A Preliminary Study on the Relationship between Serum Heparan Sulfate and Cancer-Related Cognitive Impairment: The Moderating Role of Oxidative Stress in Patients with Colorectal Cancer

Round 1

Reviewer 1 Report

1. I read this manuscript with great interest. The authors detectedthe concentrations of oxidative stress factors and HS in serum in patients with cancer-related cognitive impairment (CRCI), and examined the associations of HS, oxidative stress factors and CRCI. This study provided clues that serum HS and oxidative stress played the roles in the process of cognitive impairment in patients with colorectal cancer. But I recommend the paper for publication, after minor revisions.
2. Since the study subjectsare colorectal cancer patients, why recruit cancer patients at the start of the study?
3. “159 subjects completed the cognitive 91 assessments. Total 67 patients were enrolled in the subsequent study.”What were the inclusion criteria for these 67 patients, and how were the other 24 individuals excluded?

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

This was a very well written manuscript. This was a cross-sectional study examining the associations of heparin sulfate and moderating role of oxidative stress on cancer related cognitive impairment (CRCI). CRCI is a significant symptom for many cancer survivors that has many downstream negative effects. Identifying the underlying mechanisms of CRCI is an important endeavor to understanding how to effective address in CRC patients. This is an interesting paper but needs some more background regarding the hypotheses of the relationships of the variables involved.

• Please add more information regarding justification of examining heparin sulfate beyond that it has not been studied in the context of CRCI. 
• Please explain why if 159 had completed the cognitive assessments why only 67 were enrolled in the study “Among 334 colorectal patients, 159 subjects completed the cognitive assessments. Total 67 patients were enrolled in the subsequent study.” Were there differences in those that enrolled in the study vs. the larger sample to address selection bias.
• Please explain what stages of CRC patients were included. Were Stage IV CRC patients included who may have brain mets?
• Did the assessment control for other factors that may alter cognitive assessments - sleep, fatigue, pain, etc. 
• Please clarify methods – the authors state that all assessments and blood draw were done on the first day of their chemo treatment and that all blood samples were drawn before breakfast. Please clarify were all cognitive assessments done on prior to chemotherapy administration. Were pre-meds for the chemotherapy given? Often patients received anti-emetics preventatively pre-treatment. Were all assessments done prior to breakfast as described? It is assumed that medications (chemo) were given through a port system; when was that inserted and whether heparin was administered and what proximity be to the assessments. Was this always consistent among all CRC patients.
• “Functional Assessment of Cancer Therapy – Cognitive Function (FACT-Cog), version 3 and neuropsychological tests were completed on the first day of their regularly scheduled chemotherapy session. Blood specimen for the determination of biomarkers were obtained on the same day.”
• Page 4 line 157 – should this be described? And line 167 statistics?
• For the FACT-COG – has 4 distinct sub-scales and often suggested the PCI and PCA scales measures are related but are separate and distinct; please explain why you chose to use it as a total score.
• Cognitive performance – there were 3 separate but related cognitive domains assessed and combined for an overall cognitive performance; Were any sub-analyses completed to identify if a specific domain was most prominent in the relationships? It is assumed that the overall composite was used to reduce the number of outcomes due to sample size but an exploratory sensitivity analyses may be helpful to understand more about these relationships.
• Can you identify the power of the study? It seems that this should be identified as exploratory.
• Can you add why you did not chose to adjust the p-value with the multiple outcomes analyzed.
• The groups are already different in CysC, CRP – was there a difference in the stage of the cancer between the impaired and non-impaired groups? The association may exist but does it represent just stage of disease pre-chemotherapy treatment.
• Table 3 identifies the levels comparing impaired to non-impaired and significance level; is their a normal level range that can be reported for these values to put information in context.
• Page 11 line 343 – should it be shown vs. proven?
• Page 11 line 364 – should it be dramatic vs. dramatically?
• It is concerning that these are relationships but there is limited information discussed supporting these relationships.

Overall, this work is very interesting but it would seem that these results should be identified as preliminary due to the cross-sectional design, small sample, multiple comparisons, and multiple differences between the groups beyond cognitive impairment.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

The authors have systematically addressed the concerns addressed in the previous review. The additions help justify the study and support the need for further research in this area. 

Two recommendations to consider: 

Table 1 does identify that stage IV CRC patients were included in the sample but does not indicate whether they have had brain metastasis and although there were not statistical differences based on stage of disease; there is a significant differences clinically which could influence cognitive ability. This along without controlling for other correlated factors (symptoms - fatigue, sleep, pain, depression, anxiety) which form psychoneurological symptom cluster and can significantly influence CRCI - should be identified as a limitation to this correlational study. 

In addition, the authors response that the results are very preliminary and would recommend that this be added to the title to inform readers. 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

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.