- Email: [email protected]
The COOPERATE trial
CORRESPONDENCE
Sir—In Naoyuki Nakao and colleagues’ COOPERATE trial,1 seven patients (2·7%) were lost to follow-up because of discontinuation, moving away, or protocol invalidation according to the summary and the trial profile shown in figure 1. In fact, as mentioned in the text, 57 patients (22%) who discontinued the study because of reasons not related to the intervention were censored. Thus, data on the final outcome of more than 20% of patients seem to be missing, which casts doubt on the validity of the results. Moreover, since the trial was done in one centre, which is the only centre caring for patients with kidney diseases in that area of Japan, the extent of missing data is striking, given that only one person moved away. We would be interested to know how many of the censored patients actually reached the primary endpoint or the endpoint of end-stage renal disease. *Jutta Halbekath, Stefanie Schenk Arznei-telegramm, Bergstrasse 38A, Wasserturm, D-12169 Berlin, Germany (e-mail: [email protected]) 1
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensinconverting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003; 361: 117–24. Published online Dec 17, 2002. http://image.thelancet.com/ extras/01art11215web.pdf.
Author’s reply Sir—Contrary to what Bernd Krüger and colleagues suggest, 3 mg trandolapril is a sufficient dose for maximum renoprotection in Japanese patients with renal dysfunction. First, during a run-in period, we confirmed the individual maximum antiproteinuric efficacy—the most reliable covariate for a long-term renal outcome—using the up-titrated dose scale from 0·5 mg to 6·0 mg. Second, the antiproteinuric efficacy obtained during a follow-up period was not less than that seen in previous studies that used the higher dose of trandolapril.1 Third, repeated assessment of safety during the run-in period showed that the more a dose was up-titrated, the higher the tendency towards acute decline in renal function. Finally, pharmacokinetic or pharmacodynamic variables in Japanese patients with renal dysfunction after 7 days’ consecutive use of even 1 mg trandolapril are three times greater than those of patients with congestive heart failure treated with 4 mg trandolapril.2 Most Japanese nephrologists use the official recommendation of the Progressive Renal Disease Research Committee at the Ministry of Health,
Labor, and Welfare for starting haemodialysis. This criterion is based on the total sum of an individual’s renal function score calculated from clinical manifestations, quality of life, and laboratory data. Claire Presne and colleagues ask about the effect of salt and protein intake on the results. Baseline values and serial changes in 24-h urinary excretion of nitrogen and sodium did not reach significance for within-group differences for treatment, nor within individuals during a follow-up period (data not shown). Therefore, these variables did not affect the final renal outcomes. At randomisation, 210 participants (79·9%) took amlodipine (148 [56·4%] took 5 mg, 62 [23·5%] took 7·5 mg), and 149 (56·8%) used diuretics (20–40 mg furosemide in 111 [42·3%], 50–100 mg spironolactone in 38 [14·5%]). At the end of the trial, 150 (74·5%) were still using a calciumchannel blocker (5 mg in 110 [54·8%], 7·5 mg in 40 [19·7%]), whereas 111 (55·8%) needed the diuretics (80 [40·2%] on furosemide, 31 [15·6%] on spironolactone). In answer to Krüger and colleagues’ query about low responders to trandolapril, renal survival seemed to be different among the three treatment groups. Six of 11 on combination treatment reached the combined primary endpoints compared with nine of 11 on losartan alone and eight of ten on trandolapril alone. The better antiproteinuric response was also seen in the low responders allocated to the combination treatment. Because of the small numbers in this subgroup, it is inappropriate to do any formal statistical analysis, and therefore definitive conclusions cannot be drawn. Regarding Krüger and colleagues’ question about censored observations, those lost to follow-up were counted as if they had reached the primary endpoints in the statistical analysis. And in answer to Jutta Halbekath and Stefanie Schenk’s enquiry, the two other main reasons for censorship were a short-term observation period of less than 3 months, and irregular consultation. Details of the censored patients who had irregular consultations have now been clarified as a result of a follow-up study by their local general practitioners. Primary allocated treatments have been continued and no one has reached the primary endpoints. Therefore, these censored data do not alter the final results and conclusions. Naoyuki Nakao Division of Nephrology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-Ku, Yokohama, 227-8501, Japan (e-mail: [email protected])
THE LANCET • Vol 361 • March 22, 2003 • www.thelancet.com
1
2
Hemmelder MH, de Zeeuw D, de Jong PE. Antiproteinuric efficacy of verapamil in comparison to trandolapril in non-diabetic renal disease. Nephrol Dial Transplant 1999; 14: 98–104. Drugs in Japan. Ethical drugs, 23rd edn. Tokyo: Japan Pharmaceutical Information Center, 2000.
Sir—Naoyuki Nakao and colleagues1 show that, in patients with non-diabetic chronic renal disease, the risk of reaching end-stage renal disease or doubling of serum creatinine concentration was reduced by almost 50% after dual blockade of the reninangiotensin system (RAS) compared with use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor subtype 1 (AT1) blockers alone. The differences in renoprotection are probably due to the much larger antiproteinuric effect of dual blockade. The value of proteinuria reduction with respect to long-term renoprotection has been consistently shown in clinical and experimental studies.2 The effect of proteinuria reduction holds true not only for between-group differences for regimens with different antiproteinuric efficacies—as in Nakao and colleagues’ study—but also for within-group differences in renal outcome between individuals with a poor, compared with a good, antiproteinuric response.3 Thus, the value of proteinuria reduction is independent of the way it is obtained. Although the COOPERATE study shows the improved benefit of combination treatment, many patients still progressed to end-stage renal disease. Nakao and colleagues identified non-responding patients as having a smaller antiproteinuric response. Thus, to optimise renoprotective strategies, should we not aim for more effective proteinuria reduction?4 The individual antiproteinuric dose response to ACE inhibitor or AT1 antagonist reveals that some patients need a higher dose to obtain the same antiproteinuric effect. We have shown individual dosedependent differences in maximum reduction of proteinuria from baseline after 6 weeks of monotherapy, with a much more effective reduction of proteinuria after combined treatment.5 Given these data, we argue that for optimum renoprotection, one should not only apply dual RAS blockade with fixed dose-titration for proteinuria—as Nakoa and colleagues did—but specifically pursue the lowest level of proteinuria by individual dose-titration in combination with additive measures that enhance antiproteinuric efficacy, such as dietary sodium restriction, diuretic therapy, and protein restriction.4
1055
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
*Liffert Vogt, Gozewijn D Laverman, Dick de Zeeuw, Gerjan Navis Kidney Center, University Hospital Groningen, 9713 GZ Groningen, Netherlands (e-mail: [email protected]) 1
2
3
4
5
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting enzyme inhibitor on non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003; 361: 117–24. Published online Dec 17, 2002. http://image. thelancet.com/extras/01art11215web.pdf. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998; 339: 1448–56. Apperloo AJ, de Zeeuw D, de Jong PE. Short-term antiproteinuric response to antihypertensive therapy predicts long-term GFR decline in patients with non-diabetic renal disease. Kidney Int 1994; 45 (suppl 45): 174–78. Ruggenenti P, Schieppati A, Remuzzi G. Progression, remission, regression of chronic renal disease. Lancet 2001; 357: 1601–08. Laverman GD, Navis GJ, Henning RH, de Jong PE, de Zeeuw D. Dual reninangiotensin system blockade at optimal doses for proteinuria. Kidney Int 2002; 62: 1020–25.
HIV/AIDS and human rights Sir—Gruskin and Loff (Dec 7, p 1880)1 state that “a rights-based approach does not privilege protection of individual rights over the public good”. This statement sounds tragically ironic if we consider that the American rights-based decision to privilege the individual rights of patients with early HIV/AIDS resulted, per head, in 35 times more deaths from AIDS in the USA than in Cuba,2 whose decision to isolate people with HIV/AIDS in sanatoriums was regarded as a violation of human rights, but proved to be “the most successful national AIDS programme in the world”.2 In view of the millions of additional deaths caused by the American rightsbased approach,2 which would have led a small community to extinction,3 it is hard to agree with the recently iterated claim that the Universal Declaration of Human Rights “sets forth the ethics of public health”.4 This Declaration, unfortunately, has a defect, represented by its total failure to mention the rights of the human community, as a result of the individualistic liberalism that characteristically underpins the policies of the USA, “one of the Declaration’s chief architects”.5 Meaningfully, the Siracusa principles listed in Gruskin and Loff’s article1 have been promulgated in 1985, precisely to remedy the Declaration’s defect, which became sorely evident in the early 1980s, when the rights-based approach towards HIV/AIDS proved socially
1056
disastrous. This global tragedy was easily predictable, however, because a public-health ethic based on a Declaration that discusses extensively individual rights, but ignores completely the rights of the human community, constitutes the exact opposite of the ethic that evolution has taught human beings for millions of years, to ensure the survival of their small communities.3 Riccardo Baschetti
visible in several patients as early as 3 weeks after treatment discontinuation. Blocking of various combinations of three tyrosine kinase receptors can result in very different effects on hair pigmentation. These observations suggest that further studies of these three signalling pathways might lead to important steps towards elucidating the complex molecular events involved in melanocyte differentiation.
CP 671, 60001-970 Fortaleza (CE), Brazil (e-mail: [email protected])
Caroline Robert, Alain Spatz, Sandrine Faivre, Jean-Pierre Armand, *Eric Raymond
1
Departments of Medicine, Immunology and Pathology, Institut Gustave Roussy, 94805 Villejuif, France (e-mail: [email protected])
2
3 4 5
Gruskin S, Loff B. Do human rights have a role in public health work? Lancet 2002; 360: 1880. Burr C. Assessing Cuba’s approach to contain AIDS and HIV. Lancet 1997; 350: 647. Baschetti R. Ethical analysis in public health. Lancet 2002; 360: 416. Annas GJ. HIV/AIDS in Africa. Lancet 2002; 360: 1787. Freer R. Human rights in the USA: land of the free? Lancet 1998; 352: 1853–54.
1
2
3
Tyrosine kinase inhibition and grey hair Sir—Repigmentation of grey hair has been reported in nine of 133 patients treated with the tyrosine kinase inhibitor imatinib (STI571).1 Although the molecular mechanisms involved are unknown, they could be related to blocking of c-KIT, since imatinib inhibits this tyrosine kinase receptor and the related platelet-derived growth factor (PDGF) receptor.2 Stimulation of c-KIT normally leads to short-lived activation followed by rapid degradation of the microphthalmia transcription factor (Mi), which transactivates the tyrosinase pigmentation gene promoter in melanocytes.3,4 We have seen the opposite effect—ie, hair depigmentation—in patients with recurrent or metastatic cancers treated with the novel drug SU11428 (Sugen) during a phase 1 clinical trial. SU11428 is a new antiangiogenic oxindole that blocks the receptors for vascular endothelial growth factor (VEGF), PDGF, and stem-cell factor. Hair depigmentation was seen in 18 of 28 patients, irrespective of the origin of the primary cancer. It concerned all patients who received at least 50 mg of SU11428 per day, and who did not have grey hair before treatment. Depigmentation was detectable on all body hair after about 5–6 weeks of treatment. Microscopic examination of the hair showed that the pigment had disappeared without any other hair shaft abnormality. The process seemed to be reversible, since normally pigmented hair growth was
4
Etienne G, Cony-Makhoul P, Mahon FX. Imatinib mesylate and gray hair. N Engl J Med 2002; 347: 446. Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 2002; 1: 493–502. Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature 1998; 391: 298–301. Wu M, Hemesath TJ, Takemoto CM, et al. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev 2000; 14: 301–12.
Multicentre Aneurysm Screening Study (MASS) Sir—In Multicentre Aneurysm Screening Study (MASS; Nov 16, p 1531),1 morbidity after elective aneurysm surgery is ignored. Aneurysm surgery is associated with a high rate of serious morbidity such as myocardial infarction, colonic ischaemia, renal insufficiency, and limb ischaemia, not to mention the high rates of minor morbidity. On the basis of a conservative estimate from published studies, major morbidity is in the range of 5–10%, and minor morbidity 20–30%.2,3 In a screening programme, all harmful effects, not just mortality, should be analysed and balanced against the potential benefits of the programme. This is especially important since aneurysm surgery is done in rather fragile and symptomfree patients with a limited life expectancy. The MASS Study Group did not provide these data, and information about quality of life cannot compensate for this shortcoming. MASS shows only a very limited benefit from screening. Balancing the effects of morbidity in the endpoints would, possibly, have resulted in a different conclusion.
THE LANCET • Vol 361 • March 22, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Sir—In Naoyuki Nakao and colleagues’ COOPERATE trial,1 seven patients (2·7%) were lost to follow-up because of discontinuation, moving away, or protocol invalidation according to the summary and the trial profile shown in figure 1. In fact, as mentioned in the text, 57 patients (22%) who discontinued the study because of reasons not related to the intervention were censored. Thus, data on the final outcome of more than 20% of patients seem to be missing, which casts doubt on the validity of the results. Moreover, since the trial was done in one centre, which is the only centre caring for patients with kidney diseases in that area of Japan, the extent of missing data is striking, given that only one person moved away. We would be interested to know how many of the censored patients actually reached the primary endpoint or the endpoint of end-stage renal disease. *Jutta Halbekath, Stefanie Schenk Arznei-telegramm, Bergstrasse 38A, Wasserturm, D-12169 Berlin, Germany (e-mail: [email protected]) 1
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensinconverting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003; 361: 117–24. Published online Dec 17, 2002. http://image.thelancet.com/ extras/01art11215web.pdf.
Author’s reply Sir—Contrary to what Bernd Krüger and colleagues suggest, 3 mg trandolapril is a sufficient dose for maximum renoprotection in Japanese patients with renal dysfunction. First, during a run-in period, we confirmed the individual maximum antiproteinuric efficacy—the most reliable covariate for a long-term renal outcome—using the up-titrated dose scale from 0·5 mg to 6·0 mg. Second, the antiproteinuric efficacy obtained during a follow-up period was not less than that seen in previous studies that used the higher dose of trandolapril.1 Third, repeated assessment of safety during the run-in period showed that the more a dose was up-titrated, the higher the tendency towards acute decline in renal function. Finally, pharmacokinetic or pharmacodynamic variables in Japanese patients with renal dysfunction after 7 days’ consecutive use of even 1 mg trandolapril are three times greater than those of patients with congestive heart failure treated with 4 mg trandolapril.2 Most Japanese nephrologists use the official recommendation of the Progressive Renal Disease Research Committee at the Ministry of Health,
Labor, and Welfare for starting haemodialysis. This criterion is based on the total sum of an individual’s renal function score calculated from clinical manifestations, quality of life, and laboratory data. Claire Presne and colleagues ask about the effect of salt and protein intake on the results. Baseline values and serial changes in 24-h urinary excretion of nitrogen and sodium did not reach significance for within-group differences for treatment, nor within individuals during a follow-up period (data not shown). Therefore, these variables did not affect the final renal outcomes. At randomisation, 210 participants (79·9%) took amlodipine (148 [56·4%] took 5 mg, 62 [23·5%] took 7·5 mg), and 149 (56·8%) used diuretics (20–40 mg furosemide in 111 [42·3%], 50–100 mg spironolactone in 38 [14·5%]). At the end of the trial, 150 (74·5%) were still using a calciumchannel blocker (5 mg in 110 [54·8%], 7·5 mg in 40 [19·7%]), whereas 111 (55·8%) needed the diuretics (80 [40·2%] on furosemide, 31 [15·6%] on spironolactone). In answer to Krüger and colleagues’ query about low responders to trandolapril, renal survival seemed to be different among the three treatment groups. Six of 11 on combination treatment reached the combined primary endpoints compared with nine of 11 on losartan alone and eight of ten on trandolapril alone. The better antiproteinuric response was also seen in the low responders allocated to the combination treatment. Because of the small numbers in this subgroup, it is inappropriate to do any formal statistical analysis, and therefore definitive conclusions cannot be drawn. Regarding Krüger and colleagues’ question about censored observations, those lost to follow-up were counted as if they had reached the primary endpoints in the statistical analysis. And in answer to Jutta Halbekath and Stefanie Schenk’s enquiry, the two other main reasons for censorship were a short-term observation period of less than 3 months, and irregular consultation. Details of the censored patients who had irregular consultations have now been clarified as a result of a follow-up study by their local general practitioners. Primary allocated treatments have been continued and no one has reached the primary endpoints. Therefore, these censored data do not alter the final results and conclusions. Naoyuki Nakao Division of Nephrology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-Ku, Yokohama, 227-8501, Japan (e-mail: [email protected])
THE LANCET • Vol 361 • March 22, 2003 • www.thelancet.com
1
2
Hemmelder MH, de Zeeuw D, de Jong PE. Antiproteinuric efficacy of verapamil in comparison to trandolapril in non-diabetic renal disease. Nephrol Dial Transplant 1999; 14: 98–104. Drugs in Japan. Ethical drugs, 23rd edn. Tokyo: Japan Pharmaceutical Information Center, 2000.
Sir—Naoyuki Nakao and colleagues1 show that, in patients with non-diabetic chronic renal disease, the risk of reaching end-stage renal disease or doubling of serum creatinine concentration was reduced by almost 50% after dual blockade of the reninangiotensin system (RAS) compared with use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor subtype 1 (AT1) blockers alone. The differences in renoprotection are probably due to the much larger antiproteinuric effect of dual blockade. The value of proteinuria reduction with respect to long-term renoprotection has been consistently shown in clinical and experimental studies.2 The effect of proteinuria reduction holds true not only for between-group differences for regimens with different antiproteinuric efficacies—as in Nakao and colleagues’ study—but also for within-group differences in renal outcome between individuals with a poor, compared with a good, antiproteinuric response.3 Thus, the value of proteinuria reduction is independent of the way it is obtained. Although the COOPERATE study shows the improved benefit of combination treatment, many patients still progressed to end-stage renal disease. Nakao and colleagues identified non-responding patients as having a smaller antiproteinuric response. Thus, to optimise renoprotective strategies, should we not aim for more effective proteinuria reduction?4 The individual antiproteinuric dose response to ACE inhibitor or AT1 antagonist reveals that some patients need a higher dose to obtain the same antiproteinuric effect. We have shown individual dosedependent differences in maximum reduction of proteinuria from baseline after 6 weeks of monotherapy, with a much more effective reduction of proteinuria after combined treatment.5 Given these data, we argue that for optimum renoprotection, one should not only apply dual RAS blockade with fixed dose-titration for proteinuria—as Nakoa and colleagues did—but specifically pursue the lowest level of proteinuria by individual dose-titration in combination with additive measures that enhance antiproteinuric efficacy, such as dietary sodium restriction, diuretic therapy, and protein restriction.4
1055
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
*Liffert Vogt, Gozewijn D Laverman, Dick de Zeeuw, Gerjan Navis Kidney Center, University Hospital Groningen, 9713 GZ Groningen, Netherlands (e-mail: [email protected]) 1
2
3
4
5
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting enzyme inhibitor on non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003; 361: 117–24. Published online Dec 17, 2002. http://image. thelancet.com/extras/01art11215web.pdf. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998; 339: 1448–56. Apperloo AJ, de Zeeuw D, de Jong PE. Short-term antiproteinuric response to antihypertensive therapy predicts long-term GFR decline in patients with non-diabetic renal disease. Kidney Int 1994; 45 (suppl 45): 174–78. Ruggenenti P, Schieppati A, Remuzzi G. Progression, remission, regression of chronic renal disease. Lancet 2001; 357: 1601–08. Laverman GD, Navis GJ, Henning RH, de Jong PE, de Zeeuw D. Dual reninangiotensin system blockade at optimal doses for proteinuria. Kidney Int 2002; 62: 1020–25.
HIV/AIDS and human rights Sir—Gruskin and Loff (Dec 7, p 1880)1 state that “a rights-based approach does not privilege protection of individual rights over the public good”. This statement sounds tragically ironic if we consider that the American rights-based decision to privilege the individual rights of patients with early HIV/AIDS resulted, per head, in 35 times more deaths from AIDS in the USA than in Cuba,2 whose decision to isolate people with HIV/AIDS in sanatoriums was regarded as a violation of human rights, but proved to be “the most successful national AIDS programme in the world”.2 In view of the millions of additional deaths caused by the American rightsbased approach,2 which would have led a small community to extinction,3 it is hard to agree with the recently iterated claim that the Universal Declaration of Human Rights “sets forth the ethics of public health”.4 This Declaration, unfortunately, has a defect, represented by its total failure to mention the rights of the human community, as a result of the individualistic liberalism that characteristically underpins the policies of the USA, “one of the Declaration’s chief architects”.5 Meaningfully, the Siracusa principles listed in Gruskin and Loff’s article1 have been promulgated in 1985, precisely to remedy the Declaration’s defect, which became sorely evident in the early 1980s, when the rights-based approach towards HIV/AIDS proved socially
1056
disastrous. This global tragedy was easily predictable, however, because a public-health ethic based on a Declaration that discusses extensively individual rights, but ignores completely the rights of the human community, constitutes the exact opposite of the ethic that evolution has taught human beings for millions of years, to ensure the survival of their small communities.3 Riccardo Baschetti
visible in several patients as early as 3 weeks after treatment discontinuation. Blocking of various combinations of three tyrosine kinase receptors can result in very different effects on hair pigmentation. These observations suggest that further studies of these three signalling pathways might lead to important steps towards elucidating the complex molecular events involved in melanocyte differentiation.
CP 671, 60001-970 Fortaleza (CE), Brazil (e-mail: [email protected])
Caroline Robert, Alain Spatz, Sandrine Faivre, Jean-Pierre Armand, *Eric Raymond
1
Departments of Medicine, Immunology and Pathology, Institut Gustave Roussy, 94805 Villejuif, France (e-mail: [email protected])
2
3 4 5
Gruskin S, Loff B. Do human rights have a role in public health work? Lancet 2002; 360: 1880. Burr C. Assessing Cuba’s approach to contain AIDS and HIV. Lancet 1997; 350: 647. Baschetti R. Ethical analysis in public health. Lancet 2002; 360: 416. Annas GJ. HIV/AIDS in Africa. Lancet 2002; 360: 1787. Freer R. Human rights in the USA: land of the free? Lancet 1998; 352: 1853–54.
1
2
3
Tyrosine kinase inhibition and grey hair Sir—Repigmentation of grey hair has been reported in nine of 133 patients treated with the tyrosine kinase inhibitor imatinib (STI571).1 Although the molecular mechanisms involved are unknown, they could be related to blocking of c-KIT, since imatinib inhibits this tyrosine kinase receptor and the related platelet-derived growth factor (PDGF) receptor.2 Stimulation of c-KIT normally leads to short-lived activation followed by rapid degradation of the microphthalmia transcription factor (Mi), which transactivates the tyrosinase pigmentation gene promoter in melanocytes.3,4 We have seen the opposite effect—ie, hair depigmentation—in patients with recurrent or metastatic cancers treated with the novel drug SU11428 (Sugen) during a phase 1 clinical trial. SU11428 is a new antiangiogenic oxindole that blocks the receptors for vascular endothelial growth factor (VEGF), PDGF, and stem-cell factor. Hair depigmentation was seen in 18 of 28 patients, irrespective of the origin of the primary cancer. It concerned all patients who received at least 50 mg of SU11428 per day, and who did not have grey hair before treatment. Depigmentation was detectable on all body hair after about 5–6 weeks of treatment. Microscopic examination of the hair showed that the pigment had disappeared without any other hair shaft abnormality. The process seemed to be reversible, since normally pigmented hair growth was
4
Etienne G, Cony-Makhoul P, Mahon FX. Imatinib mesylate and gray hair. N Engl J Med 2002; 347: 446. Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 2002; 1: 493–502. Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature 1998; 391: 298–301. Wu M, Hemesath TJ, Takemoto CM, et al. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev 2000; 14: 301–12.
Multicentre Aneurysm Screening Study (MASS) Sir—In Multicentre Aneurysm Screening Study (MASS; Nov 16, p 1531),1 morbidity after elective aneurysm surgery is ignored. Aneurysm surgery is associated with a high rate of serious morbidity such as myocardial infarction, colonic ischaemia, renal insufficiency, and limb ischaemia, not to mention the high rates of minor morbidity. On the basis of a conservative estimate from published studies, major morbidity is in the range of 5–10%, and minor morbidity 20–30%.2,3 In a screening programme, all harmful effects, not just mortality, should be analysed and balanced against the potential benefits of the programme. This is especially important since aneurysm surgery is done in rather fragile and symptomfree patients with a limited life expectancy. The MASS Study Group did not provide these data, and information about quality of life cannot compensate for this shortcoming. MASS shows only a very limited benefit from screening. Balancing the effects of morbidity in the endpoints would, possibly, have resulted in a different conclusion.
THE LANCET • Vol 361 • March 22, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.