Commentary: 5-Aminolevulinic Acid-Induced Porphyrin Contents in Various Brain Tumors: Implications Regarding Imaging Device Design and Their Validation

Abstract Most brain surgeries aim to completely resection a tumor. However, the arrangement of blood vessels around brain tumors is often complex. Moreover, the tumors and blood vessels have similar colors, making it difficult to identify the boundaries between them with the naked eye. Fluorescent staining is a method used to distinguish the borders between brain tumors and blood vessels. The fluorescent contrast agents commonly used to observe tumors are 5-aminolevulinic acid (5-ALA) and fluorescein sodium (FS), which have different surgical sensitivities, depending on the type of tumor. In this article, a dual band band-pass filter (BPF) with dual-wavelength emission for 5-ALA and FS is designed, and the dual-band BPF capable of inducing simultaneous fluorescence emission of FS and 5-ALA was investigated experimentally to improve accuracy, speed, and energy efficiency in clinical settings. The possibility of dual fluorescence emission with a single irradiation is proposed. The proposed fluorescent dual-band filter has the advantage of saving energy, reducing auxiliary manpower and unit costs, and reducing operating room space requirements by producing two fluorescence diagnostic effects using a single equipment.

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Intraoperative Photodynamic Diagnosis of Brain Tumors Using 5-Aminolevulinic Acid

Diagnostic Techniques and Surgical Management of Brain Tumors ◽

10.5772/19788 ◽

2011 ◽

Cited By ~ 2

Author(s):

Satoshi Utsuki ◽

Hidehiro Oka ◽

Kiyotaka Fujii

Keyword(s):

Brain Tumors ◽

Aminolevulinic Acid ◽

Photodynamic Diagnosis

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Macroscopic fluorescence-lifetime imaging of NADH and protoporphyrin IX improves the detection and grading of 5-aminolevulinic acid-stained brain tumors

Scientific Reports ◽

10.1038/s41598-020-77268-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Mikael T. Erkkilä ◽

David Reichert ◽

Johanna Gesperger ◽

Barbara Kiesel ◽

Thomas Roetzer ◽

...

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Fluorescence Lifetime ◽

Tumor Tissue ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Low Grade ◽

Wide Field ◽

Fluorescence Lifetime Imaging ◽

Lifetime Imaging

AbstractMaximal safe tumor resection remains the key prognostic factor for improved prognosis in brain tumor patients. Despite 5-aminolevulinic acid-based fluorescence guidance the neurosurgeon is, however, not able to visualize most low-grade gliomas (LGG) and infiltration zone of high-grade gliomas (HGG). To overcome the need for a more sensitive visualization, we investigated the potential of macroscopic, wide-field fluorescence lifetime imaging of nicotinamide adenine dinucleotide (NADH) and protoporphyrin IX (PPIX) in selected human brain tumors. For future intraoperative use, the imaging system offered a square field of view of 11 mm at 250 mm free working distance. We performed imaging of tumor tissue ex vivo, including LGG and HGG as well as brain metastases obtained from 21 patients undergoing fluorescence-guided surgery. Half of all samples showed visible fluorescence during surgery, which was associated with significant increase in PPIX fluorescence lifetime. While the PPIX lifetime was significantly different between specific tumor tissue types, the NADH lifetimes did not differ significantly among them. However, mainly necrotic areas exhibited significantly lower NADH lifetimes compared to compact tumor in HGG. Our pilot study indicates that combined fluorescence lifetime imaging of NADH/PPIX represents a sensitive tool to visualize brain tumor tissue not detectable with conventional 5-ALA fluorescence.

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Intraoperative 5-aminolevulinic acid-induced photodynamic diagnosis of metastatic brain tumors with histopathological analysis

World Journal of Surgical Oncology ◽

10.1186/s12957-017-1239-8 ◽

2017 ◽

Vol 15 (1) ◽

Cited By ~ 10

Author(s):

R. Yagi ◽

S. Kawabata ◽

N. Ikeda ◽

N. Nonoguchi ◽

M. Furuse ◽

...

Keyword(s):

Brain Tumors ◽

Aminolevulinic Acid ◽

Photodynamic Diagnosis ◽

Histopathological Analysis ◽

Metastatic Brain Tumors

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Possibility of using laser spectroscopy for the intraoperative detection of nonfluorescing brain tumors and the boundaries of brain tumor infiltrates

Journal of Neurosurgery ◽

10.3171/jns.2006.104.4.618 ◽

2006 ◽

Vol 104 (4) ◽

pp. 618-620 ◽

Cited By ~ 53

Author(s):

Satoshi Utsuki ◽

Hidehiro Oka ◽

Sumito Sato ◽

Sachio Suzuki ◽

Satoru Shimizu ◽

...

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Laser Spectroscopy ◽

Aminolevulinic Acid ◽

Neoplastic Cells ◽

Excitation Light ◽

Fluorescence Techniques ◽

Light Peak ◽

Intraoperative Detection ◽

Tissue Region

✓The response of nonfluorescing infiltrating tumors that had been exposed to 5–aminolevulinic acid and irradiated using a laser at a wavelength of 405 nm was analyzed intraoperatively using spectroscopy. Histological analyses demonstrated that neoplastic cells were present in the tissue region that displayed a peak at 636 nm, whereas no neoplastic cells were present in the region that exhibited only the excitation light peak. The authors conclude that the intraoperative use of laser spectroscopy can allow the diagnosis of infiltrating tumor and the detection of boundaries of the infiltrate when standard fluorescence techniques fail.

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Use of 5-ALA fluorescence guided endoscopic biopsy of a deep-seated primary malignant brain tumor

Journal of Neurosurgery ◽

10.3171/2010.11.jns10250 ◽

2011 ◽

Vol 114 (5) ◽

pp. 1410-1413 ◽

Cited By ~ 23

Author(s):

Rainer Ritz ◽

Guenther C. Feigl ◽

Martin U. Schuhmann ◽

André Ehrhardt ◽

Soeren Danz ◽

...

Keyword(s):

Brain Tumors ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Endoscopic Biopsy ◽

Combined Approach ◽

Malignant Brain Tumors ◽

Dichroic Filter ◽

Microsurgical Resection ◽

New Strategies ◽

Primary Malignant Brain Tumor

The introduction of fluorescence-guided resection of primary malignant brain tumors was a milestone in neurosurgery. Deep-seated malignant brain tumors are often not approachable for microsurgical resection. For diagnosis and therapy, new strategies are recommended. The combination of endoscopy and 5-aminolevulinic acid–induced protoporphyrin IX (5-ALA-induced Pp IX) fluorescence–guided procedures supported by neuronavigation seems an interesting option. Here the authors report on a combined approach for 5-ALA fluorescence–guided biopsy in which they use an endoscopy system based on an Xe lamp (excitation approximately λ = 407 nm; dichroic filter system λ = 380–430 nm) to treat a malignant tumor of the thalamus and perform a ventriculostomy and septostomy. The excitation filter and emission filter are adapted to ensure that the remaining visible blue remission is sufficient to superimpose on or suppress the excited red fluorescence of the endogenous fluorochromes. The authors report that the lesion was easily detectable in the fluorescence mode and that biopsy led to histological diagnosis.

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Fluorescence-guided resection of metastatic brain tumors using a 5-aminolevulinic acid-induced protoporphyrin IX: pathological study

Brain Tumor Pathology ◽

10.1007/s10014-007-0223-3 ◽

2007 ◽

Vol 24 (2) ◽

pp. 53-55 ◽

Cited By ~ 75

Author(s):

Satoshi Utsuki ◽

Norio Miyoshi ◽

Hidehiro Oka ◽

Yoshiteru Miyajima ◽

Satoru Shimizu ◽

...

Keyword(s):

Brain Tumors ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Metastatic Brain Tumors ◽

Pathological Study

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Intraoperative fluorescence imaging with aminolevulinic acid detects grossly occult breast cancer: a phase II randomized controlled trial

Breast Cancer Research ◽

10.1186/s13058-021-01442-7 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Kathryn Ottolino-Perry ◽

Anam Shahid ◽

Stephanie DeLuca ◽

Viktor Son ◽

Mayleen Sukhram ◽

...

Keyword(s):

Breast Cancer ◽

Randomized Controlled Trial ◽

Fluorescence Imaging ◽

Phase Ii ◽

Aminolevulinic Acid ◽

Controlled Trial ◽

Imaging Device ◽

Randomized Controlled ◽

Intraoperative Fluorescence Imaging ◽

Intraoperative Fluorescence

Abstract Background Re-excision due to positive margins following breast-conserving surgery (BCS) negatively affects patient outcomes and healthcare costs. The inability to visualize margin involvement is a significant challenge in BCS. 5-Aminolevulinic acid hydrochloride (5-ALA HCl), a non-fluorescent oral prodrug, causes intracellular accumulation of fluorescent porphyrins in cancer cells. This single-center Phase II randomized controlled trial evaluated the safety, feasibility, and diagnostic accuracy of a prototype handheld fluorescence imaging device plus 5-ALA for intraoperative visualization of invasive breast carcinomas during BCS. Methods Fifty-four patients were enrolled and randomized to receive no 5-ALA or oral 5-ALA HCl (15 or 30 mg/kg). Forty-five patients (n = 15/group) were included in the analysis. Fluorescence imaging of the excised surgical specimen was performed, and biopsies were collected from within and outside the clinically demarcated tumor border of the gross specimen for blinded histopathology. Results In the absence of 5-ALA, tissue autofluorescence imaging lacked tumor-specific fluorescent contrast. Both 5-ALA doses caused bright red tumor fluorescence, with improved visualization of tumor contrasted against normal tissue autofluorescence. In the 15 mg/kg 5-ALA group, the positive predictive value (PPV) for detecting breast cancer inside and outside the grossly demarcated tumor border was 100.0% and 55.6%, respectively. In the 30 mg/kg 5-ALA group, the PPV was 100.0% and 50.0% inside and outside the demarcated tumor border, respectively. No adverse events were observed, and clinical feasibility of this imaging device-5-ALA combination approach was confirmed. Conclusions This is the first known clinical report of visualization of 5-ALA-induced fluorescence in invasive breast carcinoma using a real-time handheld intraoperative fluorescence imaging device. Trial registration Clinicaltrials.gov identifier NCT01837225. Registered 23 April 2013.

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EXTH-57. INVESTIGATION OF THE TUMORICIDAL EFFECTS OF SONODYNAMIC THERAPY IN MALIGNANT GLIOBLASTOMA BRAIN TUMORS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.411 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii99-ii99

Author(s):

Kimball Sheehan ◽

Darrah Sheehan ◽

Mohanad Sulaiman ◽

Frederic Padilla ◽

Jason Sheehan ◽

...

Keyword(s):

Cell Death ◽

Brain Tumors ◽

Cell Viability ◽

Mtt Assay ◽

Caspase 3 ◽

Focused Ultrasound ◽

Aminolevulinic Acid ◽

Glioblastoma Cell ◽

C6 Cells ◽

Sonodynamic Therapy

Abstract OBJECTIVE Glioblastoma is the most common primary brain tumor; survival is typically 12–18 months after diagnosis. We sought to study the effects of sonodynamic therapy (SDT) using 5-Aminolevulinic acid hydrochloride (5-ALA) and high frequency focused ultrasound (FUS) on 2 glioblastoma cell lines. PROCEDURE Rat C6 and human U87 glioblastoma cells were studied under the following conditions: 1mM 5-ALA (5-ALA); Focused ultrasound (FUS); 5-ALA and focused ultrasound (SDT); control. Studied responses included cell viability using an MTT assay, microscopic changes using phase contract microscopy, apoptotic induction through a caspase-3 assay, and apoptosis staining to quantify cell death. RESULTS SDT led to a marked decrease in cell extension and reduction in cell size. For C6, the MTT assay showed reductions in cell viability for 5-ALA, FUS, and SDT groups of 5%, 16%, and 47%, respectively compared to control (p< 0.05). Caspase 3 induction in C6 cells relative to control showed increases of 109%, 110%, and 278% for 5-ALA, FUS, and SDT groups, respectively (p< 0.05). For the C6 cells, caspase 3 staining positivity was 2.1%, 6.7%, 11.2%, and 39.8% for control, 5-ALA, FUS, and SDT groups, respectively. C6 Parp-1 staining positivity was 1.9%, 6.5%, 9.0%, and 37.8% for control, 5-ALA, FUS, and SDT groups, respectively. U87 cells showed similar responses to the treatments. CONCLUSIONS Sonodynamic therapy resulted in appreciable glioblastoma cell death as compared to 5-ALA or FUS alone. The approach couples two already FDA approved techniques in a novel way to treat the most aggressive and malignant of brain tumors. Further study of this promising technique is planned using glioma and also brain metastasis models.

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