Pediatric Low-Grade Glioma Classification

Pediatric Low-Grade Gliomas (PLGGs) display heterogeneity regarding morphology, genomic drivers and clinical outcomes.

They constitute the largest, yet clinically and (molecular-) a histologically heterogeneous group of pediatric brain tumors of WHO grade I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest 1).

Pediatric low-grade gliomas were shown to be characterized by an array of distinct molecular aberrations. The cIMPACT-4 consensus proposed pediatric low-grade gliomas of the diffuse type to be characterized by distinct molecular changes rather than distinct histological features.

Fukuoka et al. described a small series of pediatric oligodendroglioma-like tumors with BRAF V600E mutations. Interestingly, they exhibited molecular changes usually associated with adult high-grade gliomas: chromosome instability, chromosome 7 gains, and chromosome 10 loss, but had an indolent natural history 2) 3).

Genetic abnormalities

Mobark et al. profiled a targeted panel of cancer-related genes in 37 Saudi Arabian patients with pLGGs to identify genetic abnormalities that can inform prognostic and therapeutic decision-making. THey detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549-BRAF fusion was the most common alteration (21/37 patients) followed by AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were NOTCH1-3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4 (3/37) and NF1 (3/37). Interestingly, they identified a GOPCROS1 fusion in an 8-year-old patient whose tumor lacked BRAF alterations and histologically classified as low-grade glioma. The patient underwent gross total resection (GTR). The patient is currently disease-free. To the author’s knowledge, this is the first report of GOPC-ROS1 fusion in PLGG. Taken together, they revealed the genetic characteristics of pLGG patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG 4).


Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway.

This has led to PLGG clinical trials utilizing RAF– and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with ‘paradox breaker’ RAFi, such as PLX8394.

Jain et al. report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, this study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions 5).

References

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Gnekow AK, Kandels D, Tilburg CV, Azizi AA, Opocher E, Stokland T, Driever PH, Meeteren AYNSV, Thomale UW, Schuhmann MU, Czech T, Goodden JR, Warmuth-Metz M, Bison B, Avula S, Kortmann RD, Timmermann B, Pietsch T, Witt O. SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma. Klin Padiatr. 2019 May;231(3):107-135. doi: 10.1055/a-0889-8256. Epub 2019 May 20. PubMed PMID: 31108561.
2)

Yang RR, Li KK, Liu APY, Chen H, Chung NY, Chan AKY, Li F, Tat-Ming Chan D, Mao Y, Shi ZF, Ng HK. Low-grade BRAF V600E mutant oligodendroglioma-like tumors of children may show EGFR and MET amplification. Brain Pathol. 2020 Oct 8. doi: 10.1111/bpa.12904. Epub ahead of print. PMID: 33032379.
3)

Fukuoka K, Mamatjan Y, Ryall S, Komosa M, Bennett J, Zapotocky M, Keith J, Myrehaug S, Hazrati LN, Aldape K, Laperriere N, Bouffet E, Tabori U, Hawkins C. BRAF V600E mutant oligodendroglioma-like tumors with chromosomal instability in adolescents and young adults. Brain Pathol. 2020 May;30(3):515-523. doi: 10.1111/bpa.12799. Epub 2019 Nov 10. PMID: 31630459.
4)

Mobark NA, Alharbi M, Alhabeeb L, AlMubarak L, Alaljelaify R, AlSaeed M, Almutairi A, Alqubaishi F, Ahmad M, Al-Banyan A, Alotabi FE, Barakeh D, AlZahrani M, Al-Khalidi H, Ajlan A, Ramkissoon LA, Ramkissoon SH, Abedalthagafi M. Clinical management and genomic profiling of pediatric low-grade gliomas in Saudi Arabia. PLoS One. 2020 Jan 29;15(1):e0228356. doi: 10.1371/journal.pone.0228356. eCollection 2020. PubMed PMID: 31995621.
5)

Jain P, Fierst TM, Han HJ, Smith TE, Vakil A, Storm PJ, Resnick AC, Waanders AJ. CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles. Oncogene. 2017 Aug 14. doi: 10.1038/onc.2017.276. [Epub ahead of print] PubMed PMID: 28806393.

Awake surgery for glioma

Awake surgery for glioma

Craniotomies for glioma surgery under conscious sedation (CS) have been well-documented in the literature for glioma surgery that are in or adjacent to eloquent area1) 2) 3) 4) 5).

Awake surgery for glioma aims to maximize resection to optimize prognosis while minimizing the risk of postoperative deficits.

The oncological and functional results of awake glioma surgery during the learning curve are comparable to results from established centers. The use and utility of resection probability maps are well demonstrated. The return to work level is high 6).

AC with the input of the speech and language therapist (SLT) and an experienced neuro-physiotherapist (NP) is a key component in ensuring optimal functional outcomes for patients with gliomas in eloquently located areas 7).

5 aminolevulinic acid guidance during awake craniotomy

Awake surgery for insular glioma

To determine the benefit of awake craniotomy for language, motor, and neurological functions, as well as other clinical outcomes, Bu et al. searched Medline, Embase, the Cochrane Library, and the Chinese Biomedical Literature Database up to December 2019. Gray literature was also searched. They included randomized and non-randomized controlled studies comparing awake craniotomy versus general anesthetic resection and reporting the language and neurological outcomes. Ten studies with 833 patients were included in the meta-analysis. The pooled risk ratio (RR) suggested no significant differences in language and neurological outcomes between the general anesthesia group and the awake craniotomy group without electrical stimulation. Awake craniotomy with electrical stimulation, however, was associated with improved late language and neurological outcomes (≥ 3 months) versus general anesthesia with pooled RR of 0.44 (95% CI = 0.20-0.96) and 0.49 (95% CI = 0.30-0.79), respectively. Awake craniotomy with electrical stimulation was also associated with a better extent of resection with the pooled RR of 0.81 (95%CI = 0.71-0.92) and shorter hospital stay duration with the pooled weighted mean difference (WMD) of – 1.14 (95%CI = – 1.80 to – 0.48). This meta-analysis suggested that the application of awake craniotomy with electrical stimulation during glioma resection is associated with lower risks of long-term neurological and language deficits and higher extent of tumor resection, as well as shorter hospital stay duration 8).

Mandonnet et al. reported a case series of four patients operated on for a glioma in awake conditions and in whom task-based functional magnetic resonance imaging (fMRI) demonstrated right-dominant activity during a language production task. Language functional sites were identified intraoperatively by Electrostimulations only in the patient with a right-sided lesion. Furthermore, the pre- or postoperative cognitive evaluations in the three patients operated on for a left-sided glioma revealed right spatial neglect and dysexecutive syndrome, hence demonstrating that, in patients with right-dominant activity on language fMRI, the left hemisphere is implicated in spatial consciousness and cognitive control. This study supports the interest of presurgical task-based language fMRI to identify patients with a reversed lateralization of cognitive functions and to make an adequate selection of the battery of intraoperative cognitive tasks to be monitored in those rare outliers 9).

Corns et al. describe the case of a patient with recurrent left frontal GBM encroaching on Broca’s area (eloquent brain). Gross total resection of the tumour was achieved by combining two techniques, awake resection to prevent damage to eloquent brain and 5-ALA fluorescence guidance to maximise the extent of tumour resection.This technique led to gross total resection of all T1-enhancing tumour with the avoidance of neurological deficit. The authors recommend this technique in patients when awake surgery can be tolerated and gross total resection is the aim of surgery 10).

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Bejjani GK, Nora PC, Vera PL, Broemling L, Sekhar LN. The predictive value of intraoperative somatosensory evoked potential monitoring: Review of 244 procedures. Neurosurgery 1998;43:491-8.
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De Benedictis A, Mortiz-Gasser S, Duffau H. Awake mapping optimizes the extent of resection for low-grade gliomas in eloquent areas. Neurosurgery 2010;66:1074-84.
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Peruzzi P, Bergese SD, Viloria A, Puente EG, Abdel-Rasoul M, Chiocca EA. A retrospective cohort-matched comparison of conscious sedation versus general anesthesia for supratentorial glioma resection. Clinical article. J Neurosurg 2011;114:633-9.
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Taylor MD, Bernstein M. Awake craniotomy with brain mapping as the routine surgical approach to treating patients with supratentorial intraaxial tumors: A prospective trial of 200 cases. J Neurosurg 1999;90:35-41.
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Wiedemayer H, Sandalcioglu IE, Armbruster W, Regel J, Schaefer H, Stolke D. False negative findings in intraoperative SEP monitoring: Analysis of 658 consecutive neurosurgical cases and review of published reports. J Neurol Neurosurg Psychiatry 2004;75:280-6.
6)

Mandonnet E, De Witt Hamer P, Poisson I, Whittle I, Bernat AL, Bresson D, Madadaki C, Bouazza S, Ursu R, Carpentier AF, George B, Froelich S. Initial experience using awake surgery for glioma: oncological, functional, and employment outcomes in a consecutive series of 25 cases. Neurosurgery. 2015 Apr;76(4):382-9. doi: 10.1227/NEU.0000000000000644. PubMed PMID: 25621981.
7)

Trimble G, McStravick C, Farling P, Megaw K, McKinstry S, Smyth G, Law G, Courtney H, Quigley G, Flannery T. Awake craniotomy for glioma resection: Technical aspects and initial results in a single institution. Br J Neurosurg. 2015 Jul 13:1-7. [Epub ahead of print] PubMed PMID: 26168299.
8)

Bu LH, Zhang J, Lu JF, Wu JS. Glioma surgery with awake language mapping versus generalized anesthesia: a systematic review. Neurosurg Rev. 2020 Oct 21. doi: 10.1007/s10143-020-01418-9. Epub ahead of print. PMID: 33089447.
9)

Mandonnet E, Mellerio C, Barberis M, Poisson I, Jansma JM, Rutten GJ. When Right Is on the Left (and Vice Versa): A Case Series of Glioma Patients with Reversed Lateralization of Cognitive Functions. J Neurol Surg A Cent Eur Neurosurg. 2020 Feb 17. doi: 10.1055/s-0040-1701625. [Epub ahead of print] PubMed PMID: 32066189.
10)

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.

Glioma tumor microenvironment

Glioma tumor microenvironment

In a study, both U118 cell and GSC23 cell exhibited good printability and cell proliferation. Compared with 3D-U118, 3D-GSC23 had a greater ability to form cell spheroids, to secrete VEGFA, and to form tubule-like structures in vitro. More importantly, 3D-GSC23 cells had a greater power to transdifferentiate into functional endothelial cells, and blood vessels composed of tumor cells with an abnormal endothelial phenotype was observed in vivo. In summary, 3D bioprinted hydrogel scaffold provided a suitable tumor microenvironment (TME) for glioma cells and GSCs. This bioprinted model supported a novel TME for the research of glioma cells, especially GSCs in glioma vascularization and therapeutic targeting of tumor angiogenesis 1).


Important advances have been made in deciphering the microenvironment of GBMs, but its association with existing molecular subtypes and its potential prognostic role remain elusive. Jeanmougin et al. investigated the abundance of infiltrating immune and stromal cellin silico, from gene expression profiles. Two cohorts, including in-house normal brain and glioma samples (n=70) and a large sample set from The Cancer Genome Atlas (TCGA)(n=393), were combined into a single exploratory dataset. A third independent cohort (n=124) was used for validation. Tumors were clustered based on their microenvironment infiltration profiles, and associations with known GBM molecular subtypes and patient outcome were tested a posteriori in a multivariable setting. Jeanmougin et al. identified a subset of GBM samples with significantly higher abundances of most immune and stromal cell populations. This subset showed increased expression of both immune suppressor and immune effector genes compared to other GBMs and was enriched for the mesenchymal molecular subtype. Survival analyses suggested that the tumor microenvironment infiltration pattern was an independent prognostic factor for GBM patients. Among all, patients with the mesenchymal subtype with low immune and stromal infiltration had the poorest survival. By combining molecular subtyping with gene expression measures of tumor infiltration, the present work contributes to improving prognostic models in GBM 2).


Tumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression and therapy resistance.

This resiliency of glioma stem cells (GSCs) is, in part, due to self-remodeling of their supportive niche also known as the tumor microenvironment 3) 4) 5) 6).

The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

The tumor microenvironment contributes to tumour heterogeneity.

Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms.

Solid cancers develop in dynamically modified microenvironments in which they seem to hijack resident and infiltrating nontumor cells, and exploit existing extracellular matrices and interstitial fluids for their own benefit. Glioblastoma (GBM), the most malignant intrinsic glial brain tumor, hardly colonizes niches outside the central nervous system (CNS). It seems to need the unique composition of cranial microenvironment for growth and invasion as the incidence of extracranial metastasis of GBM is as low as 0.5%. Different nontumor cells (both infiltrating and resident), structures and substances constitute a semiprotected environment, partially behind the well-known blood–brain barrier, benefitting from the relatively immune privileged state of the CNS. This imposes a particular challenge on researchers and clinicians who try to tackle this disease and desire to penetrate efficiently into this shielded environment to weaken the GBM cells and cut them off from the Hinterland they are addicted to. In this chapter, we focus on how GBM interacts with the different components of its tumor microenvironment (TME), how we can target this TME as a useful contribution to the existing treatments, how we could make further progress in our understanding and interaction with this environment as a crucial step toward a better disease control in the future, and what efforts have already been taken thus far 7).


To characterize the glioma tumor microenvironment, a mixed collective of nine glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]FET-PET-MRI. Image-guided biopsy samples were immuno-phenotyped by multiparameter flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity.

They found a strong relationship (r = 0.84, p = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to HLA-DR+ activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714-positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution.

[18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME. 8).

References

1)

Wang X, Li X, Ding J, et al. 3D bioprinted glioma microenvironment for glioma vascularization [published online ahead of print, 2020 Aug 10]. J Biomed Mater Res A. 2020;10.1002/jbm.a.37082. doi:10.1002/jbm.a.37082
2)

Jeanmougin M, Håvik AB, Cekaite L, Brandal P, Sveen A, Meling TR, Ågesen TH, Scheie D, Heim S, Lothe RA, Lind GE. Improved prognostication of glioblastoma beyond molecular subtyping by transcriptional profiling of the tumor microenvironment. Mol Oncol. 2020 Mar 14. doi: 10.1002/1878-0261.12668. [Epub ahead of print] PubMed PMID: 32171051.
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Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11(1):69-82.
4)

Cheng L, Huang Z, Zhou W, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153(1):139- 152.
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Lathia JD, Heddleston JM, Venere M, et al. Deadly teamwork: neural cancer stem cells and the tumor microenvironment. Cell Stem Cell. 2011;8(5):482- 485.
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Wang L, Rahn JJ, Lun X, et al. Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor. PLoS Biol. 2008;6(11):e289.
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De Vleeschouwer S, Bergers G. Glioblastoma: To Target the Tumor Cell or the Microenvironment? In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 16. Available from http://www.ncbi.nlm.nih.gov/books/NBK469984/ PubMed PMID: 29251862.
8)

Zinnhardt B, Müther M, Roll W, Backhaus P, Jeibmann A, Foray C, Barca C, Döring C, Tavitian B, Dollé F, Weckesser M, Winkeler A, Hermann S, Wagner S, Wiendl H, Stummer W, Jacobs AH, Schäfers M, Grauer OM. TSPO imaging-guided characterization of the immunosuppressive myeloid tumor microenvironment in patients with malignant glioma. Neuro Oncol. 2020 Feb 12. pii: noaa023. doi: 10.1093/neuonc/noaa023. [Epub ahead of print] PubMed PMID: 32047908.
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