New bone marrow transplant method eases risk

Experimental technique just tamps down, not destroys, immune system

Bone marrow transplants are undergoing a quiet revolution: No longer just for cancer, research is under way to ease the risks so they can target more people with diseases from sickle cell to deadly metabolic disorders.

The old way: High doses of radiation and chemotherapy wipe out a patient's own bone marrow before someone else's is infused to replace it, hopefully before infection strikes.

The new way: Rather than destroying the patient's bone marrow, just tamp it down enough to make space for the donated marrow to squeeze in alongside and a sort of twin immune system takes root. It's what doctors taking a page from mythology call "mixed-cell chimerism" — patient and donor blood and immune cells living together to improve health.

To find the best methods for these less intense transplants, different mixes of low-dose radiation and immune-suppressing drugs are under study at hospitals around the country.

But the ultimate quest is to allow transplants even when donors aren't a good genetic match, says Dr. Suzanne Ildstad of the University of Louisville — whose technique involves an experimental tweaking of donated cells to help them grow better.

"It makes it possible for anyone who has a mom or dad willing to donate marrow to them to have a transplant," says Ildstad, who has families with sickle cell and other childhood genetic illnesses lining up to try.

Separately, several hospitals are testing how to combine kidney transplants with bone marrow transplants from the same donor, in hopes that a hybrid immune system lessens the need for lifelong anti-rejection drugs.

"People are watching with eager expectation," says Dr. Lakshmanan Krishnamurti of Children's Hospital of Pittsburgh, who is helping to plan a multi-hospital study of some of the new methods for hard-to-treat adults with sickle cell disease.

Doctors have long known that a traditional bone marrow transplant can cure young children of sickle cell — if they have a well-matched donor. New marrow produces healthy red blood cells to replace the sickle-shaped ones that can't squeeze through small blood vessels, the cause of the disease's pain, infections and life-threatening organ damage.

But only about 17 percent of children have a suitable donor, usually a healthy sibling. Attempts to transplant adults have failed, their bodies too ravaged from years of the disease. Another hurdle: Certain immune cells in donated marrow sometimes become too aggressive and attack the recipient, called graft-versus-host disease or GVHD.

Enter the new research.

First came a tantalizing success in severely ill adults. Nine of 10 patients who underwent a less intense transplant — using low-dose radiation and two drugs to inhibit problem immune reactions — had their sickle cell apparently eliminated, Dr. John Tisdale and colleagues at the National Institutes of Health reported in December. They developed a hybrid immunity that produces normal red blood cells with no GVHD.

But those people had perfectly matched donor cells provided by healthy siblings. Few patients do.

Back in Louisville, Ildstad gives donated marrow a boost to try to overcome that problem while avoiding GVHD, a risk that worsens with mismatched donors. She removes troublesome immune cells from the donated infusion, leaving concentrated amounts of the blood-producing stem cells patients need plus "facilitating cells" that she discovered seem to help them take root.

In an NIH-funded experiment at Louisville and Duke University, the method so far worked in two children with sickle cell who had well-matched donors and one of four with a half-match.

Dr. Joseph Leventhal of Northwestern University gave an Ildstad-treated stem cell infusion to a handful of kidney transplant recipients who developed hybrid immune systems that seem to be holding nearly a year later. The first three treated are using one anti-rejection drug instead of the usual cocktail, and one soon will attempt full weaning.

"We're doing this in patients where it could have potentially the biggest impact," those with unrelated donors, says Leventhal, who anticipates giving one patient a month the dual transplant as the study continues at Northwestern Memorial Hospital.

The attraction to families: "You don't die from the new way," is how Bob Evanosky of Aurora, Ill., puts it.

His three sons have a devastating metabolic disease called metachromatic leukodystrophy, or MLD. Last summer, son John got an experimental outpatient transplant at Duke — a far cry from the months his brother Jack had to spend in intensive care after a well-matched transplant the old-fashioned way.

Dad was John's donor even though he's only a half-match — and the new cells are making the enzyme his body had lacked, too late to reverse the brain damage that has paralyzed the 8-year-old but perhaps able to ease some complications, says Evanosky, who plans to donate to his John's twin Christopher this fall.

 

First total face transplant performed in Spain

The patient, a farmer in his 30s, accidentally shot himself in 2005

MADRID - A hospital in Spain says it has carried out the world's first full-face transplant, giving a man a new nose, skin, jaws, cheekbones, teeth and other features after he lost his face in an accident.

Other transplant experts lauded the surgery but were not sure it could technically be called 'full-face.'

The operation was carried out by a 30-member medical team in late March and took 24 hours to perform, according to the Vall d'Hebron Hospital in Barcelona. 

The patient now has a completely new face from his hairline down and only one visible scar, which looks like a wrinkle running across his neck, said Dr. Joan Pere Barret, the surgeon who led the team.

"If you look him in the face, you see a normal person, like anyone else we have as a patient in the hospital," Barret told The Associated Press on Friday.

Barret declined to name the patient or give details of the accident five years ago in which the man lost most of his face, saying only that he was a Spaniard between 20 and 40 years old and was recovering well. The man cannot yet speak, eat or smile, but can see and swallow saliva, the surgeon said.

Prior to the latest surgery, the patient had undergone surgery nine times and could only breathe and be fed through tubes. He also had problems speaking.

In Britain, the UK Facial Transplantation Research Team called the Spanish operation "the most complex face transplantation operation there has probably been in the world to date." It stopped short, however, of calling it the world's first full-face transplant.

Barret said the operation involved removing what was left of the man's face and giving him a replacement "in one piece."

"It is a little bit like the movie with John Travolta and Nicolas Cage," he said, referring to the 1997 thriller "Face/Off", in which Travolta undergoes a high-tech medical procedure to acquire the villain Cage's appearance and infiltrate his terrorist gang.

"He is coming along well. He sits up, he walks in his hospital room and he watches television," Barret said.

Barret said there have been 10 partial-face transplant operations carried out in the world so far but this was the first involving a person's whole face. The world's first partial-face transplant was done on a woman in France in 2005. Other partial-face operations have been performed in the United States and China, as well as in other Spanish hospitals in Valencia and Seville.

The Spanish operation is similar to a near-total face transplant carried out in 2008 in Cleveland, Ohio, on a woman who was shot in the face.

But the Spanish case "seems to us to be more complex," said Neil Huband, a spokesman for the British transplant research team, based at the Royal Free Hospital in London.

He said the patient in Spain had also been shot in the face.

Dr. Maria Siemionow, who operated on the woman in Ohio, said the Spanish team had done great work. But a diagram she says she has seen about the Spanish surgery does not make clear that the team replaced the man's whole face, leaving doubts about his eyelids and jaw, she told the AP.

"It would probably be much more safer for the Barcelona team to say near-total," Siemionow said. 

Barret said his team used the same plastic and microsurgery techniques as in those previous cases but decided to try a full-face transplant because the damage suffered by the man was so severe.

A week after the operation, the patient asked to look at himself in the mirror and was satisfied with what he saw, Barret said.

The patient had undergone psychiatric tests before the operation to determine if he would be able to confront having a totally new face, the hospital said.

He is expected to remain hospitalized for two months.

 

Cord blood stem cell transplant hopes lifted

A technique which may eventually remove the need for matched bone marrow transplants has been used in humans for the first time.

It is hoped that "master cells" taken from umbilical cords could be used on any patient without rejection.

The latest advance, published in the journal Nature Medicine, greatly multiplies the tiny number of cells from the cord ready for a transplant.

UK charity Leukaemia Research said this could be the "holy grail" for doctors.

Aggressive treatment

The current system of bone marrow transplantation helps patients who have diseases, such as leukaemia, which affect the stem cells in their bone marrow where new blood cells are grown.

Their own bone marrow cells are killed off by aggressive treatment and cells from a matched donor are introduced in their place.

However, a matching donor cannot always be found, despite extensive donor registries held by organisations such as the Anthony Nolan Bone Marrow Trust and, even with a carefully matched donor, there is still a risk that the patient's body will reject the new cells.

Cells extracted from umbilical cords could overcome these problems - they do not have the characteristics which would normally trigger immune rejection, so it is likely that cells from a single baby's cord could be used in any patient, without the need for matching.

However, there is one big disadvantage - there are not enough cells in a single cord to meet the needs of an adult patient.

Scientists have been looking for ways to either combine the cells from more than one baby, or to "expand" the cell numbers in the laboratory.

The second of these options is far from straightforward - simply allowing the stem cells to divide and increase in the laboratory means that many of the resulting extra cells will be simple blood cells, which do not have the ability to produce new cells themselves.

Quick to work

Researchers at the Fred Hutchinson Cancer Research Center in Seattle believe they may have found a way.

They manipulated a "signalling pathway" in the stem cells to trigger an increase in numbers without losing their stem cell status.

After success in laboratory animals, these cells were used in human patients, and the researchers found that they were accepted by the body more quickly and contributed more to the rebuilding of functioning bone marrow than "non-expanded" cord blood transplants.

Dr David Grant, Scientific Director of charity Leukaemia Research said: "The holy grail is to have an 'off the peg' source of unlimited numbers of 'neutral' stem cells which can be given to any patient safe in the knowledge that they will not cause the very difficult 'graft versus host' problems that lead to rejection and often the death of the patient.

"This is a promising development towards this because the concern has been that once stem cells start 'growing' they lose their stem cell properties and progress to ordinary blood cells with a very limited lifespan."

Henny Braund, chief executive of The Anthony Nolan Trust, said the potential for umbilical cord blood was "huge", and that the charity had already imported well over 250 units of umbilical cord blood.

"Sadly in the UK, despite our scientific expertise, umbilical cord blood is still very much an untapped resource and we are only able to collect and store a tiny amount of the cords we need.

"We really need a properly resourced UK cord blood collection programme.

"Further investment is crucial if we are to capitalise on this amazing resource and save more lives."