Breakthroughs & Advances
Breast Cancer Vaccine
A Cleveland Clinic researcher achieves intriguing results in his work with mice.
Vincent Tuohy isn't the sort of guy the medical community expected to make a major advance in cancer research. The Cleveland Clinic Lerner Research Institute staffer had spent his career forcing the common research mouse's immune system to attack various parts of its own body — work that had resulted in invaluable models for studying the development of autoimmune diseases such as multiple sclerosis.
But Tuohy made headlines in June after Nature Medicine published research on a breast cancer vaccine he and his team developed for the animals. An astounding 100 percent of mice genetically engineered to develop breast cancer at 10 months of age did not get the disease when they were vaccinated at 2 months of age. Unlike other experimental vaccines for various cancers that are administered only after tumors are discovered, Tuohy's was given before any abnormal cells appeared, just as vaccines for childhood diseases such as mumps and measles are dispensed. It's a better way, he believes, to treat people at high risk for developing specific cancers.
"You vaccinate to provide protection so that when the tumor first emerges, your immune system is ready to go," he says.
Tuohy chose to target breast cancer because it is the most common cancer in women, one that takes approximately 40,000 lives annually in the United States alone. The vaccine is based on his specialty: making the immune system attack groups of cells containing the same specific protein. In this case, it was alpha-lactalbumin, a protein generally found only in the breast tissue of nursing mammals and breast tumors. To make the mouse's immune system recognize alpha-lactalbumin as a dangerous foreign invader like a virus or bacterium, a chemical immune-system irritant was added to the protein used in the vaccine.
The only mice that suffered side effects such as inflamed, painful breasts and decreased milk production were those that bore young and, as a consequence, began lactating. Tuohy notes that only 2.6 percent of children are born to women 40 years of age and older, the group in which 95 percent of breast-cancer tumors are found.
Although Tuohy's work has generated plenty of excitement, it has yet to produce the money needed to fund clinical trials. He concedes that part of the holdup is his lack of reputation in cancer research.
"My work had multiple aspects of newness to it, and newness is something that people intrinsically resist at first," he says. "I have to be patient and let them digest it."
Prostate Cancer Screening
New research led by a University Hospitals doctor aims to create more accurate testing.
Years of research have shown that men with prostate cancer tend to have higher levels of prostate-specific antigen known as PSA, a protein made by the prostate gland to liquefy semen. That fact has made the PSA test a part of many men's medical lives, either as a routine screening or a follow-up after diagnosis and treatment.
Unfortunately, those tests can be less than reliable. Dr. Mark Stovsky, director of the Men's Health and Genitourinary Stone Center at University Hospitals Case Medical Center's Urology Institute, notes that there are other reasons why PSA levels may be elevated, some as simple as benign enlargement of the prostate or prostate infection. As a result, about one in four men with elevated PSA levels do not have cancer. Worse than the false positive results are the false negatives. Stovsky quotes a study that showed up to 15 percent of men with normal PSA levels actually might have prostate cancer.
"That gives rise to a lot of the controversy surrounding PSA screening," he says.
That controversy may be quelled by a new version of PSA screening developed by Cleveland-based biotech company AnalizaDx and tested in ongoing trials at UH and three other locations, including the Cleveland Clinic. Stovsky, who serves as the study's principal investigator, explains that the new testing process, known as prostate-specific antigen/solvent interaction analysis, uses solvents as a filter to separate PSAs produced by cancerous and benign cells according to the proteins' different physical structures.
"The PSA proteins from benign cells tend to float to one side, and the PSA proteins from cancer cells tend to float to the other side," Stovsky explains.
The aforementioned trials were conducted with blood and urine samples from men scheduled for a prostate biopsy. When compared with biopsy results, the urine tests proved to be 100 percent correct in predicting a negative result and 80.3 percent correct in predicting a positive result; blood tests proved to be 95.8 percent correct in predicting a negative result and 83.1 percent correct in predicting a positive result.
Stovsky stresses that the new testing method has not been approved yet by the Food and Drug Administration and, therefore, is not available to the public. "But this data makes our test look quite favorable compared to any other test there is for prostate cancer," he says.
A new treatment at Akron General Medical Center offers relief for asthma sufferers.
This FDA-approved outpatient procedure, performed under sedation or general anesthetic, reduces the amount of smooth muscle in the lungs' small airways. That smooth muscle, which is enlarged in asthma sufferers, causes the airways to constrict, resulting in symptoms such as shortness of breath, wheezing and chest tightness.
"If it becomes very severe, patients can end up in the hospital, sometimes even in the intensive care unit, with respiratory failure," says Akron General Medical Center chairman of medicine Dr. Sanjiv Tewari, a pulmonologist and critical-care specialist.
He says bronchial thermoplasty is an option for patients over 18 whose severe asthma is not well controlled with inhaled and oral medications. The procedure involves feeding a catheter containing electrical wires into an airway with a bronchoscope, an instrument with a tiny video camera that relays images to a monitor so doctors can see what they are doing. An electrical current passes through the wires to the attached electrodes — each of which is placed on spots inside the specific airway to be treated — and heats the tissue, in turn diminishing its ability to contract. Most patients require three one-hour sessions to complete treatment.
Complications are generally limited to minor asthma flare-ups, respiratory tract infections and airway bleeding, some of which can be minimized or eliminated by taking a steroid for a few days. Tewari says asthma sufferers are usually able to reduce their use of medications and live with fewer symptoms.
A MetroHealth Medical Center cardiologist's experimental process shows results in correcting irregular heart rhythms in animals.
For Dr. Kevin Donahue, painting has nothing to do with home improvement or creating great art. His use of the word refers to a novel application technique for a gene therapy that prevents and corrects atrial fibrillation, or an irregularly fast heartbeat. The MetroHealth Medical Center cardiologist explains that while the pacemaker is a viable long-term solution for speeding up a too-slow heartbeat, the daily medications used to slow a too-fast heartbeat can in some cases be as troubling as the condition itself.
"All of these drugs affect the basic mechanisms that control the heart's rhythm," he says. "Ninety-nine-plus percent of the time, they keep the heart in normal rhythm. But under the wrong set of circumstances, they can put the heart out of rhythm."
Donahue's experimental alternative, gene painting, solves the problem by delivering a corrective gene to each cell in the atria, or top two chambers of the heart, via the adenovirus, one of the viruses that causes the common cold. Donahue explains the virus's natural behavior — attaching to the cell, releasing its genetic material into it and using it to reproduce — makes it a perfect biological vehicle for the operation. But in this case, the virus's genetic material is removed and replaced with the corrective gene. Billions of engineered viruses are then mixed in a gel that is literally painted on the outside of the atria. The viruses, aided by an enzyme added to the gel, penetrate the atrial tissues, attach to the cells and release their therapeutic cargo.
Donahue's National Institutes of Health-funded study on pigs, published in the June issue of Circulation, showed results three days after the procedure. The animals' hearts beat at a normal rate and, more importantly, self-corrected their rhythms after being forced into atrial fibrillation with implanted pacemakers.
"The cells were physically unable to beat at the rate that could keep them in atrial fibrillation," he says.
Donahue's next step: an 18-month toxicology study on rabbits that adheres to the FDA's stringent laboratory practices. He anticipates a subsequent human trial pending FDA approval.
ER Wait Times
Lake Health's simple initiative cuts down
emergency room traffic and long waits.
Lake Health has found a revolutionary use for Twitter that promises to make your next trip to the emergency room a little more pleasant. In August, the health system became the first in Greater Cleveland to post emergency room wait times on the popular
Every two hours, a telephone operator sends a single tweet (twitter.com/LakeHealth) that updates wait times at both West Medical Center in Willoughby and TriPoint Medical Center in Concord Township. The frequency of those tweets increases when the delay from arrival to ER bed exceeds 30 minutes, according to Andrea Wasdovich, vice president of emergency critical care and perioperative services.
"We want the community to know exactly what to expect," she says.
Wasdovich says local residents can use the tweets to determine which ER to visit — because West and TriPoint medical centers are a relatively short 14 miles apart — or whether to go to an urgent-care center for treatment of minor problems such as earaches and sprained ankles. Wait times, she adds, are usually longest from 8 p.m. to 8 a.m., when doctors' offices are closed and symptoms are often more bothersome.
The tweets are just one facet of the health system's Thru Care program, an ER triage that diverts patients with minor health issues to an area where they are more quickly addressed. The result is waiting rooms that are often empty or nearly empty during the day.
"From 8 a.m. until 8 p.m., Lake Health usually has less than a 15-minute wait at both ERs," Wasdovich says.
High-field Open MRI
Mercy Regional Medical Center's open MRI machine promises quality images without the claustrophobia.
For many people, undergoing magnetic resonance imaging is a harrowing experience. The procedure, which produces internal images of the body with a magnetic scanning system, requires patients to lie completely motionless for up to an hour in a tubelike bay that provides little or no wiggle room.
"You can't see out," says Carrie Jankowski, director of diagnostic imaging services and biometrics at Mercy Regional Medical Center in Lorain. "People who are anxious, claustrophobic or of a larger build can be very uncomfortable. Depending on body weight and the circumference of that tunnel, some people literally have difficulty going into a conventional MRI."
Although open MRI scanners are available, the very openness of the patient bay diminishes the magnetic-field strength, resulting in poorer-quality images. But a new high-field counterpart at Mercy's imaging facility in Elyria provides the increased comfort of an open MRI without sacrificing image quality.
Jankowski explains that the difference lies in a powerful high-field magnet that makes the Hitachi-brand scanner the only one of its kind on the market and in the region. That magnet is supported 20 inches over the patient table by two large pillars, providing the space needed to accommodate larger patients and open sides that make the procedure more tolerable for everyone.
Pancreatic Cancer Vaccine
A treatment first tested for effectiveness at University Hospitals offers another weapon in the fight.
Pancreatic cancer is a particularly lethal disease. Dr. Jeffrey Hardacre, a surgical oncologist at University Hospitals Case Medical Center, cites sobering statistics, even for the 15 to 20 percent of patients whose tumors have not spread to other parts of the body by the time they're discovered and can be surgically removed.
"The chance of living five years after removal of the cancer is generally 15 to 20 percent," he says. "The average survival is 1 1/2 to two years."
But new hope for that relatively small group of patients is being provided by a pancreatic cancer vaccine first tested for effectiveness at University Hospitals Case Medical Center and a dozen other sites throughout the country. In July Hardacre, who serves as principal investigator at UH, presented promising preliminary results of Phase II trials on the vaccine developed by Ames, Iowa-based NewLink Genetics Corp., to an annual meeting of The American Society of Clinical Oncology. The one-year post-surgical survival rate improved from the 70 percent observed in historical controls to 91 percent when the vaccine was added to standard chemotherapy and chemoradiation. And the length of time patients lived without a recurrence increased from the approximately 11 months seen in historical controls to 16 months.
Even more interesting than the results is the way the vaccine is made. Hardacre explains that human pancreatic cancer cells are grown in the lab, each engineered to express the same unique surface molecule found on pig cells. This molecule is immediately recognized by the human immune system as foreign. In fact, it's the reason the body deploys antibodies and rejects, or attacks and destroys, organs transplanted from the animal.
"The theory is that the patient's body will recognize those vaccine cells as abnormal, attack them, and prime his or her immune system to fight his or her own pancreatic cancer," Hardacre says.
Researchers believe the reason post-surgical and disease-free survival rates have improved when the vaccine is administered in tandem with established therapies is because patients are better able to eliminate microscopic groups of cancerous cells that may remain after surgery. More about how the vaccine works will undoubtedly be discovered during Phase III trials involving 700-plus patients at more than 50 locations, including UH. But Hardacre stresses that the vaccine is not intended as a preventive measure or replacement for chemotherapy or chemoradiation.
"We're trying to hit the cancer from multiple points and improve people's odds," he says.
Activity and Alzheimer's Disease
A Cleveland Clinic study shows the importance
of exercise for those at risk.
A body in motion may be better equipped to outpace the onset of Alzheimer's disease, according to results of ongoing research at the Cleveland Clinic. Stephen Rao, director of the Schey Center for Cognitive Neuroimaging at the clinic's Neurological Institute, and his team observed that physically active older adults at risk of developing the malady maintain brain function longer than their sedentary counterparts.
Rao notes that special MRI scans showed all participants at risk of developing Alzheimer's disease — a determination researchers based on family history and genetic testing — initially displayed higher levels of activity in areas of the brain associated with memory while performing a simple task than their risk-free counterparts. The observation seems counterintuitive. But Rao believes that the increased brain activity in those at risk for Alzheimer's is actually the brain compensating for physiological changes that occur there long before symptoms of the disease are evident.
"It's as if the brain is working harder to preserve one's function," he explains. "Physical activity supports this compensatory system."
Rao points out that the at-risk individuals who showed the greatest amount of brain activity were those engaged in the greatest amount of physical activity. That finding was reinforced 18 months later, when Rao and his team asked all at-risk subjects to perform the task again. A third of all participants showed some decline in memory. Most of those individuals, however, led sedentary lives.
Rao says the ultimate goal of his studies, which will continue for another five years, is to identify lifestyle changes that can slow the progression of Alzheimer's disease before sufferers exhibit symptoms.
"Our sense is, and there's a lot of data to support it, that the biological changes of Alzheimer's disease begin as much as 10 years before the onset of symptoms," he says. "One of the reasons why most of our FDA-approved drugs are not as effective is that by the time a person is diagnosed, it's probably too late."
A robotic-arm is making for easier and less invasive partial knee replacements at EMH.
Traditionally, partial knee replacements have required a three- to four-day stay in the hospital. But a new procedure at EMH Regional Healthcare System's Center for Orthopedics in Sheffield Village has reduced the hospital stay to two days and cut rehabilitation time from one month to a mere two weeks.
According to orthopedic surgeon Dr. John Krebs, the facility is the only one in Northeast Ohio to offer MAKOplasty. The process uses a robotic arm to remove damaged areas in procedures where replacing the kneecap or inner knee is required. It also better preserves joint ligaments cut or removed during traditional partial knee-replacement surgery. "It feels more like a natural knee," Krebs says of the result. "The biomechanics really haven't changed."
Preoperative preparations involve uploading a computed tomography, or CT, scan of the problem knee to the robotic arm's computer, which creates a 3-D image of the knee. The surgeon selects replacement parts and enters information about their dimensions. The surgeon then uses the programmed robotic arm to cut away bone and cartilage while monitoring the operation's progress on the computer screen. Krebs says the device reduces chances of human error. Most patients leave the operating room with a 2-inch incision on the side of the knee.
"There was some guesswork involved in the standard way of doing a partial knee replacement," he says. "Robotics have taken away that guesswork."
A MetroHealth Medical Center doctor is studying whether an antioxidant can help stave off fetal-membrane rupture.
Preventing some premature births may be as simple as taking a dietary supplement. Dr. John Moore, head of MetroHealth Medical Center's division of neonatology, and a team working with lab tissue samples have found that lipoic acid, an antioxidant found in vegetables, prevents weakening of the fetal membrane that surrounds the baby in the womb.
According to Moore, premature rupture of the fetal membrane is responsible for roughly a third of all preterm births, a problem that has increased from 10 to 12 percent over the past 20 years.
"We know that inflammation and infection are associated with a good many, maybe 50 percent, of preterm ruptures," he says. "And we know that placental abruption, separation of the placenta from the uterine lining, is associated with a significant group as well."
In a study that appeared in a 2009 issue of Biology of Reproduction, samples of normal, healthy fetal-membrane tissue were obtained with the consent of mothers who delivered their babies by Cesarean section, before any normal tissue weakening or rupture could occur. A portion of those samples were incubated in a bath containing lipoic acid before adding cytokines, chemicals increased by inflammation that were shown to weaken samples in a previous study. Tests measuring the force required to break the tissues demonstrated that lipoic acid prevented that weakening.
A study published in the August issue of Placenta showed that thrombin, an enzyme in the blood, weakened fetal-membrane tissues. The study also illustrated that fetal-membrane tissues treated with lipoic acid were resistant to weakening by thrombin exposure. "The tissues showed no change from their original strength," Moore says.
Moore is now trying to get FDA approval for a human trial. He anticipates the first study will be done on pregnant women with no known risk of delivering prematurely just to prove the antioxidant has no adverse side effects. Although many people take lipoic acid as a supplement, there is a lack of data regarding its safety in the amounts needed to prevent premature fetal-membrane rupture.
"We just don't know the risks," he says.
12:00 AM EST
November 24, 2010