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Mass Spec-Based Pathology Tool Effectively Identifies, Subtypes Ovarian Cancer Tissue

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NEW YORK (360Dx) – Researchers at the University of Texas have demonstrated the ability of their MasSpec Pen device to provide pathological analysis of ovarian cancer tissue.

Detailed in a study published last month in Clinical Chemistry, the results indicate the device could be useful for identifying cancer margins during surgery and potentially distinguishing between different subtypes of the disease, said Marta Sans, first author on the paper and a graduate student in the lab of Livia Eberlin, assistant professor of chemistry at UT and lead inventor of the device.

Accurately assessing tumor margins is a key part of many cancer surgeries where the goal is to remove all cancerous tissue while leaving as much healthy tissue as possible. Margins are typically determined using pathology, which involves freezing and staining tissue and then interpreting the results during surgery.

This adds time to surgery, however. Additionally, the accuracy of intra-operative pathology assays can vary with the facility where the surgery is being performed and the experience of the pathologist. Post-operative pathology studies will in some cases identify cancer missed during the procedure, requiring a second surgery.

Another issue Sans noted is that when chemotherapy is given pre-operatively, it can cause changes to both the tumor and healthy tissue that can make distinguishing between the two more difficult. She said that she and her colleagues believed their approach could aid such analyses though she said they have not yet looked at this question specifically.

These challenges have led researchers and clinicians to investigate methods for more rapidly and objectively assessing tissue margins during surgery. One area of focus has been ambient ionization mass spec, in which ions are generated directly from the target sample and injected directly into the mass spec, making for a streamlined, rapid assay well-suited to an application like intra-operative tissue assessment.

The MasSpec Pen is based on ambient ionization, using drops of water to extract lipids and metabolites from tissue that are then analyzed via mass spec to generate molecular profiles that distinguish between different tissue types.

Eberlin and her team have used the device to distinguish between normal and tumor tissue ex vivo from breast, lung, thyroid, and ovary as well to analyze mouse tumors in vivo. With the recent Clinical Chemistry study, they have shown that the approach is effective in different sample sets and tissue types. They also demonstrated that it is compatible with a relatively low-performance mass spec instrument, a factor that Sans said could be important to making the approach widely accessible.

Looking at 192 samples consisting of healthy and cancerous ovarian tissue as well as normal fallopian tube and peritoneum tissue, the researchers found the device distinguished between cancerous and normal tissue with sensitivity of 94 percent and specificity of 94.4 percent.

Eberlin previously noted that it is difficult to get solid numbers on the accuracy of conventional pathological methods of assessing margins given the variance between hospitals and the fact that cancer recurrence is not always due to errors in margin assessment. However, reports have put error rates as assessing margins in gastrointestinal cancer surgery, for instance, at between 20 and 30 percent."

They also found they could distinguish between high-grade serous cancer, low-grade serous cancer, and normal tissue with an accuracy of 71.4 percent. Though these results were based on a small number (seven) of low-grade samples, they suggest that the MasSpec Pen could be useful for subtyping cancer, which Sans said could in some cases influence surgical decisions.

"That's something we need to evaluate further to see what [subtype] information would ultimately help in managing patients, but we think that especially in cases where it is a very aggressive subtype versus a subtype that can be less aggressive, [surgeons] could maybe use a more or less aggressive approach to cutting out tissue during surgery," she said.

The study also found that the device performed well when coupled to a lower performance mass spec instrument, in this case a Thermo Fisher Scientific LTQ Orbitrap instrument operated in linear ion trap mode. Using that instrument, the device distinguished between cancerous and normal ovarian tissue with sensitivity and specificity of 100 percent.

The original MasSpec Pen work, as well as much of the Clinical Chemistry work, was done using a Thermo Fisher Q Exactive instrument, which is both expensive and relatively large, making it poorly suited to placement in surgical suites.

Linear ion traps, on the other hand, are less expensive and easier to miniaturize, Sans said, which could make them a more feasible option for intra-operative analysis. She noted, however, that while the ion trap showed good performance in terms of distinguishing between cancerous and healthy tissue, the researchers did not test its performance in distinguishing between different cancer subtypes.

"In that case we think that the higher performance of the Orbitrap would be really advantageous," she said. "But that is something we need to evaluate further."

Thus far, Eberlin's lab has tested the device ex vivo in human tissue specimens and in vivo in animal models. Sans said the researchers are now planning to use the device to collect data on patients during ovarian cancer surgery.

"Essentially, we are hoping to put one of these instruments in a surgical room to gather data and test the feasibility [of using it to assess margins] for ovarian cancer," she said, noting that this would likely happen in the next three to four months.

A number of other teams are similarly working on devices to support margin assessment during cancer surgery. Waters is developing its iKnife technology, which collects surgical smoke and analyzes it via rapid evaporative ionization mass spectrometry (REIMS) for this purpose. One potential advantage of the MasSpec Pen over the iKnife technology is that the former is non-destructive as it uses water to ionize molecules for mass spec analysis.

Finnish life sciences company Olfactomics is developing an ion mobility-based system for assessing cancer margins. Unlike the MasSpec Pen and iKnife, the Olfactomics system does not need to be coupled to a mass spectrometry, which gives it a potential advantage in terms of cost and portability.

Last month, researchers at Germany's Ruhr University published on an automated pathology tool based on Fourier transform infrared (FTIR) imaging that they are likewise positioning for use in assessing cancer margins during surgery.