Successful Treatment with Selpercatinib for Ectopic Cushing’s Syndrome Due to Medullary Thyroid Cancer

Round 1

Reviewer 1 Report

I think this manuscript an interesting report. The narrative of the manuscript is well presented and easy to follow. Manuscript focused on application of selpercatinib for ectopic Cushing’s syndrome due to medullary thyroid cancer. I think that in case presentation section there is a lack of information regarding carrying mutations in the RET gene.  You should be precision describe it. This information is important to include with regard to treatment of selpercatinib.

Author Response

Thank you for your valuable comments!

I think this manuscript an interesting report. The narrative of the manuscript is well presented and easy to follow. Manuscript focused on application of selpercatinib for ectopic Cushing’s syndrome due to medullary thyroid cancer. I think that in case presentation section there is a lack of information regarding carrying mutations in the RET gene.  You should be precision describe it. This information is important to include with regard to treatment of selpercatinib.

We have added information on the RET mutation that the patient had.

Reviewer 2 Report

THe present a rare cases with medullary thyroid carcinoma who developed Cushing's syndrome.

They showed that the  treatment with selpercatinib was successful in this cases.

Concerns:

Please provide the detailed clinical, laboratory and hormone laboratory results supporting the diagnosis of Cushing's syndrome. 

The immunostaining of the removed MTC and/or lymph nodes may add further direct evidence of ACTH-secretion. PLease perform these satinings if possible.

Author Response

Thank you for your valuable comments!

THe present a rare cases with medullary thyroid carcinoma who developed Cushing's syndrome. They showed that the  treatment with selpercatinib was successful in this cases. Concerns:

Please provide the detailed clinical, laboratory and hormone laboratory results supporting the diagnosis of Cushing's syndrome. 

Additional information on clinical features and serum-cortisol at midnight are provided in the revised version of the manuscript.

The immunostaining of the removed MTC and/or lymph nodes may add further direct evidence of ACTH-secretion. PLease perform these satinings if possible.

Staining for ACTH was performed when Cushing’s syndrome was diagnosed, and was positive, which is remarkable since 7 years had elapsed since he was first operated. This information has been added to the case presentation and is briefly discussed in the discussion section.

Reviewer 3 Report

Clinically relevant case on an important topic. The paper needs more detail description of the case and issues around the case in the discussion. Needs some minor improvement in sentence structure to improve readability. 

Specifically:

• Introduction needs to be expanded; need to introduce the problem of ACTH excess and challenges posed in treatment and prognosis.
• Case
• What was the extent of disease ( structural and biochemical ) at line 37 when all treatments were ineffective, and at time of diagnosis of Cushing’s; calcitonin? Figure 1 A) what time point was this taken?
• Need to be specific on timing of Cushing’s treatment “About the same time “ is not clear.
• What dose of selpercatinib was required, any side effects to treatment? Was the dose adjusted over the clinical course over the 18 months.
• Line 42 – please indicate cortisol and ACTH levels with resolution of cushingoid features, and at what time point what normal biochemical response achieved.
• Adrenal insufficiency – how was the weaning of hydrocortisone attempted? Need to describe.
• Discussion
  Line 72 – please indicate percentage of patients with RET mutations
• Overview on how metyrapone works, as this was used in conjunction to the selpercatinib.
• Literature review needs to be expand on other patients who were treated with TKI (eg Wijewardene et al. 2017) and limitation of use, ie side effect profile. Which is important then to link with limitation of Selpercatinib specifically side effects.
• What does the author believe caused the adrenal insufficiency? This is important to explain. 

Author Response

Thank you for your valuable comments!

Clinically relevant case on an important topic. The paper needs more detail description of the case and issues around the case in the discussion. Needs some minor improvement in sentence structure to improve readability. Specifically:

1. Introductionneeds to be expanded; need to introduce the problem of ACTH excess and challenges posed in treatment and prognosis.

We have expanded the introduction, mainly emphasized that ectopic CS is a serious complication that needs to be promptly diagnosed and treated. We have also expanded the discussion on the influence of hypercortisolism on prognosis in the discussion section.

2. Case

1. What was the extent of disease ( structural and biochemical ) at line 37 when all treatments were ineffective, and at time of diagnosis of Cushing’s; calcitonin? Figure 1 A) what time point was this taken?

We had added information on the size of the largest metastasis at the time when sepercatinib was started, and that no metastasis could be seen at the last follow-up. Information on calcitonin at start and during follow-up is also provided. We have also added two new figures, abdominal CT before selpercatinib and one year later, figures that illustrate the reduced volume of abdominal lymph node metastasis.

1. Need to be specific on timing of Cushing’s treatment “About the same time “ is not clear.

This part of the case presentation has been clarified.

1. What dose of selpercatinib was required, any side effects to treatment? Was the dose adjusted over the clinical course over the 18 months.

160 mg twice daily has been used from start and no side-effects were experienced. This information has been added to the case presentation

1. Line 42 – please indicate cortisol and ACTH levels with resolution of cushingoid features, and at what time point what normal biochemical response achieved.

We have added that s-cortisol was under the limit of detection two days after treatment with metyrapone was started and that cortisol has remained low. We prefer to not report ACTH since it will be unclear for the reader (and us) if this comes from the tumor or the pituitary.

1. Adrenal insufficiency – how was the weaning of hydrocortisone attempted? Need to describe.

We have added a discussion on adrenal insufficiency to the revised version of the paper.

3. Discussion

1. Line 72 – please indicate percentage of patients with RET mutations

Done!

1. Overview on how metyrapone works, as this was used in conjunction to the selpercatinib.

In the discussion section we now explain how metyrapone works.

1. Literature review needs to be expand on other patients who were treated with TKI (eg Wijewardene et al. 2017) and limitation of use, ie side effect profile. Which is important then to link with limitation of Selpercatinib specifically side effects.

We have added to the discussion information from two studies (including Wijewardene) where TKI have been used for ectopic CS in patients with MTC.

1. What does the author believe caused the adrenal insufficiency? This is important to explain. 

We have added a discussion on adrenal insufficiency to the revised version of the paper and explained the why this happens.

Reviewer 4 Report

Interesting article that discusses the efficacy of selpercatinib in medullary thyroid ca with ectopic cushings syndrome. 

For the introduction, recommend providing a better discussion of medullary thyroid cancer, percentage that is RET mutation vs not, sporadic vs hereditary. Then discuss breakdown of secreting vs nonsecreting tumors that may lead to paraneoplastic symptoms.

For the case study:

1) The authors discuss that metyrapone and hydrocortisone were used to treat the cushings, with selpercatinib, what are the effects of the metyrapone and hydrocortisone on cushings? This aspect should be discussed since the patient was treated with 3 medications at the same time, not just selpercatinib. Need to justify that this was all due to sepercatinib and not the synergistic effect of all 3 etc.

2) Please list the typical cushinoid features that the patient presented with ie. in brackets

3) Please list the side effects that the patient experienced from vandetanib and cabozantinib.

4) Please list what block and replacement regime means for the reader

5) For the profound tumor reduction, please list what was the criteria for this statement. ie percentage reduction, size reduction etc.

Author Response

Thank you for your valuable comments!

Interesting article that discusses the efficacy of selpercatinib in medullary thyroid ca with ectopic cushings syndrome. 

For the introduction, recommend providing a better discussion of medullary thyroid cancer, percentage that is RET mutation vs not, sporadic vs hereditary. Then discuss breakdown of secreting vs nonsecreting tumors that may lead to paraneoplastic symptoms.

We have expanded the introduction as the reviewer suggest. Discussion on RET mutation has been added to the discussion.

For the case study:

1) The authors discuss that metyrapone and hydrocortisone were used to treat the cushings, with selpercatinib, what are the effects of the metyrapone and hydrocortisone on cushings? This aspect should be discussed since the patient was treated with 3 medications at the same time, not just selpercatinib. Need to justify that this was all due to sepercatinib and not the synergistic effect of all 3 etc.

In the revised version of the manuscript we provide more details about the treatment that the patient received.

2) Please list the typical cushinoid features that the patient presented with ie. in brackets

This information has been added to the revised version of the manuscript.

3) Please list the side effects that the patient experienced from vandetanib and cabozantinib.

Vendetanib was discontinued because of lack of effect and cabozantinib due to side-effects. This information has been added to the revised version of the manuscript.

4) Please list what block and replacement regime means for the reader

We have explained what block and replacement regime is in the discussion section.

5) For the profound tumor reduction, please list what was the criteria for this statement. ie percentage reduction, size reduction etc.

We had added information on the size of the largest metastasis at the time when sepercatinib was started, and that no metastasis could be seen at the last follow-up.