Glioma visualization for surgical opportunities
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor of the central nervous system, characterized by widespread infiltration and strong vascular proliferation into the surrounding brain parenchyma. Median survival is 14 months when maximum safe surgical resection with concomitant radio – chemotherapy is performed. Unfortunately, the treatment efficacy is limited due to the invasive pattern of the tumor, overall resistance to therapy and to the high rates of recurrence. Treatment with receptor blockers such as EGFR, anti VEGF or adoptive T-cell strategies for GBM have not shown any improvement in overall survival (OS) or often even in progression-free survival (PFS). The standard of care is surgical resection and diagnosis for histological confirmation and bio-molecular classification, followed by radio-chemotherapy using alkylating agents such as Temozolomide usually in adherence to Stupp protocol as first line treatment and Lomustine another alkylating agent as second line. The role of surgical resection remains a fundamental part in the treatment of GBM as overall survival is prolonged when resection can be maximized. Although the OS can be increased by augmenting surgery, we face the dilemma that the infiltrative nature of GBM goes beyond the macroscopically visible, which usually corresponds to the contrast enhancing part of the tumor in MRI. This can be shown in brain sections and clinical progression often evidences that brain invasion goes much beyond the macroscopically visible during surgery.

Increasing the photodynamic signal of glioma cells has fundamentally two important purposes:

1) to increase the visibility during surgery and thus specifically reduce the tumor burden.
2) to use the photodynamic effect for direct tumor treatment either by superficial light exposition of fiber-optically

 

Comparison between OPMI PENTERO 900 and Qp9 Zeiss microscopes. The figures show cryosectioned slice of GBM xenograft mouse model. In panel (a) and (b) visualization under OPMI PENTERO 900 with white light source and UV laser Blue 400, respectively. Panel (c) show the color coded matrix image obtained after the PpIX quantification by Qp9. * = tumor region. Scale bars = 1mm. (Reinert, M. et al. 2019. Quantitative modulation of PpIX fluorescence and improved glioma visualization. Front. Surg. 6).

TTF Fields
TTFields is a new therapeutic technology for treating newly diagnosed or recurrent GBM. It was demonstrated that it is able to suppress the growth of cancer cells destabilising microtubule elongation and increasing membrane permeability. Here, we investigate the effects of TTFields on glioma cells, with different EGFR status and consequently different PpIX fluorescence. Exposure to TTFields during or after pharmacological treatments may represent a novel strategy to act on EGFR pathway to ameliorate the visualization of PpIX fluorescence in patients where it is not enough to ensure a safe and precise removal of the tumor bulk.  In fact, if a combination of TTFields and drug treatment should give the desired results, this strategy could be applied on patients before being subjected to surgical resection.

Publications

  • Burgio F. et al (2019) SERS based imaging for the detection of glioblastoma tumor cells during surgery. In preparation.
  • Piffaretti D, F Burgio, M Thelen, A Kaelin, P Paganetti, M Reinert, ML D’Angelo (2019) Protoporphyrin IX tracer fluorescence modulation for improved brain tumor cell lines visualization. J. Photochem. Photobiol. B (in press).
  • Reinert M, D Piffaretti, M Wilzbach, C Hauger, R Guckler, F Marchi F, ML D’Angelo (2019) Quantitative modulation of PpIX fluorescence and improved glioma visualization. Front. Surg. 6, 41. doi: 10.3389/fsurg.2019.00041
  • Fontana, AO, D Piffaretti, F Marchi, F Burgio, AB Faia-Torres, P Paganetti, S Pinton, U Pieles, M Reinert (2017) Epithelial growth factor receptor expression influences 5-ALA induced glioblastoma fluorescence. J. Neurooncol. 133, 497–507.

Collaborations:
Universität Bern, Institut für angewandte Physik: Prof. Dr. phil.nat. Martin Frenz
Universität Basel, Neurochirurgische Klinik, Universitätsspital Basel: Prof. Dr. med. Luigi Mariani