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Erschienen in: Journal of Neuro-Oncology 1/2018

04.04.2018 | Clinical Study

Multi-center study finds postoperative residual non-enhancing component of glioblastoma as a new determinant of patient outcome

verfasst von: Aikaterini Kotrotsou, Ahmed Elakkad, Jia Sun, Ginu A. Thomas, Dongni Yang, Srishti Abrol, Wei Wei, Jeffrey S. Weinberg, Ali S. Bakhtiari, Moritz F. Kircher, Markus M. Luedi, John F. de Groot, Raymond Sawaya, Ashok J. Kumar, Pascal O. Zinn, Rivka R. Colen

Erschienen in: Journal of Neuro-Oncology | Ausgabe 1/2018

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Abstract

Introduction

The aim of the present study is to assess whether postoperative residual non-enhancing volume (PRNV) is correlated and predictive of overall survival (OS) in glioblastoma (GBM) patients.

Methods

We retrospectively analyzed a total 134 GBM patients obtained from The University of Texas MD Anderson Cancer Center (training cohort, n = 97) and The Cancer Genome Atlas (validation cohort, n = 37). All patients had undergone postoperative magnetic resonance imaging immediately after surgery. We evaluated the survival outcomes with regard to PRNV. The role of possible prognostic factors that may affect survival after resection, including age, sex, preoperative Karnofsky performance status, postoperative nodular enhancement, surgically induced enhancement, and postoperative necrosis, was investigated using univariate and multivariate Cox proportional hazards regression analyses. Additionally, a recursive partitioning analysis (RPA) was used to identify prognostic groups.

Results

Our analyses revealed that a high PRNV (HR 1.051; p-corrected = 0.046) and old age (HR 1.031; p-corrected = 0.006) were independent predictors of overall survival. This trend was also observed in the validation cohort (higher PRNV: HR 1.127, p-corrected  = 0.002; older age: HR 1.034, p-corrected  = 0.022). RPA analysis identified two prognostic risk groups: low-risk group (PRNV < 70.2 cm3; n = 55) and high-risk group (PRNV ≥ 70.2 cm3; n = 42). GBM patients with low PRNV had a significant survival benefit (5.6 months; p = 0.0037).

Conclusion

Our results demonstrate that high PRNV is associated with poor OS. Such results could be of great importance in a clinical setting, particularly in the postoperative management and monitoring of therapy.
Literatur
1.
Zurück zum Zitat Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. Jama 310:1842–1850CrossRefPubMed Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. Jama 310:1842–1850CrossRefPubMed
2.
Zurück zum Zitat Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109CrossRefPubMedPubMedCentral Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109CrossRefPubMedPubMedCentral
3.
Zurück zum Zitat Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMed Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMed
4.
Zurück zum Zitat Rivera AL, Pelloski CE, Sulman E, Aldape K (2008) Prognostic and predictive markers in glioma and other neuroepithelial tumors. Curr Probl Cancer 32:97–123CrossRefPubMed Rivera AL, Pelloski CE, Sulman E, Aldape K (2008) Prognostic and predictive markers in glioma and other neuroepithelial tumors. Curr Probl Cancer 32:97–123CrossRefPubMed
5.
6.
Zurück zum Zitat Donato V, Papaleo A, Castrichino A, Banelli E, Giangaspero F, Salvati M, Delfini R (2007) Prognostic implication of clinical and pathologic features in patients with glioblastoma multiforme treated with concomitant radiation plus temozolomide. Tumori 93(3):248–256CrossRefPubMed Donato V, Papaleo A, Castrichino A, Banelli E, Giangaspero F, Salvati M, Delfini R (2007) Prognostic implication of clinical and pathologic features in patients with glioblastoma multiforme treated with concomitant radiation plus temozolomide. Tumori 93(3):248–256CrossRefPubMed
7.
Zurück zum Zitat Chaichana KL, Chaichana KK, Olivi A, Weingart JD, Bennett R, Brem H, Quinones-Hinojosa A (2011) Surgical outcomes for older patients with glioblastoma multiforme: preoperative factors associated with decreased survival. J Neurosurg 114:587–594CrossRefPubMed Chaichana KL, Chaichana KK, Olivi A, Weingart JD, Bennett R, Brem H, Quinones-Hinojosa A (2011) Surgical outcomes for older patients with glioblastoma multiforme: preoperative factors associated with decreased survival. J Neurosurg 114:587–594CrossRefPubMed
8.
Zurück zum Zitat Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, Holland E et al (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95(2):190–198CrossRefPubMed Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, Holland E et al (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95(2):190–198CrossRefPubMed
9.
Zurück zum Zitat Filippini G, Falcone C, Boiardi A, Broggi G, Bruzzone MG, Caldiroli D, Farina R, Farinotti M, Fariselli L, Finocchiaro G et al (2008) Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma. Neuro-oncology 10:79–87CrossRefPubMedPubMedCentral Filippini G, Falcone C, Boiardi A, Broggi G, Bruzzone MG, Caldiroli D, Farina R, Farinotti M, Fariselli L, Finocchiaro G et al (2008) Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma. Neuro-oncology 10:79–87CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Tait MJ, Petrik V, Loosemore A, Bell BA, Papadopoulos MC (2007) Survival of patients with glioblastoma multiforme has not improved between 1993 and 2004: analysis of 625 cases. Br J Neurosurg 21:496–500CrossRefPubMed Tait MJ, Petrik V, Loosemore A, Bell BA, Papadopoulos MC (2007) Survival of patients with glioblastoma multiforme has not improved between 1993 and 2004: analysis of 625 cases. Br J Neurosurg 21:496–500CrossRefPubMed
11.
Zurück zum Zitat Pope WB, Sayre J, Perlina A, Villablanca JP, Mischel PS, Cloughesy TF (2005) MR imaging correlates of survival in patients with high-grade gliomas. AJNR Am J Neuroradiol 26(10):2466–2474PubMed Pope WB, Sayre J, Perlina A, Villablanca JP, Mischel PS, Cloughesy TF (2005) MR imaging correlates of survival in patients with high-grade gliomas. AJNR Am J Neuroradiol 26(10):2466–2474PubMed
12.
Zurück zum Zitat Al-Okaili RN, Krejza J, Wang S, Woo JH, Melhem ER (2006) Advanced MR imaging techniques in the diagnosis of intraaxial brain tumors in adults. Radiographics 26(Suppl 1):S173–S189CrossRefPubMed Al-Okaili RN, Krejza J, Wang S, Woo JH, Melhem ER (2006) Advanced MR imaging techniques in the diagnosis of intraaxial brain tumors in adults. Radiographics 26(Suppl 1):S173–S189CrossRefPubMed
13.
Zurück zum Zitat Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972CrossRefPubMed Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972CrossRefPubMed
14.
Zurück zum Zitat Grabowski MM, Recinos PF, Nowacki AS, Schroeder JL, Angelov L, Barnett GH, Vogelbaum MA (2014) Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma. J Neurosurg 121:1–9CrossRef Grabowski MM, Recinos PF, Nowacki AS, Schroeder JL, Angelov L, Barnett GH, Vogelbaum MA (2014) Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma. J Neurosurg 121:1–9CrossRef
15.
Zurück zum Zitat Hess KR (1999) Extent of resection as a prognostic variable in the treatment of gliomas. J Neurooncol 42:227–231CrossRefPubMed Hess KR (1999) Extent of resection as a prognostic variable in the treatment of gliomas. J Neurooncol 42:227–231CrossRefPubMed
16.
Zurück zum Zitat Iliadis G, Kotoula V, Chatzisotiriou A, Televantou D, Eleftheraki AG, Lambaki S, Misailidou D, Selviaridis P, Fountzilas G (2012) Volumetric and MGMT parameters in glioblastoma patients: survival analysis. BMC Cancer 12:3CrossRefPubMedPubMedCentral Iliadis G, Kotoula V, Chatzisotiriou A, Televantou D, Eleftheraki AG, Lambaki S, Misailidou D, Selviaridis P, Fountzilas G (2012) Volumetric and MGMT parameters in glioblastoma patients: survival analysis. BMC Cancer 12:3CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat Schoenegger K, Oberndorfer S, Wuschitz B, Struhal W, Hainfellner J, Prayer D, Heinzl H, Lahrmann H, Marosi C, Grisold W (2009) Peritumoral edema on MRI at initial diagnosis: an independent prognostic factor for glioblastoma? Eur J Neurol 16(7):874–878CrossRefPubMed Schoenegger K, Oberndorfer S, Wuschitz B, Struhal W, Hainfellner J, Prayer D, Heinzl H, Lahrmann H, Marosi C, Grisold W (2009) Peritumoral edema on MRI at initial diagnosis: an independent prognostic factor for glioblastoma? Eur J Neurol 16(7):874–878CrossRefPubMed
18.
Zurück zum Zitat Zinn PO, Mahajan B, Sathyan P, Singh SK, Majumder S, Jolesz FA, Colen RR (2011) Radiogenomic mapping of edema/cellular invasion MRI-phenotypes in glioblastoma multiforme. PLoS ONE 6:e25451CrossRefPubMedPubMedCentral Zinn PO, Mahajan B, Sathyan P, Singh SK, Majumder S, Jolesz FA, Colen RR (2011) Radiogenomic mapping of edema/cellular invasion MRI-phenotypes in glioblastoma multiforme. PLoS ONE 6:e25451CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Zinn PO, Sathyan P, Mahajan B, Bruyere J, Hegi M, Majumder S, Colen RR (2012) A novel volume-age-KPS (VAK) glioblastoma classification identifies a prognostic cognate microRNA-gene signature. PLoS ONE 7:e41522CrossRefPubMedPubMedCentral Zinn PO, Sathyan P, Mahajan B, Bruyere J, Hegi M, Majumder S, Colen RR (2012) A novel volume-age-KPS (VAK) glioblastoma classification identifies a prognostic cognate microRNA-gene signature. PLoS ONE 7:e41522CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, Rohde V, Oppel F, Turowski B, Woiciechowsky C et al (2008) Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62(3):564–576 (discussion 564–576)CrossRefPubMed Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, Rohde V, Oppel F, Turowski B, Woiciechowsky C et al (2008) Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62(3):564–576 (discussion 564–576)CrossRefPubMed
21.
22.
23.
Zurück zum Zitat Brandes AA, Tosoni A, Franceschi E, Sotti G, Frezza G, Amistà P, Morandi L, Spagnolli F, Ermani M (2009) Recurrence pattern after temozolomide concomitant with and adjuvant to radiotherapy in newly diagnosed patients with glioblastoma: correlation with MGMT promoter methylation status. J Clin Oncol 27(8):1275–1279CrossRefPubMed Brandes AA, Tosoni A, Franceschi E, Sotti G, Frezza G, Amistà P, Morandi L, Spagnolli F, Ermani M (2009) Recurrence pattern after temozolomide concomitant with and adjuvant to radiotherapy in newly diagnosed patients with glioblastoma: correlation with MGMT promoter methylation status. J Clin Oncol 27(8):1275–1279CrossRefPubMed
24.
Zurück zum Zitat Albert FK, Forsting M, Sartor K, Adams HP, Kunze S (1994) Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34(1):45–60 (discussion 60–41)PubMed Albert FK, Forsting M, Sartor K, Adams HP, Kunze S (1994) Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34(1):45–60 (discussion 60–41)PubMed
25.
Zurück zum Zitat Fedorov A, Beichel R, Kalpathy-Cramer J, Finet J, Fillion-Robin JC, Pujol S, Bauer C, Jennings D, Fennessy F, Sonka M et al (2012) 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn Reson Imaging 30:1323–1341CrossRefPubMedPubMedCentral Fedorov A, Beichel R, Kalpathy-Cramer J, Finet J, Fillion-Robin JC, Pujol S, Bauer C, Jennings D, Fennessy F, Sonka M et al (2012) 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn Reson Imaging 30:1323–1341CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat Valeri G, Mazza FA, Maggi S, Aramini D, La Riccia L, Mazzoni G, Giovagnoni A (2014) Open source software in a practical approach for post processing of radiologic images. Radiol Med 120:309–323CrossRefPubMed Valeri G, Mazza FA, Maggi S, Aramini D, La Riccia L, Mazzoni G, Giovagnoni A (2014) Open source software in a practical approach for post processing of radiologic images. Radiol Med 120:309–323CrossRefPubMed
27.
Zurück zum Zitat Lescher S, Schniewindt S, Jurcoane A, Senft C, Hattingen E (2014) Time window for postoperative reactive enhancement after resection of brain tumors: less than 72 hours. Neurosurg Focus 37(6):E3CrossRefPubMed Lescher S, Schniewindt S, Jurcoane A, Senft C, Hattingen E (2014) Time window for postoperative reactive enhancement after resection of brain tumors: less than 72 hours. Neurosurg Focus 37(6):E3CrossRefPubMed
28.
Zurück zum Zitat Oser AB, Moran CJ, Kaufman BA, Park TS (1997) Intracranial tumor in children: MR imaging findings within 24 hours of craniotomy. Radiology 205(3):807–812CrossRefPubMed Oser AB, Moran CJ, Kaufman BA, Park TS (1997) Intracranial tumor in children: MR imaging findings within 24 hours of craniotomy. Radiology 205(3):807–812CrossRefPubMed
29.
Zurück zum Zitat Schumacher M, Binder H, Gerds T (2007) Assessment of survival prediction models based on microarray data. Bioinformatics 23(14):1768–1774CrossRefPubMed Schumacher M, Binder H, Gerds T (2007) Assessment of survival prediction models based on microarray data. Bioinformatics 23(14):1768–1774CrossRefPubMed
30.
Zurück zum Zitat Clark TG, Bradburn MJ, Love SB, Altman DG (2003) Survival analysis part IV: further concepts and methods in survival analysis. Br J Cancer 89(5):781–786CrossRefPubMedPubMedCentral Clark TG, Bradburn MJ, Love SB, Altman DG (2003) Survival analysis part IV: further concepts and methods in survival analysis. Br J Cancer 89(5):781–786CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Park C-K, Lee S-H, Han JH, Kim C-Y, Kim D-W, Paek SH, Kim DG, Heo DS, Kim IH, Jung H-W (2009) Recursive partitioning analysis of prognostic factors in WHO grade III glioma patients treated with radiotherapy or radiotherapy plus chemotherapy. BMC Cancer 9(1):450CrossRefPubMedPubMedCentral Park C-K, Lee S-H, Han JH, Kim C-Y, Kim D-W, Paek SH, Kim DG, Heo DS, Kim IH, Jung H-W (2009) Recursive partitioning analysis of prognostic factors in WHO grade III glioma patients treated with radiotherapy or radiotherapy plus chemotherapy. BMC Cancer 9(1):450CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Alkhasawneh MS, Ngah UK, Tay LT, Mat Isa NA, Al-Batah MS (2014) Modeling and testing landslide hazard using decision tree. J Appl Math 2014:9CrossRef Alkhasawneh MS, Ngah UK, Tay LT, Mat Isa NA, Al-Batah MS (2014) Modeling and testing landslide hazard using decision tree. J Appl Math 2014:9CrossRef
33.
Zurück zum Zitat Nestler U, Lutz K, Pichlmeier U, Stummer W, Franz K, Reulen HJ, Bink A (2014) Anatomic features of glioblastoma and their potential impact on survival. Acta Neurochir 157:179–186CrossRefPubMed Nestler U, Lutz K, Pichlmeier U, Stummer W, Franz K, Reulen HJ, Bink A (2014) Anatomic features of glioblastoma and their potential impact on survival. Acta Neurochir 157:179–186CrossRefPubMed
34.
Zurück zum Zitat Ogura K, Mizowaki T, Arakawa Y, Ogura M, Sakanaka K, Miyamoto S, Hiraoka M (2013) Initial and cumulative recurrence patterns of glioblastoma after temozolomide-based chemoradiotherapy and salvage treatment: a retrospective cohort study in a single institution. Radiat Oncol 8:97CrossRefPubMedPubMedCentral Ogura K, Mizowaki T, Arakawa Y, Ogura M, Sakanaka K, Miyamoto S, Hiraoka M (2013) Initial and cumulative recurrence patterns of glioblastoma after temozolomide-based chemoradiotherapy and salvage treatment: a retrospective cohort study in a single institution. Radiat Oncol 8:97CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat Hou LC, Veeravagu A, Hsu AR, Tse VC (2006) Recurrent glioblastoma multiforme: a review of natural history and management options. Neurosurg Focus 20(4):E5CrossRefPubMed Hou LC, Veeravagu A, Hsu AR, Tse VC (2006) Recurrent glioblastoma multiforme: a review of natural history and management options. Neurosurg Focus 20(4):E5CrossRefPubMed
36.
Zurück zum Zitat Li YM, Suki D, Hess K, Sawaya R (2015) The influence of maximum safe resection of glioblastoma on survival in 1229 patients: can we do better than gross-total resection?. J Neurosurg 124:1–12 Li YM, Suki D, Hess K, Sawaya R (2015) The influence of maximum safe resection of glioblastoma on survival in 1229 patients: can we do better than gross-total resection?. J Neurosurg 124:1–12
37.
Zurück zum Zitat Lin ZX, Yang LJ, Huang Q, Fu J (2010) Activated vascular endothelia regulate invasion of glioma cells through expression of fibronectin. Chin Med J 123(13):1754–1761PubMed Lin ZX, Yang LJ, Huang Q, Fu J (2010) Activated vascular endothelia regulate invasion of glioma cells through expression of fibronectin. Chin Med J 123(13):1754–1761PubMed
38.
Zurück zum Zitat Hammoud MA, Sawaya R, Shi W, Thall PF, Leeds NE (1996) Prognostic significance of preoperative MRI scans in glioblastoma multiforme. J Neurooncol 27(1):65–73CrossRefPubMed Hammoud MA, Sawaya R, Shi W, Thall PF, Leeds NE (1996) Prognostic significance of preoperative MRI scans in glioblastoma multiforme. J Neurooncol 27(1):65–73CrossRefPubMed
39.
Zurück zum Zitat Colen RR, Wang J, Singh SK, Gutman DA, Zinn PO (2015) Glioblastoma: imaging genomic mapping reveals sex-specific oncogenic associations of cell death. Radiology 275(1):215–227CrossRefPubMed Colen RR, Wang J, Singh SK, Gutman DA, Zinn PO (2015) Glioblastoma: imaging genomic mapping reveals sex-specific oncogenic associations of cell death. Radiology 275(1):215–227CrossRefPubMed
40.
Zurück zum Zitat Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer cell 17(1):98–110CrossRefPubMedPubMedCentral Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer cell 17(1):98–110CrossRefPubMedPubMedCentral
41.
Zurück zum Zitat Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477CrossRefPubMedPubMedCentral Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477CrossRefPubMedPubMedCentral
Metadaten
Titel
Multi-center study finds postoperative residual non-enhancing component of glioblastoma as a new determinant of patient outcome
verfasst von
Aikaterini Kotrotsou
Ahmed Elakkad
Jia Sun
Ginu A. Thomas
Dongni Yang
Srishti Abrol
Wei Wei
Jeffrey S. Weinberg
Ali S. Bakhtiari
Moritz F. Kircher
Markus M. Luedi
John F. de Groot
Raymond Sawaya
Ashok J. Kumar
Pascal O. Zinn
Rivka R. Colen
Publikationsdatum
04.04.2018
Verlag
Springer US
Erschienen in
Journal of Neuro-Oncology / Ausgabe 1/2018
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-018-2850-4

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