Reviewer ’s report  
 
Title: Predictors of unexpected metastasis on exploration in patients with potentially resectable 
pancreatic cancer  
 
Version: 1 Date: 13 Sep 2018  
 
Reviewer: Giovanni Marchegiani  
 
Reviewer's report:  
 
REVIEW PREDICTORS of UNEXPECTED METASTASES  
The present paper analyzes a single -center retrospectiv e cohort of 235 patients with PDAC who 
underwent surgical exploration, identifying two groups on the basis of the presence or absence of 
distant metastases (hepatic or peritoneal) found intraoperatively. Moreover, the authors propose a 
simple pre -operative  score to predict resectability, based on independent predictors of recurrence 
identified at multivariate analysis, namely younger age, male sex, tumor dimension, ALT and 
Ca19.9 level.  
The preoperative identification of patients at high risk of radiograph ically occult metastases is 
important in order to prevent unnecessary laparotomies and to propose instead a staging 
laparoscopy in these patients. Moreover, a simple score could be a useful tool for this purpose.  
 
Some points in this paper need, however, t o be better clarified.  
- In the present paper it is not specified whether the total of 235 patients considered 
underwent upfront surgery or if a certain percentage received pre -operative chemotherapy. 
This should be clarified because, as suggested by other  papers in literature (Reappraisal of 
Staging Laparoscopy for Patients with Pancreatic Adenocarcinoma: A Contemporary 
Analysis of 1001 Patients, Ann Surg Onc 2017), pre -operative chemotherapy could be a 
"protective" factor and should be analyzed and consid ered in the score. Moreover, in these 
patients conventional radiology is less able to evaluate tumor size due to the desmoplastic 
response to neoadjuvant treatment, and tumor size could be difficult to assess.  
 
- Regarding the score calculation, the most in fluent factor is tumor size. As just said, this is 
not a reliable parameter in patients who received pre -operative chemo -radiation. Moreover, 
other papers in literature suggest that other adverse prognostic factors correlated with tumor 
size are more assoc iated with negative prognosis than tumor size itself (Re -Evaluating the 
Impact of Tumor Size on Survival Following Pancreaticoduodenectomy for Pancreatic 
Adenocarcinoma). It would maybe be more significant to consider radiological resectability 
in terms of  preoperative staging (resectable vs. borderline resectable vs. locally advanced) 
rather than just tumor size. Of note, the median tumor size of the study population was 4 cm, 
which raises several concerns regarding the actual "resectable" stage.  
 
- Which was the mean time between pre -operative imaging and surgical exploration? In Table 
2 you talk about "image delay" but no indication can be found on the time interval between 
imaging and surgery.  
 
- How was the assessment of liver/peritoneal disease carried out? Eg only by surgeon's 
palpation or by intra -operative us? Were all the intraoperatively found metastatic lesions 
confirmed by biopsy? This should be specified.  
 
MINOR REVISIONS  
- Were all the radiological imaging reviewed by a dedicated radiologist ? This should be 
specified. Moreover, how many patients of the study population received MRI together with 
the internal CT? This would have increased the sensitivity for occult liver mets and therefore 
might represent a bias for patient's selection.  
 
- Pag 8, last paragraph of the "Results" section, you talk about 9 patients of the non metastatic 
group who did not undergo surgical resection due to locally advanced tumor. Have you 
calculated the score in these patients?  
 
- Pag 11, second paragraph, you talk  about alternative diagnostic techniques to assess tumor 
resectability, such as peritoneal lavage citology and staging laparoscopy. I suppose you are 
referring to data from the literature, but it does not appear clear when reading. I suggest this 
paragraph  is changed in order to be easier to be understood.  
 
- With regards to patient's selection, was surgical indication given by a single surgeon or by a 
dedicated multi -disciplinary meeting? This latter modality has already shown to increase the 
quality of p atient's selection.  
 
- Results line 122: why 3 patients with intraop evidence of liver mets underwent PD?  
 
- One of the finding of the study is that lower ALS and AST are predictors of intra operative 
metastatic disease. This is contra -intuitive and needs further clarifications/interpretations by 
the authors.  
 
- While this reviewer acknowledges the importance o f developing a score, the reliability of 
this tool needs further validation in the clinical setting, therefore the enthusiasm in its regard 
should be curbed throughout the discussion.  
 
- The English throughout the text should be revised by a native speake r  
Are the methods appropriate and well described ? 
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some l anguage corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary fr om an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication o f this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has app lied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare t hat I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Acc ess Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Predictors of unexpected metastasis on exploration in patients with potentially resectable 
pancreatic cancer  
 
Version: 1 Date: 13 Sep 2018  
 
Reviewer: Giovanni Marchegiani  
 
Reviewer's report:  
 
REVIEW PREDICTORS of UNEXPECTED METASTASES  
The present paper analyzes a single -center retrospectiv e cohort of 235 patients with PDAC who 
underwent surgical exploration, identifying two groups on the basis of the presence or absence of 
distant metastases (hepatic or peritoneal) found intraoperatively. Moreover, the authors propose a 
simple pre -operative  score to predict resectability, based on independent predictors of recurrence 
identified at multivariate analysis, namely younger age, male sex, tumor dimension, ALT and 
Ca19.9 level.  
The preoperative identification of patients at high risk of radiograph ically occult metastases is 
important in order to prevent unnecessary laparotomies and to propose instead a staging 
laparoscopy in these patients. Moreover, a simple score could be a useful tool for this purpose.  
 
Some points in this paper need, however, t o be better clarified.  
- In the present paper it is not specified whether the total of 235 patients considered 
underwent upfront surgery or if a certain percentage received pre -operative chemotherapy. 
This should be clarified because, as suggested by other  papers in literature (Reappraisal of 
Staging Laparoscopy for Patients with Pancreatic Adenocarcinoma: A Contemporary 
Analysis of 1001 Patients, Ann Surg Onc 2017), pre -operative chemotherapy could be a 
"protective" factor and should be analyzed and consid ered in the score. Moreover, in these 
patients conventional radiology is less able to evaluate tumor size due to the desmoplastic 
response to neoadjuvant treatment, and tumor size could be difficult to assess.  
 
- Regarding the score calculation, the most in fluent factor is tumor size. As just said, this is 
not a reliable parameter in patients who received pre -operative chemo -radiation. Moreover, 
other papers in literature suggest that other adverse prognostic factors correlated with tumor 
size are more assoc iated with negative prognosis than tumor size itself (Re -Evaluating the 
Impact of Tumor Size on Survival Following Pancreaticoduodenectomy for Pancreatic 
Adenocarcinoma). It would maybe be more significant to consider radiological resectability 
in terms of  preoperative staging (resectable vs. borderline resectable vs. locally advanced) 
rather than just tumor size. Of note, the median tumor size of the study population was 4 cm, 
which raises several concerns regarding the actual "resectable" stage.  
 
- Which was the mean time between pre -operative imaging and surgical exploration? In Table 
2 you talk about "image delay" but no indication can be found on the time interval between 
imaging and surgery.  
 
- How was the assessment of liver/peritoneal disease carried out? Eg only by surgeon's 
palpation or by intra -operative us? Were all the intraoperatively found metastatic lesions 
confirmed by biopsy? This should be specified.  
 
MINOR REVISIONS  
- Were all the radiological imaging reviewed by a dedicated radiologist ? This should be 
specified. Moreover, how many patients of the study population received MRI together with 
the internal CT? This would have increased the sensitivity for occult liver mets and therefore 
might represent a bias for patient's selection.  
 
- Pag 8, last paragraph of the "Results" section, you talk about 9 patients of the non metastatic 
group who did not undergo surgical resection due to locally advanced tumor. Have you 
calculated the score in these patients?  
 
- Pag 11, second paragraph, you talk  about alternative diagnostic techniques to assess tumor 
resectability, such as peritoneal lavage citology and staging laparoscopy. I suppose you are 
referring to data from the literature, but it does not appear clear when reading. I suggest this 
paragraph  is changed in order to be easier to be understood.  
 
- With regards to patient's selection, was surgical indication given by a single surgeon or by a 
dedicated multi -disciplinary meeting? This latter modality has already shown to increase the 
quality of p atient's selection.  
 
- Results line 122: why 3 patients with intraop evidence of liver mets underwent PD?  
 
- One of the finding of the study is that lower ALS and AST are predictors of intra operative 
metastatic disease. This is contra -intuitive and needs further clarifications/interpretations by 
the authors.  
 
- While this reviewer acknowledges the importance o f developing a score, the reliability of 
this tool needs further validation in the clinical setting, therefore the enthusiasm in its regard 
should be curbed throughout the discussion.  
 
- The English throughout the text should be revised by a native speake r  
Are the methods appropriate and well described ? 
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some l anguage corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary fr om an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication o f this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has app lied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare t hat I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Acc ess Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Predictors of unexpected metastasis on exploration in patients with potentially resectable 
pancreatic cancer  
 
Version: 1 Date: 13 Sep 2018  
 
Reviewer: Giovanni Marchegiani  
 
Reviewer's report:  
 
REVIEW PREDICTORS of UNEXPECTED METASTASES  
The present paper analyzes a single -center retrospectiv e cohort of 235 patients with PDAC who 
underwent surgical exploration, identifying two groups on the basis of the presence or absence of 
distant metastases (hepatic or peritoneal) found intraoperatively. Moreover, the authors propose a 
simple pre -operative  score to predict resectability, based on independent predictors of recurrence 
identified at multivariate analysis, namely younger age, male sex, tumor dimension, ALT and 
Ca19.9 level.  
The preoperative identification of patients at high risk of radiograph ically occult metastases is 
important in order to prevent unnecessary laparotomies and to propose instead a staging 
laparoscopy in these patients. Moreover, a simple score could be a useful tool for this purpose.  
 
Some points in this paper need, however, t o be better clarified.  
- In the present paper it is not specified whether the total of 235 patients considered 
underwent upfront surgery or if a certain percentage received pre -operative chemotherapy. 
This should be clarified because, as suggested by other  papers in literature (Reappraisal of 
Staging Laparoscopy for Patients with Pancreatic Adenocarcinoma: A Contemporary 
Analysis of 1001 Patients, Ann Surg Onc 2017), pre -operative chemotherapy could be a 
"protective" factor and should be analyzed and consid ered in the score. Moreover, in these 
patients conventional radiology is less able to evaluate tumor size due to the desmoplastic 
response to neoadjuvant treatment, and tumor size could be difficult to assess.  
 
- Regarding the score calculation, the most in fluent factor is tumor size. As just said, this is 
not a reliable parameter in patients who received pre -operative chemo -radiation. Moreover, 
other papers in literature suggest that other adverse prognostic factors correlated with tumor 
size are more assoc iated with negative prognosis than tumor size itself (Re -Evaluating the 
Impact of Tumor Size on Survival Following Pancreaticoduodenectomy for Pancreatic 
Adenocarcinoma). It would maybe be more significant to consider radiological resectability 
in terms of  preoperative staging (resectable vs. borderline resectable vs. locally advanced) 
rather than just tumor size. Of note, the median tumor size of the study population was 4 cm, 
which raises several concerns regarding the actual "resectable" stage.  
 
- Which was the mean time between pre -operative imaging and surgical exploration? In Table 
2 you talk about "image delay" but no indication can be found on the time interval between 
imaging and surgery.  
 
- How was the assessment of liver/peritoneal disease carried out? Eg only by surgeon's 
palpation or by intra -operative us? Were all the intraoperatively found metastatic lesions 
confirmed by biopsy? This should be specified.  
 
MINOR REVISIONS  
- Were all the radiological imaging reviewed by a dedicated radiologist ? This should be 
specified. Moreover, how many patients of the study population received MRI together with 
the internal CT? This would have increased the sensitivity for occult liver mets and therefore 
might represent a bias for patient's selection.  
 
- Pag 8, last paragraph of the "Results" section, you talk about 9 patients of the non metastatic 
group who did not undergo surgical resection due to locally advanced tumor. Have you 
calculated the score in these patients?  
 
- Pag 11, second paragraph, you talk  about alternative diagnostic techniques to assess tumor 
resectability, such as peritoneal lavage citology and staging laparoscopy. I suppose you are 
referring to data from the literature, but it does not appear clear when reading. I suggest this 
paragraph  is changed in order to be easier to be understood.  
 
- With regards to patient's selection, was surgical indication given by a single surgeon or by a 
dedicated multi -disciplinary meeting? This latter modality has already shown to increase the 
quality of p atient's selection.  
 
- Results line 122: why 3 patients with intraop evidence of liver mets underwent PD?  
 
- One of the finding of the study is that lower ALS and AST are predictors of intra operative 
metastatic disease. This is contra -intuitive and needs further clarifications/interpretations by 
the authors.  
 
- While this reviewer acknowledges the importance o f developing a score, the reliability of 
this tool needs further validation in the clinical setting, therefore the enthusiasm in its regard 
should be curbed throughout the discussion.  
 
- The English throughout the text should be revised by a native speake r  
Are the methods appropriate and well described ? 
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some l anguage corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary fr om an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication o f this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has app lied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare t hat I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Acc ess Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant