A new technique can analyze tumors in the middle of surgery

Leo Wurpillot was ten years old when he learned he had a brain tumor. To determine its malignancy, sections of the tumor had to be surgically removed and analyzed. Now 19, he recalls the anguish that came with the subsequent three-month wait for a diagnosis. The news was good, and today Mr. Wurpillot is a thriving first-year biomedical student at Cardiff University. But the months-long postoperative anticipation remains difficult for patients to bear. That wait may one day be a thing of the past.

On June 27, a group of neurosurgeons, neuropathologists and computational biologists met at Queen’s Medical Centre in Nottingham to hear about an ultra-fast sequencing project developed by researchers at Nottingham University and the local hospital. Their work will allow brain tumours to be classified from tissue samples in two hours or less. Since brain surgeries typically take many hours, this would allow results to be returned before the surgery is finished and inform the operation itself.

Different tumors require different types of treatment. Some can be treated with radiation therapy or drugs alone, while others require surgery. But deciding how much of the tumor to cut out in the delicate area of ​​the brain, where removals can have lifelong consequences, is exceptionally tricky. And without knowing how dangerous the tumor is, surgeons can’t make the right judgments about how aggressive to be.

To help them, the Nottingham team is relying on a technology called nanopore sequencing. This sequences DNA or RNA molecules by passing them through tiny holes engineered into a membrane. By measuring how an electrical current passing through these holes changes as different parts of the molecule pass through, the DNA can be read in real time. Nanopore sequencers can also speed up analysis by doing something called adaptive sampling. This scans each strand of DNA to see if it contains specific mutations that might be of interest. If none are found, the strand is ejected from the pores, leaving them open to sequence another strand.

As the data comes out of the sequencing device, it is processed by algorithms that classify the tumor as malignant or not. Since March last year, the team has analyzed tumors from 90 patients. Thirty were retrospective samples to see if their technique matched the answers given by conventional molecular and genomic classification methods. Another 60 were prospective samples taken during surgery. Across all 90 patients, the results matched those obtained by the old techniques in more than 90% of cases, says Simon Paine, a consultant neuropathologist at the University of Nottingham and part of the project team.

Stuart Smith, a consultant neurosurgeon at Nottingham University Hospitals Trust and another member of the team, asked colleagues about the data they had previously been able to generate on patients’ tumours. Their results suggested that the new technique would have changed the surgical strategies employed between 18% and 50% of the time. In some cases, patients would have needed just one brain operation instead of two.

The approach is attracting interest. Dr. Paine says several neurology centers in Britain have contacted them about the technique. They think it could eventually be extended to other types of tumors, including lymphomas and leukemias, for which a battery of tests already exists. If ultrafast sequencing can be sped up even further, drugs that can make genetic changes in a brain tumor could one day be administered during the operation itself. The team hopes they can validate and approve the test for use as a diagnostic tool in the next few months.

Neurosurgeons aren’t the first clinicians to discover the benefit of nanopore sequencing. A recent three-year study at Guy’s and St Thomas’ NHS Foundation Trust used it to sequence pathogens found in intensive care patients and found that 3% of patients were harbouring pathogens responsible for dangerous diseases such as Legionella, as well as nasty strains of MRSA. Bringing genetic sequencing to the medical frontlines heralds a new era of diagnostic possibilities.

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