eneen Leogrande seemed to be recovering from surgery for lung cancer when, on Christmas Eve 2011, she began leaking.
Complications weren’t unexpected, given the scale of the operation — surgeons had removed Leogrande’s entire right lung, part of her chest wall, and two ribs. But this was a big one. A gap called a fistula had opened up where one of her airways had connected to the now-missing lung, causing pus to fill the space under her chest wall and igniting a serious infection and a spiking fever. She leaked air so badly that she struggled to speak and breathe.
It was the start of what would become a three-year medical nightmare. In a futile effort to close the fistula, about the size of a pencil eraser, doctors from Florida to Minnesota tried some 30 surgeries and other procedures. They made a softball-sized hole in her right side to drain the pus, and slid chunks of flesh from her abdomen toward her chest to patch her up. Leogrande, now 63, spent months in hospitals. Once, doctors told her husband it was time to summon the family to say final goodbyes.
But now she is a medical trailblazer: on Friday, researchers announced that Leogrande is the first patient to have this kind of fistula patched up with stem cells from her belly fat.
The cells, her physicians at the Mayo Clinic reported in the journal Stem Cells Translational Medicine, were packed onto a special mesh, which surgeons wrapped around the stump of the airway that ended in the fistula. “I feel like I was given a third life,” Leogrande said, counting the time the fistula nearly killed her. “I’m hoping this is the start of many, many more people benefitting from my surgery.”
The physicians who treated Leogrande are careful not to claim the stem cells helped close the fistula, however. “The honest truth is, we don’t know if there was any impact of the stem cells,” said Mayo’s Dr. Dennis Wigle. “But what we can say is that this was safe and feasible. It gives us a faint glimmer of hope that there might be some merit to studying” the use of stem cells to repair fistulas.
Although Leogrande’s “bronchopleural fistula” is rare, injury and surgery (as well as Crohn’s disease and inflammatory bowel disease) can cause other kinds of fistulas.
Stem cell therapy has become the wild west of medicine, with hundreds of clinics in the United States, and countless others overseas, offering to use stem cells derived from patients to treat everything from bum knees to arthritis to stroke despite minimal to no scientific evidence that it works. US clinics have largely evaded federal regulation.
Leogrande’s case was no rogue experiment. Physicians got approval from the Food and Drug Administration to use stem cells under a “compassionate use” exemption, which lets doctors try an unproven therapy on a desperate patient outside a formal clinical trial. But how the one-woman experiment came about speaks to the unsettled landscape of stem cell medicine.
So few rigorous scientific studies have been done that “exactly what stem cells do” when put into a patient like Leogrande “has never been determined,” said Dr. David Scadden, codirector of the Harvard Stem Cell Institute. Patients are often unwilling to participate in formal studies that might answer researchers’ questions, leading to one-off cases like Leogrande’s, which do not advance the science much.
“That said,” added Scadden, “the fact that they could help this patient is fantastic, regardless of whether we understand the mechanism.”
Doctors first tried to repair Leogrande’s fistula in early 2012. Surgeons at a Florida hospital near her home in Oviedo, created a flap out of tissue from her abdomen to patch the hole. This created a softball-sized opening in her right side, which surgeons subsequently covered by rotating one of her pectoral muscles from above the ribs. But neither the fistula, nor the hole where her pectoral muscle had been, closed.
On bad days, Leogrande said, she couldn’t speak more than a couple of words at a time: the air she inhaled leaked out the fistula rather than pushing sounds out her vocal tract. An oxygen tank was her omnipresent companion, but so little of the air she inhaled made it to her lungs that her blood levels of carbon dioxide soared. She regularly dozed off like someone with narcolepsy.
In the fall of 2012, Leogrande’s husband, Frank, was paging through a Mayo magazine while waiting for her at a doctor’s appointment when he stumbled onto an article that made him snap to attention. Mayo’s Dr. Timothy Nelson, it said, was studying the use of stem cells for various therapies.
That afternoon, Frank, now 57, wrote a letter to Nelson, asking whether anything he was working on might help his wife. Nelson called a week later, explaining that although there were no stem cell therapies yet, he’d be willing to look at her; could the couple travel to his office in Rochester, Minn.?
They made an appointment for January 2013 — only to have to cancel when, three days before their flight, Leogrande developed a massive infection from the pectoral-muscle procedure and had to be hospitalized again.
That triggered a seemingly inexorable decline. She developed septic shock and had to be placed on life support at Mayo’s Jacksonville hospital in April. Doctors told her husband it was time to notify relatives; Leogrande might not survive the night. She did, and was discharged 13 days later.
In late 2013, surgeons thought that making things worse might make them better. They did 13 “debridements,” scraping the tissue around the fistula once a day in hopes of triggering it to grow over the gap. By the end of a fortnight it was clear that wasn’t working. The surgery was so brutal on Leogrande that she gave her husband a hand sign: I’ve had enough. It’s time to stop.
She left the hospital that December with a tracheotomy and a stomach tube, the flap still open, and her fistula as bad as ever. Her husband again contacted Mayo’s Nelson — they had never been able to reschedule the consultation — telling him Leogrande’s situation had become hopeless. A registered nurse in Nelson’s regenerative medicine program connected them to Wigle, a thoracic surgeon, who began assembling paperwork to ask the FDA for a compassionate-use exemption to use stem cells.
After Frank Leogrande enlisted friends, family, and politicians to badger both the FDA and Mayo, they got the okay. “The team at Mayo was getting pissed off at me,” he said, “but you can’t let pissing people off stop you.”
The day before Halloween in 2014, Wigle cut into Leogrande’s abdominal wall and suctioned out about 13 drops of fat tissue. It was spun around in a centrifuge to separate out the mesenchymal stem cells, (MSCs), adult stem cells that have the capacity to differentiate into any of scores of specialized cells. The MSCs were then bathed in nutrients so they would multiply.
The surgical team took about 25 million of the stem cells and “seeded” a small plastic mesh with them. After four days of nourishing the cells in a bioreactor, the researchers trimmed the mesh to fit Leogrande’s fistula. In a 12-hour procedure with three other surgeons, Wigle gently put it in place, closed her up, and waited.
Leogrande and her husband flew home to Florida just before Thanksgiving, her fistula finally closed. For the first time in three years, she was able to speak a full sentence: “How did it go?”
The Mayo team can’t be certain the stem-cell-covered mesh succeeded where dozens of other procedures had failed. Nor do they know what the stem cells did. MSCs can morph into connective cells called fibroblasts and cartilage-secreting cells called chondrocytes, among others, and can summon tissue-repairing cells.
“There is no way to know” what the stem cells did, “but this [experiment] gives us a glimmer of hope for repairing bronchopleural fistulas,” said Wigle, who is designing a clinical trial for about 12 patients to figure out if what worked in Leogrande will work in others.
“Was this just a lucky break, or will MSCs work consistently better than standard approaches” to close fistulas?, he asked. “It’s almost embarrassing, the fundamental questions here that we don’t have answers to.”