Surgical Decompression and Its Effect on Angiopoetin-2 and VEGF-C Cerebrospinal Fluid Levels in Degenerative Cervical Myelopathy. A prospective Cohort Study

Surgical Decompression and Its Effect on Angiopoetin-2 and VEGF-C Cerebrospinal Fluid Levels in Degenerative Cervical Myelopathy. A prospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Surgical Decompression and Its Effect on Angiopoetin-2 and VEGF-C Cerebrospinal Fluid Levels in Degenerative Cervical Myelopathy. A prospective Cohort Study Ulf Bertram, Christian-Andreas Mueller, Thomas Pufe, Alexander Gombert, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9083241/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract Degenerative cervical myelopathy (DCM) is a leading cause of spinal cord dysfunction, driven by mechanical compression, secondary inflammatory and vascular changes. This study examines CSF Angiopoietin-2 (Ang2) and Vascular-Endothelial-Growth-Factor-C (VEGF-C) levels in DCM patients before and after decompressive surgery and their potential correlation with clinical outcomes. CSF samples were collected from 50 preoperative (DCMpre) and 20 patients three months postoperatively (DCMpost). A control group comprises 52 individuals undergoing thoracoabdominal aortic aneurysm (TAAA) surgery. Ang2 and VEGF-C levels were measured using ELISA and magnetic bead assays. Clinical assessments included modified Japanese Orthopaedic Association (mJOA) score, Neck Disability Index (NDI), and Oswestry Disability Index (ODI). Statistical analyses included ANOVA, paired t-tests, and Spearman correlation. Ang2 levels were significantly lower in DCM patients than in controls (DCMpre: 276 ± 90 pg/mL, DCMpost: 277 ± 65 pg/mL, TAAA: 463 ± 240 pg/mL; p 6 months (p < 0.05). VEGF-C levels did not differ significantly between groups. Preoperative Ang2 levels correlated with disability indices (NDI: r = -0.46, ODI: r = -0.44, p < 0.001). Ang2 levels are reduced in DCM and increase postoperatively, particularly in chronic cases, indicating a response to surgical intervention. While Ang2 correlates with disability indices, neither Ang2 nor VEGF-C serve as definitive biomarkers for disease severity or recovery. Health sciences/Biomarkers Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience Degenerative cervical myelopathy Angiopoietin-2 VEGF-C Cerebrospinal fluid biomarkers Decompressive surgery Figures Figure 1 Figure 2 Figure 3 Introduction Degenerative cervical myelopathy (DCM) is a leading cause of spinal cord injury globally and presents a substantial socioeconomic burden, particularly in aging populations in developed countries 1 , 2 . DCM involves primary damaging mechanisms, including mechanical compression of the spinal cord and ischemia, along with secondary mechanisms, such as neuroinflammation, apoptosis, and progressive ischemia, which exacerbate neuronal degeneration as downstream effects of the primary injury 1 . While the concept of secondary injury in spinal cord pathology was introduced in the early 20th century, no pharmacotherapeutic interventions currently target secondary mechanisms in DCM patients. 3 , 4 . Early decompressive surgery remains the primary recommended treatment. 4 . One of the challenges in developing pharmacological therapies is the limited understanding of pro-apoptotic, inflammatory, and angiogenetic mechanisms specific to DCM. Our previous study identified significantly decreased levels of Angiopoietin-2 (Ang2) and Vascular Endothelial Growth Factor C (VEGF-C) in cerebrospinal fluid (CSF) samples of symptomatic DCM patients at the time of decompressive surgery compared to asymptomatic patients. 5 Ang2 and VEGF-C are essential in modulating inflammation and vasculogenesis, each affecting vascular stability and immune response mechanisms. Ang2 influences vascular remodelling by binding to the Tie2 receptor on endothelial cells, generally promoting vascular instability under inflammatory conditions. 6 . Interestingly, we found both decreased Ang2 CSF levels along with clear evidence of a blood-brain/spinal cord- barrier disruption in DCM patients 5 . Similarly, VEGF-C is crucial in lymph angiogenesis, promoting immune cell trafficking and edema resolution, with implications in neurodegenerative diseases like Alzheimer's disease 7 , 8 . This study aims to investigate CSF Ang2 and VEGF-C concentrations in DCM patients before and three months after decompressive surgery, comparing these levels to a control group of neurologically healthy patients. We hypothesize that (A) Ang2 and VEGF-C levels will change following decompression and (B) these changes may correlate with clinical outcomes, potentially serving as biomarkers for treatment response. Methods Symptomatic DCM patients eligible for decompressive surgery, defined as having a modified Japanese Orthopaedic Association (mJOA) Score ≤ 17/18 and cervical spinal cord compression evident on MRI, were recruited from 2015 to 2020. CSF samples were obtained preoperatively from 50 patients (DCMpre) and from 20 patients three months post-surgery (DCMpost). All samples were acquired via lumbar puncture under sterile conditions. The control group consisted of 52 patients undergoing surgery for thoracoabdominal aortic aneurysm (TAAA) who had no neurological symptoms and received lumbar drainage as part of the standard surgical protocol. Patients with prior spine surgeries were excluded. All recruited individuals gave written consent to take part in this study. The study was conducted in accordance with the 2013 revision of the declaration of Helsinki. Demographic data, including age, sex, body mass index (BMI), and symptom duration, were recorded. Symptom burden was assessed using standardized questionnaires: mJOA Score, Neck Disability Index (NDI), Oswestry Disability Index (ODI), and a visual analog scale (VAS) for neck and arm pain, both preoperatively and three months postoperatively for the DCMpost group. Sample Acquisition Pre-surgical CSF samples from DCM patients were collected via lumbar puncture under sterile conditions following general anaesthesia but before surgical incision. Postoperative CSF samples were obtained from DCM patients three months post-surgery, with or without local anaesthesia. TAAA patient samples were collected directly from the lumbar drain. All samples were stored at -80°C until analysis. CSF Analytics Ang2 concentrations in CSF were measured using the Human Angiopoietin-2 ELISA Kit (KHC1641, Thermo Fisher Scientific, Waltham, MA, USA) with data acquisition through an Infinite M200 Plate Reader (Tecan, Männedorf, Switzerland). VEGF-C levels were analyzed using the Human Angiogenesis/Growth Factor Magnetic Bead Panel (Milliplex HAGP1MAG-12K-01, Merck, Darmstadt, Germany) on the Luminex MAGPIX system (Diasorin, Saluggia, Italy). Data were processed with ProcartaPlex Analyst 1.0 (Affymetrix eBioscience, Santa Clara, CA, USA). All assays followed manufacturer protocols, and samples were pipetted in triplicate. Statistical analysis Data were first assessed for normality. ANOVA followed by Tukey’s post hoc test was applied to Ang2 data, with ratio-paired t-tests between DCMpre and DCMpost groups. VEGF-C data were analysed using the Kruskal-Wallis test. Correlations between clinical outcomes and biomarker levels were assessed via Spearman’s correlation coefficient, with interpretations based on Cohen’s guidelines. Statistical significance was set at p ≤ .05. Ethical considerations The study was approved by the ethics committee of the medical faculty of RWTH Aachen University (EK 164/13) and conducted in accordance with the declaration of Helsinki as revised in 2013. Every participant gave written consent to participation of this study as well as interventions (surgery, lumbar puncture) after being briefed by a qualified physician. Surgical procedures were indicated following guidelines 4 regardless of participation in this study. Results Demographics and Clinical Disease Burden No significant differences in age, BMI, or gender distribution were observed among the DCMpre, DCMpost, and TAAA groups (Tab. 1). The mJOA scores were significantly different across groups, with higher scores in TAAA and an increase in DCMpost patients, suggesting partial recovery post-surgery. Disability indices (NDI and ODI) were markedly higher in DCM patients compared to controls, with no significant difference between DCMpre and DCMpost. Tab. 1 Demographics. DCMpre n=50 DCMpost n=20 TAAA n=52 Age (M [SD]) 63 [11.2] 62.6 [11.4] 62.9 [14.1] ns Body-Mass- Index (BMI) (m [SD]) 26.6 [5.0] 26.0 [4.4] 26.3 [5.1] ns mJOA-Score (m [SD]) 11 [3.1] 14 [2.0] 17 [1.3] p<0.001 Neck Disability Index (m [SD]) 40.2 [21.1] 37.4 [24.9] 6.1 [8.3] p<0.001 for TAA vs. DCM pre and TAA vs. DCM post Oswestry Disability Index (m [SD]) 41.4 [22.1] 38.8 [27.1] 7.3 [11.1] p<0.001 for TAA vs. DCM pre and TAA vs. DCM post Gender distribution (female/male ratio) 21/29 7/13 17/35 Symptom-Onset Duration 6 months (N [%]) 13 [65] DCM= degenerative cervical myelopathy; m= mean; mJOA= modified Japanese Orthopaedic Association; ns= not significant; SD= standard deviation; TAAA= thoracoabdominal aortic aneurysm CSF Angiopoetin 2 Levels Ang2 concentrations were analyzed across groups, with 9 samples excluded due to pipetting errors (1 sample of DCMpre-, 2 samples of DCMpost- and 6 sapmples of the TAAA-group). The mean Ang2 levels were 276 ± 90 pg/mL (DCMpre), 277 ± 65 pg/mL (DCMpost), and 463 ± 240 pg/mL in the TAAA group. ANOVA followed by Tukey’s test showed significantly lower Ang2 levels in both DCM groups compared to TAAA ( p < 0.001 ) (Fig. 1). Although no significant difference was observed between DCMpre and DCMpost in overall mean Ang2 levels, a paired t-test in a subset of 16 patients showed a significant increase post-surgery ( p 6 months (Fig. 2). CSF VEGF-C Levels The technical nature of the Luminex assay does not require pipetting multiplicates. Although the test was pipetted in biological triplicates, pipetting errors did not necessarily lead to exclusion of data. VEGF-C levels were measured in 49 DCMpre, 19 DCMpost, and 48 TAAA patients. Mean VEGF-C levels were 189 ± 107 pg/mL (DCMpre), 234 ± 114 pg/mL (DCMpost), and 211 ± 114 pg/mL (TAAA) (Fig. 3). Kruskal-Wallis analysis indicated no significant differences between groups. Additional analyses, including ANOVA and subgroup analysis based on symptom duration, also revealed no significant group differences. Correlation between CSF Levels and Clinical Burden Preoperative Ang2 levels showed a moderate negative correlation with NDI (r = -0.46; p <.001 ) and ODI (r = -0.44; p <.001 ), suggesting that lower Ang2 levels are associated with greater disability. However, no significant correlation was found between Ang2 levels and mJOA score changes post-surgery. VEGF-C levels did not correlate with clinical measures. A detailed overview regarding the changes in Ang2 levels and mJOA scores of the 16 patients that yielded pre and postoperative results can be found in Tab. 2. Tab. 2 Recovery data for mJOA score and Angiopoetin-2 (Ang2) CSF concentrations following surgical decompression of 16 individuals that provided pre- as well as postoperative CSF samples. DCM= degenerative cervical myelopathy; mJOA= modified Japanese Orthopaedic Association Score. DCMpre DCMpost Recovery 3 months post-surgery Patient No mJOA Ang2 pg/ml mJOA Ang2 pg/ml D mJOA D Ang2 pg/ml 1 12 178,52 12 277,09 0 98,57 2 7 189,07 13 246,08 4 57,01 3 17 167,06 17 211,258 0 44,2 4 15 171,72 15 198,14 0 26,42 5 16 245,7 16 259,2 0 13,5 6 12 171,67 15 223,29 3 51,62 7 16 208,15 17 235,1 1 26,95 8 11 214,6 12 246,48 1 31,88 9 10 294,56 13 328,7 3 34.14 10 15 126,5 16 191,73 1 65,23 11 11 311,77 15 355,73 4 43,96 12 11 347,43 13 394,61 2 47,18 13 9 280,15 11 288,96 2 8,81 14 11 269,07 16 234,46 5 -34,61 15 15 238,82 15 230,24 0 -8,58 16 12 343,27 11 347,89 -1 4,62 Discussion Our findings indicate significantly lower CSF Ang2 levels in DCM patients compared to a control group of TAAA patients, with an increase in a subset of patients post-surgery. This aligns with the role of Ang2 in inflammation and vascular remodelling, highlighting its potential in modulating the inflammatory environment following spinal decompression. Preoperative Ang2 levels were correlated with neck and back pain-associated disability (NDI and ODI), but not with myelopathy severity (mJOA score). These results suggest that Ang2 may be a marker of pain-related disability rather than direct myelopathy severity. Angiopetin-2 is a critical player in (neuro-)inflammation and angiogenesis primarily associated with vascular destabilization 6 . After traumatic spinal cord injury (SCI), Ang2 expression is typically upregulated, which contributes to the disruption of endothelial cell junctions and increases vascular permeability 9 , 10 . This disruption facilitates the migration of immune cells into the spinal cord, which can exacerbate inflammation and secondary injury processes. However, Ang2 also plays a role in subsequent vascular remodeling and angiogenesis, which are crucial for repair and regeneration following SCI 9 . Our DCM cohorts featured decreased CSF Ang2 levels, indicating, that neuroinflammation in degenerative cervical myelopathy differ distinctively compared with traumatic SCI at time of indication for surgical decompression. Of course, there is a substantial difference in time between disease-/symptom-onset to diagnosis comparing DCM with traumatic spinal cord injury. Although statistical significance was not reached, we observed a tendency towards lower Ang2 CSF levels in DCM patients that reported symptom-onset > 6 months then those who reported that first symptoms appeared less then 6 months from surgical decompression (see Fig. 2 C). Larger sample sizes might reveal a stronger time-dependent change of neuroinflammation in DCM. Increased vascular permeability, or blood-spinal-cord-barrier (BSCB) disruption, is characteristic of DCM. 5 , 11 , 12 . In contrast to traumatic SCI models, our cohort of DCM patients featured decreased CSF concentrations of Ang2 compared with our control group of TAAA patients. This control group did not show a relevant BSCB disruption as measured by Reiber’s diagnostics 12 . Therefore, Ang2 may not be the key factor maintaining BSCB disruption, at least not in DCM. Remarkably, we found Ang2 CSF levels to increase following decompressive surgery possibly indicating, that relief from chronic spinal cord compression might normalize the inflammatory milieu in the intrathecal compartment. In a previous study of ours we were able to demonstrate a recovery of the BSCB, following decompressive surgery 11 . Furthermore, the magnitude of BSCB disruption correlates with symptom serverety 12 . We did not find a correlation between Ang2 levels and changes in Ang2 levels with symptom severity or recovery. Hence, Ang2 might rather function as an indirect inducer of change in vascular permeability and recovery, following mechanical compression and decompression, but downregulated during chronic state of compression, hypoperfusion and hypoxia of the spinal cord in DCM. Limitations The study is limited due to its single center design. Although the sample size is quite large for a study of CSF samples in DCM patients, the study remains underpowered especially regarding the number of DCM patients that contributed pre- as well as postoperative CSF samples. Additionally, our control group comprises patients with a vascular pathology that features systemic inflammation. As stated above, we were previously able to demonstrate that the blood-spinal-cord-barrier remains intact in these patients 11 , 12 , making an effect of systemic endogenous inflammation trigger by TAAA on the intrathecal compartment rather unlikely. Also, neurological impairment was ruled out by clinical examination. Conclusion This study demonstrates lower CSF Ang2 levels in DCM patients relative to neurologically healthy controls, with a post-surgical increase, particularly in patients with symptom duration exceeding six months. Currently, Ang2 and VEGF-C levels are not viable biomarkers for symptom severity or recovery in DCM, though larger studies may reveal further insights into their role in disease onset and progression. Declarations Conflict of Interest Statement The authors declare not conflict of interest financially or otherwise regarding this study. Funding This study received funding by the the Deutsche Wirbelsäulenstiftung (Deutsche Wirbelsäulengesellschaft, DWG). Author Contribution U.B, C.B. and T.S. contributed to the conception and design of the study. C.B., T.S., U.B. and C.A.M. contributed to the acquisition, analysis and interpretation of data. U.B., C.B., T.S., L.B., T.P., C.A.M., A.G. and H.C. contributed to drafting the text or preparing the figures. All authors read and approved the final manuscript. Acknowledgement The authors thank all colleagues who participated in the clinical care of the patients. Special thanks go to Dr. Nicole Böttcher for coordinating sample storage with substantial personal effort. Data Availability Data and analysis are available from the corresponding author upon reasonable request. References Karadimas, S. K., Erwin, W. M., Ely, C. G., Dettori, J. R. & Fehlings, M. G. Pathophysiology and natural history of cervical spondylotic myelopathy. Spine (Phila Pa 1976) 38 , S21-36 (2013). https://doi.org/10.1097/BRS.0b013e3182a7f2c3 Kalsi-Ryan, S., Karadimas, S. K. & Fehlings, M. G. Cervical spondylotic myelopathy: the clinical phenomenon and the current pathobiology of an increasingly prevalent and devastating disorder. Neuroscientist 19 , 409-421 (2013). https://doi.org/10.1177/1073858412467377 Tator, C. H. & Fehlings, M. G. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 75 , 15-26 (1991). https://doi.org/10.3171/jns.1991.75.1.0015 Fehlings, M. G. et al. A Clinical Practice Guideline for the Management of Patients With Degenerative Cervical Myelopathy: Recommendations for Patients With Mild, Moderate, and Severe Disease and Nonmyelopathic Patients With Evidence of Cord Compression. Global Spine J 7 , 70S-83S (2017). https://doi.org/10.1177/2192568217701914 Blume, C. et al. Decreased angiogenesis as a possible pathomechanism in cervical degenerative myelopathy. Sci Rep 11 , 2497 (2021). https://doi.org/10.1038/s41598-021-81766-8 Augustin, H. G., Young Koh, G., Thurston, G. & Alitalo, K. Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system. Nature Reviews Molecular Cell Biology 10 , 165-177 (2009). https://doi.org/10.1038/nrm2639 Tammela, T. & Alitalo, K. Lymphangiogenesis: Molecular Mechanisms and Future Promise. Cell 140 , 460-476 (2010). https://doi.org/https://doi.org/10.1016/j.cell.2010.01.045 Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature 560 , 185-191 (2018). https://doi.org/10.1038/s41586-018-0368-8 Ng, M. T., Stammers, A. T. & Kwon, B. K. Vascular disruption and the role of angiogenic proteins after spinal cord injury. Transl Stroke Res 2 , 474-491 (2011). https://doi.org/10.1007/s12975-011-0109-x Durham-Lee, J. C., Wu, Y., Mokkapati, V. U., Paulucci-Holthauzen, A. A. & Nesic, O. Induction of angiopoietin-2 after spinal cord injury. Neuroscience 202 , 454-464 (2012). https://doi.org/10.1016/j.neuroscience.2011.09.058 Schmidt, T. P. et al. Blood spinal cord barrier disruption recovers in patients with degenerative cervical myelopathy after surgical decompression: a prospective cohort study. Sci Rep 13 , 7389 (2023). https://doi.org/10.1038/s41598-023-34004-2 Blume, C. et al. Patients with degenerative cervical myelopathy have signs of blood spinal cord barrier disruption, and its magnitude correlates with myelopathy severity: a prospective comparative cohort study. Eur Spine J 29 , 986-993 (2020). https://doi.org/10.1007/s00586-020-06298-7 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9083241","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":615027722,"identity":"2b43141a-b7fd-49ff-9dad-aa1d2673081b","order_by":0,"name":"Ulf Bertram","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYDACCSjNz8AGog6ACAPCWkDqJBtI1mJwgFgtBrebj33+uMcu2vhGWuKHHzV35MwZmDc+wKvlzrHkGQeeJeduu5F2WLLn2DNjywa2YrzWGNzIMWY4cIAZqCW9QYK34XDihgM8ZhL4teR/Bmqpz908I73559+Gw/VALeY/CNjCDNRyOHeDRNoxaaAtCQZAW/DpYJC8c8yY4cyB47kzzjxLs5Y5dthww2G2YrwO47vd/Jih4kB1bn97mvHNNzWH5Q2ON2/8gNcaTMBMovpRMApGwSgYBZgAACr6VqJW7rc0AAAAAElFTkSuQmCC","orcid":"","institution":"RWTH Aachen University","correspondingAuthor":true,"prefix":"","firstName":"Ulf","middleName":"","lastName":"Bertram","suffix":""},{"id":615027723,"identity":"8ce36fc5-9fa2-41d6-a484-fdaf659a71e4","order_by":1,"name":"Christian-Andreas Mueller","email":"","orcid":"","institution":"RWTH Aachen University","correspondingAuthor":false,"prefix":"","firstName":"Christian-Andreas","middleName":"","lastName":"Mueller","suffix":""},{"id":615027724,"identity":"fe714b0c-05f3-4bb2-aaec-d24ba7d72d09","order_by":2,"name":"Thomas Pufe","email":"","orcid":"","institution":"RWTH Aachen University","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Pufe","suffix":""},{"id":615027725,"identity":"e1416090-186c-4e8c-9acd-d15f4051cc07","order_by":3,"name":"Alexander Gombert","email":"","orcid":"","institution":"RWTH Aachen University","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Gombert","suffix":""},{"id":615027726,"identity":"d2afbd72-08e0-436d-a068-cf69cd0e59e1","order_by":4,"name":"Hans Clusmann","email":"","orcid":"","institution":"RWTH Aachen University","correspondingAuthor":false,"prefix":"","firstName":"Hans","middleName":"","lastName":"Clusmann","suffix":""},{"id":615027727,"identity":"99ca9ad2-309f-4f9b-9464-5642cf494284","order_by":5,"name":"Tobias Philip Schmidt","email":"","orcid":"","institution":"RWTH Aachen University","correspondingAuthor":false,"prefix":"","firstName":"Tobias","middleName":"Philip","lastName":"Schmidt","suffix":""},{"id":615027728,"identity":"920f7d84-88e1-4f19-9808-086c22d98974","order_by":6,"name":"Christian Blume","email":"","orcid":"","institution":"RWTH Aachen University","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Blume","suffix":""}],"badges":[],"createdAt":"2026-03-10 11:28:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9083241/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9083241/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105982839,"identity":"a5c3d985-77fe-4cb6-bd5e-a8a277fd567e","added_by":"auto","created_at":"2026-04-02 07:05:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56155,"visible":true,"origin":"","legend":"\u003cp\u003eAngiopoetin-2 concentrations in CSF samples. DCM= degenerative cervical myelopathy; TAA= thoracoabdominal aortic aneurysm; *** = p \u0026lt; .001; **** = p \u0026lt; .0001\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9083241/v1/7207833347000f23d50f2a53.png"},{"id":105982840,"identity":"fa67188e-d880-4ce9-95df-f68d0d47d489","added_by":"auto","created_at":"2026-04-02 07:05:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":126259,"visible":true,"origin":"","legend":"\u003cp\u003eratio-paired t-test and subgroup-analysis of Angiopetin-2 CSF levels. DCM= degenerative cervical myelopathy; TAA= thoracoabdominal aortic aneurysm; * = p \u0026lt; .05; ** = p \u0026lt; .01\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9083241/v1/c112f24dbc221c705b31de38.png"},{"id":105982841,"identity":"5347fefe-5f92-4f2c-9431-872292d48653","added_by":"auto","created_at":"2026-04-02 07:05:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":47775,"visible":true,"origin":"","legend":"\u003cp\u003eVEGF-C concentrations in CSF samples. DCM= degenerative cervical myelopathy; TAA= thoracoabdominal aortic aneurysm. Differences are not statically significant.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9083241/v1/6abb8f9df5de0528163ece1d.png"},{"id":106093933,"identity":"98ab5d5e-99bb-4288-9061-db300385e995","added_by":"auto","created_at":"2026-04-03 11:40:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":792892,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9083241/v1/6288715b-75ae-4393-8d48-8002d3e7e050.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eSurgical Decompression and Its Effect on Angiopoetin-2 and VEGF-C Cerebrospinal Fluid Levels in Degenerative Cervical Myelopathy. A prospective Cohort Study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDegenerative cervical myelopathy (DCM) is a leading cause of spinal cord injury globally and presents a substantial socioeconomic burden, particularly in aging populations in developed countries\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDCM involves primary damaging mechanisms, including mechanical compression of the spinal cord and ischemia, along with secondary mechanisms, such as neuroinflammation, apoptosis, and progressive ischemia, which exacerbate neuronal degeneration as downstream effects of the primary injury\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWhile the concept of secondary injury in spinal cord pathology was introduced in the early 20th century, no pharmacotherapeutic interventions currently target secondary mechanisms in DCM patients.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Early decompressive surgery remains the primary recommended treatment.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. One of the challenges in developing pharmacological therapies is the limited understanding of pro-apoptotic, inflammatory, and angiogenetic mechanisms specific to DCM.\u003c/p\u003e \u003cp\u003eOur previous study identified significantly decreased levels of Angiopoietin-2 (Ang2) and Vascular Endothelial Growth Factor C (VEGF-C) in cerebrospinal fluid (CSF) samples of symptomatic DCM patients at the time of decompressive surgery compared to asymptomatic patients.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAng2 and VEGF-C are essential in modulating inflammation and vasculogenesis, each affecting vascular stability and immune response mechanisms. Ang2 influences vascular remodelling by binding to the Tie2 receptor on endothelial cells, generally promoting vascular instability under inflammatory conditions.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Interestingly, we found both decreased Ang2 CSF levels along with clear evidence of a blood-brain/spinal cord- barrier disruption in DCM patients\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Similarly, VEGF-C is crucial in lymph angiogenesis, promoting immune cell trafficking and edema resolution, with implications in neurodegenerative diseases like Alzheimer's disease\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study aims to investigate CSF Ang2 and VEGF-C concentrations in DCM patients before and three months after decompressive surgery, comparing these levels to a control group of neurologically healthy patients. We hypothesize that (A) Ang2 and VEGF-C levels will change following decompression and (B) these changes may correlate with clinical outcomes, potentially serving as biomarkers for treatment response.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eSymptomatic DCM patients eligible for decompressive surgery, defined as having a modified Japanese Orthopaedic Association (mJOA) Score \u0026le; 17/18 and cervical spinal cord compression evident on MRI, were recruited from 2015 to 2020. CSF samples were obtained preoperatively from 50 patients (DCMpre) and from 20 patients three months post-surgery (DCMpost). All samples were acquired via lumbar puncture under sterile conditions. The control group consisted of 52 patients undergoing surgery for thoracoabdominal aortic aneurysm (TAAA) who had no neurological symptoms and received lumbar drainage as part of the standard surgical protocol.\u003c/p\u003e\n\u003cp\u003ePatients with prior spine surgeries were excluded. All recruited individuals gave written consent to take part in this study. The study was conducted in accordance with the 2013 revision of the declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eDemographic data, including age, sex, body mass index (BMI), and symptom duration, were recorded. Symptom burden was assessed using standardized questionnaires: mJOA Score, Neck Disability Index (NDI), Oswestry Disability Index (ODI), and a visual analog scale (VAS) for neck and arm pain, both preoperatively and three months postoperatively for the DCMpost group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSample Acquisition\u003c/p\u003e\n\u003cp\u003ePre-surgical CSF samples from DCM patients were collected via lumbar puncture under sterile conditions following general anaesthesia but before surgical incision. Postoperative CSF samples were obtained from DCM patients three months post-surgery, with or without local anaesthesia. TAAA patient samples were collected directly from the lumbar drain. All samples were stored at -80\u0026deg;C until analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCSF Analytics\u003c/p\u003e\n\u003cp\u003eAng2 concentrations in CSF were measured using the Human Angiopoietin-2 ELISA Kit (KHC1641, Thermo Fisher Scientific, Waltham, MA, USA) with data acquisition through an Infinite M200 Plate Reader (Tecan, M\u0026auml;nnedorf, Switzerland). VEGF-C levels were analyzed using the Human Angiogenesis/Growth Factor Magnetic Bead Panel (Milliplex HAGP1MAG-12K-01, Merck, Darmstadt, Germany) on the Luminex MAGPIX system (Diasorin, Saluggia, Italy). Data were processed with ProcartaPlex Analyst 1.0 (Affymetrix eBioscience, Santa Clara, CA, USA). All assays followed manufacturer protocols, and samples were pipetted in triplicate.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistical analysis\u003c/p\u003e\n\u003cp\u003eData were first assessed for normality. ANOVA followed by Tukey\u0026rsquo;s post hoc test was applied to Ang2 data, with ratio-paired t-tests between DCMpre and DCMpost groups. VEGF-C data were analysed using the Kruskal-Wallis test. Correlations between clinical outcomes and biomarker levels were assessed via Spearman\u0026rsquo;s correlation coefficient, with interpretations based on Cohen\u0026rsquo;s guidelines. Statistical significance was set at p \u0026le; .05.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthical considerations\u003c/p\u003e\n\u003cp\u003eThe study was approved by the ethics committee of the medical faculty of RWTH Aachen University (EK 164/13) and conducted in accordance with the declaration of Helsinki as revised in 2013. Every participant gave written consent to participation of this study as well as interventions (surgery, lumbar puncture) after being briefed by a qualified physician. Surgical procedures were indicated following guidelines\u003csup\u003e4\u003c/sup\u003e regardless of participation in this study.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDemographics and Clinical Disease Burden\u003c/p\u003e\n\u003cp\u003eNo significant differences in age, BMI, or gender distribution were observed among the DCMpre, DCMpost, and TAAA groups (Tab. 1). The mJOA scores were significantly different across groups, with higher scores in TAAA and an increase in DCMpost patients, suggesting partial recovery post-surgery. Disability indices (NDI and ODI) were markedly higher in DCM patients compared to controls, with no significant difference between DCMpre and DCMpost.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTab. 1\u003c/strong\u003e Demographics.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"628\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eDCMpre n=50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eDCMpost n=20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eTAAA n=52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 628px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (M [SD])\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e63 [11.2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e62.6 [11.4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e62.9 [14.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBody-Mass- Index (BMI)\u0026nbsp;\u003c/strong\u003e(m [SD])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e26.6 [5.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e26.0 [4.4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e26.3 [5.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003emJOA-Score\u0026nbsp;\u003c/strong\u003e(m [SD])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e11 [3.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e14 [2.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e17 [1.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003ep\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeck Disability Index\u0026nbsp;\u003c/strong\u003e(m [SD])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e40.2 [21.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e37.4 [24.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e6.1 [8.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003ep\u0026lt;0.001 for TAA vs. DCM pre and TAA vs. DCM post\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOswestry Disability Index\u0026nbsp;\u003c/strong\u003e(m [SD])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e41.4 [22.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e38.8 [27.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e7.3 [11.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003ep\u0026lt;0.001 for TAA vs. DCM pre and TAA vs. DCM post\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender distribution\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(female/male ratio)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e21/29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e7/13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e17/35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 628px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymptom-Onset\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 377px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration \u0026lt;6 months\u0026nbsp;\u003c/strong\u003e(N [%])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e7 [35]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration \u0026gt;6 months\u0026nbsp;\u003c/strong\u003e(N [%])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e13 [65]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cspan style=\"text-align: inherit;\"\u003eDCM= degenerative cervical myelopathy; m= mean; mJOA= modified Japanese Orthopaedic Association; ns= not significant; SD= standard deviation; TAAA= thoracoabdominal aortic aneurysm\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eCSF Angiopoetin 2 Levels\u003c/p\u003e\n\u003cp\u003eAng2 concentrations were analyzed across groups, with 9 samples excluded due to pipetting errors (1 sample of DCMpre-, 2 samples of DCMpost- and 6 sapmples of the TAAA-group). The mean Ang2 levels were 276 \u0026plusmn; 90 pg/mL (DCMpre), 277 \u0026plusmn; 65 pg/mL (DCMpost), and 463 \u0026plusmn; 240 pg/mL in the TAAA group. ANOVA followed by Tukey\u0026rsquo;s test showed significantly lower Ang2 levels in both DCM groups compared to TAAA (\u003cem\u003ep \u0026lt; 0.001\u003c/em\u003e) (Fig. 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough no significant difference was observed between DCMpre and DCMpost in overall mean Ang2 levels, a paired t-test in a subset of 16 patients showed a significant increase post-surgery (\u003cem\u003ep \u0026lt; 0.05\u003c/em\u003e), especially in patients symptomatic for \u0026gt;6 months (Fig. 2).\u003c/p\u003e\n\u003cp\u003eCSF VEGF-C Levels\u003c/p\u003e\n\u003cp\u003eThe technical nature of the Luminex assay does not require pipetting multiplicates. Although the test was pipetted in biological triplicates, pipetting errors did not necessarily lead to exclusion of data. VEGF-C levels were measured in 49 DCMpre, 19 DCMpost, and 48 TAAA patients. Mean VEGF-C levels were 189 \u0026plusmn; 107 pg/mL (DCMpre), 234 \u0026plusmn; 114 pg/mL (DCMpost), and 211 \u0026plusmn; 114 pg/mL (TAAA) (Fig. 3). Kruskal-Wallis analysis indicated no significant differences between groups. Additional analyses, including ANOVA and subgroup analysis based on symptom duration, also revealed no significant group differences.\u003c/p\u003e\n\u003cp\u003eCorrelation between CSF Levels and Clinical Burden\u003c/p\u003e\n\u003cp\u003ePreoperative Ang2 levels showed a moderate negative correlation with NDI (r = -0.46; \u003cem\u003ep \u0026lt;.001\u003c/em\u003e) and ODI (r = -0.44; \u003cem\u003ep \u0026lt;.001\u003c/em\u003e), suggesting that lower Ang2 levels are associated with greater disability. However, no significant correlation was found between Ang2 levels and mJOA score changes post-surgery. VEGF-C levels did not correlate with clinical measures.\u003c/p\u003e\n\u003cp\u003eA detailed overview regarding the changes in Ang2 levels and mJOA scores of the 16 patients that yielded pre and postoperative results can be found in Tab. 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTab. 2\u003c/strong\u003e Recovery data for mJOA score and Angiopoetin-2 (Ang2) CSF concentrations following surgical decompression of 16 individuals that provided pre- as well as postoperative CSF samples. DCM= degenerative cervical myelopathy; mJOA= modified Japanese Orthopaedic Association Score.\u0026nbsp;\u003c/p\u003e\n\u003ctable style=\"float: left;border: none;width:455.0pt;border-collapse:collapse;margin-left:4.8pt;margin-right: 4.8pt;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:130.0pt;border:solid windowtext 1.0pt;border-right:solid black 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003eDCMpre\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" colspan=\"2\" style=\"width:130.0pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid black 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003eDCMpost\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" colspan=\"2\" style=\"width:130.0pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid black 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003eRecovery 3 months post-surgery\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border:solid windowtext 1.0pt;border-right:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:18.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003ePatient No\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;padding:0cm 3.5pt 0cm 3.5pt;height:18.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003emJOA\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:18.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003eAng2\u003csub\u003epg/ml\u003c/sub\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:18.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003emJOA\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:18.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003eAng2\u003csub\u003epg/ml\u003c/sub\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:18.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Symbol;color:black;\"\u003eD\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003emJOA\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0cm 3.5pt 0cm 3.5pt;height:18.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Symbol;color:black;\"\u003eD\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e Ang2\u003csub\u003epg/ml\u003c/sub\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e1\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e178,52\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e277,09\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FFF2CC;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e98,57\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e2\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e189,07\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e13\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e246,08\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e57,01\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e3\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e17\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e167,06\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e17\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e211,258\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FFF2CC;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e44,2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e4\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e171,72\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e198,14\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FFF2CC;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cem\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e0\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e26,42\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e5\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e16\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e245,7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e16\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e259,2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FFF2CC;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e13,5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e6\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e171,67\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n 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style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e51,62\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e7\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e16\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e208,15\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e17\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e235,1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e26,95\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e8\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e214,6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e246,48\u003c/span\u003e\u003c/p\u003e\n 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style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e9\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e294,56\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e13\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e328,7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e34.14\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e10\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e126,5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e16\u003c/span\u003e\u003c/p\u003e\n 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style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e65,23\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e11\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e311,77\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e355,73\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e43,96\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e12\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e347,43\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e13\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e394,61\u003c/span\u003e\u003c/p\u003e\n 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style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e13\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e280,15\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e288,96\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e8,81\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e14\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border:solid windowtext 1.0pt;border-top:none;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e269,07\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e16\u003c/span\u003e\u003c/p\u003e\n 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style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FFB1A4;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e-34,61\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border:solid windowtext 1.0pt;border-top:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e15\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e238,82\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e230,24\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FFF2CC;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FFB1A4;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e-8,58\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width:65.0pt;border:solid windowtext 1.0pt;border-top:none;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e16\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e343,27\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:51.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:78.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e347,89\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:52.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FFB1A4;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e-1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width:77.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E2EFDA;padding:0cm 3.5pt 0cm 3.5pt;height:17.0pt;\"\u003e\n \u003cp style='margin:0cm;font-size:16px;font-family:\"Calibri\",sans-serif;text-align:right;'\u003e\u003cspan style=\"font-size:15px;font-family:Calibri;color:black;\"\u003e4,62\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur findings indicate significantly lower CSF Ang2 levels in DCM patients compared to a control group of TAAA patients, with an increase in a subset of patients post-surgery. This aligns with the role of Ang2 in inflammation and vascular remodelling, highlighting its potential in modulating the inflammatory environment following spinal decompression. Preoperative Ang2 levels were correlated with neck and back pain-associated disability (NDI and ODI), but not with myelopathy severity (mJOA score). These results suggest that Ang2 may be a marker of pain-related disability rather than direct myelopathy severity.\u003c/p\u003e \u003cp\u003eAngiopetin-2 is a critical player in (neuro-)inflammation and angiogenesis primarily associated with vascular destabilization\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. After traumatic spinal cord injury (SCI), Ang2 expression is typically upregulated, which contributes to the disruption of endothelial cell junctions and increases vascular permeability\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. This disruption facilitates the migration of immune cells into the spinal cord, which can exacerbate inflammation and secondary injury processes. However, Ang2 also plays a role in subsequent vascular remodeling and angiogenesis, which are crucial for repair and regeneration following SCI\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Our DCM cohorts featured decreased CSF Ang2 levels, indicating, that neuroinflammation in degenerative cervical myelopathy differ distinctively compared with traumatic SCI at time of indication for surgical decompression. Of course, there is a substantial difference in time between disease-/symptom-onset to diagnosis comparing DCM with traumatic spinal cord injury. Although statistical significance was not reached, we observed a tendency towards lower Ang2 CSF levels in DCM patients that reported symptom-onset\u0026thinsp;\u0026gt;\u0026thinsp;6 months then those who reported that first symptoms appeared less then 6 months from surgical decompression (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Larger sample sizes might reveal a stronger time-dependent change of neuroinflammation in DCM.\u003c/p\u003e \u003cp\u003eIncreased vascular permeability, or blood-spinal-cord-barrier (BSCB) disruption, is characteristic of DCM.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. In contrast to traumatic SCI models, our cohort of DCM patients featured decreased CSF concentrations of Ang2 compared with our control group of TAAA patients. This control group did not show a relevant BSCB disruption as measured by Reiber\u0026rsquo;s diagnostics\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Therefore, Ang2 may not be the key factor maintaining BSCB disruption, at least not in DCM. Remarkably, we found Ang2 CSF levels to increase following decompressive surgery possibly indicating, that relief from chronic spinal cord compression might normalize the inflammatory milieu in the intrathecal compartment. In a previous study of ours we were able to demonstrate a recovery of the BSCB, following decompressive surgery\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Furthermore, the magnitude of BSCB disruption correlates with symptom serverety\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. We did not find a correlation between Ang2 levels and changes in Ang2 levels with symptom severity or recovery. Hence, Ang2 might rather function as an indirect inducer of change in vascular permeability and recovery, following mechanical compression and decompression, but downregulated during chronic state of compression, hypoperfusion and hypoxia of the spinal cord in DCM.\u003c/p\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003cp\u003eThe study is limited due to its single center design. Although the sample size is quite large for a study of CSF samples in DCM patients, the study remains underpowered especially regarding the number of DCM patients that contributed pre- as well as postoperative CSF samples.\u003c/p\u003e \u003cp\u003eAdditionally, our control group comprises patients with a vascular pathology that features systemic inflammation. As stated above, we were previously able to demonstrate that the blood-spinal-cord-barrier remains intact in these patients\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, making an effect of systemic endogenous inflammation trigger by TAAA on the intrathecal compartment rather unlikely. Also, neurological impairment was ruled out by clinical examination.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrates lower CSF Ang2 levels in DCM patients relative to neurologically healthy controls, with a post-surgical increase, particularly in patients with symptom duration exceeding six months. Currently, Ang2 and VEGF-C levels are not viable biomarkers for symptom severity or recovery in DCM, though larger studies may reveal further insights into their role in disease onset and progression.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest Statement\u003c/h2\u003e \u003cp\u003eThe authors declare not conflict of interest financially or otherwise regarding this study.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study received funding by the the Deutsche Wirbels\u0026auml;ulenstiftung (Deutsche Wirbels\u0026auml;ulengesellschaft, DWG).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eU.B, C.B. and T.S. contributed to the conception and design of the study. C.B., T.S., U.B. and C.A.M. contributed to the acquisition, analysis and interpretation of data. U.B., C.B., T.S., L.B., T.P., C.A.M., A.G. and H.C. contributed to drafting the text or preparing the figures. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors thank all colleagues who participated in the clinical care of the patients. Special thanks go to Dr. Nicole B\u0026ouml;ttcher for coordinating sample storage with substantial personal effort.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData and analysis are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKaradimas, S. K., Erwin, W. M., Ely, C. G., Dettori, J. R. \u0026amp; Fehlings, M. G. Pathophysiology and natural history of cervical spondylotic myelopathy. \u003cem\u003eSpine (Phila Pa 1976)\u003c/em\u003e \u003cstrong\u003e38\u003c/strong\u003e, S21-36 (2013). https://doi.org/10.1097/BRS.0b013e3182a7f2c3\u003c/li\u003e\n\u003cli\u003eKalsi-Ryan, S., Karadimas, S. K. \u0026amp; Fehlings, M. G. Cervical spondylotic myelopathy: the clinical phenomenon and the current pathobiology of an increasingly prevalent and devastating disorder. \u003cem\u003eNeuroscientist\u003c/em\u003e \u003cstrong\u003e19\u003c/strong\u003e, 409-421 (2013). https://doi.org/10.1177/1073858412467377\u003c/li\u003e\n\u003cli\u003eTator, C. H. \u0026amp; Fehlings, M. G. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. \u003cem\u003eJ Neurosurg\u003c/em\u003e \u003cstrong\u003e75\u003c/strong\u003e, 15-26 (1991). https://doi.org/10.3171/jns.1991.75.1.0015\u003c/li\u003e\n\u003cli\u003eFehlings, M. G.\u003cem\u003e et al.\u003c/em\u003e A Clinical Practice Guideline for the Management of Patients With Degenerative Cervical Myelopathy: Recommendations for Patients With Mild, Moderate, and Severe Disease and Nonmyelopathic Patients With Evidence of Cord Compression. \u003cem\u003eGlobal Spine J\u003c/em\u003e \u003cstrong\u003e7\u003c/strong\u003e, 70S-83S (2017). https://doi.org/10.1177/2192568217701914\u003c/li\u003e\n\u003cli\u003eBlume, C.\u003cem\u003e et al.\u003c/em\u003e Decreased angiogenesis as a possible pathomechanism in cervical degenerative myelopathy. \u003cem\u003eSci Rep\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 2497 (2021). https://doi.org/10.1038/s41598-021-81766-8\u003c/li\u003e\n\u003cli\u003eAugustin, H. G., Young Koh, G., Thurston, G. \u0026amp; Alitalo, K. Control of vascular morphogenesis and homeostasis through the angiopoietin\u0026ndash;Tie system. \u003cem\u003eNature Reviews Molecular Cell Biology\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 165-177 (2009). https://doi.org/10.1038/nrm2639\u003c/li\u003e\n\u003cli\u003eTammela, T. \u0026amp; Alitalo, K. Lymphangiogenesis: Molecular Mechanisms and Future Promise. \u003cem\u003eCell\u003c/em\u003e \u003cstrong\u003e140\u003c/strong\u003e, 460-476 (2010). https://doi.org/https://doi.org/10.1016/j.cell.2010.01.045\u003c/li\u003e\n\u003cli\u003eDa Mesquita, S.\u003cem\u003e et al.\u003c/em\u003e Functional aspects of meningeal lymphatics in ageing and Alzheimer\u0026apos;s disease. \u003cem\u003eNature\u003c/em\u003e \u003cstrong\u003e560\u003c/strong\u003e, 185-191 (2018). https://doi.org/10.1038/s41586-018-0368-8\u003c/li\u003e\n\u003cli\u003eNg, M. T., Stammers, A. T. \u0026amp; Kwon, B. K. Vascular disruption and the role of angiogenic proteins after spinal cord injury. \u003cem\u003eTransl Stroke Res\u003c/em\u003e \u003cstrong\u003e2\u003c/strong\u003e, 474-491 (2011). https://doi.org/10.1007/s12975-011-0109-x\u003c/li\u003e\n\u003cli\u003eDurham-Lee, J. C., Wu, Y., Mokkapati, V. U., Paulucci-Holthauzen, A. A. \u0026amp; Nesic, O. Induction of angiopoietin-2 after spinal cord injury. \u003cem\u003eNeuroscience\u003c/em\u003e \u003cstrong\u003e202\u003c/strong\u003e, 454-464 (2012). https://doi.org/10.1016/j.neuroscience.2011.09.058\u003c/li\u003e\n\u003cli\u003eSchmidt, T. P.\u003cem\u003e et al.\u003c/em\u003e Blood spinal cord barrier disruption recovers in patients with degenerative cervical myelopathy after surgical decompression: a prospective cohort study. \u003cem\u003eSci Rep\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 7389 (2023). https://doi.org/10.1038/s41598-023-34004-2\u003c/li\u003e\n\u003cli\u003eBlume, C.\u003cem\u003e et al.\u003c/em\u003e Patients with degenerative cervical myelopathy have signs of blood spinal cord barrier disruption, and its magnitude correlates with myelopathy severity: a prospective comparative cohort study. \u003cem\u003eEur Spine J\u003c/em\u003e \u003cstrong\u003e29\u003c/strong\u003e, 986-993 (2020). https://doi.org/10.1007/s00586-020-06298-7\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Degenerative cervical myelopathy, Angiopoietin-2, VEGF-C, Cerebrospinal fluid biomarkers, Decompressive surgery","lastPublishedDoi":"10.21203/rs.3.rs-9083241/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9083241/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDegenerative cervical myelopathy (DCM) is a leading cause of spinal cord dysfunction, driven by mechanical compression, secondary inflammatory and vascular changes. This study examines CSF Angiopoietin-2 (Ang2) and Vascular-Endothelial-Growth-Factor-C (VEGF-C) levels in DCM patients before and after decompressive surgery and their potential correlation with clinical outcomes.\u003c/p\u003e \u003cp\u003eCSF samples were collected from 50 preoperative (DCMpre) and 20 patients three months postoperatively (DCMpost). A control group comprises 52 individuals undergoing thoracoabdominal aortic aneurysm (TAAA) surgery. Ang2 and VEGF-C levels were measured using ELISA and magnetic bead assays. Clinical assessments included modified Japanese Orthopaedic Association (mJOA) score, Neck Disability Index (NDI), and Oswestry Disability Index (ODI). Statistical analyses included ANOVA, paired t-tests, and Spearman correlation. Ang2 levels were significantly lower in DCM patients than in controls (DCMpre: 276\u0026thinsp;\u0026plusmn;\u0026thinsp;90 pg/mL, DCMpost: 277\u0026thinsp;\u0026plusmn;\u0026thinsp;65 pg/mL, TAAA: 463\u0026thinsp;\u0026plusmn;\u0026thinsp;240 pg/mL; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with a postoperative increase in patients symptomatic for \u0026gt;\u0026thinsp;6 months (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). VEGF-C levels did not differ significantly between groups. Preoperative Ang2 levels correlated with disability indices (NDI: r = -0.46, ODI: r = -0.44, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Ang2 levels are reduced in DCM and increase postoperatively, particularly in chronic cases, indicating a response to surgical intervention. While Ang2 correlates with disability indices, neither Ang2 nor VEGF-C serve as definitive biomarkers for disease severity or recovery.\u003c/p\u003e","manuscriptTitle":"Surgical Decompression and Its Effect on Angiopoetin-2 and VEGF-C Cerebrospinal Fluid Levels in Degenerative Cervical Myelopathy. A prospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-02 07:05:45","doi":"10.21203/rs.3.rs-9083241/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-24T06:31:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-23T13:30:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-16T00:19:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-15T18:50:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"331500137541615220070786618270147768852","date":"2026-04-12T09:06:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"50358213766243503326228438743450219856","date":"2026-04-12T02:43:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321002524232842892598484919422080725349","date":"2026-04-05T13:57:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-04T04:25:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"193010492070548967480477555365932243844","date":"2026-04-01T05:20:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"269343314507171910518660617784985055337","date":"2026-04-01T00:50:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-30T01:49:10+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-25T18:46:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-11T13:35:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-11T13:34:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-03-10T11:17:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"00b82d7a-933d-4717-97b3-f427030e819a","owner":[],"postedDate":"April 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":65560826,"name":"Health sciences/Biomarkers"},{"id":65560827,"name":"Health sciences/Diseases"},{"id":65560828,"name":"Health sciences/Medical research"},{"id":65560829,"name":"Health sciences/Neurology"},{"id":65560830,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-05-12T12:39:52+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-02 07:05:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9083241","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9083241","identity":"rs-9083241","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}