Daniel Leff is co-Chief Investigator on REI-EXCISE, a Cancer Research UK funded trial evaluating the “iKnife”, a new technology that uses rapid evaporative ionisation mass spectrometry to discriminate tumour from normal tissue. Here, Daniel tells us more about the project.

When surgeons do lumpectomies for breast cancer, we try to conserve healthy tissue so we don’t deform the breast, we know that a good cosmetic outcome is important for our patients as it can greatly affect their feelings of femininity and quality of life. However, because we try to minimize the amount of normal breast around the tumour that we take out, between 20-30% of patients have to have further surgery due to ‘positive margins’ which is when the tumour tissue is too close to the cut resection edge for us to be certain we have removed all the cancer. In cases of positive margins, 50% of patients will have more disease inside their breast.

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Re-operation for positive margins is one of the biggest unsolved problems in breast cancer surgery

Going back to have surgery makes patients anxious; in addition, the next phase of therapy is pushed back until we have found time in our operating lists to accommodate the re-excision; there is generally a two-week delay. There are economic consequences too; at a very conservative estimate, the cost to the NHS of re-operative breast surgery is at least £22M a year and the true cost in damage to the wider economy is likely to be substantial and is as yet unknown.

Re-operation for positive margins is one of the biggest unsolved problems in breast cancer surgery, and several groups have previously worked on ways of analyzing the excised tumour in the operating theatre, to supplement the current gold standard of postoperative histopathology. However, they all take time and the snag with looking at excised tissue is that when positive margins are detected, it can be difficult and even more time-consuming to work out exactly where the corresponding edge is inside the patient’s breast.

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The iKnife uses the smoke plume as a margin detection system

We’ve come up with a different solution. During breast surgery, electrocautery is routinely used to cut through tissue — an electric current produces heat to simultaneously cut through tissue and cauterise it. The resulting smoke plume has to be sucked away from the operating field as it is rather toxic, but it is also a very rich source of information about the tissue being cut. The iKnife, invented here at Imperial College London by Zoltan Takats, uses the smoke plume as a margin detection system — you’re simultaneously cutting through tissue and using mass spectrometry to analyze the chemical composition of the exploded cells in the plume. Rather neatly, the dissection tool is coupled to the recognition tool so there’s no need to train surgeons on another device.

Over the last few years, we’ve been validating the iKnife as a cancer discrimination tool for breast cancer, by looking in the lab at the spectral fingerprints of normal and cancerous breast tissue. Normal breast tissues contain more triglyceride-like fat than cancer cells, whose outer cell membranes are phospholipid-rich and we have shown that the iKnife can differentiate with extreme accuracy.

Cancer Research UK is now funding the REI-EXCISE trial, a clinical feasibility study to find out whether the iKnife can tell the difference between normal and cancerous tissue in patients undergoing breast-conserving surgery. Right now, the biggest challenges are logistical; for example, the mass spectrometer component of the iKnife has a large footprint and is heavy. Therefore, it has been necessary to modify the operating theatres at both Charing Cross Hospital and The Royal Marsden, with whom we are collaborating, to accommodate it. As co-Chief Investigators, Zoltan and I coordinate a team of clinicians, surgeons, radiologists, pathologists, trials units, research technicians, engineers, and the external company who make the system. We hope that we will be able to move on to a randomised control trial of iKnife-guided breast surgery versus the current gold standard of normal breast surgery with a pathology assessment, with the potential to demonstrate the superiority of iKnife-guided surgery.

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The philosophy here at Imperial is very much about multidisciplinary science and collaboration

To work well here one must develop the ability to negotiate the terminologies and languages from different fields. One cannot do this type of work without some fundamental understanding of how the science is working and the challenges your collaborators are facing. If one is not sympathetic to these challenges, you may completely misunderstand what your colleagues need.

However, non-clinicians also rely heavily on us; coming into the clinical space is sometimes like landing on Mars—it can be very challenging working in the system and a difficult terrain to navigate, even for those of us inside it! Therefore, the relationship is totally symbiotic — in translational medicine you need excellent collaborations for anything to work.