Title: The association between jaundice and poorly differentiated pancreatic neuroendocrine
neoplasms (Ki67 index > 55.0%)
Version: 0 Date: 07 Sep 2023
Reviewer:  Ciro Celsa
Reviewer's report:
Liu and colleagues performed a retrospective single-centre study on 93 Chinese patients with
head-neck pancreatic neuroendocrine neoplasms (PNENs) aiming to assess if jaundice was an
independent risk factor for a poor differentiation (defined by ki67 index > 55.0%). Authors found
a prevalence of jaundice in this cohort of about 8% and they showed that age, tumour size and
jaundice were independent risk factors for poor tumour differentiation by multivariate logistic
regression analysis, with a good discrimination in terms of AUC (0.86 for the overall model).
Although this study is a potentially useful addition to the literature on the risk stratification of
PNENs, the authors do not make a sufficiently convincing case that it will add significantly to
current clinical practice and to future research. Particularly, the retrospective design, the small
sample size and unproper management of confounding reduce its appeal for an audience of
clinicians.
Behind specific comments below, this Reviewer believes that there are inconsistencies between
the data reported and the interpretation proposed. Some of them are critical and may affect the
current message of the manuscript.
1) Overall, the findings of this study seem to have a poor clinical relevance. Referee agrees that
the identification of surrogate non-invasive biomarkers of tumour differentiation is an unmet
medical need in this field. However, from a clinical point of view, it is not likely that a prediction
rule based on age, tumour size and presence/absence of jaundice could substitute biopsy to assess
Ki67 levels and to guide treatment decisions. Moreover, in this small cohort, the prevalence of
jaundice was quite low, further limiting its potential usefulness in the real-world clinical practice
setting.
2) This study only included head and neck pancreatic neoplasms. Therefore, the model proposed
by the authors may be applied only to this tumour location and not to all PNENs, further reducing
its practical utility.
3) It appears intuitive that the appearance of jaundice may be related to a more aggressive
behaviour of tumours, as also known for PDAC or IPMN. Indeed, for example, in this study
patients with jaundice showed significantly worst disease characteristics compared to patients
without jaundice in terms of lymph node invasion, local organ invasions and tumour grading.
Why these covariates were not entered in the multivariate model? We can not to be sure that
the association between jaundice and Ki67 is true and not spurious in this study, but mediated
by tumour stage or grade.
4) Another relevant information is about the potential impact of jaundice on survival outcomes
of this patients, in terms of overall survival, progression-free survival or time-to-progression.
We know very little about treatment that these patients received and their subsequent outcomes,
and if jaundice could be predictive for them.
5) Authors evaluated their model in terms of discrimination by area under the  curve. However,
predictive models should be also evaluated in terms of calibration, since two model could have
the same discriminating power assessed by AUC, but they could under- (or over-)estimate the
risk of the event of interest in different ways and this is the truly important information for
physicians.
6) Retrospective studies have many problems that reduce their internal and external validity.
The most important bias is the likelihood of inappropriate selection of patients which can lead
to incorrect results and spurious associations. Particularly, authors should clarify if included
patients were consecutive and what were the criteria for selecting patients for surgical resection.
Authors were fair in underlining their limitations, but it does not make them less significant
Title: The association between jaundice and poorly differentiated pancreatic neuroendocrine
neoplasms (Ki67 index > 55.0%)
Version: 0 Date: 07 Sep 2023
Reviewer:  Ciro Celsa
Reviewer's report:
Liu and colleagues performed a retrospective single-centre study on 93 Chinese patients with
head-neck pancreatic neuroendocrine neoplasms (PNENs) aiming to assess if jaundice was an
independent risk factor for a poor differentiation (defined by ki67 index > 55.0%). Authors found
a prevalence of jaundice in this cohort of about 8% and they showed that age, tumour size and
jaundice were independent risk factors for poor tumour differentiation by multivariate logistic
regression analysis, with a good discrimination in terms of AUC (0.86 for the overall model).
Although this study is a potentially useful addition to the literature on the risk stratification of
PNENs, the authors do not make a sufficiently convincing case that it will add significantly to
current clinical practice and to future research. Particularly, the retrospective design, the small
sample size and unproper management of confounding reduce its appeal for an audience of
clinicians.
Behind specific comments below, this Reviewer believes that there are inconsistencies between
the data reported and the interpretation proposed. Some of them are critical and may affect the
current message of the manuscript.
1) Overall, the findings of this study seem to have a poor clinical relevance. Referee agrees that
the identification of surrogate non-invasive biomarkers of tumour differentiation is an unmet
medical need in this field. However, from a clinical point of view, it is not likely that a prediction
rule based on age, tumour size and presence/absence of jaundice could substitute biopsy to assess
Ki67 levels and to guide treatment decisions. Moreover, in this small cohort, the prevalence of
jaundice was quite low, further limiting its potential usefulness in the real-world clinical practice
setting.
2) This study only included head and neck pancreatic neoplasms. Therefore, the model proposed
by the authors may be applied only to this tumour location and not to all PNENs, further reducing
its practical utility.
3) It appears intuitive that the appearance of jaundice may be related to a more aggressive
behaviour of tumours, as also known for PDAC or IPMN. Indeed, for example, in this study
patients with jaundice showed significantly worst disease characteristics compared to patients
without jaundice in terms of lymph node invasion, local organ invasions and tumour grading.
Why these covariates were not entered in the multivariate model? We can not to be sure that
the association between jaundice and Ki67 is true and not spurious in this study, but mediated
by tumour stage or grade.
4) Another relevant information is about the potential impact of jaundice on survival outcomes
of this patients, in terms of overall survival, progression-free survival or time-to-progression.
We know very little about treatment that these patients received and their subsequent outcomes,
and if jaundice could be predictive for them.
5) Authors evaluated their model in terms of discrimination by area under the  curve. However,
predictive models should be also evaluated in terms of calibration, since two model could have
the same discriminating power assessed by AUC, but they could under- (or over-)estimate the
risk of the event of interest in different ways and this is the truly important information for
physicians.
6) Retrospective studies have many problems that reduce their internal and external validity.
The most important bias is the likelihood of inappropriate selection of patients which can lead
to incorrect results and spurious associations. Particularly, authors should clarify if included
patients were consecutive and what were the criteria for selecting patients for surgical resection.
Authors were fair in underlining their limitations, but it does not make them less significant
Please review this paper.
user
Title: The association between jaundice and poorly differentiated pancreatic neuroendocrine
neoplasms (Ki67 index > 55.0%)
Version: 0 Date: 07 Sep 2023
Reviewer:  Ciro Celsa
Reviewer's report:
Liu and colleagues performed a retrospective single-centre study on 93 Chinese patients with
head-neck pancreatic neuroendocrine neoplasms (PNENs) aiming to assess if jaundice was an
independent risk factor for a poor differentiation (defined by ki67 index > 55.0%). Authors found
a prevalence of jaundice in this cohort of about 8% and they showed that age, tumour size and
jaundice were independent risk factors for poor tumour differentiation by multivariate logistic
regression analysis, with a good discrimination in terms of AUC (0.86 for the overall model).
Although this study is a potentially useful addition to the literature on the risk stratification of
PNENs, the authors do not make a sufficiently convincing case that it will add significantly to
current clinical practice and to future research. Particularly, the retrospective design, the small
sample size and unproper management of confounding reduce its appeal for an audience of
clinicians.
Behind specific comments below, this Reviewer believes that there are inconsistencies between
the data reported and the interpretation proposed. Some of them are critical and may affect the
current message of the manuscript.
1) Overall, the findings of this study seem to have a poor clinical relevance. Referee agrees that
the identification of surrogate non-invasive biomarkers of tumour differentiation is an unmet
medical need in this field. However, from a clinical point of view, it is not likely that a prediction
rule based on age, tumour size and presence/absence of jaundice could substitute biopsy to assess
Ki67 levels and to guide treatment decisions. Moreover, in this small cohort, the prevalence of
jaundice was quite low, further limiting its potential usefulness in the real-world clinical practice
setting.
2) This study only included head and neck pancreatic neoplasms. Therefore, the model proposed
by the authors may be applied only to this tumour location and not to all PNENs, further reducing
its practical utility.
3) It appears intuitive that the appearance of jaundice may be related to a more aggressive
behaviour of tumours, as also known for PDAC or IPMN. Indeed, for example, in this study
patients with jaundice showed significantly worst disease characteristics compared to patients
without jaundice in terms of lymph node invasion, local organ invasions and tumour grading.
Why these covariates were not entered in the multivariate model? We can not to be sure that
the association between jaundice and Ki67 is true and not spurious in this study, but mediated
by tumour stage or grade.
4) Another relevant information is about the potential impact of jaundice on survival outcomes
of this patients, in terms of overall survival, progression-free survival or time-to-progression.
We know very little about treatment that these patients received and their subsequent outcomes,
and if jaundice could be predictive for them.
5) Authors evaluated their model in terms of discrimination by area under the  curve. However,
predictive models should be also evaluated in terms of calibration, since two model could have
the same discriminating power assessed by AUC, but they could under- (or over-)estimate the
risk of the event of interest in different ways and this is the truly important information for
physicians.
6) Retrospective studies have many problems that reduce their internal and external validity.
The most important bias is the likelihood of inappropriate selection of patients which can lead
to incorrect results and spurious associations. Particularly, authors should clarify if included
patients were consecutive and what were the criteria for selecting patients for surgical resection.
Authors were fair in underlining their limitations, but it does not make them less significant
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