GoogleNews.com, Physorg.com, March 24, 2010 – Scientists at the Stanford University School of Medicine studying cardiac development in mouse embryos have identified the source of cells that become the coronary arteries — the vessels that deliver blood to nourish the continuously pumping heart muscle. Surprisingly, the cells originate in an entirely different part of the heart than previously thought. Although they begin life as venous cells, directing blood into the chambers of the embryonic heart, they undergo a form of natural reprogramming as they migrate across and into the surface of the heart to become arteries and capillaries.
Understanding and recreating the conditions that allow these cells to switch identities from vein to artery could help the millions of people struggling with coronary artery disease, the scientists believe.
“Physicians performing coronary bypasses often use veins to reroute blood flow around clogged arteries,” said biochemist and postdoctoral scholar Kristy Red-Horse, PhD. “But these veins fail more often and more quickly than transplanted arteries.” Red-Horse is the lead author of the research, which will be published March 25 in Nature.
Few muscles in your body work as hard as your heart. Just like other muscles, the heart needs a reliable supply of oxygen. The coronary arteries encircle and burrow into the heart muscle to deliver fresh, oxygenated blood. Blocking the arteries, which occurs most commonly when a deposit of plaque ruptures in the artery’s lining, damages the heart muscle and can be fatal. It’s also quite common: Coronary artery disease is the world’s leading cause of death.
“If we can learn about how coronary arteries develop normally, we may be able to take that information and engineer better coronary bypass grafts, or even learn how to increase blood flow to the heart muscle without surgery,” said professor and chair of biochemistry Mark Krasnow, MD, PhD. Krasnow is the senior author of the study and a Howard Hughes Medical Institute investigator.
Red-Horse began her study of heart development to solve a controversy. Anatomical studies of humans and other mammals had suggested the cells that make up the coronary arteries are derived from regions around the aorta. But more recent studies in chick embryos implicated an embryonic heart structure called the proepicardium.
When Red-Horse looked closely at the cells over time, however, she found that about 11.5 days after conception, cells from an embryonic cardiac structure called the sinus venosus, which directs blood into the developing heart, began to migrate across the surface of the muscle. By 14.5 days, they had become recognizable coronary arteries.
“This was really surprising,” said Red-Horse. “I thought, as many others did, that these cells would arise from the proepicardium. The second surprise came when we realized the cells were de-differentiating from venous cells and becoming arteries.”
While veins funnel deoxygenated blood back to the heart, arteries — coronary and otherwise — deliver fresh blood throughout the body. And although it might seem that a tube is a tube is a tube, with little to distinguish it other than its entry and exit points, the cells that make up veins and arteries are very different. Each has to handle a unique set of conditions, including the pressure, flow patterns, pH and biochemical components of the blood they transport.
To confirm her finding, Red-Horse cultured developing hearts from mouse embryos in a dish. She found that, in contrast to controls, the chambers of hearts in which she had removed the sinus venosus kept beating but never developed coronary vessels.
Red-Horse then used a cell-marking technology developed by senior research scientist Hiroo Ueno, PhD, in the laboratory of Irving Weissman, MD, to label individual cells in the developing hearts of mouse embryos with different colors. The labeling experiments confirmed that a single cell from the sinus venosus could migrate across the heart and become not only the lining of the coronary arteries, but also of the veins and capillaries on the heart. Weissman is the director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, and the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research. Krasnow and Weissman are both members of the Stanford Cancer Center.
“This is a beautiful example of natural reprogramming,” said Krasnow. “The heart is somehow telling these venous cells to leave the sinus venosus and convert into coronary arteries. If we can identify these molecular signals, we might be able to use them to construct coronary arteries for bypass surgery, which could be very important therapeutically.”
Red-Horse and her colleagues are now trying to identify these signals and study how they change the cells’ gene expression patterns as they undergo this conversion. The next step will be to see whether they can induce human cells to undergo a similar transformation.
“During the past several years, scientists have made great progress in understanding how organs develop,” said Krasnow. “And other scientists have made significant advances in tissue engineering and regenerative medicine. But the two groups don’t talk to each other much. Now we’re trying to apply what we’ve learned about how a body builds a vessel or an entire organ to building vessels and organs in the laboratory.”
Provided by Stanford University Medical Center
Coronary Artery Bypass Surgery (Grafting)
New York-Presbyterian Hospital – Coronary artery bypass grafting (CABG) is the most common surgical treatment for acquired heart disease. With this method, a blood vessel taken from the tissues of the chest, arms, or legs is used to route blood around blockages in the coronary arteries to restore adequate circulation of blood to the heart.
During this procedure, the surgeon makes an incision down the center of the chest and through the breastbone to gain access to the heart. The heart is temporarily stopped and the patient’s blood is shunted into a heart-lung machine, which substitutes for the beating heart and lungs during surgery. Blood vessels from the chest cavity, arm, or legs are used as replacements for the diseased coronary vessel. These donor vessels can be removed safely because other blood vessels can adequately supply the part of the body from which they are taken. Following completion of the grafting procedure, the heart is stimulated electrically to re-establish its beat, the patient is taken off the heart-lung machine, and the incision in the chest is closed.
Minimally Invasive CABG
In certain cases, a patient may be a candidate for minimally invasive CABG. Using this method, a small (2-3 inch) incision is made in the tissue layer between the ribs. This method—made possible by a specialized surgical robot and a heart stabilizer developed by our surgeons&mdashcauses less chest trauma, less post-operative discomfort, shorter hospital stays, and faster recovery time than traditional CABG.
In certain cases, CABG can be performed without using the heart-lung machine. For more information on this surgical option, please read the section on off-pump surgery.
What is coronary artery bypass graft (CABG) surgery?
According to the American Heart Association 427,000 coronary artery bypass graft (CABG) surgeries were performed in the United States in 2004, making it one of the most commonly performed major operations. CABG surgery is advised for selected groups of patients with significant narrowings and blockages of the heart arteries (coronary artery disease). CABG surgery creates new routes around narrowed and blocked arteries, allowing sufficient blood flow to deliver oxygen and nutrients to the heart muscle.
How does coronary artery disease develop?
Coronary artery disease (CAD) occurs when atherosclerotic plaque (hardening of the arteries) builds up in the wall of the arteries that supply the heart. This plaque is primarily made of cholesterol. Plaque accumulation can be accelerated by smoking, high blood pressure, elevated cholesterol, and diabetes. Patients are also at higher risk for plaque development if they are older (greater than 45 years for men and 55 years for women), or if they have a positive family history for early heart artery disease.
The atherosclerotic process causes significant narrowing in one or more coronary arteries. When coronary arteries narrow more than 50 to 70%, the blood supply beyond the plaque becomes inadequate to meet the increased oxygen demand during exercise. The heart muscle in the territory of these arteries becomes starved of oxygen (ischemic). Patients often experience chest pain (angina) when the blood oxygen supply cannot keep up with demand. Up to 25% of patients experience no chest pain at all despite documented lack of adequate blood and oxygen supply. These patients have “silent” angina, and have the same risk of heart attack as those with angina.
When a blood clot (thrombus) forms on top of this plaque, the artery becomes completely blocked causing a heart attack.
When arteries are narrowed in excess of 90 to 99%, patients often have accelerated angina or angina at rest (unstable angina). Unstable angina can also occur due to intermittent blockage of an artery by a thrombus that eventually is dissolved by the body’s own protective clot-dissolving system.
How is coronary artery disease diagnosed?
The resting electrocardiogram (EKG) is a recording of the electrical activity of the heart, and can demonstrate signs of oxygen starvation of the heart (ischemia) or heart attack. Often, the resting EKG is normal in patients with coronary artery disease and angina. Exercise treadmill tests are useful screening tests for patients with a moderate likelihood of significant coronary artery disease (CAD) and a normal resting EKG. These stress tests are about 60 to 70% accurate in diagnosing significant CAD.
If the stress tests do not reveal the diagnosis, greater accuracy can be achieved by adding a nuclear agent (thallium or Cardiolite) intravenously during stress tests. Addition of thallium allows nuclear imaging of the blood flow to different regions of the heart, using an external camera. An area of the heart with reduced blood flow during exercise, but normal blood flow at rest, signifies significant artery narrowing in that region.
Combining echocardiography (ultrasound imaging of the heart muscle) with exercise stress testing (stress echocardiography) is also a very accurate technique to detect CAD. When a significant blockage exists, the heart muscle supplied by this artery does not contract as well as the rest of the heart muscle. Stress echocardiography and thallium stress tests are both at least 80% to 85% accurate in detecting significant coronary artery disease.
When a patient cannot undergo exercise stress test because of nervous system or joint problems, medications can be injected intravenously to simulate the stress on the heart due to exercise and imaging can be performed with a nuclear camera or ultrasound.
Cardiac catheterization with angiography (coronary arteriography) is the most accurate test to detect coronary artery narrowing. Small hollow plastic tubes (catheters) are advanced under x-ray guidance to the openings of the two main heart arteries (left and right). Iodine contrast, “dye,” is then injected into the arteries while an x-ray video is recorded. Sometimes, an exercise study is then done to determine whether a moderate narrowing (40 – 60%) is actually causing ischemia and, therefore, requires treatment.
A newer modality, high speed CT scanning angiography has recently become available. This procedure uses powerful x-ray methods to visualize the arteries to the heart. Its role in the evaluation of CAD is currently being evaluated. For more, please read the CT Scanning Angiography article.
How is coronary artery disease (CAD) treated?
Medicines used to treat angina reduce the heart muscle demand for oxygen in order to compensate for the reduced blood supply. Three commonly used classes of drugs are the nitrates, beta blockers and calcium blockers. Nitroglycerin (Nitro-Bid) is an example of a nitrate. Examples of beta blockers include propranolol (Inderal) and atenolol (Tenormin). Examples of calcium blockers include nicardipine (Cardene) and nifedipine (Procardia, Adalat). Unstable angina is also treated with aspirin and the intravenous blood thinner heparin. Aspirin prevents clumping of platelets, while heparin prevents blood clotting on the surface of plaques in a critically narrowed artery. When patients continue to have angina despite maximum medications, or when significant ischemia still occurs with exercise testing, coronary arteriography is usually indicated. Data collected during coronary arteriography help doctors decide whether the patient should be considered for percutaneous coronary intervention, or percutaneous transluminal angioplasty (PTCA), whereby a small balloon is used to inflate the blockage. Angioplasty (PTCA) is usually followed by placement of a stent or coronary artery bypass graft surgery (CABG) to increase coronary artery blood flow.
Angioplasty can produce excellent results in carefully selected patients. Under x-ray guidance, a wire is advanced from the groin to the coronary artery. A small catheter with a balloon at the end is threaded over the wire to reach the narrowed segment. The balloon is then inflated to push the artery open, and a steel mesh stent is generally inserted.
CABG surgery is performed to relieve angina in patients who have failed medical therapy and are not good candidates for angioplasty (PTCA). CABG surgery is ideal for patients with multiple narrowings in multiple coronary artery branches, such as is often seen in patients with diabetes. CABG surgery has been shown to improve long-term survival in patients with significant narrowing of the left main coronary artery, and in patients with significant narrowing of multiple arteries, especially in those with decreased heart muscle pump function.
How is CABG surgery done?
The cardiac surgeon makes an incision down the middle of the chest and then saws through the breastbone (sternum). This procedure is called a median (middle) sternotomy (cutting of the sternum). The heart is cooled with iced salt water, while a preservative solution is injected into the heart arteries. This process minimizes damage caused by reduced blood flow during surgery and is referred to as “cardioplegia.” Before bypass surgery can take place, a cardiopulmonary bypass must be established. Plastic tubes are placed in the right atrium to channel venous blood out of the body for passage through a plastic sheeting (membrane oxygenator) in the heart lung machine. The oxygenated blood is then returned to the body. The main aorta is clamped off (cross clamped) during CABG surgery to maintain a bloodless field and to allow bypasses to be connected to the aorta.
The most commonly used vessel for the bypass is the saphenous vein from the leg. Bypass grafting involves sewing the graft vessels to the coronary arteries beyond the narrowing or blockage. The other end of this vein is attached to the aorta. Chest wall arteries, particularly the left internal mammary artery, have been increasingly used as bypass grafts. This artery is separated from the chest wall and usually connected to the left anterior descending artery and/or one of its major branches beyond the blockage. The major advantage of using internal mammary arteries is that they tend to remain open longer than venous grafts. Ten years after CABG surgery, only 66% of vein grafts are open compared to 90% of internal mammary arteries. However, artery grafts are of limited length, and can only be used to bypass diseases located near the beginning (proximal) of the coronary arteries. Using internal mammary arteries may prolong CABG surgery because of the extra time needed to separate them from the chest wall. Therefore, internal mammary arteries may not be used for emergency CABG surgery when time is critical to restore coronary artery blood flow.
CABG surgery takes about four hours to complete. The aorta is clamped off for about 60 minutes and the body is supported by cardiopulmonary bypass for about 90 minutes. The use of 3 (triple), 4 (quadruple), or 5 (quintuple) bypasses are now routine. At the end of surgery, the sternum is wired together with stainless steel and the chest incision is sewn closed. Plastic tubes (chest tubes) are left in place to allow drainage of any remaining blood from the space around the heart (mediastinum). About 5% of patients require exploration within the first 24 hours because of continued bleeding after surgery. Chest tubes are usually removed the day after surgery. The breathing tube is usually removed shortly after surgery. Patients usually get out of bed and are transferred out of intensive care the day after surgery. Up to 25% of patients develop heart rhythm disturbances within the first three or four days after CABG surgery. These rhythm disturbances are usually temporary atrial fibrillation, and are felt to be related to surgical trauma to the heart. Most of these arrhythmias respond to standard medical therapy that can be weaned one month after surgery. The average length of stay in the hospital for CABG surgery has been reduced from as long as a week to only three to four days in most patients. Many young patients can even be discharged home after two days.
A new advance for many patients is the ability to do CABG with out going on cardiopulmonary bypass (“off pump”), with the heart still beating. This significantly minimizes the occasional memory defects and other complications that may be seen after CABG, and is a significant advance.
How do patients recover after CABG surgery?
Sutures are removed from the chest prior to discharge and from the leg (if the saphenous vein is used) after 7 to 10 days. Even though smaller leg veins will take over the role of the saphenous vein, a certain degree of swelling (edema) in the affected ankle is common. Patients are advised to wear elastic support stockings during the day for the first four to six weeks after surgery and to keep their leg elevated when sitting. This swelling usually resolves after about six to eight weeks. Healing of the breastbone takes about six weeks and is the primary limitation in recovering from CABG surgery. Patients are advised not to lift anything more than 10 pounds or perform heavy exertion during this healing period. They are also advised not to drive for the first four weeks to avoid any injury to the chest. Patients can return to normal sexual activity as long as they minimize positions that put significant weight on the chest or upper arms. Return to work usually occurs after the six week recovery, but may be much sooner for non-strenuous employment.
Exercise stress testing is routinely done four to six weeks after CABG surgery and signals the beginning of a cardiac rehabilitation program. Rehabilitation consists of a 12 week program of gradually increasing monitored exercise lasting one hour three times a week. Patients are also counseled about the importance of lifestyle changes to lower their chance of developing further CAD. These include stopping smoking, reducing weight and dietary fat, controlling blood pressure and diabetes, and lowering blood cholesterol levels.
What are the risks and complications of CABG surgery?
Overall mortality related to CABG is 3-4%. During and shortly after CABG surgery, heart attacks occur in 5 to 10% of patients and are the main cause of death. About 5% of patients require exploration because of bleeding. This second surgery increases the risk of chest infection and lung complications. Stroke occurs in 1-2%, primarily in elderly patients. Mortality and complications increase with:
age (older than 70 years),
poor heart muscle function,
disease obstructing the left main coronary artery,
chronic lung disease, and
chronic kidney failure.
Mortality may be higher in women, primarily due to their advanced age at the time of CABG surgery and smaller coronary arteries. Women develop coronary artery disease about 10 years later than men because of hormonal “protection” while they still regularly menstruate (although in women with risk factors for coronary artery disease, especially smoking, elevated lipids, and diabetes, the possibility for the development of coronary artery disease at a young age is very real). Women are generally of smaller stature than men, with smaller coronary arteries. These small arteries make CABG surgery technically more difficult and prolonged. The smaller vessels also decrease both short and long-term graft function.
What are the long-term results after CABG surgery?
A very small percentage of vein grafts may become blocked within the first two weeks after CABG surgery due to blood clotting. Blood clots form in the grafts usually because of small arteries beyond the insertion site of the graft causing sluggish blood run off. Another 10% of vein grafts close off between two weeks and one year after CABG surgery. Use of aspirin to thin the blood has been shown to reduce these later closings by 50%. Grafts become narrowed after the first five years as cells stick to the inner lining and multiply, causing formation of scar tissue (intimal fibrosis) and actual atherosclerosis. After 10 years, only 2/3 of vein grafts are open and 1/2 of these have at least moderate narrowings. Internal mammary grafts have a much higher (90%) 10 year rate of remaining open. This difference in longevity has caused a shift in surgical practices toward greater use of internal mammary and other arteries as opposed to veins for bypasses.
Recent data has shown that in CABG patients with elevated LDL cholesterol (bad cholesterol) levels, use of cholesterol-lowering medications (particularly the statin family of drugs) to lower LDL levels to below 80 will significantly improve long-term graft patency as well as improve survival benefit and heart attack risk. Patients are also advised about the importance of lifestyle changes to lower their chance of developing further atherosclerosis in their coronary arteries. These include stopping smoking, exercise, reducing weight and dietary fat, as well as controlling blood pressure and diabetes. Frequent monitoring of CABG patients with physiologic testing can identify early problems in grafts. PTCA (angioplasty) with stenting, in addition to aggressive risk factor modification, may significantly limit the need for repeat CABG years later. Repeat CABG surgery is occasionally necessary, but may have a higher risk of complication.
How do CABG surgery and angioplasty (PTCA) compare?
Ongoing studies are comparing the treatment results of angioplasty (PTCA) versus bypass (CABG surgery) in patients who are candidates for either procedure. Both procedures are very effective in reducing angina symptoms, preventing heart attacks, and reducing death. Many studies have either shown similar benefits or slight advantage to CABG (primarily in severe diabetics), although current studies are evaluating the two procedures utilizing the most current improved techniques (for example, newer “medicated” stents and the off-pump CABG); this data is still being collected. The best choice for an individual patient is best made by their cardiologist, surgeon, and primary doctor.
Coronary Artery Bypass Graft At A Glance
Coronary artery disease develops because of hardening of the arteries (arteriosclerosis) that supply blood to the heart muscle.
In the diagnosis of coronary artery disease, helpful tests include EKG, stress test, echocardiography, and coronary angiography.
Coronary artery bypass graft (CABG) surgery reestablishes sufficient blood flow to deliver oxygen and nutrients to the heart muscle.
The bypass graft for a CABG can be a vein from the leg or an inner chest wall artery.
References: American Heart Association, “Open-Heart Surgery Statistics”
GoogleNews.com, March 25, 2010, OCEANSIDE, Calif.–(EON: Enhanced Online News)–International Stem Cell Corporation (OTCBB: ISCO), www.internationalstemcell.com, announced today that ISCO’s Research and Therapeutic Development Group, together with a group of scientists from the University of California, Irvine (UCI), is starting a second phase of essential pre-clinical experiments to test retinal pigment epithelium derived from parthenogenetic stem cells. Follow on pre-clinical experiments will be conducted to rescue vision in disease models.
“This research will enable us to then test the ability of these cells to restore vision in rodent models of retinal degeneration.”
Retinal pigment epithelium (RPE) has been derived from parthenogenetic stem cells by ISCO scientists in close collaboration with UCI scientists. The RPE cells will be tested for the presence of specific markers and for functional activity.
Retinal pigment epithelium plays a critical role in maintaining proper eye function. Loss of function or dysfunction of RPE is involved in a range of disabling eye conditions, particularly age-related macular degeneration (AMD) that is the major cause of vision loss in seniors.
Encouraging data from animal models have shown that visual degradation caused by AMD can be slowed through the transplantation of RPE. One of the major barriers for this therapy is the lack of sufficient RPE cells from suitable donated tissue.
According to Dr. Hans Keirstead, Professor of Anatomy and Neurobiology at the University of California, Irvine, “The derivation of RPE from stem cells will allow the availability of an unlimited source of RPE for transplantation.” Referring to the upcoming work with ISCO, Dr. Keirstead said, “This research will enable us to then test the ability of these cells to restore vision in rodent models of retinal degeneration.”
Dr. Nikolay Turovets, ISCO’s Director of Research and Therapeutic Development, says, “RPE derived from human parthenogenetic stem cells can overcome the problem of immune-matching for transplantation since ISCO’s parthenogenetic stem cell lines can be made to carry the most common sets of immune genes found among various racial groups. That is why the differentiated derivatives from one hpSC line may be transplanted into millions of people.”
ABOUT INTERNATIONAL STEM CELL CORPORATION (ISCO.OB):
International Stem Cell Corporation is a California-based biotechnology company focused on therapeutic and research products. ISCO’s core technology, parthenogenesis, results in creation of pluripotent human stem cells from unfertilized oocytes (eggs). hpSCs avoid ethical issues associated with the use or destruction of viable human embryos. ISCO scientists have created the first parthenogenetic, homozygous stem cell line that can be a source of immune-matched therapeutic cells to minimize immune rejection after transplantation into hundreds of millions of individuals of differing sexes, ages and racial groups. This offers the potential to create the first true stem cell bank, UniStemCell™, while avoiding the ethical issue of using fertilized eggs. ISCO also produces and markets specialized cells and growth media for therapeutic research worldwide through its subsidiary Lifeline Cell Technology. More information is available at ISCO’s website, www.internationalstemcell.com.
ONCOLOGY. Vol. 24 No. 3
The Bennett/McKoy/Henke et al Article Reviewed
Joanne E. Mortimer, MD, FACP
Vice Chair, Medical Oncology
Associate Director for Affiliate Programs
Professor, Division of Medical Oncology
City of Hope Comprehensive Cancer Center
| March 24, 2010
CancerNetwork.com – Dr. Bennett and colleagues have provided a thorough and balanced history of the rise and fall of erythropoietin-stimulating agents (ESAs) in cancer-associated anemia. Their review encourages us to think about the lessons learned from this history—lessons about medical progress, the importance of clinical research in guiding clinical practice, and the role of the US Food and Drug Administration (FDA) in protecting patients.
In 1993, the ESAs were first approved for management of treatment-associated anemia in patients with nonmyeloid malignancies. Pooled data from six randomized trials of ESAs in patients with solid tumors treated with chemotherapy showed that administration of ESAs decreased the need for red cell transfusion (22%) compared with the placebo arm (43%). In 2002, based on similar results from use of the longer-acting ESAs administered less frequently (51% vs 21% transfusions), darbepoetin alfa (Aranesp) was approved. Physicians and patients were anxious to avoid red blood cell transfusions in the wake of the AIDS epidemic and the concern about hepatitis C transmission, for which there was no screening test.
In a report published in the New England Journal of Medicine in 1996, the risk of transfusion-transmitted viral infection was estimated on a population of over one-half million screened donors who had contributed more than 1 unit of blood between 1991 and 1993. Risk of infection was calculated based on the incidence of seroconversion over time among these individuals. The risk of HIV transmission was estimated to be 1 in 493,000, risk of hepatitis C transmission was 1 in 103,000, and risk of hepatitis B transmission was 1 in 63,000. By 2003, the safety of our blood banks had so improved that the risk of HIV transmission had decreased to < 1 in 1 million, risk for hepatitis C had dropped to < 1 in 1 million, and risk for hepatitis B was reduced to < 1 in 400,000. By improving the safety of blood products, the impetus to avoid transfusion decreased.
Lesson 1: Competing Improvements in Clinical Care May Change the Significance of an Intervention
Cancer-related fatigue is reported by more than 60% of patients receiving chemotherapy.[4-6] This fatigue is debilitating and significantly compromises the quality of life of patients. While every patient is assessed clinically as an individual, transfusion medicine specialists generally recommend that patients with chronic anemia maintain hemoglobin levels in excess of 7 to 8 g/dL. Yet the level of self-reported fatigue has been shown to be inversely related to the hemoglobin level even at levels in excess of 8 g/dL. Using the Surveillance Epidemiology and End Results (SEER)-Medicare database, Hershman identified more than 56,000 patients who were treated with chemotherapy for cancers of the colon, non–small-cell lung cancer (NSCLC), breast, and diffuse large cell lymphoma from 1991 to 2002. While use of ESAs in this population increased after drug approval, the rate of transfusions was unchanged. In clinical practice the use of ESAs was expanded to maintain hemoglobin levels in excess of what would normally dictate a red cell transfusion, on the presumption that cancer-related fatigue would be minimized.
The clinical data that were used to support use of ESAs in treatment of cancer-related fatigue were largely derived from open-label randomized trials in patients with a variety of malignancies, at different stages of disease, and receiving different cytotoxic therapies. As Dr. Bennett and his coauthors point out, the “FDA statisticians concluded that [quality of life] claims by manufacturers for cancer patients were not statistically valid.”
Lesson 2: There Is No Substitute for a Well-Designed, Randomized, Double-Blind, Placebo-Controlled Trial
It is of note that a Cochrane review entitled “Drug Therapy for the Management of Cancer-Related Fatigue” concluded that the ESAs “are effective in the management of cancer-related fatigue in patients who are anemic as a result of chemotherapy.” However, the authors caution that “These drugs are not without side effects and they should be used under expert supervision and their effect closely monitored.”
The FDA was concerned about the impact of the ESAs on cancer outcomes and reviewed the safety data at an Oncologic Drugs Advisory Committee (ODAC) meeting in May 2004. At that time, the FDA determined that two studies—a small-cell lung cancer trial (N93-004) and the Breast Cancer Erythropoietin Survival Trial (BEST)—were adequately designed to evaluate ESA safety and cancer outcomes. The committee concluded that further studies were needed to determine if ESAs had an effect on cancer-specific outcomes. No change in ESA use was recommended.
The ESAs continued to be used in patients with cancer, chronic renal failure, and in individuals undergoing orthopedic surgical procedures. With additional safety data and before the next ODAC review in May 2007, the FDA issued three separate public health advisories in November 2006, January 2007, and February 2007. These advisories raised safety concerns and cautioned that the target hemoglobin level should not exceed 12 g/dL. Later in 2007, a Black Box warning identified venous thromboembolic events (VTEs) as a complication related to ESAs.
Lesson 3: All Treatment Interventions Have Potential Side Effects
By the May 2007 ODAC meeting, adequate safety and outcome data were available from six clinical trials. The ESAs were associated with a decrease in overall survival in patients with both myeloid and nonmyeloid malignancies, as well as a decrease in local regional control of head and neck cancer and NSCLC, and an increased risk of VTEs was again observed. With these additional data, the committee recommended that ESAs be avoided in patients with potentially curative malignancies.
All ODAC meetings include an “Open Public Hearing” at which advocates provide testimony regarding the questions posed to the committee. The May 2007 meeting was particularly emotional as cancer advocates with metastatic disease questioned whether the use of ESAs during adjuvant therapy had “caused” their cancer recurrence. It is clear that additional studies will be needed to clarify whether the adverse effects of ESAs are unique to characteristics of cancer cells, too high a hemoglobin goal (> 12 g/dL), host effects, or other factors.
Lesson 4: The Systems in Place to Protect Our Patients Do Work
Until the aforementioned issues have been satisfactorily clarified, patients who are at risk for an adverse outcome do not receive ESAs, as reinforced by the review by Dr. Bennett et al. A clear lesson in the changing use of ESAs in cancer patients is the importance of evidence-based medicine as a guide for clinical practice, and the shift in recommended indications for ESAs shows that the systems in place to protect our patients do work.
—Joanne E. Mortimer, MD, FACP
MARCH 25, 2010
days after amputation. Green fluorescent protein appears in cells that are
expressing the gata4 gene. The nuclei of all cells are stained blue. – Kazu
After a non-fatal heart attack, a damaged human heart does its best to patch
itself up by forming a scar. But how much better would it be if that patch
were made up of healthy, fully functional heart muscle rather than scrappy,
stiff scar tissue?
Some animals, such as zebrafish, have the natural ability to repair their own
injured hearts. Over the last decade, scientists have become increasingly
interested in the amazing regenerative capacity of such organisms, as they
search for new ways to prompt human hearts to repair themselves. Using
advanced genetic tools, Howard Hughes Medical Institute researchers and
their colleagues now have identified key cells involved in zebrafish heart
regeneration and begun to decipher the instructions the cells use to carry out
their repair work.
Kenneth Poss, an HHMI Early Career Scientist at Duke University Medical
Center, led the research, which is reported in the March 25, 2010, issue of the
journal Nature. Coauthors on the paper are from Duke University Medical
Center, Brigham and Women’s Hospital, the University of California, San
Francisco, and Cornell University.
“As we identify these signals, we’re hopeful that
we or other researchers can use what we learn
to help people with severely injured, scarred
– Kenneth D. Poss
Poss says scientists are pursuing two basic paths to regenerate human heart
muscle. One involves giving the heart the instructions for repair, along with a
batch of fresh cells — typically stem cells — capable of carrying out those
instructions. An alternative approach, he says, is to give the instructions to
cells that are already present and try to teach them to regenerate. He and his
colleagues, including Kazu Kikuchi, who is the first author of the Naturepublication, have identified an important population of cells that participate
in zebrafish heart regeneration. They believe they now have new perspective
on which cells might be “taught” to regenerate in human hearts.
To arrive at their findings, the researchers stimulated zebrafish heart
regeneration by cutting off part of the ventricle. Then they borrowed
techniques from developmental biology and stem cell research that allowed
them to track the activity of particular cells and their progeny over time.
“We found that a population of cardiomyocytes – heart muscle cells — on the
periphery of the injury site becomes activated to carry out a specific genetic
program,” Poss says. “We don’t know everything about the program, but at
least one of the genes that becomes activated is a factor called gata4. When
the cells turn on this gene, heart muscle cells near the site begin to divide and
integrate into the gap to build a new wall of heart muscle.”
But is that wall just a static structure, or does it work like healthy heart
muscle? Results showed that by about two weeks after injury, electrical
conduction had been restored, with cells of the new wall contracting in sync,
as healthy heart muscle cells should.
The researchers went on to investigate whether heart muscle could be
regenerated even after scarring had occurred, an important question if results
are to be translated to human hearts, where scarring is the natural response to
injury. Zebrafish don’t typically repair injuries with a scar, but Poss and
colleagues developed a way to induce scar formation and found that while
regeneration didn’t completely erase the scar, as they hoped it might, some
regeneration did occur in the wounded area.
“We saw activation of gata4, and in several cases muscle was built around
the scar — so there seems to be some regenerative signal even in the presence
of scar tissue,” says Poss. “As we identify these signals, we’re hopeful that we
or other researchers can use what we learn to help people with severely
injured, scarred hearts.”
Now that the researchers have found a way to follow heart regeneration “with
a better pair of glasses,” as Poss puts it, they plan to study the process in even
greater detail by searching for molecules or manipulations that enhance or
“We’re also interested in the environment of the zebrafish heart that allows
these cardiomyocytes to be activated,” Poss says. “We have been studying
different heart cell types that are not muscle cells, investigating how those
might be involved in initiating or facilitating the regeneration process. We
wonder whether the non-muscle cells of the heart are providing a unique
environment for this to happen.”
Another logical step would be to try to induce regeneration in a
non-regenerating system, such as a mammalian heart.
“We don’t have plans to work with human cells yet, but as a first step we may
collaborate with groups that work with mice,” says Poss.
Regenerating cardiomyocytes in the ventricle of a zebrafish 30
GoogleNews.com, March 24, 2010 – Scientists have identified a gene in mice that is a key player in what could essentially be called embryonic stem cells’ “immortality.”
The finding could have a major impact on research into aging, regenerative medicine and the biology of stem cells and cancer, according to the report published online March 24 in the journal Nature.
Embryonic stem cells can develop into nearly any type of cell in the body and can produce infinite generations of new, fully operational embryonic stem cells (daughter cells). But the mechanism for this rejuvenation has been a mystery, the researchers noted in a news release from the U.S. National Institute on Aging (NIA).
In the new study, researchers at the NIA found that embryonic stem cells in mice express a unique Zscan4 gene that enables them to continuously produce vigorous daughter cells.
According to the study authors, this gene isn’t turned on every time an embryonic stem cell replicates; only about 5 percent of embryonic stem cells will have the gene activated at any one point.