How rapid autopsies bridge clinical care and research

Valerie Neff Newitt

June 2024—Meagan Chambers, MD, MS, MSc, feels like she has signed on for a life of being on call for 2 AM autopsies, and she says nothing could please her more.

She is a neuropathology fellow at the University of Washington and does many of the rapid autopsies that make possible a range of human research that would otherwise be limited or out of reach. Next year, she’ll be an assistant professor at Stanford, where she will work in Stanford’s two-year-old rapid autopsy program.

“I do rapid autopsies because it brings patients meaning, and the secondary consequence is scientific meaning,” she says.

It’s apparent to all who work in rapid autopsy programs to procure tissue for research that it “creates meaning for patients during the last moments of their life,” she says. “To me, it’s the epitome of pathology in the human experience. Giving meaning at the end of life is the main reason people are willing to be on call 24/7 in these programs.” The University of Washington’s program, which began in 1991, is the oldest such program in the United States.

Like Dr. Chambers, others are performing autopsies in the overnight hours and happy to do it. It’s about autopsies that patients consent to in advance to aid research, in programs at about 15 institutions in the U.S., one of which is Yale’s Legacy Tissue Donation Program, which started in 2023.

Typically, researchers use, among other things, animal models, human-derived stem cells, and human tissue from surgical specimens. “But all of those have limitations,” says Marcello DiStasio, MD, PhD, co-director of the Yale program and assistant professor of pathology and ophthalmology and visual science, Yale School of Medicine.

“It’s rare to see surgical tissue made available from huge parts of the neuroanatomy—the brain, spinal cord, cardiac tissue other than the atrial appendage,” he says. “In the postmortem research setting, we can provide comprehensive sampling because we’re not limited by the need to do diagnostics.” They can sample extensively, he notes, guided primarily by the research needs.

It’s not only anatomic regions or particular organs that are rarely sampled, says Harold Sanchez, MD, co-director with Dr. DiStasio of the program and assistant professor of pathology and director of the Yale School of Medicine autopsy service. Surgical specimens may provide the oncology researcher with limited access to primary tumor but not to metastasis, “because there’s typically no surgical approach to metastasis,” he says. “We can get primary tumor and metastases in quantities that are hard to obtain any other way.”

But it’s all about speed. “If someone wants to donate at the time of death,” Dr. DiStasio says, “we have their consent on file,” as well as a list of research laboratories and the tissues they want. “Everything’s in place,” which makes it possible to do the rapid autopsy within about three hours. “Even less if you’re lucky,” he says. For those outside the hospital, “it’s six hours and typically less.”

The list of laboratories to which Yale provides the tissue is now about 15 deep, and most researchers arrive within an hour of tissue removal to pick it up. Since 2022, “we’ve distributed over 400 samples to some 15 labs, all of which are supporting experiments that otherwise would not be possible,” Dr. DiStasio says. In his own laboratory a half-dozen experiments have been made possible by the tissue procured in rapid autopsies.

For patients who want to donate, which Dr. Sanchez describes as “an extraordinary act of altruism,” and for researchers in need of this tissue unavailable “any other way at any price,” the pathologist is the hub. “A central connection,” Dr. Sanchez says, between clinicians, researchers, and patients.

The core rationale behind these programs, Dr. Chambers says, is “contributing to science in a way that other biospecimens can’t.” She performs the autopsy, hands the tissue to the researcher, “and they carry it back to their lab. In some cases they implant it into mice that same night, even if it’s 2 in the morning.”

The University of Pittsburgh has two rapid autopsy programs: Hope for Others (with Magee-Womens Hospital, which has enrolled since 2016) and Simmons Center Lung/Heart, primarily for interstitial lung disease (enrolling since 2003).

Hope for Others, which is a program for metastatic breast cancer, recently enrolled its 100th patient.

“We have clinical coordinators who maintain longitudinal relationships with our patients, sometimes for years and years,” says Tanner Bartholow, MD, MS, assistant professor of pathology in the University of Pittsburgh School of Medicine and director of the UPMC Autopsy and Forensic Pathology Center of Excellence.

To understand metastatic progression, it’s critical to access metastatic sites, and the tissue procured in the Hope for Others program is a resource not only for Pitt researchers but also for breast cancer researchers worldwide, says Steffi Oesterreich, PhD, Shear Family Foundation chair in breast cancer research, co-leader of the Cancer Biology Program of the UPMC Hillman Cancer Center, and co-director of the Women’s Cancer Research Center, University of Pittsburgh.

Tissue obtained from breast cancer metastatic sites at autopsy made possible several years ago a sequencing study in three breast cancer patient cohorts that found that N-terminal ESR1 fusions involving exons 6–7 are a recurrent driver of endocrine therapy resistance and are impervious to estrogen receptor-targeted therapies (Hartmaier RJ, et al. Ann Oncol. 2018;29[4]:872–880). “The tissue we used for the study was collected even a few years before the [rapid autopsy] program was formalized and took off,” says Dr. Oesterreich, who is also a professor in the Department of Pharmacology and Chemical Biology, University of Pittsburgh.

Studies underway now of tumor dormancy, heterogeneity, and evolution were made possible by the rapid autopsy program, Dr. Oesterreich says, crediting clinical coordinator Lori Miller (“the backbone of the Hope for Others studies,” she says) and Adrian Lee, PhD, professor of pharmacology and director, Institute for Precision Medicine, who was instrumental in getting Hope for Others started.

Five patients signed up to be advocates for the program to help recruit enrollees. “There’s multiple channels through which people come to the program,” Dr. Bartholow says, among them the clinics and coordinators. And never is the person behind the autopsy forgotten, Dr. Oesterreich says. “Before the autopsy starts, we do a moment of silence to honor the patient.”

Dr. Chambers has done most of the rapid autopsies for the prostate and bladder group at UW for the past three years, and as a neuropathology fellow, she is an integral part of the brain bank and the on-call system for that. The smallest program is pancreas related. “I’ve been there for all of them,” she says of the range of rapid autopsies. For rapid autopsies in general, at UW and elsewhere, the greatest impact is in the area of tumor heterogeneity.

“We don’t usually re-sample tumors as cancer moves and metastasizes. But rapid autopsies have shown definitively that many cancers, including breast and prostate, mutate as they metastasize, and recognizing that a single tumor and/or the metastatic sites of a specific tumor often have different molecular markers is important for patient care,” she says.

Then, too, because “we don’t in any other context get post-treatment tissue, being able to monitor on the molecular level, on the histologic level, the patient’s response to treatment is huge,” Dr. Chambers says. Sequencing is done to reveal the mutations the treatment might have driven.

Being able to study the tumor microenvironment is another high-impact area. “We’re seeing that inflammation from adjacent healthy tissue into the tumor affects treatment response in many cancers, and we can study that in a human model easily with rapid tissue,” she says.

The Yale program has a collaborating laboratory that has been able to record electrophysiologic activity from neurons in the human postmortem retinas, Dr. DiStasio says. In the human retinas studied at Yale, he says, “we have been able to do exquisitely detailed single cell and spatial transcriptomic studies.” Humans have a macula; mice do not. “It’s the most densely neuronal part of the retina, and neither of those studies would be possible without this program,” he says.

High-quality control tissue is also difficult to obtain, says Dr. DiStasio. Tissue banks often have a disease focus, and requests can be made of them for a specific disease. “But often well-matched control tissue of high quality is challenging to get.” At Yale, the heart-lung cases might serve as good controls for the central nervous system researchers, and the CNS disease cases might serve as good controls for the cardiovascular lung researchers, he says.

To maximize the utility of the donations, flexibility to suit the needs of various researchers is important, Dr. DiStasio says. “We are able to accommodate whatever custom dissection or preservation methods they need in order to have the best-quality tissue for the experiments they plan to perform.” The Yale rapid autopsy program doesn’t bank tissue, he points out. “What we have is a database of researchers and what methodology they would like and what they need preserved. Are they most interested in the integrity of nucleic acids? Are they most interested in microanatomical structure and the integrity of that in their samples?”

He adds, “It is really nice to be able to tell prospective donors and families of donors that we are making the most of each person’s donation.”

Every rapid autopsy program is different, so there’s no one way to get started, though all agree it would be difficult to do at the community hospital level unless the smaller hospital partnered with a larger institution.

Among the key ingredients, Dr. Sanchez says, are an autopsy suite and people willing to be on call. In addition, there’s the consent form, disposables, liquid nitrogen, a variety of fixatives and solutions, and personal protective equipment. “Most good-sized hospitals have all of that in-house already. If you have a busy autopsy service, none of this is completely novel for you,” he says.

For most institutions, it would come down to space, technical know-how, personnel support, and funding, Dr. Bartholow says, in addition to the clinical support staff and clinical coordinators.

There must also be a way to transport people who die outside the hospital, to communicate with donors and families 24/7, and to store, protect, and track the data. Of the latter need, Dr. DiStasio says, “We leverage Yale,” where the laboratory information system, developed largely in-house, is “extremely well supported and has a lot of customizability.” The LIS team created a new prefix for the rapid autopsy cases, he explains, “so that we have a secure password-protected, well-supported system such that these are just another type of specimen that gets accessioned.”

For now, it’s Drs. Sanchez and Di­Stasio who are on call after hours, but having technical support after hours would make the rapid autopsies faster and easier. Says Dr. Sanchez: “Our PAs and technical staff are superb and extremely enthusiastic about this. During normal business hours, if a case comes in, they’re terrific. We’re trying to put together the infrastructure to have them come in after hours.”

Says Dr. Bartholow: “No one is going to have everything figured out right out of the chute. You’re going to have to adapt as you go on throughout the years.” And as the number of patients in the program grows, he adds, it becomes more difficult logistically. “There’s always going to be a learn-as-you-go process.”

Dr. Chambers cites a published article on rapid autopsies that highlights common barriers to entry, one of which is a heavily populated metropolitan area (Iocobuzio-Donahue CA, et al. Nat Rev Cancer. 2019;19[12]:686–697). “Because if you’re going to do the rapid procedure, you need a fair number of people who pass away in a relatively small area. If you try to do it in Wyoming and your nearest person who has passed away is half an hour away and everyone else in the state is two, three, four hours away, you won’t be able to get the critical volume to make the program work.”

Second is a cancer center, which attracts clinical researchers and a high volume of patients. “That tissue needs somewhere to go and preferably right away,” she says. A biorepository could be created for people to connect into, she adds, but without that connection at the outset, “the word isn’t going to get out there.” Even then, “it will sit there. I feel like it’s not honoring the best wishes of the patient, which is to be involved and contribute right away.”

Still, she says, there are models of rapid autopsy programs that are “literally one donor, one project.” Dr. Chambers uncovered this in a review with Jody Hooper, MD, director of the Stanford Research Autopsy Center, of all the published protocols of any rapid autopsy program, with an eye to models accessible to smaller institutions, perhaps without cancer centers and possibly in rural locations.

“If you have a highly motivated donor and they come to you and say they want their tissue to matter, you can potentially hook them up with a single researcher in that area and do a scaled-back version of all this to get that tissue to that researcher quickly. That can be done anywhere potentially,” Dr. Chambers says.

Other high-volume programs have partnered with medical examiner offices because of the difficulty of 24/7 call for a high caseload. The ME office with 24/7 call procures the tissue and the researcher arrives to pick it up. “That works well if you’re open to what you’re looking for. If you’re interested in only a subset of rare prostate cancer, the odds of the medical examiner being notified when that patient passes away is probably nonexistent,” she says.

UW receives emails from people who want to donate but cannot because there is no rapid autopsy program near them. “There is nothing we can do about that,” Dr. Chambers says, “because our institutional review board approval is based on donors having to be associated with the University of Washington.”

The rapid autopsy is a resource-intensive process if staffed 24/7, she says. Some large programs have what they need but not the 24/7 staffing, and thus they operate only during business hours and “don’t capture the people who pass away outside of that.” But the models vary greatly, she says, and the funding structure can be flexible. “At UW, none of our pathology departments shoulder any of the costs for these programs. It’s funded by research-based funding schemes, and I would say that’s probably the most common model.” (The UW brain bank differs in that it was the neuropathologists who started it and continue to run it.)

Dr. Sanchez is chair and Drs. Bartholow and Chambers are members of the CAP Autopsy Committee. They would like to centralize conversation about rapid autopsy programs in hopes of establishing best practices and providing helpful tips and other resources.

“We’re hoping we can develop at least a nucleus of people and attract others so we can start talking to each other,” Dr. Sanchez says, including those who run programs outside the U.S.

“We’re working on it,” Dr. Bartholow says of the committee’s effort to help others get programs off the ground. “In our committee discussions we share our own experiences, and we want to help other institutions by compiling information that will be useful across the pathology community.”

Dr. Bartholow says he would be happy to talk technical logistics all day, but most important to him and the others is expressing the gratitude they have for the program’s tissue donors. “We never lose sight of that,” he says.

“It’s an enormous benefit to the researchers,” Dr. DiStasio says. “I can’t tell you how many PIs have said they wished they had something like this sooner.”

Valerie Neff Newitt is a writer in Audubon, Pa.