Reviewer ’s report  
Title:  Increasing Mortality in the United States from Cholangiocarci noma: an Analysis of the 
National Center for Health Statistics Database  
 
Version : 0 Date:  15 Mar 2016  
 
Reviewer:  Sumera Rizvi  
 
Reviewer's report:  
The manuscript (BMGE -D-16-00050) examines CCA mortality trends based on data derived 
from the CDC Wonder database.  The primary findings of the study are i) CCA mortality has 
increased over time ii) CCA mortality increases with age iii) females of Hispanic origin have a 
higher risk of CCA mortality compared to non -Hispanic females iv) Asians have the highest risk 
of CC A mortality. The main drawback of this study is that it lacks novelty. Accordingly, the 
study findings will have limited contribution to the field. The incidence and mortality trends of 
CCA have been well -outlined in prior publications which have appropria tely classified 
intrahepatic and extrahepatic cholangiocarcinoma. 1,2  
 
MAJOR COMMENTS:  
1) The incidence and mortality trends of CCA have been well -outlined in prior publications. 
Everhart et al. described these trends thoroughly in "The Burden of Digestive Disease in the 
United States" report supported by the National Commission on Digestive  Diseases.1 
Contrary to the authors claim that prior publications have grouped intrahepatic 
cholangiocarcinoma with hepatocellular carcinoma, the report by Everhart et al. grouped 
intrahepatic and extrahepatic cholangiocarcinoma together as 'cancer of the bile ducts'. 
Everhart et al. reported that bile duct cancer mortality has increased substantially over 25 
years with the majority of deaths occurring in persons over 65 years of age and the age -
adjusted mortality is higher for males. Therefore, the primary  findings of this manuscript are 
already well -known in the field of cholangiocarcinoma.  
2) The manuscript has focused on overall mortality trends of cholangiocarcinoma. However, 
there is a plethora of preexisting epidemiological literature focused on intr ahepatic and 
extrahepatic cholangiocarcinoma. Meanwhile, there is limited information regarding the 
distinct epidemiological/mortality trends of the 3 primary subtypes of cholangiocarcinoma - 
perihilar, intrahepatic and distal. These subtypes have differen t risk factors, pathogenesis, 
and management. Therefore, characterization of the epidemiological/mortality differences 
between the 3 subtypes (rather than general epidemiological data on cholangiocarcinoma) 
would have greater significance.   
MINOR COMMENT S: 
1) The manuscript has syntax and stylistic flaws which should be addressed.  
2) The Discussion section is unnecessarily lengthy and should be more concise.  
 
References  
1. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III : Liver, 
biliary tract, and pancreas. Gastroenterology 2009;136:1134 -44. 
2. Shaib Y, El -Serag HB. The epidemiology of cholangiocarcinoma. Seminars in liver disease 
2004;24:115 -25. 
 
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 i n your comments to the authors.  
Unable to assess  
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 speci fy what aspects require further 
assessment in your comments to the editors.  
I recommend additio nal statistical review  
Quality of written English  
Please indicate the qu ality of language in the manuscript:  
Needs some language 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 rec eived 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 you hold any stocks or shares in an organisation that may in any wa y 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 received 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 com peting interests in relation to this paper?  
If you can answer no to all of the above, write 'I declare that I have no com peting 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 Access Creative Commons 
CC-BY licens e (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 polic y of the journal  
Reviewer ’s report  
Title:  Increasing Mortality in the United States from Cholangiocarci noma: an Analysis of the 
National Center for Health Statistics Database  
 
Version : 0 Date:  15 Mar 2016  
 
Reviewer:  Sumera Rizvi  
 
Reviewer's report:  
The manuscript (BMGE -D-16-00050) examines CCA mortality trends based on data derived 
from the CDC Wonder database.  The primary findings of the study are i) CCA mortality has 
increased over time ii) CCA mortality increases with age iii) females of Hispanic origin have a 
higher risk of CCA mortality compared to non -Hispanic females iv) Asians have the highest risk 
of CC A mortality. The main drawback of this study is that it lacks novelty. Accordingly, the 
study findings will have limited contribution to the field. The incidence and mortality trends of 
CCA have been well -outlined in prior publications which have appropria tely classified 
intrahepatic and extrahepatic cholangiocarcinoma. 1,2  
 
MAJOR COMMENTS:  
1) The incidence and mortality trends of CCA have been well -outlined in prior publications. 
Everhart et al. described these trends thoroughly in "The Burden of Digestive Disease in the 
United States" report supported by the National Commission on Digestive  Diseases.1 
Contrary to the authors claim that prior publications have grouped intrahepatic 
cholangiocarcinoma with hepatocellular carcinoma, the report by Everhart et al. grouped 
intrahepatic and extrahepatic cholangiocarcinoma together as 'cancer of the bile ducts'. 
Everhart et al. reported that bile duct cancer mortality has increased substantially over 25 
years with the majority of deaths occurring in persons over 65 years of age and the age -
adjusted mortality is higher for males. Therefore, the primary  findings of this manuscript are 
already well -known in the field of cholangiocarcinoma.  
2) The manuscript has focused on overall mortality trends of cholangiocarcinoma. However, 
there is a plethora of preexisting epidemiological literature focused on intr ahepatic and 
extrahepatic cholangiocarcinoma. Meanwhile, there is limited information regarding the 
distinct epidemiological/mortality trends of the 3 primary subtypes of cholangiocarcinoma - 
perihilar, intrahepatic and distal. These subtypes have differen t risk factors, pathogenesis, 
and management. Therefore, characterization of the epidemiological/mortality differences 
between the 3 subtypes (rather than general epidemiological data on cholangiocarcinoma) 
would have greater significance.   
MINOR COMMENT S: 
1) The manuscript has syntax and stylistic flaws which should be addressed.  
2) The Discussion section is unnecessarily lengthy and should be more concise.  
 
References  
1. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III : Liver, 
biliary tract, and pancreas. Gastroenterology 2009;136:1134 -44. 
2. Shaib Y, El -Serag HB. The epidemiology of cholangiocarcinoma. Seminars in liver disease 
2004;24:115 -25. 
 
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 i n your comments to the authors.  
Unable to assess  
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 speci fy what aspects require further 
assessment in your comments to the editors.  
I recommend additio nal statistical review  
Quality of written English  
Please indicate the qu ality of language in the manuscript:  
Needs some language 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 rec eived 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 you hold any stocks or shares in an organisation that may in any wa y 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 received 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 com peting interests in relation to this paper?  
If you can answer no to all of the above, write 'I declare that I have no com peting 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 Access Creative Commons 
CC-BY licens e (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 polic y of the journal  
Please review this paper.
user
Reviewer ’s report  
Title:  Increasing Mortality in the United States from Cholangiocarci noma: an Analysis of the 
National Center for Health Statistics Database  
 
Version : 0 Date:  15 Mar 2016  
 
Reviewer:  Sumera Rizvi  
 
Reviewer's report:  
The manuscript (BMGE -D-16-00050) examines CCA mortality trends based on data derived 
from the CDC Wonder database.  The primary findings of the study are i) CCA mortality has 
increased over time ii) CCA mortality increases with age iii) females of Hispanic origin have a 
higher risk of CCA mortality compared to non -Hispanic females iv) Asians have the highest risk 
of CC A mortality. The main drawback of this study is that it lacks novelty. Accordingly, the 
study findings will have limited contribution to the field. The incidence and mortality trends of 
CCA have been well -outlined in prior publications which have appropria tely classified 
intrahepatic and extrahepatic cholangiocarcinoma. 1,2  
 
MAJOR COMMENTS:  
1) The incidence and mortality trends of CCA have been well -outlined in prior publications. 
Everhart et al. described these trends thoroughly in "The Burden of Digestive Disease in the 
United States" report supported by the National Commission on Digestive  Diseases.1 
Contrary to the authors claim that prior publications have grouped intrahepatic 
cholangiocarcinoma with hepatocellular carcinoma, the report by Everhart et al. grouped 
intrahepatic and extrahepatic cholangiocarcinoma together as 'cancer of the bile ducts'. 
Everhart et al. reported that bile duct cancer mortality has increased substantially over 25 
years with the majority of deaths occurring in persons over 65 years of age and the age -
adjusted mortality is higher for males. Therefore, the primary  findings of this manuscript are 
already well -known in the field of cholangiocarcinoma.  
2) The manuscript has focused on overall mortality trends of cholangiocarcinoma. However, 
there is a plethora of preexisting epidemiological literature focused on intr ahepatic and 
extrahepatic cholangiocarcinoma. Meanwhile, there is limited information regarding the 
distinct epidemiological/mortality trends of the 3 primary subtypes of cholangiocarcinoma - 
perihilar, intrahepatic and distal. These subtypes have differen t risk factors, pathogenesis, 
and management. Therefore, characterization of the epidemiological/mortality differences 
between the 3 subtypes (rather than general epidemiological data on cholangiocarcinoma) 
would have greater significance.   
MINOR COMMENT S: 
1) The manuscript has syntax and stylistic flaws which should be addressed.  
2) The Discussion section is unnecessarily lengthy and should be more concise.  
 
References  
1. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III : Liver, 
biliary tract, and pancreas. Gastroenterology 2009;136:1134 -44. 
2. Shaib Y, El -Serag HB. The epidemiology of cholangiocarcinoma. Seminars in liver disease 
2004;24:115 -25. 
 
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 i n your comments to the authors.  
Unable to assess  
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 speci fy what aspects require further 
assessment in your comments to the editors.  
I recommend additio nal statistical review  
Quality of written English  
Please indicate the qu ality of language in the manuscript:  
Needs some language 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 rec eived 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 you hold any stocks or shares in an organisation that may in any wa y 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 received 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 com peting interests in relation to this paper?  
If you can answer no to all of the above, write 'I declare that I have no com peting 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 Access Creative Commons 
CC-BY licens e (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 polic y of the journal  
assistant