Oligodendroglioma natural history, complications, and prognosis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Sujit Routray, M.D. [3]
Overview
If left untreated, patients with oligodendroglioma may progress to develop seizures, focal neurological deficits, hydrocephalus, brain herniation, intracranial hemorrhage, and ultimately death.Common complications associated with oligodendroglioma include hydrocephalus, intracranial hemorrhage, coma, bone marrow metastasis, recurrence, venous thromboembolism, parkinsonism, and side effects of chemotherapy and radiotherapy. Oligodendroglioma is a slow growing tumor having a good prognosis overall with prolonged survival. But the prognosis of oligodendroglioma may vary depending upon various prognostic factors such as population based estimates, clinical factors, tumor grade (II versus III), mechanism of chemosensitivity, and molecular markers such as 1p/19q-codeletion, IDH1/2 mutation, and TERT promoter mutations. The median survival time for oligodendroglioma is 11.6 yearsfor grade II and 3.5 years for grade III.
Natural history
- Oligodendrogliomas tend to be low grade and less aggressive than other types of gliomas.
- These tumors are slow growing.
- The tumors may be present for many years before they are diagnosed.[1]
- Anaplastic oligodendroglioma usually grows quickly.
- These tumors may develop in one place or in many places throughout the brain.
- If left untreated, patients with oligodendroglioma may progress to develop seizures, focal neurological deficits, hydrocephalus, brain herniation, intracranial hemorrhage, and ultimately death.[2]
- Recurrence is a very common feature of oligodendrogliomas.
- Recurrence can be either of the same grade or higher grade at the primary site.[3]
- Transformation into glioblastoma (grade 4) may occur a few years later, which may be associated with gain of chromosome 7 and loss of chromosome 10.[3]
Complications
Common complications associated with oligodendroglioma include:[4][5][6][7][8][9][10]
- Hydrocephalus
- Intracranial hemorrhage
- Coma
- Bone marrow metastasis
- Recurrence
- Venous thromboembolism
- Parkinsonism
- Side effects of chemotherapy
- Side effects of radiotherapy
Prognosis
- Depending on the extent and grade of the tumor at the time of diagnosis, the prognosis of oligodendroglioma may vary.
- However, the prognosis is generally regarded as good overall.[11][12]
- Oligodendrogliomas are slowly growing tumors with prolonged survival.
- In March 2001, 7 neuropathologists and 6 surgical pathologists experienced in brain tumor-diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic during the period of 1960 to 1990. In this study, the prognostic value of histological grading of oligodendroglial tumors in tumor grading was assessed, and following parameters of significant association with survival was found:[13]
| Type of analysis | Factors significantly associated with survival |
|---|---|
| Univariate analysis |
|
| Multivariable analysis |
|
| Oligodendroglial tumor characteristics | Mean survival |
|---|---|
| 1p/19q deletion with radiation | 121 months |
| 1p/19q deletion with chemotherapy | over 160 months |
| No 1p/19q deletion with radiation | 58 months |
| No 1p/19q deletion with chemotherapy | 75 months |
| Anaplastic oligodendroglioma characteristics | Median survival |
|---|---|
| Combined 1p/19q loss | >123 months |
| 1p loss only | 71 months |
| 1p intact with TP53 mutation | 71 months |
| 1p intact with no TP53 mutation | 16 months |
Prognostic factors
Following are the few prognostic factors associated with oligodendroglial tumors:
Population based estimates
- According to the population based estimates, despite of the prolonged clinical course of oligodendroglial tumors, outcome is almost always fatal.
- Overall median survival for patients with low-grade oligodendroglioma is approximately 10 to 15 years.[16][17]
- Median survival for patients with anaplastic oligodendroglioma is approximately 5 to 9 years.[11]
- Median survival of patients with 1p/19q-codeleted oligodendrogliomas who are treated with radiation plus procarbazine, lomustine, and vincristine (PCV) may be closer to 20 years for grade II tumors and 15 years for grade III tumors.[18][19][20]
- The presence of 1p/19q codeletion is associated with a better prognosis and greater chemosensitivity.[4][21][22][23]
- Several other molecular markers have a potential clinical significance as IDH1 mutations, confirming the strong prognostic role for overall survival.[24][25][26][27][28][29]
- The presence of EGFR gene mutation is associated with a worse prognosis.[30]
Clinical factors
Following is a list of more commonly identified clinical features that predict worse overall survival:
- Older age
- Poor functional status
- Baseline neurologic deficits
- Nonepilepsy presentation
- Tumor location other than frontal and parietal lobes
- Large tumor size (>4 to 5 cm)
Clinical features that are independently associated with improved overall survival in patients with anaplastic oligodendroglial tumors include:[31][32]
- Younger age
- Confirmed absence of residual tumor by imaging after surgery
- Frontal tumor location
- Good performance status
Tumor grade (II versus III)
- WHO grade III anaplastic oligodendrogliomas have worse prognosis comparative to low-grade tumors, with an average difference of approximately five years in overall survival(11.6 years for grade II and 3.5 years for grade III).[29][33]
- The 5-year survival rates for oligodendroglioma and anaplastic oligodendroglioma varying with ages are tabulated below:[34][13]
| WHO grade of tumor | Age | 5-year survival rate |
|---|---|---|
| Oligodendroglioma (Grade II) | 20-44 | 82% |
| 45-54 | 67% | |
| 55-64 | 48% | |
| Anaplastic oligodendroglioma (Grade III) | 20-44 | 64% |
| 45-54 | 50% | |
| 55-64 | 23% |
Molecular markers
- 1p/19q-codeletion:
- Presence of 1p/19q-codeletion is associated with improved survival in patients with IDH-mutant diffuse gliomas (with regard to both natural history of disease and better response to therapy).[35][36][37][38][39][40][24]
- Presence of polysomy of chromosomes 1 and 19 may be useful in identifying patients with poorer prognosis who have a subset of both anaplastic oligodendroglioma and a characteristic 1p/19q-codeletion.[41][42]
- Patients with 1p/19q loss and polysomy have a significantly shorter median progression-free survival compared with those without polysomy.[41]
- Capicua transcriptional repressor (CIC) inactivating mutations are associated with worse outcome in 1p/19q-codeleted oligodendrogliomas.[43]
- IDH1/2 mutation:
- IDH1 and IDH2 mutations are associated with improved survival in patients of glial tumors, irrespective of the treatment received.[44][24]
- Prognostic significance of IDH1/2 mutations is equally as strong as that of the 1p/19q-codeletion.[24]
- IDH mutations are found in diffuse gliomas with and without the 1p/19q-codeletion.
- North American Radiation Therapy Oncology Group (RTOG) 9402 and 9802 studies suggested that IDH mutations are predictive for outcome to adjuvant chemotherapy, independent of other molecular factors.[18] [45]
- TERT promoter mutations:
- Prognostic significance is dependent on the genetic background of the tumor (as Telomerase reverse transcriptase (TERT) promoter mutations occur in virtually all 1p/19q-codeleted, IDH-mutant tumors and also in glioblastoma).
- Negatively associated with alpha thalassemia/mental retardation syndrome X-linked (ATRX) mutations (occur in most IDH-mutant astrocytomas).
Mechanism of chemosensitivity
- Studies have shown a high response rate with single-agent temozolomide.
- IDH mutations result in metabolic alterations, including:[46]
- Decreased alpha-ketoglutarate
- Increased levels of 2-hydroxyglutarate (2HG)
- Changes in nicotinamide adenine dinucleotide phosphate (NADP) levels
- Decrease in alpha-ketoglutarate
- Increase in 2HG
- This leads to epigenetic alterations and development of a CpG island hypermethylated phenotype (CIMP), which includes MGMT promoter methylation.[47]
- MGMT is a nuclear enzyme responsible for deoxyribonucleic acid (DNA) repair following alkylating-agent chemotherapy and may mediate part of the cellular resistance to alkylating agents.
- MGMT expression can be silenced by methylation of its promoter.[48]
References
- ↑ Survival by prognostic factors. Canadian Cancer Society 2015. http://www.cancer.ca/en/cancer-information/cancer-type/brain-spinal/prognosis-and-survival/survival-statistics/?region=on
- ↑ Manousaki M, Papadaki H, Papavdi A, Kranioti EF, Mylonakis P, Varakis J; et al. (2011). "Sudden unexpected death from oligodendroglioma: a case report and review of the literature". Am J Forensic Med Pathol. 32 (4): 336–40. doi:10.1097/PAF.0b013e3181d3dc86. PMID 20375839.
- ↑ 3.0 3.1 Kocaeli H, Yakut T, Bekar A, Taşkapilioğlu O, Tolunay S (2006). "Glioblastomatous recurrence of oligodendroglioma remote from the original site: a case report". Surg Neurol. 66 (6): 627–30, discussion 630-1. doi:10.1016/j.surneu.2006.02.049. PMID 17145331.
- ↑ 4.0 4.1 Simonetti G, Gaviani P, Botturi A, Innocenti A, Lamperti E, Silvani A (2015). "Clinical management of grade III oligodendroglioma". Cancer Manag Res. 7: 213–23. doi:10.2147/CMAR.S56975. PMC 4524382. PMID 26251628.
- ↑ Guppy KH, Akins PT, Moes GS, Prados MD (2009). "Spinal cord oligodendroglioma with 1p and 19q deletions presenting with cerebral oligodendrogliomatosis". J Neurosurg Spine. 10 (6): 557–63. doi:10.3171/2009.2.SPINE08853. PMID 19558288.
- ↑ Sharma A, Agarwal A, Sharma MC, Anand M, Agarwal S, Raina V (2003). "Bone marrow metastasis in anaplastic oligodendroglioma". Int J Clin Pract. 57 (4): 351–2. PMID 12800473.
- ↑ Solitare GB, Robinson F, Lamarche JB (1967). "Oligodendroglioma: recurrence following an exceptionally long postoperative symptom-free interval". Can Med Assoc J. 97 (14): 862–5. PMC 1923454. PMID 6051252.
- ↑ Harada K, Kiya K, Matsumura S, Mori S, Uozumi T (1982). "Spontaneous intracranial hemorrhage caused by oligodendroglioma--a case report and review of the literature". Neurol Med Chir (Tokyo). 22 (1): 81–4. PMID 6176898.
- ↑ Hentschel S, Toyota B (2003). "Intracranial malignant glioma presenting as subarachnoid hemorrhage". Can J Neurol Sci. 30 (1): 63–6. PMID 12619787.
- ↑ Krauss JK, Paduch T, Mundinger F, Seeger W (1995). "Parkinsonism and rest tremor secondary to supratentorial tumours sparing the basal ganglia". Acta Neurochir (Wien). 133 (1–2): 22–9. PMID 8561031.
- ↑ 11.0 11.1 Ohgaki H, Kleihues P (2005). "Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas". J Neuropathol Exp Neurol. 64 (6): 479–89. PMID 15977639.
- ↑ Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M; et al. (2010). "Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas". Acta Neuropathol. 120 (6): 707–18. doi:10.1007/s00401-010-0781-z. PMID 21088844.
- ↑ 13.0 13.1 Giannini C, Scheithauer BW, Weaver AL, Burger PC, Kros JM, Mork S; et al. (2001). "Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading". J Neuropathol Exp Neurol. 60 (3): 248–62. PMID 11245209.
- ↑ Hamlat A, Saikali S, Chaperon J, Le Calve M, Gedouin D, Ben-Hassel M; et al. (2005). "Oligodendroglioma: clinical study and survival analysis correlated with chromosomal anomalies". Neurosurg Focus. 19 (5): E15. PMID 16398465.
- ↑ Ino Y, Betensky RA, Zlatescu MC, Sasaki H, Macdonald DR, Stemmer-Rachamimov AO; et al. (2001). "Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis". Clin Cancer Res. 7 (4): 839–45. PMID 11309331.
- ↑ Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C; et al. (2017). "CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014". Neuro Oncol. 19 (suppl_5): v1–v88. doi:10.1093/neuonc/nox158. PMC 5693142. PMID 29117289.
- ↑ Lassman AB, Iwamoto FM, Cloughesy TF, Aldape KD, Rivera AL, Eichler AF; et al. (2011). "International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors". Neuro Oncol. 13 (6): 649–59. doi:10.1093/neuonc/nor040. PMC 3107101. PMID 21636710.
- ↑ 18.0 18.1 Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR; et al. (2016). "Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma". N Engl J Med. 374 (14): 1344–55. doi:10.1056/NEJMoa1500925. PMC 5170873. PMID 27050206.
- ↑ van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY; et al. (2013). "Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951". J Clin Oncol. 31 (3): 344–50. doi:10.1200/JCO.2012.43.2229. PMID 23071237.
- ↑ Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J; et al. (2013). "Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402". J Clin Oncol. 31 (3): 337–43. doi:10.1200/JCO.2012.43.2674. PMC 3732012. PMID 23071247.
- ↑ Molecular Pathology of Oligodendroglioma. Libre Pathology 2015. http://librepathology.org/wiki/index.php/Oligodendroglioma
- ↑ Boots-Sprenger SH, Sijben A, Rijntjes J, Tops BB, Idema AJ, Rivera AL; et al. (2013). "Significance of complete 1p/19q co-deletion, IDH1 mutation and MGMT promoter methylation in gliomas: use with caution". Mod Pathol. 26 (7): 922–9. doi:10.1038/modpathol.2012.166. PMID 23429602.
- ↑ McDonald JM, See SJ, Tremont IW, Colman H, Gilbert MR, Groves M; et al. (2005). "The prognostic impact of histology and 1p/19q status in anaplastic oligodendroglial tumors". Cancer. 104 (7): 1468–77. doi:10.1002/cncr.21338. PMID 16088966.
- ↑ 24.0 24.1 24.2 24.3 Takahashi Y, Nakamura H, Makino K, Hide T, Muta D, Kamada H; et al. (2013). "Prognostic value of isocitrate dehydrogenase 1, O6-methylguanine-DNA methyltransferase promoter methylation, and 1p19q co-deletion in Japanese malignant glioma patients". World J Surg Oncol. 11: 284. doi:10.1186/1477-7819-11-284. PMC 3874767. PMID 24160898.
- ↑ Wick W, Meisner C, Hentschel B, Platten M, Schilling A, Wiestler B; et al. (2013). "Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation". Neurology. 81 (17): 1515–22. doi:10.1212/WNL.0b013e3182a95680. PMID 24068788.
- ↑ Perrech M, Dreher L, Röhn G, Stavrinou P, Krischek B, Toliat M; et al. (2019). "Qualitative and Quantitative Analysis of IDH1 Mutation in Progressive Gliomas by Allele-Specific qPCR and Western Blot Analysis". Technol Cancer Res Treat. 18: 1533033819828396. doi:10.1177/1533033819828396. PMC 6457076. PMID 30943868.
- ↑ Lewandowska MA, Furtak J, Szylberg T, Roszkowski K, Windorbska W, Rytlewska J; et al. (2014). "An analysis of the prognostic value of IDH1 (isocitrate dehydrogenase 1) mutation in Polish glioma patients". Mol Diagn Ther. 18 (1): 45–53. doi:10.1007/s40291-013-0050-7. PMC 3899509. PMID 23934769.
- ↑ Yao Y, Chan AK, Qin ZY, Chen LC, Zhang X, Pang JC; et al. (2013). "Mutation analysis of IDH1 in paired gliomas revealed IDH1 mutation was not associated with malignant progression but predicted longer survival". PLoS One. 8 (6): e67421. doi:10.1371/journal.pone.0067421. PMC 3696098. PMID 23840696.
- ↑ 29.0 29.1 Olar A, Wani KM, Alfaro-Munoz KD, Heathcock LE, van Thuijl HF, Gilbert MR; et al. (2015). "IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas". Acta Neuropathol. 129 (4): 585–96. doi:10.1007/s00401-015-1398-z. PMC 4369189. PMID 25701198.
- ↑ Wesseling P, van den Bent M, Perry A (2015). "Oligodendroglioma: pathology, molecular mechanisms and markers". Acta Neuropathol. 129 (6): 809–27. doi:10.1007/s00401-015-1424-1. PMC 4436696. PMID 25943885.
- ↑ Gorlia T, Delattre JY, Brandes AA, Kros JM, Taphoorn MJ, Kouwenhoven MC; et al. (2013). "New clinical, pathological and molecular prognostic models and calculators in patients with locally diagnosed anaplastic oligodendroglioma or oligoastrocytoma. A prognostic factor analysis of European Organisation for Research and Treatment of Cancer Brain Tumour Group Study 26951". Eur J Cancer. 49 (16): 3477–85. doi:10.1016/j.ejca.2013.06.039. PMID 23896377.
- ↑ Panageas KS, Reiner AS, Iwamoto FM, Cloughesy TF, Aldape KD, Rivera AL; et al. (2014). "Recursive partitioning analysis of prognostic variables in newly diagnosed anaplastic oligodendroglial tumors". Neuro Oncol. 16 (11): 1541–6. doi:10.1093/neuonc/nou083. PMC 4201067. PMID 24997140.
- ↑ Suzuki H, Aoki K, Chiba K, Sato Y, Shiozawa Y, Shiraishi Y; et al. (2015). "Mutational landscape and clonal architecture in grade II and III gliomas". Nat Genet. 47 (5): 458–68. doi:10.1038/ng.3273. PMID 25848751.
- ↑ Survival statistics for gliomas. Canadian Cancer Society 2015.http://www.cancer.ca/en/cancer-information/cancer-type/brain-spinal/prognosis-and-survival/survival-statistics/?region=on
- ↑ Intergroup Radiation Therapy Oncology Group Trial 9402. Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B; et al. (2006). "Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402". J Clin Oncol. 24 (18): 2707–14. doi:10.1200/JCO.2005.04.3414. PMID 16782910.
- ↑ van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ; et al. (2006). "Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial". J Clin Oncol. 24 (18): 2715–22. doi:10.1200/JCO.2005.04.6078. PMID 16782911.
- ↑ Dubbink HJ, Atmodimedjo PN, Kros JM, French PJ, Sanson M, Idbaih A; et al. (2016). "Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial". Neuro Oncol. 18 (3): 388–400. doi:10.1093/neuonc/nov182. PMC 4767239. PMID 26354927.
- ↑ Pekmezci M, Rice T, Molinaro AM, Walsh KM, Decker PA, Hansen H; et al. (2017). "Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT". Acta Neuropathol. 133 (6): 1001–1016. doi:10.1007/s00401-017-1690-1. PMC 5432658. PMID 28255664.
- ↑ Giannini C, Burger PC, Berkey BA, Cairncross JG, Jenkins RB, Mehta M; et al. (2008). "Anaplastic oligodendroglial tumors: refining the correlation among histopathology, 1p 19q deletion and clinical outcome in Intergroup Radiation Therapy Oncology Group Trial 9402". Brain Pathol. 18 (3): 360–9. doi:10.1111/j.1750-3639.2008.00129.x. PMID 18371182.
- ↑ Hacisalihoglu P, Kucukodaci Z, Gundogdu G, Bilgic B (2017). "The Correlation Between 1p/19q Codeletion, IDH1 Mutation, p53 Overexpression and Their Prognostic Roles in 41 Turkish Anaplastic Oligodendroglioma Patients". Turk Neurosurg. 27 (5): 682–689. doi:10.5137/1019-5149.JTN.16832-15.1. PMID 27651340.
- ↑ 41.0 41.1 Snuderl M, Eichler AF, Ligon KL, Vu QU, Silver M, Betensky RA; et al. (2009). "Polysomy for chromosomes 1 and 19 predicts earlier recurrence in anaplastic oligodendrogliomas with concurrent 1p/19q loss". Clin Cancer Res. 15 (20): 6430–7. doi:10.1158/1078-0432.CCR-09-0867. PMC 2818514. PMID 19808867.
- ↑ Jiang H, Ren X, Zhang Z, Zeng W, Wang J, Lin S (2014). "Polysomy of chromosomes 1 and 19: an underestimated prognostic factor in oligodendroglial tumors". J Neurooncol. 120 (1): 131–8. doi:10.1007/s11060-014-1526-y. PMID 25007776.
- ↑ Gleize V, Alentorn A, Connen de Kérillis L, Labussière M, Nadaradjane AA, Mundwiller E; et al. (2015). "CIC inactivating mutations identify aggressive subset of 1p19q codeleted gliomas". Ann Neurol. 78 (3): 355–74. doi:10.1002/ana.24443. PMID 26017892.
- ↑ van den Bent MJ, Dubbink HJ, Marie Y, Brandes AA, Taphoorn MJ, Wesseling P; et al. (2010). "IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group". Clin Cancer Res. 16 (5): 1597–604. doi:10.1158/1078-0432.CCR-09-2902. PMID 20160062.
- ↑ Cairncross JG, Wang M, Jenkins RB, Shaw EG, Giannini C, Brachman DG; et al. (2014). "Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH". J Clin Oncol. 32 (8): 783–90. doi:10.1200/JCO.2013.49.3726. PMC 3940537. PMID 24516018.
- ↑ Clark O, Yen K, Mellinghoff IK (2016). "Molecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer". Clin Cancer Res. 22 (8): 1837–42. doi:10.1158/1078-0432.CCR-13-1333. PMC 4834266. PMID 26819452.
- ↑ van den Bent MJ, Erdem-Eraslan L, Idbaih A, de Rooi J, Eilers PH, Spliet WG; et al. (2013). "MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic Oligodendrogliomas and Oligoastrocytomas. A report from EORTC study 26951". Clin Cancer Res. 19 (19): 5513–22. doi:10.1158/1078-0432.CCR-13-1157. PMID 23948976.
- ↑ Watanabe T, Nakamura M, Kros JM, Burkhard C, Yonekawa Y, Kleihues P; et al. (2002). "Phenotype versus genotype correlation in oligodendrogliomas and low-grade diffuse astrocytomas". Acta Neuropathol. 103 (3): 267–75. doi:10.1007/s004010100464. PMID 11907807.