Current Advances and Future Perspectives of Cerebrospinal Fluid Biopsy in Midline Brain Malignancies

  • Yimin Pan
  • Wenyong Long
  • Qing LiuEmail author
Neuro-oncology (GJ Lesser, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Neuro-oncology

Opinion statement

Malignancies arising in midline brain structures, including lymphomas, teratomas, germinomas, diffuse midline gliomas, and medulloblastomas typically respond to systemic therapies, and excessive surgical excision can result in serious complications, so that total surgical removal is not routinely performed. Identifying tumor specific biomarkers that can facilitate diagnosis at early stage and allow for dynamic surveillance of the tumor is of great clinical importance. However, existing standard methods for biopsy of these brain neoplasms are high risk, time consuming, and costly. Thus, less invasive and more rapid diagnosis tests are urgently needed to detect midline brain malignancies. Currently, tools for cerebrospinal biopsy of midline brain malignancies mainly include circulating tumor DNA, circulating tumor cells, and extracellular vesicles. Circulating tumor DNA achieved minimally invasive biopsy in several brain malignancies and has advantages in detecting tumor-specific mutations. In the field of tumor heterogeneity, circulating tumor cells better reflect the genome of tumors than surgical biopsy specimens. They can be applied for the diagnosis of leptomeningeal metastasis. Extracellular vesicles contain lots of genetic information about cancer cells, so they have potential in finding therapeutic targets and studying tumor invasion and metastasis.


Liquid biopsy Brain tumor CSF ctDNA Circulating tumor cells Extracellular vesicles 



All contributors to this study are included in the list of authors.

Author contributions

Y.P., and W.L. wrote the manuscript and drew the figures. Q.L. wrote the manuscript and supervised the entire work. All the authors provided final approval for the version to be published.

Funding information

This work was supported by the National Natural Science Foundation of China (grant number 81802974) and the grant from National Key Technology Research and Development Program of the Ministry of Science and Technology of China (grant number 2014BAI04B01).

Compliance with Ethical Standards

Conflict of Interest

Yimin Pan, Wenyong Long, and Qing Liu declare they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Zorofchian S, Lu G, Zhu JJ, Duose DY, Windham J, Esquenazi Y, et al. Detection of the MYD88 p.L265P mutation in the CSF of a patient with secondary central nervous system lymphoma. Front Oncol. 2018;8:382. Scholar
  2. 2.
    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20. Scholar
  3. 3.
    Murray MJ, Bartels U, Nishikawa R, Fangusaro J, Matsutani M, Nicholson JC. Consensus on the management of intracranial germ-cell tumors. Lancet Oncol. 2015;16(9):e470–e7. Scholar
  4. 4.
    Long W, Yi Y, Chen S, Cao Q, Zhao W, Liu Q. Potential new therapies for pediatric diffuse intrinsic pontine glioma. Front Pharmacol. 2017;8:495. Scholar
  5. 5.
    • Panditharatna E, Kilburn LB, Aboian MS, Kambhampati M, Gordish-Dressman H, Magge SN, et al. Clinically relevant and minimally invasive tumor surveillance of pediatric diffuse midline gliomas using patient-derived liquid biopsy. Clin Cancer Res. 2018;24(23):5850–9. They provide a novel method for liquid biopsy of pediatric diffuse midline gliomas.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    •• Pan C, Diplas BH, Chen X, Wu Y, Xiao X, Jiang L, et al. Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA. Acta Neuropathol. 2019;137(2):297–306. first study using deep sequencing achieved biopsy for molecular profiling of brainstem glioma with a high sensitivity and specificity.CrossRefPubMedGoogle Scholar
  7. 7.
    Mohammad F, Weissmann S, Leblanc B, Pandey DP, Hojfeldt JW, Comet I, et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med. 2017;23(4):483–92. Scholar
  8. 8.
    Katagi H, Louis N, Unruh D, Sasaki T, He X, Zhang A, et al. Radiosensitization by Histone H3 demethylase inhibition in diffuse intrinsic pontine glioma. Clin Cancer Res. 2019. Scholar
  9. 9.
    Choi SA, Lee C, Kwak PA, Park CK, Wang KC, Phi JH, et al. Histone deacetylase inhibitor panobinostat potentiates the anti-cancer effects of mesenchymal stem cell-based sTRAIL gene therapy against malignant glioma. Cancer Lett. 2019;442:161–9. Scholar
  10. 10.
    Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009–2013. Neuro-oncology. 2016;18(suppl_5):v1–v75. Scholar
  11. 11.
    Kahn SA, Wang X, Nitta RT, Gholamin S, Theruvath J, Hutter G, et al. Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma. Nat Commun. 2018;9(1):4121. Scholar
  12. 12.
    Brinker T, Stopa E, Morrison J, Klinge P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS. 2014;11:10. Scholar
  13. 13.
    McComb JG. Recent research into the nature of cerebrospinal fluid formation and absorption. J Neurosurg. 1983;59(3):369–83. Scholar
  14. 14.
    Milhorat TH. The third circulation revisited. J Neurosurg. 1975;42(6):628–45. Scholar
  15. 15.
    Bulat M, Klarica M. Recent insights into a new hydrodynamics of the cerebrospinal fluid. Brain Res Rev. 2011;65(2):99–112. Scholar
  16. 16.
    Battal B, Kocaoglu M, Bulakbasi N, Husmen G, Tuba Sanal H, Tayfun C. Cerebrospinal fluid flow imaging by using phase-contrast MR technique. Br J Radiol. 2011;84(1004):758–65. Scholar
  17. 17.
    van der Vaart M, Pretorius PJ. Circulating DNA. Its origin and fluctuation. Ann N Y Acad Sci. 2008;1137:18–26. Scholar
  18. 18.
    Szpechcinski A, Rudzinski P, Kupis W, Langfort R, Orlowski T, Chorostowska-Wynimko J. Plasma cell-free DNA levels and integrity in patients with chest radiological findings: NSCLC versus benign lung nodules. Cancer Lett. 2016;374(2):202–7. Scholar
  19. 19.
    Tug S, Helmig S, Menke J, Zahn D, Kubiak T, Schwarting A, et al. Correlation between cell free DNA levels and medical evaluation of disease progression in systemic lupus erythematosus patients. Cell Immunol. 2014;292(1–2):32–9. Scholar
  20. 20.
    Ha TT, Huy NT, Murao LA, Lan NT, Thuy TT, Tuan HM, et al. Elevated levels of cell-free circulating DNA in patients with acute dengue virus infection. PLoS One. 2011;6(10):e25969. Scholar
  21. 21.
    Sorenson GD, Pribish DM, Valone FH, Memoli VA, Bzik DJ, Yao SL. Soluble normal and mutated DNA sequences from single-copy genes in human blood. Cancer Epidemiol Biomarkers Prev. 1994;3(1):67–71.PubMedGoogle Scholar
  22. 22.
    Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37(3):646–50.PubMedGoogle Scholar
  23. 23.
    Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24. Scholar
  24. 24.
    Mattos-Arruda L, Weigelt B, Cortes J, Won HH, Ng CKY, Nuciforo P, et al. Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle. Ann Oncol. 2018;29(11):2268. Scholar
  25. 25.
    Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013;497(7447):108–12. Scholar
  26. 26.
    Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368(13):1199–209. Scholar
  27. 27.
    Liu BL, Cheng JX, Zhang W, Zhang X, Wang R, Lin H, et al. Quantitative detection of multiple gene promoter hypermethylation in tumor tissue, serum, and cerebrospinal fluid predicts prognosis of malignant gliomas. Neuro-oncology. 2010;12(6):540–8. Scholar
  28. 28.
    Pan W, Gu W, Nagpal S, Gephart MH, Quake SR. Brain tumor mutations detected in cerebral spinal fluid. Clin Chem. 2015;61(3):514–22. Scholar
  29. 29.
    De Mattos-Arruda L, Mayor R, Ng CK, Weigelt B, Martinez-Ricarte F, Torrejon D, et al. Cerebrospinal fluid-derived circulating tumor DNA better represents the genomic alterations of brain tumors than plasma. Nat Commun. 2015;6:8839. Scholar
  30. 30.
    Wang Y, Springer S, Zhang M, McMahon KW, Kinde I, Dobbyn L, et al. Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. Proc Natl Acad Sci U S A. 2015;112(31):9704–9. Scholar
  31. 31.
    •• Miller AM, Shah RH, Pentsova EI, Pourmaleki M, Briggs S, Distefano N, et al. Tracking tumor evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature. 2019;565(7741):654–8. This study monitored the evolution of glioma genome by next-generation sequencing and is expected to provide new targets for genome-directed therapies through its method.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Huang TY, Piunti A, Lulla RR, Qi J, Horbinski CM, Tomita T, et al. Detection of Histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma. Acta Neuropathol Commun. 2017;5(1):28. Scholar
  33. 33.
    Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR, et al. Integrated molecular meta-analysis of 1000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell. 2017;32(4):520–37.e5. Scholar
  34. 34.
    Castel D, Philippe C, Calmon R, Le Dret L, Truffaux N, Boddaert N, et al. Histone H3F3A and HIST1H3B K27 M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 2015;130(6):815–27. Scholar
  35. 35.
    Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44(3):251–3. Scholar
  36. 36.
    Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. Driver mutations in histone H3.3 and chromatin remodeling genes in pediatric glioblastoma. Nature. 2012;482(7384):226–31. Scholar
  37. 37.
    Wang Z, Jiang W, Wang Y, Guo Y, Cong Z, Du F, et al. MGMT promoter methylation in serum and cerebrospinal fluid as a tumor-specific biomarker of glioma. Biomed Rep. 2015;3(4):543–8. Scholar
  38. 38.
    Yang H, Cai L, Zhang Y, Tan H, Deng Q, Zhao M, et al. Sensitive detection of EGFR mutations in cerebrospinal fluid from lung adenocarcinoma patients with brain metastases. J Mol Diagn. 2014;16(5):558–63. Scholar
  39. 39.
    Massague J, Obenauf AC. Metastatic colonization by circulating tumor cells. Nature. 2016;529(7586):298–306. Scholar
  40. 40.
    Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, et al. Isolation of rare circulating tumor cells in cancer patients by microchip technology. Nature. 2007;450(7173):1235–9. Scholar
  41. 41.
    Abalde-Cela S, Piairo P, Dieguez L. The significance of circulating tumour cells in the clinic. Acta Cytol. 2019:1–13. Scholar
  42. 42.
    Galletti G, Portella L, Tagawa ST, Kirby BJ, Giannakakou P, Nanus DM. Circulating tumor cells in prostate cancer diagnosis and monitoring: an appraisal of clinical potential. Mol Diagn Ther. 2014;18(4):389–402. Scholar
  43. 43.
    Negin BP, Cohen SJ. Circulating tumor cells in colorectal cancer: past, present, and future challenges. Curr Treat Options Oncol. 2010;11(1–2):1–13. Scholar
  44. 44.
    Cristofanilli M. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. Semin Oncol. 2006;33(3 Suppl 9):S9–14. Scholar
  45. 45.
    Hong Y, Zhang Q. Phenotype of circulating tumor cell: face-off between epithelial and mesenchymal masks. Tumour Biol. 2016;37(5):5663–74. Scholar
  46. 46.
    Muller C, Holtschmidt J, Auer M, Heitzer E, Lamszus K, Schulte A, et al. Hematogenous dissemination of glioblastoma multiforme. Sci Transl Med. 2014;6(247):247ra101. Scholar
  47. 47.
    Lim MC, Maubach G, Zhuo L. Glial fibrillary acidic protein splice variants in hepatic stellate cells--expression and regulation. Mol Cell. 2008;25(3):376–84.Google Scholar
  48. 48.
    Danielyan L, Tolstonog G, Traub P, Salvetter J, Gleiter CH, Reisig D, et al. Colocalization of glial fibrillary acidic protein, metallothionein, and MHC II in human, rat, NOD/SCID, and nude mouse skin keratinocytes and fibroblasts. J Investig Dermatol. 2007;127(3):555–63. Scholar
  49. 49.
    Sullivan JP, Nahed BV, Madden MW, Oliveira SM, Springer S, Bhere D, et al. Brain tumor cells in circulation are enriched for mesenchymal gene expression. Cancer Discov. 2014;4(11):1299–309. Scholar
  50. 50.
    Ozkumur E, Shah AM, Ciciliano JC, Emmink BL, Miyamoto DT, Brachtel E, et al. Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci Transl Med. 2013;5(179):179ra47. Scholar
  51. 51.
    de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302–9. Scholar
  52. 52.
    Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(19):3213–21. Scholar
  53. 53.
    Yan WT, Cui X, Chen Q, Li YF, Cui YH, Wang Y, et al. Circulating tumor cell status monitors the treatment responses in breast cancer patients: a meta-analysis. Sci Rep. 2017;7:43464. Scholar
  54. 54.
    Fehm T, Becker S, Duerr-Stoerzer S, Sotlar K, Mueller V, Wallwiener D, et al. Determination of HER2 status using both serum HER2 levels and circulating tumor cells in patients with recurrent breast cancer whose primary tumor was HER2 negative or of unknown HER2 status. Breast Cancer Res. 2007;9(5):R74. Scholar
  55. 55.
    Lin X, Fleisher M, Rosenblum M, Lin O, Boire A, Briggs S, et al. Cerebrospinal fluid circulating tumor cells: a novel tool to diagnose leptomeningeal metastases from epithelial tumors. Neuro-oncology. 2017;19(9):1248–54. Scholar
  56. 56.
    Lee JS, Melisko ME, Magbanua MJ, Kablanian AT, Scott JH, Rugo HS, et al. Detection of cerebrospinal fluid tumor cells and its clinical relevance in leptomeningeal metastasis of breast cancer. Breast Cancer Res Treat. 2015;154(2):339–49. Scholar
  57. 57.
    Nayak L, Fleisher M, Gonzalez-Espinoza R, Lin O, Panageas K, Reiner A, et al. Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology. 2013;80(17):1598–605; discussion 603. Scholar
  58. 58.
    Akers JC, Gonda D, Kim R, Carter BS, Chen CC. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neuro-Oncol. 2013;113(1):1–11. Scholar
  59. 59.
    Yanez-Mo M, Siljander PR, Andreu Z, Zavec AB, Borras FE, Buzas EI, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066. Scholar
  60. 60.••
    Indira Chandran V, Welinder C, Mansson AS, Offer S, Freyhult E, Pernemalm M, et al. Ultrasensitive immunoprofiling of plasma extracellular vesicles identifies syndecan-1 as a potential tool for minimally invasive diagnosis of glioma. Clin Cancer Res. 2019. The first study using utralsensitive immunoprofiling identified one EVs-derived protein that can differentiate between high-grade glioma and low grade glioma.CrossRefGoogle Scholar
  61. 61.
    Manda SV, Kataria Y, Tatireddy BR, Ramakrishnan B, Ratnam BG, Lath R, et al. Exosomes as a biomarker platform for detecting epidermal growth factor receptor-positive high-grade gliomas. J Neurosurg. 2018;128(4):1091–101. Scholar
  62. 62.
    Figueroa JM, Skog J, Akers J, Li H, Komotar R, Jensen R, et al. Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients. Neuro-oncology. 2017;19(11):1494–502. Scholar
  63. 63.
    Akers JC, Ramakrishnan V, Kim R, Skog J, Nakano I, Pingle S, et al. MiR-21 in the extracellular vesicles (EVs) of cerebrospinal fluid (CSF): a platform for glioblastoma biomarker development. PLoS One. 2013;8(10):e78115. Scholar
  64. 64.
    Santangelo A, Imbruce P, Gardenghi B, Belli L, Agushi R, Tamanini A, et al. A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker. J Neuro-Oncol. 2018;136(1):51–62. Scholar
  65. 65.
    Lan F, Qing Q, Pan Q, Hu M, Yu H, Yue X. Serum exosomal miR-301a as a potential diagnostic and prognostic biomarker for human glioma. Cell Oncol (Dordrecht). 2018;41(1):25–33. Scholar
  66. 66.
    Akers JC, Hua W, Li H, Ramakrishnan V, Yang Z, Quan K, et al. A cerebrospinal fluid microRNA signature as biomarker for glioblastoma. Oncotarget. 2017;8(40):68769–79. Scholar
  67. 67.
    Manterola L, Guruceaga E, Gallego Perez-Larraya J, Gonzalez-Huarriz M, Jauregui P, Tejada S, et al. A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro-oncology. 2014;16(4):520–7. Scholar
  68. 68.
    Chen WW, Balaj L, Liau LM, Samuels ML, Kotsopoulos SK, Maguire CA, et al. BEAMing and Droplet digital PCR analysis of mutant IDH1 mRNA in glioma atient serum and cerebrospinal fluid extracellular vesicles. Mol Ther Nucl Acids. 2013;2:e109. Scholar
  69. 69.
    Ebrahimkhani S, Vafaee F, Hallal S, Wei H, Lee MYT, Young PE, et al. Deep sequencing of circulating exosomal microRNA allows non-invasive glioblastoma diagnosis. NPJ Precis Oncol. 2018;2:28. Scholar
  70. 70.
    • Osti D, Del Bene M, Rappa G, Santos M, Matafora V, Richichi C, et al. Clinical significance of extracellular vesicles in plasma from glioblastoma patients. Clin Cancer Res. 2019;25(1):266–76. The study demonstrated that higher EVs level in plasma can reflect the progress of GBM.CrossRefPubMedGoogle Scholar
  71. 71.
    Nakano I, Garnier D, Minata M, Rak J. Extracellular vesicles in the biology of brain tumor stem cells--implications for inter-cellular communication, therapy and biomarker development. Semin Cell Dev Biol. 2015;40:17–26. Scholar
  72. 72.
    Mahmoudi K, Ezrin A, Hadjipanayis C. Small extracellular vesicles as tumor biomarkers for glioblastoma. Mol Asp Med. 2015;45:97–102. Scholar
  73. 73.
    Shao H, Chung J, Balaj L, Charest A, Bigner DD, Carter BS, et al. Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat Med. 2012;18(12):1835–40. Scholar
  74. 74.
    Ferreira LM. Cancer metabolism: the Warburg effect today. Exp Mol Pathol. 2010;89(3):372–80. Scholar
  75. 75.
    Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44. Scholar
  76. 76.
    Haq R, Shoag J, Andreu-Perez P, Yokoyama S, Edelman H, Rowe GC, et al. Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell. 2013;23(3):302–15. Scholar
  77. 77.
    Mishra P, Tang W, Putluri V, Dorsey TH, Jin F, Wang F, et al. ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming. J Clin Invest. 2018;128(1):323–40. Scholar
  78. 78.
    Terunuma A, Putluri N, Mishra P, Mathe EA, Dorsey TH, Yi M, et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest. 2014;124(1):398–412. Scholar
  79. 79.
    Kalinina J, Ahn J, Devi NS, Wang L, Li Y, Olson JJ, et al. Selective detection of the D-enantiomer of 2-hydroxyglutarate in the CSF of glioma patients with mutated isocitrate dehydrogenase. Clin Cancer Res. 2016;22(24):6256–65. Scholar
  80. 80.
    Ballester LY, Lu G, Zorofchian S, Vantaku V, Putluri V, Yan Y, et al. Analysis of cerebrospinal fluid metabolites in patients with primary or metastatic central nervous system tumors. Acta Neuropathol Commun. 2018;6(1):85. Scholar
  81. 81.
    von Hoff K, Rutkowski S. Medulloblastoma. Curr Treat Options Neurol. 2012;14(4):416–26. Scholar
  82. 82.
    Ankri R, Taitelbaum H, Fixler D. Reflected light intensity profile of two-layer tissues: phantom experiments. J Biomed Opt. 2011;16(8):085001. Scholar
  83. 83.
    Gershanov S, Michowiz S, Toledano H, Yahav G, Barinfeld O, Hirshberg A, et al. Fluorescence lifetime imaging microscopy, a novel diagnostic tool for metastatic cell detection in the cerebrospinal fluid of children with medulloblastoma. Sci Rep. 2017;7(1):3648. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurosurgery in Xiangya HospitalCentral South UniversityChangshaChina

Personalised recommendations