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Brigham and Women’s Hospital Researchers Develop Blood Test That Enables Rapid Diagnosis of LVO Stroke in Non-hospital Settings

Oct 23, 2024 | Laboratory Management and Operations, Laboratory News, Laboratory Pathology, Laboratory Resources, Laboratory Testing

New technique could allow emergency responders to determine severity of LVO stroke while patient is still in the ambulance

Researchers at Brigham and Women’s Hospital in Massachusetts say they have developed a clinical laboratory test that can quickly determine whether a patient is experiencing one of the deadliest types of strokes, known as an ischemic large vessel occlusion (LVO) stroke. The development team believes this new assay could be deployed as a point-of-care test to enable faster diagnosis of stroke events.

The test combines measurement of two blood plasma biomarkers with an established clinical score used by clinicians and EMS personnel to assess stroke severity. Compared with current approaches, their technique more accurately differentiates LVO strokes from other types of strokes, making it more likely that patients receive appropriate treatment in a timely manner, the researchers said in a Brigham news release.

Dark Daily has long predicted that advances in technology and computing power would make it possible for pathologists and clinical laboratory scientists to combine multiple established biomarkers (individually not associated with the disease state targeted) with other clinical and patient data to create the ability to make an accurate and earlier diagnosis.

The researchers published their findings in the journal Stroke: Vascular and Interventional Neurology titled, “Prospective Validation of Glial Fibrillary Acidic Protein, d‐Dimer, and Clinical Scales for Acute Large‐Vessel Occlusion Ischemic Stroke Detection.”

Ultimately, Brigham’s research could “aid in the development of a point‐of‐care diagnostic test capable of guiding prehospital LVO stroke triage,” wrote Joshua Bernstock, MD, PhD, Clinical Fellow in Neurosurgery at Brigham and Women’s Hospital, lead author of the study, and colleagues.

“We have developed a game-changing, accessible tool that could help ensure that more people suffering from stroke are in the right place at the right time to receive critical, life-restoring care,” said Joshua Bernstock, MD, PhD (above), Clinical Fellow in Neurosurgery at Brigham and Women’s Hospital and lead author of the Brigham study that developed the clinical laboratory test that the researchers say can enable emergency caregivers to determine quickly and accurately if a patient is having an ischemic large vessel occlusion (LVO) stroke. (Photo copyright: Brigham and Women’s Hospital.)

Early Identification of LVO Stroke

As explained in the news release, an LVO stroke is a type of ischemic stroke caused by obstruction in a major brain artery. The researchers noted that LVO strokes account for “62% of poststroke disabilities and 96% of poststroke death.”

These strokes are readily treatable using endovascular thrombectomy (EVT), in which the blockages are surgically removed, the news release note. However, the researchers observed that EVT “requires specialized teams and equipment, limiting its availability to comprehensive stroke centers and other EVT‐capable centers.”

This can lead to delays as patients are transferred to those facilities, worsening outcomes and increasing the risk of death, the researchers wrote in Stroke: Vascular and Interventional Neurology. So, early identification of LVO stroke is key to ensuring patients receive timely treatment.

Identifying False Negatives/Positives

One challenge, the news release notes, is that brain bleeds (hemorrhagic stroke) can present similar symptoms, yet require “vastly different” treatment.

“A growing body of work has, therefore, evaluated prehospital stroke assessment scales in an effort to identify LVO strokes in the field,” the researchers wrote. “However, such severity scales lack the sensitivity and specificity required for triaging LVO patients with confidence, resulting in false negatives in patients with LVO as well as false positives in patients with stroke mimics or hemorrhagic stroke.”

As explained by EMS Aware, these assessment scales, such as FAST-ED (field assessment stroke triage for emergency destination) and RACE (rapid arterial occlusion evaluation), attempt to determine the severity of a stroke by assigning scores based on symptoms such as facial palsy, arm weakness, and speech difficulties.

To develop their test, Bernstock and colleagues proposed combining the scales with measurement of two blood proteins:

In their study, they attempted to validate cutoff values for the biomarkers and scales.

To do so, the researchers analyzed data from 323 patients admitted to a Florida hospital with suspected stroke between May 2021 and August 2022. Each was assigned to one of four diagnostic categories based on clinical data from their medical records, which included results of computed tomography (CT scan) or magnetic resonance angiography (MRA). The diagnostic categories included:

The patients were assessed using five stroke severity scales. The researchers used frozen blood samples from the patients to measure the biomarkers. They then used this data to determine the likelihood of LVO stroke and compared the results with the diagnoses as determined by the clinical data.

“Combinations of the blood biomarkers with the scales FAST‐ED or RACE showed the best performance for LVO detection, with a specificity of 94% (for either scale combination) and a sensitivity of 71% for both scales,” the researchers wrote.

Sensitivity was higher in patients who presented within the first six hours from onset of symptoms.

“Critically, application of the biomarker and stroke scale algorithms ruled out all patients with hemorrhage,” the researchers wrote. However, they also suggested that their algorithm could be adjusted to enable early identification of hemorrhagic stroke.

The researchers noted that they chose biomarker cutoffs to maximize specificity, so “a certain number of LVOs are missed. However, as such patients default into ‘standard‐of‐care’ triaging pathways, such a decision is unlikely to represent much clinical risk.”

Testing in the Field

The Brigham researchers used established biological biomarkers combined with modern computing—in combination with the scores from a field assessment test—to develop their new clinical laboratory test that identifies the type of stroke.

Their next step is to carry out “another prospective trial to measure the test’s performance when used in an ambulance,” the news release states. “They have also designed an interventional trial that leverages the technology to expedite the triage of stroke patients by having them bypass standard imaging and move directly to intervention.”

“In stroke care, time is brain,” Bernstock said. “The sooner a patient is put on the right care pathway, the better they are going to do. Whether that means ruling out bleeds or ruling in something that needs an intervention, being able to do this in a prehospital setting with the technology that we built is going to be truly transformative.”

More research and clinical studies are needed. However, the fact that the Brigham team wants to deploy this approach in ambulances is an indication that there is high clinical value from this approach.

Clinical pathologists and medical laboratory managers will want to watch the ongoing development and deployment of this new assay, whether it is run in near-patient settings or core clinical laboratories in support of patients presenting in emergency departments.

—Stephen Beale

Related Information:

Researchers Develop “Game-Changing” Blood Test for Stroke Detection

Prospective Validation of Glial Fibrillary Acidic Protein, d‐Dimer, and Clinical Scales for Acute Large‐Vessel Occlusion Ischemic Stroke Detection

New Blood Test Could Spot Dangerous Type of Stroke

Researchers Develop a Blood Test That Can Detect Stroke Quickly

Blood Test a ‘Game Changer’ for Faster Diagnosis, Treatment of LVO Stroke

New Rapid Blood Test Can Accurately Detect Stroke in Six Hours, Save Lives

Experimental Low-Cost Blood Test Can Detect Multiple Cancers, Researchers Say

Feb 12, 2024 | Laboratory Instruments & Laboratory Equipment, Laboratory News, Laboratory Pathology, Laboratory Resources, Laboratory Testing

Test uses a new ultrasensitive immunoassay to detect a known clinical laboratory diagnostic protein biomarker for many common cancers

Researchers from Mass General Brigham, the Dana-Farber Cancer Institute, Harvard University’s Wyss Institute and other institutions around the world have reportedly developed a simple clinical laboratory blood test that can detect a common protein biomarker associated with multiple types of cancer, including colorectal, gastroesophageal, and ovarian cancers.

Best of all, the researchers say the test could provide an inexpensive means of early diagnosis. This assay could also be used to monitor how well patients respond to cancer therapy, according to a news release.

The test, which is still in experimental stages, detects the presence of LINE-1 ORF1p, a protein expressed in many common cancers, as well as high-risk precursors, while having “negligible expression in normal tissues,” the researchers wrote in a paper they published in Cancer Discovery titled, “Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker.”

The protein had previously been identified as a promising biomarker and is readily detectable in tumor tissue, they wrote. However, it is found in extremely low concentrations in blood plasma and is “well below detection limits of conventional clinical laboratory methods,” they noted.

To overcome that obstacle, they employed an ultra-sensitive immunoassay known as a Simoa (Single-Molecule Array), an immunoassay platform for measuring fluid biomarkers.

“We were shocked by how well this test worked in detecting the biomarker’s expression across cancer types,” said lead study author gastroenterologist Martin Taylor, MD, PhD, Instructor in Pathology, Massachusetts General Hospital and Harvard Medical School, in the press release. “It’s created more questions for us to explore and sparked interest among collaborators across many institutions.”

Kathleen Burns, MD, PhD

“We’ve known since the 1980s that transposable elements were active in some cancers, and nearly 10 years ago we reported that ORF1p was a pervasive cancer biomarker, but, until now, we haven’t had the ability to detect it in blood tests,” said pathologist and study co-author Kathleen Burns, MD, PhD (above), Chair of the Department of Pathology at Dana-Farber Cancer Institute and a Professor of Pathology at Harvard Medical School, in a press release. “Having a technology capable of detecting ORF1p in blood opens so many possibilities for clinical applications.” Clinical laboratories may soon have a new blood test to detect multiple types of cancer. (Photo copyright: Dana-Farber Cancer Institute.)

Simoa’s Advantages

In their press release, the researchers described ORF1p as “a hallmark of many cancers, particularly p53-deficient epithelial cancers,” a category that includes lung, breast, prostate, uterine, pancreatic, and head and neck cancers in addition to the cancers noted above.

“Pervasive expression of ORF1p in carcinomas, and the lack of expression in normal tissues, makes ORF1p unlike other protein biomarkers which have normal expression levels,” Taylor said in the press release. “This unique biology makes it highly specific.”

Simoa was developed at the laboratory of study co-author David R. Walt, PhD, the Hansjörg Wyss Professor of Bioinspired Engineering at Harvard Medical School, and Professor of Pathology at Harvard Medical School and Brigham and Women’s Hospital.

The Simoa technology “enables 100- to 1,000-fold improvements in sensitivity over conventional enzyme-linked immunosorbent assay (ELISA) techniques, thus opening the window to measuring proteins at concentrations that have never been detected before in various biological fluids such as plasma or saliva,” according to the Walt Lab website.

Simoa assays take less than two hours to run and require less than $3 in consumables. They are “simple to perform, scalable, and have clinical-grade coefficients of variation,” the researchers wrote.

Study Results

Using the first generation of the ORF1p Simoa assay, the researchers tested blood samples of patients with a variety of cancers along with 406 individuals, regarded as healthy, who served as controls. The test proved to be most effective among patients with colorectal and ovarian cancer, finding detectable levels of ORF1p in 58% of former and 71% of the latter. Detectable levels were found in patients with advanced-stage as well as early-stage disease, the researchers wrote in Cancer Discovery.

Among the 406 healthy controls, the test found detectable levels of ORF1p in only five. However, the control with the highest detectable levels, regarded as healthy when donating blood, “was six months later found to have prostate cancer and 19 months later found to have lymphoma,” the researchers wrote.

They later reengineered the Simoa assay to increase its sensitivity, resulting in improved detection of the protein in blood samples from patients with colorectal, gastroesophageal, ovarian, uterine, and breast cancers.

The researchers also employed the test on samples from 19 patients with gastroesophageal cancer to gauge its utility for monitoring therapeutic response. Although this was a small sample, they found that among 13 patients who had responded to therapy, “circulating ORF1p dropped to undetectable levels at follow-up sampling.”

“More Work to Be Done”

The Simoa assay has limitations, the researchers acknowledged. It doesn’t identify the location of cancers, and it “isn’t successful in identifying all cancers and their subtypes,” the press release stated, adding that the test will likely be used in conjunction with other early-detection approaches. The researchers also said they want to gauge the test’s accuracy in larger cohorts.

“The test is very specific, but it doesn’t tell us enough information to be used in a vacuum,” Walt said in the news release. “It’s exciting to see the early success of this ultrasensitive assessment tool, but there is more work to be done.”

More studies will be needed to valid these findings. That this promising new multi-cancer immunoassay is based on a clinical laboratory blood sample means its less invasive and less painful for patients. It’s a good example of an assay that takes a proteomic approach looking for protein cancer biomarkers rather than the genetic approach looking for molecular DNA/RNA biomarkers of cancer.

—Stephen Beale

Related Information:

Ultrasensitive Blood Test Detects ‘Pan-Cancer’ Biomarker

New Blood Test Could Offer Earlier Detection of Common Deadly Cancers

Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker

Noninvasive and Multicancer Biomarkers: The Promise of LINE-1 Retrotransposons

LINE-1-ORF1p Is a Promising Biomarker for Early Cancer Detection, But More Research Is Needed

‘Pan-Cancer’ Found in Highly Sensitive Blood Test

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