4 O d y s s e y

C linical trials have suffered their share of tribula-tions lately.

The April 22, 2002, issue of Time included a lengthy articletitled “At Your Own Risk” that chronicled the slipshod studyheaded up by Dr. Michael McGee at the St. John MedicalCenter in Tulsa, Oklahoma. His experimental vaccine formalignant melanoma, a particularly nasty type of cancer, wasmaking over a third of the trial’s participants sick, a fact thatMcGee kept to himself before the trial was shut down.

Far more serious was the outcome of a clinical trial inMaryland. Ellen Roche, 24, a technician at the Johns HopkinsAsthma and Allergy Center, was one of three healthy volun-teers who agreed to participate in a Hopkins clinical asthmatrial to evaluate the effects of a chemical irritant. Two daysafter inhaling the chemical, Roche developed a cough, feverand muscle pain. These ailments soon led to respiratorydistress, and within a month she was dead.

These incidents—and others that have been spotlighted inthe press—have led some people to overgeneralize the dan-gers of clinical trials.

“Although there are some risks associated with most clinicaltrials, the truth is that clinical trials are usually very safe—thevast majority of subjects are not harmed,” says Ada SueSelwitz, director of the Office of Research Integrity (ORI) at theUniversity of Kentucky. The ORI supports six federally man-dated review committees: three Medical and a NonmedicalInstitutional Review Board (IRB), the Institutional AnimalCare and Use Committee, and the Radioactive Drug ResearchCommittee.

“Clinical trials are a vital and necessary part of America’smedical research system. They have proven to be the bestmechanism for testing potential drugs and separating theones that work from the ones that are ineffective or potentiallyharmful,” says Selwitz, who is past president of the Applied

Clinical

W R I T T E N B Y

J e f f W o r l e y

A Human Safety Netfor New Drugs and Treatments

U n i v e r s i t y o f K e n t u c k y 5

“The beauty of this vaccine is

that it stimulates cells to attack

only tumor cells. It does not at-

tack normal tissue as past treat-

ments have. These cells that we

create are very, very smart.”—John Yannelli

The headlines blared WE’RENUMBER 1! The news beingtrumpeted wasn’t in thesports section. This wasn’tabout Kentucky basket-ball. It was about the lat-est lung-cancer rates inthe United States, and thebad—but not surprising—news was that Kentucky’s1999 lung cancer numbers led the nation among men andwomen.

“Kentucky stands out not only as the number one state, butit’s been that way for a long time,” says Timothy Mullett, a lungsurgeon and director of the University of Kentucky’sMultidisciplinary Lung Cancer Program. This year it’s esti-mated that 3,100 Kentuckians will die of lung cancer. “There’sabout 50 percent more lung cancer in Kentucky than thenational average,” says Alfred Cohen, director of UK’s MarkeyCancer Center. “That’s catastrophic.”

The disease kills 75 to 80 percent of those it infects. Accord-ing to the American Cancer Society, this year more people willdie from lung cancer than from breast, prostate and colorectalcancers combined.

Two UK researchers are working to reverse these stats with

Research Ethics National Association and currently a mem-ber of the NIH Regulatory Burden Working Group. “Almost allmedical and bioethical experts agree that it’s important tohave clinical trials and that it’s equally essential to put intoplace protective safeguards for patients.”

Assuring that these safeguards are in place is at the heart ofIRBs. At UK, the IRB—a group of doctors, other health-careproviders, and community members—reviews all researchstudies to protect the rights of research volunteers and ensurethat the study doesn’t cause unnecessary risk to participants.Selwitz says that even before it was required by federal regu-lations in 1981, UK established an institutional review boardbecause the university “has always been committed to con-ducting ethically appropriate research.”

Across campus in his VA Hospital office, John Thompson,who has been a professor of medicine at UK since 1980, helpsresearchers with the nuts and bolts of clinical trials. Thomp-son now heads up the University of Kentucky Clinical Re-search Organization (UKCRO), which does everything fromhelping to train researchers on how to conduct clinical trialsto providing the critical link between faculty and industry.[For more information on UKCRO, go to www.mc.uky.edu/ukcro.]

“The bottom line is, there is a web of protection that governsclinical research,” says Wendy Baldwin, UK’s new vice presi-dent for research. “The IRB is a vital part of this web, but weshouldn’t lose sight of the importance of educating all our staffwho are conducting clinical studies. Trained staff are reallythe front line in protecting people who participate in clinicaltrials. Other safeguards include data safety monitoring boardsthat are specifically constituted to assess ongoing risks andbenefits of a trial and federal agencies such as NIH and theFDA, which provide additional oversight,” says Baldwin, whobrings 30 years’ experience at NIH to her position at UK [seearticle on page 2].

There are currently 531 clinical trials under way at UK,according to Larry Iten, associate director of the ORI. Over1,400 researchers are involved in these trials, and many workon more than one. For more information on how to participateand the research expertise available at UK, go towww.mc.uky.edu/research/clinicaltrials.htm. Meanwhile,read about six of these research trials in the pages that follow.

Lung cancer

6 O d y s s e y

a novel vaccine they created to reduce the risk of lung cancerrecurrence. John Yannelli, an associate professor of medi-cine, and Edward Hirschowitz, an assistant professor of medi-cine, are heading up a two-year clinical trial that will involveup to 30 patients diagnosed with non-small lung cancer whohave already undergone surgery, radiation or chemotherapy.Non-small lung cancer is moderately fast-growing and besttreated by surgical resection, and according to Hirschowitz,accounts for 75 percent of all diagnosed lung cancers. Thetrial is being funded by the Kentucky Lung Cancer TobaccoSettlement Fund and the Cancer Treatment Research Founda-tion, a national philanthropic agency based in Chicago.

“Although the vaccine will not prevent lung cancer in thosewho have never had it, we’re hoping that it can prevent thedisease from returning and help maintain remission periodsafter treatment,” Hirschowitz says, as reported in the Lexing-ton Herald-Leader last June, adding that even after lung cancersurgery that is deemed “successful,” patients have a 15 to 50percent chance of recurrence. “Because additional medicaltherapies are not generally recommended until recurrencesare seen, we are using the window between medical andsurgical therapy and recurrence to enhance the body’s im-mune response to residual cancer.”

Hirschowitz and Yannelli, with the aid of what Yannelli callsa “very talented and indispensable” support staff, make thisvaccine in an eight-step process. First, through a procedurecalled leukapheresis, the patient’s dendritic cells—the mostpotent immune-inducing cells in the body—are taken. Tech-nicians duplicate them in the lab and mix them with cancer

John Yannelli (foreground) and Edward Hirschowitz have created a novel vaccine to reduce the

risk of lung cancer recurrence. Kentucky’s 1999 lung cancer rates were the highest in the nation

among men and women.

proteins derived from lung cancercells. Once the dendritic cells ingestthe lung cancer proteins, they areretrained to direct the immune sys-tem to target and kill cancer cells.

“This process takes seven days,”Yannelli explains. “We’ve grown thenumber of cells up to very largenumbers: at seven days we harvest ahundred million dendritic cells.” Theresearchers put the cells, which arenow in full combat gear, in an inject-able saline solution, the vaccine.

“The beauty of this vaccine,” Yannelli says, “is that it stimu-lates cells to attack only tumor cells. It does not attack normaltissue as past treatments have. These cells that we create arevery, very smart.”

Each patient receives two three-milliliter injections of thedendritic cells, one month apart. The researchers think thatwhen the cells are delivered to the patient, they will travel tothe lymph nodes and stimulate the immune system to seekand destroy cancer cells. “We don’t know everything aboutthe immune system, but we’re taking advantage of what we dounderstand, letting the biology take care of business in react-ing to an infection or other foreign proteins,” Hirschowitz says.

There have been no major side effects from the injection sofar in the trial, Yannelli says, only local reactions such as asmall welt similar to what any of us might see after an allergyshot.

“We’re doing something during a time when nothing else isoffered,” Hirschowitz says. “You can either sit on the couchwaiting for your cancer to grow, or you can try something.”

“Lung cancer is particularly aggressive,” adds Yannelli. “Weexpect a recurrence—if there is one—to happen within threeyears. If someone doesn’t have a recurrence in five years,they’re cured. My fondest hope is to see my patients back inthe clinic in five years and say—as they leave the room—‘Seeyou at the UK game.’”

For information on how to participate in this clinical trial, callthe Pulmonary Research Office at 859/257-9575.

U n i v e r s i t y o f K e n t u c k y 7

“The eye is an extremely unforgivingorgan,” says Jayakrishna Ambati, anassociate professor of ophthalmologyat UK. “And because of this, our work isall the more challenging.”

The eye places a premium on opticalclarity, he explains, and new bloodvessels that grow in the eye interferewith clarity and are the main culprits indriving the disease called macular de-generation.

Why do new blood vessels grow?“The truth is, we aren’t sure,” saysAmbati. “It could be because as the eyegrows (it’s about 50 percent larger whenwe’re adults), various deposits form inthe back of the eye and promote a milddegree of inflammation, which maytrigger the formation of new blood ves-sels.” As new blood vessels develop,they bleed and leak fluid becausethey’re so fragile, and injure the retina.

“Unfortunately, all this is happeningin the tiny, one-millimeter region in thecenter of your eye. If it happened any-where else, it wouldn’t be much of aproblem.”

Ambati, working with UK ophthal-mologist Andrew Pearson, is trying tofind answers to basic biological ques-tions about diseases of the eye, specifi-cally—in two ongoing clinicaltrials—the origin and progression ofage-related macular degeneration(AMD).

“AMD is the leading cause of blind-ness not only among the elderly in thisand other developed nations, but be-

Macular Degeneration

cause of the inver-sion of the popula-tion pyramid in thiscountry, it’s the leadingcause of blindness amongadults, period,” Ambatiexplains. “It’s now a real-ity for the baby boomers.”In the United States in 2000there were 35 million senior citizens(12.4 percent of the population wasover the age of 65), according to DavidWekstein, associate director of UK’sSanders-Brown Center on Aging. Thisnumber is expected to grow to around40 million by 2010 and to 70 million by2030.

“We are clearly becoming a moregeriatric population,” says Ambati, “andtherefore diseases associated with ag-ing are of tremendous public healthimportance.”

Currently, the only approved treat-ment for AMD is something called pho-todynamic therapy (PDT), whichinvolves injection of the dye visudine.This drug accumulates preferentiallythroughout the body, but not solely, inareas of new blood vessels. “We use alaser beam to activate that drug, whichthen closes off blood vessels and causesthem to stop leaking,” Ambati explains.But this treatment, he adds, “leaves alot to be desired.”

For one thing, only about 20 percentof people with macular degenerationare eligible for this treatment—thosewho fall into the category of “classic

Once approved, a clinical trial goesthrough four phases:

Phase I: Researchers give the drug toa small number of people to see whatdose is safe.

Phase II: Researchers give a largernumber of participants the appropriatedose over a longer period of time to seeif the drug is working and whether it hasany long-term side effects.

Phase III: Researchers give the drugto a much larger group of people overseveral months or years to see whetherthe drug remains useful or has any sideeffects that only show up after a longerperiod of time.

Phase IV: Researchers continue tostudy the drug even after it has beenapproved in what are called “post-mar-keting” trials. They can then watch forany side effects or problems that mayshow up after several years of treat-ment.

8 O d y s s e y

Ambati is trying to find answers to basic biological questions

about diseases of the eye, specifically—in two ongoing clinical

trials—the origin and progression of age-related macular

degeneration, the leading cause of blindness in adults.

“Next to life itself,

vision is the most

precious thing wehave. When people

get older and enter their

retirement years, theyhave more time to read

and to watch television,

and obviously they want tocontinue to be able to see

the faces of their grand-

children. Macular degen-eration robs them of all

these things.”—Jayakrishna Ambati

leakage.” “Most patients have the other type, occult leakage,which doesn’t respond well at all to photodynamic therapy.”Ambati is quick to add that PDT doesn’t restore vision; allit does is decrease the rate of vision loss. “Also, it’s nota permanent effect—95 percent of these vessels re-open within two to three months, so treatment has tobe repeated over and over again.”

In one of their current clinical trials—a Phase II trialfocused on patients with occult age-related maculardegeneration—Ambati and Pearson are testingthe effectiveness of an implant containing thesteroid fluocinolone acetonide. Steroids havelong been known to be potent anti-inflam-matory agents, and the idea in this study is todeliver high doses to the eye and no placeelse, since steroids given systemically areknown to have severe side effects. The

doctors will target the eye by implanting a device calledEnvision TD, developed in part by Pearson at the UK Chandler

Medical Center. The device is a tiny polymer shell contain-ing about two milligrams of the drug.

The trial, which is scheduled to run until March 2006,is fully enrolled and is well under way, with 50 trialparticipants placed at random into three groups: onegets a placebo, one gets an implant, and the third gets

the implant and photodynamic therapy. (Ambatidid the implant procedure for those who

fell into groups two and three. Whilethe patients were awake and underlocal anesthetic, he inserted the de-vice during a 15-minute procedure,suturing the polymer shell in place.)

Though he’s clearly excited by thebasic science of trying to better un-derstand the causes of macular de-generation, Ambati prefers to talkabout how such work can helppeople.

“Around 25 percent of people over65 have some form of macular degen-

eration—that’s a huge number,” he says.“Next to life itself, vision is the most

precious thing we have. When people getolder and enter their retirement years, they

have more time to read and to watch televi-sion, and obviously they want to continue to

be able to see the faces of their grandchildren.Macular degeneration robs them of all these things.

There’s a lot of human suffering behind the simplestatement ‘the leading cause of blindness.’”For information on how to participate in a related

clinical trial, call Michele Reg in the Department of Oph-thalmology at 859/323-5868.

U n i v e r s i t y o f K e n t u c k y 9

“We have an epidemic of diabetes inthis country, and unless there’s a lotmore attention paid to this disease, theproblem is just going to get worse.”

This pronouncement comes fromDennis Karounos, an associate profes-sor in the Division of Endocrinologyand Molecular Medicine at UK and theVA Medical Center, who says that therisk is increasing for people with bothof the traditional forms of diabetes—type 1 and type 2. Type 1 diabetes,previously called insulin-dependentdiabetes mellitus or juvenile-onset dia-betes, may account for 5 to 10 percentof all diagnosed cases of diabetes. Type2 diabetes, previously called non-insu-lin-dependent diabetes mellitus oradult-onset diabetes, is estimated toaccount for about 90 to 95 percent ofall diagnosed cases.

Karounos explains “previously.”“It used to be we’d hardly ever see a

child with type 2 diabetes; now 30percent of children who have diabeteshave type 2, an alarmingly high num-ber.”

In 2001, 16.7 million Americanswere diagnosed with diabetes, ac-cording to a study by the Centers forDisease Control and Prevention pub-lished in the Journal of the AmericanMedical Association last December. InKentucky in 2001, 6.6 percent ofpeople had been diagnosed with dia-betes, a steady percentage climbsince 1994.

One reason for this increase,Karounos says, is simple demograph-ics. “Baby boomers are headed right

Diabetes

Dennis Karounos is testing a vaccine to treat latent autoimmune diabetes, a commonbut unfamiliar type of adult-onset diabetes. In 2001, 6.6 percent of Kentuckians werediagnosed with diabetes, a steady percentage climb since 1994.

for their 60s and 70s, when people become more prone to developing diabetesbecause, when we’re older, the pancreas produces less insulin,” he says.

Karounos came from Baylor University 12 years ago and is director of the diabetesprogram at UK. He is currently focusing his work on what might be called a hybridtype of diabetes—type 11/2, which is also called latent autoimmune diabetes inadults (LADA).

“This is a common but unfamiliar type of adult-onset diabetes,” he explains.“LADA is a disease like type 1 diabetes in which the body’s immune system attacksand destroys insulin-producing cells in the pancreas, decreasing the body’s abilityto produce insulin.”

In testing a vaccine to treat LADA, Karounos is working with James Anderson, aprofessor in the UK endocrinology and molecular medicine division who has beenresearching diabetes for nearly 30 years. In this Phase II clinical trial, they areteaming up with researchers at Washington University in St. Louis, and the universi-ties of Colorado, Alabama, and Washington in Seattle.

“In order to tackle the problem of type 11/2 diabetes clinically, we started lookingaround at different therapies that are out there,” Karounos says. “Lo and behold,there was a group in Israel using an experimental drug that clearly improved insulinsecretion in people who’d just developed type 1 diabetes.”

For this UK trial, Karounos initially screened, through a blood sample, potentialpatients recently diagnosed with type 2 diabetes. He looked for antibodies thatindicate the autoimmune form of the disease, and if these antibodies were present,and if the volunteers meet a couple of other criteria, they were invited to join the trial.

The study is “double blind,” which means neither the participant nor thephysician knows whether the experimental drug is being administered. The 20

10 O d y s s e y

participants will get eight injectionsover two years. Half will get the vac-cine; half will get an inactive shot.

As reported in the Lexington Herald-Leader last November, Angela Blythe,a UK pediatric nurse, was one of thefirst two people enrolled in the UKstudy. Her blood test found she hasthe autoimmune form of the disease.

“I hope I never have to get to thepoint of needing insulin injections,”she says. “The trial is a chance to testsomething that could get rid of this sothat I never have to worry about it.”About 80 percent of people who haveBlythe’s type of diabetes eventuallyneed daily insulin shots, Karounos says.

The vaccine has exciting potential,he says. If found to halt the progressionof diabetes by protecting the insulin-producing cells of the pancreas, thevaccine could be injected every threeto six months—“something like a tar-geted allergy shot for pancreatic cells,”Karounos says.

If successful, the vaccine could elimi-nate or decrease the need for insulininjections for up to 25 percent of peoplewith adult-onset diabetes—up to 3.2million Americans.

“We’re hoping to prevent peoplefrom becoming dependent upon insu-lin therapy,” Karounos says. “Diabetestypically affects a person’s quality oflife. Right now, there’s no cure for dia-betes, but with new drugs we will bebetter able to control it.”

For information on how to participatein this clinical trial, call UK’s MetabolicResearch Group at 859/257-4058.

P“There are a lot of players who share responsibility for the protection of humansubjects in research,” says Ada Sue Selwitz, who has shaped UK’s researchoversight activities since 1979.

It all begins with the researcher who is required by federal law to bring his orher project before the appropriate institutional review board (UK has three IRBsfor medical research and one for non-medical projects). The IRB, a committeeof health-care professionals and community members, reviews the protocol tolook at the ethics of the research before deciding whether or not a trial can begin.After the research protocol is approved, there are several points at which the IRBcontinues to review the project: periodic review for continuing projects, reviewwhen there is any modification to the protocol, and reviews when any unantici-pated problems or adverse effects are reported.

Selwitz points to the peer review system for federally funded research asanother protection for clinical trial volunteers. “Even before a project is funded,other scientists may be raising ethical concerns about a proposal,” says Selwitz.

During the life of a clinical-trial project, the researcher is required to provideperiodic reports to the sponsor. The sponsor, in turn, is required to report anyproblems to the FDA.

In a large clinical trial, another safeguard is the Data Safety Monitoring Board,comprised of scientists who monitor a trial’s progress and who have theauthority to stop a trial if they have concerns about data as it comes in. If a trialdoes not have a monitoring board, a researcher is required to set up a data safetymonitoring plan.

The Office of Human Research Protections, a federal IRB regulatory agency inthe Department of Health and Human Services, has the responsibility to ensurethat an institution conducting clinical trials is in compliance with federalregulations and policies for the protection of human subjects in research.

The University of Kentucky will expand its mandatory human subjects protec-tion training program this fall to include all key personnel on projects involvinghuman subjects. Over 900 UK researchers have already completed this requirededucation program.

rotecting Human Subjects in Research

U n i v e r s i t y o f K e n t u c k y 11

Hormone Replacement Therapy

To be or not to be on hormone re-placement therapy (HRT)—the use ofprescription drugs to “replace” thehormones estrogen and progesteronethat the ovaries quit making at the timeof menopause—is a major questionmany postmenopausal women are try-ing to answer.

It’s a difficult question because ofsome findings from the NIH’s Women’sHealth Initiative (WHI) that were re-leased last July. The NIH halted its trialof combination hormone replacementtherapy (estrogen and progestin)—cit-ing long-term risk factors such as in-creased risks for heart attack, strokeand breast cancer. And for millions ofwomen the news, as aptly put in a Timearticle, “struck like a hot flash.”

The report concluded that for somewomen, the risks HRT outweigh thebenefits (less osteoporosis and lowercolon-cancer rates). And the HRTchoice isn’t made any easier by thefact that, right now, it’s the only medi-cal therapy available to provide relieffrom acute symptoms of menopause,such as hot flashes and night sweats.

To make matters worse, shoddy re-porting has fueled public confusion.For example, a wire-service story thatmade the rounds last January cited theFood and Drug Administration as say-ing, “women should not take estrogenor combinations of estrogen andprogesterone.” The previous day’s FDAnews release, however, said no suchthing. The release focused instead onnew FDA guidance for manufacturers

of estrogen and estrogen with proges-tin products regarding the languagethat should be used on the productlabel.

“Before the WHI results were an-nounced, it was thought that HRT usewould cut heart attack risks in half,”says Ken Muse, associate professor ofobstetrics and gynecology in the UKCollege of Medicine. “A major findingin the study was that with HRT, eventhough there’s an improvement in cho-lesterol results, the risk of heart attackand stroke increases.”

Muse says that because of these find-ings and the subsequent new and im-portant questions about the benefitsand risks of HRT, this is a particularlyexciting time to be doing research inthis area. “It’s a tremendous clinicalquestion right now—both in thewoman’s mind and doctor’s mind:How do you treat menopausal women?What’s the best way to balance thebenefits and risks?”

In September of 2000, Muse and agroup of behavioral investigators atUK including Thomas Kelly, professorof behavioral science, initiated a clini-cal trial to evaluate the effects ofraloxifene on behavior, memory andmood, a focus that has gotten scantattention, and was not part of the NIHstudy. Raloxifene is the first of the “de-signer estrogen” medicines, whichhave some of the effects of estrogen,but few, if any, of the drawbacks.

The trial is being conducted as partof the $8.3 million Center for Biomedi-

“Physicians are con-vinced that quality-of-life benefits thatresult from takingHormone Replace-ment Therapy, suchas suppression of hotflashes and improvedsleep, are important.There hasn’t beenmuch work done,though, on how HRTaffects such things asmood, memory andclear-headedness, sowe need to find outif there are benefitshere as well.”—Ken Muse

12 O d y s s e y

Thomas Kelly (left) and Ken Muse are

evaluating the effects of raloxifene,

the first of the “designer estrogen”

medicines, on behavior, memory and

mood. The clinical trial is being

conducted as part of the $8.3 million

Center for Biomedical Research Excel-

lence in Women’s Health, funded by

NIH. This is the single largest grant ever

awarded in the area of women’s health

at UK.

cal Research Excellence (COBRE) inWomen’s Health, funded by the NIH.This is the single largest grant everawarded in the area of women’s healthat UK.

“The COBRE study is particularly cru-cial because most patients and mostphysicians are convinced that quality-of-life benefits that result from takingHRT, such as suppression of hot flashesand improved sleep, are important,”Muse says. “There hasn’t been muchwork done, though, on how HRT af-fects such things as mood, memoryand clear-headedness, so we need tofind out if there are benefits here aswell.”

In this study postmenopausal womenwho are not taking any form of HRT areevaluated for memory, object orienta-

tion and mood through a battery oftests, including brief computerizedtasks and questionnaires as well as theevaluation of urine and blood samples.The women are then given estrogen,raloxifene (which targets only specificparts of the body), or a placebo.

Hormone effects will be determinedby comparing behavioral measuresbefore therapy began with those takenafter one and six months of daily treat-ment. Kelly says the original plan wasto do a one-year trial, but because ofthe recent NIH data on risks from long-term use, he and Muse cut the length ofthe study in half.

“Everybody agrees we need moreresearch on HRT,” says Vivian Pinn,head of the NIH’s Office of Research onWomen’s Health, who was quoted in

Newsweek. “It’s taking time, but moreanswers are coming.”

“Many central Kentucky women aretaking an active role in helping solvethese problems by participating in thisresearch,” Muse says. “We’re happy tohave this opportunity at UK to be leadersin advancing the science of women’shealth medicine.”

For information on how to participate inthis study, call 859/277-3799.

U n i v e r s i t y o f K e n t u c k y 13

Asthma

Patricia Burkhart in the College of Nursing holds an electronic peak-flow

monitor, which records data about a child’s breathing rates. She is head-

ing up a clinical trial to evaluate different ways of teaching kids with per-

sistent asthma to self-manage their condition at home.

It takes many researchers some time—years maybe—tofind their niche. In Pat Burkhart’s case, her research focusfound her.

“Twenty-four years ago my son, Kevin, was diagnosedwith asthma when he was two years old,” says Burkhart,an assistant professor in UK’s College of Nursing. Shebegan to read everything she could about childhoodasthma. This intensive study led her to a Ph.D. in nursingwith a research focus on child asthma and to recentlybeing certified as an asthma educator by the AmericanLung Association.

According to the Centers for Disease Control and Pre-vention, asthma is the most prevalent chronic conditionamong children in the United States, affecting over eightmillion children, including 70,000 in Kentucky. And here’san even scarier statistic: while death rates for many dis-eases are falling, the mortality rates for children age 19and younger with asthma increased by 78 percent be-tween 1980 and 1993.

Burkhart says that while there’s wide agreement on thegenetic predisposition for asthma, it’s tough to defini-tively pin down other causes.

“Some epidemiologists say that children are experienc-ing heavy-duty allergens because our houses are so air-tight. Then there’s the older theory about keeping yourkids from close contact with other kids, such as in day-care centers, because they’ll pick up more colds anddevelop airway inflammation that can lead to asthma.”

The problem is, she says, these theories have tended tochange over the years. “Here’s another theory: sincewe’ve used antibiotics extensively, maybe childrens’ im-mune systems aren’t strong enough to combat bacteriaand viruses.” She adds that having pets in the householdalso used to be taboo, but now some clinicians think kidswho are exposed to animals early tend not to be allergicto them later in life because, through such contact, chil-dren build up the necessary antibodies.

Despite the confusion about what causes asthma,Burkhart says that blame for increased rates in morbidityand mortality among children with the disease may be a

14 O d y s s e y

lack of early intervention, lack of knowl-edge regarding self-management, andnon-adherence to prescribed treatmentregimes. In a clinical trial funded bythe National Institute of Nursing Re-search at NIH, Burkhart is working tohelp resolve these issues.

Her two-year trial will involve 86 chil-dren ages 7 to 11 with persistent asthma.As principal investigator, she will evalu-ate different ways of teaching kids tomanage their asthma at home using adevice that electronically gathers data.

What Burkhart hopes to achievethrough an educational and behavioralintervention is to increase children’sadherence to daily peak expiratory flowrate (PEFR) monitoring. Peak-flowmonitoring is integral to asthma self-management for patients with persis-tent asthma in order to assess theexistence and severity of airflow ob-struction. However, there are no pub-lished studies on how to promotechildren’s adherence to daily self-moni-toring.

“Peak-flow meters are simple,handheld monitors,” Burkhart explains,“that can detect airway obstruction,often before any appearance of clini-cal signs.” If a child blows into it andthe number falls during the day, thisindicates that the airways are starting

to constrict, even before coughing,wheezing or shortness of breath occur.The child can then intervene early toprevent a major asthmatic episode. Dur-ing the trial, each child will use anelectronic peak-flow meter that recordsthe date, time and peak-flow value. Italso includes a self-report symptom andmedication diary.

Burkhart was the first nurse re-searcher to use a microprocessor-basedpeak-flow measurement instrument.“This is the centerpiece for this clinicaltrial and a huge advance over the lessaccurate self-report asthma diaries thathave been traditionally used. Now,objective data can be downloaded to acomputer and gathered electronically,”she says.

In this study the intervention groupwill receive intense asthma education.The control group will get the usualcare, she says. “Typically, the health-care provider will simply say, ‘Here’syour peak-flow meter. We’d like you toblow into it every day. Record yournumbers in a diary and send it in tous,’” Burkhart says, adding that ad-herence issues regarding regularpeak-flow monitoring are generallynot addressed.

The intervention group (childrenand their parents) will have five one-on-one sessions with a pediatric nurse,while the control group will have threeone-on-one sessions during a 16-weekperiod. Both groups will be asked toperform daily peak-flow monitoring athome and to record their peak-flowvalues, asthma symptoms, and medi-cations in an asthma diary.

“The first thing we do with the inter-vention group is to teach kids what

their peak-flow numbers mean,”Burkhart says. “We have them blowinto the meter in the morning and inthe evening for two to three weeks sowe can determine their ‘personalbest’—their highest number—to get abaseline. Then we determine their‘zones,’ which are color-coded, basedon their personal best value.” Sheteaches children to think of their zonesin terms of a traffic light.

An action plan is put in place so thatthe child and parent know exactly whatto do for each zone. “Green meansyour asthma is under control. Yellowmeans take action. It indicates thechild may need to add a bronchodila-tor medication and to increase theamount of inhaled corticosteroids inorder to control the symptoms. If thepeak-flow values drop into the red zone,we teach the children that they shouldhead to the nearest emergency depart-ment.”

Burkhart’s own son, she says, hasdiligently used the meter and workedhard all his life to manage his asthmawell and prevent asthma attacks. “He’s26 now and living in New York City,”she says. “He’s doing great—he recentlyran in the marathon there and crossedthe finish line with his family cheeringhim on.”

For information on how your childcan participate in the Children withAsthma Study, call 859/323-6874.

“With the

microprocessor-based

peak-flow instrument,

objective data

can be downloaded

to a computer.”

—Pat Burkhart

14 O d y s s e y

U n i v e r s i t y o f K e n t u c k y 15

Thyroid Cancer

In his effort to better treat thyroid can-cers, UK researcher Kenneth Ain isenlisting the aid of a drug with a univer-sally despised reputation: thalidomide.

Thalidomide was introduced in 1957in West Germany and was soon com-monly prescribed to pregnant womenas a sedative. When the drug wastaken during the first trimester, how-ever, it prevented normal growth ofthe fetus, resulting in horrific birth de-fects such as missing or shortened limbsin thousands of children around theworld. These children, born in the late’50s and early ’60s, became known as“thalidomide babies.”

Ain, a professor of medicine in theDivision of Endocrinology & Molecu-lar Medicine at UK, believes that al-though thalidomide has been usedinappropriately, that doesn’t make it a“bad” drug. He points out that thalido-mide has been FDA-approved to treatleprosy, for example, and Ain thinksthe drug can help people with particu-larly hard-to-treat thyroid cancers.

“There has been some compellinganecdotal evidence that thalidomidegiven to a patient with anaplastic thy-roid cancer, the most aggressive typeof thyroid cancer known to man, re-tarded the growth of tumors for up tosix months,” says Ain, who came to UKin 1991 after spending four years at theNational Institutes of Health. “So wewanted to do this current trial to testthat out.” Anaplastic thyroid cancer israre—only 300 cases in this countryeach year—but it’s deadly: from thetime of diagnosis, even with therapy,patients typically live only four to five

months.The thyroid gland is

situated in the frontpart of the neck belowthe skin and muscle lay-ers. This gland is shaped like a butter-fly, with the two wings beingrepresented by the left and right thy-roid lobes that wrap around the tra-chea. The function of the thyroid is toregulate the body’s metabolism. Thy-roid cancer affects the gland respon-sible for producing hormones thatcontrol heart rate, body temperatureand energy. It is diagnosed in nearly15,000 women and around 4,500 menin the United States each year.

Over the past eight years, the inci-dence of thyroid cancer is on the in-crease for reasons, Ain says, that areunclear. He adds that fighting thyroidcancer is an especially tough challengebecause no chemotherapy has beenfound to be effective.

Thyroid cells naturally pump in io-dine to make the thyroid hormone,and thyroid cancer cells often retainthis ability. This fact prompted investi-gators more than a half century ago totreat thyroid cancer, after the removalof thyroid gland, with radioactive io-dine. “Time has demonstrated the ef-fectiveness of this approach in mostpatients,” says Ain. “Unfortunately, asubset of patients has rapidly progres-sive disease that does not respond tothis treatment. For these patients, therehaven’t been any effective therapies.”

But for such patients, desperationmay soon be replaced by hope.

In a recent Phase II trial using thali-

domide to treat two types of thyroidcancers unresponsive to radioiodine,Ain and his team worked with patientswho had rapidly progressive thyroidcancer. The participants were given upto 800 milligrams of thalidomide dailyand were evaluated by CT scans everytwo months for a year; treatment wascontinued after each assessment ifthere was evidence that the cancerhad stopped growing or had regressed.If the patient’s tumor continued to growas rapidly as before treatment, the pa-tient was taken off this drug.

Of the 17 patients who have beenevaluated, 13 experienced either a pla-teau or a decline in tumor size, andbeneficial responses to thalidomidepersisted for an average of sevenmonths in half of these patients. Inaddition, patients who had experi-enced either a plateau or decline intheir tumor size but eventually notedprogression of their tumors lived longerthan patients who had no beneficialresponse from the thalidomide—ap-proximately four and a half monthslonger.

“These results suggest that thalido-mide is a potent inhibitor of tumorprogression in some aggressive,metastic thyroid cancers,” Ain says.“And patients with these advanced can-cers badly need effective treatmentsbecause there are currently none avail-able.” Ain presented these findings at

16 O d y s s e y

Kevin Williams (left), a clinical research associate, and Kenneth Ain, a professor of medicine

in the Division of Endocrinology & Molecular Medicine, discuss the latest results of a clinical

trial using thalidomide to help people with particularly hard-to-treat thyroid cancers. Ain is

heading up this study.

What’s the connection betweenbat saliva and stroke survival? Inthe Fall 2003 Odyssey, we’ll tellyou the story of a UK researcherwho’s testing what may becomethe most novel clot-buster ever—a new drug made from geneti-cally engineered bat saliva.

the Chemotherapy Foundation meet-ing in New York last December.

Funding for this trial came from theNational Cancer Institute and theCelgene Corporation, a New Jersey-based pharmaceutical company. Fur-ther support came from UK’s GeneralClinical Research Center, where muchof this work took place. The center,located in the UK hospital, includes anoutpatient clinic and a specimen-pro-cessing lab.

Ain emphasizes that the thalidomidetrial is only one of several approachesunder investigation at UK focused onunderstanding and treating thyroid can-cer. This work is part of the well-estab-lished thyroid cancer program hebegan when he arrived at UK. TheUniversity of Kentucky Thyroid Nod-ule and Oncology Clinical Service isone of only a few such programs inthe United States.

Ain reaches down to the floor andwrestles up a black book that is nearlytwo-feet thick. “These are my patients,”he says, leafing through. “Right now Ihave hundreds of patients, and I followevery one of them.” He adds that he

has one of the largest thyroid cancerpractices in the world for a single doc-tor.

How can he work on several researchprojects, do the academic work re-quired of him as a professor, and fol-low all these patients all at the sametime?

“It’s an all-consuming job, I admit it.I work every day from 7:30 a.m. untilanywhere from 11 at night to one in themorning. On weekends I catch up onmy sleep—maybe six hours a night.”And if Ain continues to spend longhours in the office, his wife-to-be, hesays, will understand.

“Sara [Rosenthal] is a thyroid can-cer survivor herself and a medicalwriter—she’s written 35 books.” Whenshe wrote a book on thyroid cancer,she asked Ain to edit it for accuracy.“In the process I met her and fell inlove.” Rosenthal, whose expertise is inbioethics, will join the UK faculty thissummer.

For information on how to participatein UK clinical thyroid cancer trials, haveyour physician call 859/323-3778.�

“The voluntary consent of

the human subject is abso-

lutely essential. This means

that the person involved

should have legal capacity

to give consent; should be

so situated as to be able to

exercise free power of

choice, without the inter-

vention of any element of

force, fraud, deceit, duress,

over-reaching, or other ul-

terior form of constraint or

coercion; and should have

sufficient knowledge and

comprehension of the deci-

sion.”—from the Nuremberg Code, “Trials ofWar Criminals Before the NurembergMilitary Tribunals Under Control Coun-cil Law,” 1946-1949