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. Quantitative modulation of PpIX fluorescence and improved glioma visualization. Front. Surg. 6, (2019)).

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:

  1. Reinert, M. et al. Quantitative modulation of PpIX fluorescence and improved glioma visualization. Front. Surg. 6, (2019).
  2. Piffaretti, D. et al. Protoporphyrin IX tracer fluorescence modulation for improved brain tumor cell lines visualization. J. Photochem. Photobiol. B (submitted).
  3. Burgio, F et al. SERS based imaging for the detection of glioblastoma tumor cells during surgery. (2019).
  4. Burgio, F. et al. Production of Anti-EGFR Gold Nanoparticles for Raman Detection of Glioblastoma Tumor Cells. in Journal of Neurological Surgery Part A: Central European Neurosurgery 79, P15 (Georg Thieme Verlag KG, 2018).
  5. Reinert, M. et al. Exploring the modulation of PpIX in glioblastoma cells. (2018). Available at: https://academy.eans.org/eans/2018/brussels/227774/michael.reinert.exploring.the.modulation.of.ppix.in.glioblastoma.cells.html?f=listing%3D3%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D1.
  6. Burgio, F., Piffaretti, D., Mariani, L., Pieles, U. & Reinert, M. P04.06 Gold nanoparticles development for Raman guided Glioblastoma visualization during surgical resection. Neuro-Oncol. 19, iii41 (2017).
  7. Fontana, A. O. et al. Epithelial growth factor receptor expression influences 5-ALA induced glioblastoma fluorescence. J. Neurooncol. 133, 497–507 (2017).

 Oral and Poster Presentations

  • Digital poster at the 8th Research Day of Southern Switzerland, March 2019, Lugano (Switzerland)
  • Poster presentation at the BENEFRI workshop: Methods in Experimental Neurosciences: From Animal Models to Humans, February 2019, Bern (Switzerland)
  • Oral presentation at the GCB symposium, January 2019, Bern (Switzerland)
  • Oral presentation at the Annual meeting Swiss Society of Neurosurgery/Swiss Society of Neuroradiology (SSNS), May 2018, Lugano (Switzerland)
  • Oral presentation at The International Conference On Nanomedicine And Nanobiotechnology, September 2018, Rome (Italy)
  • Poster presentation at The Joint Annual Meeting, May 2018, Lugano (Switzerland)
  • Poster presentation and poster flash at the BENEFRI Neuroscience Workshop: « Experimental neuroscience: from invertebrate models to human brain imaging», February 2018, Fribourg (Switzerland)
  • Poster presentation at the 14th Confocal Raman Imaging Symposium, September 2017, Ulm (Germany)
  • Poster presentation at the Ph.D. retreat, June 2017, Martigny (Switzerland)
  • Poster presentations at the 5th Meeting of the World Federation of Neuro-Oncology Societies (WFNOS), May 2017, Zurich (Switzerland)
  • Poster presentation at the 7th Research Day of Southern Switzerland, April 2017, Lugano (Switzerland)
  • Poster presentation at the BENEFRI workshop: Methods in Fundamental and Clinical Neuroscience, February 2017, Bern (Switzerland)
  • SLAM presentation at the GCB symposium, February 2017, Bern (Switzerland)
  • Poster presentation at the Biointerface International Conference, August 2016, Zurig (Switzerland)
  • Poster presentation at the Ph.D. retreat, June 2016, Romanshorne (Switzerland)
  • Poster presentation at the 6th Research Day of Southern Switzerland, April 2016, Lugano (Switzerland)
  • Raman Microscopy Workshop, ETH Zurig, February 2016, Zurig (Switzerland)

Collaborations:

 Universität Bern, Instituti für angewandte Physik: Prof. Dr. phil.nat. Martin Frenz

Universität Basel, Neurochirurgische Klinik, Universitätsspital Basel: Prof. Dr. med. Luigi Mariani

Team:

Prof. Dr. med. Michael Reinert

Dr. phil.nat. Maria Luisa D’Angelo

Deborah Piffaretti, PhD Student

Floriana Burgio, PhD Student

Alice Colavolpe, Master Student