Intraoperative 5-aminolevulinic Acid Research Articles

The Use of 5-Aminolevulinic Acid in Low-Grade Glioma Resection: A Systematic Review.

For optimizing high-grade glioma resection, 5-aminolevulinic acid is a reliable tool. However, its efficacy in low-grade glioma resection remains unclear. To study the role of 5-aminolevulinic acid in low-grade glioma resection and assess positive fluorescence rates and the effect on the extent of resection. A systematic review of PubMed, Google Scholar, and Cochrane was performed from the date of inception to February 1, 2019. Studies that correlated 5-aminolevulinic acid fluorescence with low-grade glioma in the setting of operative resection were selected. Studies with biopsy only were excluded. Positive fluorescence rates were calculated. The quality index of the selected papers was provided. No patient information was used, so Institutional Review Board approval and patient consent were not required. A total of 12 articles met the selection criteria with 244 histologically confirmed low-grade glioma patients who underwent microsurgical resection. All patients received 20 mg/kg body weight of 5-aminolevulinic acid. Only 60 patients (n=60/244; 24.5%) demonstrated visual intraoperative 5-aminolevulinic acid fluorescence. The extent of resection was reported in 4 studies; however, the data combined low- and high-grade tumors. Only 2 studies reported on tumor location. Only 3 studies reported on clinical outcomes. The Zeiss OPMI Pentero microscope was most commonly used across all studies. The average quality index was 14.58 (range: 10-17), which correlated with an overall good quality. There is an overall low correlation between 5-aminolevulinic acid fluorescence and low-grade glioma. Advances in visualization technology and using standardized fluorescence quantification methods may further improve the visualization and reliability of 5-aminolevulinic acid fluorescence in low-grade glioma resection.

Sodium fluorescein in brain tumor surgery: Assessing relative fluorescence intensity at tumor margins

Purpose:The use of intraoperative 5-aminolevulinic acid fluorescence has been shown to increase the extent of resection in high-grade glioma surgery. Sodium fluorescein is an alternate fluorescence agent with advantages of low cost, low adverse effect profile, and ability to visualize anatomical detail under the fluorescence filter. Sodium fluorescein-based fluorescence is not specific to tumor cells, and the significance of residual fluorescence at tumor margins has been questioned. In this article, the authors sought to correlate fluorescence intensity at tumor margins with the presence of residual contrast-enhancing tumor on magnetic resonance imaging (MRI).Methods:Eleven patients with a total of 12 lesions were enrolled in the study. Sodium fluorescein was administered at a dose of 5 mg/kg on induction of anesthesia. Relative intensity of fluorescence was extrapolated from intraoperative photographs through isolation of the green channel from the red/green/blue image, then graphically representing of pixel intensity through application of a thermal map. The correlation between areas of avid fluorescence at tumor cavity margins and the presence of residual contrast-enhancing tumor on postoperative MRI was evaluated.Results:All tumors demonstrated fluorescence. The presence of avid fluorescence at tumor cavity margins had a sensitivity of 66.7% and specificity of 75% for the presence of residual contrast-enhancing tumor on postoperative MRI. There were no adverse effects of fluorescein administration.Conclusion:Quantification of relative fluorescence intensity allows easy identification of areas that are high risk for residual contrast-enhancing tumor. Graphical representation of green pixel intensity requires validation through histopathological analysis but has the potential for real-time clinical application.

SURG-32. THE USE OF 5-AMINOLEVULINIC ACID IN LOW-GRADE GLIOMA RESECTION: A SYSTEMATIC REVIEW

Abstract BACKGROUND 5-aminolevulinic acid is a reliable tool for optimizing high-grade glioma resection. However, its efficacy in low-grade glioma resection remains unclear. OBJECTIVE To study the role of 5-aminolevulinic acid in low-grade glioma resection and assess positive fluorescence rates and effect on the extent of resection. METHODS A systematic review of PubMed, Google Scholar, and Cochrane was performed from the date of inception to February 1, 2019. Studies that correlated 5-aminolevulinic acid fluorescence with low-grade glioma in the setting of operative resection were selected. Studies with biopsy only were excluded. Positive fluorescence rates were calculated. Quality index of the selected papers using the Downs and Black criteria checklist was provided. RESULTS Twelve articles met the selection criteria with 244 histologically-confirmed low-grade glioma patients who underwent microsurgical resection. All patients received 20 mg/kg body weight of 5-aminolevulinic acid. Only 60 patients (n=60/244; 24.5%) demonstrated visual intra-operative 5-aminolevulinic acid fluorescence. The extent of resection was reported in 4 studies, however, the data combined low- and high-grade tumors. Only 2 studies reported on tumor location. Only 3 studies reported on clinical outcomes. The Zeiss OPMI Pentero microscope was most commonly used across all studies. The average quality index was 14.58 (range: 10–17) which correlated with an overall good quality. CONCLUSION There is an overall low correlation between 5-aminolevulinic acid fluorescence and low-grade glioma. Advances in visualization technology and using standardized fluorescence quantification methods may further improve the visualization and reliability of 5-aminolevulinic acid fluorescence in low-grade glioma resection.

SURG-13. EVALUATION OF 5-ALA FLUORESCENCE IN BRAIN METASTASES OF VARIOUS PRIMARY TUMORS: A MULTICENTER STUDY WITH EXPERIENCE IN 157 CASES

INTRODUCTION: Local recurrence of brain metastases following incomplete resection is not uncommon. One reason is insufficient intraoperative visualization of tumor tissue. Recently, visible intraoperative 5-aminolevulinic acid (5-ALA) fluorescence was reported in the first brain metastases series. Thus, the aim of this study was to investigate intraoperative 5-ALA fluorescence in brain metastases at two specialized centers in the largest patient cohort up to date. METHODS: 5-ALA was administered prior to resection of 157 brain metastases in 154 patients. Intraoperatively, the fluorescence quality (strong, vague or none) and fluorescence homogeneity (homogeneous or heterogeneous) of each brain metastasis was investigated. These 5-ALA fluorescence characteristics were correlated with primary tumor and histopathological subtype according to the current World Health Organization (WHO) 2016 criteria. RESULTS: Visible 5-ALA fluorescence was observed in 104 brain metastases (66%), whereas fluorescence was absent in the remaining 53 cases (34%).53/104 (51%) brain metastases showed strong fluorescence and 51/104 (49%) vague fluorescence. The majority of brain metastases (84%) demonstrated a heterogeneous fluorescence pattern. In context of primary tumor, visible fluorescence was less frequent in brain metastases of melanomas compared to all other tumors (p=0.037). Moreover, visible fluorescence was more common for ductal breast cancer subtype than other subtypes (p=0.008). CONCLUSION: Our data indicate that 5-ALA fluorescence is a valuable for intraoperative visualization of brain metastases to improve the extent of resection and thus patient prognosis. However, the frequent heterogeneous 5-ALA fluorescence pattern and lack of strong fluorescence limits the use of 5-ALA in brain metastases, claiming for further technical refinement.

INtraoperative photoDYnamic Therapy for GliOblastomas (INDYGO): Study Protocol for a Phase I Clinical Trial.

Glioblastoma (GBM) is characterized by marked proliferation, major infiltration, and poor prognosis. Despite current treatments, including surgery, radiation oncology, and chemotherapy, the overall median survival is 15 mo and the progression-free survival is 7 to 8 mo. Because of systematic relapse of the tumor, the improvement of local control remains an issue. In this context, photodynamic therapy (PDT) may offer a new treatment modality for GBM. To assess the feasibility of intraoperative PDT early after surgical resection of GBM without unacceptable and unexpected toxicities. The INDYGO clinical trial (INtraoperative photoDYnamic Therapy for GliOblastomas) treatment will be carried out in addition to the current standard of care (SOC) of glioblastoma: maximum resection surgery followed by concomitant radio-chemotherapy and adjuvant chemotherapy. PDT treatment will be delivered during surgery early, after the fluorescence-guided resection. Immunological responses and biomarkers will also be investigated during the follow-up. A total of 10 patients will be recruited during this study. Clinical follow-up after the SOC with PDT is expected to be similar (no significant difference) to the SOC alone. This INDYGO trial assesses the feasibility of intraoperative 5-aminolevulinic acid PDT, a novel seamless approach to treat GBM. The technology is easily embeddable within the reference treatment at a low-incremental cost. The safety of this new treatment modality is a preliminary requirement before a multicenter randomized clinical trial can be further conducted to assess local control improvement by treating infiltrating and nonresected GBM cells.

Improved treatment of glioblastoma – changes in survival over two decades at a single regional Centre

Background: Glioblastoma (GBM) is an aggressive brain tumor with a short overall survival (OS) in general. The treatment of GBM has evolved over the last decades and is today multimodal including surgical resection followed by radiochemotherapy and adjuvant chemotherapy for patients in good performance status. The aim of this study was to evaluate the development of treatment and the outcome for GBM patients at a single regional center.Patients and methods: Survival was studied for 571 patients in our region diagnosed with GBM between 1995 and 2015. Samples from 244 patients out of those treated 2005–2015 have been included in a tissue/blood bank and a clinical database has been set up with basic patient characteristics and details on surgery and non-surgical treatment.Results: The median OS for all patients from 1995 to 2015 was 9.3 months. There was a stepwise improvement from 6.9 to 10.3 months for patients diagnosed 1995–1996 and 2010–2015, respectively (p < .05). The 2-year survival for the same time periods improved from 7% to 18% (p < .01). After introduction of postoperative radiochemotherapy for patients in good performance status in 2005 an increased OS was noted and following implementation of intraoperative 5-aminolevulinic acid the number of tumor resection ≥95% did increase from 33% to 54% (p < .001). Positive prognostic factors for survival were young age, good performance status, absence of inflammatory disease, absence of diabetes or metabolic disease, tumor resection ≥95%, and completion of postoperative radiochemotherapy.Discussion: The results of this study are consistent with earlier results regarding survival and prognostic factors and confirm results from randomized controlled trials in a clinical setting. Despite the improvements made, the prognosis is still dismal and the need for further research on GBM treatment is great.

Quantitative Tumor Segmentation for Evaluation of Extent of Glioblastoma Resection to Facilitate Multisite Clinical Trials

Standard-of-care therapy for glioblastomas, the most common and aggressive primary adult brain neoplasm, is maximal safe resection, followed by radiation and chemotherapy. Because maximizing resection may be beneficial for these patients, improving tumor extent of resection (EOR) with methods such as intraoperative 5-aminolevulinic acid fluorescence-guided surgery (FGS) is currently under evaluation. However, it is difficult to reproducibly judge EOR in these studies due to the lack of reliable tumor segmentation methods, especially for postoperative magnetic resonance imaging (MRI) scans. Therefore, a reliable, easily distributable segmentation method is needed to permit valid comparison, especially across multiple sites. We report a segmentation method that combines versatile region-of-interest blob generation with automated clustering methods. We applied this to glioblastoma cases undergoing FGS and matched controls to illustrate the method's reliability and accuracy. Agreement and interrater variability between segmentations were assessed using the concordance correlation coefficient, and spatial accuracy was determined using the Dice similarity index and mean Euclidean distance. Fuzzy C-means clustering with three classes was the best performing method, generating volumes with high agreement with manual contouring and high interrater agreement preoperatively and postoperatively. The proposed segmentation method allows tumor volume measurements of contrast-enhanced T1-weighted images in the unbiased, reproducible fashion necessary for quantifying EOR in multicenter trials.

Predictive value of intraoperative 5-aminolevulinic acid–induced fluorescence for detecting bone invasion in meningioma surgery

Bone invasion is a major concern in meningioma surgery, since it is predictive of the recurrence of cranial involvement, morbidity, and mortality. Bone invasion has been reported in 20%-68% of studies with histopathologically confirmed data. Unfortunately, radical resection of bone invasion remains challenging. The aim of this study was to assess the role of 5-aminolevulinic acid (5-ALA) fluorescence in guiding the resection of bone-invading meningiomas. To this purpose, the sensitivity, specificity, and positive and negative predictive values of 5-ALA in detecting meningioma bone invasion were evaluated. Data from 12 patients affected by bone-invading meningiomas (7 with skull base and 5 with convexity meningiomas) who had undergone surgery with the assistance of 5-ALA fluorescence and neuronavigation between July 2012 and March 2013 at the Department of Neurosurgery of Padua were retrospectively analyzed. To evaluate the sensitivity and specificity of 5-ALA fluorescence in detecting meningioma tissue, a pathologist analyzed 98 surgical bone samples under blue light, according to different fluorescence patterns. Magnetic resonance images and CT scans were obtained pre- and postoperatively to determine the extent of bone invasion resection. The rate of 5-ALA-induced fluorescence of both tumor and bone invasion was 100%. Based on the pathological examination of bone specimens, 5-ALA presented a sensitivity of 89.06% (95% CI 81.41%-96.71%) and a specificity of 100% in detecting meningioma bone invasion, while the positive and negative predictive values were 100% and 82.93% (95% CI 71.41%-94.45%), respectively. At the postoperative stage, MRI did not detect cases of meningioma bone invasion, whereas CT scans revealed residual hyperostosis in 2 cases. In summary, 5-ALA fluorescence represents a suitable and reliable technique for identifying and removing bone infiltration by meningiomas. However, further studies are needed to prove the clinical consequences of this promising technique in a larger population.

Intra-operative 5-aminolevulinic acid (ALA)-induced fluorescence of medulloblastoma: phenotypic variability and CD133+ expression according to different fluorescence patterns

5-Aminolevulinic acid (5-ALA) fluorescence has been proved advantageous in glioma surgery. Conflicting results have been reported by few studies published in literature about intra-operative 5-ALA-induced fluorescence of medulloblastoma (MDB). The aim of this study is to verify if these conflicting results could be explained by intra-tumoral histological and phenotypic differences. In the present case of a 45-year-old patient affected by a cerebellar MDB, histological analysis of cell phenotype and 5-ALA and CD133 correlation were performed in multiple samples according to different fluorescence patterns. Intra-operatively, the tumor appeared unevenly fluorescent under blue-violet light. Histologically, 5-ALA-intense biopsies from inner areas were characterized by a significant amount of cancer cells, whereas 5-ALA faint regions from peripheral areas displayed normal cerebellar features, with MDB cells infiltrating healthy tissues. Presenting our findings, we show the correlation between different 5-ALA fluorescence patterns of medulloblastoma with specific histological and phenotypical features. Thus, we hypothesize that a distinct relationship between CD133 expression and fluorescence accumulation presented in our study could partially explain the divergent results published in literature.

Intraoperative 5-aminolevulinic acid–induced fluorescence in primary central nervous system lymphoma

The authors report a case of primary CNS lymphoma located in the floor of the fourth ventricle that showed intense fluorescence after preoperative administration of 5-aminolevulinic acid. The authors believe that this is the first demonstration of a 5-aminolevulinic acid-induced fluorescence pattern in primary CNS lymphoma.

Intraoperative Fluorescence-Guided Resection of High-Grade Malignant Gliomas Using 5-Aminolevulinic Acid–Induced Porphyrins: A Systematic Review and Meta-Analysis of Prospective Studies

BackgroundWe performed a systematic review and meta-analysis to address the (added) value of intraoperative 5-aminolevulinic acid (5-ALA)-guided resection of high-grade malignant gliomas compared with conventional neuronavigation-guided resection, with respect to diagnostic accuracy, extent of tumor resection, safety, and survival.Methods and FindingsAn electronic database search of Medline, Embase, and the Cochrane Library was undertaken. The review process followed the guidelines of the Cochrane Collaboration. 10 studies matched all selection criteria, and were thus used for qualitative synthesis. 5-ALA-guided resection demonstrated an overall sensitivity of 0.87 (95% confidence interval [CI], 0.81–0.92), specificity of 0.89 (95% CI, 0.79–0.94), positive likelihood ratio (LR) of 7.62 (95% CI, 3.87–15.01), negative LR of 0.14 (95% CI, 0.09–0.23), and diagnostic odds ratio (OR) of 53.06 (95% CI, 18.70–150.51). Summary receiver operating characteristic curves (SROC) showed an area under curve (AUC) of 94%. Contrast-enhancing tumor was completely resected in patients assigned 5-ALA as compared with patients assigned white light. Patients in the 5-ALA group had higher 6-month progression free survival and overall survival than those in the white light group.ConclusionBased on available literature, there is level 2 evidence that 5-ALA-guided surgery is more effective than conventional neuronavigation-guided surgery in increasing diagnostic accuracy and extent of tumor resection, enhancing quality of life, or prolonging survival in patients with high-grade malignant gliomas.

Comparison of 18F-FET PET and 5-ALA fluorescence in cerebral gliomas

The aim of the study was to compare presurgical (18)F-fluoroethyl-L: -tyrosine ((18)F-FET) uptake and Gd-diethylenetriaminepentaacetic acid (DTPA) enhancement on MRI (Gd) with intraoperative 5-aminolevulinic acid (5-ALA) fluorescence in cerebral gliomas. (18)F-FET positron emission tomography (PET) was performed in 30 patients with brain lesions suggestive of diffuse WHO grade II or III gliomas on MRI. PET and MRI data were coregistered to guide neuronavigated biopsies before resection. After oral application of 5-ALA, 38 neuronavigated biopsies were taken from predefined tumour areas that were positive or negative for (18)F-FET or Gd and checked for 5-ALA fluorescence. (18)F-FET uptake with a mean tumour to brain ratio ≥1.6 was rated as positive. Of 38 biopsies, 21 corresponded to high-grade glioma tissue (HGG) of WHO grade III (n = 19) or IV (n = 2) and 17 biopsies to low-grade glioma tissue (LGG) of WHO grade II. In biopsies corresponding to HGG, (18)F-FET PET was positive in 86% (18/21), but 5-ALA and Gd in only 57% (12/21). A mismatch between Gd and 5-ALA was observed in 6 of 21 cases of HGG biopsy samples (3 Gd-positive/5-ALA-negative and 3 Gd-negative/5-ALA-positive). In biopsies corresponding to LGG, (18)F-FET was positive in 41% (7/17), while 5-ALA and Gd were negative in all but one instance. All tumour areas with 5-ALA fluorescence were positive on (18)F-FET PET. There are differences between (18)F-FET and 5-ALA uptake in cerebral gliomas owing to a limited sensitivity of 5-ALA to detect tumour tissue especially in LGG. (18)F-FET PET is more sensitive to detect glioma tissue than 5-ALA fluorescence and should be considered as an additional tool in resection planning.

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

Intraoperative 5-aminolevulinic acid (5-ALA)-induced fluorescence guidance for resection of malignant brain tumors was correlated with histological examination to investigate false positive findings in 42 patients with malignant glioma and six patients with metastatic brain tumor. Patients received a single 1 g oral dose of 5-ALA 2 hours before surgery. The tumor site was illuminated with a laser with a peak wavelength of 405 +/- 1 nm and output of 40 mW. Samples with strong fluorescence were obtained from the tumor bulk and samples with weak fluorescence from the tumor cavity. Fluorescence was observed in 36 of the 42 malignant gliomas and four of the six metastatic brain tumors. No tumor cells were found in fluorescent samples from six of the 36 malignant gliomas and all four metastatic brain tumors. Five of the six malignant gliomas were recurrent cases. Fluorescence was found in areas of peritumoral edema or inflammatory cell and reactive astrocyte infiltration. Intraoperative 5-ALA-induced fluorescence guidance is useful for the resection of initial malignant glioma since false positive results are rare, but only non-eloquent weak positive areas should be resected. In contrast, all weak positive areas of recurrent malignant gliomas must be resected. Weak positive areas of the peritumoral edema surrounding metastatic brain tumors should be removed carefully as false positive results are common.