The pace at which Americans are getting cancer has started to decline, marking what could be a long-awaited turning point in the battle against the disease, according to an annual report that tracks progress in the war on cancer.

Cancer deaths have also continued a decline that began in the early 1990s, meaning that for the first time both trend lines are dropping.

“It is a significant milestone,” said Otis W. Brawley, chief medical officer at the American Cancer Society, which produces the report with the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries.

The drop in new cancer diagnoses has been driven largely by declines in many of the leading forms of cancer: lung, prostate and colorectal cancer in men, and breast and colorectal cancer in women.

The analysis found that the overall incidence of cancer began inching down in 1999, but not until the data for 2005 were analyzed was it clear that a long-term decline was underway.

“The take-home message is that many of the things we’ve been telling people to do to be healthy have finally reached the point where we can say that they are working,” Brawley said. “These things are really starting to pay off.”

Brawley and others cautioned, however, that part of the reduction could be the result of fewer people getting screened for prostate and breast cancers. In addition, the rates at which many other types of cancer are being diagnosed are still increasing, he said, and overall far too many Americans are still getting and dying from cancer.

Cancer is still being diagnosed in about 1.4 million Americans each year, and 560,000 die from it.

“We still have a lot to do,” Brawley said. “If you look at the data, it’s clear that we could still do much better — much, much better.”

Some experts said the drop was not surprising, noting that it was primarily the result of a fall in lung cancer because of declines in smoking that occurred decades ago. They criticized the ongoing focus on detecting and treating cancer and called for more focus on prevention.

“The whole cancer establishment has been focused on treatment, which has not been terribly productive,” said John C. Bailar III, who studies cancer trends at the National Academy of Sciences. “I think what people should conclude from this is we ought to be putting most of our resources where we know there has been progress, almost in spite of what we’ve done, and stop this single-minded focus on treatment.”

Bailar and others argue that research should emphasize identifying the underlying causes of cancer, such as environmental exposures, to prevent it from occurring in the first place.

A study performed by the team of Dr. Nabil G. Seidah, Director of the Biochemical Neuroendocrinology Research Unit at the IRCM, shows for the very first time that the degradation by PCSK9 of the LDLR receptor, which is responsible for removing the bad cholesterol (LDL-cholesterol) from the bloodstream, may be inhibited by a third protein, annexin A2.

This major discovery co-authored by Gaétan Mayer, a postdoctoral fellow, Steve Poirier, a doctoral student, and Dr. Seidah was published on November 14 in the Journal of Biological Chemistry (JBC).

Genetic studies on humans have clearly shown that PCSK9 is a prime therapeutic target for the prevention and treatment of cardiovascular diseases. PCSK9 proprotein convertase promotes the degradation of the receptor responsible for eliminating LDL-cholesterol particles. Thus, the presence of PCSK9 leads to a surplus of bad cholesterol in the bloodstream and contributes to plaque formation, leading to blockage of blood vessels and arteries.

This phenomenon is a major risk factor that can lead to cardiovascular diseases, such as heart attack, atherosclerosis and stroke. Mutations of human genes have demonstrated that a rise in PCSK9 activity results in a major increase in LDL-cholesterol and familial hypercholesterolemia. Conversely, in people with a non-functional mutation in the gene coding for PCSK9, a decrease in its activity brings down the LDL-cholesterol concentration levels in the bloodstream and diminishes by up to 88% the risks of developing cardiovascular diseases.

“By performing a series of biochemical experiments, we discovered that annexin A2 binds strongly to PCSK9 and inhibits its function,” remarks Gaétan Mayer, the article’s first author.

This discovery should pave the way toward the development of a new drug that would lower blood cholesterol to recommended levels. Currently, cholesterol lowering drugs known as “statins” are used by more than 25 million people worldwide. Statins decrease cholesterol synthesis and increase the number of LDL-receptors, thus efficiently decreasing plasma cholesterol levels; however, they also increase the amount of PCSK9, which degrades those receptors, thus reducing the effect of statins.

A drug that would block PCSK9 could either be used alone or jointly with statins and would be highly beneficial to patients in whom statins do not work or are unable to take this drug.

This work was supported by the Canadian Institutes of Health Research (CIHR) and by a Canada Research Chair.

1. Mayer G, Poirier S, and Seidah NG. Annexin A2 Is a C-terminal PCSK9-binding Protein That Regulates Endogenous Low Density Lipoprotein Receptor Levels. Journal of Biological Chemistry, 2008; 283 (46): 31791 DOI: 10.1074/jbc.M805971200

Adapted from materials provided by Institut de recherches cliniques de Montreal.

New research by The University of Texas School of Public Health shows that a medication for high blood pressure called a diuretic or water pill is particularly effective at reducing the risk for a type of heart failure that affects women more often than men.

Heart failure is a clinical syndrome characterized by an inadequate supply of oxygen rich blood as a result of impaired cardiac pump function. More than 5 million Americans are living with heart failure and most had high blood pressure before developing this potentially deadly condition.

While much research has been focused on the impact of antihypertensive medications on the prevention of heart failure associated with reduced pumping capacity in the heart’s all-important left ventricle, comparatively little research has been performed on the prevention of heart failure wherein the heart muscle is clearing a normal or preserved percentage of blood with each heart beat. This percentage is called left ventricular ejection fraction (LVEF).

“We showed that a diuretic was as good as or better than other classes of medication for high blood pressure in reducing the occurrence of heart failure in people with a wide range of left ventricular ejection fraction,” said Barry Davis, M.D., Ph.D., the study’s lead author, the Guy S. Parcel Chair in Public Health and director of the Coordinating Center for Clinical Trials at the UT School of Public Health.

The study involved 910 hypertensive adults who had been taking antihypertensive medications and who were subsequently diagnosed with heart failure in a hospital. Those with an ejection fraction of 50 percent or more were defined as Heart Failure Preserved Ejection Fraction (HFPEF) and those with an ejection fraction of 49 percent or less as Heart Failure Reduced Ejection Fraction (HFREF). Forty-four percent had preserved ejection fraction and 56 percent reduced ejection fraction.

Participants treated with a thiazide-type diuretic (chlorthalidone) had reduced risk of Heart Failure Preserved Ejection Fraction compared to those taking a calcium channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), or an alpha-adrenergic blocker (doxazosin). Chlorthalidone reduced the risk in people with reduced ejection fraction compared with amlodipine or doxazosin. Chlorthalidone was similar to lisinopril in preventing heart failure with reduced ejection fraction. “On the basis of the data from many heart failure trials, a combination of the last two agents would be expected to be particularly effective in preventing heart failure in this group,” the authors wrote.

“In both heart failure with preserved and reduced ejection fraction, the diuretic is helping to remove excess fluid - which can reduce both pre load and after load and thus increase ejection fraction,” Davis said.

Heart failure patients with preserved ejection fraction may still have big problems, Davis said. “Let’s say the heart normally should pump 70 milliliters (ml) of blood. It fills up with 100 ml and pumps 70 for an EF of 70 percent (which is good). However with reduced ejection fraction it only pumps 30 ml or has an EF of only 30 percent. On the other hand you could have preserved ejection fraction and in this case the heart fill up with just 50 ml of blood but pumps 30 ml. The EF would be 60 percent. In both cases, only 30 ml is reaching the body.”

Davis said heart failure is sometimes characterized as either systolic or diastolic heart failure. In systolic heart failure, there is reduced cardiac contractility, whereas in diastolic heart failure there is impaired cardiac relaxation and abnormal ventricular filling. Heart Failure Preserved Ejection Fraction is typically associated with the filling blood phase and Heart Failure Reduced Ejection Fraction with the forcing blood out phase.

Participants with preserved ejection fraction compared to those with reduced ejection fraction were more likely to be women (52 percent versus 38 percent) and less likely to have a history of coronary heart disease (32 percent versus 39 percent). People with heart failure with preserved ejection fraction have a subsequent mortality rate almost as high as those with reduced ejection fraction, about 50 percent at five years.

Participants in the study were from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, multi-center clinical trial that compared four classes of medications for high blood pressure. More than 42,000 people 55 years of age or more with hypertension were in the trial between 1994 and 2002.

Davis’ collaborators from the UT School of Public Health were Charles E. Ford, Ph.D., associate professor of biostatistics and Lara M. Simpson, Ph.D., faculty associate. Also contributing were: John B. Kostis, M.D., UMDNJ-Robert Wood Johnson Medical School, New Brunswick, N.J. ; Henry R. Black, M.D., New York University School of Medicine, New York, N.Y.; William C. Cushman, M.D., Memphis Veteran’s Affairs Medical Center, Memphis, Tenn.; Paula T. Einhorn, M.D., Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, Md.; Michael A. Farber, M.D., Crozer Keystone Health Network, Upland, Pa.; Daniel Levy, M.D., Framingham Heart Study/National Heart, Lung and Blood Institute Framingham, Mass.; Barry M. Massie, M.D., San Francisco Veterans Affairs Medical Center, San Francisco, Calif.; and Shah Nawaz, M.D., private practice in Sudbury, Ontario, Canada.

Research was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health and the U.S. Department of Health and Human Services, Bethesda, Md.

1. . Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation: Journal of the American Heart Association, Nov. 10 online issue

Adapted from materials provided by University of Texas Health Science Center at Houston.

Statins, the class of drugs commonly used for lowering cholesterol, are now showing promise at preventing deep vein thrombosis (DVT) or blood clots, an affliction that occurs in nearly 2 million Americans each year.

New research presented at CHEST 2008, the 74th annual international scientific assembly of the American College of Chest Physicians (ACCP), suggests that the use of statins may be associated with a significant reduction in the occurrence of venous thromboembolism (VTE), a condition that includes DVT and pulmonary embolism, in patients with solid organ tumors, including breast, lung, and colon cancers.

“The results of our research are interesting and thought provoking,” said study author Danai Khemasuwan, MD, Albert Einstein Medical Center, Philadelphia, PA. “We hope that our research alerts the scientific community to the potential of statins in reducing VTE.”

Dr. Khemasuwan and his colleagues from Albert Einstein Medical Center evaluated the influence of statins use on the incidence of VTE by reviewing 740 consecutive patients admitted to the hospital between October 2004 and September 2007 with a diagnosis of breast, lung, colon, prostate, stomach, esophagus, pancreas, ovary, kidney, or brain cancer. The occurrence of VTE, risk factors for VTE, and use of statins were recorded. Patients who either used statins for less than 2 months or who never used statins were allocated to the control group.

The mean age of the entire study population was 65 years, 52 percent of subjects were women, and 76 percent were African-American. A total of 26 percent of patients received statins, and the overall incidence of VTE was 18 percent. The analysis revealed that patients receiving statins were significantly less likely to develop VTE than the control group, with 8 percent of patients receiving statins developing VTE compared with 21 percent in the control group. A logistical regression analysis yielded the same results irrespective of smoking, documented metastatic disease, current use of chemotherapy, immobilization, and use of aspirin.

Although the authors could not draw conclusions about the cause and effect relationship between statins and VTE, Dr. Khemasuwan feels the data are promising. “If the results of our study are confirmed in a prospective randomized, controlled trial, this could have very significant implications for the medical community.”

“Recent studies have examined the use of statins for the prevention of lung disease, stroke, and other neurologic disorders,” said James A. L. Mathers, Jr., MD, FCCP, President of the American College of Chest Physicians. “The results of this study are promising and suggest a potential role for statins in the prevention of thromboembolism.”

CHEST 2008 is the 74th annual international scientific assembly of the American College of Chest Physicians, held October 25-30 in Philadelphia, PA.

The brains of individuals with major depressive disorder appear to react more strongly when anticipating pain and also display altered functioning of the neural network that modifies pain sensitivity, according to a new report.

“Chronic pain and depression are common and often overlapping syndromes,” the authors write as background information in the article. Recurring or chronic pain occurs in more than 75 percent of patients with depression, and between 30 percent and 60 percent of patients with chronic pain report symptoms of depression “Understanding the neurobiological basis of this relationship is important because the presence of comorbid pain contributes significantly to poorer outcomes and increased cost of treatment in major depressive disorder.”

Irina A. Strigo, Ph.D., of the University of California San Diego, La Jolla, and colleagues studied 15 young adults with major depressive disorder (average age 24.5) who were not taking medication and 15 individuals who were the same age (average 24.3 years) and had the same education level but did not have depression. Patients with depression completed a questionnaire that evaluated their tendencies to magnify, ruminate over or feel helpless in the face of pain. All participants underwent functional magnetic resonance imaging (fMRI) while their arms were exposed to a thermal device heated to painful levels (an average of 46.4 degrees to 46.9 degrees Celsius, or about 115 degrees to 116 degrees Fahrenheit) and also to non-painful temperatures. Visual cues (a green shape for non-painful warmth and a red shape for painful warmth) were presented before the heat was applied.

Compared with the controls, patients with depression showed increased activation in certain areas of their brain—including the right amygdala—during the anticipation of painful stimuli. They also displayed increased activation in the right amygdala and decreased activation in other areas, including those responsible for pain modulation (adjusting sensitivity to pain), during the painful experience.

To examine whether the activation of the amygdala was associated with passive coping styles, the researchers compared the percentage change in the activations of the amygdala with the helplessness, rumination and ramification reported by the participants with depression. “Significant positive correlations were observed in the major depressive disorder group between greater helplessness scores and greater activity in the right amygdala during the anticipation of pain,” the authors write.

“The anticipatory brain response may indicate hypervigilance to impending threat, which may lead to increased helplessness and maladaptative modulation during the experience of heat pain,” the authors write. “This mechanism could in part explain the high comorbidity of pain and depression when these conditions become chronic.”

“Future studies that directly examine whether maladaptive response to pain in major depressive disorder is due to emotional allodynia [a pain response to a non-painful stimulus], maladaptive control responses, lack of resilience and/or ineffectual recruitment of positive energy resources will further our understanding of pain-depression comorbidity,” they conclude.

This study was supported by Barrow Neurological Foundation, grants from the National Institute of Mental Health, the National Association for Research in Schizophrenia and Depression and the University of California San Diego Center of Excellence for Stress and Mental Health.

1. Irina A. Strigo, PhD; Alan N. Simmons, PhD; Scott C. Matthews, MD; Arthur D. (Bud) Craig, PhD; Martin P. Paulus, MD. Association of Major Depressive Disorder With Altered Functional Brain Response During Anticipation and Processing of Heat Pain. Arch Gen Psychiatry, 2008;65(11):1275-1284

Adapted from materials provided by JAMA and Archives Journals.

The diabetes medication metformin may be associated with a lower risk of death from cardiovascular disease, according to a meta-analysis of previously published studies. No associations were found between other diabetes medications and beneficial or harmful cardiovascular effects, in part because of insufficient data, the authors note.

“A wide variety of oral diabetes medications are currently available for the treatment of type 2 diabetes mellitus,” they write as background information in the article. “With the addition of newer oral therapies to the market in the late 1990s (e.g., thiazolidinediones and meglitinides), it is critical to evaluate how these agents compare with older medications. This is particularly important in light of the expense of many of the newer therapies.” The specific effects of these medications on cardiovascular health remains unclear, and recent controversy has surrounded possible cardiac risks associated with one newer drug, rosiglitazone.

Elizabeth Selvin, Ph.D., M.P.H., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues performed a meta-analysis of data from 40 clinical trials published on or before Jan. 19, 2006. All the trials assessed the benefits or harms of oral diabetes medications approved for use in the United States, including combinations of therapies commonly prescribed by physicians, and included information about heart attack, stroke or other cardiovascular events. The average age of participants ranged from 52 to 69 and 27 of the studies (68 percent) were less than one year in duration.

“Treatment with metformin hydrochloride was associated with a decreased risk of cardiovascular morality [death] compared with any other oral diabetes agent or placebo; the results for cardiovascular morbidity [illness] and all-cause mortality were similar but not statistically significant,” the authors write. “No other significant associations of oral diabetes agents with fatal or non-fatal cardiovascular disease or all-cause mortality were observed. When compared with any other agent or placebo, rosiglitazone was the only diabetes agent associated with an increased risk of cardiovascular morbidity and mortality, but this result was not statistically significant.”

Poor quality and inconsistent reporting of cardiovascular data, along with the lack of long-term studies, make it difficult to draw firm conclusions, the authors note. “Our study demonstrates that there have been few trials of oral diabetes therapies that have lasted longer than six months and that reporting of adverse events for cardiovascular disease is poor,” they continue.

“There is a critical need for studies of oral diabetes medications with long-term outcomes. The relatively modest differences in blood pressure, cholesterol levels and weight observed after treatment with oral diabetes medications in short-term trials may not translate to changes in long-term cardiovascular risk. Only long-term trials can provide definitive conclusions regarding the comparative efficacy of oral diabetes medications and long-term risks.”

This article is based on research conducted by the Johns Hopkins Evidence-Based Practice Center under a contract with the Agency for Healthcare Research and Quality. This study was also supported by grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.

Editorial: Innovative Approaches Needed to Ensure Safety of Diabetes Medications

“Selvin et al noted that, when it comes to choosing the safest oral agents, the quality of the data are problematic,” writes David M. Nathan, M.D., of Massachusetts General Hospital, Boston, in an accompanying editorial.

“The current approach to assessing the relatively rare but clinically important adverse effects of diabetes management is unsatisfactory,” he continues. “The vagaries of meta-analyses make them unreliable. On the other hand, increasing the size and duration of controlled clinical trials to provide adequate statistical power to detect relatively infrequent events would potentially bankrupt the pharmaceutical industry that supports most of the trials and delay the development of new drugs.”

New approaches are needed to ensure the safety of drugs without slowing development, Dr. Nathan concludes. “For example, the phased introduction of new medications with uniform, standardized collection of adverse outcome data might identify relatively rare complications before the drugs are used by millions. Similarly, the use of clinical databases may provide an early alert regarding adverse outcomes,” he writes. “In the meantime, there are well-established and safe treatments that, if used aggressively, can improve the long-term health of patients with type 2 diabetes.”

1. Elizabeth Selvin; Shari Bolen; Hsin-Chieh Yeh; Crystal Wiley; Lisa M. Wilson; Spyridon S. Marinopoulos; Leonard Feldman; Jason Vassy; Renee Wilson; Eric B. Bass; Frederick L. Brancati. Cardiovascular Outcomes in Trials of Oral Diabetes Medications: A Systematic Review. Arch Intern Med., 2008;168(19):2070-2080 [link]

Adapted from materials provided by JAMA and Archives Journals.