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Tough times for two new cardiovascular drugs
THE LANCET
SCIENCE AND MEDICINE
New mutation predisposes to colorectal cancer
U
s researchers have identified a new type of genetic mutation that predisposes people to familial colorectal cancer. The discovery has already led to a screening test for Ashkenazi Jews, the population at greatest risk for the mutation. Bert Vogelstein (Johns Hopkins Oncology Center, Baltimore, MD, USA) and co-workers report on a mutation in APC (adenomatous polyposis coli) previously considered a harmless polymorphism, because it did not seem to affect gene function. But, says Vogelstein, the variant turns out to be a “premutation”—a subtle alteration in genetic code that destabilises DNA in its vicinity, creating a “hypermutable” region. Subsequent mutations occurring in the region seem to be the real cancer-causing culprits (Nat Genet 1997;17: 79–83). The finding was “totally unexpected”, notes Vogelstein. The premutation and how it works “would have remained one of Nature’s bestkept secrets” if not for the visit to Hopkins by a 39-year-old man with several colorectal tumours. The man had a routine test that showed no APC mutations linked to previously defined hereditary forms of colorectal cancer. But it did detect the “polymorphic” mutation. Investigation of 211 Ashkenazi Jews with colon cancer revealed the mutation in one in six patients whose disease developed before age 66, in one in eight who got the disease at any age, and in nearly onethird of those with a family history. The mutation confers a “two-fold risk for colorectal cancer, over and above risk from diet or other genetic influences”, says Vogelstein. “Now we have to go back through a long list of polymorphisms to determine whether they are related to the neoplastic process”, he adds. And, “even if a small fraction of the variants turn out to be operating in the same way, that will be quite a boost for our understanding of other familial forms of the disease”. “There’s no reason for anyone with this mutation to die or get seriously ill with colon cancer if they are identified early and managed properly”, concludes Vogelstein. Marilynn Larkin
Vol 350 • September 6, 1997
Tough times for two new cardiovascular drugs York Heart Association class II and III heart failure received MCI-154 or placebo. There were no differences in any of the outcomes measured, including exercise time (the primary endpoint), non-fatal myocardial infarction, or death. The trial, said Philip Poole-Wilson (London, UK), was a perfect example of a neutral trial. “The drug did not show benefit, nor did it show harm.” About half of all patients with heart failure die from arrhythmias, but antiarrhythmic drugs have been singularly unsuccessful in combating this recalcitrant problem. Other news from Stockholm M Moller (Odense, Denmark) Delegates heard that two studies (FRISC reported results from the and ESSENCE) have now been completed Danish Investigation of comparing low-molecular-weight heparin Arrhythmia and Mortality on (LMWH) with unfractionated heparin in Dofetilide (DIAMOND-CHF) unstable coronary artery disease (UCAD). trial, in which 1518 patients There was general agreement that the with heart failure were given studies confirm the advantages that LMWH the class III antiarrhythmic offers over heparin in terms of convenience dofetilide or placebo. Dofetilide and economy. However, Stewart Hillis, had no beneficial effect on overconsultant cardiologist, Glasgow, UK, all mortality despite a 1-year warned against making early judgments on mortality rate in the trial of 29% the basis of these two studies alone. “The (nearly half the deaths were different population size, statistical design, caused by an arrhythmia). Also, and endpoints mean that direct comparison dofetilide caused torsades of outcomes should be made with great de pointes in a few patients, caution, if at all”, he said. For now, “we although the drug prolonged the should focus our attention on planning how time to first rehospitalisation for we can facilitate replacing unfractionated chronic heart failure and helped heparin with LMWH in UCAD”, he advised. prevent atrial fibrillation.
hile some cardiovascular drugs, like the platelet-receptor blockers and the “statins”, can seem to do no wrong, others, including a whole host of antiarrhythmics and positive inotropes, seem to take two steps backward for every step forward. This pattern continued at the European Society of Cardiology meeting in Stockholm, Sweden (Aug 24–28), where MCI-154, a new calcium sensitiser with positive inotropic activity, was reported to have no beneficial effect. In the CASCO trial, 286 patients with New
W
Peter Kandela Larry Husten
Trained ears harken to heart sounds eneralists in training lack cardiac auscultation skills, says Salvatore Mangione of Allegheny University (Philadelphia, PA, USA). “They either don’t detect a [problematic] sound or they detect it but don’t know what it is.” Mangione and coworkers tested the ability of 198 internal medicine and 255 family-practice residents to identify 12 common, “clinically very important” cardiac events by listening to cardiac sounds with a stethoscope. Only 20% of events were diagnosed correctly—a finding Mangione says is “disturbingly low”. Residents who played a musical instrument had better auscultatory
G
skills than music lovers without formal training, suggesting that a “trained ear, whatever the reason for its training, may be a prerequisite for achieving proficiency in this skill”. Residents who used audiotapes to study cardiac sounds also did better than those who just attended lectures (JAMA 1997; 278: 717–22). Mangione urges better training in the use of “timehonoured instruments” such as the stethoscope. Otherwise, he says, “we may end up like Dr McCoy of Star Trek fame—with all of our bedside skills in a little hand-held gadget”. Marilynn Larkin
719
SCIENCE AND MEDICINE
New mutation predisposes to colorectal cancer
U
s researchers have identified a new type of genetic mutation that predisposes people to familial colorectal cancer. The discovery has already led to a screening test for Ashkenazi Jews, the population at greatest risk for the mutation. Bert Vogelstein (Johns Hopkins Oncology Center, Baltimore, MD, USA) and co-workers report on a mutation in APC (adenomatous polyposis coli) previously considered a harmless polymorphism, because it did not seem to affect gene function. But, says Vogelstein, the variant turns out to be a “premutation”—a subtle alteration in genetic code that destabilises DNA in its vicinity, creating a “hypermutable” region. Subsequent mutations occurring in the region seem to be the real cancer-causing culprits (Nat Genet 1997;17: 79–83). The finding was “totally unexpected”, notes Vogelstein. The premutation and how it works “would have remained one of Nature’s bestkept secrets” if not for the visit to Hopkins by a 39-year-old man with several colorectal tumours. The man had a routine test that showed no APC mutations linked to previously defined hereditary forms of colorectal cancer. But it did detect the “polymorphic” mutation. Investigation of 211 Ashkenazi Jews with colon cancer revealed the mutation in one in six patients whose disease developed before age 66, in one in eight who got the disease at any age, and in nearly onethird of those with a family history. The mutation confers a “two-fold risk for colorectal cancer, over and above risk from diet or other genetic influences”, says Vogelstein. “Now we have to go back through a long list of polymorphisms to determine whether they are related to the neoplastic process”, he adds. And, “even if a small fraction of the variants turn out to be operating in the same way, that will be quite a boost for our understanding of other familial forms of the disease”. “There’s no reason for anyone with this mutation to die or get seriously ill with colon cancer if they are identified early and managed properly”, concludes Vogelstein. Marilynn Larkin
Vol 350 • September 6, 1997
Tough times for two new cardiovascular drugs York Heart Association class II and III heart failure received MCI-154 or placebo. There were no differences in any of the outcomes measured, including exercise time (the primary endpoint), non-fatal myocardial infarction, or death. The trial, said Philip Poole-Wilson (London, UK), was a perfect example of a neutral trial. “The drug did not show benefit, nor did it show harm.” About half of all patients with heart failure die from arrhythmias, but antiarrhythmic drugs have been singularly unsuccessful in combating this recalcitrant problem. Other news from Stockholm M Moller (Odense, Denmark) Delegates heard that two studies (FRISC reported results from the and ESSENCE) have now been completed Danish Investigation of comparing low-molecular-weight heparin Arrhythmia and Mortality on (LMWH) with unfractionated heparin in Dofetilide (DIAMOND-CHF) unstable coronary artery disease (UCAD). trial, in which 1518 patients There was general agreement that the with heart failure were given studies confirm the advantages that LMWH the class III antiarrhythmic offers over heparin in terms of convenience dofetilide or placebo. Dofetilide and economy. However, Stewart Hillis, had no beneficial effect on overconsultant cardiologist, Glasgow, UK, all mortality despite a 1-year warned against making early judgments on mortality rate in the trial of 29% the basis of these two studies alone. “The (nearly half the deaths were different population size, statistical design, caused by an arrhythmia). Also, and endpoints mean that direct comparison dofetilide caused torsades of outcomes should be made with great de pointes in a few patients, caution, if at all”, he said. For now, “we although the drug prolonged the should focus our attention on planning how time to first rehospitalisation for we can facilitate replacing unfractionated chronic heart failure and helped heparin with LMWH in UCAD”, he advised. prevent atrial fibrillation.
hile some cardiovascular drugs, like the platelet-receptor blockers and the “statins”, can seem to do no wrong, others, including a whole host of antiarrhythmics and positive inotropes, seem to take two steps backward for every step forward. This pattern continued at the European Society of Cardiology meeting in Stockholm, Sweden (Aug 24–28), where MCI-154, a new calcium sensitiser with positive inotropic activity, was reported to have no beneficial effect. In the CASCO trial, 286 patients with New
W
Peter Kandela Larry Husten
Trained ears harken to heart sounds eneralists in training lack cardiac auscultation skills, says Salvatore Mangione of Allegheny University (Philadelphia, PA, USA). “They either don’t detect a [problematic] sound or they detect it but don’t know what it is.” Mangione and coworkers tested the ability of 198 internal medicine and 255 family-practice residents to identify 12 common, “clinically very important” cardiac events by listening to cardiac sounds with a stethoscope. Only 20% of events were diagnosed correctly—a finding Mangione says is “disturbingly low”. Residents who played a musical instrument had better auscultatory
G
skills than music lovers without formal training, suggesting that a “trained ear, whatever the reason for its training, may be a prerequisite for achieving proficiency in this skill”. Residents who used audiotapes to study cardiac sounds also did better than those who just attended lectures (JAMA 1997; 278: 717–22). Mangione urges better training in the use of “timehonoured instruments” such as the stethoscope. Otherwise, he says, “we may end up like Dr McCoy of Star Trek fame—with all of our bedside skills in a little hand-held gadget”. Marilynn Larkin
719