Jewish World Review Oct. 19, 2004 / 4 Mar-Cheshvan, 5765

HRT: Are all estrogens created equal?; Hormone Replacement Therapy (HRT): Another nail in the combination hrt coffin; surgery versus stents for aortic aneurysms; topical antiinflammatory drugs & knee arthritis; coronary artery calcifications & famil history; diagnosing colon cancer in the clinic

By Robert A. Wascher, M.D., F.A.C.S. | Journal of Gastroenterology: Most colon and rectal cancers are diagnosed only after a pathologist tediously examines biopsy specimens removed during a colonoscopy. When a polyp is identified during colonoscopy, it is either removed completely or, if this is not feasible, a small piece is removed. These tissue samples are then evaluated by a pathologist, and a final diagnosis is rendered within a week or so in most cases. (Unfortunately, it is generally impossible to definitively diagnose a colon or rectal polyp as a cancer at the time of colonoscopy.) Now, a new experimental approach to colonoscopy may allow both patients and their physicians to render a highly accurate diagnosis at the time of colonoscopy.

Confocal laser microscopy is an exciting new tool that allows specially trained physicians to look at living cells and tissues in a human being, and in much the same way that pathologists look at surgically removed cells and tissues. An injection of a fluorescent dye into the blood is first performed. A sophisticated microscope, combined with a laser, then allows a physician to look at living, intact human cells, just as if one were looking at biopsy specimens under the microscope in the pathologist's office. This technology has already been extensively studied as an aid to clinical diagnosis by dermatologists, and has been found to be highly accurate in diagnosing melanoma, a potentially deadly form of skin cancer. A new study has now extended the use of this bedside technology to the colon and rectum.

In this study, more than 1,000 sites in the colons and rectums of volunteers were subjected to confocal laser microscope evaluation during colonoscopy, followed by biopsies of these same areas. The diagnoses obtained by the confocal microscope studies, at the time of colonoscopy, were then compared with the final diagnoses of the same tissues, after they were removed, by standard histopathological analysis. The results showed a surprisingly high degree of diagnostic accuracy for confocal laser microscope evaluation when compared to the standard pathologist's examination of biopsy specimens. The overall accuracy of confocal laser microscopy was 99.2 percent, suggesting that this technique has great promise in providing an essentially instantaneous diagnosis while patients are still undergoing their colonoscopy procedures. In view of the expensive and time-consuming factors associated with standard histopathological analysis of biopsy specimens, laser confocal microscopy, when applied to patients undergoing colonoscopy for polyps of the colon and rectum, may someday revolutionize the bedside diagnosis of colon and rectal cancer.

Circulation: A with many other diseases, having a family history of coronary artery disease (CAD), and premature CAD in particular, also places one at increased risk of developing this disease when compared to the general population. Undoubtedly, at least some of this increased risk results from inherited tendencies to develop this — and other — diseases from our parents and grandparents. At the same time, the use of CT scanners to detect calcifications within the coronary arteries of asymptomatic people has proven to be an important tool in screening high-risk patients for occult CAD. (It should be noted that each CT scan exposes the patient to significant doses of radiation and, for this reason, CT scans of the heart are not currently recommended for the general public.) Indeed, the extent and number of calcifications in the coronary arteries, as detected by a specialized CT scanner, correlate very well with the future risk of cardiac events, including heart attack.

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A new study evaluated more than 8,500 asymptomatic individuals (69 percent men, 31 percent women) with an average age of 52 years. Extensive family histories were taken from each volunteer, and all patients underwent CT evaluation of their coronary arteries. This study found that a family history of CAD was associated with a significantly increased risk of coronary artery calcifications, indicating early coronary artery disease in these asymptomatic volunteers. Approximately 55 percent of the male volunteer patients without a family history of CAD had detectable calcifications, while 64 percent of the males with a parental history of premature CAD had detectable calcifications. A unique finding in this study, which is somewhat contrary to previous studies, was that having a family history of siblings with premature CAD was associated with a higher likelihood of coronary artery calcifications (78 percent) than was the case when a history of premature CAD was present only in the study volunteers' parents (64 percent). Similarly, among the female volunteers, the incidence of coronary artery calcifications in women with no family history of premature CAD, a history of parental premature CAD, or a history of siblings with premature CAD was 27 percent, 36 percent, and 56 percent, respectively. These results translated into a 30 percent increase in the risk of calcifications in the presence of a family history of premature parental CAD, and a 130 percent increase in the risk of calcifications when one or more siblings had a history of premature CAD, for men. Among the women volunteers, a 30 percent increase in the risk of calcifications was associated with a parental history of premature CAD, and a 90 percent increase in the risk of calcifications was seen when one or more siblings were diagnosed with premature CAD.

This study strongly suggests, contrary to previous findings, that having a brother or sister with a history of premature CAD increases your risk of developing CAD even more than does a history of mom or dad having premature CAD. This large study suggests that doctors need to pay close attention not only to the illnesses of their patients' fathers and mothers, but also to those of their brothers and sisters as well, when trying to assess an individual patient's risk for CAD, and the risk for premature CAD in particular. The findings of this study should also be factored into making decisions about who should undergo CT scans of the heart, as well as other potentially risky cardiac tests.

Archives of Internal Medicine: Recently, a lot of attention has been focused on antiinflammatory drugs since Vioxx® was pulled off the market after growing data suggested that Vioxx® may as much as double the risk of heart attack. Vioxx®, and other antiinflammatory drugs that selectively block only the COX-2 form of the COX enzyme, were initially developed because most of the COX-nonspecific antiinflammatory drugs, also called "NSAIDs" (nonspecific antiinflammatory drug), have been associated with an increased risk of GI upset and GI bleeding. As these COX-nonspecific NSAID drugs are generally taken in pill form or by injection, and are therefore distributed throughout the body, it is logical to ask whether or not it might be safer to locally apply an NSAID to the skin over an arthritic joint. However, both the efficacy and the safety of this topical NSAID approach are unclear. As osteoarthritis is an extremely common ailment in our aging society, any new treatment approaches that might reduce the risks associated with NSAID drugs would be highly welcome.

A new study looked at combining the NSAID diclofenac with the solvent dimethyl sulfoxide (DMSO), which is capable of transporting many medications through the skin barrier, and into the deeper tissues below the skin. A total of 326 patients with osteoarthritis of the knee were randomly assigned to have the topical diclofenac-DMSO treatment versus the application of a placebo solution containing DMSO alone. Neither the patients nor the research physicians knew in advance which patients received the placebo and which patients received the NSAID-containing solution. All of the volunteer patients applied the topical solutions to their affected knees 4 times a day, for 12 weeks, and were then reassessed with a combination of surveys and clinical examinations. This study found that, compared with the placebo solution, the diclofenac-DMSO solution resulted in significant improvements in all of the outcomes that were evaluated in this study, including pain, physical function, stiffness, and overall patient well-being. Minor, temporary skin irritation was observed in 42 percent of the patients who received the diclofenac solution, while less than 1 percent of patients receiving topical diclofenac experienced sensory changes, itching or blisters. None of the patients experienced any GI side effects. The study's researchers concluded that the topical application of an NSAID to arthritic knee joints significantly improved the symptoms of osteoarthritis and, with the exception of mild and well-tolerated skin irritation, was not associated with any of the GI effects or other complications commonly seen in patients who take NSAIDs by mouth or by injection.

This is an interesting study, as the COX-nonspecific antiinflammatory drugs, or NSAIDS, do not appear, at this time, to be associated with the increased cardiac risk that has been linked to Vioxx® (the jury is still out on the cardiac effects of other COX-2-specific antiinflammatory drugs, including Celebrex® and Bextra®, at this time). This concern may increase both patients' and physicians' interest in stepping back from using the COX-2-specific antiinflammatory drugs, such as Vioxx®, in favor of the older COX-nonspecific NSAIDs. However, as already discussed, these "nonselective" COX enzyme inhibitors are associated with an increased risk of GI upset and GI bleeding.

Unfortunately, this study lasted for only 12 weeks, and many patients who develop serious GI side effects from NSAIDs do so only after prolonged use of these drugs. Therefore, a long-term evaluation of topical NSAIDs would be useful to confirm this pilot study's findings, and to ensure that the topical use of NSAIDs are indeed safer than oral NSAIDs, and that the dermatologic reactions observed in this study do not progress to more worrisome reactions.

New England Journal of Medicine: A total of 345 patients with large abdominal aortic aneurysms (a ballooning-out and weakening of the major artery to supplies blood to most of the body) were randomized to traditional repair though a large abdominal incision versus minimally-invasive repair through the use of internal stents placed through a small incision in a groin artery. Among the patients who underwent traditional surgical repair of their aneurysms, 4.9 percent died within 30 days of surgery, while only 1.2 percent of the patients who had the minimally-invasive endovascular stents placed died within 30 days. The combined risk of major postoperative complications and death was 9.8 percent in the patients who underwent standard surgical repair, and 4.7 percent in the patients who were treated with endovascular stents. Although the patients in this study were carefully selected, based upon the size and morphology of their aneurysms, this is the first high-quality prospective research study to show a significant reduction in postoperative complications, including death, with the newer minimally-invasive endovascular approach to abdominal aortic aneurysm treatment.

Of course, longer follow-up of these patients will be necessary to determine if the advantages of the minimally invasive approach persist. However, as biomedical technology improves, the limitations of the current generation of endovascular stents will also improve, allowing their use in patients with larger or more complex aneurysms than were evaluated in this study. The use of these stents has already revolutionized the treatment of abdominal aortic aneurysms, and many vascular surgery experts foresee a day, not too far off in the future, when almost all such aneurysms will be treated with minimally invasive endovascular stents. Based upon the results of this new study, that day does not seem too far off.

Journal of the American Medical Association: A new update from the Women's Health Initiative (WHI) Study continues to show adverse effects associated with hormone replacement therapy (HRT), and with the combination HRT drug Prempro®, in particular. Postmenopausal women taking this HRT pill had more than twice the risk of developing potentially fatal blood clots in major veins than did age-matched women who only took a placebo pill. When the women were evaluated based to their ages, the risk of deep venous thrombosis continued to rise, as a function of age, while taking Prempro®. A similar additive effect was seen with obesity and the use of Prempro®.

Journal of the American Medical Association: The debate rages on about the safety of various forms of estrogen used for HRT. The two most popular HRT drugs, Premarin® and Prempro®, derive their estrogen from the urine of pregnant mares. Many proponents of HRT have discounted the adverse findings of the WHI study, which evaluated women taking the two most frequently prescribed HRT preparations (Premarin® and Prempro®), claiming that the "conjugated equine estrogens" present in these pills, as well as the synthetic progesterone hormone contained in Prempro®, are "non-physiologic" in humans. Many in this camp argue for the use of human — or even plant — hormones instead. Unfortunately, there has been precious little high-quality research performed, comparing "natural" versus "equine" estrogens. A retrospective study has now looked at the incidence of blood clots in the veins among 2,854 perimenopausal and postmenopausal women, 586 of whom were previously diagnosed with blood clots in their major veins. When all of the data was analyzed, it was determined that the use of equine estrogen was associated with a 65 percent relative increase in the risk of blood clots when compared to women not taking any HRT medications.

However, women who reported the use of esterified estrogen HRT medications (most of which are derived from yams, soybeans, synthetic estrogens, or a combination of these sources) did not appear to experience any increase in the risk of blood clots. This study suggests that there may be a difference in risks associated with various HRT preparations of estrogen, at least as far as the risk of blood clots in the veins is concerned. This study, however, does not contradict earlier research showing that all preparations of estrogen can stimulate abnormal growth of cells in the breast and uterus, thus increasing the risk of cancer formation in these organs. Likewise, the deleterious effects recently associated with combination HRT drugs, which include an estrogen and a progesterone hormone for women who still have a uterus, are not likely to be ameliorated by the substitution of esterified estrogens in place of conjugated equine estrogens.

Moreover, this retrospective population-based study looked "backwards" at data contained in the charts of patients who were never enrolled in any controlled, prospective research study. In general, retrospective studies, such as this one, are deemed scientifically and statistically inferior to studies that are conducted with carefully selected and matched volunteers, and within a carefully constructed prospective research protocol. Despite all of the aforementioned caveats, this study should serve as a basis for large-scale prospective studies to comparatively evaluate the safety profiles of various HRT preparations in a long-term, prospective, randomized, and double-blinded study. This approach will provide what scientists refer to as "Level 1" evidence, and will either validate or contradict the findings of this interesting retrospective study.

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