Ultrastaging and Low-Volume Metastatic Disease in Early-Stage Cervical Cancer: State of the Art

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I read the manuscript with great interest, which falls within the aim of this journal and offers a high-quality overview of the ultrastaging technique currently in use for the assessment of nodal disease, however, the topic is not novel and many manuscripts have analyzed the subject more extensively.

Although the manuscript can be considered already of high quality, I would suggest taking into account the following minor recommendations:

- I suggest another language revision round to correct typos and improve readability.

- The abstract is extremely concise.

- The introduction could be studied in depth. Authors could take inspiration from PMID: 35598492 and PMID: 38514100

- Conclusions could be improved.

Comments on the Quality of English Language

Minor English language editing is required to make the work clearer and more readable.

Author Response

I read what the reviwer suggested.

1. The article was written in medical american english.
2. I' ll review the abstract.

Many of the conclusions are included in the text. 

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled “Ultrastaging and low volume metastatic disease in early stage cervical cancer” by Alejandro Soderini et al. as a commentary paper was submitted to Lymphatics for possible considerations. Some major issues should be carefully addressed as follows,

1) the title was seemly well-focused on “early stage cervical cancer” therefore I thought the manuscript mainly described the ultrastaging and low-volume diagnostics on cervical cancer in women. This manuscript probably worked on local area, but no geographical localization or country area was not mentioned in the title. Otherwise, it probably was improperly used and may mislead people to think and use for worldwide areas.

2) There was no single Figure or a graph in the manuscript. Was it to be perfect or corrected?

3) I am kind of confused about what’s exactly the state of the art referring to?

4) “However, ultrasataging was not used to process the surgical specimen. Therefore, the recurrence… is it really recurrence or persistent disease?”. The sentences should be revised.

5)  As for the paragraphs under “3. Something to think about:”, the main texts in this section should be re-written and is expected to show its logicality.

Comments on the Quality of English Language

The manuscript entitled “Ultrastaging and low volume metastatic disease in early stage cervical cancer” by Alejandro Soderini et al. as a commentary paper was submitted to Lymphatics for possible considerations. Some major issues should be carefully addressed as follows, 

1) the title was seemly well-focused on “early stage cervical cancer” therefore I thought the manuscript mainly described the ultrastaging and low-volume diagnostics on cervical cancer in women. This manuscript probably worked on local area, but no geographical localization or country area was not mentioned in the title. Otherwise, it probably was improperly used and may mislead people to think and use for worldwide areas.

2) There was no single Figure or a graph in the manuscript. Was it to be perfect or corrected?

3) I am kind of confused about what’s exactly the state of the art referring to?

4) “However, ultrasataging was not used to process the surgical specimen. Therefore, the recurrence… is it really recurrence or persistent disease?”. The sentences should be revised.

5)  As for the paragraphs under “3. Something to think about:”, the main texts in this section should be re-written and is expected to show its logicality.

Author Response

1. The title is clear and it is about eraly stage cervical cancer.

2.We decided not to include any figure.

3. State of the art, is clear what it means.

s4. Persistant or recurrent disease is the question to answer by the gynoncologist comunity.

5. The last observation is also related to the 4th answer.

Reviewer 3 Report

Comments and Suggestions for Authors

The article's theory says that sentinel lymph node ultrastaging is very important for finding small metastases, such as isolated tumor cells (ITCs) and micrometastases, in early-stage cervical cancer. This theory is significant and sound because it closes a clinical gap in the ability to differentiate between overt disease and low-volume metastases, which is essential for individualized patient care. The idea shows a good understanding of the possible benefits of early and accurate diagnosis of cervical cancer metastases. It also fits with recent progress in minimally invasive diagnostics by suggesting ways to improve the accuracy of ultrastaging for diagnosis.

The methodology proposed in the article is suitable for testing the hypothesis as it includes methods commonly used in oncology, such as serial sections for histologic analysis and cervical injections of various markers (e.g., blue dye, technetium-99, or indocyanine green). Given their sensitivity in identifying micrometastases, the use of molecular indicators and immunohistochemistry (IHC) is also suitable. The availability of resources in healthcare institutions with limited funds, however, may limit the viability of applying this technology on a larger scale because ultrastaging requires specialized equipment and qualified pathologists. The authors might consider explaining these limitations in more detail. The article provides a thorough review of SLN mapping and ultrastaging methods, including markers used, sectioning strategies, and staining protocols. However, reproducibility could be improved with more specific information about particular protocols for each approach. For example, a more thorough explanation of the IHC staining procedure, including antibody concentrations and incubation time, could facilitate replication of the procedure by other researchers. However, the work provides a solid foundation for replication of the study by other scientists or physicians with sufficient funding. The article does discuss the use of controls as a kind of quality check, e.g., checking lymph nodes for micrometastases in both suspicious and macroscopically healthy nodes. Nevertheless, the rigor of the study would be strengthened by a clearer explanation of outcome-neutral tests and positive controls. For example, to understand the added value of the proposed methods, statistics on the false negative rates of ultrastaging compared to conventional SLN mapping methods could be included. In summary, this article presents a valuable hypothesis regarding the role of SLN ultrastaging in improving diagnostic accuracy in early-stage cervical cancer. The methodological approach is largely sound, although the article would benefit from a more detailed description of the procedure to facilitate replication. In addition, the rigor of the study could be further improved by clarifying the outcome-neutral tests, controls, and quality checks. Overall, the proposed research holds promise for refining cervical cancer diagnostics, reducing unnecessary radical treatments, and customizing patient care.

Author Response

Agree with the comments. It is included in the text the low % of sensivity  using H&E and frozen sections.

Reviewer 4 Report

Comments and Suggestions for Authors

The initiative of the authors to carry out this development of the sentinel lymph node technique and the ultrastaging technique in cervical cancer and their benefits is commendable.

Author Response

Agree.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I am fine with the responses. Good to have revision or improvement. No more comments.