Instantaneous and unequivocal differentiation of malignant from benign tissue during tumor resection is the Holy Grail of surgical oncologists, pathologists, and innovators of biomedical technology. In yesterday’s plenary session, “Direct Mass Spectrometric Profiling of Biological Tissues – A New Paradigm in Histology,” Zoltan Takats, PhD presented how cutting-edge advances in applied mass spectrometry are making rapid, intraoperative tissue profiling a reality.

Takats directs pioneering work in the field of ambient ionization, which enables mass spectrometry to seek new applications outside the traditional laboratory, such as the surgical suite. Surgical excision remains the standard of care for most solid tumors, but the frozen section tissue histology used for intraoperative assessment of tumor margins requires at least 15 minutes for results, thus limiting the number of sampling points and overall precision of the resection.

Certain biomolecules, such as phosphopholipids, are highly tissue-specific and produce “spectacular differences” in molecular fingerprints, according to Takats, making them excellent candidates for tissue diagnostics. Takats recounted how he set out to develop a technology for in situ chemical characterization of tissues as a valid alternative to frozen sections that would enable real-time intraoperative decision-making.  His most significant discovery was that many longstanding surgical instruments relying on thermal ablation produce a large amount of tissue-originated gaseous ions, an irritating by-product that happens to be the exact input needed for mass spectrometric analysis. By slightly modifying standard surgical equipment, the aerosol produced during electrosurgery was processed using mass spectrometry and multivariate spectral analysis to create a tool known as the intelligent knife (iKnife).

Engineered for translation into routine clinical use, the iKnife has been used to evaluate tissue margin status during a wide range of oncosurgical procedures, including breast cancer lumpectomy, which has the highest reoperation rate (25%) of all cancers in the UK. Overall, it has demonstrated greater than 95% concordance with classical, post-interventional histological analysis and mis-identifies malignant tissue as healthy in less than 1% of cases. Undoubtedly the most intriguing and transformative aspect of the iKnife is “the apparent rapidity with which one can get an answer,” noted Virginia LiVolsi, MD, who presented a brief history of frozen sections during the plenary session.

In fact, the entire process from aerosol delivery to mass analysis and result interpretation can be performed in 50-100 milliseconds. Within the next decade, LiVolsi said he envision the promising iKnife technology taking over the work of anatomical pathologists evaluating intraoperative frozen sections. Currently, the iKnife instruments are in operating rooms at three hospitals throughout the UK, just a few meters away from patients undergoing procedures in a variety of specialties. The up-front cost of the instrument is a challenge barring its widespread use, though Takats speculated that, with time, popularization of the technology would reduce overall costs. A far more problematic issue discussed was how surgeons accustomed to frozen sections will accept the iKnife as an alternative tool for intra-operative decision making.

Takats’ iKnife and related variations of mass spectrometry imaging have just scratched the surface of a seemingly boundless body of meaningful applications in direct tissue profiling.  For example, the iKnife was recently integrated with an endoscopic polypectomy snare to create the iEndoscope.  Beyond differentiating healthy mucosa from adenocarcinoma and pre-cancerous adenomatous polyps, this real-time diagnostic tool could be further developed to decrease rates of perforation—one of the primary complications during endoscopy. In addition, one of the most exciting efforts in Takatss’ laboratory at the moment involves evaporating mucous and fecal matter to phenotype the gut microbiome without any intestinal tissue damage to the patient.

The molecular intelligence of the iKnife and related technologies has brought mass spectrometry to the patient’s bedside at a time when they need it most. After learning more about the iKnife during this plenary lecture, attendees can certainly imagine many ways such advances will continue to impact patient care in the future.