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The intelligent knife: a potential ‘game-changer’ for cancer surgery

The impact of reoperation is not to be underestimated.

Mr Daniel Leff, breast surgeon

Surgeons have been using electricity to cut tissue for over a century.

Their handheld electrical devices generate heat that seamlessly break tissue apart.

But these electrical blades technically don’t cut tissue like a scalpel, they burn it instead. Whilst this approach is clean and limits blood loss, it also produces a puff of smoke that could hold the key to more precise surgery.

For many people with cancer, this type of surgery is almost a guaranteed part of their treatment. In some cases, it cures them. But for others, it’s just the start of a cancer journey marked by postponed treatments and extended hospital stays because they need another operation.

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Reoperation: why we need to improve cancer surgery

Carol had surgery to remove a breast tumour. After testing it in the lab her doctors told her that they couldn’t be sure that they’d taken all the cancer out so she had to have another operation.

Reoperation: why we need to improve cancer surgery

Carol had surgery to remove a breast tumour. After testing it in the lab her doctors told her that they couldn’t be sure that they’d taken all the cancer out so she had to have another operation.

Reoperation

Mr Daniel Leff is a breast cancer surgeon at Imperial College London. Every day he takes women with breast cancer into surgery to remove their tumours. Before they go into theatre they have to sign a consent form. At the bottom of every form sits a stat that out of 100 women having this type of surgery, on average between 20 and 30 will have to go back for another operation.

“Not only do patients not like being reoperated on,” says Leff, “but if you have to go back into surgery, the risk of problems after surgery also goes up.”

“The risk of infection is greater and the cosmetic outcomes are certainly poorer.”

Leff says the cost of reoperation is financial as well as physical. Reoperation means more time off work, longer recovery and hospital beds remaining occupied. In many cases, patients who need further treatment, such as chemotherapy or radiotherapy, can’t have it until their final surgery is finished and they’re fully recovered.

All this disruption is down to a lack of technology.

Right now, surgeons don’t have a way to know for sure that they’ve removed every cancer cell from the body during the procedure, first time.

While the patient is in recovery, a tissue sample from the edge of where the surgeon has cut is already on its way to a pathology lab to be looked at under a microscope. If cancer cells are detected around the edge of where the surgeon has cut it’s called a ‘positive margin’.

“In that situation it’s 50:50, a flip of the coin, as to whether there’s more disease inside the patient,” says Leff. “The risk of leaving cancer inside them is too high, so we have to go back to theatre and check by removing more tissue.”

“Telling a patient that they have to have a second surgery is really humbling, it feels like a surgical failure.”

Mr Daniel Leff, surgeon

"I had a lot more side effects after my second operation."

Carol

“It is something that in this day and age we feel shouldn’t happen, and yet we know it does.”

Mr Daniel Leff, surgeon

"It would have saved me a lot of pain if everything was taken out the first time."

Carol

“I fear the reaction I’m going to get. How is the patient going to take this news?”

Mr Daniel Leff, surgeon

"It was scary knowing that the cancer could still be in there and still be growing. Physiologically I really struggled."

Carol

But all this could change thanks to an experimental surgical device called the intelligent knife that has the unique ability to sniff out cancer cells.

Information in the smoke

When meat cooks on a barbecue the tissues heat up and start to smoke. Surgeons say this is no different in surgery.

When the surgeon’s knife heats up the tissue to break it apart, an aerosol is created containing a complex mix of all the molecules from the tissue that has just been cut. In theatre, this aerosol has a smoky appearance. Ever since electro-surgery began, this smoke has been thought of as an irritant, which is sucked out of the operating room and thrown away.

“I remember that for a while it was thought that we as surgeons might be breathing in dangerous materials during surgery,” says Professor Lord Darzi, a world-renowned surgeon from Imperial College London. So, Darzi performed a study to see if the smoke released living cancer cells into the air.

“Various studies showed no viable airborne cancer cells, but did show cancer cell particles in the surgical smoke, and it got us wondering if we could analyse the smoke further to see if there were any usable particles for specific cancer testing,” says Darzi.

So with leading researcher Professor Jeremy Nicholson from Imperial College London, Darzi approached Hungarian chemist Zoltan Takats who had invented a technology that could analyse the surgical smoke in even greater detail.

The intelligent surgeon’s knife

Professor Takats didn’t set out to make a surgical device for cancer.

“I was developing new tools that could analyse samples directly without any treatment,” says Takats. “Tools that could tell you the composition of a sample in real time.”

His project involved a piece of technology called a mass spectrometer. This rather chunky machine can be found in most chemistry labs around the world. It reveals the different molecules inside a sample by measuring them based on their size and charge, like a very accurate molecular weighing scale.

Takats knew that he had invented a way for the mass spectrometer to recognise different tissue types. He now had to find a medical need that could benefit from his research.

After talking to various surgeons in Hungary, Takats suspected that the surgical smoke produced in theatre might not be as much of a nuisance as initially thought. In fact, it could be the perfect sample to play with.

“As we learnt more about cancer biology and cancer care we realised we could help. I was then gradually pulled into this world,” he says.

Takats proposed that the smoke made from the regular surgeon’s knife could be funnelled into his molecular weighing machine through a tube. After a few seconds of analysis, there was a chance the machine could work out the fingerprint profile of the tissue type that has just been cut.

This would mean the surgeon would know if they’re cutting through healthy tissue or cancer only a few seconds after their first cut. This would open the possibility of making decisions live in the operation based on this information.

Takats knew that if he could prove his machine was able to tell cancer tissue and healthy tissue apart in theatre, then it had the potential to boost the accuracy of cancer surgery.

“I started working with a group of surgeons in Hungary in 2008 to do the initial work and then, after conversations with Professor Darzi, I moved to Imperial in 2012,” he says.

And so he brought the now-trademarked iKnife with him to the UK.

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iKnife: the surgical device that sniffs out cancer

The iKnife works out the chemical composition of surgical smoke.

iKnife: the surgical device that sniffs out cancer

The iKnife works out the chemical composition of surgical smoke.

When I first heard about the iKnife I thought it was a genius idea.

Mr Daniel Leff, surgeon
From inception to theatre

It was Professor Lord Darzi who introduced the inventor of the iKnife to the surgeon with the ambition to take it into theatre.

“I remember meeting Zoltan when I was a registrar at Imperial in 2011. He had come to present his idea about the smoke,” says Leff. “I was pretty blown away by the concept.”

Keen to get things going, the two started initial tests to ensure the iKnife could tell the difference between healthy tissue samples and breast cancer in the controlled setting of the lab.

“We had to teach the iKnife to recognise cancer,” says Takats. “We used machine learning algorithms, which need to be trained.”

The team train these computer programs by using the iKnife on hundreds of tumour samples taken from surgery.

“We send these same samples to the lab to find out the actual environment of each individual cut,” says Takats

Because the team knows the exact origins of these samples, they can use the lab data to teach the computer, connected to the mass spectrometer, the molecular ‘fingerprints’ that tell healthy tissue from cancer.

Slowly but surely, the team has built a molecular library that means the iKnife can accurately tell the difference between a tumour sample and a healthy one.

These first steps wouldn’t have been possible without support from the Association of Breast Surgeons (ABS), which funded this initial development work. Mark Sibbering, ABS President, says devices such as the iKnife, that might help surgeons tackle uncertainty during the first surgery, will be a “major advance”. ABS “has been very pleased to support its initial development,” he adds.

Focusing on breast cancer

“The latest data we have from the UK is that on average, around 20 in 100 patients with invasive breast cancer have to go back and have another surgery,” says Leff.

“This increases to 30 in 100 patients for those who have cells with pre-cancerous changes that might develop into cancer.

“When you consider that breast cancer is the most common cancer in women, and by and large breast conserving surgery or lumpectomy is a very common operation, that’s a huge number of women that this technology could help.”

While Takats’ team is also studying the iKnife’s potential in other cancers, these stats have spurred their work with breast cancer on.

“Breast cancer was one of the ‘low-hanging fruits’ because of the high re-excision rates that women have to go through,” says Takats. “It was a place where we could really make a difference. Even if we just half the current re-excision rate then it’s already a big achievement.

Armed with the evidence that the iKnife worked on breast cancer tissue in the lab, the next step was the operating room. The challenge the team faces is seeing if the device can recognise healthy tissue and cancer tissue in breast cancer patients during surgery.

And this is where Cancer Research UK comes in.

“Cancer Research UK got involved off the back of quite a lot of the proof-of-concept work that we’d already done that was supported by the Association of Breast Surgery, Cancer Research UK’s Imperial Centre and the Biomedical Research Centre,” says Leff.

In 2017, Takats and Leff were awarded a Cancer Research UK grant to help them fund the REI-EXCISE trial. The study, now in full swing at Charing Cross Hospital, aims to find out if the iKnife can be used during breast cancer surgery.

“Without the support of Cancer Research UK we simply could not have taken the next big leap of doing this ‘first in women’ study, and for that we are incredibly grateful, ” says Leff.

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iKnife: the first human trial

Cancer Research UK is helping fund the REI-EXCISE trial that’s testing the iKnife during surgery.

iKnife: the first human trial

Cancer Research UK is helping fund the REI-EXCISE trial that’s testing the iKnife during surgery.

"Right now, it’s just me doing the operation and sending smoke to the device."

Daniel Leff, surgeon

"The surgeon explained that taking part in the trial wouldn’t affect my treatment at all."

Carol

"The trial doesn’t interfere with surgery whatsoever. I operate in exactly the same way."

Daniel Leff, surgeon

"Saying ‘no’ to taking part never occurred to me. I thought it was a good idea to be able to help somebody else."

Carol
Testing the intelligent knife in surgery

There’s still a lot of development left until the iKnife can be useful in the clinic.

Prof Zoltan Takats, inventor

If REI-EXCISE is successful, Leff says, they still can’t assume that the iKnife can be used to guide surgery. A larger trial will be needed to see if surgery using the iKnife reduces the number of women having to go back and have another operation.

“Next we’ll need to do a randomised control trial where we either give patients the usual breast conserving surgery or iKnife-guided surgery,” says Leff.

Comparing the number of women going back to theatre from these two groups is the only way to tell for sure if the iKnife could transform surgery for breast cancer.

“We simply can’t get to this stage though until we know it works in the patient. So that’s why the REI-EXCISE trial is so important,” says Leff.

There are also unanswered questions about the iKnife itself.

“We have further questions about the general usability,” says Takats.

These questions go beyond analysing tissue molecules or the surgery itself. They are rooted in the psychology of surgeons such as, ‘what’s the general attitude from the surgical community to a device like this?’ Leff and Takats hope to find out.

“We also want to work out the ideal way of feeding this information back to the surgeons,” says Takats. “In the lab we use a screen with a kind of traffic light system that flashes up as ‘cancer’ or ‘normal’ tissue. In theatre we could project some form of augmented reality over the surgical sight, or maybe use an audio signal. There are many possibilities.”

There’s a lot to do before the iKnife can become part of a cancer surgeon’s toolkit, but the REI-EXCISE trial should take it that little bit closer.

Research also continues in other types of cancer too. A newly published study from Takats and another collaborator at Imperial College London, Dr David Phelps, has shown that the iKnife can recognise ovarian cancer samples in the lab. They hope it could even flag up cells with DNA changes that mean they could become ovarian cancer which currently are very hard to spot.

So with more testing and tinkering, the surgeons of the future could have something that the surgeons today don’t always have; certainty that every last cancer cell has been removed, and the confidence to tell their patients that surgery went well, and they won’t be seeing them again.