Preservation of Pancreatic Function Should Not Be Disregarded When Performing Pancreatectomies for Pancreatoblastoma in Children

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dr. Dumitrascu presents a narrative review of the surgical treatment strategy of pancreatic neoplasms in children.

The review is up to date and sheds light on a relevant issue that is also in the current focus of adult surgeons.

The title focuses on the long-term effects, but the text does not in a similar extent. I may recommend some changes:

1. Please clearly differentiate between malignant and benign tumor entities and those in between. It might be preferrable to structure the review by the disease entity and not the surgical procedure.

2. Please omit table 1. There is plenty of literature for this information.

3. With regard to the text, I feel it would be beneficial to not only report the results of preceding series from the literature, but put them in context to each other: In how far were the included childeren different with regard to the etiology and the surgical approach and the complications.

4. The statement in lines 113-116 contradicts the one in lines 123-125. Please be consistent in your line of argument.

5. With regard to the title - which I feel could be shortened - the author should provide more information on the complication rates of the different procedures, i.e. in form of some tables, and address their long-term effects. We do know from adult data that even after tumor enucleation, the high-volume fistulas pose a relevant issue in up to a half of patients.

6. Given its favourable results, the study by Qin et al. on duodenum-preserving pancreas head resection (DOI: 10.1016/j.hpb.2019.06.009) has not been included in the review.

7. Another issue with regard to more extensive resections is the onset of diabetes in previously normoglycemic patients and exocrine dysfunctions, which are a relevant issue in adults as demonstrated by a systematic review. I also feel that this requires some consideration in the present review to a larger extent than it is currently the case.

8. The use of uncommon abbreviations is irritating: There are standard appreviations used in the field, please stick to them.

Comments for author File: Comments.pdf

Author Response

Reviewer 1

Comment 1. "Dr. Dumitrascu presents a narrative review of the surgical treatment strategy of pancreatic neoplasms in children. The review is up to date and sheds light on a relevant issue that is also in the current focus of adult surgeons".

Response to reviewer comment 1: Thank you for your comment, suggestions, and kind appreciation of the present manuscript. However, the topic of the present narrative review is specifically focused on the potential role of organ-sparing surgery in PB. It is beyond the present manuscript's scope to deal with all pancreatic neoplasms in children. The idea of the present manuscript emerged from the excellent oncological and functional results of a patient reported by our group 15 years ago: a child with central pancreatectomy for PB. At that time, the decision to perform a non-standard pancreatic resection, such as a central pancreatectomy for a pancreatoblastoma, even if negative resection margins were obtained, was challenging to make from both early complications and long-term oncological outcomes. After that, a few other cases were reported in the literature, including central pancreatectomies for PB and other organ-sparing pancreatectomies such as spleen-preserving distal pancreatectomies. Although the current literature on such a topic is minimal,  our group considered it worth summarizing in a review the current status of the role of organ-sparing surgery in children resected for PB.

Comment 2. "The title focuses on the long-term effects, but the text does not in a similar extent. I may recommend some changes; please clearly differentiate between malignant and benign tumor entities and those in between. It might be preferrable to structure the review by the disease entity and not the surgical procedure."

Response to reviewer comment 2: Thank you for your comment and suggestions. As mentioned above, the present review intended to consider only the resected children for PB; however, data about early and long-term outcomes of patients resected only for PB is minimal. That is why the analyses of early and late outcomes of pancreatic resections in children also included studies reporting data from other pancreatic tumoral pathologies. As mentioned in the manuscript, the most significant part of data reporting complications and long-term functional outcomes in children's standard and organ-sparing pancreatectomies are from pathologies other than PB. We considered including comparative data about standard and organ-sparing pancreatectomies in children, and for a few comparative analyses, even data from adult studies were considered. Nevertheless, studies reporting long-term functional outcomes for different types of pancreatectomies in children are scarce, as mentioned in the manuscript.

Comment 3. “Please omit table 1. There is plenty of literature for this information.”

Response to reviewer comment 3: Thank you for your comment and suggestions. However, the other two reviewers not only considered Table 1 as necessary, but one reviewer recommended its expansion. We do consider that not many papers report outcomes of central pancreatectomies in children. Thus, we consider keeping Table 1 to add value to our manuscript.  

Comment 4. “With regard to the text, I feel it would be beneficial to not only report the results of preceding series from the literature, but put them in context to each other: In how far were the included childeren different with regard to the etiology and the surgical approach and the complications.”

Response to reviewer comment 4: Thank you for your comment and suggestions. Please also consider the responses to comments 1 and 2. Our intention was not to compare different etiologies of tumors in children but to provide a few comparative data about early and long-term complications of standard and organ-sparing pancreatectomies in children.

Comment 5. “The statement in lines 113-116 contradicts the one in lines 123-125. Please be consistent in your line of argument.”

Response to reviewer comment 5: Thank you for your comment and suggestions. We have corrected it to be consistent with our argument.

Comment 6. “With regard to the title - which I feel could be shortened - the author should provide more information on the complication rates of the different procedures, i.e. in form of some tables, and address their long-term effects. We do know from adult data that even after tumor enucleation, the high-volume fistulas pose a relevant issue in up to a half of patients.”

Response to reviewer comment 6: Thank you for your comment and suggestions. The title of the manuscript has been shortened but without jeopardizing the central message of the present review. A Table reflecting early and long-term outcomes of different types of pancreatectomies was added. However, it was very difficult to extract data for the table because the majority of the studies did not differentiate complications or long-term outcomes for different types of pancreatectomies (presenting all together usually).

Comment 7. “Given its favourable results, the study by Qin et al. on duodenum-preserving pancreas head resection (DOI: 10.1016/j.hpb.2019.06.009) has not been included in the review.”

Response to reviewer comment 7: Thank you for your comment and suggestions. As mentioned above, the paper focused on PB. To our knowledge, no children have been reported to have had duodenum-preserving pancreatic head resection for PB. However, the reviewer's suggestion is pertinent to discuss in the present review about the role of such a procedure in children. Thus, a few paragraphs addressing the role of duodenum-preserving pancreatic head resection in children were added to the manuscript.

Comment 8. “Another issue with regard to more extensive resections is the onset of diabetes in previously normoglycemic patients and exocrine dysfunctions, which are a relevant issue in adults as demonstrated by a systematic review. I also feel that this requires some consideration in the present review to a larger extent than it is currently the case.”

Response to reviewer comment 8: Thank you for your comment and suggestions. We have expanded the paragraph addressing this topic.

Comment 9. “The use of uncommon abbreviations is irritating: There are standard abbreviations used in the field, please stick to them.”

Response to reviewer comment 9: Thank you for your comment and suggestions. Sorry for creating any inconvenience with irritating, uncommon abbreviations. Thus, a few abbreviations were eliminated from the text. However, a few other widely used abbreviations in the literature papers, such as SPT/ SPN  for solid pseudopapillary tumors/ neoplasms, PB for pancreatoblastoma, and POPF for postoperative pancreatic fistula, were kept in place.

 

Reviewer 2 Report

Comments and Suggestions for Authors

This is an interesting review. I have several comments. 

 

1. In the abstract: 

"Postoperative pancreatic functional deficiencies are fascinating to children because they may interfere with their development, considering their long life expectancy and the significant role of pancreatic functions on their nutritional status and growth."

I can understand what the authors are trying to say, but the way they have said it implies that pancreatic deficiencies are a topic of interest to the children themselves. Please rephrase. 

 

2. The authors describe only briefly that anatomy, and an ability to achieve negative margins are factors that influence standard resection vs organ sparing resection. 

So, would you advocate organ sparing pancreatectomies is all cases with favorable anatomy? Or are there other factors described in the studies you cited? Perhaps this is the most important point of this entire review. Please elaborate in detail. 

 

3. The authors offer 1 table that summarized the cited studies.

I think that a comparison of reported long-term endocrine function and exocrine function (separately) is necessary as a table. Also, long-term overall and disease free survival should be shown. 

Perhaps expand the original table, or consider adding separate tables. 

 

 

Comments on the Quality of English Language

No comments

Author Response

Reviewer 2

Comment 1. “This is an interesting review. I have several comments.” 

Response to reviewer comment 1: Thank you for your kind appreciation of the present manuscript.

Comment 2. “In the abstract: "Postoperative pancreatic functional deficiencies are fascinating to children because they may interfere with their development, considering their long life expectancy and the significant role of pancreatic functions on their nutritional status and growth." I can understand what the authors are trying to say, but the way they have said it implies that pancreatic deficiencies are a topic of interest to the children themselves. Please rephrase.”

Response to reviewer comment 2: Thank you for your comment and suggestions. We have rephrased it to express the idea better.

Comment 3. “The authors describe only briefly that anatomy, and an ability to achieve negative margins are factors that influence standard resection vs organ sparing resection. So, would you advocate organ sparing pancreatectomies is all cases with favorable anatomy? Or are there other factors described in the studies you cited? Perhaps this is the most important point of this entire review. Please elaborate in detail.”

Response to reviewer comment 3: Thank you for your comment and suggestions. We have added a paragraph to clarify this concern.  

Comment 4. “The authors offer 1 table that summarized the cited studies. I think that a comparison of reported long-term endocrine function and exocrine function (separately) is necessary as a table. Also, long-term overall and disease free survival should be shown. Perhaps expand the original table, or consider adding separate tables.” 

Response to reviewer comment 4: Thank you for your comment and suggestions. A Table reflecting early and long-term outcomes of different types of pancreatectomies was added. However, it was very difficult to extract data for the table because the majority of the studies did not differentiate complications or long-term outcomes for different types of pancreatectomies (presenting all together usually).

Reviewer 3 Report

Comments and Suggestions for Authors

The authors present an interesting review on the surgical management of pancreatoblastoma. It is an extensive review on the reported cases and the treatment in each case.

The tables are of good quality, have appropriate content.

The images are illustrative and have good quality.

The content of the manuscript is adequate, well structured and well presented. 

The bibliographic references are adequate, given the scarce literature on this type of pathology.

Comments on the Quality of English Language

I recommend proofreading the manuscript by a native speaker to correct minor syntactic and grammatical errors that are throughout the manuscript.

1. What is the main question addressed by the research? The main issue raised by this study is to address more precisely the management of pancreatoblastoma, which is a very rare paediatric tumour. 2. What parts do you consider original or relevant for the field? What specific gap in the field does the paper address? The most original part of the manuscript is that it proposes partial resection as part of the treatment of this type of tumour. There are few articles that address this issue, so it certainly adds a specific gap in this rare tumour type in children. 3. What does it add to the subject area compared with other published material? To date, only clinical cases or case series have been published, but the authors' narrative review makes it possible, on the one hand, to compile the information published to date, which is set out in a very well-structured table. In addition, they review the therapeutic options for this type of rare tumour in children. 4. What specific improvements should the authors consider regarding the methodology? What further controls should be considered? The methodology of this article is adequate with its narrative review design. To improve the design, the authors could approach the study as a systematic review. 5. Please describe how the conclusions are or are not consistent with the evidence and arguments presented. Please also indicate if all main questions posed were addressed and by which specific experiments. The conclusions of the article are absolutely consistent with the data collected in the article. 6. Are the references appropriate? The references are appropriate. Many studies are more than a decade old, but this is logical and understandable given the low frequency of occurrence of this disease.

 

7. Please include any additional comments on the tables and figures and quality of the data. Both the figures and the table are of adequate quality. The images are illustrative of radiological evidence and surgical specimens of these tumours.

Author Response

Reviewer 3

Comment 1. “The authors present an interesting review on the surgical management of pancreatoblastoma. It is an extensive review on the reported cases and the treatment in each case. The tables are of good quality, have appropriate content. The images are illustrative and have good quality. The content of the manuscript is adequate, well structured and well presented. The bibliographic references are adequate, given the scarce literature on this type of pathology.

1. What is the main question addressed by the research? The main issue raised by this study is to address more precisely the management of pancreatoblastoma, which is a very rare paediatric tumour.2. What parts do you consider original or relevant for the field? What specific gap in the field does the paper address? The most original part of the manuscript is that it proposes partial resection as part of the treatment of this type of tumour. There are few articles that address this issue, so it certainly adds a specific gap in this rare tumour type in children.3. What does it add to the subject area compared with other published material? To date, only clinical cases or case series have been published, but the authors' narrative review makes it possible, on the one hand, to compile the information published to date, which is set out in a very well-structured table. In addition, they review the therapeutic options for this type of rare tumour in children. 4. What specific improvements should the authors consider regarding the methodology? What further controls should be considered? The methodology of this article is adequate with its narrative review design. To improve the design, the authors could approach the study as a systematic review. 5. Please describe how the conclusions are or are not consistent with the evidence and arguments presented. Please also indicate if all main questions posed were addressed and by which specific experiments. The conclusions of the article are absolutely consistent with the data collected in the article. 6. Are the references appropriate? The references are appropriate. Many studies are more than a decade old, but this is logical and understandable given the low frequency of occurrence of this disease. 7. Please include any additional comments on the tables and figures and quality of the data. Both the figures and the table are of adequate quality. The images are illustrative of radiological evidence and surgical specimens of these tumours.”

Response to reviewer comment 1: Thank you for your kind appreciation of the present manuscript. A narrative review is probably a better option for the approached topic, in which the data comes mainly from case reports or small case series of patients.

Comment 2. “Comments on the Quality of English Language. I recommend proofreading the manuscript by a native speaker to correct minor syntactic and grammatical errors that are throughout the manuscript.”

Response to reviewer comment 2: Thank you for your comment and suggestions. The revised manuscript was proofread using a professional editing service to correct minor syntactic, spelling, grammar, or punctuation errors.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dr. Dumitrascu submitted a revised version of his manuscript.

While I do see the point in his responses, I feel they are partially contradictory.

In response to my introduction statement, it is said that "However, the topic of the present narrative review is specifically focused on the potential role of organ-sparing surgery in PB", while in response to my comment #2, he writes "That is why the analyses of early and late outcomes of pancreatic resections in children also included studies reporting data from other pancreatic tumoral pathologies".

I am fine with the responses regarding my initial comments. However, in light of the response it is inconsistent to include trauma patients (table 1, first row), all types of tumor (table 1, rows 11, 18), and ewing sarcoma (table 1, row 7). These are not essentially pancreatic tumoral pathologies, are they?

Moreover, given the specific focus, I feel that the tables and the sections of the text should specifically differentiate between pancreatoblastoma and other types of pancreatic tumors in order to be concordant with the specific aim the author stated in response to my comments.

Surely, I do see the issue of a lack of data. Nevertheless, this requires to be as distinctive as possible and clearly separate the entities. Even more important, it must be clearly pointed out if information is gained from adults or in comparison to adults in order to meet the self-set aim of a focus on pancreatoblastoma.

With regard to table 2, it should be Clavien-Dindo grade >2 in the legend.

Please avoid including the p-values from other studies, they do not add relevant information.

Please avoid

Author Response

Comment 1. “Dr. Dumitrascu submitted a revised version of his manuscript. While I do see the point in his responses, I feel they are partially contradictory. In response to my introduction statement, it is said that "However, the topic of the present narrative review is specifically focused on the potential role of organ-sparing surgery in PB", while in response to my comment #2, he writes "That is why the analyses of early and late outcomes of pancreatic resections in children also included studies reporting data from other pancreatic tumoral pathologies".”

Response to reviewer comment 1: Thank you for your comment and suggestions. I am sorry for the feeling of contradiction, which is most likely from our unclear response. The type of pancreatectomies and their early and long-term outcomes for PB are discussed in the context of other tumoral pathologies in children because the literature provides minimal information focusing specifically on PB.

Comment 2. “I am fine with the responses regarding my initial comments. However, in light of the response it is inconsistent to include trauma patients (table 1, first row), all types of tumor (table 1, rows 11, 18), and ewing sarcoma (table 1, row 7). These are not essentially pancreatic tumoral pathologies, are they? Moreover, given the specific focus, I feel that the tables and the sections of the text should specifically differentiate between pancreatoblastoma and other types of pancreatic tumors in order to be concordant with the specific aim the author stated in response to my comments. Surely, I do see the issue of a lack of data. Nevertheless, this requires to be as distinctive as possible and clearly separate the entities. “

Response to reviewer comment 2: Thank you. We appreciate your satisfaction with our response regarding your concerns and suggestions in the previous review. Your suggestions helped us improve the quality of our manuscript. We fully agree with the reviewer's suggestion that Table 1 should be revised and that for patients with Ewing sarcoma, all types of tumors and trauma should be eliminated. Remarkably, there is no point in this review to report outcomes of children with pancreatectomies for trauma, which is an entirely different topic. Furthermore, pancreatectomies for trauma are performed in an emergency, and emergency pancreatectomies are widely considered (at least in adults) with different complication rates compared with elective pancreatectomies (specifically higher morbidity rates). The necessary modifications were made in the new revised manuscript.  

Comment 3. “Even more important, it must be clearly pointed out if information is gained from adults or in comparison to adults in order to meet the self-set aim of a focus on pancreatoblastoma.”

Response to reviewer comment 3: Thank you for your comment and suggestions. The necessary modifications were made in the new revised manuscript.  

Comment 4. “With regard to table 2, it should be Clavien-Dindo grade >2 in the legend.”

Response to reviewer comment 4: Thank you. We have modified the manuscript according to your suggestion.

Comment 5. “Please avoid including the p-values from other studies, they do not add relevant information. Please avoid”

Response to reviewer comment 5: Thank you. We have modified the manuscript according to your suggestion.

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

nil