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.

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.
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