Title: Both the serum AFP test and AFP/GPC3/SALL4 immunohistochemistry are beneficial
for predicting the prognosis of gastric adenocarcinoma
Version: 2 Date: 06 Sep 2021
Reviewer:  Nikolaos Charalampakis
Reviewer's report:
This manuscript describes the results of a retrospective analysis of patients with rare gastric
adenocarcinoma subtypes that express AFP or manifest with primary enterocyte phenotype. The
authors separated patients into two groups based on preoperative measurements of AFP. Patients
in the operable group were further divided according to AFP expression or GAPEP phenotype
positivity. The authors of this study should be praised for touching on a rare tumor subtype,
which is usually associated with negative prognosis. The manuscript is well written, in a proper
and concise manner and study methods lead to clear and logical conclusions.
The strongest point of this study is the clear association between high AFP expression and
GAPEP phenotype, which is indicative of the fact that these tumors might represent a distinct
entity in gastric cancer, with clear and identifiable molecular and clinical characteristics.
The study has a few minor weaknesses, which should be discussed more clearly in the
manuscript:
1. AFP is a serum value that can be elevated in a variety of pathological conditions, such as liver
disease. Although patients with acute hepatitis were excluded from the study, the authors do not
mention possible comorbidities in patients with high AFP.
2. AFP expressing gastric cancer and GAPEP are rare tumors, resulting in disparities in subgroup
populations that hinder statistical analysis. Over 90% of patients included in this study did not
express AFP or GAPEP phenotype.
3. Group B included patients based on the expression of AFP alone, regardless of subsequent
treatment. The value of the findings in this subgroup is not adequately explained. There is an
association of increased AFP with worse prognosis, but as mentioned in the text, the majority
of patients in this subgroup had liver metastases. A previous study by Hirajima et al. (2013)
concluded that increased AFP could not be used as an independent prognostic marker in
AFP-producing gastric cancer and that the only independent factor was the presence of liver
metastases. Moreover, as mentioned by the authors, there was no comparator arm in group B.
4. In Group A, patients with high AFP or GAPEP, on average, presented with more advanced
disease, which is an independent negative prognostic factor. Although the PSM analysis showed
a statistically significant difference in outcomes for AFP-high patients when other factors were
taken into consideration, unequal distribution of patients between the comparator groups might
have confounded the outcomes.
5. In the paper, it is mentioned that 7 patients with high levels of preoperative AFP were
monitored afterwards and AFP dropped after surgery and within the next year. It would be
interesting if survival data of these patients were available.
Title: Both the serum AFP test and AFP/GPC3/SALL4 immunohistochemistry are beneficial
for predicting the prognosis of gastric adenocarcinoma
Version: 2 Date: 06 Sep 2021
Reviewer:  Nikolaos Charalampakis
Reviewer's report:
This manuscript describes the results of a retrospective analysis of patients with rare gastric
adenocarcinoma subtypes that express AFP or manifest with primary enterocyte phenotype. The
authors separated patients into two groups based on preoperative measurements of AFP. Patients
in the operable group were further divided according to AFP expression or GAPEP phenotype
positivity. The authors of this study should be praised for touching on a rare tumor subtype,
which is usually associated with negative prognosis. The manuscript is well written, in a proper
and concise manner and study methods lead to clear and logical conclusions.
The strongest point of this study is the clear association between high AFP expression and
GAPEP phenotype, which is indicative of the fact that these tumors might represent a distinct
entity in gastric cancer, with clear and identifiable molecular and clinical characteristics.
The study has a few minor weaknesses, which should be discussed more clearly in the
manuscript:
1. AFP is a serum value that can be elevated in a variety of pathological conditions, such as liver
disease. Although patients with acute hepatitis were excluded from the study, the authors do not
mention possible comorbidities in patients with high AFP.
2. AFP expressing gastric cancer and GAPEP are rare tumors, resulting in disparities in subgroup
populations that hinder statistical analysis. Over 90% of patients included in this study did not
express AFP or GAPEP phenotype.
3. Group B included patients based on the expression of AFP alone, regardless of subsequent
treatment. The value of the findings in this subgroup is not adequately explained. There is an
association of increased AFP with worse prognosis, but as mentioned in the text, the majority
of patients in this subgroup had liver metastases. A previous study by Hirajima et al. (2013)
concluded that increased AFP could not be used as an independent prognostic marker in
AFP-producing gastric cancer and that the only independent factor was the presence of liver
metastases. Moreover, as mentioned by the authors, there was no comparator arm in group B.
4. In Group A, patients with high AFP or GAPEP, on average, presented with more advanced
disease, which is an independent negative prognostic factor. Although the PSM analysis showed
a statistically significant difference in outcomes for AFP-high patients when other factors were
taken into consideration, unequal distribution of patients between the comparator groups might
have confounded the outcomes.
5. In the paper, it is mentioned that 7 patients with high levels of preoperative AFP were
monitored afterwards and AFP dropped after surgery and within the next year. It would be
interesting if survival data of these patients were available.
Please review this paper.
user
Title: Both the serum AFP test and AFP/GPC3/SALL4 immunohistochemistry are beneficial
for predicting the prognosis of gastric adenocarcinoma
Version: 2 Date: 06 Sep 2021
Reviewer:  Nikolaos Charalampakis
Reviewer's report:
This manuscript describes the results of a retrospective analysis of patients with rare gastric
adenocarcinoma subtypes that express AFP or manifest with primary enterocyte phenotype. The
authors separated patients into two groups based on preoperative measurements of AFP. Patients
in the operable group were further divided according to AFP expression or GAPEP phenotype
positivity. The authors of this study should be praised for touching on a rare tumor subtype,
which is usually associated with negative prognosis. The manuscript is well written, in a proper
and concise manner and study methods lead to clear and logical conclusions.
The strongest point of this study is the clear association between high AFP expression and
GAPEP phenotype, which is indicative of the fact that these tumors might represent a distinct
entity in gastric cancer, with clear and identifiable molecular and clinical characteristics.
The study has a few minor weaknesses, which should be discussed more clearly in the
manuscript:
1. AFP is a serum value that can be elevated in a variety of pathological conditions, such as liver
disease. Although patients with acute hepatitis were excluded from the study, the authors do not
mention possible comorbidities in patients with high AFP.
2. AFP expressing gastric cancer and GAPEP are rare tumors, resulting in disparities in subgroup
populations that hinder statistical analysis. Over 90% of patients included in this study did not
express AFP or GAPEP phenotype.
3. Group B included patients based on the expression of AFP alone, regardless of subsequent
treatment. The value of the findings in this subgroup is not adequately explained. There is an
association of increased AFP with worse prognosis, but as mentioned in the text, the majority
of patients in this subgroup had liver metastases. A previous study by Hirajima et al. (2013)
concluded that increased AFP could not be used as an independent prognostic marker in
AFP-producing gastric cancer and that the only independent factor was the presence of liver
metastases. Moreover, as mentioned by the authors, there was no comparator arm in group B.
4. In Group A, patients with high AFP or GAPEP, on average, presented with more advanced
disease, which is an independent negative prognostic factor. Although the PSM analysis showed
a statistically significant difference in outcomes for AFP-high patients when other factors were
taken into consideration, unequal distribution of patients between the comparator groups might
have confounded the outcomes.
5. In the paper, it is mentioned that 7 patients with high levels of preoperative AFP were
monitored afterwards and AFP dropped after surgery and within the next year. It would be
interesting if survival data of these patients were available.
assistant