Research Papers:

The metastatic infiltration at the metastasis/brain parenchyma-interface is very heterogeneous and has a significant impact on survival in a prospective study

Laila Siam _, Annalen Bleckmann, Han-Ning Chaung, Alexander Mohr, Florian Klemm, Alonso Barrantes-Freer, Raquel Blazquez, Hendrik A. Wolff, Florian Lüke, Veit Rohde, Christine Stadelmann and Tobias Pukrop

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Oncotarget. 2015; 6:29254-29267. https://doi.org/10.18632/oncotarget.4201

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Laila Siam1, Annalen Bleckmann2,3, Han-Ning Chaung2, Alexander Mohr4, Florian Klemm2, Alonso Barrantes-Freer5, Raquel Blazquez2, Hendrik A. Wolff6, Florian Lüke7, Veit Rohde1, Christine Stadelmann5, Tobias Pukrop2,7

1Department of Neurosurgery, University Medical Center, Göttingen, Germany

2Department of Hematology and Medical Oncology, University Medical Center, Göttingen, Germany

3Department of Medical Statistics, University Medical Center, Göttingen, Germany

4Department of Neuroradiology, University Medical Center, Göttingen, Germany

5Institute of Neuropathology, University Medical Center, Göttingen, Germany

6Department of Radiotherapy and Radiation Oncology, University Medical Center, Göttingen, Germany

7Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany

Correspondence to:

Tobias Pukrop, e-mail: [email protected]

Keywords: astrocytes, brain metastasis, glial-pseudo capsule, metastatic infiltration, organ-specific defense

Received: April 11, 2015     Accepted: June 08, 2015     Published: June 17, 2015


The current approach to brain metastases resection is macroscopic removal of metastasis until reaching the glial pseudo-capsule (gross total resection (GTR)). However, autopsy studies demonstrated infiltrating metastatic cells into the parenchyma at the metastasis/brain parenchyma (M/BP)-interface. Aims/Methods: To analyze the astrocyte reaction and metastatic infiltration pattern at the M/BP-interface with an organotypic brain slice coculture system. Secondly, to evaluate the significance of infiltrating metastatic tumor cells in a prospective biopsy study. Therefore, after GTR, biopsies were obtained from the brain parenchyma beyond the glial pseudo-capsule and analyzed histomorphologically. Results: The coculture revealed three types of cancer cell infiltration. Interestingly, the astrocyte reaction was significantly different in the coculture with a benign, neuroectodermal-derived cell line. In the prospective biopsy study 58/167 (34.7%) samples revealed infiltrating metastatic cells. Altogether, 25/39 patients (64.1%) had proven to exhibit infiltration in at least one biopsy specimen with significant impact on survival (OS) (3.4 HR; p = 0.009; 2-year OS was 6.6% versus 43.5%). Exceptionally, in the non-infiltrating cohort three patients were long-term survivors. Conclusions: Metastatic infiltration has a significant impact on prognosis. Secondly, the astrocyte reaction at the M/BP-interface is heterogeneous and supports our previous concept of the organ-specific defense against metastatic (organ-foreign) cells.

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