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Simple Summary: 5-aminolevulinic acid (5-ALA) is administered orally before brain tumor surgery to improve intraoperative visualization of tumor tissue. In comparison to most of the aggressive high-grade gliomas, only a few low-grade gliomas (LGG) demonstrate visible fluorescence during surgery. As the prognosis of these LGG is hard to predict, we aimed to investigate if visible fluorescence might be an intraoperative marker for aggressive tumor behavior in patients with LGG. According to our data, we could demonstrate that intraoperative visible fluorescence is a predictor for early tumor progression, transformation into more aggressive higher-grade tumors, and shorter survival in LGG patients. Therefore, visible 5-ALA fluorescence is an intraoperative marker of unfavorable prognosis during surgery of LGG. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: In a recent study, we observed 5-ALA fluorescence not only in brain metastases (BM) but also in the peritumoral brain tissue. However, the histopathological correlate of visible 5-ALA fluorescence in the peritumoral brain tissue is not fully understood. Therefore, we safely collected and analyzed tissue samples from fluorescing and non-fluorescing peritumoral brain tissue. Surprisingly, 5-ALA fluorescence in the peritumoral brain tissue did not correlate with tumor cell infiltration but did show a significant relation with angiogenesis. Moreover, the presence of angiogenesis significantly correlated with shorter time to local progression/recurrence and one-year survival. Consequently, angiogenesis in the peritumoral brain tissue might be a novel prognostic marker in BM. This represents the first study in the literature describing the prognostic impact of angiogenesis in fluorescent peritumoral brain tissue of BM, which might support individualized perioperative treatment concepts in the future. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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., Competing Interests: A.S.B. has research support from Daiichi-Sankyo (≤10,000 Euro), Roche (>10000euro) and honoraria for lectures, consultations or advisory board participation from Roche Bristol-Meyers Squibb (all<5000 Euro) as well as travel support from Roche, Amgen and AbbVie. Z.B.-H. reports personal fees from Novartis and Roche and travel support from Roche, outside the submitted work. F.F. has travel and scientific support from Comesa, Novartis, Roche, Astra-Zeneca, Pfizer, Myriad, Nanostring, Bondimed (Polytech, Integra) and honoraria for advisory board participation from Pfizer, Astra-Zeneca, Lilly, and Roche. M.P. has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, Astra-Zeneca, AbbVie, Lilly, Medahead, Daiichi-Sankyo, Sanofi, Merck Sharp & Dome, Tocagen. The following for-profit companies have supported clinical trials and contracted research conducted by M.P. with payments made to his institution: Böhringer-Ingelheim, Bristol-Myers Squibb, Roche, Daiichi-Sankyo, Merck Sharp & Dome, Novocure, GlaxoSmithKline, AbbVie. R.B. has research support from Daiichi-Sankyo, Novartis and Roche, honoraria for lectures from Accord, Astra-Zeneca, BMS, Celgene, Eli-Lilly, Novartis, Pfizer, Roche and Sandoz and honoraria for advisory board participation from Astra-Zeneca, Celgene, Daiichi-Sankyo, Eisai, Eli-Lilly, MSD, Novartis, Pfizer, Roche and Samsung. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.