In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid

Stummer, Walter; Stöcker, Susanne; Novotny, Alexander; Heimann, Axel; Sauer, Oliver; Kempski, Oliver; Plesnila, Nikolaus; Wietzorrek, Joachim; Reulen, H. J.

doi:10.1016/s1011-1344(98)00176-6

Cited by 223 publications

(164 citation statements)

References 38 publications

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“…ALA has been described to be selectively taken up by glioma cells. 25,27,28 However, the findings from this study suggest that ALA fluorescence does not have perfect correlation with tumor cell identification. 20 In samples in which no fluorescence was detected, more than half (62.3%) of those samples had tumor cells present on his- tology.…”

Section: Discussionmentioning

confidence: 67%

“…19 This is very different than the use of fluorescein, which travels through the plasma and reaches the tumor through the disrupted blood-brain barrier. 23 ALA has been shown in experimental and clinical studies to be taken up by malignant glioma cells, where it is converted into fluorescing porphyrins, 25,27,28 and has been described as an aid to enhance glioma resection. 26 ALA is a well-tolerated agent and associated with low rates of adverse events; the most common being abnormal results in liver function test (LFT), transient hypotension, and photosensitivity causing a mild rash.…”

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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

132

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: 67%

mentioning

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

132

110

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“…After metabolization into the fluorescent molecule protoporphyrin IX (PpIX) strong fluorescence could be detected in malignant gliomas after illumination with violet-blue excitation light. In these tumors, the hydrophilic 5-ALA is able to pass the disrupted blood-brain barrier (BBB) with an abnormal accumulation in the mitochondria and a tumor-specific porphyrin fluorescence [27,28]. Several additional mechanisms of PpIX accumulation in malignant glioma cells like reduced activity of ferrochelatase or decreased outflow of PpIX from the cells are reported [8,19].…”

Section: Discussionmentioning

confidence: 99%

The impact of fluorescence guidance on spinal intradural tumour surgery

Eicker

Floeth²,

Kamp

et al. 2013

Eur Spine J

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Purpose 5-Aminolevulinic acid (5-ALA)-based fluorescence-guided surgery was shown to be beneficial for cerebral malignant gliomas. Extension of this technique for resection of meningiomas and cerebral metastasis has been recently evaluated. Aim of the present study is to evaluate the impact of fluorescence-guided surgery in spinal tumor surgery. Methods Twenty-six patients with intradural spinal tumors were included in the study. 5-ALA was administered orally prior to the induction of anesthesia. Intraoperative, 440 nm fluorescence was applied after exploration of the tumor and, if positive, periodically during and at the end of resection to detect tumor-infiltrated sites. Results Tumors of WHO grade III and IV were found in five patients. In detail intra-or perimedullary metastasis of malignant cerebral gliomas was found including glioblastoma WHO grade IV (n = 2), anaplastic astrocytoma WHO grade III (n = 1), anaplastic oligoastrocytoma WHO grade III (n = 1). In addition, one patient suffered from a spinal drop metastasis of a cerebellar medulloblastoma WHO grade IV. Tumors of WHO grade I were diagnosed in 18 patients: Eight cases of meningioma (two recurrences), six cases of neurinoma, one neurofibroma, two ependymoma and one plexus papilloma. At least, benign pathologies were histologically proven in three patients. All four spinal metastasis of malignant glioma (100 %), seven of eight meningiomas (87.5 %) and one of two ependymoma (50 %) were found to be ALA-positive. Conclusion The present study demonstrates that spinal intramedullary gliomas and the majority of spinal intradural meningiomas are 5-ALA positive. As a surgical consequence, especially in intramedullary gliomas, the use of 5-ALA fluorescence seems to be beneficial.

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“…In particular, the utilization of 5-aminolevulinic acid (5-ALA), a natural biochemical precursor of hemoglobin that evokes synthesis and accumulation of fluorescent porphyrins in some kinds of tumors, including gliomas, has been shown to be useful during surgical removal of HGGs, 22,24,25 and it has been shown to increase the rates of complete resection and 6-month PFS in a randomized trial. 23 However, some limitations were found with this technique: the drug should be administered orally 2.5 to 3.5 hours before induction of anesthesia; it is recommended not to expose the patient to sunlight or strong room light for 24 hours after administration because of the risk of skin sensitization; 29 and 5-ALA is expensive (approximately 900 Euros per vial).…”

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confidence: 99%

Is fluorescein-guided technique able to help in resection of high-grade gliomas?

Acerbi¹,

Broggi²,

Eoli

et al. 2014

FOC

146

114

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Object Fluorescein, a dye that is widely used as a fluorescent tracer, accumulates in cerebral areas where the blood-brain barrier is damaged. This quality makes it an ideal dye for the intraoperative visualization of high-grade gliomas (HGGs). The authors report their experience with a new fluorescein-guided technique for the resection of HGGs using a dedicated filter on the surgical microscope. Methods The authors initiated a prospective Phase II trial (FLUOGLIO) in September 2011 with the objective of evaluating the safety of fluorescein-guided surgery for HGGs and obtaining preliminary evidence regarding its efficacy for this purpose. To be eligible for participation in the study, a patient had to have suspected HGG amenable to complete resection of the contrast-enhancing area. The present report is based on the analysis of the short- and long-term results in 20 consecutive patients with HGGs (age range 45–74 years), enrolled in the study since September 2011. In all cases fluorescein (5–10 mg/kg) was injected intravenously after intubation. Tumor resection was performed with microsurgical technique and fluorescence visualization by means of BLUE 400 or YELLOW 560 filters on a Pentero microscope. Results The median preoperative tumor volume was 30.3 cm3 (range 2.4–87.8 cm3). There were no adverse reactions related to fluorescein administration. Complete removal of contrast-enhanced tumor was achieved in 80% of the patients. The median duration of follow-up was 10 months. The 6-months progression-free survival rate was 71.4% and the median survival was 11 months. Conclusions Analysis of these 20 cases suggested that fluorescein-guided technique with a dedicated filter on the surgical microscope is safe and allows a high rate of complete resection of contrast-enhanced tumor as determined on early postoperative MRI. Clinical trial registration no.: 2011-002527-18 (EudraCT).

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In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid

Cited by 223 publications

References 38 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

The impact of fluorescence guidance on spinal intradural tumour surgery

Is fluorescein-guided technique able to help in resection of high-grade gliomas?

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