CD34 microvascularity in low-grade glioma: correlation with 5-aminolevulinic acid fluorescence and patient prognosis in a multicenter study at three specialized centers.

OBJECTIVE: Early markers are urgently needed in low-grade glioma (LGG) evaluation to rapidly estimate the individual patient's prognosis and to determine the optimal postoperative management. Generally, visible 5-aminolevulinic acid (5-ALA) fluorescence is present in only a few LGGs. Recently, the authors identified visible 5-ALA fluorescence as a powerful intraoperative marker for unfavorable outcome in LGG treatment. However, its precise histopathological correlate is unclear. Neoangiogenesis represents a crucial event in tumor evolution, and CD34 is an established marker for vascular endothelial progenitors potentially indicating tumor progression. The aim of this study was thus to correlate 5-ALA fluorescence and CD34 microvascularity as well as to investigate the prognostic value of CD34 in a large series of LGGs. METHODS: In this retrospective study including 3 specialized centers, patients with histopathologically confirmed isocitrate dehydrogenase-mutated LGGs (WHO grade II) receiving 5-ALA prior to resection were included. During surgery, the presence of visible fluorescence was analyzed and one representative tumor sample from the area with the maximum fluorescence effect (tumor with focal fluorescence or nonfluorescing tumor) was selected for each LGG. All fluorescing or nonfluorescing tumor samples were stained for CD34 and semiquantitatively analyzed for microvascular proliferation patterns (physiological vessels, branching capillaries, or microvessel clusters) as well as automatically quantified for CD34 microvessel density (MVD) by standardized histomorphometry software. These semiquantitative/quantitative CD34 data were correlated to the fluorescence status and patient outcome including progression-free survival (PFS), malignant transformation-free survival (MTFS), and overall survival (OS). RESULTS: In a total of 86 LGGs, visible fluorescence was found during surgery in 13 (15%) cases. First, the semiquantitative CD34 score significantly correlated with intraoperative fluorescence (p = 0.049). Accordingly, the quantitative CD34 MVD was significantly higher in tumors showing fluorescence (p = 0.03). Altogether, the semiquantitative CD34 score showed a strong correlation with quantitative CD34 MVD (p < 0.001). At a mean follow-up of 5.4 ± 2.6 years, microvessel clusters in semiquantitative analysis were a prognostic marker for poor PFS (p = 0.01) and MTFS (p = 0.006), but not OS (p = 0.28). Finally, quantitative CD34 MVD > 10 vessels/mm2 was a prognostic marker for poor PFS (p = 0.01), MTFS (p = 0.008), and OS (p = 0.049). CONCLUSIONS: The data indicate that CD34 microvascularity is associated with intraoperative 5-ALA fluorescence and outcomes in patients with LGG. Thus, visible fluorescence in LGGs might indicate increased CD34 microvascularity, serving as an early prognostic marker for unfavorable patient outcome that is already available during surgery.

Combined Open Surgical and Endoscopic Approach for Management of a Meningoencephalocele After Iatrogenic Perforation of the Anterior Skull Base in a Young Infant.

Traumatic iatrogenic perforation of the anterior skull base is a rare complication following endonasal intubation in preterm infants. Subsequent meningoencephaloceles with concomitant cerebrospinal fluid (CSF) fistulas bear the risk of severe complications, therefore early diagnosis and closure of the skull defect are crucial. However, there is no consensus on the management of such cases of meningoencephaloceles. This case report presents a sophisticated approach of open brain surgery in combination with endonasal endoscopy. A 15-month-old girl presented with a meningoencephalocele and a CSF fistula due to iatrogenic perforation of the left anterior skull base during attempted endonasal intubation after birth. Difficult nasal breathing and an increasing diameter of the skull base defect on imaging controls indicated surgical management. Close multidisciplinary collaboration was essential for diagnosis and decision upon treatment. Open neurosurgical resection and CSF fistula closure combined with endonasal endoscopic removal of the excised meningoencephalocele was performed. Our case report shows that this combined open surgical and endonasal endoscopic approach is a safe procedure in favor of the postoperative outcome and follow-up of the patient.

Does pigmentation, hemosiderin and blood effect visible 5-ALA fluorescence in cerebral melanoma metastasis?

INTRODUCTION: The clinical impact of 5-aminolevulinic acid (5-ALA) fluorescence during resection of brain metastases is not yet clear.. Recent data demonstrated significantly lower incidence of visible fluorescence in cerebral melanoma metastases (CMM) compared to other brain metastases (BM). The aim of this study was to investigate if characteristic melanoma features such as pigmentation, intratumoural hemosiderin and bleeding have an influence on visible fluorescence in CMM. MATERIALS AND METHODS: A retrospective study of two neurosurgical centers was performed including adult patients with resection of CMM after preoperative administration of 5-ALA. Data on the fluorescence status (visible or no fluorescence), the fluorescence quality (strong, vague, none) and fluorescence homogeneity (homogeneous or heterogeneous) of each CMM were collected. The amount of melanin, hemosiderin and intratumoural bleeding was semi-quantitatively determined and automated computer-based calculation of the relative pigmented area was performed in fluorescing and non-fluorescing CMM samples. RESULTS: Altogether, 29 CMM were surgically removed after 5-ALA administration. Visible fluorescence was detected in 8 CMM (28%), whereas no fluorescence was detected in 21 CMM (72%). In detail, 3 tumors (10%) showed strong fluorescence, 5 tumors (17%) revealed vague fluorescence and in 21 tumors (72%) no fluorescence was found. In total, 8 fluorescing and 25 non-fluorescing CMM samples were investigated. According to the semi-quantitatively calculated fluorescence status, no statistically significant difference in the median amount of melanin (p = 0.242), hemosiderin (p = 0.603) and bleeding (p = 0.762) between CMM samples with and without visible fluorescence was found. Moreover, the automatically assessed relative pigmented area did not show a statistically significant difference between samples with visible and no fluorescence (p = 0.966). CONCLUSION: Our data indicate that 5-ALA fluorescence is not dependent on the amount of pigmentation, intratumoural hemosiderin and bleeding in CMM. We thus assume that other factors are responsible for the low rate of visible fluorescence in CMM.

The Digital Brain Tumour Atlas, an open histopathology resource.

Currently, approximately 150 different brain tumour types are defined by the WHO. Recent endeavours to exploit machine learning and deep learning methods for supporting more precise diagnostics based on the histological tumour appearance have been hampered by the relative paucity of accessible digital histopathological datasets. While freely available datasets are relatively common in many medical specialties such as radiology and genomic medicine, there is still an unmet need regarding histopathological data. Thus, we digitized a significant portion of a large dedicated brain tumour bank based at the Division of Neuropathology and Neurochemistry of the Medical University of Vienna, covering brain tumour cases from 1995-2019. A total of 3,115 slides of 126 brain tumour types (including 47 control tissue slides) have been scanned. Additionally, complementary clinical annotations have been collected for each case. In the present manuscript, we thoroughly discuss this unique dataset and make it publicly available for potential use cases in machine learning and digital image analysis, teaching and as a reference for external validation.

Intraoperative magnetic resonance imaging in epilepsy surgery: systematic review of the literature and meta-analysis.

INTRODUCTION: Intraoperative magnetic resonance imaging (iopMRI) is increasingly incorporated into neurosurgery to improve outcomes. However, its usefulness in epilepsy surgery remains debated. To elucidate its current role, we conducted a systematic review of the data published to date. EVIDENCE ACQUISITION: We performed a systematic review of the available literature using the PubMed, Scopus, and Embase database. Only articles detailing the usefulness of iopMRI in quantifiable measures were included. Different aspects of iopMRI in epilepsy surgery were analyzed and two meta-analyses summarizing its impact on extent of resection and seizure outcomes performed. EVIDENCE SYNTHESIS: A total of 33 articles met the inclusion criteria, comprising a total of 1313 patients, both children and adults operated under iopMRI guidance. The mean rate of return to surgery was 29.2% in 30 articles reporting this number. Eleven publications were eligible for meta-analysis of seizure outcome in patients with refractory epilepsy, who had undergone surgery with iopMRI (N.=294) compared to controls (N.=298). Eight articles described the impact of iopMRI on the radiological extent of resection. In both regards, usage of iopMRI improved outcomes in our meta-analysis with an OR of 3.8 and 4.75, respectively. CONCLUSIONS: This work presents the first meta-analysis of the value of iopMRI in epilepsy surgery. Its use resulted in an improvement of the desired extent of resection and led to a better seizure outcome compared to conventional surgery. Understanding its benefits might help improve surgical strategies in traditional, open epilepsy surgery.

Reply to Stummer, W.; Thomas, C. Comment on "Hosmann et al. 5-ALA Fluorescence Is a Powerful Prognostic Marker during Surgery of Low-Grade Gliomas (WHO Grade II)-Experience at Two Specialized Centers. Cancers 2021, 13, 2540".

We greatly appreciate Dr. Stummer's and Dr. Thomas's interest in our study and their important comments [...].

5-ALA Fluorescence Is a Powerful Prognostic Marker during Surgery of Low-Grade Gliomas (WHO Grade II)-Experience at Two Specialized Centers.

The prediction of the individual prognosis of low-grade glioma (LGG) patients is limited in routine clinical practice. Nowadays, 5-aminolevulinic acid (5-ALA) fluorescence is primarily applied for improved intraoperative visualization of high-grade gliomas. However, visible fluorescence is also observed in rare cases despite LGG histopathology and might be an indicator for aggressive tumor behavior. The aim of this study was thus to investigate the value of intraoperative 5-ALA fluorescence for prognosis in LGG patients. We performed a retrospective analysis of patients with newly diagnosed histopathologically confirmed LGG and preoperative 5-ALA administration at two independent specialized centers. In this cohort, we correlated the visible intraoperative fluorescence status with progression-free survival (PFS), malignant transformation-free survival (MTFS) and overall survival (OS). Altogether, visible fluorescence was detected in 7 (12%) of 59 included patients in focal intratumoral areas. At a mean follow-up time of 5.3 ± 2.9 years, patients with fluorescing LGG had significantly shorter PFS (2.3 ± 0.7 vs. 5.0 ± 0.4 years; p = 0.01), MTFS (3.9 ± 0.7 vs. 8.0 ± 0.6 years; p = 0.03), and OS (5.4 ± 1.0 vs. 10.3 ± 0.5 years; p = 0.01) than non-fluorescing tumors. Our data indicate that visible 5-ALA fluorescence during surgery of pure LGG might be an already intraoperatively available marker of unfavorable patient outcome and thus close imaging follow-up might be considered.

Androgen Receptor is Expressed in Breast Cancer Brain Metastases.

BACKGROUND: Androgen receptor (AR) expression is a potential therapeutic target in breast cancer (BC) as it is frequently expressed in the luminal A and B subtypes and in approximately one third of basal-like cancers. As AR-positive BC displays a distinct biological behavior, we aimed to analyze AR expression in the particular context of BC brain metastases (BM). MATERIALS AND METHODS: Patients with newly diagnosed BC BM treated with neurosurgical resection were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, biological tumor subtypes and overall survival were obtained by retrospective chart review. Formalin-fixed and paraffin-embedded specimen containing BM tissue were retrieved from the Neuro-Biobank. Immunohistochemical staining of AR was performed and AR expression in the tumor-cell nucleus was evaluated. RESULTS: Fifty-seven BM samples from 57 individual patients with BC were available for this analysis. AR expression of ≥1% tumor cells was evident in 20/57 (35.1%) BM specimens; the median AR-expression rate was 10% (range: 1% to 60%). AR expression was observed in 11/21 (52.4%) BM of the luminal/human epidermal growth factor receptor 2 (HER2)-negative subtype, 3/13 (23.1%) of the luminal/HER2-positive subtype, 2/7 (28.6%) of the HER2-positive subtype and 4/16 (25.0%) of the triple-negative subtype (P=0.247). Median survival from diagnosis of BM was 10 months (range: 0 to 104 mo) in the entire cohort. No significant association of overall survival and AR expression ≥1% was observed (15 vs. 13 mo; P>0.05). CONCLUSION: AR is expressed in more than one third of BC BM with the highest rates among the luminal/HER2-negative BC subtype and may therefore be a potential prognostic and predictive biomarker in this particular BC population.

Prognostic Value of 5-ALA Fluorescence, Tumor Cell Infiltration and Angiogenesis in the Peritumoral Brain Tissue of Brain Metastases.

Complete resection is an indispensable treatment option in the management of brain metastases (BM). 5-aminolevulinic acid (5-ALA) fluorescence is used for improved intraoperative visualization of tumor tissue in gliomas and was recently observed in BM. We investigated the potential of 5-ALA fluorescence to visualize the infiltrative growth of BM in the peritumoral brain tissue and its histopathological correlate. Patients with BM resection after 5-ALA administration and collection of tissue samples from peritumoral brain tissue were included. Each tissue sample was histopathologically investigated for tumor cell infiltration and angiogenesis. Altogether, 88 samples were collected from the peritumoral brain tissue in 58 BM of 55 patients. Visible 5-ALA fluorescence was found in 61 (69%) of the samples, tumor infiltration in 19 (22%) and angiogenesis in 13 (15%) of samples. Angiogenesis showed a significant correlation with presence of fluorescence (p = 0.008). Moreover, angiogenesis was related to visible 5-ALA fluorescence and showed an association with patient prognosis since it was significantly correlated to shorter time to local progression/recurrence (p = 0.001) and lower one-year survival (p = 0.031). Consequently, angiogenesis in the peritumoral brain tissue of BM might be a novel prognostic marker for individualized perioperative treatment concepts in the future.

High Diagnostic Accuracy of Visible 5-ALA Fluorescence in Meningioma Surgery According to Histopathological Analysis of Tumor Bulk and Peritumoral Tissue.

BACKGROUND AND OBJECTIVES: Complete neurosurgical resection of intracranial meningiomas is essential to avoid residual tumor tissue and thus minimize the risk of tumor recurrence. However, local recurrence of meningiomas is not uncommon mainly due to insufficient intraoperative detection of residual tumor tissue within the tumor bulk or peritumoral tissue such as bone and satellite lesions. Although 5-aminolevulinic acid (5-ALA) induced fluorescence was found to visualize the majority of meningiomas, no comprehensive histopathological assessment of fluorescing samples from the tumor bulk and peritumoral tissue is available. The aim of our study was thus to histopathologically analyze a large series of tissue samples derived from meningioma surgery to assess the positive predictive value (PPV) of visible 5-ALA fluorescence. STUDY DESIGN/MATERIALS AND METHODS: In this study, we retrospectively investigated a series of tissue samples with visible 5-ALA fluorescence collected during surgery of intracranial meningiomas from the tumor bulk and peritumoral tissue including the bone flap, dura/dural tail, arachnoidea, adjacent cortex, and satellite lesions. The tumor diagnosis was established according to the World Health Organization (WHO) criteria and all collected fluorescing samples were screened for presence of tumor tissue to calculate the PPV. RESULTS: Altogether, 191 tissue samples with visible 5-ALA fluorescence derived during surgery of 85 meningiomas (63 WHO grade I, 17 WHO grade II, and 5 WHO grade III) were included. In detail, 158 samples from the tumor bulk and 33 specimens from the peritumoral tissue were investigated. According to histopathological analysis, the PPV of 5-ALA fluorescence was significantly higher in samples from the tumor bulk (100%) as compared with peritumoral tissue (73%; P < 0.001). With regard to peritumoral tissue, tumor tissue was present in most fluorescing samples from the satellite lesions (100%), the bone flap (92%), arachnoidea (83%), and dura/dural tail (75%). In contrast, tumor tissue was absent in the majority of samples from fluorescing cortex (six of seven samples; 86%). However, distinct reactive tissue alterations were found in all six tumor-free fluorescing cortex samples and additional vascular proliferation in two cases. CONCLUSION: In this largest series to date, visible 5-ALA fluorescence is characterized by a high PPV detecting tumor bulk and peritumoral tissue in intracranial meningiomas. Thus, 5-ALA fluorescence supports the neurosurgeon in identifying residual tumor tissue at relevant surgical sites to optimize meningioma surgery and minimize the risk of local recurrence. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.

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

Maximal 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.

Postoperative Magnetic Resonance Imaging After Surgery of Brain Metastases: Analysis of Extent of Resection and Potential Risk Factors for Incomplete Resection.

BACKGROUND: Extent of resection (EOR) constitutes a crucial factor for patient prognosis in surgery of brain metastases (BMs). According to early studies using postoperative magnetic resonance imaging (MRI), an unexpected residual tumor was not uncommon. Knowledge of potential risk factors for incomplete BM resection would be of major importance to optimize surgical strategies. The aim of this study was to evaluate EOR in a large cohort and analyze potential risk factors for incomplete BM resection. METHODS: Patients with BM resection and available postoperative MRI were included. Intraoperative estimation of EOR by the neurosurgeon was noted. Additionally, EOR was determined by postoperative MRI. Potential risk factors for incomplete resection were investigated. RESULTS: There were 145 patients with 163 BMs included. According to postoperative MRI, complete resection was achieved in 103 (63%) BMs, and resection was incomplete in 44 (27%) BMs. Postoperative MRI detected unexpected residual tumor in 32 (25%) BMs, and a misjudgment of the EOR by the neurosurgeon was found in 29% of cases. Regarding risk factors for incomplete resection, preoperative tumor volume was significantly larger in incompletely resected BMs compared with completely resected BMs (P = 0.011). All other analyzed risk factors had no significant influence on EOR. CONCLUSIONS: Our data indicate that postoperative MRI is able to detect a high portion of unexpected residual tumors after surgery of BMs. Preoperative tumor volume in particular represents an important risk factor for incomplete resection, and hence neurosurgeons should pay special attention to avoid residual tumor tissue.

TCGA mRNA Expression Analysis of the Heme Biosynthesis Pathway in Diffusely Infiltrating Gliomas: A Comparison of Typically 5-ALA Fluorescent and Non-Fluorescent Gliomas.

5-Aminolevulinic acid (5-ALA) is a fluorescent dye that after metabolization to Protoporphyrin IX (PpIX) by the heme biosynthesis pathway typically leads to visible fluorescence in WHO grade IV but not grade II gliomas. The exact mechanism for high PpIX levels in WHO grade IV gliomas and low PpIX levels in WHO grade II gliomas is not fully clarified. To detect relevant changes in mRNA expression, we performed an in-silico analysis of WHO grade II and IV glioma sequencing datasets provided by The Cancer Genome Atlas (TCGA) to investigate mRNA expression levels of relevant heme biosynthesis genes: Solute Carrier Family 15 Member 1 and 2 (SLC15A1 and SLC15A2), Aminolevulinate-Dehydratase (ALAD), Hydroxymethylbilane-Synthase (HMBS), Uroporphyrinogen-III-Synthase (UROS), Uroporphyrinogen-Decarboxylase (UROD), Coproporphyrinogen-Oxidase (CPOX), Protoporphyrinogen-Oxidase (PPOX), ATP-binding Cassette Subfamily B Member 6 (ABCB6)/G Member 2 (ABCG2) and Ferrochelatase (FECH). Altogether, 258 WHO grade II and 166 WHO grade IV samples were investigated. The mRNA expression levels showed significant differences in 8 of 11 examined genes between WHO grade II and IV gliomas. Significant differences in mRNA expression included increases of HMBS, UROD, FECH and PPOX as well as decreases of SLC15A2, ALAD, UROS and ABCB6 in WHO IV gliomas. Since the majority of changes was found in directions that might actually impair PpIX accumulation in WHO grade IV gliomas, additional studies are needed to analyze the corresponding factors of the heme biosynthesis also on protein level.

Improved Diagnostic Imaging of Brain Tumors by Multimodal Microscopy and Deep Learning.

Fluorescence-guided surgery is a state-of-the-art approach for intraoperative imaging during neurosurgical removal of tumor tissue. While the visualization of high-grade gliomas is reliable, lower grade glioma often lack visible fluorescence signals. Here, we present a hybrid prototype combining visible light optical coherence microscopy (OCM) and high-resolution fluorescence imaging for assessment of brain tumor samples acquired by 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery. OCM provides high-resolution information of the inherent tissue scattering and absorption properties of tissue. We here explore quantitative attenuation coefficients derived from volumetric OCM intensity data and quantitative high-resolution 5-ALA fluorescence as potential biomarkers for tissue malignancy including otherwise difficult-to-assess low-grade glioma. We validate our findings against the gold standard histology and use attenuation and fluorescence intensity measures to differentiate between tumor core, infiltrative zone and adjacent brain tissue. Using large field-of-view scans acquired by a near-infrared swept-source optical coherence tomography setup, we provide initial assessments of tumor heterogeneity. Finally, we use cross-sectional OCM images to train a convolutional neural network that discriminates tumor from non-tumor tissue with an accuracy of 97%. Collectively, the present hybrid approach offers potential to translate into an in vivo imaging setup for substantially improved intraoperative guidance of brain tumor surgeries.

Influence of Corticosteroids and Antiepileptic Drugs on Visible 5-Aminolevulinic Acid Fluorescence in a Series of Initially Suspected Low-Grade Gliomas Including World Health Organization Grade II, III, and IV Gliomas.

OBJECTIVE: 5-aminolevulinic acid (5-ALA) has been increasingly used in recent years to identify anaplastic foci in primarily suspected low-grade gliomas (LGGs). However, 5-ALA fails to visualize a subgroup of focally anaplastic gliomas. Recently, 2 in vitro studies and 1 in vivo study assumed that antiepileptic drugs (AEDs) and dexamethasone have an influence on the 5-ALA metabolism/visible fluorescence in gliomas. The aim of this study was to analyze for the first time the influence of different AEDs and dexamethasone on visible 5-ALA fluorescence in a large cohort of suspected LGG. METHODS: We retrospectively analyzed adult patients with resection of radiologically suspected diffusely infiltrating LGG after 5-ALA administration at 2 specialized centers. Clinical data on the intraoperative 5-ALA fluorescence status, preoperative treatment with AED/dexamethasone, and the total daily dose in cases of levetiracetam and dexamethasone intake were noted. RESULTS: Altogether, 110 patients with suspected LGG were included. A significantly higher percentage of visible fluorescence was present in World Health Organization grade III/IV (73%) compared with World Health Organization grade II gliomas (11%; P < 0.001). In the multivariate analysis, we did not find an independent correlation between the visible fluorescence status and intake of dexamethasone/AED. Furthermore, the median daily dose of dexamethasone and levetiracetam did not differ significantly between fluorescing and nonfluorescing gliomas. CONCLUSIONS: In the largest series to date, we did not find a drug-related influence of either dexamethasone or different AED on visible 5-ALA fluorescence in suspected LGG. According to our preliminary data, preoperative treatment with these common drugs in neurosurgery can be performed safely before 5-ALA-assisted surgery of suspected LGG.

Is Intraoperative Pathology Needed if 5-Aminolevulinic-Acid-Induced Tissue Fluorescence Is Found in Stereotactic Brain Tumor Biopsy?

BACKGROUND: Intraoperative histopathology and acquisition of multiple tissue samples in stereotactic biopsies results in a prolonged length of surgery and potentially increased complication rate. OBJECTIVE: To investigate the clinical benefits of a novel strategy for stereotactic brain tumor biopsies with the assistance of 5-aminolevulinic acid (5-ALA) induced fluorescence. METHODS: Patients that received 5-ALA prior to stereotactic biopsy of a suspected brain tumor were included. According to our strategy, the procedure was terminated in the case of strong fluorescence of the biopsy samples. In contrast, intraoperative histology was demanded in the case of vague/no fluorescence. Length of surgery, number of biopsy samples, diagnostic rate, and periprocedural complications were compared between these 2 groups. RESULTS: Altogether, 79 patients were included, and strong fluorescence was present in 62 cases (79%), vague fluorescence was in 4 cases (5%), and no fluorescence was in 13 cases (16%). The diagnostic rate was comparable in biopsies with strong fluorescence without intraoperative histopathology and cases with vague/no fluorescence with intraoperative histopathology (98% vs 100%; P = 1.000). A significantly shorter length of surgery (41 vs 77 min; P < .001) and reduced average number of biopsy samples (3.6 vs 4.9; P = .011) was found in patients with strong compared to vague/no fluorescence. However, no statically significant difference in periprocedural complications between cases with strong and vague/no fluorescence was found (7% vs 18%; P = .166). CONCLUSION: Our data demonstrate the clinical benefits of a novel strategy for stereotactic brain tumor biopsies with assistance of 5-ALA. Thus, this biopsy strategy will increase the efficiency of this standard neurosurgical procedure in the future.

Detailed analysis of 5-aminolevulinic acid induced fluorescence in different brain metastases at two specialized neurosurgical centers: experience in 157 cases.

OBJECTIVE: Incomplete neurosurgical resection of brain metastases (BM) due to insufficient intraoperative visualization of tumor tissue is a major clinical challenge and might result in local recurrence. Recently, visible 5-aminolevulinic acid (5-ALA) induced fluorescence was first reported in patients with BM. The aim of this study was thus to investigate, for the first time systematically, the value of 5-ALA fluorescence for intraoperative visualization of BM in a large patient cohort. METHODS: Adult patients (≥ 18 years) with resection of suspected BM after preoperative 5-ALA administration were prospectively recruited at two specialized neurosurgical centers. During surgery, the fluorescence status (visible or no fluorescence); fluorescence quality (strong, vague, or none); and fluorescence homogeneity (homogeneous or heterogeneous) of each BM was investigated. Additionally, these specific fluorescence characteristics of BM were correlated with the primary tumor type and the histopathological subtype. Tumor diagnosis was established according to the current WHO 2016 criteria. RESULTS: Altogether, 157 BM were surgically treated in 154 patients. Visible fluorescence was observed in 104 BM (66%), whereas fluorescence was absent in the remaining 53 cases (34%). In detail, 53 tumors (34%) showed strong fluorescence, 51 tumors (32%) showed vague fluorescence, and 53 tumors (34%) had no fluorescence. The majority of BM (84% of cases) demonstrated a heterogeneous fluorescence pattern. According to primary tumor, visible fluorescence was less frequent in BM of melanomas compared to all other tumors (p = 0.037). According to histopathological subtype, visible fluorescence was more common in BM of ductal breast cancer than all other subtypes (p = 0.008). It is of note that visible fluorescence was observed in the surrounding brain tissue after the resection of BM in 74 (67%) of 111 investigated cases as well. CONCLUSIONS: In this largest series to date, visible 5-ALA fluorescence was detected in two-thirds of BM. However, the characteristic heterogeneous fluorescence pattern and frequent lack of strong fluorescence limits the use of 5-ALA in BM and thus this technique needs further improvements.