Date: May 14, 2012
Eighteen months after receiving two new hands, Sheila Advento is back to painting—to the delight of her reconstructive transplant team at Hopkins, whose ongoing advances promise to transform the lives of patients who need new arms, hands, and legs.
By Jim Duffy | Photos by Mike Ciesielski
Sheila Advento was relaxing in front of one of her soap operas that September afternoon in 2010 when the call came in. Suddenly, her quiet day off became a whirlwind. She had a one-hour window to embark on a journey into medical history as the first woman in the United States to receive a double hand transplant.
“I called my mom and said, ‘Are you sitting down? Well, get up—we’ve got to go!’”
Advento didn’t need to pack—she’d done that nine months earlier, upon learning that she’d made it onto the transplant list. Now, she threw that bag in a car for the short drive from her home in Hackensack, NJ, to Teterboro Airport. There, she and her mother, Peachie Angeles, boarded a plane donated by a pilot working with the nonprofit Angel Flight. Meanwhile, 400 miles away, a team of surgeons was preparing to procure the hands that would soon become hers, thanks to the generosity of a family who agreed in the midst of tragedy to allow the parts of a deceased loved one to help improve the life of a complete stranger. Those hands had been carefully matched across a spectrum of categories—size, skin tone, age, gender, and more.
Advento remembers bits and pieces of the flurry that commenced upon her arrival at the University of Pittsburgh Medical Center (UPMC)—check in, gown on, central line in, wheelchair transport, elevator door opening, then ….
“The next thing I knew, I woke up with two new hands!”
She lifts those hands into the air, smiling broadly as if their arrival on her arms that day marked the end of a story. In fact, that moment marks more of a beginning, as it’s not so much the surgery itself but what comes afterward that makes Advento’s case a groundbreaking affair.
Yes, hand transplants are complex affairs that require surgical skills of the first order. In Advento’s rather typical case, the surgery lasted a dozen hours and involved a dozen different surgeons. Each human hand and wrist has 27 main bones, 19 “intrinsic” muscles (located entirely within the hand), and 24 “extrinsic” tendons running to muscles in the forearm.
But the techniques involved in making all those connections are not really new. “Don’t get me wrong—this surgery is a very big deal, and it’s not easy,” says Jaimie Shores, a plastic surgeon who is now clinical director of hand transplantation at Hopkins. “But it has surgical roots in replantation,” he explains. “If your own arm got cut off for some reason, I would reattach it—putting together blood vessels and nerves and muscles and tendons, everything. We’ve been pretty good at doing those things for a few decades now.”
What comes after the surgery is another matter. To make hand transplants more viable—only about 75 have been performed in the world to date, the vast majority in just the last few years—physicians and researchers are seeking to achieve a pair of goals that might seem contradictory. They want to minimize the risk of rejection while decreasing or eliminating the need for immune-suppressive medications.
A third goal is as fascinating: They are seeking innovative ways to speed up the nerve regeneration that will allow patients to make fuller use of their new hands over time.
“That’s why the keys for moving forward for us really lie in the laboratory,” says W.P. Andrew Lee, MD ’83, chair of the Department of Plastic and Reconstructive Surgery at Hopkins. What had been a plastic surgery division housed within the Department of Surgery became its own department when Lee came aboard as chair in October 2010.
That was two short weeks after his team at UPMC conducted Advento’s surgery. In fact, Lee’s team at Pittsburgh had transplanted the greatest number of hands in the country at that point. Six of Lee’s former Pittsburgh colleagues (including Shores) have now joined him at Hopkins, and they are working in close partnership with former colleagues who did not make the move—in an arrangement Lee describes as “one program on two campuses.”
In addition, another of Lee’s former Pittsburgh colleagues, Gerald Brandacher, has opened a new lab in the Ross Research Building that he believes is the first and only lab in the country devoted exclusively to reconstructive transplantation, a field where the focus is on transplanting damaged or deformed body parts that generally cannot be repaired using the body’s own tissue—not just hands and arms, but legs, noses, ears, eyelids, and even whole faces.
In recent months, the first two candidates have been approved to receive hand or arm transplants at Hopkins. Both are currently awaiting donors, and both are already the subject of detailed surgery planning and practice sessions being organized by Shores.
The advances being pursued hold potential down the road for many thousands of other patients in addition to amputees. Lee’s team is eyeing a day, perhaps in the not-so-distant future, when severe burn victims, cancer survivors physically scarred in resections, children with birth deformities, and many others might live richer, fuller lives after surgeries in which they receive new body parts from donors.
“If we get to the point where we are no longer limited to working with the body’s own tissue, then that’s a whole new paradigm in plastic surgery,” Lee says.
Brandacher, who started as an organ transplant surgeon in Austria and is now the scientific director of the reconstructive transplant program at Hopkins, compares the work being done on Lee’s team with the earliest days of his former field. “It’s just thrilling, being part of something that feels like the early days of liver and heart transplants ... something that’s on the verge of becoming a whole new field. This is what excites all of us coming to work every day,” he says.
Back in 2003, America’s fast-paced lifestyle felt completely natural to Advento, then 26. She and her two sisters had arrived in New Jersey with their parents from the Philippines 15 years before. Advento had just started a new job in the billing department at Quest Diagnostics.
That Fourth of July weekend she began suffering flu-like symptoms that progressed with astonishing speed to loss of strength, vision troubles, and, finally, a complete collapse on the floor of the bathroom. En route to the Hackensack Medical Center, Advento found herself gasping for air. Once there, she dropped into a coma. She’d contracted bacterial meningitis. Her doctors had serious doubts whether she would ever wake up, but eight days later, she did.
“The first thing I noticed was that my hands were all black with gangrene and absolutely lifeless,” Advento says. “All I could say right from the time I saw them that way was that they have to go—just cut them off.”
Advento soon lost both legs to the infection as well. As a quadrilateral amputee, she began the arduous journey back to a new measure of physical function using prosthetic legs and hands. She tackled the work with a characteristic focus on making measurable, point-by-point progress—an outlook she attributes in part to the firm grounding in character and faith she received from her parents.
“It was a difficult time,” she says. “That’s a level of frustration I wasn’t used to, and it was a real roller coaster of emotions. But I didn’t know what else to do but keep going.“
Almost a year to the day after losing her limbs, Advento returned to work. She got along well on her prosthetic legs but she didn’t like the hands at all. The harnesses involved were uncomfortable. The protective fabrics she had to wear on her residual arms were hot. On occasion, a cable would snap, leaving her hand in need of immediate repair. Arriving home after her workday, she’d generally take those hands off first thing—and leave them off for the rest of the evening.
By 2009, Advento’s parents had divorced and her father had remarried. It was her stepmother who sent her an article about the first bilateral hand transplant in the country—performed by Lee and his team on a 57-year-old man. Soon after, Advento was on the phone seeking to become a candidate.
Jaimie Shores finds it fitting that a team made up primarily of plastic surgeons is working to push the field of transplantation to a new level. “It’s like we’re circling back to the beginning 50 years later,” he says, pointing out that the first organ transplant—a kidney—was conducted by plastic surgeon Joseph Murray in 1954. At the time, few experts imagined just how widespread and important such surgeries would become.
Every decision to conduct a transplant involves weighing risks and benefits, but the balancing act is different for reconstructive transplants than it is for organ transplants. In the latter case, the alternative to surgery is basically death.
In a hand transplant, the ratio is a dicier proposition. The standard post-transplant regimen involves stiff daily doses of three powerful immunosuppressive agents that help avoid rejection. These agents increase risks going forward for a range of serious and potentially life-shortening health issues—infection, hypertension, diabetes, and cancers among them.
“I can’t stress too much how important of a consideration informed consent is here,” Lee says. “This is an area where we need to be very careful of the risk/benefit balance.”
The Reconstructive Transplant Program at Hopkins is aiming to build on progress Lee’s team has already made in shifting that balance. In eight transplants involving five patients over the past three years, they’ve employed a novel strategy dubbed the “Pittsburgh Protocol.” More than two decades of research went into the protocol, Lee says, and that research encompasses both small- and large-animal models.
Rather than relying exclusively on immune suppression, the protocol adds an element of immune modulation—a sort of re-education process that alters the way the immune system regards the tissue graft. The key ingredient is bone marrow cells from the donor, which are infused into the recipient shortly after the surgery.
“Our research, and now our experience, is showing that by having immune cells present from both individuals, we are able to create a delicate balance between two immune systems—and this then lessens the need for immune suppression,” Brandacher says.
Instead of taking a trio of immune-suppressive agents, Pittsburgh Protocol patients take a single agent at a comparatively low level, greatly reducing risks of life-shortening health complications.
This new protocol is being used only at Hopkins and Pittsburgh so far. It doesn’t eliminate rejection episodes altogether, as the recipient’s immune system and the donor body part need to go through a period of getting to know each other. As Brandacher puts it, such episodes “show that the immune system is actually encountering the graft and learning how to deal with it. If you don’t have any interaction, that’s not a good thing either.”
Advento has had such moments, in the form of a skin rash. If one appears, she grabs her cell phone, takes a photo, and e-mails or texts the image to her physicians. If they see it as cause for concern, the first order of treatment is a simple topical ointment. That’s been sufficient to date nearly half of the time across multiple patients. When that is not completely successful, intravenous medication is administered.
The fact that these rejection episodes are visible to the naked eye is another unique aspect of many reconstructive transplants. In organ transplants, rejection doesn’t become evident until it has progressed much further—and become more dangerous.
This is another focus of attention in Brandacher’s laboratory. By taking biopsies of the rashes, his team can study “rejection in its infancy,” examining cytokine gene expression profiles, for example, to gain a sense for how allo-immune responses begin.
Going forward, this work might help make it possible to predict whether rejection is going to happen and how serious it will be. And the work might in turn help boost outcomes in organ transplants by finding ways to diagnose rejection early on, even when it’s not visible to the naked eye.
At the moment, however, these questions rank as footnotes compared with the main thrust of work by the Reconstructive Transplant Program. “We are hoping that we can do away with all immune suppressive medication in the future,” Lee says, boldly. “Or maybe we’ll instead get to the point where people just take medication for a finite period—a year, maybe less. We’re not there yet, and that’s why research is going to continue to play such an important role.”
Shores describes immunologic tolerance as the holy grail, a development that would have implications far beyond the immediate goal. “If this works for hands and faces, then we think it’ll work for sure for organs as well. I think the work we’re doing has the power to benefit all of transplant medicine ... and potentially have crossover to other disease processes like the autoimmune diseases.”
When Advento awoke from surgery, she couldn’t see her new hands all that well. They were hidden behind big splints so that they’d be immobile for several weeks.
It did not take her long at all to get accustomed to the inevitable differences in appearance of her new hands; the fact she’d spent most of a decade without her old hands made the process even easier—the comparison she was making was more with the prosthetic hands than her old original ones.
“I was just so excited to have them,” she says.
In comparison with organs like livers and hearts, hands seem such intimate objects to transplant. Lee says he is frequently asked questions along these lines; it’s a topic considered during psychological review of transplant candidates.
“But interestingly, no one among the patients in our experience so far—or in experiences of other teams at other places, as far as I know—has had a problem adapting to a new hand,” he says. “As one patient put it, once it follows the instructions coming from my brain, then I know it’s my hand and I’m not wondering about who it belongs to.”
Even after the splints came off, Advento’s hands barely functioned at all. As she got back up and around after surgery, she experienced what doctors had warned her about over and over again in advance of the surgery—she’d actually taken a major step backward, and it would be quite a while before she even got back to the level of physical function she had with prosthetics.
Initially, recovery amounted to sitting back while therapists massaged and gently stretched her new fingers. Advento’s work began in earnest a month after the surgery. She progressed gradually from stretching her wrists to moving her fingers to basic fine motor skills, like picking up objects.
“The doctors and everybody else, they gave me the facts beforehand,” she says. “I have to start over from the very beginning, how hard that was going to be. They prepared me for that and then it was my responsibility to accept those facts. I had to just focus on keeping moving forward again.”
In evaluating transplant candidates, Lee’s team places a strong emphasis on whether the patient shows a capacity for the commitment required—physical therapy six to eight hours a day, five days a week—for up to a year in some cases.
“I think that people who lost part of their body always want to be restored whole, a very understandable feeling,” Lee says. “But if they’re going to be a candidate, they need to have realistic expectations—to understand the effort they’ll need to put in after the transplant to make the hand work.”
One key reason Advento’s new hands regained function so slowly is that nerve regeneration occurs at a snail’s pace. The donor’s nerves are not functional after the transplant; instead, the recipient needs to grow nerves that stretch from her stump into the hands—a process that happens along the scaffolding of donor nerves but only at the excruciating pace of about one millimeter a day.
This is another avenue being pursued in Brandacher’s research, in cooperation with colleagues at the Translational Tissue Engineering Center at the School of Medicine.
“We have several projects ongoing where we are looking at utilizing recipient stem cells that can be directly injected into the nerve to enhance regeneration,” Brandacher says. “We only have preliminary data so far, but it’s preliminary data that’s exciting.”
Brandacher adds that the stem cells can have a second feature of special interest here: “They are also immune regulatory, so they offer the opportunity to address both of the two main areas that are needed. We’re working in animal models to try and find what is the best source, the best number, the best application route and dosages.”
Such advances may aid future patients, but for Advento, the process remained a slow one. The most memorable sign of progress she experienced came two months after the surgery. She was washing her hands when she felt for the first time a sensation of cold.
“Before that, the only way I knew I was washing my hands was because I was visibly seeing it happen—I couldn’t feel it. To feel temperature, it came out of nowhere!” she says.
Advento returned home in early 2011, living first with her mother before finding an apartment of her own. Today, some 18 months after her surgery, she still goes to therapy every weekday at the same place where she was once in a coma—the Hackensack Medical Center. Some days she puts in six hours; other days, it’s a couple of hours before heading off to work at Quest Diagnostics.
Early on, her primary goal was gaining the ability to straighten fingers that were completely clawed. The fingers are slowly getting better; she’s hoping that with continued work she’ll be able to turn her thumbs in. She’s practiced cooking in therapy, but isn’t yet cooking for herself at home, though she does eat on her own.
“There are still a lot of muscles that need to be developed in my hands,” she says. “People ask me sometimes how long am I going to be in therapy. It’s basically going to be a lifetime thing—that’s what I’m thinking.”
Advento had always been a bit of an amateur sketch artist. About a month after surgery, she picked up a pen and tried sketching with her new hands. As her functioning progressed, her brother-in-law presented her with a gift of canvases, paints, brushes, and an easel. The works she has created since then now adorn her living room wall.
When discussing Advento’s case in his office, Lee got up at one point to reach into a drawer and pull out a sketch Advento had sent him. The pride he felt in her progress was obvious.
That progress is far from over, of course. Advento is looking forward to a day when she can better straighten her fingers, cut with a knife, and do many other things. But overall, she says, “I consider myself very blessed.” *
Hope for Wounded Warriors
This spring, Sheila Advento joined Hopkins plastic surgeon W.P. Andrew Lee for a trip to the Walter Reed National Military Medical Center. There, Advento showed off her new hands to medical experts and met several veterans who had suffered amputations in Iraq and Afghanistan.
The widespread use of improvised explosive devices (IEDs) in those two wars has caused a sharp uptick in amputations compared with previous wars. More than 850 service members have had at least one limb amputated since these wars began. In the past couple of years, top physicians at Walter Reed have expressed strong interest in Lee’s work with the Reconstructive Transplant Program at Johns Hopkins.
“They’re seeing some devastating injuries that lead to major extremity amputations,” Lee says. One of the first candidates approved for a reconstructive transplant at Hopkins—and now on a waiting list—is a veteran who lost all four limbs to a roadside IED. Lee is hopeful that the work of his program will help wounded veterans like this one live fuller, more independent lives.
“What a wonderful experience that visit was,” Advento says. “I felt like I gained more inspiration from just talking to them than maybe they gained from seeing my hands.” JD