Glioblastoma extent of resection

Glioblastoma extent of resection

Increasing the extent of resection (EOR) of glioblastoma is associated with prolonged survival 1).

Gross total resection of GBM is associated with a decreased incidence of patient safety indicators (PSIs) and hospital-acquired conditions (HACs), as compared to subtotal resection 2).


The relationship between the extent of glioblastoma (GB) resection and clinical benefit depends critically on the balance between cytoreduction and avoiding neurologic morbidity. The definition of the extent of tumor resection, how this is best-measured pre- and postoperatively, and its relation to the volume of residual tumor is still discussed. In 2020 Wykes et al. reviewed the literature supporting the extent of resection in GB, highlighting the importance of a standardized definition and measurement of the extent of resection to allow greater collaboration in research projects and trials. Recent developments in neurosurgical techniques and technologies focused on maximizing extent of resection and safety are discussed 3).


Inoue et al. investigated the relationship of tumor volume between MRI and 11C methionine positron emission tomography and also the relationship between Met uptake index and tumor activity. In ten patients, tumor-to-contralateral normal brain tissue ratio (TNR) was calculated to evaluate metabolic activity of Met uptake areas which were divided into five subareas by the degrees of TNR. In each GBM, tumor tissue was obtained from subareas showing the positive Met uptake. Immunohistochemistry was performed to examine the tumor proliferative activity and the existence of GSCs. In all patients, the volume of Met uptake area at TNR ≦ 1.4 was larger than that of the Gd-enhanced area. The Met uptake area at TNR 1.4 beyond the Gd-enhanced tumor was much wider in high invasiveness-type GBMs than in those of low invasiveness type, and survival was much shorter in the former than the latter types. Immunohistochemistry revealed the existence of GSCs in the area showing Met uptake at TNR 1.4 and no Gd enhancement. Areas at TNR > 1.4 included active tumor cells with a relatively high Ki-67 labeling index. In addition, it was demonstrated that GSCs could exist beyond the border of the Gd-enhanced tumor. Therefore, to obtain maximum resection of GBMs, including infiltrating GSCs, an aggressive surgical excision that includes the Met-positive area at TNR 1.4 should be considered 4).


Using volumetric analysis, it is possible to quantify the EOR using MR imaging. Prior studies using semi-automated methods for this purpose found a high interobserver agreement 5) 6).

However, when manual segmentation is used, a low interobserver agreement in the assessment of tumor resection rates on magnetic resonance imaging (MRI) is described. This applies particularly for post-operative tumor volume and residual tumor volume 7).

Before the general use of post-operative scanning, intraoperative estimation was used to determine partial resectionsubtotal resection, or total resection. The only study that compared this estimation with the presence of residual tumor mass on an MR image, dates back to 1994 8).


The border zone of different tissues is often the object of discussion, considering that the definition of the border is always ambiguous, especially in cases of tumor. The population of different cells in this area largely depends on the character of those cells in terms of the ability of cell motility and the status of tissue barrier, such as extracellular matrices. Gliomas, especially malignant gliomas, are known to possess a highly invasive nature. The surgical extent of resection is determined by the intraoperative macroscopic appearance, sometimes assisted by the information of a navigation system based on the preoperative images, that is easily influenced by the intraoperative brain shift in many cases. Therefore, the surgery often results in an incomplete resection 9).

The value of incomplete resection in Glioblastoma surgery remains questionable. If gross total resection (GTR) cannot be safely achieved, biopsy only might be used as an alternative surgical strategy 10).

Wounded glioma syndrome

see Wounded glioma syndrome.

Contrast-enhancing residual tumor volume (CE-RTV) alone has rarely been analyzed quantitatively to determine if it is a predictor of outcome.

CE-RTV and EOR were found to be significant predictors of survival after GBM resection. CERTV was the more significant predictor of survival compared with EOR, suggesting that the volume of residual contrast-enhancing tumor may be a more accurate and meaningful reflection of the pathobiology of GBM 11).

Difficulties

It is difficult to reproducibly judge EOR in studies due to the lack of reliable tumor segmentation methods, especially for postoperative magnetic resonance imaging (MRI) scans. Therefore, a reliable, easily distributable segmentation method is needed to permit valid comparison, especially across multiple sites.

Cordova et al. report a segmentation method that combines versatile region-of-interest blob generation with automated clustering methods. Applied this to glioblastoma cases undergoing FGS and matched controls to illustrate the method’s reliability and accuracy. Agreement and interrater variability between segmentations were assessed using the concordance correlation coefficient, and spatial accuracy was determined using the Dice similarity index and mean Euclidean distance. Fuzzy C-means clustering with three classes was the best performing method, generating volumes with high agreement with manual contouring and high interrater agreement preoperatively and postoperatively. The proposed segmentation method allows tumor volume measurements of contrast-enhanced T 1-weighted images in the unbiased, reproducible fashion necessary for quantifying EOR in multicenter trials 12).

Maximal safe resection

see Glioblastoma Maximal Safe Resection.

Case series

Glioblastoma extent of resection case series.

References

1)

Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS (2011) An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 115:3–8. https://doi.org/10.3171/2011.2. jns1099810.3171/2011.7.jns10238
2)

Laurent D, Freedman R, Cope L, Sacks P, Abbatematteo J, Kubilis P, Bova F, Rahman M. Impact of Extent of Resection on Incidence of Postoperative Complications in Patients With Glioblastoma. Neurosurgery. 2020 May 1;86(5):625-630. doi: 10.1093/neuros/nyz313. PubMed PMID: 31342060.
3)

Wykes V, Zisakis A, Irimia M, Ughratdar I, Sawlani V, Watts C. Importance and Evidence of Extent of Resection in Glioblastoma. J Neurol Surg A Cent Eur Neurosurg. 2020 Oct 13. doi: 10.1055/s-0040-1701635. Epub ahead of print. PMID: 33049795.
4)

Inoue A, Ohnishi T, Kohno S, Ohue S, Nishikawa M, Suehiro S, Matsumoto S, Ozaki S, Fukushima M, Kurata M, Kitazawa R, Shigekawa S, Watanabe H, Kunieda T. Met-PET uptake index for total tumor resection: identification of (11)C-methionine uptake index as a goal for total tumor resection including infiltrating tumor cells in glioblastoma. Neurosurg Rev. 2020 Feb 15. doi: 10.1007/s10143-020-01258-7. [Epub ahead of print] PubMed PMID: 32060762.
5)

Chow DS, Qi J, Guo X, Miloushev VZ, Iwamoto FM, Bruce JN, Lassman AB, Schwartz LH, Lignelli A, Zhao B, Filippi CG (2014) Semiautomated volumetric measurement on postcontrast MR imaging for analysis of recurrent and residual disease in glioblastoma multiforme. AJNR Am J Neuroradiol 35:498–503. https://doi.org/ 10.3174/ajnr.A3724
6)

Kanaly CW, Mehta AI, Ding D, Hoang JK, Kranz PG, Herndon JE 2nd, Coan A, Crocker I, Waller AF, Friedman AH, Reardon DA, Sampson JH (2014) A novel, reproducible, and objective method for volumetric magnetic resonance imaging assessment of enhancing glioblastoma. J Neurosurg 121:536–542. https://doi.org/10. 3171/2014.4.Jns121952
7)

Kubben PL, Postma AA, Kessels AG, van Overbeeke JJ, van Santbrink H (2010) Intraobserver and interobserver agreement in volumetric assessment of glioblastoma multiforme resection. Neurosurgery 67:1329–1334. https://doi.org/10.1227/NEU. 0b013e3181efbb08
8)

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 34:45–60 discussion 60- 41
9)

Yamaguchi F. The Border Zone of Tumor. Where is the Border? What is a Surgical Border for Patients? World Neurosurg X. 2019 Jan 24;2:100011. doi: 10.1016/j.wnsx.2019.100011. eCollection 2019 Apr. PubMed PMID: 31218286; PubMed Central PMCID: PMC6580876.
10)

Kreth FW, Thon N, Simon M, Westphal M, Schackert G, Nikkhah G, Hentschel B, Reifenberger G, Pietsch T, Weller M, Tonn JC; German Glioma Network.. Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy. Ann Oncol. 2013 Dec;24(12):3117-23. doi: 10.1093/annonc/mdt388. PubMed PMID: 24130262.
11)

Grabowski MM, Recinos PF, Nowacki AS, Schroeder JL, Angelov L, Barnett GH, Vogelbaum MA. Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma. J Neurosurg. 2014 Nov;121(5):1115-23. doi: 10.3171/2014.7.JNS132449. Epub 2014 Sep 5. PubMed PMID: 25192475.
12)

Cordova JS, Schreibmann E, Hadjipanayis CG, Guo Y, Shu HK, Shim H, Holder CA. Quantitative tumor segmentation for evaluation of extent of glioblastoma resection to facilitate multisite clinical trials. Transl Oncol. 2014 Feb 1;7(1):40-7. eCollection 2014 Feb. PubMed PMID: 24772206; PubMed Central PMCID: PMC3998691.

Bortezomib for Glioblastoma

Bortezomib for Glioblastoma

Bortezomib is a boronic acid-based potent proteasome inhibitor that has been actively studied for its anti-tumour effects through inhibition of the proteasome. The proteasome is a key component of the ubiquitin-proteasome pathway that is critical for protein homeostasis, regulation of cellular growth, and apoptosis. Overexpression of polo-like kinase 4 (PLK4) is commonly reported in tumour cells and increases their invasive and metastatic abilities. In this study, we established a cell model of PLK4 knockdown and overexpression in LN-18, A172 and LN-229 cells and found that knockdown of PLK4 expression enhanced the anti-tumour effect of bortezomib. We further found that this effect may be mediated by the PTEN/PI3K/AKT/mTOR signalling pathway and that the apoptotic and oxidative stress processes were activated, while the expression of matrix metalloproteinases (MMPs) was down-regulated. Similar phenomenon was observed using in vitro experiments. Thus, we speculate that PLK4 inhibition may be a new therapeutic strategy for GBM 1).


The addition of bortezomib to current standard radiochemotherapy in newly diagnosed glioblastoma patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients 2).


Jane et al. investigated the sensitivity of a panel of glioma cell lines (U87, T98G, U373, A172, LN18, LN229, LNZ308, and LNZ428) to TRAIL alone and in combination with the proteasome inhibitor bortezomib. Analysis of these cell lines revealed marked differences in their sensitivity to these treatments, with two (LNZ308 and U373) of the eight cell lines revealing no significant induction of cell death in response to TRAIL alone. No correlation was found between sensitivity of cells to TRAIL and expression of TRAIL receptors DR4, DR5, and decoy receptor DcR1, caspase 8, apoptosis inhibitory proteins XIAP, survivin, Mcl-1, Bcl-2, Bcl-Xl, and cFLIP. However, TRAIL-resistant cell lines exhibited a high level of basal NF-κB activity. Bortezomib was capable of potentiating TRAIL-induced apoptosis in TRAIL-resistant cells in a caspase-dependent fashion. Bortezomib abolished p65/NF-κB DNA-binding activity, supporting the hypothesis that inhibition of the NF-κB pathway is critical for the enhancement of TRAIL sensitization in glioma cells. Moreover, knockdown of p65/NF-κB by shRNA also enhanced TRAIL-induced apoptosis, indicating that p65/NF-κB may be important in mediating TRAIL sensitivity and the effect of bortezomib in promoting TRAIL sensitization and apoptosis induction 3).


Premkumar et al. demonstrated that proteasome inhibitors, such as bortezomib, dramatically sensitized highly resistant glioma cells to apoptosis induction, suggesting that proteasomal inhibition may be a promising combination strategy for glioma therapeutics.

They examined whether bortezomib could enhance response to HDAC inhibition in glioma cells. Although primary cells from glioblastoma multiforme (GBM) patients and established glioma cell lines did not show significant induction of apoptosis with vorinostat treatment alone, the combination of vorinostat plus bortezomib significantly enhanced apoptosis. The enhanced efficacy was due to proapoptotic mitochondrial injury and increased generation of reactive oxygen species. Our results also revealed that combination of bortezomib with vorinostat enhanced apoptosis by increasing Mcl-1 cleavage, Noxa upregulation, Bak and Bax activation, and cytochrome c release. Further downregulation of Mcl-1 using shRNA enhanced cell killing by the bortezomib/vorinostat combination. Vorinostat induced a rapid and sustained phosphorylation of histone H2AX in primary GBM and T98G cells, and this effect was significantly enhanced by co-administration of bortezomib. Vorinostat/bortezomib combination also induced Rad51 downregulation, which plays an important role in the synergistic enhancement of DNA damage and apoptosis. The significantly enhanced antitumor activity that results from the combination of bortezomib and HDACIs offers promise as a novel treatment for glioma patients 4).


One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m(2) IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m(2) PO on days 1-7 and 14-21 and bortezomib 1.7 mg/m(2) on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42-64) and 90 % (70-100). The median cycles post-operatively was 2 (0-4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor 5).


McCracken et al. conducted a phase I trial of dose-escalating temozolomide with bevacizumab and the proteasome inhibitor bortezomib for patients with recurrent disease. Three groups of three patients were scheduled to receive daily doses of temozolomide at 25, 50, and 75 mg/m2. Fixed doses of bortezomib and bevacizumab were given at standard intervals. Patients were monitored for dose-limiting toxicities (DLT) to determine the maximum-tolerated dose (MTD) of temozolomide with this regimen. No DLT were seen in the first two groups (25 and 50 mg/m2 temozolomide). One patient in the 75 mg/m2 group experienced a grade 4 elevation of ALT and three more patients were accrued for a total of six patients at that dose level. No other DLT occurred, thus making 75 mg/m2 the MTD. Progression-free survival was 3.27 months for all patients and mean overall survival was 20.75 months. The MTD of temozolomide was 75 mg/m2 in combination with bevacizumab and bortezomib for recurrent glioblastoma. Only one patient experienced a severe (Grade 4) elevation of ALT. This study will provide the framework for further studies to elicit effectiveness and better determine a safety profile for this drug combination 6).


Oncolytic viruses, proteasome inhibitors, and natural killer (NK)-cell immunotherapy have all been studied extensively as monotherapies but have never been evaluated in combination. Synergetic treatment of oncolytic virus-infected glioblastomas with a proteasome inhibitor induces necroptotic cell death to enhance NK-cell immunotherapy, prolonging survival against human glioblastoma 7).


The proteasome inhibitor bortezomib is effective for a variety of tumors, but not for GBM. The authors’ goal was to demonstrate that bortezomib can be effective in the orthotopic GBM murine model if the appropriate method of drug delivery is used. In this study the Alzet mini-osmotic pump was used to bring the drug directly to the tumor in the brain, circumventing the blood-brain barrier; thus making bortezomib an effective treatment for GBM. METHODS The 2 human glioma cell lines, U87 and U251, were labeled with luciferase and used in the subcutaneous and intracranial in vivo tumor models. Glioma cells were implanted subcutaneously into the right flank, or intracranially into the frontal cortex of athymic nude mice. Mice bearing intracranial glioma tumors were implanted with an Alzet mini-osmotic pump containing different doses of bortezomib. The Alzet pumps were introduced directly into the tumor bed in the brain. Survival was documented for mice with intracranial tumors. RESULTS Glioma cells were sensitive to bortezomib at nanomolar quantities in vitro. In the subcutaneous in vivo xenograft tumor model, bortezomib given intravenously was effective in reducing tumor progression. However, in the intracranial glioma model, bortezomib given systemically did not affect survival. By sharp contrast, animals treated with bortezomib intracranially at the tumor site exhibited significantly increased survival. CONCLUSIONS Bypassing the blood-brain barrier by using the osmotic pump resulted in an increase in the efficacy of bortezomib for the treatment of intracranial tumors. Thus, the intratumoral administration of bortezomib into the cranial cavity is an effective approach for glioma therapy 8).

References

1)

Wang J, Ren D, Sun Y, Xu C, Wang C, Cheng R, Wang L, Jia G, Ren J, Ma J, Tu Y, Ji H. Inhibition of PLK4 might enhance the anti-tumour effect of bortezomib on glioblastoma via PTEN/PI3K/AKT/mTOR signalling pathway. J Cell Mol Med. 2020 Mar 3. doi: 10.1111/jcmm.14996. [Epub ahead of print] PubMed PMID: 32126150.
2)

Kong XT, Nguyen NT, Choi YJ, Zhang G, Nguyen HN, Filka E, Green S, Yong WH, Liau LM, Green RM, Kaprealian T, Pope WB, Nghiemphu PL, Cloughesy T, Lassman A, Lai A. Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment. Int J Radiat Oncol Biol Phys. 2018 Apr 1;100(5):1195-1203. doi: 10.1016/j.ijrobp.2018.01.001. Epub 2018 Jan 6. PubMed PMID: 29722661.
3)

Jane EP, Premkumar DR, Pollack IF. Bortezomib sensitizes malignant human glioma cells to TRAIL, mediated by inhibition of the NF-{kappa}B signaling pathway. Mol Cancer Ther. 2011 Jan;10(1):198-208. doi: 10.1158/1535-7163.MCT-10-0725. PubMed PMID: 21220502; PubMed Central PMCID: PMC3075591.
4)

Premkumar DR, Jane EP, Agostino NR, DiDomenico JD, Pollack IF. Bortezomib-induced sensitization of malignant human glioma cells to vorinostat-induced apoptosis depends on reactive oxygen species production, mitochondrial dysfunction, Noxa upregulation, Mcl-1 cleavage, and DNA damage. Mol Carcinog. 2013 Feb;52(2):118-33. doi: 10.1002/mc.21835. Epub 2011 Nov 15. PubMed PMID: 22086447; PubMed Central PMCID: PMC4068609.
5)

Raizer JJ, Chandler JP, Ferrarese R, Grimm SA, Levy RM, Muro K, Rosenow J, Helenowski I, Rademaker A, Paton M, Bredel M. A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas. J Neurooncol. 2016 Aug;129(1):139-46. doi: 10.1007/s11060-016-2156-3. Epub 2016 Jun 14. PubMed PMID: 27300524.
6)

McCracken DJ, Celano EC, Voloschin AD, Read WL, Olson JJ. Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma. J Neurooncol. 2016 Oct;130(1):193-201. Epub 2016 Aug 9. PubMed PMID: 27502784.
7)

Suryadevara CM, Riccione KA, Sampson JH. Immunotherapy Gone Viral: Bortezomib and oHSV Enhance Antitumor NK-Cell Activity. Clin Cancer Res. 2016 Nov 1;22(21):5164-5166. Epub 2016 Aug 12. PubMed PMID: 27521450; PubMed Central PMCID: PMC5093093.
8)

Wang W, Cho HY, Rosenstein-Sisson R, Marín Ramos NI, Price R, Hurth K, Schönthal AH, Hofman FM, Chen TC. Intratumoral delivery of bortezomib: impact on survival in an intracranial glioma tumor model. J Neurosurg. 2017 Apr 14:1-6. doi: 10.3171/2016.11.JNS161212. [Epub ahead of print] PubMed PMID: 28409734.

Recurrent glioblastoma

Recurrent glioblastoma (GBM)

Glioblastoma has an unfavorable prognosis mainly due to its high propensity for tumor recurrence. It has been suggested that GBM recurrence is inevitable after a median survival time of 32 to 36 weeks 1) 2).

Natural history

The natural history of recurrent GBM, is largely undefined for the following reasons:

1) Lack of uniform definition and criteria for tumor recurrence

2) Institutional variability in treatment philosophy

3) The heterogeneous nature of the disease, including location of recurrence and distinct mechanisms believed to contribute to known subtypes of GBM.

The criteria used to define recurrent glioblastoma GBM remain ambiguous due to the varied presentation of new lesions. First, the infiltrative nature of GBM cells makes it difficult to eliminate microscopic disease despite macroscopic gross-total resection. Studies have shown that GBM recurrence most often occurs in the form of a local continuous growth within 2 to 3 cm from the border of the original lesion 3) 4) 5).

Etiology

One of the factors that cause recurrence is the strong migratory capacity of GBM cells. Wanibuchi et al., reported that actin, alpha, cardiac muscle 1 (ACTC1) could serve as a marker to detect GBM migration in clinical cases 6).

Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of cancer stem cells (CSC) that contributes to tumor propagation, maintenance, and treatment resistance.

These cells are associated with vascular niches which regulate glioma stem cells (GSC) self-renewal and survival.

Studies suggest that while blood vessels support glioma stem cells, these tumor cells in turn may regulate and contribute to the tumor vasculature by transdifferentiating into endothelial cells directly or through the secretion of regulatory growth factors such as vascular endothelial growth factor (VEGF) and hepatoma derived growth factor (HDGF) 7).

Intratumoral heterogeneity and the presence of these CSCs may contribute to the treatment-resistant nature of GBM and its propensity to recur in patients 8) 9).

Diagnosis

Recurrent Glioblastoma Diagnosis.

Differential Diagnosis

Recurrent Glioblastoma Differential Diagnosis.

Treatment

see Recurrent glioblastoma treatment.

Outcome

see Recurrent glioblastoma outcome.

Case series

see Recurrent glioblastoma case series.

Case reports

A 52-year-old woman was admitted for management of recurrent glioblastoma. After tumor removal surgery, the patient experienced sustained CSF leakage from the wound despite reparative attempts. The plastic surgery team performed wound repair procedure after remnant tumor removal by the neurosurgery team. Acellular dermal matrix was applied over the mesh plate to prevent CSF leakage and the postoperative status of the patient was evaluated. No sign of CSF leakage was found in the immediate postoperative period. After 3 years, there were no complications including CSF leakage, wound dehiscence, and infection. Lee et al. hereby propose this method as a feasible therapeutic alternative for preventing CSF leakage in patients experiencing wound problem after neurosurgical procedures 10).


Corns et al. describe the case of a patient with recurrent glioblastoma encroaching on Broca’s areaGross total resection of the tumour was achieved by combining two techniques, awake craniotomy to prevent damage to eloquent brain and 5 aminolevulinic acid fluorescence guided resection to maximise the extent of tumour resection. This technique led to gross total resection of all T1contrast enhancement tumour with the avoidance of neurological deficit. They recommend this technique in patients when awake surgery can be tolerated and gross total resection is the aim of surgery 11).

References

1) 

Ammirati M, Galicich JH, Arbit E, Liao Y. Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery. 1987 Nov;21(5):607-14. PubMed PMID: 2827051.
2) 

Choucair AK, Levin VA, Gutin PH, Davis RL, Silver P, Edwards MS, Wilson CB. Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J Neurosurg. 1986 Nov;65(5):654-8. PubMed PMID: 3021931.
3) 

Durmaz R, Erken S, Arslantas A, et al: Management of glioblastoma multiforme: with special reference to recurrence. Clin Neurol Neurosurg 99:117–123, 1997
4) 

Halperin EC, Burger PC, Bullard DE: The fallacy of the localized supratentorial malignant glioma. Int J Radiat Oncol Biol Phys 15:505–509, 1988
5) 

Lee SW, Fraass BA, Marsh LH, et al: Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys 43:79-88,1999
6) 

Wanibuchi M, Ohtaki S, Ookawa S, Kataoka-Sasaki Y, Sasaki M, Oka S, Kimura Y, Akiyama Y, Mikami T, Mikuni N, Kocsis JD, Honmou O. Actin, alpha, cardiac muscle 1 (ACTC1) knockdown inhibits the migration of glioblastoma cells in vitro. J Neurol Sci. 2018 Jul 17;392:117-121. doi: 10.1016/j.jns.2018.07.013. [Epub ahead of print] PubMed PMID: 30055382.
7) 

Jhaveri N, Chen TC, Hofman FM. Tumor vasculature and glioma stem cells: contributions to glioma progression. Cancer Lett. 2014 Dec 16. pii: S0304-3835(14)00783-6. doi: 10.1016/j.canlet.2014.12.028. [Epub ahead of print] PubMed PMID: 25527451.
8) 

Cancer Genome Atlas Research Network: Comprehensive ge- nomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068, 2008
9) 

Nickel GC, Barnholtz-Sloan J, Gould MP, McMahon S, Cohen A, Adams MD, et al: Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence. PLoS ONE 7:e35262, 2012
10) 

Lee H, Eom YS, Pyon JK. A method to prevent cerebrospinal fluid leakage: Reinforcing acellular dermal matrix. Arch Craniofac Surg. 2020 Feb;21(1):45-48. doi: 10.7181/acfs.2019.00535. Epub 2020 Feb 20. PubMed PMID: 32126620.
11) 

Corns R, Mukherjee S, Johansen A, Sivakumar G. 5-aminolevulinic acid guidance during awake craniotomy to maximise extent of safe resection of glioblastoma multiforme. BMJ Case Rep. 2015 Jul 15;2015. pii: bcr2014208575. doi: 10.1136/bcr-2014-208575. PubMed PMID: 26177997.
WhatsApp WhatsApp us
%d bloggers like this: