Dataset Information

Validating a new generation filter system for visualizing 5-ALA-induced PpIX fluorescence in malignant glioma surgery: a proof of principle study.

ABSTRACT: BACKGROUND:The BLUE 400 filter system (Carl Zeiss Meditec, Oberkochen, Germany) has provided visualization of 5-ALA-induced fluorescence-guided surgery for more than 20 years. Nevertheless, constraints, e.g., limited background discrimination during hemostasis, obstruct fluency of surgery. A novel filter with improved background visualization was developed, requiring validation regarding fluorescence discrimination. The aim of this article is to determine diagnostic accuracy and perception of protoporphyrin IX (PpIX) discrimination of a novel filter system with higher background illumination (BLUE 400 AR) compared with the gold standard, BLUE 400. METHODS:A surgical microscope equipped with both BLUE 400 and BLUE 400 AR was used. Comparisons were performed on a biological basis and on the visual perception of margins. High-resolution images were compared during and after surgery by senior neurosurgeons. In a predefined biopsy algorithm, four biopsies per patient at tumor margins of PpIX fluorescence and adjacent brain were acquired using BLUE 400 AR only from regions intended for resection and assessed for cell count and density. RESULTS:Thirty-two patients with malignant gliomas were included in this study. BLUE 400 AR markedly enhanced the brightness of the surgical field, allowing superior discrimination of brain anatomy. A total of 128 biopsies from fluorescence margins were collected. Positive predictive value (PPV) was 98.44% (95% CI, 90.06-99.77%) for malignant glioma. Residual median cell density in non-fluorescent tissue was 13% (IQR 13 to 31). Perception of the location of fluorescent margins on HD images was equivalent for both filter combinations. CONCLUSIONS:BLUE 400 AR demonstrated superior background compared with conventional BLUE 400 in malignant glioma surgery but comparable fluorescence margins and PPV. Therefore, BLUE 400 AR can be considered safe and effective in supporting malignant glioma surgery.

SUBMITTER: Suero Molina E

PROVIDER: S-EPMC7066295 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Validating a new generation filter system for visualizing 5-ALA-induced PpIX fluorescence in malignant glioma surgery: a proof of principle study.

Suero Molina Eric E Stögbauer Louise L Jeibmann Astrid A Warneke Nils N Stummer Walter W

Acta neurochirurgica 20200207 4

<h4>Background</h4>The BLUE 400 filter system (Carl Zeiss Meditec, Oberkochen, Germany) has provided visualization of 5-ALA-induced fluorescence-guided surgery for more than 20 years. Nevertheless, constraints, e.g., limited background discrimination during hemostasis, obstruct fluency of surgery. A novel filter with improved background visualization was developed, requiring validation regarding fluorescence discrimination. The aim of this article is to determine diagnostic accuracy and percepti ...[more]

PMID: 32034493

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Project description:5-Aminolevulinic acid (5-ALA) induced fluorescence to augment surgical resection for high grade glioma has become a standard of care. Protoporphyrin IX (PpIX) visibility is however subject to the variability of the single tumor expression and to the interobserver interpretation. We therefore hypothesized that in different glioma cell lines with variable 5-ALA induced fluorescence, the signal can be pharmacologically increased. We therefore analyzed in three different GBM cell lines, with different expression of epidermal growth factor receptor (EGFR), the variability of 5-ALA induced PpIX fluorescence after the pharmacological blockade at different steps of PpIX breakdown and influencing the outbound transport of PpIX. Using flow cytometry, fluorescence microplate reader, and confocal microscopy the PpIX fluorescence was analyzed after exposure to tin protoporphyrin IX (SnPP), deferoxamine (DFO), and genistein. We furthermore constructed a microscope (Qp9-microscope) being able to measure quantitatively the concentration of PpIX. These values were compared with the extraction of PpIX in tumor biopsy taken during the GBM surgery. Although all three cell lines showed an increase to 5-ALA induced fluorescence their baseline activity was different. Treatment with either SnPP, DFO and genistein was able to increase 5-ALA induced fluorescence. Qp9-microscopy of tumor sample produced a color coded PpIX concentration map which was overlaid on the tumor image. The PpIX extraction from tumor sample analyzed using the plate reader gave lower values of the concentration, as compared to the expected values of the Qp9-microscope, however still in the same decimal range of ?g/mL. This may be due to homogenization of the values during extraction and cell disaggregation. In conclusion pharmacological augmentation in GBM cell lines of PpIX signal is possible. A quantitative PpIX map for surgery is feasible and may help refine surgical excision. Further correlations of tumor tissue samples and Qp9-microscopy is needed, prior to develop an intraoperative surgical adjunct to the already existing 5-ALA induced surgery.

Project description:Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) as a cytotoxic photosensitizer could be a feasible treatment option for malignant gliomas. In a monocentric cohort of consecutive patients treated between 2006 and 2018, a risk profile analysis of salvage iPDT for local malignant glioma recurrences and associated outcome measures are presented here. It was considered indicated in patients with circumscribed biopsy-proven malignant glioma recurrences after standard therapy, if not deemed eligible for safe complete resection. A 3D treatment-planning software was used to determine the number and suitable positions of the cylindrical diffusing fibers placed stereotactically to ensure optimal interstitial irradiation of the target volume. Outcome measurements included the risk profile of the procedure, estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and prognostic factors. Forty-seven patients were treated, of which 44 (median age, 49.4 years, range, 33.4-87.0 years, 27 males) could be retrospectively evaluated. Recurrent gliomas included 37 glioblastomas (WHO grade IV) and 7 anaplastic astrocytomas (WHO grade III). Thirty (68.2%) tumors were O-6-methylguanine-DNA methyltransferase (MGMT)-methylated, 29 (65.9%)-isocitrate dehydrogenase (IDH)-wildtype. Twenty-six (59.1%) patients were treated for their first, 9 (20.5%)-for their second, 9 (20.5%)-for the third or further recurrence. The median iPDT target volume was 3.34 cm3 (range, 0.50-22.8 cm3). Severe neurologic deterioration lasted for more than six weeks in one patient only. The median TTF was 7.1 (95% confidence interval (CI), 4.4-9.8) months and the median PRS was 13.0 (95% CI, 9.2-16.8) months. The 2- and 5-year PRS rates were 25.0% and 4.5%, respectively. The treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. The promising outcome and acceptable risk profile deserve further prospective evaluation particularly to identify mechanisms and prognostic factors of favorable treatment response.

Project description:Simple Summary 5-aminolevulinic acid (5-ALA)-induced PpIX fluorescence is used in neurosurgery for intraoperative identification of high-grade glioma tissue. In this paper, using a fluorescence microscopy analysis on human tumor specimens, we assessed the actual number of fluorescence-positive tumor cells both in low-grade and high-grade glioma, and the ability of 5-ALA to cross the blood–brain barrier (BBB). We found that in high-grade gliomas, 32.7–75.5 percent of cells display 5-ALA induced PpIX fluorescence, whereas in low-grade gliomas the tumor cells did not fluoresce following 5-ALA. Immunofluorescence for BBB components suggested that 5-ALA does not cross the un-breached BBB. These findings are of crucial importance in planning neurosurgical resection of gliomas. Abstract 5-aminolevulinic acid (5-ALA)-induced PpIX fluorescence is used by neurosurgeons to identify the tumor cells of high-grade gliomas during operation. However, the issue of whether 5-ALA-induced PpIX fluorescence consistently stains all the tumor cells is still debated. Here, we assessed the cytoplasmatic signal of 5-ALA by fluorescence microscopy in a series of human gliomas. As tumor markers, we used antibodies against collapsin response-mediated protein 5 (CRMP5), alpha thalassemia/mental retardation syndrome X-linked (ATRX), and anti-isocitrate dehydrogenase 1 (IDH1). In grade III–IV gliomas, the signal induced by 5-ALA was detected in 32.7–75.5 percent of CRMP5-expressing tumor cells. In low-grade gliomas (WHO grade II), the CRMP5-expressing tumor cells did not fluoresce following 5-ALA. Immunofluorescence with antibodies that stain various components of the blood–brain barrier (BBB) suggested that 5-ALA does not cross the un-breached BBB, in spite of its small dimension. To conclude, 5-ALA-induced PpIX fluorescence has an established role in high-grade glioma surgery, but it has limited usefulness in surgery for low-grade glioma, especially when the BBB is preserved.

Dataset Information

Validating a new generation filter system for visualizing 5-ALA-induced PpIX fluorescence in malignant glioma surgery: a proof of principle study.

Publications

Validating a new generation filter system for visualizing 5-ALA-induced PpIX fluorescence in malignant glioma surgery: a proof of principle study.

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