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.