Combining 5-Aminolevulinic Acid Fluorescence and Intraoperative Magnetic Resonance Imaging in Glioblastoma Surgery

Hauser, S.; Kockro, Ralf A.; Actor, Bertrand; Sarnthein, Johannes; Bernays, René-Ludwig

doi:10.1227/neu.0000000000001035

Cited by 66 publications

(48 citation statements)

References 33 publications

(40 reference statements)

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“…34 Newer studies have demonstrated 5-ALA FGS combined with intraoperative MRI may be beneficial in maximizing resection of GBM. 35,36 This combination presents a potential solution to the problem encountered with 5-ALA in that not all GBM tissue uniformly exhibits 5-ALA fluorescence. 36 …”

Section: Discussionmentioning

confidence: 99%

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Oncologic Procedures Amenable to Fluorescence-guided Surgery

et al. 2017

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Objective: Although fluorescence imaging is being applied to a wide range of cancers, it remains unclear which disease populations will benefit greatest. Therefore, we review the potential of this technology to improve outcomes in surgical oncology with attention to the various surgical procedures while exploring trial endpoints that may be optimal for each tumor type. Background: For many tumors, primary treatment is surgical resection with negative margins, which corresponds to improved survival and a reduction in subsequent adjuvant therapies. Despite unfavorable effect on patient outcomes, margin positivity rate has not changed significantly over the years. Thus, patients often experience high rates of re-excision, radical resections, and overtreatment. However, fluorescence-guided surgery (FGS) has brought forth new light by allowing detection of subclinical disease not readily visible with the naked eye. Methods: We performed a systematic review of clinicatrials.gov using search terms ‘‘fluorescence,’’ ‘‘image-guided surgery,’’ and ‘‘near-infrared imaging’’ to identify trials utilizing FGS for those received on or before May 2016. Inclusion criteria: fluorescence surgery for tumor debulking, wide local excision, whole-organ resection, and peritoneal metastases. Exclusion criteria: fluorescence in situ hybridization, fluorescence imaging for lymph node mapping, nonmalignant lesions, nonsurgical purposes, or image guidance without fluorescence. Results: Initial search produced 844 entries, which was narrowed down to 68 trials. Review of literature and clinical trials identified 3 primary resection methods for utilizing FGS: (1) debulking, (2) wide local excision, and (3) whole organ excision. Conclusions: The use of FGS as a surgical guide enhancement has the potential to improve survival and quality of life outcomes for patients. And, as the number of clinical trials rise each year, it is apparent that FGS has great potential for a broad range of clinical applications.

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Section: Discussionmentioning

confidence: 99%

“…35,36 This combination presents a potential solution to the problem encountered with 5-ALA in that not all GBM tissue uniformly exhibits 5-ALA fluorescence. 36 …”

Section: Discussionmentioning

confidence: 99%

Oncologic Procedures Amenable to Fluorescence-guided Surgery

et al. 2017

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“…5-ALAaided surgery has been established as an efficient tool to increase the accuracy and extent of resection of high-grade tumors and thus is part of the standard procedure during tumor removal [9]. 5-ALA induced fluorescence may vary upon many factors such as cell density, proliferation index, mitochondrial mass and, furthermore, exogenous factors such as application or fading during surgery [10,23]. Moreover, Jaber et al have recently shown in patients harboring gliomas, that there is a strong correlation between tumor volume, contrast enhancement, age and 18F-fluoroethyl tyrosine positron emission tomography uptake ratio, which is predictive of the fluorescence of different grade gliomas after 5-ALA administration [32].…”

Section: Discussionmentioning

confidence: 99%

“…5-ALA is resorbed through the upper intestine into the blood, where it diffuses through the blood-brain barrier, which has been typically disrupted by infiltrative tumor cells [5][6][7][8][9]. During fluorescence assisted tumor resection a variance of the fluorescence intensity within GBM can be observed, especially at the infiltrating zone [4,8,10]. 5-ALA induced fluorescence may vary upon many factors such as cell density, proliferation index, mitochondrial mass and index and furthermore exogenous factors such as application or fading during surgery [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Epithelial Growth Factor Receptor Expression influences 5-ALA Induced Glioblastoma Fluorescence

Reinert¹,

Fontana²

2017

Journal of Neurological Surgery Part A: Central European Neurosurgery

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overexpression) compared to BS153 (EGFR overexpression/EGFRvIII+). Treatment of U87MG and LN229EGFR cells with EGF significantly reduced cellular fluorescence, by promoting HO-1 transcription and expression in a concentration-dependent manner. This effect could be reversed by EGFR-specific siRNA treatment, which reduced protein expression of about 80% in U87MG. Remarkably, inhibition of HO-1 activity by SnPP or reduction of HO-1 protein levels by siHO-1 treatment restored fluorescence in all cell lines, independently of EGFR quantitative and qualitative expression. Gefitinib treatment was able to restore fluorescence after EGF stimulation in U87MG cells but not in BS153 cells, overexpressing EGFR/EGFRvIII. In GBM cell lines, 5-ALA induced fluorescence is variable and influenced by EGF-induced downstream activation of HO-1. HO-1 protein expression was identified as a negative regulator of 5-ALA induced fluorescence in GBM cells. We further propose that co-expression of EGFRvIII but not quantitative EGFR expression influence HO-1 activity and therefore cellular fluorescence.

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“…New trials explore chemotherapy based on the dissection of the genomic landscape of GBM, chemotherapy active in other cancers that share signaling pathways active in GBM, new delivery methods to cover unresectable tumors, such as the Diffuse Intrinsic Pontine Glioma, an inoperable and very serious glioma in children (Buczkowicz, Bartels, Bouffet, Becher, & Hawkins, 2014; Buczkowicz & Hawkins, 2015; Grimm & Chamberlain, 2013; Jansen, van Vuurden, Vandertop, & Kaspers, 2012), anti-angiogenic agents (i.e., antagonists of VEGF) (Chinot et al, 2014; Fine, 2014; Gilbert et al, 2014; Gilbert, Sulman, & Mehta, 2014), the testing of novel surgical techniques to increase tumor resection with the aid of new imaging technologies (e.g., MRI (Bohman et al, 2010; Kubben et al, 2011), 5-Aminolevulinic acid (5-ALA (Hauser, Kockro, Actor, Sarnthein, & Bernays, 2015; Jaber et al, 2015; Lau et al, 2015)), Raman spectroscopy (Ji et al, 2013), as well as immunization (e.g., dendritic cells primed with unknown or known tumor antigens; with TLR agonists; with heat shock proteins) (Batich, Swartz, & Sampson, 2015; Finocchiaro & Pellegatta, 2014; Reardon et al, 2013; See et al, 2011; Weiss, Weller, & Roth, 2015). In summary, GBM remains one of the most lethal cancers, and the search for effective treatments needs to carry on.…”

Section: Towards Gene Therapy For Brain Tumors: Re-engineering the Brmentioning

confidence: 99%

The Long and Winding Road

Löwenstein

Castro

2016

Neuropsychopharmacology: A Tribute to Joseph T. Coyle

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Malignant brain tumors are one of the most lethal cancers. They originate from glial cells and invade throughout the brain. Current standard of care involves surgical resection, radiotherapy and chemotherapy, and median survival is currently ~14–20 months post-diagnosis. Glioma tumors are highly infiltrative. Given that the brain immune system is deficient in priming systemic immune responses to glioma antigens present within the brain, we proposed to reconstitute the brain immune system to achieve immunological priming from within the brain. Two adenoviral vectors are injected into the resection cavity or remaining tumor. One adenoviral vector expresses the HSV-1 derived thymidine kinase which converts ganciclovir into a compound only cytotoxic to dividing glioma cells. The second adenovirus expresses the cytokine fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L differentiates precursors into dendritic cells and acts as a chemokine for dendritic cells. HSV-1/ganciclovir killing of tumor cells releases tumor antigens that are taken up by dendritic cells within the brain tumor microenvironment. Tumor killing also releases HMGB1, a TLR2 agonist that activates dendritic cells. HMGB1 activated dendritic cells, loaded with glioma antigens, migrate to cervical lymph nodes to stimulate a systemic CD8+ T cells cytotoxic immune response against glioma. This immune response is specific to glioma tumors, induces immunological memory, and does neither cause brain toxicity nor autoimmune responses. An IND was granted by the FDA on 4/7/2011. A Phase I, first in person, to test whether re-engineering the brain immune system is potentially therapeutic is ongoing.

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Combining 5-Aminolevulinic Acid Fluorescence and Intraoperative Magnetic Resonance Imaging in Glioblastoma Surgery

Cited by 66 publications

References 33 publications

Oncologic Procedures Amenable to Fluorescence-guided Surgery

Oncologic Procedures Amenable to Fluorescence-guided Surgery

Epithelial Growth Factor Receptor Expression influences 5-ALA Induced Glioblastoma Fluorescence

The Long and Winding Road

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