Editor's Note: This is the fifth story in a five-part series about clinical research at the University of Nebraska Medical Center. To learn more what clinical research is and the role it plays at UNMC, read the introduction to this series.
OMAHA - There's two places in the United States you can try an experimental vaccine made from your own tumor cells for one type of non-Hodgkins lymphoma: California's Stanford University, or the University of Nebraska Medical Center.
Choosing between the two was Jim Benson, an engineering professor from Kentucky. He's got stage four lymphoma, the worst stage; his cancer is in several lymph nodes in his neck and groin and has spread to his blood marrow. He wanted to be in a Phase II clinical trial for the vaccine, where all patients get the vaccine. That meant California or Nebraska. In Phase III trials, available at locations other than Stanford and UNMC, you could get the vaccine, or a placebo.
Nebraska, being closer to Kentucky, was the obvious choice because of the multiple trips he had to make for treatment and blood tests. He knew he could expect a short flight to Omaha, but didn't know the other benefit of seeing the nurses and doctors at the medical center.
"The level of empathy and concern, friendliness of the actual staff that's running the actual trial, is exceptional," Benson said recently from his room in the Lied Transplant Center, where he was resting after blood tests before catching a late-morning flight back to Kentucky.
Benson, 47, has follicular lymphoma, a common variety that makes up 15 percent to 20 percent of all non-Hodgkin's lymphoma cases. It's the one variety of non-Hodgkin's being targeted by vaccine trials, including one run by UNMC's Dr. Julie Vose. Non-Hodgkin's lymphoma is not a single disease, but a category of several closely related cancers of the lymphatic system. That's one of the most important parts of the immune system; it protects the body from disease and infection. A watery fluid called lymph contains white blood cells. The lymph flows through a network of vessels branching through the body, and filters through small organs called lymph nodes. When you're sick and get "swollen glands" on your throat under your jaw, those are some of your lymph nodes working to beat your illness.
How could a vaccine treat or cure cancer? Vaccines take a very small amount of a disease-causing bacteria or virus and put it in the body, where the immune system can practice defending the invader without being overwhelmed by a full-blown attack. The immune system "remembers" how to respond to that bacteria or virus. So when influenza, say, or diptheria attack the next time, the immune system can respond better and faster.
Turns out the immune system can be trained to remember and effectively attack follicular lymphoma, too. A company in California, Genitope, uses a patient's own cancer cells to make him or her a custom vaccine. It's a slow, painstaking process. First doctors take a biopsy, or sample, of a lymph-node tumor from a readily accessible spot -- say, under the arm. Using genetic engineering and cell cloning, the sample cells are modified slightly and joined with KLH, a substance found in mussels (a sea mollusk) to which nearly everyone's immune system responds. The patented technique takes six months to complete.
It's still ready in plenty of time. Clinical-trial patients go through a standard six-month course of chemotherapy treatment to put their cancer in remission, then rest for another six months while their immune systems recover from the poisonous onslaught of the chemotherapy drugs. Only then are they given the vaccine injection -- once a month for four months, then once more three months after the fourth shot. Patients receive two subcutaneous (just beneath the skin) injections in the same spot each time. One is the vaccine/KLH combination, another a protein called Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) that helps the body identify foreign substances.
Follicular lymphoma responds well to chemotherapy, going into remission in many instances. Unfortunately, it seems to always come back. The vaccine therapy being tested at UNMC aims to stop that, but it takes quite a bit of patience to work with this treatment.
"Since the patients take 10 years to relapse, you have to wait a long time to find out beneficial results," Vose said.
This Phase II trial of the follicular lymphoma vaccine is just one of three trials Vose is now running. The doctor's busyness has meant a wealth of opportunity for her assistant, nurse Susan Blumel. She finds potential trial participants, gets and keeps them enrolled, juggles insurance requirements and travel schedules, and writes frequent reports to the medical center's Institutional Review Board and the Food and Drug Administration. As if that were not enough, she also gives the vaccine shots.
Blumel, a certified clinical research coordinator, has had the opportunity to further her career by writing abstracts and giving talks about her and Dr. Vose's work. All the while, she gets to be right there at the patient-care level seeing real people get potentially life-saving treatment. Follicular lymphoma may be a very slow-growing cancer, but it still means death 7 to 10 years after diagnosis.
"It's very fulfilling working with patients on this level, because we're looking for better ways to treat lymphoma," Blumel said.
Blumel credits Vose with a knack for finding clinical trials that have a lot of potential. This trial, for example, adds on to the traditional regimen for treating lymphoma, yet holds very little extra danger for the patient.
"We're trying to prolong remission with relatively low risk," Blumel said.
Blumel has respect for the trial participants, who fly in from all over the country to see whether they can help themselves and people like them.
"These people are in remission," she said. "They could choose not to do anything. So the people that participate in the trial, I think, are future-lookers."
Benson, the Kentucky professor, looked to the future when he volunteered -- the future of lymphoma patients he'd befriended through support networks.
"That's one of the reasons we made the decision," Benson said. "Because even though they tout this disease as a 60-year-old disease (affecting people that old and older) … these people range from 31 years old to 51 or 53.
"If this can help anybody with that much life left, that's good thing."
_____
This story originally appeared in Nebraska StatePaper on July 27, 2001.
Friday, July 27, 2001
Thursday, July 26, 2001
Tiny Radiation Beams Spare Cancer Patients Some Side Effects
Editor's Note: This is the fourth story in a five-part series about clinical research at the University of Nebraska Medical Center. To learn more what clinical research is and the role it plays at UNMC, read the introduction to this series.
OMAHA - With his throat cancer at its worst, Wayne Tobias couldn't even swallow water. After special radiation treatments available only one place in Nebraska, he's eating steak.
Even with his sense of taste deadened temporarily, Tobias has it better than many of the cancer patients who have gone before him. Because his radiation comes in hundreds of tiny beams aimed just at his tumor, he still has something most of us take for granted: saliva. He'd likely have a permanent case of dry mouth with traditional radiation.
He's also still got his voice, and just minutes after his latest treatment at the University of Nebraska Medical Center, he's happy to use it telling just how happy he is about eating steak again.
"It's about like getting my life back," he said. "Makes me think when I get my sense of taste back, I'm really going to enjoy that."
Tobias, 72, drives to Omaha from Hastings regularly to receive Intensity Modulated Radiation Therapy, a leap forward in cancer treatment available at just 80 hospitals nationwide, and just UNMC in Nebraska. The terrifically expensive and powerful machine doesn't aim a single-strength, wide beam of radiation at the tumor as in traditional therapy -- which hits and damages healthy tissue in the process. Instead, computers analyze a CAT scan of the cancerous area and figure out ways to fire hundreds of very narrow, but very powerful, beams that dodge critical healthy structures around the tumor. Like Tobias' salivary glands, voice box and -- most importantly -- his spinal cord.
"Our goal is always to deliver radiation where you can have better targeting, and spare more normal tissue," said Dr. Ken Zhen. He's one of the most experienced hands with the IMRT, having started using it in Iowa in 1998, just one year after the Food and Drug Administration approved it. He came to UNMC in 2000.
Zhen and his colleagues in radiation oncology are doing clinical research to determine how well the IMRT technique works. It's slow going; doctors need to wait 2-3 years to definitely see whether patients are cured, or suffer recurrences. Most of the data so far are on cancers in the head and neck areas, because it's easy to immobilize that part of the body. Just a tiny bit of movement can put that salivary gland you were hoping to avoid right in the path of a destructive beam.
Conversely, there's little data on using IMRT against moving targets -- such as the prostate gland, which shifts position based on bowel and bladder contents, even respiration. But another, even newer technology at UNMC is solving that problem. Called BAT, for B-mode Acquisition and Targeting, this new machine uses ultrasound imaging to find the prostate gland, then spits out a bunch of numbers that are punched into the treatment table to position the patient just so for his radiation therapy. In a great improvement for patient comfort, the ultrasound wand is applied externally to the lower abdomen, instead of inserted into the rectum.
Dr. Charles Enke is the main man with the BAT machine, which actually is all black with a big stylized bat-wing logo on the front. Men get a metal bat lapel pin when they complete their treatment.
"There is a significant amount of data emerging that indicates that the likelihood of prostate cancer control can be increased by 20 to 40 percent at 5 years by increasing the prostate dose over standard radiation doses," Enke said.
BAT works in concert with IMRT to help direct radiation beams around two critical structures near the prostate, the rectum and the bladder. The rectum's especially sensitive, and too much radiation can create a hole in it. That sentences patients to the inconvenience of a colostomy bag, external storage for the body's solid waste. Damaging the bladder can require an external bag to collect urine.
After treating 61 patients with BAT, Enke has found he can apply radiation doses of 7,600 to 7,800 rads, instead of the 6,800 to 7,100 rads many radiation therapy centers must use to avoid dangerous side effects.
Traditional therapy uses marks on the skin to indicate where the prostate was when doctors first located it and applied the initial radiation does. But preliminary results from a study Enke is conducting indicate the prostate may move as much as 10.4 millimeters from this location. Using the BAT machine, he's found, can reduce uncertainty about the prostate's location to 1 or 2 millimeters.
IMRT, with assistance from BAT in some cases, doesn't just make it possible to dodge healthy tissue. Doctors can also direct more powerful radiation at the tumor, the better to kill it faster. Think back to traditional radiation for throat cancer. Compared with IMRT, it's like putting fire hoses on both sides of your face and turning them on full blast. Sure, the tumor in the middle of your throat gets a full dose of radiation, but so do your salivary glands and spinal cord, because the radiation has to pass through those structures on its way to the spinal cord. So you have to limit the radiation sent to the tumor, because surrounding tissue can only withstand so much abuse. But with IMRT, which is like a very fine stream, you can send a tremendously powerful jet into the tumor because it's targeted to miss the parts you want kept alive. As the radiation emitter rotates around the patient, these tiny beams eventually stab through all parts of the tumor. (All this careful precision means IMRT treatment takes 30-40 minutes per treatment, while conventional therapy takes just 15 minutes.) If the fire hose and fine stream examples don't work for you, think of it this way: On a stage with 200 performers, you could light them all with one huge lamp. Or, you could use 200 spotlights , varying the color and intensity of each light to create a pleasing effect.
The idea behind IMRT therapy has been around for 20 years, Zhen said, but had to wait for computer technology to catch up with it. Medical physicist Ayyangar Komanduri explained that traditional radiation therapy can be planned with pen and paper, because there are just a few parameters to compute. But it's nearly impossible to analyze complex body scans and plot hundreds of precise coordinates without a computer's help.
"It's like trying to manage a bank account with several investors in place," Komaduri said. "How would you manage that without putting it into an accurate spreadsheet?"
For Tobias, the Hastings throat cancer patient, it's not just all this fantastic technology that's made the difference in his recovery.
"They've been wonderful people up here," he said. "They treat you like you're Warren Buffett or somebody."
_____
This story originally appeared in Nebraska StatePaper on July 26, 2001.
OMAHA - With his throat cancer at its worst, Wayne Tobias couldn't even swallow water. After special radiation treatments available only one place in Nebraska, he's eating steak.
Even with his sense of taste deadened temporarily, Tobias has it better than many of the cancer patients who have gone before him. Because his radiation comes in hundreds of tiny beams aimed just at his tumor, he still has something most of us take for granted: saliva. He'd likely have a permanent case of dry mouth with traditional radiation.
He's also still got his voice, and just minutes after his latest treatment at the University of Nebraska Medical Center, he's happy to use it telling just how happy he is about eating steak again.
"It's about like getting my life back," he said. "Makes me think when I get my sense of taste back, I'm really going to enjoy that."
Tobias, 72, drives to Omaha from Hastings regularly to receive Intensity Modulated Radiation Therapy, a leap forward in cancer treatment available at just 80 hospitals nationwide, and just UNMC in Nebraska. The terrifically expensive and powerful machine doesn't aim a single-strength, wide beam of radiation at the tumor as in traditional therapy -- which hits and damages healthy tissue in the process. Instead, computers analyze a CAT scan of the cancerous area and figure out ways to fire hundreds of very narrow, but very powerful, beams that dodge critical healthy structures around the tumor. Like Tobias' salivary glands, voice box and -- most importantly -- his spinal cord.
"Our goal is always to deliver radiation where you can have better targeting, and spare more normal tissue," said Dr. Ken Zhen. He's one of the most experienced hands with the IMRT, having started using it in Iowa in 1998, just one year after the Food and Drug Administration approved it. He came to UNMC in 2000.
Zhen and his colleagues in radiation oncology are doing clinical research to determine how well the IMRT technique works. It's slow going; doctors need to wait 2-3 years to definitely see whether patients are cured, or suffer recurrences. Most of the data so far are on cancers in the head and neck areas, because it's easy to immobilize that part of the body. Just a tiny bit of movement can put that salivary gland you were hoping to avoid right in the path of a destructive beam.
Conversely, there's little data on using IMRT against moving targets -- such as the prostate gland, which shifts position based on bowel and bladder contents, even respiration. But another, even newer technology at UNMC is solving that problem. Called BAT, for B-mode Acquisition and Targeting, this new machine uses ultrasound imaging to find the prostate gland, then spits out a bunch of numbers that are punched into the treatment table to position the patient just so for his radiation therapy. In a great improvement for patient comfort, the ultrasound wand is applied externally to the lower abdomen, instead of inserted into the rectum.
Dr. Charles Enke is the main man with the BAT machine, which actually is all black with a big stylized bat-wing logo on the front. Men get a metal bat lapel pin when they complete their treatment.
"There is a significant amount of data emerging that indicates that the likelihood of prostate cancer control can be increased by 20 to 40 percent at 5 years by increasing the prostate dose over standard radiation doses," Enke said.
BAT works in concert with IMRT to help direct radiation beams around two critical structures near the prostate, the rectum and the bladder. The rectum's especially sensitive, and too much radiation can create a hole in it. That sentences patients to the inconvenience of a colostomy bag, external storage for the body's solid waste. Damaging the bladder can require an external bag to collect urine.
After treating 61 patients with BAT, Enke has found he can apply radiation doses of 7,600 to 7,800 rads, instead of the 6,800 to 7,100 rads many radiation therapy centers must use to avoid dangerous side effects.
Traditional therapy uses marks on the skin to indicate where the prostate was when doctors first located it and applied the initial radiation does. But preliminary results from a study Enke is conducting indicate the prostate may move as much as 10.4 millimeters from this location. Using the BAT machine, he's found, can reduce uncertainty about the prostate's location to 1 or 2 millimeters.
IMRT, with assistance from BAT in some cases, doesn't just make it possible to dodge healthy tissue. Doctors can also direct more powerful radiation at the tumor, the better to kill it faster. Think back to traditional radiation for throat cancer. Compared with IMRT, it's like putting fire hoses on both sides of your face and turning them on full blast. Sure, the tumor in the middle of your throat gets a full dose of radiation, but so do your salivary glands and spinal cord, because the radiation has to pass through those structures on its way to the spinal cord. So you have to limit the radiation sent to the tumor, because surrounding tissue can only withstand so much abuse. But with IMRT, which is like a very fine stream, you can send a tremendously powerful jet into the tumor because it's targeted to miss the parts you want kept alive. As the radiation emitter rotates around the patient, these tiny beams eventually stab through all parts of the tumor. (All this careful precision means IMRT treatment takes 30-40 minutes per treatment, while conventional therapy takes just 15 minutes.) If the fire hose and fine stream examples don't work for you, think of it this way: On a stage with 200 performers, you could light them all with one huge lamp. Or, you could use 200 spotlights , varying the color and intensity of each light to create a pleasing effect.
The idea behind IMRT therapy has been around for 20 years, Zhen said, but had to wait for computer technology to catch up with it. Medical physicist Ayyangar Komanduri explained that traditional radiation therapy can be planned with pen and paper, because there are just a few parameters to compute. But it's nearly impossible to analyze complex body scans and plot hundreds of precise coordinates without a computer's help.
"It's like trying to manage a bank account with several investors in place," Komaduri said. "How would you manage that without putting it into an accurate spreadsheet?"
For Tobias, the Hastings throat cancer patient, it's not just all this fantastic technology that's made the difference in his recovery.
"They've been wonderful people up here," he said. "They treat you like you're Warren Buffett or somebody."
_____
This story originally appeared in Nebraska StatePaper on July 26, 2001.
Wednesday, July 25, 2001
Rheumatoid Arthritis Treatment Pioneer Looks to Go One Better
Editor's Note: This is the third story in a five-part series about clinical research at the University of Nebraska Medical Center. To learn more what clinical research is and the role it plays at UNMC, read the introduction to this series.
OMAHA - The doctor who pioneered the most popular treatment for rheumatoid arthritis is at it again, using genetic analysis to find even better therapies customized to individual patients.
The University of Nebraska Medical Center's Dr. Jim O'Dell in 1996 published a landmark study in The New England Journal of Medicine showing a three-drug combination was more effective at treating rheumatoid arthritis than single drugs or two-drug combinations in use at the time. Now, he's testing new therapies using genetic samples taken from hundreds of participants in his many clinical studies.
O'Dell's aim: Know from the start which drug combination will work for a particular patient, instead of letting the debilitating disease march through a patient's body for as long as a year while doctors try different treatment approaches.
Rheumatoid arthritis is a disease where the body's joints deteriorate, causing pain and disability. It afflicts more than 2 million Americans.
The future of rheumatoid arthritis treatment is to stop giving patients the drug combination that works in 70 percent of people like them, and start giving them the combination that works in 95 percent of similar people, said O'Dell, who directs the five-state Rheumatoid Arthritis Investigational Network. Ideally, the chance of harmful side effects would be very low -- like 2 percent.
Existing therapies, as greatly improved as they are, work slowly. Doctors need at least 3 to 4 months each to see whether one's working -- meanwhile, damage could be spreading from the small joints of the hand to the large joints of the elbows and knees. A painful but bearable inconvenience that might be stopped at the hands could be allowed to proceed throughout the body, causing partial or total disability.
"If I have to utilize a year in finding out the proper course, then that patient's going to be paying for that 10 years later," O'Dell said.
O'Dell's key to quickly determining the right treatment is his database of data and genetic material from the people who have participated in his arthritis-drug studies.
"What Jim O'Dell has is the best sample population in the world," said the director of clinical studies who works with him, Geoff Thiele.
O'Dell has data on patients before and after treatment with a variety of drugs; people who responded and didn't respond to certain treatments; and on people who were in control groups and received a placebo rather than the drug or drugs being tested. With all this information in hand, he can look at 20 different factors in the blood that can influence whether a person gets rheumatoid arthritis. This gets down into some tiny, tiny minutiae. For example, O'Dell has discovered how to treat the small number of people who get a certain trait they could only have inherited if both their parents had it. People have to have a certain subset of a feature on their cells, out of many possibilities, to be susceptible to this kind of rheumatoid arthritis. But there's an advantage: O'Dell has already found the drug combination that works best for them, so they don't have to try a bunch of approaches before hitting the right one.
Thiele and his assistants work in the laboratory on genetic samples from the people who have participated in O'Dell's studies. That way, when they come up with a theory that a certain treatment strategy worked because of traits unique to some people in the study, they can test the samples to see whether those traits are indeed present.
Barb Counihan, diagnosed with rheumatoid arthritis in 1979, is somewhat of a walking history of arthritis care. She received injections of gold (that's right, the metal) for 14 years, then took the steroid prednisone, then methotrexate and aspirin, and finally O'Dell's three-drug combination. She's been participating in O'Dell's clinical studies since 1995.
Counihan, an accountant at KMTV in Omaha, said she's grateful that world-class treatment for her arthritis can be found a short trip across town.
"Terrifically, immensely grateful for that," she said. "You don’t have to travel to another major city to get care."
She's also glad that while she's getting the best treatment for herself, her body's reaction to the drugs is helping doctors understand how similar people will fare.
"I'm excited that I can be a part of that study, and help patients in the future," she said.
O'Dell's next step is to compile a national database of rheumatoid arthritis patients, to put together on a large scale what he's done on a small scale. The larger the sample size, the more accurate the results. He's working now to get a National Institutes of Health grant for the effort.
"I could go and take 500 patients who responded to one treatment, 500 who didn't, and see if there's a common genetic trait," O'Dell said.
_____
This story originally appeared in Nebraska StatePaper on July 25, 2001.
OMAHA - The doctor who pioneered the most popular treatment for rheumatoid arthritis is at it again, using genetic analysis to find even better therapies customized to individual patients.
The University of Nebraska Medical Center's Dr. Jim O'Dell in 1996 published a landmark study in The New England Journal of Medicine showing a three-drug combination was more effective at treating rheumatoid arthritis than single drugs or two-drug combinations in use at the time. Now, he's testing new therapies using genetic samples taken from hundreds of participants in his many clinical studies.
O'Dell's aim: Know from the start which drug combination will work for a particular patient, instead of letting the debilitating disease march through a patient's body for as long as a year while doctors try different treatment approaches.
Rheumatoid arthritis is a disease where the body's joints deteriorate, causing pain and disability. It afflicts more than 2 million Americans.
The future of rheumatoid arthritis treatment is to stop giving patients the drug combination that works in 70 percent of people like them, and start giving them the combination that works in 95 percent of similar people, said O'Dell, who directs the five-state Rheumatoid Arthritis Investigational Network. Ideally, the chance of harmful side effects would be very low -- like 2 percent.
Existing therapies, as greatly improved as they are, work slowly. Doctors need at least 3 to 4 months each to see whether one's working -- meanwhile, damage could be spreading from the small joints of the hand to the large joints of the elbows and knees. A painful but bearable inconvenience that might be stopped at the hands could be allowed to proceed throughout the body, causing partial or total disability.
"If I have to utilize a year in finding out the proper course, then that patient's going to be paying for that 10 years later," O'Dell said.
O'Dell's key to quickly determining the right treatment is his database of data and genetic material from the people who have participated in his arthritis-drug studies.
"What Jim O'Dell has is the best sample population in the world," said the director of clinical studies who works with him, Geoff Thiele.
O'Dell has data on patients before and after treatment with a variety of drugs; people who responded and didn't respond to certain treatments; and on people who were in control groups and received a placebo rather than the drug or drugs being tested. With all this information in hand, he can look at 20 different factors in the blood that can influence whether a person gets rheumatoid arthritis. This gets down into some tiny, tiny minutiae. For example, O'Dell has discovered how to treat the small number of people who get a certain trait they could only have inherited if both their parents had it. People have to have a certain subset of a feature on their cells, out of many possibilities, to be susceptible to this kind of rheumatoid arthritis. But there's an advantage: O'Dell has already found the drug combination that works best for them, so they don't have to try a bunch of approaches before hitting the right one.
Thiele and his assistants work in the laboratory on genetic samples from the people who have participated in O'Dell's studies. That way, when they come up with a theory that a certain treatment strategy worked because of traits unique to some people in the study, they can test the samples to see whether those traits are indeed present.
Barb Counihan, diagnosed with rheumatoid arthritis in 1979, is somewhat of a walking history of arthritis care. She received injections of gold (that's right, the metal) for 14 years, then took the steroid prednisone, then methotrexate and aspirin, and finally O'Dell's three-drug combination. She's been participating in O'Dell's clinical studies since 1995.
Counihan, an accountant at KMTV in Omaha, said she's grateful that world-class treatment for her arthritis can be found a short trip across town.
"Terrifically, immensely grateful for that," she said. "You don’t have to travel to another major city to get care."
She's also glad that while she's getting the best treatment for herself, her body's reaction to the drugs is helping doctors understand how similar people will fare.
"I'm excited that I can be a part of that study, and help patients in the future," she said.
O'Dell's next step is to compile a national database of rheumatoid arthritis patients, to put together on a large scale what he's done on a small scale. The larger the sample size, the more accurate the results. He's working now to get a National Institutes of Health grant for the effort.
"I could go and take 500 patients who responded to one treatment, 500 who didn't, and see if there's a common genetic trait," O'Dell said.
_____
This story originally appeared in Nebraska StatePaper on July 25, 2001.
Tuesday, July 24, 2001
Versatile Tiny Bubbles Hold Promise Throughout the Body
Editor's Note: This is the second story in a five-part series about clinical research at the University of Nebraska Medical Center. To learn more what clinical research is and the role it plays at UNMC, read the introduction to this series.
OMAHA - In the hands of Dr. Tom Porter, miniscule bubbles smaller than red blood cells can make the heart beat normally again, test blood flow to that organ, break up blood clots and deliver drug treatments with microscopic precision.
They're called microbubbles, and they're versatile little things. Just four or five millionths of a meter in size, they can carry drugs inside or on their surface. When doctors intentionally break them inside a patient's body with ultrasound waves, their tiny explosions can shear off bits of clots blocking arteries. Not only are they effective, but every application of them is easier on the patient than the standard treatment they may one day replace.
The microbubbles are being used in two human clinical trials at the University of Nebraska Medical Center right now: terminating heart-rhythm disturbances and breaking up clots in renal dialysis grafts. The first use could reduce the need for electric shocks to pace the heart, and the second use could fix a complication patients experience when undergoing kidney hemodialysis.
The bubbles are a protein shell with a gas inside. They first contained air, but Porter and his team determined they'd hold up better filled with denser gases like fluorocarbons. UNMC makes its own bubbles with ultrasound waves.
"Ironically, it's ultrasound that creates the bubbles and that destroys them," Porter said.
This destruction seems to be able to act like a pacemaker to restore normal heart rhythms. There are many different abnormal heart rhythms, which can be dangerous. Some traditional ways of treating abnormal heart rhythms are external shocks and internal pacemaker devices. Patients must be sedated to receive external shocks, while inserting a pacemaker requires surgery. Microbubbles can be injected like medication, and manipulated with harmless ultrasound waves like the ones used to view a developing fetus inside a pregnant woman.
"In essence, it's simplifying the process and making it safer for the patient," Porter said.
Small waves are created when ultrasound makes microbubbles expand and then suddenly collapse. These waves seem to be able to pace the heart into normal rhythm, Porter has found. The waves also can erode the surface of a blood clot in an artery, such as one leading to the heart. One of the traditional ways to deal with arterial blood clots is by inserting a ballon into the artery and inflating it. But this technique can damage the artery, leading to the formation of scar tissue that can just exacerbate the blockage.
If this balloon insertion procedure, called balloon angioplasty, has already occurred, microbubbles can prevent additional blockage from developing. They can carry a special gene therapy to the precise problem area of the artery and at that spot, and only that spot, block a protein that can cause further narrowing of the artery.
"If we give a gene … we only want it to work in one area of the body," Porter said.
Clots can also be troublesome in patients undergoing hemodialysis. In this procedure, a person's blood is filtered through an external machine, instead of by the kidneys. A common way to extract the blood and then reinfuse it is through an arterial-venous graft. In a surgical procedure on the arm, doctors graft together an artery, which takes blood out to the body from the heart, and a vein, which returns blood to the heart. So blood flows into the artery, out into the dialysis machine, and then back into the vein.
Sometimes this graft between the artery and vein can get blocked with a blood clot. That can mean another surgery to create another graft elsewhere on the arm. Because these grafts take a long time to heal before they can be used for hemodialysis, it's more than just a little inconvenient to get a graft clot.
Enter the microbubbles again. Porter has a Phase I clinical trial going to determine whether they can break up clots so patients can continue using the same graft, and don't need more surgery to create a new one. He'll have to overcome some challenges to make this work; one of them is preventing small pieces of clot from traveling into smaller blood vessels and blocking them, which would create new and potentially more serious problems.
Microbubbles' ability to deliver drugs to specific locations could greatly improve chemotherapy for cancer. Chemotherapy drugs are powerful poisons used to kill cancer cells. But they must be used with extreme caution because they're toxic to healthy cells, too. Spilling one kind of chemotherapy on bare skin while trying to inject it into the body, for example, can eat away the skin. But if these poisons were contained inside microbubbles and released only when they reached the tumor, side effects from chemotherapy could be reduced.
Working closely with this cutting-edge research for three years has been Porter's assistant David Kricsfeld, who will take an already bulging resume with him when he starts medical school next month.
"A lot of investigators, when we go to these national meetings … they're amazed at how we have all these applications of microbubbles going on at once," Kricsfeld said.
What makes this possible is Porter's drive and intelligence, Kricsfeld said.
"Who would have thought that this may help break up blood clots, or help deliver drugs?" he said.
_____
This story originally appeared in Nebraska StatePaper on July 24, 2001.
OMAHA - In the hands of Dr. Tom Porter, miniscule bubbles smaller than red blood cells can make the heart beat normally again, test blood flow to that organ, break up blood clots and deliver drug treatments with microscopic precision.
They're called microbubbles, and they're versatile little things. Just four or five millionths of a meter in size, they can carry drugs inside or on their surface. When doctors intentionally break them inside a patient's body with ultrasound waves, their tiny explosions can shear off bits of clots blocking arteries. Not only are they effective, but every application of them is easier on the patient than the standard treatment they may one day replace.
The microbubbles are being used in two human clinical trials at the University of Nebraska Medical Center right now: terminating heart-rhythm disturbances and breaking up clots in renal dialysis grafts. The first use could reduce the need for electric shocks to pace the heart, and the second use could fix a complication patients experience when undergoing kidney hemodialysis.
The bubbles are a protein shell with a gas inside. They first contained air, but Porter and his team determined they'd hold up better filled with denser gases like fluorocarbons. UNMC makes its own bubbles with ultrasound waves.
"Ironically, it's ultrasound that creates the bubbles and that destroys them," Porter said.
This destruction seems to be able to act like a pacemaker to restore normal heart rhythms. There are many different abnormal heart rhythms, which can be dangerous. Some traditional ways of treating abnormal heart rhythms are external shocks and internal pacemaker devices. Patients must be sedated to receive external shocks, while inserting a pacemaker requires surgery. Microbubbles can be injected like medication, and manipulated with harmless ultrasound waves like the ones used to view a developing fetus inside a pregnant woman.
"In essence, it's simplifying the process and making it safer for the patient," Porter said.
Small waves are created when ultrasound makes microbubbles expand and then suddenly collapse. These waves seem to be able to pace the heart into normal rhythm, Porter has found. The waves also can erode the surface of a blood clot in an artery, such as one leading to the heart. One of the traditional ways to deal with arterial blood clots is by inserting a ballon into the artery and inflating it. But this technique can damage the artery, leading to the formation of scar tissue that can just exacerbate the blockage.
If this balloon insertion procedure, called balloon angioplasty, has already occurred, microbubbles can prevent additional blockage from developing. They can carry a special gene therapy to the precise problem area of the artery and at that spot, and only that spot, block a protein that can cause further narrowing of the artery.
"If we give a gene … we only want it to work in one area of the body," Porter said.
Clots can also be troublesome in patients undergoing hemodialysis. In this procedure, a person's blood is filtered through an external machine, instead of by the kidneys. A common way to extract the blood and then reinfuse it is through an arterial-venous graft. In a surgical procedure on the arm, doctors graft together an artery, which takes blood out to the body from the heart, and a vein, which returns blood to the heart. So blood flows into the artery, out into the dialysis machine, and then back into the vein.
Sometimes this graft between the artery and vein can get blocked with a blood clot. That can mean another surgery to create another graft elsewhere on the arm. Because these grafts take a long time to heal before they can be used for hemodialysis, it's more than just a little inconvenient to get a graft clot.
Enter the microbubbles again. Porter has a Phase I clinical trial going to determine whether they can break up clots so patients can continue using the same graft, and don't need more surgery to create a new one. He'll have to overcome some challenges to make this work; one of them is preventing small pieces of clot from traveling into smaller blood vessels and blocking them, which would create new and potentially more serious problems.
Microbubbles' ability to deliver drugs to specific locations could greatly improve chemotherapy for cancer. Chemotherapy drugs are powerful poisons used to kill cancer cells. But they must be used with extreme caution because they're toxic to healthy cells, too. Spilling one kind of chemotherapy on bare skin while trying to inject it into the body, for example, can eat away the skin. But if these poisons were contained inside microbubbles and released only when they reached the tumor, side effects from chemotherapy could be reduced.
Working closely with this cutting-edge research for three years has been Porter's assistant David Kricsfeld, who will take an already bulging resume with him when he starts medical school next month.
"A lot of investigators, when we go to these national meetings … they're amazed at how we have all these applications of microbubbles going on at once," Kricsfeld said.
What makes this possible is Porter's drive and intelligence, Kricsfeld said.
"Who would have thought that this may help break up blood clots, or help deliver drugs?" he said.
_____
This story originally appeared in Nebraska StatePaper on July 24, 2001.
Monday, July 23, 2001
Clinical Research Turns Laboratory Ideas into Reality for Patients
OMAHA - Basic medical research like sequencing the human genome and transforming stem cells into blood, bone and brain tissue makes headlines because the ideas involved are so new, so cutting-edge, so "Gee whiz!" But at research hospitals across the country, including the University of Nebraska Medical Center, it takes clinical research on volunteer subjects to determine whether the latest big idea can help real human beings.
In a five-part series beginning today, StatePaper will tell you about the clinical research that makes up almost a third of the externally funded science UNMC does each year. You'll learn about doctors testing:
"Clinical research is critically important because it does apply the knowledge gained (through basic research) at the bedside," said Dr. Harold Maurer, chancellor of the medical center.
Dr. Tom Rosenquist, interim vice chancellor for research, explained the difference between basic and clinical research.
"The basic science research addresses sort of fundamental questions about the biology of cells and tissues and genes and DNA those kinds of things that we predict may have some value for disease prevention or treatment. But you don't know ahead of time," Rosenquist said.
Out of that basic research can come ideas for new drugs.
"Most of the clinical research that we do here relates to either drugs or methods of applying the drugs to various diseases," Rosenquist said. "… [R]esearch that you apply directly to human beings to see if you get any improvement in their disorder."
Clinical trials are usually funded by pharmaceutical companies or medical equipment manufacturers, which want to find out whether their latest inventions are useful. Volunteers get the trial treatment and any associated examinations, like blood tests, free of charge from the company. But patients and their insurance companies are responsible for the costs of other care. For example, in the non-Hodgkin's lymphoma vaccine study you'll read about in Part 5 of this series, patients are responsible for undergoing a six-month course of chemotherapy before receiving the trial vaccine.
There are three stages of clinical research:
Rosenquist said it's usually easy to recruit volunteers for each phase.
"I think the reasons that the seriously ill patients want to participate are pretty self-evident," he said. "Those who are not convinced they may derive any benefit themselves are doing this out of a sense of duty to their fellow man."
That’s the same motivation for many in Phase II and Phase III trials.
"It makes you feel to good to participate," Rosenquist said.
UNMC values each of the volunteers who work with the dozens and dozens of trials going on at any one time.
"They're indispensable. Absolutely. Nothing can be done to advance the science without them," Rosenquist said.
Maurer agreed. "Without them, without the patients participating, there would be no research," he said.
_____
This story originally appeared in Nebraska StatePaper on July 23, 2001.
In a five-part series beginning today, StatePaper will tell you about the clinical research that makes up almost a third of the externally funded science UNMC does each year. You'll learn about doctors testing:
- A popular anticoagulant drug (also known as a blood thinner) to see whether it can safely be given in small doses over a long term to prevent recurring blood clots
- "Microbubbles" manipulated with harmless ultrasound waves that can pace the heart, deliver medications with pinpoint accuracy and break up clots
- Patient-specific rheumatoid arthritis treatments which could more quickly halt that debilitating disease's march through the body
- Machines that use pinpoint precision to safely deliver higher levels of cancer-killing radiation than ever before possible
- A vaccine made from patients' own tumor cells to prevent the recurrence of non-Hodgkin's lymphoma
"Clinical research is critically important because it does apply the knowledge gained (through basic research) at the bedside," said Dr. Harold Maurer, chancellor of the medical center.
Dr. Tom Rosenquist, interim vice chancellor for research, explained the difference between basic and clinical research.
"The basic science research addresses sort of fundamental questions about the biology of cells and tissues and genes and DNA those kinds of things that we predict may have some value for disease prevention or treatment. But you don't know ahead of time," Rosenquist said.
Out of that basic research can come ideas for new drugs.
"Most of the clinical research that we do here relates to either drugs or methods of applying the drugs to various diseases," Rosenquist said. "… [R]esearch that you apply directly to human beings to see if you get any improvement in their disorder."
Clinical trials are usually funded by pharmaceutical companies or medical equipment manufacturers, which want to find out whether their latest inventions are useful. Volunteers get the trial treatment and any associated examinations, like blood tests, free of charge from the company. But patients and their insurance companies are responsible for the costs of other care. For example, in the non-Hodgkin's lymphoma vaccine study you'll read about in Part 5 of this series, patients are responsible for undergoing a six-month course of chemotherapy before receiving the trial vaccine.
There are three stages of clinical research:
- Phase I: A very small trial where the drug is given to perhaps a dozen patients who have terminal diseases and are not expected to survive. Patients agree to take the new drug without any expectation that it will help them, although it might. At this stage, scientists want to know whether the drug has harmful side effects. Healthy people may also take very small amounts of the drug to determine its toxicity.
- Phase II: Participating at this stage are a small number of patients, perhaps 50, who haven't had luck with existing treatments. This trial determines not only whether the drug is safe for humans, but whether it's effective at treating the targeted medical condition.
- Phase III: Thousands of patients at sites across the country may participate at this stage, which tests the effectiveness of a drug over a long period of time.
Rosenquist said it's usually easy to recruit volunteers for each phase.
"I think the reasons that the seriously ill patients want to participate are pretty self-evident," he said. "Those who are not convinced they may derive any benefit themselves are doing this out of a sense of duty to their fellow man."
That’s the same motivation for many in Phase II and Phase III trials.
"It makes you feel to good to participate," Rosenquist said.
UNMC values each of the volunteers who work with the dozens and dozens of trials going on at any one time.
"They're indispensable. Absolutely. Nothing can be done to advance the science without them," Rosenquist said.
Maurer agreed. "Without them, without the patients participating, there would be no research," he said.
_____
This story originally appeared in Nebraska StatePaper on July 23, 2001.
Medical Mechanic Haire Maintains the Body’s Highways
Editor's Note: This is the first story in a five-part series about clinical research at the University of Nebraska Medical Center. To learn more what clinical research is and the role it plays at UNMC, read the introduction to this series.
OMAHA - Mechanic and medical researcher Dr. William Haire is approaching dangerous blood clots in the body somewhat like the way a street maintenance engineer approaches potholes in the road.
While the engineer wants to use as little patching material as possible to plug the holes in the road, Haire wants to use as little medicine as possible to control the clots that plug up blood vessels and can kill. The engineer's aim is to stretch the city's always-limited maintenance budget. Haire wants to make a good clot-busting drug, Coumadin, work even better by finding the lowest effective dose -- one that keeps harmful clots from forming, but prevents the bleeding complications that make the therapy tough to manage. Coumadin has a narrow therapeutic range. There's not much wiggle room between a dose that's helpful, and a dose that's harmful.
When he's not treating patients for the common medical conditions of deep-vein thrombosis (usually, clots in the leg) and pulmonary embolisms (a clot that affects the lungs), Haire can be found working in his garage restoring 1946-1948 Plymouth automobiles. Or, he might be designing album covers and stage props for local rock bands. These mechanical and artistic hobbies help him think about new ideas for practicing medicine.
"The body is nothing more than just a very, very complex machine. But it takes an artistic, kind of out of the box approach, to understand some of the subtle complexities of this machine," he said.
Haire's penchant for the complexities of blood clots won him a role in a National Institutes of Health study of the popular anticoagulant drug Coumadin. He's known nationally for his work with blood clots. The affable Haire wouldn't volunteer this information, but when asked he'll confirm that he's one of a very few University of Nebraska Medical Center researchers ever asked to write two guest editorials for the prestigious New England Journal of Medicine. Both were on blood clots, a passion of Haire's and a national health problem. About 500,000 Americans a year develop deep-vein thrombosis -- a blood clot in one of the body's large veins, usually in the leg. Pieces of these clots can break off and travel all the way to lungs and block that organ's tiny capillaries. That's called a pulmonary embolism, and can be fatal. About half the blood clots patients suffer are ideopathic, meaning doctors can't find a cause.
It’s these ideopathic blood clots that concern Haire and researchers at 60 other sites nationwide. Paul Ridker of Brigham and Women's Hospital in Boston, principal investigator for the study, said he looked for the top scientists across the country when setting up the project.
"And obviously Bill was one of those people," Ridker said.
The PREVENT study, as it's called, is fairly simple and quite convenient for participants. Patients who have been on long-term anticoagulant therapy with Coumadin get to stay on the drug for free, at a lower dose the researchers hope proves effective. Blood testing is needed just once every two months, and the testing machine is portable so study participants need not leave their home or work.
Some of these ideopathic clots run in the family and can recur over a patient's lifetime. By joining the study, participants can help themselves avoid future clots, and perhaps be of aid to their families as well.
"So Grandpa may be helping to answer questions that will be helpful to grandson or granddaughter," Haire said.
That chance to help others helped motivate Robert Volz to join the Coumadin study.
"It appears there's very minimal risk for doing it, and yet the outcome could be very beneficial," Volz said.
Doctors diagnosed Volz, vice president for facilities at Ameritrade in Omaha, with a deep-vein thrombosis of the right leg after he had taken just a one-hour plane ride to Denver. After six months on the standard Coumadin treatment, Volz wondered what should be his next step for preventing a second blood clot -- especially since doctors couldn't exactly place the cause of his first one. His doctor said he didn't know the best long-term option -- but there was a study at UNMC trying to find out.
Taking his traditional Coumadin treatment, Volz had to drive from Ameritrade in west Omaha to UNMC in central Omaha first weekly, then monthly, for blood tests. Now on the Coumadin study, someone from the medical center drives out to Ameritrade. A finger prick and five minutes later, it's goodbye for another two months.
"That's as good as it gets," Volz said. "It's awfully nice where someone's coming to you."
Haire's assistant John Schneider, a first-year medical student, is often the one driving out and doing the finger-pricking. Besides the scientific knowledge, Schneider said, he's gaining important experience dealing with all kinds of patients. He works with everyone from vice presidents like Volz to blue-collar mechanics. It's a big leg up for medical school, he said.
"Being exposed to that, I think, has really benefited me," he said.
Looking at what doctors now understand about blood clots, and what they hope to learn, is fascinating stuff. Think of the body's blood vessels like a road network, Haire says. The body's natural processes have blood vessels breaking all the time, and quickly sealing up when the blood clots as it should. This is like roads developing potholes that the roving street maintenance crew quickly fills (well, maybe not as quickly in some cities as in others). Clots also form when the body's injured; say, by a cut. Clots keep you from losing a lot of blood because they plug the hole from which the blood is leaking. It's when the natural clotting process gets out of control that problems start to occur. Then, clots can form where there are no holes to plug -- again, most often deep in the veins of the leg.
Conditions like trauma, serious illness and pregnancy can all lead to these harmful blood clots. What doctors have found in the past five years is that patients who get a clot tend to be at risk for another clot. So now they need to figure out exactly what this risk is, and whether there's a dose of the anticoagulant drug Coumadin that can be used long-term to prevent more harmful clots, while still keeping the blood's beneficial clotting tendencies around. If the balance isn't kept just right, and a patient's blood doesn't clot readily enough, he can bleed too much -- which leads to organ damage, organ failure and even death.
"It's a problematic medicine in that it's effective, but it's difficult to safely control over a long term," Haire said.
That blood testing we've been talking about is to measure a patient's prothrombin time, which means the time it takes his or her blood to clot. The term's usually shortened to "pro time," and the value is measured in units that go up or down from 1.0, which is the average clotting time for a human. When doctors are treating a blood clot with Coumadin, they're usually aiming for a pro time of 2.0-3.0, which means the blood is clotting two to three times slower than normal. The Coumadin study at UNMC wants to see whether a pro time of 1.5 can still be effective. Maintaining that kind of a pro time requires less Coumadin, so patients stay farther away from the "knife edge," as Haire puts it, between the drug's helpful and harmful dosages.
Coumadin and other anticoagulants, by the way, are not blood thinners -- even though doctors and nurses sometimes call them that to keep things simple for patients. Such drugs don't thin the blood, that is, change its viscosity. In fact, Haire said, only with some rare conditions does the blood's viscosity change. And anticoagulants don't prevent clotting outright, they simply slow down the process so the body can get it under control. Clotting is out of control when a clot forms somewhere other than where the bleeding problem is.
"If you will, (treatment with anticoagulants) is like adding a governor to your engine to make sure the engine can't go too fast," Haire said.
There's a tendency to blame bleeding complications solely on Coumadin, but people who do so forget that in order to bleed, there needs to be a hole in some blood vessel. In most bleeding incidents with Coumadin patients, a condition unrelated to the drug caused the bleeding -- such as a duodenal ulcer, a colonic polyp, or a kidney stone. Say a kidney stone scratches a person's ureter, and the bleeding doesn't stop fast enough because the Coumadin he's taking has slowed the clotting. The patient sees blood in his urine, and blames it on the drug.
"But did the Coumadin cause the bleeding? No," Haire said.
But the bleeding's still a problem, especially in older patients who are at the most risk for blood clots. They often have underlying diseases and weaker organs, both related to aging, that make it less likely they'll survive losing a lot of blood. That makes it even more important to find a long-term dose of the drug that can stave off dangerous bleeding complications.
One notable aspect of the entire PREVENT study is the diversity of its participants. While many clinical studies consist mostly of white men, PREVENT has almost half women, and 19 percent minorities. Haire has plenty more room for volunteers in the Omaha program, and he'd be glad to take calls from interested people at (402) 559-7599.
"I'll take a hundred more next week," Haire said.
_____
This story originally appeared in Nebraska StatePaper on July 23, 2001.
OMAHA - Mechanic and medical researcher Dr. William Haire is approaching dangerous blood clots in the body somewhat like the way a street maintenance engineer approaches potholes in the road.
While the engineer wants to use as little patching material as possible to plug the holes in the road, Haire wants to use as little medicine as possible to control the clots that plug up blood vessels and can kill. The engineer's aim is to stretch the city's always-limited maintenance budget. Haire wants to make a good clot-busting drug, Coumadin, work even better by finding the lowest effective dose -- one that keeps harmful clots from forming, but prevents the bleeding complications that make the therapy tough to manage. Coumadin has a narrow therapeutic range. There's not much wiggle room between a dose that's helpful, and a dose that's harmful.
When he's not treating patients for the common medical conditions of deep-vein thrombosis (usually, clots in the leg) and pulmonary embolisms (a clot that affects the lungs), Haire can be found working in his garage restoring 1946-1948 Plymouth automobiles. Or, he might be designing album covers and stage props for local rock bands. These mechanical and artistic hobbies help him think about new ideas for practicing medicine.
"The body is nothing more than just a very, very complex machine. But it takes an artistic, kind of out of the box approach, to understand some of the subtle complexities of this machine," he said.
Haire's penchant for the complexities of blood clots won him a role in a National Institutes of Health study of the popular anticoagulant drug Coumadin. He's known nationally for his work with blood clots. The affable Haire wouldn't volunteer this information, but when asked he'll confirm that he's one of a very few University of Nebraska Medical Center researchers ever asked to write two guest editorials for the prestigious New England Journal of Medicine. Both were on blood clots, a passion of Haire's and a national health problem. About 500,000 Americans a year develop deep-vein thrombosis -- a blood clot in one of the body's large veins, usually in the leg. Pieces of these clots can break off and travel all the way to lungs and block that organ's tiny capillaries. That's called a pulmonary embolism, and can be fatal. About half the blood clots patients suffer are ideopathic, meaning doctors can't find a cause.
It’s these ideopathic blood clots that concern Haire and researchers at 60 other sites nationwide. Paul Ridker of Brigham and Women's Hospital in Boston, principal investigator for the study, said he looked for the top scientists across the country when setting up the project.
"And obviously Bill was one of those people," Ridker said.
The PREVENT study, as it's called, is fairly simple and quite convenient for participants. Patients who have been on long-term anticoagulant therapy with Coumadin get to stay on the drug for free, at a lower dose the researchers hope proves effective. Blood testing is needed just once every two months, and the testing machine is portable so study participants need not leave their home or work.
Some of these ideopathic clots run in the family and can recur over a patient's lifetime. By joining the study, participants can help themselves avoid future clots, and perhaps be of aid to their families as well.
"So Grandpa may be helping to answer questions that will be helpful to grandson or granddaughter," Haire said.
That chance to help others helped motivate Robert Volz to join the Coumadin study.
"It appears there's very minimal risk for doing it, and yet the outcome could be very beneficial," Volz said.
Doctors diagnosed Volz, vice president for facilities at Ameritrade in Omaha, with a deep-vein thrombosis of the right leg after he had taken just a one-hour plane ride to Denver. After six months on the standard Coumadin treatment, Volz wondered what should be his next step for preventing a second blood clot -- especially since doctors couldn't exactly place the cause of his first one. His doctor said he didn't know the best long-term option -- but there was a study at UNMC trying to find out.
Taking his traditional Coumadin treatment, Volz had to drive from Ameritrade in west Omaha to UNMC in central Omaha first weekly, then monthly, for blood tests. Now on the Coumadin study, someone from the medical center drives out to Ameritrade. A finger prick and five minutes later, it's goodbye for another two months.
"That's as good as it gets," Volz said. "It's awfully nice where someone's coming to you."
Haire's assistant John Schneider, a first-year medical student, is often the one driving out and doing the finger-pricking. Besides the scientific knowledge, Schneider said, he's gaining important experience dealing with all kinds of patients. He works with everyone from vice presidents like Volz to blue-collar mechanics. It's a big leg up for medical school, he said.
"Being exposed to that, I think, has really benefited me," he said.
Looking at what doctors now understand about blood clots, and what they hope to learn, is fascinating stuff. Think of the body's blood vessels like a road network, Haire says. The body's natural processes have blood vessels breaking all the time, and quickly sealing up when the blood clots as it should. This is like roads developing potholes that the roving street maintenance crew quickly fills (well, maybe not as quickly in some cities as in others). Clots also form when the body's injured; say, by a cut. Clots keep you from losing a lot of blood because they plug the hole from which the blood is leaking. It's when the natural clotting process gets out of control that problems start to occur. Then, clots can form where there are no holes to plug -- again, most often deep in the veins of the leg.
Conditions like trauma, serious illness and pregnancy can all lead to these harmful blood clots. What doctors have found in the past five years is that patients who get a clot tend to be at risk for another clot. So now they need to figure out exactly what this risk is, and whether there's a dose of the anticoagulant drug Coumadin that can be used long-term to prevent more harmful clots, while still keeping the blood's beneficial clotting tendencies around. If the balance isn't kept just right, and a patient's blood doesn't clot readily enough, he can bleed too much -- which leads to organ damage, organ failure and even death.
"It's a problematic medicine in that it's effective, but it's difficult to safely control over a long term," Haire said.
That blood testing we've been talking about is to measure a patient's prothrombin time, which means the time it takes his or her blood to clot. The term's usually shortened to "pro time," and the value is measured in units that go up or down from 1.0, which is the average clotting time for a human. When doctors are treating a blood clot with Coumadin, they're usually aiming for a pro time of 2.0-3.0, which means the blood is clotting two to three times slower than normal. The Coumadin study at UNMC wants to see whether a pro time of 1.5 can still be effective. Maintaining that kind of a pro time requires less Coumadin, so patients stay farther away from the "knife edge," as Haire puts it, between the drug's helpful and harmful dosages.
Coumadin and other anticoagulants, by the way, are not blood thinners -- even though doctors and nurses sometimes call them that to keep things simple for patients. Such drugs don't thin the blood, that is, change its viscosity. In fact, Haire said, only with some rare conditions does the blood's viscosity change. And anticoagulants don't prevent clotting outright, they simply slow down the process so the body can get it under control. Clotting is out of control when a clot forms somewhere other than where the bleeding problem is.
"If you will, (treatment with anticoagulants) is like adding a governor to your engine to make sure the engine can't go too fast," Haire said.
There's a tendency to blame bleeding complications solely on Coumadin, but people who do so forget that in order to bleed, there needs to be a hole in some blood vessel. In most bleeding incidents with Coumadin patients, a condition unrelated to the drug caused the bleeding -- such as a duodenal ulcer, a colonic polyp, or a kidney stone. Say a kidney stone scratches a person's ureter, and the bleeding doesn't stop fast enough because the Coumadin he's taking has slowed the clotting. The patient sees blood in his urine, and blames it on the drug.
"But did the Coumadin cause the bleeding? No," Haire said.
But the bleeding's still a problem, especially in older patients who are at the most risk for blood clots. They often have underlying diseases and weaker organs, both related to aging, that make it less likely they'll survive losing a lot of blood. That makes it even more important to find a long-term dose of the drug that can stave off dangerous bleeding complications.
One notable aspect of the entire PREVENT study is the diversity of its participants. While many clinical studies consist mostly of white men, PREVENT has almost half women, and 19 percent minorities. Haire has plenty more room for volunteers in the Omaha program, and he'd be glad to take calls from interested people at (402) 559-7599.
"I'll take a hundred more next week," Haire said.
_____
This story originally appeared in Nebraska StatePaper on July 23, 2001.
Subscribe to:
Posts (Atom)