Nature Medicine | Spoonful of Medicine

Real-time tissue analysis could guide brain tumor surgery

The intraoperative mass spectrometry platform for image-guided surgery in the Advanced Mutimodality Image Guided Operating (AMIGO) suite at Brigham and Women's Hospital, Harvard Medical School as part of the National Center for Image Guided Therapy. Part of the team from left to right: Dr. David Calligaris, Postdoctoral Fellow, Dr. Sandro Santagata, Neuropathologist, Dr. Alexandra Golby, Neurosurgeon, and Isaiah Norton, Senior Programmer Analyst.

Santagata (second from left) and part of his team with the mass spectrometry platform for image-guided surgery in the Advanced Mutimodality Image Guided Operating (AMIGO) suite at Brigham and Women’s Hospital, Harvard Medical School.

It doesn’t get much more complicated than brain surgery. Surgeons tasked with removing brain tumors have limited information available to help them make decisions about what tissue appears cancerous and how much to excise without damaging brain regions important to key functions such as movement and speech.

But decisions about how much to cut might become easier in the near future: A study published today offers a possible way to discern which brain tissue is cancerous and guide surgeons in real time. The research, which appears in the Proceedings of the National Academy of Sciences, uses a technique formerly confined to analytical chemistry labs, called mass spectrometry, to make this determination right in the operating room.

“It’s hard to distinguish normal tissue from tumor,” explains Sandro Santagata, a pathologist at Brigham and Women’s Hospital in Boston and co-author of the study.** Thanks to the new approach, he says, “we’re many steps closer to getting a complete picture at the time of surgery.”

Techniques currently used in the operating room to guide tumor excision, such as tissue pathology and magnetic resonance imaging (MRI), can be costly and time consuming. A surgeon may have to wait 30 minutes for the biopsy results or an hour to perform MRI, adding to surgery time and increasing patient risk.

In an effort to speed up the process, Santagata and his colleagues joined with analytical chemist Graham Cooks at Purdue University in West Lafayette, Indiana, to exploit a hallmark feature of brain tumors as a way of defining the boundaries of these malignancies. As it turns out, brain tumors known as gliomas tend to express high amounts of a lipid metabolite called 2-hydroxyglutarate (2-HG).

According to Dan Cahill, a neurosurgeon at Massachusetts General Hospital in Boston who was not associated with the new study, doctors already use other methods, like polymerase chain reaction, to check tissue for 2-HG levels after surgery to ensure that they have thoroughly excised the tumor. The absence of it in the area immediately surrounding the tumor site means that all of the cancerous cells have been removed. “If you have it [2-HG], you know your margin isn’t clean,” he says. Unfortunately, current methods to detect 2-HG take far too long—about two daysto influence decisions made mid-surgery.

Santagata and his colleagues installed a mass spectrometer in an operating suite at Brigham and Women’s Hospital and analyzed 35 biopsied glioma specimens for the 2-HG metabolite. Although they performed the analysis immediately, the results were not used to inform the surgeons since the research is still in early stages. The mass spectrometry technique used, called desorption electrospray ionization, analyzes the tissue without destroying it, allowing detailed pathology, which is still the gold standard for tumor assessment, to be performed on the same sample. Pathology done for the study confirmed that 2-HG was detected at the highest levels in areas with the most tumor cells.

“I’m hoping we can start incorporating this into therapy for this subset of tumors,” says Nathalie Agar, a neuroscientist at Brigham and Women’s Hospital and co-author of the study. She and Santagata are currently advising the biotech company, BayesianDx, which is trying to develop the technology and bring it into clinical use. It may be years before this technology becomes widespread, but Agar says she is encouraged by this proof-of-concept study.

**Correction (2 July): In an earlier version of this story, Sandro Santagata was referred to as the lead author of the study. He was the first author. Nature Medicine regrets the error.