Anne Paxton

September 2021—The pandemic has pelted hospitals and laboratories with wild cards and sometimes thrown wrenches into the works. But the jolts it has delivered to normal institutional operations, forcing new solutions to business and clinical care dilemmas, have also positioned laboratories to help produce stunning new capabilities.

The clinical analytics program at NorthShore University HealthSystem in suburban Chicago provides a model for how laboratory data can help institutions redeploy clinical care resources, adeptly adjust staffing and supplies, preempt negative impacts on patient care, and recover operational capacity and financial stability during a crisis.

Though NorthShore is a large integrated system consisting of six hospitals, its methods to develop its own analytic solutions can be used by community care and academic health care providers to create their own in-house or vendor-based solutions, says Chad Konchak, MBA, assistant vice president of clinical analytics. He wants to help other institutions and laboratories discover for themselves something he asserts with confidence: “There’s incredible untapped value in your data.”

NorthShore clinical analytics, which began 11 years ago as a two-person unit, has grown to a staff of 25 and was not caught flat-footed when the pandemic hit. As in any crisis, there was a deluge of requests and requirements, Konchak says. But his unit launched its Data CART (Coronavirus Analytics Research Team) governance group around the same week in March 2020 that NorthShore admitted its first COVID-19 patient and shut down elective surgeries.

The Data CART would track and manage activities across NorthShore that were affected by SARS-CoV-2. “With analytics, the technology is the easiest part. It’s the soft-governance stuff that can be complicated, especially in a pandemic when all the timelines accelerated. It usually takes months just to define things.”

The NorthShore clinical analytics program, however, was exceptionally well prepared. NorthShore is one of only six health care organizations worldwide at the highest level of digital transformation maturity, as evaluated by the Healthcare Information and Management Systems Society, based on electronic medical record adoption, outpatient EMR adoption, and data analytics.

Before the pandemic, NorthShore had used its clinical modeling capability for disease surveillance, cardiovascular risk assessment, and diabetes care. So NorthShore was well positioned to develop comprehensive COVID-19 tracking, data visualization, and analytical dashboards to support clinicians. The analytics program’s performance during the past 18 months continued to bear out the known concept, Konchak says, that “business intelligence maturity enables hospital agility.”

NorthShore developed its own SARS-CoV-2 PCR test early on. That gave NorthShore “a relatively straightforward understanding of who’s positive, who’s negative, and who’s putative,” he says, “whereas other organizations had to draw a lot of inferences from symptoms.”

Data like these became key indicators in the Data CART dashboard. “Our system needed to understand so many different things like our volumes on our different units and historical data,” Konchak says, in order to maintain care of the stroke and heart attack patients whom NorthShore would continue to admit as well as the COVID patients. Paired with predictive analytics on the spread of the disease, the indicators allowed the system to plan critical care nurse and physician staffing and detect areas in the community where jumps in disease spread were occurring or inequities in testing were developing.

The dashboards blend real-time reporting, updated hourly, and analytical and predictive capabilities in a single format that can be accessed on demand. Originating in SoftLab, the laboratory data flows into the Epic EHR and to a COVID data mart in the enterprise data warehouse, which feeds the primary analytics tools. The process employs the statistical programming language “R” to provide advanced analytics while data manipulation for the dashboard is carried out by the visualization software Tableau, which “is what’s making the magic happen,” Konchak says.

As the pandemic continued, the data and analytics helped keep tabs on multiple parameters of the disease and the hospitals’ operations while also supporting NorthShore’s return to normal, because restoring elective surgery volumes was one of the most important goals not only for patient care but also for NorthShore’s financial stability. “The data actually predicted the pandemic waves and breaks,” Konchak says, “so we were able to hit the ground running and start to turn things back on.” With the dashboard updated hourly, “we were able to monitor the data in close to real time, which allowed us to make close to real-time adjustments.”

Just as job numbers affect predicted patterns in the stock market, the predictive model assumes that factors such as the current spread of the disease, how quickly it is happening, how many patients are hospitalized, or the ratio of people hospitalized to those in the ICU or on a ventilator all affect demands on the hospital, he says. “It’s not just how many people have COVID but how sick they are that taxes the system. And this model was able to predict those effects up to a week or two weeks ahead of time.” This capability let data analytics help drive clinical care decisions during the pandemic.

By October 2020, the CART data made it possible for NorthShore to restore 89 percent of its historical surgery volumes a month ahead of schedule and, in addition, to demonstrate that the accelerated recovery period had no negative impact on iatrogenic COVID-19 infection and did not result in increased deep vein thrombosis, pulmonary embolisms, or cerebrovascular accident. This is an example of “how a coordinated and transparent data-driven effort that was built upon a robust laboratory testing capability was essential to the operational response and recovery from the COVID-19 crisis,” write Konchak and coauthors in an article published April 20 in Academic Pathology (doi.org/10.1177/​23742895211010257).

[dropcap]T[/dropcap]he success of NorthShore’s clinical analytics programs also illustrates that health care is making headway in catching up to data companies like Amazon and Facebook in using data and information not only as an artifact of a business but also as a strategic asset to gain an advantage over the competition, in Konchak’s view.

In reality, actionable data is somewhat unusual, he says. “A lot of people build predictive models that predict outcomes, but the vast majority of U.S. predictive models don’t make it into a decision-making process, meaning they are not actionable. It goes into a research publication, which is great, but it’s not actually leading to improved decision-making.”

A former software engineer early in his career, Konchak was later drawn to health care because “there were so many gaps. Even today we have a bloated, overly expensive system with lower outcomes” than other countries experience. “And just from a technology standpoint, there are a lot of opportunities there.” He has found that conceiving of health care systems as complex manufacturing operations has helped him use his business background to good effect in this particular health care crisis.

“Obviously, all the medical science is so critical to health care, but being able to understand the fundamental economics of health care is also critical,” especially when the subject is a $3 billion hospital corporation like NorthShore. So he thinks about the throughput of patients in a health care system and how to optimize it. “It’s similar to a complex factory where you have inputs and outputs, except the inputs are complicated human bodies. And optimizing the process while being safe and minimizing other downstream outcomes like readmissions—that’s an industrial engineering problem more than it is a medical science problem.”

He hopes the Academic Pathology article will be a blueprint of sorts for other laboratories and hospitals that may want to emulate the data analytics run at NorthShore and to maximize their own data’s usefulness. He compares data to a raw material such as iron ore. “Iron ore is pretty useless sitting in a rock, but taking it through the right supply chain and the right kind of enrichment process, you can turn iron ore into steel and build bridges that get people from one community to another. It’s incredibly valuable,” he says. “Similarly, using the ones and zeros of digital data, once you enrich the data with positive tests, with comorbidities, the locations of patients’ homes, and other information, you start to paint a picture that becomes actionable and advances your ability to deliver better health care.”

One limitation of the consulting analytic tools outlined in the article, Konchak says, is that they are restricted by the populations tested by NorthShore, which has an extensive testing capacity but still tests only a sample of the region’s population. A fuller interoperable, intersystem data infrastructure would dramatically improve the analytic tools, he adds.

That’s not all that’s required, however. “A company can come in and plug in an analytics program, but that’s only one-third of the problem that needs to be solved. Establishing a culture of data is critical for the success of analytics,” Konchak says. “You need to have an analytics leader or an executive leader within your institutions who is championing this to really help drive that data-driven culture.” In addition, health care institutions need to partner with engaged physician leaders. “Physicians are the real decision-makers. Predictive analytics and descriptive analytics like the Data CART are just tools to help them make data-supported decisions.” On this basis he distinguishes analytics from artificial intelligence. “Analytics is more like augmented intelligence.”

How can smaller institutions tap into the insight that data analytics can provide? He advises beginning modestly. “I’m in favor of the way we approached it, by finding small ‘use cases’ where you can show the value of the data. Sometimes people jump too far ahead and try to deploy complicated analytics. And those can become less and less transparent to the decision-makers.”

“Start small. Start simple,” he recommends. “A simple algorithm that indicates interventions for someone who has a lot of prior admissions or a lot of comorbidities is going to be more effective than a fancy predictive model that hasn’t been well thought through.” NorthShore’s clinical analytics program that began with a two-person team was helped in its expansion by partnering with the organization’s research institute. Universities are a resource that smaller institutions can similarly draw upon through partnerships, he says.

But whether through in-house or vendor partnership-based solutions, Konchak believes many small community hospitals can up their game beyond Excel spreadsheets and benefit from better analytics. “You don’t have to have a 25-person team with PhD mathematicians to be successful,” he says. With buy-in from an institution’s executives, and with clinical and business leaders on the front lines who trust the process and use it, “really, anybody can do this.”

Anne Paxton is a writer and attorney in Seattle.

Valerie Neff Newitt

September 2021—Taking steps to protect the integrity of specimens is at the heart of new and revised requirements in this year’s edition of the accreditation program checklists, set for release Sept. 22.

A CAP team made up of members of the Checklists, Personalized Health Care, and Cytopathology committees collaborated to incorporate into the checklists the evidence-based recommendations set forth in a 2019 article on preanalytics and precision pathology (Compton CC, et al. Arch Pathol Lab Med. 2019;143[11]:1346–1363).

Many of the new and revised requirements, which are in seven checklists, are aimed at improving the quality of tissue and blood specimens that may undergo molecular testing for patients with cancer. The aim of others is to improve the preanalytic quality of specimens used for all types of testing.

The problem of faulty preanalytics that compromise the molecular integrity of specimens is long-standing, says Carolyn C. Compton, MD, PhD, who was a member of the CAP Preanalytics and Precision Pathology Project Team that determined what revisions or new requirements were needed. “It’s a problem that’s kept translational research and product and drug development from moving forward. It’s been pervasive across all of biomedicine, making it extremely hard to fix,” says Dr. Compton, professor of life sciences at Arizona State University, medical director of the ASU Biodesign clinical testing laboratory, and professor of laboratory medicine and pathology, Mayo Clinic College of Medicine.

Addressing the problem, she says, requires getting to the point of care.

“From the very moment a specimen comes out of or off of a patient we need to control preanalytic variables. Only professionals who handle specimens can specifically identify and remedy the problems.”

As the revisions took shape, the team was mindful of the impact of changes on daily practice. Says team member and Checklists Committee member Amer Mahmoud, MD: “We tried to make sure we didn’t include something that would create an impossible burden on labs. Language was carefully considered and crafted to make it the best guardian of quality yet practical and not burdensome.”

And the team invited feedback from others. “We didn’t just dictate things. We sent our thoughts to other committees for comments. When we received feedback, we’d meet to discuss various concerns and points of view and edit the requirements accordingly. The work was fully vetted by others,” says Dr. Mahmoud, a hematopathologist and molecular genetic pathologist, TriCore Reference Laboratories and Presbyterian Hospital, Albuquerque, NM, and clinical assistant professor of pathology, University of New Mexico.

[dropcap]I[/dropcap]n the anatomic pathology checklist is a new requirement that says labs must have a process to ensure optimal total fixation time in formalin for specimens clinically suspected or otherwise known to contain malignancy (ANP.10039 Total Fixation Time), because specimens of this type are likely to be submitted for ancillary testing. “This is one of the most important requirements, and I believe it will grab the most attention,” Dr. Mahmoud says. “It went through multiple iterations because we wanted to include the best possible evidence pertaining to fixation time, while making sure not to penalize any lab unnecessarily.”

“We know from our literature review,” Dr. Compton says, “that overfixation”—periods exceeding 24 to 36 hours—“start to create artifactual mutations in DNA. The cross-linking between molecules causes DNA damage that can be read on an assay as contributing to tumor mutational burden, a predictive biomarker for immunotherapy for cancer. So TMB must be reflective of the disease state and not an artifact of a process to which you subjected a specimen.” With the rise in the use of immunotherapy, she adds, “this has become critical.”

Ideally, the goal would be to treat all specimens the same, because whether a specimen contains malignancy isn’t known until after it’s analyzed, “so total fixation time is important,” says Harris S. Goodman, MD, Checklists Committee chair and member of the preanalytics team and Commission on Laboratory Accreditation. “Right now, however, this requirement is limited to specimens suspected of containing malignancies, but at some point it will apply to all specimens. This is just the start.”

The team’s members know this will be hard to do given the workflows in typical AP labs. “Specimens get tossed into buckets into which they may sit all day long, and we don’t track that,” Dr. Compton says. “Now we have to come up with a process, a system, to track this. The workflows, the settings on the tissue processors, the tracking of time zero in the formalin—these are all things that have to be followed and will likely require a workflow revision. When a lab is inspected, they will have to show how they have done this. We’re not telling labs how to do this, just that they have to do it.”

Another new requirement calls for labs to monitor the quality of the formalin used for fixation (ANP.10041 Quality of Formalin). “This will probably catch some people off guard,” says Dr. Goodman, who is chief of the Department of Pathology, Alameda Health System Highland Hospital, Oakland, Calif. “Labs need to make sure formalin is good for fixing specimens. Until now, it’s been a huge preanalytic variable.”

Dr. Compton says the fixative shown to have the best performance overall is 10 percent neutral (pH 7.0) phosphate-buffered formalin. “Here’s the problem: It has to be neutral, so its pH has to be measured on a regular basis, and it has to be 10 percent formalin by volume from a saturated formaldehyde solution—a four percent formaldehyde solution,” she says. If the labs that mix their own formalin rather than purchase it from manufacturers don’t have the pH correct, Dr. Goodman says, “it will not fix the specimens properly.”

Dr. Compton says laboratories could be compromising the quality of their formalin without realizing it. “If you are trying to cut down on costs by using old formalin over again or dumping formalin that contains a decalcification chemical into a formalin bucket, that creates problems. You may not be treating fixative with the absolute respect it needs because you are unaware of the consequences.”

[dropcap]A[/dropcap]mong the revised requirements is ANP.22969 Report Elements, which says that for IHC and ISH tests that provide independent predictive information, the patient report must include information on specimen processing, the antibody clone/probe, the scoring method used, and the limitations relating to suboptimal preanalytical factors that may have an impact on results. The laboratory performing the gross examination of the specimen must record the cold ischemia time and length of time in fixative.

“This is huge,” Dr. Compton says of the revision. “Before this, control and reporting of these variables were only required for testing in breast cancer specimens, but if it was important for one kind of molecular test for one kind of cancer, it’s likely to be important for all molecular tests in all cancers.

“And it’s a must,” she continues. “Not only are we requiring control over cold ischemia time and fixation time, but we are requiring people to report those parameters as part of the history of that specimen. Until now, we had no way of knowing what had happened to a specimen because we didn’t record it.”

Dr. Mahmoud calls the requirement to report the limitations relating to suboptimal preanalytical factors that may impact results “an extremely important change.”

“It is very important for the person signing out reports on predictive markers to be aware of preanalytic issues that could impact the accuracy of the result,” he says, “and these revisions bring everyone’s attention to the two important factors of cold ischemia and total fixation time.” The same reporting requirement has been added to the molecular pathology and cytogenetics checklists (MOL.39295 and CYG.47880). “The stakes are high when you’re talking about predictive markers,” Dr. Mahmoud says.

ANP.22983 Fixation—HER2 and ER Breast Cancer Predictive Marker Testing specifies that cold ischemia time should be one hour or less. In this revised requirement, the CAP “strongly recommends” specimens be fixed in 10 percent neutral phosphate-buffered formalin for at least six hours and up to 72 hours at room temperature and that specimens be fully submerged. The group acknowledges that a fixation time greater than the 24 to 36 hours, as put forward in the revised checklists, may be required for fatty specimens like breast tissue. Information about fixative, the actual fixation time, and the cold ischemia time for each specimen must be recorded as part of the permanent specimen record in the pathology report.

MOL.39358 and CYG.48932 Fixation—HER2 (ERBB2) Breast Predictive Marker Testing similarly require monitoring of cold ischemia time (one hour or less) and fixation time.

Histology processing requirements in the anatomic pathology and biorepository checklists also were updated. ANP.23100 and BAP.07200 Tissue Processor Solutions were revised to say that “when solutions are changed, they must be entirely replaced with new solution and not just ‘topped off.’”

“The main reason tissue specimens degrade while in paraffin blocks is because of hydrolysis, which occurs when water remains in the specimen due to inadequate dehydration during tissue processing,” Dr. Compton says. Alcohol baths in tissue processors can become contaminated with spillover from formalin buckets. “If you don’t change the alcohol baths faithfully, dehydration of the tissue is compromised. Therefore, this requirement says they must be entirely replaced on a regular basis.”

ANP.23350 and BAP.07400 Paraffin Baths, Flotation Baths, and Embedding Stations now recommend the use of high-quality, low-melt paraffin because low-melt paraffin is removed more efficiently during de-paraffinization and/or antigen retrieval, which is essential for molecular analysis.

Also revised is ANP.11670 Specimen—Gross Examination, which now says “the ideal thickness for specimen sections submitted in cassettes is 5 mm or less.”

“If you don’t cut the specimen thinly enough,” Dr. Compton says, “it won’t get fixed on the inside. It will be raw. We want the formalin to be able to penetrate the entire thickness of the specimen.”

ANP.12500 Record and Material Retention—Surgical Pathology says paraffin blocks used for patient diagnostic, prognostic, and/or predictive purposes must be stored (for 10 years) in a manner that “preserves their identity and integrity,” and tissue blocks must be stored in a temperature-controlled, pest-free environment.

“The quality of the storage is important,” Dr. Compton says, “and not all institutions have space for storage so they farm it out. If you are paying someone to store your blocks, they will have to provide you with evidence that they’ve maintained temperature control and that rats aren’t gnawing through the paraffin blocks in their facility in order for you to pass a CAP inspection.”

[dropcap]I[/dropcap]n the laboratory general checklist is a revision to GEN.40100 Specimen Collection Manual Elements—Clinical Pathology Specimens. “In this revision we’re calling out phlebotomy draw order, as well as fill volume and proper mixing,” Dr. Compton says. “Some tubes in which you’re drawing blood for a molecular study have additives in them. The ratio between the additives and the blood in the tube is important and has been precisely calculated to get optimal outcomes. If you don’t fill a tube to the proper level or you don’t mix the additive with the blood thoroughly enough, you won’t get optimal results.”

GEN.40115 Specimen Collection Manual Elements—Surgical Pathology and Cytopathology Specimens is a new requirement that “puts CAP’s stamp on the importance of preanalytical factors for surgical pathology and cytopathology specimens,” she says.

The requirement lists the seven elements for which instructions must be included in the manual, including special timing for collection, type of collection container and amount of specimen to be collected, and types and amounts of fixatives or special media, among others. “Before, the check­list required some of the seven points but only suggested others. Now they are all mandated,” Dr. Compton says.

In this requirement is a note that addresses fixation and cold ischemia time, she says, noting the use of the word “must.” “These requirements will come as no surprise to anyone. They’re well known, but now they are being enforced. This is a big stick and a big step forward.”

Says Dr. Mahmoud: “Cold ischemia time and fixation are the two preanalytical factors that most affect molecular testing. These are the biggies that show up throughout revisions and demand a lot of attention. For instance, the note spells out types and amounts of fixatives, such as 10 percent neutral buffered formalin. Some hospitals collect specimens in nonconformance to that 10 percent, send them for molecular testing, and it never works. It is a disservice to patients who could never have the chance to get that testing done.”

Requiring records on cold ischemia time and fixation generated a lot of discussion, Dr. Goodman says, “because many labs are not able to control or obtain the data pertaining to cold ischemia time and when the specimen was placed in fixative. But the idea is to make sure people acquiring specimens are aware of this. I think for labs to be compliant they’ll have policies and procedures in place on how to handle specimens, educate other physicians, and make sure their OR staff, gastroenterology staff, pulmonology staff, and others are aware of them.”

[dropcap]I[/dropcap]n the all common checklist, COM.06300 Specimen Rejection Criteria requires labs to define and follow criteria for the rejection or special handling of specimens that do not meet established laboratory criteria for the requested test, and to retain records of these specimens in the patient/client report or quality management records or in both. Eight examples of specimens that do not meet established preanalytic parameters are provided, such as broken slides or specimens submitted beyond their stability time limits.

“Each lab must define its own criteria for rejection based on the kind of tests it does and with knowledge of the types of preanalytical factors that can compromise or preclude getting the right molecular analysis result,” Dr. Compton says. “If a specimen must be rejected, that’s serious. It means the patient will not get an answer.” The people who procure and handle the specimen, including those outside the purview of the pathology department, may be implicated. With feedback from pathology, she says, they will get the message it’s their fault. “This assigns responsibility to everyone in the chain of custody. Colleagues handling specimens in the operating room or clinic suite may need to change their own practices to ensure that the molecular quality of their patients’ specimens is preserved.” To pathologists who want to run tests on good specimens and get the right answers for patients, she says, “the entire upstream process is important.”

This requirement indicates that laboratories have choices to make, Dr. Goodman says. “For example, if I receive a specimen that’s hemolyzed, I cannot measure the potassium in it, but I can measure other analytes like sodium. So I have a choice: reject the entire specimen, analyze for sodium and not potassium, or analyze everything and add a disclaimer noting hemolysis may affect the result.”

In surgical pathology, the choice to analyze or reject is a more difficult one, he says, “because we can’t just take out another gallbladder or breast mass, in the same way lab medicine could request another urine or blood sample.” Even though a specimen may not have been handled perfectly, it still may be good for some analysis, he says. “This requirement establishes that if you decide to analyze a less than optimal specimen, information must be recorded to indicate there may be a problem. We must make sure doctors understand there’s an anomaly.”

The preanalytics team weighed in on the COM.30750 Temperature Checks requirement, noting patient specimens, reagents, and controls may be stored in a frost-free freezer only if protected from thawing and that thermal containers within the freezer can be used. It also says: “Repeated freeze-thaw cycles contribute to biomolecular degradation and are detrimental to biospecimen quality” and that avoiding freeze-thaw altogether by aliquoting specimens before freezing is prudent.

“This is a data-driven recommendation to keep freeze-thaw cycles to a minimum,” Dr. Compton says, adding that data show that freezing and thawing disrupt the molecular integrity of the sample. “If you’ve done this three times, it’s like putting a little grenade into the middle of the molecule and blasting it apart. You’ve destroyed your sample. We want people to aliquot it up front, freeze all of the aliquots, and only thaw each aliquot once.”

In the molecular pathology checklist, MOL. 32365 Specimen Preservation/Storage now says the same about repeated freeze-thaw cycles contributing to degradation and avoiding it altogether. And it says peripheral blood specimens shouldn’t be frozen, unless otherwise validated.

[dropcap]I[/dropcap]n the cytopathology checklist is a new section on predictive markers, the requirements of which are similar to those in the anatomic pathology checklist. “This section was added,” Dr. Goodman says, “to take into account labs that perform predictive markers on cytopathology specimens. While it’s rare for there to be a cytology lab doing this without an anatomic pathology lab associated with it, this covers such a lab if that is the case.”

In the new section consisting of six requirements, ranging from report elements to cytology slide and block storage, is “nothing revolutionary or unique,” he says. “We just want users of the cytology checklist to be aware of information and language adapted from the ANP checklist. In short, as more testing for predictive markers is done on cytopathology specimens, we want to make sure it is done correctly.”

And with more ancillary testing performed now on cytology specimens, Dr. Mahmoud says, other cytopathology requirements were revised to include language that is more inclusive of specimens other than tissue.

The key takeaway from the checklist additions and revisions, Dr. Goodman says, is that “preanalytic variables affect our results in all areas of pathology. If we don’t have the right raw materials on which to perform our tests, the rest doesn’t make any difference. We need quality specimens to get the right results.”

Dr. Compton says it’s an initiative that changes the standard of care by improving the quality of specimens for patient care and translational research “in one fell swoop.”

“It has never before been required to record what happens to a specimen on its way to analysis in a lab. Now we must document these important preanalytics. Now every specimen will have a history.”

Valerie Neff Newitt is a writer in Audubon, Pa.

September 2021—SARS-CoV-2 spread and the staffing shortage drove the conversation when Compass Group members met Aug. 3 for their monthly call led by CAP TODAY publisher Bob McGonnagle.

“Like others, we were seeing problems before COVID, but COVID seems to have kicked it into overdrive,” Steven Carroll, MD, PhD, of the Medical University of South Carolina, said of the shortage. And more long term, it’s time to jump-start training programs, he and others say.

The Compass Group is an organization of not-for-profit IDN system laboratory leaders who collaborate to identify and share best practices and strategies. Here is what they shared last month.

Stan Schofield, has MaineHealth seen breakthrough infections?
Stan Schofield, president, NorDx, and senior VP, MaineHealth: Yes, we’re having breakthrough infections every day. So far we know of 20 breakthroughs in the past few weeks of employees of the system who are fully vaccinated. They’re doing sequencing on this to see what’s going on. Our vast majority of positives are unvaccinated people under the age of 40, 45.

Jennifer Laudadio, what’s going on in Little Rock? And are you at the mandatory vaccination stage or in discussions about it?
Jennifer Laudadio, MD, professor and chair, Department of Pathology, University of Arkansas for Medical Sciences College of Medicine: Our legislature passed a rule that as a state entity we cannot mandate vaccinations, so we’re not having the conversation, although they are trying to get the legislature to reconsider.

Test volumes are similar to those in January and February. We have 10 hospitalized patients currently who were vaccinated. Most of our vaccinated patients don’t need ICU-level care. They tend to be older or immunosuppressed or have other underlying conditions.

Clark Day, tell us what’s going on in Indianapolis.
Clark Day, VP of system laboratory services, Indiana University Health: At IU Health vaccines are mandated for 36,000 team members. The mandate went into effect in May and team members were given until September 1 to be fully vaccinated. To date, about 80 percent of IU Health team members are compliant.

In Indiana about 44 percent of our total population is vaccinated. Our health system has had a few breakthrough infections. A handful of our pathology team members have experienced the breakthrough.

Sarah Province, tell us about Orlando’s situation.
Sarah Province, director of laboratory operations, AdventHealth: Testing is increasing, and our positivity rate in central Florida is 25–35 percent. For employees only we’re running 15–20 percent positivity rate with over 200 employees tested each week. We do have breakthrough infections. We discontinued preop screening for specific outpatient populations, GI patients, and pediatrics in June. We’re running between 700 and 800 tests a day at the Orlando campus.

Stella Antonara, tell us about mandatory vaccinations in Columbus and breakthrough infections.
Stella Antonara, PhD, D(ABMM), medical director of microbiology, OhioHealth: It was announced today that we’re going to have mandatory vaccination, and they’re giving people until December. Those choosing not to be vaccinated will require weekly testing. It’s my understanding that the other health systems in central Ohio will have a similar policy.

We have seen breakthrough infections and we work with Ohio Department of Health to sequence these patients.

Steve Carroll, same question for you.
Steven Carroll, MD, PhD, chair, Department of Pathology and Laboratory Medicine, Medical University of South Carolina: We went mandatory with vaccinations almost immediately after Houston Methodist Hospital won its case. We are seeing breakthrough infections but not a large number. Yesterday’s positivity rate was just shy of 20 percent and we have a lot of people coming into the hospital. Greater than 90 percent of the cases are delta.

Peter Dysert, are you seeing what your colleagues here are reporting?
Peter Dysert, MD, chief, Department of Pathology, Baylor Scott & White Health: We’re seeing the same. Our inpatient census is probably about a third of what it was at peak. Almost all of our admissions now are unvaccinated, and those who are vaccinated but immunocompetent seem to have a five- to seven-day flulike illness not requiring hospitalization. Incubation time seems to be a little shorter with the delta variant, and they have high viral loads.

How worried are you that this is likely to spin out of control again?
Dr. Dysert (Baylor): Each day our census appears to be creeping up. We had been told to prepare for a peak that was roughly 25 percent of our peak in the early stages, but we’re already at that number and probably will exceed it.

Dwayne Breining, what is it like now in New York and what are your predictions?
Dwayne Breining, MD, executive director, Northwell Health Laboratories: The positivity rate is about three percent, which is about twice as much as it was two weeks ago. We’re above 80 percent delta variant. Almost all admissions are among the unvaccinated. In New York about 70-plus percent of the people eligible for vaccine are vaccinated, so we don’t think our numbers can get all that high, but we are watching a bit of a resurgence and it is sorting right along the zip codes where the vaccine rates are the lowest.

Greg Sossaman, Louisiana is having an outbreak and has low rates of vaccination. Tell us what you’re experiencing at Ochsner.
Gregory Sossaman, MD, system chairman and service line leader, pathology and laboratory medicine, Ochsner Health: Louisiana does have a low vaccination rate and a positivity rate now above 20 percent, and more than 90 percent of that is delta. We do not have a vaccine mandate. Our state attorney general told us we would be sued, and he has already sued a medical school within the state for mandating vaccines prior to their being fully approved. For those who are not vaccinated at Ochsner, which is still a significant portion of our employees, we are moving to mandatory N95 masks and weekly testing.

We’ve seen very few breakthrough infections, but of those we have seen the patients are all well.

Hospital beds are close to full. We put a COVID ward back in place. We’re redistributing nurses and physicians, similar to what was done in the initial surge. The biggest problem is staffing. We need staff to expand the number of our ICU beds to help the local hospitals whose beds are full.

Lauren Anthony, what is Allina seeing in Minneapolis?
Lauren Anthony, MD, system laboratory medical director, Allina Health: We’re seeing an uptick. We were starting to ease up on some of our pre-procedure testing, but now they’re looking to halt those plans and roll back to what they were doing before when everyone was tested. We have seen breakthrough infections and the risk factors are the common ones.

We’re working now on the approach to the flu season—which platform to use, because some of the best tests available for testing flu along with COVID come prebundled. They’re putting multiplex cartridges together, but what do you do when you need only flu and COVID and you have a multiplex cartridge with other things on it? How do you manage the orders for that or providing results for tests that aren’t needed or weren’t specifically ordered? Test utilization, billing, and so forth are the concerns.

Yes, there is a lot of concern around panels—their costs, getting reimbursed.

Lisa Anthony, tell us what HNL Lab Medicine is experiencing.
Lisa W. Anthony, MS, MT, DLM, senior VP for strategic initiatives, HNL Lab Medicine, Lehigh Valley Health Network, Allentown, Pa.: Today our network in conjunction with two neighboring networks jointly announced mandatory vaccinations will be required for colleagues and nonemployed partners after the first COVID-19 vaccine receives full FDA approval. We will have eight weeks post-approval to comply with this mandate.

Pennsylvania is now considered to be a high transmission state but is not currently tracking breakthrough cases. HNL is, however, performing NGS and while we are not seeing significant breakthrough case numbers, all have been the delta variant.

Eric Carbonneau, how are things in Albuquerque?
Eric Carbonneau, MS, MT(ASCP), director, laboratory operations, Woodward Labs and TriCore Research Institute at TriCore Reference Laboratories: A few breakthrough cases but most are minor illnesses. Our hospitalizations are mostly the unvaccinated. We are sitting at about 65 percent fully vaccinated in the 12 and over population. Our positivity rate jumped from about one percent to six percent and a majority is delta. We’ve also seen a spike in parainfluenza and RSV cases.

The University of New Mexico is the first public entity in the state to require vaccination to attend in person.

Dan Ingemansen, what’s the situation in Sioux Falls?
Dan Ingemansen, senior director, Sanford Health: The expectation is all employees are vaccinated or obtain an exemption by November 1. Following this announcement, we had a protest last week in front of one of our medical centers, but overall we’re getting support and good feedback from the communities we serve.

Next week we’re going to simplify our build within Epic—we will be standardized to Cepheid’s SARS-CoV-2/flu/RSV test at all of our laboratories for symptomatic patients. We will have a separate test code for SARS-CoV-2-only testing for those who may be traveling or contact tracing. Within our Cepheid order, the provider can select the analyte or analytes they’re interested in. Although the analyzer will run all four targets, our team will only result the analytes ordered.

A frequent question is what to do with positive results from tests not ordered. I’m wondering what others are doing with those results.

John Waugh, what are you doing at Henry Ford?
John Waugh, MS, MT(ASCP), system VP, pathology and laboratory medicine, Henry Ford Health System: We have order sets that are together so physicians see what is in the order set when they create the order, so we’re not coming back behind them and we did that intentionally. We did not want, for example, RSV orders to accompany seasonal influenza last year or COVID testing. We’re billing and reporting only on what was ordered at that time.

We now have a mandatory vaccine policy and it has a September 10 date on it. We’ve seen our share of protests at five hospitals, and we still need about a quarter of our employee population to get vaccinated in a short period.

I’m watching a couple of leading indicators here: Are the employee health clinics packed with people going in there to get their vaccinations, and if they have a two-dose system are they getting in there in the next couple of weeks or so? The other leading indicator I’m watching is whether people are drawing down vacation time banks, maybe in anticipation of leaving the organization.

From the start our organization has taken the position, it’s your choice, your decision. You don’t have to divulge your vaccination status unless you choose to do so. There have been a lot of listening sessions—tell us what’s on your mind, what your concerns are. That has helped move the needle for some, but others made up their mind early and are cemented into a position. So this is a polarized situation and not unique to Detroit.

We have stopped presurgical testing of vaccinated patients.

Let me turn now to a topic we spent time on in our call last month—staffing and the economics that get pulled into it. I’m assuming the headlines don’t make a laboratory or hospital a more attractive place to go work, and I have to assume the financial incentives are still first and foremost in people’s minds. Stan Schofield, is that true in your experience now?
Stan Schofield (MaineHealth): Absolutely. We just rolled out our new comp program and we’re waiting to see the results. The approximations are eight to nine percent for lab medical technologists and up to 15 percent for phlebotomists. Unprecedented numbers but it’s not just the lab—the entire health system rolled out more than $65 million in comp adjustments. Of 23,000 employees we have 3,700 openings at the system level, and of them more than 800 nurse openings. We’re not alone in this. We’re doing a big hiring blitz and having a job fair next week to promote the new wage package. For the people who left in the past three or four months, it is all about money. I can confirm that.

Is the shortage now so serious that they’re saying despite the reimbursement, revenue, bottom-line conditions, we need to increase wages because if not we won’t be able to pursue our mission?
Stan Schofield (MaineHealth): That’s part of it. The other part is we didn’t get any slack on the budget requirements. The financial requirements of the system haven’t been waived, we’re not getting much relief, and it will be an interesting year if PAMA comes in with a full cut. We’ve always been a successful, strong financial performer. We’ll just have to see. We budgeted a low COVID testing volume for the year because we weren’t sure. If this surge continues, it’s only going to help us financially but it’s not going to help us operationally with staffing.

Dwayne Breining, talk about the labor and financial issues and the pressure to continue offering service at the level you do.
Dr. Breining (Northwell): It’s similar here. Even before COVID we were seeing a steady increase in the number of open positions. I think New York has an older workforce than much of the rest of the country, so it’s even worse. And there are four or five big medical systems fighting over the same labor force, so there’s a bit of an arms race mentality as well. We just offered a new comp regional salary base and ideas to keep ahead, so that’s going to keep spiraling.

COVID has led a lot of people to consider their work-life balance. Some of those who had extended their careers well past the time when they were eligible for retirement have rethought that. And a lot of our techs juggle two and sometimes three jobs. It’s a buyers’ market; they can work as much as they want. And a lot of people are considering that work-life balance and whether they want to continue doing that. It’s good for them but bad for us in terms of keeping the lab running at the current rates.

Steve Carroll, does this labor crunch sound familiar to you?
Dr. Carroll (MUSC): We have been fighting over labor for months. Like others, we were seeing problems before COVID but COVID seems to have kicked it into overdrive. And it’s across the board; it’s virtually every kind of position. We have shortages in microbiology and hematology. HLA was a problem; histotechnology is a major problem now. And a big part of it is salaries. We had not been paying at the level of some of our competitors so they were recruited away to community hospitals. We were paying them lower wages to do a harder job and that’s not sustainable. So I had to make the case that we have to get our salaries up, and we’re in the process of doing that.

The other thing long term is the pipeline. Training programs have been contracting across the country, but if we don’t have people coming through those training programs, we’re going to have real long-term problems. So I’m now making the pitch that we have to reinstitute many of these programs. Every time we do a CAP inspection the pathologists at the places we’re inspecting ask me why we’re not training these people. They have a point—we have a responsibility to do it.

The training pipeline problem seems to be a nationwide one.
Dr. Breining (Northwell): We are opening a medical technology training program with Hofstra where we opened the medical school a few years ago.

Right before COVID we had started a community outreach type of thing. We had always been involved with the high school students, but we realized by high school a lot of students have already decided to forgo math and science. So we reached out to every middle school science teacher to invite them and their students to come through our new, shiny, state-of-the art laboratory for tours. Our team was great; they had kids learning how to do point-of-care testing and other such things. It was phenomenal, well received, and then COVID hit so it was put on the shelf. We’re hoping to start it up again, but with what’s going on with delta, I think we’re going to be waiting a few more months.

Barron’s this weekend had a cover story on how the U.S. is going to be in for a long-term labor shortage. Is training within our own systems going to be adequate, or do we need a change in paradigm about the career, the career path, and the eventual outcome of that kind of employment?
John Waugh (Henry Ford): We’re looking at reopening our school of medical technology. It’s a long road but I think it’s essential, as Dr. Carroll said, that we train people in these fields. We have the capacity to do it, and we’ve done it before. It’s challenging, but I’m not about to give up the field of pathology and laboratory medicine lightly. It’s an essential resource for the health system. We started this process pre-COVID; it got stalled and I’ve got it back on a restart. But there are not enough qualified people coming forward, unfortunately. I don’t know if that fully answers your question, Bob, but that’s some of our situation on the ground.

That does answer my question in the following way: You can open all the medical technology schools you want to, but if the word of mouth about the profession is that you’re going to be underpaid and overworked and don’t have a nice career path for promotion, it might all be in vain.
John Waugh (Henry Ford): You’re right, but I don’t know that we have any other choice but to try. If we continue to have shortages and we hire as we’re doing in some respects now—we’re hiring agency people to fill positions at big premium pay, and we have an international relationship whereby students are trained offshore—the price is going to get higher.

Market adjustments are not hard—all you need is money. But there are a lot of people standing in the money line with us on this one. At the executive level of our laboratory team, I have to fight hard to make the case, and not just hope, that somebody recognizes our people.

We’ve spoken often about the silos and splintered groups we have in the field of pathology and laboratory medicine. We have the IVD vendors on one side. We have multiple laboratory organizations, each pursuing important agendas of their own for their own memberships. Sterling Bennett, do you think there’s a need for more coalition building to help solve some of these problems like labor?
Sterling Bennett, MD, MS, senior medical director, pathology and laboratory medicine, Intermountain Healthcare: Yes, there’s a need for more coalition building. It’s unlikely we’ll see a consolidation of the organizations because, as you said, they exist for certain reasons, but I do think they could cooperate and join in unified efforts that might help us get through the current situation.

Stan Schofield (MaineHealth): A great example of cooperation is the Compass Group, but we can’t solve each other’s staffing and training problems. It’s going to take legislative and financial relief to make the career path financially viable against the high costs of a college education and the debt that comes with it. But hospitals and health systems don’t have the money—there’s just too much cost that’s not being covered operationally and financially by the patients and the insurance companies and the government. It’s a tough combination, and the government doesn’t want to pay more because it is paying too much now. And the private insurers are tired of the cost shifting, so they’re not going to do anything to raise operational expenses by higher reimbursement to pay higher salaries.

Greg Sossaman, would you like to comment on this issue?
Dr. Sossaman (Ochsner): Not to disagree with Stan, but I do wonder about the ability of the larger health systems, like the groups on this call, to partner with local community colleges or other universities for training programs. We partner with our academics group here, which established a training program for physician assistants at a local university. They saw an opportunity to talk to university students who were interested in perhaps medical or pharmacy school but probably weren’t going to make it into those graduate schools and to divert them to other kinds of programs. With that in mind, we are partnering with them to help them start an MT school. Things like that are opportunities in our larger systems. We know we’re going to need to make our own. So I think and hope there are other opportunities.

Looking for additional funding from the government is problematic. The advocacy that many of the large organizations like CAP do is aimed at reimbursement for physicians and other services—the clinical lab fee schedule, for example. The educational dollar piece has been left out for many years. There’s a well-known retirement cliff that we’ve already gone over in many areas. I know we have. I do think it would be wonderful if some of the larger organizations could come together to focus on this issue in a much larger way. A group like Compass has a lot to add to that, too, because many of our members have done the things we’re looking to do. Those are creative and valuable solutions.

Sam Terese, you’ve done a lot to help train people to work at Alverno, and you have an eye and an ear for a lot of different systems and the overall economic problems that Stan Schofield described. Give us your impressions about the discussion we’re having.
Sam Terese, president and CEO, Alverno Laboratories: We have two medical technology programs, an MLT program, and a histotech program. We’re adding another medical technology program. We have programs for training biology-degreed–level people to be technologists. So we are doing as much as we can to add to the labor pool on the supply side.

On the demand side you have to ask if the lack of labor is going to drive consolidation. This is not just a laboratory question. Go across any number of industries and you’ll notice that the hours are aligned to an eight-hour day, because that’s all the labor we have available.

There’s just not as many people, like those who had been extending their work lives into their 70s but who have now changed course because of COVID. I wonder what is going to happen on the demand side, the need to reduce and where it will be felt. My fear is that it will be felt more in rural health and we’ll see accelerated closure and disparities of care based on zip code. It’s a concern on where we’re headed. 

How one breast center used genomic profiling to plan treatment during the pandemic

Sherrie Rice

September 2021—The latest data on the use of two genomic assays in early-stage breast cancer and at the University of Rochester Medical Center as the pandemic set in were reported in a CAP TODAY webinar presented by William Audeh, MD, and David G. Hicks, MD.

Dr. Audeh, medical oncologist and chief medical officer of Agendia, developer of MammaPrint and BluePrint, presented the long-term follow-up results of the MINDACT trial and an age-related analysis, as well as new data on MammaPrint’s use in endocrine therapy decisions.

Dr. Hicks, professor and director of the IHC-ISH laboratory and breast subspecialty service, University of Rochester Medical Center, described how he and colleagues used genomic profiling in an altered workflow when “the pandemic affected nearly every aspect of life in the hospital, including the screening, diagnosis, treatment, and follow-up for the care of patients with breast cancer.”

It was the randomized MINDACT trial in which the 70-gene MammaPrint assay was prospectively validated. Nearly 7,000 patients were enrolled, and the results were first published in 2016, at which time 60 percent of the patients had at least five years of follow-up (Cardoso F, et al. N Engl J Med. 2016;375[8]:717–729). The 8.7-year follow-up was presented at the ASCO Annual Meeting in 2020, and that was followed this year by the final publication (Piccart M, et al. Lancet Oncol. 2021;22[4]:​476–488).

The aim of this trial was to determine which patients are able to avoid chemotherapy safely. “The way this was done,” Dr. Audeh said, “was to look at patients who were clinically high risk, with features that would cause me as a medical oncologist to want to give them chemotherapy, but genomically low risk according to the MammaPrint 70-gene assay.” In the long-term follow-up, the main endpoint was the five-year distant metastasis-free survival in this group that was clinically high risk, MammaPrint low risk, and treated only with endocrine therapy. These patients had an excellent outcome of 95.1 percent distant metastasis-free survival, which was not improved significantly by the addition of chemotherapy.

Another finding from the MIND­ACT trial was the ability of MammaPrint to identify patients with one to three positive lymph nodes who could also safely avoid chemotherapy. The long-term follow-up on the node-positive cohort was presented at the ASCO meeting last year and published this year (Piccart M, et al. Lancet Oncol. 2021;22[4]:476–488). “The finding is that even at eight years, the difference with the addition of chemotherapy in MammaPrint low-risk patients is still negligible and quite durable,” said Dr. Audeh, formerly of Cedars-Sinai Medical Center.

Also from MINDACT was the finding on the age effect of chemotherapy on distant metastasis-free survival in the same clinically high-risk, genomically low-risk patients separated by whether they were age 50 or younger, or over 50. “Although these patients were genomically low risk,” Dr. Audeh said, “if they were 50 years or younger, they did indeed show a small benefit of chemotherapy, but that benefit did not start to appear until four years into their course. By eight years, the difference was about five percent.” This is in contrast to the women over 50 for whom there was no benefit of chemotherapy even though they have the same clinical pathologic features and the same low risk by MammaPrint.

This raised the question: Do estrogen-receptor–positive breast cancers in women age 50 and younger have an intrinsic biological difference that makes them more chemosensitive? To answer this question, Dr. Audeh said Agendia and a number of colleagues participating in the FLEX trial, which obtains whole transcriptome data from newly diagnosed breast cancers, did an analysis of age as it affected the biology of breast cancer and presented the data this year at the ASCO meeting.

“We undertook a whole transcriptome analysis of tumors that were hormone positive and HER2 negative from women 50 years and younger and we compared them to women over 50,” he said, “not just with MammaPrint and BluePrint but also in the entire transcriptome available to us through this trial. We found no significant difference in gene expression based on age.” This made it possible to conclude, Dr. Audeh said, that there is no apparent intrinsic difference in the biology of hormone-positive breast cancers even with MammaPrint low-risk that is attributable to age. “And we believe this supports the hypothesis that the benefit of chemotherapy,” seen in MINDACT and other similar trials, “is not due to a direct chemotherapy effect, but more likely to secondary ovarian suppression by the chemotherapy.”

This led to the way he and colleagues at Agendia, as well as the MINDACT investigators, believe the MammaPrint data should be applied in making treatment decisions (Fig. 1). The data in postmenopausal women with low-risk MammaPrint identifies them as safely avoiding chemotherapy. For premenopausal women, where that small chemotherapy benefit was seen most likely due to ovarian function suppression, they believe this information should be integrated into shared decision-making in which both chemotherapy as well as ovarian function suppression can be discussed with younger women.

[dropcap]D[/dropcap]r. Audeh spoke, too, of MammaPrint’s utility in endocrine therapy decision-making. “We know that within the low-risk range, which runs as Mamma­Print is reported from above zero to plus one, there is an ultra-low risk that is above 0.355.” (Esserman LJ, et al. JAMA Oncol. 2017;3[11]:1503–1510).

MammaPrint ultra-low-risk patients had been observed to have an excellent prognosis over at least 10 years, he said. To validate this over the long term, it was necessary to return to an old cohort, the Stockholm tamoxifen trial (STO-3, 1976–1990), in which more than 650 postmenopausal women with tumors 3 cm and smaller and negative nodes were randomized to either no endocrine therapy after surgery or tamoxifen for some period, primarily two years but some for five.

The benefit of this cohort is that they had not only the paraffin-embedded blocks, but also more than 20 years of follow-up of these patients, who were treated only with surgery or with minimal endocrine therapy. “We were able to extract the RNA from the blocks and perform MammaPrint on these patient samples, and we found approximately 19 percent fell into this ultra-low-risk range. With 20 years of follow-up,” Dr. Audeh said, “the surprising findings were that there was a 97 percent breast cancer-specific survival out to 20 years if they had received any tamoxifen at all, even just two years, and that rate was 100 percent at 10 years.”

Furthermore, in the group who received only surgery, if they were ultra-low risk by MammaPrint, they had a 94 percent breast cancer-specific survival at 20 years with no endocrine therapy at all and nearly 100 percent at 10 years.

Also important in this study, he said, was to analyze the remainder of the low-risk patients who were not ultra-low. “They had a very different outcome. Unlike the ultra-low-risk patients, they had a significant benefit of endocrine therapy.”

The results of two additional trials were presented in late 2020: the IKA trial presented at ESMO and the FOCUS trial presented at the San Antonio Breast Cancer Symposium.

“Although these trials had different endpoints of recurrence-free survival and distant recurrence rates, the ultra-low-risk group consistently does better with long-term follow-up. And in these trials, women were treated with either no endocrine therapy or three years or less of tamoxifen therapy.”

Finally and most recently, he said, are data presented at the ASCO meeting this year from the original MINDACT trial. Within the nearly 7,000 patients in MINDACT, they were able to also analyze separately those with an ultra-low-risk MINDACT signature. Josephine Lopes Cardozo, MD, of the Netherlands Cancer Institute, on behalf of the European Organisation for Research and Treatment of Cancer, presented data showing that 15 percent of the MINDACT cohort fell into this ultra-low-risk range—about 1,000 patients. The majority of these women were postmenopausal and node negative. “Even though in this case we had eight years of follow-up, the ultra-low group did do exceedingly well, consistent with the prior studies,” Dr. Audeh said. The breast cancer-specific survival of the Mamma­Print ultra-low-risk patients, whether deemed clinically low risk or clinically high risk, was nearly 100 percent at eight years, similar to what had been seen in the other trials.

“Furthermore, when one looked at how these patients were treated, there was in fact a group within MINDACT that deviated from the protocol and received no adjuvant systemic therapy whatsoever.” At eight years, the distant metastasis-free interval was 97.8 percent, little different from those who received any endocrine therapy at all. “Again, showing the consistency of this ultra-low-risk group.”

“We now report this in our MammaPrint reports because we do believe that postmenopausal node-negative women who have an ultra-low-risk MammaPrint may be able, if they need to, to discontinue endocrine therapy before five years have been completed if they are experiencing severe toxicity. We do not advocate withholding endocrine therapy at the outset of therapy for the ultra-low-risk group, but endocrine therapy carries considerable side effects, and for those women who want to stop early, it may be safe for them to do so if they’re ultra-low.”

Additional data were presented at ASCO this year for the remainder of the low-risk group who are not ultra-low, specifically regarding the utility of extended endocrine therapy beyond the first five years. “This was an analysis of the original NSABP B-42 trial in which extended aromatase inhibitor therapy was analyzed,” Dr. Audeh said. MammaPrint was used to determine whether it could identify which patients would benefit from extended endocrine therapy in years five to 10.

The original NSABP B-42 study enrolled women who completed their first five years of antiestrogen therapy and had no evidence of recurrence. They were then stratified to receive an additional five years of letrozole (overall 10 years of endocrine therapy) or placebo (a total of five years of endocrine therapy). “The results of this trial without any specific biomarkers or clinical features to identify which patients would benefit did show overall a 3.3 percent disease-free survival benefit for the letrozole arm [Rastogi P, et al. J Clin Oncol. 2021;39[suppl 15]:502]. But there were no clinical indicators to identify which patients would obtain that benefit,” he said. “This was the reason MammaPrint was applied to this cohort.”

It was the MammaPrint low-risk patients, not high-risk, who showed the benefit of extended letrozole therapy. For disease-free survival, MammaPrint low-risk patients who were treated with 10 years of letrozole had a 7.8 percent absolute benefit in disease-free survival (P< .001). For breast cancer-free interval, it was the MammaPrint low-risk group that had an absolute benefit of seven percent (P< .001).

“When the ultra-low-risk are removed from this group, or at least separated, an even more significant difference can be seen,” Dr. Audeh said. The disease-free survival for the low-risk patients who are not ultra-low improves to 9.5 percent (P< .001), while the ultra-low did not appear to benefit. In low risk, the breast cancer-free interval improves to 7.9 percent (P< .001). “By using MammaPrint in this setting to determine who will benefit from extended letrozole therapy, the low-risk patients who were not ultra-low have the largest benefit,” he said, “significantly greater than what was seen in the overall group in the original B-42 trial.”

MINDACT revealed that low-risk MammaPrint patients are unlikely to benefit from chemotherapy. “And now we see from the ultra-low data that MammaPrint can be used in endocrine therapy planning for the first five years, and now for extended endocrine therapy as well.”

[dropcap]T[/dropcap]he 80-gene BluePrint is a subtyping assay developed by Agendia using a supervised gene expression clustering analysis beginning with the use of IHC and FISH, as well as single-gene mRNA expression, to ask from the transcriptome which genes adequately and accurately identify luminal-type, HER2-type, and basal-type tumors.

The clinical validation of BluePrint came with the NBRST trial of 1,072 patients who were to receive neoadjuvant therapy based on IHC/FISH using preoperative core biopsy samples. That same core biopsy sample was subjected to MammaPrint and BluePrint, and the outcomes were compared. There was a 22 percent discordance between the classification by IHC and by genomic profiling, Dr. Audeh said, and this discordance played a role in predicting which patients would achieve a pathologic complete response. The groups in which this discordance was primarily seen were the HER2-positive cancers that were genomically more dominantly driven by luminal or basal biology and the estrogen-positive cancers by IHC that were genomically basal with little or no estrogen signal.

For estrogen-positive cancers by IHC, the overall pathologic complete response to neoadjuvant chemotherapy was 10 percent. “However, when one applies MammaPrint and BluePrint to further stratify these patients, what you see are the pathologic complete response rates of two percent for luminal A, 5.6 percent for luminal B, and a very different pathologic complete response of 34 percent for the group that is genomically basal by BluePrint.” In this cohort, 13 percent of all the hormone-positive patients were reclassified as basal by BluePrint.

“With MammaPrint and BluePrint, we define luminal A as tumors that are low risk by MammaPrint and luminal in their BluePrint subtype, and we define luminal B as high risk by MammaPrint and luminal by BluePrint. The basal groups are nearly always high risk by MammaPrint. But by being basal through BluePrint, we are not detecting any hormonal signaling,” he said. When they limit their analysis to hormone-positive patients who are Mamma­Print high-risk, the basal group makes up 29 percent.

When Dr. Audeh first saw this data, he suspected, as he said most clinicians would, that these ER-positive basal cancers were limited to the hormone-positive patients with the very low estrogen receptor expression by IHC. But that is not the case, he said, pointing to a scatterplot with all of the IHC levels for the ER-positive basal breast cancers. “While they do tend to cluster at the lower range of IHC, the range goes all the way up to 99 percent,” he said.

Progesterone receptor can also be positive, generally up to 50 percent. “So these receptors don’t definitively allow the identification of which patients are basal.” A comparison of pathologic complete response (pCR) rates between IHC-defined triple-negative cancers and BluePrint-defined ER-positive basal cancers reveals they are almost identical, compared with much lower pCR rates in luminal tumors by BluePrint, he said.

The longer term outcomes are also different. The five-year data were presented in San Antonio in 2020 in which the distant metastasis-free and overall survival outcomes were determined according to whether they had achieved a pCR (Whitworth P, et al. Cancer Res. 2021;81[suppl 4]:PD9-01). The basal tumors that achieved a pCR have an excellent outcome (93.7 percent probability of DMFS at five years), and, conversely, if they do not achieve a pCR, as with triple-negative breast cancers, the ER-positive basal cancers have a poor outcome (58.2 percent at five years). The probability of overall survival for ER-positive basal cancers that achieve a pCR is 82.1 percent, and for those that do not, 58.4 percent. “They behave in every way like triple-negative breast cancers,” he said of those that don’t achieve a pCR. “So we believe that BluePrint is essential to identifying these high-risk estrogen-receptor–positive breast cancers that are biologically and genomically in every way identical to triple-negative breast cancers, except for the fact that they express estrogen receptor protein, which appears to be nonfunctional.”

[dropcap]W[/dropcap]ith the onset of the pandemic, Dr. Hicks and colleagues at the University of Rochester Medical Center began to be involved in the profiling of core needle biopsies. The recommendation made to health care systems was to delay elective care, including breast cancer surgery. In response, the Society of Surgical Oncology and the COVID-19 Pandemic Breast Cancer Consortium of the American Society of Breast Surgeons released guidelines suggesting that, in some cases, the use of core biopsies for genomic testing could be helpful in making decisions about surgical versus neoadjuvant treatment.

“In dealing with a pandemic in our breast center,” Dr. Hicks said, “we’ve struggled with the following questions: Will genomics via core biopsy impact triaging patients who are essential versus nonessential for surgery under this current and difficult circumstance? And will early access to genomic test results lead to more efficient and effective breast cancer management decisions?”

The standard workflow in pathology at the URMC when evaluating core biopsies from newly diagnosed breast cancer patients would be to order ER, PR, HER2, and Ki-67 on the diagnostic core needle biopsy, and decisions on genomic profiling typically would remain postoperatively with tissue being sent from the resection specimen. “During the pandemic, we changed that workflow,” Dr. Hicks said. “We sent unstained slides for genomic profiling at the time the breast cancer biomarkers were ordered in hopes that genomic profile results would be back in time for the patient’s surgical consultation and treatment decisions.” This was part of a program called Preoperative Clinical Impact.

Between April and September 2020 they sent 211 specimens to Agendia for MammaPrint and BluePrint studies. Ten unstained slides were sent for genomic testing, and they were cut at the same time that the receptor testing was ordered. “We wanted to evaluate, first, the success rate of testing using these core biopsy tissues. What was the average turnaround time for results? Would results be available at the time of the surgical consult? And then what was the reclassification rate? How often were the genomics discordant with our clinical morphology and immunohistochemical results?” And finally, and probably the most challenging, he said: How often did this result influence treatment planning?

The success rate of testing using core biopsy tissue was 95.3 percent: 201 of the 211 specimens that were sent had sufficient material for genomic profiling. The turnaround time was 10.02 days (biopsy to result) and the lab turnaround time was 5.04 days. Results were available for the treatment planning conference and surgical consultation 100 percent of the time.

The reclassification rate—how often the results differed from their pathologic interpretation—was 32.3 percent (65/201). One ER-positive breast cancer came back with basal genomics (1/150). Of their triple-negative breast cancers, 16 percent came back as a luminal type (2/26 luminal A, 2/26 luminal B). Seventeen percent of the estrogen-receptor-negative, HER2-positive cancers came back as basal (1/6). Of the triple positives, 37 percent came back as luminal B (7/19) and five percent as luminal A (1/19). “And for what we would consider clinical high-risk tumors that were T2 and above and lymph node-positive, 39 percent came back as a luminal A subtype [26/67]. Of our clinically low-risk group, 62 percent came back as MammaPrint ultra-low [16/26].”

Dr. Hicks shared cases of these reclassifications that reveal how the genomics influenced their thinking. The first was that of a 74-year-old postmenopausal woman with no family history. She had an 8-mm mass on routine mammography, and a core needle biopsy was performed. “It’s an invasive carcinoma of an intermediate histologic grade. It has abundant eosinophilic cytoplasm, and a suggestion of some apocrine features.” (Fig. 2).

The immunohistochemical panel came back ER-negative, PR-negative, and HER2-negative, “so the response on the part of the clinicians would be aggressive and would elicit thoughts about neoadjuvant chemotherapy.” The genomics came back with a luminal A molecular subtype and a MammaPrint low-risk. Neoadjuvant chemotherapy would be unlikely to have a good pathological response, according to the report. “So a very different genomic profile compared with our pathology,” Dr. Hicks said. This elicited an immediate call from the oncologist who wanted an explanation.

The pathology did provide hints, Dr. Hicks said. “This did not look like a typical basal phenotype breast cancer. It was an intermediate histologic grade, and it had apocrine features. So we performed an androgen receptor test, and all of the tumor cells were strongly positive for androgen receptor [Fig. 3]. What this case represents is an example of a luminal androgen receptor subtype of breast cancer, an unusual subset of triple-negative breast cancers that behave very differently from the typical triple negative.”

The second case is that of a 72-year-old postmenopausal woman who had a palpable mass that was 3.0 cm and a family history (sister with breast cancer). A core needle biopsy was performed. She had an invasive carcinoma of intermediate histologic grade (Fig. 4).

Her tumor showed fairly strong expression of estrogen receptor (Fig. 5). The progesterone receptor was negative, HER2 was negative, and the Ki-67 proliferative index was fairly high. “By immunohistochemical subtyping, I would consider this a luminal subtype of breast cancer, probably a luminal B.” The genomics indicated a basal type with a MammaPrint high-risk. “So this would be one of those ER-positive basal breast cancers you heard about from Dr. Audeh.” Unlike what they anticipated from the immunohistochemistry, he said, the response to neoadjuvant chemotherapy in a patient with these genomics would be much closer to what one would expect from basal-type breast cancer.

“So we found that this accelerated utility workflow worked very well.” The genomic profiling has been an important step, he said, in optimizing risk stratification and treatment selections.

“And the pathologist has a role in helping to interpret this information in the morphologic context for the patient’s cancer. The genomic testing did play an important role in our treatment planning during the pandemic, and it was frequently discussed at tumor board. And I would receive calls from surgeons and medical oncologists.”

The approach has great potential for clinical utility beyond the pandemic, he said. “And our breast center right now is in active discussions about how we want to use this going forward.”

[dropcap]A[/dropcap]gendia collaborates on several research protocols, one of which is the I-SPY trial, a neoadjuvant therapy trial seeking biomarkers for prediction of response. They have elected in their study design to use MammaPrint as a genomic screen for their hormone-positive patients. They will only enroll high-risk MammaPrint patients when they’re seeking pathologic complete response rates as their endpoint. Data generated by I-SPY and presented at a 2018 AACR meeting shows that as the MammaPrint index becomes higher in the high-risk range, the likelihood of a pathologic complete response goes up, indicating there is an association between MammaPrint risk and chemosensitivity (van’t Veer L, et al. Eur J Cancer. 2018;103[suppl 1]:e15–e16).

The most important finding is that the highest end of the MammaPrint high-risk range, known as High 2 or MP2, has clinical meaning. That was displayed in one of the I-SPY trials published last year, in which standard-of-care chemotherapy (paclitaxel) was compared to the experimental arm in which two targeted therapies were used—immune checkpoint inhibitor durvalumab and PARP inhibitor olaparib—in combination with chemotherapy (Pusztai L, et al. Cancer Res. 2020;80[16 suppl]:CT011). MammaPrint High 2 was found to predict IO/PARP response in ER-positive breast cancer. “And we believe this will become a helpful biomarker for identifying ER-positive patients who may benefit from immunotherapy,” Dr. Audeh said. As with the low-risk range in MammaPrint, he added, they now have additional information in the high-risk range.

“And now as we split Mamma­Print high-risk into High 1 and High 2, we also have these intriguing findings from I-SPY showing that these High 2 or ultra-high-risk MammaPrint patients are not only the most chemosensitive patients, but also they appear to have more sensitivity to immune checkpoint inhibitors such as pembrolizumab as well as PARP inhibitors and possibly even carboplatin.”

That leaves, as a subject for future research, the rest of the MammaPrint high-risk patients who are in the High 1 range, patients who need more than chemotherapy and endocrine therapy. “We believe this may be the group that may most benefit from CDK 4/6 inhibitors subject to future research that Agendia is undertaking.” Agendia’s FLEX study—it uses whole transcriptome data to expand breast cancer knowledge—enrolls all early-stage breast cancer patients, on whom MammaPrint and BluePrint are performed. “In the same run, in the same platform, with the same tissue sample, we are also able to obtain entire transcriptome data on each of these patients.” As part of this IRB-approved patient consent to trial, they also obtain multiple clinical data points and annotate the database. This database is then made available to their investigators around the country for substudies analyzing the subgroups within breast cancer.

Sherrie Rice is editor of CAP TODAY. The full webinar, made possible by a special educational grant from Agendia, is at https://www.captodayonline.com/combining-pathology-mammaprint-and-blueprint-to-inform-diagnostic-workup-and-treatment-planning-for-er-patients/.

September 2021—As my term as president of the College of American Pathologists comes to a close, I am both honored and humbled to have been selected by my peers for this position. Over the past two years our organization was presented with the greatest challenge we have ever faced. Because of our phenomenal members and staff, we have accomplished great things even though we worked under the most adverse conditions. We, yet again, backed a horse named CAP. It broke out of the gate well and had to weave through traffic on a bad track, but we are ahead. We made the right bet and I am so, so lucky to have been chosen to be the jockey for this race.

Looking back, the COVID-19 pandemic presented our community with relatively sudden and profound changes resulting in a tremendous number of challenges. It has dominated our lives. We should be proud of our accomplishments. We have not only put out many fires and sewn up deep wounds, but we have also set up the College and our fellows for continued success so that we will be able to keep serving our patients well.

Many, many people have said things to me such as, “I bet this wasn’t the presidency you expected. . . . I feel sorry for you.” Well, I would like to say how I feel. I believe that I am the most fortunate person to ever have had the opportunity to be president of this organization. No other president has been given the chance to champion pathologists and the laboratories we direct like I have. When I finish this column, I will talk with someone from the Wall Street Journal and then the New York Times. Sometimes they want to be educated, and sometimes they just want to run things by you. The important point is that they now call a pathologist first when they have questions. This is new. The pandemic gave us a chance to shine, and we are now considered by the press, by elected officials, by the FDA as well as the CMS to be an authority on testing. More than ever before, patients know who we are.

There have been many other issues that the CAP needed to address during my tenure as president. Early in my term, I worked with several of my CAP colleagues on the search for a new editor to entrust with our flagship journal, Archives of Pathology & Laboratory Medicine. Alain Borczuk, MD, has proved to be an excellent leader for the publication and will ensure that it maintains its sterling reputation among pathologists.

We have also pushed to improve committee structures and responsibilities within the CAP. We took steps to make our committee appointment process much more transparent. We developed a uniform application for these positions, and the information about our committees found on the website is much improved. By taking a close look at committee membership and involvement, we were able to make it possible for more fellows to serve in these important bodies.

I am proud that during my tenure the CAP, in no uncertain terms, took a stand against racism—all racism, of any kind, anywhere. In addition, the CAP, in no uncertain terms, took a stand against violence—all violence, of any kind, anywhere. We formed our first Diversity, Equity, and Inclusion Committee. It will take a long time to accomplish our DEI goals, but I have no doubt the CAP is going to do it right and create lasting change.

We found a new home for our Pathologists Quality Registry as a Qualified Clinical Data Registry, which is the first clinical data registry designed by pathologists for pathologists. The QCDR will now be overseen by the new Quality and Clinical Data Registry Affairs Committee.

We also improved the accreditation process, an important step in our ongoing mission to ensure the best quality across all clinical laboratories. Our Council on Accreditation had to find a way to make sure our inspection processes continued to assure quality while meeting the access challenges dealt by COVID-19. We achieved that, and the CAP continues to be the gold standard for laboratory accreditation throughout the world.

We have worked hard to modernize the CAP in the past two years. We now have a standing Information Technology Leadership Committee, and by the time you read this, the CAP will have its first ever app. I have had a preview, and it is fantastic! It is an example of how well our membership-staff partnership works. We are embracing technology that will serve CAP fellows for years to come. As part of that push, we have worked hard to make education programs available online, and the uptake has been huge. All of these programs were developed by FCAPs, because I believe there is no one better to provide top-notch training about pathology.

I have also worked closely with my CAP colleagues to ensure the financial stability of our organization. Something that’s fun and a part of this effort is that the CAP now offers pathologist-focused merchandise through an online store. You can now order CAP-branded hoodies, notebooks, masks, and hats. The last item is particularly important for people with my hairstyle. We updated PathPAC to enable donations by credit card and to allow monthly automated donations, making it easier than ever for pathologists to support the CAP’s peerless advocacy work.

Our efforts in Washington, DC, have been incredibly successful. From mitigating expected cuts to pathology services from the Centers for Medicare and Medicaid Services to securing financial support in the COVID-19 pandemic and making digital/remote sign-out possible, the CAP has accomplished a great deal for pathologists in the past two years.

There has also been time for celebrating. During my term, the CAP reached its 75th anniversary. We marked the milestone with the publication of a book about the CAP written by past CAP president Paul Bachner, MD; managing editor James Crumley; and CAP staff Mary Katherine Krause, Nancy Johnson, Drew Davis, Opel Aguila, and Clemmie Lozano. In addition, we created a new award to recognize medical students who have a promising future in pathology. This has been a goal of mine for the past 10 years, and this year we finally gave out the first award.

While I have enjoyed being your president, I am pleased to be handing the reins to Emily Volk, MD. She and I have a long history of collaboration through the CAP and I consider her a trusted confidante. I have a great deal of respect for Dr. Volk and for many years have been the beneficiary of her advice. She will be an excellent leader, and I look forward to seeing the great things she will achieve during her tenure.

One of the best things about being active in the CAP is all the people you get to meet and get to know. This includes both pathologists and staff as well as their families. My wife, Donna Godbey, our daughter, Elizabeth Godbey, MD, FCAP, and I have all had our lives greatly enriched because of this. By the way, of the three Godbeys who are involved in the CAP, the author of this column is the least impressive.

In closing, I’d like to reiterate a point I have made often on these pages. As pathologists, we exist for one reason and one reason only: to benefit our patients. And the CAP exists for one reason and one reason only: to benefit our members so we can do the best job possible taking care of our patients. I believe that over the past two years we have indeed justified our existence in trumps, and we should be proud of the work we have done. I am grateful for the privilege to lead the CAP and to have had the opportunity to show the world who we are and what we can do. Thank you all!

Dr. Godbey welcomes communication from CAP members. Write to him at [email protected].

Editor: Deborah Sesok-Pizzini, MD, MBA, chief medical officer, Labcorp Diagnostics, Burlington, NC, and adjunct professor, Department of Clinical Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Screening for colorectal cancer: a U.S. Preventive Services Task Force recommendation statement

September 2021—Colorectal cancer is the third leading cause of cancer death for men and women, with approximately 52,980 deaths projected this year. Although colorectal cancer is most frequently diagnosed in adults between the ages of 65 and 74 years, about 10.5 percent of new colorectal cancer cases will occur in those younger than 50 years of age. The incidence of colorectal cancer in adults 40 to 49 years old has increased almost 15 percent from 2000–2002 to 2014–2016. In 2016, 25.6 percent of eligible adults in the United States were reported to have never been screened for colorectal cancer. A follow-up in 2018 showed that 31.2 percent were not up to date with screening. The U.S. Preventive Services Task Force (USPSTF) performed a systematic review to update its 2016 recommendation. The review evaluated the benefits and drawbacks of screening adults 40 years and older for colorectal cancer. It also examined how these findings varied based on age, gender, and race/ethnicity to determine if these factors impacted recommendations for screening adults 40 years and older. The assessment used information generated by comparative modeling to demonstrate how estimated life-years gained, colorectal cancer cases averted, colorectal cancer deaths averted, and colonoscopy burden and harms vary based on different beginning and ending ages for various screening strategies. The task force studied asymptomatic adults 45 years and older who were at average risk of colorectal cancer and had no known risk factors. It concluded with a high degree of certainty that screening for colorectal cancer in adults ages 50 to 75 years had a substantial net benefit. The task force also concluded with moderate certainty that colorectal cancer screening had a moderate net benefit in adults 45 to 49 years old. Of interest, the USPSTF reached a consensus, with a moderate degree of certainty, that screening for colorectal cancer in adults 76 to 85 years old, who were previously screened, had only a small net benefit. However, adults in this age range who had never been screened were more likely to benefit. A draft of these recommendations was posted for public comment on the USPSTF website from Oct. 27, 2020 to Nov. 23, 2020. The newer USPSTF recommendation to screen adults 45 to 49 years of age for colorectal cancer received many comments. Some supported the recommendation, while others advocated for beginning screening at a younger age. Still others disagreed with screening prior to age 50 years. Based on empirical, modeling, and epidemiologic data, the USPSTF reported that there is adequate evidence that colorectal cancer screening for the 45- to 49-year-old age group provides a moderate net benefit. The task force emphasized that benefits of screening can only be fully achieved when combined with follow-up for abnormal screening.

U.S. Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965–1977.

Correspondence: Dr. Karina W. Davidson at [email protected]

Changes in test volumes due to COVID-19: a laboratory stewardship opportunity

The COVID-19 pandemic changed the way patients access and use health care due to government shutdowns designed to mitigate the spread of SARS-CoV-2. The pandemic led to fewer patients accessing health care and undergoing surgeries and patients and medical facilities cancelling or postponing nonurgent procedures. This raised concerns that delaying or eliminating care may place patients at risk for adverse outcomes. The authors conducted a study to identify opportunities to close the gaps in care using laboratory data. They focused on laboratory testing information that can provide guidance on addressing health care gaps and reduce the adverse consequences of missed interventions that occurred during the pandemic. The authors’ retrospective time series-designed study examined laboratory services before and during the pandemic at a large health system serving women and children. The authors found that laboratory test volumes displayed three patterns: a decrease during state lockdown followed by a full or near-complete recovery; no change; or a persistent decrease. Testing used to diagnose or monitor chronic illnesses has recovered only partially since the pandemic began. This includes hemoglobin A_1c and blood lead testing, both of which had a sustained drop in testing up to one year later. The concern is that the pandemic has taken a toll on patients and practitioners and that some patients may not have returned to care for their chronic conditions or participated in general wellness screening. Tests that decreased in volume and did not completely recover are of special concern. For example, the decrease in HbA_1c testing may suggest that pediatric patients are not receiving proper diabetes monitoring. And the decrease in lead screening for at-risk children can impede appropriate interventions that reduce developmental delays. The authors concluded that a laboratory stewardship program focused on peri-pandemic care can position pathologists as leaders to ensure appropriate, equitable, and efficient care and close some of the pandemic-related gaps in the use of laboratory tests.

Singh IR, Dowlin M, Chong TH, et al. Changes in test volumes during coronavirus disease 2019 (COVID-19): A laboratory stewardship opportunity. Arch Pathol Lab Med. 2021;145:821–824.

Correspondence: Dr. Ila R. Singh at [email protected]

Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Shaomin Hu, MD, PhD, staff pathologist, Cleveland Clinic; S. Emily Bachert, MD, breast pathology fellow, Brigham and Women’s Hospital, Boston; and Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center.

Morphology of tumor and nontumor liver tissue in hepatocellular carcinoma patients treated with nivolumab

September 2021—Nivolumab is an immune checkpoint inhibitor approved for treating many types of cancer, including hepatocellular carcinoma (HCC). Liver injury is a known complication in patients treated with nivolumab for nonliver tumors. The morphologic changes to tumor and nontumor liver have not been well-characterized in HCC patients. Therefore, the authors conducted a study to characterize morphologic changes in tumor and nontumor liver tissue from patients who underwent partial or total hepatectomy following nivolumab therapy for HCC. They identified 20 patients who underwent partial hepatectomy or liver transplantation after receiving nivolumab for the disease. The authors obtained demographics, laboratory values, and imaging results from patients’ medical records. They evaluated all available slides from resection specimens for tumor necrosis, tumor-infiltrating lymphocytes, and features of liver injury. The study included 16 male and four female patients, who were a median age of 56 years. The underlying liver disease was hepatitis B virus in 10, hepatitis C virus in six, and unknown/other in four. Twelve patients were treated with nivolumab in the neoadjuvant setting, and eight were treated with nivolumab, usually with other therapies, before undergoing liver transplantation. On review of resection specimens, three patients, all of whom were from the neoadjuvant group, demonstrated marked treatment response attributable to nivolumab. Tumor-infiltrating lymphocytes were present in 17 of 20 cases. One case that showed treatment response in the neoadjuvant group demonstrated non-necrotizing granulomas and prominent bile duct intraepithelial lymphocytes in the nontumor liver. One case from the transplant group showed bile duct damage and prominent ductular reaction after long-term nivolumab therapy (32 doses). The authors’ findings indicate that nivolumab is effective in a subset of patients, including in the neoadjuvant setting. Granulomas and bile duct intraepithelial lymphocytes are rare findings in patients treated with nivolumab, but they may indicate potential response to therapy. Bile duct damage and ductular reaction may be manifestations of long-term nivolumab therapy. Future prospective and longitudinal studies with pretreatment tumor biopsies may help identify patients likely to respond to immune checkpoint inhibitor therapy and further characterize patterns of ICI-related liver injury.

Simoes CC, Thun SW, Fiel MI, et al. Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy. Mod Pathol. 2021;34:823–833.

Correspondence: Dr. Stephen C. Ward at [email protected]

Diagnostic value of cell blocks in urine cytopathology: a pilot study

The utility of cell block preparation is well established in cytopathology. Yet even though 23.3 percent of College of American Pathologists-accredited laboratories use cell blocks with liquid-based preparations on urine cytology cases, few studies addressing their performance have been conducted. To determine the usefulness of cell blocks, the authors conducted a retrospective review of urine cytology specimens that underwent cell block preparation. They identified 27 urine cytology cases at their institution involving ThinPrep and cell block preparation between 2016 and 2020 and compiled clinical history and follow-up data on patients. Two pathologists and two cytotechnologists performed a blinded review of ThinPrep alone and ThinPrep with cell blocks. Diagnoses were rendered in accordance with The Paris System for Reporting Urine Cytology. Blood and acute inflammation were common in patients who underwent cell block preparation. The authors found that cell block preparation upgraded the diagnosis in 26 percent (seven of 27) of cases. The maximum utility of cell block preparation was seen in indeterminate cases in which 60 percent (six of 10) were upgraded, including 71 percent (five of seven) of atypical urothelial cells and 30 percent (one of three) of suspicious for high-grade urothelial carcinomas (HGUC). One (one of 12; eight percent) case diagnosed as negative for HGUC with ThinPrep was diagnosed as low-grade urothelial neoplasia via cell block. The authors concluded that their results demonstrate that adjunct use of cell block preparation aids in a definitive diagnosis in the atypical urothelial cell category and may be helpful in cases with cell clusters or tissue fragments and cases suspicious for HGUC. Additional correlation studies are warranted to further understand the utility of cell blocks in urine cytology.

Wilson BL, Russel D, Evans SK, et al. Cell blocks in urine cytopathology: Do they add value to the diagnosis? A pilot study. J Am Soc Cytopathol. 2021;10(1):47–55.

Correspondence: Dr. Tanupriya Agrawal at [email protected]

Screening for AIN in women with a history of CIN or cancer

High-risk human papillomavirus has been identified in the pathogenesis of anal cancer. The authors conducted a study to assess the prevalence of abnormal anal cytology and human papillomavirus (HPV) in women 40 years and older who had a history of high-grade cervical squamous intraepithelial lesion (SIL) or cancer and to estimate the prevalence of anal intraepithelial neoplasia (AIN) using cytology as the primary screening modality. Anal cytology with HPV-DNA testing was performed. All patients with abnormal anal cytology were referred for high-resolution anoscopy (HRA), and abnormal lesions were biopsied and treated if confirmed pathologically. Abnormal anal cytology correlated with HPV status, HRA findings, and clinical and demographic characteristics. Of 317 women who completed the study, 96 (30.3 percent) had abnormal anal cytology (high-grade SIL, 12.5 percent; low-grade SIL, 19.8 percent; atypical squamous cells, cannot exclude high-grade SIL, 6.3 percent; atypical squamous cells of undetermined significance, 61.5 percent) and 101 (31.9 percent) were HPV-DNA positive. A significant association between abnormal cytology results and presence of high-risk HPV was found. Of the 96 patients with abnormal cytology, 30 (31.3 percent) had biopsy-proven AIN on HRA, representing 9.5 percent of the total patient cohort. Ten (33.3 percent) patients in the latter group had low-grade AIN and 20 (66.7 percent) had high-grade AIN. Older age and smoking were significant risk factors for abnormal anal cytology. The authors concluded that women 40 years and older who have a history of high-grade cervical SIL or cancer have a high rate of AIN. Therefore, screening for anal cancer should be considered in this patient population. The optimal screening approach should be addressed in future studies.

Wohlmuth C, Ghorab Z, Shier M, et al. Cytology-based screening for anal intraepithelial neoplasia in women with a history of cervical intraepithelial neoplasia or cancer. Cancer Cytopathol. 2021;129(2):140–147.

Correspondence: Dr. Danielle Vicus at [email protected]

Varicella zoster virus infection of the upper gastrointestinal tract

Reactivation of latent varicella zoster virus may be limited to a dermatome or involve multiple organs, including the gastrointestinal tract. Although gastrointestinal manifestations of disseminated zoster have been likened to those of herpes simplex virus (HSV), histologic features of varicella zoster virus (VZV)-related injury to the tubular gut are not well documented. The authors performed a study to describe the clinicopathologic features of VZV-related gastrointestinal injury. They identified six patients with VZV infection. All infections involved the upper gastrointestinal tract, affecting the esophagus (n = 3), stomach (n = 2), or both (n = 1). All patients were immunocompromised adults with hematologic malignancies (n = 5) or a heart transplant (n = 1). Three of the patients with hematologic malignancies had received stem cell transplants. Five patients had cutaneous and gastrointestinal zoster and one had gastrointestinal disease alone. The authors found notable differences when comparing the study participants who had VZV with 14 cases of HSV-related esophagitis used as controls. Among the findings was that VZV caused hemorrhagic ulcers with nodularity or erythema, whereas HSV produced round, shallow ulcers on a background of nearly normal mucosa (P = .01). VZV-related ulcers also featured fibrin-rich, pauci-inflammatory exudates, in contrast to the macrophage-rich exudates of HSV (P = .003). The cytopathic changes of VZV were present at all levels of the squamous epithelium, especially in a peripapillary distribution. In contrast, HSV inclusions were located in the superficial layers (P = .003) and detached keratinocytes. Unlike HSV, VZV involved the stomach, producing hemorrhage accompanied by striking apoptosis in the deep glands. The authors concluded that VZV produces unique patterns of gastrointestinal injury that facilitate its diagnosis. Recognition of gastrointestinal VZV infection is important because the infection heralds potentially life-threatening disseminated disease.

Mostyka M, Shia J, Neumann WL, et al. Clinicopathologic features of varicella zoster virus infection of the upper gastrointestinal tract. Am J Surg Pathol. 2021;45(2):209–214.

Correspondence: Dr. M. Mostyka at [email protected]

Comparison of immune checkpoint inhibitor-induced upper GI tract inflammation to other entities

Immune checkpoint inhibitor therapies are associated with multi-organ immune-related adverse events. Although colonic mucosal changes have been described, inflammatory changes in the upper gastrointestinal tract incited by immune checkpoint inhibitors (ICI) have not been well characterized. The authors conducted a study to investigate morphologic and immunologic changes in the upper gastrointestinal tract incited by ICI therapy. They compared the morphology and immune cell phenotype of gastric and duodenal biopsies from patients treated with anti-cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) or anti-programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) antibodies with biopsies from patients with Helicobacter pylori gastritis or celiac disease and normal controls. Gastric biopsies from patients on ICIs showed chronic gastritis mimicking H. pylori gastritis. However, ICI-induced gastritis demonstrated greater numbers of CD8⁺ intraepithelial lymphocytes, less lamina propria inflammation, fewer plasma cells and CD20⁺ B cells, fewer lymphoid aggregates, and a reduced CD4:CD8 ratio in the lamina propria and epithelial layer. There were no differences between anti-CTLA-4– and anti-PD-1/PD-L1–associated gastritis, except for more lymphoid aggregates in the latter. Duodenal biopsies from patients on ICIs revealed chronic duodenitis with villous blunting, mimicking celiac disease. Compared with celiac disease, ICI-associated duodenitis demonstrated a higher prevalence of neutrophilic infiltrates and erosions, increased lamina propria CD3 and CD8 T cells, and a reduced CD4:CD8 ratio. Upper gastrointestinal tract biopsies were more inflamed than concomitant colonic biopsies in the majority of patients. The authors concluded that the morphologic and immunophenotypic distinctions between ICI-associated upper gastrointestinal tract injuries and common infectious and autoimmune diseases may provide useful discriminators when clinicians are confronted with gastric and duodenal inflammatory changes in patients receiving ICI therapy.

Irshaid L, Robert ME, Zhang X. Immune checkpoint inhibitor–induced upper gastrointestinal tract inflammation shows morphologic similarities to, but is immunologically distinct from, Helicobacter pylori gastritis and celiac disease. Arch Pathol Lab Med. 2021;145(2):191–200.

Correspondence: Dr. Xuchen Zhang at [email protected]

Editors: Liron Pantanowitz, MD, director of anatomical pathology, Department of Pathology, University of Michigan, Ann Arbor, and David McClintock, MD, associate chief medical information officer for pathology, Department of Pathology, University of Michigan.

A machine-learning model to predict CML using retrospective EHR data

September 2021—Chronic myelogenous leukemia is a clonal stem cell disorder driven by the BCR-ABL1 fusion oncogene and accounts for 15 percent of adult leukemias. Patients typically present with abnormalities in their complete blood cell counts with differential classification. While a “CBC with diff” collected immediately before the diagnosis of chronic myelogenous leukemia (CML) can predict presence of the disease, the authors conducted a study to determine whether it is possible to predict a CML diagnosis from CBCs collected at various time intervals between six months and five years prior to a definitive diagnosis of the disease via BCR-ABL1 mutation testing. Using data collected between 1999 and 2020 from the Veterans Health Administration, the authors identified 12,112 patients who had undergone BCR-ABL1 testing, of whom 1,623 patients had a continuous electronic health record and 10,489 patients had incomplete records. Data from the patients with continuous health records were split into two groups to train/validate (80 percent) and test (20 percent) two machine-learning models—LASSO and XGBoost. Seven data sets were created, each using the same 1,623 patients but differentiated by time from CML diagnosis (time = 0, 6 months, and 1, 2, 3, 4, and 5 years), to assess the ability of each machine-learning model to predict CML status. Using the test data, the authors showed that model performance, as measured by area under the curve (AUC), was best at the time of diagnosis and declined for each time period thereafter (AUC range of 0.87–0.96 for time = 0; 0.75–0.80 for time = 6 months to 1 year; and 0.59–0.67 for time = 2 to 5 years). Adding incomplete data records into the test data had no impact on model performance, suggesting that even partial data can be used to predict a patient’s potential for CML. Overall, the authors demonstrated how longitudinal clinical laboratory data could be used to predict a patient’s risk for CML, leading to earlier diagnosis, treatment, and, ideally, better prognosis.

Hauser RG, Esserman D, Beste LA, et al. A machine learning model to successfully predict future diagnosis of chronic myelogenous leukemia with retrospective electronic health records data. Am J Clin Pathol. 2021. doi:10.1093/ajcp/aqab086

Correspondence: Dr. Ronald G. Hauser at [email protected]

Use of three-dimensional surface imaging and printing in anatomic pathology

Many pathologists may be familiar with three-dimensional imaging in the entertainment or gaming industry. However, 3D imaging is also increasingly being incorporated into various medical specialties, including surgery and radiology. Anatomic pathology has been evolving into an image-intensive discipline, so innovative 3D technology is particularly relevant to this field. The authors shared their experience at the Mayo Clinic and expertise regarding the use of 3D imaging within AP for patient care, education, and research. They discussed specific use cases, including utilizing 3D digital files for viewing on a two-dimensional screen, populating 3D extended reality platforms (that is, virtual reality, augmented reality, and mixed reality), and generating 3D printed photorealistic specimen models. For example, in the Mayo Clinic’s solid-organ transplant practice, offering patients the opportunity to interact with a digital image or a 3D printout of their explant has several benefits. Not only does it allow them to achieve closure and learn about their disease, but it facilitates a healthy relationship between the pathologist and patient. In the solid-organ transplant practice, images of explanted organs were generated using a handheld 3D scanner (Space Spider, Artec 3D) with Artec Studio modeling software. The specimens were formalin fixed prior to scanning and dissected to optimally demonstrate key anatomic or other pathologic features. Specimens were printed on binder jetting on a Projet 660 (3D Systems) or material jetting on a Mimaki 3D UJ-553 and Stratasys Objet 500 or J55. The authors make a strong case for investing in this emerging technology.

Bois MC, Morris JM, Boland JM, et al. Three-dimensional surface imaging and printing in anatomic pathology. J Pathol Inform. 2021;12:22. doi:10.4103/jpi.jpi_8_21

Correspondence: Dr. Joseph J. Maleszewski at [email protected]

Editors: Donna E. Hansel, MD, PhD, chair of pathology, Oregon Health and Science University, Portland; Richard D. Press, MD, PhD, professor and director of molecular pathology, OHSU; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Sounak Gupta, MBBS, PhD, senior associate consultant, Mayo Clinic, Rochester, Minn.; Fei Yang, MD, assistant professor, Department of Pathology, OHSU; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; and Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU.

Host genetic factors affecting COVID-19 disease susceptibility and severity

September 2021—More than a year into the COVID-19 pandemic, an essential question remains unanswered: Why do some people infected with SARS-CoV-2 develop severe life-threatening disease or die while others are asymptomatic or have only mild disease symptoms? Severity of COVID-19 has been shown to be negatively affected by “typical” host factors, such as increasing age, underlying medical conditions, male gender, higher body mass index, smoking, and lower socioeconomic status. Collectively, however, these traditional risk factors do not explain all of the variability in disease severity in the general population. Adding to the complexity of host factors, an international collaborative network of investigators, called the COVID-19 Host Genetics Initiative, has shown in a large genome-wide association study that many polymorphic loci across the human genome are highly correlated with COVID-19 disease susceptibility and severity. To better understand the role of genetics in SARS-CoV-2 infection, the network, a consortium of approximately 3,000 researchers and clinicians, pooled clinical and genetic data from 49,562 SARS-CoV2–infected patients in 46 studies across 19 countries and six ancestry groups. Two million control subjects were accrued from a variety of sources, including biobanks, other clinical studies, and direct-to-consumer genetic companies. This large number of study participants allowed the investigators to amass sufficient statistical power to address the role of human host genetic factors in disease severity. The latter is defined categorically as infection without hospitalization, hospitalization, or critical illness requiring respiratory support or causing death. By combining this phenotypic information with detailed genotype data, the investigators identified 13 human genomic loci that were associated with SARS-CoV-2 infection susceptibility (four loci) or disease severity (nine loci). Two of the loci were discovered only after including studies of people of East Asian ancestry in the meta-analysis, highlighting the value of including diverse populations in human genetic studies. In the genomic proximity of these 13 COVID-19 disease susceptibility loci were 40 candidate genes, many of which play a role in immune function or pulmonary pathophysiology, or both. One intriguing loci was near the FOXP4 gene, which is linked to lung cancer. The FOXP4 variant associated with severe COVID-19 increases expression of the gene, suggesting that inhibiting the gene could be a potential therapeutic strategy. Other loci associated with severe COVID-19 included DPP9, a gene linked to lung cancer and pulmonary fibrosis, and TYK2, which is implicated in some autoimmune diseases. Results of the meta-analysis may inform future efforts to identify those at greatest risk of severe SARS-CoV-2 infection and identify novel therapies and vaccines to ameliorate poor outcomes.

COVID-19 Host Genetics Initiative. Mapping the human genetic architecture of COVID-19. Nature. 2021. https://doi.org/10.1038/s41586-021-03767-x

Correspondence: Dr. Andrea Ganna at [email protected]

Predicting protein structures using artificial intelligence

It has long been theorized that the primary amino acid sequence of any protein should directly predict its active folded three-dimensional structure that largely dictates the protein’s biological function. However, even though researchers have known for years the primary sequence of the approximately 20,000 proteins in the human proteome, only about one-third of those proteins have had their 3D structures determined experimentally. Accurate computer models of protein structure based solely on primary sequence would be a scientific advance over laborious, resource-intensive experimental methods for determining protein structures, such as x-ray crystallography and cryo-electron microscopy. Understanding how a protein or protein complex is three-dimensionally oriented is a key step toward designing drugs that can modulate protein function and, therefore, treat a myriad of health issues, such as cancer, infections, and inflammatory conditions. Recent articles in Nature and Science described advanced computer modeling programs that can predict the 3D atomic structures of proteins given their primary sequence. One such artificial intelligence tool, called AlphaFold (DeepMind, London), has been shown to predict the structure of not only 98 percent of the proteins in the human proteome but also hundreds of thousands of nonhuman proteins from model organisms. For the human proteome, 58 percent of the software’s predictions for the locations of individual amino acids were sufficiently accurate to inform the precise shape of the protein’s folds. A subset of those predictions (36 percent) were potentially precise enough to detail atomic features useful for drug design, such as the active site of an enzyme. The approximately 350,000 predicted protein structures are more than twice as many as had been previously solved by experimental methods. The AlphaFold tool uses a novel machine-learning approach that incorporates physical and biological knowledge about protein structure, leveraging multisequence alignments, into the design of the deep-learning algorithm. Open-source code for the AlphaFold tool is accessible online (https://github.com/deepmind/alphafold), as is the database of its structural protein predictions (https://alphafold.ebi.ac.uk). Inspired by the AlphaFold tool, an academic team from the University of Washington has also created an artificial intelligence program for predicting protein structures, called RoseTTAFold. Open-source code for RoseTTAFold is accessible online at https://github.com/RosettaCommons/RoseTTAFold. The UW team has already used the tool to model more than 4,500 protein sequences submitted by other researchers. RoseTTAFold is nearly as accurate as AlphaFold and works on not only individual proteins but also complexes of proteins. For example, RoseTTAFold was used to create a structure database of hundreds of G-protein–coupled receptors, a class of common drug targets. Both programs use AI to spot folding patterns in vast databases of solved protein structures. The programs compute the most likely structure of unknown proteins by also considering basic physical and biological rules governing how the neighboring amino acids in a protein interact. These highly accurate in silico tools for predicting protein structure could initiate a fundamental paradigm shift in understanding how thousands of unknown proteins function. The practical applications for this new technology are immense and varied and include drug design and optimization, creation of novel enzymes for breaking down waste materials such as plastic, and development of crops that are resistant to viruses or extreme weather. The tools have already been used to better understand the novel viral proteins encoded by the SARS-CoV-2 virus.

Baek M, DiMaio F, Anishchenko I, et al. Accurate prediction of protein structures and interactions using a three-track neural network. Science. 2021. doi:10.1126/science.abj8754

Correspondence: Dr. David Baker at [email protected]

Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021. https://doi.org/10.1038/s41586-021-03819-2

Correspondence: Dr. John Jumper at [email protected]

Editor: Frederick L. Kiechle, MD, PhD

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Q.  What is the ideal collection tube for measuring the level of ammonia in blood? Is a tube containing EDTA suitable?

A. September 2021—Importance of measuring ammonia. Ammonia measurement is part of the differential diagnosis for hyperammonemia. Although ammonia is a normal by-product of amino acid metabolism, low plasma ammonia concentrations are caused by glutamine synthesis and urea synthesis in the liver.¹ An elevated level of ammonia suggests an abnormality in nitrogen homeostasis, most likely due to liver dysfunction.² Other possible causes of hyperammonemia include inborn errors of metabolism, gastric bypass, and drugs that have a direct effect on ammonia metabolism (e.g. valproic acid) or cause hepatotoxicity (e.g. acetaminophen).³

High concentrations of ammonia are toxic, especially to the central nervous system, and often manifest as encephalopathy, lethargy, vomiting, and seizures, among other symptoms.¹ When hyperammonemia is confirmed, prompt intervention is required to avoid long-term neurological damage. Further investigation is required to establish the cause of the condition.¹

Methods used to measure ammonia. Although several methods can be used to measure ammonia, the most common are an enzymatic method (direct) and a microdiffusion method (indirect).^1,4,5 The enzymatic approach consists of reducing ammonia and alpha-ketoglutarate to glutamate by glutamate dehydrogenase in the presence of NADH or NADPH. The decrease in concentration of NADH or NADPH can be detected as a change in absorbance using reflectance spectroscopy.

In the microdiffusion method, ammonium ions are converted to gaseous ammonia in an alkaline environment in which free ammonia passes through a semipermeable membrane to an indicator layer (e.g. bromophenol blue). The color change in the presence of ammonia can be detected spectrophotometrically.

Considerations in sample handling. Whenever plasma ammonia results are elevated, sampling artifacts should be taken into account. Preanalytical errors are a main confounding factor in interpreting ammonia results. The following are recommendations for handling blood samples used to measure ammonia.

• Collect blood in an ammonia-free environment, avoiding exposure to air and water or to tubes contaminated with ammonia.
• Promptly centrifuge the sample to separate plasma from cell components. A hemolyzed sample is unacceptable because red blood cells contain high concentrations of ammonium.
• Measure the ammonia concentration within 15 minutes of collecting a blood sample, keeping the sample on ice until it is analyzed. (Maintaining the sample on ice delays spontaneous ammonia formation.)
• Freeze the sample if it cannot be processed within 15 minutes.
• Repeat the blood ammonia measurement if sample-handling errors are suspected.

Blood collection tube selection. Common practice is to collect a blood sample in an ethylenediaminetetraacetic acid or heparin tube to measure blood ammonia. There is no general consensus on the superiority of EDTA versus heparin as an anticoagulant in blood collection for measuring this waste product.^5-7

Avoid using any tube that could be contaminated with ammonia. A serum sample in a tube with a clot activator (red top) is not acceptable because clotting increases ammonia production.⁸

Overall, plasma ammonia’s sensitivity to temperature and time elapsed since collection are the major considerations when evaluating ammonia concentration in blood.^9-11

1. Green A. When and how should we measure plasma ammonia? Ann Clin Biochem. 1988;25(pt 3):199–209.
2. Barsotti RJ. Measurement of ammonia in blood. J Pediatr. 2001;138(1 suppl):S11–S20.
3. Smith LD, Garg U. Urea cycle and other disorders of hyperammonemia. In: Garg U, Smith LD, eds. Biomarkers in Inborn Errors of Metabolism: Clinical Aspects and Laboratory Determination. Elsevier; 2017:103–123.
4. Hawke L. Ammonia (plasma, blood). Association for Clinical Biochemistry and Laboratory Medicine. Feb. 1, 2012. www.acb.org.uk/our-resources/science-knowledge-hub/analyte-monographs.html
5. Huizenga JR, Tangerman A, Gips CH. Determination of ammonia in biological fluids. Ann Clin Biochem. 1994;31(pt 6):529–543.
6. Dorwart WV, Saner M. Heparinized plasma is an unacceptable specimen for ammonia determination. Clin Chem. 1992;38(1):161.
7. da Fonseca-Wollheim F, van Dam M. Interference by heparin in enzymatic determination of plasma ammonia depends on reagent composition. Clin Chem. 1992;38(9):1921–1922.
8. Mousli S, Wakid NW. Ammonia production during clot retraction and its use in assay of fibrinoligase. Clin Chem. 1977;23(9):1739–1743.
9. Lindner A, Bauer S. Effect of temperature, duration of storage and sampling procedure on ammonia concentration in equine blood plasma. Eur J Clin Chem Clin Biochem. 1993;31(7):473–476.
10. Lowe WC. Freezing as a method of preserving blood ammonia. Clin Chem. 1968;14(11):1074–1079.
11. da Fonseca-Wollheim F. Preanalytical increase of ammonia in blood specimens from healthy subjects. Clin Chem. 1990;36(8 pt 1):1483–1487.

Sridevi Devaraj, PhD, DABCC
Medical Director, Clinical Chemistry and Point of Care Technology
Texas Children’s Hospital and Pavilion for Women
Professor, Pathology and Immunology
Baylor College of Medicine
Houston, Tex.
Member, CAP Clinical Chemistry Committee

Izmarie Poventud-Fuentes, PhD
Fellow, Clinical Chemistry
Baylor College of Medicine
Houston, Tex.

Q. Is there a requirement to notify nursing personnel or doctors about each critical value obtained for a patient after the initial occurrence of the critical result?

A. CAP checklist requirement COM.30000 Critical Result Notification defines critical results as test results that may require rapid clinical attention to avert significant patient morbidity or mortality. Each laboratory may define its own critical values and critical results that pertain to its patient population. A laboratory may also establish different critical results for specific patient subpopulations (e.g. dialysis clinic patients, oncology patients, newborns). The policy may also define additional rules for critical result notification, such as notifications needed for additional critical test results obtained on a patient after an initial occurrence. Policies for reporting critical results should be approved by the laboratory director and allow for prompt patient-management decisions.

The CAP recommends that laboratories develop critical values and result notification policies in consultation with clinicians since clinicians are strongly discouraged from opting out of receiving critical result notifications. Developing clear-cut policies, coupled with educating staff about those policies, is the key to success.

Clinical and Laboratory Standards Institute. GP47: Management of Clinical- and Significant-Risk Results, 1st ed.; 2015.

Standard: Test Report. 42 CFR §493.1291(g). https://j.mp/CLIA_493-1291g

Trudy R. Darden, MA, MT(ASCP)
Manager, Accreditation Services
CAP Accreditation Programs
College of American Pathologists
Northfield, Ill.