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Quantification of PpIX-fluorescence of cerebral metastases: a pilot study

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Abstract

5-ALA fluorescence-guided surgery (FGS) is a major advance in neuro-oncological surgery. So far, Protoporphyrin IX (PpIX)-fluorescence has been observed in about half of cerebral metastases resected with routinely equipped microscopes during 5-ALA FGS. The aim of the present pilot study was to quantify PpIX-induced fluorescence of cerebral metastases with a spectrometer. We hypothesize that non-fluorescing metastases under the operating microscope may have spectrometrically measurable levels of fluorescence. A second aim was to analyze correlations between quantified 5-ALA fluorescence and histology or primary tumor type, respectively. Standard FGS was performed in all patients. The fluorescence intensity of the metastasis was semi-quantitatively determined in vivo by a senior surgeon using a special surgical microscope equipped for FGS. A systematic spectrometric ex vivo evaluation of tumor specimens and PpIX-induced fluorescence was performed using a spectrometer connected by optic fibers to a handheld probe. Quantification of 5-ALA-derived fluorescence was measured in a standardized manner with direct contact between mini-spectrometer and metastasis. The difference between the maximum PpIX-fluorescence at 635 nm and the baseline fluorescence was defined as the PpIX fluorescence intensity of the metastasis and given in arbitrary units (AU). Diagnosis of a cerebral metastasis was confirmed by histopathological analysis. A total of 29 patients with cerebral metastases were included. According to neuropathological analysis, 11 patients suffered from non-small cell lung cancer, 10 patients from breast cancer, 6 patients from cancer originating in the gastro-intestinal tract, 1 patient suffered from a malignant melanoma and one patient from renal cancer. The mean age was 63 years (37–81 years). 15 patients were female, 14 patients male. 13 cerebral metastases were considered as ALA-positive by the surgeon. In nine metastases, 5-ALA fluorescence was not visible to the naked eye and could only be detected using the spectrometer. The threshold for an ALA signal rated as “positive” by the surgeon was PpIX fluorescence above 1.1 × 106 AU. The mean PpIX fluorescence of all analyzed cerebral metastases was 1.29 × 106 ± 0.23 × 106 AU. After quantification, we observed a significant difference between the mean 5-ALA-derived fluorescence in NSCLC and breast cancer metastases (Mean Diff: − 1.2 × 106; 95% CI of difference: − 2.2 × 106 to − 0.15 × 106; Šidák-adjusted p = 0.026). In our present pilot series, about half of cerebral metastases showed a 5-ALA fluorescence invisible to the naked eye. Over 50% of these non-fluorescent metastases show a residual 5-ALA fluorescence which can be detected and quantified using a spectrometer. Moreover, the quantified 5-ALA signal significantly differed with respect to the primary tumor of the corresponding cerebral metastasis. Further studies should evaluate the predictive value of the 5-ALA signal and if a quantified 5-ALA signal enables a reliable intraoperative differentiation between residual tumor tissue and edematous brain—in particular in metastases with a residual fluorescence signal invisible to the naked eye.

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Abbreviations

5-ALA:

5-Aminolevulinic acid

AU:

Arbitrary unit

PpIX:

Protoporphyrin IX

FGS:

Fluorescence guided surgery

NSCLC:

Non-small-cell lung cancer

SCLC:

Small-cell lung cancer

nm:

Nanometer

CI:

Confidence interval

p:

p-value

U.S.:

United States of America

PFS:

Progression-free survival

min:

Minute

e.g.:

Exempli gratia

EGFR:

Epidermal growth factor receptor

ALK:

Anaplastic lymphoma kinase

HER2/neu:

Human epidermal growth factor receptor 2

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Acknowledgements

We thank Maria Smuga and Osman Auale for their help.

Funding

The present study was not funded.

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Authors and Affiliations

  1. Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany

    Johannes Knipps, Lisa M. Neumann, Marion Rapp, Maxine Dibué-Adjei, Christiane Freiin von Saß, Jan-Malte Placke, Hendrik-Jan Mijderwijk, Hans-Jakob Steiger, Michael Sabel, Jan-Frederick Cornelius & Marcel A. Kamp

  2. Division of Informatics and Statistics, Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany

    Igor Fischer & Hendrik-Jan Mijderwijk

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  1. Johannes Knipps
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Prof. Sabel and PD Dr. Rapp work as consultants for Johnson & Johnson Company and Integra Company. Dr. Dibué-Adjei is an employee of LivaNova PLC, manufacturer of vagus nerve stimulators. All other authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

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Knipps, J., Fischer, I., Neumann, L.M. et al. Quantification of PpIX-fluorescence of cerebral metastases: a pilot study. Clin Exp Metastasis 36, 467–475 (2019). https://doi.org/10.1007/s10585-019-09986-x

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