Impact of Diabetes on Short-Term and Long-Term Outcomes of Ampullary Adenocarcinoma Patients after Curative Pancreatoduodenectomy
Round 1
Reviewer 1 Report (Previous Reviewer 2)
Why they did not get HaA1c data although they used patients data like as pathological data, their prognosis, intraoperative data?
Author Response
Manuscript ID: curroncol-1897223
Title: Impact of diabetes on short-term and long-term outcomes of ampullary adenocarcinoma patients after curative pancreatoduodenectomy
Dear Editor,
We have carefully revised the whole manuscript and hope our work is eligible for publication in Journal of Cancer. A list of responses to all issues that the reviewers raised is provided below.
Reviewer 1:
Why they did not get HaA1c data although they used patients data like as pathological data, their prognosis, intraoperative data?
√We sincerely appreciate your valuable advice. Please see Page 10 Line 226-229.
Firstly, please forgive us for wondering if the “HaA1c” you mentioned refers to "HbA1c"?
In the current study, we collected some clinicopathological data, intraoperative data as you mentioned. However, we sincerely regret that we failed to collect enough data of HbA1c, which you proposed, and include it in the final study. This mainly lies in two reasons.
Firstly, in this retrospective study, patients with diabetes were diagnosed by clinical history. Blood glucose monitoring and management were carried out before surgery for ampullary carcinoma. However, in routine clinical biochemical assays, we mainly focused on the level of fasting blood glucose and did not test HbA1c separately, which may be a problem in our management before surgery. Secondly, ampullary carcinoma is a relatively rare tumor type with a low incidence. Our study retrospectively analyzed patients within the last 20 years, during which only a few patients were able to have complete HbA1c results due to advances in clinical practices.
We also added this limitation into the Discussion part in the present study.
Once again, thank you very much for your interest in our article and for the opportunity to respond to the reviewer comments. We believe that the peer-review process has strengthened the manuscript. However, please let me know if you have any additional comments.
Yours sincerely,
Dongbing Zhao
Author Response File: 
Author Response.docx
Reviewer 2 Report (Previous Reviewer 3)
the manuscript improved, however I still have some important comments:
- Maybe I was not sufficiently clear, however the (%) in the tables are not correctly calculated. Please carefully look at the table I'm attaching: I suggest the authors to present data and to calculate the (%) similar to this table.
- the manuscript still contains some grammatical errors: please carefully check and correct.
- However, the most important point is that the study bias due to a significantly higher rate of advanced tumors in the diabetic patients group, compared to non diabetic patients, has not been adequately taken in consideration in the discussion. Such unbalance in study patients characteristics is probably the reason for shorter survival among diabetic patients. Such concept should be highlighted in the text as an important study limitation. In this context, the subgroup survival analysis according to tumor stage probably mitigates such bias, suggesting that diabetes per se does not impact long term survivals, except than in the stage I group patients (PFS). With such limitations, I do not believe that the study conclusions are supported by results, thus I think the discussion and the conclusions should be deeply modified accordingly.
Comments for author File: Comments.docx
Author Response
Manuscript ID: curroncol-1897223
Title: Impact of diabetes on short-term and long-term outcomes of ampullary adenocarcinoma patients after curative pancreatoduodenectomy
Dear Editor,
We have carefully revised the whole manuscript and hope our work is eligible for publication in Journal of Cancer. A list of responses to all issues that the reviewers raised is provided below.
Reviewer 2:
- Maybe I was not sufficiently clear, however the (%) in the tables are not correctly calculated. Please carefully look at the table I'm attaching: I suggest the authors to present data and to calculate the (%) similar to this table.
√Done as suggested. Please see Page 3 Line 106 and Table 1, Table 2, Table 3.
- The manuscript still contains some grammatical errors: please carefully check and correct.
√Done as suggested.
Thank you very much for your valuable comments, we have carefully revised the manuscript and corrected grammatical errors. At the same time, we carried out the interactive modification between authors. We ended up having our native English-speaking colleague do the final language correction.
- However, the most important point is that the study bias due to a significantly higher rate of advanced tumors in the diabetic patients group, compared to non diabetic patients, has not been adequately taken in consideration in the discussion. Such unbalance in study patients characteristics is probably the reason for shorter survival among diabetic patients. Such concept should be highlighted in the text as an important study limitation. In this context, the subgroup survival analysis according to tumor stage probably mitigates such bias, suggesting that diabetes per se does not impact long term survivals, except than in the stage I group patients (PFS). With such limitations, I do not believe that the study conclusions are supported by results, thus I think the discussion and the conclusions should be deeply modified accordingly.
√Done as suggested. Please see Page 9 Line 197-202 and Page 10 Line 222-223.
In the discussion of the article, we discuss the results of the subgroup analysis. Such difference in the subgroup may be due to the smaller number of patients in the diabetes group. During the sub-group analysis, there were fewer cases in each subgroup (10 patients in stage I, 9 patients in stage II, and 13 patients in stage III).
Moreover, in the limitation, we further clarified that the small number of cases may reduce the statistical effect.
Once again, thank you very much for your interest in our article and for the opportunity to respond to the reviewer comments. We believe that the peer-review process has strengthened the manuscript. However, please let me know if you have any additional comments.
Yours sincerely,
Dongbing Zhao
Author Response File: Author Response.docx
Round 2
Reviewer 1 Report (Previous Reviewer 2)
OK. Reiviewer understood their situations.
Author Response
Manuscript ID: curroncol-1897223-R2
Title: Impact of diabetes on short-term and long-term outcomes of ampullary adenocarcinoma patients after curative pancreatoduodenectomy
Reviewer 1:
Thank you for your kindly comments and understanding.
Once again, thank you very much for your interest in our article and for the opportunity to respond to the reviewer comments. We believe that the peer-review process has strengthened the manuscript. However, please let me know if you have any additional comments.
Yours sincerely,
Dongbing Zhao
Reviewer 2 Report (Previous Reviewer 3)
the tables are fine now, except for table one, TNM stage, Stage III, non diabetic column (should be 45 (19%), not 0 (0%)), which needs to be corrected.
IN addition, I suggest to be more specific in table 2 about Fistula: which fistula are they speaking about? POPF? according to which definition?
However, most important, the authors continue to ignore the fact that a higher rate of stage 3 disease among diabetic patients is the most probable reason for worse survival among diabetic patients when comparing two groups independently from the tumor stage. Tumor stage is universally recognized as one of the most robust prognostic factor following ampullary carcinoma resection and an unbalance in its rates is the most probable cause of different survivals in the current case, while a lack of statistical difference in subgroup analysis is related to the fact that patients in the same TNM stage are compared. I recognize a trend toward worse survival among diabetic patients in different TNM stages, however stating that in the subgroup analysis the patients number reduction may be responsible for a statistical significancy reduction may represent a mistake of results interpretation.
Thus, I suggest the authors to change the discussion and the conclusion accordingly.
Author Response
Manuscript ID: curroncol-1897223-R2
Title: Impact of diabetes on short-term and long-term outcomes of ampullary adenocarcinoma patients after curative pancreatoduodenectomy
Dear Editor,
We have carefully revised the whole manuscript and hope our work is eligible for publication in Journal of Cancer. A list of responses to all issues that the reviewers raised is provided below.
Reviewer 2:
- The tables are fine now, except for table one, TNM stage, Stage III, non diabetic column (should be 45 (19%), not 0 (0%)), which needs to be corrected.
√Done as suggested. Please see Page 4 Table 1.
2．In addition, I suggest to be more specific in table 2 about Fistula: which fistula are they speaking about? POPF? according to which definition?
√Done as suggested. Please see Page 2 Line 70-74 and Table 2.
3．However, most important, the authors continue to ignore the fact that a higher rate of stage 3 disease among diabetic patients is the most probable reason for worse survival among diabetic patients when comparing two groups independently from the tumor stage. Tumor stage is universally recognized as one of the most robust prognostic factor following ampullary carcinoma resection and an unbalance in its rates is the most probable cause of different survivals in the current case, while a lack of statistical difference in subgroup analysis is related to the fact that patients in the same TNM stage are compared. I recognize a trend toward worse survival among diabetic patients in different TNM stages, however stating that in the subgroup analysis the patients number reduction may be responsible for a statistical significancy reduction may represent a mistake of results interpretation.
√Done as suggested. Please see Page 9 Line 201-208 and Page 10 Line 238-241.
We are very sorry for not being able to resolve your issue in our last respond. We carefully discussed and revised the manuscript. In the Discuss section and Conclusion section, we have discussed the results of the subgroup according to the TNM stage. The impact of diabetes on the prognosis of ampullary cancer patients may be a long-term process. However, for patients with ampullary carcinoma invading sur-rounding with lymph node metastasis, the 5-year survival rate is less than 30% 26. Thus, diabetes might only have an adverse effect on the prognosis of early-stage AC.
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Once again, thank you very much for your interest in our article and for the opportunity to respond to the reviewer comments. We believe that the peer-review process has strengthened the manuscript. However, please let me know if you have any additional comments.
Yours sincerely,
Dongbing Zhao
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
No information about surgical technique ( data about standard vs. extended pancreatectomy, techniques of anastomotic reconstruction)
Reviewer 2 Report
The authors stated that diabetes adversely affect the recurrence of patients with AC after curative pancreaticoduodenectomy in this study.
Question,
1. DM value was not present in a table such as HbA1c. They should included those.
2. Light Degree was included in DM group? Which means the degree of DM was ignored in this study.
3. Usually, DM patients have other lifestyle-related diseases. Did they evaluate these before conclusion?
4. They should describe the regimen of adjuvant chemotherapy at least.
4. Finally, DM samples were too small to conclude their hypothesis.
Reviewer 3 Report
In this manuscript the authors comapred the short and long term results of pancreatoduodenectomy for ampullary carcinoma, according to the presence or not of preoperative diabete.
the authors found similar short-term postoperative results between patients affected by diabetes VS not, but also found that diabetic patients had shorter RFS and OS, compared to non-diabetic.
My comments:
- the manuscript contains minimal grammar / ortographic errors (for example: methods, patients and study design, line 5: followings should be follows, line 7: missed should be missing; line 1 of results, patients characteristics: a total of 266 AC patients met THE inclusion criteria and WERE enrolled....): a review by an english mother tongue scientific editor is recommended.
Table 1-2-3: I strongly recommend the authors to change the (%) values in the columns "Diabetes" and "No Diabetes". the correct (%) values should be calculated in this way: for example
table 1 diabetes no diabetes
sex male 20 (20/32:62%) 125 (125/234: 53%)
female 12 (38%) 103 (47%)
this will allow an easier comparison of patients characteristics between diabetic and non diabetic patients.
- I recommend to show the results of multivariate analysis for RFS and OS predictors, in order to assess the impact and weight of additional factors on survivals.
- looking at the results, diabetic patients have a significanlty more advanced disease at the time of surgery, compared to non-diabetic patients. The shorter survivals of diabetic patients may be affected by the more advanced disease they were affected by. This may represent an important selection bias, which needs to be seriously taken into account and if possible managed by statistical methods to increase comparability between two study groups.
