Diffuse midline glioma H3 K27M-altered case series

Diffuse midline glioma H3 K27M-altered case series

Forty-one cases of childhood Diffuse midline glioma H3 K27-altered were collected at Children’s Hospital of Fudan University (39 cases) and Xi’an Children’s Hospital (2 cases), from July 2016 to July 2020. The clinical manifestations, imaging data, histopathology, immunohistochemical phenotype and molecular genetics features, tumor size, site and histological grading were evaluated. Among the 41 cases, 21 were males and 20 females, the age of onset was 3-14 years, the average and median age was 7.6 years and 7.0 years, respectively. The tumor sites were brain stem (n=36) and other locations (n=5). The clinical manifestations were dizzinessgait disturbance, and limb weakness, etc. The MRI features were variable. The histology varied from low-grade to high-grade glioma with neuron differentiation. Immunohistochemistry showed that the tumor cells expressed H3K27MGFAP, and Olig2. Genetic study showed that 76% (16/21) of tumors had H3F3A gene mutation, mostly accompanied by TP53 (62%, 13/21) missense mutation; five tumors (24%, 5/21) had HIST1H3B gene mutation, accompanied by missense mutations in ACVR1 and PI3K pathway-related gene PIK3CA (4/5) and PIK3R1 (1/5) mutations. The prognosis was dismal with only one alive and others died. The average and median overall survival time was 7 months and 4 months, respectively. Cox multivariate regression analysis showed that age, tumor location, radiologically maximum tumor diameter, histologic grading, and surgical methods were not significantly associated with overall survival rate (P>0.05). Pediatric diffuse midline gliomas with H3K27 alteration have unique clinicopathological and genetic characteristics. The prognosis is poor. The tumor location and histopathologic grading are not related to prognosis. New specific drugs and comprehensive treatment are needed to improve the prognosis 1).

Piccardo et al., from Genoa, Italy. retrospectively analyzed 22 pediatric patients with DMG histologically proved and molecularly classified as H3K27M-mutant (12 subjects) and wild-type (10 subjects) who underwent DWIProton magnetic resonance spectroscopic imaging, and ASL performed within 2 weeks of 18F-FDOPA PET. DWI-derived relative minimum apparent diffusion coefficient (rADC min), 1H-MRS data choline/N-acetylaspartate (Cho/NAA), choline/creatine (Cho/Cr), and presence of lactate and relative ASL-derived cerebral blood flow max (rCBF max) were compared with 18F-DOPA uptake Tumor/Normal tissue (T/N) and Tumor/Striatum (T/S) ratios, and correlated with histological and molecular features of DMG. Statistics included Pearson’s chi-square and Mann-Whitney U tests, Spearman’s rank correlation and receiver operating characteristic (ROC) analysis.

The highest degrees of correlation among different techniques were found between T/S, rADC min and Cho/NAA ratio (p < 0.01), and between rCBF max and rADC min (p < 0.01). Significant differences between histologically classified low- and high-grade DMG, independently of H3K27M-mutation, were found among all imaging techniques (p ≤ 0.02). Significant differences in terms of rCBF max, rADC min, Cho/NAA and 18F-DOPA uptake were also found between molecularly classified mutant and wild-type DMG (p ≤ 0.02), even though wild-type DMG included low-grade astrocytomas, not present among mutant DMG. When comparing only histologically defined high-grade mutant and wild-type DMG, only the 18F-DOPA PET data T/S demonstrated statistically significant differences independently of histology (p < 0.003). ROC analysis demonstrated that T/S ratio was the best parameter for differentiating mutant from wild-type DMG (AUC 0.94, p < 0.001).

Advanced MRI and 18F-DOPA PET characteristics of DMG depend on histological features; however, 18F-DOPA PET-T/S was the only parameter able to discriminate H3K27M-mutant from wild-type DMG independently of histology 2).

Baseline diffusion or apparent diffusion coefficient (ADC) characteristics have been shown to predict outcome related to DIPG, but the predictive value of post-radiation ADC is less well understood. ADC parametric mapping (FDM) was used to measure radiation-related changes in ADC and compared these metrics to baseline ADC in predicting progression-free survival and overall survival using a large multi-center cohort of DIPG patients (Pediatric Brain Tumor Consortium-PBTC).

MR studies at baseline and post-RT in 95 DIPG patients were obtained and serial quantitative ADC parametric maps were generated from diffusion-weighted imaging based on T2/FLAIR and enhancement regions of interest (ROIs). Metrics assessed included total voxels with: increase in ADC (iADC); decrease in ADC (dADC), no change in ADC (nADC), fraction of voxels with increased ADC (fiADC), fraction of voxels with decreased ADC (fdADC), and the ratio of fiADC and fdADC (fDM Ratio).

A total of 72 patients were included in the final analysis. Tumors with higher fiADC between baseline and the first RT time point showed a trend toward shorter PFS with a hazard ratio of 6.44 (CI 0.79, 52.79, p = 0.083). In contrast, tumors with higher log mean ADC at baseline had longer PFS, with a hazard ratio of 0.27 (CI 0.09, 0.82, p = 0.022). There was no significant association between fDM derived metrics and overall survival.

Baseline ADC values are a stronger predictor of outcome compared to radiation related ADC changes in pediatric DIPG. We show the feasibility of employing parametric mapping techniques in multi-center studies to quantitate spatially heterogeneous treatment response in pediatric tumors, including DIPG 3).

Meyronet et al., from Lyon analyzed the characteristics of 21 adult H3 K27M-mutant gliomas and compared them with those of 135 adult diffuse gliomas without histone H3 and without isocitrate dehydrogenase (IDH) mutation (IDH/H3 wild type).

The median age at diagnosis in H3 K27M-mutant gliomas was 32 years (range: 18-82 y). All tumors had a midline location (spinal cord n = 6, thalamus n = 5, brainstem n = 5, cerebellum n = 3, hypothalamus n = 1, and pineal region n = 1) and were IDH and BRAF-V600E wild type. The identification of an H3 K27M mutation significantly impacted the diagnosis in 3 patients (14%) for whom the histological aspect initially suggested a diffuse low-grade glioma and in 7 patients (33%) for whom pathological analysis hesitated between a diffuse glioma, ganglioglioma, or pilocytic astrocytoma. Compared with IDH/H3 wild-type gliomas, H3 K27M-mutant gliomas were diagnosed at an earlier age (32 vs 64 y, P < .001), always had a midline location (21/21 vs 21/130, P < .001), less frequently had a methylated MGMT promoter (1/21 vs 52/129, P = .002), and lacked EGFR amplification (0/21 vs 26/128, P = .02). The median survival was 19.6 months in H3 K27M-mutant gliomas and 17 months in IDH/H3 wild-type gliomas (P = .3).

In adults, as in children, H3 K27M mutations define a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis 4).

130 cases of DIPG biopsies and previous published data, these procedures appear to have a diagnostic yield and morbidity rates similar to those reported for other brain locations (3.9 % of transient morbidity in our series). In addition, the quality and the quantity of the material obtained allow to (1) confirm the diagnosis, (2) reveal that WHO grading was useless to predict outcome, and (3) perform an extended molecular screen, including biomarkers study and the development of preclinical models. Recent studies reveal that DIPG may comprise more than one biological entity and a unique oncogenesis involving mutations never described in other types of cancers, i.e., histones H3 K27M and activin receptor ACVR1.

Stereotactic biopsies of DIPG can be considered as a safe procedure in well-trained neurosurgical teams and could be incorporated in protocols. It is a unique opportunity to integrate DIPG biopsies in clinical practice and use the biology at diagnosis to drive the introduction of innovative targeted therapies, in combination with radiotherapy 5).

A suboccipital, transcerebellar approach was used to obtain biopsy samples in 24 children.

Two patients suffered deficits. Both had a transient (< 2 months) new cranial nerve palsy; one of these patients also experienced an exacerbation of a preoperative hemiparesis. No patient died during the perioperative period. A histological diagnosis was made in all 24 patients as follows: 22 had a malignant infiltrative astrocytoma, one had a low-grade astrocytoma, and one had a pilocytic astrocytoma. The diagnosis of the latter two patients affected the initial treatment after the biopsy.

The findings of this study imply that stereotactic biopsy sampling of a diffuse pontine tumor is a safe procedure, is associated with minimal morbidity, and has a high diagnostic yield. A nonmalignant tumor was identified in two of the 24 patients in whom the imaging findings were characteristic of a malignant infiltrative astrocytoma. With the advent of new treatment protocols, stereotactic biopsy sampling, which would allow specific tumor characterization of diffuse pontine lesions, may become standard 6).


Li J, Ma YY, Feng J, Zhao D, Ding F, Tian L, Chen R, Zhao R. [Diffuse midline gliomas with H3K27 alteration in children: a clinicopathological analysis of forty-one cases]. Zhonghua Bing Li Xue Za Zhi. 2022 Apr 8;51(4):319-325. Chinese. doi: 10.3760/cma.j.cn112151-20210830-00625. PMID: 35359043.

Piccardo A, Tortora D, Mascelli S, Severino M, Piatelli G, Consales A, Pescetto M, Biassoni V, Schiavello E, Massollo M, Verrico A, Milanaccio C, Garrè ML, Rossi A, Morana G. Advanced MR imaging and (18)F-DOPA PET characteristics of H3K27M-mutant and wild-type pediatric diffuse midline gliomas. Eur J Nucl Med Mol Imaging. 2019 Apr 27. doi: 10.1007/s00259-019-04333-4. [Epub ahead of print] PubMed PMID: 31030232.

Ceschin R, Kocak M, Vajapeyam S, Pollack IF, Onar-Thomas A, Dunkel IJ, Poussaint TY, Panigrahy A. Quantifying radiation therapy response using apparent diffusion coefficient (ADC) parametric mapping of pediatric diffuse intrinsic pontine glioma: a report from the pediatric brain tumor consortium. J Neurooncol. 2019 Feb 27. doi: 10.1007/s11060-019-03133-y. [Epub ahead of print] PubMed PMID: 30810873.

Meyronet D, Esteban-Mader M, Bonnet C, Joly MO, Uro-Coste E, Amiel-Benouaich A, Forest F, Rousselot-Denis C, Burel-Vandenbos F, Bourg V, Guyotat J, Fenouil T, Jouvet A, Honnorat J, Ducray F. Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol. 2017 Aug 1;19(8):1127-1134. doi: 10.1093/neuonc/now274. PubMed PMID: 28201752; PubMed Central PMCID: PMC5570304.

Puget S, Beccaria K, Blauwblomme T, Roujeau T, James S, Grill J, Zerah M, Varlet P, Sainte-Rose C. Biopsy in a series of 130 pediatric diffuse intrinsic Pontine gliomas. Childs Nerv Syst. 2015 Oct;31(10):1773-80. doi: 10.1007/s00381-015-2832-1. Epub 2015 Sep 9. PubMed PMID: 26351229.

Roujeau T, Machado G, Garnett MR, Miquel C, Puget S, Geoerger B, Grill J, Boddaert N, Di Rocco F, Zerah M, Sainte-Rose C. Stereotactic biopsy of diffuse pontine lesions in children. J Neurosurg. 2007 Jul;107(1 Suppl):1-4. PubMed PMID: 17647306.

5-aminolevulinic acid fluorescence guided resection of low-grade glioma

5-aminolevulinic acid fluorescence guided resection of low-grade glioma

Radiologically suspected low-grade gliomas (LGG) represent a special challenge for the neurosurgeon during surgery due to their histopathological heterogeneity and indefinite tumor margin. Therefore, new techniques are required to overcome these current surgical drawbacks. Intraoperative visualization of brain tumors with the assistance of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is one of the major advancements in the neurosurgical field in the last decades. Initially, this technique was exclusively applied for fluorescence-guided surgery of high-grade glioma (HGG). In the last years, the use of 5-ALA was also extended to other indications such as radiologically suspected LGG. Kiesel et al. discussed the current role of 5-ALA for intraoperative visualization of focal malignant transformation within suspected LGG. Furthermore, they discussed the current limitations of the 5-ALA technology in pure LGG which usually cannot be visualized by visible fluorescence. Finally, they introduced new approaches based on fluorescence technology for improved detection of pure LGG tissue such as spectroscopic PpIX quantification fluorescence lifetime imaging of PpIX and confocal microscopy to optimize surgery 1).

A growing body of evidence has revealed the potential utility of 5-aminolevulinic acid (5-ALA) as a surgical adjunct in selected lower-grade gliomas. However, a reliable means of identifying which lower-grade gliomas will fluoresce has not been established.

Widhalm found that 5-ALA induced PpIX fluorescence is capable as a novel intra-operative marker to detect anaplastic foci within initially suspected low-grade gliomas independent of brainshift 2).

A systematic review of PubMedGoogle Scholar, and Cochrane was performed from the date of inception to February 1, 2019. Studies that correlated 5-aminolevulinic acid fluorescence with low-grade glioma in the setting of operative resection were selected. Studies with biopsy only were excluded. Positive fluorescence rates were calculated. The quality index of the selected papers was provided. No patient information was used, so Institutional Review Board approval and patient consent were not required.

A total of 12 articles met the selection criteria with 244 histologically confirmed low-grade glioma patients who underwent microsurgical resection. All patients received 20 mg/kg body weight of 5-aminolevulinic acid. Only 60 patients (n = 60/244; 24.5%) demonstrated visual intraoperative 5-aminolevulinic acid fluorescence. The extent of resection was reported in 4 studies; however, the data combined low- and high-grade tumors. Only 2 studies reported on tumor location. Only 3 studies reported on clinical outcomes. The Zeiss OPMI Pentero microscope was most commonly used across all studies. The average quality index was 14.58 (range: 10-17), which correlated with an overall good quality.

There is an overall low correlation between 5-aminolevulinic acid fluorescence and low-grade glioma. Advances in visualization technology and using standardized fluorescence quantification methods may further improve the visualization and reliability of 5-aminolevulinic acid fluorescence in low-grade glioma resection 3).

Müther et al. investigated a cohort of patients with WHO Grade 2 glioma and WHO Grade 3 gliomas who received 5-ALA before resection at a single institution. Using a logistic regression-based model, they evaluated 14 clinical and molecular variables considered plausible determinants of fluorescence. They then distilled the most predictive features to develop a model for predicting both fluorescence and tumor grade. They also explored the relationship between intraoperative fluorescence and diagnostic molecular markers.

One hundred seventy-nine subjects were eligible for inclusion. Our logistic regression classifier accurately predicted intraoperative fluorescence in our cohort with 91.9% accuracy and revealed enhancement as the singular variable in determining intraoperative fluorescence. There was a direct relationship between enhancement on MRI and the likelihood of observed fluorescence. Observed fluorescence correlated with MIB-1 index but not with isocitrate dehydrogenase (IDH) status, 1p19q codeletion, or methylguanine DNA methyltransferase promoter methylation.

They demonstrated a strong correlation between enhancement on preoperative MRI and the likelihood of visible fluorescence during surgery in patients with intermediate-grade glioma. The analysis provides a robust method for predicting 5-ALA-induced fluorescence in patients with grade II and grade III gliomas 4).

Valdés et al. describe their initial experience with 5-aminolevulinic acid (ALA)-induced PpIX fluorescence in twelve patients with presumed LGGs after receiving 20 mg/kg of ALA approximately 3 hours prior to surgery under an institutional review board-approved protocol.

Intraoperative assessments of the resulting PpIX emissions using both qualitative, visible fluorescence and quantitative measurements of PpIX concentration were obtained from tissue locations that were subsequently biopsied and evaluated histopathologically. Mixed models for random effects and receiver operating characteristic curve analysis for diagnostic performance were performed on the fluorescence data relative to the gold-standard histopathology.

Five of the 12 LGGs (1 ganglioglioma, 1 oligoastrocytoma, 1 pleomorphic xanthoastrocytoma, 1 oligodendroglioma, and 1 ependymoma) demonstrated at least 1 instance of visible fluorescence during surgery. Visible fluorescence evaluated on a specimen-by-specimen basis yielded a diagnostic accuracy of 38.0% (cutoff threshold: visible fluorescence score ≥ 1, area under the curve = 0.514). Quantitative fluorescence yielded a diagnostic accuracy of 67% (for a cutoff threshold of the concentration of PpIX [CPpIX] > 0.0056 μg/ml, area under the curve = 0.66). The authors found that 45% (9/20) of nonvisibly fluorescent tumor specimens, which would have otherwise gone undetected, accumulated diagnostically significant levels of CPpIX that were detected quantitatively.

The authors’ initial experience with ALA-induced PpIX fluorescence in LGGs concurs with other literature reports that the resulting visual fluorescence has poor diagnostic accuracy. However, the authors also found that diagnostically significant levels of CPpIX do accumulate in LGGs, and the resulting fluorescence emissions are very often below the detection threshold of current visual fluorescence imaging methods. Indeed, at least in the authors’ initial experience reported here, if quantitative detection methods are deployed, the diagnostic performance of ALA-induced PpIX fluorescence in LGGs approaches the accuracy associated with visual fluorescence in HGGs 5).


Kiesel B, Freund J, Reichert D, Wadiura L, Erkkilae MT, Woehrer A, Hervey-Jumper S, Berger MS, Widhalm G. 5-ALA in Suspected Low-Grade Gliomas: Current RoleLimitations, and New Approaches. Front Oncol. 2021 Jul 30;11:699301. doi: 10.3389/fonc.2021.699301. PMID: 34395266; PMCID: PMC8362830.

Widhalm G. Intra-operative visualization of brain tumors with 5-aminolevulinic acid-induced fluorescence. Clin Neuropathol. 2014 Jul-Aug;33(4):260-78. PubMed PMID: 24986206.

Almekkawi AK, El Ahmadieh TY, Wu EM, Abunimer AM, Abi-Aad KR, Aoun SG, Plitt AR, El Tecle NE, Patel T, Stummer W, Bendok BR. The Use of 5-Aminolevulinic Acid in Low-Grade Glioma Resection: A Systematic Review. Oper Neurosurg (Hagerstown). 2020 Jul 1;19(1):1-8. doi: 10.1093/ons/opz336. Erratum in: Oper Neurosurg (Hagerstown). 2020 Jul 1;19(1):107. PMID: 31828346.

Müther M, Jaber M, Johnson TD, Orringer DA, Stummer W. A Data-Driven Approach to Predicting 5-Aminolevulinic Acid-Induced Fluorescence and World Health Organization Grade in Newly Diagnosed Diffuse Gliomas. Neurosurgery. 2022 Mar 16. doi: 10.1227/NEU.0000000000001914. Epub ahead of print. PMID: 35285461.

Valdés PA, Jacobs V, Harris BT, Wilson BC, Leblond F, Paulsen KD, Roberts DW. Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin IX biomarker as a surgical adjunct in low-grade glioma surgery. J Neurosurg. 2015 Jul 3:1-10. [Epub ahead of print] PubMed PMID: 26140489.

Fluorescein sodium guided resection of high-grade glioma

Fluorescein sodium guided resection of high-grade glioma

Naik et al. compared 5 aminolevulinic acid fluorescence guided resection of high-grade gliomaFluorescein sodium guided resection of high-grade glioma. (FS), and Intraoperative magnetic resonance imaging-guided resection of high-grade glioma (IMRI) with no image guidance to determine the best intraoperative navigation method to maximize rates of gross total resection (GTR) and outcomes. A frequentist network meta-analysis was performed following standard PRISMA guidelines (PROSPERO registration CRD42021268659). Surface-under-the-cumulative ranking (SUCRA) analysis was executed to hierarchically rank modalities by the outcome of interestHeterogeneity was measured by the I2 statisticPublication bias was assessed by funnel plots and the use of Egger’s test. Statistical significance was determined by p < 0.05. Twenty-three studies were included for analysis with a total of 2,643 patients. Network meta-analysis comparing 5-ALA, IMRI, and FS was performed. The primary outcome assessed was the rate of GTR. Analysis revealed the superiority of all intraoperative navigation to control (no navigation). SUCRA analysis revealed the superiority of IMRI + 5-ALA, IMRI alone, followed by FS, and 5-ALA. Overall survival (OS) and progression-free survival (PFS) were also examined. FS (vs. control) was associated with improved OS, while IMRI was associated with improved PFS (vs. control, FS, and 5-ALA). Intraoperative navigation using IMRI, FS, and 5-ALA lead to greater rates of GTR in HGGs. FS and 5-ALA also yielded improvement in OS and PFS. Further studies are needed to evaluate differences in survival benefit, operative duration, and cost 1).

Fluorescein can be used as a viable alternative to 5-ALA for intraoperative fluorescent guidance in brain tumor surgery. Comparative, prospective, and randomized studies are much needed 2).

5-ALA fluorescence-guided surgery has shortcomings such as drug’s phototoxicity, extortionate price, and not being approved by Food and Drug Administration, which limited its widespread application.

Due to the above limitations, sodium fluorescein guided surgery had been paid more attention by neurosurgeons than 5-ALA. FL is an easily available and biosafe fluorescein dye with a peak excitation at 465 to 490 nm and emission between 500 and 550 nm and has been used extensively and safely for many years especially in ophthalmology 3) 4).

5 aminolevulinic acid is still the preferred and more established fluorescent dye used during high-grade gliomas resection, with Fluorescein sodium gaining-attention, really cheaper and more ductile alternative 5).

The use of fluorescein fluorescence-guided stereotactic needle biopsy has been shown to improve diagnostic accuracy and to expedite operative procedure in the stereotactic needle biopsy of high-grade gliomas.

see Fluoropen.

The first use of fluorescence for brain tumour surgery was in 1948 by G.E. Moore 6) using fluorescein sodium, a strongly fluorescing and non-toxic (apart from rare anaphylaxis 7) compound). In malignant brain tumours with their inherent blood-brain barrier breakdown, fluorescein is extravasated and might serve to mark tumours.

Today, fluorescein sodium is again under scrutiny 8) 9). using a novel filter system by Zeiss (YELLOW 560) for the microscope. This filter visualises fluorescein and allows good background discrimination. Furthermore, fluorescein can be injected any time and is low in cost. Nevertheless, its use in brain tumour surgery is off-label and thus restricted to clinical studies. Little is known about the best timing of i.v. fluorescein application before resection. Injecting fluorescein too early might result in unspecific propagation with oedema, whereas acute injections might be useful for detecting abnormally perfused tumour tissue. Levels in the blood will be high, especially with acute injections, leading to fluorescence of all perfused brain tissue. Such time-resolved in- formation on the specificity of fluorescein are not available.

Overall, Schwake et al observed no clear value of fluorescein in a small study, which they closed prematurely. Clearly, further work elucidating optimal timing and dosing of fluorescein is warranted. 10)

Sodium fluorescein (SF) was first used for the identification of different types of brain tumors in 1948 11).

Since then, the use of SF and others fluorescent tracers have been described in literature particularly that dealing with glioblastoma multiforme resection 12) 13) 14)

Metastatic lesion were also enhanced by SF 15)16).

Also in skull base tumors 17).

“Fluorescein sodium”, the sodium salt of fluorescein, is used extensively as a diagnostic tool in the field of ophthalmology and optometry, where topical fluorescein is used in the diagnosis of corneal abrasions, corneal ulcers and herpetic corneal infections. It is also used in rigid gas permeable contact lens fitting to evaluate the tear layer under the lens. It is available as sterile single-use sachets containing lint-free paper applicators soaked in fluorescein sodium.

Intravenous or oral fluorescein is used in fluorescein angiography in research and to diagnose and categorize vascular disorders including retinal disease macular degeneration, diabetic retinopathy, inflammatory intraocular conditions, and intraocular tumors. It is also being used increasingly during surgery for brain tumors.

Diluted fluorescein dye has been used to localise multiple muscular ventricular septal defects during open heart surgery and confirm the presence of any residual defects.

Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross total resection (GTR) using high doses of fluorescein sodium under white light. The introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore.

Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell rich locations, suggesting that fluorescein is a marker for areas of compromised blood brain barrier within high grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions 18).

Magnetic resonance diffusion tensor imaging (MR-DTI) and fluorescein sodium dyeing guiding for surgery of glioma located in brain motor functional areas can increase the gross total resection rate, decrease the paralysis rate caused by surgery, and improve patient quality of life compared with traditional glioma surgery 19).

Intrathecal fluorescein (ITF) is extremely specific and very sensitive for detecting intraoperative CSF leaks. Although false negatives can occur, these patients do not appear to be at risk for postoperative CSF leak. The use of ITF may help surgeons prevent postoperative CSF leaks by intraoperatively detecting and confirming a watertight repair 20).


Naik A, Smith EJ, Barreau A, Nyaeme M, Cramer SW, Najafali D, Krist DT, Arnold PM, Hassaneen W. Comparison of fluorescein sodium, 5-ALA, and intraoperative MRI for resection of high-grade gliomas: A systematic review and network meta-analysis. J Clin Neurosci. 2022 Feb 22;98:240-247. doi: 10.1016/j.jocn.2022.02.028. Epub ahead of print. PMID: 35219089.

Hansen RW, Pedersen CB, Halle B, Korshoej AR, Schulz MK, Kristensen BW, Poulsen FR. Comparison of 5-aminolevulinic acid and sodium fluorescein for intraoperative tumor visualization in patients with high-grade gliomas: a single-center retrospective study. J Neurosurg. 2019 Oct 4:1-8. doi: 10.3171/2019.6.JNS191531. [Epub ahead of print] PubMed PMID: 31585425.

Novotny H. R., Alvis D. L. A method of photographing fluorescence in circulating blood in the human retina. Circulation. 1961;24:82–86. doi: 10.1161/01.cir.24.1.82.

Kwan A. S. L., Barry C., McAllister I. L., Constable I. Fluorescein angiography and adverse drug reactions revisited: the Lions Eye experience. Clinical and Experimental Ophthalmology. 2006;34(1):33–38. doi: 10.1111/j.1442-9071.2006.01136.x.

Acerbi F, Restelli F, De Laurentis C, Falco J, Cavallo C, Broggi M, Höhne J, Schebesch KM, Schiariti M, Ferroli P. Fluorescent tracers in neurosurgical procedures: an European survey. J Neurosurg Sci. 2018 Jul 17. doi: 10.23736/S0390-5616.18.04494-6. [Epub ahead of print] PubMed PMID: 30014688.

Moore GE, Peyton WT, French LA, Walker WW (1948) The clinical use of fluorescein in neurosurgery; the localization of brain tumors. J Neurosurg 5:392–398

Dilek O, Ihsan A, Tulay H (2011) Anaphylactic reaction after fluo- rescein sodium administration during intracranial surgery. J Clin Neurosci 18:430–431

Acerbi F, Broggi M, Eoli M, Anghileri E, Cuppini L, Pollo B, Schiariti M, Visintini S, Ori C, Franzini A, Broggi G, Ferroli P (2013) Fluorescein-guided surgery for grade IV gli- omas with a dedicated filter on the surgical microscope: pre- liminary results in 12 cases. Acta Neurochir (Wien) 155: 1277–1286

Schebesch KM, Proescholdt M, Höhne J, Hohenberger C, Hansen E, Reimenschneider MJ, Ullrich W, Doenitz C, Schlair J, Lange M, Brawanski A (2013) Sodium fluorescein-guided resection under the YELLOW 560 nm surgical microscope filter in malignant brain tumor surgery—a feasibility study. Acta Neurochir (Wien) 155:693–699

Schwake M, Stummer W, Suero Molina EJ, Wölfer J. Simultaneous fluorescein sodium and 5-ALA in fluorescence-guided glioma surgery. Acta Neurochir (Wien). 2015 May;157(5):877-9. doi: 10.1007/s00701-015-2401-0. Epub 2015 Mar 28. PubMed PMID: 25820632.
11) , 15)

Moore GE, Peyton WT, French LA, Walker WW. The clinical use of fluorescein in neurosurgery. J Neurosurg. 1948;5:392–8.

Chae MP, Song SW, Park SH, Park CK. Experience with 5- aminolevulinic Acid in fluorescence-guided resection of a deep sylvian meningioma. J Korean Neurosurg Soc. 2012;52:558–60.

Kuroiwa T, Kajimoto Y, Ohta T. Development of a fluorescein operative microscope for use during malignant glioma surgery: A technical note and preliminary report. Surg Neurol. 1998;50:41–9.

Kuroiwa T, Kajimoto Y, Ohta T. Comparison between operative findings on malignant glioma by a fluorescein surgical microscopy and histological findings. Neurol Res. 1999;21:130–4.

Okuda T, Kataoka K, Taneda M. Metastatic brain tumor surgery using fluorescein sodium: Technical note. Minim Invasive Neurosurg. 2007;50:382–4.

da Silva CE, da Silva JL, da Silva VD. Use of sodium fluorescein in skull base tumors. Surg Neurol Int. 2010;1:70.

Diaz RJ, Dios RR, Hattab EM, Burrell K, Rakopoulos P, Sabha N, Hawkins C, Zadeh G, Rutka JT, Cohen-Gadol AA. Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance. J Neurosurg. 2015 Jun;122(6):1360-9. doi: 10.3171/2015.2.JNS132507. Epub 2015 Apr 3. PubMed PMID: 25839919.

Liu JG, Yang SF, Liu YH, Wang X, Mao Q. Magnetic resonance diffusion tensor imaging with fluorescein sodium dyeing for surgery of gliomas in brain motor functional areas. Chin Med J (Engl). 2013 Jul;126(13):2418-23. PubMed PMID: 23823811.

Raza SM, Banu MA, Donaldson A, Patel KS, Anand VK, Schwartz TH. Sensitivity and specificity of intrathecal fluorescein and white light excitation for detecting intraoperative cerebrospinal fluid leak in endoscopic skull base surgery: a prospective study. J Neurosurg. 2016 Mar;124(3):621-6. doi: 10.3171/2014.12.JNS14995. Epub 2015 Aug 21. PubMed PMID: 26295912.
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