Reviewer ’s report  
 
Title: p53 expression in patients with ulcerative colitis - associated with dysplasia and 
carcinoma: a systematic meta -analysis  
 
Version: 0 Date: 12 Jun 2017  
 
Reviewer: Julajak Limsrivilai  
 
Reviewer's report:  
 
The study concept is good. This is the first meta -analysis to determine the association between 
p53 expression and the risk of dysplasia  and cancer in patients with ulcerative colitis (UC). 
However, the meta -analysis of the association between KRAS and TP53 mutations with IBD -
associated colorectal cancer has recently been published (Du L et al., Oncotarget 2017). Please 
find my comments be low. 
1. The study by Vento et al. (ref. 16 in the manuscript) included 52 patients who underwent 
restorative proctocolectomy with construction of an ileal reservoir (42 patients with 
pouchitis, 10 patients normal ileoanal pouch), and 9 healthy subjects. T he specimens in this 
study were ileal tissue and not colonic tissue. Should this study be included in the meta -
analysis?  
2. The criteria to categorize the patients/tissues into each group in this meta -analysis is 
confusing. The tissues without dysplasia but from the patient with UC and dysplasia were 
categorized as UC without dysplasia group in some studies (e.g. Friis -Ottessen et al., ref. 14 
in manuscript), but were categorized as UC with dysplasia in the study by Sato et al. (ref. 25 
in manuscript). Pl ease kindly clarify this issue.  
3. The authors stated that the literature search was performed up to February 13th, 2017. 
However, some studies may have been missed. Some examples are among the studies 
below.  
- Wong NA, Mayer NJ, MacKell S, Gilm our HM, Harrison DJ: Immunohistochemical 
assessment of Ki67 and p53 expression assists the diagnosis and grading of ulcerative colitis -
related dysplasia. Histopathology 2000, 37(2):108 -114. 
- Ilyas M, Talbot IC: p53 expression in ulcerative colitis : a longitudinal study. Gut 1995, 
37(6):802 -804. 
 Could the authors kindly provide the reasons for excluding these studies?  
4. The authors did not include the studies which included both Crohn's disease and ulcerative 
colitis patients in this meta -analysis. The data would be more complete if the authors can 
obtain more information specifically for UC patients in those studies and include them in 
this meta -analysis. One example is the following study.  
- Laurent C, Svrcek M, Flejou JF, Chenard  MP, Duclos B, Freund JN, Reimund JM: 
Immunohistochemical expression of CDX2, beta -catenin, and TP53 in inflammatory bowel 
disease -associated colorectal cancer. Inflamm Bowel Dis 2011, 17(1):232 -240.  
(20 of 31 IBD patients with colorectal cancer had UC)  
5. In the search strategy section, Boolean operators in the search term, such as AND and OR, 
should be entered in uppercase letter.  
6. I do not understand how the authors interpreted the results of sensitivity analysis in the 
section 3.5. To the best of my knowledge, sensitivity analysis is performed to investigate the 
validity and robustness of the meta -analysis. There are 2 main methods.  
1. Applying the meta -analysis to subsets of studies based on high -quality versus low -quality 
studies, early studies versus late studies, and etc.  
2. Applying the leave -one-out method  
       In this meta -analysis, the authors stated in the Method section that they used the leave -one-
out method, which is done by performing a meta -analysis on each subset of  the studies obtained 
by leaving out exactly one study. Thus, there should be 12 meta -analyses in the sensitivity 
analysis in UC with dysplasia vs. without dysplasia or carcinoma (the same numbers as the 
numbers of studies included in the meta -analysis com paring UC with dysplasia vs. UC without 
dysplasia or carcinoma). If the results of each meta -analysis in these 12 meta -analyses are 
consistent, then there is confidence that the overall meta -analysis is robust and not dependent on 
any single study.  
       However, in the Results section, the authors reported the results of sensitivity analysis by 
reporting the result of only one meta -analysis with removal of the study by Klump et al.. This 
looks like the way to report the results when sensitivity analysis i s done by the 1st method. In 
this case, the authors should have stated the criteria of selection or removal of the studies for the 
sensitivity analysis.   
7. I would like to see the grading of quality of the studies included in this meta -analysis.  
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, ple ase 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 furthe r 
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, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publi cation 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 of this manuscript, either now or in the future?  
 
3. Do you hold or are you curr ently 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 competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that 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 repo rt 
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 understan d 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: p53 expression in patients with ulcerative colitis - associated with dysplasia and 
carcinoma: a systematic meta -analysis  
 
Version: 0 Date: 12 Jun 2017  
 
Reviewer: Julajak Limsrivilai  
 
Reviewer's report:  
 
The study concept is good. This is the first meta -analysis to determine the association between 
p53 expression and the risk of dysplasia  and cancer in patients with ulcerative colitis (UC). 
However, the meta -analysis of the association between KRAS and TP53 mutations with IBD -
associated colorectal cancer has recently been published (Du L et al., Oncotarget 2017). Please 
find my comments be low. 
1. The study by Vento et al. (ref. 16 in the manuscript) included 52 patients who underwent 
restorative proctocolectomy with construction of an ileal reservoir (42 patients with 
pouchitis, 10 patients normal ileoanal pouch), and 9 healthy subjects. T he specimens in this 
study were ileal tissue and not colonic tissue. Should this study be included in the meta -
analysis?  
2. The criteria to categorize the patients/tissues into each group in this meta -analysis is 
confusing. The tissues without dysplasia but from the patient with UC and dysplasia were 
categorized as UC without dysplasia group in some studies (e.g. Friis -Ottessen et al., ref. 14 
in manuscript), but were categorized as UC with dysplasia in the study by Sato et al. (ref. 25 
in manuscript). Pl ease kindly clarify this issue.  
3. The authors stated that the literature search was performed up to February 13th, 2017. 
However, some studies may have been missed. Some examples are among the studies 
below.  
- Wong NA, Mayer NJ, MacKell S, Gilm our HM, Harrison DJ: Immunohistochemical 
assessment of Ki67 and p53 expression assists the diagnosis and grading of ulcerative colitis -
related dysplasia. Histopathology 2000, 37(2):108 -114. 
- Ilyas M, Talbot IC: p53 expression in ulcerative colitis : a longitudinal study. Gut 1995, 
37(6):802 -804. 
 Could the authors kindly provide the reasons for excluding these studies?  
4. The authors did not include the studies which included both Crohn's disease and ulcerative 
colitis patients in this meta -analysis. The data would be more complete if the authors can 
obtain more information specifically for UC patients in those studies and include them in 
this meta -analysis. One example is the following study.  
- Laurent C, Svrcek M, Flejou JF, Chenard  MP, Duclos B, Freund JN, Reimund JM: 
Immunohistochemical expression of CDX2, beta -catenin, and TP53 in inflammatory bowel 
disease -associated colorectal cancer. Inflamm Bowel Dis 2011, 17(1):232 -240.  
(20 of 31 IBD patients with colorectal cancer had UC)  
5. In the search strategy section, Boolean operators in the search term, such as AND and OR, 
should be entered in uppercase letter.  
6. I do not understand how the authors interpreted the results of sensitivity analysis in the 
section 3.5. To the best of my knowledge, sensitivity analysis is performed to investigate the 
validity and robustness of the meta -analysis. There are 2 main methods.  
1. Applying the meta -analysis to subsets of studies based on high -quality versus low -quality 
studies, early studies versus late studies, and etc.  
2. Applying the leave -one-out method  
       In this meta -analysis, the authors stated in the Method section that they used the leave -one-
out method, which is done by performing a meta -analysis on each subset of  the studies obtained 
by leaving out exactly one study. Thus, there should be 12 meta -analyses in the sensitivity 
analysis in UC with dysplasia vs. without dysplasia or carcinoma (the same numbers as the 
numbers of studies included in the meta -analysis com paring UC with dysplasia vs. UC without 
dysplasia or carcinoma). If the results of each meta -analysis in these 12 meta -analyses are 
consistent, then there is confidence that the overall meta -analysis is robust and not dependent on 
any single study.  
       However, in the Results section, the authors reported the results of sensitivity analysis by 
reporting the result of only one meta -analysis with removal of the study by Klump et al.. This 
looks like the way to report the results when sensitivity analysis i s done by the 1st method. In 
this case, the authors should have stated the criteria of selection or removal of the studies for the 
sensitivity analysis.   
7. I would like to see the grading of quality of the studies included in this meta -analysis.  
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, ple ase 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 furthe r 
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, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publi cation 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 of this manuscript, either now or in the future?  
 
3. Do you hold or are you curr ently 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 competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that 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 repo rt 
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 understan d 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: p53 expression in patients with ulcerative colitis - associated with dysplasia and 
carcinoma: a systematic meta -analysis  
 
Version: 0 Date: 12 Jun 2017  
 
Reviewer: Julajak Limsrivilai  
 
Reviewer's report:  
 
The study concept is good. This is the first meta -analysis to determine the association between 
p53 expression and the risk of dysplasia  and cancer in patients with ulcerative colitis (UC). 
However, the meta -analysis of the association between KRAS and TP53 mutations with IBD -
associated colorectal cancer has recently been published (Du L et al., Oncotarget 2017). Please 
find my comments be low. 
1. The study by Vento et al. (ref. 16 in the manuscript) included 52 patients who underwent 
restorative proctocolectomy with construction of an ileal reservoir (42 patients with 
pouchitis, 10 patients normal ileoanal pouch), and 9 healthy subjects. T he specimens in this 
study were ileal tissue and not colonic tissue. Should this study be included in the meta -
analysis?  
2. The criteria to categorize the patients/tissues into each group in this meta -analysis is 
confusing. The tissues without dysplasia but from the patient with UC and dysplasia were 
categorized as UC without dysplasia group in some studies (e.g. Friis -Ottessen et al., ref. 14 
in manuscript), but were categorized as UC with dysplasia in the study by Sato et al. (ref. 25 
in manuscript). Pl ease kindly clarify this issue.  
3. The authors stated that the literature search was performed up to February 13th, 2017. 
However, some studies may have been missed. Some examples are among the studies 
below.  
- Wong NA, Mayer NJ, MacKell S, Gilm our HM, Harrison DJ: Immunohistochemical 
assessment of Ki67 and p53 expression assists the diagnosis and grading of ulcerative colitis -
related dysplasia. Histopathology 2000, 37(2):108 -114. 
- Ilyas M, Talbot IC: p53 expression in ulcerative colitis : a longitudinal study. Gut 1995, 
37(6):802 -804. 
 Could the authors kindly provide the reasons for excluding these studies?  
4. The authors did not include the studies which included both Crohn's disease and ulcerative 
colitis patients in this meta -analysis. The data would be more complete if the authors can 
obtain more information specifically for UC patients in those studies and include them in 
this meta -analysis. One example is the following study.  
- Laurent C, Svrcek M, Flejou JF, Chenard  MP, Duclos B, Freund JN, Reimund JM: 
Immunohistochemical expression of CDX2, beta -catenin, and TP53 in inflammatory bowel 
disease -associated colorectal cancer. Inflamm Bowel Dis 2011, 17(1):232 -240.  
(20 of 31 IBD patients with colorectal cancer had UC)  
5. In the search strategy section, Boolean operators in the search term, such as AND and OR, 
should be entered in uppercase letter.  
6. I do not understand how the authors interpreted the results of sensitivity analysis in the 
section 3.5. To the best of my knowledge, sensitivity analysis is performed to investigate the 
validity and robustness of the meta -analysis. There are 2 main methods.  
1. Applying the meta -analysis to subsets of studies based on high -quality versus low -quality 
studies, early studies versus late studies, and etc.  
2. Applying the leave -one-out method  
       In this meta -analysis, the authors stated in the Method section that they used the leave -one-
out method, which is done by performing a meta -analysis on each subset of  the studies obtained 
by leaving out exactly one study. Thus, there should be 12 meta -analyses in the sensitivity 
analysis in UC with dysplasia vs. without dysplasia or carcinoma (the same numbers as the 
numbers of studies included in the meta -analysis com paring UC with dysplasia vs. UC without 
dysplasia or carcinoma). If the results of each meta -analysis in these 12 meta -analyses are 
consistent, then there is confidence that the overall meta -analysis is robust and not dependent on 
any single study.  
       However, in the Results section, the authors reported the results of sensitivity analysis by 
reporting the result of only one meta -analysis with removal of the study by Klump et al.. This 
looks like the way to report the results when sensitivity analysis i s done by the 1st method. In 
this case, the authors should have stated the criteria of selection or removal of the studies for the 
sensitivity analysis.   
7. I would like to see the grading of quality of the studies included in this meta -analysis.  
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, ple ase 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 furthe r 
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, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publi cation 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 of this manuscript, either now or in the future?  
 
3. Do you hold or are you curr ently 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 competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that 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 repo rt 
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 understan d 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