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Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas
摘要： Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) has become the main treatment modality in malignant gliomas. However unlike glioblastomas, there are inconsistent result about fluorescence status in WHO grade III gliomas. Here, we show that mutational status of IDH1 is linked to 5-ALA fluorescence. Using genetically engineered malignant glioma cells harboring wild type (U87MG-IDH1WT) or mutant (U87MG-IDH1R132H) IDH1, we demonstrated a lag in 5-ALA metabolism and accumulation of protoporphyrin IX (PpIX) in U87MG-IDH1R132H cells. Next, we used liquid chromatography–mass spectrometry (LC-MS) to screen for tricarboxylic acid (TCA) cycle-related metabolite changes caused by 5-ALA exposure. We observed low baseline levels of NADPH, an essential cofactor for the rate-limiting step of heme degradation, in U87MG-IDH1R132H cells. High levels of NADPH are required to metabolize excessive 5-ALA, giving a plausible reason for the temporarily enhanced 5-ALA fluorescence in mutant IDH1 cells. This hypothesis was supported by the results of metabolic screening in human malignant glioma samples. In conclusion, we have discovered a relationship between enhanced 5-ALA fluorescence and IDH1 mutations in WHO grade III gliomas. Low levels of NADPH in tumors with mutated IDH1 is responsible for the enhanced fluorescence.
关键词： 5-ALA,glioma,oncology,fluorescence,brain tumors,IDH1,NADPH
更新于2025-09-23 15:22:29
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Regression Analysis of Protoporphyrin IX Measurements Obtained During Dermatological Photodynamic Therapy
摘要： Photodynamic therapy (PDT) is a light activated drug therapy that can be used to treat a number of dermatological cancers and precancers. Improvement of efficacy is required to widen its application. Clinical protoporphyrin IX (PpIX) fluorescence data were obtained using a pre-validated, non-invasive imaging system during routine methyl aminolevulinate (MAL)-PDT treatment of 172 patients with licensed dermatological indications (37.2% actinic keratosis, 27.3% superficial basal cell carcinoma and 35.5% Bowen’s disease). Linear and logistic regressions were employed to model any relationships between variables that may have affected PpIX accumulation and/or PpIX photobleaching during irradiation and thus clinical outcome at three months. Patient age was found to be associated with lower PpIX accumulation/photobleaching, however only a reduction in PpIX photobleaching appeared to consistently adversely affect treatment efficacy. Clinical clearance was reduced in lesions located on the limbs, hands and feet with lower PpIX accumulation and subsequent photobleaching adversely affecting the outcome achieved. If air cooling pain relief was employed during light irradiation, PpIX photobleaching was lower and this resulted in an approximate three-fold reduction in the likelihood of achieving clinical clearance. PpIX photobleaching during the first treatment was concluded to be an excellent predictor of clinical outcome across all lesion types.
关键词： photobleaching,aminolevulinic acid (ALA; Ameluz),dermatology,protoporphyrin IX (PpIX),imaging,methyl aminolevulinate (MAL; Metvix),photodynamic therapy (PDT),fluorescence,non-melanoma skin cancer (NMSC)
更新于2025-09-23 15:22:29
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Fluorescence guided surgery by 5-ALA and intraoperative MRI in high grade glioma: a systematic review
摘要： Purpose Fluorescence guided surgery by 5-aminolevulinic acid (5-ALA) and intraoperative MRI (iMRI) are currently the most important intraoperative imaging techniques in high grade glioma (HGG) surgery. Few comparative studies exist for these techniques. This review aims to systematically compare 5-ALA and iMRI assisted surgery based on the current literature and discuss the potential impact of a combined use of both techniques. Methods A systematic literature search based on preferred reporting items for systematic reviews and meta-analysis was performed concerning accuracy of tumor detection; extent of resection; neurological deficits (ND); Quality of life (QoL); usability and combined use of both techniques. Original clinical articles on HGG published until March 31st were screened. Results 169 publications were screened, 81 were eligible and 22 were finally included in the review using. Overall, there is evidence that both imaging techniques improve gross total resection rate in non-eloquent lesions. Imaging results do not correlate at the border zone of a HGG. 5-ALA and contrast-enhanced iMRI seem to have a supplementary effect in tumor detection. Overall, both imaging techniques alone or combined do not seem to increase rate of permanent ND or decrease QoL in HGG surgery when used with intraoperative monitoring/mapping. Conclusion Based on the currently available literature no superiority of one technique over the other can be found in the most important outcome parameters. Based on the available information a combined use of 5-ALA and iMRI seems very promising to achieve a resection beyond gadolinium-enhancement. However, only low quality of evidence exists for this approach.
关键词： PRISMA,5-ALA,Neurological deficit,Extent of resection,Quality of life,Usability,iMRI
更新于2025-09-23 15:21:21
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Combined Fluorescence Using 5-Aminolevulinic Acid and Fluorescein Sodium at Glioblastoma Border: Intraoperative Findings and Histopathologic Data About 3 Newly Diagnosed Consecutive Cases
摘要： Fluorescence-guided glioblastoma surgery is an intraoperative technique developed in recent years. Two main compounds have been used so far: 5-amilovelulinic acid (5-ALA) and fluorescein sodium (Fl-Na). Despite a large amount of literature on both techniques, few data are available on the use of both compounds in the same patient. Three consecutive patients affected by a newly diagnosed glioblastoma underwent surgical resection using both 5-ALA and Fl-Na. 5-ALA was orally administered 3 hours before induction of anesthesia at a dosage of 20 mg/kg, whereas fluorescein was intravenously administered at induction of anesthesia at a dosage of 4 mg/kg. Tumor resection was carried out combining these fluorophores. At tumor borders, multiple samples were collected, and fluorescent pattern of each sample was registered. Samples were then analyzed by a neuropathologist blinded for intraoperative fluorescence findings. Eighteen samples were analyzed. At tumor margin, bright pink fluorescence was highly indicative of residual tumor (positive predictive value [PPV], 94%), and it was superior to faint pink and fluorescein (PPVs, 89% and 87%, respectively). The gradual reduction of pink fluorescence warned of the risk of gradually entering healthy tissue (specificity of 67% compared with 33% with fluorescein). Using 5-ALA, detecting no fluorescence was highly suggestive of healthy tissue (negative predictive value of 100% compared with 50% with fluorescence). In our experience with 3 patients, the 2 techniques presented different advantages and limitations in specific steps of tumor resection, showing complementary properties. Larger studies are mandatory to investigate the synergistic use of both techniques.
关键词： Tumor border,5-ALA,Fluorescein,Glioblastoma
更新于2025-09-23 15:21:21
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Fluorescence-Guided Neurosurgery (Neuro-oncology and Cerebrovascular Applications) || 1 Current Fluorescence-Guided Neurosurgery and Moving Forward
摘要： This introductory chapter provides a current overview of fluorescence-guided neurosurgery and includes future directions. The concepts of fluorescence and fluorescence-guided surgery (FGS) are introduced. Currently used fluorescent contrast agents in patients are summarized, including 5-aminolevulinic acid (5-ALA), fluorescein, and indocyanine green. Excitation light sources are discussed for each fluorescent contrast agent. Targeted fluorophores under clinical development for FGS are also introduced. Future directions in fluorescence-guided neurosurgery including handheld devices to better detect tumor fluorescence, dual fluorophore imaging, metabolic imaging in combination with FGS, and detection of the tumor margin will be discussed.
关键词： near-infrared imaging,fluorophore,indocyanine green,fluorescence-guided neurosurgery,fluorescence,operative microscope,fluorescence-guided surgery,fluorescein sodium,5-ALA
更新于2025-09-19 17:15:36
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Advanced Application of Holmium: YAG Laser Combined ALA-PDT for the Treatment of Refractory Condylomata Acuminata in Anal Canal
摘要： Background: Anal canal condylomata acuminata is a disease caused by the human papilloma virus. Conventional cauterizing laser treatment cannot achieve a satisfactory result owing to a high recurrence rate, and the application of 5-aminolaevulinic acid-photodynamic therapy (ALA-PDT) also has limitations in the anal canal. Holmium yttrium aluminum garnet (Ho: YAG) laser with fiber is found to be effective at removing canal lesions, and may create suitable conditions for ALA-PDT. We aim to investigate the feasibility of Ho: YAG laser combined with ALA-PDT and to explore a more optimal therapy in refractory anal canal condylomata. Methods: Data of 37 patients with anal canal condylomata (number of warts≥ 10 lesions) from May 2017 to March 2019 were reviewed. In total 17 cases were treated with Ho: YAG laser plus ALA-PDT, and 20 patients treated with CO2 laser plus ALA-PDT were selected as control. Wart clearance and recurrence rates were evaluated as well as laser complications. Results: Most warts (88.23 %) were removed after a session of Ho: YAG laser pretreatment. The average number of laser sessions required to clear all warts was 1.94 in the Ho: YAG laser plus ALA-PDT group. Meanwhile, no wound infections or defecation disfunctions were found. Ho: YAG laser with ALA-PDT could significantly reduce wart recurrence rates (17.6 %) in comparison with CO2 laser with ALA-PDT (55 %). Conclusions: Ho: YAG laser combined with ALA-PDT raised the cure rate of refractory anal canal condylomata and has important guidance implications for clinical application.
关键词： Anal canal,ALA-PDT,Condylomata acuminata,Holmium: YAG laser
更新于2025-09-19 17:13:59
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Preparation of α-Linolenic-Acid-Loaded Water-in-Oil-in-Water Microemulsion and Its Potential as a Fluorescent Delivery Carrier with a Free Label
摘要： Our previous work has demonstrated that α-linolenic acid (ALA)-loaded oil-in-water (O/W) microemulsion could enhance ALA antioxidant capacity. Meanwhile, we also observed that synthesized microemulsion itself had ?uorescence. In this work, we have prepared a multiple water-in-oil-in-water (W/O/W) microemulsion to further enhance ALA antioxidant capacity and activate this delivery carrier application potential with a free label. The compositions of primary water-in-oil (W/O) microemulsion were obtained using pseudo-ternary phase diagrams, and then W/O/W microemulsion was prepared adopting the “two-step heterotherm method”. The conductivity of W/O/W microemulsion was measured to lie between 250.0 and 350.0 μs/cm. The spherical droplets with a mean particle diameter of 10.0?20.0 nm were con?rmed by transmission electron microscopy and dynamic light scattering. Nuclear magnetic resonance con?rmed that ALA di?used to the multiple water?oily interface simultaneously. In addition, the in vitro release and antioxidant capacity measurements of ALA-loaded W/O/W microemulsion concluded the sustained-release e?ect and excellent antioxidant capacity. The ?uorescent intensity of W/O/W microemulsion was markedly increased in comparison to O/W microemulsion. The synthesized microemulsion could lead to important applications and have advantages of a label-free ?uorescent carrier for optical imaging purposes.
关键词： ALA-loaded W/O/W microemulsion,?uorescent delivery carrier,characterization,antioxidant capacity
更新于2025-09-10 09:29:36
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Accumulation of protoporphyrin IX in medulloblastoma cell lines and sensitivity to subsequent photodynamic treatment
摘要： Background: Medulloblastoma (MB) is the most common malignant primary brain tumor of childhood. High risk patients still have a poor outcome, and especially young patients suffer from standard therapy induced sequelae. Therefore, other therapeutic options need to be explored. In glioblastoma (GBM), application of 5-aminolaevulinic acid (5-ALA) results in selective accumulation of protoporphyrin IX (PPIX) in the tumor cells, which can be exploited during fluorescence-guided surgery to increase the extent of resection or for photodynamic therapy (PDT) induced phototoxicity. It is not entirely clear, whether MB cells accumulate PPIX and are sensitive to PDT. Methods: Human MYC-amplified (Med8A and D283) and non-amplified (UW228–2 and ONS76) MB cell lines were incubated for 2, 4 or 6 h with increasing doses (0–100 μg/ml) of 5-ALA, and PPIX accumulation was determined by flow cytometry. To assess sensitivity to 5-ALA/PDT, cells were incubated with 5-ALA and subsequently exposed to laser light of 635 nm wavelength (18.75 J/cm2). After an additional 24 h culture period, viability of cells was quantified using the WST-1 assay. Expression of ferrochelatase was detected by reverse transcription and quantitative polymerase chain reaction. Ferrochelatase activity was quantified by measuring the enzymatic conversion of PPIX to zinc-protoporphyrin. Expression of the ABCG2 transporter protein CD338 was detected by flow cytometry. Results: All MB cell lines showed a time- and dose-dependent accumulation of PPIX after exposure to exogenous 5-ALA and became sensitive to 5-ALA/PDT-induced phototoxicity. PPIX accumulation was reduced compared to U373 GBM cells at shorter incubation periods and limiting 5-ALA doses. Moreover, not all MB cells became PPIX positive and overall phototoxicity was lower in the MB cell lines. Notably, the MYC-amplified MB cells demonstrated a more pronounced photosensitivity compared to their non-amplified counterparts. There was no difference in expression of ferrochelatase, but enzymatic activity appeared to be reduced in the MB cells compared to U373 GBM cells, whereas CD338 was expressed on the MB cells only. Conclusion: Medulloblastoma cell lines accumulate PPIX after application of 5-ALA and become sensitive to PDT, associated with low ferrochelatase expression and activity. Photosensitivity is more pronounced in MYC-amplified cell lines. In contrast to GBM cells, however, PPIX accumulation appears to be reduced, restricted to a subset of cells and associated with lower photosensitivity of the MB cell lines, possibly due to expression of the ABCG2 transporter protein CD338 on MB cells.
关键词： ABCG2,Ferrochelatase,Photodiagnosis,Medulloblastoma,PDT,5-ALA
更新于2025-09-10 09:29:36
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Comparison of different treatment schemes in 5-ALA interstitial photodynamic therapy for high-grade glioma in a preclinical model: An MRI study
摘要： Background: There is currently no therapy that prevents high-grade glioma recurrence. Thus, these primary brain tumors have unfavorable outcomes. Recently, 5-ALA photodynamic therapy (PDT) has been proposed to delay relapse and is highly expected to have potential synergistic effects with the current standard of care. However, PDT treatment delivery needs to be optimized by evaluating the impact of both the number of fractions and the light power used. Objectives: Our study aimed to compare MRI markers across different treatment schemes that use interstitial PDT in high-grade glioma in a preclinical model. Materials and Methods: Forty-eight “nude” rats were grafted with human U87 cells into the right putamen and subsequently submitted to interstitial PDT. The rats were randomized into six groups, including two different sham groups and four different treated groups (5 fractions at 5 mW or 30 mW and 2 fractions at 5 mW or 30 mW). After photosensitizer (PS) precursor (5-ALA) intake, an optical fiber was introduced into the tumor. Treatment effects were assessed with early high-field MRI to acquire T1 and T2 diffusion and perfusion images. Results: There was no difference in the variation of the diffusion coefficient among the six groups (p=0.0549, Kruskal-Wallis test). However, a significant difference was identified among the six groups in terms of variation in perfusion (p=0.048, Kruskal-Wallis test), supporting a lesional effect in the treated groups. Additionally, the sham groups had significantly smaller edema volumes than were observed in the treated groups. Moreover, the 5-fraction group treated with 30 mW was associated with edema volumes that were significantly greater than those in the 5-fraction group treated with 5 mW (p=0.019). Conclusion: Based on observations of MRI data and considering treatment effects, the 5-fraction group treated at 5 mW was not significantly different from the other treated groups in terms of cell deaths, characterized by diffusion imaging, or necrosis level. However, the significantly lower level of edema observed in this group indicated that this treatment scheme had limited toxicity.
关键词： Glioblastoma,Photodynamic Therapy,High-Grade Glioma,PDT,PpIX,MRI,5-ALA,Magnetic Resonance Imaging
更新于2025-09-04 15:30:14