German Feasibility Study Shows Cerenkov Luminescence Imaging May Provide New Technique for Identifying Positive Margins during Prostatectomies

Prostate cancer currently has the highest positive surgical margin rate of any cancer in men, with 21% of patients left with cancer cells at the resection site

Cancer surgeons may soon have a new technology to help them completely remove cancerous tissue during prostate cancer surgery. Called Cerenkov luminescence imaging (CLI), this new diagnostic technology under development at the Essen University Hospital in Essen, Germany, will be of interest to surgical pathologists since it could become a common intraoperative strategy to improve surgical precision during radical cancer procedures.

For example, radical prostatectomy is the removal of the entire prostate gland and surrounding tissues. It is one of the primary treatments for malignant cancer. Failure to remove all the cancer tissue during the procedure typically leads to poor clinical outcomes, including tumor reoccurrence and subsequent increased risk of metastasis and death.

A 2018 study published in Nature Scientific Reports, titled, “Positive Surgical Margins in the 10 Most Common Solid Cancers,” noted that prostate cancer has the highest positive surgical margin rate of any cancer in men, with 21.03% of patients left with remaining cancer cells at the resection site.

Currently, intraoperative frozen-section analysis of the prostate is the most common intraoperative method for real-time analysis of surgical margins. But research into CLI may provide surgeons with an additional strategy for reducing positive surgical margins.

Comparing CLI to Postoperative Histopathology

The Essen University Hospital researchers published the results of their feasibility study in the Journal of Nuclear Medicine (JNM), titled, “Intraoperative 68Ga-PSMA Cerenkov Luminescence Imaging for Surgical Margins in Radical Prostatectomy: A Feasibility Study.”

“Our objective was to assess the feasibility and accuracy of Cerenkov luminescence imaging (CLI) for assessment of surgical margins intraoperatively during radical prostatectomy,” they wrote.

According to the Essen researchers, the “single-center” study “included 10 patients with high-risk primary prostate cancer. 68Ga-PSMA PET scans were performed followed by radical prostatectomy and intraoperative CLI of the excised prostate. CLI images were analyzed postoperatively to determine regions of interest based on signal intensity, and tumor-to-background ratios were calculated. CLI tumor margin assessment was performed by analyzing elevated signals at the surface of the intact prostate images.

“To determine accuracy, tumor margin status as detected by CLI was compared to postoperative histopathology. Tumor cells were successfully detected on the incised prostate CLI images and confirmed by histopathology. Three patients had positive surgical margins, and in two of the patients, elevated signal levels enabled correct identification on CLI. Overall, 25 out of 35 CLI regions of interest proved to visualize tumor signaling according to standard histopathology,” the Essen researchers concluded.

The research showed that CLI can accurately assess surgical margins during radical prostatectomy. This first in vivo research of the technique was conducted over a 17-month period between 2018 and 2019.

Christopher Darr, PhD

“Intraoperative radio guidance with CLI may help surgeons in the detection of extracapsular extension, positive surgical margins, and lymph node metastases with the aim of increasing surgical precision,” said the study’s first author Christopher Darr, PhD (above), a resident urologist at Essen University Hospital, in a Society of Nuclear Medicine and Molecular Imaging (SNMMI) news release. “The intraoperative use of CLI would allow the examination of the entire prostate surface and provide the surgeon with real-time feedback on the resection margins.” (Photo copyright: Essen University Hospital.)

The researchers found that two of three patients who had positive surgical margins were correctly identified using CLI images. Overall, 25 of 35 CLI regions of interest successfully visualized tumor signaling, which is a result in line with standard histopathology. The one positive surgical margin CLI missed had group 3 prostate cancer at the surgical margin.

Essen Study Finds CLI Results in ‘Higher than Expected’ False Positives

A companion article published in the JNM, titled, “Cerenkov Luminescence Imaging for Surgical Margins in Radical Prostatectomy: A Surgical Perspective,” noted that, “Although this is consistent with other studies showing reduced PSMA (prostate-specific membrane antigen) expression in lower-grade prostate cancer, the interval between PSMA-agent injection and CLI (median, 333 min) was long and potentially detrimental to identification of lower-grade [prostate cancer]. Future studies may aim to reduce the interval between PSMA-agent injection and commencement of surgery to improve signal intensity and potentially the overall sensitivity of CLI.”

The Essen University Hospital’s CLI feasibility study also revealed the technique resulted in a higher-than-expected number of false positives, with 10 of 35 regions of interest showing “elevated signal levels without histopathologic evidence of PC tissue at the resection margin.” Most of the false positives occurred at the prostate base.

The Essen study authors speculated that the presence of radioactive tracer in the urinary bladder and other factors may explain the false positive rate. They suggested that, “Further optimization of the CLI protocol, or the use of lower-energy imaging tracers such as 18F-PSMA, is required to reduce false-positives.”

The researchers called for a larger study to assess CLI’s diagnostic performance.

Boris A. Hadaschik, PhD, Director of the Clinic for Urology at Essen University Hospital, added, “Radical prostatectomy could achieve significantly higher accuracy and oncological safety, especially in patients with high-risk prostate cancer, through the intraoperative use of radioligands that specifically detect prostate cancer cells. In the future, a targeted resection of lymph node metastases could also be performed in this way. This new imaging combines urologists and nuclear medicine specialists in the local treatment of patients with prostate cancer.”

Because of the high reoccurrence rate of prostate cancer in men, surgical pathologists will find this potential new strategy for reducing positive surgical margins a welcomed advancement, but additional investigation will be needed to ensure its promise can be realized.

Andrea Downing Peck

Related Information

Cerenkov Luminescence Imaging Identifies Surgical Margin Status in Radical Prostatectomy

Positive Surgical Margins in 10 Most Common Solid Cancers

Intraoperative 68Ga-PSMA Cerenkov Luminescence Imaging for Surgical Margins in Radical Prostatectomy: A Feasibility Study

Cerenkov Luminescence Imaging for Surgical Margins in Radical Prostatectomy: A Surgical Perspective

University of Washington and Microsoft Research Encode Data into DNA, Demonstrating Potential New Use for Genetic Sequences

The proof-of-concept experiment showed data can be encoded in DNA and retrieved using automated systems, a development that may have positive significance for clinical laboratories

It may seem far-fetched, but computer scientists and research groups have worked for years to discover if it is possible to store data on Deoxyribonucleic acid (DNA). Now, Microsoft Research (MR) and the University of Washington (UW) have achieved just that, and the implications of their success could be far-reaching.

Clinical pathologists are increasingly performing genetic DNA sequencing in their medical laboratories to identify biomarkers for disease, help clinicians understand their patients’ risk for a specific disease, and track the progression of a disease. The ability to store data in DNA would take that to another level and could have an impact on diagnostic pathology. Pathologist familiar with DNA sequencing may find a whole new area of medical service open to them.

The MR/UW researchers recently demonstrated a fully automated system that encoded data into DNA and then recovered the information as digital data. “In a simple proof-of-concept test, the team successfully encoded the word ‘hello’ in snippets of fabricated DNA and converted it back to digital data using a fully automated end-to-end system,” Microsoft stated in a news release.

The MR/UW team published their findings in Nature Scientific Reports.

DNA’s Potential Storage Capacity and Why We Need It

Thus far, the challenge of using DNA for data storage has been that there wasn’t a way to easily code and retrieve the information. That, however, seems to be changing quite rapidly. Several major companies have invested heavily in research, with consumer offerings expected soon.

At Microsoft Research, ‘consumer interest’ in genetic testing has driven the research into using DNA for data storage. “As People get better access to their own DNA, why not also give them the ability to read any kind of data written in DNA?” asked Doug Carmean, an Architect at Microsoft, during an interview with Wired.

Scientists are interested in using DNA for data storage because humanity is creating more data than ever before, and the pace is accelerating. Currently, most of that data is stored on tape, which is inexpensive, but has drawbacks. Tape degrades and has to be replaced every 10 years or so. But DNA, on the other hand, lasts for thousands of years!

“DNA won’t degrade over time like cassette tapes and CDs, and it won’t become obsolete,” Yaniv Erlich, PhD, Chief Science Officer at MyHeritage, an online genealogy platform located in Israel, and Associate Professor, Columbia University, told Science Mag.

Tape also takes up an enormous amount of physical space compared to DNA. One single gram of DNA can hold 215 petabytes (roughly one zettabyte) of data. Wired puts the storage capacity of DNA into perspective: “Imagine formatting every movie ever made into DNA; it would be smaller than the size of a sugar cube. And it would last for 10,000 years.”

Researchers at the University of Washington claim, “All the movies, images, emails and other digital data from more than 600 basic smartphones (10,000 gigabytes) can be stored in the faint pink smear of DNA at the end of this test tube.” (Photo and caption copyright: Tara Brown/University of Washington.)

Victor Zhirnov, Chief Scientist at Semiconductor Research Corporation says the worries over storage space aren’t simply theoretical. “Today’s technology is already close to the physical limits of scaling,” he told Wired, which stated, “Five years ago humans had produced 4.4 zettabytes of data; that’s set to explode to 160 zettabytes (each year!) by 2025. Current infrastructure can handle only a fraction of the coming data deluge, which is expected to consume all the world’s microchip-grade silicon by 2040.”

MIT Technology Review agrees, stating, “Humanity is creating information at an unprecedented rate—some 16 zettabytes every year. And this rate is increasing. Last year, the research group IDC calculated that we’ll be producing over 160 zettabytes every year by 2025.”

Heavy Investment by Major Players

The whole concept may seem like something out of a science fiction story, but the fact that businesses are investing real dollars into it is evidence that DNA for data storage will likely be a reality in the near future. Currently, there are a couple of barriers, but work is commencing to overcome them.

First, the cost of synthesizing DNA in a medical laboratory for the specific purpose of data storage must be cheaper for the solution to become viable. Second, the sequencing process to read the information must also become less expensive. And third is the problem of how to extract the data stored in the DNA.

In a paper published in ASPLOS ‘16, the MR/UW scientists wrote: “Today, neither the performance nor the cost of DNA synthesis and sequencing is viable for data storage purposes. However, they have historically seen exponential improvements. Their cost reductions and throughput improvements have been compared to Moore’s Law in Carlson’s Curves … Important biotechnology applications such as genomics and the development of smart drugs are expected to continue driving these improvements, eventually making data storage a viable application.”

Automation appears to be the final piece of the puzzle. Currently, too much human labor is necessary for DNA to be used efficiently as data storage.

 “Our ultimate goal is to put a system into production that, to the end user, looks very much like any other cloud storage service—bits are sent to a datacenter and stored there and then they just appear when the customer wants them,” said Microsoft principal researcher Karin Strauss (above), in the Microsoft news release. “To do that, we needed to prove that this is practical from an automation perspective.” Click here to watch a Microsoft Research video on the DNA storage process. (Photo copyright: Microsoft Research/YouTube.)

It may take some time before DNA becomes a viable medium for data storage. However, savvy pathology laboratory managers should be aware of, and possibly prepared for, this coming opportunity.

While it’s unlikely the average consumer will see much difference in how they save and retrieve data, medical laboratories with the ability to sequence DNA may find themselves very much in demand because of their expertise in sequencing DNA and interpreting gene sequences.

—Dava Stewart

Related Information:

With a “Hello,” Microsoft and UW Demonstrate First Fully Automated DNA Data Storage

Demonstration of End-to-End Automation of DNA Data Storage

UW Team Stores Digital Images in DNA—and Retrieves Them Perfectly

Microsoft and UW Demonstrate First Fully Automated DNA Data Storage

Storing Data in DNA Is A Lot Easier than Getting It Back Out

DNA Could Store All of the World’s Data in One Room

The Rise of DNA Data Storage

Forget Silicon—SQL On DNA Is the Next Frontier for Databases

Canadian Researchers Develop Low-Cost, Lens-Free Light-Field Microscope; Could Make Anatomic Pathology Labs Portable and More Affordable

Second-generation spectral fusion microscope captures light-field images in full color using artificial intelligence and mathematical models of light to develop large-scale 3D images

Researchers in Canada have developed an inexpensive, lens-free microscope that uses artificial intelligence (AI) and mathematical models of light to develop three-dimensional (3D) images. This invention has the potential to make the clinical pathology laboratory portable and affordable. And the advancement could improve access to anatomic pathology services in remote regions and less developed countries that cannot afford conventional microscopic diagnostic equipment.

New Microscope a Boon to Pathology Laboratories Worldwide

This spectral light-fusion microscope, developed by a pair of researchers from the University of Waterloo in Ontario, uses second-generation spectral light-fusion technology for capturing light-field images in full color.

“The several-hundred-dollar microscope has no lens, and uses artificial intelligence and mathematical models of light to develop 3D images at a large scale,” states a University of Waterloo news release.

The new microscope’s low price point provides a major advantage over larger traditional microscopes that require a skilled technician to electronically “stitch” together multiple images using a machine costing several hundred thousand dollars to get the same 3D effect.

“In medicine, we know that pathology is the gold standard in helping to analyze and diagnose patients, but that standard is difficult to come by in areas that can’t afford it. This technology has the potential to make pathology labs more affordable for communities that currently don’t have access to conventional equipment,” Associate Professor of Engineering Alexander Wong, PhD, PEng, said in the University of Waterloo news release.

Wong, Associate Professor and Canada Research Chair in Medical Imaging, and Systems Design Engineer Farnoud Kazemzadeh, PhD, a Postdoctoral Fellow at Environmental Bio-Detection Products and Adjunct Professor at University of Waterloo, led the research.

“Currently the technology required to operate a pathology lab is quite expensive and is largely restricted to places such as Europe and North America, which can afford them,” Kazemzadeh noted in the news release. “It would be interesting to see what a more affordable mobile pathology lab could achieve.”

Alexander Wong, PhD, PEng (above left), and Farnoud Kazemzadeh, PhD (above right), of the University of Waterloo in Ontario, Canada, developed their new spectral light-fusion microscope to make pathology more affordable for communities that cannot access conventional equipment. They patented the first version of the microscope last year and expect their technology to be a boon to mobile anatomic pathology labs. (Photo copyright: University of Waterloo.)

Wong and Kazemzadeh described the first generation of their instrument in a research paper published in Nature Scientific Reports. In that paper, the pair demonstrated for the first time that laser light-field fusion phase contrast microscopy could detect particles at nanometer resolutions.

“We introduced a wide-field lens-free on-chip phase contrast microscopy instrument capable of detecting particles at the nanometer resolution. The instrument does not require hologram magnification, specialized sample preparation, or the use of synthetic aperture- or lateral shift-based techniques to accomplish detection of nanoparticles,” they wrote.

The researchers understand the potential of their invention to expand access to pathology. They describe the microscope as “extremely simple and economical to implement, allowing for democratization and proliferation of such systems at every level of healthcare, industry, education, or research.”

The researchers’ new second-generation device can construct nanometer-resolution images with an ultra-wide field-of-view. “The microscope captures light fields that can be analyzed using the mathematical models of light and artificial intelligence to construct 3D images that are around 100 times larger than the 2D images captured by traditional microscopes,” reported The Engineer, a United Kingdom-based publication.

Shaping the Future of Clinical Laboratories

The spectral light-fusion microscope is one example of research teams exploring how to use different technologies for the assessment of human tissue. Another example that we covered in a previous Dark Daily e-briefing involved the development of a lens-free smartphone microscope by UCLA researchers. That microscope produces holographic images of tissue samples that enable pathologists to view cancer and other abnormalities at the cellular level with the same accuracy as larger and more expensive optical microscopes.

The discipline of pathology and laboratory medicine is evolving to embrace technologies that were science fiction yesterday, but today are science fact. These technologies will continue to shape the clinical laboratory industry for years to come.

—Andrea Downing Peck


Related Information:

Lens-free Microscope Enables Full-Color Pathology at Low Cost

Artificial Intelligence-driven Imaging Research Makes Diagnosing Disease Easier

Laser Light-field Fusion for Wide-field Lens-Free On-chip Phase Contrast Microscopy of Nanoparticles

Cheap, Full-Color Images from Lens-Free Microscope

UCLA Researchers develop Lens-Free Smartphone Microscope, Pathologists May be Able to Take the Clinical Pathology Laboratory Just About Anywhere