Reviewer ’s report  
 
Title: The development of early ascites is associated with shorter overall survival in patients 
with hepatocellular carcinoma treated with drug -eluting embolic chemoembolization  
 
Version: 0 Date: 26 Jan 2020  
 
Reviewer: Fabio Piscaglia  
 
Reviewer's report:  
 
Please include all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of you r report which cannot be included in a text format.  
 
Please overwrite this text when adding your comments to the authors.  
 
Study BMGE -D-19-01059 investigates possibile predictors of shorter survival after TACE for 
HCC.  
 
Although the topic is of interest the re are limitations which make the impact of the findings of 
limited clinical value.  
 
One is the absence of new predictors of shorter survival that can be applied prior to TACE 
performance, which might help avoid the procedure in patients who are expected n ot benefit 
from it. The information that development of ascites is associated with shorter survival does not 
help much in managing patients, as when ascites has developed nothing more can be done to 
avoid the occurrence of this situation.  
 
One of the reas ons that might have lead to the identification of development of ascites as a 
significant predictor of shorter OS is the fact that only a limited number of sicker patients is 
selected for this variable. For most other variables the median was selected as c ut-off, which 
means that half patients fall in each category, making the variable of almost absent clinical 
utility. Even from a statistical pont of view mixing continous and categorial variables make the 
analysis weaker. I would rather select clinically m eaningful thresholds (e.g. Bilirubin 
&gt;2mg/dl, rather than median). Most likely such selection would provide more helpful 
information for the clinical practice. This is really a key weak point of the study.  
 
Median values that work as thresholds would obviously be different at baseline and at T1, thus 
setting the cut -off at the median rather than at a prespecified thresholds make the data difficult to 
apply in the clinical practice. Moreover the median values are not reported. For instance AFP 
values at T0 and at T1 would have had a different median value most likely, as well as albumin, 
therefore the reader does not understand the impact and clinical values of the findings.  
 
Different variables were selected at baseline and at T1 to be analyzed. Why?  
 
Page 2. In the declarations the fact that patients signed an informed consent for the procedure is 
not of interest, as this applies to standard of practice regardless of any research. What is relevant 
to be repor ted here is whether patients had to sign an informed consent for research (e.g for 
having their data introduced in a prospective general registry) or whether such consent retrieval 
was waived because of the retrospective nature of the study.  
 
Abstract. Th e flow between background and study methods is not straight. The study was 
declared to have been "performed to identify independent factors associated with the overall 
survival", but in the methods the authors declare that "the analysis of prognostic facto rs 
associated with DEB —TACE complications was performed". They do not mention survival.  
 
The authors analyzed the role of alkaline phosphatase and found it to be significant. However, 
apparently the did not analyzed other factors commonly associated with prognosis, such as 
changes in liver enzymes like AST, ALT or GGT. I suggest to analyse these as well.  
 
PAGE 5 .In the methods, 4 lines from bottom add the word "currently" before decompensated as 
some patients suffered from previous decompensation.  
 
The authors did not include in the analysis the year of TACE performance which was associated 
with different beads size, but they report in the text that this was not associated with adverse 
events or survival. Since DEB -TACE is the focus of the study I believ e some data have to be 
shown, at least in supplementary tables.  
 
Page 9. Section Response to treatment. The authors report some data as percentages and some as 
absolute numbers. This is confusing and make it difficult to read. Please report both for each 
finding.  
 
Page 11. The authors report the median time of onset of early ascites. This does not make sense 
as the time is related not to the time required for ascites to appear but simply to the fact that the 
first imaging performed that could have detecte d ascites was CT at 6 weeks (42 days, 
corresponding to the median of 40 days reported by the authors). Unless there were other interval 
imaging showing that ascites was not present in the early days after TACE it does not make 
sense to report the days.  
 
Why the authors included Hemoglobin in their analysis? I guess because potentially reflecting 
hypersplenism. Then why not also not platelet count? I would prefer to see the role of platelet 
count or of both platelet and hemoglobin to understand which is str onger, but not only of 
hemoglobin (which moreover became a very relevant variable up to be included in the final 
model).  
 
Tables. Usually data of median values are reported as median and range rather than IQR. For 
diuretics in Table 1 please report (if th is is the case) the number of patients for which the 
information was missing. I would redraw the table adding percentages aside of absolute numbers 
for the first 2 to 7 variables in Table 1. In table 2 the median values have to be reported rather 
than stat ing below or above the median (you could report below or above a certain specied value 
and state in the legend that the value for each variable was the median).   
Mixing together BCLC -A and -B makes the findings of lesser clinical impact. For instance I 
would be interested to understand whether CSPH might have an impact when BCLC -B patients 
are analysed separately as they tend to require larger embolization making the potential risk 
related to CSPH higher.  
 
Tables. It does not make sense to report three d igits after the comma for most variables (for 
instance one decimal for month of survival is more than enough, three digits in the 95%CI are 
too much, please round them as they are disturbing, as the median is reported rounded to zero 
decimals).  
 
The analy sis of Table 2 is confusing. Some parameters include others (Child -Pugh includes 
various others, BCLC include various others) and this is problematic when multivariate analyses 
are run and relevant ones are missing (e.g. AST, GGT, platelets). Putting toget her BCLC 0/A vs 
B induce a segregation of only Child -Pugh A patients in BCLC -0, which favour the difference in 
survival apart from the tumor load.  
 
Why did the authors selected different lab variables to be tested at baseline and at T1?  
 
Suppl Table 3. Does AFP_t really impact only for 1% (HR 1.01) every 1000 units of change?  
 
Altogether the work has potential but needs substantial revision before any conclusion about the 
utility in HCC management can be drawn  
 
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.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to t he authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy 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:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, consideri ng the following questions:  
 
1.  Have you in the past five years received reimbursements, f ees, funding, or salary 
from an organisation that may in any way gain or lose financial ly from the 
publication of this manuscript, either now or in the future?  
 
2.  Do y ou hold any stocks or shares in an organisation t hat may in any way gain or 
lose financially from the publication of 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 re ceived reimbursements, fees, funding, or salary from an organization 
that holds or has applied 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 that I have  no competi ng interests' 
below. If your reply is yes to any, please give details below.  
 
Speaker bureau or advisory board honoraria  from Alkermes, A strazeneca, Bayer, Bracco, BMS, 
EISAI, GE, IPSEN, La Force Guerbet , Roche, Siemens Healthcare, Tiziana Life Sciences  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the aut hors and, if the manuscript is accepted f or 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 Access 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 in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer r eview policy of the journal  
Reviewer ’s report  
 
Title: The development of early ascites is associated with shorter overall survival in patients 
with hepatocellular carcinoma treated with drug -eluting embolic chemoembolization  
 
Version: 0 Date: 26 Jan 2020  
 
Reviewer: Fabio Piscaglia  
 
Reviewer's report:  
 
Please include all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of you r report which cannot be included in a text format.  
 
Please overwrite this text when adding your comments to the authors.  
 
Study BMGE -D-19-01059 investigates possibile predictors of shorter survival after TACE for 
HCC.  
 
Although the topic is of interest the re are limitations which make the impact of the findings of 
limited clinical value.  
 
One is the absence of new predictors of shorter survival that can be applied prior to TACE 
performance, which might help avoid the procedure in patients who are expected n ot benefit 
from it. The information that development of ascites is associated with shorter survival does not 
help much in managing patients, as when ascites has developed nothing more can be done to 
avoid the occurrence of this situation.  
 
One of the reas ons that might have lead to the identification of development of ascites as a 
significant predictor of shorter OS is the fact that only a limited number of sicker patients is 
selected for this variable. For most other variables the median was selected as c ut-off, which 
means that half patients fall in each category, making the variable of almost absent clinical 
utility. Even from a statistical pont of view mixing continous and categorial variables make the 
analysis weaker. I would rather select clinically m eaningful thresholds (e.g. Bilirubin 
&gt;2mg/dl, rather than median). Most likely such selection would provide more helpful 
information for the clinical practice. This is really a key weak point of the study.  
 
Median values that work as thresholds would obviously be different at baseline and at T1, thus 
setting the cut -off at the median rather than at a prespecified thresholds make the data difficult to 
apply in the clinical practice. Moreover the median values are not reported. For instance AFP 
values at T0 and at T1 would have had a different median value most likely, as well as albumin, 
therefore the reader does not understand the impact and clinical values of the findings.  
 
Different variables were selected at baseline and at T1 to be analyzed. Why?  
 
Page 2. In the declarations the fact that patients signed an informed consent for the procedure is 
not of interest, as this applies to standard of practice regardless of any research. What is relevant 
to be repor ted here is whether patients had to sign an informed consent for research (e.g for 
having their data introduced in a prospective general registry) or whether such consent retrieval 
was waived because of the retrospective nature of the study.  
 
Abstract. Th e flow between background and study methods is not straight. The study was 
declared to have been "performed to identify independent factors associated with the overall 
survival", but in the methods the authors declare that "the analysis of prognostic facto rs 
associated with DEB —TACE complications was performed". They do not mention survival.  
 
The authors analyzed the role of alkaline phosphatase and found it to be significant. However, 
apparently the did not analyzed other factors commonly associated with prognosis, such as 
changes in liver enzymes like AST, ALT or GGT. I suggest to analyse these as well.  
 
PAGE 5 .In the methods, 4 lines from bottom add the word "currently" before decompensated as 
some patients suffered from previous decompensation.  
 
The authors did not include in the analysis the year of TACE performance which was associated 
with different beads size, but they report in the text that this was not associated with adverse 
events or survival. Since DEB -TACE is the focus of the study I believ e some data have to be 
shown, at least in supplementary tables.  
 
Page 9. Section Response to treatment. The authors report some data as percentages and some as 
absolute numbers. This is confusing and make it difficult to read. Please report both for each 
finding.  
 
Page 11. The authors report the median time of onset of early ascites. This does not make sense 
as the time is related not to the time required for ascites to appear but simply to the fact that the 
first imaging performed that could have detecte d ascites was CT at 6 weeks (42 days, 
corresponding to the median of 40 days reported by the authors). Unless there were other interval 
imaging showing that ascites was not present in the early days after TACE it does not make 
sense to report the days.  
 
Why the authors included Hemoglobin in their analysis? I guess because potentially reflecting 
hypersplenism. Then why not also not platelet count? I would prefer to see the role of platelet 
count or of both platelet and hemoglobin to understand which is str onger, but not only of 
hemoglobin (which moreover became a very relevant variable up to be included in the final 
model).  
 
Tables. Usually data of median values are reported as median and range rather than IQR. For 
diuretics in Table 1 please report (if th is is the case) the number of patients for which the 
information was missing. I would redraw the table adding percentages aside of absolute numbers 
for the first 2 to 7 variables in Table 1. In table 2 the median values have to be reported rather 
than stat ing below or above the median (you could report below or above a certain specied value 
and state in the legend that the value for each variable was the median).   
Mixing together BCLC -A and -B makes the findings of lesser clinical impact. For instance I 
would be interested to understand whether CSPH might have an impact when BCLC -B patients 
are analysed separately as they tend to require larger embolization making the potential risk 
related to CSPH higher.  
 
Tables. It does not make sense to report three d igits after the comma for most variables (for 
instance one decimal for month of survival is more than enough, three digits in the 95%CI are 
too much, please round them as they are disturbing, as the median is reported rounded to zero 
decimals).  
 
The analy sis of Table 2 is confusing. Some parameters include others (Child -Pugh includes 
various others, BCLC include various others) and this is problematic when multivariate analyses 
are run and relevant ones are missing (e.g. AST, GGT, platelets). Putting toget her BCLC 0/A vs 
B induce a segregation of only Child -Pugh A patients in BCLC -0, which favour the difference in 
survival apart from the tumor load.  
 
Why did the authors selected different lab variables to be tested at baseline and at T1?  
 
Suppl Table 3. Does AFP_t really impact only for 1% (HR 1.01) every 1000 units of change?  
 
Altogether the work has potential but needs substantial revision before any conclusion about the 
utility in HCC management can be drawn  
 
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.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to t he authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy 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:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, consideri ng the following questions:  
 
1.  Have you in the past five years received reimbursements, f ees, funding, or salary 
from an organisation that may in any way gain or lose financial ly from the 
publication of this manuscript, either now or in the future?  
 
2.  Do y ou hold any stocks or shares in an organisation t hat may in any way gain or 
lose financially from the publication of 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 re ceived reimbursements, fees, funding, or salary from an organization 
that holds or has applied 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 that I have  no competi ng interests' 
below. If your reply is yes to any, please give details below.  
 
Speaker bureau or advisory board honoraria  from Alkermes, A strazeneca, Bayer, Bracco, BMS, 
EISAI, GE, IPSEN, La Force Guerbet , Roche, Siemens Healthcare, Tiziana Life Sciences  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the aut hors and, if the manuscript is accepted f or 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 Access 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 in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer r eview policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: The development of early ascites is associated with shorter overall survival in patients 
with hepatocellular carcinoma treated with drug -eluting embolic chemoembolization  
 
Version: 0 Date: 26 Jan 2020  
 
Reviewer: Fabio Piscaglia  
 
Reviewer's report:  
 
Please include all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of you r report which cannot be included in a text format.  
 
Please overwrite this text when adding your comments to the authors.  
 
Study BMGE -D-19-01059 investigates possibile predictors of shorter survival after TACE for 
HCC.  
 
Although the topic is of interest the re are limitations which make the impact of the findings of 
limited clinical value.  
 
One is the absence of new predictors of shorter survival that can be applied prior to TACE 
performance, which might help avoid the procedure in patients who are expected n ot benefit 
from it. The information that development of ascites is associated with shorter survival does not 
help much in managing patients, as when ascites has developed nothing more can be done to 
avoid the occurrence of this situation.  
 
One of the reas ons that might have lead to the identification of development of ascites as a 
significant predictor of shorter OS is the fact that only a limited number of sicker patients is 
selected for this variable. For most other variables the median was selected as c ut-off, which 
means that half patients fall in each category, making the variable of almost absent clinical 
utility. Even from a statistical pont of view mixing continous and categorial variables make the 
analysis weaker. I would rather select clinically m eaningful thresholds (e.g. Bilirubin 
&gt;2mg/dl, rather than median). Most likely such selection would provide more helpful 
information for the clinical practice. This is really a key weak point of the study.  
 
Median values that work as thresholds would obviously be different at baseline and at T1, thus 
setting the cut -off at the median rather than at a prespecified thresholds make the data difficult to 
apply in the clinical practice. Moreover the median values are not reported. For instance AFP 
values at T0 and at T1 would have had a different median value most likely, as well as albumin, 
therefore the reader does not understand the impact and clinical values of the findings.  
 
Different variables were selected at baseline and at T1 to be analyzed. Why?  
 
Page 2. In the declarations the fact that patients signed an informed consent for the procedure is 
not of interest, as this applies to standard of practice regardless of any research. What is relevant 
to be repor ted here is whether patients had to sign an informed consent for research (e.g for 
having their data introduced in a prospective general registry) or whether such consent retrieval 
was waived because of the retrospective nature of the study.  
 
Abstract. Th e flow between background and study methods is not straight. The study was 
declared to have been "performed to identify independent factors associated with the overall 
survival", but in the methods the authors declare that "the analysis of prognostic facto rs 
associated with DEB —TACE complications was performed". They do not mention survival.  
 
The authors analyzed the role of alkaline phosphatase and found it to be significant. However, 
apparently the did not analyzed other factors commonly associated with prognosis, such as 
changes in liver enzymes like AST, ALT or GGT. I suggest to analyse these as well.  
 
PAGE 5 .In the methods, 4 lines from bottom add the word "currently" before decompensated as 
some patients suffered from previous decompensation.  
 
The authors did not include in the analysis the year of TACE performance which was associated 
with different beads size, but they report in the text that this was not associated with adverse 
events or survival. Since DEB -TACE is the focus of the study I believ e some data have to be 
shown, at least in supplementary tables.  
 
Page 9. Section Response to treatment. The authors report some data as percentages and some as 
absolute numbers. This is confusing and make it difficult to read. Please report both for each 
finding.  
 
Page 11. The authors report the median time of onset of early ascites. This does not make sense 
as the time is related not to the time required for ascites to appear but simply to the fact that the 
first imaging performed that could have detecte d ascites was CT at 6 weeks (42 days, 
corresponding to the median of 40 days reported by the authors). Unless there were other interval 
imaging showing that ascites was not present in the early days after TACE it does not make 
sense to report the days.  
 
Why the authors included Hemoglobin in their analysis? I guess because potentially reflecting 
hypersplenism. Then why not also not platelet count? I would prefer to see the role of platelet 
count or of both platelet and hemoglobin to understand which is str onger, but not only of 
hemoglobin (which moreover became a very relevant variable up to be included in the final 
model).  
 
Tables. Usually data of median values are reported as median and range rather than IQR. For 
diuretics in Table 1 please report (if th is is the case) the number of patients for which the 
information was missing. I would redraw the table adding percentages aside of absolute numbers 
for the first 2 to 7 variables in Table 1. In table 2 the median values have to be reported rather 
than stat ing below or above the median (you could report below or above a certain specied value 
and state in the legend that the value for each variable was the median).   
Mixing together BCLC -A and -B makes the findings of lesser clinical impact. For instance I 
would be interested to understand whether CSPH might have an impact when BCLC -B patients 
are analysed separately as they tend to require larger embolization making the potential risk 
related to CSPH higher.  
 
Tables. It does not make sense to report three d igits after the comma for most variables (for 
instance one decimal for month of survival is more than enough, three digits in the 95%CI are 
too much, please round them as they are disturbing, as the median is reported rounded to zero 
decimals).  
 
The analy sis of Table 2 is confusing. Some parameters include others (Child -Pugh includes 
various others, BCLC include various others) and this is problematic when multivariate analyses 
are run and relevant ones are missing (e.g. AST, GGT, platelets). Putting toget her BCLC 0/A vs 
B induce a segregation of only Child -Pugh A patients in BCLC -0, which favour the difference in 
survival apart from the tumor load.  
 
Why did the authors selected different lab variables to be tested at baseline and at T1?  
 
Suppl Table 3. Does AFP_t really impact only for 1% (HR 1.01) every 1000 units of change?  
 
Altogether the work has potential but needs substantial revision before any conclusion about the 
utility in HCC management can be drawn  
 
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.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to t he authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy 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:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, consideri ng the following questions:  
 
1.  Have you in the past five years received reimbursements, f ees, funding, or salary 
from an organisation that may in any way gain or lose financial ly from the 
publication of this manuscript, either now or in the future?  
 
2.  Do y ou hold any stocks or shares in an organisation t hat may in any way gain or 
lose financially from the publication of 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 re ceived reimbursements, fees, funding, or salary from an organization 
that holds or has applied 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 that I have  no competi ng interests' 
below. If your reply is yes to any, please give details below.  
 
Speaker bureau or advisory board honoraria  from Alkermes, A strazeneca, Bayer, Bracco, BMS, 
EISAI, GE, IPSEN, La Force Guerbet , Roche, Siemens Healthcare, Tiziana Life Sciences  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the aut hors and, if the manuscript is accepted f or 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 Access 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 in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer r eview policy of the journal  
assistant