Reviewer’s report
Title: 
Sex difference in the incidence of cardia and non-cardia gastric cancer in the United States, 1992-
2014
Version: 
0 
Date: 
26 Aug 2020
Reviewer's report:
In this manuscript, Yao et al. rely on data from 13 registries in the SEER Program to examine trends in
male to female ratios for cardia and non-cardia gastric cancer incidence in the United States from 1992 to
2014. The authors further track these ratios across different age groups, ethnicities, and histologic
subtypes. These observations highlight interesting and thought-provoking trends in gastric cancer and
present new evidence that might prove useful when trying to understand protective effects against the
development of gastric cancer. While I found the manuscript to be straightforward in its approach, I do
have some concerns in the authors' interpretation of these trends and how this fits with what is known in
the field. The manuscript is purely observational, and the Discussion speculates on explanations for these
observed trends, but I think that some of the conclusions are not consistent with previous reports or even
with the results that are presented. More specific comments are included below:
* The authors do not have a clear hypothesis that states what they are seeking to study. "Etiological clues"
(p.4, lines 56-58) seems open-ended and not hypothesis-driven. The authors may want to explicitly state
that they are seeking to identify how male:female ratios for cardia and non-cardia gastric cancer differ with
respect to age, ethnicity, and histologic subtype.
* Were white patients further divided into Hispanic and non-Hispanic? If not, this might overestimate the
non-cardia gastric cancer burden among whites, given the high incidence of gastric cancer and high
prevalence of Helicobacter pylori (H. pylori) in patients of Latin American origin. Similarly, it may
underestimate the burden of cardia gastric cancer, since some evidence suggests that cardia gastric cancer
is more prevalent among non-Hispanic whites than Hispanic whites. 
* On p. 7 (lines 34-36), what do the authors mean by "relatively similar distinct patterns across ethnic
groups?"
* Can diffuse type gastric cancer be limited to the cardia? How many patients with diffuse type gastric
cancer had involvement of the cardia alone as opposed to involvement of the non-cardia alone, or both?
* Though there is a greater number of cases of non-cardia gastric cancer compared to cardia gastric cancer,
the M:F incidence rates seem to be more variable and pronounced for cardia gastric cancer compared to
non-cardia gastric cancer. That ratio also seems to increase more rapidly with respect to age for cardia
gastric cancer compared to non-cardia gastric cancer. The authors may want to explain why they think that
this is the case.
* On p. 7 (lines 36-41), I am not sure that I completely agree with the statement that the M:F ratios in non-
cardia gastric cancer increased with age for blacks up until age 60, then decreased, while it generally
increased for whites and Asians/Pacific Islanders. In Figure 1, it seems to me that the ratios seem to
slightly increase across all ethnic groups up until age ~60. That ratio decreases somewhat in blacks
thereafter but appears to be generally stable in whites and Asians/Pacific Islanders.
* I would not expect there to be significant differences in sex ratios in patients with diffuse gastric cancer,
as that has a known genetic basis and is less dependent on environmental risk factors (i.e., H. pylori
infection). 
* In Figure 3, there seems to be high variability in the rate difference and rate ratios for cardia and non-
cardia gastric cancers among blacks and Asians/Pacific Islanders over the time period studied. How would
the authors explain this?
* The rate difference in non-cardia gastric cancer seems to be increasing in Blacks toward the end of the
time period studied (2010-2014). Why might this be, in the authors' opinion?
* How exactly are the rate ratios calculated? Why is the rate ratio for cardia gastric cancer so variable
(wide range for confidence intervals) among all ethnic groups (Table 2)?
* I would contend with some of the authors' interpretations of the data that are mentioned in the
Discussion. For example, while it is possible that the decrease in estrogens during the post-menopausal
years may result in a decreased protective effect against cardia gastric cancer, as the authors suggest, the
decrease in M:F ratio does not appear until more than a decade after when most women experience
menopause (~age 50) across all ethnic groups studied (Figure 1). Among whites with cardia gastric
cancer, for example, that ratio decreases slightly at older ages, but it still remains heavily skewed toward
males (ratio > 3). The lack of decrease in the M:F ratio in non-cardia gastric cancer is likely independent
of estrogen, since the biggest risk factor for non-cardia gastric cancer is chronic infection with H. pylori,
which often occurs during childhood (pre-puberty).
* Related to the previous comment, I think that it might be oversimplifying to suggest that hormones alone
account for differences in the sex ratios for cardia gastric cancer. Since cardia gastric cancer is likely
similar to esophageal adenocarcinoma, other factors, such as visceral abdominal fat, should be considered.
The authors should also mention and/or reference studies looking at exposure prevalence in other risk
factors, such as smoking, between men and women within and across ethnic groups.
* Though this is not directly related to this study, did these registries show a similar trend between cardia
gastric cancer and esophageal adenocarcinoma? Did men and women with cardia gastric cancer have
similar rates of Barrett's esophagus? If they did, then this might support the idea that estrogens can protect
against the development of esophageal adenocarcinoma and/or cardia gastric cancer.
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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 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.
Reviewer Publication Consent.
 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
) if this manuscript is
accepted for publication. Any comments that I do not wish to be included in the published report have
been included as confidential comments to the editor, which will not be published.
If you are not happy for us to publish this report, please contact the editorial office before completing
the review.
If you wish, you can include your name in your published report. Please note you must decide whether
to include your name at the start of the process and confirm this decision whenever prompted. If you
change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name with my report. (default)
Is the study design appropriate to answer the research question (including the use of appropriate controls),
and are the conclusions supported by the evidence presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free from apparent
manipulation?
Yes
Reviewer’s report
Title: 
Sex difference in the incidence of cardia and non-cardia gastric cancer in the United States, 1992-
2014
Version: 
0 
Date: 
26 Aug 2020
Reviewer's report:
In this manuscript, Yao et al. rely on data from 13 registries in the SEER Program to examine trends in
male to female ratios for cardia and non-cardia gastric cancer incidence in the United States from 1992 to
2014. The authors further track these ratios across different age groups, ethnicities, and histologic
subtypes. These observations highlight interesting and thought-provoking trends in gastric cancer and
present new evidence that might prove useful when trying to understand protective effects against the
development of gastric cancer. While I found the manuscript to be straightforward in its approach, I do
have some concerns in the authors' interpretation of these trends and how this fits with what is known in
the field. The manuscript is purely observational, and the Discussion speculates on explanations for these
observed trends, but I think that some of the conclusions are not consistent with previous reports or even
with the results that are presented. More specific comments are included below:
* The authors do not have a clear hypothesis that states what they are seeking to study. "Etiological clues"
(p.4, lines 56-58) seems open-ended and not hypothesis-driven. The authors may want to explicitly state
that they are seeking to identify how male:female ratios for cardia and non-cardia gastric cancer differ with
respect to age, ethnicity, and histologic subtype.
* Were white patients further divided into Hispanic and non-Hispanic? If not, this might overestimate the
non-cardia gastric cancer burden among whites, given the high incidence of gastric cancer and high
prevalence of Helicobacter pylori (H. pylori) in patients of Latin American origin. Similarly, it may
underestimate the burden of cardia gastric cancer, since some evidence suggests that cardia gastric cancer
is more prevalent among non-Hispanic whites than Hispanic whites. 
* On p. 7 (lines 34-36), what do the authors mean by "relatively similar distinct patterns across ethnic
groups?"
* Can diffuse type gastric cancer be limited to the cardia? How many patients with diffuse type gastric
cancer had involvement of the cardia alone as opposed to involvement of the non-cardia alone, or both?
* Though there is a greater number of cases of non-cardia gastric cancer compared to cardia gastric cancer,
the M:F incidence rates seem to be more variable and pronounced for cardia gastric cancer compared to
non-cardia gastric cancer. That ratio also seems to increase more rapidly with respect to age for cardia
gastric cancer compared to non-cardia gastric cancer. The authors may want to explain why they think that
this is the case.
* On p. 7 (lines 36-41), I am not sure that I completely agree with the statement that the M:F ratios in non-
cardia gastric cancer increased with age for blacks up until age 60, then decreased, while it generally
increased for whites and Asians/Pacific Islanders. In Figure 1, it seems to me that the ratios seem to
slightly increase across all ethnic groups up until age ~60. That ratio decreases somewhat in blacks
thereafter but appears to be generally stable in whites and Asians/Pacific Islanders.
* I would not expect there to be significant differences in sex ratios in patients with diffuse gastric cancer,
as that has a known genetic basis and is less dependent on environmental risk factors (i.e., H. pylori
infection). 
* In Figure 3, there seems to be high variability in the rate difference and rate ratios for cardia and non-
cardia gastric cancers among blacks and Asians/Pacific Islanders over the time period studied. How would
the authors explain this?
* The rate difference in non-cardia gastric cancer seems to be increasing in Blacks toward the end of the
time period studied (2010-2014). Why might this be, in the authors' opinion?
* How exactly are the rate ratios calculated? Why is the rate ratio for cardia gastric cancer so variable
(wide range for confidence intervals) among all ethnic groups (Table 2)?
* I would contend with some of the authors' interpretations of the data that are mentioned in the
Discussion. For example, while it is possible that the decrease in estrogens during the post-menopausal
years may result in a decreased protective effect against cardia gastric cancer, as the authors suggest, the
decrease in M:F ratio does not appear until more than a decade after when most women experience
menopause (~age 50) across all ethnic groups studied (Figure 1). Among whites with cardia gastric
cancer, for example, that ratio decreases slightly at older ages, but it still remains heavily skewed toward
males (ratio > 3). The lack of decrease in the M:F ratio in non-cardia gastric cancer is likely independent
of estrogen, since the biggest risk factor for non-cardia gastric cancer is chronic infection with H. pylori,
which often occurs during childhood (pre-puberty).
* Related to the previous comment, I think that it might be oversimplifying to suggest that hormones alone
account for differences in the sex ratios for cardia gastric cancer. Since cardia gastric cancer is likely
similar to esophageal adenocarcinoma, other factors, such as visceral abdominal fat, should be considered.
The authors should also mention and/or reference studies looking at exposure prevalence in other risk
factors, such as smoking, between men and women within and across ethnic groups.
* Though this is not directly related to this study, did these registries show a similar trend between cardia
gastric cancer and esophageal adenocarcinoma? Did men and women with cardia gastric cancer have
similar rates of Barrett's esophagus? If they did, then this might support the idea that estrogens can protect
against the development of esophageal adenocarcinoma and/or cardia gastric cancer.
Publons Reviewer Recognition
. Springer Nature can send verification of this review directly to Publons
(a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on
the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted to Publons upon
publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt
of this review and update your profile 
as per your settings and their policy. If you are not registered with
Publons, you will receive an email from them asking you to register in order for them to be able to
recognize your review on your new profile page. Publons may use the Review Data to generate derivative
metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such
information. For example, Publons may verify your record as a reviewer by updating your profile
published on its webservice if you have registered for such service or help editors to identify candidate
reviewers. Please find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
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 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.
Reviewer Publication Consent.
 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
) if this manuscript is
accepted for publication. Any comments that I do not wish to be included in the published report have
been included as confidential comments to the editor, which will not be published.
If you are not happy for us to publish this report, please contact the editorial office before completing
the review.
If you wish, you can include your name in your published report. Please note you must decide whether
to include your name at the start of the process and confirm this decision whenever prompted. If you
change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name with my report. (default)
Is the study design appropriate to answer the research question (including the use of appropriate controls),
and are the conclusions supported by the evidence presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free from apparent
manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
Sex difference in the incidence of cardia and non-cardia gastric cancer in the United States, 1992-
2014
Version: 
0 
Date: 
26 Aug 2020
Reviewer's report:
In this manuscript, Yao et al. rely on data from 13 registries in the SEER Program to examine trends in
male to female ratios for cardia and non-cardia gastric cancer incidence in the United States from 1992 to
2014. The authors further track these ratios across different age groups, ethnicities, and histologic
subtypes. These observations highlight interesting and thought-provoking trends in gastric cancer and
present new evidence that might prove useful when trying to understand protective effects against the
development of gastric cancer. While I found the manuscript to be straightforward in its approach, I do
have some concerns in the authors' interpretation of these trends and how this fits with what is known in
the field. The manuscript is purely observational, and the Discussion speculates on explanations for these
observed trends, but I think that some of the conclusions are not consistent with previous reports or even
with the results that are presented. More specific comments are included below:
* The authors do not have a clear hypothesis that states what they are seeking to study. "Etiological clues"
(p.4, lines 56-58) seems open-ended and not hypothesis-driven. The authors may want to explicitly state
that they are seeking to identify how male:female ratios for cardia and non-cardia gastric cancer differ with
respect to age, ethnicity, and histologic subtype.
* Were white patients further divided into Hispanic and non-Hispanic? If not, this might overestimate the
non-cardia gastric cancer burden among whites, given the high incidence of gastric cancer and high
prevalence of Helicobacter pylori (H. pylori) in patients of Latin American origin. Similarly, it may
underestimate the burden of cardia gastric cancer, since some evidence suggests that cardia gastric cancer
is more prevalent among non-Hispanic whites than Hispanic whites. 
* On p. 7 (lines 34-36), what do the authors mean by "relatively similar distinct patterns across ethnic
groups?"
* Can diffuse type gastric cancer be limited to the cardia? How many patients with diffuse type gastric
cancer had involvement of the cardia alone as opposed to involvement of the non-cardia alone, or both?
* Though there is a greater number of cases of non-cardia gastric cancer compared to cardia gastric cancer,
the M:F incidence rates seem to be more variable and pronounced for cardia gastric cancer compared to
non-cardia gastric cancer. That ratio also seems to increase more rapidly with respect to age for cardia
gastric cancer compared to non-cardia gastric cancer. The authors may want to explain why they think that
this is the case.
* On p. 7 (lines 36-41), I am not sure that I completely agree with the statement that the M:F ratios in non-
cardia gastric cancer increased with age for blacks up until age 60, then decreased, while it generally
increased for whites and Asians/Pacific Islanders. In Figure 1, it seems to me that the ratios seem to
slightly increase across all ethnic groups up until age ~60. That ratio decreases somewhat in blacks
thereafter but appears to be generally stable in whites and Asians/Pacific Islanders.
* I would not expect there to be significant differences in sex ratios in patients with diffuse gastric cancer,
as that has a known genetic basis and is less dependent on environmental risk factors (i.e., H. pylori
infection). 
* In Figure 3, there seems to be high variability in the rate difference and rate ratios for cardia and non-
cardia gastric cancers among blacks and Asians/Pacific Islanders over the time period studied. How would
the authors explain this?
* The rate difference in non-cardia gastric cancer seems to be increasing in Blacks toward the end of the
time period studied (2010-2014). Why might this be, in the authors' opinion?
* How exactly are the rate ratios calculated? Why is the rate ratio for cardia gastric cancer so variable
(wide range for confidence intervals) among all ethnic groups (Table 2)?
* I would contend with some of the authors' interpretations of the data that are mentioned in the
Discussion. For example, while it is possible that the decrease in estrogens during the post-menopausal
years may result in a decreased protective effect against cardia gastric cancer, as the authors suggest, the
decrease in M:F ratio does not appear until more than a decade after when most women experience
menopause (~age 50) across all ethnic groups studied (Figure 1). Among whites with cardia gastric
cancer, for example, that ratio decreases slightly at older ages, but it still remains heavily skewed toward
males (ratio > 3). The lack of decrease in the M:F ratio in non-cardia gastric cancer is likely independent
of estrogen, since the biggest risk factor for non-cardia gastric cancer is chronic infection with H. pylori,
which often occurs during childhood (pre-puberty).
* Related to the previous comment, I think that it might be oversimplifying to suggest that hormones alone
account for differences in the sex ratios for cardia gastric cancer. Since cardia gastric cancer is likely
similar to esophageal adenocarcinoma, other factors, such as visceral abdominal fat, should be considered.
The authors should also mention and/or reference studies looking at exposure prevalence in other risk
factors, such as smoking, between men and women within and across ethnic groups.
* Though this is not directly related to this study, did these registries show a similar trend between cardia
gastric cancer and esophageal adenocarcinoma? Did men and women with cardia gastric cancer have
similar rates of Barrett's esophagus? If they did, then this might support the idea that estrogens can protect
against the development of esophageal adenocarcinoma and/or cardia gastric cancer.
Publons Reviewer Recognition
. Springer Nature can send verification of this review directly to Publons
(a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on
the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted to Publons upon
publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt
of this review and update your profile 
as per your settings and their policy. If you are not registered with
Publons, you will receive an email from them asking you to register in order for them to be able to
recognize your review on your new profile page. Publons may use the Review Data to generate derivative
metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such
information. For example, Publons may verify your record as a reviewer by updating your profile
published on its webservice if you have registered for such service or help editors to identify candidate
reviewers. Please find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
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 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.
Reviewer Publication Consent.
 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
) if this manuscript is
accepted for publication. Any comments that I do not wish to be included in the published report have
been included as confidential comments to the editor, which will not be published.
If you are not happy for us to publish this report, please contact the editorial office before completing
the review.
If you wish, you can include your name in your published report. Please note you must decide whether
to include your name at the start of the process and confirm this decision whenever prompted. If you
change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name with my report. (default)
Is the study design appropriate to answer the research question (including the use of appropriate controls),
and are the conclusions supported by the evidence presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free from apparent
manipulation?
Yes
assistant