The cutting edge…
by Jim Caryl
Surgeons operating to remove malignant tumours often struggle to differentiate such tumours from surrounding healthy tissues. To ensure the complete removal of a tumour, surgeons also need to remove some of the surrounding healthy tissue, which of course isn’t desirable, especially in the brain.
A surgical electrode is a popular means to bisect (cut out) tissues. This makes use of a high-frequency electric current that is focussed into a highly localised ‘blade’ that effectively evaporates biological tissue as it comes into contact: water in the cells rapidly boils, proteins are precipitated and the membranes of the cells disintegrate forming a gaseous cloud of molecular ions of the major tissue components.
An innovative study published by team of researchers in Budapest, lead by Zoltán Takáts2, makes use of the fact that thermal evaporation of different tissues results in gaseous clouds with potentially different ion signatures. The team coupled a suction tube to a surgical electrode, and when cutting begins the tube draws the ions into an instrument called a mass spectrometer, something with which all CSI fans should be familiar. Using this process Takáts’ team found they could differentiate between healthy and malignant tissues, which provides a great basis for real-time tissue analysis under the knife, so to speak.
If you’re interested, a mass spectrometer is basically a means of identifying the elemental make-up of a material on the basis of mass to charge ratios (m/z). Essentially, ionized molecules (molecules with a charge) are accelerated into a curved deflector that uses magnets to deflect the ions. The degree of deflection depends on the mass of the ion (lighter ions are deflected more than heavier ones); and on the charge of the ion (ions with greater charge are deflected more). From this the chemical make-up of the sample can be determined. A detector at the end of the tube lets you know what ions made it and the relative abundance of the different ions
In this case, the mass spectrometer gave readings over a range of mass:charge ratios that correspond with phospholipids, the major components of cell membranes and thus the major component of any tissue. The team produced a library of tissue spectra taken from different tissues, each showing their own unique character, and developed an algorithm that allowed them to identify a particualr tissue with good confidence. They then used this to differentiate between a breast cancer and healthy tissue, and additionally with a dog melanoma model.
Takáts’ team have been able to demonstrate their ability to not only distinguish between healthy and malignant tissue, but also distinguish between the grade and necrotic state of the tumour. Furthermore, as analysis of the tissues is in the range of 0.1–0.3 s and data analysis takes 0.1–0.15 s, the principles of this system could be further developed into a real-time feedback monitor to a surgeon.
I have visions of a car parking sensor beeping more frequently as the surgeon starts to encroach upon healthy tissue.
It should be noted that this isn’t the first technique to try and differentiate tumour tissue from healthy tissue. It is known that tumour cells scatter light differently from the surrounding tissue, thus approaches using special optical light sources and detectors have been attached to the surgeon’s instrument.
Another approach is to make use of a selective stain that only stains the tumour cells. In a recent publication3, a team of scientists at Heidelburg university made use of the fact that in the process of sating their large energy demands, tumour cells take up a large amount of a blood protein called albumin. Albumin has been used in several studies as a means to target anti-cancer drugs specifically to tumour cells, but in this case scientists attached a fluorescent chemical to the albumin that ultimately makes the tumour cells glow yellow-green. This was used to differentiate a type of brain tumour called a glioma from surrounding tissue, and so reducing the margin of healthy surrounding tissue to be removed.
My thought is that perhaps a future refinement to the electrosurgical-Mass Spec approach is to use a similar process of targeting tumours with specific compounds that upon evaporation can further differentiate the spectrographic profile of the tissues.
1 Nature editors (2009). Analytical chemistry: Evaporating flesh Nature, 461 (7263), 451-451 DOI: 10.1038/461451d
2 Schäfer, K., Dénes, J., Albrecht, K., Szaniszló, T., Balog, J., Skoumal, R., Katona, M., Tóth, M., Balogh, L., & Takáts, Z. (2009). In Vivo, In Situ Tissue Analysis Using Rapid Evaporative Ionization Mass Spectrometry Angewandte Chemie International Edition DOI: 10.1002/anie.200902546
3 Kremer, P. et al. (2009) Intraoperative Fluorescence Staining of Malignant Brain Tumors Using 5-Aminofluorescein-Labeled Albumin, Neurosurgery 64 (3), 53-61 [access]
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