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Next Generation: Smoking Out Cancer

Researchers analyze smoke generated during surgical tumor removal to distinguish healthy and diseased tissues in real time.

By | July 17, 2013

Tumors in a skin tissue section.WIKIMEDIA, LWozniak & KWZielinskiThe device: Often, the best way to rid patients of cancer is to cut out the tumor itself, but this strategy risks removing healthy tissue along with malignant. Surgeons hoping to extract tumors without slicing away healthy tissue send samples to pathologists for analysis—a process that can take more than half an hour and is often required several times during surgery. But now, according to a report published today (July 17) in Science Translational Medicine, researchers have successfully used mass spectrometry to distinguish between healthy and cancerous tissue in the operating room, giving surgeons on-the-spot information about the tissue they’re considering removing.

“I believe it’s the first time mass spectrometry has been used this way”—to give real-time information on biological samples in humans, said Zheng Ouyang, a biomedical engineer at Purdue University, who was not involved in the research.

The researchers, led by Zoltán Takáts, an analytical chemist at Imperial College London, created a device they dubbed the iKnife (for “intelligent knife”), which transmits the smoke generated by hot surgical tools to a mass spectrometer for near-instant analysis. After testing the device in mice in 2010, Takáts and his team were ready to make the jump to human patients.

What’s new: Although mass-spectrometry analysis of tumor samples is nothing new, and many researchers are working on devising mass-spec-based biomedical applications, the technique has been difficult to bring into operating rooms because biological samples need to be ionized before the mass spectrometer can read them. Surgeons also balked at the notion of extra equipment in the operating room, which they feared would interfere with the surgeries they’d honed, explained, who collaborated on the current study with biological chemist Jeremy Nicholson, also at Imperial College London.

But Takáts and first author Júlia Balog hit upon an intriguing idea: surgeons use knives that generate an electric current that singes the tissue they’re cutting—creating smoke filled with already ionized molecules that could be fed into a mass spectrometer. What if surgeons could use that smoke to analyze the composition of the tissue?

The iKnife, a small device that attaches to the end of a surgeon’s electrosurgical knife, “inhales” some of the smoke, and immediately sends it to be analyzed in a nearby mass spectrometer.  After compiling a database of more than 3,000 lipid profiles of tumor and healthy tissue samples, Balog and the team tested their method in the operating room. By comparing tissue spectra to their database and a pathologist’s expert diagnosis, the researchers found that their technique could consistently identify cancerous tissue among healthy samples: it had an impressively low rate of false positives—about 3.5 percent—and false negatives, at 2.3 percent. The researchers could even distinguish between different tumor types.

“The major achievement is getting the experiment done in a clinical or surgical setting,” said R. Graham Cooks, an analytical chemist at Purdue University who also aims to devise a mass spectrometry-based tool to aid surgeons but was not involved in the project.

The importance: The new device could help streamline the surgical process by giving surgeons immediate information about the tissue they’re dealing with, noted Ouyang. Additionally, because the iKnife-coupled mass spectrometry technique can analyze samples without previous modification of tissue, it avoids risks inherent in other visualization strategies, like the side effects that can come with injected fluorescent dyes, Takáts noted.

The work is also part of “a paradigm change in histology,” he explained. In the future, Takáts predicts that tissues will be defined by their metabolomic fingerprint instead of characteristics measured by the human eye.

Needs improvement: As promising as the technique is, Cooks cautioned that it’s not yet ready to replace a pathologist. In addition to giving more detailed information about a particular tumor, a pathologist can often make a prognosis, which mass-spec-based bioanalysis cannot yet do.  Such techniques “need to go from diagnosis to prognosis,” he explained.

In the future, adding different molecules to their profiles will allow Takáts’s team to make finer distinctions between tissue types, said Gary Siuzdak, a chemist at The Scripps Research Institute who focuses on metabolomics and did not participate in the study. Additionally, Ouyang predicted that mass spectrometers will be miniaturized to look “like any ordinary equipment you see in the surgical room,” rather than a research lab’s behemoth.

In the meantime, the researchers are already planning studies to examine how their technique affects surgical outcomes, like total time in surgery, the tumor recurrence rate, and the amount of healthy tissue that is spared.

J. Balog et al., “Intraoperative tissue identification using rapid evaporative ionization mass spectrometry,” Science Translational Medicine, 5:194ra93, 2013.

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