Insular glioma surgery

Shawn Hervey-Jumper and Berger from the UCSF Medical Center reviewed the literature for published reports focused on insular region anatomyneurophysiology, surgical approaches, and outcomes for adults with who grade II-IV gliomas.

While originally considered to pose too great a riskinsular glioma surgery can be performed safely due to the collective efforts of many individuals. Similar to resection of gliomas located within other cortical regions, maximal resection of gliomas within the insula offers patients greater survival time and superior seizure control for both newly diagnosed and recurrent tumors in this region. The identification and the preservation of M2 perforating and lateral lenticulostriate artery are critical steps to preventing internal capsulestroke and hemiparesis. The transcortical approach and intraoperative mapping are useful tools to maximize safety.

The insula’s proximity to middle cerebral and lenticulostriate arteries, primary motor areas, and perisylvian language areas makes accessing and resecting gliomas in this region challenging. Maximal safe resection of insular gliomas not only is possible but also is associated with excellent outcomes and should be considered for all patients with low- and high-grade gliomas in this area 1).


Advances in microsurgical anatomy and brain mapping techniques have allowed an increase in the extent of resection with acceptable morbidity rates. Transsylvian and transcortical approaches constitute the main surgical corridors, the latter providing considerable advantages and a high degree of reliability. Nevertheless, both surgical corridors yield remarkable difficulties in reaching the most posterior insular region.

see Insular tumor surgery.


Small deep infarcts constitute a well-known risk of motor and speech deficit in insulo-opercular glioma surgery. However, the risk of cognitive deterioration in relation to stroke occurrence in so-called silent areas is poorly known.

In a paper, Loit et al. propose to build a distribution map of small deep infarcts in glioma surgery, and to analyze patients’ cognitive outcome in relation to stroke occurrence.

They retrospectively studied a consecutive series of patients operated on for a diffuse glioma between June 2011and June 2017. Patients with lower-grade glioma were cognitively assessed, both before and 4 months after surgery. Areas of decreased apparent diffusion coefficient (ADC) on the immediate postoperative MRI were segmented. All images were registered in the MNI reference by ANTS algorithm, allowing to build a distribution map of the strokes. Stroke occurrence was correlated with the postoperative changes in semantic fluency score in the lower-grade glioma cohort.

One hundred fifteen patients were included. Areas of reduced ADC were observed in 27 out of 54 (50%) patients with a lower-grade glioma, and 25 out of 61 (41%) patients with a glioblastoma. Median volume was 1.6 cc. The distribution map revealed five clusters of deep strokes, corresponding respectively to callosal, prefrontal, insulo-opercular, parietal, and temporal tumor locations. No motor nor speech long-term deficits were caused by these strokes. Cognitive evaluations at 4 months showed that the presence of small infarcts correlated with a slight decrease of semantic fluency scores.

Deep small infarcts are commonly found after glioma surgery, but their actual impact in terms of patients’ quality of life remains to be demonstrated. Further studies are needed to better evaluate the cognitive consequences-if any-for each of the described hotspots and to identify risk factors other than the surgery-induced damage of microvessels 2).

Videos

Awake Brain Mapping in Dominant Side Insular Glioma Surgery: 2-Dimensional Operative Video 3).

References

1)

Hervey-Jumper SL, Berger MS. Insular glioma surgery: an evolution of thought and practice. J Neurosurg. 2019 Jan 1;130(1):9-16. doi: 10.3171/2018.10.JNS181519. Review. PubMed PMID: 30611160.
2)

Loit MP, Rheault F, Gayat E, Poisson I, Froelich S, Zhi N, Velut S, Mandonnet E. Hotspots of small strokes in glioma surgery: an overlooked risk? Acta Neurochir (Wien). 2018 Nov 10. doi: 10.1007/s00701-018-3717-3. [Epub ahead of print] PubMed PMID: 30415385.
3)

Hameed NUF, Zhu Y, Qiu T, Wu J. Awake Brain Mapping in Dominant Side Insular Glioma Surgery: 2-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2018 Feb 16. doi: 10.1093/ons/opx299. [Epub ahead of print] PubMed PMID: 29471530

Hemorrhagic low grade glioma

Intracerebral hematoma is an unusual clinical presentation for low grade gliomas and it has been described in a small number of cases in adults 1) 2) 3).

Hemorrhagic low grade glioma (LGG) without malignant transformation is rare, accounting for less than 1% of cases.

It is now generally accepted that the main cause of mortality in these tumors is their dedifferentiation to a higher degree of malignancy 4) 5) 6).

Case reports

Hemorrhagic LGG with an arteriovenous(AV)shunt has not been reported.

Matsuura et al., from the Toho University Medical Center Omori Hospital, report the case of a 17-year-old man with low grade glioma (LGG) with an arteriovenous fistula. He presented to the hospital with seizureComputed tomography(CT) demonstrated a hypodense lesion with mass effect in the right frontal lobeT1-weighted images(WI)and T2WI on magnetic resonance imaging(MRI) revealed acute-onset hemorrhage in the right frontal lobe. Furthermore, a ring enhancing lesion was noted on gadolinium (Gd)-DTPA T1WI, and an AV shunt was found in the same region on angiographyGross total tumor resection was performed. The pathological diagnosis was diffuse astrocytoma with pilomyxoid features (WHO grade II). Without adjuvant therapy, no residual tumor was found on MRI at the 6-year follow-up examination. They treated a case of hemorrhagic LGG with an AV shunt. Intratumoral hemorrhage in LGG may occur and should be considered for the differential diagnosis 7).


A 53-year old woman presenting to the hospital with a hemorrhagic low-grade glioma (LGG). She was admitted to a nearby general hospital where she had presented with aphasia, right hemiplegia and change of mental status. Computer tomography (CT) images showed a left temporo-parietal hemorrhage with mass effect. She was transferred to the neuro-intensive care unit where emergency craniotomy was performed. A tumor with hematoma was removed and further histopathology analysis revealed tumor progression. They reviewed the literature reporting cases of central nervous system tumors hemorrhage and found that these types of events are exquisitely rare in adults with LGG. However these events are possible, suggesting that it should be included in the differential diagnosis of any patient presenting with intracranial hemorrhage. This case raises questions regarding the benefit of early versus late intervention for patients known to have LGG 8).


Della Puppa et al., reviewed the literature of such cases and reported another case of a haemorrhagic low-grade glioma in a 54-year-old woman presenting with a left hemiparesis. Computer tomography (CT) images showed a right basal ganglia haemorrhage with no mass effect. Vascular malformations were ruled out by angiography. Eighteen fluoro-fluoro deossiglucosio (18F-FDG) positron emission tomography (PET/CT) showed a large hypometabolic area corresponding to the lesion. We waited for patient’s improvement. Late magnetic resonance images revealed a low-grade glioma at the bleeding site. Tumour was removed and histopathologic examination revealed a WHO grade II mixed glioma. The authors emphasize that this evidence has to be kept in mind since it has important therapeutic implications 9).


Memon et al., treated three cases of brain tumor that presented with intracranial hemorrhage. Two of the three tumors were metastatic. They presented with hemorrhage into the tumor, but no blood in the cerebrospinal fluid. One tumor was a low grade astrocytoma that presented as subarachnoid and intraventricular hemorrhage in a 15-year-old child. It was removed with no neurological sequelae 10).

References

1)

Gottfried ON, Fults DW, Townsend JJ, Couldwell WT: Spontaneous hemorrhage associated with a pilomyxoid astrocytoma: Case report. J Neurosurg 99: 416-420, 2003
2)

Kondziolka D, Bernstein M, Resch L, Tator CH, Fleming JF, Vanderlinden RG, Schutz H: Significance of hemorrhage into brain tumor: clinicopathological study. J Neurosurg 67:852–857, 1987
3)

Licata B, Turazzi S: Bleeding cerebral neoplasm’s with symptomatic hematoma. J Neurosurg Sci 47:201–210, 2003
4)

Mineo JF, Bordron A, Baroncini M, Maurage CA, Ramirez C, Siminski RM, Berthou C, Dam Hieu P: Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma. J Neurooncol 85:281-287, 2007
5)

Radulović D: Natural history of supratentorial low-grade astrocytoma: Case report. Srp Arh Celok Lek 134:537-540, 2006
6)

Tungaria A, Sahu RN, Kumar R, Srivastava A: Intratumoral hemorrhage in brainstem low-grade glioma. Neurol India 60: 243-245, 2012
7)

Matsuura C, Sakaeyama Y, Node Y, Ueda K, Ando S, Masuda H, Kondo K, Harada N, Nemoto M, Sugo N. [Diffuse Astrocytoma with Pilomyxoid Features Presenting as Intratumoral Hemorrhage:A Case Report]. No Shinkei Geka. 2018 Dec;46(12):1073-1079. doi: 10.11477/mf.1436203870. Japanese. PubMed PMID: 30572304.
8)

Joković M, Bogosavljević V, Nikolić I, Jovanović N. Spontaneous Intracerebral Hematoma in Low-Grade Glioma After 14 Years of Follow-Up. Turk Neurosurg. 2016;26(3):452-5. doi: 10.5137/1019-5149.JTN.11004-14.1. PubMed PMID: 27161476.
9)

Della Puppa A, Zustovich F, Gardiman M, Manara R, Cecchin D, Scienza R. Haemorrhagic presentation of low-grade glioma in adults. Acta Neurochir (Wien). 2007 Nov;149(11):1151-5; discussion 1155. Epub 2007 Aug 6. Review. PubMed PMID: 17676407.
10)

Memon MY, Neal A, Imami R, Villareal N. Low grade glioma presenting as subarachnoid hemorrhage. Neurosurgery. 1984 May;14(5):574-7. PubMed PMID: 6728165.

11C methionine positron emission tomography for glioma

MET PET appears to be useful in evaluating grade, type, and proliferative activity of astrocytic tumor (AT). CHO PET may be useful in evaluating the potential malignancy of oligodendroglial tumors (OTs). In terms of visual evaluation of tumor localization, MET PET is superior to FDG and CHO PET in all of the gliomas, due to its straightforward detection of “hot lesions” 1).


MET-PET is a helpful tool for pretreatment evaluation of non-contrast media enhancing, suggestive low-grade intracerebral lesions. MET-PET adds valuable information for the decision-making for surgery or stereotactic biopsy 2).


The aim of a study of Beppu et al., was to clarify whether arterial spin labeling (ASL) perfusion imaging can assess biological effects from bevacizumab (BEV) therapy as reliably as PET with 11C methionine positron emission tomography.

Twenty-four patients with recurrent glioblastoma were examined using both ASL and C-met-PET before and 4 and 8 weeks after starting BEV treatment. Tumor-to-normal brain (T/N) ratios, fluctuations in T/N ratio, and tumor volumes were compared between ASL and C-met-PET. Accuracy of predicting patient with long progression free survival (PFS) was assessed for T/N ratios and fluctuations for ASL and C-met-PET in each phase and in each period using receiver operating characteristic curves. Between 2 groups of patients assigned by cutoff values from receiver operating characteristic curves, PFS was compared in each phase or in each period.

T/N ratios, fluctuations in ratio, and tumor volumes correlated significantly between ASL and C-met-PET at all time points and all periods. Arterial spin labeling was eligible as a predictor for long PFS only in assessment of fluctuations in T/N ratio. However, the most accurate predictors for long PFS were T/N ratio from C-met-PET at 8 weeks and the fluctuation from baseline to 4 weeks in T/N ratio from C-met-PET.

Blood flows on ASL correlated with accumulations of C-met on PET in recurrent glioblastoma under BEV treatment. Although C-met-PET offered superior accuracy for predicting patients with long PFS from time points, ASL offered reliable prediction of long PFS, provided that fluctuations in T/N ratio between consecutive scans are assessed 3).


The metabolically active tumour volume observed in (11)C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in (11)C-methionine PET/MRI integration patterns can be assigned to tumour grades according to the WHO classification. This finding may improve tumour delineation and therapy planning for gliomas 4).


11C methionine positron emission tomography parameters are significantly correlated with histological grade and IDH1 mutation status in patients with glioma. Grade, pathological classification, molecular biomarkers, SUVmax and SUVratio were prognostic factors for PFS in a cohort of patients. The trial was registered with ClinicalTrials.gov (registration: NCT02518061) 5).

References

1)

Kato T, Shinoda J, Nakayama N, Miwa K, Okumura A, Yano H, Yoshimura S, Maruyama T, Muragaki Y, Iwama T. Metabolic assessment of gliomas using 11C-methionine, [18F] fluorodeoxyglucose, and 11C-choline positron-emission tomography. AJNR Am J Neuroradiol. 2008 Jun;29(6):1176-82. doi: 10.3174/ajnr.A1008. Epub 2008 Apr 3. PubMed PMID: 18388218.
2)

Gumprecht H, Grosu AL, Souvatsoglou M, Dzewas B, Weber WA, Lumenta CB. 11C-Methionine positron emission tomography for preoperative evaluation of suggestive low-grade gliomas. Zentralbl Neurochir. 2007 Feb;68(1):19-23. PubMed PMID: 17487804.
3)

Beppu T, Sato Y, Sasaki T, Terasaki K, Yamashita F, Sasaki M, Ogasawara K. Comparisons Between PET With 11C-Methyl-L-Methionine and Arterial Spin Labeling Perfusion Imaging in Recurrent Glioblastomas Treated With Bevacizumab. Clin Nucl Med. 2018 Dec 17. doi: 10.1097/RLU.0000000000002417. [Epub ahead of print] PubMed PMID: 30562194.
4)

Arbizu J, Tejada S, Marti-Climent JM, Diez-Valle R, Prieto E, Quincoces G, Vigil C, Idoate MA, Zubieta JL, Peñuelas I, Richter JA. Quantitative volumetric analysis of gliomas with sequential MRI and ¹¹C-methionine PET assessment: patterns of integration in therapy planning. Eur J Nucl Med Mol Imaging. 2012 May;39(5):771-81. doi: 10.1007/s00259-011-2049-9. Epub 2012 Jan 19. PubMed PMID: 22258713.
5)

Lopci E, Riva M, Olivari L, Raneri F, Soffietti R, Piccardo A, Bizzi A, Navarria P, Ascolese AM, Rudà R, Fernandes B, Pessina F, Grimaldi M, Simonelli M, Rossi M, Alfieri T, Zucali PA, Scorsetti M, Bello L, Chiti A. Prognostic value of molecular and imaging biomarkers in patients with supratentorial glioma. Eur J Nucl Med Mol Imaging. 2017 Jan 21. doi: 10.1007/s00259-017-3618-3. [Epub ahead of print] PubMed PMID: 28110346.

UpToDate: Fluorescence guided surgery of glioma

Fluorescence guided surgery of glioma

It must be remembered that intraoperative visualization of fluorescence depends on the sensitivity of both the microscope filters and the cameraused 1).


The use of the optical contrast agent sodium fluorescein (NaFl) to guide resection of gliomas has been under investigation for decades. Although this imaging strategy assumes the agent remains confined to the vasculature except in regions of blood brain barrier (BBB) disruption, clinical studies have reported significant NaFl signal in normal brain tissue, limiting tumor-to-normal contrast. A possible explanation arises from earlier studies, which reported that NaFl exists in both pure and protein-bound forms in the blood, the former being small enough to cross the BBB.

A study of Folaron et al. from the Thayer School of Engineering and Department of Surgery Geisel School of Medicine, Dartmouth College, Hanover; and Section of Neurosurgery, and Norris Cotton Cancer Center, Dartmouth Hitchcock Medical CenterLebanonNew Hampshire, aimed to elucidate the kinetic binding behavior of NaFl in circulating blood and its effect on NaFl accumulation in brain tissue and tumor contrast. Additionally, they examined the blood and tissue kinetics, as well as tumor uptake, of a pegylated form of fluorescein selected as a potential optical analog of gadolinium-based MRI contrast agents.

Cohorts of mice were administered one of the following doses/forms of NaFl: 1) high human equivalent dose (HED) of NaFl, 2) low HED of NaFl, or 3) pegylated form of fluorescein. In each cohort, groups of animals were euthanized 15, 30, 60, and 120 minutes after administration for ex vivo analysis of fluorescein fluorescence. Using gel electrophoresis and fluorescence imaging of blood and brain specimens, the authors quantified the temporal kinetics of bound NaFl, unbound NaFl, and pegylated fluorescein in the blood and normal brain tissue. Finally, they compared tumor-to-normal contrast for NaFl and pegylated-fluorescein in U251 glioma xenografts.

Administration of NaFl resulted in the presence of unbound and protein-bound NaFl in the circulation, with unbound NaFl constituting up to 70% of the signal. While protein-bound NaFl was undetectable in brain tissue, unbound NaFl was observed throughout the brain. The observed behavior was time and dose dependent. The pegylated form of fluorescein showed minimal uptake in brain tissue and improved tumor-to-normal contrast by 38%.

Unbound NaFl in the blood crosses the BBB, limiting the achievable tumor-to-normal contrast and undermining the inherent advantage of tumor imaging in the brain. Dosing and incubation time should be considered carefully for NaFl-based fluorescence-guided surgery (FGS) of glioma. A pegylated form of fluorescein showed more favorable normal tissue kinetics that translated to higher tumor-to-normal contrast. These results warrant further development of pegylated-fluorescein for FGS of glioma 2).


Senders et al., systematically review all clinically tested fluorescent agents for application in FGS for glioma and all preclinically tested agents with the potential for FGS for glioma.

They searched the PubMed and Embase databases for all potentially relevant studies through March 2016.

They assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.

The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5 aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein(11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.

5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives. 3).


Mounting evidence suggests that a more extensive surgical resection is associated with an improved life expectancy for both low grade glioma and high grade glioma patients. However, radiographically complete resections are not often achieved in many cases because of the lack of sensitivityand specificity of current neurosurgical guidance techniques at the margins of diffuse infiltrative gliomas. Intraoperative fluorescence imaging offers the potential to improve the extent of resection and to investigate the possible benefits of resecting beyond the radiographic margins.

Liu et al., in 2014 provided a review of wide-field and high-resolution fluorescence-imaging strategies that are being developed for neurosurgical guidance, with a focus on emerging imaging technologies and clinically viable contrast agents. The strengths and weaknesses of these approaches will be discussed, as well as issues that are being addressed to translate these technologies into the standard of care 4).


322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670.

FINDINGS: Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery.

INTERPRETATION: Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma 5).

References

1)

Moiyadi A, Syed P, Srivastava S. Fluorescence-guided surgery of malignant gliomas based on 5-aminolevulinic acid: paradigm shifts but not a panacea. Nat Rev Cancer. 2014 Feb;14(2):146. doi: 10.1038/nrc3566-c1. PubMed PMID: 24457418.
2)

Folaron M, Strawbridge R, Samkoe KS, Filan C, Roberts DW, Davis SC. Elucidating the kinetics of sodium fluorescein for fluorescence-guided surgery of glioma. J Neurosurg. 2018 Sep 7:1-11. doi: 10.3171/2018.4.JNS172644. [Epub ahead of print] PubMed PMID: 30192200.
3)

Senders JT, Muskens IS, Schnoor R, Karhade AV, Cote DJ, Smith TR, Broekman ML. Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir (Wien). 2017 Jan;159(1):151-167. doi: 10.1007/s00701-016-3028-5. Review. PubMed PMID: 27878374; PubMed Central PMCID: PMC5177668.
4)

Liu JT, Meza D, Sanai N. Trends in fluorescence image-guided surgery for gliomas. Neurosurgery. 2014 Jul;75(1):61-71. doi: 10.1227/NEU.0000000000000344. Review. PubMed PMID: 24618801; PubMed Central PMCID: PMC4062574.
5)

Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006 May;7(5):392-401. PubMed PMID: 16648043.

UpToDate: Glioma biomarker

Glioma biomarker

see also Glioblastoma biomarker.

Gliomas are difficult to classify precisely because of interobserver variability during histopathologic grading. Identifying biological signatures of each glioma subtype through protein biomarker profiling of tumor or tumor-proximal fluids is therefore of high priority. Such profiling not only may provide clues regarding tumor classification but may identify clinical biomarkers and pathologic targets for the development of personalized treatments.

In the past, differential proteomic profiling techniques have utilized tumor, cerebrospinal fluid, and plasma from glioma patients to identify the first candidate diagnostic, prognostic, predictive, and therapeutic response markers, highlighting the potential for glioma biomarker discovery. The number of markers identified, however, has been limited, their reproducibility between studies is unclear, and none have been validated for clinical use.

Technological advancements in methodologies for high-throughput profiling, which provide easy access, rapid screening, low sample consumption, and accurate protein identification, are anticipated to accelerate brain tumor biomarker discovery. Reliable tools for biomarker verification forecast translation of the biomarkers into clinical diagnostics in the foreseeable future 1).

Glioma shed extracellular vesicles (EVs), which invade the surrounding tissue and circulate within both the cerebrospinal fluid and the systemic circulation. These tumor-derived EVs and their content serve as an attractive source of biomarkers.

In a review, Hochberg et al., discuss the current state of the art of biomarkers for glioma with emphasis on their EV derivation 2).


A study identified an 18-cytokine signature for distinguishing glioma sera from normal healthy individual sera and also demonstrated the importance of their differential abundance in glioma biology 3).


Shi et al., from Hangzhou, Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai. Department of Neurosurgery, Huai’an Second People’s Hospital, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, China, extracted data sets from the Gene Expression Omnibus data set by using “glioma” as the keyword. Then, a coexpression module was constructed with the help of Weighted Gene Coexpression Network Analysis software. Besides, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the genes in these modules. As a result, the critical modules and target genes were identified. Eight coexpression modules were constructed using the 4,000 genes with a high expression value of the total 141 glioma samples. The result of the analysis of the interaction among these modules showed that there was a high scale independence degree among them. The GO and KEGG enrichment analyses showed that there was a significant difference in the enriched terms and degree among these eight modules, and module 5 was identified as the most important module. Besides, the pathways it was enriched in, hsa04510: Focal adhesion and hsa04610: Complement and coagulation cascades, were determined as the most important pathways. In summary, module 5 and the pathways it was enriched in, hsa04510: Focal adhesion and has 04610: Complement and coagulation cascades, have the potential to serve as glioma biomarkers 4).

References

1)

Kalinina J, Peng J, Ritchie JC, Van Meir EG. Proteomics of gliomas: initial biomarker discovery and evolution of technology. Neuro Oncol. 2011 Sep;13(9):926-42. doi: 10.1093/neuonc/nor078. Review. PubMed PMID: 21852429; PubMed Central PMCID: PMC3158015.

2)

Hochberg FH, Atai NA, Gonda D, Hughes MS, Mawejje B, Balaj L, Carter RS. Glioma diagnostics and biomarkers: an ongoing challenge in the field of medicine and science. Expert Rev Mol Diagn. 2014 May;14(4):439-52. doi: 10.1586/14737159.2014.905202. Review. PubMed PMID: 24746164; PubMed Central PMCID: PMC5451266.

3)

Nijaguna MB, Patil V, Hegde AS, Chandramouli BA, Arivazhagan A, Santosh V, Somasundaram K. An Eighteen Serum Cytokine Signature for Discriminating Glioma from Normal Healthy Individuals. PLoS One. 2015 Sep 21;10(9):e0137524. doi: 10.1371/journal.pone.0137524. eCollection 2015. PubMed PMID: 26390214.

4)

Shi T, Chen J, Li J, Yang BY, Zhang QL. Identification of key gene modules and pathways of human glioma through coexpression network. J Cell Physiol. 2018 Aug 1. doi: 10.1002/jcp.27059. [Epub ahead of print] PubMed PMID: 30067869.

Selenio y glioma

Selenio y glioma

La administración de selenio es importante ya que los compuestos de selenio pueden afectar el microambiente tumoral y neoangiogénesis en el glioma maligno por inducción de apoptosis y alteración de la expresión de la metaloproteinasa de matriz.
En 1990, Philipov y Tzatchev agregaron tabletas de selenio a la dieta de 15 pacientes con tumores cerebrales malignos. En doce pacientes con glioblastoma multiforme este tratamiento no prolongó la supervivencia postoperatoria 1).


En la publicación de Yakubov et al. sobre el selenio, los resultados se centran en las propiedades antitóxicas y preventivas en cáncer y su implicación en las terapias multimodales actuales, que incluyen temozolomida (Temodal),ciclofosfamida (Endoxan) y cisplatino (DDP, Platiblastin y Platinol).
Arroja luz sobre los efectos secundarios no deseados en quimioterapia y los desarrollos de nuevos agentes quimioterapéuticos combinatorios con compuestos de selenio. Descubrieron que los compuestos de selenio y selenio tienen perfiles de doble acción con efectos directos contra el cáncer e intensificador de la quimioterapia, así como con agentes neuroprotectores y citoprotectores 2).


La Tiorredoxina reductasa (TrxR) como antioxidante que contiene selenio juega un papel clave en la regulación del estado redox intracelular.
ver Selenocisteína.


En un estudio de casos y controles en gliomas, Peeri et al., examinaron las asociaciones de selenio en uñas de los pies y variantes genéticas de la selenoenzima con el riesgo de glioma y la supervivencia del paciente. Se estudiaron un total de 423 variantes genéticas en 29 genes candidatos en la vía selenoenzimática en 1547 casos de glioma y 1014 controles sanos. Las asociaciones genéticas también se examinaron en la cohorte de la UK Biobank compuesta por 313,868 personas con 322 casos de glioma. El selenio de la uña del pie se midió en una subcohorte de 300 casos de glioma y 300 controles de la misma edad del estudio de casos y controles.
Ninguna de las 423 variantes estudiadas se asoció consistentemente con el riesgo de glioma en los estudios de casos y controles y de cohortes. Además, el selenio de la uña del pie en el estudio de casos y controles no tuvo una asociación significativa con el riesgo de glioma (tendencia p = 0,70) o la supervivencia del paciente entre 254 pacientes con tumores de alto grado (tendencia p = 0,70).
El presente estudio no ofrece respaldo para la hipótesis de que el selenio desempeña un papel en la aparición del glioma o en el resultado del paciente 3).
1)

Philipov P, Tzatchev K. Selenium in the treatment of patients with brain gliomas. A pilot study. Zentralbl Neurochir. 1990;51(3):145-6. PubMed PMID: 1965466.
2)

Yakubov E, Buchfelder M, Eyüpoglu IY, Savaskan NE. Selenium action in neuro-oncology. Biol Trace Elem Res. 2014 Dec;161(3):246-54. doi: 10.1007/s12011-014-0111-8. Epub 2014 Aug 28. Review. PubMed PMID: 25164034.
3)

Peeri NC, Creed JH, Anic GM, Thompson RC, Olson JJ, LaRocca RV, Chowdhary SA, Brockman JD, Gerke TA, Nabors LB, Egan KM. Toenail selenium, genetic variation in selenoenzymes and risk and outcome in glioma. Cancer Epidemiol. 2018 May 16;55:45-51. doi: 10.1016/j.canep.2018.05.002. [Epub ahead of print] PubMed PMID: 29777993.

Update: Selenium and glioma

Selenium and glioma

Reliable supply of selenium is important since selenium compounds can affect tumor microenvironment and neoangiogenesis in malignant gliomas via induction of apoptosis and alteration of matrix metalloproteinases expression.

In 1990 Philipov and Tzatchev added selenium tablets to the diet of 15 patients with malignant brain tumors. In twelve patients with glioblastoma multiforme this treatment didn’t prolong the postoperative survival 1).


Yakubov et al. summarized findings focusing on the anti-toxicity and cancer-preventive properties of selenium and their implication in current multimodal therapies including temozolomide (Temodal), cyclophosphamide (Endoxan), and cisplatin (DDP, Platiblastin, and Platinol).

They sheded light on unintended side effects in chemotherapy and the developments of novel combinatorial chemotherapeutics with selenium compounds. They found that selenium and selenium compounds have dual action profiles with direct anti-cancer and chemotherapy-intensifier effects as well as neuroprotective and cytoprotective agents 2).


Thioredoxin reductase (TrxR) as a selenium (Se)-containing antioxidase plays key role in regulating intracellular redox status. Selenocystine (SeC) a natural available Se-containing amino acid showed novel anticancer potential through triggering oxidative damage-mediated apoptosis. However, whether TrxR-mediated oxidative damage was involved in SeC-induced apoptosis in human glioma cells has not been elucidated yet. Herein, SeC-induced human glioma cell apoptosis was detected in vitro, accompanied by PARP cleavage, caspases activation and DNA fragmentation. Mechanically, SeC caused mitochondrial dysfunction and imbalance of Bcl-2 family expression. SeC treatment also triggered ROS-mediated DNA damage and disturbed the MAPKs and AKT pathways. However, inhibition of ROS overproduction effectively attenuated SeC-induced oxidative damage and apoptosis, and normalized the expression of MAPKs and AKT pathways, indicating the significance of ROS in SeC-induced apoptosis. Importantly, U251 human glioma xenograft growth in nude mice was significantly inhibited in vivo. Further investigation revealed that SeC-induced oxidative damage was achieved by TrxR1-targeted inhibition in vitro and in vivo.

The findings validated the potential of SeC to inhibit human glioma growth by oxidative damage-mediated apoptosis through triggering TrxR1-targeted inhibition 3).


In a case-control study of glioma, Peeri et al., examined the associations of selenium in toenails and genetic variants in the selenoenzyme pathwaywith the risk of glioma and patient survival. A total of 423 genetic variants in 29 candidate genes in the selenoenzyme pathway were studied in 1547 glioma cases and 1014 healthy controls. Genetic associations were also examined in the UK Biobank cohort comprised of 313,868 persons with 322 incident glioma cases. Toenail selenium was measured in a subcohort of 300 glioma cases and 300 age-matched controls from the case-control study.

None of the 423 variants studied were consistently associated with glioma risk in the case-control and cohort studies. Moreover, toenail selenium in the case-control study had no significant association with glioma risk (p trend = 0.70) or patient survival among 254 patients with high grade tumors (p trend = 0.70).

The present study offers no support for the hypothesis that selenium plays a role in the onset of glioma or patient outcome 4).

References

1)

Philipov P, Tzatchev K. Selenium in the treatment of patients with brain gliomas. A pilot study. Zentralbl Neurochir. 1990;51(3):145-6. PubMed PMID: 1965466.

2)

Yakubov E, Buchfelder M, Eyüpoglu IY, Savaskan NE. Selenium action in neuro-oncology. Biol Trace Elem Res. 2014 Dec;161(3):246-54. doi: 10.1007/s12011-014-0111-8. Epub 2014 Aug 28. Review. PubMed PMID: 25164034.

3)

Fan CD, Fu XY, Zhang ZY, Cao MZ, Sun JY, Yang MF, Fu XT, Zhao SJ, Shao LR, Zhang HF, Yang XY, Sun BL. Selenocysteine induces apoptosis in human glioma cells: evidence for TrxR1-targeted inhibition and signaling crosstalk. Sci Rep. 2017 Jul 25;7(1):6465. doi: 10.1038/s41598-017-06979-2. PubMed PMID: 28743999; PubMed Central PMCID: PMC5526989.

4)

Peeri NC, Creed JH, Anic GM, Thompson RC, Olson JJ, LaRocca RV, Chowdhary SA, Brockman JD, Gerke TA, Nabors LB, Egan KM. Toenail selenium, genetic variation in selenoenzymes and risk and outcome in glioma. Cancer Epidemiol. 2018 May 16;55:45-51. doi: 10.1016/j.canep.2018.05.002. [Epub ahead of print] PubMed PMID: 29777993.

Update: 5 aminolevulinic acid fluorescence guided resection of high grade glioma

5 aminolevulinic acid fluorescence guided resection of high grade glioma

J.Sales-Llopis
Neurosurgery Service, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL – FISABIO Foundation), Alicante, Spain.
Fluorescence guided resection (FGR) in high grade glioma aims at increasing complete resections and, thus, local control. This technique uses 5 aminolevulinic acid (5-ALA), a natural intermediate substance in the heme-porphyrin biosynthesis pathway, and a protoporphyrin IX (PpIX) precursor. PpIX is fluorescent under blue light exposure 1).

Doses

The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence 2).

History

In 2000 Stummer et al published that Five-aminolevulinic acid (5-ALA)-derived fluorescence was approved for fluorescence-guided resections of malignant gliomas, relying on selective synthesis and accumulation of protoporphyrin IX (PPIX) within malignant glioma cells 3).
In 2006 Stummer et al., published that tumour fluorescence derived from 5 aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma 4).
The positive predictive value (PPV) of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the negative predictive value (NPV) of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence 5).


Many studies have shown that the ratio of gross total resections was higher if the fluorescence technique was used. The fluorescence signal intensity is correlated to the cell density and the PpIX concentration. The current method has a very high specificity but still lower sensitivity, particularly regarding the zones with poor tumoral infiltration 6).
PpIX fluorescence was also identified as a novel marker for intraoperative detection of anaplastic foci in nonenhancing gliomas that ensures a precise histopathological diagnosis and optimal patient treatment. Furthermore, 5 prospective studies have confirmed that PpIX fluorescence is able to identify residual tumor tissue after assumed maximal resection of malignant gliomas with conventional white-light microscopy. Because intraoperative detection of malignant glioma tissue is significantly improved by 5-ALA FGS, high rates of complete tumor resections are achieved, especially in combination with intraoperative monitoring and mapping 7).
In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments 8).

Limitations

Visual assessment of PpIX fluorescence is subjective and limited by the distorting effects of light attenuation and tissue autofluorescence 9).


Resection of reactive tissue without active recurrent tumor after multimodal treatment for glioblastoma is frequently associated with solid or vague 5-AIF. Therefore, neurosurgeons should remain cautious when attempting to employ intraoperative 5-ALA induced fluorescence (5-AIF) to discriminate radiation- and chemotherapy-induced tissue changes from true disease progression. Nevertheless, 5-AIF-guided resection remains a valid tool in the neurosurgical treatment of recurrent gliomas 10).
The resection cavity underestimates the volume of resected tissue and 5-ALA complete resections go significantly beyond the volume of pre-operative contrast-enhancing tumor bulk on MRI, indicating that 5-ALA also stains MRI non-enhancing tumor tissue. Use of 5-ALA may thus enable extension of coalescent tumor resection beyond radiologically evident tumor. The impact of this more extended resection method on time to progression and overall survival has not been determined, and potentially puts adjacent and functionally intact tissue at risk 11).

Systematic reviews

In 2013 based on available literature, there was level of evidence 2 that 5-ALA-guided surgery is more effective than conventional neuronavigation-guided surgery in increasing diagnostic accuracy and extent of tumor resection, enhancing quality of life, or prolonging survival in patients with high-grade malignant gliomas 12).


Barone et al., in a Cochrane Database Systematic Review published in 2014, that there is low to very low quality evidence (according to GRADE criteria) that image guided surgery using iMRI, 5-ALA or DTI-neuronavigation increases the proportion of patients with high grade glioma that have a complete tumour resection on post-operative MRI. There is a theoretical concern that maximising the extent of resection may lead to more frequent adverse events but this was poorly reported in the included studies. Effects of image guided surgery on survival quality of life (QoL) are unclear. Further research, including studies of ultrasound guided surgery, is needed 13).


In 2015, a literature review produced 503 potential publications; only 20 of these fulfilled the inclusion criteria of this analysis, including a total of 565 patients treated with 5-ALA-FIGR reporting on its outcomes and 800 histological samples reporting 5-ALA-FIGR sensitivity and specificity.
The mean gross total resection (GTR) rate was 75.4% (95% CI: 67.4-83.5, p<0.001). The mean time to tumor progression (TTP) was 8.1 months (95% CI: 4.7-12, p<0.001). The mean overall survival gain reported was 6.2 months (95% CI: -1-13, p<0.001). The specificity was 88.9% (95% CI: 83.9-93.9, p<0.001) and the sensitivity was 82.6% (95% CI: 73.9-91.9, p<0.001).
5-ALA-FIGR in GBM is highly sensitive and specific, and imparts significant benefits to patients in terms of improved GTR and TTP 14).

Alternatives

CLR1501 (green) and CLR1502 (near infrared) are novel tumor-selective fluorescent agents for discriminating tumor from normal brain 15).

Case series

2017

Data of 47 consecutive patients with HGG have been collected in our study (25 males, 22 females; mean age: 60.3 years, range: 27-86 years). Fluorescein (5 mg/kg of body weight) was injected intravenously right after the induction of general anesthesia. A YELLOW 560 filter was used on an OPMI Pentero 900 microscope (Carl Zeiss Meditec, Oberkochen, Germany) to complete a microsurgical tumor removal. Glioma resection and quality of life were evaluated preoperative and postoperatively.
Gross total resection (GTR) was achieved in 53.2% (n = 25) of patients. A subtotal resection (STR) (>95%) was achieved in 29.8% (n = 14), while a partial resection (PR) (<95%) was obtained in 17% (n = 8) of patients. Overall, in 83% (n = 39) of patients who underwent fluorescence-guided surgery the resection rate achieved was >95%. No adverse effects correlated to fluorescein have been recorded.
Fluorescein seems to be safe and effective in the resection of HGGs, allowing a high rate of gross total removal of contrast enhanced areas 16).

2016

Thirty-two patients received fluorescein sodium (3 mg/kg) intravenously prior to resection. Fluorescence was intraoperatively visualized using a Zeiss Pentero surgical microscope equipped with a YELLOW 560 filter. Stereotactically localized biopsy specimens were acquired from CE and NCE regions based on preoperative MRI in conjunction with neuronavigation. The fluorescence intensity of these specimens was subjectively classified in real time with subsequent quantitative image analysis, histopathological evaluation of localized biopsy specimens, and radiological volumetric assessment of the extent of resection. RESULTS Bright fluorescence was observed in all GBMs and localized to the CE regions and portions of the NCE margins of the tumors, thus serving as a visual guide during resection. Gross-total resection (GTR) was achieved in 84% of the patients with an average resected volume of 95%, and this rate was higher among patients for whom GTR was the surgical goal (GTR achieved in 93.1% of patients, average resected volume of 99.7%). Intraoperative fluorescein staining correlated with histopathological alteration in both CE and NCE regions, with positive predictive values by subjective fluorescence evaluation greater than 96% in NCE regions.
Intraoperative administration of fluorescein provides an easily visualized marker for glioma pathology in both CE and NCE regions of GBM. These findings support the use of fluorescein as a microsurgical adjunct for guiding GBM resection to facilitate safe maximal removal 17).


A single-center, prospective, single-arm, open-label Phase II clinical trial of ALA fluorescence-guided resection of high-grade gliomas (Grade III and IV) was held over a 43-month period (August 2010 to February 2014). ALA was administered at a dose of 20 mg/kg body weight. Intraoperative biopsies from resection cavities were collected. The biopsies were graded on a 4-point scale (0 to 3) based on ALA fluorescence intensity by the surgeon and independently based on tumor cellularity by a neuropathologist. The primary outcome of interest was the correlation of ALA fluorescence intensity to tumor cellularity. The secondary outcome of interest was ALA adverse events. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Spearman correlation coefficients were calculated. RESULTS A total of 211 biopsies from 59 patients were included. Mean age was 53.3 years and 59.5% were male. The majority of biopsies were glioblastoma (GBM) (79.7%). Slightly more than half (52.5%) of all tumors were recurrent. ALA intensity of 3 correlated with presence of tumor 97.4% (PPV) of the time. However, absence of ALA fluorescence (intensity 0) correlated with the absence of tumor only 37.7% (NPV) of the time. For all tumor types, GBM, Grade III gliomas, and recurrent tumors, ALA intensity 3 correlated strongly with cellularity Grade 3; Spearman correlation coefficients ® were 0.65, 0.66, 0.65, and 0.62, respectively. The specificity and PPV of ALA intensity 3 correlating with cellularity Grade 3 ranged from 95% to 100% and 86% to 100%, respectively. In biopsies without tumor (cellularity Grade 0), 35.4% still demonstrated ALA fluorescence. Of those biopsies, 90.9% contained abnormal brain tissue, characterized by reactive astrocytes, scattered atypical cells, or inflammation, and 8.1% had normal brain. In nonfluorescent (ALA intensity 0) biopsies, 62.3% had tumor cells present. The ALA-associated complication rate among the study cohort was 3.4%.
The PPV of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the NPV of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence18).

2015

58 patients with high grade gliomas (°III and °IV) were included. 10 of 63 tumors (15.9 %) failed to fluoresce intraoperatively of which nine (90 %) had been adjuvantly treated prior to recurrence, as were 46 of the 53 fluorescing tumors (86.8 %). Non-fluorescing tumors were IDH mutated significantly more often (p = 0.005). 30 tumors (47.6 %) were located eloquently. 51 (80.9 %) patients showed no new neurologic deficits postoperatively. 13 patients (20.6 %) showed no signs of recurrence at their latest follow up. Eight patients were lost to follow up. Overall survival was significantly longer in the 5-ALA group (p = 0.025). Fluorescence-guided surgery in recurrent gliomas is safe and allows for a good surgical and neurological outcome in a difficult surgical environment, especially when used in combination with neuronavigation and intraoperative ultrasound to prevent over-resection. Adjuvant therapy did not significantly influence fluorescing properties 19).

2014

Clinical and surgical data from patients affected by HGG who underwent surgery guided by 5-ALA fluorescence between June 2011 and February 2014 were retrospectively evaluated. Surgical outcome was evaluated by assessing the resection rate as gross total resection (GTR) > 98% and GTR > 90%. We finally stratified data for recurrent surgery, tumor location, tumor size, and tumor grade (IV versus III grade sec. WHO).
94 patients were finally enrolled. Overall GTR > 98% and GTR > 90% was achieved in 93% and 100% of patients. Extent of resection (GTR > 98%) was dependent on tumor location, tumor grade (P < 0.05), and tumor size (P < 0.05). In 43% of patients the boundaries of fluorescent tissue exceeded those of tumoral tissue detected by neuronavigation, more frequently in larger (57%) (P < 0.01) and recurrent (60%) tumors.
5-ALA fluorescence in HGG surgery enables a GTR in 100% of cases even if selection of patients remains a main bias. Recurrent surgery, and location, size, and tumor grade can predict both the surgical outcome and the intraoperative findings 20).


Schucht et al., prospectively studied 72 consecutive patients who underwent 5-ALA-guided surgery for a glioblastoma adjacent to the corticospinal tract (CST; < 10 mm) with continuous dynamic monopolar motor mapping (short-train interstimulus interval 4.0 msec, pulse duration 500 μsec) coupled to an acoustic motor evoked potential (MEP) alarm. The extent of resection was determined based on early (< 48 hours) postoperative MRI findings. Motor function was assessed 1 day after surgery, at discharge, and at 3 months.
Five patients were excluded because of nonadherence to protocol; thus, 67 patients were evaluated. The lowest motor threshold reached during individual surgery was as follows (motor threshold, number of patients): > 20 mA, n = 8; 11-20 mA, n = 13; 6-10 mA, n = 10; 4-5 mA, n = 13; and 1-3 mA, n = 23. Motor deterioration at postsurgical Day 1 and at discharge occurred in 30% (n = 20) and 10% (n = 7) of patients, respectively. At 3 months, 3 patients (4%) had a persisting postoperative motor deficit, 2 caused by vascular injury and 1 by mechanical injury. The rates of intra- and postoperative seizures were 1% and 0%, respectively. Complete resection of enhancing tumor was achieved in 73% of patients (49/67) despite proximity to the CST.
A rather high rate of CRET can be achieved in glioblastomas in motor eloquent areas via a combination of 5-ALA for tumor identification and intraoperative mapping for distinguishing between presumed and actual motor eloquent tissues. Continuous dynamic mapping was found to be a very ergonomic technique that localizes the motor tissue early and reliably 21).


Schucht et al., selected 13 patients who had received a complete resection according to intraoperative 5-ALA induced fluorescence and CRET according to post-operative T1 contrast-enhanced MRI. The volumes of pre-operative contrast enhancing tissue, post-operative resection cavity and resected tissue were determined through shift-corrected volumetric analysis.
The mean resection cavity (29 cm(3)) was marginally smaller than the pre-operative contrast-enhancing tumor (39 cm(3), p = 0.32). However, the mean overall resection volume (84 cm(3)) was significantly larger than the pre-operative contrast-enhancing tumor (39 cm(3), p = 0.0087). This yields a mean volume of resected 5-ALA positive, but radiological non-enhancing tissue of 45 cm(3). The mean calculated rim of resected tissue surpassed pre-operative tumor diameter by 6 mm (range 0-10 mm).
Results of the current study imply that (i) the resection cavity underestimates the volume of resected tissue and (ii) 5-ALA complete resections go significantly beyond the volume of pre-operative contrast-enhancing tumor bulk on MRI, indicating that 5-ALA also stains MRI non-enhancing tumor tissue. Use of 5-ALA may thus enable extension of coalescent tumor resection beyond radiologically evident tumor. The impact of this more extended resection method on time to progression and overall survival has not been determined, and potentially puts adjacent and functionally intact tissue at risk 22).

2013

A retrospective review found 118 consecutive patients with high-grade gliomas operated on with the use of fluorescence-guided surgery with 5-aminolevulinic acid. Within that series, the 52 patients with newly diagnosed GBM and complete resection of enhancing tumor (CRET) in early MRI were selected for analysis. They studied the influence of residual fluorescence in the surgical field on overall survival and neurological complication rate. Multivariate analysis included potential relevant factors: age, Karnofsky Performance Scale, O-methylguanine methyltransferase methylation promoter status, tumor eloquent location, preoperative tumor volume, and adjuvant therapy.
The median overall survival was 27.0 months (confidence interval = 22.4-31.6) in patients with nonresidual fluorescence (n = 25) and 17.5 months (confidence interval = 12.5-22.5) for the group with residual fluorescence (n = 27) (P = .015). The influence of residual fluorescence was maintained in the multivariate analysis with all covariables, hazard ratio = 2.5 (P = .041). The neurological complication rate was 18.5% in patients with nonresidual fluorescence and 8% for the group with residual fluorescence (P = .267).
GBM patients with CRET in early MRI and no fluorescent residual tissue had longer overall survival than patients with CRET and residual fluorescent tissue 23).

2012

One hundred three consecutive patients underwent resection of glioblastoma from August 2008 to November 2010. Eligibility for CRET was based on the initial magnetic resonance imaging assessed by 2 reviewers. The primary end point was the number of patients with CRET and GTR. Secondary end points were volume of residual contrast-enhancing tissue and new postoperative neurological deficits.
Fifty-three patients were eligible for GTR/CRET (n = 43 newly diagnosed glioblastoma, n = 10 recurrent); 13 additional patients received surgery for GTR/CRET-ineligible glioblastoma. GTR was achieved in 96% of patients (n = 51, no residual enhancement >0.175 cm); CRET was achieved in 89% (n = 47, no residual enhancement). Postoperatively, 2 patients experienced worsening of preoperative hemianopia, 1 patient had a new mild hemiparesis, and another patient sustained sensory deficits.
Using 5-aminolevulinic acid imaging and intraoperative mapping/monitoring together leads to a high rate of CRET and an increased rate of GTR compared with the literature without increasing the rate of permanent morbidity. The combination of safety and resection-enhancing intraoperative technologies was likely to be the major drivers for this high rate of CRET/GTR 24).

2006

322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670.
Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery.
Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma 25).

2000

Fifty-two consecutive patients with GBM received oral doses of 5-ALA (20 mg/kg body weight) 3 hours before induction of anesthesia. Intraoperatively, tumor fluorescence was visualized using a modified operating microscope. Fluorescing tissue was removed whenever it was considered safely possible. Residual enhancement on early postoperative MR imaging was quantified and related to each patient’s characteristics to determine which factors influenced resection. Survival was analyzed using the Kaplan-Meier method and multivariate analysis was performed in which the Karnofsky Performance Scale (KPS) score, residual fluorescence, patient age, and residual enhancement on MR images were considered. Intraoperatively, two fluorescence qualities were perceived: solid fluorescence generally reflected coalescent tumor, whereas vague fluorescence mostly corresponded to infiltrative tumor. Complete resection of contrast-enhancing tumor was accomplished in 33 patients (63%). Residual intraoperative tissue fluorescence left unresected for safety reasons predicted residual enhancement on MR images in 18 of the 19 remaining patients. Age, residual solid fluorescence, and absence of contrast enhancement in MR imaging were independent explanatory factors for survival, whereas the KPS score was significant only in univariate analysis. No perioperative deaths and one case of permanent morbidity were encountered.
The observations in this study indicate the usefulness of 5-ALA-induced tumor fluorescence for guiding tumor resection. The completeness of resection, as determined intraoperatively from residual tissue fluorescence, was related to postoperative MR imaging findings and to survival in patients suffering from GBM 26).
1)

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Neira JA, Ung TH, Sims JS, Malone HR, Chow DS, Samanamud JL, Zanazzi GJ, Guo X, Bowden SG, Zhao B, Sheth SA, McKhann GM 2nd, Sisti MB, Canoll P, D’Amico RS, Bruce JN. Aggressive resection at the infiltrative margins of glioblastoma facilitated by intraoperative fluorescein guidance. J Neurosurg. 2016 Oct 7:1-12. [Epub ahead of print] PubMed PMID: 27715437.
19)

Hickmann AK, Nadji-Ohl M, Hopf NJ. Feasibility of fluorescence-guided resection of recurrent gliomas using five-aminolevulinic acid: retrospective analysis of surgical and neurological outcome in 58 patients. J Neurooncol. 2015 Mar;122(1):151-60. doi: 10.1007/s11060-014-1694-9. PubMed PMID: 25557106.
20)

Della Puppa A, Ciccarino P, Lombardi G, Rolma G, Cecchin D, Rossetto M. 5-Aminolevulinic acid fluorescence in high grade glioma surgery: surgical outcome, intraoperative findings, and fluorescence patterns. Biomed Res Int. 2014;2014:232561. doi: 10.1155/2014/232561. PubMed PMID: 24804203; PubMed Central PMCID: PMC3997860.
21)

Schucht P, Seidel K, Beck J, Murek M, Jilch A, Wiest R, Fung C, Raabe A. Intraoperative monopolar mapping during 5-ALA-guided resections of glioblastomas adjacent to motor eloquent areas: evaluation of resection rates and neurological outcome. Neurosurg Focus. 2014 Dec;37(6):E16. doi: 10.3171/2014.10.FOCUS14524. PubMed PMID: 25434385.
22)

Schucht P, Knittel S, Slotboom J, Seidel K, Murek M, Jilch A, Raabe A, Beck J. 5-ALA complete resections go beyond MR contrast enhancement: shift corrected volumetric analysis of the extent of resection in surgery for glioblastoma. Acta Neurochir (Wien). 2014 Feb;156(2):305-12; discussion 312. doi: 10.1007/s00701-013-1906-7. PubMed PMID: 24449075.
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Aldave G, Tejada S, Pay E, Marigil M, Bejarano B, Idoate MA, Díez-Valle R. Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic Acid-guided surgery. Neurosurgery. 2013 Jun;72(6):915-20; discussion 920-1. doi: 10.1227/NEU.0b013e31828c3974. PubMed PMID: 23685503.
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Schucht P, Beck J, Abu-Isa J, Andereggen L, Murek M, Seidel K, Stieglitz L, Raabe A. Gross total resection rates in contemporary glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic acid intraoperative fluorescence imaging and brain mapping. Neurosurgery. 2012 Nov;71(5):927-35; discussion 935-6. doi: 10.1227/NEU.0b013e31826d1e6b. PubMed PMID: 22895402.
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Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ. Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg. 2000 Dec;93(6):1003-13. PubMed PMID: 11117842.

Butterfly glioma

 

Butterfly glioma is a high grade astrocytoma, usually a glioblastoma (WHO grade IV), which crosses the midline via the corpus callosum. Other white matter commissures are also occasionally involved. The term butterfly refers to the symmetric wing like extensions across the midline.

Epidemiology

Most frequently butterfly gliomas occur in the frontal lobes, crossing via the genu of the corpus callosum, however posterior butterflies are also encountered.

Differential diagnosis

Primary central nervous system lymphoma: especially in AIDS patients
cerebral toxoplasmosis: especially in AIDS patients
tumefactive demyelination
cerebral metastases (rare)
occasionally a leptomeningeal process which fills the quadrigeminal and ambient cisterns can cause confusion.
A meningioma can mimic butterfly glioma when it arises from the falx cerebri and crosses the midline. Presence of a cerebrospinal fluid intensity cleft between the tumour and adjacent brain cortex is a useful sign to identify the extra-axial location of these lesions and differentiate them from butterfly gliomas 1).

Treatment

Gliomas invading the anterior corpus callosum are commonly deemed unresectable due to an unacceptable risk/benefit ratio, including the risk of abulia.
Burks et al. in a study presents evidence that anterior butterfly gliomas can be safely removed using a novel, attention-task based, awake brain surgery technique that focuses on preserving the anatomical connectivity of the cingulum and relevant aspects of the cingulate gyrus 2).
Current management options include biopsy only, followed by radiation and chemotherapy; surgical decompression followed by radiation and chemotherapy; or biopsy followed by palliative measures (comfort care). Management decisions are subjective, based upon physician experience and/or patient/family preferences in light of the prognosis of this disease.

Outcome

The prognosis of glioblastoma multiforme (GBM) is poor even with aggressive first-line therapy, which includes surgery, radiation therapy, and adjuvant chemotherapy. Although the ideal course of treatment for elderly patients with newly diagnosed GBM is still undecided and requires further studies, the new chemotherapeutic agents administered with or without concomitant radiation therapy have shown promising results. However, in our setting, where resources are limited and newer treatment options are expensive, it is often difficult to deliver the best care to the patient 3).

Case series

2017

Burks et al. reviewed clinical data on all patients undergoing glioma surgery performed by the senior author during a 4-year period at the University of Oklahoma Health Sciences Center. Forty patients were identified who underwent surgery for butterfly gliomas. Each patient was designated as having undergone surgery either with or without the use of awake subcortical mapping and preservation of the cingulum. Data recorded on these patients included the incidence of abulia/akinetic mutism. In the context of the study findings, the authors conducted a detailed anatomical study of the cingulum and its role within the DMN using postmortem fiber tract dissections of 10 cerebral hemispheres and in vivo diffusion tractography of 10 healthy subjects.
Forty patients with butterfly gliomas were treated, 25 (62%) with standard surgical methods and 15 (38%) with awake subcortical mapping and preservation of the cingulum. One patient (1/15, 7%) experienced postoperative abulia following surgery with the cingulum-sparing technique. Greater than 90% resection was achieved in 13/15 (87%) of these patients.
This study presents evidence that anterior butterfly gliomas can be safely removed using a novel, attention-task based, awake brain surgery technique that focuses on preserving the anatomical connectivity of the cingulum and relevant aspects of the cingulate gyrus 4).

2014

Of 336 patients with newly diagnosed GBM who were operated on, 48 (14 %) presented with bGBM, where 29 (60 %) and 19 (40 %) underwent surgical resection and biopsy, respectively. In multivariate analysis, a bGBM was independently associated with poorer survival [HR (95 % CI) 1.848 (1.250-2.685), p < 0.003]. In matched-pair analysis, patients who underwent surgical resection had improved median survival than biopsy patients (7.0 vs. 3.5 months, p = 0.03). In multivariate analysis, increasing percent resection [HR (95 % CI) 0.987 (0.977-0.997), p = 0.01], radiation [HR (95 % CI) 0.431 (0.225-0.812), p = 0.009], and temozolomide [HR (95 % CI) 0.413 (0.212-0. 784), p = 0.007] were each independently associated with prolonged survival among patients with bGBM. This present study shows that while patients with bGBM have poorer prognoses compared to non-bGBM, these patients can also benefit from aggressive treatments including debulking surgery, maximal safe surgical resection, temozolomide chemotherapy, and radiation therapy 5).

2011

Median age was 59 years; 52 % were female; median preoperative Karnofsky performance score (KPS) was 80. Twelve patients underwent biopsy and eleven underwent surgical decompression. The median tumor volume for the biopsy group was 60.6 cm(3) and for the surgically decompressed group 40.5 cm(3). In the biopsy group, five patients received adjuvant therapy but one died prior to its completion; two died prior to the initiation of adjuvant therapy and five were lost to follow up. In the surgical decompression group, seven patients received adjuvant therapy, one died prior to the initiation of adjuvant therapy, two were treated with palliative measures only, and one was lost to follow up. Kaplan-Meier estimates of overall median post surgical-survival of the whole group was 180 days, the biopsy group 48 days, and the surgically decompressed group 265 days (p = 0.14). Our results show that there was a higher median survival in the surgically decompressed group; but a direct correlation could not be established, and that the median KPS did not improve in either group after treatment. A larger multicenter review is required to quantitatively assess the factors, including tumor biomarkers that are associated with patient outcome 6).

Case reports

A 54-year-old man presented with change in behaviour, nocturnal enuresis, abnormal limb movement and headache of one week’s duration. The diagnosis of butterfly glioma (glioblastoma multiforme) was made based on imaging characteristics and was further confirmed by biopsy findings. As the corpus callosum is usually resistant to infiltration by tumours, a mass that involves and crosses the corpus callosum is suggestive of an aggressive neoplasm 7).
1)

Watts J, Box G, Galvin A, et al. Magnetic resonance imaging of meningiomas: a pictorial review. Insights Imaging. 2014;5:113–22.
2) , 4)

Burks JD, Bonney PA, Conner AK, Glenn CA, Briggs RG, Battiste JD, McCoy T, O’Donoghue DL, Wu DH, Sughrue ME. A method for safelyresecting anterior butterfly gliomas: the surgical anatomy of the default mode network and the relevance of its preservation. J Neurosurg. 2017 Jun;126(6):1795-1811. doi: 10.3171/2016.5.JNS153006. Epub 2016 Sep 16. PubMed PMID: 27636183.
3)

Agrawal A. Butterfly glioma of the corpus callosum. J Cancer Res Ther. 2009 Jan-Mar;5(1):43-5. PubMed PMID: 19293489.
5)

Chaichana KL, Jusue-Torres I, Lemos AM, Gokaslan A, Cabrera-Aldana EE, Ashary A, Olivi A, Quinones-Hinojosa A. The butterfly effect on glioblastoma: is volumetric extent of resection more effective than biopsy for these tumors? J Neurooncol. 2014 Dec;120(3):625-34. doi: 10.1007/s11060-014-1597-9. Epub 2014 Sep 6. PubMed PMID: 25193022; PubMed Central PMCID: PMC4313925.
6)

Dziurzynski K, Blas-Boria D, Suki D, Cahill DP, Prabhu SS, Puduvalli V, Levine N. Butterfly glioblastomas: a retrospective review and qualitative assessment of outcomes. J Neurooncol. 2012 Sep;109(3):555-63. doi: 10.1007/s11060-012-0926-0. Epub 2012 Jul 18. PubMed PMID: 22806339; PubMed Central PMCID: PMC3992290.
7)

Krishnan V, Lim TC, Ho FC, Peh WC. Clinics in diagnostic imaging (175). Corpus callosum glioblastoma multiforme (GBM): butterfly glioma. Singapore Med J. 2017 Mar;58(3):121-125. doi: 10.11622/smedj.2017017. PubMed PMID: 28361164; PubMed Central PMCID: PMC5360865.

12th European Low Grade Glioma Network

12th European Low Grade Glioma Network

June 1 — June 3

Bilbao, Spain
More Information


09:00 – 09:15
Registration
09:15 – 09:30
Welcome Address & Introduction of the Attendees
Ignacio García-Alonso. Surgery Department. University of the Basque Country
Iñigo Pomposo. Neurosurgery Cruces University Hospital. BioCruces, Bizkaia
Santiago Gil-Robles. Neurosurgery Quirón Madrid. BioCruces, Bizkaia
All the Participants.
09:30 – 10:00
Lecture 1: Anatomy of the insula and peri-insular region.
José Luís Bueno-López. Human Anatomy and Embryology UPV-EHU
10:00 – 10:40
Lecture 2: Brain preparation for fiber dissection and subcortical anatomy review.
Juan Martino. Neurosurgery Valdecilla University Hospital.
10:45 – 11:45
Hands-on 1: Brain cortex removal and brain preparation for fiber dissection.
Juan Martino. Neurosurgery Valdecilla University Hospital
Emmanuel Mandonnet. Neurosurgery Hôspital Lariboisière
Leonor Hennequet. Anatomy UPV-EHU
11:45 – 12:00
Break
12:00 – 12:40
Lecture 3: Overview of the functions of the tracks. Laboratory model to simulate opercular approaches to insular tumors.
Emmanuel Mandonnet. Neurosurgery Hôspital Lariboisière
12:40 – 14:00
Hands-on 2: Dissection of the arcuate fasciculus.
Juan Martino. Neurosurgery Valdecilla University Hospital
Emmanuel Mandonnet. Neurosurgery Hôspital Lariboisière
14:00 – 14:30
Lunch
14:30 – 16:10
Hands-on 3: Dissection of the inferior longitudinal fasciculus, middle longitudinal fasciculus.
Emmanuel Mandonnet. Neurosurgery Hôspital Lariboisière
Juan Martino. Neurosurgery Valdecilla University Hospital
16:10 – 16:20
Break
16:20 – 17:50
Hands-on 4: Dissection of the tracts related to the insula: inferior fronto-occipital fasciculus and uncinate fasciculus.
Juan Martino. Neurosurgery Valdecilla University Hospital
Emmanuel Mandonnet. Neurosurgery Hôspital Lariboisière
17:50 – 18:00
Closing remarks.
All the Participants.
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