The Role of Sentinel Node Mapping and Lymphadenectomies in Veterinary Surgical Oncology

Round 1

Reviewer 1 Report

I’ve read this Articles with great interest. 
Topic of this review is on time and we note a numbers of research on image guided surgery which includes sentinel node technique.

Article needs major revisions to consider further evaluation.

Remarks:

Structure

 - introduction  - should be more consistent

 - lack of chapter covering future perspectives and novel development in this field

Authors should add:

 - table with available SLN techniques instead of listing them all one by one in the text (lines 92-104)

 - table summarizing results of SLN technique in dogs in different tumors

Same statements should be avoided as SLN technique in most of tumours in humans isn’t standard technique. Therefore it’s hard to say that some form of imaging is gold standard.

Authors not included informations about usage of SPECT-CT in animals and also different tracers like  magnetics or iron-oxide ultra-small particles (USPIO). 

Whole text needs thorough English correction. 

Author Response

Reviewer 1.

Dear reviewer,

Thank you for your remarks, the article has been send to professional language editing, and we hope it now fulfills your expectations.

Remarks:

Structure

 - introduction  - should be more consistent

Introduction has been amended based on the comments of reviewer 2 and 3.

 - lack of chapter covering future perspectives and novel development in this field

Dear reviewer,

Thank you for this suggestion. A very short passage has been added at the end.

Authors should add:

 - table with available SLN techniques instead of listing them all one by one in the text (lines 92-104)

 - table summarizing results of SLN technique in dogs in different tumors

Thank you for the request. We decided to include a table with the results of different SLN mapping techniques in tumor bearing dogs at the end of the passage on SLN techniques as requested, the first table however we consider redundant. I hope this finds your approval.

Same statements should be avoided as SLN technique in most of tumors in humans isn’t standard technique. Therefore, it’s hard to say that some form of imaging is gold standard.

Thank you for this remark, however based on several metareviews (including 10.1245/s10434-020-09288-7 , 10.1097/SLA.0000000000005633 ) as well as veterinary studies (10.1111/vru.12995 ), lymphoscintigraphy is currently frequently referred to as gold standard. Based on the reviewer comments of reviewer 2 and 3, we would prefer to keep this statement. We added a sentence, that future validations might require adaption of this statement.

Line 158

Authors not included informations about usage of SPECT-CT in animals and also different tracers like magnetics or iron-oxide ultra-small particles (USPIO). 

Both of these techniques are not widely available and so far, only published in a very limited number of dogs. I was only able to detect a single pilot for USPIO in dogs, and no paper on SPECT lymphography. While they might be interesting in the future, they are clearly the least available and investigated techniques so far, so I would rather not include them at this point. I however included a very short section -future perspective- that now includes a remark mentioning them as potential techniques to maybe detect metastatic nodes rather than sentinels.  

Whole text needs thorough English correction. 

As mentioned, the text has been send for language correction to a professional service.

I’ve read this Articles with great interest. 
Topic of this review is on time and we note a numbers of research on image guided surgery which includes sentinel node technique.

Article needs major revisions to consider further evaluation.

Dear reviewer,

Thank you for your remarks, the article has been send to professional language editing, and we hope it now fulfills your expectations.

Remarks:

Structure

 - introduction  - should be more consistent

Introduction has been amended based on the comments of reviewer 2 and 3.

 - lack of chapter covering future perspectives and novel development in this field

Dear reviewer,

Thank you for this suggestion. A very short passage has been added at the end.

Authors should add:

 - table with available SLN techniques instead of listing them all one by one in the text (lines 92-104)

 - table summarizing results of SLN technique in dogs in different tumors

Thank you for the request. We decided to include a table with the results of different SLN mapping techniques in tumor bearing dogs at the end of the passage on SLN techniques as requested, the first table however we consider redundant. I hope this finds your approval.

Same statements should be avoided as SLN technique in most of tumors in humans isn’t standard technique. Therefore, it’s hard to say that some form of imaging is gold standard.

Thank you for this remark, however based on several metareviews (including 10.1245/s10434-020-09288-7 , 10.1097/SLA.0000000000005633 ) as well as veterinary studies (10.1111/vru.12995 ), lymphoscintigraphy is currently frequently referred to as gold standard. Based on the reviewer comments of reviewer 2 and 3, we would prefer to keep this statement. We added a sentence, that future validations might require adaption of this statement.

 

Reviewer 2 Report

lymphatics-2096763

The role of lymphadenectomies and sentinel node mapping in veterinary surgical oncology

 

Comments to the Author

Thank you for submitting this interesting review. This review is overall well-written, interesting with valuable practical applications. I Have suggested a few comments for you

 

Title: “the role of lymphadenectomies and sentinel lymph node mapping in veterinary medicine”. I rather start with SLN mapping techniques and then the role/impact of lymphadenectomy ….

 

line 25-26: “Lymph node (LN) status is an important prognostic factor for staging of various cancers in human and veterinary medicine, and resection of metastatic nodes can improve outcome in selected cancer types. Please add references (Mendetz VCO 2020, Chalfon JSAP 2022, Marconato VCO 2018; Marconato VCO 2020)

line 28: “regional LNs” you can use the abbreviation RLN

line 36-37: please add references

line 73-74: “Although Suami’s research yielded important results, some findings are in disagreement with the findings of recent SLN studies in dogs “. Please specify that in Suami’s study healthy dogs were included. 

Line 82-83: “the SLN is defined as…” rather than “A so-called SLN”

 

Line 110: “provides” rather than “gives”

 

Line 140 please add that cats had various solid tumors (Chiti 2022)

 

Line 2014: “clinicians” rather than “users”

Line 233: “given the relatively low sensitivity of blue dye compared to other techniques “. This sentence should be referenced  

Line 242-243: “As resection and identification of an individual lymph node can be challenging, especially in nodes that are not enlarged, all methods for presurgical mapping are of limited value in identifying the node of question during surgery”.

Line 356-357: “did you mean if routine SLN mapping and removal of METASTATIC SLN impacts outcome?

Line 393-394: “Solid MCT are among the most frequent skin tumors encountered in dogs, and also in cats”. Mast cell tumors are not the most common skin tumor in cats (basal cell tumor are the most common skin tumors in cats), please rephrase accordantly (for example: “MCT are the most common skin/cutaneous tumors in dogs, and represent the second most common cutaneous tumor in cats”)

Section 4.3 mast cell tumors: please report the results from Ferrari’s study (REF 20; Ferrari el al Vet Surg 2020) (SLN differs from the RLN in 63% of cases and SLN metastasis was detected in 56% SLN excised)

 

Author Response

Reviewer 2.

Thank you for submitting this interesting review. This review is overall well-written, interesting with valuable practical applications. I Have suggested a few comments for you

Dear reviewer, thank you for the valuable review. Your suggestions have been addressed as follows:

Title: “the role of lymphadenectomies and sentinel lymph node mapping in veterinary medicine”. I rather start with SLN mapping techniques and then the role/impact of lymphadenectomy ….

Has been adapted as requested.

line 25-26: “Lymph node (LN) status is an important prognostic factor for staging of various cancers in human and veterinary medicine, and resection of metastatic nodes can improve outcome in selected cancer types. Please add references (Mendetz VCO 2020, Chalfon JSAP 2022, Marconato VCO 2018; Marconato VCO 2020)

added.

line 28: “regional LNs” you can use the abbreviation RLN

added.

line 36-37: please add references

As these are discussed in detail in the respective passages, I prefer to refer to the review at this point and give the more detailed references in the passages for each condition as presently done. As the other reviewer did not make this specific request here, I would ask you to consider if this is acceptable for you ( instead of listing >20 references here).

line 73-74: “Although Suami’s research yielded important results, some findings, are in disagreement with the findings of recent SLN studies in dogs “. Please specify that in Suami’s study healthy dogs were included. 

Included this information.

Line 82-83: “the SLN is defined as…” rather than “A so-called SLN”

Changed.

Line 110: “provides” rather than “gives”

Changed.

Line 140 please add that cats had various solid tumors (Chiti 2022)

Added.

Line 2014: “clinicians” rather than “users”

Changed.

Line 233: “given the relatively low sensitivity of blue dye compared to other techniques “. This sentence should be referenced 

References added.

Line 242-243: “As resection and identification of an individual lymph node can be challenging, especially in nodes that are not enlarged, all methods for presurgical mapping are of limited value in identifying the node of question during surgery”.

I am not sure which change you request here.

Line 356-357: “did you mean if routine SLN mapping and removal of METASTATIC SLN impacts outcome?

Changed into removal of SLN, unfortunately most SLN mapping techniques cannot clearly identify metastatic nodes. So there is no option to be sure about the nodal status in surgery.

Line 393-394: “Solid MCT are among the most frequent skin tumors encountered in dogs, and also in cats”. Mast cell tumors are not the most common skin tumor in cats (basal cell tumor are the most common skin tumors in cats), please rephrase accordantly (for example: “MCT are the most common skin/cutaneous tumors in dogs, and represent the second most common cutaneous tumor in cats”)

Dear reviewer, different incidence studies give different incidences here. This is why we phrased it accordingly (among the most frequent skin tumors) instead of giving a concrete position in the rank list. We are happy to rephrase, but given the different rankings that exist, would like to avoid giving a concrete position in a list but rather keep it more general.

Section 4.3 mast cell tumors: please report the results from Ferrari’s study (REF 20; Ferrari el al Vet Surg 2020) (SLN differs from the RLN in 63% of cases and SLN metastasis was detected in 56% SLN excised)

Included  in the section describing the detection of SLN compared to RLN and the new table.

Reviewer 3 Report

In this manuscript, Beer et al. summarize the present findings regarding lymphadenectomies and SLN mapping, and concluded that NIR lymphography seems to have the highest SLN detection rate compared to the gold standard, lymphoscintigraphy.

 

This review manuscript is written clearly, comprehensive, and of relevance to veterinary surgical oncology. However, several points need attention:

 

 

1.     The first author published the review article regarding SLN mapping in small animal (reference 2). I wonder what is the difference of review aim and findings between the previous article and the present article. The authors didn’t mention that in this article.

 

2.     Some abbreviations are not explained completely, and they should be mentioned (AGASAC in line 36, Near infrared lymphography in line 277). It would be easier for readers to understand if an abbreviations list is made. 

 

3.     I think “node” is “Lymph node (LN)”. You should use “LN”. Please check all sentences.

For examples:

-       lymph node in line 40 should be changed to LN

-       tier-1 and tier-2 node in line 85 should be changed to tier-1 and tier-2 LN

- “sentinel node” of the title should be changed to “sentinel lymph node”

 

4.     In several sentences, there is a comma before "that". In my opinion, it’s difficult to read and it would be easier to read if the comma were removed.

For example:

-       “although studies have repeatedly shown, that size of the lymph node is no predictor of nodal involvement.” in line 41 should be changed to “although studies have repeatedly shown that size of the lymph node is no predictor of nodal involvement.”

 

5.     In conclusions in line 493, the authors mentioned that NIR lymphography seems to have the highest SLN detection rate compared to the gold standard, lymphoscintigraphy. However, in line 410, lymphoscintigraphy combined with intra surgical methylene blue injection were able to detect a SLN in 95% of cases. In line 476, the combined use of indirect CT lymphography and vital dyes for SLN biopsy in dogs with oral tumors and reported a detection rate of 100% with the combined technique. I think the combination of preoperative and intraoperative SLN mappings is the best to detect SLN. How do you think this point? Is there any difficulty to do both mapping in clinical setting?

 

 

6.     I found that reference 10 and reference 45 is the same article. Pease carefully check all references again.

Author Response

Reviewer 3.

1. The first author published the review article regarding SLN mapping in small animal (reference 2). I wonder what is the difference of review aim and findings between the previous article and the present article. The authors didn’t mention that in this article.

This article has been referenced- this was an invited review and includes more recent works that were published after 2018 the last review, a section on comparative aspect of the canine and human lymphatics, as well as sections on the proposed impact of lymphadenectomy in selected conditions in dogs and cats.

I am unsure were exactly this information should be included, however if the reviewer insists, and indicated where we should give this information, we are happy to add it.

 

2. Some abbreviations are not explained completely, and they should be mentioned (AGASAC in line 36, Near infrared lymphography in line 277). It would be easier for readers to understand if an abbreviations list is made. 

Thank you for this valuable comment, an abbreviations list has been included.

 

3. I think “node” is “Lymph node (LN)”. You should use “LN”. Please check all sentences.

Changed.

For examples:

-       lymph node in line 40 should be changed to LN

-       tier-1 and tier-2 node in line 85 should be changed to tier-1 and tier-2 LN

- “sentinel node” of the title should be changed to “sentinel lymph node”

 

4. In several sentences, there is a comma before "that". In my opinion, it’s difficult to read and it would be easier to read if the comma were removed.

For example:

-       “although studies have repeatedly shown, that size of the lymph node is no predictor of nodal involvement.” in line 41 should be changed to “although studies have repeatedly shown that size of the lymph node is no predictor of nodal involvement.”

The entire manuscript will be revised by a native speaker. 

4. In conclusions in line 493, the authors mentioned that NIR lymphography seems to have the highest SLN detection rate compared to the gold standard, lymphoscintigraphy. However, in line 410, lymphoscintigraphy combined with intra surgical methylene blue injection were able to detect a SLN in 95% of cases. In line 476, the combined use of indirect CT lymphography and vital dyes for SLN biopsy in dogs with oral tumors and reported a detection rate of 100% with the combined technique. I think the combination of preoperative and intraoperative SLN mappings is the best to detect SLN. How do you think this point? Is there any difficulty to do both mapping in clinical setting?

NIR lymphography is the technique with the highest detection rate as a single technique. As it also greatly facilitates LN removal and reduces the rate of unsuccessful resections, we really believe it could become a broad based method ( we currently do a prospective controlled study comparing it to scintigraphy that includes timing of lymphadenectomy, and NIRF also makes lymphadenectomies much faster. I just cannot include this as we are not yet done.

In general, considering that scintigraphy is rarely available, and CT adds another procedure requiring an additional anesthesia (or prolonging anesthesia) and additional radiation, of cause combinations could be used. But using one technique that does not need any additional radiation burden for patient and personal, and that can help you in surgery is quite attractive.

I think combination techniques are probably going to be needed in locations, were internal nodes need to be evaluated, and a routine approach to the cavity is not generally planned (such as MCT of the perineum), as here these techniques could spare the patient the additional access that would be needed to use ICG.

Added the remark regarding sensitivity as stand-alone technique in the text.

5. I found that reference 10 and reference 45 is the same article. Pease carefully check all references again.

Thanks for this remark, we checked and amended the references accordingly.

 

 

Round 2

Reviewer 1 Report

No further comments. 

Introduced changes improved quality of this review. 

Congratulations.