Such a test, if proved safe and accurate for clinical use, could be a useful diagnostic tool for anatomic pathologists
What would it mean to anatomic pathology if breast cancer could be diagnosed in an hour from a fine needle aspiration (FNA) rather than a core biopsy? A new test created by researchers affiliated with Massachusetts General Hospital in Boston may be just such a game changer. Especially in remote locations where clinical laboratory resources are in short supply.
Regardless of how the next round of research and clinical studies turn out, one reason this development is significant is that it demonstrates how newer technologies and analytical software are being combined to create a faster diagnostic test for different types of cancer.
Another benefit to this research is that it may utilize simpler, less expensive instruments. In fact, the researchers said this test can be performed for about $5. For these reasons, pathologists may want to follow the progress of these researchers as they work to improve this test so it can be used in clinical care.
Affordable Image Cytometry of FNA Specimens
Though still in development, the new image cytometry system, dubbed CytoPAN, has demonstrated the ability to diagnose breast cancer within a one-hour time frame, and, according to the study published in Science Translational Medicine, “is devoid of moving parts for stable operations, harnesses optimized antibody kits for multiplexed analysis, and offers a user-friendly interface with automated analysis for rapid diagnoses.”
The international researcher team included scientists from:
“Here, we report the development and validation of an affordable image cytometry system that allows automated and same-day molecular analyses of fine needle aspiration (FNA) specimens. Termed CytoPAN, for portable fluorescence-based image cytometry analyzer, the system performs multichannel imaging for cancer diagnosis and subtyping,” the researchers wrote.
The CytoPAN technique is minimally invasive, they note, and only requires a few cellular specimens to determine if breast cancer cells are present, with results available in one hour.
The researchers are hopeful the CytoPAN diagnostic tool (above) can be a valuable resource in developing countries and remote areas where patients face long wait times before receiving a cancer diagnosis. In these areas, diagnoses typically come after advanced symptoms, such as palpable mass lesions and malaise, become present, which can have a negative impact on patientoutcomes. And anatomic pathologists worldwide would benefit greatly from such an advance in cancer diagnostics. (Photo copyright: Jouha Min, Lip Ket Chin Center for Systems Biology, Massachusetts General Hospital.)
“Unfortunately, in many low- and middle-income countries, [breast cancer] diagnosis often takes an extraordinarily long time—up to a few months—due to a lack of specialists and limited laboratory infrastructure,” Hyungsoon Im, PhD, Assistant Professor at Harvard Medical School and one of the researchers involved in the project, told United Press International (UPI).
“From a public health aspect, it is critically important to develop new diagnostic methods that overcome these barriers,” he added.
Because FNA testing is less invasive than surgical biopsy collection, it has fewer complications and is generally considered safe. Thus, it is “feasible to be performed even in resource-limiting settings at much lower costs,” Im told UPI. “This could lead to earlier treatment and accelerate new drug testing in clinical trials.”
CytoPAN Testing and Additional Trials
The researchers tested CytoPAN on 68 breast cancer patients in South Korea.
“To determine the clinical utility of the approach,” they wrote in the published study, “we next conducted a prospective clinical study in which the FNA could be directly compared to conventional pathology results. We enrolled treatment-native patients at the Kyungpook National University Chilgok Hospital (Daegu, South Korea) and who were referred for primary surgery. All patients consented to have a preoperative breast FNA before clinically indicated surgery. The breast masses were visualized by ultrasound or computed tomography, and a coaxial needle was introduced through which FNA samples (CytoPAN) and core biopsies were obtained. Surgical specimens and/or core biopsies were processed by routine pathology and served as the gold standard.”
The CytoPAN platform detected the presence of breast cancer cells with a 100% accuracy, using as few as 50 harvested cells per collected specimen.
The test also successfully identified two key breast cancer biomarkers:
“We are also preparing additional trials in the US and other countries,” Im told UPI. “The success in those trials will (hopefully) accelerate … widespread adoption of the technology.”
The researchers are currently testing CytoPAN on a larger number of patients in Botswana, with funding from the US federal National Institutes of Health (NIH).
According to the American Cancer Society (ACS), approximately 300,000 individuals are diagnosed with breast cancer annually in the US. The Union for International Cancer Control (UICC) states on their website that, globally, there are more than two million new cases of breast cancer diagnosed each year. And more than 600,000 people died from breast cancer worldwide in 2018. A disproportionate number of those deaths occurred in developing countries that have limited resources to diagnose and treat the disease.
Additional Research for Other Applications in Cancer Testing and Pathology
The new CytoPAN technology requires minimal training, according to the researchers, and only costs about $5 per test kit. This is substantially less expensive than the price associated with other tests available on the market, UPI noted.
Though additional research and clinical trials are needed before CytoPAN will be available for widespread clinical use, a cost-effective, relatively non-invasive test that can accurately diagnose cancer within an hour would be transformational for anatomic pathology and, potentially, could save many lives.
Payers are unwilling to reimburse for autopsies despite the fact that autopsies are a proven way to learn more about new diseases and how they attack the human body
Each year, less money is spent by Medicare and private health insurers on autopsies. However, autopsies regularly provide pathologists with relevant, clinically useful information about exact causes of death and other elements of disease in the deceased. Some diseases cannot be identified any other way but by autopsy. And data from autopsies have helped developers bring critical new medical laboratory tests, therapeutic drugs, and vaccines to market.
Thus, the healthcare system is losing valuable research that would bring a better understanding of diseases and processes in the body that contribute to poor health and death. This is true with COVID-19. Autopsy results have already provided revelations into how the SARS-CoV-2 coronavirus affects the body, and yielded clues that are helping pathologists combat the illness.
“Many lives have been saved by looking closely at someone’s death,” he added.
Autopsies performed on deceased patients could help clarify why there is such a wide array of symptoms for those affected by COVID-19 and provide details that cannot be detected in living patients.
For example, autopsies completed early in the pandemic confirmed that the SARS-CoV-2 coronavirus causes respiratory disease, and that extended use of ventilators could cause considerable damage to the lungs, the AP article noted. This discovery led physicians to re-evaluate how ventilators should be used on COVID-19 patients.
The AP story also stated that pathologists learned the SARS-CoV-2 coronavirus may spread the illness to other organs such as the heart, brain, liver, kidneys, and colon.
Through autopsies, COVID-19 patients also were discovered to have dramatic blood clotting issues in almost every organ of the body and micro-clotting in the lungs.
“The clotting was not only in the large vessels but also in the smaller vessels,” said Amy Rapkiewicz, MD, an anatomic and forensic pathologist, Chair of the Department of Pathology at NYU Langone Medical Center and Associate Professor, Department of Pathology at NYU Long Island School of Medicine, in an Advisory Board Daily Briefing. “And this was dramatic, because though we might have expected it in the lungs, we found it in almost every organ that we looked at in our autopsy study.”
Doctors are now exploring whether blood thinners should be utilized to prevent blood clots from forming in COVID-19 patients.
“When you’re able to see what’s happening at the level of the cells, you just have a broader picture of the potential mechanism by which the disease is happening,” Amy Rapkiewicz, MD (above), Chair of the Department of Pathology at NYU Langone Medical Center and Associate Professor, Department of Pathology at NYU Long Island School of Medicine, told Undark. (Photo copyright: Associated Press.)
Autopsies Identify Secondary Causes of Death
Autopsies also have shown that some COVID-19 patients are dying from secondary bacterial infections that appear alongside the disease. This discovery may help doctors understand lingering symptoms that plague some coronavirus patients.
“What you see at autopsy represents an effective catalogue of the injury that occurs in patients who have COVID,” pathologist Stephen Hewitt, MD, PhD, associate research physician, Laboratory of Pathology, and head of the Experimental Pathology Laboratory at the National Cancer Institute Center for Cancer Research, told Undark. “And it gives you an understanding and a basis to try and forecast forward what we’re going to see in post-COVID syndrome.”
Shortage in Funding and Forensic Pathologists
With advances in technology, clinical laboratory testing, and imaging scans, autopsies are performed much less than they were in the past. In the 1950s, autopsies were performed on about half of the patients who passed away in hospital situations, but now that number is somewhere between only five and 11%, ABC News reported.
At this time, hospitals are not required to provide autopsy services and the costs to perform autopsies are often not covered by private or government insurance.
“As medicine has become closer to the bottom line, community hospitals don’t want to perform the autopsies because they’re not getting any functional reimbursement for them,” Hewitt told Undark.
Hospitals usually have to cover costs associated with autopsies themselves or pass those expenditures along to the deceased patient’s family. Autopsies typically cost anywhere from $1,000 to $5,000 per patient, Undark reported.
“When you consider there’s no reimbursement for this, it’s almost an altruistic practice,” Billie Fyfe-Kirschner, MD, a pathologist with Rutgers University, told the Associated Press. “It’s vitally important, but we don’t have to fund it.”
According to the AP, the US faces a critical shortage of forensic pathologists who are trained to perform autopsies. It is estimated, AP reported, that “the US has only a few hundred forensic pathologists but could use several thousand—and less than one in 100 graduating medical school students enters the profession each year.”
Clearly, pathologists have much to offer in the field of autopsies. Autopsying patients who died from COVID-19 may provide data that could greatly affect treatment for those diagnosed with the disease and improve patient outcomes overall.
Pathologists may be interested to learn that though a substitute for horseshoe crab blood has been available for nearly 20 years, it has not been widely adopted in the US
Since the 1970s, the blue blood of the horseshoe crab has saved countless human lives by detecting deadly toxins in medical products, as well as its use in a number of medical laboratory tests. Now, that unique blood is playing a vital role in the fight against COVID-19 as well, by enabling pharma companies to ensure the coronavirus vaccines they are giving are free of bacterial contaminants—such as endotoxins—that can harm or kill patients.
Microbiologists and clinical laboratory scientists are familiar with the Endotoxin Activity Assay (EAA), which uses LAL as a way to detect if a critically-ill patient may have whole blood endotoxemia. Published studies show that the detection of elevated endotoxin activity levels is associated with an increased disease severity in patients with sepsis and septic shock.
Horseshoe crab blood is an opaque blue color due to its high copper content. The blood contains limulus amebocyte lysate or LAL (pronounced “el-ay-el”), which either clots or changes color in the presence of bacterial endotoxins. LAL has become the standard to test the safety of many medical devices and pharmaceuticals—including coronavirus vaccines. There are currently no other tests that can analyze the purity of medications and cleanliness of medical devices with the same accuracy as the LAL test.
“The crabs live only on the east coasts of Asia and North America,” Yahoo News reported. “The world’s largest population of American horseshoes winters off Maryland shores and spawns each spring in Delaware Bay. The latest trawl survey puts this population at more than 14 million mature crabs.”
Futuristic Clean Rooms for Extracting Blood
After the crabs are dredged from the ocean floor, or captured as they come ashore for breeding, they are transported to one of a handful of facilities authorized to perform the bleeding process. Once there, the horseshoe crabs are cleaned and sterilized, suspended upside down, and inserted with a needle which extracts approximately one third of their blood.
“These things are being produced in ‘clean rooms’ that look like the stuff they make microchips in,” Glenn Gauvry, Founder and President of the Ecological Research and Development Group Inc. (ERDG) told Yahoo News. ERDG is a 501(c)3 non-profit wildlife conservation organization. Its primary focus is the conservation of the world’s four horseshoe crab species.
In futuristic-looking labs (above), technicians withdraw the prized blood cells from the tubular heart of the crab and then spin the blood in a centrifuge to isolate the LAL. The resulting product is then sold as endotoxin test kits to pharmaceutical companies that test medical and clinical laboratory supplies, including COVID-19 vaccines. (Photo copyright: Popular Mechanics.)
Certain laboratory tests developed from horseshoe crab blood are used to detect bacterial contamination in everything from heart stents, saline drips, and flu shots, to surgical implants such as pacemakers and prosthetic devices.
Federal law mandates that any medical device that is inserted or injected into a human body must pass the LAL test for contamination. This makes horseshoe crab blood vital for ensuring the new COVID-19 vaccinations are free of potentially-deadly toxins.
“Without LAL, you’re not going to be able to produce the billions of inoculations that are going to have to come about to handle this pandemic,” John Tanacredi, PhD, Professor of Earth and Environmental Sciences, Department of Biology, Chemistry and Environmental Studies at Molloy College, told CBS News.
A $60 Million/Year Industry
Once the LAL has been withdrawn, the crabs are returned to the wild. The horseshoe crabs typically spend one to three days in the lab while the LAL is extracted. They can survive out of water for up to four days, as long as their gills stay moist.
The crabs are then returned to the fishermen who originally caught them, to be gently placed back into the sea. “We treat these crabs like babies,” Yahoo News reported one fisherman saying. “Blue bloods save lives,” said another fisherman.
The Atlantic States Marine Fisheries Commission estimates that in 2019 labs extracted blood from approximately 640,000 horseshoe crabs in the US. Researchers estimate the industry makes about $60 million per year and that the coveted blue blood is worth about $60,000 per gallon, Yahoo News reported.
There are only four labs in the US authorized to extract blood from the horseshoe crabs. They are located in Maryland, Virginia, South Carolina, and Cape Cod. In Maryland, only three trawlers hold permits to catch the horseshoe crabs from the waters surrounding that state.
“We have a 450 million-year-old creature that for the last 45 years has improved the safety of medicines for humans and animals,” John Dubczak, Director of Operations at Charles River Laboratories, told CBS News.
Allen Burgenson, Global Subject Matter Expert-Testing Solutions, Lonza Walkersville, a division of Lonza Bioscience, told Yahoo News “the [pharmaceutical] industry produces enough tests in one day to screen five billion doses of coronavirus vaccine.”
Synthetic Substitute for Horseshoe Crab Blood Available, But Not Widely Used in US
In response to pressure from conservation groups, researchers in Singapore successfully cloned the blood of horseshoe crabs and developed a synthetic test for endotoxins. The synthetic test, known as Recombinant Factor C (rFC), has been commercially available since 2003 and in some countries in Europe is accepted as equal to tests using horseshoe crab blood. However, rFC has not yet been approved for widespread use in the US.
“You’ve got a very large, biomedical bleeding industry with a vested interest in keeping those horseshoes crabs coming in and basically protecting this monopoly,” Ryan Phelan, co-founder and Executive Director of Revive and Restore, a wildlife conservation group based in California that lobbied for the synthetic, told Yahoo News.
In 2017, Dark Daily reported on the potential threat to horseshoe crabs due to blood harvesting. In “Medical Laboratories Could Be Threatening the Survival of Horseshoe Crabs,” we noted growing concerns that the biomedical industry was having a negative impact on the horseshoe crab population. Since then, not much movement has been made toward establishing the synthetic as the standard test in the US.
Recombinant Factor C might eventually eliminate the need to harvest blood from living creatures. But for now, horseshoe crabs continue to provide a critical component for safeguarding humans against contaminants in medical supplies and pharmaceuticals, including COVID-19 vaccinations.
According to Dubczak, the LAL test “has unequivocally elevated the quality and safety of injectable pharmaceutical drugs and medical devices, and that includes all of the vaccines that protect us,” he told USA Today.
Walmart may be the largest, but it is not the only retailer offering clinical laboratory testing and primary care services at conveniently-located retail stores
Earlier this month in “How Walmart Plans to Take Over Health Care,” CNBC asked, “Is Walmart the future of healthcare?” Good question. In the midst of the COVID-19 pandemic, Walmart (NYSE:WMT) managed to open six Walmart Health locations in Georgia and Arkansas. In addition, the giant retailer announced plans to open more primary care clinics at Walmart Supercenters in Chicago and Florida.
Clinical laboratory managers who struggle to keep revenues flowing should take notice. These retail clinics may not have their own medical laboratories, but their primary care physicians will be generating lab specimens.
And because Walmart offers medical laboratory tests at these locations, with so many people opting to visit health clinics installed within retail stores, independent clinical labs could see a noticeable drop in business as Walmart Health expands its network across the US.
Therefore, clinical labs near Walmart Health locations would be wise to develop strategies and services toward becoming a lab test provider to these retail clinics.
Walmart Health Eyes Florida Primary Care Market
“The past few months in particular have exposed the vulnerabilities of our healthcare system and left many without access to adequate health resources,” said Lori Flees, Senior Vice President and Chief Operating Officer, Walmart US Health and Wellness, in a blog post. “We know our customers need us more than ever, which is why we’re announcing an expansion of Walmart Health.
“We’re planning to open seven Walmart Health locations in the Jacksonville [Florida] market in 2021, with at least one opening in early 2021, and we’re beginning conversations in the Orlando and Tampa markets. Our new health centers will be in communities in need of affordable, accessible preventive care, which we will help deliver through Walmart Health,” Flees wrote.
Walmart could be operating 22 Walmart Health locations like that shown above in Georgia, Florida, Arkansas, and Illinois by the end of 2021, Fierce Healthcare reported. This means Walmart Health may double its locations by the end of this year. Clinical laboratories near these locations may want to reach out and offer lab testing services to these retail clinics. Notice that, in the picture of the exterior of a Walmart Health clinic, “Labs” is a service that is prominently displayed as one of the important clinical services offered at that site. (Photo copyright: Walmart.)
Can Clinical Laboratories Compete or Collaborate with Walmart?
A news release announcing the opening of the Walmart Health Centers in Chicago stated that Walmart Health partners with “local, on-the-ground health providers to deliver primary care, labs, x-ray and diagnostics, counseling, dental, and hearing services all in one facility at transparent pricing regardless of a patient’s insurance status.”
However, clinical laboratories wanting to be a testing provider to Walmart Health may have to keep their costs of tests and services down in order to be competitive.
Walmart Health’s “Summary Price List” provides a complete list of medical laboratory tests and services offered at the retail clinics.
Other Primary Care Disruptors
Walmart is not the only retailer offering primary care services amid the COVID-19 pandemic.
Walgreens Boots Alliance (NASDAQ:WBA) partnered with VillageMD, a provider of primary care services, to open 500-700 “Village Medical at Walgreens” primary care clinics “in more than 30 US markets in the next five years, with the intent to build hundreds more thereafter,” according to a news release.
By end of summer 2021, 40 “Village Medical at Walgreens” primary care sites (above) are expected to open in Texas, Arizona, and Florida, according to a January 2021 news release. Walgreens is investing $1 billion over three years in the clinics, which will be situated near its stores. “Through these conveniently located clinics at our neighborhood stores, we will uniquely integrate the pharmacist as a critical member of VillageMD’s multi-disciplinary care team to provide patients with personalized and coordinated care,” said Stefano Pessina, Walgreens Executive Vice Chairman and CEO, in the news release. (Photo copyright: Walgreens Boots Alliance.)
Clinical laboratory managers and pathologists will want to be on the alert for opportunities to forge relationships with Walmart Health, Walgreens, and CVS Health to capture new primary care-related testing business coming out of these non-traditional healthcare providers.
CAP president maintains medical laboratory staff are ‘indispensable’ in pandemic fight and should be in ‘top tier’ for vaccination
As COVID-19 vaccinations continue to roll out, the College of American Pathologists (CAP) is lobbying for clinical pathologists and medical laboratory staff to be moved up the priority list for vaccinations, stating they are “indispensable” in the pandemic fight.
In a news release, CAP’s President Patrick Godbey, MD, FCAP argued for the early vaccination of laboratory workers, “It is essential that early access to the vaccine be provided to all pathologists and laboratory personnel,” he said. “Pathologists have led throughout this pandemic by bringing tests for the coronavirus online in communities across the country and we must ensure that patient access to testing continues. We must also serve as a resource to discuss the facts about the vaccine and answer questions patients, family members, and friends have about why they should get the vaccine when it is available to them.”
In a phone call following a virtual press conference, pathologists and CAP President Patrick Godbey, MD (above), told MedPage Today that even if medical laboratory staff are not directly in contact with patients, they should be considered “top tier” (designated as Phase 1a) for getting the vaccine. “I think they [clinical laboratory workers] should be considered in the same tier as nurses,” said Godbey, who also is Laboratory Director at Southeastern Pathology Associates and Southeast Georgia Health System in Brunswick, Ga. “They’re indispensable. Without them, there’d be no one to run the tests.” (Photo copyright: Southeast Georgia Health System.)
Who Does CDC Think Should Be First to Be Vaccinated?
According toThe New York Times (NYT), there are an estimated 21 million healthcare workers in the United States, making it basically “impossible,” the NYT wrote, for them all to get vaccinated in the first wave of COVID-19 vaccinations.
A December 11, 2020, CDC Morbidity and Mortality Weekly Report, titled, “ACIP Interim Recommendation for Allocating Initial Supplies of COVID-19 Vaccine—United States, 2020,” notes that “The [federal] Advisory Committee on Immunization Practices (ACIP) recommended, as interim guidance, that both 1) healthcare personnel and 2) residents of long-term care facilities be offered COVID-19 vaccine in the initial phase of the vaccination program.”
The ACIP report defines healthcare personnel as “paid and unpaid persons serving in healthcare settings who have the potential for direct or indirect exposure to patients or infectious materials.”
However, a CDC terminology guidance document listed at the bottom of the ACIP report states, “For this update, HCP [Healthcare Personnel] does not include dental healthcare personnel, autopsy personnel, and laboratory personnel, as recommendations to address occupational infection prevention and control (IPC) services for these personnel are posted elsewhere.”
In part, the letter stated, “We are convinced that ACIP did not intend to exclude any healthcare workers from its recommendation to offer vaccinations to healthcare personnel in the initial phase of the COVID-19 vaccination program (Phase 1a). However, we would hate for jurisdictions to overlook dental, autopsy, and laboratory personnel because of a minor footnote in [CDC] guidance that was developed for an entirely different purpose (i.e., infection control).
“We respectfully ask CDC to clarify,” the letter continues, “… that all healthcare workers—including dental, autopsy, and laboratory personnel—are among those who should be given priority access to vaccine during the initial phase of the COVID-19 vaccination program.”
“In the laboratory, they are encountering and handling thousands of samples that have active live virus in them,” said Karger, who called clinical laboratory staff and phlebotomists the “forgotten” frontline healthcare workers. “We’re getting 10,000 samples a day. That’s a lot of handling of infectious specimens, and we do want [staff] to be prioritized for vaccination.”
Karger continued to stress the vital role clinical laboratories play not only in COVID-19 testing but also in the functioning of the overall health system. She added that staff burnout is a concern since laboratory staff have been working “full throttle” since March.
“From an operational standpoint, we do need to keep our lab up and running,” she said. “We don’t want to have staff out such that we would have to decrease our testing capacity, which would have widespread impacts for our health system and state.”
Testing for Post-Vaccine Immunity
The CAP panelists also highlighted the need to prepare for the aftermath of widespread COVID-19 vaccinations—the need to test for post-vaccine immunity.
“It’s not routine practice to check antibody levels after getting a vaccine but given the heightened interest in COVID testing, we are anticipating there is going to be some increased in demand for post-vaccine antibody testing,” Karger said. “We’re at least preparing for that and preparing to educate our providers.”
Karger pointed out that clinical pathologists will play an important role in educating providers about the type of antibody tests necessary to test for COVID-19 immunity, because, she says, only the SARS-CoV-2 spike protein antibody test will check for an immune response.
With the pandemic expected to stretch far into 2021, clinical laboratories will continue to play a crucial role in the nation’s healthcare response to COVID-19. As essential workers in the fight against infectious disease, clinical pathologists, clinical chemists, and all medical laboratory staff should be prioritized as frontline healthcare workers.
