Oriented to Thoracic Transplant Recipients -- March 2000

New Drug Reduces Heart Rejection

May be a Major Break Through

Reuters Health Information
New York 3/1/00 --A new drug appears to reduce the chance of rejection In heart transplant pawns shout increasing their risk of infections and cancer -common problems in such patients.

The drug is known as daclizumab (Zenapax), according to the report in The March 2nd issue of The New England Journal of Medicine.

"Daclizumab safely reduces the frequency and severity of heart transplant rejection, report Dr. Ainat Beniaminovitz and colleagues of the Columbia-Presbyterian Medical Center in New York.

Organ rejection is a potentially life threatening problem in transplant patients and occurs when the immune system attacks the organ tissue. In order to avoid this patients take drags that suppress the immune system and hopefully prevent the rejection. Unfortunately, this makes patients susceptible to infections and the development of cancer.

The major benefit of daclizumab is that it appears to reduce rejection without increasing infections and cancer, Beniaminovitz told Reuters Health. The drag may be able to do this because it is more specific than other drugs used to suppress the immune system. It only blocks activated immune system cells that would attack the heart whereas other immunosuppressing drugs block the immune system in general, she said.

In the study, Beniaminovitz and colleagues gave 28 heart transplant patients daclizumab in addition to other immunosuppressive drugs.

On average, these patients experienced a fewer number of rejections of the new heart than did 27 patients who did not receive daclizumab. Also, the daclizumab patients experienced a longer time to their first episode of rejection, which is important because most episodes of rejection occur within the first 3 months after surgery.

The doclizumab patients were just as likely to experience infections or cancers compared with people who did not receive the drug, according to the report. Overall, none of the patients in the daclizumab group developed a cancer while one person in the control group was diagnosed with lymphoma. The new drag did not appear to cause any major side effects in the patients.

Beniaminovitz and co-authors note that daclizumab produced similar beneficial results in patients who received a kidney transplant. The center now uses daclizumab routinely as heart transplant patents, she said.

Another benefit of the drug is that it enables physicians "to use less prednisone and other immunosuppressive drugs," according to Beniaminovitz. This might lead to a long-term benefit by reducing chronic rejection, she said.

Source: The New England Journal of Medicine 2000;342:613-619

Now for those who would regard the preceding article as of questionable scientific value, here's the whole truth supplied by Tx Dave Cannavo.

Prevention of Rejection in Cardiac Transplantation by Blockade of the Interleukin-2 Receptor with a Monoclonal Antibody

Ainat Beniaminovitz, et al

Background. Alloantigen-activated T cells express the high-affinity interleukin-2 receptor. Specific blockade of this receptor with the human IgG1 monoclonal antibody daclizumab may prevent rejection of allografts after cardiac transplantation without inducing global immunosuppression.

Methods. We randomly assigned 55 nonsensitized patients undergoing a first cardiac transplantation to receive either induction therapy with daclizumab (1.0 mg per kilogram of body weight), given intravenously within 24 hours after cardiac transplantation and every two weeks thereafter, for a total of five doses, or generalized immunosuppressive therapy. Concomitant immunosuppression was achieved in both groups with cyclosporine, mycophenolate mofetil, and prednisone. The primary end points were the incidence and severity of acute rejection, and the length of time to a first episode of biopsy-confirmed rejection.

Results. Of the 55 patients in the study, 28 were randomly assigned to receive daclizumab and 27 served as the control group. During induction therapy, the mean frequency of acute rejection episodes (defined as a histologic grade of 2 or higher according to the classification of the International Society of Heart and Lung Transplants) was 0.64 per patient in the control group and 0.19 per patient in the daclizumab group (P=0.02). Acute rejection developed in 17 of 27 patients in the control group (63 percent), as compared with 5 of 28 patients in the daclizumab group (18 percent; relative risk, 2.8; 95 percent confidence interval, 1.1 to 7.4; P=0.04). Throughout follow-up, there were nine patients with episodes of acute rejection of histologic grade 3 in the control group, as compared with two in the daclizumab group (P=0.03), and the time to a first episode of rejection was significantly longer in the daclizumab group (P=0.04). There were no adverse reactions to daclizumab and no significant differences between the groups in the incidence of infection or cancer during followup.

Conclusions. Induction therapy with daclizumab safely reduces the frequency and severity of cardiac-allograft rejection during the induction period.

(N Engl J Med 2000;342:613-9.)

The New England Journal of Medicine -- March 2, 2000 -- Vol. 342, No. 9

Improving the Success of Organ Transplantation

The concept of drug-induced immunosuppression arose in the late 1950s with the observation by Schwartz and Dameshek that 6-mercaptopurine, developed as an antileukemic drug, was effective in blocking primary, but not secondary, antibody responses in rabbits. Several synthetic congeners prepared by Hitchings and Elion at the Wellcome Laboratories were then screened by Murray and Calne in dogs with renal transplants. With the discovery in 1962 that one of these congeners, azathioprine, was clinically useful as an immunosuppressive drug, the era of clinical organ transplantation began. The initial success rate for patients receiving cadaveric renal transplants, previously zero, was relatively poor, but with the addition of prednisone to azathioprine, 45 to 50 percent of transplanted kidneys survived for one year, a remarkable first step. By the 1970s, the transplantation of kidneys from living related donors had been shown to result in better initial and long-term rates of graft survival than those of kidneys from cadaveric donors.

In the search for new drugs, three criteria essential for safe clinical use emerged: specificity to cells of the immune system, weak potency against memory responses, and minimal side effects. It was not until 1979 that the next drug found to be clinically useful, cyclosporine (cyclosporin A), became available. This molecule was discovered by screening soil fungi for antifungal antibiotics, but it was initially set aside because of its immunosuppressive side effects in animals. It is a peptide of 11 amino acids that inhibits the calcineurin pathway of T-cell activation directed by the binding of major-histocompatibility-complex molecule-antigen complexes to T-cell antigen receptors. In fact, the calcineurin pathway was discovered when cyclosporine was used as a ligand to discover cyclophilin, and later the next component of the pathway, calcineurin. Two other fungal products with immunosuppressive actions that are now in clinical use are sirolimus (rapamycin) and tacrolimus (FK 506). Most striking is the fact that sirolimus and tacrolimus are macrolides that bind to the same cytoplasmic protein, FK-binding protein, but each of these complexes then binds to different third molecules; sirolimus binds to TOR (target of rapamycin), and tacrolimus to calcineurin. Inhibition of TOR blocks the entry of activated T cells into the G1 phase of replication. In functional terms, inhibition of the calcineurin pathway prevents the production of growth factors, such as interleukin-2, and inhibition of the TOR pathway prevents the cellular response to such growth factors.

Another recent addition to the armamentarium of immunosuppressive drugs is mycophenolate mofetil, which is converted in vivo to mycophenolic acid. This substance, a natural product of penicillium fungi, has a general mode of action on pufine metabolism similar to that of azathioprine. Mycophenolate mofetil was developed as an agent that would prevent the proliferation of lymphocytes. It inhibits the proliferation of T cells, B cells, and arterial smooth-muscle cells; most other tissues are relatively resistant to the drug because they have an alternative pathway for nucleotide acid synthesis. Mycophenolate mofetil causes bone marrow suppression much less often than does azathioprine, and the use of mycophenolate mofetil in combination with a calcineurin inhibitor and prednisone has resulted in substantially reduced rates of early rejection.

Various antibodies, made first against lymphocytes and later against specific molecules, have been used as adjunctive agents to improve the results of transplantation, either as rescue therapy in patients with acute rejection or as prophylaxis against rejection. Muromonab-CD3 (OKT3), a monoclonal antibody to the CD3 component of the Tcell antigen receptor, has been a mainstay for these purposes since the early 1980s, but other murine monoclonal antibodies proved to be ineffective until the recent introduction of genetically engineered humanized monoclonal antibodies, in which most of the molecule is of human origin and only the antigen-binding sites are of murine origin. In particular, antibodies against the interleukin-2 receptor have proved effective in preventing rejection, as reported by Beniaminovitz et al. in this issue of the Journal. Under development is a new generation of engineered monoclonal antibodies and other protein ligands targeted to portions of the lymphocyte-activation pathways that are necessary for providing costimulatory signals to T cells after the binding of antigen to the T-cell antigen receptor.

Given the growing number of effective agents and the need to increase the long-term survival of grafts, which are in short supply, a substantial number of well-designed clinical trials will be required. Fortunately, we start with a good data base. The United Network for Organ Sharing maintains a registry of transplants in the United States, with over 10,000 kidney transplants added each year. In this issue of the Journal, Hariharan et al. report that both graft survival at one year and the projected half-life of grafts have progressively improved from 1988 to 1995. The improvement is not attributable to any of the newer immunosuppressive drugs, because it took place in the era of treatment with cyclosporine, azathioprine, and prednisone. What the study does not address are the possible contributions of better clinical care, inclading perhaps better treatment of hypertension, more effective treatment or prophylaxis against serious infectious diseases, and an increased use of kidneys from cadaveric donors in HLA-matched recipients. One consequence of the continuous increase in the rate of graft survival at one year, which was already approaching 90 percent for cadaveric transplants in 1996, is that short-term graft survival is no longer a very useful criterion for evaluating the outcomes of transplantation. More attention must be paid to other end points, such as kidney function and episodes of rejection. As therapeutic targeting of very specific components of the immune pathways improves, whether through antibody-like large molecules or synthesized small molecules, it may be necessary to assess selected immune mechanisms by direct testing in patients in order to establish the end points for tolerance.

Charles B. Carpenter, M.D.
Brigham and Women's Hospital

Are We Lucky, or What? Or Ain't Progress Grand?

Well it's been a long time coming, but it finally may have finally arrived - a new transplant drug that is effective in preventing rejection without being destructive. Boy, there are some fortunate people out there waiting for a transplant who are going to be really lucky to be treated with this new drug, if it actually works as the research seems to show it will. They'll never know what it was like for us poor, unlucky, human test tubes that came before them. Unlucky? Well I guess not in the truest sense of the term. After all we were definitely terminally ill (Yes, there's a good discussion there that we still are.), and yet were "saved" by a transplant and "miracle drugs".

Lucky, you bet. We were at least on the cutting edge of the available therapies. So what if we had enough superfluous prednisone that our bodies came to require it to keep going. So what if we had to seemingly shave our foreheads and even buy larger shoes because of the hair growing out of the soles of our feet. It's only slightly embarrassing that one's nose runs constantly at even the thought of food. Who cares if the "hungries" caused weight gains of Nellie the Elephant Woman proportions, while another wonder drug cyclosporine used the increased intake to raise our cholesterol levels and BP to the scale of "must see your physician immediately." These new people will never know these little idiosyncrasies we learned to live with.

And hopefully they will totally escape the disasters that have struck so many of us in the form of total kidney failure due to cyclosporine. The many forms of cancer that have seemed to strike about half of the heart/ lung transplant population due to immuran and the general lowered immunity again. And the poor blokes, who have had amputations due to rapidly advancing diabetes acquired after transplant. Almost all these people are still smiling and might even say they were lucky - lucky to still be here that is.

But we've all got to admit it, unless I am the singular most selfish, egocentric, wimp around, I'll bet most of us are going to be jealous as all get out of those who are going to come after us. It's just a bit like hearing your brother-in-law is getting a brand new Volvo station wagon. Or you graduate from your crummy high school the year they announce construction of a new one. Better yet, you unknowingly get in under the wire and have the last standard, and painful, gall bladder surgery before your hospital goes to strictly laproscopic technique. Why are we jealous, my gosh we've already got a bundle to be thankful for even though there are some events we'd rather forget.

I believe it is legitimate envy, because plain and simply very shortly we will no longer be receiving the best possible therapeutic methods to treat our terminal illness. Again if the drug works, the "cutting edge" of medicine will have left us behind, rather akin to retired experimental lab animals. There's no going back; we're down the road so far that the negative side effects are irreversible. I don't like that feeling, but there is nothing I can do about it, except perhaps to suggest in the future we segregate support group meetings into the cyclosporine versus the Zenapax patients. (Grin)

And another little annoyance, as long as I'm whining. It appears like it won't be long before the "Pac-Man Pluck" invasive biopsy will no longer be a necessary requirement to determine rejection. Special materials that show rejection areas up on x-ray may well indicate rejection. And the feared chronic rejection in the form of TCAD may no longer be the problem it is today. Sincerely, may the wonders never cease.

But darn, what positive worth is it in that we'll be the only ones qualified to talk about the good old days of heart and lung transplantation - Man, those were the challenging days before it was a walk in the park.

Let me add a postscript about luck. Yours truly and his wife of some 39 years have agreed that Don will be allowed one more car purchase. It was to be a soup to nuts, the entire add-ons vehicle, for which the wait was just over 3 months. It arrived the other night, and as they took it off the truck, the upper tracks fell on it, smashing the hood and blowing out a front tire. It's now awaiting a post-natal full hood/grill transplant and skin graft to the right front ankle, assuming donor parts can be found that fit this new model. If it ever fully recovers, we're going to call it "Cyclo." Now that's bad luck!
Don M., Tx Class of '88


News of the death of transplant recipients is sadly rather common and certainly normally not a matter for discussion here. However, I was quite surprised to hear that Cal Miller had passed away last summer as I had spoken to him only three months prior about the ongoing condition of his transmyocardiai revascularization laser procedure. At that time Cal was very positive and indicated the results had seemingly completely stabilized his heart. As this therapy is gaining acceptance as a treatment of choice for long-term transplant recipients suffering from transplant coronary artery disease (TCAD), I wondered what had gone wrong in Cal's case.

As is all too often the "situation normal" in the life of heart/lung transplant recipients, when I talked with Mrs. Miller, she indicated that the heart was not the real problem, it was the sudden onset of terminal lymphoma in the stomach area, of course due to lowered immunity and various required medications. All involved felt that the TMR was functioning as intended. As we have often said, we are all pioneers and Cal Miller hopefully, will have led the way for potential extended salvation for many future heart recipients.

By coincidence, here's a PR release that appeared just this week regarding TMR:

Cardiac patient Achieves 10 Years of Pain Free Living

Franklin, Mass, 3/1/00- PLC Systems Inc., the leader in carbon dioxide (co2) transmyocardial revascularization (TMR), achieves a clinical milestone with the announcement of the l0th anniversary of the first TMR procedure performed using PLC's Heart Laser System. Eroll Taylor, PLC's first TMR recipient stated, "In 1990, I was suffering from debilitating chest pain, which restricted my activities. For the past ten years, I have been able to enjoy life and share in my family's lives. I am so happy and still pain free." Today, March 1, 2000, Mr. Taylor is celebrating his 93rd birthday.

There's a new book about a heart transplant coming out. It's called Where There's Love ... There's Miracles. It is written by Terry Lemons wife of Tx Wes Lemons of Victorville, CA. It's basically the story of Wes' heart transplant, but with a number of other amazing medical situations in addition.

Now I know Wes, he had his heart transplant about a year prior to mine at Loma Linda University Medical Center. Briefly I think I can sum up Wes' medical history since transplant as a series of situations that would have been easier handled medically if Wes had just stood in the middle of the San Bernardino Freeway and taken a direct hit from an 18 wheeler. It's truly an amazing story and one that will make you appreciate what sincere medical people do for us everyday. There will be a book signing by Wes and Terry at the Medical Center on March 21, 2000 outside the girl shop from I0 AM until 3 PM. Or the book may be ordered from Lemons Publishing, P.O. Box 3594, Victorville, CA 92393-3594. Please print the name you want signed along with $11.95 for the book, 93 cents tax, and $4.95 for shipping and handling. Allow four to six weeks for delivery.

Skin Cancer In Kidney And Heart Transplant Recipients And Different Long-Term Immunosuppressive Therapy Regimens

Petter Jensen, MD et al Oslo, Norway


Background: Nonmelanoma skin cancer occurs frequently in organ transplant recipients, but the relative importance of different immunosuppressive therapy regimens is unclear.
Objective: We studied the risk of skin cancer in the complete, single-center Norwegian cohort of kidney and heart transplant recipients (n = 2561). Methods: We determined cancer risk estimation by means of standardized incidence ratios and multivariate Cox regression.
Results: Transplant recipients had an increased risk of cutaneous squamous cell carcinoma (scc) (65-fold), malignant melanoma (3-fold), and Kaposi's sarcoma (84-fold), and of lip SCC (20-fold), compared with the general population. After adjustment for age, kidney transplant recipients receiving cyclosporine, azathioprine, and prednisolone had a significantly (2.8 times) higher risk of cutaneous SCC relative to those receiving azathioprine and prednisolone. After adjustment for age and type of immunosuppressive regimen, heart transplant recipients had a significantly (2.9 times) higher risk than kidney transplant recipients.
Conclusion: The risk of cutaneous SCC, malignant melanoma, Kaposi's sarcoma, and lip SCC is increased in kidney and heart transplant recipients. The risk of posttransplant cutaneous SCC is related to the degree of immunosuppression caused by long-term immunosuppressive therapy. (J Am Acad Dermatol 1999;40:177-86.)
From the Departments of Dermatology,a Surgery,a and Medicine,e and Institute of Transplantation Immunology, C Rikshospitalet, University of Oslo, and The Cancer Registry of Norway.

Animal Tissue Recipients Should Not Give Blood, Say Experts

Reuters Health Information Gaithersburg. MD (1 / 17/00)-- A panel of Food and Drug Administration (FDA) adders recommended Thursday that people who have had live animal tissue or cell transplants should not be allowed to donate blood or plasma products

The concern is that people receiving animal tissue might transmit disease-causing organisms such as porcine (pig) endogenous retrovirus to others through their blood.

The scientific term for tissue or cell transplants from other species is "xenotransplantion." One example of the use of animal tissues in humans includes pig cells and tissues, which are being studied as therapies for diseases such as Parkinson's and diabetes.

Members of the FDA's Xenotransplantaton Subcommittee of the Biological Response Modifiers Advisory Committee also recommended that blood and plasma already donated by xentransplant recipients should be recalled and destroyed.

A slight majority of the advisers -- 9 versus 7 -- agreed with the FDA's suggestion that people who have had "intimate contact with xenotransplant recipients should not give blood or plasma ether. The committee did not agree with the FDA's suggestion for a ban on donations by healthcare workers who might be exposed by needle stick or open wounds or by lab workers doing animal research.

FDA proposed to add three questions on xenotransplants to the 32-question donor screen already in use. But the blood banking Industry objected. The panel agreed, and said there should be no additional questions for donors.

Instead, clinicians should continue to warn xenotransplant patients that they and their intimates should never donate blood or plasma.

If the new blood deferral policy is adopted - the FDA is still collecting opinions -- it would initially only apply to a small number of transplant recipients. Only about 50 people have had animal tissues or organs directly transplanted into their bodies. But at least 700 others have had their own cells or tissues augmented outside their bodes with animal cells or tissue, FDA's Jay Siegel told Reuters Health.

And, "The numbers are likely to grow," as research explodes, said Siegel, director of the Office of Therapeutic Research and Review at the FDA's Center for Biologics.

Blood banking industry representatives backed the proposed deferrals of xenotransplant recipients, but said that a ban on intimates' donations would decrease the blood supply and warned against it.

"It is a slippery slope from such donor deferrals to disqualification of large populations with significant occupational animal exposures such as abattoir workers. farmers. veterinarians, and medical researchers working with large animal models." said Kay Gregory. director of regulatory affairs for the American Association of Blood Banks.

The agency first broached blood donation by xenotransplant recipients in 1996. when it advised clinical investigators that patents should be warned against donation as part of the informed consent process.

In December the FDA updated that guidance, expanding the definition of xenotransplant to include any procedure involving the transplantation, implantation or infusion into humans of live cells, tissues, or organs from a nonhuman animal source, or human body fluids, cells, tissues, or organs that had ex vivo contact with live, nonhuman animal cells, tissues, or organs.)

Two Studies Fault St. John's Wort

By EMMA ROSS - Associated Press Writer
LONDON (AP 2/11/00) -- St. John's wort, a popular herbal remedy used to relieve mild depression, can interfere with drugs used to treat HIV-infected people and heart transplant patients, new research shows.

Scientists said the findings add to growing concerns that the herb may interact dangerously with prescription medicines. Two studies published this week in The Lancet medical journal found that St. John's wort dulls the effectiveness of both the HIV medicine indinavir and the transplant drug cyclosporin, used to suppress transplant patients' immune systems so their bodies don't reject the new organs.

The U.S. Food and Drug Administration took note of the studies, cautioning health care providers about using St. John's wort with the medications. In its advisory Thursday, the FDA said it was working with drug manufacturers to ensure that labeling of the medications be revised "to highlight the potential for drug interactions with St. Johns wort."

Although both studies involved few participants, independent experts say the way they were conducted and the strength of the results render the findings significant. In one study, the level of medicine in the bloodstream when St. John's wort was taken dropped dramatically enough for patients to begin to reject their transplanted hearts.

The other showed that St. John's wort depressed the effectiveness of a drug used to treat HIV patients.

"This is a cautionary note," said Dr. Fred Valentine, professor of medicine at New York University Medical Center, who was not connected with either study. "These (herbal remedies) really aren't necessarily benign compounds."

St. John's wort is widely used in Germany as a treatment for depression and anxiety. Some U.S. physicians have started recommending it to patients and report that the herb has shown effectiveness in stemming depression.

"There is definitely a potential problem with St. John's wort that is only recently becoming apparent," said Mark Blumenthal, executive director of the American Botanical Council in Austin, Texas.

This information "is coming out as the herb increases in popularity and is being used by millions of people in combination with over-the-counter or prescription medications," Blumenthal said.

Last month, CVS Corp., the second largest drugstore chain in the United States, said it had started asking customers to list the herbal supplements they use -- in addition to their prescription drugs -- in an effort to avoid potentially dangerous drug interactions.

In one of the new studies in The Lancet, Stephen Piscitelli and other researchers at the Clinical Center at the National Institutes of Health in Bethesda, Md., gave eight HIV-negative volunteers indinavir, a class of HIV drug called a protease inhibitor, three times a day.

On the experiment's third day, St. John's wort tablets were added and the volunteers continued taking both pills for two weeks.

Blood tests were taken the day before the volunteers started taking the herb and at the experiment's end, to see if the concentration of the HIV medicine in their blood changed by adding St. John's wort.

The blood concentration of indinavir immediately before another dose was due was an average of 81 percent lower when St. John's wort was added than when the drug was taken alone, the researchers said. Overall, levels of the HIV medicine in the blood dropped 57 percent when taken with St. John's wort.

"When blood levels get so low, it leads to resistance and treatment failure," Piscitelli said.

"This is very important for HIV patients. St. John's wort is a commonly used product in the HIV population," he said.

In the second study, scientists from University Hospital in Zurich, Switzerland, reported that two heart transplant patients were hospitalized with heart trouble three weeks after starting to take St. John's wort to alleviate depression.

The scientists found the herb had lowered the level of the rejection-fighting drug cyclosporin. When the patients stopped taking St. John's wort, the problem ended, the researchers said.

Baghdad Bans Arabs From Buying Iraqi Body Parts

Jerusalem,(Reuters 2/7/00) - The Palestinian ambassador to Baghdad said on Monday the sale of kidneys and other body parts has become a flourishing business in sanctions-hit Iraq.

The ambassador, Azaam al-Ahmad, said in statement broadcast on the Voice of Palestine that kidneys were selling for $300 in Iraq and that 86 cash-strapped Palestinians were among those who have sold their organs for money.

"The sale of kidneys and other body parts has become a profitable business in Iraq," alAhmad said.

"It has a special market and some have exploited in a very ugly way the needs of the Iraqis and others as a result of the embargo imposed on them," he said.

Iraq has been under United Nations sanctions since it invaded Kuwait in 1990. It is allowed to sell oil, under U.N. supervision, to buy food, medicine and other goods approved by the international body to ease the sanctions.

Arabs from nearby states have been flocking to Iraqi hospitals for treatment, attracted by the low cost of care in spite of health risks because the sanctions have limited Iraq's supply of medical equipment and drugs.

Iraq has warned Palestinians and other Arabs to keep their hands of f the kidneys of its nationals, A1-Ahmad said.

The Palestinian embassy in Baghdad issued instructions to Palestinian residents of Iraq to abide by the Iraqi government's orders or risk deportation. The instructions were also broadcast by Voice of Palestine in the West Bank and Gaza.

Al-Ahmad said the Iraqi government had banned hospitals from carrying out transplants for Arabs and foreigners unless the donated organs came from a non-Iraqi residing outside Iraq.

The donor must accompany the non-Iraqi patient to Iraq and leave the country immediately after the transplant.

Bird Fungus May Threaten People

By Joann Loviglio - Associated Press Writer
Philadelphia (AP 1/31/00) -- People with weakened immune systems who come in contact with birds may be putting themselves at risk for developing life-threatening illnesses, according to a study.

The meningitis death of 72-year-old Boston woman might have been caused by breathing an airborne fungus found in bird feces, researchers report in a study published Tuesday in the Annals of Internal Medicine.

The woman was infected with the Cryptococcus neoformans fungus and died 39 days after she was diagnosed. The fungus enters through the lungs and the resulting infection can develop into meningitis or other ailments.

The fungus typically causes no problems for people with normal immune systems. However, the woman had undergone a liver transplant in 1989 and was taking rejection-fighting drugs, which suppress the body's immune system.

The woman did not live on the same floor as or provide care for a pet cockatoo kept in the house where she lived, but she did pass its cage often.

Researchers from New York's Albert Einstein Medical Center and the Boston University School of Medicine found that the fungus strains in the bird's feces and in the woman's body were virtually the same, which they say strongly suggests the woman was infected by the bird.

Though many researchers believe exposure to birds and cryptococcal infection in humans are linked, it has never been proven. The fungus is found throughout nature, said Dr. Arturo Casadevali of Einstein Medical Center, one of the study's authors.

"We don't know a lot on the basis of one case so we shouldn't be making any sweeping recommendations about what people should do," Casadevall said. "Ideally, what we want is for physicians and patients to be aware that this is a potential problem for immunnsuppressed people."

Firm Sees Trials of Pig Organ Transplants

By Kathy Fieweger
CHICAGO (Reuters 2/16/00) - It's a scenario recurring thousands of times each year: Patients lie critically ill,waiting for a kidney, heart or liver. Minutes, days, weeks tick by but no organ arrives in time to thwart death.

There are simply not enough organs for everyone.

Two companies are hoping to solve this unending problem and one, Baxter International Inc., appears ready to take the next step.

The firm's Nextran subsidiary, located in Princeton, New Jersey, concluded trials in late 1999 in which specially engineered pig livers were used as filters outside the body to perform human liver functions, Baxter spokeswoman Deborah Spaktold Reuters.

"The results were very encouraging," she said. "There were several patients who bridged." That is, they stayed alive on the pig liver apparatus until a human organ was available.

Spak said this so-called "ex vivo" trial involved a handful of patients, but the researchers have enough data to publish results in a major scientific journal within a few months. Next Step Is 'In Vivo' Trials

The next step after that is to ask the U.S. Food and Drug Administration for permission to perform "in vivo" trials --where the organ is actually transplanted inside the body. Spak said she anticipates this submission in the next 18 months.

Baxter chief executive Harry Kraemer said in a recent interview he is pleased with Nextran' s progress. Whether it is first in its quest to transplant an organ is not critical,Kraemer said, but just that it be one of the leaders.

Nextran's long-term goal is not to have its genetically engineered pig organs supplant human transplants, which will always be preferred. Instead, it hopes to provide a viable alternative when no human organ is available -- a sad and all-too-common event for those on transplant lists.

"The whole reason that we're doing this stuff that may seem so crazy to people is that there are just not enough organs to go around and the number of people who are waiting and dying is absolutely staggering," said Dr. Marlon Levy, a transplant surgeon at Baylor University Medical Center in Dallas.

Levy performed the two "ex vivo" liver trials that have taken place at Baylor and said both patients -- who were literally on death' s doorstep -- are doing quite well. "This is, on our part, an act of desperation to try to solve the crisis in organ availability," he said.

Critical Shortage
According to data from the United Network for Organ Sharing,them is a critical shortage.

As of January 2000, more than 67,000 patients in the United States were on its waiting list for organs: nearly 44,000 for kidneys; another 4,000 for hearts; 3,600 for lungs.

Thousands of people die waiting. Another 100,000 never even qualify to get on the list in the first place.

Baxter sees this need as a logical fit with its own leading position in kidney dialysis. In the mid 1990s, the company began to study xenotransplantation -- or transplant of organs between species -- as a possible alternative.

"If we're successful, the way we look at it is: What would medicine be like if there were an unlimited supply of organs available? That's clearly our goal," said Nextran chief executive Marvin Miller in an interview. "If we reach it or not, that remains to be seen. We hope we will."

According to Miller, there would be 125,000 organ transplants yearly in the United States if everyone who could benefit actually got one. In 1998 only 21,000 people were lucky enough -- most of them were kidney recipients. Furthermore,Baxter says, the demand for transplants increases 15 percent each year while the supply of organs is static.

Pig Kidney, Head Transplants Foreseen.
Research into using animals for transplant purposes is not new but started as far back as the late 1960s. In the early 1990s, worldwide attention focused on two patients in Pittsburgh, Pennsylvania, who received baboon livers but eventually died. Use of pig tissue heart valves is common today, but unlike organs, the pig cells are killed first.

Dr. Goran Klintmalm, another Baylor transplant surgeon, said critical new information was learned in each attempt of animal-to-human transplantation. Only now are specially engineered animals being studied, a whole new realm.

Unlike the "ex vivo" trials, Nextran's trials of fully transplanted organs will involve hearts and kidneys, he said. That is because if the transgenic kidneys or hearts do not work,doctors can turn to other alternatives like kidney dialysis or a heart device called a left-ventricular assist device to keep patients alive. For livers, there is simply no alternative.

Also, the liver acts like a biochemical factory performing numerous complex functions that may be hard to replicate. But doctors said what has been learned about rejection in livers can readily be applied to other organ systems.

Biggest Challenges Involve Immune System
While some people question the ethics of breeding animals for this type of use, the chief obstacles are immunological in nature, according to John Logan, vice president of research and development and Nextran.

First is preventing what Logan said is called hyperacute rejection -- the process by which foreign tissue is turned into a pulpy mess almost immediately by a human's immune system.

Nextran is engineering pig organs to express a human gene that prevents this rapid rejection. Even with the transgenic organs, however, patients still need to take special immunosuppressive drugs every day for the rest of their lives.

Researchers are also very concerned with a certain virus contained by most if not all pigs -- the porcine endogenous-retrovirnses (PER v). They pose no threat to pigs and at least so far, seem not to infect humans who have undergone pig tissue transplants. But concerns linger.

"The results so far cause us to be cautiously optimistic,"Levy said. "Two or three years ago, everybody was ready to bring these trials to a screeching halt because of the concern that PER V viruses could infect human cells in a tissue culture. Now, just a short two years later, we've got data on my two patients that show no PERV infectability in serial sampling overtime."

In addition, Levy pointed to a recent study conducted by Imutran, the unit of Swiss pharmaceutical giant Novartis AG, and the only other major company studying xenotransplatation of whole organs. Imutran studied 160 people who had some form of pig tissue transplant and found no evidence of PERV infection.

To Dr. Klintmalm, tremendous progress has been made to date with the transgenic animals. "Just the fact that we've tried is progress," he said. "We have much, much more to do than we've done, but we've started."

Hand Transplant-Future

By James Ritchie - Associated Press Writer

Louisville, Ky. (AP 3/2/00) -- Not long ago, Matthew ScOtt did something he had wanted to do for years. He started wearing his wedding ring on his left hand.

It is an indication of how comfortable Scott now feels with the limb doctors took from a cadaver and attached to his forearm in a 14 1/2 hour operation at Jewish Hospital a year ago.

When surgeons in Louisville began talking about performing the nation's first hand transplant, many in their field had serious reservations. The likelihood of success was too small, critics said, the ethical concerns too great.

Despite promising results so far, the debate over the future of transplants of such nonvital organs has yet to be settled.

Medical ethicists have been most concerned that transplant patients must take anti-rejection drugs for the rest of their lives to keep the body from trying to destroy the foreign tissue. The drugs suppress the immune system, leading to an increased risk for infections, cancer and even death.

But according to Linda Emanuel, director of the American Medical Association's Institute on Ethics, the basic question has not changed: Do the potential gains of the procedure justify the risks.

The answer is clear for a heart or liver transplant because the patient will die without the organ. Nonvital parts such as a hand require further contemplation.

Scott, 38, lost his hand in a firecracker accident in 1985 and did not adjust well to a prosthesis. He knows the transplanted hand he received in January 1999 will never be as good as his real one, but he has no regrets about the surgery.

"I'm a different person now than I was a year ago," he said.

"A lot of those daily frustrations -- the kind that would send a pen flying across the room -are gone now."

Scott's doctors say his progress has met all of their expectations. They recently showed video Of him using the new left hand to write his name, pour a glass of water, deal cards and tie his shoes. It is those things that most people never think about that matter most to Scott, who works as an administrator for an emergency medical center in New Jersey.

At first, many doctors doubted he would ever develop useful function or sensation in the new extremity. But he now has some feeling in his fingertips, can feel changes in temperature and can move his thumb as he begins to gain function in the small muscles of the hand.

The progress is part of the reason why in January, on his last visit to Louisville for a checkup, Scott and his wife, Dawn, went to a jeweler and got his wedding band resized.

At the very least, Scott's case shows that such an operation has some benefits for the patient.

"I think people are more optimistic about it now. Someone has lived to talk about it a year later," Emanuel said.

Given what is known, Emanuel believes the surgeons in Louisville are justified in continuing their work on hand transplants. But the situation still bears watching.

"I have some reservations," Emanuel said. "Those reservations are somewhat diminished, but they're not completely gone."

Scott's doctors, meanwhile, say they are ready to perform another transplant as soon as a suitable match can be found between patient and donor. It's a plan the American Society for Surgery of the Hand opposes, even as it advises caution.

The group's president, Dr. William P. Cooney, said no further hand transplants should be performed until doctors from around the country can examine Scott and confirm his progress. The group would also like to see more animal research.

Scott's doctors cannot guarantee that he will not lose the hand, nor can they be sure that future patients would keep transplanted hands. Cooney said it would be a shame to perform the operation on several more patients, only to learn eventually that the transplants had a high rate of failure.

Dr. Matthew Tomaino, chief of microsurgery for the University of Pittsburgh's orthopedic surgery department, said he is closely observing ScoWs case. Initially skeptical that a transplanted hand would ever have much sensation, Tomaino said he's been impressed by Scott's improvement. If Scott continues to improve after a couple of years, he said, he could foresee the University of Pittsburgh attempting the procedure.

"I think the future of nonvital transplantation is very bright. !t makes complete sense," he said.

Tomaino was particularly encouraged when he learned that ScoWs regimen of anti-rejection drugs is similar to what kidney transplant recipients take. That means his immune system is not suppressed as much as those of patients who receive other organs, such as a heart.

Five people in the world are living with transplanted hands. Two of them underwent surgery in France, with the first receiving a hand in September 1998. Two have had hands attached in recent months in China.

Dr. Jon Jones, the lead transplant surgeon for Scott, said he anticipates hand transplants will continue to be performed on a low-volume basis for several years until there are major advances in preventing rejection -- possibly treatments that do not affect the immune system.

Then the benefits of the surgery would be proportionately higher and larger numbers of people might opt for it, he said, as long as doctors can show that transplanted hands can consistently develop good function and improve quality of life.

A Journey Of The Heart For A PGA Tour Player

By Doug Ferguson

Miami (AP 3/1/00) -- Erik Compton is in awe.

Since he was a kid, he has been romping around the famed Blue Monster course at the Doral-Ryder Open, watching Greg Norman and other stars. This week, he has a locker next to them. He practices next to them on the range. But when Compton goes to bed Wednesday night on the eve of his first PGA Tour event, he will be thinking about other things-like the beating of his heart.

On Thursday at 9:09 a.m., Compton will become the first heart-transplant recipient to compete on the PGA Tour.

"Deep down inside when I go to bed every night, I'm not thinking so much about the golf," he said. "I am with somebody else's heart. I think about somebody is not here, and I am here right now. That's what keeps driving me to do better."

He has done plenty well already.

Two years ago, he became the first player with a heart transplant to compete in the U.S. Amateur and earn a scholarship to an NCAA school when he signed with Georgia.

But he received a sponsor's exemption to Doral not just because he has a new heart, but because he can play-a three-time Miami high school player of the year, the top-ranked junior in the world in 1998. "I know he can make the cut," said Jim McLean, Doral's teaching pro and Compton's personal coach. "I will be very surprised if Erik doesn't play well."

Compton is personable and chatty, no different from any other 20-year-old. But ask him about his heart and he measures his sentences, fearing he might break down before a room full of people.

"I don't know where to start with the story," he said. "You can write 12 movies about it."

Compton was diagnosed with cardiomyopathy at age 9, a disease that enlarges and attacks the heart. Three years later, he became the youngest heart-transplant recipient at Jackson Memorial Hospital. He got out of the hospital in time to graduate from the sixth grade. Compton's heart came from a 15-year-old girl who died in a car accident in Tampa eight years ago. He is not comfortable talking about it, something he prefers to keep in the family-his and hers. He will meet the donor family when the time is right.

"They will be with me throughout the week," he said. That Compton has made it this far-from a high school star to the U.S. Amateur to a college scholarship to a spot in a field that includes Norman, David Duval and Phil Mickelson-goes back to his first post-transplant tournament.

He played the U.S. Transplant Games in Utah just six months after his surgery, shot a 92 and was thrilled.

It was an important week, a chance to see so many others with transplant who have gone on to lead a normal life and pursue their dreams. It gave him a chance to look forward instead of back, and he liked what he saw. "I have convinced myself that I am normal," he said, "and that I can do anything." It is never so simple as plugging in a new heart and getting on with life. Compton takes pills in the morning and night to manage his body, anti-rejection medicine that lowers his immune system but also brings some side effects.

He compensates by staying fit, and by staying away from things that normal 20-year-olds might do. Exactly what those side effects are, he isn't saying. "Do you see any yet?" he asked, sounding like a college student ready to seize his chance of teeing it up against his heroes. Compton never planned on making a living on the links. He took the game with hopes of growing old with it, maybe breaking 80 every once in a while. He never got serious about it until the transplant, which left him too weak to stay competitive in baseball.

Golf is important. He gets upset when he misses a shot. But he also has a perspective that few others have about the game. "I'm just like any normal 20-year-old," he said. "I say the wrong things and jump around. I can be a punk. But when I look at everything at the end of the day, I realize how far I have come with my golf game and my life. "I hope my story can be inspiring for other people that are going through the same thing, and to do know that they can do just as well as I am in anything."

(Compton played all four days, which is a major achievement. However, he finished well out of the money. ED.)

Liver Transplant Rules May Change

By Laura Meckler - Associated Press Writer
WASHINGTON (AP 2/17/00) -- The network that runs the nation's transplant system is proposing a more sophisticated system of ranking patients waiting for new livers and said it will consider sharing donated organs over larger areas.

Both proposals are attempts to move closer to the Department of Health and Human Services, which wants a new allocation system that would direct more livers to the sickest transplant patients.

Under the current system, patients in certain parts of the country get transplants much quicker than those in other areas, partly because donated livers are distributed to local patients first, even if there is someone sicker in a neighboring community or region.

HHS and the United Network for Organ Sharing have been battling over allocation policy for nearly two years now, since HHS issued regulations that directed the network to develop new policies for distribution of livers and other donated organs.

Congress has put those regulations on hold several times, with the latest moratorium set to expire next month. The issue has been subject to an intense battle among transplant centers and patient groups, which have aggressively lobbied Congress. Congress has also clashed sharply with the White House, which wanted the HHS rules to take effect last year.

But despite the fighting in Washington, the transplant network's liver committee has proposed the outline of a new way to distribute. livers, the organ that has engendered the most controversy.

Under the proposal released Wednesday, . patients would be ranked based on a sophisticated, objective point system. Patients would get points based on their symptoms. The presence or absence of certain chemicals in the blood stream, for instance, would translate into a certain number of points. Those with the most points would be at the top of the list for donated livers.

Once the point system is developed, the network said it would examine creating larger allocation areas -- which HHS has pushed for and the Institute of Medicine recommended.

The proposal is now available for public comment, and still must be approved by the network's board, which intends to submit it to HHS by March 16.

HHS was cautiously optimistic, said John Nelson, who oversees the transplant program for HHS. "It's moving in the right direction."

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