Review Reports - Recurrent Hodgkin’s Lymphoma Detected Using Abnormal NIPT in Pregnancy: A Case Report and Literature Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

I have read a case report about recurrent Hodgkin's Lymphoma (HL) in pregnancy with the help of NIPT. While interesting, there are several points that need addressing:

Major Point

This manuscript is supposedly a case report. Of all the 15 pages, the case report with the discussion starts at the 10th page, with the 14th-15th page being the ethical statement and references. The first 10 pages can be omitted or summarized for use in the discussion section. If the authors still think that the first 10 pages are necessary, please re-purpose this draft as a literature review.

Minor Point

1) Figure 1 does not add anything to the manuscript. Instead, an ultrasound image of the baby, confirming the normal fetal anatomy, would be more important at this point.

2) Figure 2 is a table. Please do not screenshot the table and present the table as such (The neatness of the table cannot be used as an argument, as it is only a 3x8 table)

3) If the initial NIPT was a "no-call", why was she offered amniocentesis anyway?

4) In Line 434, when was the second NIPT performed?

5) The authors mention on line 463 that the premature delivery is due to unstable FHR. However, on line 460, this delivery was scheduled beforehand. What was the reasoning?

Author Response

Major Point

Comment: Thank you for this comment. The manuscript was significantly expanded to include all the information presented at the request of the editorial staff after initial submission of this paper. As a result, we have changed this to be a review of the literature and a case report and have updated the title to reflect this.

Minor Point

1) Figure 1 does not add anything to the manuscript. Instead, an ultrasound image of the baby, confirming the normal fetal anatomy, would be more important at this point.

Comment 1: We appreciate this point. We have added an ultrasound image of the baby in the first trimester, which shows the normal fetal anatomy as Figure 2 (Line 465).

2) Figure 2 is a table. Please do not screenshot the table and present the table as such (The neatness of the table cannot be used as an argument, as it is only a 3x8 table)

Comment 2: Thank you! Regarding Figure 2, we are happy to make this change, and we have changed it to “Table 2” and removed the screenshot of the table. The figures have been cited in the text.

3) If the initial NIPT was a "no-call", why was she offered amniocentesis anyway?

Comment 3: Since a no call for technical reasons is associated with an increased residual risk of aneuploidy, it is appropriate to offer diagnostic testing and then, if she declines to proceed with additional screening methodologies.

4) In Line 434, when was the second NIPT performed?

Comment 4: The timing of both NIPT studies have been added into the manuscript (lines 460 and lines 467).

5) The authors mention on line 463 that the premature delivery is due to unstable FHR. However, on line 460, this delivery was scheduled beforehand. What was the reasoning?

Comment 5: The patient was originally scheduled for a vaginal delivery. She was admitted to the hospital after a 6/10 biophysical profile and received antenatal steroids. Once she was fully steroid mature, she was induced for a vaginal delivery. However, she had to be delivered by an unscheduled cesarean section for non-reassuring fetal heart tones only a couple of hours later. We have made this clearer in the manuscript (lines 502 to 505).

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to Diagnostics-4138209 (V1)

Entitled “Recurrent Hodgkin’s Lymphoma Detected by Abnormal NIPT in Pregnancy: A Case Report”

General Comments:

This is a rare article in the published literature.
Many need to be revised.
The English needs a complete revision to enhance the paper's value.

Specific Comments:

In the Abstract:

The abstract is too extended and should be concise; ideally, it should be no more than 150 words.

In the Keywords:

Hodgkin's lymphoma, ICE chemotherapy, and BEAM or BEAM conditioning, and autologous stem cell transplantation need to be added.
ICE chemotherapy and BEAM. All abbreviations must be written in full when you first describe the name.

In the Introduction:

The introduction does not need to be so lengthy; it is not asking you to write a review article. It is meant to provide the reader with the background information about this case report. Are there any relevant findings in the literature?
If you wish to change your topic to “A case report and the literature review”, you should list a table to discuss the published papers.
Most of the introductions are already known by the Obstetrics and Gynecologists. You need to make significant revisions to the introduction.

In the Case Presentation:

Please illustrate all the prenatal ultrasounds and findings of other examinations.
Please add a study workflow for this case (including Maternal and fetus)
Why did this mother receive two NIPT tests in different laboratories? What is the indication? What is the time period for these two NIPT tests?
Are there any delays in the lung biopsy to the diagnosis of recurrent Hodgkin’s lymphoma?
You should show the serial chest x-ray from the beginning to the discharge. What X-ray changes occur during different chemotherapies?

In the discussion and conclusions:

What kinds of abnormal NIPT results are associated with maternal malignancy? What are the reasons? If you can not know the correct answer, what is the possible mechanism?
Basically, the NIPT test is not a good screening method to check congenital anomalies; if any structural anomaly is detected from prenatal ultrasound, or different results from different NIPT, receiving a complete amniocentesis and checking the whole chromosomes is better than having a standardized protocol for reporting such NIPT results. How do you think?

Comments on the Quality of English Language

The English could be improved after revision.

Author Response

In the Keywords:

Hodgkin's lymphoma, ICE chemotherapy, and BEAM or BEAM conditioning, and autologous stem cell transplantation need to be added.
ICE chemotherapy and BEAM. All abbreviations must be written in full when you first describe the name.

Keywords comment: Thank you! The keywords suggested have been added to the manuscript. BEAM (line 509) and ICE (line 493) have also been expanded and added to the abbreviation list (line 562).

In the Introduction:

The introduction does not need to be so lengthy; it is not asking you to write a review article. It is meant to provide the reader with the background information about this case report. Are there any relevant findings in the literature?
If you wish to change your topic to “A case report and the literature review”, you should list a table to discuss the published papers.
Most of the introductions are already known by the Obstetrics and Gynecologists. You need to make significant revisions to the introduction.

Introduction comment: We appreciate your comment. After our initial manuscript submission as a case report, the editorial office requested that we significantly expand the introduction, so the manuscript was resubmitted as a case report and review of the literature. The title has been changed to reflect this.

In the Case Presentation:

Please illustrate all the prenatal ultrasounds and findings of other examinations.
Please add a study workflow for this case (including Maternal and fetus)
Why did this mother receive two NIPT tests in different laboratories? What is the indication? What is the time period for these two NIPT tests?
Are there any delays in the lung biopsy to the diagnosis of recurrent Hodgkin’s lymphoma?
You should show the serial chest x-ray from the beginning to the discharge. What X-ray changes occur during different chemotherapies?

Case Presentation Comment: We appreciate your thoughtful comments. More specific gestational ages and ultrasound findings of the patient have been added into the case report (lines 460, 467, 470, 487, 496, 501). The NIPT was repeated in a different laboratory which utilized a different methodology in the hopes that this would increase the chances of informative results. The NIPT time frame has been added to the case report in lines 460 and 467. The patient was referred to her oncologist because of the cell free DNA results and they declined to perform the imaging. Subsequently, when the patient became symptomatic with pulmonary symptoms, she was admitted and directly consulted pulmonary medicine for imaging and biopsy confirmation. (lines 477 to 487, line 492).

In the discussion and conclusions:

What kinds of abnormal NIPT results are associated with maternal malignancy? What are the reasons? If you can not know the correct answer, what is the possible mechanism?
Basically, the NIPT test is not a good screening method to check congenital anomalies; if any structural anomaly is detected from prenatal ultrasound, or different results from different NIPT, receiving a complete amniocentesis and checking the whole chromosomes is better than having a standardized protocol for reporting such NIPT results. How do you think?

Discussion comments: Thank you for your comments! Beginning at line 404, these sentences address the abnormal NIPT results that are the most predictive of malignancy under the subsection “Cancer Detection”. We do not endorse NIPT in the presence of a congenital anomaly (Lines 352-358), however, having a standardized protocol for reporting unexpected results is still appropriate.

Reviewer 3 Report

Comments and Suggestions for Authors The quality of the material is good, with only a few omissions during the editing process. For example, the figure 2 is in fact a table. Figure 3.
All figures are not cited in text.
However, in my opinion, the big problem is a high discrepancy between the case presentation and the size of introduction. Thus, in introduction is made a review concerning the factors that change quality of NIPT procedure.
On the other hand, case presentation is made in a laconic manner.
I suggest to split the information of this paper in two: the material from introduction will be used for a paper, type "review", while the rest will remain as case presentation with an upgrade of content.

Author Response

For example, the figure 2 is in fact a table. Figure 3. All figures are not cited in text.

Comment: Thank you for these corrections. Figure 2 has been changed to Table 2, and the figures have been cited in the text.

However, in my opinion, the big problem is a high discrepancy between the case presentation and the size of introduction. Thus, in introduction is made a review concerning the factors that change quality of NIPT procedure.
On the other hand, case presentation is made in a laconic manner.
I suggest to split the information of this paper in two: the material from introduction will be used for a paper, type "review", while the rest will remain as case presentation with an upgrade of content.

Comment: After initial manuscript submission as a case report, the editorial office requested that we significantly expand the introduction, so the manuscript was resubmitted as a case report and review of the literature. The title has been changed to reflect this.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors:

1) Even if this is a literature review, the introduction should explain only briefly about the purpose of this manuscript, as well as the gap presented. Tie the case closely with the literature review, and not the other way around. Please rearrange the whole manuscript.

2) Why was the previous Figure 2 deleted? I only asked it to be changed into a table, not replaced

3) "Since a no call for technical reasons is associated with an increased residual risk of aneuploidy, it is appropriate to offer diagnostic testing and then, if she declines to proceed with additional screening methodologies." This explanation is not reflected in the manuscript

4) Please annotate your chest x-ray properly, indicating where the lesion is. Also, the figure 3's caption can be done better in order to explain the pathologies found, and not just a generic "Patient’s chest x-ray around time of diagnosis"

Author Response

Dear Reviewer:

Thank you for your comments! Below are our responses.

Comment 1: Thank you so much for this comment! We have gone through and rearranged our manuscript to better reflect this.

2) Why was the previous Figure 2 deleted? I only asked it to be changed into a table, not replaced.

Comment 2: Thank you! Figure 2 was not deleted from the previous version. Figures were just rearranged so the figure names were changed accordingly. The table is located after line 307 after the sub-paragraph labeled “Non-reportable Results”.

Comment 3: We agree that diagnostic testing should be offered as indicated on lines 93-97 and 100-106.

Comment 4: Thank you for this comment. We have made edits to reflect this in line 124.

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to Diagnostics-4138209 (V2)

Entitled “Recurrent Hodgkin’s Lymphoma Detected by Abnormal NIPT in Pregnancy: A Case Report”