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Clinical Laboratories and Pathology Groups

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Clinical Laboratories and Pathology Groups

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Johns Hopkins Research Team Uses Machine Learning on DNA “Dark Matter” in Blood to Identify Cancer

Findings could lead to new biomarkers clinical laboratories would use for identifying cancer in patients and monitoring treatments

As DNA “dark matter” (the DNA sequences between genes) continues to be studied, researchers are learning that so-called “junk DNA” (non-functional DNA) may influence multiple health conditions and diseases including cancer. This will be of interest to pathologists and clinical laboratories engaged in cancer diagnosis and may lead to new non-invasive liquid biopsy methods for identifying cancer in blood draws.

Researchers at Johns Hopkins Kimmel Cancer Center in Baltimore, Md., developed a technique to identify changes in repeat elements of genetic code in cancerous tissue as well as in cell-free DNA (cf-DNA) that are shed in blood, according to a Johns Hopkins news release.

The Hopkins researchers described their machine learning approach—called ARTEMIS (Analysis of RepeaT EleMents in dISease)—in the journal Science Translational Medicine titled, “Genomewide Repeat Landscapes in Cancer and Cell-Free DNA.”

ARTEMIS “shows potential to predict cases of early-stage lung cancer or liver cancer in humans by detecting repetitive genetic sequences,” Genetic Engineering and Biotechnology News (GEN) reported.

This technique could enable non-invasive monitoring of cancer treatment and cancer diagnosis, Technology Networks noted.

“Our study shows that ARTEMIS can reveal genomewide repeat landscapes that reflect dramatic underlying changes in human cancers,” said study co-leader Akshaya Annapragada (above), an MD/PhD student at the Johns Hopkins University School of Medicine, in a news release. “By illuminating the so-called ‘dark genome,’ the work offers unique insights into the cancer genome and provides a proof-of-concept for the utility of genomewide repeat landscapes as tissue and blood-based biomarkers for cancer detection, characterization, and monitoring.” Clinical laboratories may soon have new biomarkers for the detection of cancer. (Photo copyright: Johns Hopkins University.)

Detecting Early Lung, Liver Cancer

Artemis is a Greek word meaning “hunting goddess.” For the Johns Hopkins researchers, ARTEMIS also describes a technique “to analyze junk DNA found in tumors” and which float in the bloodstream, Financial Times explained.

“It’s like a grand unveiling of what’s behind the curtain,” said geneticist Victor Velculescu, MD, PhD, Professor of Oncology and co-director of the Cancer Genetics and Epigenetics Program at Johns Hopkins Kimmel Cancer Center, in the news release.

“Until ARTEMIS, this dark matter of the genome was essentially ignored, but now we’re seeing that these repeats are not occurring randomly,” he added. “They end up being clustered around genes that are altered in cancer in a variety of different ways, providing the first glimpse that these sequences may be key to tumor development.”

ARTEMIS could “lead to new therapies, new diagnostics, and new screening approaches for cancer,” Velculescu noted.

Repeats of DNA Sequences Tough to Study

For some time technical limitations have hindered analysis of repetitive genomic sequences by scientists. 

“Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches,” the study authors wrote in their Science Translational Medicine paper.

“We developed a de novo k-mer (short sequences of DNA)-finding approach called ARTEMIS to identify repeat elements from whole-genome sequencing,” the researchers wrote.

The scientists put ARTEMIS to the test in laboratory experiments.

The first analysis involved 1,280 types of repeating genetic elements “in both normal and tumor tissues from 525 cancer patients” who participated in the Pan-Cancer Analysis of Whole Genomes (PCAWG), according to Technology Networks, which noted these findings:

  • A median of 807 altered elements were found in each tumor.
  • About two-thirds (820) had not “previously been found altered in human cancer.”

Second, the researchers explored “genomewide repeat element changes that were predictive of cancer,” by using machine learning to give each sample an ARTEMIS score, according to the Johns Hopkins news release. 

The scoring detected “525 PCAWG participants’ tumors from the healthy tissues with a high performance” overall Area Under the Curve (AUC) score of 0.96 (perfect score being 1.0) “across all cancer types analyzed,” the Johns Hopkins’ release states.

Liquid Biopsy Deployed

The scientists then used liquid biopsies to determine ARTEMIS’ ability to noninvasively diagnose cancer. Researchers used blood samples from:

Results, according to Johns Hopkins:

  • ARTEMIS classified patients with lung cancer with an AUC of 0.82.
  • ARTEMIS detected people with liver cancer, as compared to others with cirrhosis or viral hepatitis, with a score of AUC 0.87.

Finally, the scientists used their “ARTEMIS blood test” to find the origin of tumors in patients with cancer. They reported their technique was 78% accurate in discovering tumor tissue sources among 12 tumor types.

“These analyses reveal widespread changes in repeat landscapes of human cancers and provide an approach for their detection and characterization that could benefit early detection and disease monitoring of patients with cancer,” the researchers wrote in Science Translational Medicine.

Large Clinical Trials Planned

Velculescu said more research is planned, including larger clinical trials.

“While still at an early stage, this research demonstrates how some cancers could be diagnosed earlier by detecting tumor-specific changes in cells collected from blood samples,” Hattie Brooks, PhD, Research Information Manager, Cancer Research UK (CRUK), told Financial Times.

Should ARTEMIS prove to be a viable, non-invasive blood test for cancer, it could provide pathologists and clinical laboratories with new biomarkers and the opportunity to work with oncologists to promptly diagnosis cancer and monitor patients’ response to treatment.

—Donna Marie Pocius

Related Information:

“Junk DNA” No More: Johns Hopkins Investigators Develop Method of Identifying Cancers from Repeat Elements of Genetic Code

Genomewide Repeat Landscapes in Cancer and Cell-Free DNA

AI Detects Cancer VIA DNA Repeats in Liquid Biopsies

Genetic “Dark Matter” Could Help Monitor Cancer

AI Explores “Dark Genome” to Shed Light on Cancer Growth

Columbia University Researchers Say New High-Speed 3D Microscope Could Replace Traditional Biopsy, with Implications for Surgical Pathology

Columbia University’s MediSCAPE enables surgeons to examine tissue structures in vivo and a large-scale clinical trial is planned for later this year

Scientists at Columbia University in New York City have developed a high-speed 3D microscope for diagnosis of cancers and other diseases that they say could eventually replace traditional biopsy and histology “with real-time imaging within the living body.”

The technology is designed to enable in situ tissue analysis. Known as MediSCAPE, the microscope is “capable of capturing images of tissue structures that could guide surgeons to navigate tumors and their boundaries without needing to remove tissues and wait for pathology results,” according to a Columbia University news story.

The research team, led by Columbia University professor of biomedical engineering and radiology Elizabeth Hillman, PhD, described the technology in a paper published in Nature Biomedical Engineering, titled, “High-Speed Light-Sheet Microscopy for the In-Situ Acquisition of Volumetric Histological Images of Living Tissue.”

“The way that biopsy samples are processed hasn’t changed in 100 years, they are cut out, fixed, embedded, sliced, stained with dyes, positioned on a glass slide, and viewed by a pathologist using a simple microscope. This is why it can take days to hear news back about your diagnosis after a biopsy,” said Hillman in the Columbia news story.

“Our 3D microscope overcomes many of the limitations of prior approaches to enable visualization of cellular structures in tissues in the living body. It could give a doctor real-time feedback about what type of tissue they are looking at without the long wait,” she added in I News.

Hillman’s team previously used the technology—originally dubbed SCAPE for “Swept Confocally Aligned Planar Excitation” microscopy—to capture 3D images of neurological activity in living samples of worms, fish, and flies. In their recent study, the researchers tested the technology with human kidney tissue, a human volunteer’s tongue, and a mouse with pancreatic cancer.

Shana M. Coley, MD, PhD
“This was something I didn’t expect—that I could actually look at structures in 3D from different angles,” said nephropathologist and study co-author Shana M. Coley, MD, PhD (above), Director, Transplant Translational Research and Multiplex Imaging Center at Arkana Laboratories, in the Columbia news story. At the time of the Columbia study, Coley was an assistant professor at Columbia University and a renal pathologist at the Columbia University Medical Center. “We found many examples where we would not have been able to identify a structure from a 2D section on a histology slide, but in 3D we could clearly see its shape. In renal pathology in particular, where we routinely work with very limited amounts of tissue, the more information we can derive from the sample, the better for delivering more effective patient care,” she added. (Photo copyright: Arkana Laboratories.)

How MediSCAPE Works

Unlike traditional 3D microscopes that use a laser to scan tiny spots of a tissue sample and then assemble those points into a 3D image, the MediSCAPE 3D microscope “illuminates the tissue with a sheet of light—a plane formed by a laser beam that is focused in a special way,” I News reported.

The MediSCAPE microscope thus captures 2D slices which are rapidly stacked into 3D images at a rate of more than 10 volumes per second, according to I News.

“One of the first tissues we looked at was fresh mouse kidney, and we were stunned to see gorgeous structures that looked a lot like what you get with standard histology,” said optical systems engineer and the study’s lead author, Kripa Patel, PhD, in the Columbia news story. “Most importantly, we didn’t add any dyes to the mouse—everything we saw was natural fluorescence in the tissue that is usually too weak to see.

“Our microscope is so efficient that we could see these weak signals well,” she continued, “even though we were also imaging whole 3D volumes at speeds fast enough to rove around in real time, scanning different areas of the tissue as if we were holding a flashlight.”

A big advantage of the technology, Hillman noted, is the ability to scan living tissue in the body.

“Understanding whether tissues are staying healthy and getting good blood supply during surgical procedures is really important,” she said in the Columbia news story. “We also realized that if we don’t have to remove (and kill) tissues to look at them, we can find many more uses for MediSCAPE, even to answer simple questions such as ‘what tissue is this?’ or to navigate around precious nerves. Both of these applications are really important for robotic and laparoscopic surgeries, where surgeons are more limited in their ability to identify and interact with tissues directly.”

Clinical Trials and FDA Clearance

Early versions of the SCAPE microscopes were too large for practical use by surgeons, so Columbia post-doctoral research scientist Wenxuan Liang, PhD, co-author of the study, helped the team develop a smaller version that would fit into an operating room.

Later this year, the researchers plan to launch a large-scale clinical trial, I News reported. The Columbia scientists hope to get clearance from the US Food and Drug Administration (FDA) to develop a commercialized version of the microscope.

“They will initially seek permission to use it for tumor screening and guidance during operations—a lower and easier class of approval—but ultimately, they hope to be allowed to use it for diagnosis,” Liang wrote.

Charles Evans, PhD, research information manager at Cancer Research UK, told I News, “Using surgical biopsies to confirm a cancer diagnosis can be time-consuming and distressing for patients. And ensuring all the cancerous tissue is removed during surgery can be very challenging unaided.”

He added, “more work will be needed to apply this technique in a device that’s practical for clinicians and to demonstrate whether it can bring benefits for people with cancer, but we look forward to seeing the next steps.” 

Will the Light Microscope be Replaced?

In recent years, research teams at various institutions have been developing technologies designed to enhance or even replace the traditional light microscope used daily by anatomic pathologists across the globe.

And digital scanning algorithms for creating whole-slide images (WSIs) that can be analyzed by pathologists on computer screens are gaining in popularity as well.

Such developments may spark a revolution in surgical pathology and could signal the beginning of the end of the light microscope era.

Surgical pathologists should expect to see a steady flow of technologically advanced systems for tissue analysis to be submitted to the FDA for pre-market review and clearance for use in clinical settings. The light microscope may not disappear overnight, but there are a growing number of companies actively developing different technologies they believe can diagnose either or both tissue and digital images of pathology slides with accuracy comparable to a pathologist.

Stephen Beale

Related Information:

New Technology Could Make Biopsies a Thing of the Past

Cancer Care: 3D Microscope That Could Replace Tumor Biopsies Is ‘As Revolutionary as Ultrasound’

High-Speed Light-Sheet Microscopy for the In-Situ Acquisition of Volumetric Histological Images of Living Tissue

SCAPE Microscopy

UC Davis Researchers Develop Microscope That Uses Ultraviolet Light for Diagnosis, Eliminates Need for Traditional Histology Slide Preparation

Attention All Surgical Pathologists: Algorithms for Automated Primary Diagnosis of Digital Pathology Images Likely to Gain Regulatory Clearance in Near Future

GlaxoSmithKline to Use a ‘Breath Biopsy’ Test by Owlstone Medical in a Phase II Clinical Trial of a Respiratory Drug

It has been regularly demonstrated in recent decades that human breath contains elements that could be incorporated into clinical laboratory tests, so the decision to use this “breath biopsy” test in a therapeutic drug trial will be closely watched

When a major pharma company pays attention to a breath test, implications for clinical laboratories are often forthcoming. Such may be the case with GlaxoSmithKline (GSK). The global healthcare company has selected Owlstone Medical’s Breath Biopsy technology for use in its Phase II clinical trial of danirixin (DNX), a respiratory drug under development by GSK for treatment of chronic obstructive pulmonary disease (COPD), an Owlstone Medical news release announced.

Anatomic pathologists and medical laboratory leaders will be intrigued by GSK’s integration of breath-based specimens in a clinical trial of a respiratory drug. The partners in the trial aim to analyze breath samples to better understand the drug’s treatment effects and to discover personalized medicine (AKA, precision medicine) opportunities.

GSK (NYSE:GSK), headquartered in the UK but with a large presence in the US, researches and develops pharmaceutical medicines, vaccines, and other consumer health products.

Owlstone Medical, a diagnostic company, is developing a breathalyzer for disease and says it is on a mission to save 100,000 lives and $1.5 billion in healthcare costs. Dark Daily previously reported on Owlstone Medical’s Breath Biopsy platform. The Cambridge, England-based company has raised significant funding ($23.5 million) and already garnered credible cancer trial collaborators including the UK’s National Health Service (NHS).

Now, Owlstone Medical has brought its breath analysis technology to bear on chronic disease outside of cancer diagnostics development. A pharmaporum article called Owlstone’s Medical’s work with GSK an “additional boost of confidence” in the company’s technology, as well as a means for revenue.

Billy Boyle, co-founder and Chief Executive Officer, Owlstone Medical (above), shown with the company’s ReCIVA Breath Sampler device. This will be used by GSK in its Phase II respiratory disease clinical trial of danirixin to “capture VOC biomarkers in breath samples.” (Photo copyright: Business Weekly UK.)

GSK Studying Future Treatments for Respiratory Diseases

COPD affects about 700 million people worldwide, an increase of about 65% since 1990, GSK pointed out. In September 2017, GSK presented respiratory disease data and its pipeline medications at the European Respiratory Society in Milan, Italy. Included was information on danirixin (an oral CXCR2 antagonist), which is part of the company’s focus on COPD disease modification, according to a GSK news release.

“Each of our studies sets the bar for our future research and innovation,” noted Neil Barnes, MA Cantab, FRCP, FCCP(Hon), Vice President, Global Franchise Medical Head, GSK Respiratory, in the GSK press release.

Clinical Trial Aimed at Identifying the ‘Right’ Patients

With Owlstone Medical’s breathalyzer, GSK plans to explore how volatile organic compounds (VOCs) can help identify patients who will benefit most from the company’s medications, as well as evaluate Danirixin’s effects. A critical element of personalized medicine.

“It’s part of our efforts to identify the right patient for the right treatment,” said Ruth Tal-Singer, PhD, GSK’s Vice President of Medicine Development Leader and Senior Fellow, Respiratory Research and Development, in the Owlstone Medical news release.

VOCs in breath will be captured in a non-invasive way from patients who wear Owlstone Medical’s ReCIVA Breath Sampler, which, according to Owlstone Medical, has CE-mark clearance, a certification noting conformity with European health and safety standards. The VOCs breath samples will then be sent to Owlstone Medical’s lab for high-sensitivity analysis.

“Non-invasive Breath Biopsy can establish a role in precision medicine applications such as patient stratification and monitoring treatment response,” said Billy Boyle, Owlstone Medical’s co-Founder and Chief Executive Officer.

 VOC Biomarkers in Respiratory Disease

VOC profiles can be characteristic of COPD as well as other respiratory diseases including asthma, tuberculosis, and cystic fibrosis, reported Science/Business.

According to Owlstone Medical’s Website, VOCs are gaseous molecules produced by the human body’s metabolism that are suitable for Breath Biopsy. Their research suggests that exhaled breath reflects molecular processes responsible for chronic inflammation. Thus, VOCs captured through Breath Biopsy offer insight into respiratory disease biomarkers.

Breath also includes VOCs that originate from circulation, which can provide information on a patient’s response to medications.

How the Breath Biopsy Platform Works

Owlstone Medical’s platform relies on its patented Field Asymmetric Ion Mobility Spectrometry (FAIMS) technology, which “has the ability to rapidly monitor a broad range of VOC biomarkers from breath, urine and other bodily fluids with high sensitivity and selectivity,” according to the company’s website. During the process:

  • Gases are exchanged between circulating blood and inhaled fresh air in the lungs;
  • VOC biomarkers pass from the circulation system into the lungs along with oxygen, carbon dioxide, and other gases;
  • Exhaled breath contains exiting biomarkers.

It takes about a minute for blood to flow around the body. So, a breath sample during that time makes possible collection and analysis of VOC biomarkers from any part of the body touched by the circulatory system.

The medical analysis is enabled by software in the Owlstone Medical lab, Boyle told the Cambridge Independent.

“There’s an analogy with blood prints—you get the blood and can look for different diseases, and we’ve developed core hardware and technology to analyze the breath sample,” he said.

Another Breath Sample Device 

The ReCIVA Breath Sampler is not the only breathalyzer focused on multiple diseases.  Dark Daily reported on research conducted by Technion, Israel’s Institute of Technology, into a breath analyzer that can detect up to 17 cancers, and inflammatory and neurological diseases.

But Owlstone Medical stands out due, in part, to its noteworthy partners: the UK’s National Health Service, as well as the:

And now the company can add collaboration with GSK to its progress. Though some question the reliability of breath tests as biomarkers in the areas of sensitivity and specificity required for cancer diagnosis, Owlstone Medical appears to have the wherewithal to handle those hurdles. It is a diagnostics company that many pathologists and medical laboratory professionals may find worth watching.

—Donna Marie Pocius

Related Information:

Owlstone Medical’s Breath Biopsy Platform Integrated into GSK’s Phase II Respiratory Disease Clinical Trial

GSK Utilizes Owlstone Disease Breathalyser for Key Clinical Trials

GSK Presents Respiratory Data from Pipeline to Clinical Practice at ERS

GSK Boosts Medtech First Owlstone with Use of Breath Biopsy in Respiratory Trial

Glaxo to Stratify COPD Trial Using Breath Biopsy Device

Billy Boyle of Owlstone Medical on the Inspiration Behind His Mission to Save 100,000 From Dying of Cancer

Owlstone Medical and UK’s NHS Study Whether Breath Contains Useful Biomarkers

Breath Based Biomarker Detection: Informing Drug Development and Future Treatment Regimes

Clinical Laboratories Could Soon Diagnose 17 Diseases with a Single Breath Analyzer Test from Israel’s Institute of Technology

Pathologists and Physicians in United Kingdom Comment on How Shortage of Medical Laboratory Professionals Could Soon Delay Essential Diagnostic, Therapeutic Testing

As chronic disease and aging populations strain the UK’s medical systems, staffing shortages at pathology laboratories contribute to lengthening delays of critical diagnostic services

In the United Kingdom (UK), pathologists and other physicians are going public with their concerns that a growing shortage of pathologists and medical laboratory scientists will soon contribute to delays in performing the lab tests needed to diagnose patients—particularly those with cancer—and identify which therapies will work best for them.

Thanks to vast improvements to both medical laboratory capabilities and treatment options, the cancer survival rate in the UK doubled over the past four decades. However, early diagnosis is a critical component to a successful outcome. As further strain is placed on medical laboratories and diagnostic providers, wait times continue to increase beyond the thresholds created by the UK’s National Health Service (NHS).

Worsening an already dire situation, a November 2016 report from Cancer Research UK, “Testing Times to Come? An Evaluation of Pathology Capacity Across the UK,” predicts a critical shortage in laboratory staffing within the next decade. Data on Provider-based Cancer Waiting Times for August 2016 from National Health Service England shows that 17.2% of patients with an urgent referral for suspected cancer fail to start treatment within two months of the referral. (more…)

In the UK, Pathologists Are Watching Phase II of a Clinical Trial for a Breathalyzer System That Uses Only a Breath Specimen to Diagnose Lung Cancer

If the clinical study validates this patient-friendly, non-invasive approach to diagnosing lung cancer, it could eventually mean fewer referrals of tissue biopsies to medical laboratories

For almost a decade, pathologists have seen a regular stream of news stories about technologies that utilize a sample of human breath to diagnose a disease or health condition. Now comes news that just such a diagnostic test for lung cancer is beginning clinical trials in the United Kingdom.

The clinical trials will evaluate breathalyzer technology developed by Engineer Billy Boyle, M.S., Co-founder and President of Operations at Cambridge-based Owlstone Ltd.. The clinical trials of this new breathalyzer technology to detect lung cancer are taking place at two National Health Service (NHS) hospitals: University Hospitals of Leicester and Cambridge’s Papworth Hospital in the United Kingdom.

The reason why so much research is happening in this field will be familiar to clinical laboratory managers and pathologists. Use of volatile organic compound (VOC) biomarkers in breath to diagnose disease is an ideal concept because it is convenient, non-invasive, and well tolerated by patients. However, until the start of this clinical study, researchers have explored the potential of this diagnostic approach for some time, but with limited success. (more…)

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