#Product Trends
From Chemistry to Clinical
A new tool designed and tested in the chemistry lab is making a difference during brain surgery in the OR.
One wouldn’t think twice about spotting a mass spectrometer in a research laboratory, but seeing one in the operating room may make you do a double take. It’s that reaction that a team from Purdue Univ. and Brigham and Women’s Hospital (BWH) are hoping to change—they want a mass spectrometer to be just as common in the OR as it is in the lab. Their successful design and implementation of a new tool that helps brain surgeons test and more precisely remove cancerous tissue from tumors moves them one step closer to making that a reality.
The Purdue-designed, mass spectrometry-based tool sprays a microscopic stream of charged solvent onto a tissue surface to gather information about its molecular makeup, and produces a color-coded image that reveals the location, nature and concentration of tumor cells. The tool relies on an ambient mass spec analysis technique developed by Purdue professor R. Graham Cooks called desorption electrospray ionization, or DESI.
Conventional mass spectrometry requires a good amount of sample prep; between the analytes, matrix and vacuum conditions, the process can be time-consuming. DESI, however, eliminates the need for all that by performing the ionization step directly on surfaces outside of mass spectrometers. This makes the technique faster, simpler and much more applicable to surgical settings.
In developing the tool, the researchers used DESI to evaluate the distribution and amounts of fatty substances, called lipids, within brain tissue. A software program, also designed by the team, then used the results to accurately identify the cancer type, grade and tumor margins. Additionally, researchers evaluated a molecule associated with cell growth and differentiation that is considered a biomarker for certain types of brain cancer.
The “fast and simple” characteristics of DESI are what caught BWH neuroscientist Nathalie Agar’s attention. She began collaborating with Cooks in 2009 when she heard about DESI in her quest to establish better care for patients suffering from brain tumors.
The first part of their study was validation in the laboratory, which came in early 2013 when the tool successfully identified the cancer type, grade and tumor margins in five specimens removed from brain surgery patients. The second stage was validation in the operating room, which came recently with successful real-time analysis during surgery in the Advanced Multi-modality Image Guided Operating (AMIGO) suite at BWH.
How it works
During brain surgery, surgeons work from a pre-operative MRI and use neuro-navigation to help them correlate the image to features on the patient’s head. However, when the brain is first opened, the pressure changes and the brain gently shifts, which renders the MRI no long accurate. Additionally, the more the surgeon removes of the tumor, the less accurate the image becomes. And to make matters more complicated, tumor looks exactly like normal brain.
According to Agar, this leaves surgeons constantly questioning if they removed the entire tumor, while also leaving healthy brain tissue undisturbed.
“During brain surgery, it is extremely important to be able to remove as much as possible of the tumor, but equally as important to preserve the healthy surrounding tissue,” says Agar. “You want to make sure the disease is gone, but the quality of life, like the ability to talk and walk, are preserved for the patient.”
Pathological examination of specimens taken from the brain during surgery provides the most specific information about the tissue and diagnosis of the cancer. But, Agar says, the examination can take up to 30 minutes, which is too long when guiding surgery, and it is just not sustainable to have a pathologist in the OR for every surgery.
That’s where the mass spec-based tool comes into play.
For this study, which included validation on samples and use during two patients’ surgical procedures, the tool was tuned to identify the lipid metabolite 2-hydroxyglutarate or 2-HG. This biomarker is associated with more than 70 percent of brain tumors, and can be used to classify them.
By following that specific metabolite, Agar says, surgeons were able to follow the presence of cancer along the border of the tumor.
“With DESI, all we do is put the tissue on the surface and spray the charged solvent,” she says. “The molecules then come off the tissue and into the mass spectrometer. It’s this interface that enables us to do those analyses in real-time.”
According to Cooks, additional classification methodologies and metabolite biomarkers could be added to tailor the tool to different types of cancer. Agar’s lab is already actively exploring its use with breast and prostate cancers.
“Ambient ionization mass spectrometry allows us to look directly at unmanipulated tissue, just as a surgeon does, and get simple but extremely valuable molecular information,” says Cooks. “These molecules have a story to tell, not just in terms of aiding diagnosis, but also perhaps in terms of prognosis and our understanding of disease.”
Better treatment, better collaboration
The first line of treatment for brain tumors is surgery—there is currently no drug doctors can give patients to shrink or eliminate their tumor. Therefore, better surgery is better treatment. Of course, that knowledge doesn’t stop Agar and her team from trying new approaches.
“My lab has been focused on developing tools for a better surgery, but also to better treat patients with drugs,” she says.
For example, Agar is currently using mass spec analysis of brain tissue to look at the distribution of drugs to a tumor. In this case, a patient would receive a drug in a clinical trial prior to surgery. During surgery, samples are taken for subsequent examination of the presence of drugs. Being able to figure out if a drug made it to a tumor and hit its target allows even more precise treatment.
“A lot of pharmaceutical companies are enthused about combining those two lines of work,” says Agar.
Speaking of combining, it was a collaboration between the chemistry lab and the clinical/medical lab that brought this mass spec tool to life. People often separate the traditional laboratory aspect of research from the medical/surgical part, but this tool is the perfect marriage between the two “labs.”
“The program [in my lab at BWH] allows us to develop methodology in the laboratory and then bring it to the OR to help surgery,” says Agar.
For researchers wishing to cross the divide, Agar says it is extremely important to physically get in the OR and understand what the questions, needs and limitations are. Since operating rooms are like no other environment in the world, it’s important to study them first, or the feasibility of any idea may be squashed before it even starts.
“Here at BWH, we have the basic chemistry lab as well as this other component within the operating room, and we go back and forth,” Agar says. “What we do in the lab informs our next step in the OR, and what we do in the OR informs what we’ll do next in the lab. It takes a conversation between the two spaces to succeed.”
