Title: Long-standing Diabetes Mellitus Increases Concomitant Pancreatic Cancer Risk in
Patients with Intraductal Papillary Mucinous Neoplasms
Version: 3 Date: 18 Sep 2022
Reviewer's report:
In this retrospective study of 547 patients with pancreatic cysts, Yamaguchi et al sought to
identify risk factors for developing concomitant (i.e., not associated with IPMN) PDAC. Patients
with IPMN may be at higher risk of developing concomitant PDAC; given the poor prognosis
of PDAC but its relatively low incidence and the high costs of regular surveillance, the authors’
goal was to identify subpopulations of patients with IPMN who are at particularly higher risk
of developing concomitant PDAC. The authors found that patients with IPMN and diabetes
mellitus were at significantly higher risk of developing concomitant PDAC. I commend the
authors on their work, below are some points that I think should be addressed.
MAJOR POINTS
1. Methods. Patient selection is at risk of important biases (especially selection bias) that
should be more thoroughly addressed. Patients were diagnosed within a span of 14 years and
management of pancreatic cystic lesions changed a lot throughout that period. It is likely that
patients who were considered to require surgery in 2005 were different from those diagnosed in
2019. Can the authors please elaborate on how this patient selection may influence their results?
It would help to know what the proportion of patients was diagnosed in, for example, 5-year
intervals from 2005 to 2019.
2. Methods: Please describe in more detail how data on past medical history and health-
related behaviors were obtained, especially (but not limited to) diabetes history. Was the
diagnosis of diabetes self-reported or based on chart review? Was it confirmed by A1c values
or other objective data at the time of initial diagnosis? Please describe how these variables were
categorized and why – for example, did you consider alternative cutoffs to define new-onset
vs long-onset diabetes? What was considered “usual alcohol consumption”? I appreciate that
it is challenging to have highly detailed data and consistency when performing retrospective
chart review, but this needs to be acknowledged during the interpretation of data since the main
conclusion of the study is based on the diabetes history.
3. Methods: Can you explain in more detail how the multivariable-adjusted logistic regression
model was built for the analyses in Tables 3 and 4? What were the selected covariates and how
were they chosen? This becomes particularly relevant when the number of events (n = 14) is
so small.
4. Results: The authors do a great job explaining the reasons for further therapy in patients in
Supplementary Table 1, but there’s no such data in Supplementary Table 2, which describes
patients with concomitant PDAC. I think this is the patient group where that information is most
relevant.
5. Results: Would avoid qualifiers when describing the results in this section. For example, page
16: “The median period from onset of diabetes mellitus to induction of concomitant PDAC was
very long (median 12 [2.5-22] years).” The description of the time period would fit better in
the discussion. Also, it seems to me that more than being very long, the time period is rather
highly variable, which may be very relevant since evidence suggests that the association between
diabetes and pancreatic cancer is bimodal (both new-onset and long-standing).
MINOR POINTS
1. Abstract: Nomenclature remains inconsistent. Under Results, authors refer to “intraductal
papillary mucinous adenocarcinomas” as opposed to “intraductal papillary mucinous neoplasm
with associated invasive carcinoma” or “IPMN-derived carcinoma”
2. Methods: Portions of the Methods are duplicated (after the first “Statistical analyses”
paragraph”).
3. Results, Page 13: Would revise sentence saying that “IPMNs… seemed to carry a higher risk
of concomitant PDAC than other cysts…”. The P value is not significant, can’t make meaningful
inferences based on this. If authors still wish to comment on it, would move to Discussion instead
of in Results.
Title: Long-standing Diabetes Mellitus Increases Concomitant Pancreatic Cancer Risk in
Patients with Intraductal Papillary Mucinous Neoplasms
Version: 3 Date: 18 Sep 2022
Reviewer's report:
In this retrospective study of 547 patients with pancreatic cysts, Yamaguchi et al sought to
identify risk factors for developing concomitant (i.e., not associated with IPMN) PDAC. Patients
with IPMN may be at higher risk of developing concomitant PDAC; given the poor prognosis
of PDAC but its relatively low incidence and the high costs of regular surveillance, the authors’
goal was to identify subpopulations of patients with IPMN who are at particularly higher risk
of developing concomitant PDAC. The authors found that patients with IPMN and diabetes
mellitus were at significantly higher risk of developing concomitant PDAC. I commend the
authors on their work, below are some points that I think should be addressed.
MAJOR POINTS
1. Methods. Patient selection is at risk of important biases (especially selection bias) that
should be more thoroughly addressed. Patients were diagnosed within a span of 14 years and
management of pancreatic cystic lesions changed a lot throughout that period. It is likely that
patients who were considered to require surgery in 2005 were different from those diagnosed in
2019. Can the authors please elaborate on how this patient selection may influence their results?
It would help to know what the proportion of patients was diagnosed in, for example, 5-year
intervals from 2005 to 2019.
2. Methods: Please describe in more detail how data on past medical history and health-
related behaviors were obtained, especially (but not limited to) diabetes history. Was the
diagnosis of diabetes self-reported or based on chart review? Was it confirmed by A1c values
or other objective data at the time of initial diagnosis? Please describe how these variables were
categorized and why – for example, did you consider alternative cutoffs to define new-onset
vs long-onset diabetes? What was considered “usual alcohol consumption”? I appreciate that
it is challenging to have highly detailed data and consistency when performing retrospective
chart review, but this needs to be acknowledged during the interpretation of data since the main
conclusion of the study is based on the diabetes history.
3. Methods: Can you explain in more detail how the multivariable-adjusted logistic regression
model was built for the analyses in Tables 3 and 4? What were the selected covariates and how
were they chosen? This becomes particularly relevant when the number of events (n = 14) is
so small.
4. Results: The authors do a great job explaining the reasons for further therapy in patients in
Supplementary Table 1, but there’s no such data in Supplementary Table 2, which describes
patients with concomitant PDAC. I think this is the patient group where that information is most
relevant.
5. Results: Would avoid qualifiers when describing the results in this section. For example, page
16: “The median period from onset of diabetes mellitus to induction of concomitant PDAC was
very long (median 12 [2.5-22] years).” The description of the time period would fit better in
the discussion. Also, it seems to me that more than being very long, the time period is rather
highly variable, which may be very relevant since evidence suggests that the association between
diabetes and pancreatic cancer is bimodal (both new-onset and long-standing).
MINOR POINTS
1. Abstract: Nomenclature remains inconsistent. Under Results, authors refer to “intraductal
papillary mucinous adenocarcinomas” as opposed to “intraductal papillary mucinous neoplasm
with associated invasive carcinoma” or “IPMN-derived carcinoma”
2. Methods: Portions of the Methods are duplicated (after the first “Statistical analyses”
paragraph”).
3. Results, Page 13: Would revise sentence saying that “IPMNs… seemed to carry a higher risk
of concomitant PDAC than other cysts…”. The P value is not significant, can’t make meaningful
inferences based on this. If authors still wish to comment on it, would move to Discussion instead
of in Results.
Please review this paper.
user
Title: Long-standing Diabetes Mellitus Increases Concomitant Pancreatic Cancer Risk in
Patients with Intraductal Papillary Mucinous Neoplasms
Version: 3 Date: 18 Sep 2022
Reviewer's report:
In this retrospective study of 547 patients with pancreatic cysts, Yamaguchi et al sought to
identify risk factors for developing concomitant (i.e., not associated with IPMN) PDAC. Patients
with IPMN may be at higher risk of developing concomitant PDAC; given the poor prognosis
of PDAC but its relatively low incidence and the high costs of regular surveillance, the authors’
goal was to identify subpopulations of patients with IPMN who are at particularly higher risk
of developing concomitant PDAC. The authors found that patients with IPMN and diabetes
mellitus were at significantly higher risk of developing concomitant PDAC. I commend the
authors on their work, below are some points that I think should be addressed.
MAJOR POINTS
1. Methods. Patient selection is at risk of important biases (especially selection bias) that
should be more thoroughly addressed. Patients were diagnosed within a span of 14 years and
management of pancreatic cystic lesions changed a lot throughout that period. It is likely that
patients who were considered to require surgery in 2005 were different from those diagnosed in
2019. Can the authors please elaborate on how this patient selection may influence their results?
It would help to know what the proportion of patients was diagnosed in, for example, 5-year
intervals from 2005 to 2019.
2. Methods: Please describe in more detail how data on past medical history and health-
related behaviors were obtained, especially (but not limited to) diabetes history. Was the
diagnosis of diabetes self-reported or based on chart review? Was it confirmed by A1c values
or other objective data at the time of initial diagnosis? Please describe how these variables were
categorized and why – for example, did you consider alternative cutoffs to define new-onset
vs long-onset diabetes? What was considered “usual alcohol consumption”? I appreciate that
it is challenging to have highly detailed data and consistency when performing retrospective
chart review, but this needs to be acknowledged during the interpretation of data since the main
conclusion of the study is based on the diabetes history.
3. Methods: Can you explain in more detail how the multivariable-adjusted logistic regression
model was built for the analyses in Tables 3 and 4? What were the selected covariates and how
were they chosen? This becomes particularly relevant when the number of events (n = 14) is
so small.
4. Results: The authors do a great job explaining the reasons for further therapy in patients in
Supplementary Table 1, but there’s no such data in Supplementary Table 2, which describes
patients with concomitant PDAC. I think this is the patient group where that information is most
relevant.
5. Results: Would avoid qualifiers when describing the results in this section. For example, page
16: “The median period from onset of diabetes mellitus to induction of concomitant PDAC was
very long (median 12 [2.5-22] years).” The description of the time period would fit better in
the discussion. Also, it seems to me that more than being very long, the time period is rather
highly variable, which may be very relevant since evidence suggests that the association between
diabetes and pancreatic cancer is bimodal (both new-onset and long-standing).
MINOR POINTS
1. Abstract: Nomenclature remains inconsistent. Under Results, authors refer to “intraductal
papillary mucinous adenocarcinomas” as opposed to “intraductal papillary mucinous neoplasm
with associated invasive carcinoma” or “IPMN-derived carcinoma”
2. Methods: Portions of the Methods are duplicated (after the first “Statistical analyses”
paragraph”).
3. Results, Page 13: Would revise sentence saying that “IPMNs… seemed to carry a higher risk
of concomitant PDAC than other cysts…”. The P value is not significant, can’t make meaningful
inferences based on this. If authors still wish to comment on it, would move to Discussion instead
of in Results.
assistant