Skip to main content

Advertisement

SpringerLink
Log in

Assessment of radiographic and prognostic characteristics of programmed death-ligand 1 expression in high-grade gliomas

  • Research
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Purpose

Gliomas are characterized by immunosuppressive features. Programmed death-ligand 1 (PD-L1) is overexpressed and plays an important role in the immunosuppressive tumor microenvironments of gliomas. However, the radiographical and prognostic significance of PD-L1 expression remains unclear.

Methods

Using tissue microarrays, we evaluated PD-L1 expression and the presence of tumor-infiltrating CD4+ and CD8+T cells and CD204+macrophages using immunohistochemical analysis. Contrast enhancement area and fluid-attenuated inversion recovery (FLAIR) hyperintensity area were evaluated by two-dimensional analysis. Kaplan–Meier analysis was performed to evaluate the overall survival time in 44 patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma.

Results

We evaluated 71 patients with newly diagnosed high-grade gliomas who were treated between October 1998 and April 2012. PD-L1 expression was observed in 15 patients (21.1%). A significant association of PD-L1 expression with the CD4+ and CD8+ T cell densities, but not with CD204+ macrophage densities, was observed (p = 0.025, p = 0.0098, and p = 0.19, respectively). The FLAIR-to-enhancement ratio was significantly higher in PD-L1+ tumors than in PD-L1− tumors (p = 0.0037). PD-L1 expression did not show a significant association with the median survival time (PD-L1 + vs. PD-L1−: 19.2 vs 14.9 months; p = 0.39).

Conclusion

PD-L1 expression was associated with CD4+ and CD8+ T cell infiltration, indicating a significant interplay between PD-L1 and immune cells. The positive correlation of PD-L1 expression with an increased FLAIR-to-enhancement ratio suggested that radiographical characteristics could reflect the immunological status. Our results did not support the prognostic impact of PD-L1 in patients with IDH-wildtype glioblastomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Committee of Brain Tumor Registry of Japan (2017) Report of brain tumor registry of Japan (2005–2008)14 edition. Neurol Med Chir (Tokyo) 57:9–102

    Article  Google Scholar 

  2. Lee KS, Lee K, Yun S, Moon S, Park Y, Han JH, Kim CY, Lee HS, Choe G (2018) Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma. J Neurooncol 136:453–461. https://doi.org/10.1007/s11060-017-2675-6

    Article  CAS  PubMed  Google Scholar 

  3. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466. https://doi.org/10.1016/S1470-2045(09)70025-7

    Article  CAS  PubMed  Google Scholar 

  4. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. https://doi.org/10.1056/NEJMoa0808710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Grabowski MM, Sankey EW, Ryan KJ, Chongsathidkiet P, Lorrey SJ, Wilkinson DS, Fecci PE (2021) Immune suppression in gliomas. J Neurooncol 151:3–12. https://doi.org/10.1007/s11060-020-03483-y

    Article  PubMed  Google Scholar 

  6. Desland FA, Hormigo A (2020) The CNS and the brain tumor microenvironment: implications for glioblastoma immunotherapy. Int J Mol Sci. https://doi.org/10.3390/ijms21197358

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lim M, Xia Y, Bettegowda C, Weller M (2018) Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol 15:422–442. https://doi.org/10.1038/s41571-018-0003-5

    Article  CAS  PubMed  Google Scholar 

  8. Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wohrer A, Dieckmann K, Filipits M, Brandstetter A, Weller M, Kurscheid S, Hegi ME, Zielinski CC, Marosi C, Hainfellner JA, Preusser M, Wick W (2015) Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro-Oncology 17:1064–1075. https://doi.org/10.1093/neuonc/nou307

    Article  CAS  PubMed  Google Scholar 

  9. Han J, Hong Y, Lee YS (2017) PD-L1 Expression and combined status of PD-L1/PD-1-positive tumor infiltrating mononuclear cell density predict prognosis in glioblastoma patients. J Pathol Transl Med 51:40–48. https://doi.org/10.4132/jptm.2016.08.31

    Article  PubMed  Google Scholar 

  10. Nduom EK, Wei J, Yaghi NK, Huang N, Kong LY, Gabrusiewicz K, Ling X, Zhou S, Ivan C, Chen JQ, Burks JK, Fuller GN, Calin GA, Conrad CA, Creasy C, Ritthipichai K, Radvanyi L, Heimberger AB (2016) PD-L1 expression and prognostic impact in glioblastoma. Neuro-Oncology 18:195–205. https://doi.org/10.1093/neuonc/nov172

    Article  CAS  PubMed  Google Scholar 

  11. Pratt D, Dominah G, Lobel G, Obungu A, Lynes J, Sanchez V, Adamstein N, Wang X, Edwards NA, Wu T, Maric D, Giles AJ, Gilbert MR, Quezado M, Nduom EK (2019) Programmed death ligand 1 Is a negative prognostic marker in recurrent isocitrate dehydrogenase-wildtype glioblastoma. Neurosurgery 85:280–289. https://doi.org/10.1093/neuros/nyy268

    Article  PubMed  Google Scholar 

  12. Xiu J, Piccioni D, Juarez T, Pingle SC, Hu J, Rudnick J, Fink K, Spetzler DB, Maney T, Ghazalpour A, Bender R, Gatalica Z, Reddy S, Sanai N, Idbaih A, Glantz M, Kesari S (2016) Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies. Oncotarget 7:21556–21569. https://doi.org/10.18632/oncotarget.7722

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wintterle S, Schreiner B, Mitsdoerffer M, Schneider D, Chen L, Meyermann R, Weller M, Wiendl H (2003) Expression of the B7-related molecule B7–H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res 63:7462–7467

    CAS  PubMed  Google Scholar 

  14. Antonios JP, Soto H, Everson RG, Moughon D, Orpilla JR, Shin NP, Sedighim S, Treger J, Odesa S, Tucker A, Yong WH, Li G, Cloughesy TF, Liau LM, Prins RM (2017) Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma. Neuro Oncol 19:796–807. https://doi.org/10.1093/neuonc/now287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. DiDomenico J, Lamano JB, Oyon D, Li Y, Veliceasa D, Kaur G, Ampie L, Choy W, Lamano JB, Bloch O (2018) The immune checkpoint protein PD-L1 induces and maintains regulatory T cells in glioblastoma. Oncoimmunology 7:e1448329. https://doi.org/10.1080/2162402X.2018.1448329

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhu Z, Zhang H, Chen B, Liu X, Zhang S, Zong Z, Gao M (2020) PD-L1-mediated immunosuppression in glioblastoma is associated with the infiltration and M2-polarization of tumor-associated macrophages. Front Immunol 11:588552. https://doi.org/10.3389/fimmu.2020.588552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen RQ, Liu F, Qiu XY, Chen XQ (2018) The prognostic and therapeutic value of PD-L1 in glioma. Front Pharmacol 9:1503. https://doi.org/10.3389/fphar.2018.01503

    Article  CAS  PubMed  Google Scholar 

  18. Zeng J, Zhang XK, Chen HD, Zhong ZH, Wu QL, Lin SX (2016) Expression of programmed cell death-ligand 1 and its correlation with clinical outcomes in gliomas. Oncotarget 7:8944–8955. https://doi.org/10.18632/oncotarget.6884

    Article  PubMed  PubMed Central  Google Scholar 

  19. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, Piha-Paul SA, Doi T, Gao B, Chung HC, Lopez-Martin J, Bang YJ, Frommer RS, Shah M, Ghori R, Joe AK, Pruitt SK, Diaz LA Jr (2020) Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II keynote-158 study. J Clin Oncol 38:1–10. https://doi.org/10.1200/JCO.19.02105

    Article  CAS  PubMed  Google Scholar 

  20. Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, Baehring J, Ahluwalia MS, Roth P, Bahr O, Phuphanich S, Sepulveda JM, De Souza P, Sahebjam S, Carleton M, Tatsuoka K, Taitt C, Zwirtes R, Sampson J, Weller M (2020) Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the checkmate 143 phase 3 randomized clinical trial. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2020.1024

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, Wang AC, Ellingson BM, Rytlewski JA, Sanders CM, Kawaguchi ES, Du L, Li G, Yong WH, Gaffey SC, Cohen AL, Mellinghoff IK, Lee EQ, Reardon DA, O’Brien BJ, Butowski NA, Nghiemphu PL, Clarke JL, Arrillaga-Romany IC, Colman H, Kaley TJ, de Groot JF, Liau LM, Wen PY, Prins RM (2019) Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med 25:477–486. https://doi.org/10.1038/s41591-018-0337-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, Lopez-Janeiro A, Porciuncula A, Idoate MA, Inoges S, de Andrea C, Lopez-Diaz de Cerio A, Tejada S, Berraondo P, Villarroel-Espindola F, Choi J, Gurpide A, Giraldez M, Goicoechea I, Gallego Perez-Larraya J, Sanmamed MF, Perez-Gracia JL, Melero I (2019) Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med 25:470–476. https://doi.org/10.1038/s41591-018-0339-5

    Article  CAS  PubMed  Google Scholar 

  23. Dubinski D, Won SY, Rauch M, Behmanesh B, Ngassam LDC, Baumgarten P, Senft C, Harter PN, Bernstock JD, Freiman TM, Seifert V, Gessler F (2021) Association of isocitrate dehydrogenase (IDH) status with edema to tumor ratio and its correlation with immune infiltration in glioblastoma. Front Immunol 12:627650. https://doi.org/10.3389/fimmu.2021.627650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Narang S, Kim D, Aithala S, Heimberger AB, Ahmed S, Rao D, Rao G, Rao A (2017) Tumor image-derived texture features are associated with CD3 T-cell infiltration status in glioblastoma. Oncotarget 8:101244–101254. https://doi.org/10.18632/oncotarget.20643

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tamura R, Ohara K, Sasaki H, Morimoto Y, Kosugi K, Yoshida K, Toda M (2018) Difference in immunosuppressive cells between peritumoral area and tumor core in glioblastoma. World Neurosurg 120:e601–e610. https://doi.org/10.1016/j.wneu.2018.08.133

    Article  PubMed  Google Scholar 

  26. WHO Classification of Tumours Editorial Board (2021) Central nervous system tumours WHO classification of tumours, 5th edn. IARC Press, Lyon

    Google Scholar 

  27. Sato J, Kitano S, Motoi N, Ino Y, Yamamoto N, Watanabe S, Ohe Y, Hiraoka N (2020) CD20(+) tumor-infiltrating immune cells and CD204(+) M2 macrophages are associated with prognosis in thymic carcinoma. Cancer Sci 111:1921–1932. https://doi.org/10.1111/cas.14409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Katsuya Y, Fujita Y, Horinouchi H, Ohe Y, Watanabe S, Tsuta K (2015) Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer 88:154–159. https://doi.org/10.1016/j.lungcan.2015.03.003

    Article  PubMed  Google Scholar 

  29. Arita H, Narita Y, Matsushita Y, Fukushima S, Yoshida A, Takami H, Miyakita Y, Ohno M, Shibui S, Ichimura K (2015) Development of a robust and sensitive pyrosequencing assay for the detection of IDH1/2 mutations in gliomas. Brain Tumor Pathol 32:22–30. https://doi.org/10.1007/s10014-014-0186-0

    Article  CAS  PubMed  Google Scholar 

  30. Arita H, Narita Y, Fukushima S, Tateishi K, Matsushita Y, Yoshida A, Miyakita Y, Ohno M, Collins VP, Kawahara N, Shibui S, Ichimura K (2013) Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol 126:267–276. https://doi.org/10.1007/s00401-013-1141-6

    Article  CAS  PubMed  Google Scholar 

  31. Ohno M, Miyakita Y, Takahashi M, Igaki H, Matsushita Y, Ichimura K, Narita Y (2019) Survival benefits of hypofractionated radiotherapy combined with temozolomide or temozolomide plus bevacizumab in elderly patients with glioblastoma aged >/= 75 years. Radiat Oncol 14:200. https://doi.org/10.1186/s13014-019-1389-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972. https://doi.org/10.1200/JCO.2009.26.3541

    Article  PubMed  Google Scholar 

  33. van den Bent MJ, Wefel JS, Schiff D, Taphoorn MJ, Jaeckle K, Junck L, Armstrong T, Choucair A, Waldman AD, Gorlia T, Chamberlain M, Baumert BG, Vogelbaum MA, Macdonald DR, Reardon DA, Wen PY, Chang SM, Jacobs AH (2011) Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol 12:583–593. https://doi.org/10.1016/S1470-2045(11)70057-2

    Article  PubMed  Google Scholar 

  34. Holzl D, Hutarew G, Zellinger B, Schlicker HU, Schwartz C, Winkler PA, Sotlar K, Kraus TFJ (2021) Integrated analysis of programmed cell death ligand 1 expression reveals increased levels in high-grade glioma. J Cancer Res Clin Oncol 147:2271–2280. https://doi.org/10.1007/s00432-021-03656-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L (2012) Colocalization of inflammatory response with B7–h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. https://doi.org/10.1126/scitranslmed.3003689

    Article  PubMed  PubMed Central  Google Scholar 

  36. Berghoff AS, Kiesel B, Widhalm G, Wilhelm D, Rajky O, Kurscheid S, Kresl P, Wohrer A, Marosi C, Hegi ME, Preusser M (2017) Correlation of immune phenotype with IDH mutation in diffuse glioma. Neuro Oncol 19:1460–1468. https://doi.org/10.1093/neuonc/nox054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lasocki A, Gaillard F (2019) Non-contrast-enhancing tumor: a new frontier in glioblastoma research. AJNR Am J Neuroradiol 40:758–765. https://doi.org/10.3174/ajnr.A6025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stummer W (2007) Mechanisms of tumor-related brain edema. Neurosurg Focus 22:E8. https://doi.org/10.3171/foc.2007.22.5.9

    Article  PubMed  Google Scholar 

  39. Zoccarato M, Nardetto L, Basile AM, Giometto B, Zagonel V, Lombardi G (2021) Seizures, edema, thrombosis, and hemorrhages: an update review on the medical management of gliomas. Front Oncol 11:617966. https://doi.org/10.3389/fonc.2021.617966

    Article  PubMed  PubMed Central  Google Scholar 

  40. Fujii T, Hirakata T, Kurozumi S, Tokuda S, Nakazawa Y, Obayashi S, Yajima R, Oyama T, Shirabe K (2020) VEGF-A is associated With the degree of TILs and PD-L1 expression in primary breast cancer. In Vivo 34:2641–2646. https://doi.org/10.21873/invivo.12082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shin SJ, Jeon YK, Kim PJ, Cho YM, Koh J, Chung DH, Go H (2016) Clinicopathologic analysis of PD-L1 and PD-L2 expression in renal cell carcinoma: association with oncogenic proteins status. Ann Surg Oncol 23:694–702. https://doi.org/10.1245/s10434-015-4903-7

    Article  PubMed  Google Scholar 

  42. Yue Q, Zhang X, Ye HX, Wang Y, Du ZG, Yao Y, Mao Y (2014) The prognostic value of Foxp3+ tumor-infiltrating lymphocytes in patients with glioblastoma. J Neurooncol 116:251–259. https://doi.org/10.1007/s11060-013-1314-0

    Article  CAS  PubMed  Google Scholar 

  43. Teng MW, Ngiow SF, Ribas A, Smyth MJ (2015) Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 75:2139–2145. https://doi.org/10.1158/0008-5472.CAN-15-0255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by JSPS KAKENHI Grant Number JP16K10776.

Funding

This work was supported by JSPS KAKENHI [Grant Number JP16K10776].

Author information

Authors and Affiliations

  1. Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan

    Makoto Ohno, Yasuji Miyakita, Masamichi Takahashi, Shunsuke Yanagisawa, Yukie Tamura & Yoshitaka Narita

  2. Advanced Medical Development Center, Cancer Institute Hospital, 3-8-31, Ariake, Koto-Ku, Tokyo, 135-8550, Japan

    Shigehisa Kitano

  3. Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan

    Kaishi Satomi & Akihiko Yoshida

  4. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan

    Koichi Ichimura

  5. Department of Brain Disease Translational Research, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan

    Koichi Ichimura

Authors
  1. Makoto Ohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shigehisa Kitano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kaishi Satomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akihiko Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasuji Miyakita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masamichi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shunsuke Yanagisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yukie Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Koichi Ichimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshitaka Narita
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MO, SK, and YN designed the study. MO and SK conducted the statistical analysis. AY and KS contributed to tissue microarray preparation, diagnosis, and data acquisition. MO, YM, MT, SY, YT, and YN contributed to the patients’ management. MO, YM, MT, SY, YT, KI, and YN contributed to sample collection, molecular analysis, data acquisition, and interpretation. MO, KS and YN wrote the first draft of the manuscript, and all authors edited it. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Makoto Ohno.

Ethics declarations

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional review board and the 1964 Helsinki Declaration and its later amendments. This study was approved by the Institutional Review Board of the National Cancer Center (2004–066 or 2007–086).

Consent to publish

No individual personal data is contained in this manuscript.

Consent to participate

Written informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 200 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ohno, M., Kitano, S., Satomi, K. et al. Assessment of radiographic and prognostic characteristics of programmed death-ligand 1 expression in high-grade gliomas. J Neurooncol 160, 463–472 (2022). https://doi.org/10.1007/s11060-022-04165-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-022-04165-7

Keywords

Search

Navigation