Title: Mixed adenoneuroendocrine carcinomas of stomach and ampulla of vater after curative-
intent resection: a single center cases series
Version: 1 Date: 05 Jun 2021
Reviewer:  Manabu Ohashi
Reviewer's report:
The reviewer really appreciates having an opportunity to evaluate this manuscript entitled
“Mixed adenoneuroendocrine carcinomas of stomach and ampulla of vater after curative-
intent resection: a single center cases series” written by Sishu Yang et al.  MANEC is a
rare clinical manifestation, especially in the gastric and ampullary. The purpose of this study
was to investigate the clinicopathological features and prognosis of MANEC. In 32 patients
with gastric and ampullary MANEC, the demographic, clinicopathological and survival data
were retrospectively reviewed. The 1-year, 3-year and 5-year survival rates were 78.1%,
28.1% and 9.4%, respectively. A multivariate analysis revealed that TNM stage, lymph nodes
metastasis, vascular invasion, grade of the adenocarcinoma component and CD56 positivity
were independent predictors of overall survival. According to the results, the authors concluded
that MANECM is an aggressive clinical entity with a poor prognosis. Taking both the
neuroendocrine component and the adenocarcinoma component into consideration of optimal
treatment is strongly recommended. The manuscript is well written and easy to be understood.
However, some critical and minor problems below were raised.
1. Did the authors experience only the 32 patients enrolled in this study? In this study, patients
who had gastric or ampulla MANEC were analyzed. The selection of patients is curious. But if
the patients were all that the authors experienced in the study period, the selection is convinced. If
the authors had excluded patients, they should describe that and a flow chart of patient selection
will help the readers to understand this study.
2. However, the patient selection is still curious. The reviewer does not think whether it was
proper MANECs arising the different organs were analyzed in the same study.
3. In the multivariate analysis, the authors made a technical error. Generally, the number of input
factors to multivariate analysis must be less than 10% of events. If an investigator uses more
than 10% of events, an overfitting phenomenon will occur. In this study, the authors described
that the DFS events were 16. Thus, the authors should input 2 factors at most to multivariate
analysis. The authors input 7 factors to the multivariate analysis, which is not proper. In the
patients enrolled in this study, multivariate analysis foe DFS is not reasonable analysis. The
same can be said in OS. This is a critical problem of this study.
4. The reviewer does not understand why the authors focused on the survival outcomes according
to the 3 factors. The univariate analysis reveals the difference of survival outcomes according
to the factors. The reviewer considers that the 3 figures are not required.
5. The authors stated in conclusions that “Radical resection of the tumor with aggressive
multidisciplinary cancer management may improve the prognosis”. What data induced the
conclusion?
6. As MANEC is rare disease, the differences of clinical outcomes according to some
clinicopathological factors even though the sample size is very small. In this viewpoint, the
article may be valuable for physicians who will experience MANEC patients. But what should
be done for patients with MANEC is still unclear.
Title: Mixed adenoneuroendocrine carcinomas of stomach and ampulla of vater after curative-
intent resection: a single center cases series
Version: 1 Date: 05 Jun 2021
Reviewer:  Manabu Ohashi
Reviewer's report:
The reviewer really appreciates having an opportunity to evaluate this manuscript entitled
“Mixed adenoneuroendocrine carcinomas of stomach and ampulla of vater after curative-
intent resection: a single center cases series” written by Sishu Yang et al.  MANEC is a
rare clinical manifestation, especially in the gastric and ampullary. The purpose of this study
was to investigate the clinicopathological features and prognosis of MANEC. In 32 patients
with gastric and ampullary MANEC, the demographic, clinicopathological and survival data
were retrospectively reviewed. The 1-year, 3-year and 5-year survival rates were 78.1%,
28.1% and 9.4%, respectively. A multivariate analysis revealed that TNM stage, lymph nodes
metastasis, vascular invasion, grade of the adenocarcinoma component and CD56 positivity
were independent predictors of overall survival. According to the results, the authors concluded
that MANECM is an aggressive clinical entity with a poor prognosis. Taking both the
neuroendocrine component and the adenocarcinoma component into consideration of optimal
treatment is strongly recommended. The manuscript is well written and easy to be understood.
However, some critical and minor problems below were raised.
1. Did the authors experience only the 32 patients enrolled in this study? In this study, patients
who had gastric or ampulla MANEC were analyzed. The selection of patients is curious. But if
the patients were all that the authors experienced in the study period, the selection is convinced. If
the authors had excluded patients, they should describe that and a flow chart of patient selection
will help the readers to understand this study.
2. However, the patient selection is still curious. The reviewer does not think whether it was
proper MANECs arising the different organs were analyzed in the same study.
3. In the multivariate analysis, the authors made a technical error. Generally, the number of input
factors to multivariate analysis must be less than 10% of events. If an investigator uses more
than 10% of events, an overfitting phenomenon will occur. In this study, the authors described
that the DFS events were 16. Thus, the authors should input 2 factors at most to multivariate
analysis. The authors input 7 factors to the multivariate analysis, which is not proper. In the
patients enrolled in this study, multivariate analysis foe DFS is not reasonable analysis. The
same can be said in OS. This is a critical problem of this study.
4. The reviewer does not understand why the authors focused on the survival outcomes according
to the 3 factors. The univariate analysis reveals the difference of survival outcomes according
to the factors. The reviewer considers that the 3 figures are not required.
5. The authors stated in conclusions that “Radical resection of the tumor with aggressive
multidisciplinary cancer management may improve the prognosis”. What data induced the
conclusion?
6. As MANEC is rare disease, the differences of clinical outcomes according to some
clinicopathological factors even though the sample size is very small. In this viewpoint, the
article may be valuable for physicians who will experience MANEC patients. But what should
be done for patients with MANEC is still unclear.
Please review this paper.
user
Title: Mixed adenoneuroendocrine carcinomas of stomach and ampulla of vater after curative-
intent resection: a single center cases series
Version: 1 Date: 05 Jun 2021
Reviewer:  Manabu Ohashi
Reviewer's report:
The reviewer really appreciates having an opportunity to evaluate this manuscript entitled
“Mixed adenoneuroendocrine carcinomas of stomach and ampulla of vater after curative-
intent resection: a single center cases series” written by Sishu Yang et al.  MANEC is a
rare clinical manifestation, especially in the gastric and ampullary. The purpose of this study
was to investigate the clinicopathological features and prognosis of MANEC. In 32 patients
with gastric and ampullary MANEC, the demographic, clinicopathological and survival data
were retrospectively reviewed. The 1-year, 3-year and 5-year survival rates were 78.1%,
28.1% and 9.4%, respectively. A multivariate analysis revealed that TNM stage, lymph nodes
metastasis, vascular invasion, grade of the adenocarcinoma component and CD56 positivity
were independent predictors of overall survival. According to the results, the authors concluded
that MANECM is an aggressive clinical entity with a poor prognosis. Taking both the
neuroendocrine component and the adenocarcinoma component into consideration of optimal
treatment is strongly recommended. The manuscript is well written and easy to be understood.
However, some critical and minor problems below were raised.
1. Did the authors experience only the 32 patients enrolled in this study? In this study, patients
who had gastric or ampulla MANEC were analyzed. The selection of patients is curious. But if
the patients were all that the authors experienced in the study period, the selection is convinced. If
the authors had excluded patients, they should describe that and a flow chart of patient selection
will help the readers to understand this study.
2. However, the patient selection is still curious. The reviewer does not think whether it was
proper MANECs arising the different organs were analyzed in the same study.
3. In the multivariate analysis, the authors made a technical error. Generally, the number of input
factors to multivariate analysis must be less than 10% of events. If an investigator uses more
than 10% of events, an overfitting phenomenon will occur. In this study, the authors described
that the DFS events were 16. Thus, the authors should input 2 factors at most to multivariate
analysis. The authors input 7 factors to the multivariate analysis, which is not proper. In the
patients enrolled in this study, multivariate analysis foe DFS is not reasonable analysis. The
same can be said in OS. This is a critical problem of this study.
4. The reviewer does not understand why the authors focused on the survival outcomes according
to the 3 factors. The univariate analysis reveals the difference of survival outcomes according
to the factors. The reviewer considers that the 3 figures are not required.
5. The authors stated in conclusions that “Radical resection of the tumor with aggressive
multidisciplinary cancer management may improve the prognosis”. What data induced the
conclusion?
6. As MANEC is rare disease, the differences of clinical outcomes according to some
clinicopathological factors even though the sample size is very small. In this viewpoint, the
article may be valuable for physicians who will experience MANEC patients. But what should
be done for patients with MANEC is still unclear.
assistant