Skin Cancer in Transplant Patients
John C. 0 ‘Brien, MD et al Baylor University Medical Center
Skin cancer is the most frequently seen malignancy in the USA. Although most physicians have experience in dealing with skin cancer in the general population, transplant patients are particularly susceptible to complications of these neoplasm's, and their treatment warrants special consideration. Because of immune suppression, seemingly innocuous lesions can become large, locally aggressive, and at times life threatening. Patient and physician education is needed to address the specific issues of skin cancer prevention and treatment in general, with emphasis on the immune-compromised patient.
One of every 3 newly diagnosed cancers is found on the skin. Because of a rapidly increasing incidence, skin cancer will affect almost one half of the US population by age 65. Skin type and ultraviolet radiation exposure are primary risk factors in the development of these tumors. The most common forms of skin cancer are basal cell carcinoma (BCC) and scams cell carcinoma (SAC). There were an estimated 900,000 new cases of these cancers in the USA in 1997. A number of ablative procedures, including electrode cessation/curettage and cryoablation, are efficacious in treating BCC and SAC, but these may not be ad-equate in organ transplant recipients and should be discouraged. The following patients should be counseled and treated aggressively in the pre-transplant and post-transplant intervals: those with skin types I-Ill, those with a previous history of skin cancers, and those with solar-damaged skin or preexisting actinic kurtosis. Avoiding sun exposure, wearing sun protective clothing and hats, and using sunscreen are several simple measures that are beneficial for preventing skin cancer in organ trains-plant patients. These patients should have complete skin examinations at least once per year or, for those with continuing or developing skin problems, more often. Patient instruction relating to skin cancer prophytaxis and self-examination must be a part of the transplant candidates education.
Table 1. Skin Types
I. Always burns, never tans
II. Usually burns, occasionally tans
III. Sometimes burns, usually tans
IV. Never burns, always tans
V. Moderate pigmentation - dark brown, tans darkly
VI. Marked pigmentation - black
Transplant patients develop cancer at an earlier age (mean, 45 years) compared with the general population (mean, 65.5 years). Overall, post-transplant malignancies have been diagnosed in 4% to 18% (mean, 6%) of renal recipients and 3% to 9% (mean, 6%) of cardiac patients. The most common cancers are skin cancer (37%), lymphomas (primarily non-Hodgkin's type)(17%), and lung cancer (6%). The average age of cardiac recipients is 56 compared with 40 years for renal patients. Time to first tumor after transplant averages 3.73 and 8.75 years, respectively. Heart patients (and other external organ recipients) are subjected to intense amino-suppression that lasts a lifetime. This may be the reason for the shortened delay in cancer development. Immune suppression may be decreased over time, depending on the philosophy and experience of the transplant team. Renal recipients who develop cancer who develop cancer can have their suppression decreased or stopped; if rejection occurs, the patients can resume dialysis. This option is not available to non-renal organ recipients.
The incidence of cancer increases with time post-transplantation. After heart transplant, the incidence of cancer is 3% at 1 year and 26% at 5 years. Scams cell carcinoma of the skin is more common and more aggressive in transplant patients than in the general population. In a carefully studied cohort of non-transplant patients with non-melanoma skin cancer, a high risk of developing more skin malignancies in the follow-up period was found (up to 50% at 5 years in fair-skinned males over 60 years who previously had skin cancer and severe actinic skin damage). The ratio of SAC:BCC is 0.2:1.0 in non-transplant patients. After transplant, the ratio changes. The incidence of SAC increases greatly, but BCC increases only slightly, resulting in a ration of SAC:BCC of 1.8:1.0. Skin cancer is responsible for 5% of the deaths in the transplant group. Scams cell carcinoma is responsible for 60% of these deaths, malignant melanoma for 33%, and BCC, 1%.
Other cancers occur at relatively predictable intervals in the post-transplant period: Kaposi’s sarcoma at a mean of 21 months; lymphoma (primarily non-Hodgkin's type) at an average of 32 months, epithelial carcinomas (excluding ovular and perennial) on an average of 67 months; and carcinoma of the vulva, perineum, and carcinoma in situ of the cervix with an average of 112 months. Interestingly, the incidence of lung, prostate, rectal, breast, and invasive carcinoma of the uterine cervix is not in-creased in this cohort, although it is prevalent in the general population. This may be due to a longer latent period for these cancers in the non-transplant group.
Skin cancers are prevalent in locales with high sun exposure rates. Citizens in urban areas who have indoor occupations and outdoor recreational pursuits and those in rural areas comprising farming and ranching communities (particularly persons with fair complexions) have many skin lesions, both benign and malignant. Ultraviolet A and B radiation's cause sunburn and skin dam-age in fair skinned persons and can damage the local immune function in patients of all skin types. Ultraviolet radiation can produce p53 tumor-suppresser gene mutations that can promote skin cancer. There is also a well-characterized deficit in immune function with advancing age. These older patients tend to accumulate genetic damage over time that can result in cancer. Age-related impairment of the deoxyribonucleic acid repair mechanism may account for the earlier development of cancer in older transplant recipients than in the general population.
Cyclosporine inhibits the production of inter-leaking-l and inter-leaking-2 by macrophages and lymphocytes. This inhibition interferes with antigen presentation (by Langerhans cells in the skin) and blunts the immune response at its inception. Azathio-prime-treated patients may have an increased incidence of skin cancers, because azathioprine’s breakdown products, imidazoles, sensitize the skin to sunlight. An active metabolite of azathioprine, 6-thioguanine, is claimed to be carcinogenic to the skin.
Neoplasm's in patients who have primary and acquired immune deficiency and in patients who have auto-immune and inflammatory diseases treated with amino-suppressive drugs show a striking similarity to the tumors that affect transplant patients. Activation of oncogenic viruses, blunting of the immune surveillance and response, and stimulation of oncogenesis are involved.
The immune-suppressed state may allow activation of oncogenic viruses, resulting in cancer. Some well-known examples are Epstein-Bar virus associated with non-Hodgkin's lymphoma; human papillomavirus and herpes virus associated with cancers of the skin, vulva, cervix, and anus; hepatitis viruses B and C associated with Kaposi ‘s sarcoma. Post-transplant patients are often given anti-viral prophylactics. Our patients take acylovir daily.
CANCER AND TRANSPLANTATION
While previous skin cancer does not preclude organ transplantation, a history of internal malignancy has been a contraindication to transplantation in the past. How-ever, recent studies of carefully selected patients with antecedent cancers who had received transplants report good results. These studies include patients who had childhood cancer (usually due to anthracycline-induced cardiomyopathy) or adult cancers. Penn estimated the potential for recurrence of cancer as low (0%-10%) for incidentally found renal tumors, lymphomas, and testicular, uterine, cervical, and thyroid cancers; intermediate (1 1%-25%) for carcinomas of the uterine body, colon, prostate, breast, and Wills’ tumor; and high (>26%) for cancer of the bladder, sarcoma, malignant melanoma, symptomatic renal carcinoma, non-melanoma skin cancer, and myeloma. The recommendation of a 2-year waiting period for transplant following cancer treatment seems prudent for most renal transplant patients; waiting more than 2 years for transplant is necessary for most melanoma, breast, and colorectal cancer patients. Cancers that arose were treated after transplantation recurred in 23% of the cases, with a short follow-up period (52 months).
DIAGNOSIS AND TREATMENT
Physicians who care for amino-compromised patients need to understand that several recommendations may help control skin cancers. Before transplantation, the routine work should include taking a history of sun exposure; taking family and personal histories of malignancy, and performing complete cutaneous and head and neck examinations. All suspicious skin lesions should be biopsies and removed. Kurtosis can be treated with elector-desiccation/curettage, cryotherapy, and topical 5-fluorouracil. A high index of suspicion and the frequent use of skin biopsies are critical. Amino-compromised patients have an increased incidence of both pre-malignant and malignant lesions that may be atypical in presentation and appearance. We also recommend that these patients avoid sun exposure as much as possible and that they follow the guidelines of the American Academy of Dermatology if they must be in the sun. Warts should be removed, because they are often associated with human papillomavirus and can lead to the formation of cutaneous malignancies.
After transplantation, routine skin examinations are critical, with the frequency guided by the patients history and post-transplant course. These patients have a high incidence of multiple lesions, 44% in one series. All skin lesions suspicious for malignancy should be biopsies and then removed, with histology margin control of malignancies. If there is a question about adequacy of resection, more tissue should be removed. This precaution will result in cancer control in most instances. Most recurrent or locally advanced primaries T2, T3, or T4 should be referred to a Mhos micro-graphic surgeon for resection. This technique yields a lower recurrence rate than does routine resection, particularly with poorly differentiated cancers and difficult lesions near or involving the eyes, ears, nose, and lips. These head and neck primary lesions are in functionally and cosmetically critical areas where clear (wide) margins are difficult if not impossible. Irradiation therapy can be used as primary treatment in similar cases, with preservation of anatomic structures and function. Postoperative radiation therapy should be considered in an effort to increase local and regional control. Even using these modalities, control may not be complete.
Frequent use of CT scans to search for metastic disease is recommended, because heart transplant recipients have a significant risk of primary lung cancer, particularly if there is a history of smoking.
Modified or radical neck dissection should be done for patients with positive nodes or when the neck is entered to remove the primary lesion. Resection of involved tissues must be done aggressively to give the best opportunity for cure. The right jugular vein should be preserved if ontologically feasible, to facilitate heart biopsies. Although other veins can be used, the approach is more difficult.
Decreasing the level of immune suppression should be considered at the time of recurrence or with the appearance of an advanced primary tumor. Euvrard and associates reported on 5 post-transplantation patients (kidney: n=3; heart: n=2) with aggressive skin cancer. Cyclosporine was discontinued in all patients on triple-drug therapy, and azathioprine was omitted in all but 1 cardiac patient whose dose was lowered to 25 mg/day. Despite this drastic reduction in immune suppression, there were no episodes of rejection in the follow-up period.
Chemo-prevention using cis- or transretinoic acid or topical retinoids is a consideration for preventing skin cancer. Although this intervention can help, high doses must be used, and attendant side effects such as mucosal dryness and hyperlipidemia may occur. The recurrence rate is high after decreasing or discontinuing therapy. The addition of interferon-a to cis-retinoic acid has been used with encouraging results; however, treatment with a cytosine may smite-late a rejection reaction.
Chemotherapy has produced some successful results for advanced and metastatic skin cancer, using a combination of capsulation and 5-fluorouracil ±..bleomycin sulfate. Rowe et al raised the question of triple drug therapy, with induction chemotherapy, surgery, and radiation for difficult cases.
As the drugs and techniques for post-transplant immune suppression improve, these patients will live longer. Perhaps we will see an increase in the more common cancers. Conversely, as suppression regimens improve, it may be possible to target only those clones of cells responsible for rejection, making the insult to the immune system more specific and limited, possibly leading to a decrease in the incidence of cancer. At present, it is advantageous to keep maintenance immune suppression at the lowest level compatible with survival and function of the transplanted organ. Baylor University Medical Center Proceedings Volume 12, Number 2 103-09, April 1999
This report was contributed by one of the patient's presented, Tx David Winter of Garland, Texas. UpBeat has omitted the two specific patient reports as being of medical practitioner interest only. Suffice to say David has been through an extremely difficult medical therapy, which is on-going. His identification here is with his permission.
IS THIS RESEARCH REALLY SCIENTIFIC? FDA IS EXAMINING
Although Dr. Reitz accepted no stock from Heartport - only a consulting fee - other Stanford faculty members who were testing the procedure got thousands of shares each. Dr. Steven's, as a co-founder, had 2.5 mil-lion shares, which after the 1996 public offering briefly became worth more than $100 million. Heartport says it disclosed doctors’ stock ownership and other company ties to patients in consent forms and to medical journals. But some journals that published their research, while reporting that it was funded by Heartport, initially didn't mention that the researchers held stock in the company.
The editor of the Journal of Thoracic and Cardiovascular Surgery says maybe he was naive not to feel that stockholdings needed to be disclosed; he has changed his policy and now reports such ties. Another journal, the Annals of Thoracic Surgery, began to disclose Heartport stockholdings after being chastised by a reader for not doing so.
Disclosure or not, some doctors say that to use and test a medical device while owning stock in its manufacturer is unacceptable. “Its very problematic,” says John C. Baldwin, dean of Dartmouth's medical school. “Ones objectivity in decision-making in patient care is obscured by that situation.. . . I think its improper.”
Transplant pioneer Norman Shumway, who, as Dr. Reitz's predecessor, built Stanford's heart-surgery reputation, says. “I think its wrong, I really do. I would never do it.”
One Stanford team member, R. Scott Mitchell, says his sense of a financial conflict prompted him to quit Heartport research after the dog studies. But “other people here didn't feel as compromised,” he observes.
Heartport says start-up makers of medical devices routinely give researchers stock in exchange for their ideas and their time, because few can pay cash. “Its an insurmountable conflict, but you just have to let the patients know what the issues are as candidly as possible,” Dr. Steven's says. “The only way to counteract that is with optimal disclosure.”
Dr. Reitz says the faculty members “were working in the lab trying to improve peoples lives, and the business aspect was not motivating people at that time. I do not think our motivations were at all tainted.” Other Heartport researchers who are still at Stanford didn't return phone calls seeking comment.
Stanford itself didn't invest in Heartport. But the association with its name was critical to the procedure. “The thing that made people stand up and take notice is that it had the Stanford stamp of approval,” says Robert Tranbaugh, a surgeon at New York's Beth Israel Medical Center. “That p me off more than anything else.”
Dr. Steven's, while an assistant professor of heart surgery at Stanford, organized two educational conferences for surgeons, called the Stanford Symposium on Minimally Invasive Cardiac Surgery. Heartport consultants dominated the conferences, but the company's financial backing was scarcely mentioned in conference solicitations. A Montana surgeon, Alan Muskett, later wrote to a medical journal that he “felt deceived” by Stanford's sponsorship. He calls the Stanford conferences “a Heartport commercial.”
Kenneth Melmon, a Stanford associate dean who approved the conferences, says he also feels deceived, having been unaware that Dr. Steven's had such a close tie to the company. “I'm disappointed,” Dr. Melmon says. “It gives the perception that he was hiding it.” Dr. Steven's says he disclosed all his Heartport ties in paperwork submitted to Dr. Melmons office. It was “squeaky clean,” he says.
Meanwhile, some surgeons began to dispute the company's public statements and marketing. The loudest critic was Frederick Wilhelm Mohr, a German surgeon picked by Heartport to conduct human tests prior to FDA clearance. At a Washington, DC, conference two years ago, Dr. Mohr presented his results. Out of 51 patients, there were five deaths, one of which was clearly related to the procedure. One patient who died and one who survived had aortic dissections - rupture of the big artery - related to the procedure.
Aortic dissection has been the Heartport procedures “Achilles’ heel,” says Dr. Reitz. Dr. Steven's himself had it happen to a patient of his in late 1996 - an event that Heartport says led it to tell surgeons to screen out patients with very diseased arteries.
Even so, in doctors’ voluntary reports on 610 early Heartport patients, aortic dissection occurred in II of them, a rate 10 times that seen in open-chest heart surgery. Reports on 1,063 later cases showed only eight, but that was still four times the rate in conventional heart surgery. These are the latest published data. The company says its unpublished data now show a rate close to that of open-heart surgery.
Dr. Mohr blamed the burst arteries on Heartport’s centerpiece, its special catheter, which a surgeon puts in after first threading a guide wire up the aorta from the groin to the heart. Dr. Moor said the wire and the catheter were “very stiff’ and might cause artery damage, which could lead to a tear once blood began to flow-pumped in a “retrograde” direction from the groin to the top of the aorta.
His thesis drew instant fire. A Heartport advocate at the meeting questioned his surgical skills, and Wall Street analysts challenged him. Dr. Mohr says Heartport prodded him to include more-positive data from other doctors if he was going to present his own negative data. They “wanted to imply I wasn't doing it right,” he says. “The company doesn't like this data.”
Replies Dr. Steven's: “The reality was that he had bad results and others didn't. He was very candid about a very tough experience, but then he concluded that everyone else must be underreporting.”
Almost the very day Dr. Mohr spoke, the company introduced a modified catheter and guide wire that were more flexible. Heartport says the change didn't imply that the previous ones were defective, and it hasn't recalled them.
By early 1998, as reports of cases gone awry circulated, some surgeons coined a grim phrase for those who died or were injured during the surgery: “Heartport road kill.” Dr. Steven's says he himself has been confronted with the term - by a Stanford faculty member.
Demand for Heartport’s system cooled so fast that, last May, the company abruptly brought in new management and cut back the staff. Mr. Fisher replaced Dr. Sterman as CEO; Dr. Sterman now is chairman. Heartport’s sales in 1998 declined 20%. The stock closed yesterday at $5.375, far off its high of $43.75. Dr. Steven's, who had sold 12% of his Heartport stock for $7.4 million in 1997, stepped down from his post as technology officer in 1998 but remains a director. At Stanford, he has reduced his role to that of consulting assistant professor.
The FDA is looking anew at the procedure. When the agency approved it 2 1/ 2 years ago without requiring full clinical trials, its rationale was that the approach merely used previously approved devices in a slightly different way. But Pittsburgh's Dr. Griffith says, “This was not a substitute for one instrument but a whole new way of thinking about how to protect the heart in surgery and how to approach the heart. It was a technological leap that most surgeons were unprepared for.”
In any case, he says, “even though you have FDA clearance, that doesn't mean you've got to sell it to everyone you can. Its better to take another year refining the system.”
The FDA now is “concerned” about the number of death and injury reports, says Susan Alpert, director of its office of device evaluation. “We are looking into this to see if its procedurally related and if the procedure can be changed to decrease the frequency of these events,” Dr. Alpert says. “We are determining what actions need to be taken. We are not done yet.”
In any event, Heartport no longer actively promotes the original catheter. It introduced a new model late last year that goes in close to the heart and sends blood along its natural path, instead of forcing it against the grain from the groin to the heart. But it continues to sell the old model for those who want it. The company says it now concentrates its marketing on fewer, better-trained surgeons.
One of them is Dr. Mohr. He says his latest 110 Heartport cases, using the early catheters, have produced just one fatal aortic dissection.
As for Dr. Reitz, Stanford's chief of heart surgery, he says he has no regrets about his involvement with Heartport. Dr. Shumway, who no longer practices surgery but still spends time at Stanford, says his successor “is a very fine gentleman, and I think to some extent he was used in this business.” Dr. Shumway considers the proud reputation of the department he once ran, and says: “Its a little tarnished, isn't it?”
Responds Dr. Reitz: “A new field of cardiac surgery was being opened up. The many people that also worked at it here at Stanford were trying to advance that concept and trying to help people. And its working out that way.”
Then, after a pause, Dr. Reitz adds, “Though maybe not with the Heartport technique.”
Dow Jones 5/5/99
I had a strange realization the other day as a mail order firm called to get a correct credit card number. As I took one of my more senior cards out and looked at the expiration date, I commented, “Gee, 10/05, the card will probably last longer than I do. Wonder who'll get to it first.” But my “downer’ was somewhat abated when I picked up the days mail and found with delight that somehow it has been seen fit to include me on the Playboy catalog mailing list.
And speaking of long forgotten fantasies. Remember in about 7th or 8th grade when you used to dream that maybe you'd escape that rotten Latin test by having the school burn down. (Of course, I'm not sure one is even allowed to think such heinous thoughts in the culture of today.) But anyway a couple of Fridays ago I arose as usual and prepared to dress in my “go get sweaty” clothes for my last cardiac rehab. session of the week. I really felt like taking a “cut”, but I was haunted by the “you're only cheating yourself” syndrome of days of yore. I had just finished the tooth brushing ritual and was about to turn the bathroom radio off when I caught, “and there will be no activities at the Gloucester Wellness and Fitness Center for at least a couple of days due to the fire last night.” My God, I was free! My dream had come true, no class because the place burned up its laundry room. Did I immediately go out and walk a quick two miles to replace the lost cardiac stimulation - of course not, I was exhausted with exuberance and needed a quick nap.
Some See Alternative To Heart Transplants In Lads
By Raymond Hennessey
New York (Dow Jones 5/13/99)-Jeff Abner should not be fishing.
The 43-year-old Beaver Dam, Ky., resident came within a hair of dying in 1996 as his heart failed and traditional therapy did nothing to help him.
Only through the implantation of a mechanical device that takes over the beating function of the heart - a late l990s version of the more controversial artificial heart of the early 1980s - was Abner able to survive.
But, because the device - known as a left-ventricular assist device, or LVAD - is powered by external batteries, Abner isn't supposed to get wet, and his doctors still cringe at the thought of him on a boat, reeling in a bass. -
That doesn't bother Abner, known to his friends as “Bo.” After his LVAD gave him a new lease on life, Abner decided to return to doing the things that gave him the most pleasure, namely turkey hunting and fishing.
“Surgeons are sharp, but they aren't that smart,” Abner said. “I told them I was going to do what I wanted to. I needed to go live my life and that's what 1 did.”
What is most unusual about Abner’s story is not his survival, but his longevity and quality of life. LVADs are approved in the United States only as a temporary fix to keep patients alive until a donor heart can be found.
But the devices’ manufacturers, Baxter International Inc. (BAX), which makes Abner’s Novocor model, and Thermo Cardiosystems Inc. (TCA), which produces the HeartMate device, are both planning to ask the Food and Drug Administration for approval to use them as an alternative to transplant. They are approved for such use in Europe.
From a medical perspective, an expansion of LVADs' use would be welcome to many doctors. Physicians have long lamented that the demand for healthy hearts for transplantation far exceeds the supply. Last year, there were 4,237 patients on transplant lists in the United States, though just 2,340 procedures were per-formed, according to the United Network for Organ Sharing.
Thousands of other patients could use mechanical help for their hearts, although, for a number of reasons, they are ineligible to get on transplant waiting lists. The American Heart Association estimates that 40,000 people ages 65 and younger could benefit from a transplant.
Financially, an expansion of eligible patients will be a boon for Baxter, Thermo Cardiosystems and others trying to get into the market simply because they aren't limited to the handful of patients currently on transplant lists.
The annual market for these devices as a bridge to transplant is about $100 million, said Sheryl Zimmer, an analyst with Deutsche Bank Securities Inc. “When you increase the number of patients, that could expand by a factor of 10 or more,” she said. “Were talking about more than $1 billion."
Barney Clark Still Haunts Field
Standing in the way of LVADs, though, is a history of failed attempts to find a re-placement for the human heart. The early 1980s saw the most promising activity in the field since the first successful transplant was performed by Dr. Christiaan Bernard in 1967.
The world was captivated by Dr. Barney Clark, a retired dentist who was kept alive with the Jarvik heart and a battery of flunky machines at the University of Utah Medical Center in 1982.
The same attention was brought in 1984 to the transplantation of a baboons heart into the newborn known to the world as “Baby Fae” at California's Loma Linda University Medical Center.
But, rather than medical milestones, both events are now viewed by the public as colossal failures. Clark lived just 112 days and, because of the machines, was unable to get out of bed. Baby Fae died a week after her new heart was put in, when her seven-month-old body rejected it.
Both cases taught researchers a number of important lessons, but they also helped turn public opinion against innovations that might ultimately replace traditional transplantation. It has taken more than 15 years for LVADs to emerge as one such option.
LVADs have an advantage over fully mechanical artificial hearts because they augment the heart, rather than replace it. Researchers learned in recent years that the whole heart didn't need to be replaced. If a device could be made to help the left ventricle, which controls the hearts pumping function, that should be sufficient to sustain the muscle.
It would also sidestep the body's natural urge to reject a foreign organ, like a donor heart.
For the most part, the devices have worked, buying patients time before a suitable heart is found. “Before (LVADs), people died,” said Dr. Mehmet Oz, associate professor of surgery at Columbia-Presbyterian Medical Center, who uses Thermo Cardiosystems’ HeartMate.
And they have also proved helpful in restoring some of the hearts function. There are cases where a patient implanted with an LVAD had had the device removed and has not needed to undergo a transplant, Oz said.
Improvements To LVADs in Offing
Despite the positives, there are some drawbacks that may make it difficult for the current models to be accepted as alternatives to transplant. For one thing, the LVADs now commercially available require large battery packs that patients have to wear in either vests or pouches that look like fanny packs. The implants themselves are also fairly bulky, resembling a small metal Frisbee, and make a noise as the heart pumps.
Abner, for one, has tried to make light of the bulkiness. Once, in an elevator; two elderly women stared at him and whispered to one another that he must be carrying a bomb. Abner, ever the prankster, promptly yelled “Boom!”
“They jumped high, they were so scared,” he said. “It was a big time.”
But patients may not have to joke about the clumsiness for long. While the current models most likely will be the ones to undergo the FDA approval process, they will be followed by a slew of smaller ones. Columbia-Presbyterians Oz, for instance, said he has been working with one “smaller than your thumb.” Smaller batteries are also under development.
Oz likens the development of LVADs as an alternative to a heart transplant to the emergence of the automobile. “When the Model T was introduced, people didn't give up their horses, but there was a general understanding that the automotive field would emerge over time,” he said.
Part of what will drive these products - as it drove automobiles early on - is the great deal of capital behind the medical-device industry. “You can invest in a car company, but you can't invest in a horse,” Oz said.
To be sure, it is not guaranteed that, in a few years, people with failing hearts will have a small, unobtrusive mechanical im-plant that will maintain their heart functions indefinitely. In fact, observers say, many patients who are in the latest stages of heart disease will still have problems, LVAD or not.
But LVADs do represent “a very important steppingstone,” Oz said. “Plenty of people will die on these pumps,” he said. “But if we consider these failures, then, as a society, we'll never advance.”
For his part, Abner isn't sure if he ever wants a transplant. On New Years Eve, he snagged one of his main LVAD cords in his kitchen and disabled the device. He had to be flown by helicopter to Louisville for an emergency implant of a new device, and, for three and a half hours, the machine didn't make its telltale noise.
While he recovered after the new LVAD was implanted, it did make him wish he could have a natural heart. But that has been tempered by the fact that Hess been unable to find a donor heart, and Hess had to sit and comfort the wife of a fellow LVAD patient whose body rejected the new organ.
“Your imagination can go wild with this,” Abner said. “You just thank the Lord for every day you get. We've all got to go sometime.”
Organ-Rejection Remedy Tested
By MALCOLM RITTER - AP Science Writer
New York (AP 6/1/99) - Drugs designed to teach the body to accept transplanted organs have remained effective for up to a year in monkeys that received kidneys, according to researchers.
Scientists hope the experimental treatment will one day free some transplant patients from having to take anti-rejection drugs for the rest of their lives. The standard drugs suppress the immune system and leave patients vulnerable to infections and tumors.
Researchers are planning studies of the experimental treatment in people, said Dr. Allan Kirk of the Naval Medical Research Center in Beheads, Md. He and co-authors describe the monkey study in the June issue of the journal Nature Medicine. Two years ago, Kirk and colleagues reported on a similar treatment that staved off rejection for more than nine months in monkeys. The new treatment includes only one of the two substances administered in the prior work.
The goal is to teach the immune system to accept the transplanted tissue rather than attack it. To do that, researchers injected the monkeys with a protein to prevent certain blood cells from delivering a “danger” signal to other cells, an initial event in rejection.
The protein is called hu5C8. The researchers gave it to nine monkeys the morning of the kidney transplant, just after the surgery, about once a week for four weeks after that, and finally once a month for five months.
Eight of the nine treated monkeys remain alive and well with no organ rejection. Two have lived about a year so far since the end of treatment, and another more than six months. The ninth monkey died from an unrelated cause.
In a commentary accompanying the article, immune-system expert Polly Matzinger of the National Institutes of Health said a 1996 study had shown the approach works in mice.
But transplant researchers largely overlooked that report, she said.
“Well,” she wrote, “it is time to pay attention!”
Texas Heart Institute Uses Theoretic AD System as Bridge to Recovery for Patient Eliminating Need for Heart Transplant
Patient Removed from Device and Sent Home after 46 Days of Support
Pleasant, Calif. (BW HealthWire 6/3/99) Thoratec Laboratories Corporation (Nasdaq/NMS:THOR), a medical device company, said today that the Texas Heart Institute(R) has used its Ventricular Assist Device (VAD) System to successfully treat a patient recovering from heart failure.
The patient, a 32-year-old mother of two, fully recovered and has been discharged from the hospital after receiving support from the VAD System for 46 days.
“In the past, this patient would have been a priority candidate for a heart transplant,” said D. Keith Grossman, president and chief executive officer of Theoretic. “However, Thoratec’s technology is helping to mitigate the problems associated with the scarcity of available donor hearts by supporting a patient until a donor organ can be found, or - as in the case of this patient - until the heart recovers on its own,” he added.
The Thoratec(R) VAD System consists of a blood pump, inflow and outflow canulae and a power source. It is being marketed in the US and internationally for use as a bridge-to-heart transplant and for patients recovering from open-heart surgery and heart failure. It is the only FDA-approved device that can provide left, right or bi-ventricular support, which is required in approximately 20-40 percent of patients in need of ventricular assistance.
The device has provided both short- and long-term support, well in excess of one year, for patients weighing from 17 kg to 144 kg and as young as seven years old. The Thoratec VAD System has been used to help more than 1,000 patients worldwide.
The 32-year-old woman, who was suffering from symptoms such as dizzy spells and sleeplessness, was airlifted to the Texas Heart Institute at St. Luke's Episcopal Hospital and diagnosed with profound heart failure.
Dr. OH. Frazier, co-director of the Institutes Cullen Cardiovascular Research Laboratory and director of surgical research, implanted a Thoratec VAD System which took over the work of the patients left ventricle, allowing her heart to rest and heal itself.
“In the past we would have transplanted this patient. The understanding that a heart can eject only 5% and still recover is new,” Dr. Frazier said. “However, the ability of Thoratec’s device to assist the heart in pumping blood, and thus allow the heart to recover, represents a new paradigm of treatment for those suffering from critical heart disease,” he added.
Drug Fights Organ-Transplant Rejection
By ELIZABETH MANNING
UP Science News
An experimental drug derived from a microorganism in the soil on Easter Island shows promise in preventing chronic rejection of human kidney transplants, considered the most serious hurdle in transplantation.
Researchers from the University of Texas-Houston Health Science Center say raising blood levels of a new immuno-suppressant called sirolimus significantly reduces the risk of chronic rejection, a process in which the donated kidney fails over a period of months to years.
At the American Society of Transplantation’s annual meeting, Dr. Barry Kahan of the presented findings from 142 renal transplant patients treated with sirolimus for at least two years in a regimen that included another immuno-suppressant, cyclosporine, and the steroid prednisone. Sirolimus, now under review by the Food and Drug Administration, could be the first successful treatment for chronic rejection. A kidney is the organ most commonly transplanted in the United States, although there is a significant shortage of donors.
SangStat Announces Filing for Approval of Celsior - WouId Be the First Solution for Donor Hearts Indicated for Use in the US
Menlo Park, Calif --(BW HealthWire 5/19/99) SangStat announced announced today the Celsior(tm) filing for clearance with the US Food and Drug Administration. Results of the prospective, randomized, North American multi-center study of the safety and efficacy of Celsior solution will be presented valve, surgeons at UCSF Stanford Health today at the annual meeting of the American Care went to an unlikely source: the other Society of Transplant Surgeons in Chicago.
“We are excited to report the completion of yet another milestone," said Jean-Jacques Bienaime, President and CEO of SangStat. "Celsior rounds out our product portfolio and demonstrates our commitment to help improve outcomes throughout all of the phases of transplantation."
Recent surveys have noted that there was no consistent accepted standard solution for cardiac preservation in the United States. Historical use and regional influences are the primary factors in determining which preservation solution is used at a transplant center. However, none of the solutions currently used are cleared by the FDA for cardiac preservation. If cleared, Celsior would be the first standardized flush and cold storage solution for donor hearts in the US.
Thanks to advances in transplantation, from surgical technique to effective immuno-suppression, the clinical outcomes of heart transplantation have continued to improve over the past decade with 1 and 5 year graft survival rates (1991-1997) at 90.5% and 84.9%, respectively. However, early graft loss remains a significant problem associated with cardiac transplantation, and damage to the heart tissue, due to inadequate preservation, is a major contributing factor to these compromised outcomes. Effective organ preservation, a key component in preventing damage to the organs during cardiac transplantation, includes initial flushing of the heart tissues during the retrieval process and cold storage while the donor heart is transported to the recipient.
Surgeons Use Novel Approach to Repair Faulty Heart Valves
STANFORD, Calif.-(BW Health Wire 6/1/ 99) When Dan Thorn learned during a routine company physical that a valve on the left side of his heart was leaking, at first he refused to believe it. After all, the Menlo Park resident was in his early thirties and jogged regularly, lifted weights and participated in martial arts. He hardly fit the profile of someone who needed heart surgery.
Thorn's youth and fitness weren't the only things about his case that were unusual. To get the materials to correct the defective valve, surgeons at UCSF Stanford Health Care went to an unlikely source: the other side of Thorn's heart.
The surgeons, led by Bruce Reitz, MD, chairman and professor of cardiothoracic surgery at Stanford University School of Medicine, used the pulmonary valve from the right side of Thorn’s heart to replace the defective aortic valve on the left side of the heart.
The pulmonary valve makes an ideal substitute, Reitz said, because it is about the same size and shape as the aortic valve and is able to close tightly even under high pressure. And the valve is not rejected by the immune system because it is the patient’s own tissue.
The aortic valve must form a solid seal to prevent blood from reversing into the heart during contraction. Leakage can occur if the flaps of the valve are congenitally malformed or are corroded by infections or diseases like rheumatoid arthritis. For the patient, a faulty aortic valve causes shortness of breath and fatigue because the heart begins to fail due to the extra work load.
The heart responds to the inadequate circulation by enlarging and pumping harder, which over the long term weaken its muscle. If not corrected, the condition can lead to heart failure and death.
Reitz said the alternatives implantation of a mechanical valve or one taken from a pig’s heart - give inferior results over time because the immune system attacks the animal implants, and blood clots may form on the mechanical ones. A pulmonary valve transplant, however, can last the lifetime of the patient, Reitz said. To replace the relocated pulmonary valve, surgeons implant a pulmonary valve taken from the hospital’s tissue bank of donated human valves.
Stanford surgeons started regularly performing the procedure in 1993. They now carry out 15 to 20 of the surgeries a year, more than any other hospital in the Bay Area, Reitz said.
But the procedure is not really new. In the early 1960s, Stanford heart-transplant pioneer Norman Shumway, MD, PhD, conceived of using the pulmonary valve as a replacement for the aortic valve. Shumway, who is now an emeritus professor of cardiothoracic surgery, showed the procedure would work in dogs, but he never tried it in humans. It became known as the Ross procedure after English surgeon Donald Ross perfected the technique and proved it was safe and effective for people.
Thorn and his doctors decided the time had come for surgery when he started to black out occasionally. “About a month or two before the surgery, 1 started getting blackouts where you fade in and out, almost like an elongated deja vu,” he said. Thorn felt that the Ross procedure offered the best chance of returning to normal. He said that a mechanical valve is noisier than a natural valve, and the sound of a mechanical valve slamming shut would constantly remind him of his problem.
Thorn only spent three days in the hospital after his April 1997 operation and went back to work about two months later. He said he eased into his athletic routine, but his recovery was slowed by knee and ankle operations that were unrelated to his heart surgery. “I should have my ‘Your Fifth Surgery Is Free’ card,” he said. Thorn has now resumed all of his pre-surgery activities.
“In the two years I’ve had it, I would say it’s better than my original heart,” he said.
Why did the Ross procedure take so long to win converts? “It took quite a few years for results to accrue and for people to see the outcome,” said Reitz. Initially, surgeons were hesitant to try the operation because they thought it was more challenging and had greater potential for side effects than standard valve replacement, he said. However, heart surgeons throughout the world are now performing the Ross procedure, he noted.
Baby Receives Rare Heart Valve Implant
INDIANAPOLIS (UPI 5/24/99) - An Indiana baby is recovering in an Indianapolis children’s hospital following an experimental surgical procedure in which a valve from a cow was implanted in the boy’s heart.
Ryan Doty was born without a functioning pulmonary heart valve, one of four valves in the heart. At 4 months of age he received a transplant from a human infant that had died, but the transplanted valve began deteriorating.
The Indianapolis Star says pigs’ heart valves are routinely implanted in adults. But Ryan’s doctors needed an alternative because of the 13- month-old boy’s size.
They chose a small valve taken from a cow’s jugular vein. Because cows’ necks are so long, their jugular veins have small valves that keep blood from flowing back into the heart. The size was right for the baby’s heart, and the bovine neck valve is more pliable than that of a pig.
Little Ryan underwent transplant surgery May 4. The operation was performed by Indiana University's Dr. John Brown, with special permission from the US Food and Drug Administration.
Unlike pig valves, the FDA has not approved the use of bovine valves. The procedure has been approved in several European countries, and US regulators could follow suit this year.
The boy was listed in stable condition Sunday night at Raillery Hospital for Children. Randy Bills, the transplant coordinator for Clan Health Systems, told the Star that the baby's prognosis was “very good.”
Because the cows valve will not grow, Ryan would have to undergo more surgery as he approaches his teenage years.
The baby has already undergone three heart surgeries, and his father, Chris Dol,ty, told the newspaper Hess looking forward to more time away from the hospital.
Doty said, “Hopefully, well get moving after this and we wont have to go through this for several years.”
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