Reviewer ’s report  
 
Title: Prognostic and clinical significance of syndecan -1 in colorectal cancer: a meta -analysis  
 
Version: 0 Date: 06 Aug 2015  
 
Reviewer: Jeroen Goos  
 
Reviewer's report:  
 
The study performed by Hao -tang Wei et al. assessed the association of syndecan -1 expression in 
CRC with several clinical parameters and survival, using meta -analysis. Syndecan -1 expressi on 
appeared to be lower in CRC tissue compared to normal colorectal tissue and was associated 
with differentiation grade and tumor stage, but not with lymph node and/or distant metastasis. 
The study was well -performed and the manuscript was clearly written , however, some issues 
need to be addressed.  
 
1) Table 1 provides some information on the selected studies, however, more detail is 
required. That is, information on the clinical parameters should be added per study 
(which of the parameters were assessed i n each study, what were the numbers of patients 
in each of the categories for a particular clinical parameter?) and also information on the 
immunohistochemistry results needs to be added (which categories were used for scoring 
the syndecan -1 expression and  how many patients were in each category, what was 
scored, intensity and/or percentage of stained cells?). Additionally, if antibody source and 
dilution are mentioned, adding the epitope retrieval method may have some added value.  
 
2) Currently, not much c onsensus exists on the evaluation of immunohistochemistry data. 
How did the authors correct for the different scoring systems used in the different 
studies?  
 
 
3) The association between syndecan -1 and "patient survival" is calculated. What do the 
investiga ted studies define as "patient survival"? Is this overall survival, disease -free 
survival, disease -specific survival? If different between studies, how did the authors deal 
with the different survival measures?  
 
4) Syndecan -1 is involved in resistance to c hemotherapy, as is described by X. Wang et al 
(Br J Cancer 2014) to which the authors also refer. Therefore, syndecan -1 expression 
may affect survival of patients treated with chemotherapy and this may confound the 
results regarding the (lack of) prognosti c value. Vice versa, chemotherapy also affects 
syndecan -1 expression (V. Ramani et al., Matrix Biol 2014). Do the investigated studies 
provide information on chemotherapy? If so, the authors should correct for treatment 
with chemotherapy, as this may confo und all analysis.  
 
 
 
5) Results, "Study … Assessment": According to the authors, only four studies provided 
follow -up data, which is also demonstrated in Figure 2F. However, Table 1 shows that 
five studies provided follow -up data. That is, the survival data provided by Wang et  al. 
should also be included in the survival analysis and the calculation of the pooled HR.  
 
6) The authors mention that two different staging systems are used, Dukes and TNM, and 
that syndecan -1 expression was only associated with Dukes staging. In the co nclusion of 
the paper, the authors state that syndecan -1 expression does not correlate with tumor 
stage. First of all, this contradicts the conclusion of the abstract, in which is stated that 
syndecan -1 expression is associated with stage. Second, in order  to fully address this 
issue, the authors may combine both the Dukes and TNM staging systems in - for 
example - the AJCC staging system and reassess the association between syndecan -1 
expression and this combined staging system using all studies.  
  
7) Discussion, second paragraph: The authors state that their finding regarding the lack of 
association between expression and metastasis was consistent with the results of Fujiya et 
al. and contrary to those of Lundin et al. However, according to Figure 2 neithe r study 
provides data on distant metastasis and only Fujiya et al. provides (significant!) 
information on lymph node metastasis.  
 
8) Discussion, second paragraph: The authors state that loss of syndecan -1 is not involved in 
CRC progression. This may be tru e for late stages, based on its lack of association with 
metastasis, however, syndecan -1 may still be involved in early stages of CRC 
progression.  
 
9) Discussion, third paragraph: Regarding the prognostic value of syndecan -1, the authors 
suggest that stat istical power of the analysis was not sufficient. However, the four studies 
included in this analysis contain 531 (60%) patients, which seems to provide sufficient 
statistical power. Nevertheless, even if statistical power is sufficient, the HR is 
approxim ately 1 for three out of the four investigated studies, indicating that the 
prognostic value will be limited anyway.  
 
10) The authors provide a thorough discussion of the limitations of their study. Even though 
it is indicated that the possibility of certa in bias could not be excluded, it may be noted 
that 78% (697/888) of the investigated patients comes from Asiatic studies. This may 
cause some selection bias, as it is well known that CRC incidence greatly differs between 
Asian countries and for example Eu rope, North America and Australia - presumably due 
to environmental factors - which may also involve syndecan -1 expression and its (lack 
of) associations with clinical parameters and survival.  
 
11) More detail should be provided in the legend of Figure 2 ( e.g. used abbreviations and 
statistical tests).  
 
12) There is no reference to Figure 3 in the paper, nor is there a corresponding figure legend.  
 
 
Minor:  
 
- The first sentence of the abstract needs some modification: a comma should be added 
between "suppres sion"  and "transformation" and "cancer cells" should be adjusted to 
"cancer types"  
 
- Third sentence of the abstract: "using published literatures" may be removed  
 
- Materials and methods, "Search strategy … criteria": a reference to the PRISMA 
statement sh ould be added  
 
- Results, "Study … Assessment": the last sentence states that ultrasonography data is 
provided in Table 1. This is not the case.  
 
- Results, "Syndecan -1 … tissue": last sentence of this paragraph is a discussion rather that 
a result and may b e removed  
 
- Results, "Association … prognosis in CRC", first sentence: "in CRC patients" should be 
adjusted to "of CRC patients"  
 
- Table 1: Feng et al. have used EnVision as antibody source, this seems incorrect 
(EnVision is a antibody detection method fro m Dako)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify w hich 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 the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would y ou 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 recommend additional statistical review  
 
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 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 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 competing interests in relation to this paper?  
If you can answer no to al l 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 nam e 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 availabl e 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 included as confidential comments  
to the editors, which will no t be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Prognostic and clinical significance of syndecan -1 in colorectal cancer: a meta -analysis  
 
Version: 0 Date: 06 Aug 2015  
 
Reviewer: Jeroen Goos  
 
Reviewer's report:  
 
The study performed by Hao -tang Wei et al. assessed the association of syndecan -1 expression in 
CRC with several clinical parameters and survival, using meta -analysis. Syndecan -1 expressi on 
appeared to be lower in CRC tissue compared to normal colorectal tissue and was associated 
with differentiation grade and tumor stage, but not with lymph node and/or distant metastasis. 
The study was well -performed and the manuscript was clearly written , however, some issues 
need to be addressed.  
 
1) Table 1 provides some information on the selected studies, however, more detail is 
required. That is, information on the clinical parameters should be added per study 
(which of the parameters were assessed i n each study, what were the numbers of patients 
in each of the categories for a particular clinical parameter?) and also information on the 
immunohistochemistry results needs to be added (which categories were used for scoring 
the syndecan -1 expression and  how many patients were in each category, what was 
scored, intensity and/or percentage of stained cells?). Additionally, if antibody source and 
dilution are mentioned, adding the epitope retrieval method may have some added value.  
 
2) Currently, not much c onsensus exists on the evaluation of immunohistochemistry data. 
How did the authors correct for the different scoring systems used in the different 
studies?  
 
 
3) The association between syndecan -1 and "patient survival" is calculated. What do the 
investiga ted studies define as "patient survival"? Is this overall survival, disease -free 
survival, disease -specific survival? If different between studies, how did the authors deal 
with the different survival measures?  
 
4) Syndecan -1 is involved in resistance to c hemotherapy, as is described by X. Wang et al 
(Br J Cancer 2014) to which the authors also refer. Therefore, syndecan -1 expression 
may affect survival of patients treated with chemotherapy and this may confound the 
results regarding the (lack of) prognosti c value. Vice versa, chemotherapy also affects 
syndecan -1 expression (V. Ramani et al., Matrix Biol 2014). Do the investigated studies 
provide information on chemotherapy? If so, the authors should correct for treatment 
with chemotherapy, as this may confo und all analysis.  
 
 
 
5) Results, "Study … Assessment": According to the authors, only four studies provided 
follow -up data, which is also demonstrated in Figure 2F. However, Table 1 shows that 
five studies provided follow -up data. That is, the survival data provided by Wang et  al. 
should also be included in the survival analysis and the calculation of the pooled HR.  
 
6) The authors mention that two different staging systems are used, Dukes and TNM, and 
that syndecan -1 expression was only associated with Dukes staging. In the co nclusion of 
the paper, the authors state that syndecan -1 expression does not correlate with tumor 
stage. First of all, this contradicts the conclusion of the abstract, in which is stated that 
syndecan -1 expression is associated with stage. Second, in order  to fully address this 
issue, the authors may combine both the Dukes and TNM staging systems in - for 
example - the AJCC staging system and reassess the association between syndecan -1 
expression and this combined staging system using all studies.  
  
7) Discussion, second paragraph: The authors state that their finding regarding the lack of 
association between expression and metastasis was consistent with the results of Fujiya et 
al. and contrary to those of Lundin et al. However, according to Figure 2 neithe r study 
provides data on distant metastasis and only Fujiya et al. provides (significant!) 
information on lymph node metastasis.  
 
8) Discussion, second paragraph: The authors state that loss of syndecan -1 is not involved in 
CRC progression. This may be tru e for late stages, based on its lack of association with 
metastasis, however, syndecan -1 may still be involved in early stages of CRC 
progression.  
 
9) Discussion, third paragraph: Regarding the prognostic value of syndecan -1, the authors 
suggest that stat istical power of the analysis was not sufficient. However, the four studies 
included in this analysis contain 531 (60%) patients, which seems to provide sufficient 
statistical power. Nevertheless, even if statistical power is sufficient, the HR is 
approxim ately 1 for three out of the four investigated studies, indicating that the 
prognostic value will be limited anyway.  
 
10) The authors provide a thorough discussion of the limitations of their study. Even though 
it is indicated that the possibility of certa in bias could not be excluded, it may be noted 
that 78% (697/888) of the investigated patients comes from Asiatic studies. This may 
cause some selection bias, as it is well known that CRC incidence greatly differs between 
Asian countries and for example Eu rope, North America and Australia - presumably due 
to environmental factors - which may also involve syndecan -1 expression and its (lack 
of) associations with clinical parameters and survival.  
 
11) More detail should be provided in the legend of Figure 2 ( e.g. used abbreviations and 
statistical tests).  
 
12) There is no reference to Figure 3 in the paper, nor is there a corresponding figure legend.  
 
 
Minor:  
 
- The first sentence of the abstract needs some modification: a comma should be added 
between "suppres sion"  and "transformation" and "cancer cells" should be adjusted to 
"cancer types"  
 
- Third sentence of the abstract: "using published literatures" may be removed  
 
- Materials and methods, "Search strategy … criteria": a reference to the PRISMA 
statement sh ould be added  
 
- Results, "Study … Assessment": the last sentence states that ultrasonography data is 
provided in Table 1. This is not the case.  
 
- Results, "Syndecan -1 … tissue": last sentence of this paragraph is a discussion rather that 
a result and may b e removed  
 
- Results, "Association … prognosis in CRC", first sentence: "in CRC patients" should be 
adjusted to "of CRC patients"  
 
- Table 1: Feng et al. have used EnVision as antibody source, this seems incorrect 
(EnVision is a antibody detection method fro m Dako)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify w hich 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 the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would y ou 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 recommend additional statistical review  
 
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 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 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 competing interests in relation to this paper?  
If you can answer no to al l 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 nam e 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 availabl e 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 included as confidential comments  
to the editors, which will no t be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Prognostic and clinical significance of syndecan -1 in colorectal cancer: a meta -analysis  
 
Version: 0 Date: 06 Aug 2015  
 
Reviewer: Jeroen Goos  
 
Reviewer's report:  
 
The study performed by Hao -tang Wei et al. assessed the association of syndecan -1 expression in 
CRC with several clinical parameters and survival, using meta -analysis. Syndecan -1 expressi on 
appeared to be lower in CRC tissue compared to normal colorectal tissue and was associated 
with differentiation grade and tumor stage, but not with lymph node and/or distant metastasis. 
The study was well -performed and the manuscript was clearly written , however, some issues 
need to be addressed.  
 
1) Table 1 provides some information on the selected studies, however, more detail is 
required. That is, information on the clinical parameters should be added per study 
(which of the parameters were assessed i n each study, what were the numbers of patients 
in each of the categories for a particular clinical parameter?) and also information on the 
immunohistochemistry results needs to be added (which categories were used for scoring 
the syndecan -1 expression and  how many patients were in each category, what was 
scored, intensity and/or percentage of stained cells?). Additionally, if antibody source and 
dilution are mentioned, adding the epitope retrieval method may have some added value.  
 
2) Currently, not much c onsensus exists on the evaluation of immunohistochemistry data. 
How did the authors correct for the different scoring systems used in the different 
studies?  
 
 
3) The association between syndecan -1 and "patient survival" is calculated. What do the 
investiga ted studies define as "patient survival"? Is this overall survival, disease -free 
survival, disease -specific survival? If different between studies, how did the authors deal 
with the different survival measures?  
 
4) Syndecan -1 is involved in resistance to c hemotherapy, as is described by X. Wang et al 
(Br J Cancer 2014) to which the authors also refer. Therefore, syndecan -1 expression 
may affect survival of patients treated with chemotherapy and this may confound the 
results regarding the (lack of) prognosti c value. Vice versa, chemotherapy also affects 
syndecan -1 expression (V. Ramani et al., Matrix Biol 2014). Do the investigated studies 
provide information on chemotherapy? If so, the authors should correct for treatment 
with chemotherapy, as this may confo und all analysis.  
 
 
 
5) Results, "Study … Assessment": According to the authors, only four studies provided 
follow -up data, which is also demonstrated in Figure 2F. However, Table 1 shows that 
five studies provided follow -up data. That is, the survival data provided by Wang et  al. 
should also be included in the survival analysis and the calculation of the pooled HR.  
 
6) The authors mention that two different staging systems are used, Dukes and TNM, and 
that syndecan -1 expression was only associated with Dukes staging. In the co nclusion of 
the paper, the authors state that syndecan -1 expression does not correlate with tumor 
stage. First of all, this contradicts the conclusion of the abstract, in which is stated that 
syndecan -1 expression is associated with stage. Second, in order  to fully address this 
issue, the authors may combine both the Dukes and TNM staging systems in - for 
example - the AJCC staging system and reassess the association between syndecan -1 
expression and this combined staging system using all studies.  
  
7) Discussion, second paragraph: The authors state that their finding regarding the lack of 
association between expression and metastasis was consistent with the results of Fujiya et 
al. and contrary to those of Lundin et al. However, according to Figure 2 neithe r study 
provides data on distant metastasis and only Fujiya et al. provides (significant!) 
information on lymph node metastasis.  
 
8) Discussion, second paragraph: The authors state that loss of syndecan -1 is not involved in 
CRC progression. This may be tru e for late stages, based on its lack of association with 
metastasis, however, syndecan -1 may still be involved in early stages of CRC 
progression.  
 
9) Discussion, third paragraph: Regarding the prognostic value of syndecan -1, the authors 
suggest that stat istical power of the analysis was not sufficient. However, the four studies 
included in this analysis contain 531 (60%) patients, which seems to provide sufficient 
statistical power. Nevertheless, even if statistical power is sufficient, the HR is 
approxim ately 1 for three out of the four investigated studies, indicating that the 
prognostic value will be limited anyway.  
 
10) The authors provide a thorough discussion of the limitations of their study. Even though 
it is indicated that the possibility of certa in bias could not be excluded, it may be noted 
that 78% (697/888) of the investigated patients comes from Asiatic studies. This may 
cause some selection bias, as it is well known that CRC incidence greatly differs between 
Asian countries and for example Eu rope, North America and Australia - presumably due 
to environmental factors - which may also involve syndecan -1 expression and its (lack 
of) associations with clinical parameters and survival.  
 
11) More detail should be provided in the legend of Figure 2 ( e.g. used abbreviations and 
statistical tests).  
 
12) There is no reference to Figure 3 in the paper, nor is there a corresponding figure legend.  
 
 
Minor:  
 
- The first sentence of the abstract needs some modification: a comma should be added 
between "suppres sion"  and "transformation" and "cancer cells" should be adjusted to 
"cancer types"  
 
- Third sentence of the abstract: "using published literatures" may be removed  
 
- Materials and methods, "Search strategy … criteria": a reference to the PRISMA 
statement sh ould be added  
 
- Results, "Study … Assessment": the last sentence states that ultrasonography data is 
provided in Table 1. This is not the case.  
 
- Results, "Syndecan -1 … tissue": last sentence of this paragraph is a discussion rather that 
a result and may b e removed  
 
- Results, "Association … prognosis in CRC", first sentence: "in CRC patients" should be 
adjusted to "of CRC patients"  
 
- Table 1: Feng et al. have used EnVision as antibody source, this seems incorrect 
(EnVision is a antibody detection method fro m Dako)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify w hich 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 the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would y ou 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 recommend additional statistical review  
 
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 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 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 competing interests in relation to this paper?  
If you can answer no to al l 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 nam e 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 availabl e 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 included as confidential comments  
to the editors, which will no t be published.  
 
I agree to the open peer review policy of the journal  
assistant