Incidence and Risk Factors for Cerebrovascular-Specific Mortality in Patients with Colorectal Cancer: A Registry-Based Cohort Study Involving 563,298 Patients

Round 1

Reviewer 1 Report

I have no further comment for authors.

Reviewer 2 Report

The authors have revised the manuscript completely and appropriately. I suggest to publish this article without further revision.

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

Comments and Suggestions for Authors

Appreciate the authors providing us with answers regarding increased and risk factors for cerebrovascular specific mortality in patients with colorectal cancer

1. The authors mentioned that a potential role for CRC in the incidence of CVSM and also identify several significant predictors of CVSM, which may be helpful for risk stratification and therapeutic optimization of cerebrovascular-specific diseases in CRC patients. However, as we knowns, there are many risk factors for cerebrovascular disease like hypertension, diabetes mellitus, hyperlipidemia, …etc. In your data, would you show data about sociodemographic characteristics (age and occupation) and comorbidities related to CVSD among you CRC cohorts first and analysis between CDSD/non-CVSD cohorts.
2. The information from figure 3-10 is uninformative and redendent. For analysis of CVSD incidence in CRC cohorts, would you calculate Incidence of CVSD/CVSM and CRC cancer cohorts to reference cohort(non CRC cohort) and show adjusted hazard ratio by age, type of treatment, years after diagnosis….etc. The aHR should be adjusted for risk factors of CVSD/CVSM.
3. As we known, cerebrovascular diseases are divided into ischemic and hemorrhagic type. In your data, would you analyze of CVSD/CVSM in CRC cohort separated into these different types. Because the patholgenesis about these two types of CVSD may be different.

Reviewer 2 Report

The is an interesting research to apply the recently released dataset to find out the potential risk factors for CVSM in CRC patients. However, there were some points should be improved and clarified.

Introduction:

1. Previous research have mentioned about the CVSDs was common in cancer patients and CSVDs be a major factor for the mortality of CRC patients. Therefore, the association between CSVM and CRC have been observed. The specific points and study aims should be described clearer in the Introduction Section. And try to add more background information to strengthen the importance of the current study.
2. There were some important descriptions in the third paragraph of Introduction Section, but there was no reference be cited. Please cite appropriate reference in the content.

Materials and Methods:

1. This is a long-term study depending on the dataset cross around 40years. It should mention in the content how to correct or standardize the change of diagnosis and treatment for CVS and CRC in decades. In addition, please provide the description for dealing with the ICD coding for the 40years data.

Results:

1. For the Section of Cumulative mortality, I am curious about the meaning of these present results. Please explain or describe and discuss more clarified in Material and Method, Result, or Discussion Sections.
2. As to Table 1 and 3, please modify the confused typesetting for the column 1 of Factors.
3. I suggest that some factors could be added the trend analysis to enhance the importance of the factor in Table 2 and 3, such as age and year of diagnosis.
4. Have any interaction among the factors? Please describe it or try to make some analysis.

Discussion:

1. There were many factors with strong significant results, but there were few factors with detailed descriptions. Please add more discussion for the factors.
2. There were some technical limitations by applying this long-term dataset should be described. And the possible effects on this current results should be mentioned.

Reviewer 3 Report

This study was well designed, well written and easy to follow, I think this manuscript is a nice work, my comments are below:

1. The authors found that age displayed a positive association with CVSM in CRC in Table 3. However, age showed a inverse association with cSMR CVS between CRC patients and the USA general population in Table 2. Would the authors please explain this discrepancy?

2. This study disclosed that CRC patients who underwent surgery had an increased risk of CVSM, and the authors said “in accordance with preceding data indicating that hemodynamic changes during the perioperative period may cause the thrombus to fall off, thereby leading to stroke in CRC patients. Another possible explanation for such an association is that surgical procedure especially in patients with advanced CRC may trigger tumor cells to release more proinflammatory factors entering the blood-brain barrier and therefore promote the occurrence of CVSDs”. How to suggest the prevention strategies and therapeutic optimization of CVSM in CRC patients on clinical guideline?