Histological Examination of False Positive Tissue Resection Using 5-Aminolevulinic Acid-Induced Fluorescence Guidance

Utsuki, Satoshi; Oka, Hiroyuki; Sato, Sumito; Shimizu, Satoru; Suzuki, Sachio; Tanizaki, Yoshinori; Kawasaki, Koji; Miyajima, Yoshiteru; Fujii, Kiyotaka

doi:10.2176/nmc.47.210

Cited by 120 publications

(100 citation statements)

References 15 publications

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“…11,30 Interestingly, there was 1 biopsy among our study cohort that demonstrated ALA fluorescence in the presence of completely normal brain tissue. While additional samples are needed to support this finding, this may suggest that even in the absence of tumor, surrounding brain may take up ALA and fluoresce.…”

Section: Discussionmentioning

confidence: 87%

“…This finding is similar to a prior study, which showed that approximately 17% of GBM samples with ALA fluorescence showed no tumor cells but contained areas of peritumoral edema, inflammatory cells, and reactive astrocyte infiltration. 30 It is also suggested that inflammatory cells such as macrophages may be able to accumulate and convert ALA to its associated fluorescent porphyrins.…”

Section: Discussionmentioning

confidence: 99%

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A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

Lau

Hervey-Jumper

Chang

et al. 2016

JNS

139

110

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OBJECT There is evidence that 5-aminolevulinic acid (ALA) facilitates greater extent of resection and improves 6-month progression-free survival in patients with high-grade gliomas. But there remains a paucity of studies that have examined whether the intensity of ALA fluorescence correlates with tumor cellularity. Therefore, a Phase II clinical trial was undertaken to examine the correlation of intensity of ALA fluorescence with the degree of tumor cellularity. METHODS 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 (r) 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%. CONCLUSIONS 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 fluorescence.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

Lau

Hervey-Jumper

Chang

et al. 2016

JNS

139

110

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“…Based on our experience, PpIX fluorescence is observed even when there are no tumor cells, for example, in cases with brain abscess, multiple sclerosis, or remarkable infiltration of reactive astrocytes and macrophages in relapsed tumors Utsuki et al, 2007b). PpIX fluorescence is observed even in cases of radiation necrosis without tumor recurrence or a metastatic brain tumor's edema field (Utsuki et al, 2007a).…”

Section: Psudopositive Fluorescencementioning

confidence: 96%

Intraoperative Photodynamic Diagnosis of Brain Tumors Using 5-Aminolevulinic Acid

Utsuki¹,

Oka²,

Fujii³

2011

Diagnostic Techniques and Surgical Management of Brain Tumors

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Diagnostic Techniques and Surgical Management of Brain Tumors 228 2. 5-ALA metabolic pathway 2.1 5-ALA metabolism in normal cells 5-ALA is a substance that naturally exists in the body. In the first stage, 5-Ala is produced via the condensation of glycine and succinyl-CoA by ALA synthetase (ALAS) in the mitochondria. This process receives negative feedback from heme, which is the endproduct. 5-ALA is actively transported via cytoplasm. In the next step, porphobilinogen (PBG) is created from ALA via ALA dehydratase. The actions of PBG deaminase (PBGD) and uroporphyrinogen III synthase compress 4 PBG molecules, effectively cyclizing a tetrapyrrole chain and producing uroporphyrinogen III. Uroporphyrinogen III is converted by uroporphyrinogen decarboxylase into coproporphyrinogen III, which is exposed to coproporphyrinogen oxidase in the mitochondrial intermembrane space. Decarboxylation and oxidation of the propionic side chains of the vinyl groups' rings A and B ultimately form protoporphyrinogen IX in the cell nucleus. PpIX is synthesized from protoporphyrinogen IX via protoporphyrinogen oxidase activity, and heme is synthesized via the uptake of iron into the tetrapyrrole structure by ferrochelatase in the mitochondrial membrane ( Fig.

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“…These phase III clinical trials have shown that the use of 5-ALA in surgery produces reliable results. This surgical method is more convenient for tumor resection and enables better resection of the tumor boundary, which improves survival rate [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Review of Neurosurgical Fluorescence Imaging Systems for Clinical Application

Kim

Lee

Yoo

et al. 2016

Journal of the Optical Society of Korea

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A number of fluorescence imaging techniques for use in the surgical removal of glioma have been developed over the course of the long history of neurosurgery. Various biomarkers, biochemical agents, and detection systems for glioma have also been developed. This review focuses on 5-aminolevulinic acid (5-ALA), which is used to detect glioma. Numerous forms of fluorescence-guided surgery use 5-ALA, which is helpful to the surgeon. The surgical microscope system is the observational method generally used with 5-ALA, while the loupe, endoscope, and exoscope are simpler alternatives. A system is needed for minimal resection and other issues that arise during neurosurgery. Such an enhanced system should be able to detect low-grade tumors and provide information on microinvasive diseases, resulting in an improved survival rate and better surgical skills. Development of systems that fulfill certain needs would help protect the brain function of the patient and broaden the use of such systems in neurosurgery.

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Histological Examination of False Positive Tissue Resection Using 5-Aminolevulinic Acid-Induced Fluorescence Guidance

Cited by 120 publications

References 15 publications

A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

Intraoperative Photodynamic Diagnosis of Brain Tumors Using 5-Aminolevulinic Acid

Review of Neurosurgical Fluorescence Imaging Systems for Clinical Application

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