Alzheimer’s Disease Linked to Diabetes, Study Suggests

ScienceDaily (July 18, 2012) — Researchers from the University of Medicine and Dentistry of New Jersey (UMDNJ), collaborating with scientists from Northwestern University in Illinois, have provided direct experimental evidence that diabetes is linked to the onset of Alzheimer’s disease. The study, published online this week in the Journal of Alzheimer’s Disease, used an experimental model that shows potential as an important new tool for investigations of Alzheimer’s disease and of drugs being developed to treat Alzheimer’s.

 

UMDNJ researchers Peter Frederikse, PhD, and Chinnaswamy Kasinathan, PhD, collaborated with William Klein, PhD, at Northwestern University, to build on prior studies from the Klein lab and others that indicated close links between Alzheimer’s disease and diabetes. Working with Claudine Bitel and Rajesh Kaswala, students at UMDNJ, the researchers tested whether untreated diabetes would provide a physiological model of Alzheimer neuropathology.

“The results were striking,” Frederikse said. “Because we used diabetes as an instigator of the disease, our study shows — for the first time directly — the link between Alzheimer’s and diabetes.”

The researchers found substantial increases in amyloid beta peptide pathology — a hallmark of Alzheimer’s disease — in the brain cortex and hippocampus concurrent with diabetes. They also found significant amyloid beta pathology in the retina and by contrast, when diabetes is not present, no observable pathology was detected in either the brain or the retina.

“Second, our study examined the retina, which is considered an extension of the brain, and is more accessible for diagnostic exams,” Frederikse added. “Our findings indicate that scientists may be able to follow the onset and progression of Alzheimer’s disease through retinal examination, which could provide a long sought after early-warning sign of the disease.”

This experimental model replicated spontaneous formation of amyloid beta “oligomer” assemblies in brain and retina which may help to explain one of the most widely recognized symptoms of Alzheimer’s. “This is exciting,” Klein said. “Oligomers are the neurotoxins now regarded as causing Alzheimer’s disease memory loss. What could cause them to appear and buildup in late-onset Alzheimer’s disease has been a mystery, so these new findings with diabetes represent an important step.”

Previous research indicated that insulin plays an important role in the formation of memories. Once attached to neurons, oligomers cause insulin receptors to be eliminated from the surface membranes, contributing to insulin resistance in the brain. This launches a vicious cycle in which diabetes induces oligomer accumulation which makes neurons even more insulin resistant.

“In light of the near epidemic increases in Alzheimer’s disease and diabetes today, developing a physiological model of Alzheimer neuropathology has been an important goal,” Kasinathan added. “It allows us to identify a potential biomarker for Alzheimer’s disease and may also make important contributions to Alzheimer drug testing and development.”

The current research was supported by a grant from the National Eye Institute of the National Institutes of Health, the National Institute of Aging, and the Neuroscience Research and Education Foundation. Drs. Kasinathan and Frederikse have applied for patent protection regarding this novel experimental model of Alzheimer neuropathology

 

Moderate Red Wine Drinking May Help Cut Women’s Breast Cancer Risk, Study Suggests

ScienceDaily (Jan. 6, 2012) — Drinking red wine in moderation may reduce one of the risk factors for breast cancer, providing a natural weapon to combat a major cause of death among U.S. women, new research from Cedars-Sinai Medical Center shows.

The study, published online in the Journal of Women’s Health, challenges the widely-held belief that all types of alcohol consumption heighten the risk of developing breast cancer. Doctors long have determined that alcohol increases the body’s estrogen levels, fostering the growth of cancer cells.

But the Cedars-Sinai study found that chemicals in the skins and seeds of red grapes slightly lowered estrogen levels while elevating testosterone among premenopausal women who drank eight ounces of red wine nightly for about a month.

White wine lacked the same effect.

Researchers called their findings encouraging, saying women who occasionally drink alcohol might want to reassess their choices.

“If you were to have a glass of wine with dinner, you may want to consider a glass of red,” said Chrisandra Shufelt, MD, assistant director of the Women’s Heart Center at the Cedars-Sinai Heart Institute and one of the study’s co-authors. “Switching may shift your risk.”

Shufelt noted that breast cancer is the leading type of women’s cancer in the U.S., accounting for more than 230,000 new cases last year, or 30 percent of all female cancer diagnoses. An estimated 39,000 women died from the disease in 2011, according to the American Cancer Society.

In the Cedars-Sinai study, 36 women were randomized to drink either Cabernet Sauvignon or Chardonnay daily for almost a month, then switched to the other type of wine. Blood was collected twice each month to measure hormone levels.

Researchers sought to determine whether red wine mimics the effects of aromatase inhibitors, which play a key role in managing estrogen levels. Aromatase inhibitors are currently used to treat breast cancer.

Investigators said the change in hormone patterns suggested that red wine may stem the growth of cancer cells, as has been shown in test tube studies.

Co-author Glenn D. Braunstein, MD, said the results do not mean that white wine increases the risk of breast cancer but that grapes used in those varieties may lack the same protective elements found in reds.

“There are chemicals in red grape skin and red grape seeds that are not found in white grapes that may decrease breast cancer risk,” said Braunstein, vice president for Clinical Innovation and the James R. Klinenberg, MD, Chair in Medicine.

The study will be published in the April print edition of the Journal of Women’s Health, but Braunstein noted that large-scale studies still are needed to evaluate the safety and effectiveness of red wine to see if it specifically alters breast cancer risk. He cautioned that recent epidemiological data indicated that even moderate amounts of alcohol intake may generally increase the risk of breast cancer in women. Until larger studies are done, he said, he would not recommend that a non-drinker begin to drink red wine.

The research team also included C. Noel Bairey Merz, MD, director of the Women’s Heart Center, director of the Preventive and Rehabilitative Cardiac Center and the Women’s Guild Chair in Women’s Health, as well as researchers from the University of Southern California Keck School of Medicine and Hartford Hospital in Connecticut.

Popular Colorectal Cancer Drug May Cause Permanent Nerve Damage, Study Suggests

ScienceDaily (Sep. 28, 2011) — Oxaliplatin, a platinum-based anticancer drug that’s made enormous headway in recent years against colorectal cancer, appears to cause nerve damage that may be permanent and worsens even months after treatment ends. The chemotherapy side effect, described by Johns Hopkins researchers in the September issue of Neurology, was discovered in what is believed to be the first effort to track oxaliplatin-based nerve damage through relatively cheap and easy punch skin biopsies.

The Johns Hopkins investigators emphasize that the drug therapy clearly improves length of survival in advanced cancer by months to years, and that the goal of their new study is to find ways of preventing or slowing the damage through nerve-protective therapies identfied through simple skin testing.

Many patients who take oxaliplatin report bothersome neurological side effects, including pain in the hands and feet and a numbness or tingling in the throat that affects swallowing, according to study leader Michael Polydefkis, M.D., M.H.S., associate professor of neurology at the Johns Hopkins University School of Medicine and director of the EMG Laboratory and Cutaneous Nerve Laboratory at Johns Hopkins Bayview Medical Center. Though these symptoms develop over time in the majority of patients, some report neuropathies as early as when the drug is first infused.

To get a better sense of how oxaliplatin affects nerve cells, Polydefkis and his colleagues recruited eight cancer patients about to begin oxaliplatin treatment at The Johns Hopkins Hospital. All had been diagnosed with advanced colon cancer.

Before their first oxaliplatin infusion, each patient underwent a comprehensive neurological examination, including nerve conduction testing, a clinical exam to look for signs of nerve damage, and a punch biopsy that removed tiny (3-mm diameter) portions of skin near their knees and ankles. Once oxaliplatin treatment began, consisting of infusions over two days once every two weeks for 12 cycles, the researchers performed the same tests after 30, 90 and 180 days. Another 180 days after they finished with treatment, the patients received one final exam.

Test results showed that each of the patients’ nerve function and neuropathy symptoms worsened over time and that results from the punch skin biopsies neatly mirrored the side effect arc. Using a microscope, the researchers saw that nerve cells’ long extensions, called axons, degenerated over the course of oxaliplatin therapy. This progression persisted after treatment stopped. Even 180 days after their last doses, seven out of the eight patients’ axons continued to wither.

“This drug has rapidly become the standard of care for people with advanced colon cancer, but we really knew little about how oxaliplatin affects nerves over time,” he says. “With people living longer lives on oxaliplatin, it’s important to know more about these neurological side effects so patients and their physicians can make educated choices on how this drug is used, and perhaps suggest ways to limit the damage.”

The new study strongly suggests that punch skin biopsies could be an easy and inexpensive way to follow nerve cell degeneration, a crucial prerequisite for testing the effectiveness of drugs currently in development to trace, prevent or slow nerve damage.

“Skin biopsies can be done pretty easily, uniformly and cheaply anywhere, including hospitals, doctors’ offices and clinics, and those places can have the tissue sent to Hopkins for analysis,” Polydefkis says. “High-quality neurological testing isn’t nearly as easy or economical to do, so it’s possible that the biopsies could play a pivotal role in bringing neuroprotective drugs to fruition.”

Other Johns Hopkins researchers who participated in this study include Ahmet Z. Burakgazi, M.D., Wells Messersmith, M.D., Dhananjay Vaidya, M.D., Ph.D., Peter Hauer, B.S., and Ahmet Hoke, M.D., Ph.D.

Vitamin C May Be Beneficial for Asthmatic Children, Study Suggests

ScienceDaily (Aug. 30, 2011) — Depending on the age of asthmatic children, on their exposure to molds or dampness in their bedroom, and on the severity of their asthma, vitamin C has greater or smaller beneficial effect against asthma, according to a study published in the journal Clinical and Translational Allergy.

Proposals that vitamin C might be beneficial in the treatment of asthma date back to the 1940s, but the findings from controlled trials have been conflicting.

Drs Mohammed Al-Biltagi from the Tanta University in Egypt and Harri Hemila from the University of Helsinki in Finland analyzed the effect of 0.2 grams per day of vitamin C on 60 asthmatic children aged 7 to 10 years. The effect of vitamin C on the forced expiratory volume per one second (FEV1) was modified by age and exposure to molds or dampness. In the younger children aged 7.0 to 8.2 years with no exposure to molds or dampness, vitamin C administration increased the FEV1 level by 37%. In the older children aged 8.3 to 10 years with exposure to molds or dampness in their bedroom more than one year before the study, vitamin C increased the FEV1 level by only 21%.

The effect of vitamin C on the asthma symptoms was modified by age and the severity of asthma symptoms. In the younger children aged 7.0 to 8.2 years with mild asthma symptoms, the benefit of vitamin C was greatest. In the older children aged 8.3 to 10 years who had severe asthma symptoms, the benefit of vitamin C was smallest.

Drs Al-Biltagi and Hemila conclude that there is strong evidence that the effect of vitamin C on asthmatic children is heterogeneous. They consider that it is important to carry out further research to confirm their findings and to more accurately identify the groups of children who would receive the greatest benefit from vitamin C supplementation.

Naturally Occurring Plant Alkaloids Could Slow Down Alzheimer’s Disease, Study Suggests

ScienceDaily (May 26, 2011) — A family of naturally occurring plant compounds could help prevent or delay memory loss associated with Alzheimer’s disease, according to a new study by the Translational Genomics Research Institute (TGen).

Beta-carboline alkaloids could potentially be used in therapeutic drugs to stop, or at least slow down, the progressively debilitating effects of Alzheimer’s, according to the study published recently in the scientific journal Public Library of Science (PLoS) One.

One of these alkaloids, called harmine, inhibits a protein known as DYRK1A, which has been implicated by this and other studies in the formation tau phosphorylation. This process dismantles the connections between brain cells, or neurons, and has been linked in past TGen studies to Alzheimer’s disease.

Tau is a protein critical to the formation of the microtubule bridges in neurons. These bridges support the synaptic connections that, like computer circuits, allow brain cells to communicate with each other.

“Pharmacological inhibition of DYRK1A through the use of beta-carboline alkaloids may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in Alzheimer’s disease,” said Dr. Travis Dunckley, Head of TGen’s Neurodegenerative Research Unit, and the study’s senior author.

Beta-carboline alkaloids are found in a number of medicinal plants. They have antioxidant properties, and have been shown to protect brain cells from excessive stimulation of neurotransmitters. “(They) are natural occurring compounds in some plant species that affect multiple central nervous system targets,” the study said.

Under normal circumstances, proteins regulate tau by adding phosphates. This process of tau phosphorylation enables connections between brain cells to unbind and bind again, allowing neurons to connect and reconnect with other brain cells. However, this process can go awry, allowing the formation of neurofibrillary tangles, one of the signature indicators of Alzheimer’s.

In this study, laboratory tests showed that harmine, and several other beta-carboline alkaloids, “potently reduced” the expression of three forms of phosphorylated tau, and inhibited the ability of DYRK1A to phosphorylate tau protein at multiple genetic sites associated with tau pathology.

“These results suggest that this class of compounds warrant further investigation as candidate tau-based therapeutics to alter the onset or progression of tau dysfunction and pathology in Alzheimer’s disease,” Dr. Dunckley said.

The Arizona Alzheimer’s Consortium, the National Institute on Aging, and the Louis Charitable Trust funded the study. The Consortium is funded in part by the Arizona Legislature through the Arizona Department of Health Services, which supported a portion of the study. Members of the Consortium also participated in the study. MediProPharma Inc. supported portions of the study.

Routine Periodic Fasting Is Good for Your Health, and Your Heart, Study Suggests

ScienceDaily (May 20, 2011) — Fasting has long been associated with religious rituals, diets, and political protests. Now new evidence from cardiac researchers at the Intermountain Medical Center Heart Institute demonstrates that routine periodic fasting is also good for your health, and your heart.

Research cardiologists at the Intermountain Medical Center Heart Institute are reporting that fasting not only lowers one’s risk of coronary artery disease and diabetes, but also causes significant changes in a person’s blood cholesterol levels. Both diabetes and elevated cholesterol are known risk factors for coronary heart disease.

The discovery expands upon a 2007 Intermountain Healthcare study that revealed an association between fasting and reduced risk of coronary heart disease, the leading cause of death among men and women in America. In the new research, fasting was also found to reduce other cardiac risk factors, such as triglycerides, weight, and blood sugar levels.

The findings were presented on April 3, at the annual scientific sessions of the American College of Cardiology in New Orleans.

“These new findings demonstrate that our original discovery was not a chance event,” says Dr. Benjamin D. Horne, PhD, MPH, director of cardiovascular and genetic epidemiology at the Intermountain Medical Center Heart Institute, and the study’s principal investigator. “The confirmation among a new set of patients that fasting is associated with lower risk of these common diseases raises new questions about how fasting itself reduces risk or if it simply indicates a healthy lifestyle.”

Unlike the earlier research by the team, this new research recorded reactions in the body’s biological mechanisms during the fasting period. The participants’ low-density lipoprotein cholesterol (LDL-C, the “bad” cholesterol) and high-density lipoprotein cholesterol (HDL-C, the “good” cholesterol) both increased (by 14 percent and 6 percent, respectively) raising their total cholesterol — and catching the researchers by surprise.

“Fasting causes hunger or stress. In response, the body releases more cholesterol, allowing it to utilize fat as a source of fuel, instead of glucose. This decreases the number of fat cells in the body,” says Dr. Horne. “This is important because the fewer fat cells a body has, the less likely it will experience insulin resistance, or diabetes.”

This recent study also confirmed earlier findings about the effects of fasting on human growth hormone (HGH), a metabolic protein. HGH works to protect lean muscle and metabolic balance, a response triggered and accelerated by fasting. During the 24-hour fasting periods, HGH increased an average of 1,300 percent in women, and nearly 2,000 percent in men.

In this most recent trial, researchers conducted two fasting studies of over 200 individuals — both patients and healthy volunteers — who were recruited at Intermountain Medical Center. A second 2011 clinical trial followed another 30 patients who drank only water and ate nothing else for 24 hours. They were also monitored while eating a normal diet during an additional 24-hour period. Blood tests and physical measurements were taken from all to evaluate cardiac risk factors, markers of metabolic risk, and other general health parameters.

While the results were surprising to researchers, it’s not time to start a fasting diet just yet. It will take more studies like these to fully determine the body’s reaction to fasting and its effect on human health. Dr. Horne believes that fasting could one day be prescribed as a treatment for preventing diabetes and coronary heart disease.

To help achieve the goal of expanded research, the Deseret Foundation (which funded the previous fasting studies) recently approved a new grant to evaluate many more metabolic factors in the blood using stored samples from the recent fasting clinical trial. The researchers will also include an additional clinical trial of fasting among patients who have been diagnosed with coronary heart disease.

“We are very grateful for the financial support from the Deseret Foundation. The organization and its donors have made these groundbreaking studies of fasting possible,” added Dr. Horne.

Members of the Intermountain Medical Center Heart Institute research team included Dr. Horne, Jeffrey L. Anderson, MD, John F. Carlquist, PhD, J. Brent Muhlestein, MD, Donald L. Lappé, MD, Heidi T. May, PhD, MSPH, Boudi Kfoury, MD, Oxana Galenko, PhD, Amy R. Butler, Dylan P. Nelson, Kimberly D. Brunisholz, Tami L. Bair, and Samin Panahi

Taking Additional Selenium Will Not Reduce Cancer Risk, Study Suggests

ScienceDaily (May 13, 2011) — Although some people believe that taking selenium can reduce a person’s risk of cancer, a Cochrane Systematic Review of randomised controlled clinical trials found no protective effect against non-melanoma skin cancer or prostate cancer. In addition, there is some indication that taking selenium over a long period of time could have toxic effects.

These conclusions were reached after researchers scanned the medical literature, looking for trials that studied the effects of taking selenium supplements and observational studies on selenium intake. The researchers located 49 prospective observational studies and six randomised controlled trials.

Looking at the data from observational studies gave some indication that people may be marginally protected from cancer if they had a higher selenium intake than those with a lower intake, and that the effect was slightly greater for men than women. “These conclusions have limitations because the data came from a wide variety of trials, and so it is difficult to summarise their findings,” says lead researcher Dr Gabriele Dennert of the Institute for Transdisciplinary Health Research, Berlin, Germany, who coordinated the work of the international team of experts.

When the team of researchers looked at the more carefully conducted randomised controlled trials, any sign of benefit disappeared. “In fact, the results of the Nutritional Prevention of Cancer Trial and the Selenium and Vitamin E Cancer Prevention Trial raised concerns about possible harmful effects from long-term use of selenium supplements,” says Dennert.

The researchers believe that there is a need for more research looking at selenium’s effect on liver cancer and think that it would be worth investigating the possible gender differences that appear to be present in the uncontrolled studies.

“However, we could find no evidence to recommend regular intake of selenium supplements for cancer prevention in people whether or not they already have enough selenium,” says Dennert.

Estrogen-Lowering Drugs Reduce Mastectomy Rates for Breast Cancer Patients, Study Suggests

ScienceDaily (May 9, 2011) — In the first large trial of its kind in the United States, researchers have shown that estrogen-lowering drugs can shrink tumors and reduce mastectomy rates for patients with stage 2 or 3 breast cancer. Patients with these larger breast tumors have two options, says Matthew J. Ellis, MD, PhD, of Washington University School of Medicine in St. Louis and principal investigator of the trial conducted by the American College of Surgeons Oncology Group. “One option is to undergo mastectomy. The second is to receive medication before surgery to reduce the size of the tumor so that breast-conserving surgery becomes possible,” he says.

Those who choose the second option usually receive chemotherapy. But now, Ellis and colleagues have shown that post-menopausal women with estrogen-receptor positive breast cancer can benefit from a class of drugs called aromatase inhibitors that lower the amount of estrogen in the body. Since estrogen-receptor positive breast cancers feed off estrogen, aromatase inhibitors can slow or stop the growth of these tumors in women who have undergone menopause.

Though estrogen no longer comes from the ovaries, post-menopausal women still make small amounts of estrogen with the enzyme aromatase. Aromatase inhibitors block this enzyme, eliminating the body’s remaining estrogen. Because aromatase inhibitors don’t stop the ovaries from making estrogen, they only work in post-menopausal women.

The results appear online May 9, in the Journal of Clinical Oncology.

Of the 159 women in the trial who were originally told they required mastectomy, 81 or slightly more than half saw sufficient tumor shrinkage after 16 weeks of aromatase inhibitor treatment to undergo breast-conserving surgery instead.

“At the beginning, all of these patients were going to get mastectomy and at the end of the trial only half got mastectomy,” says Ellis, also an oncologist who treats patients at the Alvin J. Siteman Cancer Center at Washington University and Barnes-Jewish Hospital. “That’s a very substantial improvement in surgical outcomes.”

In addition, of the 189 women originally considered “marginal” for breast conservation (because it would likely be disfiguring), 83 percent saw enough tumor regression to undergo breast conserving-surgery rather than mastectomy. And of the four patients originally classified as inoperable (because mastectomy would not remove all the cancer), three saw enough tumor regression to undergo breast-conserving surgery and only one received mastectomy.

Beyond these benefits, aromatase inhibitors do not have the toxic side effects of traditional chemotherapy. And for this particular group of patients, Ellis says it is well established that aromatase inhibitors are more active in preventing relapses than chemotherapy.

In all, 352 women were randomly assigned to receive one of three FDA-approved aromatase inhibitors — letrozole, anastrozole and exemestane. Letrozole and anastrozole were slightly better than exemestane in shrinking tumors. But there were no other differences between the three drugs in surgery rates and in a key measure of how well the drugs stopped cancer cells from dividing, called the Ki67 cell proliferation biomarker.

“These aromatase inhibitors were subject to a lot of debate as to whether one was better than another,” Ellis says. “We found some minor differences in the amount of tumor shrinkage the patients experienced. But there was no difference between the three drugs in terms of how effectively they stopped the tumor growing.”

Ellis points out that this smaller trial came to the same conclusions as much larger, more expensive trials designed to compare the same drugs. Instead of looking at the final outcome for the patient in the larger trials, Ellis stresses the importance of using biomarkers such as the Ki67 measure of cell division to look at the tumors’ biological response to the drugs.

“If we can show the drugs are biologically equivalent with a few hundred patients, we should not waste our time with superiority trials involving thousands of patients comparing the same agents,” he says.

But according to Ellis, if one drug is shown to be superior in the smaller trial, then a larger trial to test the outcomes for patients becomes worthwhile.

“This concept is critical in terms of how we target our research investments. Large trials that find no difference between drugs should be avoided as much as possible given the tens of millions of dollars required to complete these studies,” he says.

Despite the improved surgical outcomes for some patients in this trial, Ellis points out that many women still required mastectomy because their tumors did not respond adequately to the aromatase inhibitor treatment.

“The biggest question in my mind is how best to treat the aromatase inhibitor-resistant patients,” he says. “These patients have poor outcomes and currently there is no known targeted therapy for them. The question of aromatase inhibitor resistance is a critical issue to understand and address therapeutically.”

In an effort to find out why certain tumors are resistant to these drugs, Ellis and colleagues at Washington University’s Genome Institute just reported the complete tumor and healthy DNA sequences of 50 breast cancer patients enrolled in this trial. Twenty-six of the 50 tumors responded to treatment and 24 tumors did not.

“The patients gifted a sample of their tumor to the study and, because we know whether a tumor is responsive or resistant, we can start doing really profound studies to understand the molecular basis for variation in response,” he says. “Ultimately, we hope the genomics instruct which new drugs to use to develop more effective treatment strategies.”

Presentation: Ellis MJ et al. Analysis of luminal-type breast cancer by massively parallel sequencing. Presented Apr. 2, 2011 at the 102nd Annual Meeting of the American Association for Cancer Research in Orlando, FL.

This work was supported by grants from the National Cancer Institute, the Breast Cancer Research Foundation, the Komen St. Louis Affiliate Clinical Trials Grant, and grants to support the American College of Surgeons Oncology Group for the conduct of this trial from Pfizer and Novartis.

Estrogen-Lowering Drugs Reduce Mastectomy Rates for Breast Cancer Patients, Study Suggests

ScienceDaily (May 9, 2011) — In the first large trial of its kind in the United States, researchers have shown that estrogen-lowering drugs can shrink tumors and reduce mastectomy rates for patients with stage 2 or 3 breast cancer.

Patients with these larger breast tumors have two options, says Matthew J. Ellis, MD, PhD, of Washington University School of Medicine in St. Louis and principal investigator of the trial conducted by the American College of Surgeons Oncology Group. “One option is to undergo mastectomy. The second is to receive medication before surgery to reduce the size of the tumor so that breast-conserving surgery becomes possible,” he says.

Those who choose the second option usually receive chemotherapy. But now, Ellis and colleagues have shown that post-menopausal women with estrogen-receptor positive breast cancer can benefit from a class of drugs called aromatase inhibitors that lower the amount of estrogen in the body. Since estrogen-receptor positive breast cancers feed off estrogen, aromatase inhibitors can slow or stop the growth of these tumors in women who have undergone menopause.

Though estrogen no longer comes from the ovaries, post-menopausal women still make small amounts of estrogen with the enzyme aromatase. Aromatase inhibitors block this enzyme, eliminating the body’s remaining estrogen. Because aromatase inhibitors don’t stop the ovaries from making estrogen, they only work in post-menopausal women.

The results appear online May 9, in the Journal of Clinical Oncology.

Of the 159 women in the trial who were originally told they required mastectomy, 81 or slightly more than half saw sufficient tumor shrinkage after 16 weeks of aromatase inhibitor treatment to undergo breast-conserving surgery instead.

“At the beginning, all of these patients were going to get mastectomy and at the end of the trial only half got mastectomy,” says Ellis, also an oncologist who treats patients at the Alvin J. Siteman Cancer Center at Washington University and Barnes-Jewish Hospital. “That’s a very substantial improvement in surgical outcomes.”

In addition, of the 189 women originally considered “marginal” for breast conservation (because it would likely be disfiguring), 83 percent saw enough tumor regression to undergo breast conserving-surgery rather than mastectomy. And of the four patients originally classified as inoperable (because mastectomy would not remove all the cancer), three saw enough tumor regression to undergo breast-conserving surgery and only one received mastectomy.

Beyond these benefits, aromatase inhibitors do not have the toxic side effects of traditional chemotherapy. And for this particular group of patients, Ellis says it is well established that aromatase inhibitors are more active in preventing relapses than chemotherapy.

In all, 352 women were randomly assigned to receive one of three FDA-approved aromatase inhibitors — letrozole, anastrozole and exemestane. Letrozole and anastrozole were slightly better than exemestane in shrinking tumors. But there were no other differences between the three drugs in surgery rates and in a key measure of how well the drugs stopped cancer cells from dividing, called the Ki67 cell proliferation biomarker.

“These aromatase inhibitors were subject to a lot of debate as to whether one was better than another,” Ellis says. “We found some minor differences in the amount of tumor shrinkage the patients experienced. But there was no difference between the three drugs in terms of how effectively they stopped the tumor growing.”

Ellis points out that this smaller trial came to the same conclusions as much larger, more expensive trials designed to compare the same drugs. Instead of looking at the final outcome for the patient in the larger trials, Ellis stresses the importance of using biomarkers such as the Ki67 measure of cell division to look at the tumors’ biological response to the drugs.

“If we can show the drugs are biologically equivalent with a few hundred patients, we should not waste our time with superiority trials involving thousands of patients comparing the same agents,” he says.

But according to Ellis, if one drug is shown to be superior in the smaller trial, then a larger trial to test the outcomes for patients becomes worthwhile.

“This concept is critical in terms of how we target our research investments. Large trials that find no difference between drugs should be avoided as much as possible given the tens of millions of dollars required to complete these studies,” he says.

Despite the improved surgical outcomes for some patients in this trial, Ellis points out that many women still required mastectomy because their tumors did not respond adequately to the aromatase inhibitor treatment.

“The biggest question in my mind is how best to treat the aromatase inhibitor-resistant patients,” he says. “These patients have poor outcomes and currently there is no known targeted therapy for them. The question of aromatase inhibitor resistance is a critical issue to understand and address therapeutically.”

In an effort to find out why certain tumors are resistant to these drugs, Ellis and colleagues at Washington University’s Genome Institute just reported the complete tumor and healthy DNA sequences of 50 breast cancer patients enrolled in this trial. Twenty-six of the 50 tumors responded to treatment and 24 tumors did not.

“The patients gifted a sample of their tumor to the study and, because we know whether a tumor is responsive or resistant, we can start doing really profound studies to understand the molecular basis for variation in response,” he says. “Ultimately, we hope the genomics instruct which new drugs to use to develop more effective treatment strategies.”

Presentation: Ellis MJ et al. Analysis of luminal-type breast cancer by massively parallel sequencing. Presented Apr. 2, 2011 at the 102nd Annual Meeting of the American Association for Cancer Research in Orlando, FL.

This work was supported by grants from the National Cancer Institute, the Breast Cancer Research Foundation, the Komen St. Louis Affiliate Clinical Trials Grant, and grants to support the American College of Surgeons Oncology Group for the conduct of this trial from Pfizer and Novartis.

Prolonged Bottle Feeding Increases the Risk of Obesity, Study Suggests

ScienceDaily (May 6, 2011) — Experts agree that obesity prevention should begin before children enter school. But due to a lack of conclusive data, health care providers often have trouble advising parents about which interventions are the most beneficial. A new study soon to be published in The Journal of Pediatrics suggests that limiting prolonged bottle use in children may be an effective way to help prevent obesity.

 

Dr. Robert Whitaker and Rachel Gooze of the Center for Obesity Research and Education at Temple University, and Dr. Sarah Anderson of The Ohio State University College of Public Health, analyzed data from the Early Childhood Longitudinal Study, Birth Cohort, a large national study of children born in 2001. They analyzed data from 6750 children to estimate the association between bottle use at 24 months of age and the risk of obesity at 5.5 years of age.

Of the children studied, 22% were prolonged bottle users, meaning that at 2 years of age they used a bottle as their primary drink container and/or were put to bed with a calorie-containing bottle. Nearly 23% of the prolonged bottle users were obese by the time they were 5.5 years old. “Children who were still using a bottle at 24 months were approximately 30% more likely to be obese at 5.5 years, even after accounting for other factors such as the mother’s weight, the child’s birth weight, and feeding practices during infancy,” Dr. Whitaker notes.

Drinking from a bottle beyond infancy may contribute to obesity by encouraging the child to consume too many calories. “A 24-month-old girl of average weight and height who is put to bed with an 8-ounce bottle of whole milk would receive approximately 12% of her daily caloric needs from that bottle,” Rachel Gooze explains. She notes that weaning children from the bottle by the time they are 1 year of age is unlikely to cause harm and may prevent obesity. The authors suggest that pediatricians and other health professionals work with parents to find acceptable solutions for stopping bottle use at the child’s first birthday.