Jewish World Review June 14, 2004 / 25 Sivan, 5764

A possible cure for the flu?; more statin news…; lung cancer: men vs. women; Pipe smoking and tobacco-associated disease; more

By Robert A. Wascher, M.D., F.A.C.S. | As I write this column, my throat feels as if it is filled with broken glass shards each time I swallow, I am burning with fever, every muscle in my body aches, my head pounds with each beat of my heart, and every other breath sparks a fit of raspy coughing that exacerbates all of my other symptoms. While many different viruses are capable of causing the constellation of symptoms that I have been suffering with over the past three days, they are classic for infections caused by the influenza virus, or "the flu." For most flu sufferers, these symptoms wane over about 72 hours, and a complete recovery ensues.

Meanwhile, hours and days lost from work, and the significant discomfort experienced with even relatively mild bouts of the flu, exact their toll on both individuals and society.

However, the more vulnerable among us, primarily the very young, the very old, and others with impaired immune systems, may become seriously ill, or even die, after exposure to the influenza virus.

Year after year, the influenza virus causes hundreds of thousands of death around the world. Periodically, the prevalent strain of influenza virus can undergo a peculiar rearrangement of its protein envelope through mutation, yielding a particularly virulent and lethal strain of virus. This mutation may result in a flu pandemic, or an epidemic that occurs on a global basis. Rarely, as occurred in the 1918 Spanish Flu Pandemic, the virus may mutate into an especially lethal strain, lethal even to young healthy adults. During the Spanish Flu Pandemic, at least 675,000 people died in the US alone, and estimates of the worldwide death toll from influenza over the fall and winter of 1918 exceed 30 to 40 million.

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Every year, the US Centers for Disease Control (CDC) in Atlanta collects influenza virus samples from around the world. These viral samples are analyzed by the CDC to determine their protein envelope composition. (It is primarily the configuration of these variably expressed proteins that is associated with the virulence of each individual strain of flu virus.) During the first two or three months of each year, the CDC, in cooperation with the US Food and Drug Administration and the World Health Organization, reviews the prevalent strains of the flu virus, and chooses the strains that will be transformed into the flu vaccine in time for the flu season later in the year.

Unfortunately, as was recently demonstrated during the 2003 influenza season, the strain of flu virus that becomes dominant in affected populations may turn out not to have been one of the strains that were previously selected by the CDC, earlier in the year, for inclusion in the flu vaccine for a given year. Unfortunately, our immune systems are easily fooled by the constant rearrangement of key viral proteins in different strains of the influenza virus, and if the flu vaccine in a given year is not representative of the prevalent strains in our society, then it will not be effective.

Two new studies in the current issue of the Proceedings of the National Academy of Science suggest that it may soon be possible to prevent or even "cure" the flu using an intriguing new approach. Both studies looked at the use of small interfering RNAs (siRNAs) to essentially switch off the genetic machinery of the influenza virus, thus preventing the virus from reproducing itself in an animal host. RNA, short for ribonucleic acid, occurs in a variety of forms within the cells of most organisms, including humans. The best known function of RNA is to serve as a template for each of our genes. After the DNA (deoxyribonucleic acid) sequence within each of our genes is "transcribed" into an RNA template, highly specialized enzymes within each of our cells then "translate" the genetic code contained within each gene-specific RNA molecule into the protein that each individual gene encodes.

This translation of RNA templates into proteins can, in turn, be inhibited by designing strands of siRNAs so that they bind to the RNA templates before they can be translated into proteins necessary for cellular or viral survival and reproduction. In the first of these two studies, researchers found that they could protect laboratory mice from lethal doses of influenza virus by pretreating them with siRNAs. In the second study, mice were first exposed to the influenza virus, and were then treated with siRNAs.

Once again, the siRNAs appeared to block the reproduction of the influenza virus within their animal hosts, protecting them from developing flu infections even after they had been inoculated with the virus. In an attempt to assess the applicability of this therapeutic approach to humans, the research scientists also administered DNA molecules coding for the influenza-specific siRNAs to mice, using intravenous and intranasal routes. This so-called gene therapy also proved to be efficacious in preventing the onset of the flu syndrome in the mice.

Taken together, these two studies raise the hope that an effective means of both preventing and effectively "curing" influenza viral infections in humans may soon be achievable. Of course, additional studies will be required, and at some point, these studies must use human subjects. However, in view of the extensive human and economic misery caused each year by the influenza virus, and the variable effectiveness of the annual influenza vaccine, this new "molecular" approach to flu prevention and treatment is a very exciting development. (Unfortunately, this treatment will not be available in time to alleviate my current bout of flu!)

Regular readers of this column are well-informed about recent research into the effects of the statin-class of cholesterol-lowering drugs. With the possible exception of the humble aspirin tablet, few classes of medications have been shown to have such powerful heart protective effects as the statin drugs. However, this relatively new drug class has not been around long enough for the entire story to be known yet. A new study, just published in the Annals of Internal Medicine, assessed the impact of statin use on patients presenting to the hospital with acute coronary syndromes (acute angina or acute heart attack). This large study included almost 20,000 patients in 94 hospitals, in 14 different countries, and lasted from 1999 to 2002.

Current treatments for patients presenting with a new heart attack involve the use of so-called "clot busting" drugs, including aspirin tablets and powerful intravenous clot-dissolving drugs. Other medications that are sometimes used when someone is experiencing a new heart attack include "beta blockers" to reduce heart rate and decrease the heart's workload, and "ACE Inhibitors" to increase blood flow to the heart itself. More recently, statins have also been added to the heart attack treatment armamentarium. Although statins drugs are most commonly prescribed for the long-term control of high blood cholesterol levels, they appear to exert their beneficial effects not only through cholesterol reduction, but also as anti-inflammatory agents (similar to aspirin's anti-inflammatory effects in addition to its blood thinning properties). However, the scientific evidence to support the routine use of statins in the face of an acute coronary event, such as severe angina or heart attack, is still very preliminary at this time.

In this new study, the effects of prior statin use by patients presenting to the emergency room with an acute coronary syndrome, as well as the initiation of a statin upon arrival in the ER, were assessed. The results, as reported in this study, continue to support a powerful role for statins in both the prevention of acute coronary syndromes, as well as in the initial treatment of severe angina or acute heart attack.

Among those patients who were already taking statins prior to the onset of their acute coronary syndrome, the incidence of actual heart attack, where some of the heart muscle actually dies, was about 20 percent less when compared to patients who were not previously taking statins. Among those patients who previously took statins, and continued taking them during their hospitalization for acute coronary syndrome, the risk of death or other serious complications was 33 percent less than for patients who had never taken a statin drug before.

The study also evaluated the impact of beginning, for the first time, statin therapy in patients arriving at the hospital with an acute coronary syndrome. When compared with patients who were not started on statins upon arrival at the hospital, the maximum reduction in the risk of death was found to be as high as 62 percent in some hospitals, while the overall average reduction in the death rate among all hospitals was still a respectable 16 percent. (This suggests, of course, that the medical management of acute coronary syndrome may be more effective in some hospitals when compared to others, irrespective of the use or non-use of stain drugs.) In summary, this large study strongly supports a therapeutic role for the use of statins in patients presenting to the hospital with acute coronary syndromes, although a formal prospective randomized trial will be necessary to confirm the findings of this single study.

Lung cancer is the number one cause of cancer death for both men and women. Epidemiological data has, for years, suggested that women who smoke are at greater risk of developing lung cancer than men with equivalent smoking habits. Various theories have been proposed to explain this finding, including the smaller size of the airways in the lungs of women compared to those of men. However, a new study in the Journal of the National Cancer Institute (JNCI) contradicts this thinking.

Two very large ongoing gender-specific studies were utilized to reach this new conclusion: the Nurses' Health Study of women and the Health Professionals Follow-up Study of men. A total of 60,296 women and 25,397 men were included in this JNCI study. Among the men and women followed from 1986 to 2000, a total of 955 women and 311 men developed lung cancer. Using exquisitely detailed data for all of the participants in the two large gender-specific studies, the authors were able to calculate the incidence of lung cancer, in both men and women, based upon their smoking histories. In a nutshell, the risk of developing lung cancer as a function of cumulative exposure to tobacco smoke did not differ between men and women in this very large group of almost 86,000 study volunteers. These results are in keeping with other recent prospective studies that have, also, found no significant differences in the incidence of tobacco-induced lung cancer between men and women. On a brighter note, after years of successive annual increases in the number of lung cancer cases diagnosed in women, the incidence of both smoking and lung cancer among women have begun to decrease, slightly, each year since 1998.

As a cancer surgeon, I consider it my ethical responsibility to politely counsel patients regarding the known hazards of smoking. Although pipe smoking is not as prevalent today as it was in the 1960s, I still see an occasional pipe-smoking patient in my office, and in the interest of their health and wellbeing, I mention the increased risk of cardiovascular disease and cancer that has been long associated with smoking. In almost every case, these men (I have yet to meet a woman who smokes a pipe!) inform me that, as they do not inhale tobacco smoke directly as cigarette smokers do, they consider themselves to be at minimal, if any, risk of tobacco-associated diseases.

While there is some prior evidence that pipe smokers may not experience the same level of risk of developing these diseases as their cigarette-smoking counterparts, we do know that the incidence of oral and lung cancers, as well as respiratory and cardiovascular diseases, are still higher in pipe smokers than in non-smokers. A new study, also appearing in the current issue of the JNCI, looked at the association between pipe smoking and tobacco-associated diseases using data from the huge Cancer Prevention Study II, an American Cancer Society prospective study that enrolled 138,307 men, 15,263 of whom reported current or previous pipe smoking. Among this group of nearly 140,000 men, 23,589 have so far died during the 18-year course of this study.

Based upon this study's results, the current pipe smokers, when compared to the men who had never smoked tobacco in any form, experienced a 400 percent relative increase in the risk of lung cancer. A nearly 300 percent increase in the relative risk of oral cavity cancer was also observed in the group of men who were active pipe smokers, when compared with men who had never smoked before. The bad news continues… a 144 percent increase in the relative risk of esophageal cancer… a 41 percent increase in the relative risk of colorectal cancer… a 61 percent increase in the relative risk of pancreatic cancer… and a whopping 1200 percent increase in the relative risk of laryngeal (voice box) cancer. When looking at the risk of non-cancer diseases associated with pipe smoking, there is still more bad news for pipe smokers. The relative risk of coronary heart disease was 30 percent higher among the active pipe smokers, while the relative risk of cerebrovascular disease, including strokes, was 27 percent higher, and the relative risk of emphysema was almost 200 percent higher, when compared to never-smokers. When compared to the data on cigarette and cigar smoking, the deleterious health risks associated with pipe smoking were generally smaller than for cigarette smokers, and on par with those associated with cigar smoking.

JNCI: A new study has identified at least one mechanism whereby the female sex hormone estrogen might stimulate normal breast cells to become breast cancer cells, and breast cancer cells to divide and grow into breast tumors. Among breast cancer cells that were sensitive to estrogen, the addition of estrogen decreased the production of soluble VEGFR-1, a substance which reduces the recruitment of new blood cells by cancer cells. When studied in an animal model, estrogen-sensitive breast cancer tumors significantly increased production of new tumor-nourishing blood vessels following exposure to estrogen, while levels of soluble VEGFR-1 concomitantly decreased. This newly discovered mechanism of estrogen's effect on estrogen-sensitive breast cancer tumors may allow for novel treatments to halt—or at least slow—breast cancer progression.

Archives of Pediatric & Adolescent Medicine: Adolescents who watch 3 or more hours of television per day were at significantly increased risk of developing sleep problems in early adulthood when compared to teens who watched fewer than 3 hours of TV per day.

Journal of the American Medical Association: The management of early stage prostate cancer continues to be a controversial subject. Some experts recommend aggressive treatment with surgery or radiation or hormonal drugs, while others recommend "watchful waiting" in view of the frequently indolent course of many of these tumors. A Swedish study looked at 223 men with early stage prostate cancer, and followed them for 20 years. During the first 10 to 15 years, most of the prostate cancers did, indeed, behave in an indolent manner, with little evidence of spread or impairment in health.

However, during the 15 to 20 year interval following initial diagnosis, it became apparent that the death rate from prostate cancer, as well as the spread of prostate tumors outside of the prostate gland, were significantly more common among the men who were treated with "watchful waiting" alone. Although this study is rather small, and hence should be repeated on a larger scale, it reveals a potential weakness in the argument of the "watchful waiting" camp. It may be that previous studies that have shown little increased morbidity or mortality with non-aggressive treatment of early prostate cancer did not follow their prostate cancer patients long enough to identify an increased risk of disease spread and death in untreated or minimally treated patients.

The authors of this study propose, based upon these results, that prostate cancer patients who are otherwise expected to live for at least 15 years should strongly consider aggressive treatment of their prostate cancers.

JWR contributor Dr. Robert Wascher is an oncologic surgeon, professor of surgery, oncology research scientist, and author. He lives in Honolulu with his wife and two daughters. Comment by clicking here.



© 2004, Dr. Robert A. Wascher