- Email: [email protected]
Calcification in chronic renal failure
CORRESPONDENCE
bowel movements a day, and the urgency may be compelling. Blood is also often seen. Tenesmus is frequent, and cramping pain is often associated with defecation. Radiation proctitis frequently is associated with pain and bleeding; the latter may be severe and persistent, occasionally requiring transfusions . . . Severe or complete obstruction may develop.”4 Any assessment of radiation therapy must take into account not just the statistical effect of treatment on recurrences, but what patients actually experience as a result of the treatment. What patients and their families need is the complete picture, of costs as well as benefits, without which it is impossible for them to make educated treatment decisions. But how many rectal cancer patients, I wonder, are told that adjuvant radiation therapy has not been proven to extend life but may in fact cause serious short-term and long-term adverse effects? How many are told that adjuvant radiation may in fact lead to their untimely deaths? Ralph W Moss The Moss Reports, PO Box 8183, State College, PA 16803, USA (e-mail: [email protected]) 1
2
3
4
Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8507 patients from 22 randomised trials. Lancet 2001; 358: 1291–304. Minsky BD. Adjuvant radiation therapy for rectal cancer: is there finally an answer? Lancet 2001; 358: 1285–86. Kollmorgen CE, Meagher AP, Wolff BG, Pemberton JH, Martenson JA, Illstrup DM. The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 1994; 1220: 676–82. Fajardo LF, Berthrong M, Anderson RE. Radiation Pathology. Oxford: Oxford University Press, 2001: 244–45.
Authors’ reply Sir—In response to Calogero Cammá and colleagues, we were unable to confirm that the three excluded studies were properly randomised by checking individual patients’ data or by contact with the investigators. Moreover, the exact matching of the number of men and women, and of older and younger patients in each group in the São Paulo study (in which an unusually large benefit was reported for radiotherapy) suggested that matched rather than randomised controls may have been used, which would have made this trial ineligible. Given the small size of the omitted studies, however, their inclusion or exclusion makes no material difference to the findings—the reduction in the
yearly odds of death is 5·7% (SE 2·6) with, and 5·4% (2·9) without these studies. As we described, we included the Essen and Japanese studies as unconfounded trials of preoperative radiotherapy. We report a nonsignificant trend towards benefit for controls in the Essen study, which is consistent with the published findings. Separation of the MRCI 5 Gy and 20 Gy comparisons in figures 1, 5, 6, and 7 (but not figures 2, 3, or 4) makes no difference; for example, the reduction in the odds of death in all preoperative radiotherapy studies is 5·6% (3·3) with the studies separated and 5·9% (3·4) when the combined groups are compared with the control group. A more important point is that the subgroup analyses should be confined to the 2954 patients in studies of biologically effective doses of 30 Gy or more with local recurrence data. There was no apparent treatment effect at lower biologically effective doses and inclusion of these groups would dilute any real subgroup differences (ie, add noise without signal). Again, however, inclusion of the 1616 patients in these groups does not alter the findings that the net benefits are greater for younger and for higher-risk patients. We agree with Ralph Moss that the benefits of radiotherapy in preventing recurrence and death from rectal cancer need to be balanced against short-term and long-term adverse effects. However, we believe that the available data suggest that the benefits from adding radiotherapy to surgery for rectal cancer probably outweigh the negative consequences for many patients. Radiotherapy, at adequate preoperative doses, significantly improved overall survival, even though some of the included trials used outdated—and hazardous—radiation techniques. Thus, although an extension of life has not been the primary aim of radiotherapy, modern techniques that deliver radiotherapy more accurately will probably produce a net survival benefit. Long-term follow-up of late effects in recent trials is needed to be sure, but adverse effects on quality of life so far seem mild.1,2 Finally, we believe that most patients offered radiotherapy for rectal cancer are adequately informed about the potential negative consequences as well as the established benefits. It would not be helpful to list the postradiation symptoms cited by Moss, however, since they are hardly ever seen with the doses used to kill microscopic disease that might be left
THE LANCET • Vol 359 • March 23, 2002 • www.thelancet.com
after apparently curative rectal cancer surgery. *Richard Gray, Bengt Glimelius, Robert Hills, Joanna Marro, Rebecca Stowe, for the Colorectal Cancer Collaborative Group Birmingham Clinical Trials Unit, Park Grange, Edgbaston, Birmingham B15 2RR, UK (e-mail: [email protected]) 1
2
Glimelius B, Isacsson U. Preoperative radiotherapy for rectal cancer—is 5⫻5 Gy good or a bad schedule? Acta Oncol 2001; 40: 958–67. Marijnen CAM, Kapiteijn E, van de Velde CJH, et al. Acute side-effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol 2002; 20: 817–25.
Calcification in chronic renal failure Sir—In his Oct 6 commentary on vascular calcification in chronic renal failure (CRF), William Goodmanl discusses the unusual syndrome commonly known as calciphylaxis. He correctly reminds us of the experimental origin of that name and of why it is inappropriate for this syndrome of subcutaneous and skin necrosis associated with vascular calcification. However, his comments on the latter disorder require correction. In this syndrome, the primary vascular lesion that is directly linked to the necrosis is calcification of resistance-type arterioles in the subcutis. It is quite different from Monckeberg’s sclerosis of muscular arteries, which can be seen without CRF. Thus, the calcific uraemic arteriolopathy described by Coates and colleagues2 is a more specific designation for this lesion in CRF, and not simply a broader term, as Goodman claims. The lesion is silent, but since it is accompanied by intimal thickening, sometimes severe, it contributes in a major way to the clinically dramatic ischaemic infarcts of the subcutaneous fat and skin with ulcerations. The infarcts vary in distribution— typically in the mid-body (proximal), lower extremities (distal), or both, and rarely, in hands and feet. Dry gangrene of toes and fingers due to arteriosclerotic lesions, whether calcified or not, may coexist with the syndrome lesions. Goodman makes no mention of the role of obesity. Bleyer and colleagues3 have clearly shown that morbid obesity is a risk factor for the mid-body and
1069
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
generally devastating lesions. They suggested that excess subcutaneous adipose tissue was a pathogenetic factor through an effect on local arterioles. One effect may be physical.4 The arterioles traverse the subcutaneous compartment attached to and supported by the septa that fix the skin to the deep fascia. Expansion of the compartment by excess adipose tissue—sometimes up to 15 cm thick— subjects the septa and arterioles to increased tensile stress. Oedema, if present, adds to the expansion. Because CRF patients are at risk of metastatic calcification, this tensile factor may play a role in targeting the arterioles and septa (which also calcify) for mineral deposition—ie, dystrophic calcification in a metastatic setting.4 The characteristic absence of syndrome lesions in other organs correlates with the absence of a similar physical environment there.
for precise pathological discussions and for describing specific clinical presentations. As he indicates, however, the process of vascular calcification in renal failure is a continuing and generalised one. The occurrence of ischaemia and necrosis of tissues represents only the most advanced stage of the process. Obesity as a predisposing factor for tissue ischaemia in patients with calcific uraemic arteriolopathy was mentioned previously and has been noted by several investigators. The explanation for this association is uncertain. The role of localised physical or structural disturbances within adipose tissue as contributors to impaired tissue perfusion remains speculative. William G Goodman Division of Nephrology, Department of Medicine, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA (e-mail: [email protected])
David T Janigan Department of Pathology and Laboratory Medicine, Queen Elizabeth Health Sciences Centre, VGH Site, Halifax, NS B3H 1V8, Canada (e-mail: [email protected]) 1
2
3
4
Goodman WG. Vascular calcification in chronic renal failure. Lancet 2001; 358: 1115–16. Coates T, Kirkland GS, Dymock RS, et al. Cutaneous necrosis from calcific uremic arteriolopathy. Am J Kidney Dis 1998; 32: 384–91. Bleyer AJ, Choi M, lgwemezie B, et al. A case control study of proximal calciphylaxis. Am J Kidney Dis 1998; 32: 376–83. Janigan DT, Hirsch DJ, Klassen GA, MacDonald AS. Calcified subcutaneous arterioles with infarcts of the subcutis and skin (“calciphylaxis”) in chronic renal failure. Am J Kidney Dis 2000; 35: 588–97.
Author’s reply Sir—The general thrust of my comments was to remind clinicians of the generalised nature of the process of vascular calcification in chronic renal failure and to make note of observations about potential contributing factors. The term calciphylaxis is commonly applied inappropriately to refer to various soft-tissue calcifications, but not specifically to arterial calcification leading to tissue ischaemia in patients with chronic renal disease. For this reason, the term calcific uraemic arteriolopathy more accurately highlights the role of calcium deposition as an integral component of the vascular pathology that develops in small and in large arteries in patients with chronic renal failure. David Janigan’s comments are somewhat more narrowly focused. They are appropriate and suitable
1070
Peripheral arterial disease Sir—In a seminar on peripheral arterial disease (PAD) Kenneth Ouriel (Oct 13, p 1257)1 states that atherosclerosis of the lower extremities is more common in elderly than in younger individuals. However, PAD also occurs in young adults (younger than 50 years). Young patients with PAD are of interest because early manifestation of disease is associated with severe symptoms, high comorbidity rate, and aggressive course producing early disability and death. Differences in presence of cardiovascular risk factors presumably distinguishes the manifestation of premature PAD from that seen in older adults.2 Most young patients with PAD are men. Hormonal protection of premenopausal women is generally cited as the major reason for delayed symptom presentation in women, although PAD does sometimes occur in young women. In the past few decades, several groups have studied this population and tried to identify specific determinants of disease.3 The reported case series conclude that young women with PAD seemed to be heavily loaded with atherosclerotic risk factors. A high prevalence of smoking, hypercholesterolaemia, hypertension, and oral contraceptive use was noted. However, the number of patients in these studies was limited and no controls were included. Large case-control studies have been done to investigate the risk factors for PAD. However, in these studies young women formed only a
small part of the study population or were not included at all. Therefore, information on strength and distribution of risk factors in women younger than 50 years is still scarce.4 We did a case-control study to identify risk factors for PAD in young women. All patients—220 patients and 629 controls—were women aged 18–49 years with no history of cardiovascular disease, who had been referred with first symptoms of intermittent claudication between 1990 and 1999. In all patients, PAD was confirmed by angiography. Risk factors for PAD were diabetes, smoking, hypertension, hypercholesterolaemia, hyperhomocysteinaemia, and obesity. 58% of women were exposed to three or more risk factors at time of diagnosis. We noted a strong synergy between risk factors studied. However, the risk factors studied could not explain the development of PAD in all young women. The reason why such severe PAD occurs decades earlier in hormonally protected patients is still not fully understood. Until now, the role of genetic factors in the development of PAD has not been defined. Only Valentine and colleagues5 have investigated the prevalence of atherosclerotic occlusive disease among family members of young PAD patients. We noted a family history of atherosclerotic vessel disease in 63% of our patients and we suggest that manifestation of PAD in young women has a familial basis. Further research should focus on the role of genetic factors in relation to PAD in these patients. *Maurice A A J van den Bosch, Willem P Th M Mali, Daisy G M Bloemenkamp, Yolanda van der Graaf Julius Center for General Practice and Patient Oriented Research, and *Department of Radiology, University Medical Center, Room E01–132, 3584CX Utrecht, Netherlands (e-mail: [email protected]) 1 2
3
4
5
Ouriel K. Peripheral arterial disease. Lancet 2001; 358: 1257–64. Levy PJ, Hornung CA, Haynes JL, Rush DS. Lower extremity ischemia in adults younger than forty years of age: a community-wide survey of premature atherosclerotic arterial disease. J Vasc Surg 1994; 19: 873–81. Cronenwett JL, Davis JT, Gooch JB, Garrett HE. Aortoiliac occlusive disease in women. Surgery 1980; 88: 775–84. Dormandy J, Heeck L, Vig S. Predictors of early disease in the lower limbs. Semin Vasc Surg 1999; 12: 109–17. Valentine RJ, Verstraete R, Clagett P, Cohen JC. Premature cardiovasculair disease is common in relatives of patients with premature peripheral atheroslcerosis. Arch Intern Med 2000; 160: 1343–48.
THE LANCET • Vol 359 • March 23, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
bowel movements a day, and the urgency may be compelling. Blood is also often seen. Tenesmus is frequent, and cramping pain is often associated with defecation. Radiation proctitis frequently is associated with pain and bleeding; the latter may be severe and persistent, occasionally requiring transfusions . . . Severe or complete obstruction may develop.”4 Any assessment of radiation therapy must take into account not just the statistical effect of treatment on recurrences, but what patients actually experience as a result of the treatment. What patients and their families need is the complete picture, of costs as well as benefits, without which it is impossible for them to make educated treatment decisions. But how many rectal cancer patients, I wonder, are told that adjuvant radiation therapy has not been proven to extend life but may in fact cause serious short-term and long-term adverse effects? How many are told that adjuvant radiation may in fact lead to their untimely deaths? Ralph W Moss The Moss Reports, PO Box 8183, State College, PA 16803, USA (e-mail: [email protected]) 1
2
3
4
Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8507 patients from 22 randomised trials. Lancet 2001; 358: 1291–304. Minsky BD. Adjuvant radiation therapy for rectal cancer: is there finally an answer? Lancet 2001; 358: 1285–86. Kollmorgen CE, Meagher AP, Wolff BG, Pemberton JH, Martenson JA, Illstrup DM. The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 1994; 1220: 676–82. Fajardo LF, Berthrong M, Anderson RE. Radiation Pathology. Oxford: Oxford University Press, 2001: 244–45.
Authors’ reply Sir—In response to Calogero Cammá and colleagues, we were unable to confirm that the three excluded studies were properly randomised by checking individual patients’ data or by contact with the investigators. Moreover, the exact matching of the number of men and women, and of older and younger patients in each group in the São Paulo study (in which an unusually large benefit was reported for radiotherapy) suggested that matched rather than randomised controls may have been used, which would have made this trial ineligible. Given the small size of the omitted studies, however, their inclusion or exclusion makes no material difference to the findings—the reduction in the
yearly odds of death is 5·7% (SE 2·6) with, and 5·4% (2·9) without these studies. As we described, we included the Essen and Japanese studies as unconfounded trials of preoperative radiotherapy. We report a nonsignificant trend towards benefit for controls in the Essen study, which is consistent with the published findings. Separation of the MRCI 5 Gy and 20 Gy comparisons in figures 1, 5, 6, and 7 (but not figures 2, 3, or 4) makes no difference; for example, the reduction in the odds of death in all preoperative radiotherapy studies is 5·6% (3·3) with the studies separated and 5·9% (3·4) when the combined groups are compared with the control group. A more important point is that the subgroup analyses should be confined to the 2954 patients in studies of biologically effective doses of 30 Gy or more with local recurrence data. There was no apparent treatment effect at lower biologically effective doses and inclusion of these groups would dilute any real subgroup differences (ie, add noise without signal). Again, however, inclusion of the 1616 patients in these groups does not alter the findings that the net benefits are greater for younger and for higher-risk patients. We agree with Ralph Moss that the benefits of radiotherapy in preventing recurrence and death from rectal cancer need to be balanced against short-term and long-term adverse effects. However, we believe that the available data suggest that the benefits from adding radiotherapy to surgery for rectal cancer probably outweigh the negative consequences for many patients. Radiotherapy, at adequate preoperative doses, significantly improved overall survival, even though some of the included trials used outdated—and hazardous—radiation techniques. Thus, although an extension of life has not been the primary aim of radiotherapy, modern techniques that deliver radiotherapy more accurately will probably produce a net survival benefit. Long-term follow-up of late effects in recent trials is needed to be sure, but adverse effects on quality of life so far seem mild.1,2 Finally, we believe that most patients offered radiotherapy for rectal cancer are adequately informed about the potential negative consequences as well as the established benefits. It would not be helpful to list the postradiation symptoms cited by Moss, however, since they are hardly ever seen with the doses used to kill microscopic disease that might be left
THE LANCET • Vol 359 • March 23, 2002 • www.thelancet.com
after apparently curative rectal cancer surgery. *Richard Gray, Bengt Glimelius, Robert Hills, Joanna Marro, Rebecca Stowe, for the Colorectal Cancer Collaborative Group Birmingham Clinical Trials Unit, Park Grange, Edgbaston, Birmingham B15 2RR, UK (e-mail: [email protected]) 1
2
Glimelius B, Isacsson U. Preoperative radiotherapy for rectal cancer—is 5⫻5 Gy good or a bad schedule? Acta Oncol 2001; 40: 958–67. Marijnen CAM, Kapiteijn E, van de Velde CJH, et al. Acute side-effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol 2002; 20: 817–25.
Calcification in chronic renal failure Sir—In his Oct 6 commentary on vascular calcification in chronic renal failure (CRF), William Goodmanl discusses the unusual syndrome commonly known as calciphylaxis. He correctly reminds us of the experimental origin of that name and of why it is inappropriate for this syndrome of subcutaneous and skin necrosis associated with vascular calcification. However, his comments on the latter disorder require correction. In this syndrome, the primary vascular lesion that is directly linked to the necrosis is calcification of resistance-type arterioles in the subcutis. It is quite different from Monckeberg’s sclerosis of muscular arteries, which can be seen without CRF. Thus, the calcific uraemic arteriolopathy described by Coates and colleagues2 is a more specific designation for this lesion in CRF, and not simply a broader term, as Goodman claims. The lesion is silent, but since it is accompanied by intimal thickening, sometimes severe, it contributes in a major way to the clinically dramatic ischaemic infarcts of the subcutaneous fat and skin with ulcerations. The infarcts vary in distribution— typically in the mid-body (proximal), lower extremities (distal), or both, and rarely, in hands and feet. Dry gangrene of toes and fingers due to arteriosclerotic lesions, whether calcified or not, may coexist with the syndrome lesions. Goodman makes no mention of the role of obesity. Bleyer and colleagues3 have clearly shown that morbid obesity is a risk factor for the mid-body and
1069
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
generally devastating lesions. They suggested that excess subcutaneous adipose tissue was a pathogenetic factor through an effect on local arterioles. One effect may be physical.4 The arterioles traverse the subcutaneous compartment attached to and supported by the septa that fix the skin to the deep fascia. Expansion of the compartment by excess adipose tissue—sometimes up to 15 cm thick— subjects the septa and arterioles to increased tensile stress. Oedema, if present, adds to the expansion. Because CRF patients are at risk of metastatic calcification, this tensile factor may play a role in targeting the arterioles and septa (which also calcify) for mineral deposition—ie, dystrophic calcification in a metastatic setting.4 The characteristic absence of syndrome lesions in other organs correlates with the absence of a similar physical environment there.
for precise pathological discussions and for describing specific clinical presentations. As he indicates, however, the process of vascular calcification in renal failure is a continuing and generalised one. The occurrence of ischaemia and necrosis of tissues represents only the most advanced stage of the process. Obesity as a predisposing factor for tissue ischaemia in patients with calcific uraemic arteriolopathy was mentioned previously and has been noted by several investigators. The explanation for this association is uncertain. The role of localised physical or structural disturbances within adipose tissue as contributors to impaired tissue perfusion remains speculative. William G Goodman Division of Nephrology, Department of Medicine, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA (e-mail: [email protected])
David T Janigan Department of Pathology and Laboratory Medicine, Queen Elizabeth Health Sciences Centre, VGH Site, Halifax, NS B3H 1V8, Canada (e-mail: [email protected]) 1
2
3
4
Goodman WG. Vascular calcification in chronic renal failure. Lancet 2001; 358: 1115–16. Coates T, Kirkland GS, Dymock RS, et al. Cutaneous necrosis from calcific uremic arteriolopathy. Am J Kidney Dis 1998; 32: 384–91. Bleyer AJ, Choi M, lgwemezie B, et al. A case control study of proximal calciphylaxis. Am J Kidney Dis 1998; 32: 376–83. Janigan DT, Hirsch DJ, Klassen GA, MacDonald AS. Calcified subcutaneous arterioles with infarcts of the subcutis and skin (“calciphylaxis”) in chronic renal failure. Am J Kidney Dis 2000; 35: 588–97.
Author’s reply Sir—The general thrust of my comments was to remind clinicians of the generalised nature of the process of vascular calcification in chronic renal failure and to make note of observations about potential contributing factors. The term calciphylaxis is commonly applied inappropriately to refer to various soft-tissue calcifications, but not specifically to arterial calcification leading to tissue ischaemia in patients with chronic renal disease. For this reason, the term calcific uraemic arteriolopathy more accurately highlights the role of calcium deposition as an integral component of the vascular pathology that develops in small and in large arteries in patients with chronic renal failure. David Janigan’s comments are somewhat more narrowly focused. They are appropriate and suitable
1070
Peripheral arterial disease Sir—In a seminar on peripheral arterial disease (PAD) Kenneth Ouriel (Oct 13, p 1257)1 states that atherosclerosis of the lower extremities is more common in elderly than in younger individuals. However, PAD also occurs in young adults (younger than 50 years). Young patients with PAD are of interest because early manifestation of disease is associated with severe symptoms, high comorbidity rate, and aggressive course producing early disability and death. Differences in presence of cardiovascular risk factors presumably distinguishes the manifestation of premature PAD from that seen in older adults.2 Most young patients with PAD are men. Hormonal protection of premenopausal women is generally cited as the major reason for delayed symptom presentation in women, although PAD does sometimes occur in young women. In the past few decades, several groups have studied this population and tried to identify specific determinants of disease.3 The reported case series conclude that young women with PAD seemed to be heavily loaded with atherosclerotic risk factors. A high prevalence of smoking, hypercholesterolaemia, hypertension, and oral contraceptive use was noted. However, the number of patients in these studies was limited and no controls were included. Large case-control studies have been done to investigate the risk factors for PAD. However, in these studies young women formed only a
small part of the study population or were not included at all. Therefore, information on strength and distribution of risk factors in women younger than 50 years is still scarce.4 We did a case-control study to identify risk factors for PAD in young women. All patients—220 patients and 629 controls—were women aged 18–49 years with no history of cardiovascular disease, who had been referred with first symptoms of intermittent claudication between 1990 and 1999. In all patients, PAD was confirmed by angiography. Risk factors for PAD were diabetes, smoking, hypertension, hypercholesterolaemia, hyperhomocysteinaemia, and obesity. 58% of women were exposed to three or more risk factors at time of diagnosis. We noted a strong synergy between risk factors studied. However, the risk factors studied could not explain the development of PAD in all young women. The reason why such severe PAD occurs decades earlier in hormonally protected patients is still not fully understood. Until now, the role of genetic factors in the development of PAD has not been defined. Only Valentine and colleagues5 have investigated the prevalence of atherosclerotic occlusive disease among family members of young PAD patients. We noted a family history of atherosclerotic vessel disease in 63% of our patients and we suggest that manifestation of PAD in young women has a familial basis. Further research should focus on the role of genetic factors in relation to PAD in these patients. *Maurice A A J van den Bosch, Willem P Th M Mali, Daisy G M Bloemenkamp, Yolanda van der Graaf Julius Center for General Practice and Patient Oriented Research, and *Department of Radiology, University Medical Center, Room E01–132, 3584CX Utrecht, Netherlands (e-mail: [email protected]) 1 2
3
4
5
Ouriel K. Peripheral arterial disease. Lancet 2001; 358: 1257–64. Levy PJ, Hornung CA, Haynes JL, Rush DS. Lower extremity ischemia in adults younger than forty years of age: a community-wide survey of premature atherosclerotic arterial disease. J Vasc Surg 1994; 19: 873–81. Cronenwett JL, Davis JT, Gooch JB, Garrett HE. Aortoiliac occlusive disease in women. Surgery 1980; 88: 775–84. Dormandy J, Heeck L, Vig S. Predictors of early disease in the lower limbs. Semin Vasc Surg 1999; 12: 109–17. Valentine RJ, Verstraete R, Clagett P, Cohen JC. Premature cardiovasculair disease is common in relatives of patients with premature peripheral atheroslcerosis. Arch Intern Med 2000; 160: 1343–48.
THE LANCET • Vol 359 • March 23, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.