Postoperative Acute Intracranial Hemorrhage and Venous Thromboembolism in Patients with Brain Metastases Receiving Acetylsalicylic Acid Perioperatively

Response to Reviewer 1 Comments

1. Summary

We are very glad about the the evaluation of our current study. All pointed-out comments and suggestions were answered and we believe that this developed the manuscript in a positive way. The implemented correction to the Result-section, adressing the classification of surgical and medical complications in neurosurgery, aimed to offer a more clear representation of our results.

2. Questions for General Evaluation

Reviewer’s Evaluation

Response and Revisions

Does the introduction provide sufficient background and include all relevant references?

Yes/Can be improved/Must be improved/Not applicable

We are confident that after revision and clarification of the undermentioned comments we could achieve even more clear introduction.

Are all the cited references relevant to the research?

Yes/Can be improved/Must be improved/Not applicable

Is the research design appropriate?

Yes/Can be improved/Must be improved/Not applicable

Are the methods adequately described?

Yes/Can be improved/Must be improved/Not applicable

Are the results clearly presented?

Yes/Can be improved/Must be improved/Not applicable

Are the conclusions supported by the results?

Yes/Can be improved/Must be improved/Not applicable

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1: What remains a question, other than the limitation of retrospective study, to show whether the resulting statement about aspirin would apply to tumor subtypes that are known to have higher rates of bleeding like melanoma, renal cell carcinoma, choriocarcinoma, or papillary carcinoma of the thyroid and whether can we extract from the data any information about this subgroup either in this manuscript or in a follow-up manuscript. 

Response 1: We were able to identify 12 patients with melanoma, 22 with renal cell carcinoma and none with choriocarcinoma or papillary carcinoma of the thyroid. Among these, only one patient experienced surgically relevant postoperatie hemorrhage, indicated for revision surgery. Because of this distribution of the patients it was not possible to derive any statistically relevant conclusion on the question, whether these types of metastases are connected with higher hemmorhage rates or not. Additional chart with the patients´ distribution according to histology was added. We are currently conducting a study with a larger number of patients and hope that this study will enable us to answer the question adequately.

Comments 2: Some abbreviations might be less common and make it difficult for the reader, such as listed 169-171, which is the use of ICB for intracerebral hemorrhage rather than ICH or  SAB rather than SAH for subarachnoid hemorrhage. Additionally, CAV is not a familiar abbreviation for surgical cavity bleeding, but I'm unsure if there is a better one.

Response 2: We revised and corrected the pointed abbreviations in accordance to the aforementioned recommendation. The definition of surgical cavity bleeding is not popullar, however we found it relevant to distinguis between intracerebral hemorrhage. A hemorrhage in the surgical cavity is most commonly described by radiological reports. This minimal hemorrhage is usually asymptomatic in patients and has no clinical relevance, so in most cases it is treated conservatively.

Comments 3: The other question is regarding the following statement:

253- 254 "Moreover, patients with Ibanez grade IV complications exhibited a significantly higher association with a history of ASA (P=0.038)."

Would you please clarify what you mean by the history of aspirin in this statement, and would it be relevant to comment on it in the discussion section?

Response 3: Thank you for mentioning this specific question and proposal for further explanation. The correlation between Grad IV surgical complication and patients with history of ASA (means ASA-impact patients, p=0.038) should be interpreted in the context of poor outcome among those.  Patients with ASA Impact had more comorbidities such as heart disease, hypertension and liver disease, as shown in Table 5. Surgical complications were associated with a worse outcome in this group.

It can be assumed that patients who were unable to stop taking ASA were mostly at increased risk of an unfavorable surgical outcome in the event of a complication occurring after surgery.

Response to Reviewer 2 Comments

1. Summary

We highly appreaciate your thorough review and specific comments on different aspects of this study. During the revision process we tried to adress all comments in order to make the manuscript even more clear and informative for the readers. Some limitations in the data-acquisition and evaluatione, however, makes it impossible to answer all scientifically interesting questions in accordance to the current topic.

2. Questions for General Evaluation

Reviewer’s Evaluation

Response and Revisions

Does the introduction provide sufficient background and include all relevant references?

Yes/Can be improved/Must be improved/Not applicable

Are all the cited references relevant to the research?

Yes/Can be improved/Must be improved/Not applicable

Is the research design appropriate?

Yes/Can be improved/Must be improved/Not applicable

Are the methods adequately described?

Yes/Can be improved/Must be improved/Not applicable

Are the results clearly presented?

Yes/Can be improved/Must be improved/Not applicable

We believe that through the suggested corrections the results from the current study are even more clear to the readers.

Are the conclusions supported by the results?

Yes/Can be improved/Must be improved/Not applicable

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1: Please provide the number of melanoma patients, as those are known to be more at risk of hemorrhage.

Response 1: In our cohort we were able to recognise only 12 patients with intracranial metastases, having been histologically verified as melanoma malignum. None of these patients, however, developed an intraoperative or postoperative bleeding, thus we were not able to make a significant conclusion on this question.

Comments 2: In section 3.2, it is mentioned that histopathological subtype had no influence on the occurence of hemorrhage. Please provide a breakdown per histological subtype in Table 2 (incorporating melanoma as a separate entity as previously requested), like is shown for tumor location and side.

Response 2: We were able to recognise 12 patients with intracranial metastasis from malignant melanoma. None of them was diagnosed with intra- or postoperative hemorrhage, thus such sub-typization in our case would bring no additional new information. The small number of patients with this subtype of metastasis did not allow us to draw a significant statement. We added an additional chart as Figure 4 representing the distribution among the different subtypes of metastasis.

Comments 3: Hospital stay length, KPS and GOS were found to be significantly affected by occurence of hemorrhage, but the way those parameters are presented in Table 3 seems inappropriate. Those are neither laboratory parameters or intra-operative characteristics, and they are also not risk factors for hemorrhage, but rather consequences of having an hemorrhage so I suggest removing them from Table 3 and reporting them in a separate Table.

Response 3: We revized the structure of Table 3 and depicted the outcome parameters in a separate Table 4. This, of course, should elicit the correlation between postoperative bleeding and worse clinical performance and outcome for the patients.

Comments 4: Regarding the risk and occurence of VTE, what is the practice at your institution for prophylaxis? Do you administer low-dose heparin or LMWH routinely to all patients? Please add this information in the paper.

Response 4: All patients were provided with standard-issue compression stockings following the surgical procedure and were encouraged to mobilise themselves on the first postoperative day. Even patients who had sustained paralysis and were unable to undergo full mobilisation were offered professional physiotherapy with movement exercises in bed in the postoperative period.

Comments 5: Section 3.5 is written in an unclear way. Should the readers understand that although AAS did not increase the absolute risk of hemorrhage, patients who had an hemorrhage had a worse outcome if they were on AAS (implying a higher severity of hemorrhage in those patients)? Please rephrase to make this more understandable to readers.

Response 5: Thank you for mentioning this specific question and proposal for further explanation. The correlation between Grad IV surgical complication and patients with history of ASA (means ASA-impact patients, p=0.038) should be interpreted in the context of poor outcome among those. Patients with ASA Impact had more comorbidities such as heart disease, hypertension and liver disease, as shown in Table 5. Surgical complications were associated with a worse outcome in this group.

It can be assumed that patients who were unable to stop taking ASA were mostly at increased risk of an unfavorable surgical outcome in the event of a complication occurring after surgery.

Comments 6: Authors mention in the discussion that partial tumor resection could increase the risk of hemorrhage according to prior studies. However, they did not seem to assess this in their population. This is interesting information that the authors should evaluate in their series to validate the information reported in other studies.

Response 6: Following your advice we included this information in the result section. The data analysis was made during the initial statistical evaluation and showed no relevant difference between both grous (with and without pICH). For better undertanding we included box chart, that represents in an easier way our findings. The presented results show tumor volume resection for the whole patient-cohort and not for a precific subpopulation group (lung cancer, renal cell cancer etc.).