First, they recommended to describe the rationale behind the selection of specific immunostaining markers (laminin, α-smooth muscle actin [αSMA] and podoplanin) and to discuss their relevance to the study objectives. To understand the vascular changes in the dura mater of patients with chronic subdural hematoma (cSDH), we selected specific immunostaining markers to observe the representative proteins of vessels in different layers of the dura. These markers were chosen for their relevance to the study’s objectives of elucidating the mechanisms of neovascularization and lymphangiogenesis in cSDH pathology. Laminin is a basal membrane protein that underlies the endothelium and encases pericytes and smooth muscle cells in the vessel wall. It was selected to visualize the overall vascular architecture. Laminin-positive staining revealed a significant increase in vascular structures in the outer membrane (OM) of a cSDH patient, highlighting the extent of neovascularization. αSMA is the major isoform in vascular smooth muscle and serves as a marker for arterial vessels. The use of αSMA allowed us to identify and confirm the increased presence of arterial structures derived from the middle meningeal artery (MMA) in the OM of a cSDH patient. The αSMA-positive vessels indicated that the arteries in the OM were significantly increased, providing insight into the arterial contributions to cSDH pathology. Podoplanin is widely used as a marker for lymphatic endothelial cells. Its use in this study demonstrated the formation of new lymphatic vessels alongside blood vessels in the OM of a cSDH patient. This finding is crucial for understanding the role of lymphangiogenesis in the disease process. By using these markers, we were able to comprehensively analyze the vascular changes in the dura mater of cSDH patients, providing valuable insights into the mechanisms underlying neovascularization and lymphangiogenesis, and their contributions to cSDH recurrence.

Second, they recommended us to describe the impact of the study on future treatment strategies for cSDHs, and to address potential challenges or limitations in translating our research findings into clinical practice. As MMA embolization has recently been focused, management strategies also have being shifting from the operation to the endovascular procedures for recurrent and even primary cSDH. So, we began this translational research to find out the basal relationship between recurrence of cSDH and MMA with the aid of cutting-edge methods. However, this study has some limitations in terms of case number and target situation. Readers can easily imagine that pathological samples of full layers of dura, OM and cSDH are difficult to obtain during a small burr hole trephination and cSDH evacuation. And, Korean governmental health insurance system is working only for the MMA embolization of the recurrent ones after previous surgical treatment. Based on this research, we look forward to successive challenges from abroad research groups for pathomechanism of the primary cSDH and effects of some drugs on the neovascualarization in OM of cSDH.

Third, they wanted to know the potential mechanisms underlying neovascularization in the OM of cSDHs by exploring possible connections with known pathways involved in angiogenesis and vascular remodeling, furthermore, they wanted to discuss how these mechanisms may contribute to cSDH recurrence. The potential mechanisms of neovascularization are a complex process involving various cellular and molecular mechanisms which were mechanical and chemical stimuli like hypoxia, proinflammation, growth factors and degradation of extracellular matrix. In the context of cSDHs, inflammatory responses which recruits neutrophils, lymphocytes and macrophages to release pro-inflammatory cytokines and angiogenic factors such as vascular endothelial growth factor are expected to be a major mechanism for neovascularization. The angiogenic factors promote new blood vessel formation from pre-existing vessels by stimulating endothelial cell proliferation, migration and the formation of new capillaries. Therefore, Inflammation-induced formation of new blood vessels included fragile and leaky sinusoidal capillaries. The neovascularization in OM is expected to contribute to the recurrence of cSDHs through several interrelated mechanisms : 1) the formation of fragile and leaky sinusoidal capillaries; 2) a sustained inflammatory response that promotes continuous vessel formation and rupture; 3) A robust blood supply from the MMAs that exacerbates the fragility of the new vessels, increasing the risk of rupture and re-bleeding; and 4) impaired lymphatic drainage that exacerbates fluid accumulation and pressure. Understanding these mechanisms provides insight into the pathological changes in cSDH and potential therapeutic targets to prevent recurrence.

Fourth, the authors mention about the discrepancy in the recurrence rate of cSDH. In the manuscript, we previously mentioned a recurrence rate of upto 37% for primary cSDHs. Upon further review, however, this specific rate could not be corroborated by the literature. The recurrence rates reported in the literature vary widely, ranging from 0.36% to 33.3%, with postoperative rates reaching up to 76% in some cases. Only 10% to 20% of recurrent cases typically require reoperation. This variability in recurrence rates can be attributed to differences in patient demographics, such as age and gender as well as risk factors including head trauma, alcohol overuse and medication use.