you on the urgent need of reporting as much as possible events like the one presented by you, since they develop in a field,(i.e. immunotherapy-related adverse events, also including the rarest ones), which is still partially unexplored. Misdiagnoses in such cases may be particularly detrimental and require an ever updated awareness. For these reasons and enhancing visibility, I suggest to cite two other very peculiar reports linked to the administration of pembrolizumab in your report: PMID: 34233544 and PMID: 38270846.

3) I noted some typos: for example, hilomediastinal is spelled in many different manners, check them. I think it should be better to use hilar only, since they are already included in the mediastinum. The caption of figure 5 should be rephrased. In the last box of this figure I found August and not July, as described in the main text.

4) The abbreviations of mesenteric panniculitis and retractile mesenteritis should be MP and RM, respectively. From line 50 onwards, the letters are sometimes inverted. Please, correct them.

Comments on the Quality of English Language

Typos throughout the paper.

Author Response

Dear authors,

My sincere congratulationg for having compiled such an interesting case report. It is really well-written and -organized. I have only few suggestions to address:

• Do you think there is a pathogenic link between sarcoidosis-like reaction and mesenteric panniculitis? If so, what would it be? Or, conversely, do you think that these events are two independents phenomena?

Response: First of all, we would like to thank you for taking the time to review our work. Secondly, we have not found a strong association in the medical literature linking mesenteric panniculitis with sarcoidosis-like reactions. In our opinion, in the case we present, the hypothesis is that these were two different phenomena that could have been triggered by the same cause: an alteration in the immune response secondary to the use of pembrolizumab. Although several years have passed since its emergence, we are still learning about new effects of this type of therapy. Sarcoidosis-like reactions have already been strongly associated with immunotherapy. However, fewer than 10 cases have been reported describing the occurrence of mesenteric panniculitis in these patients, although in this condition, abnormal activation of the immune system could play an important role.

• I agree with you on the urgent need of reporting as much as possible events like the one presented by you, since they develop in a field,(i.e. immunotherapy-related adverse events, also including the rarest ones), which is still partially unexplored. Misdiagnoses in such cases may be particularly detrimental and require an ever updated awareness. For these reasons and enhancing visibility, I suggest to cite two other very peculiar reports linked to the administration of pembrolizumab in your report: PMID: 34233544 and PMID: 

Response: We agree that, as physicians, within our clinical work, we must report unusual events that may or may not be attributed to newly introduced drugs. In these cases, only time and knowing whether similar reports are made in other regions will help determine if these effects should be taken into consideration. Formulating hypotheses is the foundation of scientific knowledge. Regarding the articles you mentioned, we consider it appropriate to reference the article with PMID 38270846 in our work, as it describes a completely unusual effect, similar to our case. We do not find it suitable to reference the other paper, as it involves a side effect in which radiotherapy likely played a very significant role.

• I noted some typos: for example, hilomediastinal is spelled in many different manners, check them. I think it should be better to use hilar only, since they are already included in the mediastinum. The caption of figure 5 should be rephrased. In the last box of this figure I found August and not July, as described in the main text.

Response: We have made the required change. "Hiliomediastinal" is now expressed as "hilar" for better comprehension of the text.

Regarding Figure 5, we appreciate your suggestion. However, the authors have decided to present the events starting from July 2023 in a "box," which includes the performance of a laparotomy and bronchoscopy with biopsy. Chemotherapy was subsequently resumed. The text provides more detailed information indicating that all these events took place from July 2023 to October 2023. However, in the figure, due to the need for greater brevity, we preferred to present it this way.

• The abbreviations of mesenteric panniculitis and retractile mesenteritis should be MP and RM, respectively. From line 50 onwards, the letters are sometimes inverted. Please, correct them.

We have made the required corrections.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have compiled a case report on sarcoid-like reactions following Pembrolizumab administration. Based on their paper, I wondered whether this adverse event can be definitively attributed to Pembrolizumab. I also found the overall structure of the manuscript challenging to follow. The authors should reference other papers and reconsider the entire structure.

Author Response

Response: Thank you for your valuable feedback and for taking the time to review our manuscript. We appreciate your suggestions and have carefully considered them. Below are our responses to your comments:

1. Attribution of the Adverse Event to Pembrolizumab:We acknowledge your concern regarding whether the sarcoid-like reaction and mesenteric panniculitis can be definitively attributed to pembrolizumab. In the literature, there are documented cases linking immune checkpoint inhibitors, including pembrolizumab, with sarcoidosis-like reactions and, to a much lesser extent, with mesenteric panniculitis. However, given the rarity of these events and the complexity of immune-related reactions, we agree that establishing a definitive causal relationship remains challenging. In our revised manuscript, we have included additional references and discussions to reflect this complexity and highlight that while the association is plausible, it is not conclusive. We have cited G. Kuang et al. (2023), who described a case of sclerosing mesenteritis secondary to pembrolizumab, supporting the possibility of an immune-mediated mechanism.
2. Manuscript Structure:We understand that some parts of the manuscript may have been difficult to follow. To improve clarity, we have reorganized the manuscript by restructuring sections and ensuring a more logical flow. We have made changes to better clarify the dates for more accurate follow-up.
3. Additional References:Based on your suggestion, we have added relevant references to other cases involving similar immune-mediated adverse events.

Following your suggestion, we have added relevant references to enhance the context and understanding of our case. Specifically, we included the suggested reference: Ferini G, Zagardo V, Boncoraglio A, Aiello MM, Pontoriero A. Leptomeningeal tumor spread or immune checkpoint inhibitor-related encephalitis/(poli-)neuritis? An unsolved dilemma in a patient on pembrolizumab for a history of brain metastases from lung adenocarcinoma. Acta Neurol Belg. 2024. [Available at: https://link.springer.com/article/10.1007/s13760-023-02462-0].

We believe these changes will enhance the manuscript and address your concerns. Thank you again for your constructive feedback, which has helped us improve the quality of our work.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

Thank you for having addressed all my comments. However, "hiliar" should be corrected in "hilar" (without the second i). Make this correction before sending the manuscript out for publication.

Comments on the Quality of English Language

"hiliar" must be corrected in "hilar".

Author Response

Dear reviewer

Response: We have replaced the term "hiliar" with "hilar."

Reviewer 2 Report

Comments and Suggestions for Authors

My opinion remains the same as before.

Author Response

Response to reviewer 2

RESPONSE

Dear Reviewer,

Thank you for your feedback. We have carefully considered your previous comments and made changes to address your concerns, including adding relevant references, clarifying manuscript structure, and discussing the complexity of attributing the adverse events to pembrolizumab. We believe the current version reflects these considerations adequately.